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Background Effective treatments for irritable bowel syndrome with constipation (IBS-C) are lacking.
Aim To assess the efficacy and safety of lubiprostone in IBS-C.
Methods A combined analysis was performed among 1171 patients with a Rome II diagnosis of IBS-C in two phase-3 randomized trials of lubiprostone 8 mcg vs. placebo twice daily for 12 weeks. Using a balanced seven-point Likert scale ranging from significantly relieved (+3), to significantly worse (−3), patients responded on their electronic diary to the question: ‘How would you rate your relief of IBS symptoms over the past week compared to how you felt before you entered the study?’. The primary efficacy endpoint was the percentage of overall responders.
Results Using an intent-to-treat analysis with last observation carried forward, a significantly higher percentage of lubiprostone-treated patients were considered overall responders compared with those treated with placebo (17.9% vs. 10.1%, P = 0.001). Patients treated with lubiprostone reported a similar incidence of adverse events to those treated with placebo.
Conclusions The percentage of overall responders based on patient-rated assessments of IBS-C symptoms was significantly improved in patients treated with lubiprostone 8 mcg twice daily compared to those treated with placebo. Lubiprostone was well tolerated with a favourable safety profile.
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The irritable bowel syndrome (IBS) is defined by the presence of abdominal discomfort or pain in association with altered bowel habits (i.e. constipation, diarrhoea or a mixture of both).1 Of the approximately 30 million individuals in North America who meet the diagnostic criteria for IBS, approximately one-third experience constipation during episodes of disease activity.2 The remaining patients experience diarrhoea or mixed episodes between constipation and diarrhoea.2, 3 Several underlying mechanisms have been implicated in the pathophysiology of IBS, although much remains poorly understood.4, 5 As a consequence, most currently available therapies are aimed at alleviating specific symptoms.
Lubiprostone is an orally active prostone that stimulates chloride secretion through activation of type-2 chloride channels (ClC-2) in the gastrointestinal tract. Through this action, lubiprostone enhances gastrointestinal fluid secretion and transit and improves the symptoms of constipation.6, 7 Recent animal studies also suggest a role for this drug in stabilizing mucosal membranes, which may help reduce mucosal inflammation and membrane sensitization.8, 9 Lubiprostone was approved in the US for the treatment of adults with chronic idiopathic constipation (CC) in 2006 and for the treatment of IBS with constipation (IBS-C) in adult females in 2008.10 In a post hoc analysis of patients from a pivotal phase-3 trial of patients with CC who indicated IBS as a confounding condition, treatment with lubiprostone was associated with significant improvement in bowel movement frequency as well as symptoms of abdominal discomfort/pain and bloating as compared to placebo.11 A subsequent phase-2b dose ranging study also identified benefits of lubiprostone for IBS-C.7
Based on the encouraging results of the post hoc analysis from the pivotal CC trials and phase-2b IBS-C trial, two phase-3 trials were designed to evaluate the efficacy and safety of lubiprostone 8 mcg administered twice daily in patients with IBS-C.
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The subject disposition of both studies is presented in Figure 3. In total, 1171 patients in both studies were randomized to receive either lubiprostone or placebo after completing the 4-week screening/baseline period and satisfying the inclusion criteria. In both studies, four patients withdrew before receiving study medication and therefore were not included in either safety or efficacy analyses. A total of 13 patients withdrew after receiving study drug but before undergoing any postdosing evaluations. These patients were included in the safety, but not in the efficacy analysis. Thus, 1154 patients were included in the efficacy (ITT) analysis and 1167 were included in the safety analysis.
