Clinical Trial Results:
An Extension Protocol For Multiple Sclerosis Patients Who Participated in Genzyme-Sponsored Studies of Alemtuzumab
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Summary
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EudraCT number |
2009-010788-18 |
Trial protocol |
GB DE BE SE AT PL CZ NL DK ES IT |
Global end of trial date |
16 Feb 2016
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Results information
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Results version number |
v1(current) |
This version publication date |
05 Mar 2017
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First version publication date |
05 Mar 2017
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Other versions |
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Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
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Trial identification
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Sponsor protocol code |
CAMMS03409
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT00930553 | ||
WHO universal trial number (UTN) |
- | ||
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Sponsors
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Sponsor organisation name |
Sanofi aventis recherche & développement
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Sponsor organisation address |
1 avenue Pierre Brossolette, ChillyMazarin, France, 91380
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Public contact |
Trial Transparency Team, Sanofi aventis recherche & développement, Contact-US@sanofi.com
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Scientific contact |
Trial Transparency Team, Sanofi aventis recherche & développement, Contact-US@sanofi.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 |
05 Jan 2017
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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 |
16 Feb 2016
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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 main objectives of the study were to examine:
1) the long term safety and efficacy of alemtuzumab in multiple sclerosis (MS) subjects who received alemtuzumab during prior company-sponsored studies CAMMS223, CAMMS323, and
CAMMS324;
2) the safety and efficacy of as-needed alemtuzumab retreatment in these previously alemtuzumab-treated subjects;
3) the safety and efficacy of 2 fixed, annual, alemtuzumab courses followed by optional, as-needed, retreatment in subjects who had previously received subcutaneous (SC) interferon beta-1a (INFB-1a) during CAMMS223, CAMMS323, or CAMMS324.
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Protection of trial subjects |
Subjects were fully informed of all pertinent aspects of the clinical trial as well as the possibility to discontinue at any time in language and terms appropriate for the subject and considering the local culture. During the course of the trial, subjects were provided with individual subject cards indicating the nature of the trial the subject is participating, contact details and any information needed in the event of a medical emergency.
Collected personal data and human biological samples were processed in compliance with the Sanofi-Aventis Group Personal Data Protection Charter ensuring that the Group abides by the laws governing personal data protection in force in all countries in which it operates.
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Background therapy |
- | ||
Evidence for comparator |
- | ||
Actual start date of recruitment |
05 Aug 2009
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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 |
Netherlands: 4
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Country: Number of subjects enrolled |
Poland: 59
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Country: Number of subjects enrolled |
Spain: 10
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Country: Number of subjects enrolled |
Sweden: 7
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Country: Number of subjects enrolled |
United Kingdom: 100
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Country: Number of subjects enrolled |
Austria: 1
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Country: Number of subjects enrolled |
Belgium: 5
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Country: Number of subjects enrolled |
Czech Republic: 27
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Country: Number of subjects enrolled |
Denmark: 3
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Country: Number of subjects enrolled |
France: 11
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Country: Number of subjects enrolled |
Germany: 40
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Country: Number of subjects enrolled |
Italy: 14
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Country: Number of subjects enrolled |
Argentina: 7
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Country: Number of subjects enrolled |
Australia: 53
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Country: Number of subjects enrolled |
Brazil: 29
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Country: Number of subjects enrolled |
Canada: 33
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Country: Number of subjects enrolled |
Russian Federation: 158
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Country: Number of subjects enrolled |
Croatia: 133
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Country: Number of subjects enrolled |
Israel: 7
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Country: Number of subjects enrolled |
Mexico: 13
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Country: Number of subjects enrolled |
Serbia: 62
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Country: Number of subjects enrolled |
Ukraine: 67
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Country: Number of subjects enrolled |
United States: 471
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Worldwide total number of subjects |
1314
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EEA total number of subjects |
414
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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) |
1314
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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 |
This extension study enrolled subjects from previous 3 studies: CAMMS223 (NCT00050778), CAMMS323 (NCT00530348), and CAMMS324 (NCT00548405). Subjects were enrolled in this study only after their Month 24 visit in CAMMS323 and CAMMS324. CAMMS223 subjects were enrolled within 6 months once their site received approval of extension study. | ||||||||||||||||||||||||||||
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Pre-assignment
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Screening details |
Efficacy outcome data was analysed only on CAMMS323 and CAMMS324 subjects; safety data was analysed on all subjects, as pre-specified in protocol. | ||||||||||||||||||||||||||||
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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 |
Non-randomised - controlled
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Blinding used |
Single blind | ||||||||||||||||||||||||||||
Roles blinded |
Assessor [1] | ||||||||||||||||||||||||||||
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Arms
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Arm title
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Alemtuzumab | ||||||||||||||||||||||||||||
Arm description |
Subjects enrolled from any of the prior studies received long-term follow-up in this study. Subjects randomised to receive interferon beta-1a (IFNB-1a) in prior studies received alemtuzumab 12 mg/day infusion intravenously (IV) once daily (QD) for 5 consecutive days in treatment Course 1, and for 3 consecutive days in treatment Course 2, 12 months later in this study. Subjects who received 2 treatment courses with alemtuzumab could be treated with additional alemtuzumab courses of 12 mg/day infusion IV QD, for 3 consecutive days at least 48 weeks after the prior course if they had documented evidence of resumed disease activity (defined as >=1 protocol-defined relapse and/or >=2 new or enlarging brain or spinal lesions on magnetic resonance imaging [MRI]), unless they met safety-related retreatment disqualifying criteria. | ||||||||||||||||||||||||||||
Arm type |
Experimental | ||||||||||||||||||||||||||||
Investigational medicinal product name |
Alemtuzumab
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Solution for infusion
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Routes of administration |
Intravenous use
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Dosage and administration details |
Alemtuzumab was administered by IV infusion over a period of at least 4 hours.
