Introduction Treatment of severe chronic constipation (CC) is suboptimal. This study evaluates the combined efficacy results of prucalopride (PRU) in three identical pivotal, randomised, placebo (PLA)-controlled trials. The objective of each trial was to compare the efficacy and safety of a 12 week once daily treatment of 2 mg or 4 mg PRU with PLA in CC.
Methods All three trials were of identical design with three parallel treatment groups: PLA, PRU 2 mg and PRU 4 mg. Treatment phase followed a 2-week run-in. Two trials were executed in the US and one in Europe, Canada, Australia and South Africa. The main inclusion criterion was ≤2 spontaneous complete bowel movements (SCBM) per week in combination with straining, sensation of incomplete evacuation or hard stools, at least 25% of the time. The primary efficacy parameter was the percentage of patients with an average of ≥3 SCBM/week over the 12-week treatment period. The two main secondary endpoints were the percentage of patients with an average increase of ≥1 SCBM/week and the percentage of patients with an improvement ≥1 on the satisfaction subscale of the validated quality of life instrument, PAC-QOL. Other endpoints were based on number of (S) BM, time to first BM, stool consistency, straining and patient-reported global evaluation of severity of constipation. Data analysis followed intent-to-treat (ITT) principles.
Results Total 1924 ITT patients, 89% female, average age 47 years, average duration of constipation ∼20 years, prior treatments rated inadequate for 83%. Main Complaints: Infrequent defecation (30%), abdominal bloating (24%), abdominal pain (14%), during 2-week run-in ∼57% of the patients had no SCBM, and average weekly number of SCBM was 0.47. In each individual trial the results for the primary endpoint and secondary endpoints were significantly better for both PRU groups compared to PLA. For the three trials combined, the percentage of patients with an average of ≥3 SCBM per week over the 12 week treatment period (primary endpoint) were 11.3%, 23.6% end 24.7% for PLA, PRU 2 mg and PRU 4 mg, respectively (both p<0.001 PRU vs PLA); similar for subjects who rated their previous therapy as inadequate. Response was highest in week 1 of treatment and stable over the remaining 11 weeks. PRU 2 mg and 4 mg consistently showed significant differences with PLA on all other secondary endpoints. Except for higher incidences of diarrhoea, nausea and headache on first day of treatment, PRU was well tolerated.
Conclusion Both 2 and 4 mg PRU significantly improve bowel function and associated symptoms in CC compared to PLA. Results are reflected consistently in all observed efficacy parameters, including QOL.