Clinical Trial Results:
A Phase 2, Randomized, Double-blind, Placebo-controlled, Parallel group, Adaptive, Combined Proof of Concept and Dose-Finding Study to Investigate Efficacy, Safety, Pharmacodynamics and Pharmacokinetics of ASP3652 in the Treatment of Female Subjects with Bladder Pain Syndrome / Interstitial Cystitis
Summary
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EudraCT number |
2011-004555-39 |
Trial protocol |
BE NL CZ DE LV PT ES PL DK LT |
Global end of trial date |
18 Mar 2014
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Results information
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Results version number |
v2(current) |
This version publication date |
04 Jun 2016
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First version publication date |
25 Jun 2015
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Other versions |
v1 |
Version creation reason |
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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 |
3652-CL-0018
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT01613586 | ||
WHO universal trial number (UTN) |
- | ||
Sponsors
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Sponsor organisation name |
Astellas Pharma Global Development
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Sponsor organisation address |
Sylviusweg 62, Leiden, Netherlands, 2333 BE
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Public contact |
Clinical Trial Disclosure, Astellas Pharma Global Development, Astellas.resultsdisclosure@astellas.com
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Scientific contact |
Clinical Trial Disclosure, Astellas Pharma Global Development, Astellas.resultsdisclosure@astellas.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 |
18 Mar 2014
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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 |
18 Mar 2014
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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 investigate efficacy of ASP3652 in female subjects with Bladder Pain Syndrome / Interstitial Cystitis (BPS/IC).
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Protection of trial subjects |
This clinical study was written, conducted and reported in accordance with the protocol, ICH GCP
Guidelines, and applicable local regulations, including the European Directive 2001/20/EC, on the
protection of human rights, and with the ethical principles that have their origin in the Declaration of
Helsinki.
Astellas ensures that the use and disclosure of protected health information (PHI) obtained during a
research study complies with the federal and/or regional legislation related to the privacy and protection of personal information.
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Background therapy |
- | ||
Evidence for comparator |
- | ||
Actual start date of recruitment |
31 May 2012
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Long term follow-up planned |
No
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Independent data monitoring committee (IDMC) involvement? |
Yes
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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 |
Romania: 47
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Country: Number of subjects enrolled |
Russian Federation: 48
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Country: Number of subjects enrolled |
Netherlands: 10
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Country: Number of subjects enrolled |
Poland: 41
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Country: Number of subjects enrolled |
Portugal: 9
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Country: Number of subjects enrolled |
Spain: 10
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Country: Number of subjects enrolled |
Belgium: 15
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Country: Number of subjects enrolled |
Czech Republic: 45
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Country: Number of subjects enrolled |
Denmark: 7
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Country: Number of subjects enrolled |
Germany: 19
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Country: Number of subjects enrolled |
Latvia: 24
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Country: Number of subjects enrolled |
Lithuania: 12
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Worldwide total number of subjects |
287
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EEA total number of subjects |
239
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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 |
65
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85 years and over |
0
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Recruitment
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Recruitment details |
- | |||||||||||||||||||||||||||||||||||||||||||||
Pre-assignment
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Screening details |
During the 3-week run-in period, patients were treated with single-blind placebo (3 tablets twice a day). To be eligible for randomization, the mean daily pain (MDP) score had to be at least 4.0 on an 11-point numerical rating scale from 0-10. | |||||||||||||||||||||||||||||||||||||||||||||
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, Assessor | |||||||||||||||||||||||||||||||||||||||||||||
Blinding implementation details |
Allocation: Randomised 1:1:1:1 for burn-in period of 40 subjects; thereafter Bayesian adaptive allocation based on monthly interim analyses.
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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 took three matching placebo tablets twice a day for 12 weeks, followed by a 2-week follow-up period. | |||||||||||||||||||||||||||||||||||||||||||||
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 |
Administered orally twice a day.
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Arm title
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ASP3652 50 mg BID | |||||||||||||||||||||||||||||||||||||||||||||
Arm description |
Subjects took two 25 mg ASP3652 tablets and one placebo tablet twice a day (BID) for 12 weeks, followed by a 2-week follow-up period. | |||||||||||||||||||||||||||||||||||||||||||||
Arm type |
Experimental | |||||||||||||||||||||||||||||||||||||||||||||
Investigational medicinal product name |
ASP3652
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Investigational medicinal product code |
ASP3652
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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 |
Administered orally twice a day.
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Arm title
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ASP3652 150 mg BID | |||||||||||||||||||||||||||||||||||||||||||||
Arm description |
Subjects took two 25 mg and one 100 mg ASP3652 tablet twice a day for 12 weeks, followed by a 2-week follow-up period. | |||||||||||||||||||||||||||||||||||||||||||||
Arm type |
Experimental | |||||||||||||||||||||||||||||||||||||||||||||
Investigational medicinal product name |
ASP3652
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Investigational medicinal product code |
ASP3652
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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 |
Administered orally twice a day.
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Arm title
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ASP3652 300 mg BID | |||||||||||||||||||||||||||||||||||||||||||||
Arm description |
Subjects took three 100 mg ASP3652 tablets twice a day for 12 weeks, followed by a 2-week follow-up period. | |||||||||||||||||||||||||||||||||||||||||||||
Arm type |
Experimental | |||||||||||||||||||||||||||||||||||||||||||||
Investigational medicinal product name |
ASP3652
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Investigational medicinal product code |
ASP3652
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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 |
Administered orally twice a day.
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Baseline characteristics reporting groups
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Reporting group title |
Placebo
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Reporting group description |
Subjects took three matching placebo tablets twice a day for 12 weeks, followed by a 2-week follow-up period. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
ASP3652 50 mg BID
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Reporting group description |
Subjects took two 25 mg ASP3652 tablets and one placebo tablet twice a day (BID) for 12 weeks, followed by a 2-week follow-up period. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
ASP3652 150 mg BID
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Reporting group description |
Subjects took two 25 mg and one 100 mg ASP3652 tablet twice a day for 12 weeks, followed by a 2-week follow-up period. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
ASP3652 300 mg BID
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Reporting group description |
Subjects took three 100 mg ASP3652 tablets twice a day for 12 weeks, followed by a 2-week follow-up period. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
Placebo
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Reporting group description |
Subjects took three matching placebo tablets twice a day for 12 weeks, followed by a 2-week follow-up period. | ||
Reporting group title |
ASP3652 50 mg BID
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Reporting group description |
Subjects took two 25 mg ASP3652 tablets and one placebo tablet twice a day (BID) for 12 weeks, followed by a 2-week follow-up period. | ||
Reporting group title |
ASP3652 150 mg BID
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Reporting group description |
Subjects took two 25 mg and one 100 mg ASP3652 tablet twice a day for 12 weeks, followed by a 2-week follow-up period. | ||
Reporting group title |
ASP3652 300 mg BID
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Reporting group description |
Subjects took three 100 mg ASP3652 tablets twice a day for 12 weeks, followed by a 2-week follow-up period. |
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End point title |
Change from Baseline to End of Treatment in Mean Daily Pain (MDP) | ||||||||||||||||||||
End point description |
The MDP is the mean of the 7 daily consecutive pain measurements, i.e. the mean of the 7 daily consecutive scores of item 4 of the Female GenitoUrinary Pain Index (F-GUPI)-24h, recorded in the last week prior to Baseline and Week 12. The F-GUPI-24h is a validated instrument for evaluating symptoms of BPS/IC. Item 4 in the F-GUPI-24h rates the average pain over the past 24 hours on an 11-point numerical rating scale (NRS) ranging from 0 (no pain) to 10 (pain as bad as you can imagine).
