Clinical Trial Results:
Proof of Mechanism Study to Assess the Potential of GSK239512 to Remyelinate Lesions in Subjects with Relapsing Remitting Multiple Sclerosis.
Summary
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EudraCT number |
2012-003627-38 |
Trial protocol |
SE DE ES CZ BG GB |
Global end of trial date |
12 Sep 2014
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Results information
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Results version number |
v2(current) |
This version publication date |
26 Mar 2016
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First version publication date |
29 Apr 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 |
H3M116477
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
- | ||
WHO universal trial number (UTN) |
- | ||
Sponsors
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Sponsor organisation name |
GlaxoSmithKline
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Sponsor organisation address |
980 Great West Road, Brentford, Middlesex, United Kingdom,
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Public contact |
GSK Response Center, GlaxoSmithKline, 1 866-435-7343,
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Scientific contact |
GSK Response Center, GlaxoSmithKline, 1 866-435-7343,
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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 |
31 Oct 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 |
12 Sep 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 |
Estimation of the effects of GSK239512 on lesion remyelination in subjects with Relapsing Remitting Multiple Sclerosis on stable treatment
with Avonex [interferon-beta1a] or Copaxone [glatiramer acetate].
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Protection of trial subjects |
A 4-week flexible titration period was used to achieve the final dose for each participant to minimize the occurrence of adverse events. In addition, participants were permitted to down-titrate during the maintenance period, if they experienced tolerability issues.
This study did not require participants to return to the study site for evaluation of relapses, if they chose to go to their local physician. This study did not restrict the use of rescue medications (e.g. glucocorticoids) to manage the occurrence of a relapse. However, due to the potential interference with the magnetic resonance imaging (MRI), , if a relapse requiring management with glucocorticoids occurred around the time of a scheduled MRI, the MRI was to be rescheduled to ensure that the subject has a minimum of a 1 week washout period following completion of treatment with glucocorticoids.
The study included flexible visit day scheduling to allow inclusion of holiday periods over the 1 year duration with intensive visit schedule.
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Background therapy |
- | ||
Evidence for comparator |
- | ||
Actual start date of recruitment |
01 Feb 2013
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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 |
Spain: 23
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Country: Number of subjects enrolled |
Sweden: 1
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Country: Number of subjects enrolled |
United Kingdom: 9
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Country: Number of subjects enrolled |
Bulgaria: 12
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Country: Number of subjects enrolled |
Czech Republic: 4
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Country: Number of subjects enrolled |
Germany: 26
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Country: Number of subjects enrolled |
Canada: 5
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Country: Number of subjects enrolled |
Ukraine: 51
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Worldwide total number of subjects |
131
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EEA total number of subjects |
75
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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) |
131
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From 65 to 84 years |
0
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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 |
Participants (par.) diagnosed with a relapsing-remitting multiple sclerosis (RRMS) on stable background treatment with either avonex or copaxone were eligible to participate. | |||||||||||||||||||||||||||
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, Monitor, Data analyst, Carer, Assessor | |||||||||||||||||||||||||||
Arms
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Are arms mutually exclusive |
Yes
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Arm title
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Placebo QD | |||||||||||||||||||||||||||
Arm description |
Participants received GSK239512 matching placebo tablets orally once daily (QD) during the 4 week titration period followed by the 44 week treatment maintenance period. The treatment period could be adapted to a 5 week titration and 43 week maintenance period, if needed. A single down-titration was allowed during the maintenance period if MTD was lower than the maximum dose achieved during titration. Participants continued with their current standard of care background disease modifying therapy (DMT) of either avonex or copaxone throughout the study. | |||||||||||||||||||||||||||
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 |
Placebo - 10 µg, 20 µg, 40 µg, or 80 µg once daily
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Arm title
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GSK239512 QD | |||||||||||||||||||||||||||
Arm description |
Participants received titration doses of GSK239512 tablets orally QD, starting at 10 micrograms (μg) and increased up to 80 μg during the 4 week titration period (10 μg first week, 20 μg second week, 40 μg third week, 80 μg fourth week) in order to select the maximum tolerated dose (MTD). Participants continued on the MTD of GSK239512 during the 44 week treatment maintenance period. The treatment period could be adapted to a 5 week titration and 43 week maintenance period, if needed. A single down-titration was allowed during the maintenance period if MTD was lower than the maximum dose achieved during titration. Participants continued with their current standard of care background DMT of either avonex or copaxone throughout the study. | |||||||||||||||||||||||||||
Arm type |
Experimental | |||||||||||||||||||||||||||
Investigational medicinal product name |
GSK239512
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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 |
10 µg, 20 µg, 40 µg, or 80 µg once daily
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Baseline characteristics reporting groups
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Reporting group title |
Placebo QD
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Reporting group description |
Participants received GSK239512 matching placebo tablets orally once daily (QD) during the 4 week titration period followed by the 44 week treatment maintenance period. The treatment period could be adapted to a 5 week titration and 43 week maintenance period, if needed. A single down-titration was allowed during the maintenance period if MTD was lower than the maximum dose achieved during titration. Participants continued with their current standard of care background disease modifying therapy (DMT) of either avonex or copaxone throughout the study. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
GSK239512 QD
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Reporting group description |
Participants received titration doses of GSK239512 tablets orally QD, starting at 10 micrograms (μg) and increased up to 80 μg during the 4 week titration period (10 μg first week, 20 μg second week, 40 μg third week, 80 μg fourth week) in order to select the maximum tolerated dose (MTD). Participants continued on the MTD of GSK239512 during the 44 week treatment maintenance period. The treatment period could be adapted to a 5 week titration and 43 week maintenance period, if needed. A single down-titration was allowed during the maintenance period if MTD was lower than the maximum dose achieved during titration. Participants continued with their current standard of care background DMT of either avonex or copaxone throughout the study. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
Placebo QD
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Reporting group description |
Participants received GSK239512 matching placebo tablets orally once daily (QD) during the 4 week titration period followed by the 44 week treatment maintenance period. The treatment period could be adapted to a 5 week titration and 43 week maintenance period, if needed. A single down-titration was allowed during the maintenance period if MTD was lower than the maximum dose achieved during titration. Participants continued with their current standard of care background disease modifying therapy (DMT) of either avonex or copaxone throughout the study. | ||
Reporting group title |
GSK239512 QD
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Reporting group description |
Participants received titration doses of GSK239512 tablets orally QD, starting at 10 micrograms (μg) and increased up to 80 μg during the 4 week titration period (10 μg first week, 20 μg second week, 40 μg third week, 80 μg fourth week) in order to select the maximum tolerated dose (MTD). Participants continued on the MTD of GSK239512 during the 44 week treatment maintenance period. The treatment period could be adapted to a 5 week titration and 43 week maintenance period, if needed. A single down-titration was allowed during the maintenance period if MTD was lower than the maximum dose achieved during titration. Participants continued with their current standard of care background DMT of either avonex or copaxone throughout the study. |
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End point title |
Mean change in gadolinium enhanced (GdE) lesion magnetization transfer ratio (MTR) value post-Lesion (PoL) from pre-Lesion (PrL) | ||||||||||||
End point description |
Brain magnetic resonance imaging (MRI) scans were performed to assess MTR values for gadolinium GdE lesions. GdE lesions are areas of inflammation detected by injecting GdE. Changes in MTR values are indicative of changes in brain myelin content associated with lesion remyelination. MRI scans were performed at Baseline, Weeks 6, 12, 18, 24, 30, 36, 42 and 48. The change in MTR value PoL from PrL was the change in the average PoL MRI scans MTR from the average PrL MRI scans MTR. The analysis method used was the mixed-model repeated measures (MMRM) adjusted for treatment, relative MRI, lesion volume, background MS DMT, average PrL MTR, and treatment, lesion volume, background DMT and average PrL MTR all by relative MRI. Analysis excluded MRI scans within 70 days of lesion occurrence and included data for lesions with at least 2 MRI assessments PrL and PoL. Intent-to-Treat (ITT) Population: par. who received >=1 dose of investigational product post randomization.
