Julie C. Harper, MD

Selection of oral agents for treatment of AV in adult women is dependent on multiple factors including the patient’s age, medication history, child-bearing potential, clinical presentation, and treatment preference following a discussion of the anticipated benefits versus potential risks.^1,2 In patients with the mixed inflammatory and comedonal clinical pattern of AV, oral antibiotics can be used concurrently with topical therapies when moderate to severe inflammatory lesions are noted.^3,4 However, many adult women who had AV as teenagers have already utilized oral antibiotic therapies in the past and often are interested in alternative options, express concerns regarding antibiotic resistance, report a history of antibiotic-associated yeast infections or other side effects, and/or encounter issues related to drug-drug interactions.^3,5-8 Oral hormonal therapies such as combination oral contraceptives (COCs) or spironolactone often are utilized to treat adult women with AV, sometimes in combination with each other or other agents. Combination oral contraceptives appear to be especially effective in the management of the U-shaped clinical pattern or predominantly inflammatory, late-onset AV.^1,5,9,10 Potential warnings, contraindications, adverse effects, and drug-drug interactions are important to keep in mind when considering the use of oral hormonal therapies.^8-10 Oral isotretinoin, which should be prescribed with strict adherence to the iPLEDGE™ program (https://www.ipledgeprogram.com/), remains a viable option for cases of severe nodular AV and selected cases of refractory inflammatory AV, especially when scarring and/or marked psychosocial distress are noted.^1,2,5,11 Although it is recognized that adult women with AV typically present with either a mixed inflammatory and comedonal or U-shaped clinical pattern predominantly involving the lower face and anterolateral neck, the available data do not adequately differentiate the relative responsiveness of these clinical patterns to specific therapeutic agents.

Combination Oral Contraceptives

Combination oral contraceptives are commonly used to treat AV in adult women, including those without and those with measurable androgen excess (eg, polycystic ovary syndrome [PCOS]). Combination oral contraceptives contain ethinyl estradiol and a progestational agent (eg, progestin); the latter varies in terms of its nonselective receptor interactions and the relative magnitude or absence of androgenic effects.^10,12,13 Although some COCs are approved by the US Food and Drug Administration (FDA) for AV, there is little data available to determine the comparative efficacy among these and other COCs.^10,14 When choosing a COC for treatment of AV, it is best to select an agent whose effectiveness is supported by evidence from clinical studies.^10,15

Mechanisms of Action

The reported mechanisms of action for COCs include inhibition of ovarian androgen production and ovulation through gonadotropin suppression; upregulated synthesis of sex hormone–binding globulin, which decreases free testosterone levels through receptor binding; and inhibition of 5α-reductase (by some progestins), which reduces conversion of testosterone to dihydrotestosterone, the active derivative that induces androgenic effects at peripheral target tissues.^10,13,16,17

Therapeutic Benefits

Use of COCs to treat AV in adult women who do not have measurable androgen excess is most rational in patients who also desire a method of contraception. Multiple monotherapy studies have demonstrated the efficacy of COCs in the treatment of AV on the face and trunk.^{4,10,12,15,17,18} It may take a minimum of 3 monthly cycles of use before acne lesion counts begin to appreciably decrease.^12,15,19-21 Initiating COC therapy during menstruation ensures the absence of pregnancy. Combination oral contraceptives may be used with other topical and oral therapies for AV.^2,3,9,10 Potential ancillary benefits of COCs include normalization of the menstrual cycle; reduced premenstrual dysphoric disorder symptoms; and reduced risk of endometrial cancer (approximately 50%), ovarian cancer (approximately 40%), and colorectal cancer.^22-24

Risks and Contraindications

It is important to consider the potential risks associated with the use of COCs, especially in women with AV who are not seeking a method of contraception. Side effects of COCs can include nausea, breast tenderness, breakthrough bleeding, and weight gain.^25,26 Potential adverse associations of COCs are described in the Table. The major potential vascular associations include venous thromboembolism, myocardial infarction, and cerebrovascular accident, all of which are influenced by concurrent factors such as a history of smoking, age (≥35 years), and hypertension.^27-32 It is recommended that blood pressure be measured before initiating COC therapy as part of the general examination.³³

The potential increase in breast cancer risk appears to be low, while the cervical cancer risk is reported to increase relative to the duration of use.^34-37 This latter observation may be due to the greater likelihood of unprotected sex in women using a COC and exposure to multiple sexual partners in some cases, which may increase the likelihood of oncogenic human papillomavirus infection of the cervix. If a dermatologist elects to prescribe a COC to treat AV, it has been suggested that the patient also consult with her general practitioner or gynecologist to undergo pelvic and breast examinations and a Papanicolaou test.³³ The recommendation for initial screening for cervical cancer is within 3 years of initiation of sexual intercourse or by 21 years of age, whichever is first.^33,38,39

Combination oral contraceptives are not ideal for all adult women with AV. Absolute contraindications are pregnancy and history of thromboembolic, cardiac, or hepatic disease; in women aged 35 years and older who smoke, relative contraindications include hypertension, diabetes, migraines, breastfeeding, and current breast or liver cancer.³³ In adult women with AV who have relative contra-indications but are likely to benefit from the use of a COC when other options are limited or not viable, consultation with a gynecologist is prudent. Other than rifamycin antibiotics (eg, rifampin) and griseofulvin, there is no definitive evidence that oral antibiotics (eg, tetracycline) or oral antifungal agents reduce the contraceptive efficacy of COCs, although cautions remain in print within some approved package inserts.⁸

Spironolactone

Available since 1957, spironolactone is an oral aldos-terone antagonist and potassium-sparing diuretic used to treat hypertension and congestive heart failure.⁹ Recognition of its antiandrogenic effects led to its use in dermatology to treat certain dermatologic disorders in women (eg, hirsutism, alopecia, AV).^1,4,5,9,10 Spironolactone is not approved for AV by the FDA; therefore, available data from multiple independent studies and retrospective analyses that have been collectively reviewed support its efficacy when used as both monotherapy or in combination with other agents in adult women with AV, especially those with a U-shaped pattern and/or late-onset AV.^9,40-43

Mechanism of Action

Spironolactone inhibits sebaceous gland activity through peripheral androgen receptor blockade, inhibition of 5α-reductase, decrease in androgen production, and increase in sex hormone–binding globulin.^9,10,40

Therapeutic Benefits

Good to excellent improvement of AV in women, many of whom are postadolescent, has ranged from 66% to 100% in published reports^9,40-43; however, inclusion and exclusion criteria, dosing regimens, and concomitant therapies were not usually controlled. Spironolactone has been used to treat AV in adult women as monotherapy or in combination with topical agents, oral antibiotics, and COCs.^9,40-42 Additionally, dose-ranging studies have not been completed with spironolactone for AV.^9,40 The suggested dose range is 50 mg to 200 mg daily; however, it usually is best to start at 50 mg daily and increase to 100 mg daily if clinical response is not adequate after 2 to 3 months. The gastrointestinal (GI) absorption of spironolactone is increased when ingested with a high-fat meal.^9,10

Once effective control of AV is achieved, it is optimal to use the lowest dose needed to continue reasonable suppression of new AV lesions. There is no defined end point for spironolactone use in AV, with or without concurrent PCOS, as many adult women usually continue treatment with low-dose therapy because they experience marked flaring shortly after the drug is stopped.⁹

Risks and Contraindications

Side effects associated with spironolactone are dose related and include increased diuresis, migraines, menstrual irregularities, breast tenderness, gynecomastia, fatigue, and dizziness.^9,10,40-44 Side effects (particularly menstrual irregularities and breast tenderness) are more common at doses higher than 100 mg daily, especially when used as monotherapy without concurrent use of a COC.^9,40

Spironolactone-associated hyperkalemia is most clinically relevant in patients on higher doses (eg, 100–200 mg daily), in those with renal impairment and/or congestive heart failure, and when used concurrently with certain other medications. In any patient on spironolactone, the risk of clinically relevant hyperkalemia may be increased by coingestion of potassium supplements, potassium-based salt substitutes, potassium-sparing diuretics (eg, amiloride, triamterene); aldosterone antagonists and angiotensin-converting enzyme inhibitors (eg, lisinopril, benazepril); angiotensin II receptor blockers (eg, losartan, valsartan); and tri-methoprim (with or without sulfamethoxazole).^8,9,40,45 Spironolactone may also increase serum levels of lithium or digoxin.^9,40,45,46 For management of AV, it is best that spironolactone be avoided in patients taking any of these medications.⁹

In healthy adult women with AV who are not on medications or supplements that interact adversely with spironolactone, there is no definitive recommendation regarding monitoring of serum potassium levels during treatment with spironolactone, and it has been suggested that monitoring serum potassium levels in this subgroup is not necessary.⁴⁷ However, each clinician is advised to choose whether or not they wish to obtain baseline and/or periodic serum potassium levels when prescribing spironolactone for AV based on their degree of comfort and the patient’s history. Baseline and periodic blood testing to evaluate serum electrolytes and renal function are reasonable, especially as adult women with AV are usually treated with spironolactone over a prolonged period of time.⁹

The FDA black box warning for spironolactone states that it is tumorigenic in chronic toxicity studies in rats and refers to exposures 25- to 100-fold higher than those administered to humans.^9,48 Although continued vigilance is warranted, evaluation of large populations of women treated with spironolactone do not suggest an association with increased risk of breast cancer.^49,50

Spironolactone is a category C drug and thus should be avoided during pregnancy, primarily due to animal data suggesting risks of hypospadias and feminization in male fetuses.⁹ Importantly, there is an absence of reports linking exposure during pregnancy with congenital defects in humans, including in 2 known cases of high-dose exposures for maternal Bartter syndrome.⁹

The active metabolite, canrenone, is known to be present in breast milk at 0.2% of the maternal daily dose, but breastfeeding is generally believed to be safe with spironolactone based on evidence to date.⁹

Oral Antibiotics

Oral antibiotic therapy may be used in combination with a topical regimen to treat AV in adult women, keeping in mind some important caveats.^1-7 For instance, monotherapy with oral antibiotics should be avoided, and concomitant use of benzoyl peroxide is suggested to reduce emergence of antibiotic-resistant Propionibacterium acnes strains.^3,4 A therapeutic exit plan also is suggested when prescribing oral antibiotics to limit treatment to 3 to 4 months, if possible, to help mitigate the emergence of antibiotic-resistant bacteria (eg, staphylococci and streptococci).^3-5,51

Tetracyclines, especially doxycycline and minocycline, are the most commonly prescribed agents. Doxycycline use warrants patient education on measures to limit the risks of esophageal and GI side effects and phototoxicity; enteric-coated and small tablet formulations have been shown to reduce GI side effects, especially when administered with food.^3,52-55 In addition to vestibular side effects and hyperpigmentation, minocycline may be associated with rare but potentially severe adverse reactions such as drug hypersensitivity syndrome, autoimmune hepatitis, and lupus-like syndrome, which are reported more commonly in women.^5,52,54 Vestibular side effects have been shown to decrease with use of extended-release tablets with weight-based dosing.⁵³

Oral Isotretinoin

Oral isotretinoin is well established as highly effective for treatment of severe, recalcitrant AV, including nodular acne on the face and trunk.^4,56 Currently available oral isotretinoins are branded generic formulations based on the pharmacokinetic profile of the original brand (Accutane [Roche Pharmaceuticals]) and with the use of Lidose Technology (Absorica [Cipher Pharmaceuticals]), which substantially increases GI absorption of isotretinoin in the absence of ingestion with a high-calorie, high-fat meal.⁵⁷ The short- and long-term efficacy, dosing regimens, safety considerations, and serious teratogenic risks for oral isotretinoin are well published.^4,56-58 Importantly, oral isotretinoin must be prescribed with strict adherence to the federally mandated iPLEDGE risk management program.

Low-dose oral isotretinoin therapy (<0.5 mg/kg–1 mg/kg daily) administered over several months longer than conventional regimens (ie, 16–20 weeks) has been suggested with demonstrated efficacy.⁵⁷ However, this approach is not optimal due to the lack of established sustained clearance of AV after discontinuation of therapy and the greater potential for exposure to isotretinoin during pregnancy. Recurrences of AV do occur after completion of isotretinoin therapy, especially if cumulative systemic exposure to the drug during the initial course of treatment was inadequate.^56,57

Oral isotretinoin has been shown to be effective in AV in adult women with or without PCOS with 0.5 mg/kg to 1 mg/kg daily and a total cumulative exposure of 120 mg/kg to 150 mg/kg.⁵⁹ In one study, the presence of PCOS and greater number of nodules at baseline were predictive of a higher risk of relapse during the second year posttreatment.⁵⁹

Conclusion

All oral therapies that are used to treat AV in adult women warrant individual consideration of possible benefits versus risks. Careful attention to possible side effects, patient-related risk factors, and potential drug-drug interactions is important. End points of therapy are not well established, with the exception of oral isotretinoin therapy. Clinicians must use their judgment in each case along with obtaining feedback from patients regarding the selection of therapy after a discussion of the available options.

Selection of oral agents for treatment of AV in adult women is dependent on multiple factors including the patient’s age, medication history, child-bearing potential, clinical presentation, and treatment preference following a discussion of the anticipated benefits versus potential risks.^1,2 In patients with the mixed inflammatory and comedonal clinical pattern of AV, oral antibiotics can be used concurrently with topical therapies when moderate to severe inflammatory lesions are noted.^3,4 However, many adult women who had AV as teenagers have already utilized oral antibiotic therapies in the past and often are interested in alternative options, express concerns regarding antibiotic resistance, report a history of antibiotic-associated yeast infections or other side effects, and/or encounter issues related to drug-drug interactions.^3,5-8 Oral hormonal therapies such as combination oral contraceptives (COCs) or spironolactone often are utilized to treat adult women with AV, sometimes in combination with each other or other agents. Combination oral contraceptives appear to be especially effective in the management of the U-shaped clinical pattern or predominantly inflammatory, late-onset AV.^1,5,9,10 Potential warnings, contraindications, adverse effects, and drug-drug interactions are important to keep in mind when considering the use of oral hormonal therapies.^8-10 Oral isotretinoin, which should be prescribed with strict adherence to the iPLEDGE™ program (https://www.ipledgeprogram.com/), remains a viable option for cases of severe nodular AV and selected cases of refractory inflammatory AV, especially when scarring and/or marked psychosocial distress are noted.^1,2,5,11 Although it is recognized that adult women with AV typically present with either a mixed inflammatory and comedonal or U-shaped clinical pattern predominantly involving the lower face and anterolateral neck, the available data do not adequately differentiate the relative responsiveness of these clinical patterns to specific therapeutic agents.

