Clinical Trial Results:
A Phase 3, Randomized, Double-blind, Sham-Procedure Controlled Study to Assess the Clinical Efficacy and Safety of ISIS 396443 Administered Intrathecally in Patients with Later-onset Spinal Muscular Atrophy
Summary
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EudraCT number |
2014-001947-18 |
Trial protocol |
DE GB SE ES IT FR |
Global end of trial date |
20 Feb 2017
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Results information
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Results version number |
v1(current) |
This version publication date |
06 Sep 2017
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First version publication date |
06 Sep 2017
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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 |
ISIS 396443-CS4
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT02865109 | ||
WHO universal trial number (UTN) |
- | ||
Sponsors
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Sponsor organisation name |
Biogen
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Sponsor organisation address |
225 Binney Street, Cambridge, United States, 02142
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Public contact |
Biogen Study Medical Director, Biogen, clinicaltrials@biogen.com
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Scientific contact |
Biogen Study Medical Director, Biogen, +1 866-633-4636, clinicaltrials@biogen.com
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Paediatric regulatory details
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Is trial part of an agreed paediatric investigation plan (PIP) |
Yes
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EMA paediatric investigation plan number(s) |
EMEA-001448-PIP13-02 | ||
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? |
Yes
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Results analysis stage
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Analysis stage |
Final
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Date of interim/final analysis |
20 Feb 2017
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Is this the analysis of the primary completion data? |
Yes
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Primary completion date |
20 Feb 2017
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Global end of trial reached? |
Yes
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Global end of trial date |
20 Feb 2017
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Was the trial ended prematurely? |
Yes
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General information about the trial
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Main objective of the trial |
The primary objective of this study is to examine the clinical efficacy of nusinersen (ISIS 396443) administered intrathecally to participants with later-onset Spinal Muscular Atrophy (SMA). The secondary objective is to examine the safety and tolerability of nusinersen administered intrathecally to participants with later-onset SMA.
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Protection of trial subjects |
Written informed consent was obtained from the parent or legal guardian of the subject and, in cases where institutional guidelines and the subject’s age dictate, informed assent from the subject after
adequate explanation of the aims, methods, anticipated benefits, and potential hazards of the
study and before any protocol-specific screening procedures or any study treatment was
administered. Sufficient time was given to consider whether to participate in the study.
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Background therapy |
- | ||
Evidence for comparator |
- | ||
Actual start date of recruitment |
24 Nov 2014
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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 |
United States: 65
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Country: Number of subjects enrolled |
Italy: 19
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Country: Number of subjects enrolled |
Germany: 12
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Country: Number of subjects enrolled |
Japan: 8
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Country: Number of subjects enrolled |
Spain: 6
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Country: Number of subjects enrolled |
Canada: 5
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Country: Number of subjects enrolled |
France: 3
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Country: Number of subjects enrolled |
Hong Kong: 3
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Country: Number of subjects enrolled |
Korea, Republic of: 3
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Country: Number of subjects enrolled |
Sweden: 2
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Worldwide total number of subjects |
126
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EEA total number of subjects |
42
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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) |
126
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Adolescents (12-17 years) |
0
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Adults (18-64 years) |
0
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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 |
After parental informed consent was obtained and prior to any treatment, participants entered a Screening Period of up to 21 days to determine their eligibility for the study. Of the 179 participants screened, 53 were screening failures. | ||||||||||||
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 |
Investigator, Monitor, Carer, Assessor, Subject | ||||||||||||
Arms
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Are arms mutually exclusive |
Yes
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Arm title
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Sham procedure | ||||||||||||
Arm description |
Sham comparator on Days 1, 29, 85 and 274. | ||||||||||||
Arm type |
Sham procedure | ||||||||||||
Investigational medicinal product name |
No investigational medicinal product assigned in this arm
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Arm title
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Nusinersen | ||||||||||||
Arm description |
Nusinersen 12 mg solution via intrathecal (IT) injection on Days 1, 29, 85 and 274. | ||||||||||||
Arm type |
Experimental | ||||||||||||
Investigational medicinal product name |
Nusinersen
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Investigational medicinal product code |
ISIS 396443
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Other name |
BIIB058, Spinraza, IONIS-SMN Rx, ISIS SMNRx
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Pharmaceutical forms |
Solution for injection
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Routes of administration |
Intrathecal use
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Dosage and administration details |
Nusinersen 12 mg solution via intrathecal (IT) injection on Days 1, 29, 85 and 274.