This endpoint was analyzed using a Bayesian longitudinal dose-response model. In the table below, the row for "arithmetic mean (standard deviation)" is actually summarizing the posterior mean change from Baseline to end of treatment (EoT) and corresponding standard deviation.
For subjects who withdrew due to an adverse event, the change from baseline to EoT in MDP score was set to 0.
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End point type |
Primary
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End point timeframe |
Baseline and Week 12
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Notes [1] - Full analysis set with available baseline data [2] - Full analysis set with available baseline data [3] - Full analysis set with available baseline data [4] - Full analysis set with available baseline data |
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Statistical analysis title |
Bayesian Analysis | ||||||||||||||||||||
Statistical analysis description |
A Bayesian longitudinal dose-response model was used to model changes from baseline to end of treatment in MDP score. The posterior difference versus placebo and 95% credibility interval are presented, along with the posterior probability of the dose group being the maximum effective dose.
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Comparison groups |
Placebo v ASP3652 50 mg BID
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Number of subjects included in analysis |
123
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Analysis specification |
Pre-specified
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Analysis type |
other | ||||||||||||||||||||
P-value |
= 0.183 [5] | ||||||||||||||||||||
Method |
Bayesian longitudinal dose-response mode | ||||||||||||||||||||
Parameter type |
Posterior difference versus placebo | ||||||||||||||||||||
Point estimate |
0.23
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Confidence interval |
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level |
95% | ||||||||||||||||||||
sides |
2-sided
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lower limit |
-0.54 | ||||||||||||||||||||
upper limit |
1 | ||||||||||||||||||||
Variability estimate |
Standard deviation
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Dispersion value |
0.395
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Notes [5] - Posterior probability of maximum effective dose |
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Statistical analysis title |
Bayesian Analysis | ||||||||||||||||||||
Statistical analysis description |
A Bayesian longitudinal dose-response model was used to model changes from baseline to end of treatment in MDP score. The posterior difference versus placebo and 95% credibility interval are presented, along with the posterior probability of the dose group being the maximum effective dose.
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Comparison groups |
Placebo v ASP3652 150 mg BID
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Number of subjects included in analysis |
126
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Analysis specification |
Pre-specified
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Analysis type |
other | ||||||||||||||||||||
P-value |
= 0.231 [6] | ||||||||||||||||||||
Method |
Bayesian longitudinal dose-response mode | ||||||||||||||||||||
Parameter type |
Posterior difference versus placebo | ||||||||||||||||||||
Point estimate |
0.15
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Confidence interval |
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level |
95% | ||||||||||||||||||||
sides |
2-sided
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lower limit |
-0.59 | ||||||||||||||||||||
upper limit |
0.9 | ||||||||||||||||||||
Variability estimate |
Standard deviation
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Dispersion value |
0.379
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Notes [6] - Posterior probability of maximum effective dose |
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Statistical analysis title |
Bayesian Analysis | ||||||||||||||||||||
Statistical analysis description |
A Bayesian longitudinal dose-response model was used to model changes from baseline to end of treatment in MDP score. The posterior difference versus placebo and 95% credibility interval are presented, along with the posterior probability of the dose group being the maximum effective dose.
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Comparison groups |
Placebo v ASP3652 300 mg BID
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Number of subjects included in analysis |
163
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Analysis specification |
Pre-specified
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Analysis type |
other | ||||||||||||||||||||
P-value |
= 0.586 [7] | ||||||||||||||||||||
Method |
Bayesian longitudinal dose-response mode | ||||||||||||||||||||
Parameter type |
Posterior difference versus placebo | ||||||||||||||||||||
Point estimate |
-0.02
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Confidence interval |
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level |
95% | ||||||||||||||||||||
sides |
2-sided
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lower limit |
-0.7 | ||||||||||||||||||||
upper limit |
0.66 | ||||||||||||||||||||
Variability estimate |
Standard deviation
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Dispersion value |
0.349
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Notes [7] - Posterior probability of maximum effective dose |
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End point title |
Change from Baseline to End of Treatment in F-GUPI Total Score | ||||||||||||||||||||
End point description |
The Female GenitoUrinary Pain Index (F-GUPI) is a validated instrument used to assess symptoms in women with genitourinary pain complaints. The F-GUPI combines aspects of the 3 most important symptom domains of BPS/IC with a recall period of one week:
- Pain subscale: comprises 4 questions (Items 1 to 4) on location, symptomatology, frequency and severity;
- Voiding problems/Urinary subscale: comprises 2 questions (Items 5 and 6) on irritative and obstructive symptoms;
- Effects on the quality of life (QoL): comprises 3 questions (Items 7 to 9) on impact.
The F-GUPI Total score ranges from 0 to 45 with higher scores indicating increasing disease activity.
This endpoint was analyzed using a Bayesian longitudinal dose-response model. In the table below, the
data are summarizing the posterior mean change from Baseline to EoT and corresponding standard deviation.
For subjects who withdrew due to an adverse event, the change from baseline to EoT was set to 0.
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End point type |
Secondary
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End point timeframe |
Baseline and Week 12
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Notes [8] - Full analysis set with available baseline data [9] - Full analysis set with available baseline data [10] - Full analysis set with available baseline data [11] - Full analysis set with available baseline data |
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Statistical analysis title |
Bayesian Analysis | ||||||||||||||||||||
Statistical analysis description |
A Bayesian longitudinal dose-response model was used to model changes from baseline to end of
treatment in F-GUPI total score. The posterior difference versus placebo and 95% credibility interval are
presented, along with the posterior probability of the dose group being the maximum effective dose.
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Comparison groups |
Placebo v ASP3652 50 mg BID
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Number of subjects included in analysis |
123
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Analysis specification |
Pre-specified
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Analysis type |
other | ||||||||||||||||||||
P-value |
= 0.28 | ||||||||||||||||||||
Method |
Bayesian longitudinal dose-response mode | ||||||||||||||||||||
Parameter type |
Posterior difference versus placebo | ||||||||||||||||||||
Point estimate |
0.9
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Confidence interval |
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level |
95% | ||||||||||||||||||||
sides |
2-sided
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lower limit |
-1.9 | ||||||||||||||||||||
upper limit |
3.8 | ||||||||||||||||||||
Variability estimate |
Standard deviation
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Dispersion value |
1.43
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Statistical analysis title |
Bayesian Analysis | ||||||||||||||||||||
Statistical analysis description |
A Bayesian longitudinal dose-response model was used to model changes from baseline to end of
treatment in F-GUPI total score. The posterior difference versus placebo and 95% credibility interval are
presented, along with the posterior probability of the dose group being the maximum effective dose.
|
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Comparison groups |
Placebo v ASP3652 150 mg BID
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Number of subjects included in analysis |
124
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Analysis specification |
Pre-specified
|
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Analysis type |
other | ||||||||||||||||||||
P-value |
= 0.143 | ||||||||||||||||||||
Method |
Bayesian longitudinal dose-response mode | ||||||||||||||||||||
Parameter type |
Posterior difference versus placebo | ||||||||||||||||||||
Point estimate |
1
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Confidence interval |
|||||||||||||||||||||
level |
95% | ||||||||||||||||||||
sides |
2-sided
|
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lower limit |
-1.6 | ||||||||||||||||||||
upper limit |
3.8 | ||||||||||||||||||||
Variability estimate |
Standard deviation
|
||||||||||||||||||||
Dispersion value |
1.38
|
||||||||||||||||||||
Statistical analysis title |
Bayesian Analysis | ||||||||||||||||||||
Statistical analysis description |
A Bayesian longitudinal dose-response model was used to model changes from baseline to end of
treatment in F-GUPI total score. The posterior difference versus placebo and 95% credibility interval are
presented, along with the posterior probability of the dose group being the maximum effective dose.