Combination Oral Contraceptives

Combination oral contraceptives are commonly used to treat AV in adult women, including those without and those with measurable androgen excess (eg, polycystic ovary syndrome [PCOS]). Combination oral contraceptives contain ethinyl estradiol and a progestational agent (eg, progestin); the latter varies in terms of its nonselective receptor interactions and the relative magnitude or absence of androgenic effects.^10,12,13 Although some COCs are approved by the US Food and Drug Administration (FDA) for AV, there is little data available to determine the comparative efficacy among these and other COCs.^10,14 When choosing a COC for treatment of AV, it is best to select an agent whose effectiveness is supported by evidence from clinical studies.^10,15

Mechanisms of Action

The reported mechanisms of action for COCs include inhibition of ovarian androgen production and ovulation through gonadotropin suppression; upregulated synthesis of sex hormone–binding globulin, which decreases free testosterone levels through receptor binding; and inhibition of 5α-reductase (by some progestins), which reduces conversion of testosterone to dihydrotestosterone, the active derivative that induces androgenic effects at peripheral target tissues.^10,13,16,17

Therapeutic Benefits

Use of COCs to treat AV in adult women who do not have measurable androgen excess is most rational in patients who also desire a method of contraception. Multiple monotherapy studies have demonstrated the efficacy of COCs in the treatment of AV on the face and trunk.^{4,10,12,15,17,18} It may take a minimum of 3 monthly cycles of use before acne lesion counts begin to appreciably decrease.^12,15,19-21 Initiating COC therapy during menstruation ensures the absence of pregnancy. Combination oral contraceptives may be used with other topical and oral therapies for AV.^2,3,9,10 Potential ancillary benefits of COCs include normalization of the menstrual cycle; reduced premenstrual dysphoric disorder symptoms; and reduced risk of endometrial cancer (approximately 50%), ovarian cancer (approximately 40%), and colorectal cancer.^22-24

Risks and Contraindications

It is important to consider the potential risks associated with the use of COCs, especially in women with AV who are not seeking a method of contraception. Side effects of COCs can include nausea, breast tenderness, breakthrough bleeding, and weight gain.^25,26 Potential adverse associations of COCs are described in the Table. The major potential vascular associations include venous thromboembolism, myocardial infarction, and cerebrovascular accident, all of which are influenced by concurrent factors such as a history of smoking, age (≥35 years), and hypertension.^27-32 It is recommended that blood pressure be measured before initiating COC therapy as part of the general examination.³³

The potential increase in breast cancer risk appears to be low, while the cervical cancer risk is reported to increase relative to the duration of use.^34-37 This latter observation may be due to the greater likelihood of unprotected sex in women using a COC and exposure to multiple sexual partners in some cases, which may increase the likelihood of oncogenic human papillomavirus infection of the cervix. If a dermatologist elects to prescribe a COC to treat AV, it has been suggested that the patient also consult with her general practitioner or gynecologist to undergo pelvic and breast examinations and a Papanicolaou test.³³ The recommendation for initial screening for cervical cancer is within 3 years of initiation of sexual intercourse or by 21 years of age, whichever is first.^33,38,39

Combination oral contraceptives are not ideal for all adult women with AV. Absolute contraindications are pregnancy and history of thromboembolic, cardiac, or hepatic disease; in women aged 35 years and older who smoke, relative contraindications include hypertension, diabetes, migraines, breastfeeding, and current breast or liver cancer.³³ In adult women with AV who have relative contra-indications but are likely to benefit from the use of a COC when other options are limited or not viable, consultation with a gynecologist is prudent. Other than rifamycin antibiotics (eg, rifampin) and griseofulvin, there is no definitive evidence that oral antibiotics (eg, tetracycline) or oral antifungal agents reduce the contraceptive efficacy of COCs, although cautions remain in print within some approved package inserts.⁸

Spironolactone

Available since 1957, spironolactone is an oral aldos-terone antagonist and potassium-sparing diuretic used to treat hypertension and congestive heart failure.⁹ Recognition of its antiandrogenic effects led to its use in dermatology to treat certain dermatologic disorders in women (eg, hirsutism, alopecia, AV).^1,4,5,9,10 Spironolactone is not approved for AV by the FDA; therefore, available data from multiple independent studies and retrospective analyses that have been collectively reviewed support its efficacy when used as both monotherapy or in combination with other agents in adult women with AV, especially those with a U-shaped pattern and/or late-onset AV.^9,40-43

Mechanism of Action

Spironolactone inhibits sebaceous gland activity through peripheral androgen receptor blockade, inhibition of 5α-reductase, decrease in androgen production, and increase in sex hormone–binding globulin.^9,10,40

Therapeutic Benefits

Good to excellent improvement of AV in women, many of whom are postadolescent, has ranged from 66% to 100% in published reports^9,40-43; however, inclusion and exclusion criteria, dosing regimens, and concomitant therapies were not usually controlled. Spironolactone has been used to treat AV in adult women as monotherapy or in combination with topical agents, oral antibiotics, and COCs.^9,40-42 Additionally, dose-ranging studies have not been completed with spironolactone for AV.^9,40 The suggested dose range is 50 mg to 200 mg daily; however, it usually is best to start at 50 mg daily and increase to 100 mg daily if clinical response is not adequate after 2 to 3 months. The gastrointestinal (GI) absorption of spironolactone is increased when ingested with a high-fat meal.^9,10

Once effective control of AV is achieved, it is optimal to use the lowest dose needed to continue reasonable suppression of new AV lesions. There is no defined end point for spironolactone use in AV, with or without concurrent PCOS, as many adult women usually continue treatment with low-dose therapy because they experience marked flaring shortly after the drug is stopped.⁹

Risks and Contraindications

Side effects associated with spironolactone are dose related and include increased diuresis, migraines, menstrual irregularities, breast tenderness, gynecomastia, fatigue, and dizziness.^9,10,40-44 Side effects (particularly menstrual irregularities and breast tenderness) are more common at doses higher than 100 mg daily, especially when used as monotherapy without concurrent use of a COC.^9,40

Spironolactone-associated hyperkalemia is most clinically relevant in patients on higher doses (eg, 100–200 mg daily), in those with renal impairment and/or congestive heart failure, and when used concurrently with certain other medications. In any patient on spironolactone, the risk of clinically relevant hyperkalemia may be increased by coingestion of potassium supplements, potassium-based salt substitutes, potassium-sparing diuretics (eg, amiloride, triamterene); aldosterone antagonists and angiotensin-converting enzyme inhibitors (eg, lisinopril, benazepril); angiotensin II receptor blockers (eg, losartan, valsartan); and tri-methoprim (with or without sulfamethoxazole).^8,9,40,45 Spironolactone may also increase serum levels of lithium or digoxin.^9,40,45,46 For management of AV, it is best that spironolactone be avoided in patients taking any of these medications.⁹

In healthy adult women with AV who are not on medications or supplements that interact adversely with spironolactone, there is no definitive recommendation regarding monitoring of serum potassium levels during treatment with spironolactone, and it has been suggested that monitoring serum potassium levels in this subgroup is not necessary.⁴⁷ However, each clinician is advised to choose whether or not they wish to obtain baseline and/or periodic serum potassium levels when prescribing spironolactone for AV based on their degree of comfort and the patient’s history. Baseline and periodic blood testing to evaluate serum electrolytes and renal function are reasonable, especially as adult women with AV are usually treated with spironolactone over a prolonged period of time.⁹

The FDA black box warning for spironolactone states that it is tumorigenic in chronic toxicity studies in rats and refers to exposures 25- to 100-fold higher than those administered to humans.^9,48 Although continued vigilance is warranted, evaluation of large populations of women treated with spironolactone do not suggest an association with increased risk of breast cancer.^49,50

Spironolactone is a category C drug and thus should be avoided during pregnancy, primarily due to animal data suggesting risks of hypospadias and feminization in male fetuses.⁹ Importantly, there is an absence of reports linking exposure during pregnancy with congenital defects in humans, including in 2 known cases of high-dose exposures for maternal Bartter syndrome.⁹

The active metabolite, canrenone, is known to be present in breast milk at 0.2% of the maternal daily dose, but breastfeeding is generally believed to be safe with spironolactone based on evidence to date.⁹

Oral Antibiotics

Oral antibiotic therapy may be used in combination with a topical regimen to treat AV in adult women, keeping in mind some important caveats.^1-7 For instance, monotherapy with oral antibiotics should be avoided, and concomitant use of benzoyl peroxide is suggested to reduce emergence of antibiotic-resistant Propionibacterium acnes strains.^3,4 A therapeutic exit plan also is suggested when prescribing oral antibiotics to limit treatment to 3 to 4 months, if possible, to help mitigate the emergence of antibiotic-resistant bacteria (eg, staphylococci and streptococci).^3-5,51

Tetracyclines, especially doxycycline and minocycline, are the most commonly prescribed agents. Doxycycline use warrants patient education on measures to limit the risks of esophageal and GI side effects and phototoxicity; enteric-coated and small tablet formulations have been shown to reduce GI side effects, especially when administered with food.^3,52-55 In addition to vestibular side effects and hyperpigmentation, minocycline may be associated with rare but potentially severe adverse reactions such as drug hypersensitivity syndrome, autoimmune hepatitis, and lupus-like syndrome, which are reported more commonly in women.^5,52,54 Vestibular side effects have been shown to decrease with use of extended-release tablets with weight-based dosing.⁵³

Oral Isotretinoin

Oral isotretinoin is well established as highly effective for treatment of severe, recalcitrant AV, including nodular acne on the face and trunk.^4,56 Currently available oral isotretinoins are branded generic formulations based on the pharmacokinetic profile of the original brand (Accutane [Roche Pharmaceuticals]) and with the use of Lidose Technology (Absorica [Cipher Pharmaceuticals]), which substantially increases GI absorption of isotretinoin in the absence of ingestion with a high-calorie, high-fat meal.⁵⁷ The short- and long-term efficacy, dosing regimens, safety considerations, and serious teratogenic risks for oral isotretinoin are well published.^4,56-58 Importantly, oral isotretinoin must be prescribed with strict adherence to the federally mandated iPLEDGE risk management program.

Low-dose oral isotretinoin therapy (<0.5 mg/kg–1 mg/kg daily) administered over several months longer than conventional regimens (ie, 16–20 weeks) has been suggested with demonstrated efficacy.⁵⁷ However, this approach is not optimal due to the lack of established sustained clearance of AV after discontinuation of therapy and the greater potential for exposure to isotretinoin during pregnancy. Recurrences of AV do occur after completion of isotretinoin therapy, especially if cumulative systemic exposure to the drug during the initial course of treatment was inadequate.^56,57

Oral isotretinoin has been shown to be effective in AV in adult women with or without PCOS with 0.5 mg/kg to 1 mg/kg daily and a total cumulative exposure of 120 mg/kg to 150 mg/kg.⁵⁹ In one study, the presence of PCOS and greater number of nodules at baseline were predictive of a higher risk of relapse during the second year posttreatment.⁵⁹

Conclusion

All oral therapies that are used to treat AV in adult women warrant individual consideration of possible benefits versus risks. Careful attention to possible side effects, patient-related risk factors, and potential drug-drug interactions is important. End points of therapy are not well established, with the exception of oral isotretinoin therapy. Clinicians must use their judgment in each case along with obtaining feedback from patients regarding the selection of therapy after a discussion of the available options.

Selection of oral agents for treatment of AV in adult women is dependent on multiple factors including the patient’s age, medication history, child-bearing potential, clinical presentation, and treatment preference following a discussion of the anticipated benefits versus potential risks.^1,2 In patients with the mixed inflammatory and comedonal clinical pattern of AV, oral antibiotics can be used concurrently with topical therapies when moderate to severe inflammatory lesions are noted.^3,4 However, many adult women who had AV as teenagers have already utilized oral antibiotic therapies in the past and often are interested in alternative options, express concerns regarding antibiotic resistance, report a history of antibiotic-associated yeast infections or other side effects, and/or encounter issues related to drug-drug interactions.^3,5-8 Oral hormonal therapies such as combination oral contraceptives (COCs) or spironolactone often are utilized to treat adult women with AV, sometimes in combination with each other or other agents. Combination oral contraceptives appear to be especially effective in the management of the U-shaped clinical pattern or predominantly inflammatory, late-onset AV.^1,5,9,10 Potential warnings, contraindications, adverse effects, and drug-drug interactions are important to keep in mind when considering the use of oral hormonal therapies.^8-10 Oral isotretinoin, which should be prescribed with strict adherence to the iPLEDGE™ program (https://www.ipledgeprogram.com/), remains a viable option for cases of severe nodular AV and selected cases of refractory inflammatory AV, especially when scarring and/or marked psychosocial distress are noted.^1,2,5,11 Although it is recognized that adult women with AV typically present with either a mixed inflammatory and comedonal or U-shaped clinical pattern predominantly involving the lower face and anterolateral neck, the available data do not adequately differentiate the relative responsiveness of these clinical patterns to specific therapeutic agents.

Combination Oral Contraceptives

Combination oral contraceptives are commonly used to treat AV in adult women, including those without and those with measurable androgen excess (eg, polycystic ovary syndrome [PCOS]). Combination oral contraceptives contain ethinyl estradiol and a progestational agent (eg, progestin); the latter varies in terms of its nonselective receptor interactions and the relative magnitude or absence of androgenic effects.^10,12,13 Although some COCs are approved by the US Food and Drug Administration (FDA) for AV, there is little data available to determine the comparative efficacy among these and other COCs.^10,14 When choosing a COC for treatment of AV, it is best to select an agent whose effectiveness is supported by evidence from clinical studies.^10,15

Mechanisms of Action

The reported mechanisms of action for COCs include inhibition of ovarian androgen production and ovulation through gonadotropin suppression; upregulated synthesis of sex hormone–binding globulin, which decreases free testosterone levels through receptor binding; and inhibition of 5α-reductase (by some progestins), which reduces conversion of testosterone to dihydrotestosterone, the active derivative that induces androgenic effects at peripheral target tissues.^10,13,16,17

Therapeutic Benefits

Use of COCs to treat AV in adult women who do not have measurable androgen excess is most rational in patients who also desire a method of contraception. Multiple monotherapy studies have demonstrated the efficacy of COCs in the treatment of AV on the face and trunk.^{4,10,12,15,17,18} It may take a minimum of 3 monthly cycles of use before acne lesion counts begin to appreciably decrease.^12,15,19-21 Initiating COC therapy during menstruation ensures the absence of pregnancy. Combination oral contraceptives may be used with other topical and oral therapies for AV.^2,3,9,10 Potential ancillary benefits of COCs include normalization of the menstrual cycle; reduced premenstrual dysphoric disorder symptoms; and reduced risk of endometrial cancer (approximately 50%), ovarian cancer (approximately 40%), and colorectal cancer.^22-24

Risks and Contraindications

It is important to consider the potential risks associated with the use of COCs, especially in women with AV who are not seeking a method of contraception. Side effects of COCs can include nausea, breast tenderness, breakthrough bleeding, and weight gain.^25,26 Potential adverse associations of COCs are described in the Table. The major potential vascular associations include venous thromboembolism, myocardial infarction, and cerebrovascular accident, all of which are influenced by concurrent factors such as a history of smoking, age (≥35 years), and hypertension.^27-32 It is recommended that blood pressure be measured before initiating COC therapy as part of the general examination.³³

The potential increase in breast cancer risk appears to be low, while the cervical cancer risk is reported to increase relative to the duration of use.^34-37 This latter observation may be due to the greater likelihood of unprotected sex in women using a COC and exposure to multiple sexual partners in some cases, which may increase the likelihood of oncogenic human papillomavirus infection of the cervix. If a dermatologist elects to prescribe a COC to treat AV, it has been suggested that the patient also consult with her general practitioner or gynecologist to undergo pelvic and breast examinations and a Papanicolaou test.³³ The recommendation for initial screening for cervical cancer is within 3 years of initiation of sexual intercourse or by 21 years of age, whichever is first.^33,38,39

Combination oral contraceptives are not ideal for all adult women with AV. Absolute contraindications are pregnancy and history of thromboembolic, cardiac, or hepatic disease; in women aged 35 years and older who smoke, relative contraindications include hypertension, diabetes, migraines, breastfeeding, and current breast or liver cancer.³³ In adult women with AV who have relative contra-indications but are likely to benefit from the use of a COC when other options are limited or not viable, consultation with a gynecologist is prudent. Other than rifamycin antibiotics (eg, rifampin) and griseofulvin, there is no definitive evidence that oral antibiotics (eg, tetracycline) or oral antifungal agents reduce the contraceptive efficacy of COCs, although cautions remain in print within some approved package inserts.⁸