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| Notes [1] - The roles blinded appear inconsistent with a simple blinded trial. Justification: Only outcome assessor was blinded in the study. |
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Baseline characteristics reporting groups
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Reporting group title |
Overall study
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Reporting group description |
Subjects enrolled from any of the previous studies received long-term follow-up in this study. Subjects randomised to receive IFNB-1a in any of the previous studies received alemtuzumab 12 mg/day infusion IV, QD for 5 consecutive days in treatment Course 1, and for 3 consecutive days in treatment Course 2, 12 months later in this study. Subjects who received 2 treatment courses with alemtuzumab could be treated with additional alemtuzumab courses of 12 mg/day infusion IV QD, for 3 consecutive days at least 48 weeks after the prior course if they had documented evidence of resumed disease activity (defined as >=1 protocol-defined relapse and/or >=2 new or enlarging brain or spinal lesions on MRI), unless they met safety-related retreatment disqualifying criteria. | |||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
Alemtuzumab
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Reporting group description |
Subjects enrolled from any of the prior studies received long-term follow-up in this study. Subjects randomised to receive interferon beta-1a (IFNB-1a) in prior studies received alemtuzumab 12 mg/day infusion intravenously (IV) once daily (QD) for 5 consecutive days in treatment Course 1, and for 3 consecutive days in treatment Course 2, 12 months later in this study. Subjects who received 2 treatment courses with alemtuzumab could be treated with additional alemtuzumab courses of 12 mg/day infusion IV QD, for 3 consecutive days at least 48 weeks after the prior course if they had documented evidence of resumed disease activity (defined as >=1 protocol-defined relapse and/or >=2 new or enlarging brain or spinal lesions on magnetic resonance imaging [MRI]), unless they met safety-related retreatment disqualifying criteria. | ||
Subject analysis set title |
IFNB-1a/Alemtuzumab Switch CAMMS323/03409 (Pre Alemtuzumab)
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Subject analysis set type |
Sub-group analysis | ||
Subject analysis set description |
Subjects who received IFNB-1a in CAMMS323, were treated with alemtuzumab in CAMMS03409. IFNB-1a treatment period
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Subject analysis set title |
IFNB-1a/Alemtuzumab Switch CAMMS323/03409 (Post Alemtuzumab)
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Subject analysis set type |
Sub-group analysis | ||
Subject analysis set description |
Subjects who received IFNB-1a in CAMMS323, were treated with alemtuzumab in CAMMS03409. Alemtuzumab treatment period
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Subject analysis set title |
IFNB-1a/Alemtuzumab Switch CAMMS324/03409 (Pre Alemtuzumab)
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Subject analysis set type |
Sub-group analysis | ||
Subject analysis set description |
Subjects who received IFNB-1a in CAMMS324, were treated with alemtuzumab in CAMMS03409. IFNB-1a treatment period
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Subject analysis set title |
IFNB-1a/Alemtuzumab Switch CAMMS324/03409 (Post Alemtuzumab)
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Subject analysis set type |
Sub-group analysis | ||
Subject analysis set description |
Subjects who received IFNB-1a in CAMMS324, were treated with alemtuzumab in CAMMS03409. Alemtuzumab treatment period
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Subject analysis set title |
Alemtuzumab Retreatment
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Subject analysis set type |
Sub-group analysis | ||
Subject analysis set description |
Subjects who received alemtuzumab in CAMMS323 (NCT00530348) or CAMMS324 (NCT00548405), received an additional course of alemtuzumab in this study.
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Subject analysis set title |
Alemtuzumab Treatment CAMMS323 Extension
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Subject analysis set type |
Sub-group analysis | ||
Subject analysis set description |
Subjects who were randomised to alemtuzumab 12 mg/day treatment in CAMMS323 (NCT00530348) and enrolled in enrolled in this extension study (CAMMS03409).
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Subject analysis set title |
Alemtuzumab Treatment CAMMS324 Extension
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Subject analysis set type |
Sub-group analysis | ||
Subject analysis set description |
Subjects who were randomised to alemtuzumab 12 mg/day treatment in CAMMS324 (NCT00548405) and enrolled in this extension study (CAMMS03409).
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End point title |
Annualized Relapse Rate (ARR) [1] | ||||||||||||||||||||||||
End point description |
Relapse was defined as new neurological symptoms or worsening of previous neurological symptoms with an objective change on neurological examination, attributable to MS that last for at least 48 hours, present at normal body temperature, and that were preceded by at least 30 days of clinical stability. ARR was obtained from the total number of confirmed relapses that occurred during the treatment period divided by the sum of all subjects involved in certain treatment groups. ARR was estimated through negative binomial regression with robust variance estimation and covariate adjustment for geographic region. Subset of full analysis set (FAS - defined as all subjects randomised in CAMMS223, CAMMS323, and CAMMS324 and who received at least 1 dose of study drug) ) included subjects who had received at least 1 dose of alemtuzumab in CAMMS323 and CAMMS324. Number of subjects analysed = Subjects with available data for this endpoint.
