Sildenafil added to nintedanib offers no benefit in IPF patients

PARIS – Despite the promise of sildenafil for idiopathic pulmonary fibrosis (IPF), adding this therapy to nintedanib in IPF patients who have significantly impaired gas exchange did not improve quality of life (QOL), according to a randomized trial presented at the annual congress of the European Respiratory Society and simultaneously published in the New England Journal of Medicine (2018 Sep 15. doi: 10.1056/NEJMoa18117).

“Sildenafil and nintedanib in combination were well tolerated, but there was no significant benefit for these two drugs relative to nintedanib alone in patients with IPF and severe gas exchange impairment,” reported Fernando J. Martinez, MD, of the department of internal medicine, Cornell University, New York.In the multicenter INSTAGE trial, 274 IPF patients with impaired gas exchange, defined as diffusing capacity of the lungs for carbon monoxide of 35% or less, were randomized to 20 mg of sildenafil or placebo three times daily. Both groups received 150 mg twice daily of nintedanib, which is approved for the treatment of IPF.

The primary endpoint of the study was change from baseline in the St. George’s Respiratory Questionnaire (SGRQ), a 50-item quality of life (QOL) survey that captures the impact of symptoms on activities and well-being. With lower scores representing improved QOL, Dr. Martinez reported that a change of 4 or more points is considered to be clinically meaningful.

At week 12, the SGRQ score fell by 1.28 points in the group that received sildenafil and by 0.77 points in the group randomized to placebo, a difference that did not approach significance (P = .72). There was also no significant difference after 12 weeks of treatment in dyspnea, a secondary endpoint measured with the University of California, San Diego Shortness of Breath Questionnaire (UCSD-SOBQ).

When both measures were reassessed after 24 weeks of treatment, the slight persistent numerical advantage in the sildenafil arm remained statistically and clinically insignificant, according to Dr. Martinez. Rates of acute exacerbations (7.3% vs. 7.4%) and all-cause mortality (10.2% vs. 11.0%) were also reported to be similar in the experimental and control arms, respectively.

Nintedanib, which has been shown to slow decline in forced vital capacity in patients with IPF, inhibits tyrosine kinases involved in IPF progression. However, it has not been associated with an improvement in QOL in this population.

In contrast, sildenafil, a phosphodiesterase-5 inhibitor that relaxes smooth muscle, has been associated with an improvement in both SGRQ score and in dyspnea in a large IPF trial even though it failed the primary endpoint of an improvement in the 6-minute walk test (N Engl J Med 2010;363:620-28).

The hypothesis of the INSTAGE trial was that combining sildenafil with nintedanib in patients with severely impaired gas exchange might have an additive or synergistic effect for IPF symptom control by providing two distinct mechanisms of action.

This was not seen, according to Dr. Martinez. Although those receiving the combination had “a lower risk of an absolute 5-percentage-point decline in FVC of the predicted value or death than those who received nintedanib alone,” Dr. Martinez said this was not a study endpoint, and was of unclear clinical significance. Rather, although nintedanib and sildenafil were well tolerated when taken together, Dr. Martinez concluded that this trial was unable to show any definitive clinical benefit from this combination.

Dr. Martinez has financial relationships with AstraZeneca, Boehringer-Ingelheim, Cheisi, ConCert, Genentech, GlaxoSmithKline, Inova, Novartis, Roche, Sunovion, Theravance, and Teva.

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PARIS – Despite the promise of sildenafil for idiopathic pulmonary fibrosis (IPF), adding this therapy to nintedanib in IPF patients who have significantly impaired gas exchange did not improve quality of life (QOL), according to a randomized trial presented at the annual congress of the European Respiratory Society and simultaneously published in the New England Journal of Medicine (2018 Sep 15. doi: 10.1056/NEJMoa18117).

“Sildenafil and nintedanib in combination were well tolerated, but there was no significant benefit for these two drugs relative to nintedanib alone in patients with IPF and severe gas exchange impairment,” reported Fernando J. Martinez, MD, of the department of internal medicine, Cornell University, New York.In the multicenter INSTAGE trial, 274 IPF patients with impaired gas exchange, defined as diffusing capacity of the lungs for carbon monoxide of 35% or less, were randomized to 20 mg of sildenafil or placebo three times daily. Both groups received 150 mg twice daily of nintedanib, which is approved for the treatment of IPF.

The primary endpoint of the study was change from baseline in the St. George’s Respiratory Questionnaire (SGRQ), a 50-item quality of life (QOL) survey that captures the impact of symptoms on activities and well-being. With lower scores representing improved QOL, Dr. Martinez reported that a change of 4 or more points is considered to be clinically meaningful.

At week 12, the SGRQ score fell by 1.28 points in the group that received sildenafil and by 0.77 points in the group randomized to placebo, a difference that did not approach significance (P = .72). There was also no significant difference after 12 weeks of treatment in dyspnea, a secondary endpoint measured with the University of California, San Diego Shortness of Breath Questionnaire (UCSD-SOBQ).