|
||||||||||||||||||||
Comparison groups |
Placebo v ASP3652 300 mg BID
|
||||||||||||||||||||
Number of subjects included in analysis |
163
|
||||||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||||||
Analysis type |
other | ||||||||||||||||||||
P-value |
= 0.577 | ||||||||||||||||||||
Method |
Bayesian longitudinal dose-response mode | ||||||||||||||||||||
Parameter type |
Posterior difference versus placebo | ||||||||||||||||||||
Point estimate |
0.4
|
||||||||||||||||||||
Confidence interval |
|||||||||||||||||||||
level |
95% | ||||||||||||||||||||
sides |
2-sided
|
||||||||||||||||||||
lower limit |
-2.1 | ||||||||||||||||||||
upper limit |
3 | ||||||||||||||||||||
Variability estimate |
Standard deviation
|
||||||||||||||||||||
Dispersion value |
1.29
|
|
|||||||||||||||||||||
End point title |
Change from Baseline to End of Treatment in F-GUPI Pain Domain Score | ||||||||||||||||||||
End point description |
The Female GenitoUrinary Pain Index (F-GUPI) is a validated instrument used to assess the degree of symptoms in women with genitourinary pain complaints. The pain subscale comprises 4 questions (Items 1 to 4) on location, symptomatology, frequency and severity, with a recall period of one week. The pain subscale score ranges from 0 to 23 where higher scores indicate increasing pain.
Least squares (LS) means were generated from an analysis of covariance (ANCOVA) model with treatment group and country as factors and the Baseline value as a covariate.
Last observation carried forward (LOCF) imputation was used; for subjects who withdrew due to an adverse event, change from baseline to EoT was set to 0.
|
||||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||||
End point timeframe |
Baseline and Week 12
|
||||||||||||||||||||
|
|||||||||||||||||||||
Notes [12] - Full analysis set with available baseline data [13] - Full analysis set with available baseline data [14] - Full analysis set with available baseline data [15] - Full analysis set with available baseline data |
|||||||||||||||||||||
Statistical analysis title |
Frequentist Analysis | ||||||||||||||||||||
Statistical analysis description |
The F-GUPI pain domain score was analyzed in an analysis of covariance (ANCOVA) model with treatment group and country as factors and baseline value as covariate.
|
||||||||||||||||||||
Comparison groups |
Placebo v ASP3652 50 mg BID
|
||||||||||||||||||||
Number of subjects included in analysis |
123
|
||||||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||||||
Analysis type |
superiority | ||||||||||||||||||||
Method |
|||||||||||||||||||||
Parameter type |
LS mean difference vs placebo | ||||||||||||||||||||
Point estimate |
0
|
||||||||||||||||||||
Confidence interval |
|||||||||||||||||||||
level |
95% | ||||||||||||||||||||
sides |
2-sided
|
||||||||||||||||||||
lower limit |
-1.6 | ||||||||||||||||||||
upper limit |
1.6 | ||||||||||||||||||||
Variability estimate |
Standard error of the mean
|
||||||||||||||||||||
Dispersion value |
0.79
|
||||||||||||||||||||
Statistical analysis title |
Frequentist Analysis | ||||||||||||||||||||
Statistical analysis description |
The F-GUPI pain domain score was analyzed in an analysis of covariance (ANCOVA) model with treatment group and country as factors and baseline value as covariate.
|
||||||||||||||||||||
Comparison groups |
Placebo v ASP3652 150 mg BID
|
||||||||||||||||||||
Number of subjects included in analysis |
124
|
||||||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||||||
Analysis type |
superiority | ||||||||||||||||||||
Method |
|||||||||||||||||||||
Parameter type |
LS mean difference vs placebo | ||||||||||||||||||||
Point estimate |
0.7
|
||||||||||||||||||||
Confidence interval |
|||||||||||||||||||||
level |
95% | ||||||||||||||||||||
sides |
2-sided
|
||||||||||||||||||||
lower limit |
-0.8 | ||||||||||||||||||||
upper limit |
2.3 | ||||||||||||||||||||
Variability estimate |
Standard error of the mean
|
||||||||||||||||||||
Dispersion value |
0.78
|
||||||||||||||||||||
Statistical analysis title |
Frequentist Analysis | ||||||||||||||||||||
Statistical analysis description |
The F-GUPI pain domain score was analyzed in an analysis of covariance (ANCOVA) model with treatment group and country as factors and baseline value as covariate.
|
||||||||||||||||||||
Comparison groups |
Placebo v ASP3652 300 mg BID
|
||||||||||||||||||||
Number of subjects included in analysis |
163
|
||||||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||||||
Analysis type |
superiority | ||||||||||||||||||||
Method |
|||||||||||||||||||||
Parameter type |
LS mean difference vs placebo | ||||||||||||||||||||
Point estimate |
-0.3
|
||||||||||||||||||||
Confidence interval |
|||||||||||||||||||||
level |
95% | ||||||||||||||||||||
sides |
2-sided
|
||||||||||||||||||||
lower limit |
-1.6 | ||||||||||||||||||||
upper limit |
1 | ||||||||||||||||||||
Variability estimate |
Standard error of the mean
|
||||||||||||||||||||
Dispersion value |
0.67
|
|
|||||||||||||||||||||
End point title |
Change from Baseline to End of Treatment in Mean Number of Micturitions per 24 Hours | ||||||||||||||||||||
End point description |
The average number of micturitions (urinations) per 24 hours was derived from the number of times a subject urinated (excluding incontinence only episodes) per day as recorded by the subject in a micturition diary for 3 days prior to the Baseline and Week 12 clinic visits. LS means were generated from an ANCOVA model with treatment group and country as factors and the Baseline value as a covariate. Last observation carried forward imputation was used.
|
||||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||||
End point timeframe |
Baseline and Week 12
|
||||||||||||||||||||
|
|||||||||||||||||||||
Notes [16] - Full analysis set with available Baseline data [17] - Full analysis set with available Baseline data [18] - Full analysis set with available Baseline data [19] - Full analysis set with available Baseline data |
|||||||||||||||||||||
Statistical analysis title |
Frequentist Analysis | ||||||||||||||||||||
Statistical analysis description |
The change from baseline in the number of micturitions per 24 hours was analyzed in an analysis of covariance (ANCOVA) model with treatment group and country as factors and baseline value as covariate.
|
||||||||||||||||||||
Comparison groups |
Placebo v ASP3652 50 mg BID
|
||||||||||||||||||||
Number of subjects included in analysis |
115
|
||||||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||||||
Analysis type |
superiority | ||||||||||||||||||||
Method |
|||||||||||||||||||||
Parameter type |
LS Mean difference vs placebo | ||||||||||||||||||||
Point estimate |
2.08
|
||||||||||||||||||||
Confidence interval |
|||||||||||||||||||||
level |
95% | ||||||||||||||||||||
sides |
2-sided
|
||||||||||||||||||||
lower limit |
0.02 | ||||||||||||||||||||
upper limit |
4.15 | ||||||||||||||||||||
Variability estimate |
Standard error of the mean
|
||||||||||||||||||||
Dispersion value |
1.046
|
||||||||||||||||||||
Statistical analysis title |
Frequentist Analysis | ||||||||||||||||||||
Statistical analysis description |
The change from baseline in the number of micturitions per 24 hours was analyzed in an analysis of covariance (ANCOVA) model with treatment group and country as factors and baseline value as covariate.