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End point type |
Primary
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End point timeframe |
Year 3, 4, 5, 6 from the Baseline (Month 0 of CAMMS323 and Month 0 of CAMMS324 for “Alemtuzumab Treatment CAMMS323 Extension” group and “Alemtuzumab Treatment CAMMS324 Extension” group, respectively)
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| Notes [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: Only descriptive data was reported for this endpoint. |
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| No statistical analyses for this end point | |||||||||||||||||||||||||
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End point title |
Annualized Relapse Rate (ARR) Before and After Receiving Alemtuzumab [2] | ||||||||||||||||||||
End point description |
Relapse was defined as new neurological symptoms or worsening of previous neurological symptoms with an objective change on neurological examination, attributable to MS that last for at least 48 hours, present at normal body temperature, and that were preceded by at least 30 days of clinical stability. ARR was obtained from the total number of confirmed relapses that occurred during the treatment follow-up time of all subjects divided by the sum of total follow-up time of all subjects involved in certain treatment groups. ARR was estimated through repeated negative binomial regression with robust variance estimation and covariate adjustment for geographic region. The IFNB-1a/Alemtuzumab switch from CAMMS323 or CAMMS324 to CAMMS03409 pre alemtuzumab reporting group consisted of the same subjects as those in the corresponding post alemtuzumab reporting group. Subset of FAS who received IFNB-1a in CAMMS323 or CAMMS324 and who were treated with alemtuzumab in CAMMS03409.
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End point type |
Primary
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End point timeframe |
Baseline (Year 0 of initial studies) up to Year 4
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| Notes [2] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: Only descriptive data was reported for this endpoint. |
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| No statistical analyses for this end point | |||||||||||||||||||||
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End point title |
Annualized Relapse Rate (ARR) Before and After Alemtuzumab Retreatment [3] | ||||||||||||||||
End point description |
Relapse was defined as new neurological symptoms or worsening of previous neurological symptoms with an objective change on neurological examination, attributable to MS that last for at least 48 hours, present at normal body temperature, and that were preceded by at least 30 days of clinical stability. ARR was obtained from the total number of confirmed relapses that occurred during the treatment period divided by the sum of all subjects involved in certain treatment groups. ARR was estimated through negative binomial regression with robust variance estimation and covariate adjustment for geographic region. Subset of FAS included subjects who had received alemtuzumab in CAMMS323 or CAMMS324 and received an additional course of alemtuzumab in this extension study.
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End point type |
Primary
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End point timeframe |
Year 1 prior to retreatment, Year 1, 2, 3 after retreatment
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| Notes [3] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: Only descriptive data was reported for this endpoint. |
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| No statistical analyses for this end point | |||||||||||||||||
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End point title |
Number of Subjects With Sustained Accumulation of Disability (SAD) [4] | ||||||||||||
End point description |
SAD: increase of>=1.5 points in Expanded Disability Status Scale (EDSS) score for subjects with prior study baseline score (PSBS) of 0 and increase of>=1.0 point for subjects with a PSBS of 1.0 or more; persisted over a 6-month consecutive period. EDSS is ordinal scale in half-point increments, quantifying disability in subjects with MS. It assesses 7 functional systems (visual,brainstem, pyramidal, cerebellar,sensory,bowel/bladder,cerebral) and ambulation. EDSS total score ranges 0 (normal neurological examination) to 10 (death due to MS), higher scores indicating worse neurological function. Baseline was Year 0 of CAMMS323 and Year 0 of CAMMS324 for “alemtuzumab treatment CAMMS323 extension” and “alemtuzumab Treatment CAMMS324 Extension”, respectively. Subset of full analysis set (FAS -all subjects randomised in CAMMS223, CAMMS323, and CAMMS324 and who received at least 1 dose of study drug) included subjects who had received at least 1 dose of alemtuzumab in CAMMS323 and CAMMS324.
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End point type |
Primary
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End point timeframe |
Baseline (Year 0) up to Year 6
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| Notes [4] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: Statistical analysis has been provided separately as an attachment. |
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Attachments |
Statistical Analysis 1 |
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| No statistical analyses for this end point | |||||||||||||
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End point title |
Number of Subjects With Sustained Accumulation of Disability (SAD) Before and After Alemtuzumab Treatment: 2 Year Comparison [5] | ||||||||||||||||||||
End point description |
SAD: An increase of at least 1.5 points in EDSS score for subjects with PSBS of 0 and increase of at least 1.0 point for subjects with a PSBS of 1.0 or more; and the increase persisted over a 6-month consecutive period. EDSS is an ordinal scale in half-point increments that quantifies disability in subjects with MS. It assesses 7 functional systems (visual, brainstem, pyramidal, cerebellar, sensory, bowel/bladder and cerebral) and ambulation. EDSS total score ranges from 0 (normal neurological examination) to 10 (death due to MS), higher scores indicating worse neurological function. Number of subjects with SAD over 2 years before and 2 years after alemtuzumab treatment were estimated by Kaplan-Meier method. The IFNB-1a/Alemtuzumab switch pre alemtuzumab reporting group consisted of the same subjects as those in the corresponding post alemtuzumab reporting group. Subset of FAS who received IFNB-1a in CAMMS323 or CAMMS324 and who were treated with alemtuzumab in CAMMS03409.