Spironolactone

Available since 1957, spironolactone is an oral aldos-terone antagonist and potassium-sparing diuretic used to treat hypertension and congestive heart failure.⁹ Recognition of its antiandrogenic effects led to its use in dermatology to treat certain dermatologic disorders in women (eg, hirsutism, alopecia, AV).^1,4,5,9,10 Spironolactone is not approved for AV by the FDA; therefore, available data from multiple independent studies and retrospective analyses that have been collectively reviewed support its efficacy when used as both monotherapy or in combination with other agents in adult women with AV, especially those with a U-shaped pattern and/or late-onset AV.^9,40-43

Mechanism of Action

Spironolactone inhibits sebaceous gland activity through peripheral androgen receptor blockade, inhibition of 5α-reductase, decrease in androgen production, and increase in sex hormone–binding globulin.^9,10,40

Therapeutic Benefits

Good to excellent improvement of AV in women, many of whom are postadolescent, has ranged from 66% to 100% in published reports^9,40-43; however, inclusion and exclusion criteria, dosing regimens, and concomitant therapies were not usually controlled. Spironolactone has been used to treat AV in adult women as monotherapy or in combination with topical agents, oral antibiotics, and COCs.^9,40-42 Additionally, dose-ranging studies have not been completed with spironolactone for AV.^9,40 The suggested dose range is 50 mg to 200 mg daily; however, it usually is best to start at 50 mg daily and increase to 100 mg daily if clinical response is not adequate after 2 to 3 months. The gastrointestinal (GI) absorption of spironolactone is increased when ingested with a high-fat meal.^9,10

Once effective control of AV is achieved, it is optimal to use the lowest dose needed to continue reasonable suppression of new AV lesions. There is no defined end point for spironolactone use in AV, with or without concurrent PCOS, as many adult women usually continue treatment with low-dose therapy because they experience marked flaring shortly after the drug is stopped.⁹

Risks and Contraindications

Side effects associated with spironolactone are dose related and include increased diuresis, migraines, menstrual irregularities, breast tenderness, gynecomastia, fatigue, and dizziness.^9,10,40-44 Side effects (particularly menstrual irregularities and breast tenderness) are more common at doses higher than 100 mg daily, especially when used as monotherapy without concurrent use of a COC.^9,40

Spironolactone-associated hyperkalemia is most clinically relevant in patients on higher doses (eg, 100–200 mg daily), in those with renal impairment and/or congestive heart failure, and when used concurrently with certain other medications. In any patient on spironolactone, the risk of clinically relevant hyperkalemia may be increased by coingestion of potassium supplements, potassium-based salt substitutes, potassium-sparing diuretics (eg, amiloride, triamterene); aldosterone antagonists and angiotensin-converting enzyme inhibitors (eg, lisinopril, benazepril); angiotensin II receptor blockers (eg, losartan, valsartan); and tri-methoprim (with or without sulfamethoxazole).^8,9,40,45 Spironolactone may also increase serum levels of lithium or digoxin.^9,40,45,46 For management of AV, it is best that spironolactone be avoided in patients taking any of these medications.⁹

In healthy adult women with AV who are not on medications or supplements that interact adversely with spironolactone, there is no definitive recommendation regarding monitoring of serum potassium levels during treatment with spironolactone, and it has been suggested that monitoring serum potassium levels in this subgroup is not necessary.⁴⁷ However, each clinician is advised to choose whether or not they wish to obtain baseline and/or periodic serum potassium levels when prescribing spironolactone for AV based on their degree of comfort and the patient’s history. Baseline and periodic blood testing to evaluate serum electrolytes and renal function are reasonable, especially as adult women with AV are usually treated with spironolactone over a prolonged period of time.⁹

The FDA black box warning for spironolactone states that it is tumorigenic in chronic toxicity studies in rats and refers to exposures 25- to 100-fold higher than those administered to humans.^9,48 Although continued vigilance is warranted, evaluation of large populations of women treated with spironolactone do not suggest an association with increased risk of breast cancer.^49,50

Spironolactone is a category C drug and thus should be avoided during pregnancy, primarily due to animal data suggesting risks of hypospadias and feminization in male fetuses.⁹ Importantly, there is an absence of reports linking exposure during pregnancy with congenital defects in humans, including in 2 known cases of high-dose exposures for maternal Bartter syndrome.⁹

The active metabolite, canrenone, is known to be present in breast milk at 0.2% of the maternal daily dose, but breastfeeding is generally believed to be safe with spironolactone based on evidence to date.⁹

Oral Antibiotics

Oral antibiotic therapy may be used in combination with a topical regimen to treat AV in adult women, keeping in mind some important caveats.^1-7 For instance, monotherapy with oral antibiotics should be avoided, and concomitant use of benzoyl peroxide is suggested to reduce emergence of antibiotic-resistant Propionibacterium acnes strains.^3,4 A therapeutic exit plan also is suggested when prescribing oral antibiotics to limit treatment to 3 to 4 months, if possible, to help mitigate the emergence of antibiotic-resistant bacteria (eg, staphylococci and streptococci).^3-5,51

Tetracyclines, especially doxycycline and minocycline, are the most commonly prescribed agents. Doxycycline use warrants patient education on measures to limit the risks of esophageal and GI side effects and phototoxicity; enteric-coated and small tablet formulations have been shown to reduce GI side effects, especially when administered with food.^3,52-55 In addition to vestibular side effects and hyperpigmentation, minocycline may be associated with rare but potentially severe adverse reactions such as drug hypersensitivity syndrome, autoimmune hepatitis, and lupus-like syndrome, which are reported more commonly in women.^5,52,54 Vestibular side effects have been shown to decrease with use of extended-release tablets with weight-based dosing.⁵³

Oral Isotretinoin

Oral isotretinoin is well established as highly effective for treatment of severe, recalcitrant AV, including nodular acne on the face and trunk.^4,56 Currently available oral isotretinoins are branded generic formulations based on the pharmacokinetic profile of the original brand (Accutane [Roche Pharmaceuticals]) and with the use of Lidose Technology (Absorica [Cipher Pharmaceuticals]), which substantially increases GI absorption of isotretinoin in the absence of ingestion with a high-calorie, high-fat meal.⁵⁷ The short- and long-term efficacy, dosing regimens, safety considerations, and serious teratogenic risks for oral isotretinoin are well published.^4,56-58 Importantly, oral isotretinoin must be prescribed with strict adherence to the federally mandated iPLEDGE risk management program.

Low-dose oral isotretinoin therapy (<0.5 mg/kg–1 mg/kg daily) administered over several months longer than conventional regimens (ie, 16–20 weeks) has been suggested with demonstrated efficacy.⁵⁷ However, this approach is not optimal due to the lack of established sustained clearance of AV after discontinuation of therapy and the greater potential for exposure to isotretinoin during pregnancy. Recurrences of AV do occur after completion of isotretinoin therapy, especially if cumulative systemic exposure to the drug during the initial course of treatment was inadequate.^56,57

Oral isotretinoin has been shown to be effective in AV in adult women with or without PCOS with 0.5 mg/kg to 1 mg/kg daily and a total cumulative exposure of 120 mg/kg to 150 mg/kg.⁵⁹ In one study, the presence of PCOS and greater number of nodules at baseline were predictive of a higher risk of relapse during the second year posttreatment.⁵⁹

Conclusion

All oral therapies that are used to treat AV in adult women warrant individual consideration of possible benefits versus risks. Careful attention to possible side effects, patient-related risk factors, and potential drug-drug interactions is important. End points of therapy are not well established, with the exception of oral isotretinoin therapy. Clinicians must use their judgment in each case along with obtaining feedback from patients regarding the selection of therapy after a discussion of the available options.

It was not long ago that acne vulgaris (AV) was commonly considered to be a skin disease that affected teenagers with little attention given to preadolescent and postadolescent AV. This perspective has changed, with more attention being given to AV across a broad range of affected 
age groups, including preadolescent, adolescent, and postadolescent subgroups.^1-5 Earlier onset of adrenarche has led to earlier development of AV in many young girls, with a higher range of dehydroepiandrosterone sulfate (DHEAS) levels observed overall in those with AV as compared to a normal age-matched population.^3,4 At the other end of the age spectrum, AV is a common phenomenon in adult females, with at least half of women estimated to exhibit some form of AV.^1,2,5-8 Based on a 
large survey of females and males (N=1013), the prevalence of AV in adult females has been reported to be 50.9%, 35.2%, 26.3%, and 15.3% among women aged 20 to 29 years, 30 to 39 years, 40 to 49 years, and 50 years and older, respectively.² Acne vulgaris that persists beyond adolescence into adulthood is termed persistent acne, or early-onset acne, and the development of AV in women 25 years and older who have not previously been affected by AV has been termed late-onset acne.^6,8,9 Publications on the management of AV in adult women have focused primarily on systemic hormonal therapies; however, topical therapies more recently have received greater attention in this subpopulation^9-12 and will be discussed in part 2 of this series. Because data on AV in women are 
limited primarily to involvement of the face and neck region, this article does not address truncal AV unless otherwise specified. Table 1 depicts factors that can influence the management of AV in adult women.

Visible Patterns and Considerations for Clinical Evaluation 


Clinical Patterns

Although epidemiologic and demographic data are limited in the subpopulation of women with AV, it is reported that females account for up to 82% of adults with AV, with approximately 75% presenting with AV that is clinically similar to their disease course in adolescence.^2,5,13 Among those women with persistent AV, some state that their AV is worse compared to adolescence, while others report it is not as severe. The pattern of AV often is similar to that seen in adolescence, presenting as mixed comedonal and inflammatory papular/pustular lesions diffusely distributed on the face; in other cases, a more selectively distributed U-shaped pattern is noted, characterized predominantly by inflammatory papules and/or nodules involving the lower cheeks and jawline margin, with lesions also commonly noted on the anterior and lateral neck.^5,8,9,13-16 A U-shaped pattern is believed to be more common in late-onset AV, often with persistence into the mid-40s.^1,15,17 It is important to emphasize the need for additional studies on the demographics and clinical characteristics of AV in adult females, especially correlations between onset, age, and clinical patterns of AV.

An international, prospective, observational study assessed the clinical characteristics of AV in adults (aged ≥25 years) at a dermatology visit for acne (N=374).¹⁶ Participants who were under management for their AV showed severity grades of mild (clear/almost clear) in 47.3% of cases. Involvement of multiple facial sites—cheeks, forehead, mandibular region, and temples—was noted in 89.8% of women, often with both inflammatory and comedonal lesions, which is a pattern similar to adolescent AV. Inflammatory lesions alone were observed in 6.4% of women, 17.1% had comedonal AV only, 
and truncal AV was present in 48.4%.¹⁶ Additional well-designed studies are needed to determine if this study reflects an accurate qualitative and 
quantitative depiction of the spectrum of AV in adult females.

Mandibular Pattern

In the observational study of AV in adults, AV localized to the mandibular area was noted in only 11.2% of participants.¹⁶ Women with localized mandibular AV were more likely than women without localized AV to be employed, noted greater daily stress levels, and tended to report more psychologically stressful jobs. Interestingly, the subgroup with mandibular acne alone was much less likely 
to exhibit a global severity grade of moderate or higher (7.1% vs 50.1%), truncal acne 
(19.0% vs 51.9%), postinflammatory hyperpigmentation (23.8% vs 51.9%), and erythema (19.0% vs 48.4%), suggesting a unique subset of AV presentation.¹⁶

Ethnicity/Skin Color

Women of all ethnicities and skin types may be affected by AV.^1,18-20 Earlier age of onset of AV has been suggested in white women; however, earlier onset of adrenarche may be more frequent in black girls, which supports an earlier age of onset of AV in this subpopulation.^15-17 Women with skin of color usually express greater concern with persistent dyschromia at sites where lesions have resolved, and presence of acne scars is a concern among women regardless of skin color, ethnicity, or race.^18,20-22

Scarring

Acne scarring has been noted to affect up to 
three-fourths of adult women in one report¹⁷ and 
often is stated by patients to be a cause of concern 
and frustration.^1,5,17

Perimenstrual Flaring

Flaring associated with menses is commonly reported in adult females with AV, with 56%, 17%, and 
3% of women in one study (n=230) reporting worsening before, during, or after menses, respectively.²¹

External Factors

Comedogenic products used for skin care, cover-up makeup, or hair care may be important to consider in selected cases as potential etiologic or exacerbating factors in adult females with AV; they also may be used in the management of AV.^23-25 Adult females often are perplexed and frustrated by the presence of AV after their 
teenaged years and anxiously wonder about or search for the potential causes. Many women use cosmetic products to cover up facial AV.^5,23-25 Therefore, even if skin care or personal hygiene products or makeup are not believed to be an etiologic factor, many patients appreciate that their dermatologist addressed skin care and cosmetics as a component of AV management and provided appropriate recommendations.^5,13

Ingestion of dietary supplements containing whey protein have been associated with precipitation of AV.^26,27 Diets with specific content characteristics have been implicated as potential etiologic or exacerbating factors for AV; however, data are limited and specific recommendations remain elusive at present. Individual cases may warrant consideration of dietary factors, especially when treatment resistance is noted.²⁸ Importantly, progestin-only contraceptives (ie, injectables, intrauterine devices) also can exacerbate or induce AV.²⁹

Hyperandrogenism

Although most adult females with AV are reported to have normal serum androgen levels when tested, it is important to explore potential signs and symptoms that are suggestive of underlying hyperandrogenism through both the patient’s history and physical examination.^{9-11,21,29-33} Some investigators have suggested that underlying peripheral hyperandrogenism is the leading cause of AV in adult females, 
with or without concurrent polycystic ovarian syndrome (PCOS), though it is believed that most women with AV exhibit normal results when 
undergoing laboratory testing for androgen excess.^{10,11,21,29,30} Nevertheless, it is important to consider the possibility of underlying causes of androgen excess (Table 2), the most common being PCOS and late-onset congenital adrenal hyperplasia; an androgen-secreting tumor is less common.^11,29-33 It is suggested that screening for underlying endocrinopathy should be conducted in women presenting with (1) AV recalcitrant to conventional treatment, (2) sudden emergence of severe AV, 
(3) concurrent signs/symptoms of androgen 
excess, and/or (4) AV relapse shortly after isotretinoin therapy.^7,11,16,33

Hirsutism and acanthosis nigricans have been reported to be more reliable predictors of hyperandrogenism than androgenic alopecia.²¹ Although it may be subtle in some cases, acanthosis nigricans is harder to camouflage, so the clinician can usually detect it if a thorough physical examination is performed. However, a patient may not voluntarily report to the clinician and their staff that she has hair removed, so despite a thorough examination, the clinician may not detect hirsutism. Therefore, it is important to inquire directly about the presence of hairs (pigmented terminal vs “peach fuzz” hairs), their anatomic location, and any hair removal practices the patient has used. The absence of androgenic alopecia does not exclude underlying hyperandrogenism; however, its presence, especially in younger women, may serve as a clinical marker for underlying hyperandrogenism.⁵ Some women may camouflage more subtle alopecia through hairstyling, but obtaining this history usually is not problematic, as most women are distressed by any degree of hair loss.

Laboratory Evaluation—A relatively straightforward approach to the workup of androgen excess includes assessment of serum DHEAS, free testosterone, and total testosterone levels.^10,30 Elevation of serum DHEAS levels indicates an adrenal source of androgen production. Elevation of testosterone is associated with excess androgens 
produced by the ovaries. Modest elevations of 
DHEAS are most commonly associated with late-onset congenital adrenal hyperplasia that may not have been previously diagnosed. Modest elevation 
of testosterone is most commonly associated with PCOS, which also can be accompanied by an 
elevated luteinizing hormone:follicle-stimulating hormone ratio of 2.5:1 to 3:1.^10,30 Marked elevations of DHEAS or testosterone can be indicative of adrenal or ovarian tumors, respectively.³⁰

In some cases, a woman might have 
elevated DHEAS and testosterone levels. A 17-hydroxyprogesterone test can help discriminate between an adrenal or ovarian source of 
androgen excess in these cases, as elevated 
17-hydroxyprogesterone levels indicate that the androgens are coming from the adrenal gland.^10,30

It is important that laboratory evaluation be performed when ovulation is not occurring. Blood tests can be drawn just prior to or during menses. It is important that a woman is not taking an oral contraceptive at the time of testing, which can mask an underlying endocrine abnormality.^10,11,29,30 Generally, testing can be performed at least 4 to 6 weeks after stopping the oral contraceptive.

