Prucalopride (Resolor) for Chronic Constipation December 2008

Prucalopride (Resolor) for chronic constipation

December 2008

This technology summary is based on information available at the time of research and a limited literature search. It is not intended to be a definitive statement on the safety, efficacy or effectiveness of the health technology covered and should not be used for commercial purposes.

The National Horizon Scanning Centre Research Programme is part of the National Institute for Health Research

December 2008 National Horizon Scanning Centre News on emerging technologies in healthcare

Prucalopride (Resolor) for chronic constipation

Target group • Chronic constipation: in adults whom laxatives fail to provide adequate relief.

Technology description Prucalopride (Resolor) is a selective, high-affinity, enterokinetic 5-HT4 receptor agonist, which increases colon motility and restores the slow movement of the bowels. Prucalopride is an oral formulation administered at 1 or 2mg once daily and is intended to be used in laxative-refractory patients.

Innovation and/or advantages Prucalopride is a first-in-class drug for this indication with a novel mechanism of action. While, none of the clinical trials compare the efficacy of prucalopride with current therapies, the drug was studied in patients who were dissatisfied with current laxatives.

Developer Movetis NV.

Availability, launch or marketing dates, and licensing plans: The company submitted a Marketing Authorisation Application with the EMEA in May 2008.

NHS or Government priority area: This topic is relevant to The National Services Framework for Older People (2001).

Relevant guidance • Clinical Knowledge Summaries. Constipation-care guidelines. 20081. • World Gastroenterology Organisation. Constipation-care guidelines. 20072.

Clinical need and burden of disease The prevalence of constipation is difficult to estimate and varies widely depending on the definition and criteria employed, and whether self-assessment or physician-diagnosis is used. Estimates of the UK prevalence of constipation vary between 8.2% and 52% in women3. Constipation is more common in women than men, increases with age (estimated prevalence of 20% in elderly), and is higher amongst those living in nursing homes4. Health-related quality of life in people with constipation is generally worse than those without constipation5.

Constipation generates around 450,000 GP consultations per year in England and Wales at an estimated cost of £4.5 million6. In 2007, approximately 15 million prescriptions were filled for laxatives, at a cost of almost £64 million in England and Wales7,8.

The company estimate that about 363,000 patients in the UK are eligible to benefit from prucalopride based on an average prevalence of 7.7% for severe chronic constipation and assuming that 10% of patients with constipation are refractory to laxatives, which may be an over estimate.

Existing comparators and treatments The current treatment options for chronic constipation include: • Dietary and lifestyle changes. 2 December 2008 National Horizon Scanning Centre News on emerging technologies in healthcare

• Bulk-forming laxatives, e.g. Ispaghula Husk. • Stimulant laxatives, e.g. Bisacodyl. • Faecal softeners, e.g. Liquid paraffin, Arachis Oil. • Osmotic laxatives, e.g. Lactulose.

Efficacy and safety

Trial PRU-INT-6; PRU-USA-13; PRU-USA-11; NCT004881379: NCT0048594010: NCT0048388611: prucalopride vs placebo; prucalopride vs placebo; prucalopride vs placebo; phase III. phase III. phase III. Sponsor Movetis. Movetis. Movetis. Status Completed, published12. Completed, published13. Completed, published5.

