Clinical Trial Results:
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
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Summary
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EudraCT number |
2009-015719-42 |
Trial protocol |
BE DE CZ GB FR NL BG DK |
Global end of trial date |
25 Oct 2013
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Results information
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Results version number |
v1(current) |
This version publication date |
04 Sep 2018
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First version publication date |
25 Jan 2015
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Other versions |
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Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
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Trial identification
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Sponsor protocol code |
SPD555-302
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT01147926 | ||
WHO universal trial number (UTN) |
- | ||
Other trial identifiers |
Study Number: M0001-C302 | ||
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Sponsors
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Sponsor organisation name |
Shire Development LLC
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Sponsor organisation address |
725 Chesterbrook Boulevard, Wayne, Pennsylvania, United States, 19087
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Public contact |
Study Physician, Shire, 1866 8425335,
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Scientific contact |
Study Physician, Shire, 1866 8425335,
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Paediatric regulatory details
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Is trial part of an agreed paediatric investigation plan (PIP) |
No
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Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Results analysis stage
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Analysis stage |
Final
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Date of interim/final analysis |
25 Oct 2013
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Is this the analysis of the primary completion data? |
No
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Global end of trial reached? |
Yes
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Global end of trial date |
25 Oct 2013
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Was the trial ended prematurely? |
No
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General information about the trial
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Main objective of the trial |
To evaluate the efficacy of prucalopride versus placebo over 12 weeks of treatment in male subjects with chronic constipation.
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Protection of trial subjects |
This study was conducted in accordance with International Conference on Harmonisation of Good Clinical Practice (GCP), the principles of the Declaration of Helsinki, as well as other applicable local ethical and legal requirements.
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Background therapy |
- | ||
Evidence for comparator |
- | ||
Actual start date of recruitment |
23 Sep 2010
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Long term follow-up planned |
No
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Independent data monitoring committee (IDMC) involvement? |
No
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Population of trial subjects
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Number of subjects enrolled per country |
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Country: Number of subjects enrolled |
Netherlands: 10
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Country: Number of subjects enrolled |
Poland: 56
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Country: Number of subjects enrolled |
United Kingdom: 24
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Country: Number of subjects enrolled |
Belgium: 20
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Country: Number of subjects enrolled |
Bulgaria: 18
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Country: Number of subjects enrolled |
Czech Republic: 29
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Country: Number of subjects enrolled |
Denmark: 41
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Country: Number of subjects enrolled |
France: 41
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Country: Number of subjects enrolled |
Germany: 21
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Country: Number of subjects enrolled |
Romania: 114
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Worldwide total number of subjects |
374
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EEA total number of subjects |
374
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Number of subjects enrolled per age group |
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In utero |
0
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Preterm newborn - gestational age < 37 wk |
0
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Newborns (0-27 days) |
0
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Infants and toddlers (28 days-23 months) |
0
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Children (2-11 years) |
0
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Adolescents (12-17 years) |
0
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Adults (18-64 years) |
222
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From 65 to 84 years |
145
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85 years and over |
7
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Recruitment
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Recruitment details |
- | |||||||||||||||||||||||||||||||||||||||||||||
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Pre-assignment
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Screening details |
