The PAC-SYM questionnaire for chronic constipation: defining the minimal important difference.

BACKGROUND: The Patient Assessment of Constipation-Symptoms (PAC-SYM) questionnaire is frequently used in clinical trials of constipation. However, the threshold for reduction in total PAC-SYM score used to define a clinical response on this 0-4 point scale has not undergone formal appraisal, and its relationship with clinical benefit as perceived by patients has not been defined. AIM: To determine the minimal important difference in PAC-SYM score, and the optimum cut-off value for defining responders. METHODS: The minimal important difference was estimated using data from six international phase 3/4, double-blind, randomised controlled trials of prucalopride in patients with chronic constipation (NCT01147926, NCT01424228, NCT01116206, NCT00485940, NCT00483886, NCT00488137), with anchor- and distribution-based approaches. Five appropriate patient-reported outcomes were selected as anchors. In addition, receiver operating characteristics (ROC) curve analyses were used to investigate responder discrimination for each anchor. RESULTS: Data from 2884 patients were included. Minimal important difference estimates ranged from -0.52 to -0.63 across the five anchors. Estimates were not affected by study location but were consistently lower for rectal symptoms than for abdominal and stool symptoms. Distribution-based estimates were considerably lower than anchor-based estimates. ROC curve analyses showed optimum cut-off scores for discriminating responders to be similar to anchor-based minimal important difference estimates. CONCLUSIONS: Anchor-based methods gave consistent results for the minimal important difference, at approximately -0.6, and this value was close to the ROC-determined optimal cut-off scores for responder discrimination. This value could be considered in clinical practice. A slightly more conservative threshold (eg -0.75) could be used in clinical trials to reduce the placebo response rate.

A randomized, double-blind, placebo-controlled trial to evaluate the efficacy, safety, and tolerability of long-term treatment with prucalopride.

BACKGROUND: Randomized trials have confirmed the efficacy of prucalopride for the treatment of chronic constipation up to 12 weeks. This study aimed to assess the efficacy of prucalopride over a 24-week period (ClinicalTrials.gov: NCT01424228). METHODS: Adults with chronic constipation and ≤2 spontaneous complete bowel movements (SCBMs)/week were randomized to receive prucalopride 2 mg or placebo daily for 24 weeks. The primary endpoint was the proportion of patients achieving a mean of ≥3 SCBMs/week over the treatment period, assessed using daily e-diaries. Secondary outcomes and safety parameters were assessed throughout the study. KEY RESULTS: Overall, 361 patients were randomized and received prucalopride or placebo. Baseline characteristics were similar in the prucalopride (N = 181) and placebo (N = 180) groups. Mean age was 48.9 years (standard deviation, 16.0) and most patients were women. The proportion of participants achieving the primary endpoint was not statistically different between the prucalopride and placebo groups (25.1% vs 20.7%; p = 0.367). There was also no statistically significant difference between groups over the first 12-week period (prucalopride, 25.1%; placebo, 20.1%; p = 0.341). There were no statistically significant differences between groups for most secondary endpoints. No new safety concerns were identified. CONCLUSIONS & INFERENCES: This trial did not show statistically significant improvements in primary or secondary outcomes with prucalopride compared with placebo over 24 or 12 weeks. This is in contrast to the results of four previous 12-week trials, which demonstrated prucalopride to be significantly more effective than placebo. An extensive evaluation did not provide an explanation for the null efficacy results of this study.

Association between health-related quality of life and symptoms in patients with chronic constipation: an integrated analysis of three phase 3 trials of prucalopride.