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End point type |
Primary
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End point timeframe |
Up to Week 48
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Notes [1] - ITT Population. Par. with evaluable lesions available at the specified time points were analyzed. [2] - ITT Population. Par. with evaluable lesions available at the specified time points were analyzed. |
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Statistical analysis title |
Analysis 1 | ||||||||||||
Comparison groups |
Placebo QD v GSK239512 QD
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Number of subjects included in analysis |
55
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Analysis specification |
Pre-specified
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Analysis type |
superiority [3] | ||||||||||||
Method |
Mixed models analysis | ||||||||||||
Parameter type |
Effect Size | ||||||||||||
Point estimate |
0.344
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Confidence interval |
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level |
90% | ||||||||||||
sides |
2-sided
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lower limit |
0.018 | ||||||||||||
upper limit |
0.671 | ||||||||||||
Notes [3] - The standardized Effect Sizes were derived as the treatment difference divided by the standard deviation (estimated as the between subject variability from the analysis model) of the treatment difference averaged across visits 'Relative MRIs'". Posterior Probability that Effect Size is >0 is 0.955 |
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End point title |
Mean change in Delta-MTR Lesions MTR value PoL from PrL | ||||||||||||
End point description |
Brain magnetic resonance imaging (MRI) scans were performed to assess MTR of Delta-MTR lesions. Delta-MTR lesions are areas of change in MTR detected by comparison to prior images. Changes in MTR values are indicative of changes in brain myelin content associated with lesion remyelination. MRI scans were performed at Baseline, Weeks 6, 12, 18, 24, 30, 36, 42 and 48. The change in MTR value PoL from PrL was the change in average PoL MRI scans MTR from the average PrL MRI scans MTR. The analysis method was MMRM adjusted for treatment, relative MRI, lesion volume, background MS DMT, average PrL MTR, treatment by relative MRI, lesion volume by relative MRI, background DMT by relative MRI and average PrL MTR by relative MRI. Analysis excluded MRI scans within 70 days of lesion occurrence and included data for lesions with at least 2 MRI assessments PrL and PoL.
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End point type |
Primary
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End point timeframe |
Up to Week 48
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Notes [4] - ITT Population. Par. with evaluable lesions available at the specified time points were analyzed. [5] - ITT Population. Par. with evaluable lesions available at the specified time points were analyzed. |
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Statistical analysis title |
Analysis 1 | ||||||||||||
Comparison groups |
Placebo QD v GSK239512 QD
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Number of subjects included in analysis |
53
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Analysis specification |
Pre-specified
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Analysis type |
superiority [6] | ||||||||||||
Method |
Mixed models analysis | ||||||||||||
Parameter type |
Effect Size | ||||||||||||
Point estimate |
0.243
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Confidence interval |
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level |
90% | ||||||||||||
sides |
2-sided
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lower limit |
-0.112 | ||||||||||||
upper limit |
0.598 | ||||||||||||
Notes [6] - The standardized Effect Sizes were derived as the treatment difference divided by the standard deviation (estimated as the between subject variability from the analysis model) of the treatment difference averaged across visits 'Relative MRIs'". Posterior Probability that Effect Size is >0 is 0.877 |
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End point title |
Change from Baseline in T2 lesion MTR at Week 48 | ||||||||||||
End point description |
Brain MRI scans were performed to assess MTR of T2 lesions, which is indicative of brain myelin content. Changes in MTR values are indicative of changes in brain myelin content associated with lesion remyelination. T2 lesions are also called hyperintense lesions, meaning that they appear as bright spots on the MRI image. Baseline was defined as the participant’s last available assessment prior to initiation of study medication. Change from Baseline was calculated as the Week 48 value minus the Baseline value. The analysis method was MMRM adjusted for treatment, visit, screening T2 lesion MTR value, background MS DMT, treatment by visit, screening T2 lesion MTR value by visit and background DMT by visit.
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End point type |
Secondary
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End point timeframe |
Baseline and Week 48
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Notes [7] - ITT Population. Par. with evaluable lesions available at the specified time points were analyzed. [8] - ITT Population. Par. with evaluable lesions available at the specified time points were analyzed. |
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Statistical analysis title |
Analysis 1 | ||||||||||||
Comparison groups |
Placebo QD v GSK239512 QD
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Number of subjects included in analysis |
107
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Analysis specification |
Pre-specified
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Analysis type |
superiority [9] | ||||||||||||
Method |
Mixed models analysis | ||||||||||||
Parameter type |
Effect Size | ||||||||||||
Point estimate |
-0.246
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Confidence interval |
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level |
90% | ||||||||||||
sides |
2-sided
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lower limit |
-0.588 | ||||||||||||
upper limit |
0.095 | ||||||||||||
Notes [9] - The standardized Effect Sizes were derived as the treatment difference divided by the standard deviation (estimated as the between subject variability from the analysis model) of the treatment difference averaged across visits 'Relative MRIs'". |
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End point title |
Cumulative number of new GdE lesions, new enlarging T2 lesions and combined unique active lesions at Week 48 | |||||||||||||||||||||
End point description |
The cumulative number of new GdE lesions (NGL), new enlarging T2 lesions (NET2L) and cumulative unique active lesions (CUAL) per scan at Week 48 were analyzed. The analysis was performed by general linear model assuming an underlying negative binomial distribution with a log-link function adjusted for treatment, background DMT and gadolinium enhancing lesion screening status to evaluate the mean number of lesions per MRI scan. The all evaluable scans dataset was used which included all evaluable on-treatment MRI scans for each participant.
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End point type |
Secondary
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End point timeframe |
Week 48
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Notes [10] - ITT Population. Par. with post-Baseline MRI were analyzed. [11] - ITT Population. Par. with post-Baseline MRI were analyzed. |
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Statistical analysis title |
Analysis 1 | |||||||||||||||||||||
Comparison groups |
Placebo QD v GSK239512 QD
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Number of subjects included in analysis |
130
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Analysis specification |
Pre-specified
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Analysis type |
superiority [12] | |||||||||||||||||||||
Method |
General Linear Model | |||||||||||||||||||||
Parameter type |
Ratio | |||||||||||||||||||||
Point estimate |
1.72
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Confidence interval |
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level |
90% | |||||||||||||||||||||
sides |
2-sided
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lower limit |
1.05 | |||||||||||||||||||||
upper limit |
2.82 | |||||||||||||||||||||
Notes [12] - Treatment Comparison ratio for NGL at Week 48. |
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Statistical analysis title |
Analysis 2 | |||||||||||||||||||||
Comparison groups |
Placebo QD v GSK239512 QD
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Number of subjects included in analysis |
130
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Analysis specification |
Pre-specified
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Analysis type |
superiority [13] | |||||||||||||||||||||
Method |
General Linear Model | |||||||||||||||||||||
Parameter type |
Ratio | |||||||||||||||||||||
Point estimate |
1.18
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Confidence interval |
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level |
90% | |||||||||||||||||||||
sides |
2-sided
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lower limit |
0.75 | |||||||||||||||||||||
upper limit |
1.85 | |||||||||||||||||||||
Notes [13] - Treatment Comparison ratio for NET2L at Week 48. |
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Statistical analysis title |
Analysis 3 | |||||||||||||||||||||
Comparison groups |
Placebo QD v GSK239512 QD
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Number of subjects included in analysis |
130
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Analysis specification |
Pre-specified
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Analysis type |
superiority [14] | |||||||||||||||||||||
Method |
General Linear Model | |||||||||||||||||||||
Parameter type |
Ratio | |||||||||||||||||||||
Point estimate |
1.17
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Confidence interval |
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level |
90% | |||||||||||||||||||||
sides |
2-sided
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lower limit |
0.74 | |||||||||||||||||||||
upper limit |
1.85 | |||||||||||||||||||||
Notes [14] - Treatment Comparison ratio for CUAL at Week 48. |
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End point title |
Change from Baseline in whole brain volume at Week 48 | ||||||||||||
End point description |
Whole brain volume is a measure of brain size determined by a MRI scan. Baseline is defined as the participant’s last available assessment prior to initiation of study medication. The normalized brain volume at Week 48 was derived from the dataset presenting change from baseline as follows: Week 48 Volume = Baseline Volume plus (Baseline Volume x Relative Change at Week 48). The analysis was performed by the analysis of covariance adjusted for treatment, screening brain volume, and background MS DMT. The observed case (OC) dataset was used which contained all the available change from Baseline responses for each participant without missing values being estimated or data carried forward.
