Efficacy and Safety Study of Prucalopride for the Treatment of Chronic Constipation

A Double-blind, Placebo-controlled Trial to Evaluate the Efficacy and Safety of Prucalopride (R108512) Tablets in Subjects With Chronic Constipation.

The purpose of this study is to determine whether prucalopride is safe and effective in the treatment of chronic constipation.

Hypothesis:

Prucalopride 2 mg and 4 mg given once daily for 12 weeks is superior to placebo for the treatment of patients with chronic constipation and is well tolerated in those patients.

This is a multicentre, Phase III trial with a parallel-group design, consisting of a 2 week drug-free run-in period, followed by a 12-week, double-blind, placebo-controlled treatment period.

During the run-in period, the subject's bowel habit will be documented and the existence of constipation confirmed. At the start of this period, all existing laxative medication will be withdrawn and subjects will be instructed not to change their diet or lifestyle during the trial.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) as a rescue medication throughout the trial, but only if they have not had a bowel movement for three or more consecutive days. No Dulcolax or enemas should be taken within 48 hours prior to the start of double-blind treatment and 48 hours following the start of double-blind treatment. Subjects will enter the double-blind period if constipation is shown to be present during the run-in period.

If the definition of constipation is not met during the 2-week run-in, the subject will be considered ineligible for the double-blind period and will be discontinued from the study.

During the double-blind, randomised, placebo-controlled period, subjects will be treated for 12 weeks with either 2 mg or 4 mg R108512 or placebo, given once daily before breakfast.

Inclusion Criteria:

• 1. Male and non-pregnant, non breast-feeding female outpatients at least 18 years of age (no upper age limit).

• 2. History of constipation; the subject reports, on average, two or fewer spontaneous bowel movements per week that result in a feeling of complete evacuation and or one or more of the following for at least 6 months before the selection visit:

  1. very hard (little balls) and/or hard stools at least a quarter of the stools
  2. sensation of incomplete evacuation following at least a quarter of the stools
  3. straining at defecation at least a quarter of the time. The above criteria are only applicable for spontaneous bowel movements, i.e., not preceded within a period of 24 hours by the intake of a laxative agent or by the use of an enema.

Subjects who never have spontaneous bowel movements are considered to be constipated and are eligible for the trial.

Exclusion Criteria:

• 1. Subjects in whom constipation is thought to be drug-induced, or subjects using any disallowed medication.
• 2. Subjects suffering from endocrine disorders, metabolic disorders or neurologic disorders.
• 3. Subjects with a megacolon/megarectum or a diagnosis of pseudo-obstruction.
• 4. Constipation as a result of surgery.
• 5. Known or suspected organic disorders of the large bowel, i.e. obstruction, carcinoma, or inflammatory bowel disease.
• 6. Subjects with severe and clinically uncontrolled cardiovascular, liver, or lung disease, neurologic or psychiatric disorders (including active alcohol or drug abuse), cancer or AIDS, and other gastrointestinal or endocrine disorders.
• 7. Subjects with impaired renal function.
• 8. Subjects with clinically significant abnormalities of haematology, urinalysis, or blood chemistry.
• 9. Females of child-bearing potential without adequate contraceptive protection during the trial.