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Linaclotide is safe and effective, even in severe cases of irritable bowel syndrome with constipation, according to a post-hoc analysis of phase III trial data.
Indeed, more acute patients "responded ... just as well as, if not better than, the intent-to-treat population, which included patients with milder abdominal symptoms," wrote Dr. Satish S. C. Rao and colleagues in the April issue of Clinical Gastroenterology and Hepatology (doi:10.1053/j.gastro.2014.01.0130).
According to Dr. Rao of Georgia Regents University, Augusta, although the guanylate cyclase-C agonist is already Food and Drug Administration approved for irritable bowel syndrome–constipation (IBS-C) subtype in 2012, it has not been explicitly tested in patients with more severe disease.
In the current study, Dr. Rao and his fellow investigators looked specifically at several symptoms common to this population: pain, cramping, bloating, fullness, and discomfort.
Patients who ranked at least one of these as being greater than or equal to 7 at baseline were scored as severe, where 0 represents no symptoms and 10 represents the worst possible symptoms.
Overall, out of a total intent-to-treat population of 1,602 patients, 376 reported severe pain, 507 reported severe discomfort, 702 reported severe bloating, 708 reported severe fullness, and 359 reported severe cramping.
Given the overlap between the pain/cramping and bloating/fullness cohorts, the investigators organized the severe IBS group into four subgroups: patients reporting severe pain as their primary complaint (including cramping), severe bloating (including fullness), severe discomfort, and those patients who reported severe symptoms in all three realms.
Demographics were similar between each subgroup and in the overall study population, "although the subpopulations tended to be younger, more female, and more non-white than the intent-to-treat population," the investigators wrote.
Patients were randomized to receive placebo or linaclotide 290 mcg once daily; primary endpoints for this study were assessed at 12 weeks.
The investigators found that, among all severe IBS patients in all subgroups, the mean changes from baseline were significantly greater for linaclotide-treated patients compared with placebo patients for pain, discomfort, bloating, fullness, and cramping (P less than .0001 for all).
Looking at the whole severe IBS cohort, the authors found that 59%-61% of linaclotide patients reported adequate relief of IBS symptoms at week 12, compared with 28%-32% of placebo patients (P less than .0001).
Of those with severe IBS, 70%-77% of linaclotide-treated patients reported being "moderately, quite, or very satisfied" with treatment at week 12, but only 41%-43% of placebo-treated patients said the same (P less than .0001).
Finally, looking specifically at severe versus more mild IBS cases, the investigators found that, overall, the severe IBS cohort reported significantly greater improvements with the drug, compared with their less severe, drug-treated counterparts in the intent-to-treat population.
The most common side effect – diarrhea – occurred in almost one-fifth of linaclotide-treated patients with severe IBS, versus an occurrence rate of 1.6%-2.1% among placebo-treated patients.
In addition to the finding that linaclotide is effective in severe IBS-C, the investigators also wrote that their finding of severe bloating and fullness in many of these patients should give clinicians pause.
"Pain or discomfort is considered a clinical hallmark of IBS," they wrote, but "the presence of bloating and fullness in patients with IBS-C may warrant greater attention in clinical practice as well as in clinical trial design."
Several of the investigators are employees of Ironwood Pharmaceuticals, maker of linaclotide. Additionally, Dr. Rao and another investigator disclosed financial relationships with the pharmaceutical company, which also funded the study.
Irritable bowel syndrome with constipation is a heterogeneous disorder. Heterogeneity exists both with regard to the predominant symptom (constipation vs. pain vs. bloating) and the severity of those symptoms.
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The severity of IBS-C symptoms is unique to each patient and is influenced by multiple factors, including the duration, intensity, frequency, and unpredictability of symptoms; quality of life; fears and concerns about the disease state; coping skills; sex, ethnicity, and culture; and the presence of coexisting functional gastrointestinal disorders, psychological disorders, and medical disorders.
