Clinical Trial Results:
An 8-week, dose ranging, open label, randomized, Phase 2 study with a 44-week extension, to evaluate the safety and efficacy of MBX-8025 in subjects with Primary Biliary Cholangitis (PBC) and an inadequate response to or intolerance to ursodeoxycholic acid (UDCA).
Summary
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EudraCT number |
2016-002996-91 |
Trial protocol |
DE GB |
Global end of trial date |
08 Jul 2019
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Results information
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Results version number |
v1(current) |
This version publication date |
04 Jan 2021
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First version publication date |
04 Jan 2021
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Other versions |
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 |
CB8025-21629
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT02955602 | ||
WHO universal trial number (UTN) |
- | ||
Sponsors
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Sponsor organisation name |
CymaBay Therapeutics, Inc.
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Sponsor organisation address |
7575 Gateway Blvd, Suite 110, Newark, United States, 94560
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Public contact |
Mary Standen, CymaBay Therapeutics, Inc., 001 5102938800, mstanden@cymabay.com
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Scientific contact |
Alexandra (Sasha) Steinberg, CymaBay Therapeutics, Inc., 001 5102938800, asteinberg@cymabay.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 |
30 Jul 2020
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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 |
08 Jul 2019
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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 |
The primary objective of this study was to evaluate the safety and efficacy of seladelpar 2 mg, 5 mg and 10 mg over 8 weeks of treatment in subjects of primary biliary cholangitis (PBC) as measured by the mean percent change from baseline in serum alkaline phosphatase (ALP) levels. After completion of the 8-week initial treatment period, subjects entered a 44-week open-label extension period for a total of up to 52 weeks of treatment. During the extension period subjects took seladelpar orally once daily for up to 52 weeks. The 2 mg group was started in order to define the lower dose range for efficacy after review of initial treatment period results for the 5 mg and the 10 mg groups.
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Protection of trial subjects |
The study was conducted in accordance with the Declaration of Helsinki and its revisions and the International Conference on Harmonisation (ICH) Harmonized Tripartite Guideline for Good Clinical Practice (GCP). The study was also in compliance with the applicable local regulatory requirements and laws of each country in which the study was conducted, as well as with any applicable guidelines.
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Background therapy |
- | ||
Evidence for comparator |
- | ||
Actual start date of recruitment |
01 Nov 2016
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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 |
United Kingdom: 20
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Country: Number of subjects enrolled |
United States: 82
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Country: Number of subjects enrolled |
Canada: 6
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Country: Number of subjects enrolled |
Germany: 11
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Worldwide total number of subjects |
119
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EEA total number of subjects |
31
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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) |
90
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From 65 to 84 years |
29
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85 years and over |
0
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Recruitment
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Recruitment details |
The study was conducted at 33 sites in the Canada, Germany, United Kingdom, and United States between 28 November 2016 and 08 July 2019. | ||||||||||||||||||||||||||||||||||||
Pre-assignment
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Screening details |
A total of 192 subjects were screened of which 121 subjects randomized (2 subjects were not treated) into study and 71 were screen failures. Subjects were randomized to the 5 and 10 mg treatment groups for entry to the 8-week initial treatment period study, while those in the 2 mg treatment group entered after being sequentially assigned their dose | ||||||||||||||||||||||||||||||||||||
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 |
Not applicable
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Blinding used |
Not blinded | ||||||||||||||||||||||||||||||||||||
Arms
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Are arms mutually exclusive |
Yes
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Arm title
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Seladelpar 2 mg | ||||||||||||||||||||||||||||||||||||
Arm description |
Subjects received two seladelpar 1 mg capsules orally once daily for 8 weeks with a 44-week extension period. Dose up-titration for efficacy reasons could be made after 12 weeks of treatment up to 10 mg. | ||||||||||||||||||||||||||||||||||||
Arm type |
Experimental | ||||||||||||||||||||||||||||||||||||
Investigational medicinal product name |
Seladelpar
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Investigational medicinal product code |
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Other name |
MBX-8025
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Pharmaceutical forms |
Capsule
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Routes of administration |
Oral use
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Dosage and administration details |
Seladelpar capsules taken once a day (QD) orally in initial treatment period and dose adjusted as necessary in the extension period. Dose up-titration up to 10 mg for efficacy reasons could be made after 12 weeks of treatment.
