Clinical Trial Results:
A 12-week, randomised, double-blind, placebo-controlled trial to evaluate the efficacy and safety of prucalopride in subjects with chronic non-cancer pain suffering from opioid induced constipation
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Summary
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EudraCT number |
2009-015652-20 |
Trial protocol |
BE PL DE CZ FR NL BG GB ES HU |
Global end of trial date |
13 Aug 2012
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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 |
31 May 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 |
M0001-C301/SPD555-301
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Additional study identifiers
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ISRCTN number |
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US NCT number |
NCT01117051 | ||
WHO universal trial number (UTN) |
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Sponsors
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Sponsor organisation name |
Shire-Movetis NV
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Sponsor organisation address |
B-2300 Turnhout, Veedijk, Belgium, 58 (1004)
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Public contact |
Shire-Movetis Clinical Trials, Shire-Movetis NV, +32 14404390, Shire-Movetis.clinicaltrials@shire.com
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Scientific contact |
Shire-Movetis Clinical Trials, Shire-Movetis NV, +32 14404390, Shire-Movetis.clinicaltrials@shire.com
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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 |
13 Aug 2012
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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 |
13 Aug 2012
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Was the trial ended prematurely? |
Yes
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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 subjects aged 18 years and older with chronic non-cancer pain, suffering from opioid-induced constipation (OIC).
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Protection of trial subjects |
This study was conducted in accordance with International Conference on Harmonisation (ICH) Good Clinical Practice. The subject’s informed consent was obtained in writing prior to performing any study-related procedures. Subjects were allowed to take a laxative (bisacodyl DULCOLAX®; Boehringer-Ingelheim) as rescue medication throughout the study, but only if they had not had a bowel movement (BM) in the preceding 48 hours.
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Background therapy |
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Evidence for comparator |
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Actual start date of recruitment |
19 May 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: 1
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Country: Number of subjects enrolled |
Poland: 11
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Country: Number of subjects enrolled |
Romania: 11
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Country: Number of subjects enrolled |
United Kingdom: 27
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Country: Number of subjects enrolled |
Belgium: 17
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Country: Number of subjects enrolled |
Bulgaria: 9
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Country: Number of subjects enrolled |
Czech Republic: 78
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Country: Number of subjects enrolled |
France: 4
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Country: Number of subjects enrolled |
Germany: 13
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Country: Number of subjects enrolled |
Hungary: 3
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Worldwide total number of subjects |
174
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EEA total number of subjects |
174
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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) |
132
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From 65 to 84 years |
42
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85 years and over |
0
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Recruitment
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Recruitment details |
- | ||||||||||||||||||||||||||||||||||||
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Pre-assignment
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Screening details |
Subjects were screened and entered a 2-week Run-in Period (or a 3-week Run-in Period if the subject was using agents that influence bowel habit) during which the presence and severity of opioid-induced constipation (OIC) was documented (the subject completed an e-diary). | ||||||||||||||||||||||||||||||||||||
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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 | ||||||||||||||||||||||||||||||||||||
Blinding implementation details |
Placebo matched investigational product.
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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 |
Subjects received placebo once daily before breakfast for up to 12 weeks. | ||||||||||||||||||||||||||||||||||||
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 |
Tablet
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Routes of administration |
Oral use
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Dosage and administration details |
Matching placebo was administered once daily before breakfast for 12 weeks. Adult subjects ≥18 to <65 years of age took a placebo tablet matching a 2mg prucalopride tablet. Elderly subjects ≥65 years took a placebo tablet matching a 1mg prucalopride tablet. In case of insufficient response, defined as an average of <3 spontaneous bowel movements (SBM)/week during the preceding 2 weeks of treatment at Week 2 or Week 4, the daily dose had to be increased to one placebo tablet matching a 2mg prucalopride tablet. Once the placebo dose was increased to match 2mg once daily the subject stayed on this dose for the remainder of the study. Further increases or decreases in dose were not permitted, ie, no changes in dose occurred at the Week 8 visit or thereafter.
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Arm title
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Prucalopride | ||||||||||||||||||||||||||||||||||||
Arm description |
Participants received prucalopride once daily before breakfast for up to 12 weeks. | ||||||||||||||||||||||||||||||||||||
Arm type |
Experimental | ||||||||||||||||||||||||||||||||||||
Investigational medicinal product name |
Prucalopride
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Tablet
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Routes of administration |
Oral use
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Dosage and administration details |
Prucalopride was administered once daily before breakfast for 12 weeks. Adult subjects ≥18 to <65 years of age took one 2mg tablet. Elderly subjects ≥65 years took one 1mg tablet. In case of insufficient response, defined as an average of <3 spontaneous bowel movements (SBM)/week during the preceding 2 weeks of treatment at Week 2 or Week 4, the daily dose had to be increased to one 2mg tablet. Once the dose was increased to 2mg once daily the subject stayed on this dose for the remainder of the study. Further increases or decreases in dose were not permitted, ie, no changes in dose occurred at the Week 8 visit or thereafter.