Location USA, Canada, EU (inc UK), USA. USA. Australia, Norway and South Africa. Design Randomised, double-blind, Randomised, double-blind, Randomised, double-blind, placebo controlled. placebo controlled. placebo controlled. Participants n=720; adults; constipation n= 641; adults; constipation n= 628; adults; constipation in trial <2 SCBM per week for ≥6 <2 SCBM per week for ≥6 <2 SCBMa per week for ≥6 months. months. months. Randomised to prucalopride Randomised to prucalopride Randomised to prucalopride 2mg, 4mg or placebo once 2mg, 4mg or placebo once 2mg, 4mg or placebo once daily for 12 weeks. daily for 12 weeks. daily for 12 weeks. Follow-up 12 week treatment period. 12 week treatment period. 12 week treatment period. Primary ≥3 SCBM per week. ≥3 SCBM per week. ≥3 SCBM per week. outcome Secondary ≥1 SCBM per week; ≥1 SCBM per week; ≥1 SCBM per week; outcomes symptom severity; and symptom severity; and symptom severity; and QOL. QOL. QOL. Key results ≥3 SCBM per week in ≥3 SCBM per week in ≥3 SCBM per week in weeks 1-12: 19.5% (p≤0.01 weeks 1-12: 23.9% (p≤0.01 weeks 1-12: 28.9% vs placebo), 23.6% vs placebo), 23.5% (p≤0.01 (p≤0.001 vs placebo), (p≤0.001 vs placebo) and vs placebo) and 12.1% of 28.9% (p≤0.001 vs placebo) 9.6% of prucalopride 2mg, prucalopride 2mg, 4mg and and 13.0% for prucalopride 4mg and placebo placebo respectively. 2mg, 4mg and placebo respectively. Mean change Improvement ≥1 on PAC- respectively. in overall PAC-SYM score SYM score at week 12: PAC-SYMc score at week at week 12: -0.66 (p≤0.001 38.0% (p≤0.001 vs 4: 31.4% (p≤0.001 vs vs placebo), -0.71 (p≤0.001 placebo), 29.1% and 23.6% placebo), 34.9% (p≤0.001 vs placebo) and respectively. Improvement vs placebo) and 15.1% -0.37 respectively. ≥1 on overall PAC-QOLb respectively. Improvement ≥1 on overall score at week 12: 43.5% Improvement ≥1 on PAC- PAC-QOL score at week (p≤0.001 vs placebo), SYM score at week 12: 12: 33.5% (p≤0.001 vs 44.4% (p≤0.001 vs placebo) 31.2%, 33.5%, 23.1% placebo), 29.4% (p≤0.001 and 26.0% respectively. respectively (non- vs placebo) and 16.4% significant). Improvement respectively. ≥1 on overall PAC-QOLd score at week 12: 39.4% a SCBM: spontaneous complete bowel movements b PAC-QOL: patient assessment of constipation-quality of life c PAC-SYM: patient assessment of constipation – symptoms questionnaire d PAC-QOL: patient assessment of constipation –quality of life 3 December 2008 National Horizon Scanning Centre News on emerging technologies in healthcare

(p≤0.001 vs placebo), 40.5% (p≤0.001 vs placebo) and 21.7% respectively. Adverse Most frequently reported Most frequently reported Most frequently reported effects (AEs) AEs included headache, AEs included headache, AEs included headache, nausea, diarrhoea and nausea, diarrhoea, flatulence nausea, diarrhoea, flatulence abdominal pain. AEs in and abdominal pain. Severe and abdominal pain. 71.4%, 74.8% and 67.1% AEs in 15%, 21% and 10% Discontinuation rate of for prucalopride 2mg, 4mg for prucalopride 2mg, 4mg 8.2% with prucalopride 2mg and placebo respectively. and placebo respectively. compared to 1.9% in Discontinuation rate of Discontinuation rate of 4%, placebo. 6.3%, 15.1% and 6.7% 6% and 2% respectively. respectively.