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End point type |
Secondary
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End point timeframe |
Baseline and Week 48
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Notes [15] - ITT Population. Only those par. available at the specified time points were analyzed. [16] - ITT Population. Only those par. available at the specified time points were analyzed. |
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Statistical analysis title |
Analysis 1 | ||||||||||||
Comparison groups |
GSK239512 QD v Placebo QD
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Number of subjects included in analysis |
109
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Analysis specification |
Pre-specified
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Analysis type |
superiority [17] | ||||||||||||
Method |
ANCOVA | ||||||||||||
Parameter type |
Effect Size | ||||||||||||
Point estimate |
-0.2
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Confidence interval |
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level |
90% | ||||||||||||
sides |
2-sided
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lower limit |
-0.5 | ||||||||||||
upper limit |
0.2 | ||||||||||||
Notes [17] - Placebo QD versus GSK239512 QD for whole brain volume at Week 48. Effect size is the difference of the means in the two treatment groups divided by the standard deviation from the statistical model. |
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End point title |
Change from Baseline in white matter volume and grey matter volume at Week 48 | ||||||||||||||||||
End point description |
White matter volume and grey matter volume are measures of size of different areas of the brain determined by a MRI scan. Baseline is defined as the participant’s last available assessment prior to initiation of study medication. The white matter volume and grey matter volume at a post Baseline MRI was derived as follows: Post Baseline Volume = Baseline Volume plus (Baseline Volume x Relative Change Post Baseline). Change from Baseline in each volume was calculated as the Week 48 value minus the Baseline value. The analysis was performed using a mixed model for repeated measures adjusted for treatment, visit, baseline volume, background MS DMT, interactions between visit are also included. The observed case (OC) dataset was used which contained all the available change from Baseline responses for each participant at each visit, without missing values being estimated or data carried forward.
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End point type |
Secondary
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End point timeframe |
Baseline and Week 48
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Notes [18] - ITT Population. Only those par. available at the specified time points were analyzed. [19] - ITT Population. Only those par. available at the specified time points were analyzed. |
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Statistical analysis title |
Analysis 1 | ||||||||||||||||||
Comparison groups |
Placebo QD v GSK239512 QD
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Number of subjects included in analysis |
109
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Analysis specification |
Pre-specified
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Analysis type |
superiority [20] | ||||||||||||||||||
Method |
Mixed models analysis | ||||||||||||||||||
Parameter type |
Effect Size | ||||||||||||||||||
Point estimate |
-0.3
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Confidence interval |
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level |
90% | ||||||||||||||||||
sides |
2-sided
|
||||||||||||||||||
lower limit |
-0.6 | ||||||||||||||||||
upper limit |
0.1 | ||||||||||||||||||
Notes [20] - Placebo QD versus GSK239512 QD for white matter volume at Week 48. Effect size is the difference of the means in the two treatment groups divided by the standard deviation from the statistical model. |
|||||||||||||||||||
Statistical analysis title |
Analysis 2 | ||||||||||||||||||
Comparison groups |
Placebo QD v GSK239512 QD
|
||||||||||||||||||
Number of subjects included in analysis |
109
|
||||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||||
Analysis type |
superiority [21] | ||||||||||||||||||
Method |
Mixed models analysis | ||||||||||||||||||
Parameter type |
Effect Size | ||||||||||||||||||
Point estimate |
-0.1
|
||||||||||||||||||
Confidence interval |
|||||||||||||||||||
level |
90% | ||||||||||||||||||
sides |
2-sided
|
||||||||||||||||||
lower limit |
-0.5 | ||||||||||||||||||
upper limit |
0.3 | ||||||||||||||||||
Notes [21] - Placebo QD versus GSK239512 QD for grey matter volume at Week 48. Effect size is the difference of the means in the two treatment groups divided by the standard deviation from the statistical model. |
|
|||||||||||||
End point title |
Cumulative number of new unenhancing T1 lesions at Week 48 | ||||||||||||
End point description |
The cumulative number of new GdE lesions evolving into black holes (NGLEB) by Week 48 were analyzed. The analysis was performed by the general linear model assuming an underlying negative binomial distribution with a log-link function adjusted for treatment, background DMT and gadolinium enhancing lesion screening status. The all evaluable scans dataset was used which included all evaluable on-treatment MRI scans for each participant.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Week 48
|
||||||||||||
|
|||||||||||||
Notes [22] - ITT Population. Par. with post-Baseline MRI were analyzed. [23] - ITT Population. Par. with post-Baseline MRI were analyzed. |
|||||||||||||
Statistical analysis title |
Analysis 1 | ||||||||||||
Comparison groups |
Placebo QD v GSK239512 QD
|
||||||||||||
Number of subjects included in analysis |
130
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
superiority [24] | ||||||||||||
Method |
General Linear Model | ||||||||||||
Parameter type |
Ratio | ||||||||||||
Point estimate |
1.38
|
||||||||||||
Confidence interval |
|||||||||||||
level |
90% | ||||||||||||
sides |
2-sided
|
||||||||||||
lower limit |
0.87 | ||||||||||||
upper limit |
2.18 | ||||||||||||
Notes [24] - Treatment Comparison ratio for UT1L at Week 48. |
|
|||||||||||||
End point title |
Cumulative number of new GdE lesions evolving into black holes by Week 48 | ||||||||||||
End point description |
The cumulative number of new GdE lesions evolving into black holes (NGLEB) by Week 48 were analyzed. The analysis was performed by the general linear model assuming an underlying negative binomial distribution with a log-link function adjusted for treatment, background DMT and gadolinium enhancing lesion screening status. The all evaluable scans dataset was used which included all evaluable on-treatment MRI scans for each participant.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Week 48
|
||||||||||||
|
|||||||||||||
Notes [25] - ITT Population. Only those par. available at the specified time points were analyzed. [26] - ITT Population. Only those par. available at the specified time points were analyzed. |
|||||||||||||
Statistical analysis title |
Analysis 1 | ||||||||||||
Comparison groups |
Placebo QD v GSK239512 QD
|
||||||||||||
Number of subjects included in analysis |
120
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
superiority [27] | ||||||||||||
Method |
General Linear Model | ||||||||||||
Parameter type |
Ratio | ||||||||||||
Point estimate |
1.71
|
||||||||||||
Confidence interval |
|||||||||||||
level |
90% | ||||||||||||
sides |
2-sided
|
||||||||||||
lower limit |
1.05 | ||||||||||||
upper limit |
2.78 | ||||||||||||
Notes [27] - Treatment Comparison ratio for NGLEB at Week 48. |
|
|||||||||||||||||||||||||
End point title |
Change from Baseline (BL) in CogState battery total score (TS), executive function composite score (EFCS), memory composite score (MCS) and attention composite score (ACS) at Week 48 | ||||||||||||||||||||||||
End point description |
The CogState battery used in this study consists of 7 tasks for which multiple outcome measures are collected and used in the derivation of the composite cognitive domain scores. Test scores were interpreted on the basis of normative data and expected level of performance. The assessment was conducted at Screen (twice), BL, and Weeks 12, 24 and 48. Change from BL in TS, EFCS, MCS and ACS is summarised at Week 48.The BL is the mean of the second Screening assessment and the BL (pre-dose) assessment, if both were avail or the non-missing value if only one was avail. Change from BL is calculated as post-BL value minus BL value. The analysis method was MMRM adjusted for treatment, visit, BL executive function score, background MS DMT, and interaction by visit. Only those par. available at specified time points were analyzed. Different par. may have been analyzed at different time points, so the overall number of par. analyzed reflects everyone in the ITT Population.
