Clinical Trial Results:
The SPD489-322 Phase 3, Multicenter, Randomized, Double-blind, Parallel-group, Placebo-controlled, Flexible Dose Titration, Efficacy and Safety Study of SPD489 in Combination with an Antidepressant in the Treatment of Adults with Major Depressive Disorder with Inadequate Response to Prospective Treatment with an Antidepressant
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Summary
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EudraCT number |
2011-003018-17 |
Trial protocol |
ES |
Global end of trial date |
23 Dec 2013
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Results information
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Results version number |
v1 |
This version publication date |
23 Oct 2018
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First version publication date |
08 Feb 2015
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Other versions |
v2 |
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 |
SPD489-322
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT01436149 | ||
WHO universal trial number (UTN) |
- | ||
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Sponsors
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Sponsor organisation name |
Shire Development LLC
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Sponsor organisation address |
725 Chesterbrook Boulevard, Wayne, PA, United States, 19087
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Public contact |
Study Physician, Shire Pharmaceuticals Ltd, +1 866 842 5335,
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Scientific contact |
Study Physician, Shire Pharmaceuticals Ltd, +1 866 842 5335,
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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 |
23 Dec 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 |
23 Dec 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 |
The primary objective was to demonstrate the efficacy of SPD489 when used as augmentation therapy in the treatment of major depressive disorder (MDD) in inadequate responders following an 8-week course of treatment with an antidepressant, as measured by the mean change in Montgomery-Asberg Depression Rating Scale (MADRS) total scores.
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Protection of trial subjects |
This study was conducted in accordance with International Conference on Harmonisation (ICH) Good Clinical Practice, the principles of the Declaration of Helsinki, as well as other applicable local ethical and legal requirements. The subject’s informed consent was a mandatory condition for taking part in the study. It was obtained in writing at the Screening Visit (Visit 1) prior to the performance of any study-specific procedures. The subject’s informed consent was documented (on an appropriate form approved by the EC) by the dated signature of the subject and the dated signature of the investigator or investigator's delegate.
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Background therapy |
The background products provided for this study were the following selective serotonin reuptake inhibitor (SSRI) and serotonin norepinephrine reuptake inhibitor (SNRI) antidepressants: escitalopram oxalate, sertraline HCl, venlafaxine HCl extended-release, and duloxetine HCl. Randomized subjects were assigned to receive either SPD489 or placebo orally once daily in addition to their assigned background product. If not already on 1 of the 4 permitted background products at the Screening Visit (Visit 1), a subject was assigned 1 of the 4 background products, as available and provided by the sponsor, at the Lead-in Baseline Visit (Visit 2). Assignment of background product was based on investigator assessment of clinical factors, including prior antidepressant use, response, and tolerability. Investigators were to distribute background product choices equally at their site and were to have made an effort not to assign any 1 background product to more than 40% of their subjects. | ||
Evidence for comparator |
- | ||
Actual start date of recruitment |
27 Oct 2011
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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: 15
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Country: Number of subjects enrolled |
Canada: 83
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Country: Number of subjects enrolled |
Croatia: 10
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Country: Number of subjects enrolled |
Mexico: 58
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Country: Number of subjects enrolled |
United States: 1096
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Worldwide total number of subjects |
1262
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EEA total number of subjects |
25
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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) |
1256
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From 65 to 84 years |
6
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85 years and over |
0
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Recruitment
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Recruitment details |
The study was conducted at 76 sites in 5 countries (Canada, Croatia, Mexico, Spain, United States). | ||||||||||||||||||||||||||||||||||||||||||||
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Pre-assignment
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Screening details |
Adults (18-65 years of age, inclusive) who met all study eligibility criteria, including a primary diagnosis of non-psychotic major depressive disorder (single or recurrent) as defined by the SCID-CT, that had lasted at least 8 weeks prior to the Screening Visit (Visit 1), were eligible for evaluation to participate in this study. | ||||||||||||||||||||||||||||||||||||||||||||
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Period 1
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Period 1 title |
Antidepressant Lead-in Phase
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Is this the baseline period? |
Yes | ||||||||||||||||||||||||||||||||||||||||||||
Allocation method |
Non-randomised - controlled
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Blinding used |
Single blind | ||||||||||||||||||||||||||||||||||||||||||||
Roles blinded |
Subject | ||||||||||||||||||||||||||||||||||||||||||||
Blinding implementation details |
Placebo capsules to match the over-encapsulated SPD489.