Trial PRU-USA-28; PRU-INT-12; PRU-USA-25; NCT0059833814: NCT0048742215: NCT0057701816: prucalopride vs. placebo; re- prucalopride vs. placebo; prucalopride vs. placebo; treatment; phase III. phase III. phase III. Sponsor Movetis. Movetis. Movetis. Status Completed, conference Completed, conference Completed, not published. abstract17. abstract18. Location USA. EU (inc UK), Canada, USA. Norway and South Africa. Design Randomised, double-blind, Randomised, double-blind, Randomised, double-blind, placebo controlled. placebo controlled. placebo controlled. Participants n= 516; adults; constipation n= 303; adults >65 years; n=755; adults; constipation in trial <2 SCBM per week for ≥6 constipation <2 SCBM per <2 SCBM per week for ≥6 months. week for ≥6 months. months. Randomised to prucalopride Randomised to prucalopride Randomised to 4mg or placebo once daily 1mg, 2mg, 4mg or placebo prucalopride 1mg for 2 for 4 weeks (Trt I), 2 week once daily for 4 weeks. days, 2mg for 2 days and 4 wash out period and second mg once daily thereafter, or 4 week (weeks 7-10) prucalopride 4mg once treatment period (Trt II). daily or placebo. Follow-up 8 week treatment period. 4 week treatment period. 4 week treatment period. Primary ≥3 SCBM per week. ≥3 SCBM per week. ≥3 SCBM per week. outcome Secondary ≥1 SCBM per week; ≥1 SCBM per week; ≥1 SCBM per week; outcomes symptom severity; and symptom severity; and symptom severity; and QOL. QOL. QOL. Key Results ≥3 SCBM per week: weeks ≥3 SCBM per week in - 1-4 (Trt I); 38.6% (p≤0.001 weeks 1-4: 39.5%, 32.0%, vs placebo) and 10.7% for 31.6% and 20.0% for prucalopride and placebo prucalopride 1mg, 2mg,4mg respectively. Weeks 7-10 and placebo respectively (Trt II): 36.0% (p≤0.001 vs. (non-significant). placebo) and 11.2% for 1≥ SCBM per week in prucalopride and placebo. weeks 1-4 : 61.1% (p≤0.05 vs placebo), 56.9% (p≤0.05 vs placebo), 50.7% (p≤0.05 vs placebo) and 33.8 % respectively. Expected - - Study started August 1998 reporting and completed September date 1999.

4 December 2008 National Horizon Scanning Centre News on emerging technologies in healthcare

Adverse Most frequently reported Most frequently reported - Effects AEs were gastrointestinal in AEs included headache and (AEs) nature and headache. nausea.

There are 3 large, complete, but not fully published open-label long-term follow up trials of patients involved in phase II and III trials, and new recruits with 1, 2 or 4mg prucalopride for up to 24 months. There is a reported maintenance of patient satisfaction and quality of life improvement. Predominant adverse effects remain mostly gastrointestinal and are more frequent in new recruits to the trial.

Estimated cost and cost impact The cost of prucalopride is yet to be determined. The costs of other products used in constipation are:

Drug Dose Estimated cost per 12 weeks19 Fybogel 1 sachet daily £6.36 Bisacodyl 5-10mg daily £2.70-£5.40 Lactulose 15ml twice daily £13.15

Potential or intended impact – speculative

Patients ; Reduced morbidity Reduced mortality or increased ; Improved quality of life for survival patients and/or carers Quicker, earlier or more accurate Other: None identified diagnosis or identification of disease

Services Increased use Service reorganisation required Staff or training required

; Decreased use: reduction of Other: None identified number of visits to GPs and/or specialists.

Costs Increased unit cost compared to Increased costs: more patients Increased costs: capital alternative coming for treatment investment needed ; New costs: additional therapy ; Savings: reduction of number of Other: visits to GPs and/or specialists. Reduction in use of laxatives.