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Baseline characteristics reporting groups
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Reporting group title |
Placebo
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Reporting group description |
Subjects received placebo once daily before breakfast for up to 12 weeks. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Prucalopride
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Reporting group description |
Participants received prucalopride once daily before breakfast for up to 12 weeks. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
Placebo
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Reporting group description |
Subjects received placebo once daily before breakfast for up to 12 weeks. | ||
Reporting group title |
Prucalopride
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Reporting group description |
Participants received prucalopride once daily before breakfast for up to 12 weeks. | ||
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End point title |
Percent of Subjects With an Average Frequency of >=3 Spontaneous Bowel Movements (SBM) Per Week | ||||||||||||
End point description |
A bowel movement (BM) was defined as spontaneous if no laxatives were taken in the 24 hours preceding that BM.
This end point analysed the Intent-to-Treat (ITT) population, defined as all subjects who were randomised into the study and who had received at least 1 dose of investigational medication.
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End point type |
Primary
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End point timeframe |
12 weeks
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Statistical analysis title |
Analysis of SBM | ||||||||||||
Comparison groups |
Placebo v Prucalopride
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Number of subjects included in analysis |
169
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Analysis specification |
Pre-specified
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Analysis type |
superiority | ||||||||||||
P-value |
= 0.305 | ||||||||||||
Method |
Cochran-Mantel-Haenszel | ||||||||||||
Confidence interval |
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End point title |
Plasma Concentration of Prucalopride at Week 2 [1] | ||||||||||||
End point description |
This end point analysed the ITT population, defined as all subjects who were randomised into the study and who had received at least 1 dose of investigational medication. Subjects in the ITT whose post-dose samples were collected outside the 5-hour sampling window were not used in the plasma concentration calculation.
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End point type |
Secondary
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End point timeframe |
Week 2
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| Notes [1] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: This is a subgroup analysis of the Prucalopride treatment arm. Prucalopride concentration was not assessed for subjects who received placebo. |
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| No statistical analyses for this end point | |||||||||||||
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End point title |
Plasma Concentration of Prucalopride at Week 8 [2] | ||||||||||||
End point description |
This end point analysed the ITT population, defined as all subjects who were randomised into the study and who had received at least 1 dose of investigational medication. Subjects in the ITT whose post-dose samples were collected outside the 5-hour sampling window were not used in the plasma concentration calculation.
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End point type |
Secondary
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End point timeframe |
Week 8
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| Notes [2] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: This is a subgroup analysis of the Prucalopride treatment arm. Prucalopride concentration was not assessed for subjects who received placebo. |
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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 |
12 weeks
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Adverse event reporting additional description |
AEs were assessed for the Safety Population, defined as all subjects who were randomised into the study and who had received at least 1 dose of investigational product.
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Assessment type |
Systematic | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Dictionary used for adverse event reporting
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Dictionary name |
MedDRA | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
12.1
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Reporting groups
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Reporting group title |
Placebo
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Reporting group description |
Subjects received placebo once daily before breakfast for up to 12 weeks. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Prucalopride
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Reporting group description |
Participants received prucalopride once daily before breakfast for up to 12 weeks. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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| Frequency threshold for reporting non-serious adverse events: 2% | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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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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23 Apr 2010 |
The following changes were made to the protocol:
* Exclusion criterion 4: Intestinal perforation was added as an organic disorder of the large bowel
* Exclusion criterion 10: In the following phrase “serum creatinine concentration greater than 2mg/dL (<180micromole/L)”, the “180micromole/L” was deleted
* The following was added to the list of prohibitions and restrictions “Women of childbearing potential should be instructed that in case of severe diarrhoea, the efficacy of oral contraceptives may be reduced and the use of an additional contraceptive method is recommended to prevent possible failure of oral contraception (see the prescribing information of the oral contraceptive).” |
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19 May 2011 |
Protocol Amendment 2: The pharmacovigilance reporting methods were changed in order to be in line with the sponsor’s procedures. |
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13 Jan 2012 |
Protocol Amendment 3:The main reason for this protocol amendment was the lowering of the planned number of subjects to be included in the study from 510 (255 in each treatment arm) to 342 (171 in each treatment arm). Furthermore, several changes were made in order to clarify that it should be included in the subject’s medical history in case he/she was lactose intolerant. All subjects with lactose intolerance had to strictly adhere to their diet during the entire study (added to the list of prohibitions and restrictions in Section 3.9) since in subjects with lactose intolerance low doses of lactose could lead to diarrhea (added to Exclusion Criterion 14).
In addition, the following changes were made:
* Exclusion criterion 4: the wording was changed to clarify that subjects with “insulin-dependent diabetes mellitus, even if adequately controlled” were excluded
* Exclusion criterion 10: the serum creatinine lower limit concentration was changed from 2mg/dL to 180micromole/L and the calculated creatinine clearance was changed from 50 to </= 30mL/min
* Additional exclusion criterion 16 “subjects who previously used prucalopride” was added
* It was clarified in the section on screening failures that these subjects could not be rescreened without prior approval from the sponsor
* A paragraph was added to the section on dose regimen and administration period (Section 4.5.1) on what subjects had to do in case they forgot to take their daily dose of investigational product in the morning
* The definition of overdose was added to the section of overdose management (Section 4.5.5)
* In the section on sample size (Section 6.1), the 2-sided significance level was changed from 1 to 5%. |
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Interruptions (globally) |
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| Were there any global interruptions to the trial? Yes | |||||||
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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. | |||||||
| Due to the early termination of the study, results should be interpreted with caution. | |||||||
