Clinical Trial Results:
A randomized, double-blind, parallel-group study of the safety and efficacy of RO4917523 versus placebo, as adjunctive therapy in patients with major depressive disorder with inadequate response to ongoing antidepressant treatment.
Summary
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EudraCT number |
2011-001436-33 |
Trial protocol |
DE |
Global end of trial date |
27 Sep 2013
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Results information
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Results version number |
v1(current) |
This version publication date |
22 Apr 2016
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First version publication date |
08 Aug 2015
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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 |
NP25620
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT01437657 | ||
WHO universal trial number (UTN) |
- | ||
Sponsors
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Sponsor organisation name |
F. Hoffmann-LaRoche AG
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Sponsor organisation address |
Grenzacherstrasse 124, Basel, Switzerland, CH-4070
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Public contact |
Roche Trial Information Hotline, F.Hoffmann-La Roche AG, +41 61 6878333, global.trial_information@roche.com
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Scientific contact |
Roche Trial Information Hotline, F.Hoffmann-La Roche AG, +41 61 6878333, global.trial_information@roche.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 |
27 Sep 2013
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Is this the analysis of the primary completion data? |
No
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Global end of trial reached? |
Yes
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Global end of trial date |
27 Sep 2013
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Was the trial ended prematurely? |
No
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General information about the trial
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Main objective of the trial |
To evaluate the efficacy of two fixed doses of RO4917523 (basimglurant) compared to placebo in a confirmatory manner over 6 weeks as adjunctive therapy in patients with major depressive disorder (MDD) with inadequate response to ongoing antidepressant treatment. The change will be measured based on the mean change in the Montgomery Asberg Depression Rating Scale (MADRS) total score from baseline to end of treatment.
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Protection of trial subjects |
The study was conducted in accordance with the principles of the “Declaration of Helsinki” and Good Clinical Practice (GCP).
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Background therapy |
Ongoing treatment with a single antidepressant of the SSRI or SNRI class was continued for the duration of the double-blind treatment period without modification of the dosing schedule. | ||
Evidence for comparator |
- | ||
Actual start date of recruitment |
05 Oct 2011
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Long term follow-up planned |
No
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Independent data monitoring committee (IDMC) involvement? |
Yes
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Population of trial subjects
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Number of subjects enrolled per country |
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Country: Number of subjects enrolled |
Poland: 86
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Country: Number of subjects enrolled |
Germany: 25
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Country: Number of subjects enrolled |
Chile: 25
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Country: Number of subjects enrolled |
Japan: 39
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Country: Number of subjects enrolled |
Mexico: 15
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Country: Number of subjects enrolled |
Russian Federation: 21
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Country: Number of subjects enrolled |
United States: 106
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Country: Number of subjects enrolled |
Romania: 16
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Worldwide total number of subjects |
333
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EEA total number of subjects |
127
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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) |
321
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From 65 to 84 years |
12
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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 were screened over a period of 2 weeks. | ||||||||||||||||||||||||||||||||
Period 1
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Period 1 title |
Overall Study (overall period)
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Is this the baseline period? |
Yes | ||||||||||||||||||||||||||||||||
Allocation method |
Randomised - controlled
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Blinding used |
Double blind | ||||||||||||||||||||||||||||||||
Roles blinded |
Subject, Investigator | ||||||||||||||||||||||||||||||||
Blinding implementation details |
Matching placebo capsules
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Arms
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Are arms mutually exclusive |
Yes
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Arm title
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RO4917523 0.5 mg | ||||||||||||||||||||||||||||||||
Arm description |
Subjects received 0.5 mg of RO4917523 once daily for 6 weeks, then were followed for 3 weeks. | ||||||||||||||||||||||||||||||||
Arm type |
Experimental | ||||||||||||||||||||||||||||||||
Investigational medicinal product name |
RO4917523
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Investigational medicinal product code |
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Other name |
basimglurant
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Pharmaceutical forms |
Capsule, hard
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Routes of administration |
Oral use
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Dosage and administration details |
One basimglurant 0.5 mg capsule was administered by the patient once a day in the morning immediately after breakfast. On visit days, treatment was taken after pre-dose assessments.