References

1 Clinical Knowledge Summaries. Constipation in adults. Care guideline. January 2008. 2 World Gastroenterology Organisation. Constipation. Care guideline. January 2007. 3 MeRec Bulletin. The management of constipation. Volume 14, number 6. 2006. 4 Petticrew M, Watt I, Brand M. What’s the ‘best buy’ for treatment of constipation? Results of a systematic review of the efficacy and comparative efficacy of laxatives in the elderly. British Journal of General Practice 1999;49:387-393. 5 Camilleri M, Kerstens R, Rykx A, et al. A placebo-controlled trial of prucalopride for severe chronic constipation. New England Journal of Medicine 2008;358:2344-54. 6 National Institute of Health Research Health Technology Assessment Programme (NIHR HTA). LIFELAX- diet and lifestyle vs. laxatives in the management of constipation in older people. Abstract of ongoing project. http://www.hta.ac.uk/1310 Accessed 04 September 2008. 5 December 2008 National Horizon Scanning Centre News on emerging technologies in healthcare

7 The NHS Information Centre. Prescription cost analysis. England; 2007 8 Prescribing Services. Prescription cost analysis. Wales; 2007. http://www.wales.nhs.uk/sites3/page.cfm?orgid=428&pid=13533 Accessed 10 September 2008. 9 ClinicalTrials.gov. Efficacy and safety study of prucalopride to treat chronic constipation. http://www.clinicaltrials.gov/ct2/show/NCT00488137?term=NCT00488137&rank=1 Accessed 23 September 2008. 10 ClinicalTrials.gov. Efficacy and safety study of prucalopride for the treatment of patients with chronic constipation. http://www.clinicaltrials.gov/ct2/show/NCT00485940?term=NCT00485940&rank=1 Accessed 23 September 2008. 11 ClinicalTrials.gov. Efficacy and safety study of prucalopride for the treatment of chronic constipation. http://www.clinicaltrials.gov/ct2/show/NCT00483886?term=NCT00483886&rank=1 Accessed 23 September 2008. 12 Tack J, Van Outryve M, Beyens G, et al. Prucalopride (Resolor) in the treatment of severe chronic constipation in patients dissatisfied with laxatives. Gut 2009;58:357-365. 13 Quigley EMM, Vandeplassche L, Kerstens R, et al. A 12-week, randomised, double-blind, placebo-controlled trial to evaluate the efficacy, impact on quality of life, and safety and tolerability of prucalopride in severe chronic constipation. Alimentary Pharmacology & Therapeutics 2009;29:315-328. 14 ClinicalTrials.gov. Efficacy and safety study of prucalopride for the re-treatment of chronic constipation. http://www.clinicaltrials.gov/ct2/show/NCT00598338?term=NCT00598338&rank=1 Accessed 23 September 2008. 15 ClinicalTrials.gov. Efficacy and safety study of prucalopride for the treatment of elderly patients with chronic constipation. http://www.clinicaltrials.gov/ct2/show/NCT00487422?term=NCT00487422&rank=1 Accessed 23 September 2008. 16 ClinicalTrials.gov. Efficacy and safety study of the effect of dose-titration of prucalopride for the treatment of chronic constipation. http://www.clinicaltrials.gov/ct2/show/NCT00577018?term=NCT00577018&rank=1 Accessed 23 September 2008. 17 Galandiuk S, Rykx A, Ausma J, et al. A two-period, double-blind, placebo-controlled study to evaluate the effects of re-treatment of prucalopride (RESOLOR®) on efficacy and safety in patients with chronic constipation. Gut 2008; 57 (Suppl II) A86. 18 Van Outryve M, Beyens G, Kerstens R et al. Long-term follow-up study of oral prucalopride (Resolor) administered to patients with chronic constipation. Gastroenterology 2008;134 (4 Suppl 1):A-547. 19 British Medical Association and Royal Pharmaceutical Society of Great Britain. British National Formulary. BMJ Group and RPS Publishing. London; March 2008.

The National Institute for Health Research National Horizon Scanning Centre Research Programme is funded by the Department of Health. The views expressed in this publication are those of the author and not necessarily those of the NHS, the NIHR or the Department of Health

The National Horizon Scanning Centre, Department of Public Health and Epidemiology University of Birmingham, Edgbaston, Birmingham, B15 2TT, England Tel: +44 (0)121 414 7831 Fax +44 (0)121 414 2269 www.pcpoh.bham.ac.uk/publichealth/horizon