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Arms
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Arm title
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Antidepressant + Single-blind Placebo (Lead-in Phase) | ||||||||||||||||||||||||||||||||||||||||||||
Arm description |
Subjects received assigned, unblinded, antidepressant therapy (escitalopram oxalate, sertraline hydrochloride, venlafaxine hydrochloride extended-release, or duloxetine hydrochloride) plus placebo (matching SPD489) for 8 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
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Routes of administration |
Oral use
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Dosage and administration details |
Placebo capsule once-daily
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Period 2
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Period 2 title |
Randomized Phase
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Is this the baseline period? |
No | ||||||||||||||||||||||||||||||||||||||||||||
Allocation method |
Randomised - controlled
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Blinding used |
Double blind | ||||||||||||||||||||||||||||||||||||||||||||
Roles blinded |
Subject, Investigator | ||||||||||||||||||||||||||||||||||||||||||||
Blinding implementation details |
SPD489 was over-encapsulated and appeared identical to placebo. Background product (standard antidepressant therapy) was not blinded.
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Arms
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Are arms mutually exclusive |
Yes
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Arm title
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Antidepressant + Single-blind Placebo (Randomized Phase) | ||||||||||||||||||||||||||||||||||||||||||||
Arm description |
Subjects received assigned, unblinded, antidepressant therapy (escitalopram oxalate, sertraline hydrochloride, venlafaxine hydrochloride extended-release, or duloxetine hydrochloride) plus placebo (matching SPD489) for 8 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
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Routes of administration |
Oral use
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Dosage and administration details |
Placebo capsule once-daily
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Arm title
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Antidepressant + Double-blind Placebo | ||||||||||||||||||||||||||||||||||||||||||||
Arm description |
Subjects received assigned, unblinded antidepressant therapy (escitalopram oxalate, sertraline hydrochloride, venlafaxine hydrochloride extended release, or duloxetine hydrochloride) plus placebo (matching SPD489) for 8 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
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Routes of administration |
Oral use
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Dosage and administration details |
Placebo capsule once-daily
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Arm title
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Antidepressant + Double-blind SPD489 | ||||||||||||||||||||||||||||||||||||||||||||
Arm description |
Subjects received assigned, unblinded antidepressant therapy (escitalopram oxalate, sertraline hydrochloride, venlafaxine hydrochloride extended release, or duloxetine hydrochloride) plus SPD489 for 8 weeks. | ||||||||||||||||||||||||||||||||||||||||||||
Arm type |
Experimental | ||||||||||||||||||||||||||||||||||||||||||||
Investigational medicinal product name |
SPD489
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Investigational medicinal product code |
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Other name |
Lisdexamfetamine dimesylate, Vyvanse
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Pharmaceutical forms |
Capsule
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Routes of administration |
Oral use
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Dosage and administration details |
Over-encapsulated SPD489 capsules optimized among 20, 30, 50, or 70 mg dose once-daily
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Baseline characteristics reporting groups
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Reporting group title |
Antidepressant Lead-in Phase
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Reporting group description |