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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 |
Capsule, hard
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Routes of administration |
Oral use
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Dosage and administration details |
One placebo capsule was administered by the patient once a day in the morning immediately after breakfast. On visit days, treatment was taken after pre-dose
assessments.
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Arm title
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RO4917523 1.5 mg | ||||||||||||||||||||||||||||||||
Arm description |
Subjects received 1.5 mg of RO4917523 once daily for 6 weeks, then were followed for 3 weeks. | ||||||||||||||||||||||||||||||||
Arm type |
Experimental | ||||||||||||||||||||||||||||||||
Investigational medicinal product name |
RO4917523
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Investigational medicinal product code |
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Other name |
basimglurant
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Pharmaceutical forms |
Capsule, hard
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Routes of administration |
Oral use
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Dosage and administration details |
One basimglurant 0.5 mg capsule and 1 basimglurant 1.0 mg capsule were administered by the patient once a day in the morning immediately after breakfast. On visit days, treatment was taken after pre-dose assessments.
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Arm title
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Placebo | ||||||||||||||||||||||||||||||||
Arm description |
Subjects received placebo once daily for 6 weeks, then were followed for 3 weeks. | ||||||||||||||||||||||||||||||||
Arm type |
Placebo | ||||||||||||||||||||||||||||||||
Investigational medicinal product name |
Placebo
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Capsule, hard
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Routes of administration |
Oral use
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Dosage and administration details |
Two placebo capsules were administered by the patient once a day in the morning immediately after breakfast. On visit days, treatment was taken after pre-dose assessments.
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Notes [1] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left. Justification: Subjects who discontinued treatment could enter the follow-up period. [2] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left. Justification: Subjects who discontinued treatment could enter the follow-up period. [3] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left. Justification: Subjects who discontinued treatment could enter the follow-up period. |
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Baseline characteristics reporting groups
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Reporting group title |
Overall Study
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Reporting group description |
- | |||||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
RO4917523 0.5 mg
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Reporting group description |
Subjects received 0.5 mg of RO4917523 once daily for 6 weeks, then were followed for 3 weeks. | ||
Reporting group title |
RO4917523 1.5 mg
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Reporting group description |
Subjects received 1.5 mg of RO4917523 once daily for 6 weeks, then were followed for 3 weeks. | ||
Reporting group title |
Placebo
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Reporting group description |
Subjects received placebo once daily for 6 weeks, then were followed for 3 weeks. |
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End point title |
Change From Baseline in The Montgomery Asberg Depression Rating Scale (MADRS) Total Score | ||||||||||||||||
End point description |
The clinician-rated MADRS is a 10-item instrument designed to assess the overall severity of depressive symptoms on a scale of 0 to 6, with 0 being the least amount of symptoms and 6 being the most amount of symptoms. The total score ranges from 0 to 60 and is equal to the sum of all items. A negative change from baseline indicates that symptoms improved.
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End point type |
Primary
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End point timeframe |
From Baseline to Day 42
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Statistical analysis title |
Analysis of MADRS total score for RO4917523 0.5 mg | ||||||||||||||||
Comparison groups |
Placebo v RO4917523 0.5 mg
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Number of subjects included in analysis |
221
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Analysis specification |
Pre-specified
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Analysis type |
superiority | ||||||||||||||||
P-value |
= 0.742 | ||||||||||||||||
Method |
mixed-effect model repeat measures | ||||||||||||||||
Confidence interval |
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Statistical analysis title |
Analysis of MADRS total score for RO4917523 1.5 mg | ||||||||||||||||
Comparison groups |
RO4917523 1.5 mg v Placebo
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Number of subjects included in analysis |
220
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Analysis specification |
Pre-specified
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Analysis type |
superiority | ||||||||||||||||
P-value |
= 0.416 | ||||||||||||||||
Method |
mixed-effect model repeat measures | ||||||||||||||||
Confidence interval |
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End point title |
Change From Baseline in The Quick Inventory of Depressive Symptomatology-Self Report 16-Item Version (QIDS-SR16) Total Score | ||||||||||||||||
End point description |
The QIDS-SR16 is a 16-item scale completed by patients to assess the severity of their depressive symptoms. The scale assesses all nine symptom domains selected by DSMIV to diagnose a major depressive episode. Each of the 16 items is scored on a 4-point anchored scale, representing least severe (0) to most severe (3). Specific instructions for calculating a total score are included in the scale. Total scores range from 0 to 27 with a higher score indicating greater severity. A negative change from baseline indicates that symptoms improved.