|
||||||||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||||||||
End point timeframe |
Baseline and Week 48
|
||||||||||||||||||||||||
|
|||||||||||||||||||||||||
Notes [28] - ITT Population [29] - ITT Population |
|||||||||||||||||||||||||
Statistical analysis title |
Analysis 1 | ||||||||||||||||||||||||
Comparison groups |
Placebo QD v GSK239512 QD
|
||||||||||||||||||||||||
Number of subjects included in analysis |
131
|
||||||||||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||||||||||
Analysis type |
superiority [30] | ||||||||||||||||||||||||
Method |
Mixed models analysis | ||||||||||||||||||||||||
Parameter type |
Effect Size | ||||||||||||||||||||||||
Point estimate |
-0.237
|
||||||||||||||||||||||||
Confidence interval |
|||||||||||||||||||||||||
level |
90% | ||||||||||||||||||||||||
sides |
2-sided
|
||||||||||||||||||||||||
lower limit |
-0.588 | ||||||||||||||||||||||||
upper limit |
0.113 | ||||||||||||||||||||||||
Notes [30] - Placebo QD versus GSK239512 QD for TS at Week 48. Effect size is the difference of the means in the two treatment groups divided by the standard deviation from the statistical model. |
|||||||||||||||||||||||||
Statistical analysis title |
Analysis 2 | ||||||||||||||||||||||||
Comparison groups |
GSK239512 QD v Placebo QD
|
||||||||||||||||||||||||
Number of subjects included in analysis |
131
|
||||||||||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||||||||||
Analysis type |
superiority [31] | ||||||||||||||||||||||||
Method |
Mixed models analysis | ||||||||||||||||||||||||
Parameter type |
Effect Size | ||||||||||||||||||||||||
Point estimate |
-0.045
|
||||||||||||||||||||||||
Confidence interval |
|||||||||||||||||||||||||
level |
90% | ||||||||||||||||||||||||
sides |
2-sided
|
||||||||||||||||||||||||
lower limit |
-0.373 | ||||||||||||||||||||||||
upper limit |
0.283 | ||||||||||||||||||||||||
Notes [31] - Placebo QD versus GSK239512 QD for EFCS at Week 48. Effect size is the difference of the means in the two treatment groups divided by the standard deviation from the statistical model. |
|||||||||||||||||||||||||
Statistical analysis title |
Analysis 3 | ||||||||||||||||||||||||
Comparison groups |
Placebo QD v GSK239512 QD
|
||||||||||||||||||||||||
Number of subjects included in analysis |
131
|
||||||||||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||||||||||
Analysis type |
superiority [32] | ||||||||||||||||||||||||
Method |
Mixed models analysis | ||||||||||||||||||||||||
Parameter type |
Effect Size | ||||||||||||||||||||||||
Point estimate |
-0.311
|
||||||||||||||||||||||||
Confidence interval |
|||||||||||||||||||||||||
level |
90% | ||||||||||||||||||||||||
sides |
2-sided
|
||||||||||||||||||||||||
lower limit |
-0.65 | ||||||||||||||||||||||||
upper limit |
0.028 | ||||||||||||||||||||||||
Notes [32] - Placebo QD versus GSK239512 QD for MCS at Week 48. Effect size is the difference of the means in the two treatment groups divided by the standard deviation from the statistical model. |
|||||||||||||||||||||||||
Statistical analysis title |
Analysis 4 | ||||||||||||||||||||||||
Comparison groups |
Placebo QD v GSK239512 QD
|
||||||||||||||||||||||||
Number of subjects included in analysis |
131
|
||||||||||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||||||||||
Analysis type |
superiority [33] | ||||||||||||||||||||||||
Method |
Mixed models analysis | ||||||||||||||||||||||||
Parameter type |
Effect Size | ||||||||||||||||||||||||
Point estimate |
-0.092
|
||||||||||||||||||||||||
Confidence interval |
|||||||||||||||||||||||||
level |
90% | ||||||||||||||||||||||||
sides |
2-sided
|
||||||||||||||||||||||||
lower limit |
-0.447 | ||||||||||||||||||||||||
upper limit |
0.263 | ||||||||||||||||||||||||
Notes [33] - Placebo QD versus GSK239512 QD for ACS at Week 48. Effect size is the difference of the means in the two treatment groups divided by the standard deviation from the statistical model. |
|
|||||||||||||
End point title |
Relapse rate during the treatment phase | ||||||||||||
End point description |
A relapse is defined as participant-reported symptoms or objectively observed signs typical of an acute inflammatory demyelinating event in the central nervous system (CNS). It must occur in the absence of fever or infection and should follow improvement from a previous relapse, occur at least 30 days following the onset of a previous relapse, and be persistent for at least 24 hours. The analysis method was a maximum likelihood based analysis, assuming the Negative Binomial distribution with time on treatment measured in days as an offset variable for relapse occurrence. The model included adjustment for background DMT and treatment.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Up to Week 48
|
||||||||||||
|
|||||||||||||
Notes [34] - ITT Population [35] - ITT Population |
|||||||||||||
Statistical analysis title |
Analysis 1 | ||||||||||||
Comparison groups |
Placebo QD v GSK239512 QD
|
||||||||||||
Number of subjects included in analysis |
131
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
superiority [36] | ||||||||||||
Method |
Binomial Model | ||||||||||||
Parameter type |
Ratio | ||||||||||||
Point estimate |
1.044
|
||||||||||||
Confidence interval |
|||||||||||||
level |
90% | ||||||||||||
sides |
2-sided
|
||||||||||||
lower limit |
0.615 | ||||||||||||
upper limit |
1.772 | ||||||||||||
Notes [36] - Treatment Comparison Ratio for Relapse Rate |
|
||||||||||
End point title |
Number of participants relapsing during the treatment phase | |||||||||
End point description |
A relapse is defined as:"participant-reported symptoms or objectively observed signs typical of an acute inflammatory demyelinating event in the central nervous system (CNS), current or historical". It must occur in the absence of fever or infection and should - follow improvement from a previous relapse, occur at least 30 days following the onset of a previous relapse, and be persistent for at least 24 hours. Number of participants relapsing during the treatment phase was analyzed using logistic regression adjusted for treatment and background DMT.
|
|||||||||
End point type |
Secondary
|
|||||||||
End point timeframe |
Up to Week 48
|
|||||||||
|
||||||||||
Notes [37] - ITT Population [38] - ITT Population |
||||||||||
Statistical analysis title |
Analysis 1 | |||||||||
Comparison groups |
Placebo QD v GSK239512 QD
|
|||||||||
Number of subjects included in analysis |
131
|
|||||||||
Analysis specification |
Pre-specified
|
|||||||||
Analysis type |
superiority [39] | |||||||||
Method |
Regression, Logistic | |||||||||
Parameter type |
Odds ratio (OR) | |||||||||
Point estimate |
0.88
|
|||||||||
Confidence interval |
||||||||||
level |
90% | |||||||||
sides |
2-sided
|
|||||||||
lower limit |
0.47 | |||||||||
upper limit |
1.66 | |||||||||
Notes [39] - Treatment Comparison Odds Ratio (GSK239512/Placebo). A ratio <1 indicates a lower risk with GSK239512 compared with placebo. |
|
||||||||||
End point title |
Analysis of the time to first relapse | |||||||||
End point description |
A relapse is defined as participant-reported symptoms or objectively observed signs typical of an acute inflammatory demyelinating event in the central nervous system (CNS). It must occur in the absence of fever or infection and should follow improvement from a previous relapse, occur at least 30 days following the onset of a previous relapse, and be persistent for at least 24 hours. Date of relapse was captured for each subject and occurrence, if a relapse occurred. Time tofirst relapse was calculated as the relapse onset date minus date study medication was started plus one day. Analysis was performed using using a Cox’s Proportional Hazards model adjusting for background DMT. A hazard ratio <1 indicates a lower risk with GSK239512 compared with placebo.
