This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.To compare the efficacy and safety of prucalopride, a novel selective high-affinity 5-hydroxytryptamine type 4 receptor agonist, versus placebo, in Asian and non-Asian women with chronic constipation (CC).
Data of patients with CC, receiving once-daily prucalopride 2-mg or placebo for 12-weeks, were pooled from 4 double-blind, randomized, phase-III trials (NCT00488137, NCT00483886, NCT00485940 and NCT01116206). The efficacy endpoints were: average of ≥ 3 spontaneous complete bowel movements (SCBMs)/week; average increases of ≥ 1 SCBMs/week; and change from baseline in each CC-associated symptom scores (bloating, abdominal pain, hard stool and straining).
Overall, 1,596 women (Asian [26.6%], non-Asian [73.4%]) were included in this analysis. Significantly more patients in the prucalopride group versus placebo experienced an average of ≥ 3 SCBMs/week in Asian (34% vs. 11%,
Prucalopride 2-mg once-daily treatment over 12-weeks was more efficacious than placebo in promoting SCBMs and improvement of CC-associated symptoms in Asian and non-Asian women, and was found to be safe and well-tolerated. There were numeric differences between Asian and non-Asian patients on efficacy and treatment emergent adverse events, which may be partially due to the overlap with functional gastrointestinal disorders in non-Asian patients.
Chronic constipation (CC) is a common disorder with prevalence rates reported between 2% to 27% in the general population.1,2 In developed countries, prevalence estimates range from 10% to 15%.3,4 Consistent with the observations from Western populations, constipation in Asian populations is more prevalent in women and the elderly, especially among those over 65 years of age.5-8 Previously defined by health care providers, mainly in terms of the reduction in the frequency of bowel movements (BMs), CC is currently viewed as a symptom complex encompassing such complaints as straining, difficulty in passing stool, discomfort during defecation and feeling of incomplete evacuation,9 which are included in the Rome III diagnostic criteria for CC.10,11 The nature and severity of CC-associated symptoms profoundly affect patients’ normal daily activities and overall quality of life.2,7 In addition, the economic impact of CC makes it an important health and social issue.3,7
Various guidelines with sufficient evidence recommend lifestyle and dietary changes, followed by fiber supplements for the management of constipation. Although bulk forming or stimulant and osmotic laxatives are recommended as the first-line drug treatment for constipation, evidence supporting their long-term use is limited.12 A significant number of patients report dissatisfaction with therapy; globally, women use laxatives at a greater frequency than men but the majority are dissatisfied.5,13 Therefore, there is an unmet need for a more effective and well-tolerated drug(s) to treat CC and its associated symptoms.
Prucalopride is a novel, selective, high-affinity, 5-hydroxytryptamine type 4 (5-HT4) receptor agonist with prokinetic activities mediated through the stimulation of colonic contractions that are closely associated with defecation.14 Prucalopride has no clinically relevant interactions at non-target site (e.g., 5-HT1 and 5-HT2) receptors, unlike other 5-HT4 agonists, such as tegaserod and cisapride.15,16 Most importantly, prucalopride has been shown to be effective and well-tolerated in the treatment of CC in a number of randomized controlled clinical trials and follow-up studies lasting as long as 18 months.9,15,17,18
Prucalopride is approved in many countries for the symptomatic treatment of CC in women, in whom laxatives have failed to provide adequate relief, at a recommended daily dose of 2 mg.19 To further evaluate the efficacy and safety of prucalopride in certain patient subgroups, an integrated analysis was performed on the pooled data from 4 phase-III, randomized multicenter studies, on CC-associated symptoms, normalization of bowel function and safety, in Asian and non-Asian women, over 12 weeks.
