CARE-MS I: Comparison of Alemtuzumab and Rebif® Efficacy in Multiple Sclerosis, Study One

• Sponsor: Genzyme, a Sanofi Company (Industry)
• Overall Status: Completed
• CT.gov ID: NCT00530348
• Collaborator: Bayer (Industry)
• Enrollment: 581
• Locations: 101
• Arms: 2
• Duration (Months): 44
• Patients Per Site: 5.8
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

The purpose of this study was to establish the efficacy and safety of alemtuzumab (Lemtrada™) as a treatment for relapsing-remitting multiple sclerosis (MS), in comparison with subcutaneous (SC) interferon beta-1a (Rebif®). The study had enrolled participants who had not previously received MS disease-modifying therapies. Participants had monthly laboratory tests and comprehensive testing every 3 months.

Condition or Disease	Intervention/Treatment	Phase
Multiple Sclerosis, Relapsing-Remitting	Biological: Alemtuzumab; Biological: Interferon beta-1a	Phase 3

Detailed Description

Every participant had received active treatment; there was no placebo. Participants who qualified were randomly assigned to treatment with either alemtuzumab or SC interferon beta-1a at a 2:1 ratio (that is, 2 given alemtuzumab for every 1 given interferon beta-1a). Alemtuzumab was administered in two annual courses, once at the beginning of the study and again 1 year later. Interferon beta-1a was self-injected 3 times per week for 2 years. All participants were required to return to their study site every 3 months for neurologic assessment. In addition, safety-related laboratory tests were performed at least monthly. Participation in this study ended 2 years after the start of treatment for each participant. Additionally, participants who received alemtuzumab might be followed in CAMMS03409 (NCT00930553) an extension study for safety and efficacy assessments. Participants who received interferon beta-1a and completed 2 years on study might be eligible to receive alemtuzumab on the extension study.

Study Design

• Study Type: Interventional
• Actual Enrollment: 581 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Single (Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: A Phase 3 Randomized, Rater-Blinded Study Comparing Two Annual Cycles of Intravenous Alemtuzumab to Three-Times Weekly Subcutaneous Interferon Beta-1a (Rebif®) in Treatment-Naïve Patients With Relapsing-Remitting Multiple Sclerosis
• Study Start Date: Aug 1, 2007
• Actual Primary Completion Date: Apr 1, 2011
• Actual Study Completion Date: Apr 1, 2011

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Alemtuzumab	Biological: Alemtuzumab; Alemtuzumab 12 milligram (mg) per day intravenous (IV) infusion on 5 consecutive days at Month 0, followed by alemtuzumab 12 mg per day IV infusion on 3 consecutive days at Month 12.; Other Names: Lemtrada
Active Comparator: Interferon Beta-1a	Biological: Interferon beta-1a; Interferon beta-1a 44 microgram (mcg) subcutaneously 3-times weekly for 24 months. Dose adjustment was done as per Investigator's discretion.; Other Names: Rebif®

Outcome Measures

Primary Outcome Measures

1. Percentage of Participants With Sustained Accumulation of Disability (SAD) [Up to 2 years]

   EDSS is an ordinal scale in half-point increments that quantifies disability in participants with MS. It assesses 7 functional systems (visual, brainstem, pyramidal, cerebellar, sensory, bowel/bladder and cerebral) as well as ambulation. EDSS total score: 0 (normal neurological examination) to 10 (death due to MS). As measured by EDSS score, SAD was defined as increase of at least 1.5 points for participants with Baseline score of 0 and increase of at least 1.0 point for participants with a Baseline score of 1.0 or more; and the increase persisted for at least next 2 scheduled assessments, that is, 6 consecutive months. Onset date of SAD was date of first EDSS assessment that began 6 month consecutive period of SAD. Participants who did not reach SAD endpoint were censored at their last visit. Percentage of participants with SAD, estimated by Kaplan-Meier (KM) method, was reported.