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End point type |
Primary
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End point timeframe |
Baseline (Year 0 of initial studies) up to Year 4
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| Notes [5] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: Statistical analysis has been provided separately as an attachment. |
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Attachments |
Statistical Analysis 2 |
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| No statistical analyses for this end point | |||||||||||||||||||||
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End point title |
Number of Subjects With Sustained Reduction in Disability (SRD) Assessed by EDSS at Year 6 | ||||||||||||
End point description |
SRD was defined as a ≥1 point decrease in EDSS score lasting ≥6 months. SRD is only applicable to subjects with a baseline EDSS score of ≥2.0. EDSS is an ordinal scale in half-point increments that quantifies disability in subjects with MS. It assesses 7 functional systems (visual, brainstem, pyramidal, cerebellar, sensory, bowel/bladder and cerebral) as well as ambulation. EDSS total score ranges from 0 (normal neurological examination) to 10 (death due to MS), where higher scores indicate worse neurological function. Number of subjects with SRD at Year 6 was estimated using Kaplan-Meier method and reported in this endpoint. Subset of full analysis set (FAS - defined as all subjects randomised in CAMMS223, CAMMS323, and CAMMS324 and who received at least 1 dose of study drug) included subjectss who had received at least 1 dose of alemtuzumab in CAMMS323 and CAMMS324. Number of subjects analysed = subjects with available data for this endpoint.
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End point type |
Secondary
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End point timeframe |
Baseline (Year 0) up to Year 6
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Attachments |
Statistical Analysis 3 |
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| No statistical analyses for this end point | |||||||||||||
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End point title |
Number of Subjects With Sustained Reduction in Disability (SRD) Assessed by EDSS (After Alemtuzumab Treatment) at Year 2 of the Extension Study | ||||||||||||
End point description |
SRD: a ≥1 point decrease in EDSS score lasting ≥6 months. SRD is only applicable to subjects with baseline EDSS score of ≥2.0. EDSS is an ordinal scale in half-point increments that quantifies disability in subjects with MS. It assesses 7 functional systems (visual, brainstem, pyramidal, cerebellar, sensory, bowel/bladder and cerebral) as well as ambulation. EDSS total score ranges from 0 (normal neurological examination) to 10 (death due to MS), where higher scores indicate worse neurological function. Number of subjects with SRD at Year 2 of CAMMS03409 was estimated using Kaplan-Meier method. The IFNB-1a/Alemtuzumab switch from CAMMS323 or CAMMS324 to CAMMS03409 pre alemtuzumab reporting group consisted of the same subjects as those in the corresponding post alemtuzumab reporting group. Subset of FAS who received IFNB-1a in CAMMS323 or CAMMS324 and who were treated with alemtuzumab in CAMMS03409. Number of subjects analysed = subjects with available data for this endpoint.
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End point type |
Secondary
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End point timeframe |
Extension study (CAMMS03409) baseline up to Extension Year 2
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Attachments |
Statistical Analysis 4 |
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| No statistical analyses for this end point | |||||||||||||
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End point title |
Change From Initial Study Baseline in EDSS Score at Year 3, 4, 5 and 6 | ||||||||||||||||||||||||
End point description |
EDSS is an ordinal scale in half-point increments that quantifies disability in participants with MS. It assesses the 7 functional systems (visual, brainstem, pyramidal, cerebellar, sensory, bowel/bladder and cerebral) as well as ambulation. EDSS total score ranges from 0 (normal neurological examination) to 10 (death due to MS), where higher scores indicate worse neurological function. Change was calculated by subtracting baseline (Month 0 of the study CAMMS323 [NCT00530348] or CAMMS324 [NCT00548405]) value from EDSS scores at specified time points. Subset of full analysis set (FAS - defined as all subjects randomised in CAMMS223, CAMMS323, and CAMMS324 and who received at least 1 dose of study drug) included subjects who had received at least 1 dose of alemtuzumab in CAMMS323 and CAMMS324. Number of subjects analysed = subjects with available data for this endpoint.
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End point type |
Secondary
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End point timeframe |
Baseline (Month 0 of CAMMS323 and Month 0 of CAMMS324 for “Alemtuzumab Treatment CAMMS323 Extension” group and “Alemtuzumab Treatment CAMMS324 Extension” group, respectively), Year 3, 4, 5, 6
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| No statistical analyses for this end point | |||||||||||||||||||||||||
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End point title |
Change From Initial Study Baseline in EDSS Score Before and After Alemtuzumab Treatment: 2 Year Comparison | ||||||||||||||||||||||||||||||
End point description |
EDSS is an ordinal scale in half-point increments that quantifies disability in subjects with MS. It assesses the 7 functional systems (visual, brainstem, pyramidal, cerebellar, sensory, bowel/bladder and cerebral) as well as ambulation. EDSS total score ranges from 0 (normal neurological examination) to 10 (death due to MS), where higher scores indicate worse neurological function.Change was calculated by subtracting baseline (Month 0 of the study CAMMS323 or CAMMS324 for pre alemtuzumab period or CAMMS03409 baseline for post alemtuzumab period) value, from EDSS scores at specified time points. The IFNB-1a/Alemtuzumab switch pre alemtuzumab reporting group consisted of the same subjects as those in the corresponding post alemtuzumab reporting groups. Baseline was Year 0 of
CAMMS323 and Year 0 of CAMMS324 for "CAMMS323" and "CAMMS324" subjects, respectively. Subset of FAS who received IFNB-1a in CAMMS323 or CAMMS324 and who were treated with alemtuzumab in CAMMS03409.