Subjects received assigned, unblinded, antidepressant therapy (escitalopram oxalate, sertraline hydrochloride, venlafaxine hydrochloride extended-release, or duloxetine hydrochloride) plus placebo (matching SPD489) for 8 weeks. | |||||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
Antidepressant + Single-blind Placebo (Lead-in Phase)
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Reporting group description |
Subjects received assigned, unblinded, antidepressant therapy (escitalopram oxalate, sertraline hydrochloride, venlafaxine hydrochloride extended-release, or duloxetine hydrochloride) plus placebo (matching SPD489) for 8 weeks. | ||
Reporting group title |
Antidepressant + Single-blind Placebo (Randomized Phase)
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Reporting group description |
Subjects received assigned, unblinded, antidepressant therapy (escitalopram oxalate, sertraline hydrochloride, venlafaxine hydrochloride extended-release, or duloxetine hydrochloride) plus placebo (matching SPD489) for 8 weeks. | ||
Reporting group title |
Antidepressant + Double-blind Placebo
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Reporting group description |
Subjects received assigned, unblinded antidepressant therapy (escitalopram oxalate, sertraline hydrochloride, venlafaxine hydrochloride extended release, or duloxetine hydrochloride) plus placebo (matching SPD489) for 8 weeks. | ||
Reporting group title |
Antidepressant + Double-blind SPD489
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Reporting group description |
Subjects received assigned, unblinded antidepressant therapy (escitalopram oxalate, sertraline hydrochloride, venlafaxine hydrochloride extended release, or duloxetine hydrochloride) plus SPD489 for 8 weeks. | ||
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End point title |
Mean Change From Baseline in the Montgomery-Asberg Depression Rating Scale (MADRS) Total Score at 8 Weeks | ||||||||||||
End point description |
MADRS is a validated, 10-item rating scale with each item being scored on a scale from 0-6 with a total score ranging from 0-60. Lower scores indicate a decreased severity of depression.
This end point used the Full Analysis Set, which included subjects who took at least 1 dose of randomized investigational product and who had at least 1 valid primary efficacy measurement of the MADRS total score after the Augmentation Baseline Visit (Visit 8).
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End point type |
Primary
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End point timeframe |
8 weeks
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Statistical analysis title |
Change From Baseline in MADRS Total Score | ||||||||||||
Comparison groups |
Antidepressant + Double-blind Placebo v Antidepressant + Double-blind SPD489
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Number of subjects included in analysis |
400
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Analysis specification |
Pre-specified
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Analysis type |
superiority | ||||||||||||
P-value |
= 0.883 | ||||||||||||
Method |
Mixed-effects Model for Repeat Measures | ||||||||||||
Parameter type |
Difference in LS Mean | ||||||||||||
Point estimate |
0.1
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Confidence interval |
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level |
95% | ||||||||||||
sides |
2-sided
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lower limit |
-1.7 | ||||||||||||
upper limit |
2 | ||||||||||||
Variability estimate |
Standard error of the mean
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Dispersion value |
0.96
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End point title |
Change From Baseline in the Sheehan Disability Scale (SDS) Total Score at 8 Weeks | ||||||||||||
End point description |
SDS is designed to evaluate the extent to which illness symptoms impact a subject's life in 3 areas: work/school, social, and family/home. Each area is scored on a scale from 0 (no impairment) to 10 (highly impaired) with a total score ranging from 0 (unimpaired) to 30 (highly impaired). Lower scores translate into less impairment.
This end point used the Full Analysis Set, which included subjects who took at least 1 dose of randomized investigational product and who had at least 1 valid primary efficacy measurement of the MADRS total score after the Augmentation Baseline Visit (Visit 8).