BACKGROUND: Prucalopride is a high-affinity 5-HT4 receptor agonist for the treatment of chronic constipation. The aims of this study were to investigate the relationship between health-related quality of life (HRQoL) and symptoms of constipation, and to assess the response of HRQoL to treatment using integrated data from three phase III trials of prucalopride. METHODS: This was an integrated analysis of data from three pivotal multicenter, double-blind, randomized, placebo-controlled, parallel-group trials (ClinicalTrials.gov Identifiers: NCT00488137, NCT00483886 and NCT00485940). Relationships were investigated between Patient Assessment of Constipation Quality of Life (PAC-QOL) scores, Patient Assessment of Constipation Symptoms (PAC-SYM) scores, bowel movement frequency (assessed using daily diaries), and treatment. KEY RESULTS: Patients treated with prucalopride 2 mg (n = 659) and placebo (n = 661) were included in the analysis. An improvement in PAC-SYM scores correlated well with an improvement in PAC-QOL overall score (r = 0.711) and satisfaction subscale score (r = 0.589). After 12 weeks, PAC-QOL overall score and satisfaction subscale score significantly (p < 0.001) improved by ≥ 1 point (clinically relevant) in 36.5% and 44.1% of patients treated with prucalopride, compared with 18.5% and 22.4% with placebo respectively. Moreover, 39.0% of patients with an improvement in satisfaction of ≥ 1 point achieved ≥ 3 spontaneous complete bowel movements/week, compared with 7.4% of those with no improvement in satisfaction (<1 point). CONCLUSIONS & INFERENCES: Improvements in PAC-QOL overall score and satisfaction score were associated with improvements in symptoms of chronic constipation. Compared with placebo, treatment with prucalopride significantly improved HRQoL.

Effect of prucalopride on symptoms of chronic constipation.

BACKGROUND: Prucalopride is a 5-HT4 receptor agonist with gastrointestinal prokinetic activities. This integrated analysis of data from three 12-week, double-blind trials evaluated the effect of prucalopride 2 mg q.d. on common constipation symptoms in women in whom laxatives had failed to provide adequate relief. The effect of prucalopride on bowel function was outside the scope of the analysis and has been described elsewhere. METHODS: Women with self-reported inadequate relief from laxatives and included in the prucalopride 2 mg or placebo arm of the trials were selected for analysis. Symptom severity was determined with the Patient Assessment of Constipation Symptoms (PAC-SYM) questionnaire. Observed changes from baseline in individual item scores were also evaluated by calculating Cohen's D effect sizes using baseline standard deviation (SD) (>0.2-0.5, >0.5-0.8 and >0.8 for small, moderate and large effects, respectively). KEY RESULTS: Data were analyzed for 936 women. The proportion of women with a PAC-SYM severity score >2 at baseline was 50.0% for abdominal symptoms, 71.4% for stool symptoms, and 15.5% for rectal symptoms. Excluding the women without presence of a symptom at baseline from the effect size calculations showed that prucalopride 2 mg had a large effect (>0.8) on all PAC-SYM items, including abdominal pain, abdominal discomfort, bloating, straining, and painful bowel movements. For abdominal symptoms and stool symptoms, effect sizes with prucalopride 2 mg were 1.3-2.3 times larger than those with placebo. CONCLUSIONS & INFERENCES: Prucalopride 2 mg q.d. for 12 weeks alleviates common constipation symptoms in women in whom laxatives had failed to provide adequate relief.

Randomised clinical trial: the efficacy of prucalopride in patients with chronic intestinal pseudo-obstruction--a double-blind, placebo-controlled, cross-over, multiple n = 1 study.