|
||||||||||||||||||||
Comparison groups |
Placebo v ASP3652 150 mg BID
|
||||||||||||||||||||
Number of subjects included in analysis |
120
|
||||||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||||||
Analysis type |
superiority | ||||||||||||||||||||
Method |
|||||||||||||||||||||
Parameter type |
LS Mean difference vs placebo | ||||||||||||||||||||
Point estimate |
0.36
|
||||||||||||||||||||
Confidence interval |
|||||||||||||||||||||
level |
95% | ||||||||||||||||||||
sides |
2-sided
|
||||||||||||||||||||
lower limit |
-1.62 | ||||||||||||||||||||
upper limit |
2.35 | ||||||||||||||||||||
Variability estimate |
Standard error of the mean
|
||||||||||||||||||||
Dispersion value |
1.007
|
||||||||||||||||||||
Statistical analysis title |
Frequentist Analysis | ||||||||||||||||||||
Statistical analysis description |
The change from baseline in the number of micturitions per 24 hours was analyzed in an analysis of covariance (ANCOVA) model with treatment group and country as factors and baseline value as covariate.
|
||||||||||||||||||||
Comparison groups |
Placebo v ASP3652 300 mg BID
|
||||||||||||||||||||
Number of subjects included in analysis |
158
|
||||||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||||||
Analysis type |
superiority | ||||||||||||||||||||
Method |
|||||||||||||||||||||
Parameter type |
LS Mean difference vs placebo | ||||||||||||||||||||
Point estimate |
0.83
|
||||||||||||||||||||
Confidence interval |
|||||||||||||||||||||
level |
95% | ||||||||||||||||||||
sides |
2-sided
|
||||||||||||||||||||
lower limit |
-0.89 | ||||||||||||||||||||
upper limit |
2.55 | ||||||||||||||||||||
Variability estimate |
Standard error of the mean
|
||||||||||||||||||||
Dispersion value |
0.873
|
|
|||||||||||||||||||||||||||||||||||||||||
End point title |
Change from Baseline in MDP Scores at Weeks 4, 8, 12 and at Follow-up | ||||||||||||||||||||||||||||||||||||||||
End point description |
The MDP is the mean of the 7 daily consecutive pain measurements, i.e. the mean of the 7 daily
consecutive scores of item 4 of the Female GenitoUrinary Pain Index (F-GUPI)-24h, recorded in the last
week prior to Baseline and Week 12. The F-GUPI-24h is a validated instrument for evaluating symptoms
of BPS/IC. Item 4 in the F-GUPI-24h rates the average pain over the past 24 hours on an 11-point
numerical rating scale ranging from 0 (no pain) to 10 (pain as bad as you can imagine).
This endpoint was analysed using the full analysis set with no imputation for missing data.
LS means were generated from an ANCOVA model with treatment group and country as factors and the Baseline value as a covariate.
|
||||||||||||||||||||||||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||||||||||||||||||||||||
End point timeframe |
Baseline and Weeks 4, 8, 12 and follow-up (2 weeks after the end of treatment)
|
||||||||||||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||||||||||||
No statistical analyses for this end point |
|
|||||||||||||||||||||||||||||||||||||||||
End point title |
Change from Baseline in F-GUPI Total Score at Weeks 4, 8, 12 and Follow-up | ||||||||||||||||||||||||||||||||||||||||
End point description |
The Female GenitoUrinary Pain Index (F-GUPI) is a validated instrument used to assess symptoms in women with genitourinary pain complaints. The F-GUPI combines aspects of the 3 most important symptom domains of BPS/IC with a recall period of one week:
- Pain subscale: comprises 4 questions (Items 1 to 4) on location, symptomatology, frequency and severity;
- Voiding problems/Urinary subscale: comprises 2 questions (Items 5 and 6) on irritative and obstructive symptoms;
- Effects on the quality of life (QoL): comprises 3 questions (Items 7 to 9) on impact.
The F-GUPI Total score ranges from 0 to 45 with higher scores indicating increasing disease activity.
This endpoint was analysed using the full analysis set with no imputation for missing data.
LS means were generated from an ANCOVA model with treatment group and country as factors and the
Baseline value as a covariate.
|
||||||||||||||||||||||||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||||||||||||||||||||||||
End point timeframe |
Baseline and Weeks 4, 8, 12 and Follow-up (2 weeks after end of treatment)
|
||||||||||||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||||||||||||
No statistical analyses for this end point |
|
|||||||||||||||||||||||||||||||||||||||||
End point title |
Change from Baseline in F-GUPI Pain Domain Score at Weeks 4, 8, 12 and Follow-Up | ||||||||||||||||||||||||||||||||||||||||
End point description |
The Female GenitoUrinary Pain Index (F-GUPI) is a validated instrument used to assess the degree of symptoms in women with genitourinary pain complaints. The pain subscale comprises 4 questions (Items 1 to 4) on location, symptomatology, frequency and severity, with a recall period of one week. The pain subscale score ranges from 0 to 23 where higher scores indicate increasing pain.
This endpoint was analysed using the full analysis set with no imputation for missing data.
LS means were generated from an ANCOVA model with treatment group and country as factors and the
Baseline value as a covariate.
|
||||||||||||||||||||||||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||||||||||||||||||||||||
End point timeframe |
Baseline and Weeks 4, 8, 12 and follow-up (2 weeks after the end of treatment)
|
||||||||||||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||||||||||||
No statistical analyses for this end point |
|
||||||||||||||||||||||||||||||||||||||||||||||
End point title |
Change from Baseline to Each Visit in F-GUPI Urinary Symptoms Score | |||||||||||||||||||||||||||||||||||||||||||||
End point description |
The Female GenitoUrinary Pain Index (F-GUPI) is a validated instrument used to assess the degree of
symptoms in women with genitourinary pain complaints. The voiding problems/urinary subscale comprises 2 questions (Items 5 and 6) on irritative and obstructive symptoms with a recall period of one week. The urinary subscale score ranges from 0 to 10, where 10 indicates worse symptoms.
This endpoint was analysed using the full analysis set with no imputation for missing data, except for End of Treatment where LOCF was used.
LS means were generated from an ANCOVA model with treatment group and country as factors and the
Baseline value as a covariate.
|
|||||||||||||||||||||||||||||||||||||||||||||
End point type |
Secondary
|
|||||||||||||||||||||||||||||||||||||||||||||
End point timeframe |
Baseline and Weeks 4, 8, 12 and follow-up (2 weeks after the end of treatment)
|
|||||||||||||||||||||||||||||||||||||||||||||
|
||||||||||||||||||||||||||||||||||||||||||||||
No statistical analyses for this end point |
|
||||||||||||||||||||||||||||||||||||||||||||||
End point title |
Change from Baseline to Each Visit in F-GUPI Quality of Life Impact Score | |||||||||||||||||||||||||||||||||||||||||||||
End point description |
The Female GenitoUrinary Pain Index (F-GUPI) is a validated instrument used to assess the degree of
symptoms in women with genitourinary pain complaints. The effects on the quality of life (QoL) subscale comprises 3 questions (Items 7 to 9) on impact with a recall period of one week. The quality of life impact subscale score ranges from 0 to 12, where 12 indicates more impact on quality of life.