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End point type |
Secondary
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End point timeframe |
From Baseline to Day 42
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Statistical analysis title |
Analysis of QIDS-SR16 for RO4917523 0.5 mg | ||||||||||||||||
Comparison groups |
RO4917523 0.5 mg v Placebo
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Number of subjects included in analysis |
221
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Analysis specification |
Pre-specified
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Analysis type |
superiority | ||||||||||||||||
P-value |
= 0.362 [1] | ||||||||||||||||
Method |
mixed-effect model repeat measures | ||||||||||||||||
Confidence interval |
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Notes [1] - Unadjusted 1-sided lower p-value |
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Statistical analysis title |
Analysis of QIDS-SR16 for RO4917523 1.5 mg | ||||||||||||||||
Comparison groups |
RO4917523 1.5 mg v Placebo
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Number of subjects included in analysis |
220
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Analysis specification |
Pre-specified
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Analysis type |
superiority | ||||||||||||||||
P-value |
= 0.004 [2] | ||||||||||||||||
Method |
mixed-effect model repeat measures | ||||||||||||||||
Confidence interval |
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Notes [2] - Unadjusted 1-sided lower p-value |
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End point title |
Change From Baseline in The Clinician Global Impression-Severity (CGI-S) Rating Score-LOCF | ||||||||||||||||
End point description |
The CGI-S was used to evaluate the overall clinical status (severity of illness). The CGI-S is rated on a scale of 1 to 7 with 1 referring to “normal” and 7 referring to “most severely ill." A negative change from baseline indicates that symptoms have improved. The analysis was applied to the last observation carried forward (LOCF) values.
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End point type |
Secondary
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End point timeframe |
From Baseline to Day 42
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Statistical analysis title |
Analysis of CGI-S for RO4917523 0.5 mg | ||||||||||||||||
Comparison groups |
RO4917523 0.5 mg v Placebo
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Number of subjects included in analysis |
221
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Analysis specification |
Pre-specified
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Analysis type |
superiority | ||||||||||||||||
P-value |
= 0.775 [3] | ||||||||||||||||
Method |
Wilcoxon (Mann-Whitney) | ||||||||||||||||
Confidence interval |
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Notes [3] - Unadjusted 1-sided lower p-value |
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Statistical analysis title |
Analysis of CGI-S for RO4917523 1.5 mg | ||||||||||||||||
Comparison groups |
Placebo v RO4917523 1.5 mg
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Number of subjects included in analysis |
220
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Analysis specification |
Pre-specified
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Analysis type |
superiority | ||||||||||||||||
P-value |
= 0.268 [4] | ||||||||||||||||
Method |
Wilcoxon (Mann-Whitney) | ||||||||||||||||
Confidence interval |
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Notes [4] - Unadjusted 1-sided lower p-value |
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End point title |
Distribution of Rating Scores For The Clinician Global Impression-Improvement (CGI-I) Scale-LOCF | ||||||||||||||||
End point description |
The CGI-I was used to evaluate the change from baseline in clinical status. The CGI-I is rated on a scale of 1 to 7 with 1 referring to “very much improved”and 7 referring to “very much worse." The analysis was applied to the last observation carried forward (LOCF) values.
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End point type |
Secondary
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End point timeframe |
From Baseline to Day 42
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Statistical analysis title |
Analysis of CGI-I for RO4917523 0.5 mg | ||||||||||||||||
Comparison groups |
RO4917523 0.5 mg v Placebo
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Number of subjects included in analysis |
221
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Analysis specification |
Pre-specified
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Analysis type |
superiority | ||||||||||||||||
P-value |
= 0.851 [5] | ||||||||||||||||
Method |
Wilcoxon (Mann-Whitney) | ||||||||||||||||
Confidence interval |
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Notes [5] - Unadjusted 1-sided lower p-value |
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Statistical analysis title |
Analysis of CGI-I for RO4917523 1.5 mg | ||||||||||||||||
Comparison groups |
RO4917523 1.5 mg v Placebo
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Number of subjects included in analysis |
220
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Analysis specification |
Pre-specified
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Analysis type |
superiority | ||||||||||||||||
P-value |
= 0.068 [6] | ||||||||||||||||
Method |
Wilcoxon (Mann-Whitney) | ||||||||||||||||
Confidence interval |
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Notes [6] - Unadjusted 1-sided lower p-value |
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End point title |
Distribution of Rating Scores For The Patient Global Impression-Improvement (PGI-I) Scale | ||||||||||||||||
End point description |
The PGI-I is a self-reported instrument to record the patient’s own assessment of improvement since baseline. The patient is asked to rate their condition now, as compared to how it was before they began study medication, using a 7-point scale ranging from very much better (1) to very much worse (7). The PGI-I is essentially a patient-reported version of the CGI-I.