Psychosocial Impact

Facial AV exhibits a broad range of adverse psychological and social effects on many adult females.^2,5,13,18 It can be associated with depression, anxiety, psychological stress, and suicidal ideation; therefore, thorough screening for these comorbidities may be warranted in some patients.^2,18

Conclusion

The epidemiology, clinical presentation, and clinical and laboratory evaluation of AV in adult females was reviewed in part 1 of this 3-part series. It is important for the clinician to assess the clinical presentation, psychosocial effects, and the possibility of underlying causes of androgen excess. In part 2, skin care 
and topical management of AV in adult females will be discussed.

It was not long ago that acne vulgaris (AV) was commonly considered to be a skin disease that affected teenagers with little attention given to preadolescent and postadolescent AV. This perspective has changed, with more attention being given to AV across a broad range of affected 
age groups, including preadolescent, adolescent, and postadolescent subgroups.^1-5 Earlier onset of adrenarche has led to earlier development of AV in many young girls, with a higher range of dehydroepiandrosterone sulfate (DHEAS) levels observed overall in those with AV as compared to a normal age-matched population.^3,4 At the other end of the age spectrum, AV is a common phenomenon in adult females, with at least half of women estimated to exhibit some form of AV.^1,2,5-8 Based on a 
large survey of females and males (N=1013), the prevalence of AV in adult females has been reported to be 50.9%, 35.2%, 26.3%, and 15.3% among women aged 20 to 29 years, 30 to 39 years, 40 to 49 years, and 50 years and older, respectively.² Acne vulgaris that persists beyond adolescence into adulthood is termed persistent acne, or early-onset acne, and the development of AV in women 25 years and older who have not previously been affected by AV has been termed late-onset acne.^6,8,9 Publications on the management of AV in adult women have focused primarily on systemic hormonal therapies; however, topical therapies more recently have received greater attention in this subpopulation^9-12 and will be discussed in part 2 of this series. Because data on AV in women are 
limited primarily to involvement of the face and neck region, this article does not address truncal AV unless otherwise specified. Table 1 depicts factors that can influence the management of AV in adult women.

Visible Patterns and Considerations for Clinical Evaluation 


Clinical Patterns

Although epidemiologic and demographic data are limited in the subpopulation of women with AV, it is reported that females account for up to 82% of adults with AV, with approximately 75% presenting with AV that is clinically similar to their disease course in adolescence.^2,5,13 Among those women with persistent AV, some state that their AV is worse compared to adolescence, while others report it is not as severe. The pattern of AV often is similar to that seen in adolescence, presenting as mixed comedonal and inflammatory papular/pustular lesions diffusely distributed on the face; in other cases, a more selectively distributed U-shaped pattern is noted, characterized predominantly by inflammatory papules and/or nodules involving the lower cheeks and jawline margin, with lesions also commonly noted on the anterior and lateral neck.^5,8,9,13-16 A U-shaped pattern is believed to be more common in late-onset AV, often with persistence into the mid-40s.^1,15,17 It is important to emphasize the need for additional studies on the demographics and clinical characteristics of AV in adult females, especially correlations between onset, age, and clinical patterns of AV.

An international, prospective, observational study assessed the clinical characteristics of AV in adults (aged ≥25 years) at a dermatology visit for acne (N=374).¹⁶ Participants who were under management for their AV showed severity grades of mild (clear/almost clear) in 47.3% of cases. Involvement of multiple facial sites—cheeks, forehead, mandibular region, and temples—was noted in 89.8% of women, often with both inflammatory and comedonal lesions, which is a pattern similar to adolescent AV. Inflammatory lesions alone were observed in 6.4% of women, 17.1% had comedonal AV only, 
and truncal AV was present in 48.4%.¹⁶ Additional well-designed studies are needed to determine if this study reflects an accurate qualitative and 
quantitative depiction of the spectrum of AV in adult females.

Mandibular Pattern

In the observational study of AV in adults, AV localized to the mandibular area was noted in only 11.2% of participants.¹⁶ Women with localized mandibular AV were more likely than women without localized AV to be employed, noted greater daily stress levels, and tended to report more psychologically stressful jobs. Interestingly, the subgroup with mandibular acne alone was much less likely 
to exhibit a global severity grade of moderate or higher (7.1% vs 50.1%), truncal acne 
(19.0% vs 51.9%), postinflammatory hyperpigmentation (23.8% vs 51.9%), and erythema (19.0% vs 48.4%), suggesting a unique subset of AV presentation.¹⁶

Ethnicity/Skin Color

Women of all ethnicities and skin types may be affected by AV.^1,18-20 Earlier age of onset of AV has been suggested in white women; however, earlier onset of adrenarche may be more frequent in black girls, which supports an earlier age of onset of AV in this subpopulation.^15-17 Women with skin of color usually express greater concern with persistent dyschromia at sites where lesions have resolved, and presence of acne scars is a concern among women regardless of skin color, ethnicity, or race.^18,20-22

Scarring

Acne scarring has been noted to affect up to 
three-fourths of adult women in one report¹⁷ and 
often is stated by patients to be a cause of concern 
and frustration.^1,5,17

Perimenstrual Flaring

Flaring associated with menses is commonly reported in adult females with AV, with 56%, 17%, and 
3% of women in one study (n=230) reporting worsening before, during, or after menses, respectively.²¹

External Factors

Comedogenic products used for skin care, cover-up makeup, or hair care may be important to consider in selected cases as potential etiologic or exacerbating factors in adult females with AV; they also may be used in the management of AV.^23-25 Adult females often are perplexed and frustrated by the presence of AV after their 
teenaged years and anxiously wonder about or search for the potential causes. Many women use cosmetic products to cover up facial AV.^5,23-25 Therefore, even if skin care or personal hygiene products or makeup are not believed to be an etiologic factor, many patients appreciate that their dermatologist addressed skin care and cosmetics as a component of AV management and provided appropriate recommendations.^5,13

Ingestion of dietary supplements containing whey protein have been associated with precipitation of AV.^26,27 Diets with specific content characteristics have been implicated as potential etiologic or exacerbating factors for AV; however, data are limited and specific recommendations remain elusive at present. Individual cases may warrant consideration of dietary factors, especially when treatment resistance is noted.²⁸ Importantly, progestin-only contraceptives (ie, injectables, intrauterine devices) also can exacerbate or induce AV.²⁹

Hyperandrogenism

Although most adult females with AV are reported to have normal serum androgen levels when tested, it is important to explore potential signs and symptoms that are suggestive of underlying hyperandrogenism through both the patient’s history and physical examination.^{9-11,21,29-33} Some investigators have suggested that underlying peripheral hyperandrogenism is the leading cause of AV in adult females, 
with or without concurrent polycystic ovarian syndrome (PCOS), though it is believed that most women with AV exhibit normal results when 
undergoing laboratory testing for androgen excess.^{10,11,21,29,30} Nevertheless, it is important to consider the possibility of underlying causes of androgen excess (Table 2), the most common being PCOS and late-onset congenital adrenal hyperplasia; an androgen-secreting tumor is less common.^11,29-33 It is suggested that screening for underlying endocrinopathy should be conducted in women presenting with (1) AV recalcitrant to conventional treatment, (2) sudden emergence of severe AV, 
(3) concurrent signs/symptoms of androgen 
excess, and/or (4) AV relapse shortly after isotretinoin therapy.^7,11,16,33

Hirsutism and acanthosis nigricans have been reported to be more reliable predictors of hyperandrogenism than androgenic alopecia.²¹ Although it may be subtle in some cases, acanthosis nigricans is harder to camouflage, so the clinician can usually detect it if a thorough physical examination is performed. However, a patient may not voluntarily report to the clinician and their staff that she has hair removed, so despite a thorough examination, the clinician may not detect hirsutism. Therefore, it is important to inquire directly about the presence of hairs (pigmented terminal vs “peach fuzz” hairs), their anatomic location, and any hair removal practices the patient has used. The absence of androgenic alopecia does not exclude underlying hyperandrogenism; however, its presence, especially in younger women, may serve as a clinical marker for underlying hyperandrogenism.⁵ Some women may camouflage more subtle alopecia through hairstyling, but obtaining this history usually is not problematic, as most women are distressed by any degree of hair loss.

Laboratory Evaluation—A relatively straightforward approach to the workup of androgen excess includes assessment of serum DHEAS, free testosterone, and total testosterone levels.^10,30 Elevation of serum DHEAS levels indicates an adrenal source of androgen production. Elevation of testosterone is associated with excess androgens 
produced by the ovaries. Modest elevations of 
DHEAS are most commonly associated with late-onset congenital adrenal hyperplasia that may not have been previously diagnosed. Modest elevation 
of testosterone is most commonly associated with PCOS, which also can be accompanied by an 
elevated luteinizing hormone:follicle-stimulating hormone ratio of 2.5:1 to 3:1.^10,30 Marked elevations of DHEAS or testosterone can be indicative of adrenal or ovarian tumors, respectively.³⁰

In some cases, a woman might have 
elevated DHEAS and testosterone levels. A 17-hydroxyprogesterone test can help discriminate between an adrenal or ovarian source of 
androgen excess in these cases, as elevated 
17-hydroxyprogesterone levels indicate that the androgens are coming from the adrenal gland.^10,30

It is important that laboratory evaluation be performed when ovulation is not occurring. Blood tests can be drawn just prior to or during menses. It is important that a woman is not taking an oral contraceptive at the time of testing, which can mask an underlying endocrine abnormality.^10,11,29,30 Generally, testing can be performed at least 4 to 6 weeks after stopping the oral contraceptive.

Psychosocial Impact

Facial AV exhibits a broad range of adverse psychological and social effects on many adult females.^2,5,13,18 It can be associated with depression, anxiety, psychological stress, and suicidal ideation; therefore, thorough screening for these comorbidities may be warranted in some patients.^2,18

Conclusion

The epidemiology, clinical presentation, and clinical and laboratory evaluation of AV in adult females was reviewed in part 1 of this 3-part series. It is important for the clinician to assess the clinical presentation, psychosocial effects, and the possibility of underlying causes of androgen excess. In part 2, skin care 
and topical management of AV in adult females will be discussed.

It was not long ago that acne vulgaris (AV) was commonly considered to be a skin disease that affected teenagers with little attention given to preadolescent and postadolescent AV. This perspective has changed, with more attention being given to AV across a broad range of affected 
age groups, including preadolescent, adolescent, and postadolescent subgroups.^1-5 Earlier onset of adrenarche has led to earlier development of AV in many young girls, with a higher range of dehydroepiandrosterone sulfate (DHEAS) levels observed overall in those with AV as compared to a normal age-matched population.^3,4 At the other end of the age spectrum, AV is a common phenomenon in adult females, with at least half of women estimated to exhibit some form of AV.^1,2,5-8 Based on a 
large survey of females and males (N=1013), the prevalence of AV in adult females has been reported to be 50.9%, 35.2%, 26.3%, and 15.3% among women aged 20 to 29 years, 30 to 39 years, 40 to 49 years, and 50 years and older, respectively.² Acne vulgaris that persists beyond adolescence into adulthood is termed persistent acne, or early-onset acne, and the development of AV in women 25 years and older who have not previously been affected by AV has been termed late-onset acne.^6,8,9 Publications on the management of AV in adult women have focused primarily on systemic hormonal therapies; however, topical therapies more recently have received greater attention in this subpopulation^9-12 and will be discussed in part 2 of this series. Because data on AV in women are 
limited primarily to involvement of the face and neck region, this article does not address truncal AV unless otherwise specified. Table 1 depicts factors that can influence the management of AV in adult women.

Visible Patterns and Considerations for Clinical Evaluation 


Clinical Patterns

Although epidemiologic and demographic data are limited in the subpopulation of women with AV, it is reported that females account for up to 82% of adults with AV, with approximately 75% presenting with AV that is clinically similar to their disease course in adolescence.^2,5,13 Among those women with persistent AV, some state that their AV is worse compared to adolescence, while others report it is not as severe. The pattern of AV often is similar to that seen in adolescence, presenting as mixed comedonal and inflammatory papular/pustular lesions diffusely distributed on the face; in other cases, a more selectively distributed U-shaped pattern is noted, characterized predominantly by inflammatory papules and/or nodules involving the lower cheeks and jawline margin, with lesions also commonly noted on the anterior and lateral neck.^5,8,9,13-16 A U-shaped pattern is believed to be more common in late-onset AV, often with persistence into the mid-40s.^1,15,17 It is important to emphasize the need for additional studies on the demographics and clinical characteristics of AV in adult females, especially correlations between onset, age, and clinical patterns of AV.

An international, prospective, observational study assessed the clinical characteristics of AV in adults (aged ≥25 years) at a dermatology visit for acne (N=374).¹⁶ Participants who were under management for their AV showed severity grades of mild (clear/almost clear) in 47.3% of cases. Involvement of multiple facial sites—cheeks, forehead, mandibular region, and temples—was noted in 89.8% of women, often with both inflammatory and comedonal lesions, which is a pattern similar to adolescent AV. Inflammatory lesions alone were observed in 6.4% of women, 17.1% had comedonal AV only, 
and truncal AV was present in 48.4%.¹⁶ Additional well-designed studies are needed to determine if this study reflects an accurate qualitative and 
quantitative depiction of the spectrum of AV in adult females.