This endpoint was analysed using the full analysis set with no imputation for missing data, except for
End of Treatment where LOCF was used.
LS means were generated from an ANCOVA model with treatment group and country as factors and the
Baseline value as a covariate.
|
|||||||||||||||||||||||||||||||||||||||||||||
End point type |
Secondary
|
|||||||||||||||||||||||||||||||||||||||||||||
End point timeframe |
Baseline and Weeks 4, 8, 12 and follow-up (2 weeks after the end of treatment)
|
|||||||||||||||||||||||||||||||||||||||||||||
|
||||||||||||||||||||||||||||||||||||||||||||||
No statistical analyses for this end point |
|
||||||||||||||||||||||||||||||||||||||||||||||
End point title |
Change from Baseline to Each Visit in Severity of Pain | |||||||||||||||||||||||||||||||||||||||||||||
End point description |
Severity of pain was assessed by item 4 of the F-GUPI. The F-GUPI is a validated instrument for evaluating symptoms of BPS/IC. Item 4 in the F-GUPI rates the average pain over the past week on an 11-point numerical rating scale ranging from 0 (no pain) to 10 (pain as bad as you can imagine).
This endpoint was analysed using the full analysis set with no imputation for missing data, except for
End of Treatment where LOCF was used.
LS means were generated from an ANCOVA model with treatment group and country as factors and the
Baseline value as a covariate.
|
|||||||||||||||||||||||||||||||||||||||||||||
End point type |
Secondary
|
|||||||||||||||||||||||||||||||||||||||||||||
End point timeframe |
Baseline and Weeks 4, 8, 12 and follow-up (2 weeks after the end of treatment)
|
|||||||||||||||||||||||||||||||||||||||||||||
|
||||||||||||||||||||||||||||||||||||||||||||||
No statistical analyses for this end point |
|
||||||||||||||||||||||||||||||||||||||||||||||
End point title |
Percentage of Subjects with at Least 4 Points Decrease in F-GUPI Total Score at Each Visit | |||||||||||||||||||||||||||||||||||||||||||||
End point description |
The Female GenitoUrinary Pain Index (F-GUPI) is a validated instrument used to assess symptoms in women with genitourinary pain complaints. The F-GUPI combines aspects of the 3 most important symptom domains of BPS/IC with a recall period of one week:
- Pain subscale: comprises 4 questions (Items 1 to 4) on location, symptomatology, frequency and severity;
- Voiding problems/Urinary subscale: comprises 2 questions (Items 5 and 6) on irritative and obstructive symptoms;
- Effects on the quality of life (QoL): comprises 3 questions (Items 7 to 9) on impact.
The F-GUPI Total score ranges from 0 to 45 with higher scores indicating increasing disease activity.
This endpoint was analysed using the full analysis set with no imputation for missing data, except for
End of Treatment where LOCF was used. For subjects who withdrew due to an AE, change from Baseline to EoT value is set equal to 0.
|
|||||||||||||||||||||||||||||||||||||||||||||
End point type |
Secondary
|
|||||||||||||||||||||||||||||||||||||||||||||
End point timeframe |
Baseline and Weeks 4, 8, 12 and follow-up (2 weeks after the end of treatment)
|
|||||||||||||||||||||||||||||||||||||||||||||
|
||||||||||||||||||||||||||||||||||||||||||||||
No statistical analyses for this end point |
|
||||||||||||||||||||||||||||||||||||||||||||||
End point title |
Percentage of Subjects with at Least 7 Points Decrease in F-GUPI Total Score at Each Visit | |||||||||||||||||||||||||||||||||||||||||||||
End point description |
The Female GenitoUrinary Pain Index (F-GUPI) is a validated instrument used to assess symptoms in women with genitourinary pain complaints. The F-GUPI combines aspects of the 3 most important symptom domains of BPS/IC with a recall period of one week:
- Pain subscale: comprises 4 questions (Items 1 to 4) on location, symptomatology, frequency and severity;
- Voiding problems/Urinary subscale: comprises 2 questions (Items 5 and 6) on irritative and obstructive symptoms;
- Effects on the quality of life (QoL): comprises 3 questions (Items 7 to 9) on impact.
The F-GUPI Total score ranges from 0 to 45 with higher scores indicating increasing disease activity.
This endpoint was analysed using the full analysis set with no imputation for missing data, except for
End of Treatment where LOCF was used. For subjects who withdrew due to an AE, change from Baseline to EoT value is set equal to 0.
|
|||||||||||||||||||||||||||||||||||||||||||||
End point type |
Secondary
|
|||||||||||||||||||||||||||||||||||||||||||||
End point timeframe |
Baseline and Weeks 4, 8, 12 and follow-up (2 weeks after the end of treatment)
|
|||||||||||||||||||||||||||||||||||||||||||||
|
||||||||||||||||||||||||||||||||||||||||||||||
No statistical analyses for this end point |
|
||||||||||||||||||||||||||||||||||||||||||||||
End point title |
Change from Baseline to Each Visit in Mean Daily F-GUPI-24h Total Score | |||||||||||||||||||||||||||||||||||||||||||||
End point description |
The Female GenitoUrinary Pain Index-24 hour (F-GUPI-24h) is a validated instrument used to assess symptoms in women with genitourinary pain complaints over the past 24 hours. The F-GUPI combines aspects of the 3 most important symptom domains of BPS/IC with a recall period of 24 hours:
- Pain subscale: comprises 4 questions (Items 1 to 4) on location, symptomatology, frequency and severity;
- Voiding problems/Urinary subscale: comprises 2 questions (Items 5 and 6) on irritative and obstructive symptoms;
- Effects on the quality of life (QoL): comprises 3 questions (Items 7 to 9) on impact.
The F-GUPI-24h total score ranges from 0 to 45 with higher scores indicating increasing disease activity.
This endpoint was analysed using the full analysis set with no imputation for missing data, except for
End of Treatment where LOCF was used.
LS means were generated from an ANCOVA model with treatment group and country as factors and
the Baseline value as a covariate.
|
|||||||||||||||||||||||||||||||||||||||||||||
End point type |
Secondary
|
|||||||||||||||||||||||||||||||||||||||||||||
End point timeframe |
Baseline and Weeks 4, 8, 12 and follow-up (2 weeks after the end of treatment)
|
|||||||||||||||||||||||||||||||||||||||||||||
|
||||||||||||||||||||||||||||||||||||||||||||||
No statistical analyses for this end point |
|
||||||||||||||||||||||||||||||||||||||||||||||
End point title |
Percentage of Subjects with a Successful Global Response Assessment Response at Each Visit | |||||||||||||||||||||||||||||||||||||||||||||
End point description |
Patient-assessed treatment effect was measured using a global response assessment (GRA). A self-reported 7 grade GRA was used to evaluate a patient’s clinical condition relative to Baseline (grades: markedly worse, moderately worse, slightly worse, no change, slightly improved, moderately improved or markedly improved). Successful GRA response was defined as the scores moderately improved or markedly improved disease on the patient-rated 7-point scale.