2. Annualized Relapse Rate [Up to 2 years]

   Relapse was defined as new neurological symptoms or worsening of previous neurological symptoms with an objective change on neurological examination, attributable to multiple sclerosis that lasted for at least 48 hours, that were present at normal body temperature, and that were preceded by at least 30 days of clinical stability. Annualized relapse rate was estimated through negative binomial regression with robust variance estimation and covariate adjustment for geographic region using observed number of relapses as dependent variable, the log total amount of follow-up from date of first study treatment for each participant as an offset variable, and treatment group and geographic region as model covariates.

Secondary Outcome Measures

1. Percentage of Participants Who Were Relapse Free at Year 2 [Year 2]

   Participants were considered relapse free at Year 2 if they did not experience a relapse from the date of first study treatment to study completion at 24 months. Percentage of participants who were relapse free at Year 2, estimated using the KM method, was reported.

2. Change From Baseline in Expanded Disability Status Scale (EDSS) Score at Year 2 [Baseline, Year 2]

   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). Change was calculated by subtracting Baseline value from value at Year 2.

3. Change From Baseline in Multiple Sclerosis Functional Composite (MSFC) Score at Year 2 [Baseline, Year 2]

   MSFC is a multidimensional measure consisting of quantitative tests of ambulation (Timed 25-Foot Walk), manual dexterity (9-Hole Peg Test; 9HPT), and cognitive function (Paced Auditory Serial Addition Test; PASAT). The MSFC score was calculated as the mean of the Z-scores of the 3 components. A Z-score was calculated by subtracting the mean of the reference population from the test result, then dividing by the standard deviation of the reference population. Higher Z-scores reflected better neurological function and a positive change from Baseline indicates improvement. An increase in score indicated an improvement (Z-score range: -3 to +3). Acquisition of disability was measured by change from Baseline in MSFC score at Year 2.

4. Percent Change From Baseline in Magnetic Resonance Imaging Time Constant 2 (MRI-T2) Hyperintense Lesion Volume at Year 2 [Baseline, Year 2]

   Percent change in MS lesion volume as measured by MRI-T2 scan was calculated from MRI-T2-weighted scans as the following: (lesion volume at 2 years - lesion volume at Baseline)*100/ (lesion volume at Baseline).

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 50 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Given written/signed informed consent

• Age 18 to 50 years old (inclusive) as of the date the informed consent form (ICF) was signed

• Diagnosis of MS per updated McDonald criteria, and cranial magnetic resonance imaging (MRI) scan demonstrating white matter lesions attributable to MS within 5 years of screening

• Onset of MS symptoms (as determined by a neurologist, either at screening or retrospectively) within 5 years of the date the ICF was signed

• Expanded Disability Status Scale (EDSS) score 0.0 to 3.0 (inclusive) at screening

• Greater than or equal to (>=) 2 MS attacks (first episode or relapse) occurring in the 24 months prior to the date the ICF was signed, with >=1 attack in the 12 months prior to the date the ICF was signed, with objective neurological signs confirmed by a physician, nurse practitioner, or other Genzyme-approved health-care provider and the objective signs could be identified retrospectively

Exclusion Criteria:

• Received prior therapy for MS other than corticosteroids, for example, alemtuzumab, interferons, intravenous immunoglobulin, glatiramer acetate, natalizumab, and mitoxantrone

• Exposure to azathioprine, cladribine, cyclophosphamide, cyclosporine A, methotrexate, or any other immunosuppressive agent other than systemic corticosteroid treatment

• Any progressive form of MS

• History of malignancy (except basal skin cell carcinoma)

• CD4 + , CD8 + count, B cell, or absolute neutrophil count less than (<) lower limit of normal (LLN) at screening

• Known bleeding disorder (for example, dysfibrinogenemia, factor IX deficiency, hemophilia, Von Willebrand's disease, disseminated intravascular coagulation, fibrinogen deficiency, or clotting factor deficiency)