Mandibular Pattern

In the observational study of AV in adults, AV localized to the mandibular area was noted in only 11.2% of participants.¹⁶ Women with localized mandibular AV were more likely than women without localized AV to be employed, noted greater daily stress levels, and tended to report more psychologically stressful jobs. Interestingly, the subgroup with mandibular acne alone was much less likely 
to exhibit a global severity grade of moderate or higher (7.1% vs 50.1%), truncal acne 
(19.0% vs 51.9%), postinflammatory hyperpigmentation (23.8% vs 51.9%), and erythema (19.0% vs 48.4%), suggesting a unique subset of AV presentation.¹⁶

Ethnicity/Skin Color

Women of all ethnicities and skin types may be affected by AV.^1,18-20 Earlier age of onset of AV has been suggested in white women; however, earlier onset of adrenarche may be more frequent in black girls, which supports an earlier age of onset of AV in this subpopulation.^15-17 Women with skin of color usually express greater concern with persistent dyschromia at sites where lesions have resolved, and presence of acne scars is a concern among women regardless of skin color, ethnicity, or race.^18,20-22

Scarring

Acne scarring has been noted to affect up to 
three-fourths of adult women in one report¹⁷ and 
often is stated by patients to be a cause of concern 
and frustration.^1,5,17

Perimenstrual Flaring

Flaring associated with menses is commonly reported in adult females with AV, with 56%, 17%, and 
3% of women in one study (n=230) reporting worsening before, during, or after menses, respectively.²¹

External Factors

Comedogenic products used for skin care, cover-up makeup, or hair care may be important to consider in selected cases as potential etiologic or exacerbating factors in adult females with AV; they also may be used in the management of AV.^23-25 Adult females often are perplexed and frustrated by the presence of AV after their 
teenaged years and anxiously wonder about or search for the potential causes. Many women use cosmetic products to cover up facial AV.^5,23-25 Therefore, even if skin care or personal hygiene products or makeup are not believed to be an etiologic factor, many patients appreciate that their dermatologist addressed skin care and cosmetics as a component of AV management and provided appropriate recommendations.^5,13

Ingestion of dietary supplements containing whey protein have been associated with precipitation of AV.^26,27 Diets with specific content characteristics have been implicated as potential etiologic or exacerbating factors for AV; however, data are limited and specific recommendations remain elusive at present. Individual cases may warrant consideration of dietary factors, especially when treatment resistance is noted.²⁸ Importantly, progestin-only contraceptives (ie, injectables, intrauterine devices) also can exacerbate or induce AV.²⁹

Hyperandrogenism

Although most adult females with AV are reported to have normal serum androgen levels when tested, it is important to explore potential signs and symptoms that are suggestive of underlying hyperandrogenism through both the patient’s history and physical examination.^{9-11,21,29-33} Some investigators have suggested that underlying peripheral hyperandrogenism is the leading cause of AV in adult females, 
with or without concurrent polycystic ovarian syndrome (PCOS), though it is believed that most women with AV exhibit normal results when 
undergoing laboratory testing for androgen excess.^{10,11,21,29,30} Nevertheless, it is important to consider the possibility of underlying causes of androgen excess (Table 2), the most common being PCOS and late-onset congenital adrenal hyperplasia; an androgen-secreting tumor is less common.^11,29-33 It is suggested that screening for underlying endocrinopathy should be conducted in women presenting with (1) AV recalcitrant to conventional treatment, (2) sudden emergence of severe AV, 
(3) concurrent signs/symptoms of androgen 
excess, and/or (4) AV relapse shortly after isotretinoin therapy.^7,11,16,33

Hirsutism and acanthosis nigricans have been reported to be more reliable predictors of hyperandrogenism than androgenic alopecia.²¹ Although it may be subtle in some cases, acanthosis nigricans is harder to camouflage, so the clinician can usually detect it if a thorough physical examination is performed. However, a patient may not voluntarily report to the clinician and their staff that she has hair removed, so despite a thorough examination, the clinician may not detect hirsutism. Therefore, it is important to inquire directly about the presence of hairs (pigmented terminal vs “peach fuzz” hairs), their anatomic location, and any hair removal practices the patient has used. The absence of androgenic alopecia does not exclude underlying hyperandrogenism; however, its presence, especially in younger women, may serve as a clinical marker for underlying hyperandrogenism.⁵ Some women may camouflage more subtle alopecia through hairstyling, but obtaining this history usually is not problematic, as most women are distressed by any degree of hair loss.

Laboratory Evaluation—A relatively straightforward approach to the workup of androgen excess includes assessment of serum DHEAS, free testosterone, and total testosterone levels.^10,30 Elevation of serum DHEAS levels indicates an adrenal source of androgen production. Elevation of testosterone is associated with excess androgens 
produced by the ovaries. Modest elevations of 
DHEAS are most commonly associated with late-onset congenital adrenal hyperplasia that may not have been previously diagnosed. Modest elevation 
of testosterone is most commonly associated with PCOS, which also can be accompanied by an 
elevated luteinizing hormone:follicle-stimulating hormone ratio of 2.5:1 to 3:1.^10,30 Marked elevations of DHEAS or testosterone can be indicative of adrenal or ovarian tumors, respectively.³⁰

In some cases, a woman might have 
elevated DHEAS and testosterone levels. A 17-hydroxyprogesterone test can help discriminate between an adrenal or ovarian source of 
androgen excess in these cases, as elevated 
17-hydroxyprogesterone levels indicate that the androgens are coming from the adrenal gland.^10,30

It is important that laboratory evaluation be performed when ovulation is not occurring. Blood tests can be drawn just prior to or during menses. It is important that a woman is not taking an oral contraceptive at the time of testing, which can mask an underlying endocrine abnormality.^10,11,29,30 Generally, testing can be performed at least 4 to 6 weeks after stopping the oral contraceptive.

Psychosocial Impact

Facial AV exhibits a broad range of adverse psychological and social effects on many adult females.^2,5,13,18 It can be associated with depression, anxiety, psychological stress, and suicidal ideation; therefore, thorough screening for these comorbidities may be warranted in some patients.^2,18

Conclusion

The epidemiology, clinical presentation, and clinical and laboratory evaluation of AV in adult females was reviewed in part 1 of this 3-part series. It is important for the clinician to assess the clinical presentation, psychosocial effects, and the possibility of underlying causes of androgen excess. In part 2, skin care 
and topical management of AV in adult females will be discussed.

Rosacea is a common dermatologic disorder that generally is characterized by erythema as well as papules and pustules on the cheeks, chin, forehead, and nose. Moreover, telangiectasia and burning or stinging sensations often occur.^1,2 These clinical manifestations and other related ones frequently lead to the perception of “sensitive skin.” Rosacea patients often experience low self-esteem, anxiety, and social embarrassment.³ Reports of the gender distribution of the disease vary but often show female predominance.⁴ Although it also occurs in darker skin types, rosacea is more common in individuals with lighter skin.¹         

The etiology of rosacea is not yet fully understood, but the underlying pathology has been attributed to dysregulated immune responses. Although the flares of a typical fluctuating disease course often are caused by exogenous triggers, there is evidence that an underlying genetic component predisposes some individuals to pathologic changes associated with the condition.⁵ Augmented immune activity and proinflammatory signaling appear to induce the infiltration of inflammatory elements into affected areas.² These regions show dilated vasculature and increased cutaneous blood flow secondary to inflammation. Systemic oxidative stress also may contribute to epidermal dysfunction, as the antioxidant capacity of the skin in patients with rosacea is depleted relative to that of healthy individuals. The biochemical and vascular changes characteristic of rosacea coincide with aberrant permeability of the stratum corneum.⁶ The resulting decreased hydration and water loss across the skin contribute to the sensitivity and irritation typical of the disease.²

Current guidelines for the optimal management of rosacea with papulopustular lesions recommend skin care, photoprotection, and topical therapy. Depending on the severity of disease and the likelihood of adherence to a topical regimen, use of oral agents may be warranted.⁷

Azelaic acid (AzA), an unbranched saturated dicarboxylic acid (1,7-heptanedicarboxylic acid) that occurs in plants, is one of several US Food and Drug Administration–approved topical agents for the treatment of inflammatory lesions in rosacea.⁸ Although the pathophysiology of rosacea is not yet fully understood, there is a growing consensus about the role of proinflammatory molecules (eg, kallikrein 5, cathelicidins) as well as reactive oxygen species (ROS).⁹ Azelaic acid has been demonstrated to modulate the inflammatory response in normal human keratinocytes through several pathways, including modulation of the signaling pathways of peroxisome proliferator-activated receptor g and nuclear factor kB, concurrent with the observed inhibition of proinflammatory cytokine secretion.¹⁰ Additionally, AzA can inhibit the release of ROS from neutrophils and also may reduce ROS by direct scavenging effects.¹¹ Further, AzA shows direct inhibition of kallikrein 5 in human keratinocytes as well as a reduction of the expression of kallikrein 5 and cathelicidin in murine skin and the facial skin of patients with rosacea.¹²

In a series of randomized trials in patients with papulopustular rosacea (PPR), AzA has shown clinical efficacy and safety as a topical treatment.^13-15 Based on these studies, a gel formulation of AzA with a 15% concentration has been approved for treating inflammatory papules and pustules of mild to moderate rosacea.¹⁶

Although AzA delivered in a gel matrix is an effective therapy, topical delivery of active pharmaceutical ingredients via foam is often preferred over traditional vehicles in patients with sensitive skin. Patient rationale for favoring foam includes improved appearance and ease of application, namely easier to spread with a reduced need to manipulate inflamed skin.¹⁷ Also, data reveal that patients may be more compliant with a treatment that meets their needs such as an optimized foam formulation.¹⁸ In addition, the lipid components of an optimized formulation are thought to contribute to an improved skin condition.¹⁹ The foam vehicle used in this study is a proprietary oil-in-water formulation that includes fatty alcohols and triglycerides. The novel delivery of AzA in a foam formulation will provide clinicians and patients with a new option for improved individualized care.

We report the primary results of a phase 3 study in patients with PPR comparing the efficacy and safety of twice-daily AzA foam 15% with vehicle foam. The phase 3 study builds on the results of a prior randomized double-blind trial (N=401) that demonstrated significant improvements relative to vehicle in therapeutic success rate (P=.017) and decreased inflammatory lesion count (ILC)(P<.001) among patients treated with AzA foam 15%.⁸

Methods

Study Design

This phase 3 randomized, double-blind, vehicle-controlled, parallel-group, multicenter study was conducted in patients with PPR according to Good Clinical Practice guidelines in 48 study centers in the United States. The objective was to evaluate a 12-week, twice-daily (morning and evening) course of AzA foam 15% versus vehicle.

Participants were men and women aged 18 years or older with moderate to severe PPR (as determined by investigator global assessment [IGA]) presenting with 12 to 50 papules and/or pustules and persistent erythema with or without telangiectasia. Informed consent was obtained from all participants before any study-related activities were carried out.

The study products were applied to the entire facial area each morning and evening at a dose of 0.5 g, thus administering 150 mg of AzA daily in the active arm of the trial (computerized randomization 1:1). The treatment period lasted 12 weeks, and participants were evaluated at baseline and weeks 4, 8, and 12. The follow-up period lasted 4 weeks following the end of treatment (EoT) and was concluded with one final end-of-study visit.

Efficacy Evaluations

There were 2 coprimary efficacy end points. Therapeutic success rate was evaluated using the IGA scale (clear, minimal, mild, moderate, or severe). Treatment success was defined as an IGA score of either clear or minimal (with at least a 2-step improvement) at EoT, whereas treatment failure was constituted by IGA scores of mild, moderate, or severe.

The second coprimary end point was the nominal change in ILC from baseline to EoT as determined by the total number of facial papules and pustules. Efficacy and safety parameters were evaluated at weeks 4, 8, and 12, as well as at the end of the 4-week follow-up period. Throughout the study, the investigator, participants, and all study personnel remained blinded.

Safety

Information about adverse events (AEs) was collected at each study visit, and AEs were graded according to seriousness (yes or no) and intensity (mild, moderate, or severe).

Statistical Analysis

Efficacy was confirmed by analysis of the treatment success rate at EoT with Cochran-Mantel-Haenszel test statistics, including a point estimate and 95% confidence interval (CI) for the odds ratio. Change in ILC at EoT was analyzed via an analysis of covariance model using treatment, center, and baseline lesion count as factors. (Additional methods can be found in the Appendix below.)

Results

Study Participants

Of the 1156 patients who were screened for eligibility, 961 were randomized to treatment with AzA foam (n=484) or vehicle (n=477)(Figure 1). Sixty-four (13.2%) participants in the AzA foam group and 79 (16.6%) in the vehicle group discontinued treatment before completing the study. The most common reasons for discontinuation were participant withdrawal from the study and lost to follow-up. Six (1.2%) participants from the AzA foam group and 12 (2.5%) from the vehicle group discontinued because of AEs. All safety and efficacy data presented are based on the full analysis set, which consisted of the 961 participants randomized to treatment.

Figure 1. Study disposition and reasons for study discontinuation. Percentages of participants who discontinued prior to treatment randomization are based on the number of patients screened, whereas all other percentages are based on the number of participants randomized. After completion of treatment, all participants (including those who prematurely discontinued treatment) were invited to enter the follow-up phase.

Demographic and baseline characteristics were balanced between the treatment groups (Table 1). The majority of participants were female (73.0%) and white (95.5%), reflecting the patient populations of independent studies that found a higher prevalence of rosacea in women and lighter skin types.4 There were no significant differences in baseline measures of PPR severity between the treatment groups. Participants in the AzA foam and vehicle groups had a mean ILC of 21.7 and 21.2, respectively, and 76.4% of participants had more than 14 lesions. All participants had an IGA score of moderate (86.8%) or severe (13.2%). Moderate or severe erythema was present in 91.5% of participants.

Treatment compliance, as measured by the percentage of expected doses that were actually administered, was 97.1% in the AzA foam group and 95.9% in the vehicle group.

Efficacy

Results from both primary end points demonstrated superior efficacy of AzA foam over vehicle. The AzA foam group achieved a greater IGA success rate at EoT compared with the vehicle group (32.0% vs 23.5%; Cochran-Mantel-Haenszel test center-adjusted P<.001; odds ratio, 1.6; 95% CI, 1.2-2.2). Treatment success rate was higher in the AzA foam group than in the vehicle group at every time point past baseline (Figure 2). Similarly, the decrease in mean nominal ILC values was greater in the AzA foam group at every time point after baseline (Figure 3), and the treatment difference at EoT was statistically significant in favor of AzA foam (-2.7, F_1,920=23.7, P<.001; 95% CI, -3.8 to -1.6). The divergence between treatment groups at week 4 reveals an onset of AzA effect early in the study.

Figure 2. Percentages of participants who had successful treatment outcomes based on investigator global assessment scores (clear or minimal) at weeks 4, 8, 12, and 16 (FU). P values were calculated from the Pearson c² test. Last observation carried forward was not applied to FU analysis. EoT indicates end of treatment; FU, after 4 weeks of follow-up without treatment.

Figure 3. Mean nominal change in inflammatory lesion count from baseline at weeks 4, 8, 12, and 16 (FU). P values were calculated from 2-sided t tests. Last observation carried forward was not applied to FU analysis. SD indicates standard deviation; EoT, end of treatment; FU, after 4 weeks of follow-up without treatment.

Although the AzA foam group showed significantly better efficacy results than the vehicle group for the coprimary end points, participants in the vehicle group did show appreciable IGA success rates (23.5%) and changes in ILC (-10.3) at EoT (Figures 2 and 3).

Notably, the AzA foam group maintained better results than vehicle for both primary end points even at the end of the 4-week follow-up after EoT (Figures 2 and 3). Sensitivity analysis (data not shown) confirmed the findings from the full analysis set.

Safety

Adverse events were experienced by 149 (30.8%) participants in the AzA foam group and 119 (24.9%) in the vehicle group. The most common noncutaneous AEs (>1% of participants) reported during AzA foam treatment were nasopharyngitis, headache, upper respiratory tract infection, and influenza. In the vehicle group, the most common noncutaneous AEs reported were nasopharyngitis and headache. Drug-related AEs (relationship assessed by the investigator) were reported slightly more often in the AzA foam group (7.6%) than in the vehicle group (4.6%). Drug-related AEs were predominantly cutaneous and occurred at the site of application (Table 2). Drug-related cutaneous AEs were more common in the AzA foam group (7.0%) than in the vehicle group (4.4%). Although serious AEs were more common in the vehicle group, all were regarded as unrelated to the study medication. A single death occurred in the vehicle group due to an accident unrelated to the study drug.

The most frequent drug-related AEs in participants treated with AzA foam versus vehicle were application-site pain (3.5% vs 1.3%), application-site pruritus (1.4% vs 0.4%), and application-site dryness (1.0% vs 0.6%). The classical rosacea symptom of stinging is subsumed under the term application-site pain, according to MedDRA (Medical Dictionary for Regulatory Activities).

All other drug-related AEs occurred at a frequency of less than 1% in participants from both groups. Serious AEs were rare and unrelated to treatment, with 3 AEs reported in the AzA foam group and 4 in the vehicle group. Adverse events leading to study drug withdrawal occurred in less than 2% of participants and were more common in the vehicle group (2.5%) than in the AzA foam group (1.2%). Of the 3 drug-related AEs leading to withdrawal in the AzA foam group, 2 were due to cutaneous reaction and 1 was due to a burning sensation. The number of active drug-related cutaneous AEs was highest during the first 4 weeks of treatment and declined over the course of the study (eFigure).

eFigure. Number of active drug-related cutaneous AEs at each study interval (full analysis set). AE indicates adverse event; EoT, end of treatment; FU, after 4 weeks of follow-up without treatment.