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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: 1 participant completed the study but did not complete treatments due to early study closure |
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Baseline characteristics reporting groups
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Reporting group title |
Sham procedure
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Reporting group description |
Sham comparator on Days 1, 29, 85 and 274. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Nusinersen
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Reporting group description |
Nusinersen 12 mg solution via intrathecal (IT) injection on Days 1, 29, 85 and 274. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
Sham procedure
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Reporting group description |
Sham comparator on Days 1, 29, 85 and 274. | ||
Reporting group title |
Nusinersen
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Reporting group description |
Nusinersen 12 mg solution via intrathecal (IT) injection on Days 1, 29, 85 and 274. |
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End point title |
Change from Baseline in Hammersmith Functional Motor Scale - Expanded (HFMSE) Score at Month 15 | ||||||||||||
End point description |
The HFMSE consists of 33 scored activities used to assess motor function in children with SMA. The scale was originally developed with 20 scored activities and was devised for use in children with SMA Type 2 and Type 3 with limited ambulation to give objective information on motor ability and clinical progression. The expanded scale includes an additional module of 13 items developed to allow for evaluation of ambulatory SMA patients. Participants were asked to do a specific activity (such as rolling) and they were then graded on the quality and execution of that movement on a scale of 0=being unable, 1=performed with some compensation, and 2=unaided. The overall score is the sum of the scores for all activities with a maximum achievable score of 66. Higher scores indicate increased motor function. A positive change from Baseline indicates improvement.
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End point type |
Primary
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End point timeframe |
Baseline and Month 15
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Statistical analysis title |
Statistical Analysis 1 | ||||||||||||
Comparison groups |
Nusinersen v Sham procedure
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Number of subjects included in analysis |
126
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Analysis specification |
Pre-specified
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Analysis type |
superiority [1] | ||||||||||||
P-value |
= 1E-7 [2] | ||||||||||||
Method |
ANCOVA | ||||||||||||
Parameter type |
LS Mean Difference | ||||||||||||
Point estimate |
4.9
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Confidence interval |
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level |
95% | ||||||||||||
sides |
2-sided
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lower limit |
3.1 | ||||||||||||
upper limit |
6.7 | ||||||||||||
Variability estimate |
Standard error of the mean
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Dispersion value |
0.91
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Notes [1] - ITT Set: All participants who were randomized and received at least 1 dose of study drug/sham procedure. Missing postbaseline HFMSE data were imputed using multiple imputation. [2] - ANCOVA model with treatment group as a factor and age at Screening and baseline HFMSE score as covariates. Missing postbaseline HFMSE data were imputed using multiple imputation. |
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End point title |
Percentage of Participants Who Achieved a 3-Point Increase from Baseline in HFMSE Score at Month 15 | ||||||||||||
End point description |
The HFMSE consists of 33 scored activities used to assess motor function in children with SMA. The scale was originally developed with 20 scored activities and was devised for use in children with SMA Type 2 and Type 3 with limited ambulation to give objective information on motor ability and clinical progression. The expanded scale includes an additional module of 13 items developed to allow for evaluation of ambulatory SMA patients. Participants were asked to do a specific activity (such as rolling) and they were then graded on the quality and execution of that movement on a scale of 0=being unable, 1=performed with some compensation, and 2=unaided. The overall score is the sum of the scores for all activities with a maximum achievable score of 66. Higher scores indicate increased motor function. A positive change from Baseline indicates improvement.
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End point type |
Secondary
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End point timeframe |
Baseline and Month 15
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Statistical analysis title |
Statistical Analysis 1 | ||||||||||||
Comparison groups |
Sham procedure v Nusinersen
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Number of subjects included in analysis |
126
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Analysis specification |
Pre-specified
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Analysis type |
superiority [3] | ||||||||||||
P-value |
= 0.0006 [4] | ||||||||||||
Method |
Regression, Logistic | ||||||||||||
Parameter type |
Odds ratio (OR) | ||||||||||||
Point estimate |
5.59
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Confidence interval |
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level |
95% | ||||||||||||
sides |
2-sided
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lower limit |
2.09 | ||||||||||||
upper limit |
14.91 | ||||||||||||
Notes [3] - ITT Set: All participants who were randomized and received at least 1 dose of study drug/sham procedure. Missing postbaseline HFMSE data were imputed using multiple imputation. [4] - Based on logistic regression with treatment effect and adjustment for each participant's age at screening and HFMSE score at baseline. Missing postbaseline HFMSE data were imputed using multiple imputation. |
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Statistical analysis title |
Statistical Analysis 2 | ||||||||||||
Statistical analysis description |
Difference in proportions of Nusinersen minus Sham Procedure are from the MI procedure and are based on binomial proportions.