This endpoint was analysed using the full analysis set with no imputation for missing data, except for
End of Treatment where LOCF was used.
|
|||||||||||||||||||||||||||||||||||||||||||||
End point type |
Secondary
|
|||||||||||||||||||||||||||||||||||||||||||||
End point timeframe |
Baseline and Weeks 4, 8, 12 and follow-up (2 weeks after the end of treatment)
|
|||||||||||||||||||||||||||||||||||||||||||||
|
||||||||||||||||||||||||||||||||||||||||||||||
No statistical analyses for this end point |
|
|||||||||||||||||||||
End point title |
Change from Baseline to End of Treatment in Bladder Pain/Interstitial Cystitis Symptom Scale (BPIC-SS) Total Score | ||||||||||||||||||||
End point description |
The BPIC-SS questionnaire consists of eight questions concerning bladder pain over the previous seven days. Items 1 to 5 address pain and are rated from 0 (never) to 4 (always), Items 6 and 7 address the impact of bladder pain, rated from 0 (not at all) to 4 (a great deal) and Item 8 is an 11-point NRS describing the worst bladder pain experienced in the previous seven days ranging from 0 (no bladder pain) to 10 (worst possible bladder pain).
The BPIC-SS Total score ranges from 0 up to 38, with higher scores indicative of worse pain. A total score of 19 or more is taken to indicate moderate/severe disease.
This endpoint was analysed using the full analysis set; LOCF imputation was used.
LS means were generated from an ANCOVA model with treatment group and country as factors and
the Baseline value as a covariate.
|
||||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||||
End point timeframe |
Baseline and Week 12
|
||||||||||||||||||||
|
|||||||||||||||||||||
No statistical analyses for this end point |
|
|||||||||||||||||||||
End point title |
Change from Baseline to End of Treatment in BPIC-SS Worst Bladder Pain Score | ||||||||||||||||||||
End point description |
Item 8 of the BPIC-SS is an 11-point NRS describing the worst bladder pain experienced in the previous seven days. The response for this question ranges from 0 (no bladder pain) to 10 (worst possible bladder pain).
This endpoint was analysed using the full analysis set; LOCF imputation was used.
LS means were generated from an ANCOVA model with treatment group and country as factors and
the Baseline value as a covariate.
|
||||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||||
End point timeframe |
Baseline and Week 12
|
||||||||||||||||||||
|
|||||||||||||||||||||
No statistical analyses for this end point |
|
|||||||||||||||||||||
End point title |
Change from Baseline to End of Treatment in Interstitial Cystitis Symptom Index (ICSI) Total Score | ||||||||||||||||||||
End point description |
The Interstitial Cystitis Symptom Index (ICSI) consists of 4 questions which are all rated from 0 (not at all/none) to 5 (almost always):
- Frequency of strong need to urinate with little or no warning
- Needing to urinate again within two hours of urinating
- Frequency of having to get up to urinate at night
- Experience of pain or burning in the bladder
The ICSI Total score ranges from 0 to 20 and can be categorized to indicate mild (0 to 6), moderate (7 to 14), or severe (15 to 20) symptoms.
This endpoint was analysed using the full analysis set; LOCF imputation was used.
LS means were generated from an ANCOVA model with treatment group and country as factors and
the Baseline value as a covariate.
|
||||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||||
End point timeframe |
Baseline and Week 12
|
||||||||||||||||||||
|
|||||||||||||||||||||
No statistical analyses for this end point |
|
|||||||||||||||||||||
End point title |
Change from Baseline to End of Treatment in Interstitial Cystitis Problem Index (ICPI) Total Score | ||||||||||||||||||||
End point description |
The Interstitial Cystitis Problem Index (ICPI) consists of 4 questions which ask if symptoms of IC have been a problem. Responses are rated from 0 (no problem) to 4 (big problem):
- Frequency of urination
- Getting up at night to urinate
- Needing to urinate with little warning
- Burning pain, discomfort or pressure in the bladder
The ICPI Total score ranges from 0 to 16, with higher scores indicating more severe symptoms.
This endpoint was analysed using the full analysis set; LOCF imputation was used.
LS means were generated from an ANCOVA model with treatment group and country as factors and
the Baseline value as a covariate.
|
||||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||||
End point timeframe |
Baseline and Week 12
|
||||||||||||||||||||
|
|||||||||||||||||||||
No statistical analyses for this end point |
|
|||||||||||||||||||||
End point title |
Change from Baseline to End of Treatment in Short Form of the McGill Pain Questionnaire (SF-MPQ) Total Score | ||||||||||||||||||||
End point description |
The short form of the McGill pain questionnaire (SF-MPQ) asks about the sensory, affective and evaluative dimensions of pain experience. Higher scores on the SF-MPQ are indicative of more severe disease. The sensory and affective dimensions of the SF-MPQ ask the respondent how each of a set of different adjectives describe their pain over the previous week. Responses to each question range from 0 (None) to 3 (Severe).
The sum of the responses within each dimension give the SF-MPQ Sensory score (ranging from 0 to 33) and the SF-MPQ Affective score (ranging from 0 to 12). These sum of these two scores gives the SF-MPQ Total score.
This endpoint was analysed using the full analysis set; LOCF imputation was used.
LS means were generated from an ANCOVA model with treatment group and country as factors and
the Baseline value as a covariate.
|
||||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||||
End point timeframe |
Baseline and Week 12
|
||||||||||||||||||||
|
|||||||||||||||||||||
No statistical analyses for this end point |
|
|||||||||||||||||||||
End point title |
Change from Baseline to End of Treatment in Female Sexual Function Index (FSFI) Total Score | ||||||||||||||||||||
End point description |
Sexual functioning was assessed using the FSFI, a validated 19-item, self-administered questionnaire from which scores for assessing six key domains of sexual function and satisfaction can be derived. Each of the 19 items ranges from 0 or 1 (a score of 0 in some questions indicates that no sexual activity occurred in the previous month) up to a maximum of 5. The sum of the responses within each domain are added together and multiplied by a domain factor to give a domain score which can vary up to a maximum value of 6. The FSFI Total score is then calculated as the sum of the six separate domains and ranges from 2 to 36. A FSFI total score of less than or equal to 26.55 has been classified as “Female sexual Dysfunction”.
This endpoint was analysed using the full analysis set; LOCF imputation was used.
|
||||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||||
End point timeframe |
Baseline and Week 12
|
||||||||||||||||||||
|
|||||||||||||||||||||
No statistical analyses for this end point |
|
|||||||||||||||||||||||||||||||||||||||||
End point title |
Change from Baseline in Mean Number of Micturitions per 24 Hours at Weeks 4, 8, 12 and Follow-up | ||||||||||||||||||||||||||||||||||||||||
End point description |
The average number of micturitions (urinations) per 24 hours was derived from the number of times a
subject urinated (excluding incontinence only episodes) per day as recorded by the subject in a micturition diary for 3 days prior to each visit.
This endpoint was analysed using the full analysis set with no imputation for missing data.
LS means were generated from an ANCOVA model with treatment group and country as factors and
the Baseline value as a covariate.
|
||||||||||||||||||||||||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||||||||||||||||||||||||
End point timeframe |
Baseline and Weeks 4, 8, 12 and follow-up (2 weeks after the end of treatment)
|
||||||||||||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||||||||||||
No statistical analyses for this end point |
|
||||||||||||||||||||||||||||||||||||||||||||||
End point title |
Change from Baseline to Each Visit in Mean Number of Nocturia Episodes per 24 Hours | |||||||||||||||||||||||||||||||||||||||||||||
End point description |
Nocturia is defined as waking at night one or more times to void (i.e. any voiding associated with sleep
disturbance between the time the subject goes to bed with the intention to sleep until the time the subjects gets up in the morning with the intention to stay awake). A “night time” episode of incontinence only was not considered a nocturia episode. The number of nocturia episodes per 24 hours was derived from the average number of times a subject urinated during sleeping time in the 3 day prior to each visit as recorded in the micturition diary.