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Arm title
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Seladelpar 5 mg | ||||||||||||||||||||||||||||||||||||
Arm description |
Subjects were randomized to receive one seladelpar 5 mg capsule orally once daily for 8 weeks with a 44-week extension period. Dose up-titration to 10 mg for efficacy reasons could be made after 12 weeks of treatment. | ||||||||||||||||||||||||||||||||||||
Arm type |
Experimental | ||||||||||||||||||||||||||||||||||||
Investigational medicinal product name |
Seladelpar
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Investigational medicinal product code |
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Other name |
MBX-8025
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Pharmaceutical forms |
Capsule
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Routes of administration |
Oral use
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Dosage and administration details |
Seladelpar capsules taken QD orally in initial treatment period and dose adjusted as necessary in the extension period. Dose up-titration for efficacy reasons could be made after 12 weeks of treatment to up to 10 mg.
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Arm title
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Seladelpar 10 mg | ||||||||||||||||||||||||||||||||||||
Arm description |
Subjects were randomized to receive one seladelpar 10 mg capsule orally once daily for 8 weeks with a 44-week extension period. | ||||||||||||||||||||||||||||||||||||
Arm type |
Experimental | ||||||||||||||||||||||||||||||||||||
Investigational medicinal product name |
Seladelpar
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Investigational medicinal product code |
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Other name |
MBX-8025
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Pharmaceutical forms |
Capsule
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Routes of administration |
Oral use
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Dosage and administration details |
Seladelpar capsules taken QD orally in initial treatment period and dose adjusted as necessary in the extension period
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Baseline characteristics reporting groups
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Reporting group title |
Seladelpar 2 mg
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Reporting group description |
Subjects received two seladelpar 1 mg capsules orally once daily for 8 weeks with a 44-week extension period. Dose up-titration for efficacy reasons could be made after 12 weeks of treatment up to 10 mg. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Seladelpar 5 mg
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Reporting group description |
Subjects were randomized to receive one seladelpar 5 mg capsule orally once daily for 8 weeks with a 44-week extension period. Dose up-titration to 10 mg for efficacy reasons could be made after 12 weeks of treatment. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Seladelpar 10 mg
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Reporting group description |
Subjects were randomized to receive one seladelpar 10 mg capsule orally once daily for 8 weeks with a 44-week extension period. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
Seladelpar 2 mg
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Reporting group description |
Subjects received two seladelpar 1 mg capsules orally once daily for 8 weeks with a 44-week extension period. Dose up-titration for efficacy reasons could be made after 12 weeks of treatment up to 10 mg. | ||
Reporting group title |
Seladelpar 5 mg
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Reporting group description |
Subjects were randomized to receive one seladelpar 5 mg capsule orally once daily for 8 weeks with a 44-week extension period. Dose up-titration to 10 mg for efficacy reasons could be made after 12 weeks of treatment. | ||
Reporting group title |
Seladelpar 10 mg
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Reporting group description |
Subjects were randomized to receive one seladelpar 10 mg capsule orally once daily for 8 weeks with a 44-week extension period. |
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End point title |
Relative Change from Baseline in Serum Alkaline Phosphatase (ALP) Levels at Week 8 (Endpoint) | ||||||||||||||||||||
End point description |
Relative change from baseline is in serum ALP levels at Week 8 (endpoint). The modified Intent-to-Treat (mITT) analysis set included all randomized subjects with confirmed PBC who received at least one study drug dose and had at least one post baseline ALP evaluation on treatment. n, denotes number of subjects evaluable for the respective timepoints
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End point type |
Primary
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End point timeframe |
Week 8 (Endpoint)
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Statistical analysis title |
Statistical Analysis 1, 5 mg vs 2 mg | ||||||||||||||||||||
Statistical analysis description |
The analyses will assess the change from baseline in each treatment group and will assess the hypothesis that there are no differences in the percent change in ALP serum level between seladelpar 2 mg and 5 mg treatment groups after 8 weeks of treatment
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Comparison groups |
Seladelpar 2 mg v Seladelpar 5 mg
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Number of subjects included in analysis |
60
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Analysis specification |
Pre-specified
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Analysis type |
equivalence | ||||||||||||||||||||
P-value |
= 0.2242 | ||||||||||||||||||||
Method |
ANCOVA | ||||||||||||||||||||
Confidence interval |
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Statistical analysis title |
Statistical Analysis 2, 2 mg vs 10 mg | ||||||||||||||||||||
Statistical analysis description |
The analyses will assess the change from baseline in each treatment group and will assess the hypothesis that there are no differences in the percent change in ALP serum level between seladelpar 2 mg and 10 mg treatment groups after 8 weeks of treatment.