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End point type |
Secondary
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End point timeframe |
8 weeks
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Statistical analysis title |
Change From Baseline in SDS Total Score | ||||||||||||
Comparison groups |
Antidepressant + Double-blind Placebo v Antidepressant + Double-blind SPD489
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Number of subjects included in analysis |
400
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Analysis specification |
Pre-specified
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Analysis type |
superiority | ||||||||||||
P-value |
= 0.576 | ||||||||||||
Method |
Mixed- effects Model for Repeat Measures | ||||||||||||
Parameter type |
Difference in LS Mean | ||||||||||||
Point estimate |
-0.4
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Confidence interval |
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level |
95% | ||||||||||||
sides |
2-sided
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lower limit |
-1.8 | ||||||||||||
upper limit |
1 | ||||||||||||
Variability estimate |
Standard error of the mean
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Dispersion value |
0.69
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End point title |
Percentage of Participants Achieving a 25% Response on the MADRS | ||||||||||||
End point description |
The percentage of subjects who achieved a 25% response (i.e., ≥25% reduction in MADRS total score from Lead-in Baseline, Visit 2; Week 0). A comparison was performed at Visit 14/Early Termination (ET) (Week 16/ET).
This end point used the Full Analysis Set, which included subjects who took at least 1 dose of randomized investigational product and who had at least 1 valid primary efficacy measurement of the MADRS total score after the Augmentation Baseline Visit (Visit 8).
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End point type |
Secondary
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End point timeframe |
Up to 8 weeks
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| No statistical analyses for this end point | |||||||||||||
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End point title |
Percentage of Participants Achieving a 50% Response on the MADRS | ||||||||||||
End point description |
The percentage of subjects who achieved a 50% response (i.e., ≥50% reduction in MADRS total score from Lead-in Baseline, Visit 2; Week 0). A comparison was performed at Visit 14/ET (Week 16/ET).
This end point used the Full Analysis Set, which included subjects who took at least 1 dose of randomized investigational product and who had at least 1 valid primary efficacy measurement of the MADRS total score after the Augmentation Baseline Visit (Visit 8).
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End point type |
Secondary
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End point timeframe |
Up to 8 weeks
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| No statistical analyses for this end point | |||||||||||||
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End point title |
Percentage of Participants Achieving Remission on the MADRS | ||||||||||||
End point description |
MADRS remission was defined as a MADRS total score of ≤10. A comparison was performed at Visit 14/ET (Week 16/ET).
This end point used the Full Analysis Set, which included subjects who took at least 1 dose of randomized investigational product and who had at least 1 valid primary efficacy measurement of the MADRS total score after the Augmentation Baseline Visit (Visit 8).
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End point type |
Secondary
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End point timeframe |
Up to 8 weeks
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| No statistical analyses for this end point | |||||||||||||
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End point title |
Mean Change From Baseline Over Time in the MADRS Total Score | ||||||||||||||||||||||||||||||
End point description |
MADRS is a validated, 10-item rating scale with each item being scored on a scale from 0-6 with a total score ranging from 0-60. Lower scores indicate a decreased severity of depression.
This end point used the Full Analysis Set, which included subjects who took at least 1 dose of randomized investigational product and who had at least 1 valid primary efficacy measurement of the MADRS total score after the Augmentation Baseline Visit (Visit 8).
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End point type |
Secondary
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End point timeframe |
Baseline and up to 8 weeks
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| No statistical analyses for this end point | |||||||||||||||||||||||||||||||
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End point title |
Mean Change From Baseline in the Quick Inventory of Depressive Symptomatology - Self Report (QIDS SR) | ||||||||||||
End point description |
The QIDS-SR is a self-administered questionnaire designed to rate depressive symptoms. The scale contains 16 items, each scored using a 4-point scale ranging from 0 (representing the most favorable response [low amount of symptoms]) to 3 (representing the least favorable response [frequent/intense symptoms]). The total score could range from 0 (no depression) to 27 (very severe depression). Higher scores represent more severe depressive symptoms.
This end point used the Full Analysis Set, which included subjects who took at least 1 dose of randomized investigational product and who had at least 1 valid primary efficacy measurement of the MADRS total score after the Augmentation Baseline Visit (Visit 8).