Data were pooled from the 4 phase-III, double-blind, randomized, placebo-controlled, parallel group prucalopride studies (3 pivotal studies: NCT00488137, NCT00483886 and NCT00485940, and one Asia-Pacific study, NCT01116206) with similar study designs. The methodologies for the original trials have been published earlier, and are briefly summarized in this paper.9,15,17,20
All 4 studies recruited adults (≥ 18 years; ≥ 18?65 years, Asia-Pacific study) with a history of CC for at least 6 months before their enrollment. To be included in the study, patients should document ≤ 2 spontaneous complete bowel movements (SCBMs) (≤ 2 spontaneous bowel movements [SBMs], Asia-Pacific study) per week during the run-in period, as well as the occurrence of any one of the following: hard/very hard stools, a sensation of incomplete evacuation or straining during defecation on at least 25% of all efforts at defecation. The BMs were considered spontaneous when they occurred more than 24 hours after the last intake of a laxative. Patients were considered ineligible for participation, if constipation was secondary to either drugs or underlying medical disorders (endocrine, metabolic or neurologic), prior surgery, or to any organic disorder of the large intestine or megacolon; if uncontrolled cardiovascular disease, liver and lung diseases, psychiatric disorder, or impaired renal function (serum creatinine > 180 μmol/L) was present or abnormal laboratory values were evident. In addition, pregnant (a positive serum β-human chorionic gonadotropin test), breast-feeding women or women of child-bearing potential were excluded from the study.
All 4 studies consisted of a 2-week, drug-free, run-in period followed by a 12-week double-blind treatment period wherein the patients were randomized (1:1:1) to receive prucalopride 2 mg, 4 mg or matching placebo tablets once-daily before breakfast; the Asia-Pacific study included only prucalopride 2 mg and placebo groups (1:1). For this integrated analyses, data from prucalopride 2 mg and placebo treatment groups were included. Patients did not receive a regular laxative, but bisacodyl up to 15 mg daily was allowed as a rescue medication if a patient did not have BMs for ≥ 3 consecutive days. If required, an enema could be administered. The administration of rescue medications was not permitted during the 48 hours before, and after the start of study treatment to avoid interference in the assessment of the time to the first BM after the treatment was started. The details about the use of rescue medication were documented in patient diaries. Imputations were performed for patients who had incomplete data but had ≥ 7 completed diary days after week 1 of the treatment period; the last 7 diary days with available data were carried forward to fill in the missing diary days.
All the studies were conducted in accordance with the Good Clinical Practice Guidelines of the International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use, the Declaration of Helsinki, and local laws and regulations. Each clinical trial protocol was reviewed and approved by the respective institutional ethics committees or local independent review boards of participating centers. All the patients provided written informed consent.
The efficacy data were collected using patient diary and validated questionnaire, where patients provided the details of study medications, stool frequency, and stool characteristics during the 2-week run-in, and the 12-week treatment periods. Also, the following variables were derived from the diary information: the proportion of patients with an average of ≥ 3 SCBMs/week over 12 weeks (primary endpoint in all 4 studies); the proportion of patients with an average of ≥ 3 SCBMs/week (1?4 weeks); the proportion of patients with an average increase of ≥ 1 SCBMs/week and ≥ 1 SBMs/week, over 12 weeks compared to baseline; the average number of SBMs and SCBMs/week; patients’ satisfaction with their bowel function and treatment, and their perception of the severity of constipation symptoms. Patient Assessment of Constipation-Symptoms (PAC-SYM) surveys21 for the presence of, and changes in constipation related symptoms (bloating, abdominal pain, hard stool and straining) were performed at weeks 2, 4, 8 and 12. Patient Assessments of Constipation-Quality of Life (PAC-QOL) subscales22 (physical discomfort, psychosocial discomfort, worries and concerns, and dissatisfaction) for the effect of constipation on their daily lives were performed at weeks 4 and 12.
In addition to the primary and secondary endpoints of the original studies, the associations between improvement in the subscale scores (≥ 1 point increase, baseline to Week 12) of PAC-SYM and PAC-QOL and efficacy response (increase of ≥ 1 SCBMs/week or ≥ 1 SBMs/week) in Asian and non-Asian women were also evaluated using the pooled data.
Safety and tolerability were continuously monitored throughout the study period by assessing treatment emergent adverse events (TEAEs), vital signs, clinically relevant changes in physical examination, laboratory tests (hematology, biochemistry and urinalysis), and electrocardiogram parameters. A follow-up of approximately 7 days post-treatment was conducted for all the patients to complete the evaluations.