Out of a total of 553 subjects screened, 374 were randomized and 370 were treated with study drug. Reasons for 4 'randomized subjects but not treated': 2 subjects withdrew consent (1 each in placebo and prucalopride groups), 1 subject was non-compliant in prucalopride group, and 1 subject did not meet selection criteria in prucalopride group. | |||||||||||||||||||||||||||||||||||||||||||||
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Pre-assignment period milestones
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Number of subjects started |
374 | |||||||||||||||||||||||||||||||||||||||||||||
Number of subjects completed |
370 | |||||||||||||||||||||||||||||||||||||||||||||
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Pre-assignment subject non-completion reasons
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Reason: Number of subjects |
Consent withdrawn by subject: 2 | |||||||||||||||||||||||||||||||||||||||||||||
Reason: Number of subjects |
Non-compliance: 1 | |||||||||||||||||||||||||||||||||||||||||||||
Reason: Number of subjects |
Did not meet selection criteria: 1 | |||||||||||||||||||||||||||||||||||||||||||||
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Period 1
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Period 1 title |
Overall study (overall period)
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Is this the baseline period? |
Yes | |||||||||||||||||||||||||||||||||||||||||||||
Allocation method |
Randomised - controlled
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Blinding used |
Double blind | |||||||||||||||||||||||||||||||||||||||||||||
Roles blinded |
Subject, Investigator, Carer, Assessor | |||||||||||||||||||||||||||||||||||||||||||||
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Arms
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Are arms mutually exclusive |
Yes
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Arm title
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Placebo | |||||||||||||||||||||||||||||||||||||||||||||
Arm description |
Placebo matched to Prucalopride tablet orally once daily. | |||||||||||||||||||||||||||||||||||||||||||||
Arm type |
Placebo | |||||||||||||||||||||||||||||||||||||||||||||
Investigational medicinal product name |
Placebo
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Film-coated tablet
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Routes of administration |
Oral use
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Dosage and administration details |
Subjects received oral dose of placebo matching with prucalopride once daily.
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Arm title
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Prucalopride | |||||||||||||||||||||||||||||||||||||||||||||
Arm description |
Prucalopride 2 milligram (mg) tablet orally once daily for subjects greater than or equal to (≥) 18 to less than (<) 65 years; 1 mg once daily orally for subjects ≥65 years, and in case of insufficient response, increased to 2 mg once daily orally at Week 2 or Week 4. | |||||||||||||||||||||||||||||||||||||||||||||
Arm type |
Experimental | |||||||||||||||||||||||||||||||||||||||||||||
Investigational medicinal product name |
Prucalopride
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Investigational medicinal product code |
M0001, SPD555
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Other name |
Resolor®
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Pharmaceutical forms |
Film-coated tablet
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Routes of administration |
Oral use
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Dosage and administration details |
Subjects received prucalopride 2 mg once daily orally (subjects ≥18 to <65 years); 1 mg once daily orally (subjects ≥65 years), and in case of insufficient response, increased to 2 mg once daily orally at Week 2 or Week 4.
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| Notes [1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same. Justification: Not all enrolled subjects were treated with study drugs. Since baseline period included only treated subjects, the worldwide number enrolled in the trial differs with the number of subjects reported in the baseline period. |
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Baseline characteristics reporting groups
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Reporting group title |
Placebo
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Reporting group description |
Placebo matched to Prucalopride tablet orally once daily. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Prucalopride
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Reporting group description |
Prucalopride 2 milligram (mg) tablet orally once daily for subjects greater than or equal to (≥) 18 to less than (<) 65 years; 1 mg once daily orally for subjects ≥65 years, and in case of insufficient response, increased to 2 mg once daily orally at Week 2 or Week 4. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
Placebo
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Reporting group description |
Placebo matched to Prucalopride tablet orally once daily. | ||
Reporting group title |
Prucalopride
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Reporting group description |
Prucalopride 2 milligram (mg) tablet orally once daily for subjects greater than or equal to (≥) 18 to less than (<) 65 years; 1 mg once daily orally for subjects ≥65 years, and in case of insufficient response, increased to 2 mg once daily orally at Week 2 or Week 4. | ||
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End point title |
The Percentage of Subjects With an Average of ≥3 Spontaneous Complete Bowel Movements (SCBM) Per Week | ||||||||||||
End point description |
Spontaneous Bowel Movements defined as a bowel movement that was not preceded within a period of 24 hours by the intake of a laxative agent or by the use of an enema. Modified Intent-to-treat Population (mITT) included all subjects randomized into the study except those excluded due to a major GCP breach at one site, who took at least 1 dose of the investigational product.