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Comparison groups |
Seladelpar 2 mg v Seladelpar 10 mg
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Number of subjects included in analysis |
63
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Analysis specification |
Pre-specified
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Analysis type |
equivalence | ||||||||||||||||||||
P-value |
= 0.0021 | ||||||||||||||||||||
Method |
ANCOVA | ||||||||||||||||||||
Confidence interval |
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Statistical analysis title |
Statistical Analysis 3, 5 mg vs 10 mg | ||||||||||||||||||||
Statistical analysis description |
The analyses will assess the change from baseline in each treatment group and will assess the hypothesis that there are no differences in the percent change in ALP serum level between seladelpar 5 mg and 10 mg treatment groups after 8 weeks of treatment.
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Comparison groups |
Seladelpar 5 mg v Seladelpar 10 mg
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Number of subjects included in analysis |
101
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Analysis specification |
Pre-specified
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Analysis type |
equivalence | ||||||||||||||||||||
P-value |
= 0.0024 | ||||||||||||||||||||
Method |
ANCOVA | ||||||||||||||||||||
Confidence interval |
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End point title |
Absolute Change in Serum Alkaline Phosphatase (ALP) Levels from Baseline to Weeks 12 and 52 (Endpoint) | ||||||||||||||||||||||||
End point description |
Absolute change in ALP from baseline to Weeks 12 and 52
The mITT analysis set included all randomized subjects with confirmed PBC who received at least one study drug dose and had at least one post baseline ALP evaluation on treatment.
n, denotes number of subjects evaluable for the respective timepoints
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End point type |
Secondary
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End point timeframe |
Weeks 12 and 52 (Endpoint)
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No statistical analyses for this end point |
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End point title |
Relative Change from Baseline in Serum Alkaline Phosphatase (ALP) Levels at Weeks 12 and 52 (Endpoint) | ||||||||||||||||||||||||
End point description |
Mean percent change in ALP from baseline to Weeks 12 and 52 (Endpoint)
The mITT analysis set included all randomized subjects with confirmed PBC who received at least one study drug dose and had at least one post baseline ALP evaluation on treatment. n, denotes number of subjects evaluable for the respective timepoints
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End point type |
Secondary
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End point timeframe |
Weeks 12 and 52 (Endpoint)
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Statistical analysis title |
Statistical Analysis 1, 5 mg vs 2 mg (12 weeks) | ||||||||||||||||||||||||
Statistical analysis description |
The analyses will assess the percent change from baseline in each treatment group and will assess the hypothesis that there are no differences in the percent change in ALP serum level between seladelpar 2 mg and 5 mg treatment groups after 12 weeks of treatment.
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Comparison groups |
Seladelpar 2 mg v Seladelpar 5 mg
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Number of subjects included in analysis |
60
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Analysis specification |
Pre-specified
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Analysis type |
equivalence | ||||||||||||||||||||||||
P-value |
= 0.0493 | ||||||||||||||||||||||||
Method |
ANCOVA | ||||||||||||||||||||||||
Confidence interval |
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Statistical analysis title |
Statistical Analysis 2, 2 mg vs 10 mg (12 weeks) | ||||||||||||||||||||||||
Statistical analysis description |
The analyses will assess the percent change from baseline in each treatment group and will assess the hypothesis that there are no differences in the percent change in ALP serum level between seladelpar 2 mg and 10 mg treatment groups after 12 weeks of treatment.
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Comparison groups |
Seladelpar 10 mg v Seladelpar 2 mg
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Number of subjects included in analysis |
63
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Analysis specification |
Pre-specified
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Analysis type |
equivalence | ||||||||||||||||||||||||
P-value |
= 0.0003 | ||||||||||||||||||||||||
Method |
ANCOVA | ||||||||||||||||||||||||
Confidence interval |
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Statistical analysis title |
Statistical Analysis 3, 5 mg vs 10 mg (12 weeks) | ||||||||||||||||||||||||
Statistical analysis description |
The analyses will assess the percent change from baseline in each treatment group and will assess the hypothesis that there are no differences in the percent change in ALP serum level between seladelpar 5 mg vs 10 mg treatment groups after 12 weeks of treatment.