Understanding the level of severity in an IBS-C patient is important as it may influence both diagnostic tests and treatment options. However, despite the prevalence of IBS and its impact on the health care system, few research studies have attempted to categorize IBS-C patients by level of severity to determine their responsiveness to therapy.
In the study by Dr. Rao and his colleagues, a post-hoc analysis of two previously published phase III clinical trials of linaclotide in patients with IBS-C was performed to assess the prevalence of severe abdominal symptoms and the efficacy of linaclotide on these severe symptoms. Abdominal symptoms were evaluated prospectively in each trial using an 11-point numerical rating scale (0 = none; 10 = very severe).
In this post-hoc analysis, the effects of linaclotide were measured for patients with scores greater than 7.0 at baseline. Interestingly, 44% of patients (n = 1,602) reported severe bloating and abdominal fullness. Abdominal discomfort (32%), pain (23%), and cramping (22%) were less common. Not surprisingly, there was considerable overlap with these symptoms, and 21% reported that three symptoms were severe (bloating, pain, and discomfort). Linaclotide improved all five severe symptoms to a greater degree than did placebo, but, more importantly, improved symptoms to a greater degree in these severe patients compared with the study population as a whole.
This study sets the stage for future prospective therapeutic trials. Regardless of IBS subtype (constipation vs. diarrhea vs. mixed) we need to better understand the severity of symptoms of IBS patients enrolled in research studies.
It is likely that critical information is being lost by grouping all IBS patients together with regard to the efficacy of a particular therapeutic agent. This could explain the low therapeutic gain seen in some IBS drug trials. It is likely that differential effects will be observed based on symptom severity. Thus, a patient with moderate to severe IBS symptoms (and thus a reduced quality of life and greater impact on the health care system) may respond better to a particular medication than someone with very mild symptoms (usually with a better quality of life and less impact on the health care system).
One could envision a future practice strategy based on symptom severity with less risky/less expensive treatments (education, reassurance, diet, and exercise) recommended to those with mild symptoms and more aggressive, multimodal therapy (behavioral therapy, psychological therapy, and overlapping medications for visceral/somatic/psychological distress) recommended to those with more severe symptoms. This study provides a framework for future IBS studies to better categorize symptom severity.
Dr. Brian Lacy is section chief of gastroenterology and hepatology and associate professor of medicine at the Geisel School of Medicine, Dartmouth University, Lebanon, N.H. He has received research funding from the National Institutes of Health and is on the advisory boards of Takeda, Prometheus, and Ironwood.
Irritable bowel syndrome with constipation is a heterogeneous disorder. Heterogeneity exists both with regard to the predominant symptom (constipation vs. pain vs. bloating) and the severity of those symptoms.
|
|
The severity of IBS-C symptoms is unique to each patient and is influenced by multiple factors, including the duration, intensity, frequency, and unpredictability of symptoms; quality of life; fears and concerns about the disease state; coping skills; sex, ethnicity, and culture; and the presence of coexisting functional gastrointestinal disorders, psychological disorders, and medical disorders.
Understanding the level of severity in an IBS-C patient is important as it may influence both diagnostic tests and treatment options. However, despite the prevalence of IBS and its impact on the health care system, few research studies have attempted to categorize IBS-C patients by level of severity to determine their responsiveness to therapy.
In the study by Dr. Rao and his colleagues, a post-hoc analysis of two previously published phase III clinical trials of linaclotide in patients with IBS-C was performed to assess the prevalence of severe abdominal symptoms and the efficacy of linaclotide on these severe symptoms. Abdominal symptoms were evaluated prospectively in each trial using an 11-point numerical rating scale (0 = none; 10 = very severe).
In this post-hoc analysis, the effects of linaclotide were measured for patients with scores greater than 7.0 at baseline. Interestingly, 44% of patients (n = 1,602) reported severe bloating and abdominal fullness. Abdominal discomfort (32%), pain (23%), and cramping (22%) were less common. Not surprisingly, there was considerable overlap with these symptoms, and 21% reported that three symptoms were severe (bloating, pain, and discomfort). Linaclotide improved all five severe symptoms to a greater degree than did placebo, but, more importantly, improved symptoms to a greater degree in these severe patients compared with the study population as a whole.
