Gastroenterology

Gastroenterology

Volume 147, Issue 6, December 2014, Pages 1285-1295.e1
Gastroenterology

Original Research
Full Report: Clinical—Alimentary Tract
Prucalopride Is No More Effective Than Placebo for Children With Functional Constipation

https://doi.org/10.1053/j.gastro.2014.09.005Get rights and content

Background & Aims

Prucalopride is a selective, high-affinity agonist of the 5-hydroxytryptamine (serotonin) receptor 4 that enhances motility in the gastrointestinal tract. We performed a multicenter, randomized, placebo-controlled, double-blind, phase 3 trial to evaluate the efficacy and safety of prucalopride in children (6 months to 18 years old) with functional constipation.

Methods

Children with functional constipation, based on the Rome III criteria, were given prucalopride (children ≤50 kg were given a 0.04 mg/kg oral solution; children >50 kg were given a 2-mg tablet) or placebo once daily for 8 weeks. The primary efficacy end point was the proportion of children with toileting skills who had a mean of ≥3 spontaneous bowel movements/week and ≤1 episode of fecal incontinence/2 weeks, from study weeks 5–8 (responders). Adverse events, clinical laboratory values, and electrocardiograms were monitored.

Results

Efficacy and safety were assessed in 213 children (106 prucalopride, 107 placebo). Twenty-five percent were younger than 4 years old, 50% were 4–11 years old, and 25% were 12–18 years old; 55.4% were girls. At screening, 62.3% of patients in the prucalopride group and 55.1% in the placebo group had a history of fecal incontinence; 60.4% and 55.1% in the prucalopride and placebo groups, respectively, had a mean of ≤1 spontaneous bowel movements/week. The proportion of responders was similar between groups (prucalopride, 17.0% and placebo, 17.8%). There were no statistically significant differences in the primary efficacy end point when patients were stratified by sex, age group, or country. The incidence of treatment-emergent adverse events was similar in the prucalopride (69.8%) and placebo (60.7%) groups.

Conclusions

Prucalopride, although generally well tolerated, was not more effective than placebo in children with functional constipation. ClinicalTrials.gov Number: NCT01330381.

Section snippets

Study Design

A multicenter, randomized phase 3 trial was conducted from April 2011 to March 2013 at 33 centers in Europe (ClinicalTrials.gov: NCT01330381). The trial comprised an 8-week double-blind, placebo-controlled period and a 16-week, open-label, active-controlled period (Figure 1).

The study was conducted in accordance with the International Conference on Harmonisation of Good Clinical Practice, the principles of the Declaration of Helsinki, and applicable local ethical and legal requirements. The

Enrollment

Of the 304 screened patients, 89 were excluded before randomization (Figure 2). Therefore, 215 patients were randomized, 107 to the prucalopride group and 108 to the placebo group. Two patients withdrew consent before investigational product dosing and, as a result, the safety population comprised 213 children (prucalopride: 106; placebo: 107). The per-protocol set excluded 12 patients who stopped treatment with the investigational product before day 37, and 43 who had a protocol violation that

Discussion

This multicenter, placebo-controlled, double-blind trial used a carefully chosen primary end point to evaluate the efficacy of prucalopride in children fulfilling the Rome III criteria for functional constipation. In contrast to adults with constipation, the majority of children have infrequent defecation accompanied by FI as a result of rectal fecal impaction; therefore, effective treatment should lead not only to an increase in defecation frequency but also to a decrease in FI. For this

Acknowledgments

The authors would like to thank the following investigators who, together with their site personnel, enrolled patients into the study. Belgium: G. Veereman-Wauter, I. Paquot, M. Scaillon, E. Sokal; France: F. Gottrand; Germany: S. Koletsko, A. Krahl; Hungary: J. Biro, F. Fekete, L. Karsza, E. Stunya, E. Szakos, C. Szekely, E. Tomsits, G. Toth; Italy: A. Staiano; Netherlands: M. Groeneweg, O. Norbruis, N. van den Berg; Poland: E. Happyn, B. Iwanczak, J. Kierkus, H. Szajewska; UK: N., Croft, R.,

References (36)

  • M.E. Bongers et al.

    Long-term prognosis for childhood constipation: clinical outcomes in adulthood

    Pediatrics

    (2010)
  • M.A. Pijpers et al.

    Currently recommended treatments of childhood constipation are not evidence based: a systematic literature review on the effect of laxative treatment and dietary measures

    Arch Dis Child

    (2009)
  • M.R. Briejer et al.

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

    Neurogastroenterol Motil

    (2001)
  • E.P. Bouras et al.

    Selective stimulation of colonic transit by the benzofuran 5HT4 agonist, prucalopride, in healthy humans

    Gut

    (1999)
  • A.M. De Schryver et al.

    The effects of the specific 5HT(4) receptor agonist, prucalopride, on colonic motility in healthy volunteers

    Aliment Pharmacol Ther

    (2002)
  • M. Camilleri et al.

    A placebo-controlled trial of prucalopride for severe chronic constipation

    N Engl J Med

    (2008)
  • A.V. Emmanuel et al.

    Prucalopride, a systemic enterokinetic, for the treatment of constipation

    Aliment Pharmacol Ther

    (2002)
  • G. Coremans et al.

    Prucalopride is effective in patients with severe chronic constipation in whom laxatives fail to provide adequate relief. Results of a double-blind, placebo-controlled clinical trial

    Digestion

    (2003)
  • Cited by (0)

    Conflicts of interest These authors disclose the following: Alexandra Green and Amy Levine are employees of Shire. Rene Kerstens, Jannie Ausma, and Magnus Ruth are former employees of Shire-Movetis. Marc A. Benninga is a consultant for AstraZeneca, Danone, Shire, Sucampo, and Zeria. The remaining authors disclose no conflicts.

    Funding This study was sponsored by Shire Development LLC.

    View full text