Patient level data of Asian and non-Asian women from all 4 studies were pooled and analyzed using similar statistical tests, as those in the original published studies. For both the treatment groups, the efficacy and safety analyses included all randomized patients who received at least one dose of the study medication after randomization, i.e., the intent-to-treat analysis set. Missing data were imputed with the last observation carried forward (LOCF) method. Baseline demographic factors: race (discrete variable); age, weight, and duration of CC (continuous variables); and constipation history were summarized. The Cochran-Mantel-Haenszel Chi-square test controlling for baseline severity and study was performed to compare the treatment groups for categorical efficacy endpoints. Changes from baseline at prescribed endpoints in each of the 4 item scores of PAC-SYM sub-scales (on a 5-point Likert scale) were calculated; a negative value of change in scores indicated improvement in the symptoms from baseline. An analysis of covariance (ANCOVA) model was applied in the analysis of the change from baseline in each symptom score, with treatment, study and baseline SBM frequency as factors, and baseline symptom score as a covariate for each subgroup. The associations between improvement of ≥ 1 point in each of the 4 items of PAC-SYM and PAC-QOL from baseline to week 12 and efficacy response (average increase of 1 SCBM/week and ≥ 1 SBMs/week) were evaluated by the estimated OR and the 95% CI of the OR.
All the reported
Summary of demography and constipation history for all women included in this analysis are provided in Table 1. Overall 1,596 women (26.6% Asian, 73.4% non-Asian) were included in the analysis. Average age was 44.1 years and the mean body mass index was 24.3 kg/m2. At baseline, more severe constipation (< 1 average SBM/week) was present in 45% of Asian and 28.6% of non-Asian patients, mean (SD) SBMs/week was 1.1 (0.84) vs. 3.4 (3.79), respectively; and overall, the mean (SD) SCBMs/week was 0.4 (0.63). The average number of bisacodyl tablets used per week was 1.9 (Table 1). At baseline, bloating, abdominal pain, hard stool, and straining of severe to very severe category were present in 50.7%, 24.2%, 43.2% and 58.4% of patients, respectively. Abdominal pain was more prevalent in non-Asian patients (84.7%) than in Asian patients (47.1%) (Table 2).
The results from the analyses of the primary and secondary endpoints in Asian and non-Asian women are presented in Table 3. Significantly more (
Table 4 illustrates an association between improvements in the PAC-SYM or PAC-QOL subscale scores and each of the responses in constipation outcomes (average increase of ≥ 1 SCBMs/week and ≥ 1 SBMs/week) in both subgroups at week 12 (LOCF). Associations were significant if the estimated OR was > 1 and 95% CIs excluded the value 1 for both the subgroups. Improvements in each item of PAC-SYM subscales scores (≥ 1 points, yes/no) were significantly associated with clinical efficacy in both subgroups, with the exception of the association between abdominal pain, and average increase of ≥ 1 SCBMs/week (yes/no) in Asian patients. Furthermore, the response in efficacy was significantly associated with improvements (≥ 1 points, yes/no) in PAC-QOL subscales in both Asian and non-Asian patients with the exception of physical discomfort, psychosocial discomfort, and worries and concerns in relation to an average increase of ≥ 1 SCBMs/week (yes/no) in Asian patients.
TEAEs were observed in 35.9% and 68.5% (Asian and non-Asian) patients in the placebo group and 58.1% and 78.2% (Asian and non-Asian) patients in the prucalopride group. A significant difference was observed between the Asian and non-Asian subgroups in the prucalopride group for total patients reporting at least 1 TEAE (
Fig. 1. Symptom Changes (Patient Assessment of Constipation-Symptoms scores) from Baseline after treatment (week 12, last observation carried forward) for Asian and Non-Asian women (intent-to-treat analysis set) (A-H). The statistical tests were performed for no difference between treatments from ANCOVA model with factor(s) treatment, base, trial and baseline severity (type III SS); lower scores reflect improvement.
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