More than 96% of AEs were resolved by the end of the study. Of the participants experiencing AEs that did not resolve during the course of the study, 16 were in the AzA foam group and 10 in the vehicle group. Six unresolved AEs were drug related, with 3 occurring in each treatment group. Unresolved drug-related cutaneous AEs in the AzA foam group were pain, pruritus, and dryness at the application site.

Comment

Overall, the results from this phase 3 trial demonstrate that the new foam formulation of AzA was efficacious and safe in a 12-week, twice-daily course of treatment for moderate to severe PPR. The AzA foam formulation was significantly superior to vehicle (P<.001) for both primary efficacy end points. Participants in the AzA foam group achieved therapeutic success at a higher rate than the vehicle group, and the change in nominal ILC at EoT was significantly greater for participants treated with AzA foam than for those treated with vehicle (P<.001). Differences between the 2 treatment groups for the coprimary end point measures arose early in the study, demonstrating that symptoms were rapidly controlled. Between weeks 8 and 12 (EoT), the rate of increase of beneficial effects in the AzA foam group remained high, while the vehicle group showed a notable slowing. There was no indication of any rebound effect in overall disease severity subsequent to EoT. After 4 weeks of follow-up, there was still a beneficial treatment effect present in favor of the AzA foam group, as indicated by the persistence of improvements in both coprimary end point measures throughout the follow-up period.

Analyses of alternative populations and secondary end points (data not shown) supported the efficacy results reported here. There was no indication of irregular study center effects, and the sensitivity analyses demonstrated robustness of the data for the observed treatment effects.

The use of vehicle foam alone appeared to be beneficial in reducing ILC and improving IGA rating, which suggests that the properties of the new foam formulation are favorable for the inflamed lesional skin of rosacea. Of note, other dermatology studies, including trials in rosacea, have reported therapeutic effects of vehicle treatment that may be attributable to the positive effects of skin care with certain formulations.²⁰

Azelaic acid foam was well tolerated in the current study. More than 93% of AEs in either treatment group were of mild or moderate severity. The incidence of drug-related AEs was low in both groups and mainly occurred at the application site. There were no drug-related severe or serious AEs. The low incidence of reported drug-related noncutaneous AEs in the AzA foam group (dysgeusia in 1 patient and headache in 2 patients) supports the known favorable systemic tolerance profile of AzA.

Although most drug-related AEs occurred at the application site, they were generally transient, with the majority of events in the AzA foam group lasting no more than 1 hour. Most cutaneous AEs developed early in the study. In the AzA foam group, the prevalence of drug-related cutaneous AEs dropped at every time interval as the study progressed (eFigure). Very few AEs of any type persisted through the end of the study. These safety results were accompanied by a high compliance rate and a high participation rate throughout the course of the study. Taken together, the available data for this AzA foam formulation support a favorable tolerability profile. The results of this study are consistent with and expand on data from an earlier investigation of similar design.⁸

Conclusion

The development of an AzA foam formulation with higher lipid content was intended to expand the treatment options available to physicians and patients who are managing rosacea. Most topical dermatologic treatments are currently delivered in classical formulations such as creams or gels, but patients who use topical therapies have rated messiness and ease of application among the most important characteristics affecting quality of life.^17,21 Foam formulations may offer improvements in this regard; ease of application may minimize unnecessary manipulation of inflamed skin and contribute to a high level of user satisfaction.²² However, the design of the current study was limited to evaluating only the AzA foam formulation versus a foam vehicle, and direct comparisons of clinical efficacy and tolerability to other AzA topical preparations were not performed. Nonetheless, patients have previously reported that they would be more likely to comply with a recommended course of dermatologic foam therapy than other topical formulations.¹⁸ The proposed foam formulation was designed to attend to the specific needs of the dry and sensitive skin in rosacea by combining the demonstrated efficacy properties exhibited by AzA gel 15% with the good tolerability and acceptability of a lipid-containing foam formulation. Development of this formulation was targeted to obtain a product that would be highly spreadable, dry quickly, and be easy to apply. The available data for this AzA foam formulation support the value of this option in the topical treatment of rosacea. The success in reduction of overall disease severity, lack of any rebound after EoT, and the observed tolerability and high adherence rates suggest that this novel formulation is a useful addition to current treatment options for rosacea.

Addendum

After release of the study data for unblinding and statistical evaluation, the following inconsistency regarding patient distribution was noted: 1 participant was incorrectly evaluated as part of the AzA foam analysis group when in fact this patient was randomized to vehicle and was treated throughout the study with vehicle. This participant did not experience any AE and did not show any IGA improvement at the EoT. As this single case did not have an impact on the statistical conclusions or interpretation of the results, the released study data have not been changed. This deviation was described as a database erratum in the study report.

Acknowledgement—Editorial support through inVentiv Medical Communications, New York, New York, was provided by Bayer HealthCare Pharmaceuticals Inc.

APPENDIX

Supplementary Methods

Supplementary Study Design

This study met all local legal and regulatory requirements and was conducted according to the principles of the Declaration of Helsinki and the International Conference on Harmonization Good Clinical Practice guidelines. Before the start of the study and implementation, the protocol and all amendments were approved by the appropriate independent ethics committee or institutional review board at each study site. Two protocol amendments were implemented before the first participant visit.

Exclusion criteria included the presence of dermatoses that could interfere with rosacea diagnosis or evaluation, facial laser surgery or topical use of any medication to treat rosacea within 6 weeks before randomization, systemic use of any medications to treat rosacea, and known unresponsiveness to AzA treatment. Further standard exclusion criteria included alcohol or drug use or parallel participation in other clinical studies, which were necessary to exclude undue influence on study evaluations and/or participant safety. The study was conducted by qualified investigators at 48 centers in the United States.

The investigational product was filled in identical containers according to the randomization list generated by a computer program using blocks. Complete blocks of study medication were distributed to the centers. Eligible participants were randomized 1:1 into either AzA foam or vehicle treatment groups by assignment of a randomization number at baseline. A blind investigational product under the same randomization number was dispensed to and returned from participants by study personnel who were not involved in the assessments. Blinding was achieved by using labels on the investigational products that did not allow identification of the true medication.

Compliance was evaluated from participant diaries as well as the number of expected doses and actually applied doses.

Additional Efficacy Evaluations

A number of secondary variables (not reported here) were assessed, including changes in other manifestations of PPR, as well as participant assessments of treatment response, tolerability, cosmetic preferences, and quality of life.

Additional Safety

Investigators reported a yes or no response as to whether there was a reasonable causal relationship between AEs and treatment. Moreover, AEs that began at the start of or during treatment were considered treatment emergent. Cutaneous AEs were further assessed regarding location and duration. An AE was deemed local if it occurred at the application site and transient if it subsided within 60 minutes of onset.

Statistical Analysis

The primary efficacy analyses presented here were based on the full analysis set of participants who were randomized and had medication dispensed. For participants with no EoT value, the last nonmissing value was used including baseline (last-observation-carried-forward methodology). Participants who discontinued treatment prematurely because of lack of efficacy were considered to be treatment failures, regardless of the reported IGA score. Statistical significance was needed for both coprimary efficacy variables at a 1-sided 2.5% significance level to show confirmed superiority of AzA foam versus vehicle.

A number of sensitivity analyses were performed, including an analysis of the coprimary end points using observed data, analysis of the per-protocol population of participants who did not prematurely discontinue treatment and had no major protocol deviations, subgroup analyses, and the use of statistical methods to investigate the effect of missing observations. Analyses of success rate and nominal change in ILC were repeated for each postbaseline visit using χ² and t tests, respectively. All summary and statistical analyses were performed according to the study protocol (unchanged after the start of the study) using SAS version 9.2.

Results from a prior study provided the basis for the sample size, which was calculated to show a significant difference in both primary efficacy end points with a power of 90%.⁸ To allow for dropouts, 480 participants in each treatment group were to be randomized for a total of 960 participants.

eFigure. Number of active drug-related cutaneous AEs at each study interval (full analysis set). AE indicates adverse event; EoT, end of treatment; FU, after 4 weeks of follow-up without treatment.

Rosacea is a common dermatologic disorder that generally is characterized by erythema as well as papules and pustules on the cheeks, chin, forehead, and nose. Moreover, telangiectasia and burning or stinging sensations often occur.^1,2 These clinical manifestations and other related ones frequently lead to the perception of “sensitive skin.” Rosacea patients often experience low self-esteem, anxiety, and social embarrassment.³ Reports of the gender distribution of the disease vary but often show female predominance.⁴ Although it also occurs in darker skin types, rosacea is more common in individuals with lighter skin.¹         

The etiology of rosacea is not yet fully understood, but the underlying pathology has been attributed to dysregulated immune responses. Although the flares of a typical fluctuating disease course often are caused by exogenous triggers, there is evidence that an underlying genetic component predisposes some individuals to pathologic changes associated with the condition.⁵ Augmented immune activity and proinflammatory signaling appear to induce the infiltration of inflammatory elements into affected areas.² These regions show dilated vasculature and increased cutaneous blood flow secondary to inflammation. Systemic oxidative stress also may contribute to epidermal dysfunction, as the antioxidant capacity of the skin in patients with rosacea is depleted relative to that of healthy individuals. The biochemical and vascular changes characteristic of rosacea coincide with aberrant permeability of the stratum corneum.⁶ The resulting decreased hydration and water loss across the skin contribute to the sensitivity and irritation typical of the disease.²

Current guidelines for the optimal management of rosacea with papulopustular lesions recommend skin care, photoprotection, and topical therapy. Depending on the severity of disease and the likelihood of adherence to a topical regimen, use of oral agents may be warranted.⁷

Azelaic acid (AzA), an unbranched saturated dicarboxylic acid (1,7-heptanedicarboxylic acid) that occurs in plants, is one of several US Food and Drug Administration–approved topical agents for the treatment of inflammatory lesions in rosacea.⁸ Although the pathophysiology of rosacea is not yet fully understood, there is a growing consensus about the role of proinflammatory molecules (eg, kallikrein 5, cathelicidins) as well as reactive oxygen species (ROS).⁹ Azelaic acid has been demonstrated to modulate the inflammatory response in normal human keratinocytes through several pathways, including modulation of the signaling pathways of peroxisome proliferator-activated receptor g and nuclear factor kB, concurrent with the observed inhibition of proinflammatory cytokine secretion.¹⁰ Additionally, AzA can inhibit the release of ROS from neutrophils and also may reduce ROS by direct scavenging effects.¹¹ Further, AzA shows direct inhibition of kallikrein 5 in human keratinocytes as well as a reduction of the expression of kallikrein 5 and cathelicidin in murine skin and the facial skin of patients with rosacea.¹²

In a series of randomized trials in patients with papulopustular rosacea (PPR), AzA has shown clinical efficacy and safety as a topical treatment.^13-15 Based on these studies, a gel formulation of AzA with a 15% concentration has been approved for treating inflammatory papules and pustules of mild to moderate rosacea.¹⁶

Although AzA delivered in a gel matrix is an effective therapy, topical delivery of active pharmaceutical ingredients via foam is often preferred over traditional vehicles in patients with sensitive skin. Patient rationale for favoring foam includes improved appearance and ease of application, namely easier to spread with a reduced need to manipulate inflamed skin.¹⁷ Also, data reveal that patients may be more compliant with a treatment that meets their needs such as an optimized foam formulation.¹⁸ In addition, the lipid components of an optimized formulation are thought to contribute to an improved skin condition.¹⁹ The foam vehicle used in this study is a proprietary oil-in-water formulation that includes fatty alcohols and triglycerides. The novel delivery of AzA in a foam formulation will provide clinicians and patients with a new option for improved individualized care.

We report the primary results of a phase 3 study in patients with PPR comparing the efficacy and safety of twice-daily AzA foam 15% with vehicle foam. The phase 3 study builds on the results of a prior randomized double-blind trial (N=401) that demonstrated significant improvements relative to vehicle in therapeutic success rate (P=.017) and decreased inflammatory lesion count (ILC)(P<.001) among patients treated with AzA foam 15%.⁸

Methods

Study Design

This phase 3 randomized, double-blind, vehicle-controlled, parallel-group, multicenter study was conducted in patients with PPR according to Good Clinical Practice guidelines in 48 study centers in the United States. The objective was to evaluate a 12-week, twice-daily (morning and evening) course of AzA foam 15% versus vehicle.

Participants were men and women aged 18 years or older with moderate to severe PPR (as determined by investigator global assessment [IGA]) presenting with 12 to 50 papules and/or pustules and persistent erythema with or without telangiectasia. Informed consent was obtained from all participants before any study-related activities were carried out.

The study products were applied to the entire facial area each morning and evening at a dose of 0.5 g, thus administering 150 mg of AzA daily in the active arm of the trial (computerized randomization 1:1). The treatment period lasted 12 weeks, and participants were evaluated at baseline and weeks 4, 8, and 12. The follow-up period lasted 4 weeks following the end of treatment (EoT) and was concluded with one final end-of-study visit.

Efficacy Evaluations

There were 2 coprimary efficacy end points. Therapeutic success rate was evaluated using the IGA scale (clear, minimal, mild, moderate, or severe). Treatment success was defined as an IGA score of either clear or minimal (with at least a 2-step improvement) at EoT, whereas treatment failure was constituted by IGA scores of mild, moderate, or severe.

The second coprimary end point was the nominal change in ILC from baseline to EoT as determined by the total number of facial papules and pustules. Efficacy and safety parameters were evaluated at weeks 4, 8, and 12, as well as at the end of the 4-week follow-up period. Throughout the study, the investigator, participants, and all study personnel remained blinded.

Safety

Information about adverse events (AEs) was collected at each study visit, and AEs were graded according to seriousness (yes or no) and intensity (mild, moderate, or severe).

Statistical Analysis

Efficacy was confirmed by analysis of the treatment success rate at EoT with Cochran-Mantel-Haenszel test statistics, including a point estimate and 95% confidence interval (CI) for the odds ratio. Change in ILC at EoT was analyzed via an analysis of covariance model using treatment, center, and baseline lesion count as factors. (Additional methods can be found in the Appendix below.)

Results

Study Participants

Of the 1156 patients who were screened for eligibility, 961 were randomized to treatment with AzA foam (n=484) or vehicle (n=477)(Figure 1). Sixty-four (13.2%) participants in the AzA foam group and 79 (16.6%) in the vehicle group discontinued treatment before completing the study. The most common reasons for discontinuation were participant withdrawal from the study and lost to follow-up. Six (1.2%) participants from the AzA foam group and 12 (2.5%) from the vehicle group discontinued because of AEs. All safety and efficacy data presented are based on the full analysis set, which consisted of the 961 participants randomized to treatment.

Figure 1. Study disposition and reasons for study discontinuation. Percentages of participants who discontinued prior to treatment randomization are based on the number of patients screened, whereas all other percentages are based on the number of participants randomized. After completion of treatment, all participants (including those who prematurely discontinued treatment) were invited to enter the follow-up phase.

Demographic and baseline characteristics were balanced between the treatment groups (Table 1). The majority of participants were female (73.0%) and white (95.5%), reflecting the patient populations of independent studies that found a higher prevalence of rosacea in women and lighter skin types.4 There were no significant differences in baseline measures of PPR severity between the treatment groups. Participants in the AzA foam and vehicle groups had a mean ILC of 21.7 and 21.2, respectively, and 76.4% of participants had more than 14 lesions. All participants had an IGA score of moderate (86.8%) or severe (13.2%). Moderate or severe erythema was present in 91.5% of participants.