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End point type |
Primary
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End point timeframe |
Over 12-week treatment period
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Statistical analysis title |
Statistical analysis 1 | ||||||||||||
Comparison groups |
Placebo v Prucalopride
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Number of subjects included in analysis |
358
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Analysis specification |
Pre-specified
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Analysis type |
superiority | ||||||||||||
P-value |
< 0.0001 | ||||||||||||
Method |
Cochran-Mantel-Haenszel | ||||||||||||
Confidence interval |
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End point title |
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 | ||||||||||||
End point description |
mITT population included all subjects randomized into the study except those excluded due to a major GCP breach at one site, who took at least 1 dose of the investigational product.
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End point type |
Secondary
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End point timeframe |
Over 12-week treatment period
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| No statistical analyses for this end point | |||||||||||||
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End point title |
Percentage of Subjects With an Increase of at Least 1 SCBM Per Week | ||||||||||||
End point description |
mITT population included all subjects randomized into the study except those excluded due to a major GCP breach at one site, who took at least 1 dose of the investigational product.
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End point type |
Secondary
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End point timeframe |
Over 12-week treatment period
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| No statistical analyses for this end point | |||||||||||||
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End point title |
SCBM Per Week | ||||||||||||
End point description |
mITT population included all subjects randomized into the study except those excluded due to a major GCP breach at one site, who took at least 1 dose of the investigational product.
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End point type |
Secondary
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End point timeframe |
Over 12-week treatment period
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| Notes [1] - Not all subjects in the mITT population had data for this outcome. [2] - Not all subjects in the mITT population had data for this outcome. |
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| No statistical analyses for this end point | |||||||||||||
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End point title |
Percent spontaneous bowel movements (SBM) With a Consistency of Normal and Hard/Very Hard | ||||||||||||||||||
End point description |
Consistency measured using the 7-point Bristol scale where 1-2 indicate constipation (=hard/very hard), 3-4 are ideal stools (=normal), and 5-7 tending toward diarrhea. mITT population included all subjects randomized into the study except those excluded due to a major GCP breach at one site, who took at least 1 dose of the investigational product.
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End point type |
Secondary
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End point timeframe |
Over 12-week treatment period
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| Notes [3] - Not all subjects in the mITT population had data for this outcome. [4] - Not all subjects in the mITT population had data for this outcome. |
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| No statistical analyses for this end point | |||||||||||||||||||
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End point title |
Percent SCBM With No Straining and Severe/Very Severe Straining | ||||||||||||||||||
End point description |
Straining was evaluated on a 5-point scale (0=none, 1=mild, 2=moderate, 3=severe, or 4=very severe). mITT population included all subjects randomized into the study except those excluded due to a major GCP breach at one site, who took at least 1 dose of the investigational product.
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End point type |
Secondary
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End point timeframe |
Over 12 week treatment period
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| Notes [5] - Not all subjects in the mITT population had data for this outcome. [6] - Not all subjects in the mITT population had data for this outcome. |
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| No statistical analyses for this end point | |||||||||||||||||||
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End point title |
Percent SBM With Sensation of Complete Evacuation | ||||||||||||
End point description |
mITT population included all subjects randomized into the study except those excluded due to a major GCP breach at one site, who took at least 1 dose of the investigational product.
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End point type |
Secondary
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End point timeframe |
Over 12 week treatment period
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| Notes [7] - Not all subjects in the mITT population had data for this outcome. [8] - Not all subjects in the mITT population had data for this outcome. |
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| No statistical analyses for this end point | |||||||||||||
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End point title |
Time to First SCBM After Investigational Product Intake on Day 1 | ||||||||||||
End point description |
mITT population included all subjects randomized into the study except those excluded due to a major GCP breach at one site, who took at least 1 dose of the investigational product.
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End point type |
Secondary
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End point timeframe |
Day 1
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| No statistical analyses for this end point | |||||||||||||
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End point title |
Bisacodyl Tablets Taken Per Week | ||||||||||||
End point description |
mITT population included all subjects randomized into the study except those excluded due to a major GCP breach at one site, who took at least 1 dose of the investigational product.