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End point type |
Secondary
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End point timeframe |
From Baseline to Day 42
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Statistical analysis title |
Analysis of PGI-I for RO4917523 0.5 mg | ||||||||||||||||
Comparison groups |
RO4917523 0.5 mg v Placebo
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Number of subjects included in analysis |
221
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Analysis specification |
Pre-specified
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Analysis type |
superiority | ||||||||||||||||
P-value |
= 0.534 [7] | ||||||||||||||||
Method |
Wilcoxon (Mann-Whitney) | ||||||||||||||||
Confidence interval |
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Notes [7] - Unadjusted 1-sided lower p-value |
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Statistical analysis title |
Analysis of PGI-I for RO4917523 1.5 mg | ||||||||||||||||
Comparison groups |
Placebo v RO4917523 1.5 mg
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Number of subjects included in analysis |
220
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Analysis specification |
Pre-specified
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Analysis type |
superiority | ||||||||||||||||
P-value |
= 0.045 [8] | ||||||||||||||||
Method |
Wilcoxon (Mann-Whitney) | ||||||||||||||||
Confidence interval |
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Notes [8] - Unadjusted 1-sided lower p-value |
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End point title |
Percent of Subjects Exhibiting Response After 6 Weeks of Treatment | ||||||||||||||||
End point description |
Response was defined as a ≥ 50% improvement in the total score of the clinician-rated Montgomery Asberg Depression Rating Scale (MADRS) from Baseline to Day 42.
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End point type |
Secondary
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End point timeframe |
From Baseline to Day 42
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Statistical analysis title |
Analysis of response for RO4917523 0.5 mg | ||||||||||||||||
Comparison groups |
RO4917523 0.5 mg v Placebo
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Number of subjects included in analysis |
221
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Analysis specification |
Pre-specified
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Analysis type |
superiority | ||||||||||||||||
P-value |
= 0.804 [9] | ||||||||||||||||
Method |
Fisher exact | ||||||||||||||||
Confidence interval |
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Notes [9] - Unadjusted 1-sided upper p-value |
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Statistical analysis title |
Analysis of response for RO4917523 1.5 mg | ||||||||||||||||
Comparison groups |
Placebo v RO4917523 1.5 mg
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Number of subjects included in analysis |
220
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Analysis specification |
Pre-specified
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Analysis type |
superiority | ||||||||||||||||
P-value |
= 0.342 [10] | ||||||||||||||||
Method |
Fisher exact | ||||||||||||||||
Confidence interval |
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Notes [10] - Unadjusted 1-sided upper p-value |
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End point title |
Percent of Subjects With Remission After 6 Weeks of Treatment | ||||||||||||||||
End point description |
Remission was defined as having a clinician-rated Montgomery Asberg Depression Rating Scale (MADRS) total score of ≤ 10 at Day 42
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End point type |
Secondary
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End point timeframe |
From Baseline to Day 42
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Statistical analysis title |
Analysis of remission for RO4917523 0.5 mg | ||||||||||||||||
Comparison groups |
RO4917523 0.5 mg v Placebo
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Number of subjects included in analysis |
221
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Analysis specification |
Pre-specified
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Analysis type |
superiority | ||||||||||||||||
P-value |
= 0.765 [11] | ||||||||||||||||
Method |
Fisher exact | ||||||||||||||||
Confidence interval |
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Notes [11] - Unadjusted 1-sided upper p-value |
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Statistical analysis title |
Analysis of remission for RO4917523 1.5 mg | ||||||||||||||||
Comparison groups |
Placebo v RO4917523 1.5 mg
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Number of subjects included in analysis |
220
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Analysis specification |
Pre-specified
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Analysis type |
superiority | ||||||||||||||||
P-value |
= 0.222 [12] | ||||||||||||||||
Method |
Fisher exact | ||||||||||||||||
Confidence interval |
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Notes [12] - Unadjusted 1-sided upper p-value |
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End point title |
Change From Baseline in The Patient-Rated Montgomery Asberg Depression Rating Scale (MADRS) Total Score | ||||||||||||||||
End point description |
Following the assessment of the MADRS by the rater, the patient then completed the MADRS as a self-assessment using the same laptop computer (the “patient-rated MADRS”; Sachs et al., 2011). The assessment of the patient-rated MADRS was made at all visits where the clinician-rated MADRS was assessed (excluding follow up). It was administered as a computerized, interactive interview, involving a series of probe and follow-up questions with multiple choice response options. A negative change from baseline indicates that symptoms improved.
