Clinical trial NCT01147926: Evaluation of Prucalopride in Male Subjects With Chronic Constipation.
Official title: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Male Subjects With Chronic Constipation
Keywords: Constipation
Male
Lead sponsor: Takeda
Sponsor class: INDUSTRY
First posted: 2010-06-22
Enrollment: 374
Sex: MALE
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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.

Detailed description: 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 At the start of run-in, all existing laxative medication will be withdrawn and subjects will be instructed not to change their diet or lifestyle during the trial.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.

Eligibility criteria: 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.

Primary outcomes:
measure: The Percentage of Subjects With an Average of ≥3 Spontaneous Complete Bowel Movements (SCBM) Per Week
timeFrame: Over 12 week treatment period
Secondary outcomes:
measure: Percentage of Subjects With an Average Weekly Frequency of at Least 3 SCBM Per Week and an Increase of ≥ 1 SCBM Per Week for ≥ 75% of the 12-week Treatment Period and ≥ 75% of the Last Third of the 12-week Treatment Period
timeFrame: Over 12 week treatment period
measure: Percentage of Subjects With an Increase of at Least 1 SCBM Per Week
timeFrame: Over 12 week treatment period
measure: SCBM Per Week
timeFrame: Over 12 week treatment period
measure: Percent SBM With a Consistency of Normal and Hard/Very Hard
timeFrame: Over 12 week treatment period
measure: Percent SCBM With No Straining and Severe/Very Severe Straining
timeFrame: Over 12 week treatment period
measure: Percent SBM With Sensation of Complete Evacuation
timeFrame: Over 12 week treatment period
measure: Time to First SCBM After Investigational Product Intake on Day 1
timeFrame: Day 1
measure: Bisacodyl Tablets Taken Per Week
timeFrame: Over 12 week treatment period
measure: Days With Rescue Medication Taken Per Week
timeFrame: Over 12 week treatment period
measure: Percent of Subjects With an Improvement of ≥ 1 Point on the Patient Assessment of Constipation - Symptom (PAC-SYM) Questionnaire Total Score at Final On Treatment Assessment
timeFrame: Over 12 week treatment period
measure: Percent of Subjects With an Improvement of ≥ 1 Point on the Patient Assessment of Constipation - Quality of Life (PAC-QOL) Total Score at Final On Treatment Assessment
timeFrame: Over 12 week treatment period
measure: Percent of Subjects on the Subject Global Evaluation on Severity of Constipation Score Rating Constipation as Severe to Very Severe at Final On-Treatment Assessment
timeFrame: Over 12 week treatment period
measure: Percent of Subjects on the Subject Global Evaluation on Efficacy of Treatment Score Rating Treatment as Quite a Bit to Extremely Effective at Final On-Treatment Assessment
timeFrame: Over 12 week treatment period
Other outcomes:
Locations:
city: Antwerpen 7
country: Belgium
facility: Gastro-Kliniek cvba
city: Bruxelles
country: Belgium
facility: Cliniques Universitaires St Luc
city: Deurne
country: Belgium
facility: GP / Huisartsenpraktijk De Regenboog
city: Leuven
country: Belgium
facility: UZ Leuven Gasthuisberg
city: Liege
country: Belgium
facility: CHU Sart Tilman
city: Wetteren
country: Belgium
facility: Private Practice
city: Sofia
country: Bulgaria
facility: 4 MHAT
city: Brno
country: Czechia
facility: CCBR Czech Republic Brno
city: Karlovy Vary
country: Czechia
facility: KKN a.s.
city: Pardubice
country: Czechia
facility: CCBR Czech Republic Pardubice
city: Prague 10
country: Czechia
facility: Universtiy Hospital Kralovske Vinhorady
city: Prague
country: Czechia
facility: MONSE s.r.o.
city: Slany
country: Czechia
facility: Hospital Slany
city: Usti nad Orlici
country: Czechia
facility: Orlickoustecka nemocnice
city: Zlin
country: Czechia
facility: Krajska Nemocnice T. Bati a.s., Interni oddeleni - klinika IPVZ; Nemocnicni Lekarna
city: Zlin
country: Czechia
facility: Krajska Nemocnice T. Bati a.s.
city: Aalborg
country: Denmark
facility: CCBR DK Aalborg
city: Ballerup
country: Denmark
facility: CCBR DK Ballerup
city: Vejle
country: Denmark
facility: CCBR DK Vejle
city: Amiens
country: France
facility: CHU - Hopital Nord, service gastro-enterologie et hepatologie
city: Angers
country: France
facility: ARK Clinical Research (Jean XXIII)
city: Angers
country: France
facility: ARK Clinical Research (Proust)
city: Angers
country: France
facility: ARK Clinical Research - Chanzy
city: Avrille
country: France
facility: ARK Clinical Research
city: Bobigny
country: France
facility: Hopital Avicenne, Centre d'exploitation fonctionnelle et reducation digestive