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End point type |
Secondary
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End point timeframe |
Baseline (Year 0 of initial studies) up to Year 4
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| No statistical analyses for this end point | |||||||||||||||||||||||||||||||
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End point title |
Change From Retreatment Baseline in EDSS Score After Alemtuzumab Retreatment | ||||||||||||||||
End point description |
EDSS is an ordinal scale in half-point increments that quantifies disability in subjects with MS. It assesses the 7 functional systems (visual, brainstem, pyramidal, cerebellar, sensory, bowel/bladder and cerebral) as well as ambulation. EDSS total score ranges from 0 (normal neurological examination) to 10 (death due to MS), where higher scores indicate worse neurological function.Change was calculated by subtracting retreatment baseline (annual visit prior to the retreatment start date) value from EDSS scores at specified time points. Subset of FAS included subjects who had received alemtuzumab in CAMMS323 or CAMMS324 and received an additional course of alemtuzumab in this extension study.
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End point type |
Secondary
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End point timeframe |
Retreatment baseline, Year 1, 2 and 3 after retreatment baseline
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| No statistical analyses for this end point | |||||||||||||||||
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End point title |
Percentage of Subjects Without New or Enlarging Magnetic Resonance Imaging (MRI)-T2-Hypertense Lesion Activity | ||||||||||||||||||||||||
End point description |
Analysis of new or enlarging lesions that appear hyperintense on T2-weighted MRI scans performed annually. Subset of full analysis set (FAS - defined as all subjects randomised in CAMMS223, CAMMS323, and CAMMS324 and who received at least 1 dose of study drug) included subjects who had received at least 1 dose of alemtuzumab in CAMMS323 and CAMMS324. Number of subjects analysed = subjects with available data for this endpoint.
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End point type |
Secondary
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End point timeframe |
Year 3, 4, 5 and 6
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| No statistical analyses for this end point | |||||||||||||||||||||||||
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End point title |
Percentage of Subjects Without New or Enlarging MRI-T2-Hypertense Lesion Activity Before and After Alemtuzumab Treatment | ||||||||||||||||||||||||||||||
End point description |
Analysis of new or enlarging lesions that appear hyperintense on T2-weighted MRI scans performed annually. The IFNB-1a/Alemtuzumab switch from CAMMS323 or CAMMS324 to CAMMS03409 pre alemtuzumab reporting group consisted of the same subjects as those in the corresponding post alemtuzumab reporting group. Subset of FAS who received IFNB-1a in CAMMS323 or CAMMS324 and who were treated with alemtuzumab in CAMMS03409. Here 'n' signifies number of subjects with available data for specified category.
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End point type |
Secondary
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End point timeframe |
Baseline (Year 0 of initial studies) up to Year 4
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| No statistical analyses for this end point | |||||||||||||||||||||||||||||||
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End point title |
Percentage of Subjects Without New or Enlarging MRI-T2-Hypertense Lesion Activity Before and After Alemtuzumab Retreatment | ||||||||||||||||
End point description |
Analysis of new or enlarging lesions that appear hyperintense on T2-weighted MRI scans performed annually. Retreatment baseline was the annual visit prior to the retreatment start date. Subset of FAS included subjects who had received alemtuzumab in CAMMS323 or CAMMS324 and received an additional course of alemtuzumab in this extension study. Here 'n' signifies number of subjects with available data for specified category.
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End point type |
Secondary
|
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End point timeframe |
Retreatment Baseline, Year 1, 2 and 3 after retreatment
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| No statistical analyses for this end point | |||||||||||||||||
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End point title |
Percentage Change From Baseline in MRI-T2-Hypertense Lesion Volumes at Year 3, 4, 5, 6 | ||||||||||||||||||||||||
End point description |
Lesion volume was quantitatively assessed by hyperintensity on T2-weighted MRI scans. Subset of full analysis set (FAS - defined as all subjects randomised in CAMMS223, CAMMS323, and CAMMS324 and who received at least 1 dose of study drug) included subjects who had received at least 1 dose of alemtuzumab in CAMMS323 and CAMMS324. Here 'n' signifies number of subjects with available data for specified category.
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End point type |
Secondary
|
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End point timeframe |
Baseline (Month 0 of CAMMS323 and Month 0 of CAMMS324 for “Alemtuzumab Treatment CAMMS323 Extension” group and “Alemtuzumab Treatment CAMMS324 Extension” group, respectively), Year 3, 4, 5, 6
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| No statistical analyses for this end point | |||||||||||||||||||||||||
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End point title |
Percentage of Subjects Without New Gadolinium-enhancing MRI Lesion Activity | ||||||||||||||||||||||||
End point description |
Analysis of new gadolinium-enhancing lesions that appear on MRI scans performed annually. Baseline was the prior annual visit. Subset of full analysis set (FAS - defined as all subjects randomised in CAMMS223, CAMMS323, and CAMMS324 and who received at least 1 dose of study drug) included subjects who had received at least 1 dose of alemtuzumab in CAMMS323 and CAMMS324. Number of subjects analysed = subjects with available data for this endpoint. Here 'n' signifies number of subjects with available data for specified category.