BACKGROUND: Chronic intestinal pseudo-obstruction is a disabling condition for which there are no established drug therapies. The condition is caused by a diverse range of intestinal myopathies and neuropathies. AIM: To assess the therapeutic efficacy of prucalopride, a selective high-affinity 5-HT(4) receptor agonist, we employed a multiple n = 1 study design. Each patient acted as his/her own control, each day counting as one treatment episode, allowing comparison of 168 days on each of active drug and placebo. METHODS: Double-blind, randomised, placebo-controlled, cross-over trial of four 12-week treatment periods, with 2-4 mg prucalopride or placebo daily. In each of the first and second 6 months there was a prucalopride and a placebo treatment. Patients with proven chronic intestinal pseudo-obstruction, including dilated gut, were included. Evaluation was by patient diary and global evaluation. RESULTS: Seven patients participated (mean 42 years, five female, median symptom duration 11 years). Three discontinued, two due to study length, and one on prucalopride due to unrelated malnutrition and bronchopneumonia. Four patients (three visceral myopathy and one visceral neuropathy) completed the study; prucalopride significantly improved pain in three of four patients, nausea in two, vomiting in one, bloating in four and analgesic intake. Bowel function was not changed substantially. CONCLUSIONS: n = 1 studies in rare conditions allow drug efficacy assessment. Prucalopride relieves symptoms in selected patients with chronic pseudo-obstruction.

Clinical trial: the efficacy of open-label prucalopride treatment in patients with chronic constipation - follow-up of patients from the pivotal studies.

BACKGROUND: Prucalopride is approved in Europe for symptomatic treatment of chronic constipation in women with inadequate relief from laxatives. AIM: To evaluate efficacy of prucalopride during long-term treatment of patients with chronic constipation. METHODS: Patients from three pivotal double-blind, placebo-controlled, 12-week studies with prucalopride could continue treatment in open-label studies up to 24 months. Efficacy was evaluated every 3 months using the Patient Assessment of Constipation-Quality of Life (PAC-QOL) satisfaction scale. Laxative use and reasons for study discontinuation were recorded. RESULTS: Eighty-six percent of patients who completed the pivotal studies continued prucalopride treatment in the open-label studies (n = 1455, 90% female). Improvement in average PAC-QOL satisfaction score observed after 12-week, double-blind prucalopride was maintained during open-label treatment for up to 18 months; in each 3 month period, 40-50% of patients did not use any laxatives. Most frequent adverse events (AEs) resulting in discontinuation were gastrointestinal events (3.3%) and headache (1.0%). Only 10% of patients who had normalized bowel function on prucalopride at the end of pivotal trials discontinued due to insufficient response during open-label treatment. CONCLUSION: Satisfaction with bowel function is maintained for up to 18 months of treatment with prucalopride. Gastrointestinal events and headache cause discontinuation of prucalopride treatment in ∼5% of patients (ClinicalTrials.gov identifiers: NCT01070615 and NCT00987844).

A double-blind, placebo-controlled study of prucalopride in elderly patients with chronic constipation.

BACKGROUND: Constipation affects up to 50% of the elderly; this study evaluates the efficacy, safety, and tolerability of the selective 5-HT(4) agonist prucalopride in chronically constipated elderly patients. METHODS: Three hundred chronic constipation patients aged >or=65 years were randomized to prucalopride (1, 2, or 4 mg once daily) or placebo for 4 weeks. The primary endpoint was the percentage of patients with >or=3 spontaneous complete bowel movements (SCBM) per week. Secondary endpoints included the percentage with an increase of >or=1 SCBM per week, BM frequency, constipation-related symptoms, quality of life (QoL), safety, and tolerability. KEY RESULTS: More patients achieved >or=3 SCBM per week with prucalopride than with placebo. This difference was largest and significant during the first week of 4 mg prucalopride (P or=1 SCBM per week from baseline vs placebo (e.g. 60% with 1 mg prucalopride vs 34% with placebo at week 4; P or=1 with 1 mg prucalopride than with placebo (P

Safety assessment of prucalopride in elderly patients with constipation: a double-blind, placebo-controlled study.