|
|||||||||
End point type |
Secondary
|
|||||||||
End point timeframe |
Up to Week 48
|
|||||||||
|
||||||||||
Notes [40] - ITT Population [41] - ITT Population |
||||||||||
Statistical analysis title |
Analysis 1 | |||||||||
Comparison groups |
Placebo QD v GSK239512 QD
|
|||||||||
Number of subjects included in analysis |
131
|
|||||||||
Analysis specification |
Pre-specified
|
|||||||||
Analysis type |
superiority [42] | |||||||||
Method |
Cox's Proportional Hazards model | |||||||||
Parameter type |
Hazard ratio (HR) | |||||||||
Point estimate |
0.965
|
|||||||||
Confidence interval |
||||||||||
level |
90% | |||||||||
sides |
2-sided
|
|||||||||
lower limit |
0.565 | |||||||||
upper limit |
1.647 | |||||||||
Notes [42] - A hazard ratio <1 indicates a lower risk with GSK239512 compared with placebo. |
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point title |
Expanded Disability Status Scale (EDSS) score at Week 48 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point description |
EDSS is a scale to measure the disability status of participants with multiple sclerosis based on the presence of certain symptoms. EDSS provides a total score on a scale that ranges from 0 to 10 based on functional system (FS) scores and walking abilities. The first levels 1.0 to 4.5 refer to participants with a high degree of ambulatory ability and the subsequent levels 5.0 to 9.5 are highly influenced by changes in walking ability. FS (with max score) are: visual converted (VC;4), brainstem (BS;5), pyramidal (P;6), cerebellar (Cr;5), sensory (S;6), bowel and bladder converted (BB;5), cerebral (Cb;5) and ambulatory (A; 12). Values are represented as mean values for the population at Baseline and Week 48.
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point timeframe |
Week 48
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Notes [43] - ITT Population [44] - ITT Population |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
No statistical analyses for this end point |
|
||||||||||||||||||||||||||||||||||
End point title |
Number of participants with the indicated change from the BL in EDSS score over 48 weeks | |||||||||||||||||||||||||||||||||
End point description |
EDSS is a scale to measure the disability status of par. with multiple sclerosis based on the presence of certain symptoms. EDSS provides a total score on a scale that ranges from 0 to 10 based on functional system (FS) scores and walking abilities. The first levels 1.0 to 4.5 refer to par.with high degree of ambulatory ability and the subsequent levels 5.0 to 9.5 are highly influenced by changes in walking ability. Change from the Baseline in EDSS is summarised up to Week 48. Baseline is defined as the par’s last available assessment prior to initiation of study medication. Improved is defined as a 1.0 decrease and worsened is defined as a 1.0 increase in EDSS score from baseline score. Only those par.available at the specified time points were analyzed (represented by n=X,X in category titles). Different par.may have been analyzed at different time points, so the overall number of par.analyzed reflects everyone in the ITT Population.
|
|||||||||||||||||||||||||||||||||
End point type |
Secondary
|
|||||||||||||||||||||||||||||||||
End point timeframe |
Baseline and Week 12, 24, 36 and 48
|
|||||||||||||||||||||||||||||||||
|
||||||||||||||||||||||||||||||||||
Notes [45] - ITT Population [46] - ITT Population |
||||||||||||||||||||||||||||||||||
No statistical analyses for this end point |
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point title |
Number of participants with sustained worsening of the Expanded Disability Status Scale (EDSS) score at Week 48 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point description |
EDSS is a scale to measure the disability status of participants with multiple sclerosis based on the presence of certain symptoms. EDSS provides a total score on a scale that ranges from 0 to 10 based on functional system (FS) scores and walking abilities. The first levels 1.0 to 4.5 refer to participants with a high degree of ambulatory ability and the subsequent levels 5.0 to 9.5 are highly influenced by changes in walking ability. FS are: pyramidal (P), cerebellar (Cr), brainstem (BS), sensory (S), bowel and bladder converted (BB), visual converted (VC), cerebral (Cb) and ambulatory (A). A sustained change is defined as a change that has been sustained for at least 12 weeks at Week 48. Participants that had worsened from BL by 2 or more points are included in the >=1 point and the >=2 points categories for that FS. BL is defined as the participants last available assessment prior to initiation of study medication.
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point type |
Secondary
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point timeframe |
Week 48
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Notes [47] - ITT Population [48] - ITT Population |
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
No statistical analyses for this end point |
|
|||||||||||||||||||
End point title |
Change from Baseline at Week 48 in MSQoL Physical Function and Mental Function Composite Score | ||||||||||||||||||
End point description |
MSQoL is a 54 item assessment of the quality of life status of patients with multiple sclerosis and the Overall Quality of Life score is a composite of the physical function and mental function health composite scores. Scale scores were generated by averaging the items within scales and transforming the mean scores linearly from 0 to 100 possible scores, with higher scores indicating a better quality of life. BL is defined as the participants last available assessment prior to initiation of study medication. The assessment was conducted before randomized to treatment and at the end of treatment (Early Withdrawal or Week 48). The analysis was performed using an analysis of covariance adjusted for treatment, baseline composite score and background MS disease modifying therapy.