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Comparison groups |
Sham procedure v Nusinersen
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Number of subjects included in analysis |
126
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Analysis specification |
Pre-specified
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Analysis type |
superiority [5] | ||||||||||||
Method |
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Parameter type |
Difference in Proportions | ||||||||||||
Point estimate |
30.5
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Confidence interval |
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level |
95% | ||||||||||||
sides |
2-sided
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lower limit |
12.74 | ||||||||||||
upper limit |
48.31 | ||||||||||||
Notes [5] - ITT Set: All participants who were randomized and received at least 1 dose of study drug/sham procedure. Missing postbaseline HFMSE data were imputed using the MI. |
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End point title |
Percentage of Participants that Achieved any New Motor Milestone at Month 15 | ||||||||||||
End point description |
New motor milestones are defined as sitting without support, hands-and-knees crawling, standing with assistance, walking with assistance, standing alone and walking alone.
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End point type |
Secondary
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End point timeframe |
Month 15
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Statistical analysis title |
Statistical Analysis 1 | ||||||||||||
Statistical analysis description |
Difference in proportions of Nusinersen minus Sham Procedure is based on exact unconditional confidence interval.
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Comparison groups |
Sham procedure v Nusinersen
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Number of subjects included in analysis |
100
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Analysis specification |
Pre-specified
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Analysis type |
superiority [6] | ||||||||||||
Method |
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Parameter type |
Difference in Proportions | ||||||||||||
Point estimate |
13.8
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Confidence interval |
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level |
95% | ||||||||||||
sides |
2-sided
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lower limit |
-6.64 | ||||||||||||
upper limit |
34.17 | ||||||||||||
Notes [6] - Efficacy Set: All participants with a Day 456 Visit and all participants with a time difference of at least 463 days (456 days plus a 7-day window) between the date of first dose and the date for the final analysis. Based on imputed data where there was missing data. |
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End point title |
Number of New Motor Milestones Achieved per Participant | ||||||||||||
End point description |
New motor milestones are defined as sitting without support, hands-and-knees crawling, standing with assistance, walking with assistance, standing alone and walking alone.
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End point type |
Secondary
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End point timeframe |
Month 15
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Statistical analysis title |
Statistical Analysis 1 | ||||||||||||
Statistical analysis description |
Based on ANCOVA with treatment as a fixed effect and adjustment for each participant's age at screening and number of milestones at baseline.
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Comparison groups |
Sham procedure v Nusinersen
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Number of subjects included in analysis |
100
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Analysis specification |
Pre-specified
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Analysis type |
superiority [7] | ||||||||||||
Method |
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Parameter type |
LS Mean Difference | ||||||||||||
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 |
0.2 | ||||||||||||
upper limit |
0.7 | ||||||||||||
Notes [7] - Efficacy Set: All participants with a Day 456 Visit and all participants with a time difference of at least 463 days (456 days plus a 7-day window) between the date of first dose and the date for the final analysis. Based on imputed data where there was missing data. |
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End point title |
Change from Baseline in Revised Upper Limb Module (RULM) Test | ||||||||||||
End point description |
The RULM Test is used in patients with SMA to assess upper limb functional ability items that are reflective of activities of daily living (i.e., raise a can to mouth as if drinking, take a coin and place it in a box, remove the lid of a container). The RULM test has a total of 20 items with an entry item that serves as functional class identification and does not contribute to the total score. The remaining 19 scorable items reflect different functional domains and are graded on a 3-point system with a score of 0 (unable), 1 (able, with modification), and a maximum of 2 (able, no difficulty). There is only 1 item (item I) that is scored as a can/cannot score, with 1 as the highest score. Scorable items are summed for a total score range of 0-37, with higher scores increased great upper limb function. A positive change from Baseline indicates improvement.
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End point type |
Secondary
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End point timeframe |
Baseline and Month 15
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Statistical analysis title |
Statistical Analysis 1 | ||||||||||||
Statistical analysis description |
From multiple imputation procedure, based on ANCOVA with treatment as a fixed effect and adjustment for each participant's age at screening and derived total score at baseline.