Chronic constipation is common among nursing home residents. The aim of this study was to evaluate safety, tolerability and pharmacokinetics of the selective 5HT(4) receptor agonist prucalopride in elderly, chronically constipated patients in nursing homes. A multicentre, phase II, randomized, double-blind dose-escalation study in 89 elderly constipated nursing home residents treated with placebo, 0.5, 1 or 2 mg prucalopride once daily for 28 days was analysed. Adverse events, vital signs, ECG, Holter monitor and pharmacokinetics were assessed (Clinicaltrials.gov identifier: NCT00627692). Patients' mean age was 83 years; 88% had a history of cardiovascular diseases. Most frequent adverse events, at least possibly related to prucalopride, were diarrhoea and abdominal pain. Relative to placebo, there were no differences in vital signs, ECG corrected QT interval, ECG morphology parameters, or incidence of supraventricular or ventricular arrhythmias on Holter monitoring. Plasma prucalopride concentrations increased proportionally with administered dose. Prucalopride up to 2 mg once daily for 4 weeks was safe and well-tolerated by constipated elderly patients, with no differences vs placebo in ECG or a range of Holter-monitoring parameters.

Clinical trial: the efficacy, impact on quality of life, and safety and tolerability of prucalopride in severe chronic constipation--a 12-week, randomized, double-blind, placebo-controlled study.

BACKGROUND: Chronic constipation may result in disabling symptoms, is often unsatisfactorily treated by laxatives and negatively impacts quality of life (QoL). AIM: A randomized, double-blind, placebo-controlled, phase III trial to evaluate the efficacy and safety of a selective, high-affinity 5-HT(4) receptor agonist, prucalopride, in patients with chronic constipation [or=3 SCBMs/week, averaged over 12 weeks. Other assessments included BM frequency, constipation-related QoL and symptoms and tolerability. RESULTS: Among 641 patients, significantly more patients taking prucalopride 2 or 4 mg (24%) than placebo (12%), achieved the primary efficacy endpoint (>or=3 SCBMs/week) or an increase of >or=1 SCBMs/week; 43% and 47% vs. 28% respectively. Prucalopride-treated patients also achieved significantly greater satisfaction with treatment and bowel function, and improved perception of constipation severity and constipation-related QoL, compared with placebo. Most frequent treatment-related adverse events were headache, abdominal pain, nausea and diarrhoea (mainly during day 1). There were no differences in comparison to placebo in the incidence of serious adverse effects or cardiovascular events. CONCLUSION: Over 12 weeks, prucalopride was effective and well tolerated in chronic constipation.

Prucalopride (Resolor) in the treatment of severe chronic constipation in patients dissatisfied with laxatives.

OBJECTIVE: To determine the efficacy, impact on quality of life (QOL) and safety of prucalopride, a selective, high-affinity 5-HT(4) receptor agonist, in patients with chronic constipation. METHODS: In this multicentre, randomised, placebo controlled, parallel-group, phase III study, patients with chronic constipation (two or fewer spontaneous complete bowel movements (SCBM)/week) received 2 mg or 4 mg prucalopride or placebo, once daily, for 12 weeks. The primary efficacy endpoint was the proportion of patients reaching three or more SCBM/week. The key secondary efficacy endpoint was the proportion of patients having an increase of one or more SCBM/week. The primary QOL endpoint was the patient assessment of constipation QOL satisfaction subscale score. Safety parameters included adverse events, laboratory values and cardiovascular events. RESULTS: Efficacy was evaluated over 713 patients. Averaged over 12 weeks, higher proportions of patients on prucalopride 2 mg (19.5%; p<0.01), 4 mg (23.6%; p<0.001) had three or more SCBM/week (or normalisation of bowel function) compared with placebo (9.6%). Similar results were seen in the subgroup (83%) of patients dissatisfied with previous laxative treatment. Both doses of prucalopride also significantly improved secondary efficacy and QOL endpoints, including the proportion of patients with an increase of one or more SCBM/week, evacuation completeness, perceived disease severity and treatment effectiveness and QOL. Prucalopride 4 mg significantly reduced the need for straining versus placebo (p<0.05). The most frequent treatment-related adverse events were headache and diarrhoea. Both doses of prucalopride were safe and well tolerated. CONCLUSION: Prucalopride significantly and consistently improved bowel function, associated symptoms and satisfaction in chronically constipated patients.