city: Dijon Cedex
country: France
facility: Service de Gastroenterologie & INSERM CIC-P 803 - CHU de Dijon
city: Le Plessis-Grammoire
country: France
facility: ARK Clinical Research
city: Lyon cedex 3
country: France
facility: Hôpital Edouard Herriot
city: Nice
country: France
facility: Hopital Archet 2- service gastro-enterologie et hepatologie
city: Rennes
country: France
facility: Hôpital Pontchaillou - Service des Maladies de l'Appareil Digestif
city: Thouars
country: France
facility: Cabinet Médical
city: Vendome
country: France
facility: ARK Clinical Research
city: Berlin
country: Germany
facility: emovis GmbH
city: Leipzig
country: Germany
facility: Gastroenterologie und Hepatologie am Johannisplatz
city: Wiesbaden
country: Germany
facility: Fachartzpraxis für Innere Medizin
city: Amersfoort
country: Netherlands
facility: Meander Medisch Centrum
city: Amsterdam
country: Netherlands
facility: VU Medisch Centrum
city: Beek
country: Netherlands
facility: PT&R / PreCare Trial & Recruitment
city: Ede
country: Netherlands
facility: Ziekenhuis Gelderse Vallei
city: Maastricht
country: Netherlands
facility: Maastricht Universitair medisch Centrum
city: Rotterdam
country: Netherlands
facility: Erasmus MC
city: Rotterdam
country: Netherlands
facility: Ikazia Ziekenhuis
city: Bydgoszcz
country: Poland
facility: Gabinet Lekarski Janusz Rudziński
city: Lublin
country: Poland
facility: Instytut Medycyny Wsi im. Witolda Chodźki - Zaklad Endoskopowych Badań Kliniczncyh
city: Lublin
country: Poland
facility: Samodzielny Publiczny Szpital Kliniczny Nr 4 w Lublinie
city: Sopot
country: Poland
facility: Endoskopia Sp. z o.o.
city: Torun
country: Poland
facility: Indywidualna Specjalistyczna Praktyka Lekarska w Dziedzinie Chirurgii Ogólnej i Gastroenterologii
city: Warszawa
country: Poland
facility: Przychodnia Polskiej Fundacji Gastroenterologii Filia Nr 1 NZOZ
city: Warszawa
country: Poland
facility: NZOZ Vivamed
city: Oradea
country: Romania
facility: CMI Dr. Lenghel Augustin
state: Bihor
city: Ploiesti
country: Romania
facility: Centrul Medical Valahia SRL
state: Prahova
city: Bucuresti
country: Romania
facility: Spitalul Universitar de Urgenta Militar Central "Dr. Carol Davila"
state: Sector 1
city: Bucuresti
country: Romania
facility: SC Quantum Medical Center SRL
state: Sector 1
city: Bucuresti
country: Romania
facility: Endocenter Medicina Integrativa SRL
state: Sector 2
city: Bucuresti,
country: Romania
facility: SC Cabinet Medical Dr. Blaj Stefan SRL
state: Sector 5
city: Bucuresti
country: Romania
facility: SC Mediclass Sananova SRL
state: Sector 5
city: Bucuresti,
country: Romania
facility: Centrul Medical Humanitas
state: Sector 6
city: Timisoara
country: Romania
facility: Centrul Medical Tuculanu SRL
state: Timis
city: Bucuresti
country: Romania
facility: Centrul Medical Sana
city: Cluj
country: Romania
facility: Spitalul Clinic Judetean Cluj,Clinica Medicala I
city: Iasi
country: Romania
facility: Gastromedica SRL
city: Miercurea Ciuc
country: Romania
facility: Cabinet Medical Dr. Lokos Barna-Csaba
city: Sibiu
country: Romania
facility: Spitalul Clinic Judetean de Urgenta Sibiu
city: Targu-Mures
country: Romania
facility: CMI de Gastroenterologie Dobru Daniela
city: Timisoara
country: Romania
facility: Policlinic Algomed SRL
city: Bath
country: United Kingdom
facility: Oldfield Surgery
city: Chesterfield
country: United Kingdom
facility: Avondale Surgery
city: Coventry
country: United Kingdom
facility: University Hospital & Warwickshire -
city: Durham
country: United Kingdom
facility: County Durham & Darlington NHS Foundation Trust
city: Hinckley
country: United Kingdom
facility: Burbage Surgery
city: Irvine
country: United Kingdom
facility: Townhead Research
city: Leamington Spa
country: United Kingdom
facility: Sherbourne Medical Centre
city: Manchester
country: United Kingdom
facility: Wythenshawe Hospital
Study officials:
affiliation: Takeda
name: Study Director
role: STUDY_DIRECTOR
References:
citation: Staller K, Hinson J, Kerstens R, Spalding W, Lembo A. Efficacy of Prucalopride for Chronic Idiopathic Constipation: An Analysis of Participants With Moderate to Very Severe Abdominal Bloating. Am J Gastroenterol. 2022 Jan 1;117(1):184-188. doi: 10.14309/ajg.0000000000001521.
citation: Yiannakou Y, Piessevaux H, Bouchoucha M, Schiefke I, Filip R, Gabalec L, Dina I, Stephenson D, Kerstens R, Etherson K, Levine A. A randomized, double-blind, placebo-controlled, phase 3 trial to evaluate the efficacy, safety, and tolerability of prucalopride in men with chronic constipation. Am J Gastroenterol. 2015 May;110(5):741-8. doi: 10.1038/ajg.2015.115. Epub 2015 Apr 14.