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Comparison groups |
Sham procedure v Nusinersen
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Number of subjects included in analysis |
126
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Analysis specification |
Pre-specified
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Analysis type |
[8] | ||||||||||||
Method |
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Parameter type |
LS Mean Difference | ||||||||||||
Point estimate |
3.7
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Confidence interval |
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level |
95% | ||||||||||||
sides |
2-sided
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lower limit |
2.3 | ||||||||||||
upper limit |
5 | ||||||||||||
Notes [8] - ITT Set: All participants who were randomized and received at least 1 dose of study drug/sham procedure. Missing postbaseline data were imputed using the multiple imputation. |
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End point title |
Percentage of Participants that Achieved Standing Alone | ||||||||||||
End point description |
If the participant was unable to achieve standing alone at Baseline but could achieve this at Month 15 then they were considered a responder. If they could not achieve this or if a participant terminated the study prior to the 15-month assessment due to treatment failure or death, then any imputed value was ignored and the participant was considered as a non-responder.
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End point type |
Secondary
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End point timeframe |
Month 15
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Statistical analysis title |
Statistical Analysis 1 | ||||||||||||
Statistical analysis description |
Difference in proportions of Nusinersen minus Sham Procedure is based on exact unconditional confidence interval.
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Comparison groups |
Sham procedure v Nusinersen
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Number of subjects included in analysis |
100
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Analysis specification |
Pre-specified
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Analysis type |
superiority [9] | ||||||||||||
Method |
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Parameter type |
Difference in Proportions | ||||||||||||
Point estimate |
-1.4
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Confidence interval |
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level |
95% | ||||||||||||
sides |
2-sided
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lower limit |
-21.84 | ||||||||||||
upper limit |
19.34 | ||||||||||||
Notes [9] - Efficacy Set: All participants with a Day 456 Visit and all participants with a time difference of at least 463 days (456 days plus a 7-day window) between the date of first dose and the date for the final analysis. Based on imputed data where there was missing data. |
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End point title |
Percentage of Participants that Achieved Walking with Assistance | ||||||||||||
End point description |
If the participant was unable to achieve walking with assistance at baseline but could achieve this at Month 15 then they were considered a responder. If they could not achieve this or if a participant terminated the study prior to the 15-month assessment due to treatment failure or death, then any imputed value was ignored and the participant was considered as a non-responder.
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End point type |
Secondary
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End point timeframe |
Month 15
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Statistical analysis title |
Statistical Analysis 1 | ||||||||||||
Statistical analysis description |
Difference in proportions of Nusinersen minus Sham Procedure is based on exact unconditional confidence interval.
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Comparison groups |
Sham procedure v Nusinersen
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Number of subjects included in analysis |
100
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Analysis specification |
Pre-specified
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Analysis type |
superiority [10] | ||||||||||||
Method |
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Parameter type |
Difference in Proportions | ||||||||||||
Point estimate |
1.5
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Confidence interval |
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level |
95% | ||||||||||||
sides |
2-sided
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lower limit |
-19.1 | ||||||||||||
upper limit |
22.1 | ||||||||||||
Notes [10] - Efficacy Set: All participants with a Day 456 Visit and all participants with a time difference of at least 463 days (456 days plus a 7-day window) between the date of first dose and the date for the final analysis. Based on imputed data where there was missing data. |
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End point title |
Number of Participants that Experienced Adverse Events (AEs) and Serious Adverse Events (SAEs) | |||||||||||||||
End point description |
AEs: any sign, symptom, or diagnosis/disease that is unfavorable or unintended, that is new, or if pre-existing, worsens in participants administered a pharmaceutical product and that does not necessarily have a causal relationship with this treatment. SAEs: an event that results in death; an event that, in the view of the investigator, places the participant at immediate risk of death (a life-threatening event); an outcome that results in a congenital anomaly/birth defect diagnosed in a child of a participant; an event that requires or prolongs inpatient hospitalization; an event that results in persistent or significant disability/incapacity. Any other medically important event that, in the opinion of the investigator, may jeopardize the participant or may require intervention to prevent one of the other outcomes listed in the definition above.
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End point type |
Secondary
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End point timeframe |
Baseline through Month 15
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No statistical analyses for this end point |
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End point title |
Number of Participants with Clinically Significant Vital Sign Abnormalities | |||||||||
End point description |
Vital signs assessed for clinical significance include resting blood pressure, pulse, respiratory rate, and temperature.
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End point type |
Secondary
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End point timeframe |
Baseline through Month 15
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Notes [11] - New or worsening vital sign findings were reported as AEs and are presented in the AE/SAE section. [12] - New or worsening vital sign findings were reported as AEs and are presented in the AE/SAE section. |
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No statistical analyses for this end point |
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End point title |
Number of Participants with Clinically Significant Weight Abnormalities | |||||||||
End point description |
Weight changes assessed for clinical significance include body weight (including weight for age), ulnar length, and height (including height for age).