This study sets the stage for future prospective therapeutic trials. Regardless of IBS subtype (constipation vs. diarrhea vs. mixed) we need to better understand the severity of symptoms of IBS patients enrolled in research studies.
It is likely that critical information is being lost by grouping all IBS patients together with regard to the efficacy of a particular therapeutic agent. This could explain the low therapeutic gain seen in some IBS drug trials. It is likely that differential effects will be observed based on symptom severity. Thus, a patient with moderate to severe IBS symptoms (and thus a reduced quality of life and greater impact on the health care system) may respond better to a particular medication than someone with very mild symptoms (usually with a better quality of life and less impact on the health care system).
One could envision a future practice strategy based on symptom severity with less risky/less expensive treatments (education, reassurance, diet, and exercise) recommended to those with mild symptoms and more aggressive, multimodal therapy (behavioral therapy, psychological therapy, and overlapping medications for visceral/somatic/psychological distress) recommended to those with more severe symptoms. This study provides a framework for future IBS studies to better categorize symptom severity.
Dr. Brian Lacy is section chief of gastroenterology and hepatology and associate professor of medicine at the Geisel School of Medicine, Dartmouth University, Lebanon, N.H. He has received research funding from the National Institutes of Health and is on the advisory boards of Takeda, Prometheus, and Ironwood.
Irritable bowel syndrome with constipation is a heterogeneous disorder. Heterogeneity exists both with regard to the predominant symptom (constipation vs. pain vs. bloating) and the severity of those symptoms.
|
|
The severity of IBS-C symptoms is unique to each patient and is influenced by multiple factors, including the duration, intensity, frequency, and unpredictability of symptoms; quality of life; fears and concerns about the disease state; coping skills; sex, ethnicity, and culture; and the presence of coexisting functional gastrointestinal disorders, psychological disorders, and medical disorders.
Understanding the level of severity in an IBS-C patient is important as it may influence both diagnostic tests and treatment options. However, despite the prevalence of IBS and its impact on the health care system, few research studies have attempted to categorize IBS-C patients by level of severity to determine their responsiveness to therapy.
In the study by Dr. Rao and his colleagues, a post-hoc analysis of two previously published phase III clinical trials of linaclotide in patients with IBS-C was performed to assess the prevalence of severe abdominal symptoms and the efficacy of linaclotide on these severe symptoms. Abdominal symptoms were evaluated prospectively in each trial using an 11-point numerical rating scale (0 = none; 10 = very severe).
In this post-hoc analysis, the effects of linaclotide were measured for patients with scores greater than 7.0 at baseline. Interestingly, 44% of patients (n = 1,602) reported severe bloating and abdominal fullness. Abdominal discomfort (32%), pain (23%), and cramping (22%) were less common. Not surprisingly, there was considerable overlap with these symptoms, and 21% reported that three symptoms were severe (bloating, pain, and discomfort). Linaclotide improved all five severe symptoms to a greater degree than did placebo, but, more importantly, improved symptoms to a greater degree in these severe patients compared with the study population as a whole.
This study sets the stage for future prospective therapeutic trials. Regardless of IBS subtype (constipation vs. diarrhea vs. mixed) we need to better understand the severity of symptoms of IBS patients enrolled in research studies.
It is likely that critical information is being lost by grouping all IBS patients together with regard to the efficacy of a particular therapeutic agent. This could explain the low therapeutic gain seen in some IBS drug trials. It is likely that differential effects will be observed based on symptom severity. Thus, a patient with moderate to severe IBS symptoms (and thus a reduced quality of life and greater impact on the health care system) may respond better to a particular medication than someone with very mild symptoms (usually with a better quality of life and less impact on the health care system).