|
||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||
End point timeframe |
Early Withdrawal, Week 48
|
||||||||||||||||||
|
|||||||||||||||||||
Notes [49] - ITT Population. Only those par. with data available at the specified timepoints were analyzed. [50] - ITT Population. Only those par. with data available at the specified timepoints were analyzed. |
|||||||||||||||||||
Statistical analysis title |
Analysis 1 | ||||||||||||||||||
Comparison groups |
Placebo QD v GSK239512 QD
|
||||||||||||||||||
Number of subjects included in analysis |
128
|
||||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||||
Analysis type |
superiority [51] | ||||||||||||||||||
Method |
ANCOVA | ||||||||||||||||||
Parameter type |
Mean difference (net) | ||||||||||||||||||
Point estimate |
-2.95
|
||||||||||||||||||
Confidence interval |
|||||||||||||||||||
level |
90% | ||||||||||||||||||
sides |
2-sided
|
||||||||||||||||||
lower limit |
-6.72 | ||||||||||||||||||
upper limit |
0.82 | ||||||||||||||||||
Notes [51] - Placebo QD vs GSK239512 QD for Physical Function. A comparison of the mean change from baselinesin each treatment group. |
|||||||||||||||||||
Statistical analysis title |
Analysis 2 | ||||||||||||||||||
Comparison groups |
Placebo QD v GSK239512 QD
|
||||||||||||||||||
Number of subjects included in analysis |
128
|
||||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||||
Analysis type |
superiority [52] | ||||||||||||||||||
Method |
ANCOVA | ||||||||||||||||||
Parameter type |
Mean difference (net) | ||||||||||||||||||
Point estimate |
-5.02
|
||||||||||||||||||
Confidence interval |
|||||||||||||||||||
level |
90% | ||||||||||||||||||
sides |
2-sided
|
||||||||||||||||||
lower limit |
-9.06 | ||||||||||||||||||
upper limit |
-0.98 | ||||||||||||||||||
Notes [52] - Placebo QD vs GSK239512 QD for Mental Function. A comparison of the mean change from baselines in each treatment group. |
|
||||||||||||||||||||||||||||||||||||||||
End point title |
Number of participants with any adverse events (AEs) and any serious adverse events (SAEs) | |||||||||||||||||||||||||||||||||||||||
End point description |
An AE is any untoward medical occurrence in a par. temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. An AE can therefore be any unfavorable and unintended sign, symptom, or disease temporally associated with the use of a medicinal product. An SAE is any untoward medical occurrence that, at any dose, results in death, is life threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, a congenital anomaly/birth defect, important medical events that jeopardize the par. or may require medical or surgical intervention to prevent one of the other outcomes listed in the above definition. AEs and SAEs were assessed at Pre-TT phase (prior to first dose of investigational product (IP)), TT phase-48 Weeks (from first dose of IP to 3 days after last dose, including Titratration (T) and Maintenance (M) Periods) and Follow-Up phase (more than 3 days after last dose of IP)
|
|||||||||||||||||||||||||||||||||||||||
End point type |
Secondary
|
|||||||||||||||||||||||||||||||||||||||
End point timeframe |
Up to Week 50
|
|||||||||||||||||||||||||||||||||||||||
|
||||||||||||||||||||||||||||||||||||||||
Notes [53] - ITT Population [54] - ITT Population |
||||||||||||||||||||||||||||||||||||||||
No statistical analyses for this end point |
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point title |
Number of mild, moderate and severe AEs | ||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point description |
The Common Terminology Criteria for Adverse Events (CTCAE, Version 4) has categorised AEs in five grades. Grade refers to the severity of the AE. Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; intervention not indicated. Moderate; minimal, local or non-invasive intervention indicated; limiting age-appropriate instrumental activities of daily living. Severe or medically significant but not immediately life-threatening; hospitalization or prolongation of hospitalization indicated; disabling; limiting self care activities of daily living. AEs and SAEs were assessed at Pre-TT phase (period prior to the first dose of investigational product (IP)), TT phase-48 Weeks (from first dose of IP to 3 days after last dose with Titration (T) and Maintenace (M) Periods ) and Follow-Up phase (from more than 3 days after last dose of IP).
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point timeframe |
Up to Week 50
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||
Notes [55] - ITT Population [56] - ITT Population |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||
No statistical analyses for this end point |
|
||||||||||
End point title |
Number of participants withdrawn due to AEs | |||||||||
End point description |
An AE is defined as any untoward medical occurrence in a participant temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. An AE can therefore be any unfavorable and unintended sign, symptom, or disease temporally associated with the use of a medicinal product. An SAE is defined as any untoward medical occurrence that, at any dose, results in death, is life threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, a congenital anomaly/birth defect, important medical events that jeopardize the participants or may require medical or surgical intervention to prevent one of the other outcomes listed in the above definition.
|
|||||||||
End point type |
Secondary
|
|||||||||
End point timeframe |
Up to Week 50
|
|||||||||
|
||||||||||
Notes [57] - ITT Population [58] - ITT Population |
||||||||||
No statistical analyses for this end point |
|
||||||||||
End point title |
Number of participants within each category of the Columbia Suicide Severity Rating Scale | |||||||||
End point description |
Prospective assessment of suicidality was conducted using an Interactive Voice Response System delivery of Columbia-Suicide Severity Rating Scale (eC-SSRS), a brief questionnaire designed to assess severity and change in suicidality by integrating both behavior and ideation using a validated interview algorithm. The result is a score from 1-9 for eC-SSRS based on increasing order of severity with 1-5 identifying suicidal ideation and 6-9 identifying suicidal behaviors. Data is presented for number of participants with any non-zero score for an ideation or a behaviour.
|
|||||||||
End point type |
Secondary
|
|||||||||
End point timeframe |
Up to Week 50
|
|||||||||
|
||||||||||
Notes [59] - ITT Population [60] - ITT Population |
||||||||||
No statistical analyses for this end point |
|
|||||||||||||||||||
End point title |
Maximum on-treatment change from Baseline in the albumin and total protein values | ||||||||||||||||||
End point description |
Albumin and total protein values were assessed at Baseline and Week 1, 2, 3, 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, and 48. Maximum on-treatment value was derived including values at scheduled and unscheduled assessments. Baseline value was defined as the last pre-treatment value observed Change from Baseline was calculated as the post-Baseline value minus the Baseline value.
|
||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||
End point timeframe |
From Baseline up to Week 48
|
||||||||||||||||||
|
|||||||||||||||||||
Notes [61] - ITT Population [62] - ITT Population |
|||||||||||||||||||
No statistical analyses for this end point |
|
|||||||||||||||||||||||||
End point title |
Maximum on-treatment change from Baseline in the alkaline phosphatase, alanine amino transferase, aspartate amino transferase and gamma glutamyl transferase values | ||||||||||||||||||||||||
End point description |
Alkaline phosphatase (ALP), alanine amino transferase (ALT), aspartate amino transferase (AST) and gamma glutamyl transferase (GGT) values were assessed at Baseline and Week 1, 2, 3, 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, and 48. Maximum on-treatment value was derived including values at scheduled and unscheduled assessments. Baseline value was defined as the last pre-treatment value observed Change from Baseline was calculated as the post-Baseline value minus the Baseline value.
|
||||||||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||||||||
End point timeframe |
From Baseline up to Week 48
|
||||||||||||||||||||||||
|
|||||||||||||||||||||||||
Notes [63] - ITT Population [64] - ITT Population |
|||||||||||||||||||||||||
No statistical analyses for this end point |
|
||||||||||||||||||||||||||||
End point title |
Maximum on-treatment change from Baseline in the calcium, glucose, potassium, sodium and Urea/BUN values | |||||||||||||||||||||||||||
End point description |
Calcium, glucose, potassium, sodium and Urea/BUN values were assessed at Baseline and Week 1, 2, 3, 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, and 48. Maximum on-treatment value was derived including values at scheduled and unscheduled assessments. Baseline value was defined as the last pre-treatment value observed Change from Baseline was calculated as the post-Baseline value minus the Baseline value.
|
|||||||||||||||||||||||||||
End point type |
Secondary
|
|||||||||||||||||||||||||||
End point timeframe |
From Baseline up to Week 48
|
|||||||||||||||||||||||||||
|
||||||||||||||||||||||||||||
Notes [65] - ITT Population [66] - ITT Population |
||||||||||||||||||||||||||||
No statistical analyses for this end point |
|
||||||||||||||||||||||
End point title |
Maximum on-treatment change from Baseline in the creatinine, direct and total bilirubin values | |||||||||||||||||||||
End point description |
Creatinine, direct and total bilirubin values were assessed at Baseline and Week 1, 2, 3, 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, and 48. Maximum on-treatment value was derived including values at scheduled and unscheduled assessments. Baseline value was defined as the last pre-treatment value observed Change from Baseline was calculated as the post-Baseline value minus the Baseline value.
|
|||||||||||||||||||||
End point type |
Secondary
|
|||||||||||||||||||||
End point timeframe |
From Baseline up to Week 48
|
|||||||||||||||||||||
|
||||||||||||||||||||||
Notes [67] - ITT Population [68] - ITT Population |
||||||||||||||||||||||
No statistical analyses for this end point |
|
|||||||||||||
End point title |
Maximum on-treatment change from Baseline in the creatinine clearance values | ||||||||||||
End point description |
Creatinine clearance values were assessed at Baseline and Week 1, 2, 3, 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, and 48. Maximum on-treatment value was derived including values at scheduled and unscheduled assessments. Baseline value was defined as the last pre-treatment value observed Change from Baseline was calculated as the post-Baseline value minus the Baseline value.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
From Baseline up to Week 48
|
||||||||||||
|
|||||||||||||
Notes [69] - ITT Population [70] - ITT Population |
|||||||||||||
No statistical analyses for this end point |
|
||||||||||||||||||||||||||||||||||
End point title |
Maximum on-treatment change from Baseline in the basophils, eosinophils, lymphocytes, monocytes, platelets, total neutrophils and WBC count | |||||||||||||||||||||||||||||||||
End point description |
Basophils, eosinophils, lymphocytes, monocytes, platelets, total neutrophils and white blood cell (WBC) count were assessed at Baseline and Week 1, 2, 3, 4, 8, 16, 24, 32, 36, 40, and 48. Maximum on-treatment value was derived including values at scheduled and unscheduled assessments. Baseline value was defined as the last pre-treatment value observed Change from Baseline was calculated as the post-Baseline value minus the Baseline value.