|
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End point type |
Secondary
|
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End point timeframe |
Year 3, 4, 5 and 6
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| No statistical analyses for this end point | |||||||||||||||||||||||||
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End point title |
Percent Change From Baseline in Brain Parenchymal Fractions (BPF) at Year 3, 4, 5 and 6 | ||||||||||||||||||||||||
End point description |
Brain parenchymal fraction (calculated as the ratio of brain parenchymal volume to total intradural volume), is a sensitive indicator of brain atrophy. Subset of full analysis set (FAS - defined as all subjects randomised in CAMMS223, CAMMS323, and CAMMS324 and who received at least 1 dose of study drug) included subjects who had received at least 1 dose of alemtuzumab in CAMMS323 and CAMMS324. Number of subjects analysed = subjects with available data for this endpoint. Here 'n' signifies number of subjects with available data for specified category.
|
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End point type |
Secondary
|
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End point timeframe |
Baseline (Month 0 of CAMMS323 and Month 0 of CAMMS324 for “Alemtuzumab Treatment CAMMS323 Extension” group and “Alemtuzumab Treatment CAMMS324 Extension” group, respectively), Year 3, 4, 5 and 6
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| No statistical analyses for this end point | |||||||||||||||||||||||||
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End point title |
Percentage of Relapse Free Subjects | ||||||||||||||||||||||||
End point description |
Relapse was defined as new neurological symptoms or worsening of previous neurological symptoms with an objective change on neurological examination, attributable to MS that last for at least 48 hours, present at normal body temperature, and that were preceded by at least 30 days of clinical stability. Subset of full analysis set (FAS - defined as all subjects randomised in CAMMS223, CAMMS323, and CAMMS324 and who received at least 1 dose of study drug) included subjects who had received at least 1 dose of alemtuzumab in CAMMS323 and CAMMS324. Number of subjects analysed = subjects with available data for this endpoint.
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End point type |
Secondary
|
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End point timeframe |
Year 3, 4, 5 and 6
|
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| No statistical analyses for this end point | |||||||||||||||||||||||||
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End point title |
Change From Baseline in Physical Component Score (PCS) of Short Form-36 (SF-36) Health Survey at Year 3, 4, 5 and 6 | ||||||||||||||||||||||||
End point description |
SF-36 is a subject reported standardized survey designed to assess generic health related quality of life. It consisted of 36 items evaluating 8 aspects of functional health and well-being: 1) physical functioning, 2) role physical, 3) bodily pain, 4) general health, 5) vitality, 6) social functioning, 7) role emotional and 8) mental health. The score range for each of the 8 health aspects was from 0 (poor health) to 100 (better health), higher scores indicating good health condition. Scores of first four health aspects (1 - 4) were aggregated to derive the PCS ranging from 0 (worst) to 100 (best), where higher scores indicated good health condition. Subset of full analysis set (FAS - defined as all subjects randomised in CAMMS223, CAMMS323, and CAMMS324 and who received at least 1 dose of study drug) included subjects who had received at least 1 dose of alemtuzumab in CAMMS323 and CAMMS324. Number of subjects analysed = subjects with available data for this endpoint.
|
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End point type |
Secondary
|
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End point timeframe |
Baseline (Month 0 of CAMMS323 and Month 0 of CAMMS324 for “alemtuzumab treatment CAMMS323 extension group”, “alemtuzumab Treatment CAMMS324 Extension” group, respectively),Year 3, 4, 5 and 6
|
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| No statistical analyses for this end point | |||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||
End point title |
Change From Baseline in Physical Component Score (PCS) of Short Form-36 (SF-36) Health Survey (Before and After Alemtuzumab Treatment): 2 Year Comparison | ||||||||||||||||||||||||||||||
End point description |
SF-36 is a standardised survey designed to assess generic health related quality of life. It consisted of 36 items evaluating 8 aspects of functional health and well-being: 1) physical functioning, 2) role physical, 3) bodily pain, 4) general health, 5) vitality, 6) social functioning, 7) role emotional and 8) mental health. The score range for each health aspects was from 0 (poor health) to 100 (better health), higher scores indicating good health. Scores of first four health aspects (1 - 4) were aggregated to derive the PCS ranging from 0 (worst) to 100 (best), higher scores indicating good health. The IFNB-1a/Alemtuzumab switch from CAMMS323 or CAMMS324 to CAMMS03409 pre alemtuzumab group consisted of same subjects as those in corresponding post alemtuzumab group. Baseline was Year 0 of CAMMS323 and Year 0 of CAMMS324 for “CAMMS323” and “CAMMS324” subjects, respectively. Subset of FAS who received IFNB-1a in CAMMS323 or CAMMS324 and who were treated with alemtuzumab in CAMMS03409.
|
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End point type |
Secondary
|
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End point timeframe |
Baseline (Year 0 of initial studies) up to Year 4
|
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| No statistical analyses for this end point | |||||||||||||||||||||||||||||||
|
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End point title |
Change From Baseline in Mental Component Score (MCS) of Short Form-36 (SF-36) at Year 3, 4, 5, and 6 | ||||||||||||||||||||||||
End point description |
SF-36 is a subject reported standardized survey designed to assess generic health related quality of life. It consisted of 36 items evaluating 8 aspects of functional health and well-being: 1) physical functioning, 2) role physical, 3) bodily pain, 4) general health, 5) vitality, 6) social functioning, 7) role emotional and 8) mental health. The score range for each of the 8 health aspects was from 0 (poor health) to 100 (better health), higher scores indicating good health condition. Scores of last four health aspects (5 - 8) were aggregated to derive the MCS ranging from 0 (worst) to 100 (best), where higher scores indicated good health condition. Subset of full analysis set (FAS - defined as all subjects randomised in CAMMS223, CAMMS323, and CAMMS324 and who received at least 1 dose of study drug) included subjects who had received at least 1 dose of alemtuzumab in CAMMS323 and CAMMS324. Number of subjects analysed = subjects with available data for this endpoint.
