Horizon Scanning Centre September 2014 Prucalopride (Resolor) for adult males with chronic constipation – third line SUMMARY NIHR HSC ID: 10238 Prucalopride (Resolor) is intended to be used as third line therapy for the treatment of chronic constipation in adult males. If licensed, it would offer an additional treatment option for this patient group who do not respond to at least two previous laxative treatments. Prucalopride is a highly selective This briefing is serotonin 5-HT4 receptor antagonist that has demonstrated prokinetic properties on gastric, intestinal and colonic smooth muscle. Prucalopride is based on currently licensed for the treatment of chronic constipation in women in information whom laxatives fail to provide adequate relief. available at the time of research and a It is estimated that the prevalence of chronic constipation is 16%. It is more limited literature common in women than men and prevalence increases with age. Patients search. It is not with constipation report a decreased quality of life, more job absenteeism, intended to be a and loss of work productivity. In 2012, there were 60,567 admissions for definitive statement constipation in England, resulting in 151,319 bed days and 72,567 finished on the safety, consultant episodes; in the same year there were 58 deaths registered in efficacy or England and Wales due to constipation. effectiveness of the health technology Management of chronic constipation may involve dietary and lifestyle covered and should changes in addition to medication such as bulk-forming laxatives, stimulant not be used for laxatives, osmotic laxatives or faecal softeners. When oral laxative therapy is commercial ineffective, use of suppositories, enemas, lubiprostone, prucalopride (for purposes or women), rectal irrigation or manual disimpaction may be appropriate. commissioning Prucalopride is currently in one phase III clinical trial comparing its effect on without additional spontaneous bowel movements against treatment with placebo. information. This briefing presents independent research funded by the National Institute for Health Research (NIHR). The views expressed are those of the author and not necessarily those of the NHS, the NIHR or the Department of Health. NIHR Horizon Scanning Centre, University of Birmingham Email: [email protected] Web: http://www.hsc.nihr.ac.uk NIHR Horizon Scanning Centre TARGET GROUP • Chronic constipation: adult males – third line. DESCRIPTION Prucalopride (Resolor) is a highly selective serotonin 5-HT4 receptor antagonist that has been shown to have prokinetic properties on gastric, intestinal and colonic smooth muscle. In animal models it increases the peristaltic reflexes and giant colonic migrating contractions. The mechanism of action of prucalopride is thought to be through facilitation of non- cholinergic/cholinergic and non-adrenergic neurotransmission1. In the phase III clinical trial, prucalopride is administered orally at 1 or 2mg once daily2. Prucalopride is currently licensed for the treatment of chronic constipation in women in whom laxatives fail to provide adequate relief. Very common (>10%) adverse effects (AEs) of prucalopride when used for its licensed indication include headache, nausea, diarrhoea, and abdominal pain. Common (1% to <10%) AEs include dizziness, vomiting, dyspepsia, rectal haemorrhage, flatulence, abnormal bowel sounds, pollakiuria and fatigue. INNOVATION and/or ADVANTAGES If licensed, prucalopride will offer an additional treatment option for adult males with chronic constipation who do not respond to at least two previous laxative treatments. DEVELOPER Janssen; Shire (UK licence holder). AVAILABILITY, LAUNCH OR MARKETING Prucalopride is currently in phase III clinical trials. PATIENT GROUP BACKGROUND The term constipation describes the subjective impression that the contents of the intestine are not evacuated at adequate frequency, and/or in adequate volumes, the consistency of the stool is too hard, and/or the stool is passed with discomfort3. Constipation can also contribute to secondary complications including abdominal distension, urinary retention, nausea, vomiting, anorexia, haemorrhoids, anal fissures, perianal abscesses, and intestinal obstruction, which may lead to life-threatening faecal impaction3. The Rome III criteria for Functional Bowel Disorders define chronic constipation as 2 or more of the following symptoms for at least 3 months with symptom onset at least 6 months prior to diagnosis4: • Straining during at least 25% of defecations. • Lumpy or hard stools in at least 25% of defecations. • Sensation of incomplete evacuation for at least 25% of defecations. • Sensation of anorectal obstruction/blockage for at least 25% of defecations. 