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Comparison groups |
Seladelpar 5 mg v Seladelpar 10 mg
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Number of subjects included in analysis |
101
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Analysis specification |
Pre-specified
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Analysis type |
equivalence | ||||||||||||||||||||||||
P-value |
= 0.0053 | ||||||||||||||||||||||||
Method |
ANCOVA | ||||||||||||||||||||||||
Confidence interval |
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Statistical analysis title |
Statistical Analysis 4, 2 mg vs 5 mg (52 weeks) | ||||||||||||||||||||||||
Statistical analysis description |
The analyses will assess the percent change from baseline in each treatment group and will assess the hypothesis that there are no differences in the percent change in ALP serum level between seladelpar 2 mg and 5 mg treatment groups after 52 weeks of treatment.
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Comparison groups |
Seladelpar 2 mg v Seladelpar 5 mg
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Number of subjects included in analysis |
60
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Analysis specification |
Pre-specified
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Analysis type |
equivalence | ||||||||||||||||||||||||
P-value |
= 0.3466 | ||||||||||||||||||||||||
Method |
ANCOVA | ||||||||||||||||||||||||
Confidence interval |
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Statistical analysis title |
Statistical Analysis 5, 2 mg vs 10 mg (52 weeks) | ||||||||||||||||||||||||
Statistical analysis description |
The analyses will assess the percent change from baseline in each treatment group and will assess the hypothesis that there are no differences in the percent change in ALP serum level between seladelpar 2 mg vs 10 mg treatment groups after 52 weeks of treatment.
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Comparison groups |
Seladelpar 2 mg v Seladelpar 10 mg
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Number of subjects included in analysis |
63
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Analysis specification |
Pre-specified
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Analysis type |
equivalence | ||||||||||||||||||||||||
P-value |
= 0.0949 | ||||||||||||||||||||||||
Method |
ANCOVA | ||||||||||||||||||||||||
Confidence interval |
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Statistical analysis title |
Statistical Analysis 6, 5 mg vs 10 mg (52 weeks) | ||||||||||||||||||||||||
Statistical analysis description |
The analyses will assess the percent change from baseline in each treatment group and will assess the hypothesis that there are no differences in the percent change in ALP serum level between seladelpar 5 mg vs 10 mg treatment groups after 52 weeks of treatment.
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Comparison groups |
Seladelpar 5 mg v Seladelpar 10 mg
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Number of subjects included in analysis |
101
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Analysis specification |
Pre-specified
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Analysis type |
equivalence | ||||||||||||||||||||||||
P-value |
= 0.251 | ||||||||||||||||||||||||
Method |
ANCOVA | ||||||||||||||||||||||||
Confidence interval |
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End point title |
Percentage of Subjects with Response Defined by Composite Risk Scores (ALP< 1.67 x Upper Limit of Normal [ULN] at Endpoint, Total Bilirubin [BIL] Within Normal Limits at Endpoint, and Greater Than Equal To [≥] 15% ALP Reduction from Baseline to Endpoint | ||||||||||||||||||||||||
End point description |
Reporting was done for percentage of subjects with response defined by Composite Risk Scores (ALP Less than [<] 1.67 x ULN at endpoint, Total BIL within normal limits at endpoint, and ≥15% ALP reduction from baseline to Endpoint).
The mITT analysis set included all randomized subjects with confirmed PBC who received at least one study drug dose and had at least one post baseline ALP evaluation on treatment. The mITT analysis was performed in a manner similar to primary endpoint.
n, denotes number of subjects evaluable for the respective timepoints
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End point type |
Secondary
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End point timeframe |
12 Weeks and 52 Weeks
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No statistical analyses for this end point |
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End point title |
Percentage of Subjects with Response Based on PARIS I Risk Score at Weeks 12 and 52 (Endpoint) | ||||||||||||||||||||||||
End point description |
Percentage of subjects with response based on Paris I risk score was defined as ALP less than or equal to (≤) 3x ULN and aspartate aminotransferase (AST) less than or equal to (≤) 2 x ULN and Total Bilirubin ≤ 1 mg/dL.