This endpoint was analysed using the full analysis set with no imputation for missing data, except for
End of Treatment where LOCF was used.
|
|||||||||||||||||||||||||||||||||||||||||||||
End point type |
Secondary
|
|||||||||||||||||||||||||||||||||||||||||||||
End point timeframe |
Baseline and Weeks 4, 8, 12 and follow-up (2 weeks after the end of treatment)
|
|||||||||||||||||||||||||||||||||||||||||||||
|
||||||||||||||||||||||||||||||||||||||||||||||
No statistical analyses for this end point |
|
||||||||||||||||||||||||||||||||||||||||||||||
End point title |
Change from Baseline to Each Visit in Mean Number of Urgency Episodes per 24 Hours | |||||||||||||||||||||||||||||||||||||||||||||
End point description |
Urgency is defined as the complaint of a sudden, compelling desire to pass urine, which is difficult to defer. Each episode was graded using the following 5 point scale based on Patient Perception of Intensity of Urgency Scale (PPIUS):
0 = No urgency; 1 = Mild urgency, could postpone voiding as long as necessary; 2 = Moderate urgency, could postpone voiding for a short time; 3 = Severe urgency, could not postpone voiding, had to rush to the toilet; 4 = Urge incontinence, leaked before arriving to the toilet.
The mean number of urgency episodes per 24 hours was derived from the average number of times a subject recorded an urgency episode of severity of 3 or 4 per day during the 3-day micturition diary period.
This endpoint was analysed using the full analysis set with no imputation for missing data, except for
End of Treatment where LOCF was used. LS means were generated from an ANCOVA model with treatment group and country as factors and the Baseline value as a covariate.
|
|||||||||||||||||||||||||||||||||||||||||||||
End point type |
Secondary
|
|||||||||||||||||||||||||||||||||||||||||||||
End point timeframe |
Baseline and Weeks 4, 8, 12 and follow-up (2 weeks after the end of treatment)
|
|||||||||||||||||||||||||||||||||||||||||||||
|
||||||||||||||||||||||||||||||||||||||||||||||
No statistical analyses for this end point |
|
||||||||||||||||||||||||||||||||||||||||||||||
End point title |
Change from Baseline to Each Visit in Mean Level of Urgency per Micturition | |||||||||||||||||||||||||||||||||||||||||||||
End point description |
Each episode was graded using the following 5 point scale based on Patient Perception of Intensity of
Urgency Scale (PPIUS):
0 = No urgency; 1 = Mild urgency, could postpone voiding as long as necessary; 2 = Moderate urgency, could postpone voiding for a short while; 3 = Severe urgency, could not postpone voiding, but had to rush to the toilet in order not to wet myself; 4 = Urge incontinence, leaked before arriving to the toilet.
The mean level of urgency was derived from the average severity grade recorded by the subject for each micturition, with or without incontinence, during the 3-day micturition diary period.
This endpoint was analysed using the full analysis set with no imputation for missing data, except for
End of Treatment where LOCF was used.
LS means were generated from an ANCOVA model with treatment group and country as factors and
the Baseline value as a covariate.
|
|||||||||||||||||||||||||||||||||||||||||||||
End point type |
Secondary
|
|||||||||||||||||||||||||||||||||||||||||||||
End point timeframe |
Baseline and Weeks 4, 8, 12 and follow-up (2 weeks after the end of treatment)
|
|||||||||||||||||||||||||||||||||||||||||||||
|
||||||||||||||||||||||||||||||||||||||||||||||
No statistical analyses for this end point |
|
||||||||||||||||||||||||||||||||||||||||||||||
End point title |
Change from Baseline to Each Visit in Total Urgency Score (TUS) per 24 Hours | |||||||||||||||||||||||||||||||||||||||||||||
End point description |
The total urgency score (TUS) per 24 hours is the sum of the PPIUS urgency gradings from all valid diary days recorded by the subject in the 3 days prior to each visit in the micturition diary divided by the number of valid days. Each episode was graded using the following 5 point scale based on Patient Perception of Intensity of Urgency Scale (PPIUS):
0 = No urgency; 1 = Mild urgency, could postpone voiding as long as necessary; 2 = Moderate urgency,
could postpone voiding for a short while; 3 = Severe urgency, could not postpone voiding, but had to
rush to the toilet in order not to wet myself; 4 = Urge incontinence, leaked before arriving to the toilet.
This endpoint was analysed using the full analysis set with no imputation for missing data, except for
End of Treatment where LOCF was used.
LS means were generated from an ANCOVA model with treatment group and country as factors and
the Baseline value as a covariate.
|
|||||||||||||||||||||||||||||||||||||||||||||
End point type |
Secondary
|
|||||||||||||||||||||||||||||||||||||||||||||
End point timeframe |
Baseline and Weeks 4, 8, 12 and follow-up (2 weeks after the end of treatment)
|
|||||||||||||||||||||||||||||||||||||||||||||
|
||||||||||||||||||||||||||||||||||||||||||||||
No statistical analyses for this end point |
|
|||||||||||||||||||||
End point title |
Change from Baseline to End of Treatment in European Quality of Life Visual Analogue Scale (EQ VAS) | ||||||||||||||||||||
End point description |
On the EQ visual analogue scale (EQ-VAS) the subject is asked to rate their health as a number between 0 (The worst health you can imagine) and 100 (the best health you can imagine).
This endpoint was analysed using the full analysis set; LOCF imputation was used.
LS means were generated from an ANCOVA model with treatment group and country as factors and
the Baseline value as a covariate.
|
||||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||||
End point timeframe |
Baseline and Week 12
|
||||||||||||||||||||
|
|||||||||||||||||||||
No statistical analyses for this end point |
|
|||||||||||||||||||||||||||||
End point title |
ASP3652 Plasma Concentration [20] | ||||||||||||||||||||||||||||
End point description |
The lower limit of quantification (LLOQ) of ASP3652 is 0.5 ng/ml in plasma.
Values that are below the LLOQ were set to 0. This endpoint was analysed using the Pharmacokinetics Analysis Set which comprised all subjects who received active treatment, for whom at least 1 blood sample was collected for measurement of the ASP3652 plasma concentrations, and for whom the time of sampling and the time of dosing on the day of sampling was known.
|
||||||||||||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||||||||||||
End point timeframe |
Week 4 and Week 8, 1-4 hours post morning dose, Week 12 (or end of treatment), 12-16 hours post previous evening dose
|
||||||||||||||||||||||||||||
Notes [20] - 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: Plasma concentration of ASP3652 not calculated for subjects in the placebo group. |
|||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||
No statistical analyses for this end point |
|
|||||||||||||||||||||||||||||||||||||||||
End point title |
N-arachidonoyl-ethanolamide (Anandamide) Plasma Concentration | ||||||||||||||||||||||||||||||||||||||||
End point description |
The LLOQ of N-arachidonoyl-ethanolamide is 0.05 ng/mL in plasma.