2 NIHR Horizon Scanning Centre • Manual manoeuvres to facilitate at least 25% of defecations (e.g. digital evacuation, support of the pelvic floor). • Fewer than 3 defecations per week. • Loose stools are rarely present without the use of laxatives. • Insufficient criteria for irritable bowel syndrome (IBS). NHS or GOVERNMENT PRIORITY AREA This topic is relevant to: • Improving quality of life for people with long term conditions (2013). CLINICAL NEED and BURDEN OF DISEASE Reported prevalence rates for constipation in the UK vary widely between studies, with figures ranging from 4% to 20%5. Research suggests that the prevalence of chronic constipation is approximately 16%6. Constipation is more common in women than men and prevalence increases with age1. Patients with constipation report a decreased quality of life, more job absenteeism, and loss of work productivity7. Additionally, research estimates that only half of patients using prescription laxatives feel that such products are effective in relieving the symptoms of constipation8. In 2012, there were 60,567 admissions for constipation (ICD-10 K59.0) in England, resulting in 151,319 bed days and 72,567 finished consultant episodes9. In the same year there were 58 deaths registered in England and Wales due to constipation10. The population likely to be eligible to receive prucalopride could not be estimated from available published sources. PATIENT PATHWAY RELEVANT GUIDANCE NICE Guidance • NICE technology appraisal. Lubiprostone for treating chronic idiopathic constipation. (TA318). July 2014. • NICE technology appraisal. Prucalopride for the treatment of chronic constipation in women (TA211). December 2010. Other Guidance • World Gastroenterology Organisation. Practice Guidelines: Constipation. 200711 CURRENT TREATMENT OPTIONS Guidelines recommend that the first step in the management of constipation should be appropriate dietary and lifestyle changes12. Patients should be advised on adequate fluid intake and consuming adequate amounts of food with a high fibre content (such as fruit, vegetables, high-fibre bread, baked beans and wholegrain breakfast cereals)13. A short course of laxatives may relieve symptoms and restore normal bowel function. There are several laxatives available for this purpose, including14,15: • Bulk-forming laxatives such as methylcellulose, ispaghula (psyllium) husk, sterculia, • Stimulant laxatives such as bisacodyl, senna, sodium picosulfate. • Faecal softeners such as liquid paraffin and docusate sodium. 3 NIHR Horizon Scanning Centre • Osmotic laxatives such as macrogols (polyethylene glycols), lactulose, and magnesium salts (magnesium hydroxide or magnesium sulphate). Long-term laxative use should be avoided where possible. When oral laxative therapy is ineffective at producing a bowel movement, a suppository (such as glycerol or sodium phosphate) or enema may be appropriate13,14. For women in whom treatment with at least two laxatives from different classes, at the highest tolerated recommended doses (for at least 6 months) has failed to provide adequate relief, and invasive treatment for constipation is being considered, current guidance suggests prucalopride may also be used13. Lubiprostone is recommended as an option for treating adults with chronic idiopathic constipation, in whom treatment with at least 2 laxatives from different classes, at the highest tolerated recommended dose for at least 6 months, has failed to provide adequate relief and for whom invasive treatment for constipation is being considered13. Rectal irrigation and manual disimpaction are alternative treatment options for those who continue to have rectal emptying difficulties13. EFFICACY and SAFETY Trial NCT01147926, prucalopride vs. placebo; phase III. Sponsor Shire. Status Complete and published in abstract. Source of Abstract16, trial registry2, manufacturer. information Location EU (incl UK). Design Randomised, placebo-controlled. Participants n=374; aged ≥18 years; males; chronic constipation; ≤2 spontaneous bowel movementsa/week that result in a feeling of complete evacuation, and one or more of the following in ≥25% of stools for ≥6 months: very hard and/or hard stools; sensation of incomplete evacuation; straining at defecation; no SBMs. Schedule Randomised to: prucalopride 1mg oral daily for subjects >65 years (in case of insufficient response, 2 mg at week 2 or week 4) and 2mg oral daily for subjects >18 to <65 years; or placebo oral daily. Follow-up Active treatment for 12 weeks. Primary Percentage of subjects with an average ≥3 spontaneous bowel movements week that outcome/s result in a feeling of complete evacuation (SCBM)/week over treatment period. Secondary Safety and tolerability, quality of life (QoL) measured using the patient assessment of outcome/s constipation-quality