The mITT analysis set included all randomized subjects with confirmed PBC who received at least one study drug dose and had at least one post baseline ALP evaluation on treatment. n, denotes number of subjects evaluable for the respective timepoints
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End point type |
Secondary
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End point timeframe |
At Weeks 12, 52 (Endpoint)
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No statistical analyses for this end point |
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End point title |
Percentage of Subjects with Response Based on PARIS II Risk Score at Weeks 12 and 52 (Endpoint) | ||||||||||||||||||||||||
End point description |
Percentage of subjects with response based on Paris II risk score was defined as ALP≤1.5xULN and AST≤1.5xULN and Total Bilirubin ≤ 1 mg/dL.
The mITT analysis set included all randomized subjects with confirmed PBC who received at least one study drug dose and had at least one post baseline ALP evaluation on treatment. n, denotes number of subjects evaluable for the respective timepoints
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End point type |
Secondary
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End point timeframe |
At Weeks 12 and 52 (Endpoint)
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No statistical analyses for this end point |
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End point title |
Percentage of Subjects with Response Based on Toronto I Risk Score at Weeks 12 and 52 (Endpoint) | ||||||||||||||||||||||||
End point description |
Percentage of subjects with response based on Toronto I risk score defined as ALP ≤ 1.67 x ULN. The mITT analysis set included all randomized subjects with confirmed PBC who received at least one study drug dose and had at least one post baseline ALP evaluation on treatment. n, denotes number of subjects evaluable for the respective timepoints
|
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End point type |
Secondary
|
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End point timeframe |
At Weeks 12 and 52 (Endpoint)
|
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|
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No statistical analyses for this end point |
|
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End point title |
Percentage of Subjects with Response Based on Barcelona Risk Score at Weeks 12 and 52 (Endpoint) | ||||||||||||||||||||||||
End point description |
Percentage of subjects with response based on Barcelona risk scores was defined as Normalization of ALP or a Decrease of ALP ≥ 40%. The mITT analysis set included all randomized subjects with confirmed PBC who received at least one study drug dose and had at least one post baseline ALP evaluation on treatment. . n, denotes number of subjects evaluable for the respective timepoints
|
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End point type |
Secondary
|
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End point timeframe |
At Weeks 12 and 52 (Endpoint)
|
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|
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No statistical analyses for this end point |
|
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End point title |
Percentage of Subjects with Response Based on Rotterdam Risk Score at Weeks 12 and 52 (Endpoint) | ||||||||||||||||||||||||||||||||||||||||
End point description |
Percentage of subjects with response based on Rotterdam risk scores was defined in terms of populations of early stage (normal Total Bilirubin and normal Albumin), moderately advanced stage (either abnormal Albumin or abnormal Total Bilirubin), and advanced stages (both abnormal Albumin and abnormal Total Bilirubin).
The mITT analysis set included all randomized subjects with confirmed PBC who received at least one study drug dose and had at least one post baseline ALP evaluation on treatment. n, denotes number of subjects evaluable for the respective timepoints
|
||||||||||||||||||||||||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||||||||||||||||||||||||
End point timeframe |
At Weeks 12 and 52 (Endpoint)
|
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|
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No statistical analyses for this end point |
|
|||||||||||||||||||||||||
End point title |
Change from Baseline in Total bilirubin (TB) Levels at Weeks 12 and 52 (Endpoint) | ||||||||||||||||||||||||
End point description |
Change from baseline in TB levels at endpoint is being reported.
The mITT analysis set included all randomized subjects with confirmed PBC who received at least one study drug dose and had at least one post baseline ALP evaluation on treatment.
n, denotes number of subjects evaluable for the respective timepoints
|
||||||||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||||||||
End point timeframe |
Weeks 12 and 52 (Endpoint)
|
||||||||||||||||||||||||
|
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No statistical analyses for this end point |
|
|||||||||||||||||||||||||
End point title |
Change from Baseline in Aspartate Aminotransferase (AST) Levels at Weeks 12 and 52 (Endpoint) | ||||||||||||||||||||||||
End point description |
Change from baseline in AST levels at endpoint was reported. The mITT analysis set included all randomized subjects with confirmed PBC who received at least one study drug dose and had at least one post baseline ALP evaluation on treatment.