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End point type |
Secondary
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End point timeframe |
Up to 8 weeks
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| No statistical analyses for this end point | |||||||||||||
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End point title |
Mean Change From Baseline in the Short Form-12 Health Survey V2 (SF-12V2) | ||||||||||||||||||
End point description |
The SF-12V2 total score ranges from 0 (lowest level of health) to 100 (highest level of health) on the assumption that each question carries equal weight. The lower the score the more disability. The higher the score the less disability (i.e. a score of zero is equivalent to maximum disability and a score of 100 is equivalent to no disability). Higher scores are associated with better quality of life.
This end point used the Full Analysis Set, which included subjects who took at least 1 dose of randomized investigational product and who had at least 1 valid primary efficacy measurement of the MADRS total score after the Augmentation Baseline Visit (Visit 8).
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End point type |
Secondary
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End point timeframe |
Up to 8 weeks
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| No statistical analyses for this end point | |||||||||||||||||||
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End point title |
Mean Change From Baseline in the Quality of Life Enjoyment Satisfaction Questionnaire Short Form (Q-LES-Q-SF) | ||||||||||||
End point description |
The Q-LES-Q-SF is a 16-item self-report questionnaire that evaluates general subject satisfaction with health, mood, relationships, functioning in daily life, and the treatment being taken. The overall level of satisfaction is evaluated on a 5-point scale from 1 (very poor) to 5 (very good). The total score ranges from 14-70 (the last two items on the form are not included in the total score). A higher score indicates a better quality of life.
This end point used the Full Analysis Set, which included subjects who took at least 1 dose of randomized investigational product and who had at least 1 valid primary efficacy measurement of the MADRS total score after the Augmentation Baseline Visit (Visit 8).
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End point type |
Secondary
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End point timeframe |
Up to 8 weeks
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| No statistical analyses for this end point | |||||||||||||
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End point title |
Clinical Global Impressions - Global Improvement (CGI-I) | |||||||||||||||||||||
End point description |
Clinical Global Impression-Improvement (CGI-I) consists of a 7-point scale ranging from 1 (very much improved) to 7 (very much worse). Improvement is defined as a score of 1 (very much improved) or 2 (much improved) on the scale.
This end point used the Full Analysis Set, which included subjects who took at least 1 dose of randomized investigational product and who had at least 1 valid primary efficacy measurement of the MADRS total score after the Augmentation Baseline Visit (Visit 8).
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End point type |
Secondary
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End point timeframe |
Up to 8 weeks
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| No statistical analyses for this end point | ||||||||||||||||||||||
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End point title |
Columbia Suicide Severity Rating Scale (C-SSRS) | ||||||||||||||||||
End point description |
C-SSRS is a semi-structured interview that captures the occurrence, severity, and frequency of suicide-related thoughts and behaviors during the assessment period. The interview includes definitions and suggested questions to solicit the type of information needed to determine if a suicide-related thought or behavior occurred. The assessment is done by the nature of the responses, not by a numbered scale.
This end point used the Full Analysis Set, which included subjects who took at least 1 dose of randomized investigational product and who had at least 1 valid primary efficacy measurement of the MADRS total score after the Augmentation Baseline Visit (Visit 8).
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End point type |
Secondary
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End point timeframe |
Up to 8 weeks
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| No statistical analyses for this end point | |||||||||||||||||||
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End point title |
Amphetamine Cessation Symptom Assessment (ACSA) | ||||||||||||
End point description |
The ACSA scale has 16 symptom items rated on a scale from 0 (not at all) to 4 (extremely) with a possible total score range of 0 to 64. Higher scores indicate greater withdrawal symptom severity.
This end point used the Full Analysis Set, which included subjects who took at least 1 dose of randomized investigational product and who had at least 1 valid primary efficacy measurement of the MADRS total score after the Augmentation Baseline Visit (Visit 8).