Early bactericidal activity and pharmacokinetics of the diarylquinoline TMC207 in treatment of pulmonary tuberculosis.

Tibotec Medicinal Compound 207 (TMC207) is a novel diarylquinoline with a unique mode of action that targets mycobacterial ATP synthase. TMC207 exhibits high in vitro activity against mycobacterial strains either susceptible or resistant to all first-line and many second-line drugs, including fluoroquinolones, and has shown exceptional in vivo activity against several mycobacterial species in different animal models. In this early bactericidal activity study, 75 treatment-naïve patients with smear-positive pulmonary tuberculosis were randomized to once-daily oral TMC207 (25 mg, 100 mg, or 400 mg), 600 mg rifampin (RIF), or 300 mg isoniazid (INH) for 7 days. Sixteen-hour overnight sputum collected at baseline and on each treatment day was plated in serial dilutions on selective agar plates. The bactericidal activity was expressed as the log(10) decrease in CFU/ml sputum/day. Pharmacokinetic sampling was performed on day 7 of TMC207 administration up to 24 h postdose. The decreases in log(10) CFU counts (+/- standard deviation) from baseline to day 7 were 0.04 +/- 0.46 for 25 mg TMC207 (n = 14), 0.26 +/- 0.64 for 100 mg TMC207 (n = 14), 0.77 +/- 0.58 for 400 mg TMC207 (n = 14), 1.88 +/- 0.74 for INH (n = 11), and 1.70 +/- 0.71 for RIF (n = 14). Significant bactericidal activity of 400 mg TMC207 was observed from day 4 onward and was similar in magnitude to those of INH and RIF over the same period. The pharmacokinetics of TMC207 were linear across the dose range. In summary, TMC207 demonstrated bactericidal activity with a delayed onset and was well tolerated, and no study drug-related serious adverse events occurred.

Efficacy and tolerability of prucalopride in patients with constipation due to spinal cord injury.

BACKGROUND: Chronic constipation (CC) often occurs after spinal cord injury (SCI). Prucalopride is a novel, highly selective, specific serotonin4 receptor agonist with enterokinetic properties. We evaluate the tolerability and pilot efficacy of prucalopride in the treatment of CC due to SCL. METHODS: Double-blind, placebo-controlled, pilot, phase 11, dose-escalation study. After 4 weeks' run in, patients received prucalopride 1 mg (n = 8) or placebo (n = 4); 11 new patients were randomized to prucalopride 2 mg (n = 8) or placebo (n = 3) once daily for 4 weeks. Patients recorded bowel function (diary) and assessed constipation severity and treatment efficacy (visual analogue scale (VAS) 0-100 mm). Colonic transit times were determined. RESULTS: Compared with run in. mean changes in constipation severity (VAS) increased with placebo, but decreased with prucalopride 1 and 2 mg. The VAS score for treatment efficacy showed a clear dose response (medians 4, 52 and 73 for placebo, 1 and 2 mg, respectively). Diary data showed an improvement in average weekly frequency of all bowel movements over 4 weeks within the 2 mg group (median 0.6; 95% CI 0.2; 1.2). There was a significant reduction in median colonic transit time with 2 mg (n = 4; -38.5 h (95% CI -80; -5)). Four patients (2 mg) reported moderate/severe abdominal pain, and two of these discontinued treatment. There were no clinically relevant effects on any of the safety parameters. CONCLUSION: This pilot study indicates that prucalopride can play an important role in the management of patients with CC due to SCI.

Effects of prucalopride on colonic transit, anorectal function and bowel habits in patients with chronic constipation.