This endpoint was analysed using the Pharmacodynamic Analysis Set (PDAS) which comprised subjects who received at least 1 dose of study drug and for whom at least 1 blood sample was collected for measurement of the anandamide concentrations.
|
||||||||||||||||||||||||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||||||||||||||||||||||||
End point timeframe |
Baseline (pre-dose), Weeks 4 and 8, 1-4 hours post morning dose and Week 12 (or end of treatment), 12-16 hours post previous evening dose.
|
||||||||||||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||||||||||||
No statistical analyses for this end point |
|
|||||||||||||||||||||||||||||||||||||||||
End point title |
Oleoylethanolamide Plasma Concentration | ||||||||||||||||||||||||||||||||||||||||
End point description |
The LLOQ for oleoylethanolamide is 0.5 ng/mL in plasma.
This endpoint was analysed using the pharmacodynamics analysis set.
|
||||||||||||||||||||||||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||||||||||||||||||||||||
End point timeframe |
Baseline (pre-dose), Weeks 4 and 8, 1-4 hours post morning dose and Week 12 (or end of treatment), 12-16 hours post previous evening dose.
|
||||||||||||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||||||||||||
No statistical analyses for this end point |
|
|||||||||||||||||||||||||||||||||||||||||
End point title |
Palmitoylethanolamide Plasma Concentration | ||||||||||||||||||||||||||||||||||||||||
End point description |
The LLOQ for palmitoylethanolamide in plasma is 0.5 ng/mL.
This endpoint was analysed using the pharmacodynamics analysis set.
|
||||||||||||||||||||||||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||||||||||||||||||||||||
End point timeframe |
Baseline (pre-dose), Weeks 4 and 8, 1-4 hours post morning dose and Week 12 (or end of treatment), 12-16 hours post previous evening dose.
|
||||||||||||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||||||||||||
No statistical analyses for this end point |
|
|||||||||||||||||||||
End point title |
Change from Baseline to End of Treatment in Post-Void Residual (PVR) Volume | ||||||||||||||||||||
End point description |
PVR volume was assessed by a transabdominal ultrasound bladder scan.
This endpoint was analysed using the safety analysis set; LOCF imputation was used.
|
||||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||||
End point timeframe |
Baseline and Week 12
|
||||||||||||||||||||
|
|||||||||||||||||||||
No statistical analyses for this end point |
|
|||||||||||||||||||||
End point title |
Change from Baseline to End of Treatment in Profile of Mood States (POMS) Total Mood Disturbance Score | ||||||||||||||||||||
End point description |
Psychotropic effects emerging during the study were measured using the POMS questionnaire, which asks subjects to rate how they feel in relation to each of 65 adjectives commonly used to describe mood states. Responses are given on a 5-point scale (0=Not at all, 1=A little, 2=Moderate, 3=Quite a bit, and 4=Extremely). The responses to groups of questions can be summed to calculate six factors: Tension-Anxiety (range 0 to 36), Depression-Rejection (range 0 to 60), Anger-Hostility (range 0 to 48), Vigor-Activity (range 0 to 32), Fatigue-Inertia (range 0 to 28) and Confusion-Bewilderment (range 0 to 28). The Total Mood Disturbance (TMD) score is calculated by summing the six factors while weighting the Vigor-Activity score negatively. The range of this total score is from -32 to 200. A score below -30 or above 68 is considered abnormal.
This endpoint was analysed using the safety analysis set; LOCF imputation was used.
|
||||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||||
End point timeframe |
Baseline and Week 12
|
||||||||||||||||||||
|
|||||||||||||||||||||
No statistical analyses for this end point |
|
|||||||||||||||||||||
End point title |
Change from Baseline to End of Treatment in Center for Epidemiologic Studies Depression Scale (CES-D) score | ||||||||||||||||||||
End point description |
The 20-item CES-D scale questionnaire is a validated, short, self-report scale designed to measure depressive symptomatology. Responses to each item are from 0 (“rarely or not at all”) to 3 (“most or all of the time”). The total score is calculated as the sum of the scores for the 20 questions and has a range from 0 to 60. Negative changes from Baseline indicate improvements in depressive symptoms during the study.
This endpoint was analysed in the safety analysis set; LOCF imputation was used.
|
||||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||||
End point timeframe |
Baseline and Week 12
|
||||||||||||||||||||
|
|||||||||||||||||||||
No statistical analyses for this end point |
|
|||||||||||||||||||||
End point title |
Change from End of Treatment to Follow-up in the Physician Withdrawal Checklist (PWC) Score | ||||||||||||||||||||
End point description |
Withdrawal effects from study drug were measured by the PWC. The PWC has twenty items, each rated on a 4-point scale (0=not present; 1=mild; 2=moderate; 3=severe). It is evaluated after permanent discontinuation of treatment, i.e., at the Follow-up visit. The total score was calculated as the sum of the scores provided in response to the 20 items. It has a range from 0 to 60. Missing value were not imputed.
This endpoint was analysed using the safety analysis set.
|
||||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||||
End point timeframe |
Week 12 (or end of treatment if earlier) and 2 weeks after the end of treatment
|
||||||||||||||||||||
|
|||||||||||||||||||||
No statistical analyses for this end point |
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Adverse events information
|
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Timeframe for reporting adverse events |
From the first dose of study medication until 2 days after the last dose. Overall mean duration of drug exposure was 78 days.
|
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Assessment type |
Systematic | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary used for adverse event reporting
|
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Dictionary name |
MedDRA | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
11.1
|
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Reporting groups
|
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Reporting group title |
Placebo
|
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Reporting group description |
Subjects took matching placebo tablets twice a day for 12 weeks, followed by a 2-week follow-up period. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
ASP3652 150 mg BID
|
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Reporting group description |
Subjects took two 25 mg and one 100 mg ASP3652 tablet twice a day for 12 weeks, followed by a 2-week follow-up period. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
ASP3652 300 mg BID
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Reporting group description |
Subjects took three 100 mg ASP3652 tablets twice a day for 12 weeks, followed by a 2-week follow-up period. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
ASP3652 50 mg BID
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Reporting group description |
Subjects took two 25 mg ASP3652 tablets and one placebo tablet twice a day (BID) for 12 weeks, followed by a 2-week follow-up period. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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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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26 Apr 2013 |
1. Initially, patients were required to undergo a cystoscopy at Screening to ascertain BPS/IC disease characteristics (i.e., the presence/absence of Hunner’s lesions and glomerulations). The cystoscopy at Screening could be omitted provided results of a previous cystoscopy with hydrodistension were available which could enable the classification of patients into subgroups with and without Hunner’s lesions (glomerulations have been implied in previous diagnostic criteria, but are currently not regarded as specific for BPS/IC). However, the omission of the procedure had no consequences for selection criteria, as the cystoscopy was not meant for diagnosing confounding or confusable bladder conditions.
2. The original protocol stated that the use of antibiotics was not permitted between visit 1/screening and visit 7/FU. In the protocol amendment, these restrictions were reduced to allow antibiotic treatments of up to 2 weeks in duration for indications/infections not including the genitourinary tract. Short regimens of systemic antibiotics for treatment of infections other than UTI were not expected to influence BPS/IC efficacy and safety endpoints. A clinical study with long term antibiotics in BPS/IC did not show convincing efficacy (Warren et al, 2000) and AUA (Hanno et al, 2011) and EAU (2010) guidelines do not regard the use of antibiotics as an effective treatment of BPS/IC. |
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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 |