When both measures were reassessed after 24 weeks of treatment, the slight persistent numerical advantage in the sildenafil arm remained statistically and clinically insignificant, according to Dr. Martinez. Rates of acute exacerbations (7.3% vs. 7.4%) and all-cause mortality (10.2% vs. 11.0%) were also reported to be similar in the experimental and control arms, respectively.

Nintedanib, which has been shown to slow decline in forced vital capacity in patients with IPF, inhibits tyrosine kinases involved in IPF progression. However, it has not been associated with an improvement in QOL in this population.

In contrast, sildenafil, a phosphodiesterase-5 inhibitor that relaxes smooth muscle, has been associated with an improvement in both SGRQ score and in dyspnea in a large IPF trial even though it failed the primary endpoint of an improvement in the 6-minute walk test (N Engl J Med 2010;363:620-28).

The hypothesis of the INSTAGE trial was that combining sildenafil with nintedanib in patients with severely impaired gas exchange might have an additive or synergistic effect for IPF symptom control by providing two distinct mechanisms of action.

This was not seen, according to Dr. Martinez. Although those receiving the combination had “a lower risk of an absolute 5-percentage-point decline in FVC of the predicted value or death than those who received nintedanib alone,” Dr. Martinez said this was not a study endpoint, and was of unclear clinical significance. Rather, although nintedanib and sildenafil were well tolerated when taken together, Dr. Martinez concluded that this trial was unable to show any definitive clinical benefit from this combination.

Dr. Martinez has financial relationships with AstraZeneca, Boehringer-Ingelheim, Cheisi, ConCert, Genentech, GlaxoSmithKline, Inova, Novartis, Roche, Sunovion, Theravance, and Teva.

.

PARIS – Despite the promise of sildenafil for idiopathic pulmonary fibrosis (IPF), adding this therapy to nintedanib in IPF patients who have significantly impaired gas exchange did not improve quality of life (QOL), according to a randomized trial presented at the annual congress of the European Respiratory Society and simultaneously published in the New England Journal of Medicine (2018 Sep 15. doi: 10.1056/NEJMoa18117).

“Sildenafil and nintedanib in combination were well tolerated, but there was no significant benefit for these two drugs relative to nintedanib alone in patients with IPF and severe gas exchange impairment,” reported Fernando J. Martinez, MD, of the department of internal medicine, Cornell University, New York.In the multicenter INSTAGE trial, 274 IPF patients with impaired gas exchange, defined as diffusing capacity of the lungs for carbon monoxide of 35% or less, were randomized to 20 mg of sildenafil or placebo three times daily. Both groups received 150 mg twice daily of nintedanib, which is approved for the treatment of IPF.

The primary endpoint of the study was change from baseline in the St. George’s Respiratory Questionnaire (SGRQ), a 50-item quality of life (QOL) survey that captures the impact of symptoms on activities and well-being. With lower scores representing improved QOL, Dr. Martinez reported that a change of 4 or more points is considered to be clinically meaningful.

At week 12, the SGRQ score fell by 1.28 points in the group that received sildenafil and by 0.77 points in the group randomized to placebo, a difference that did not approach significance (P = .72). There was also no significant difference after 12 weeks of treatment in dyspnea, a secondary endpoint measured with the University of California, San Diego Shortness of Breath Questionnaire (UCSD-SOBQ).

When both measures were reassessed after 24 weeks of treatment, the slight persistent numerical advantage in the sildenafil arm remained statistically and clinically insignificant, according to Dr. Martinez. Rates of acute exacerbations (7.3% vs. 7.4%) and all-cause mortality (10.2% vs. 11.0%) were also reported to be similar in the experimental and control arms, respectively.

Nintedanib, which has been shown to slow decline in forced vital capacity in patients with IPF, inhibits tyrosine kinases involved in IPF progression. However, it has not been associated with an improvement in QOL in this population.

In contrast, sildenafil, a phosphodiesterase-5 inhibitor that relaxes smooth muscle, has been associated with an improvement in both SGRQ score and in dyspnea in a large IPF trial even though it failed the primary endpoint of an improvement in the 6-minute walk test (N Engl J Med 2010;363:620-28).

The hypothesis of the INSTAGE trial was that combining sildenafil with nintedanib in patients with severely impaired gas exchange might have an additive or synergistic effect for IPF symptom control by providing two distinct mechanisms of action.

This was not seen, according to Dr. Martinez. Although those receiving the combination had “a lower risk of an absolute 5-percentage-point decline in FVC of the predicted value or death than those who received nintedanib alone,” Dr. Martinez said this was not a study endpoint, and was of unclear clinical significance. Rather, although nintedanib and sildenafil were well tolerated when taken together, Dr. Martinez concluded that this trial was unable to show any definitive clinical benefit from this combination.

Dr. Martinez has financial relationships with AstraZeneca, Boehringer-Ingelheim, Cheisi, ConCert, Genentech, GlaxoSmithKline, Inova, Novartis, Roche, Sunovion, Theravance, and Teva.

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