n, denotes number of subjects evaluable for the respective timepoints
|
||||||||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||||||||
End point timeframe |
Weeks 12, 52 (Endpoint)
|
||||||||||||||||||||||||
|
|||||||||||||||||||||||||
No statistical analyses for this end point |
|
|||||||||||||||||||||||||
End point title |
Change from Baseline in Alanine Aminotransferase (ALT) Levels at Weeks 12 and 52 (Endpoint) | ||||||||||||||||||||||||
End point description |
Change from baseline in ALT levels at endpoint was reported. The mITT analysis set included all randomized subjects with confirmed PBC who received at least one study drug dose and had at least one post baseline ALP evaluation on treatment. n, denotes number of subjects evaluable for the respective timepoints
|
||||||||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||||||||
End point timeframe |
Weeks 12 and 52 (Endpoint)
|
||||||||||||||||||||||||
|
|||||||||||||||||||||||||
No statistical analyses for this end point |
|
|||||||||||||||||||||||||
End point title |
Change from Baseline in Gamma-glutamyl Transferase (GGT) Levels at Weeks 12 and 52 (Endpoint) | ||||||||||||||||||||||||
End point description |
Change from baseline in GGT levels at endpoint was reported. The mITT analysis set included all randomized subjects with confirmed PBC who received at least one study drug dose and had at least one post baseline ALP evaluation on treatment.
n, denotes number of subjects evaluable for the respective timepoints
|
||||||||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||||||||
End point timeframe |
Weeks 12 and 52 (Endpoint)
|
||||||||||||||||||||||||
|
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No statistical analyses for this end point |
|
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End point title |
Change from Baseline in Model for End-stage Liver Disease (MELD) score at Weeks 12 and 52 (Endpoint) | ||||||||||||||||||||||||
End point description |
The prognostic model for estimating disease severity and survival was utilized for subjects by assessing the Model for End-stage Liver Disease (MELD) score. To calculate the MELD score, samples for creatinine, bilirubin, international normalized ratio (INR), and sodium values were taken as specified in assessment schedule. The MELD scores were calculated as per following formulae:
MELD(i) score = 10×(0.957×ln[creatinine, mg/dL]+0.378×ln[bilirubin, mg/dL]+1.120×ln[INR] + 0.643).
If MELD(i) is less than or equal to 11 then MELD score = MELD(i).
If MELD(i) is greater than 11 then MELD score = MELD(i) + (1.32 *(137 - (Na)) – (0.033*MELD(i)*(137 – Na))
The mITT analysis set included all randomized subjects with confirmed PBC who received at least one study drug dose and had at least one post baseline ALP evaluation on treatment.
mITT, included population; n, denotes number of subjects evaluable for the respective timepoints
|
||||||||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||||||||
End point timeframe |
Weeks 12 and 52 (Endpoint)
|
||||||||||||||||||||||||
|
|||||||||||||||||||||||||
No statistical analyses for this end point |
|
|||||||||||||||||||||||||
End point title |
Change from Baseline in Global PBC Study Group (GLOBE) score at Weeks 12 and 52 (Endpoint) | ||||||||||||||||||||||||
End point description |
The Global PBC Study Group (GLOBE) score was assessed using the validated tool to accurately stratify patients into high- and low- risk for liver transplantation or death at 12 months of ursodeoxycholic acid (UDCA) treatment. Samples for bilirubin, ALP, albumin, and platelet count determination were used as per specifications to calculate the GLOBE score. Formula used : (0.044378×age+0.93982×ln[total bilirubin/ULN]+[0.335648×ln(alkaline phosphatase/ULN)]-2.266708×albumin /LLN-0.002581×platelet count per 109/L)+1.216865.
The modified Intent-to-Treat (mITT) analysis set included all randomized subjects with confirmed PBC who received at least one study drug dose and had at least one post baseline ALP evaluation on treatment.
mITT, included population; n, denotes number of subjects evaluable for the respective timepoints
|
||||||||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||||||||
End point timeframe |
Weeks 12 and 52 (Endpoint)
|
||||||||||||||||||||||||
|
|||||||||||||||||||||||||
No statistical analyses for this end point |
|
|||||||||||||||||||||||||||||||||||||||||
End point title |
Risk as Assessed by United Kingdom-Primary Biliary Cholangitis (UK-PBC) Score at Weeks 12 and 52 (Endpoint) | ||||||||||||||||||||||||||||||||||||||||
End point description |
The UK-PBC Risk Score at endpoint is defined by the mean percentage risk that a PBC patient treated with ursodeoxycholic acid (UDCA) would develop liver failure requiring liver transplantation in 5, 10 and 15 years from diagnosis. Formula used for UK-PBC risk score = 1- 0.982 ^EXP(0.0287854*(AP12 x ULN-1.722136304) - 0.0422873*(((TA12 xULN/10)^-1) - 8.675729006) + 1.4199 * (LN(BIL12 x ULN/10)+2.709607778)-1.960303*(Albumin x LLN-1.17673001)-0.4161954*(Platelet x LLN-1.873564875)). Where, Baseline survivor function = 0.982, 0.941, and 0.893 for 5 years, 10 years and 15 years respectively. AP12, TA12 and BIL12 refers to the AP, transaminases (ALT, AST), and total bilirubin assessments, respectively.
