Evaluation of Prucalopride in Male Subjects With Chronic Constipation.

A 12-week, Randomised, Double-blind, Placebo-controlled Trial to Evaluate the Efficacy, Quality of Life, Safety and Tolerability of Prucalopride in Male Subjects With Chronic Constipation

This is a multi-centre, randomised, parallel-group, double-blind, placebo-controlled phase III trial to evaluate the efficacy of prucalopride versus placebo over 12 weeks of treatment in male subjects with chronic constipation.

Furthermore the safety, tolerability, effect on quality of life and effect on symptoms of prucalopride will be assessed.

In this phase III trial subjects will be screened and enter a 2-week run-in period (or a 3-week run-in period if the subject is using agents that influence bowel habit) during which the presence of constipation will be confirmed [the subject will complete an electronic daily diary (e-diary)]. At the start of run-in, all existing laxative medication will be withdrawn and subjects will be instructed not to change their diet or lifestyle during the trial. Subjects will be allowed to take a laxative [Dulcolax (bisacodyl)] as rescue medication during the trial, but only if they have not had a bowel movement (BM) for 3 or more consecutive days. An enema can only be used after unsuccessful use of Dulcolax (bisacodyl). No Dulcolax (bisacodyl) should be taken or enemas used between 48 hours before and 48 hours after the first intake of study medication.

After the run-in subjects will be randomly assigned to placebo or prucalopride in an equal ratio (1:1) if the subject fulfils the constipation criteria for inclusion. Randomisation will be stratified by country and by the average number of complete bowel movements (CBM) during run-in: 0 CBM/week and > 0 CBM/week.

Adult subjects (i.e. subjects ≥18 to <65 years of age) will take 2 mg prucalopride or matching placebo once daily before breakfast during the entire 12-week treatment period. Elderly subjects (i.e. subjects ≥65 years of age) will start at a dose of 1 mg prucalopride or matching placebo once daily before breakfast. In case of insufficient response, defined as an average of <3 spontaneous complete bowel movements (SCBM)/week during the preceding 2 weeks of treatment (i.e. since the previous visit) at Week 2 or Week 4, the daily dose has to be increased to 2 mg (or matching placebo). Once the dose is increased to 2 mg once daily the subject will stay on this dose for the remainder of the trial. After Week 4 (Visit 4) no changes in dose are allowed anymore.

Inclusion Criteria:

1. Subject is a male out-patient ≥18 years of age (no upper age limit).

2. Subject has a history of constipation. The subject reports an average of ≤ 2 SBM/week that result in a feeling of complete evacuation (SCBM) and one or more of the following for at least 6 months before the selection visit:

   1. Very hard (little balls) and/or hard stools for at least a quarter of the stools;
   2. Sensation of incomplete evacuation following for at least a quarter of the stools;
   3. Straining at defecation for at least a quarter of the time. This includes subjects who never have SBMs. The above criteria are only applicable for SBMs, i.e. BMs not preceded within a period of 24 hours by the intake of a laxative agent or by the use of an enema.

3. Subject agrees to stop his current laxative treatment and is willing to use rescue medication according to the rescue rule [Dulcolax® (bisacodyl)/enemas]

4. Subject's constipation is chronic.

5. Subject is able and willing to complete the questionnaires (if a validated version in the language of the subject is available) and the e-diary.

6. Subject voluntarily signs the written Informed Consent Form (ICF) in accordance with the regional laws/regulations, prior to the first trial-related activity.

7. Subject is willing to adhere to all trial requirements (amongst others colonoscopy/sigmoidoscopy, if required).

Exclusion Criteria:

1. Subjects in whom constipation is thought to be drug-induced.

2. Subjects using any disallowed medication

3. Subjects suffering from secondary causes of chronic constipation, such as:

   Endocrine disorders, e.g. hypopituitarism, hypothyroidism, hypercalcaemia, pseudohypoparathyroidism, pheochromocytoma or glucagon-producing tumours, unless these are controlled by appropriate medical therapy. Subjects with insulin-dependent diabetes mellitus should always be excluded, also if the subjects are under appropriate medical therapy; Metabolic disorders (e.g. porphyria, uraemia, hypokalaemia or amyloid neuropathy, unless these are controlled by appropriate medical therapy); Neurological disorders (e.g. Parkinson's disease, cerebral tumours, cerebrovascular accidents, multiple sclerosis, meningocele, aganglionosis, hypoganglionosis, hyperganglionosis, autonomic neuropathy or neuropathy due to chemotherapy, spinal cord injury, Chaga's disease, major depression); Surgery. Subjects with insulin-dependent diabetes mellitus should always be excluded, irrespective of whether the constipation started prior to or after the onset of diabetes.

4. Subjects with a significant history of cancer (i.e. less than a 5-year disease-free survival).

5. Subjects with intestinal perforation or obstruction due to structural or functional disorder of the gut wall, obstructive ileus, severe inflammatory conditions of the intestinal tract, such as Crohn's disease, and ulcerative colitis and toxic megacolon/megarectum. Results of an endoscopy or radiologic bowel evaluation is required to rule out polyps, cancer, stricture or other structural or organic disease:

   1. For patients ≤ 50 years: a flexible sigmoidoscopy or colonoscopy after the onset of constipation symptoms and within the previous 5 years;
   2. For patients > 50 years: a flexible sigmoidoscopy /double contrast barium enema or colonoscopy after the onset of constipation symptoms and within the previous 5 years.
   3. For subjects, regardless of age, even if results of this test are available within the previous 5 years but if the patient has alarm symptoms such as anemia, weight loss, heme positive stool, or rectal bleeding: a flexible sigmoidoscopy and double contrast barium enema or colonoscopy is needed after the onset of symptoms.
   4. If abnormalities have been detected during the sigmoidoscopy or colonoscopy e.g., because of polyps, the subject can be included in the trial if the polyps were removed. If clinically indicated, a repeat colonoscopy/sigmoidoscopy needs to be performed at latest within one week after the screening visit. If no barium enema with flexible sigmoidoscopy or a colonoscopic examination has been performed within the period as described above, the assessment is to be scheduled on the screening visit or within the week following screening. When it is clinically indicated that a repeat colonoscopy/sigmoidoscopy is needed to confirm results of a colonoscopy/sigmoidoscopy performed after the screening visit, the subject should be a screen failure.

6. Subjects with known serious illness: clinically significant cardiac, vascular, liver, pulmonary, or psychiatric disorders (as evaluated by the Investigator).

7. Subjects with any condition that in the opinion of the Investigator would complicate or compromise the trial or the well-being of the subject or evidence of clinically relevant pathology that could interfere with the trial results or put the subject's safety at risk.

8. Subjects known to have human immunodeficiency virus (HIV) infection or AIDS, hepatitis B or hepatitis C.

9. Subjects with impaired renal function, i.e. serum creatinine concentration >180 μmol/l or calculated creatinine clearance ≤30 ml/min, including subjects requiring dialysis.

10. Subjects with clinically significant abnormalities of haematology, urinalysis, or blood chemistry as determined by the Investigator. If the results of the haematology, biochemistry or urinalysis tests are not within the laboratory's reference ranges, the subject can be included only on the condition that the Investigator judges that the deviations are not clinically significant. This should be clearly recorded in the electronic Case Report Form (e-CRF).

11. Subjects with a known history of alcohol or drug abuse in the previous 6 months.

12. Subjects with lactose intolerance for whom it is expected that low doses of lactose can lead to diarrhoea, or a known allergy to ingredients or excipients of the trial medication.

13. Subjects who received an investigational drug in the 30 days preceding the run-in period of the trial.

14. Subjects who previously used prucalopride.