One could envision a future practice strategy based on symptom severity with less risky/less expensive treatments (education, reassurance, diet, and exercise) recommended to those with mild symptoms and more aggressive, multimodal therapy (behavioral therapy, psychological therapy, and overlapping medications for visceral/somatic/psychological distress) recommended to those with more severe symptoms. This study provides a framework for future IBS studies to better categorize symptom severity.
Dr. Brian Lacy is section chief of gastroenterology and hepatology and associate professor of medicine at the Geisel School of Medicine, Dartmouth University, Lebanon, N.H. He has received research funding from the National Institutes of Health and is on the advisory boards of Takeda, Prometheus, and Ironwood.
Linaclotide is safe and effective, even in severe cases of irritable bowel syndrome with constipation, according to a post-hoc analysis of phase III trial data.
Indeed, more acute patients "responded ... just as well as, if not better than, the intent-to-treat population, which included patients with milder abdominal symptoms," wrote Dr. Satish S. C. Rao and colleagues in the April issue of Clinical Gastroenterology and Hepatology (doi:10.1053/j.gastro.2014.01.0130).
According to Dr. Rao of Georgia Regents University, Augusta, although the guanylate cyclase-C agonist is already Food and Drug Administration approved for irritable bowel syndrome–constipation (IBS-C) subtype in 2012, it has not been explicitly tested in patients with more severe disease.
In the current study, Dr. Rao and his fellow investigators looked specifically at several symptoms common to this population: pain, cramping, bloating, fullness, and discomfort.
Patients who ranked at least one of these as being greater than or equal to 7 at baseline were scored as severe, where 0 represents no symptoms and 10 represents the worst possible symptoms.
Overall, out of a total intent-to-treat population of 1,602 patients, 376 reported severe pain, 507 reported severe discomfort, 702 reported severe bloating, 708 reported severe fullness, and 359 reported severe cramping.
Given the overlap between the pain/cramping and bloating/fullness cohorts, the investigators organized the severe IBS group into four subgroups: patients reporting severe pain as their primary complaint (including cramping), severe bloating (including fullness), severe discomfort, and those patients who reported severe symptoms in all three realms.
Demographics were similar between each subgroup and in the overall study population, "although the subpopulations tended to be younger, more female, and more non-white than the intent-to-treat population," the investigators wrote.
Patients were randomized to receive placebo or linaclotide 290 mcg once daily; primary endpoints for this study were assessed at 12 weeks.
The investigators found that, among all severe IBS patients in all subgroups, the mean changes from baseline were significantly greater for linaclotide-treated patients compared with placebo patients for pain, discomfort, bloating, fullness, and cramping (P less than .0001 for all).
Looking at the whole severe IBS cohort, the authors found that 59%-61% of linaclotide patients reported adequate relief of IBS symptoms at week 12, compared with 28%-32% of placebo patients (P less than .0001).
Of those with severe IBS, 70%-77% of linaclotide-treated patients reported being "moderately, quite, or very satisfied" with treatment at week 12, but only 41%-43% of placebo-treated patients said the same (P less than .0001).
Finally, looking specifically at severe versus more mild IBS cases, the investigators found that, overall, the severe IBS cohort reported significantly greater improvements with the drug, compared with their less severe, drug-treated counterparts in the intent-to-treat population.
The most common side effect – diarrhea – occurred in almost one-fifth of linaclotide-treated patients with severe IBS, versus an occurrence rate of 1.6%-2.1% among placebo-treated patients.
In addition to the finding that linaclotide is effective in severe IBS-C, the investigators also wrote that their finding of severe bloating and fullness in many of these patients should give clinicians pause.
"Pain or discomfort is considered a clinical hallmark of IBS," they wrote, but "the presence of bloating and fullness in patients with IBS-C may warrant greater attention in clinical practice as well as in clinical trial design."
Several of the investigators are employees of Ironwood Pharmaceuticals, maker of linaclotide. Additionally, Dr. Rao and another investigator disclosed financial relationships with the pharmaceutical company, which also funded the study.