|
|||||||||||||||||||||||||||||||||
End point type |
Secondary
|
|||||||||||||||||||||||||||||||||
End point timeframe |
From Baseline up to Week 48
|
|||||||||||||||||||||||||||||||||
|
||||||||||||||||||||||||||||||||||
Notes [71] - ITT Population [72] - ITT Population |
||||||||||||||||||||||||||||||||||
No statistical analyses for this end point |
|
|||||||||||||||||||
End point title |
Maximum on-treatment change from Baseline in the RBC and reticulocytes count | ||||||||||||||||||
End point description |
Red blood cell (RBC) and reticulocyte count were assessed at Baseline and Week 1, 2, 3, 4, 8, 16, 24, 32, 36, 40, and 48. Maximum on-treatment value was derived including values at scheduled and unscheduled assessments. Baseline value was defined as the last Pre-treatment value observed Change from Baseline was calculated as the post-Baseline value minus the Baseline value.
|
||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||
End point timeframe |
From Baseline up to Week 48
|
||||||||||||||||||
|
|||||||||||||||||||
Notes [73] - ITT Population [74] - ITT Population |
|||||||||||||||||||
No statistical analyses for this end point |
|
|||||||||||||||||||
End point title |
Maximum on-treatment change from Baseline in the hemoglobin and MCHC value | ||||||||||||||||||
End point description |
Hemoglobin and mean corpuscular hemoglobin concentration (EMCHC) values were assessed at Baseline and Week 1, 2, 3, 4, 8, 16, 24, 32, 36, 40, and 48. Maximum on-treatment value was derived including values at scheduled and unscheduled assessments. Baseline value was defined as the last Pre-treatment value observed Change from Baseline was calculated as the post-Baseline value minus the Baseline value.
|
||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||
End point timeframe |
From Baseline up to Week 48
|
||||||||||||||||||
|
|||||||||||||||||||
Notes [75] - ITT Population [76] - ITT Population |
|||||||||||||||||||
No statistical analyses for this end point |
|
|||||||||||||
End point title |
Maximum on-treatment change from Baseline in the MCH value | ||||||||||||
End point description |
Mean corpuscular hemoglobin (MCH) values were assessed at Baseline and Week 1, 2, 3, 4, 8, 16, 24, 32, 36, 40, and 48. Maximum on-treatment value was derived including values at scheduled and unscheduled assessments. Baseline value was defined as the last pre-treatment value observed Change from Baseline was calculated as the post-Baseline value minus the Baseline value.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
From Baseline up to Week 48
|
||||||||||||
|
|||||||||||||
Notes [77] - ITT Population [78] - ITT Population |
|||||||||||||
No statistical analyses for this end point |
|
|||||||||||||
End point title |
Maximum on-treatment change from Baseline in the MCV value | ||||||||||||
End point description |
Mean corpuscular volume (MCV) values were assessed at Baseline and Week 1, 2, 3, 4, 8, 16, 24, 32, 36, 40, and 48. Maximum on-treatment value was derived including values at scheduled and unscheduled assessments. Baseline value was defined as the last pre-treatment value observed Change from Baseline was calculated as the post-Baseline value minus the Baseline value.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
From Baseline up to Week 48
|
||||||||||||
|
|||||||||||||
Notes [79] - ITT Population [80] - ITT Population |
|||||||||||||
No statistical analyses for this end point |
|
|||||||||||||
End point title |
Maximum on-treatment change from Baseline in the hematocrit value | ||||||||||||
End point description |
Hematocrit values were assessed at Baseline and Week 1, 2, 3, 4, 8, 16, 24, 32, 36, 40, and 48. Maximum on-treatment value was derived including values at scheduled and unscheduled assessments. Baseline value was defined as the last pre-treatment value observed Change from Baseline was calculated as the post-Baseline value minus the Baseline value.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
From Baseline up to Week 48
|
||||||||||||
|
|||||||||||||
Notes [81] - ITT Population [82] - ITT Population |
|||||||||||||
No statistical analyses for this end point |
|
|||||||||||||
End point title |
Urinalysis parameters at the indicated time points up to Week 50 | ||||||||||||
End point description |
Urine samples were collected, tested and monitored at Baseline and Week 1, 2, 3, 4, 8, 16, 24, 32, 36, 40, 48 and 50. Baseline value was defined as the last pre-treatment value observed. The data were monitored for safety throughout the conduct of the study and no summary analysis or change from baseline was conducted. The urinalysis assessments were: Appearance/clarity, Color, pH, Specific Gravity. Urine was checked for presence of the following by dipstick: bilirubin, occult blood, glucose, ketones, nitrite, protein and a marker for white blood cells. Data are available only at the participant level for each assessment performed.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
From Baseline up to Week 50
|
||||||||||||
|
|||||||||||||
Notes [83] - ITT Population [84] - ITT Population |
|||||||||||||
No statistical analyses for this end point |
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point title |
Number of participants with chemistry laboratory values outside the clinical concern range at any time on-treatment | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point description |
Clinical chemistry parameters of potential clinical concern were assessed at Baseline and at Week 1, 2, 3, 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, and 48. Any time on-treatment value was derived including values at scheduled and unscheduled assessments. Clinical chemistry parameters included ALP, ALT, AST, GGT, albumin, total protein, calcium, glucose, potassium, sodium, Urea/BUN, creatinine, direct bilirubin, total bilirubin and creatinine clearance. Number of participants with values in high and low categories based on deviation in parameter values from normal range are summarized.
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point timeframe |
From Baseline up to Week 48
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Notes [85] - ITT Population [86] - ITT Population |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
No statistical analyses for this end point |
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point title |
Number of participants with hematology laboratory values outside the clinical concern range at any time on-treatment | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point description |
Clinical hematology parameters of potential clinical concern were assessed at Baseline and Week 1, 2, 3, 4, 8, 16, 24, 32, 40, and 48. The any time on-treatment value was derived including values at scheduled and unscheduled assessments.Clinical hematology parameters included basophils, eosinophils, hematocrit, hemoglobin, lymphocytes, MCH, MCHC, MCV, monocytes, platelets, RBC, reticulocytes, total neutrophils and WBC. Number of participants with values in high and low categories based on deviation in parameter values from normal range are summarized.