Treatment compliance, as measured by the percentage of expected doses that were actually administered, was 97.1% in the AzA foam group and 95.9% in the vehicle group.

Efficacy

Results from both primary end points demonstrated superior efficacy of AzA foam over vehicle. The AzA foam group achieved a greater IGA success rate at EoT compared with the vehicle group (32.0% vs 23.5%; Cochran-Mantel-Haenszel test center-adjusted P<.001; odds ratio, 1.6; 95% CI, 1.2-2.2). Treatment success rate was higher in the AzA foam group than in the vehicle group at every time point past baseline (Figure 2). Similarly, the decrease in mean nominal ILC values was greater in the AzA foam group at every time point after baseline (Figure 3), and the treatment difference at EoT was statistically significant in favor of AzA foam (-2.7, F_1,920=23.7, P<.001; 95% CI, -3.8 to -1.6). The divergence between treatment groups at week 4 reveals an onset of AzA effect early in the study.

Figure 2. Percentages of participants who had successful treatment outcomes based on investigator global assessment scores (clear or minimal) at weeks 4, 8, 12, and 16 (FU). P values were calculated from the Pearson c² test. Last observation carried forward was not applied to FU analysis. EoT indicates end of treatment; FU, after 4 weeks of follow-up without treatment.

Figure 3. Mean nominal change in inflammatory lesion count from baseline at weeks 4, 8, 12, and 16 (FU). P values were calculated from 2-sided t tests. Last observation carried forward was not applied to FU analysis. SD indicates standard deviation; EoT, end of treatment; FU, after 4 weeks of follow-up without treatment.

Although the AzA foam group showed significantly better efficacy results than the vehicle group for the coprimary end points, participants in the vehicle group did show appreciable IGA success rates (23.5%) and changes in ILC (-10.3) at EoT (Figures 2 and 3).

Notably, the AzA foam group maintained better results than vehicle for both primary end points even at the end of the 4-week follow-up after EoT (Figures 2 and 3). Sensitivity analysis (data not shown) confirmed the findings from the full analysis set.

Safety

Adverse events were experienced by 149 (30.8%) participants in the AzA foam group and 119 (24.9%) in the vehicle group. The most common noncutaneous AEs (>1% of participants) reported during AzA foam treatment were nasopharyngitis, headache, upper respiratory tract infection, and influenza. In the vehicle group, the most common noncutaneous AEs reported were nasopharyngitis and headache. Drug-related AEs (relationship assessed by the investigator) were reported slightly more often in the AzA foam group (7.6%) than in the vehicle group (4.6%). Drug-related AEs were predominantly cutaneous and occurred at the site of application (Table 2). Drug-related cutaneous AEs were more common in the AzA foam group (7.0%) than in the vehicle group (4.4%). Although serious AEs were more common in the vehicle group, all were regarded as unrelated to the study medication. A single death occurred in the vehicle group due to an accident unrelated to the study drug.

The most frequent drug-related AEs in participants treated with AzA foam versus vehicle were application-site pain (3.5% vs 1.3%), application-site pruritus (1.4% vs 0.4%), and application-site dryness (1.0% vs 0.6%). The classical rosacea symptom of stinging is subsumed under the term application-site pain, according to MedDRA (Medical Dictionary for Regulatory Activities).

All other drug-related AEs occurred at a frequency of less than 1% in participants from both groups. Serious AEs were rare and unrelated to treatment, with 3 AEs reported in the AzA foam group and 4 in the vehicle group. Adverse events leading to study drug withdrawal occurred in less than 2% of participants and were more common in the vehicle group (2.5%) than in the AzA foam group (1.2%). Of the 3 drug-related AEs leading to withdrawal in the AzA foam group, 2 were due to cutaneous reaction and 1 was due to a burning sensation. The number of active drug-related cutaneous AEs was highest during the first 4 weeks of treatment and declined over the course of the study (eFigure).

eFigure. Number of active drug-related cutaneous AEs at each study interval (full analysis set). AE indicates adverse event; EoT, end of treatment; FU, after 4 weeks of follow-up without treatment.

More than 96% of AEs were resolved by the end of the study. Of the participants experiencing AEs that did not resolve during the course of the study, 16 were in the AzA foam group and 10 in the vehicle group. Six unresolved AEs were drug related, with 3 occurring in each treatment group. Unresolved drug-related cutaneous AEs in the AzA foam group were pain, pruritus, and dryness at the application site.

Comment

Overall, the results from this phase 3 trial demonstrate that the new foam formulation of AzA was efficacious and safe in a 12-week, twice-daily course of treatment for moderate to severe PPR. The AzA foam formulation was significantly superior to vehicle (P<.001) for both primary efficacy end points. Participants in the AzA foam group achieved therapeutic success at a higher rate than the vehicle group, and the change in nominal ILC at EoT was significantly greater for participants treated with AzA foam than for those treated with vehicle (P<.001). Differences between the 2 treatment groups for the coprimary end point measures arose early in the study, demonstrating that symptoms were rapidly controlled. Between weeks 8 and 12 (EoT), the rate of increase of beneficial effects in the AzA foam group remained high, while the vehicle group showed a notable slowing. There was no indication of any rebound effect in overall disease severity subsequent to EoT. After 4 weeks of follow-up, there was still a beneficial treatment effect present in favor of the AzA foam group, as indicated by the persistence of improvements in both coprimary end point measures throughout the follow-up period.

Analyses of alternative populations and secondary end points (data not shown) supported the efficacy results reported here. There was no indication of irregular study center effects, and the sensitivity analyses demonstrated robustness of the data for the observed treatment effects.

The use of vehicle foam alone appeared to be beneficial in reducing ILC and improving IGA rating, which suggests that the properties of the new foam formulation are favorable for the inflamed lesional skin of rosacea. Of note, other dermatology studies, including trials in rosacea, have reported therapeutic effects of vehicle treatment that may be attributable to the positive effects of skin care with certain formulations.²⁰

Azelaic acid foam was well tolerated in the current study. More than 93% of AEs in either treatment group were of mild or moderate severity. The incidence of drug-related AEs was low in both groups and mainly occurred at the application site. There were no drug-related severe or serious AEs. The low incidence of reported drug-related noncutaneous AEs in the AzA foam group (dysgeusia in 1 patient and headache in 2 patients) supports the known favorable systemic tolerance profile of AzA.

Although most drug-related AEs occurred at the application site, they were generally transient, with the majority of events in the AzA foam group lasting no more than 1 hour. Most cutaneous AEs developed early in the study. In the AzA foam group, the prevalence of drug-related cutaneous AEs dropped at every time interval as the study progressed (eFigure). Very few AEs of any type persisted through the end of the study. These safety results were accompanied by a high compliance rate and a high participation rate throughout the course of the study. Taken together, the available data for this AzA foam formulation support a favorable tolerability profile. The results of this study are consistent with and expand on data from an earlier investigation of similar design.⁸

Conclusion

The development of an AzA foam formulation with higher lipid content was intended to expand the treatment options available to physicians and patients who are managing rosacea. Most topical dermatologic treatments are currently delivered in classical formulations such as creams or gels, but patients who use topical therapies have rated messiness and ease of application among the most important characteristics affecting quality of life.^17,21 Foam formulations may offer improvements in this regard; ease of application may minimize unnecessary manipulation of inflamed skin and contribute to a high level of user satisfaction.²² However, the design of the current study was limited to evaluating only the AzA foam formulation versus a foam vehicle, and direct comparisons of clinical efficacy and tolerability to other AzA topical preparations were not performed. Nonetheless, patients have previously reported that they would be more likely to comply with a recommended course of dermatologic foam therapy than other topical formulations.¹⁸ The proposed foam formulation was designed to attend to the specific needs of the dry and sensitive skin in rosacea by combining the demonstrated efficacy properties exhibited by AzA gel 15% with the good tolerability and acceptability of a lipid-containing foam formulation. Development of this formulation was targeted to obtain a product that would be highly spreadable, dry quickly, and be easy to apply. The available data for this AzA foam formulation support the value of this option in the topical treatment of rosacea. The success in reduction of overall disease severity, lack of any rebound after EoT, and the observed tolerability and high adherence rates suggest that this novel formulation is a useful addition to current treatment options for rosacea.

Addendum

After release of the study data for unblinding and statistical evaluation, the following inconsistency regarding patient distribution was noted: 1 participant was incorrectly evaluated as part of the AzA foam analysis group when in fact this patient was randomized to vehicle and was treated throughout the study with vehicle. This participant did not experience any AE and did not show any IGA improvement at the EoT. As this single case did not have an impact on the statistical conclusions or interpretation of the results, the released study data have not been changed. This deviation was described as a database erratum in the study report.

Acknowledgement—Editorial support through inVentiv Medical Communications, New York, New York, was provided by Bayer HealthCare Pharmaceuticals Inc.

APPENDIX

Supplementary Methods

Supplementary Study Design

This study met all local legal and regulatory requirements and was conducted according to the principles of the Declaration of Helsinki and the International Conference on Harmonization Good Clinical Practice guidelines. Before the start of the study and implementation, the protocol and all amendments were approved by the appropriate independent ethics committee or institutional review board at each study site. Two protocol amendments were implemented before the first participant visit.

Exclusion criteria included the presence of dermatoses that could interfere with rosacea diagnosis or evaluation, facial laser surgery or topical use of any medication to treat rosacea within 6 weeks before randomization, systemic use of any medications to treat rosacea, and known unresponsiveness to AzA treatment. Further standard exclusion criteria included alcohol or drug use or parallel participation in other clinical studies, which were necessary to exclude undue influence on study evaluations and/or participant safety. The study was conducted by qualified investigators at 48 centers in the United States.

The investigational product was filled in identical containers according to the randomization list generated by a computer program using blocks. Complete blocks of study medication were distributed to the centers. Eligible participants were randomized 1:1 into either AzA foam or vehicle treatment groups by assignment of a randomization number at baseline. A blind investigational product under the same randomization number was dispensed to and returned from participants by study personnel who were not involved in the assessments. Blinding was achieved by using labels on the investigational products that did not allow identification of the true medication.

Compliance was evaluated from participant diaries as well as the number of expected doses and actually applied doses.

Additional Efficacy Evaluations

A number of secondary variables (not reported here) were assessed, including changes in other manifestations of PPR, as well as participant assessments of treatment response, tolerability, cosmetic preferences, and quality of life.

Additional Safety

Investigators reported a yes or no response as to whether there was a reasonable causal relationship between AEs and treatment. Moreover, AEs that began at the start of or during treatment were considered treatment emergent. Cutaneous AEs were further assessed regarding location and duration. An AE was deemed local if it occurred at the application site and transient if it subsided within 60 minutes of onset.

Statistical Analysis

The primary efficacy analyses presented here were based on the full analysis set of participants who were randomized and had medication dispensed. For participants with no EoT value, the last nonmissing value was used including baseline (last-observation-carried-forward methodology). Participants who discontinued treatment prematurely because of lack of efficacy were considered to be treatment failures, regardless of the reported IGA score. Statistical significance was needed for both coprimary efficacy variables at a 1-sided 2.5% significance level to show confirmed superiority of AzA foam versus vehicle.

A number of sensitivity analyses were performed, including an analysis of the coprimary end points using observed data, analysis of the per-protocol population of participants who did not prematurely discontinue treatment and had no major protocol deviations, subgroup analyses, and the use of statistical methods to investigate the effect of missing observations. Analyses of success rate and nominal change in ILC were repeated for each postbaseline visit using χ² and t tests, respectively. All summary and statistical analyses were performed according to the study protocol (unchanged after the start of the study) using SAS version 9.2.

Results from a prior study provided the basis for the sample size, which was calculated to show a significant difference in both primary efficacy end points with a power of 90%.⁸ To allow for dropouts, 480 participants in each treatment group were to be randomized for a total of 960 participants.

eFigure. Number of active drug-related cutaneous AEs at each study interval (full analysis set). AE indicates adverse event; EoT, end of treatment; FU, after 4 weeks of follow-up without treatment.

Rosacea is a common dermatologic disorder that generally is characterized by erythema as well as papules and pustules on the cheeks, chin, forehead, and nose. Moreover, telangiectasia and burning or stinging sensations often occur.^1,2 These clinical manifestations and other related ones frequently lead to the perception of “sensitive skin.” Rosacea patients often experience low self-esteem, anxiety, and social embarrassment.³ Reports of the gender distribution of the disease vary but often show female predominance.⁴ Although it also occurs in darker skin types, rosacea is more common in individuals with lighter skin.¹         

The etiology of rosacea is not yet fully understood, but the underlying pathology has been attributed to dysregulated immune responses. Although the flares of a typical fluctuating disease course often are caused by exogenous triggers, there is evidence that an underlying genetic component predisposes some individuals to pathologic changes associated with the condition.⁵ Augmented immune activity and proinflammatory signaling appear to induce the infiltration of inflammatory elements into affected areas.² These regions show dilated vasculature and increased cutaneous blood flow secondary to inflammation. Systemic oxidative stress also may contribute to epidermal dysfunction, as the antioxidant capacity of the skin in patients with rosacea is depleted relative to that of healthy individuals. The biochemical and vascular changes characteristic of rosacea coincide with aberrant permeability of the stratum corneum.⁶ The resulting decreased hydration and water loss across the skin contribute to the sensitivity and irritation typical of the disease.²

Current guidelines for the optimal management of rosacea with papulopustular lesions recommend skin care, photoprotection, and topical therapy. Depending on the severity of disease and the likelihood of adherence to a topical regimen, use of oral agents may be warranted.⁷

Azelaic acid (AzA), an unbranched saturated dicarboxylic acid (1,7-heptanedicarboxylic acid) that occurs in plants, is one of several US Food and Drug Administration–approved topical agents for the treatment of inflammatory lesions in rosacea.⁸ Although the pathophysiology of rosacea is not yet fully understood, there is a growing consensus about the role of proinflammatory molecules (eg, kallikrein 5, cathelicidins) as well as reactive oxygen species (ROS).⁹ Azelaic acid has been demonstrated to modulate the inflammatory response in normal human keratinocytes through several pathways, including modulation of the signaling pathways of peroxisome proliferator-activated receptor g and nuclear factor kB, concurrent with the observed inhibition of proinflammatory cytokine secretion.¹⁰ Additionally, AzA can inhibit the release of ROS from neutrophils and also may reduce ROS by direct scavenging effects.¹¹ Further, AzA shows direct inhibition of kallikrein 5 in human keratinocytes as well as a reduction of the expression of kallikrein 5 and cathelicidin in murine skin and the facial skin of patients with rosacea.¹²

In a series of randomized trials in patients with papulopustular rosacea (PPR), AzA has shown clinical efficacy and safety as a topical treatment.^13-15 Based on these studies, a gel formulation of AzA with a 15% concentration has been approved for treating inflammatory papules and pustules of mild to moderate rosacea.¹⁶

Although AzA delivered in a gel matrix is an effective therapy, topical delivery of active pharmaceutical ingredients via foam is often preferred over traditional vehicles in patients with sensitive skin. Patient rationale for favoring foam includes improved appearance and ease of application, namely easier to spread with a reduced need to manipulate inflamed skin.¹⁷ Also, data reveal that patients may be more compliant with a treatment that meets their needs such as an optimized foam formulation.¹⁸ In addition, the lipid components of an optimized formulation are thought to contribute to an improved skin condition.¹⁹ The foam vehicle used in this study is a proprietary oil-in-water formulation that includes fatty alcohols and triglycerides. The novel delivery of AzA in a foam formulation will provide clinicians and patients with a new option for improved individualized care.