In both studies, patients were mostly female (91.6%), Caucasian (77.4%) and had a mean age of 46.6 years. At baseline, mean total abdominal scores for abdominal discomfort/pain (2.08; moderate), abdominal bloating (2.26; moderate), constipation severity (2.23; moderate), weekly SBM frequency (3.88), stool consistency (2.76; normal-hard) and straining (2.39; moderate) were similar between the lubiprostone and placebo groups. Only the category of age showed a statistically significant (P < 0.05) difference between lubiprostone and placebo groups, which was not deemed clinically meaningful. Baseline demographics and disease-specific characteristics are presented in Table 1. There were no significant differences in baseline symptom scores between the two combined studies, thus permitting the combined analysis of data.
Table 1. Combined demographic and baseline characteristics of patients receiving at least one dose of study medication and having at least one postbaseline efficacy measurement
|Parameter||Treatment group||Total (n = 1154)||P-value|
|Placebo (n = 385)||Lubiprostone (n = 769)|
| Mean (min, max)||47.7 (18.0, 85.0)||46.1 (19.0, 83.0)||46.6 (18.0, 85.0)|
| Female||359 (93.2%)||698 (90.8%)||1057 (91.6%)||0.152|
| Male||26 (6.8%)||71 (9.2%)||97 (8.4%)|
| American Indian/Alaska Native||0 (0.0%)||1 (0.1%)||1 (0.1%)||0.053|
| Asian||2 (0.5%)||3 (0.4%)||5 (0.4%)|
| Black/African American||50 (13.0%)||102 (13.3%)||152 (13.2%)|
| Caucasian||298 (77.4%)||595 (77.4%)||893 (77.4%)|
| Hispanic/Latino||30 (7.8%)||68 (8.8%)||98 (8.5%)|
| Other||5 (1.3%)||0 (0.0%)||5 (0.4%)|
| Mean (min, max)||2.08 (0.46, 4.00)||2.07 (0.36, 4.00)||2.08 (0.36, 4.00)|
| Mean (min, max)||2.26 (0.57, 4.00)||2.26 (0.62, 4.00)||2.26 (0.57, 4.00)|
| Mean (min, max)||2.25 (0.32, 4.00)||2.22 (0.00, 3.96)||2.23 (0.00, 4.00)|
|Weekly SBM frequency|
| Mean (min, max)||3.84 (0.00, 28.81)||2.22 (0.00, 36.5)||3.88 (0.00, 36.5)|
|SBM stool consistency|
| Mean (min, max)||2.75 (0.57, 4.00)||2.76 (0.00, 4.00)||2.76 (0.00, 4.00)|
|SBM bowel straining|
| Mean (min, max)||2.40 (0.00, 4.00)||2.39 (0.00, 4.00)||2.39 (0.00, 4.00)|
In a combined (ITT with LOCF) analysis, the total number of overall responders in the lubiprostone group (17.9%) was significantly higher than that in the placebo group (10.1%; P = 0.001). These results are depicted in Figure 4).
Individually, both studies showed a statistically significantly higher number of overall responders and significance at the first month as well as at other months with respect to responders who received lubiprostone treatment (Table 2).
Table 2. Overall and monthly responder rates by individual study (intent-to-treat, last observation carried forward population)
| ||Treatment group (Study 0431)||P-value*||Treatment group (Study 0432)||P-value*|
|Placebo (n = 193) (%)||Lubiprostone (n = 390) (%)||Placebo (n = 192) (%)||Lubiprostone (n = 379) (%)|
| Month 1||7.8||11.0||0.174||7.3||10.6||0.278|
| Month 2||10.9||18.7||0.016||12.0||17.9||0.074|
| Month 3||14.5||21.3||0.053||14.6||22.7||0.026|
The symptoms of abdominal discomfort/pain, bloating, constipation severity, stool consistency and straining correlated with responder status (Figure 5), indicating the validity of the seven-point balanced scale. On average, responders had a greater than one point reduction in their assessment of the IBS-C symptoms, whereas nonresponders showed only a one-third point reduction in their ratings. This also correlates with a clinically meaningful change (one point on a five-point scale, or a shift towards normal stools)14 in the responder group.