|
||||||||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||||||||
End point timeframe |
Baseline (Month 0 of CAMMS323 and Month 0 of CAMMS324 for “Alemtuzumab Treatment CAMMS323 Extension” group and “Alemtuzumab Treatment CAMMS324 Extension” group, respectively), Year 3, 4, 5 and 6
|
||||||||||||||||||||||||
|
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| No statistical analyses for this end point | |||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||
End point title |
Change From Baseline in Mental Component Score (MCS) of Short Form-36 (SF-36) Before and After Alemtuzumab Treatment: 2 Year Comparison | ||||||||||||||||||||||||||||||
End point description |
SF-36 is a standardized survey designed to assess generic health related quality of life. It consisted of 36 items evaluating 8 aspects of functional health and well-being: 1) physical functioning, 2) role physical, 3) bodily pain, 4) general health, 5) vitality, 6) social functioning, 7) role emotional and 8) mental health. The score range for each health aspects was from 0 (poor health) to 100 (better health), higher scores indicating good health. Scores of last four health aspects (5 - 8) were aggregated to derive the MCS ranging from 0 (worst) to 100 (best), higher scores indicating good health. The IFNB-1a/Alemtuzumab switch from CAMMS323 or CAMMS324 to CAMMS03409 pre alemtuzumab group consisted of same subjects as those in corresponding post alemtuzumab group. Baseline was Year 0 of CAMMS323 and Year 0 of CAMMS324 for “CAMMS323” and “CAMMS324” subjects, respectively. Subset of FAS who received IFNB-1a in CAMMS323 or CAMMS324 and who were treated with alemtuzumab in CAMMS03409.
|
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End point type |
Secondary
|
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End point timeframe |
Baseline (Year 0 of initial studies) up to Year 4
|
||||||||||||||||||||||||||||||
|
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| No statistical analyses for this end point | |||||||||||||||||||||||||||||||
|
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End point title |
Change From Baseline in Self-reported Quality of Life as Assessed by Functional Assessment of Multiple Sclerosis (FAMS) Score at Year 3, 4, 5 and 6 | ||||||||||||||||||||||||
End point description |
FAMS comprised of 58 items on 7 subscales: mobility (7 items); symptoms (7 items); emotional well-being (7 items); general contentment (7 items); thinking and fatigue (9 items); family/social well-being (7 items); and additional concerns (14 items, these are not scored). Subjects provided their response based on the recall of past week. Each item was rated on a 5-point scale ranges from 0 (poor) to 4 (best), where higher scores indicated higher/better quality of life. Scores from 44 calculable items were summed to provide FAMS total score. FAMS total score ranges from 0 (poor) to 176 (best), where higher scores indicated higher/better quality of life. Subset of full analysis set (FAS - defined as all subjects randomised in CAMMS223, CAMMS323, and CAMMS324 and who received at least 1 dose of study drug) included subjects who had received at least 1 dose of alemtuzumab in CAMMS323 and CAMMS324. Number of subjects analysed = subjects with available data for this endpoint.
|
||||||||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||||||||
End point timeframe |
Baseline (Month 0 of CAMMS323 and Month 0 of CAMMS324 for “Alemtuzumab Treatment CAMMS323 Extension” group and “Alemtuzumab Treatment CAMMS324 Extension” group, respectively), Year 3, 4, 5, 6
|
||||||||||||||||||||||||
|
|||||||||||||||||||||||||
| No statistical analyses for this end point | |||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||
End point title |
Change From Baseline in Self-reported Quality of Life as Assessed by Functional Assessment of Multiple Sclerosis (FAMS) Score Before and After Alemtuzumab Treatment: 2 Year Comparison | ||||||||||||||||||||||||||||||
End point description |
FAMS comprised of 58 items on 7 subscales: mobility (7 items); symptoms (7 items); emotional well-being (7 items); general contentment (7 items); thinking and fatigue (9 items); family/social well-being (7 items); and additional concerns (14 items, these are not scored). Subjects provided their response based on the recall of past week. Each item was rated on a 5-point scale ranges from 0 (poor) to 4 (best), where higher scores indicated higher/better quality of life. Scores from 44 calculable items were summed to provide FAMS total score. FAMS total score ranges from 0 (poor) to 176 (best), where higher scores indicated higher/better quality of life. The IFNB-1a/Alemtuzumab switch from CAMMS323 or CAMMS324 to CAMMS03409 pre alemtuzumab reporting group consisted of the same subjects as those in the corresponding post alemtuzumab reporting group. Subset of FAS who received IFNB-1a in CAMMS323 or CAMMS324 and who were treated with alemtuzumab in CAMMS03409.
|
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End point type |
Secondary
|
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End point timeframe |
Baseline (Year 0 of initial studies) up to Year 4
|
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| No statistical analyses for this end point | |||||||||||||||||||||||||||||||
|
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End point title |
Change From Baseline in European Ouality of Life -5 Dimension (EQ-5D) Visual Analog Scale Score at Year 3, 4, 5 and 6 | ||||||||||||||||||||||||
End point description |
EQ-5D is a standardized instrument for measuring health status and consisting of EQ-5D descriptive system and Visual Analogue Scale (VAS). EQ-5D descriptive system comprised of 5 dimensions of health: mobility, self-care, usual activities, pain/discomfort and anxiety/depression. Each dimension was measured on 3 levels (no problem, some problems and extreme problems). These 5-dimensional 3-level measurements were converted into single index utility score. Possible values for single index utility score ranged from -0.594 (severe problems in all dimensions) to 1.0 (no problem in all dimensions) on scale where 1 represented best possible health state.Subset of full analysis set (FAS - defined as all subjects randomised in CAMMS223, CAMMS323, and CAMMS324 and who received at least 1 dose of study drug) included subjects who had received at least 1 dose of alemtuzumab in CAMMS323 and CAMMS324. Number of subjects analysed = subjects with available data for this endpoint.
