According to the findings of a Phase III study published in the journal ‘Gut’, the investigational selective 5-HT4 receptor agonist prucalopride improves bowel function in patients who are chronically constipated.

The authors note that prucalopride is structurally different from other serotonergic prokinetic agents (e.g. cisapride, tegaserod), which are less selective for 5-HT4 receptors and interact with others such as 5-HT3 and 5-HT1B/D .  In addition, prucalopride is eliminated without extensive metabolism and therefore has a low potential for drug-drug interactions.  The aim of this trial was to assess the safety and efficacy of this investigational agent in the short-term treatment of patients with chronic constipation. 

There was an initial two-week run-in phase (baseline; constipation confirmed with patient diaries), after which eligible adult patients with less than two spontaneous complete bowel movements (SCBM) per week for a minimum of 6 months were randomised to double-blind treatment with prucalopride (2mg or 4mg) or placebo daily for 12 weeks.  Laxatives were not permitted, except for rescue medication with bisacodyl (given to those patients who did not have a bowel movement for three or more consecutive days throughout the trial). Those with constipation associated with medication, or secondary to endocrine, metabolic or neurological disorders, surgery, or known/suspected organic disorders of the large intestine, were excluded from the study.  The primary endpoint was the proportion of patients reaching three or more SCBM per week, as documented in the patient diaries.  Health-related quality of life (QOL) was rated by the patients at baseline, week 4 and week 12 using the validated patient assessment of constipation quality of life (PAC-QOL) questionnaire.

The intention-to-treat population consisted of 713 patients (2mg n=236; 4mg n=237; placebo n=240).  The mean duration of constipation was 17.5 years and 38.5% reported no spontaneous bowel movements during the 6 months before study entry. Previous therapies for constipation were considered inadequate by 83.2% of patients.  The main findings were as follows:

• 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%).

• The percentage of patients with an average increase of one or more SCBM/week over 12 weeks was 38.1% for 2 mg prucalopride, 44.1% for 4 mg prucalopride and 20.9% for placebo (p≤0.001)

• The mean decrease in the number of days with laxative use per week observed during the 12-week treatment period in both prucalopride groups was greater than the change in the placebo group (p≤0.001; no specific data given in the text)

• At week 12, the mean improvement from baseline in the patient satisfaction subscale of the PAC-QOL (scale of 0-4; primary QOL endpoint) was –0.76 and –0.87 for the prucalopride 2 mg and 4 mg, respectively, compared to -0.30 in the placebo group (p≤0.001)

The most frequently reported adverse events were headache, nausea, abdominal pain and diarrhoea.  The authors comment that “Further studies will be beneficial to determine the long-term efficacy and safety of prucalopride in larger populations as a constipation-reducing medication in the long term.”