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point type |
Secondary
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point timeframe |
From Baseline up to Week 48
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Notes [87] - ITT Population [88] - ITT Population |
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
No statistical analyses for this end point |
|
|||||||||||||||||||
End point title |
Maximum on-treatment change from Baseline in the systolic blood pressure and diastolic blood pressure | ||||||||||||||||||
End point description |
Systolic blood pressure (BP) and diastolic BP were assessed at Baseline and at Week 1, 2, 3, 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, and 48. Maximum on-treatment value was derived including values at scheduled and unscheduled assessments. Baseline value was defined as the last Pre-treatment value observed. Change from Baseline was calculated as the post-Baseline value minus the Baseline value.
|
||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||
End point timeframe |
From Baseline up to Week 48
|
||||||||||||||||||
|
|||||||||||||||||||
Notes [89] - ITT Population [90] - ITT Population |
|||||||||||||||||||
No statistical analyses for this end point |
|
|||||||||||||
End point title |
Maximum on-treatment change from Baseline in the heart rate | ||||||||||||
End point description |
Heart rate was assessed at Baseline and Week 1, 2, 3, 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, and 48. Maximum on-treatment value was derived including values at scheduled and unscheduled assessments. Baseline value was defined as the last pre-treatment value observed. Change from Baseline was calculated as the post-Baseline value minus the Baseline value.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
From Baseline up to Week 48
|
||||||||||||
|
|||||||||||||
Notes [91] - ITT Population [92] - ITT Population |
|||||||||||||
No statistical analyses for this end point |
|
|||||||||||||
End point title |
Maximum on-treatment change from Baseline in the weight | ||||||||||||
End point description |
Weight was assessed at Baseline and Week 1, 2, 3, 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, and 48. Maximum on-treatment value was derived including values at scheduled and unscheduled assessments. Baseline value was defined as the last pre-treatment value observed. Change from Baseline was calculated as the post-Baseline value minus the Baseline value.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
From Baseline up to Week 48
|
||||||||||||
|
|||||||||||||
Notes [93] - ITT Population [94] - ITT Population |
|||||||||||||
No statistical analyses for this end point |
|
|||||||||||||
End point title |
Maximum on-treatment change from Baseline in the heart rate as a measure of ECG assessment | ||||||||||||
End point description |
Heart rate as a measure of electrocardiogram (ECG) assessment was assessed at Baseline and Week 2, 4, 12, 24, 36, and 48. Maximum on-treatment value was derived including values at scheduled and unscheduled assessments. Baseline value was defined as the last pre-treatment value observed. Change from Baseline was calculated as the post-Baseline value minus the Baseline value.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
From Baseline up to Week 48
|
||||||||||||
|
|||||||||||||
Notes [95] - ITT Population [96] - ITT Population |
|||||||||||||
No statistical analyses for this end point |
|
|||||||||||||||||||||||||||||||
End point title |
Maximum on-treatment change from Baseline in the PR Interval, QRS duration, QT interval, QTcB, QTcF and RR Interval as a measure of the ECG assessment | ||||||||||||||||||||||||||||||
End point description |
PR Interval, QRS duration, QT interval, QTcB, QTcF and RR interval as a measure of electrocardiogram (ECG) assessment were assessed at Baseline and Week 2, 4, 12, 24, 36, and 48. Maximum on-treatment value was derived including values at scheduled and unscheduled assessments. Baseline value was defined as the last pre-treatment value observed. Change from Baseline was calculated as the post-Baseline value minus the Baseline value.
|
||||||||||||||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||||||||||||||
End point timeframe |
From Baseline up to Week 48
|
||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||
Notes [97] - ITT Population [98] - ITT Population |
|||||||||||||||||||||||||||||||
No statistical analyses for this end point |
|
||||||||||||||||||||||||||||||||||
End point title |
Number of participants with change in the indicated vital sign with respect to the reference range and Baseline value | |||||||||||||||||||||||||||||||||
End point description |
Vital sign parameters were assessed at Baseline and Week 1, 2, 3, 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44 and 48. Any time on-treatment value was derived including values at scheduled and unscheduled assessments. Vital signs included systolic BP, diastolic BP, heart rate and weight. Vital signs are presented as: systolic BP: <90 or >140 and increase or decrease from Baseline >=30; diastolic BP: <50 or >90 and increase or decrease from Baseline >=20; Weight: Increase or decrease from Baseline >=7%; heart Rate: <50 or >100 and increase or decrease from Baseline >=30. Change from Baseline was calculated as the individual post-Baseline value minus the Baseline value. Baseline value is defined as the last pre-treatment value observed.
|
|||||||||||||||||||||||||||||||||
End point type |
Secondary
|
|||||||||||||||||||||||||||||||||
End point timeframe |
From Baseline up to Week 48
|
|||||||||||||||||||||||||||||||||
|
||||||||||||||||||||||||||||||||||
Notes [99] - ITT Population [100] - ITT Population |
||||||||||||||||||||||||||||||||||
No statistical analyses for this end point |
|
||||||||||||||||||||||||||||
End point title |
Number of participants with indicated change from Baseline in the indicated potential clinical concern ECG values | |||||||||||||||||||||||||||
End point description |
ECG values were assessed at Baseline and Week 2, 4, 12, 24, 36, and 48. Maximum on-treatment value was derived including values at scheduled and unscheduled assessments. ECG parameters included QTcB and QTcF. ECG values are presented as: 0 - <=30 increase; >30 - <=60 increase and >60 increase from BL. Change from Baseline was calculated as the individual post-Baseline value minus the Baseline value. Baseline value is defined as the last Pre-treatment value observed.
|
|||||||||||||||||||||||||||
End point type |
Secondary
|
|||||||||||||||||||||||||||
End point timeframe |
From Baseline up to Week 48
|
|||||||||||||||||||||||||||
|
||||||||||||||||||||||||||||
Notes [101] - ITT Population [102] - ITT Population |
||||||||||||||||||||||||||||
No statistical analyses for this end point |
|
|||||||||||||||||||||||||||||||||||||||
End point title |
Mean GSK2586184 trough plasma concentrations at Weeks 4, 8, 24, 36 and 48 [103] | ||||||||||||||||||||||||||||||||||||||
End point description |
Trough pharmacokinetic (PK) samples were collected for all participants at Weeks 4, 8, 24, 36 and 48 prior to the daily dose (20 microgram (µg), 40 µg and 80 µg) of GSK239512. PK Population comprised of all participants for whom a pharmacokinetic sample was obtained and analyzed. Only those participants available at the specified time points were analyzed (represented by n=X, X in the category titles). Different participants may have been analyzed at different time points, so the overall number of participants analyzed reflects everyone in the PK Population.
|
||||||||||||||||||||||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||||||||||||||||||||||
End point timeframe |
Weeks 4, 8, 24, 36 and 48
|
||||||||||||||||||||||||||||||||||||||
Notes [103] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: This endpoint only applies to the GSK2586184 arm. |
|||||||||||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||||||||||
Notes [104] - PK Population |
|||||||||||||||||||||||||||||||||||||||
No statistical analyses for this end point |
|
|||||||||||||||||||||||||||||||||
End point title |
Mean GSK2586184 plasma concentrations at Weeks 8 [105] | ||||||||||||||||||||||||||||||||
End point description |
Pharmacokinetic (PK) samples were collected for all participants on Weeks 8 at pre dose, 0.5 hour (H), 2 H and 6 H post dose (20 µg, 40 µg and 80 µg) of GSK239512. Only those participants available at the specified time points were analyzed (represented by n=X, X in the category titles). Different participants may have been analyzed at different time points, so the overall number of participants analyzed reflects everyone in the ITT Population.
|
||||||||||||||||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||||||||||||||||
End point timeframe |
Week 8
|
||||||||||||||||||||||||||||||||
Notes [105] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: This endpoint only applies to the GSK2586184 arm. |
|||||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||||
Notes [106] - PK Population |
|||||||||||||||||||||||||||||||||
No statistical analyses for this end point |
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Adverse events information
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Timeframe for reporting adverse events |
Serious adverse events (SAEs) and non-serious adverse events (AEs) were collected from the start of administration of the study drug until the follow-up contact (up to Week 50).
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Adverse event reporting additional description |
SAEs and non-serious AEs were reported for members of the ITT population, comprised of all participants who were randomised to treatment, and received at least one dose of study medication.
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Assessment type |
Systematic | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary used for adverse event reporting
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Dictionary name |
MedDRA | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
17.0
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Reporting groups
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Reporting group title |
GSK239512 QD
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Reporting group description |
Add text | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Placebo QD
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Reporting group description |
ENTER TEXT | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Frequency threshold for reporting non-serious adverse events: 5% | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Substantial protocol amendments (globally) |
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Were there any global substantial amendments to the protocol? No | |||
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 |