The modified Intent-to-Treat (mITT) analysis set included all randomized subjects with confirmed PBC who received at least one study drug dose and had at least one post baseline ALP evaluation on treatment.
mITT, included population; n, denotes number of subjects evaluable for timepoint
|
||||||||||||||||||||||||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||||||||||||||||||||||||
End point timeframe |
Weeks 12 and 52 (Endpoint)
|
||||||||||||||||||||||||||||||||||||||||
|
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No statistical analyses for this end point |
|
|||||||||||||||||||||||||
End point title |
Change from Baseline in Pruritus as Assessed by Visual Analogue Scale (VAS) Total Score at Weeks 12 and 52 (Endpoint) | ||||||||||||||||||||||||
End point description |
VAS is the commonly used graphic tool for self-reporting of pruritus intensity in patients. VAS is a simple to use, validated, reliable and widely applicable too that does not determine the impact of pruritus to quality of life. It comprises of a 100-mm horizontal line labelled as “no symptom” on left end and “worst imaginable symptom” on right end. Based on the intensity of the itch patient is instructed to draw a vertical line on the horizontal scale having a range [VAS values (unit: mm) ranging from 0 to 100, where 0 represents “no itching” and 100 “worst possible itching”]. The modified Intent-to-Treat (mITT) analysis set included all randomized subjects with confirmed PBC who received at least one study drug dose and had at least one post baseline ALP evaluation on treatment. mITT, included population; n, denotes number of subjects evaluable for the respective timepoints
|
||||||||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||||||||
End point timeframe |
Weeks 12 and 52 (Endpoint)
|
||||||||||||||||||||||||
|
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No statistical analyses for this end point |
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point title |
Change from Baseline in Primary Biliary Cholangitis-40 (PBC-40) Quality of Life Questionnaire Scores at Weeks 12 and 52 (Endpoint) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point description |
The PBC-40 QoL questionnaire is a disease-specific health-related tool developed for measuring the psychometric profile in PBC patients. It has 10 domains and a 43 questions relevant to PBC, including Cognitive, Social, Emotional Function, Fatigue, Itch, and Other Symptoms. Questions in domains: 1) digestion and diet (questions 1-3); 2) experiences (questions 4-7); 3) itching (questions 8-10); 4) fatigue (questions 11-18); 5) effort and planning (questions 19-21); 6) memory and concentration (questions 22-27); 7) affects to you as person (questions 28-33); 8) affects to your social life (questions 34-37); 9) overall impact on your life (questions 38-40); 10) general health and well-being (questions A-C).
Within a domain, items are scored from 1 to 5 and the individual item scores are summed to give a total domain score. High scores represent high impact and low scores low impact of PBC on QoL.