The combined percentage of monthly responders using LOCF (Figure 6) was also significantly higher among those treated with lubiprostone compared with those treated with placebo at month 2 (18.3% vs. 11.4%, P = 0.003) and at month 3 (22.0% vs. 14.5%, P = 0.003). There was a trend towards a significantly higher percentage of monthly responders with lubiprostone compared with placebo at month 1 (10.8% vs. 7.5%, P = 0.078). For weekly responder rates, significant improvements were seen in the combined analysis with lubiprostone vs. placebo at weeks 2, 4, 5, 6, 10 and 12 (P ≤ 0.030; Figure 7).
Mean improvement from baseline in abdominal discomfort/pain was significantly greater in lubiprostone-treated patients compared with placebo-treated patients at month 2 (−0.43 vs. −0.35, P = 0.039) and month 3 (−0.45 vs. −0.36, P = 0.028). Mean improvement from baseline in the lubiprostone group was significantly greater than the mean observed with placebo for abdominal bloating at month 2 (P = 0.044); BM frequency at month 1 (P = 0.021); stool consistency at months 1, 2 and 3 (P ≤ 0.022); and degree of straining at months 1 and 2 (P ≤ 0.013) (Table 3).
Table 3. Combined secondary efficacy endpoint summary (intent-to-treat, last observation carried forward population)
|Symptom measure||Month 1||Month 2||Month 3|
|Abdominal discomfort/pain|| ||*||*|
|Abdominal bloating|| ||*|| |
|Bowel movement Frequency||*|| || |
Quality of life
In the overall analysis of IBS-QOL, there was a trend towards greater improvement with lubiprostone at week 12 (P = 0.066). Analysis of subdomains demonstrated that ‘body image’ and ‘health worry’ were significantly improved in the lubiprostone group at week 12 (P ≤ 0.025). With a third domain, dysphoria, there was a trend for improvement in lubiprostone-treated patients, but this was not statistically significant (P = 0.086). Lubiprostone produced clinically meaningful changes (>14 points)13 in the IBS-QOL domains of social reaction, food avoidance, health worry, body image and dysphoria.
Safety and adverse events
Overall, 588 (50%) patients reported at least one adverse event (Table 4). There was a similar incidence of adverse events in both treatment groups: 50% of lubiprostone and 51% of placebo-treated patients reported at least one adverse event. Most adverse events were mild-to-moderate in intensity and resolved without intervention. The most frequently reported adverse events were related to the gastrointestinal tract (i.e. nausea, diarrhoea and abdominal distension) and occurred with similar incidence in both treatment groups (lubiprostone = 19%, placebo = 14%). Patients who withdrew because of an adverse event are detailed in Figure 3. There were no significant differences between patients who withdrew from the lubiprostone groups and those in the placebo group.
Table 4. Combined summary of adverse events (safety population) (%)
| Safety-evaluable patients*||Placebo (n = 387)||Lubiprostone (n = 779)|
|Serious adverse events||1||1|
|Treatment-related serious adverse event||0||0.1†|
|Treatment-related adverse events||21||22|
| Abdominal distension||2||2|
|Study discontinuation because of adverse event||7||5|
A total of 11 serious adverse events (defined as those that were fatal, life-threatening, required hospitalization or intensive medical intervention) were reported during the trials, seven (1%) in the lubiprostone group and four (1%) in the placebo group. One serious adverse event was considered possibly related to lubiprostone, an episode of noncardiac chest pain in a 69-year-old female with a pre-existing cardiac medical history who was hospitalized one day after initiating treatment with lubiprostone. A cardiac workup ruled out cardiac cause, and the patient’s chest pain resolved the next day. One patient randomized to the lubiprostone treatment arm died during the study. The patient, a 71-year-old male with a history of diabetes mellitus, hyperlipoidaemia and obesity, experienced a fatal cardiac arrest after 72 days of lubiprostone treatment. The investigator did not consider the patient’s death as related to administration of lubiprostone given the patient’s longstanding medical history.