|
||||||||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||||||||
End point timeframe |
Baseline (Month 0 of CAMMS323 and Month 0 of CAMMS324 for “Alemtuzumab Treatment CAMMS323 Extension” group and “Alemtuzumab Treatment CAMMS324 Extension” group, respectively), Year 3, 4, 5 and 6
|
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|
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| No statistical analyses for this end point | |||||||||||||||||||||||||
|
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End point title |
Change From Baseline in European Ouality of Life -5 Dimension (EQ-5D) Visual Analog Scale Score Before and After Alemtuzumab Treatment: 2 Year Comparison | ||||||||||||||||||||||||||||||
End point description |
EQ-5D is a standardized instrument for measuring health status and consisting of EQ-5D descriptive system and VAS. EQ-5D descriptive system comprised of 5 dimensions of health: mobility, self-care, usual activities, pain/discomfort and anxiety/depression. Each dimension was measured on 3 levels (no problem, some problems and extreme problems). These 5-dimensional 3-level measurements were converted into single index utility score. Possible values for single index utility score ranged from -0.594 (severe problems in all dimensions) to 1.0 (no problem in all dimensions) on scale where 1 represented best possible health state. The IFNB-1a/Alemtuzumab switch from CAMMS323 or CAMMS324 to CAMMS03409 pre alemtuzumab reporting group consisted of the same subjects as those in the corresponding post alemtuzumab reporting group. Subset of FAS who received IFNB-1a in CAMMS323 or CAMMS324 and who were treated with alemtuzumab in CAMMS03409.
|
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End point type |
Secondary
|
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End point timeframe |
Baseline (Year 0 of initial studies) up to Year 4
|
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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 |
All Adverse Events (AE) were collected from signature of the informed consent form in the extension study up to the end of extension study visit (up to Year 6) regardless of seriousness or relationship to investigational product.
|
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Adverse event reporting additional description |
Reported AEs are treatment-emergent adverse events (TEAEs), AEs that developed/worsened during or at any time after first alemtuzumab treatment. Alemtuzumab TEAEs were defined as AEs with start dates and start times on or after the date and time of the first alemtuzumab treatment in CAMMS03409 or in prior studies (CAMMS223, CAMMS323, or CAMMS324).
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Assessment type |
Systematic | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Dictionary used for adverse event reporting
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Dictionary name |
MedDRA | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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18.1
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Reporting groups
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Reporting group title |
Alemtuzumab
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Reporting group description |
Subjects enrolled in any of the previous studies who had received alemtuzumab. Subjects enrolled in any of the previous studies who had received IFNB-1a, who received alemtuzumab 12 mg/day infusion in this study. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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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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25 Feb 2010 |
• Allowed use of disease modifying therapies including follow-up.
• Revision to allow female subjects to become pregnant 6 months after infusion.
• Addition of substudy to evaluate effect of alemtuzumab on cardiac repolarization via QT assessments.
• Allowed one-time blood sample collection for future genotyping.
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26 Aug 2010 |
• Addition of one time point for a PK sample and triplicate electrocardiogram (ECG) collection on study Day 6 or 8 in order to assess any potential delayed alemtuzumab effects on QT.
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18 Apr 2012 |
• To extend study by 1 additional year; from 3 years (36 months) to 4 years (48 months). |
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26 Jun 2013 |
• Study extended to allow subjects to remain in the study through the time of drug approval or until long term care was available.
• Added collection of vital signs during alemtuzumab infusion.
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20 Jun 2014 |
• Medical events of interest (MEOI) table revised to list specific examples and reporting times.
• To specify that an enrolled subject could remain in the Extension Study for a minimum of 48 months from study entry
• To specify assessment of rater blinding to include annual visits after 24 months.
• Clarification of ITP (immune thrombocytopenic purpura) and anti-glomerular basement membrane (GBM) surveillance monitoring.
• To revise that last completion of CARE-MS monthly monitoring survey occurred at the end of the study.
• Added Section 9.4.19 to define symptomatic overdose with Investigational Medicinal Product.
• Duration of the study was extended to allow subjects in the United States to remain on the study until a follow-up study was available or through Month 72, whichever occurred first.
• MEOI table revised to list specific examples and reporting times.
• Revised number of Months (from 59 to 71) that subjects would have to qualify and receive treatment after enrollment.
• Protocol updated throughout to add monthly visits for Months 61 through 71, accordingly.
• Clarification of ITP and Anti-GBM surveillance monitoring.
• Revised Section 9.4.19 to clarify symptomatic overdose with IMP.
• Revised that last completion of CARE-MS monthly monitoring survey occurred at the end of the study.
• Specified assessment of rater blinding to be done at Month 72 visit.
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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 | |||
Online references |
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| http://www.ncbi.nlm.nih.gov/pubmed/18946064 http://www.ncbi.nlm.nih.gov/pubmed/16044212 |
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