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End point type |
Secondary
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End point timeframe |
Up to 8 weeks
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| No statistical analyses for this end point | |||||||||||||
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Adverse events information
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Timeframe for reporting adverse events |
17 weeks
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Assessment type |
Systematic | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Dictionary used for adverse event reporting
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Dictionary name |
MedDRA | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
14.0
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Reporting groups
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Reporting group title |
Antidepressant + Double-blind Placebo
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Reporting group description |
Subjects received assigned oral, once-daily antidepressant therapy (escitalopram oxalate, sertraline hydrochloride, venlafaxine hydrochloride extended release, or duloxetine hydrochloride) plus double-blind placebo (matching SPD489) for 8 weeks. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Antidepressant + Double-blind SPD489
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Reporting group description |
Subjects received assigned oral, once-daily antidepressant therapy (escitalopram oxalate, sertraline hydrochloride, venlafaxine hydrochloride extended release, or duloxetine hydrochloride) plus SPD489 for 8 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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11 Nov 2011 |
1-Updated information for emergency contact, MADRS, and Q-LES-Q-SF
2-Specified that the 4 antidepressants were “as available and provided by the sponsor”
3- Revised exclusion criteria
4- Added that subjects with no improvement in depressive symptoms from Visit 2 to Visit 8 were to be discontinued
5-Qualified that subjects “whose depressive symptoms have improved, but” who did not meet randomization criteria at Visit 8 were allowed to continue in the study receiving placebo
6-Reduced the duration after the study that a subject was to use contraception.
7- Specified that the management of blood pressure and pulse during the study were to be based on an “average of 3 readings” for each respective measurement as well as on an “average” value for each respective measurement on 2 consecutive visits
8- Expanded permitted concomitant medications to include any medication not affecting blood pressure, heart rate, or the CNS. Antibiotics were excluded.
9-Specified that background product was to be taken in conjunction with investigational product
10-Defined target dose of background product
11-Titration to a target dose of the background product was clarified to be consistent with the labeling guidelines
12- Listed study assessments to be performed when background product was tapered or investigational product was down-titrated
13- Dosing and re-dispensing of background and investigational products was expanded upon
14- Specified that controlled substances were to be stored based on the label
15-Removed the following sentence: “Continued antidepressant treatment will not be provided by the sponsor” from the section describing study procedures performed during the follow-up period
16- Specified tapering of background product after the study
17- Specified that any urine drug screen at Visit 2 was to be negative
18-Listed specific items of interest on the C-SSRS for the investigator to use when evaluating a subject’s suitability to remain in the study |
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12 Nov 2012 |
1-Updated emergency contact information
2-Removed the secondary objective to evaluate the efficacy of SPD489 augmentation based on the CGI-S
3- Increased the number of subjects to be screened
4-Increased the number of planned sites
5-Revised exclusion criteria
6- Specified Visit 2 as the start for evaluation of additional randomization assessments
7- Specified intervals for QTcF and QTcB that would trigger discontinuation
8- Removed the following sentence from the analysis of secondary efficacy variables: “The CGI-S data at Visit 14 will be compared between augmentation treatment groups using the Wilcoxon rank sum test”
9- Specified Visit 2 as the time of enrolment
10- Specified that any Visit 1 assessment requiring a repeat measurement should be performed before confirming eligibility
11- Subject discontinuation based on laboratory or ECG results that would preclude treatment with SPD489 was to be agreed upon by the investigator in conjunction with the CRO Medical Monitor
12-Added that contraceptive requirements were to be reviewed at all study
visits
13-The following (in “quotes”) was removed regarding removal of a subject from drug or therapy: the reason for withdrawal (by the sponsor or investigator) should be “discussed where possible with the contract research organization (CRO) Medical Monitor before the subject stops investigational product”
14-Added that subjects requiring a prohibited change to their treatment must be discontinued
15-Added reasons for discontinuation under the category of Other:
Change in background product required
Treatment with a prohibited medication required
Other reasons must be specified
16-Expanded the processes for discontinuing medications
17-Prohibited “chronic” use of an herbal treatment
18- Specified that the investigator was to contact the CRO Medical Monitor as soon as possible after unblinding
19-Added the formula for medication compliance
20- Changed reporting requirements of SAEs and pregnancies |
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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 | |||