No clinically significant differences between the two patient groups were detected in the analyses of laboratory values, vital signs or physical examination.
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In the past, therapeutic modalities for IBS-C included bulking agents, osmotic laxatives and tegaserod, a partial 5-HT4 receptor agonist. Bulking agents may confer benefit to some patients, but are generally not more effective than placebo at relieving global IBS symptoms and may increase important IBS abdominal symptoms such as bloating. There exists very limited clinical trial evidence that supports the efficacy of osmotic laxatives in relieving abdominal discomfort or pain.15, 16 Tegaserod has demonstrated clinical efficacy in ameliorating different IBS-related symptoms, but has recently been withdrawn in many countries because of concerns regarding cardiovascular safety issues.17 In the US, tegaserod is now only available through an emergency treatment investigational new drug application for patients with clinical circumstances, which are ‘immediately life-threatening or serious enough to qualify for hospitalization’.18
The two trials described here contributed to FDA’s approval in May 2008 of lubiprostone for the treatment of IBS-C in adult women.10 The results of the combined data from these two phase-3 trials provide support for the efficacy of lubiprostone at a dosage of 8 mcg twice daily in treating the global and individual symptoms experienced by patients with IBS-C. Lubiprostone significantly improved the chances of an IBS-C patient to become a responder (vs. a nonresponder) compared to placebo. Importantly, patients in the lubiprostone group had statistically significantly more (approximately twofold) treatment responders than those in the placebo group. These significant differences also occurred for the monthly responder rate at months 2 and 3 in both trials. Patients treated with lubiprostone experienced significant improvement in all secondary endpoints: abdominal discomfort/pain, bloating, straining and severity of constipation, as well as increased BM frequency and stool consistency. For most of these symptoms, the effect of lubiprostone persisted for the 3-month duration of the studies.
The relatively low response rates reported in the lubiprostone and placebo groups for the primary endpoint deserve discussion. These studies utilized a novel, highly rigorous responder definition, which was developed in conjunction with the US Food and Drug Administration. To be considered a monthly responder, patients had to report moderate relief of their IBS symptoms for 4 of 4 weeks or significant relief for more than 2 of 4 weeks. To be an overall responder, patients had to be a monthly responder for 2 of 3 months of the randomization period. It is possible that this highly rigorous endpoint may have underestimated the proportion of patients whom a practicing clinician would have considered successfully treated. For example, patients who reported moderate relief of their IBS symptoms for 3 of 4 weeks were not considered a monthly responder using this endpoint. Similarly, those with moderate relief of their IBS symptoms for 2 weeks and significant relief for 1 week were not considered a monthly responder. Furthermore, these studies’ responder definition included not only patient self-assessment but also disallowed increased rescue medication use and study discontinuation because of lack of treatment efficacy. The rigour of the primary endpoint is highlighted by the placebo response of ∼10%, a value lower than has been reported in previous IBS treatment trials.19 Despite the rigour of the primary endpoint, patients randomized to lubiprostone were nearly twice as likely to experience an overall improvement in IBS symptoms compared to those receiving placebo.