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End point type |
Secondary
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End point timeframe |
Baseline through Month 15
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Notes [13] - New or worsening weight abnormalities were reported as AEs and are presented in the AE/SAE section. [14] - New or worsening weight abnormalities were reported as AEs and are presented in the AE/SAE section. |
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No statistical analyses for this end point |
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End point title |
Number of Participants with Clinically Significant Neurological Examination Abnormalities | |||||||||
End point description |
Neurological changes assessed for clinical significance include assessment of mental status, level of consciousness, sensory function, motor function, cranial nerve function, and reflexes.
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End point type |
Secondary
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End point timeframe |
Baseline through Month 15
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Notes [15] - New or worsening neurological findings were reported as AEs and are presented in the AE/SAE section. [16] - New or worsening neurological findings were reported as AEs and are presented in the AE/SAE section. |
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No statistical analyses for this end point |
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End point title |
Number of Participants with Clinically Significant Physical Examination Abnormalities | |||||||||
End point description |
Physical examination changes were assessed for clinical significance.
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End point type |
Secondary
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End point timeframe |
Baseline through Month 15
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Notes [17] - New or worsening physical exam findings were reported as AEs and are in the AE/SAE section. [18] - New or worsening physical exam findings were reported as AEs and are in the AE/SAE section. |
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No statistical analyses for this end point |
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End point title |
Number of Participants with Clinically Significant Laboratory Parameters | |||||||||
End point description |
Laboratory parameter changes assessed for clinical significance include serum chemistry, hematology, coagulation and urinalysis.
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End point type |
Secondary
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End point timeframe |
Baseline through Month 15
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Notes [19] - New or worsening laboratory parameter findings were reported as AEs and are in the AE/SAE section. [20] - New or worsening laboratory parameter findings were reported as AEs and are in the AE/SAE section. |
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No statistical analyses for this end point |
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End point title |
Number of Participants with Abnormal, Clinically Relevant Post-Baseline Worsening in Electrocardiogram (ECG) in Results | |||||||||
End point description |
The number of participants with abnormal, clinically relevant worsening, defined as participants with an ECG interpreted as abnormal and clinically relevant, with a comparison with Baseline value is reported.
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End point type |
Secondary
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End point timeframe |
Baseline through Month 15
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No statistical analyses for this end point |
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End point title |
Number of Participants Taking Any Concomitant Medication Related to Dosing Procedure or Sham Procedure | |||||||||
End point description |
Concomitant medications include prescription and over-the-counter medications administered to participants on or after the first day of study treatment.
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End point type |
Secondary
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End point timeframe |
Baseline through Month 15
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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 |
From signing of Informed Consent to the end of the Follow-up period (Month 15)
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Adverse event reporting additional description |
Treatment emergent AEs are presented regardless of seriousness or relationship to investigational product.
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Assessment type |
Systematic | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary used for adverse event reporting
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Dictionary name |
MedDRA | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
17.1
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Reporting groups
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Reporting group title |
Nusinersen
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Reporting group description |
Nusinersen 12 mg solution via intrathecal (IT) injection on Days 1, 29, 85 and 274. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Sham procedure
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Reporting group description |
Sham comparator on Days 1, 29, 85 and 274. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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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 |
||
26 Sep 2014 |
Revised the statistical methods used to perform the interim analysis, revised the statistical methods used to perform the interim analysis, clarified the intention to continue safety follow-up via scheduled study visits for subjects who discontinue treatment without withdrawal of consent, added the main findings from nonclinical studies with ISIS 396443, clarified that general and local anesthesia and sedation were allowed to be used for LP procedure, added the neurological examination and HFMSE as appendices. |
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30 Jun 2016 |
Clarified the interim analysis plan, including its timing, subset of the total study population to be included, endpoints, and analytical methods used, clarified disposition of study subjects under the scenario of a premature study termination based on the results of a positive interim analysis, added language to describe the potential changes to study conduct that may occur on the basis of a positive benefit-risk assessment of the results of the interim analysis, added a statement regarding unblinding of certain representatives of the Sponsor during the interim analysis, updated clinical experience information to match Investigator’s Brochure, Version 6.0, January 2016, clarified adjustment of visit schedule for subjects who experience treatment delays as a result of illness, specific descriptions of the methodology for the efficacy endpoints was added, made minor changes to correct errors and improve clarity. |
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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. | |||
After the positive interim analysis of the study, the decision was made in October 2016 to terminate the study early and participants were invited for end-of-study visits. |