BACKGROUND: There is a need for better tolerated drugs to normalize bowel function in chronic constipation. Prucalopride is a highly selective, specific, serotonin4 receptor agonist with enterokinetic properties. AIM: To evaluate the effects of prucalopride on bowel function, colonic transit and anorectal function in patients with chronic constipation. METHODS: Twenty-eight patients were enrolled in this double-blind, placebo-controlled, crossover study (prucalopride: 1 mg, n=12; 2 mg, n=16). Patients kept a bowel function diary. Colonic transit times and anorectal function (anal manometry, rectal sensitivity and rectal compliance) were assessed. RESULTS: Prucalopride (1 mg) compared to placebo significantly increased the mean number of spontaneous complete, spontaneous and all bowel movements per week. Prucalopride (1 mg) significantly decreased the percentage of bowel movements with hard/lumpy stools and straining and increased the urge to defecate. Prucalopride (1 and 2 mg) decreased the mean total colonic transit time by 12.0 h (prucalopride 42.8 h vs. placebo 54.8 h; P=0.074). No statistically significant effects were found in any of the anorectal function parameters. Prucalopride was well tolerated. There were no clinically relevant changes in standard safety parameters. CONCLUSIONS: Prucalopride significantly improves stool frequency and consistency, and the urge to defecate, and may decrease colonic transit times in patients with chronic constipation.

Immunogenicity and tolerability of a trivalent influenza subunit vaccine (Influvac) in high-risk children aged 6 months to 4 years.

Fifty-two children, aged less than 5 years, with chronic lung disease or congenital heart disease were entered into a two-centre open study to determine the immunogenicity and tolerability of Influvac, a trivalent influenza sub-unit vaccine. Seroresponses were determined following two intramuscular vaccinations with 0.25 ml of Influvac, four weeks apart. Any local or systemic reaction was sought. Seroresponses were age and antigen specific, with children older than 9 months showing better seroresponses to all three antigens. Both A/Taiwan and B/Panama strains met all efficacy criteria. A/Shangdong met two of the three criteria: seroconversion and mean geometric titre increase. Local (23%) and systemic (48%) reactions following either of the two vaccinations were minor in nature and resolved within a few days. The vaccine induced a strong antibody response against all three haemagglutinin antigens and was well tolerated. The incidence of local and systemic reactions was comparable with those reported in healthy adults.

Adjuvancy and reactogenicity of N-acetylglucosaminyl-N-acetylmuramyl-dipeptide (GMDP) orally administered just prior to trivalent influenza subunit vaccine. A double-blind placebo-controlled study in nursing home residents.

One hundred and fifty-three nursing home residents received 0, 5, 25 or 50 mg N-acetylglucosaminyl-N-acetylmuramyl-dipeptide (GMDP) orally, and trivalent influenza subunit vaccine intramuscularly. One day after intervention, there was a strong increase of total leucocytes, monocytes and neutrophils in the groups receiving 25 or 50 mg GMDP. A GMDP dose dependent increase in systemic, but not in local, vaccine side-effects was observed. No significant differences in post-vaccination haemagglutination inhibiting serum antibody titres were observed between the four groups, indicating that oral administration of GMDP together with influenza vaccination, does not lead to a higher vaccine efficacy.

Gender differences in local and systemic reactions to inactivated influenza vaccine, established by a meta-analysis of fourteen independent studies.

In order to determine whether there is a difference between genders in reported adverse reactions to inactivated influenza vaccine, a computerized database of serological studies was investigated. A standardized questionnaire was used to evaluate vaccine reactogenicity. A total of 1,800 vaccinees in 14 studies were analyzed separately for two age groups ( < 60 and > or = 60 years of age). Females reported significantly more local reactions than males. The pooled odds ratio for the outcome measure "any local reaction" was 0.32 (95% confidence interval, 0.26-0.40, significant) and 0.54 (95% Cl, 0.41-0.70, significant) for young and elderly adults, respectively. Similar results were obtained for the outcome measure "any systemic reaction." Previous exposure to influenza or influenza vaccine had no influence on reactogenicity. There were no gender differences in sero-responses. In conclusion, gender should be regarded as a predictor of reported reactions to influenza vaccine in both young and elderly adults and should be addressed in future study designs.