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End point type |
Secondary
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End point timeframe |
Over 12 week treatment period
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| Notes [9] - Not all subjects in the mITT population had data for this outcome. [10] - Not all subjects in the mITT population had data for this outcome. |
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| No statistical analyses for this end point | |||||||||||||
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End point title |
Days With Rescue Medication Taken Per Week | ||||||||||||
End point description |
mITT population included all subjects randomized into the study except those excluded due to a major GCP breach at one site, who took at least 1 dose of the investigational product.
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End point type |
Secondary
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End point timeframe |
Over 12-week treatment period
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| Notes [11] - Not all subjects in the mITT population had data for this outcome. [12] - Not all subjects in the mITT population had data for this outcome. |
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| No statistical analyses for this end point | |||||||||||||
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End point title |
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 | ||||||||||||
End point description |
The PAC-SYM is a validated 12-item questionnaire for the evaluation of severity of symptoms of constipation in subjects with constipation. Items were rated on a 5-point Likert scale: 0=absent, 1=mild, 2=moderate, 3=severe, 4=very severe. Total score ranged from 0 to 48. Lower scores indicate improvement in symptoms. A 1-point improvement in PAC-SYM total score was considered clinically meaningful. mITT population included all subjects randomized into the study except those excluded due to a major GCP breach at one site, who took at least 1 dose of the investigational product.
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End point type |
Secondary
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End point timeframe |
Over 12-week treatment period
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| Notes [13] - Not all subjects in the mITT population had data for this outcome. [14] - Not all subjects in the mITT population had data for this outcome. |
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| No statistical analyses for this end point | |||||||||||||
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End point title |
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 | ||||||||||||
End point description |
The PAC-QOL is a validated 28-item questionnaire for the evaluation of quality of life in subjects with constipation. Items were rated on a 5-point Likert scale: 0=not at all/none of the time, 1=a little bit/a little bit of the time, 2=moderately/some of the time, 3=quite a bit/most of the time, 4=extremely/all of the time. Total score ranged from 0-112. Lower scores indicate improvement in symptoms. A 1-point improvement in PAC-QOL total score was considered clinically meaningful. mITT population included all subjects randomized into the study except those excluded due to a major GCP breach at one site, who took at least 1 dose of the investigational product.
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End point type |
Secondary
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End point timeframe |
Over 12-week treatment period
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| Notes [15] - Not all subjects in the mITT population had data for this outcome. [16] - Not all subjects in the mITT population had data for this outcome. |
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| No statistical analyses for this end point | |||||||||||||
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End point title |
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 | ||||||||||||
End point description |
Subject was asked to rate the severity of his constipation using a 5-point Likert scale: 0=absent, 1=mild, 2=moderate, 3=severe, 4=very severe. mITT population included all subjects randomized into the study except those excluded due to a major GCP breach at one site, who took at least 1 dose of the investigational product.
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End point type |
Secondary
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End point timeframe |
Over 12-week treatment period
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| Notes [17] - Not all subjects in the mITT population had data for this outcome. [18] - Not all subjects in the mITT population had data for this outcome. |
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| No statistical analyses for this end point | |||||||||||||
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End point title |
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 | ||||||||||||
End point description |
The subject was asked to rate his global evaluation of the efficacy of treatment using the following 5-point scale:
0=not at all effective
1=a little bit effective
2=moderately effective
3=quite a bit effective
4=extremely effective.
mITT population included all subjects randomized into the study except those excluded due to a major GCP breach at one site, who took at least 1 dose of the investigational product.