Linaclotide is safe and effective, even in severe cases of irritable bowel syndrome with constipation, according to a post-hoc analysis of phase III trial data.
Indeed, more acute patients "responded ... just as well as, if not better than, the intent-to-treat population, which included patients with milder abdominal symptoms," wrote Dr. Satish S. C. Rao and colleagues in the April issue of Clinical Gastroenterology and Hepatology (doi:10.1053/j.gastro.2014.01.0130).
According to Dr. Rao of Georgia Regents University, Augusta, although the guanylate cyclase-C agonist is already Food and Drug Administration approved for irritable bowel syndrome–constipation (IBS-C) subtype in 2012, it has not been explicitly tested in patients with more severe disease.
In the current study, Dr. Rao and his fellow investigators looked specifically at several symptoms common to this population: pain, cramping, bloating, fullness, and discomfort.
Patients who ranked at least one of these as being greater than or equal to 7 at baseline were scored as severe, where 0 represents no symptoms and 10 represents the worst possible symptoms.
Overall, out of a total intent-to-treat population of 1,602 patients, 376 reported severe pain, 507 reported severe discomfort, 702 reported severe bloating, 708 reported severe fullness, and 359 reported severe cramping.
Given the overlap between the pain/cramping and bloating/fullness cohorts, the investigators organized the severe IBS group into four subgroups: patients reporting severe pain as their primary complaint (including cramping), severe bloating (including fullness), severe discomfort, and those patients who reported severe symptoms in all three realms.
Demographics were similar between each subgroup and in the overall study population, "although the subpopulations tended to be younger, more female, and more non-white than the intent-to-treat population," the investigators wrote.
Patients were randomized to receive placebo or linaclotide 290 mcg once daily; primary endpoints for this study were assessed at 12 weeks.
The investigators found that, among all severe IBS patients in all subgroups, the mean changes from baseline were significantly greater for linaclotide-treated patients compared with placebo patients for pain, discomfort, bloating, fullness, and cramping (P less than .0001 for all).
Looking at the whole severe IBS cohort, the authors found that 59%-61% of linaclotide patients reported adequate relief of IBS symptoms at week 12, compared with 28%-32% of placebo patients (P less than .0001).
Of those with severe IBS, 70%-77% of linaclotide-treated patients reported being "moderately, quite, or very satisfied" with treatment at week 12, but only 41%-43% of placebo-treated patients said the same (P less than .0001).
Finally, looking specifically at severe versus more mild IBS cases, the investigators found that, overall, the severe IBS cohort reported significantly greater improvements with the drug, compared with their less severe, drug-treated counterparts in the intent-to-treat population.
The most common side effect – diarrhea – occurred in almost one-fifth of linaclotide-treated patients with severe IBS, versus an occurrence rate of 1.6%-2.1% among placebo-treated patients.
In addition to the finding that linaclotide is effective in severe IBS-C, the investigators also wrote that their finding of severe bloating and fullness in many of these patients should give clinicians pause.
"Pain or discomfort is considered a clinical hallmark of IBS," they wrote, but "the presence of bloating and fullness in patients with IBS-C may warrant greater attention in clinical practice as well as in clinical trial design."
Several of the investigators are employees of Ironwood Pharmaceuticals, maker of linaclotide. Additionally, Dr. Rao and another investigator disclosed financial relationships with the pharmaceutical company, which also funded the study.
FROM CLINICAL GASTROENTEROLOGY AND HEPATOLOGY
Major finding: Up to 61% of linaclotide-treated patients with severe irritable bowel symptoms had adequate relief by 12 weeks, compared with 32% of placebo patients (P less than .0001).
Data source: A post hoc analysis of 1,602 patients in a phase III study.
Disclosures: Several investigators are employees of Ironwood Pharmaceuticals, maker of linaclotide. Additionally, Dr. Rao and another investigator disclosed financial relationships with the pharmaceutical company, which also funded the study.