We report the primary results of a phase 3 study in patients with PPR comparing the efficacy and safety of twice-daily AzA foam 15% with vehicle foam. The phase 3 study builds on the results of a prior randomized double-blind trial (N=401) that demonstrated significant improvements relative to vehicle in therapeutic success rate (P=.017) and decreased inflammatory lesion count (ILC)(P<.001) among patients treated with AzA foam 15%.⁸

Methods

Study Design

This phase 3 randomized, double-blind, vehicle-controlled, parallel-group, multicenter study was conducted in patients with PPR according to Good Clinical Practice guidelines in 48 study centers in the United States. The objective was to evaluate a 12-week, twice-daily (morning and evening) course of AzA foam 15% versus vehicle.

Participants were men and women aged 18 years or older with moderate to severe PPR (as determined by investigator global assessment [IGA]) presenting with 12 to 50 papules and/or pustules and persistent erythema with or without telangiectasia. Informed consent was obtained from all participants before any study-related activities were carried out.

The study products were applied to the entire facial area each morning and evening at a dose of 0.5 g, thus administering 150 mg of AzA daily in the active arm of the trial (computerized randomization 1:1). The treatment period lasted 12 weeks, and participants were evaluated at baseline and weeks 4, 8, and 12. The follow-up period lasted 4 weeks following the end of treatment (EoT) and was concluded with one final end-of-study visit.

Efficacy Evaluations

There were 2 coprimary efficacy end points. Therapeutic success rate was evaluated using the IGA scale (clear, minimal, mild, moderate, or severe). Treatment success was defined as an IGA score of either clear or minimal (with at least a 2-step improvement) at EoT, whereas treatment failure was constituted by IGA scores of mild, moderate, or severe.

The second coprimary end point was the nominal change in ILC from baseline to EoT as determined by the total number of facial papules and pustules. Efficacy and safety parameters were evaluated at weeks 4, 8, and 12, as well as at the end of the 4-week follow-up period. Throughout the study, the investigator, participants, and all study personnel remained blinded.

Safety

Information about adverse events (AEs) was collected at each study visit, and AEs were graded according to seriousness (yes or no) and intensity (mild, moderate, or severe).

Statistical Analysis

Efficacy was confirmed by analysis of the treatment success rate at EoT with Cochran-Mantel-Haenszel test statistics, including a point estimate and 95% confidence interval (CI) for the odds ratio. Change in ILC at EoT was analyzed via an analysis of covariance model using treatment, center, and baseline lesion count as factors. (Additional methods can be found in the Appendix below.)

Results

Study Participants

Of the 1156 patients who were screened for eligibility, 961 were randomized to treatment with AzA foam (n=484) or vehicle (n=477)(Figure 1). Sixty-four (13.2%) participants in the AzA foam group and 79 (16.6%) in the vehicle group discontinued treatment before completing the study. The most common reasons for discontinuation were participant withdrawal from the study and lost to follow-up. Six (1.2%) participants from the AzA foam group and 12 (2.5%) from the vehicle group discontinued because of AEs. All safety and efficacy data presented are based on the full analysis set, which consisted of the 961 participants randomized to treatment.

Figure 1. Study disposition and reasons for study discontinuation. Percentages of participants who discontinued prior to treatment randomization are based on the number of patients screened, whereas all other percentages are based on the number of participants randomized. After completion of treatment, all participants (including those who prematurely discontinued treatment) were invited to enter the follow-up phase.

Demographic and baseline characteristics were balanced between the treatment groups (Table 1). The majority of participants were female (73.0%) and white (95.5%), reflecting the patient populations of independent studies that found a higher prevalence of rosacea in women and lighter skin types.4 There were no significant differences in baseline measures of PPR severity between the treatment groups. Participants in the AzA foam and vehicle groups had a mean ILC of 21.7 and 21.2, respectively, and 76.4% of participants had more than 14 lesions. All participants had an IGA score of moderate (86.8%) or severe (13.2%). Moderate or severe erythema was present in 91.5% of participants.

Treatment compliance, as measured by the percentage of expected doses that were actually administered, was 97.1% in the AzA foam group and 95.9% in the vehicle group.

Efficacy

Results from both primary end points demonstrated superior efficacy of AzA foam over vehicle. The AzA foam group achieved a greater IGA success rate at EoT compared with the vehicle group (32.0% vs 23.5%; Cochran-Mantel-Haenszel test center-adjusted P<.001; odds ratio, 1.6; 95% CI, 1.2-2.2). Treatment success rate was higher in the AzA foam group than in the vehicle group at every time point past baseline (Figure 2). Similarly, the decrease in mean nominal ILC values was greater in the AzA foam group at every time point after baseline (Figure 3), and the treatment difference at EoT was statistically significant in favor of AzA foam (-2.7, F_1,920=23.7, P<.001; 95% CI, -3.8 to -1.6). The divergence between treatment groups at week 4 reveals an onset of AzA effect early in the study.

Figure 2. Percentages of participants who had successful treatment outcomes based on investigator global assessment scores (clear or minimal) at weeks 4, 8, 12, and 16 (FU). P values were calculated from the Pearson c² test. Last observation carried forward was not applied to FU analysis. EoT indicates end of treatment; FU, after 4 weeks of follow-up without treatment.

Figure 3. Mean nominal change in inflammatory lesion count from baseline at weeks 4, 8, 12, and 16 (FU). P values were calculated from 2-sided t tests. Last observation carried forward was not applied to FU analysis. SD indicates standard deviation; EoT, end of treatment; FU, after 4 weeks of follow-up without treatment.

Although the AzA foam group showed significantly better efficacy results than the vehicle group for the coprimary end points, participants in the vehicle group did show appreciable IGA success rates (23.5%) and changes in ILC (-10.3) at EoT (Figures 2 and 3).

Notably, the AzA foam group maintained better results than vehicle for both primary end points even at the end of the 4-week follow-up after EoT (Figures 2 and 3). Sensitivity analysis (data not shown) confirmed the findings from the full analysis set.

Safety

Adverse events were experienced by 149 (30.8%) participants in the AzA foam group and 119 (24.9%) in the vehicle group. The most common noncutaneous AEs (>1% of participants) reported during AzA foam treatment were nasopharyngitis, headache, upper respiratory tract infection, and influenza. In the vehicle group, the most common noncutaneous AEs reported were nasopharyngitis and headache. Drug-related AEs (relationship assessed by the investigator) were reported slightly more often in the AzA foam group (7.6%) than in the vehicle group (4.6%). Drug-related AEs were predominantly cutaneous and occurred at the site of application (Table 2). Drug-related cutaneous AEs were more common in the AzA foam group (7.0%) than in the vehicle group (4.4%). Although serious AEs were more common in the vehicle group, all were regarded as unrelated to the study medication. A single death occurred in the vehicle group due to an accident unrelated to the study drug.

The most frequent drug-related AEs in participants treated with AzA foam versus vehicle were application-site pain (3.5% vs 1.3%), application-site pruritus (1.4% vs 0.4%), and application-site dryness (1.0% vs 0.6%). The classical rosacea symptom of stinging is subsumed under the term application-site pain, according to MedDRA (Medical Dictionary for Regulatory Activities).

All other drug-related AEs occurred at a frequency of less than 1% in participants from both groups. Serious AEs were rare and unrelated to treatment, with 3 AEs reported in the AzA foam group and 4 in the vehicle group. Adverse events leading to study drug withdrawal occurred in less than 2% of participants and were more common in the vehicle group (2.5%) than in the AzA foam group (1.2%). Of the 3 drug-related AEs leading to withdrawal in the AzA foam group, 2 were due to cutaneous reaction and 1 was due to a burning sensation. The number of active drug-related cutaneous AEs was highest during the first 4 weeks of treatment and declined over the course of the study (eFigure).

eFigure. Number of active drug-related cutaneous AEs at each study interval (full analysis set). AE indicates adverse event; EoT, end of treatment; FU, after 4 weeks of follow-up without treatment.

More than 96% of AEs were resolved by the end of the study. Of the participants experiencing AEs that did not resolve during the course of the study, 16 were in the AzA foam group and 10 in the vehicle group. Six unresolved AEs were drug related, with 3 occurring in each treatment group. Unresolved drug-related cutaneous AEs in the AzA foam group were pain, pruritus, and dryness at the application site.

Comment

Overall, the results from this phase 3 trial demonstrate that the new foam formulation of AzA was efficacious and safe in a 12-week, twice-daily course of treatment for moderate to severe PPR. The AzA foam formulation was significantly superior to vehicle (P<.001) for both primary efficacy end points. Participants in the AzA foam group achieved therapeutic success at a higher rate than the vehicle group, and the change in nominal ILC at EoT was significantly greater for participants treated with AzA foam than for those treated with vehicle (P<.001). Differences between the 2 treatment groups for the coprimary end point measures arose early in the study, demonstrating that symptoms were rapidly controlled. Between weeks 8 and 12 (EoT), the rate of increase of beneficial effects in the AzA foam group remained high, while the vehicle group showed a notable slowing. There was no indication of any rebound effect in overall disease severity subsequent to EoT. After 4 weeks of follow-up, there was still a beneficial treatment effect present in favor of the AzA foam group, as indicated by the persistence of improvements in both coprimary end point measures throughout the follow-up period.

Analyses of alternative populations and secondary end points (data not shown) supported the efficacy results reported here. There was no indication of irregular study center effects, and the sensitivity analyses demonstrated robustness of the data for the observed treatment effects.

The use of vehicle foam alone appeared to be beneficial in reducing ILC and improving IGA rating, which suggests that the properties of the new foam formulation are favorable for the inflamed lesional skin of rosacea. Of note, other dermatology studies, including trials in rosacea, have reported therapeutic effects of vehicle treatment that may be attributable to the positive effects of skin care with certain formulations.²⁰

Azelaic acid foam was well tolerated in the current study. More than 93% of AEs in either treatment group were of mild or moderate severity. The incidence of drug-related AEs was low in both groups and mainly occurred at the application site. There were no drug-related severe or serious AEs. The low incidence of reported drug-related noncutaneous AEs in the AzA foam group (dysgeusia in 1 patient and headache in 2 patients) supports the known favorable systemic tolerance profile of AzA.

Although most drug-related AEs occurred at the application site, they were generally transient, with the majority of events in the AzA foam group lasting no more than 1 hour. Most cutaneous AEs developed early in the study. In the AzA foam group, the prevalence of drug-related cutaneous AEs dropped at every time interval as the study progressed (eFigure). Very few AEs of any type persisted through the end of the study. These safety results were accompanied by a high compliance rate and a high participation rate throughout the course of the study. Taken together, the available data for this AzA foam formulation support a favorable tolerability profile. The results of this study are consistent with and expand on data from an earlier investigation of similar design.⁸

Conclusion

The development of an AzA foam formulation with higher lipid content was intended to expand the treatment options available to physicians and patients who are managing rosacea. Most topical dermatologic treatments are currently delivered in classical formulations such as creams or gels, but patients who use topical therapies have rated messiness and ease of application among the most important characteristics affecting quality of life.^17,21 Foam formulations may offer improvements in this regard; ease of application may minimize unnecessary manipulation of inflamed skin and contribute to a high level of user satisfaction.²² However, the design of the current study was limited to evaluating only the AzA foam formulation versus a foam vehicle, and direct comparisons of clinical efficacy and tolerability to other AzA topical preparations were not performed. Nonetheless, patients have previously reported that they would be more likely to comply with a recommended course of dermatologic foam therapy than other topical formulations.¹⁸ The proposed foam formulation was designed to attend to the specific needs of the dry and sensitive skin in rosacea by combining the demonstrated efficacy properties exhibited by AzA gel 15% with the good tolerability and acceptability of a lipid-containing foam formulation. Development of this formulation was targeted to obtain a product that would be highly spreadable, dry quickly, and be easy to apply. The available data for this AzA foam formulation support the value of this option in the topical treatment of rosacea. The success in reduction of overall disease severity, lack of any rebound after EoT, and the observed tolerability and high adherence rates suggest that this novel formulation is a useful addition to current treatment options for rosacea.

Addendum

After release of the study data for unblinding and statistical evaluation, the following inconsistency regarding patient distribution was noted: 1 participant was incorrectly evaluated as part of the AzA foam analysis group when in fact this patient was randomized to vehicle and was treated throughout the study with vehicle. This participant did not experience any AE and did not show any IGA improvement at the EoT. As this single case did not have an impact on the statistical conclusions or interpretation of the results, the released study data have not been changed. This deviation was described as a database erratum in the study report.

Acknowledgement—Editorial support through inVentiv Medical Communications, New York, New York, was provided by Bayer HealthCare Pharmaceuticals Inc.

APPENDIX

Supplementary Methods

Supplementary Study Design

This study met all local legal and regulatory requirements and was conducted according to the principles of the Declaration of Helsinki and the International Conference on Harmonization Good Clinical Practice guidelines. Before the start of the study and implementation, the protocol and all amendments were approved by the appropriate independent ethics committee or institutional review board at each study site. Two protocol amendments were implemented before the first participant visit.

Exclusion criteria included the presence of dermatoses that could interfere with rosacea diagnosis or evaluation, facial laser surgery or topical use of any medication to treat rosacea within 6 weeks before randomization, systemic use of any medications to treat rosacea, and known unresponsiveness to AzA treatment. Further standard exclusion criteria included alcohol or drug use or parallel participation in other clinical studies, which were necessary to exclude undue influence on study evaluations and/or participant safety. The study was conducted by qualified investigators at 48 centers in the United States.

The investigational product was filled in identical containers according to the randomization list generated by a computer program using blocks. Complete blocks of study medication were distributed to the centers. Eligible participants were randomized 1:1 into either AzA foam or vehicle treatment groups by assignment of a randomization number at baseline. A blind investigational product under the same randomization number was dispensed to and returned from participants by study personnel who were not involved in the assessments. Blinding was achieved by using labels on the investigational products that did not allow identification of the true medication.

Compliance was evaluated from participant diaries as well as the number of expected doses and actually applied doses.

Additional Efficacy Evaluations

A number of secondary variables (not reported here) were assessed, including changes in other manifestations of PPR, as well as participant assessments of treatment response, tolerability, cosmetic preferences, and quality of life.

Additional Safety

Investigators reported a yes or no response as to whether there was a reasonable causal relationship between AEs and treatment. Moreover, AEs that began at the start of or during treatment were considered treatment emergent. Cutaneous AEs were further assessed regarding location and duration. An AE was deemed local if it occurred at the application site and transient if it subsided within 60 minutes of onset.

Statistical Analysis

The primary efficacy analyses presented here were based on the full analysis set of participants who were randomized and had medication dispensed. For participants with no EoT value, the last nonmissing value was used including baseline (last-observation-carried-forward methodology). Participants who discontinued treatment prematurely because of lack of efficacy were considered to be treatment failures, regardless of the reported IGA score. Statistical significance was needed for both coprimary efficacy variables at a 1-sided 2.5% significance level to show confirmed superiority of AzA foam versus vehicle.

A number of sensitivity analyses were performed, including an analysis of the coprimary end points using observed data, analysis of the per-protocol population of participants who did not prematurely discontinue treatment and had no major protocol deviations, subgroup analyses, and the use of statistical methods to investigate the effect of missing observations. Analyses of success rate and nominal change in ILC were repeated for each postbaseline visit using χ² and t tests, respectively. All summary and statistical analyses were performed according to the study protocol (unchanged after the start of the study) using SAS version 9.2.

Results from a prior study provided the basis for the sample size, which was calculated to show a significant difference in both primary efficacy end points with a power of 90%.⁸ To allow for dropouts, 480 participants in each treatment group were to be randomized for a total of 960 participants.

eFigure. Number of active drug-related cutaneous AEs at each study interval (full analysis set). AE indicates adverse event; EoT, end of treatment; FU, after 4 weeks of follow-up without treatment.