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End point type |
Secondary
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End point timeframe |
Over 12-week treatment period
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| Notes [19] - Not all subjects in the mITT population had data for this outcome. [20] - Not all subjects in the mITT population had data for this outcome. |
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| No statistical analyses for this end point | |||||||||||||
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Adverse events information
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Timeframe for reporting adverse events |
Baseline up to Week 12
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Assessment type |
Non-systematic | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Dictionary used for adverse event reporting
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Dictionary name |
MedDRA | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
16.1
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Reporting groups
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Reporting group title |
Placebo
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Reporting group description |
Placebo matched to Prucalopride tablet orally once daily. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Prucalopride
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Reporting group description |
Prucalopride 2 mg tablet orally once daily for subjects ≥18 to <65 years; 1 mg once daily orally for subjects ≥65 years, and in case of insufficient response, increased to 2 mg once daily orally at Week 2 or Week 4. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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| Frequency threshold for reporting non-serious adverse events: 5% | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Substantial protocol amendments (globally) |
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| Were there any global substantial amendments to the protocol? Yes | |||
Date |
Amendment |
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04 Apr 2011 |
1. A colonoscopy/sigmoidoscopy was added at the Screening Visit (Visit 1) in subjects for which organic disorders needed to be ruled out (these subjects had a 4-week Run-in Period)
2. Study duration was prolonged up to 16 weeks to allow for a possible 4-week Run-in Period
3. Inclusion criterion was reworded to specify that subjects with a history of on average less than or equal to 2 SBM/week that resulted in a feeling of complete evacuation were to be excluded
4. Subjects with insulin-dependent diabetes mellitus should always be excluded, also if they were under appropriate medical therapy. In addition, for all other conditions listed in this exclusion criterion, the following was added: if a subject was experiencing chronic constipation prior to the onset of the condition and the constipation had not been worsened by the condition, the subject was eligible for screening. However, if the constipation had started after the onset of the condition and the relation between both could not be excluded (it was not certain whether it was secondary to it or not), or when the constipation had worsened after the onset of 1 of the above conditions, the subject was not allowed to be screened for this study
5. Summarized information on excluded conditions of the gastrointestinal tract. In addition, it was specified in which circumstances an endoscopy or radiologic bowel evaluation was required
6. An exclusion criterion was added to exclude subjects who previously used prucalopride
7. It was clarified that serious adverse events needed to be reported within 1 working day (instead of within 24 hours) |
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11 Aug 2011 |
1. Exclusion Criterion was reworded to reflect clinical practice and to allow for clinical judgment in those instances when a repeat procedure would be indicated. Colonoscopy and/or sigmoidoscopy with or without barium enema (depending on age) was performed in this study to prevent subjects from being randomized into the study with primarily obstructive or inflammatory disease as the cause of constipation. A procedure within 5 years was sufficient to screen subjects for serious colonic disease and to remove polyps. In clinical practice, removal of a polyp would not warrant repeat colonoscopy prior to a 5-year time point unless there were special circumstances
2. Updated from milligram per deciliter to micromole per liter, to reflect the current International System of Units for serum creatinine concentration. Also, the creatinine clearance cut-off was changed from 50 milliliter per minute (mL/min) to 30 mL/min to be in line with the Summary of Product Characteristics which mentions that subjects with severe renal impairment (creatinine clearance less than or equal to 30mL/min) had to start at a dose of 1 mg
3. Subjects could not be rescreened without prior approval from the sponsor
4. It was clarified that subjects received 1 package of bisacodyl at the Screening Visit (Visit 1) and from then on, they received bisacodyl as required
5. The timing of dosing was specified in Dose Regimen and Administration Period and instructions were added on what to do in case of a missed dose
6. The relatedness categories were updated to the dichotomized categories “related” (includes very likely, probably, and possibly related) and “not related” (includes doubtful and not related)
6. The time period prior to the start of investigational product during which no bisacodyl could be used was changed from “48 hours before the start of the Double-blind Treatment (Visit)” to “24 hours before the start of Double-blind Treatment (morning after Visit 2)" |
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Interruptions (globally) |
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| Were there any global interruptions to the trial? No | |||
Limitations and caveats |
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| Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data. | |||
| None reported | |||