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End point type |
Post-hoc
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End point timeframe |
From Baseline to Day 42
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Statistical analysis title |
Analysis of MADRS total score for RO4917523 0.5 mg | ||||||||||||||||
Comparison groups |
RO4917523 0.5 mg v Placebo
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Number of subjects included in analysis |
221
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Analysis specification |
Pre-specified
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Analysis type |
superiority | ||||||||||||||||
P-value |
= 0.547 [13] | ||||||||||||||||
Method |
mixed-effect model repeat measures | ||||||||||||||||
Confidence interval |
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Notes [13] - Unadjusted 1-sided lower p-value |
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Statistical analysis title |
Analysis of MADRS total score for RO4917523 1.5 mg | ||||||||||||||||
Comparison groups |
RO4917523 1.5 mg v Placebo
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Number of subjects included in analysis |
220
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Analysis specification |
Pre-specified
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Analysis type |
superiority | ||||||||||||||||
P-value |
= 0.021 [14] | ||||||||||||||||
Method |
mixed-effect model repeat measures | ||||||||||||||||
Confidence interval |
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Notes [14] - Unadjusted 1-sided lower p-value |
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Adverse events information
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Timeframe for reporting adverse events |
9 weeks after start of treatment
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Assessment type |
Systematic | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary used for adverse event reporting
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Dictionary name |
MedDRA | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
16.0
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Reporting groups
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Reporting group title |
RO4917523 0.5 mg
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Reporting group description |
Subjects received 0.5 mg of RO4917523 once daily for 6 weeks, then were followed for 3 weeks. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
RO4917523 1.5 mg
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Reporting group description |
Subjects received 1.5 mg of RO4917523 once daily for 6 weeks, then were followed for 3 weeks. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Placebo
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Reporting group description |
Subjects received placebo once daily for 6 weeks, then were followed for 3 weeks. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Frequency threshold for reporting non-serious adverse events: 5% | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Substantial protocol amendments (globally) |
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Were there any global substantial amendments to the protocol? Yes | |||
Date |
Amendment |
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01 Jul 2011 |
This amendment introduced the following key changes:
-Blood sampling for the purpose of clinical genoptying was added to the collection of specimens from patients during the study (3 mL blood sample on Day 1).
-An electrocardiogram (ECG) measurement on Day 14 was added to the schedule of assessments.
-Individuals whose occupation is to drive or operate mass transportation (i.e., buses, trains), large vehicles (i.e., trucks), or heavy machinery were added to the exclusion criteria.
-Fluvoxamine, pregabalin and gabapentin were added to the list of prohibited concomitant medications. |
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02 Apr 2012 |
This amendment introduced the following key changes:
-The inclusion criteria were amended to enable enrollment of patients up to 70 years of age, and patients with a body mass index (BMI) between 18 and 38 kg/m2 inclusive.
-By health authority request, patients with a positive finding on the Columbia-Suicide Severity Rating Scale (C-SSRS) or with liver function test abnormalities that met Hy’s law were required to be withdrawn.
-Assumptions for sample size calculation were clarified, and the description of handling of missing data was updated.
-The option for the Drug Safety Monitoring Board (DSMB) to review efficacy data during safety reviews was added. |
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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 |