mITT, included population; n, number of subjects evaluable at respective timepoint
|
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End point type |
Secondary
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point timeframe |
Weeks 12 and 52 (Endpoint)
|
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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 |
Up to week 56
|
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Adverse event reporting additional description |
Adverse events
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Assessment type |
Systematic | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary used for adverse event reporting
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Dictionary name |
MedDRA | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
22.0
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Reporting groups
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Reporting group title |
Seladelpar 2 mg
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Reporting group description |
Subjects received seladelpar 2 milligram (mg) capsules orally once daily for 8 weeks with a 44-week extension period. Subjects entered the 44-week extension on their assigned dose. The dose was up-titrated after safety and efficacy data review of the first 8 weeks of treatment. During the extension, a subject's dose may have been re-adjusted for safety or efficacy reasons. The 2 mg group was started after safety and efficacy review of the 5 mg and the 10 mg groups was completed. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Seladelpar 10 mg
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Reporting group description |
Subjects were randomized to receive seladelpar 10 milligram (mg) capsules orally once daily for 8 weeks with a 44-week extension period. Subjects entered the 44-week extension on their assigned dose. The dose was up- or down-titrated after safety and efficacy data review of the first 8 weeks of treatment. During the extension, a subject's dose may have been re-adjusted for safety or efficacy reasons. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Seladelpar 5 mg
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Reporting group description |
Subjects were randomized to receive seladelpar 5 milligram (mg) capsules orally once daily for 8 weeks with a 44-week extension period. Subjects entered the 44-week extension on their assigned dose. The dose was up- or down-titrated after safety and efficacy data review of the first 8 weeks of treatment. During the extension, a subject's dose may have been re-adjusted for safety or efficacy reasons. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Frequency threshold for reporting non-serious adverse events: 5% | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Substantial protocol amendments (globally) |
|||
Were there any global substantial amendments to the protocol? Yes | |||
Date |
Amendment |
||
24 Feb 2017 |
•Enrollment in the 5 and 10 mg dose groups was changed from ~12 to ~18 subjects each. Subjects in the 2 mg (n ~ 6) and 20 mg (n ~ 12) dose groups were to be registered in the study.
•Because of the level of activity observed in the 5 and 10 mg dose groups at Interim Analysis 1, the 2 mg dose group was added and the next highest dose was decreased from 25 mg to 20 mg to limit exposure to seladelpar.
•Dose titration options for the extension period were changed from 5, 10, and 25 mg to 1, 2, 5, 10, 15, and 20 mg.
•microRNA-122 was added as a biomarker of liver disease.
|
||
25 Apr 2017 |
•After Interim Analysis 2, the extension period was changed from 18 to 44 weeks, and the treatment period was extended from 26
to 52 weeks. The total study duration (8 weeks’ initial treatment + extension period + 4 weeks’ follow-up) was extended from 30
to 56 weeks.
•An exclusion criterion was added: total bilirubin > ULN and albumin < LLN with the exception of subjects with Gilbert’s syndrome.
Subjects with Gilbert’s syndrome were to be excluded if direct bilirubin was >ULN.
•During the extension period, dose up-titration to above 10 mg could not be performed until interim analysis results were available
and the 20 mg dose group was initiated.
•Barcelona PBC response criteria were added to outcome measures.
•Prohibited systemic steroids were specified as long term (>2 weeks).
•Review of medical history was to include history of liver related symptoms.
•Physical examinations were to include evaluation of liver related symptoms.
•A post-dose adjustment visit was added for subjects whose dose was adjusted at any time during the extension period.
•Prothrombin time was removed from laboratory evaluations.
•Subjects who withdrew from the study could be replaced.
|
||
17 Jul 2017 |
•During the extension period, dose up-titration to above 10 mg was prohibited until interim analysis results were available.
•The time for the second 24-hour PK determination was changed from after 2 weeks of treatment to after 12 weeks of treatment.
•The size of the 2 mg dose group was changed from ~6 to up to 18 subjects, and the size of the 5 and 10 mg dose groups was changed from ~18 to ~49 subjects each. The size of the 20 mg dose group remained ~12 subjects.
•The number of subjects undergoing 24-hour PK determinations was changed from ~3 to up to 6 subjects receiving 2 mg, from ~6
to up to 12 receiving 5 mg, from ~6 to up to 12 receiving 10 mg, and from ~6 to up to 12 receiving 20 mg.
•Prohibited systemic steroids were specified as long term (>2 weeks).
•Review of medical history was to include history of liver related symptoms.
•Physical examinations were to include evaluation of liver related symptoms.
•A post-dose adjustment visit was added for subjects whose dose was adjusted at any time during the extension period.
|
||
20 Jul 2017 |
•The 20 mg dose was removed.
•Dose up-titration to 15 mg could take place only within 26 weeks of treatment. Beyond 26 weeks the highest dose was to be 10 mg.
•The time for the second 24-hour PK determination was changed from after 2 weeks of treatment to after 12 weeks of treatment.
•The size of the 2 mg dose group was changed from ~6 to up to 18 subjects, and the size of the 5 and 10 mg dose groups was changed from ~18 to ~49 subjects each.
•The number of subjects undergoing 24-hour PK determinations was changed from ~3 to up to 6 subjects receiving 2 mg, from ~6 to up to 12 receiving 5 mg, and from ~6 to up to 12 receiving 10 mg.
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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 |