These current studies further demonstrate the benefit of lubiprostone in treating the constipation-associated symptoms of IBS. It is likely that these clinical benefits are mediated through the activation of ClC-2 channels20, 21 leading to increased fluid secretion into the intestinal lumen. Furthermore, the activation by lubiprostone of ClC-2 channels has been shown in animal studies to initiate restoration of tight junctions, leading to recovery of mucosal barrier function.9, 22 Recent studies suggest that increased intestinal permeability may be a contributing factor to the IBS clinical state.23 Thus, it is attractive to speculate that reduced intestinal permeability associated with an increased inflammatory response23–26 may enable the development of visceral hypersensitivity that is often present in patients with IBS. Possibly, lubiprostone may inhibit this effect in IBS which in turn may explain the improved global symptoms and pain scores. This finding may have important clinical implications for IBS-C as other anticonstipation agents like polyethylene glycol do not show pain benefit.27
Overall, lubiprostone at a dose of 8 mcg twice daily was well-tolerated. There were no significant differences between the lubiprostone and placebo groups in reporting adverse events or serious adverse events. The most frequently-reported AEs were gastrointestinal-related and included nausea (8% with lubiprostone and 4% with placebo), diarrhoea (6% with lubiprostone and 4% with placebo) and abdominal distension (2% in both groups). With respect to the nausea, most events were mild or moderate in nature, were much less frequent compared with higher dosages used for treating chronic constipation and resolved without intervention. The higher rate of diarrhoea in the lubiprostone group is consistent with the drug’s mechanism of action.21 The reason for the higher incidence of nausea among IBS-C patients receiving lubiprostone is unknown, but consistent with results seen in previous chronic constipation studies.7, 11 The only serious adverse event that was considered possibly related to treatment, noncardiac chest pain in a patient with a pre-existing cardiac medical history, resolved within 24 h. In previous clinical trials of constipated adults receiving 24 mcg lubiprostone twice daily, no treatment-related cardiac deaths or serious adverse events have been reported.7, 11
Based on results from a previous phase-2 trial,7 lubiprostone significantly improved gastrointestinal symptoms of IBS-C across three dosing groups (8, 16 and 24 mcg twice daily each) and the benefit in terms of pain was similar across all doses. The study determined that the 8 mcg twice daily dose of lubiprostone demonstrated the optimal combination of efficacy and safety for IBS-C. The results of this combined analysis of two phase-3 trials confirm the findings of the earlier phase-2 trial, with significant improvement in IBS-C symptoms reported for most parameters and a demonstrated an acceptable safety profile. For reasons of the unique primary endpoint response definition, the results are not comparable across IBS trials using a different primary endpoint definition.
In these 2 trials, lubiprostone treatment was associated with a trend towards improvement in overall QOL. Furthermore, statistically significant improvements were seen in key subdomains (body image, health worry) with lubiprostone as compared to placebo. The overall trend was not seen in the previous phase-2 study, where no treatment differences were seen. The significant health worry improvement with lubiprostone was also seen in the previous trial.
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Declaration of personal interests: D. A. Drossman is a consultant and has received research funding from Takeda Pharmaceuticals North America, Inc. and is a consultant for Sucampo Pharmaceuticals, Inc. J. F. Johanson is on the speaker bureaux of and is a consultant for Takeda Pharmaceuticals North America, Inc. and Sucampo Pharmaceuticals, Inc. J. F. Johanson owns stock options in Sucampo Pharmaceuticals, Inc. W. D. Chey is on the speaker bureau of Takeda Pharmaceuticals North America, Inc. and has received research funding from Sucampo Pharmaceuticals, Inc. R. Fass receives research funding from Takeda Pharmaceuticals North America, Inc. and Sucampo Pharmaceuticals, Inc. R. Ueno is an employee of Sucampo Pharmaceuticals, Inc. and a shareholder in this company. R. Panas and A. Wahle are employees of Sucampo Pharmaceuticals, Inc. Declaration of funding interests: These studies were funded, designed, conducted and supervised in full by the sponsor, Sucampo Pharmaceuticals, Inc., Bethesda, MD. They were performed in compliance with Good Clinical Practice, including the archiving of essential documents. Sucampo Pharmaceuticals, Inc. analysed and interpreted the studies’ data and oversaw the writing of the study reports. The Principal Investigator, D. A. Drossman, served as the guarantor of the submission. He and co-investigators were responsible for analysis and interpretation of the data and are the guarantors of the manuscript and its contents. All authors were involved in the development of the draft document and review of subsequent revisions. The writing of this manuscript, and subsequent writing and editorial support in the subsequent revisions, was supported in part by Sucampo Pharmaceuticals, Inc. and in part by Takeda Pharmaceuticals North America, Inc.