Prucalopride in the treatment of chronic constipation in patients from the Asia‐Pacific region: a randomized,double‐blind,placebo‐controlled study

Background The study evaluated efficacy and safety of the 2 mg dose of prucalopride compared to placebo in patients with chronic constipation (CC) from the Asia‐Pacific region. Methods Randomized, placebo‐controlled, parallel‐group, phase III study with 2‐week run‐in, 12‐week treatment phase, and 1‐week follow‐up. Adult patients with CC (≤2 spontaneous bowel movements per week) received 2 mg prucalopride or placebo, once‐daily, for 12 weeks. Primary efficacy measure was percentage of patients with average of ≥3 spontaneous complete bowel movements (SCBMs) per week (Responders) during the 12‐week treatment. A key secondary endpoint was Responders during first 4 weeks of treatment. Other efficacy assessments were based on patient diaries, their assessments of symptoms and quality of life, and investigator’s assessment on efficacy of treatment. Safety assessments included adverse events, laboratory values, and cardiovascular events. Key Results Efficacy and safety were evaluated for 501 patients who received study drug. On the primary endpoint, prucalopride was significantly more effective than placebo with 83 (33.3%) vs 26 (10.3%) patients having a weekly average of ≥3 SCBMs during the 12‐week treatment (P < 0.001). Respective percentages were 34.5%vs 11.1% over first 4 weeks (P < 0.001). On other secondary endpoints, clinical improvement was generally larger and statistically superior (P < 0.001) in the prucalopride group. Most frequently reported adverse events were diarrhea, nausea, abdominal pain, and headache. Conclusion & Inferences Prucalopride 2 mg given once‐daily significantly improved bowel function, associated symptoms, and satisfaction in CC over a 12‐week treatment period, and was safe and well tolerated by patients in the Asia‐Pacific region.     

Effects of the enterokinetic prucalopride (R093877) on colonic motility in fasted dogs

The novel enterokinetic drug prucalopride was tested at various intravenous and oral doses in fasted dogs to assess: (i) the effects on colonic contractile motility patterns; and (ii) the mediation of these effects by 5-hydroxytryptamine (5-HT4) receptors. Colonic motility patterns were assessed in conscious dogs with four chronically implanted strain-gauge force transducers that were sutured on the serosal side of the colon. Prucalopride altered colonic contractile motility patterns in a dose-dependent fashion by stimulating high-amplitude clustered contractions in the proximal colon and by inhibiting contractile activity in the distal colon. Prucalopride was equipotent after oral and intravenous administration, as reflected by the values for the effective dose that induced 50% of maximum effect (95% confidence limits): 0.04 mg kg(-1) p.o. (0.01-0.1 mg kg(-1)) and 0.01 mg kg(-1) i.v. (0.006-0.04 mg kg(-1)). Prucalopride also caused a dose-dependent decrease in the time to the first giant migrating contraction (GMC); at higher doses of prucalopride, the first GMC generally occurred within the first half-hour after treatment. Subcutaneous pretreatment with the 5-HT4 receptor antagonist GR125487 (40 microg kg(-1) bodyweight) completely prevented the effects of orally administered prucalopride (0.31 mg kg(-1) bodyweight). Prucalopride, given orally or intravenously, alters colonic motility in the fasted conscious dog in a dose-dependent fashion. It induces GMCs and causes proximal colon stimulation and distal colon inhibition of contractile motility patterns by stimulating 5-HT4 receptors.     

Luminal 5‐HT4 receptors—A successful target for prokinetic actions

The prokinetic effects of 5‐HT₄ receptor (5‐HT₄R) agonists have been utilized clinically for almost three decades to relieve symptoms of constipation. Surprisingly, the mechanism(s) of action of these compounds is still being debated. Recent studies highlight luminal 5‐HT₄Rs as an alternative and effective target for these prokinetic agents. These include the study by Shokrollahi et al (2019, Neurogastroenterol Motil, e13598) published in the current issue of Neurogastroenterology and Motility, who found that activation of mucosal 5‐HT₄Rs by intraluminal prucalopride, significantly enhanced propulsive motor patterns in rabbit colon. The authors highlight the idea that development of agonists targeting luminal 5‐HT₄Rs in the colonic mucosa might be more effective and safer in achieving prokinetic effects on intestinal motility. The purpose of this mini‐review is to discuss the evidence for luminal 5‐HT₄Rs as an emerging target for prokinetic agents in facilitating propulsive motor patterns in the colon.     

Effects of treatment cessation and re-treatment in randomized controlled trials of prucalopride in patients with chronic idiopathic constipation

Background

Prucalopride is a selective, high-affinity serotonin type 4 receptor agonist approved for the treatment of chronic idiopathic constipation (CIC) in adults. We investigated the impact of prucalopride cessation and re-treatment on efficacy and safety.

Methods

Data were from two randomized controlled trials in adults with CIC. In a dose-finding trial, complete spontaneous bowel movements (CSBMs) and treatment-emergent adverse events (TEAEs) were assessed during a 4-week run-out period after a 4-week treatment period (TP; prucalopride 0.5–4 mg once daily or placebo). In a re-treatment trial, CSBMs and TEAEs were assessed during two 4-week TPs (prucalopride 4 mg once daily or placebo) separated by a 2- or 4-week washout period.

Key Results

In the dose-finding trial (N = 234; 43–48 patients/group), mean CSBMs/week and the proportion of responders (≥3 CSBMs/week) were higher with prucalopride than placebo during the TP, but similar in all groups 1–4 weeks after treatment cessation. TEAEs were less frequent following treatment cessation. In the re-treatment trial (efficacy analyses: prucalopride, n = 189; placebo, n = 205), the proportion of responders was similar in both TPs and significantly higher (p ≤ 0.001) with prucalopride (TP1, 38.6%; TP2, 36.0%) than placebo (TP1, 10.7%; TP2, 11.2%). Most patients who responded to prucalopride in TP1 responded again in TP2 (71.2%). TEAEs were less frequent in TP2 than TP1.

Conclusions and Inferences

Prucalopride cessation resulted in a loss of clinical effect to baseline levels within 7 days. Similar efficacy and safety were observed between TP1 and TP2 after prucalopride was re-initiated following a washout period.     

Randomized, 8‐week,double‐blind,placebo‐controlled trial of vortioxetine in Japanese adults with major depressive disorder,followed by a 52‐week open‐label extension trial

Aim

Safety and efficacy of vortioxetine (5–20 mg/day) in Japanese patients with major depressive disorder were evaluated in two phase 3 studies consisting of a short‐term, 8‐week, placebo‐controlled, double‐blind study followed by a long‐term, 52‐week, open‐label extension study.

Methods

The primary end‐point of the short‐term study was change from baseline in Montgomery–Åsberg Depression Rating Scale (MADRS) total score at week 8. The primary objective of the extension study was vortioxetine's long‐term safety; efficacy end‐points included change in MADRS total score, Clinical Global Impression Scale (CGI)–Severity (S) score from the long‐term study baseline, and CGI–Improvement (CGI‐I) score over 52 weeks.

Results

Of the 366 randomized patients, 338 completed the short‐term study, and 119 patients continued into the extension study. Primary (analysis of covariance) and secondary (mixed model for repeated measurements) analyses in the short‐term study showed numerically greater, but not statistically significant, decreases in change in MADRS total score from baseline between the vortioxetine and placebo groups at week 8. In the long‐term study, 86.6% of patients reported at least one treatment‐emergent adverse event, with the most common being nasopharyngitis (40.3%) and nausea (21%). MADRS total score and CGI‐I and CGI‐S scores improved with continued vortioxetine treatment from baseline of the open‐label study to week 52.

Conclusion

Vortioxetine failed to meet significance versus placebo in the primary efficacy analysis at week 8 in the short‐term study. The extension trial indicated continued improvement of depressive symptoms from baseline of this study throughout the 52‐week treatment period. Vortioxetine treatment was safe and well tolerated in both studies.     

A randomized,double‐blind,placebo‐controlled phase II study of eculizumab in patients with refractory generalized myasthenia gravis

Introduction: Complement activation at the neuromuscular junction is a primary cause of acetylcholine receptor loss and failure of neuromuscular transmission in myasthenia gravis (MG). Eculizumab, a humanized monoclonal antibody, blocks the formation of terminal complement complex by specifically preventing the enzymatic cleavage of complement 5 (C5). Methods: This study was a randomized, double‐blind, placebo‐controlled, crossover trial involving 14 patients with severe, refractory generalized MG (gMG). Results: Six of 7 patients treated with eculizumab for 16 weeks (86%) achieved the primary endpoint of a 3‐point reduction in the quantitative myasthenia gravis (QMG) score. Examining both treatment periods, the overall change in mean QMG total score was significantly different between eculizumab and placebo (P = 0.0144). After assessing data obtained from all visits, the overall change in mean QMG total score from baseline was found to be significantly different between eculizumab and placebo (P < 0.0001). Eculizumab was well tolerated. Conclusion: The data suggest that eculizumab may have a role in treating severe, refractory MG. Muscle Nerve, 2013