• Significant autoimmune disease including but not limited to immune cytopenias, rheumatoid arthritis, systemic lupus erythematosus, other connective tissue disorders, vasculitis, inflammatory bowel disease, severe psoriasis

• Presence of anti-thyroid stimulating hormone (TSH) receptor (TSHR) antibodies (that is, above the LLN)

• Active infection or at high risk for infection

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	North Central Neurology Associates, P.C.	Cullman	Alabama	United States
2	Barrow Neurological Institute, St. Joseph's Hospital & Medical Center	Phoenix	Arizona	United States
3	Mayo Clinic Arizona	Scottsdale	Arizona	United States
4	Northwest NeuroSpecialists, PLLC	Tucson	Arizona	United States
5	Advanced Neurosciences Research	Fort Collins	Colorado	United States
6	Neurological Associates	Pompano Beach	Florida	United States
7	Axiom Clinical Research of Florida	Tampa	Florida	United States
8	Idaho Falls Multiple Sclerosis Center, PLLC	Idaho Falls	Idaho	United States
9	Consultants in Neurology, Ltd.	Northbrook	Illinois	United States
10	Fort Wayne Neurological Center	Fort Wayne	Indiana	United States
11	University of Kansas Medical Center	Kansas City	Kansas	United States
12	MidAmerican Neuroscience Institute	Lenexa	Kansas	United States
13	Associates in Neurology, PSC	Lexington	Kentucky	United States
14	University of Louisville Research Foundation	Louisville	Kentucky	United States
15	Louisiana State University Health Sciences Center	Shreveport	Louisiana	United States
16	UMass Memorial Medical Center	Worcester	Massachusetts	United States
17	University of Michigan Health System	Ann Arbor	Michigan	United States
18	Wayne State University	Detroit	Michigan	United States
19	University of Nevada School of Medicine	Las Vegas	Nevada	United States
20	Dartmouth-Hitchcock Medical Center	Lebanon	New Hampshire	United States
21	University of New Mexico, Health Sciences Center, MS Specialty Clinic	Albuquerque	New Mexico	United States
22	Empire Neurology	Latham	New York	United States
23	Comprehensive Multiple Sclerosis Care Center at South Shore Neurologic Associates, P.C.	Patchogue	New York	United States
24	University of Rochester Medical Center	Rochester	New York	United States
25	Carolinas Medical Center (CMC), Neurosciences & Spine Institute (NSSI)	Charlotte	North Carolina	United States
26	The Ohio State University Medical Center, Multiple Sclerosis Center	Columbus	Ohio	United States
27	Oak Clinic for Multiple Sclerosis	Uniontown	Ohio	United States
28	MS Center of Oklahoma	Oklahoma City	Oklahoma	United States
29	Lehigh Valley Hospital Neurosciences and Pain Research	Allentown	Pennsylvania	United States
30	Advanced Neurosciences Institute	Franklin	Tennessee	United States
31	Biomedical Research Alliance of NY, LLC	Franklin	Tennessee	United States
32	Hope Neurology PC	Knoxville	Tennessee	United States
33	Baylor College of Medicine, Maxine Mesinger MS Clinic	Houston	Texas	United States
34	Central Texas Neurology	Round Rock	Texas	United States
35	Integra Clinical Research	San Antonio	Texas	United States
36	Neurology Center of San Antonio	San Antonio	Texas	United States
37	DIABAID	Buenos Aires		Argentina
38	The Wesley Research Institute	Auchenflower	Queensland	Australia	4066
39	Griffith University School of Medicine	Southport	Queensland	Australia
40	The Queen Elizabeth Hospital	Woodville South	South Australia	Australia
41	Royal Hobart Hospital	Hobart	Tasmania	Australia	7000
42	St Vincent's Hospital	Fitzroy	Victoria	Australia	3065
43	Austin Health	Heidelberg	Victoria	Australia	3084
44	Royal Melbourne Hospital, Department of Neurology, Ward 4 East	Parkville	Victoria	Australia	3050
45	Concord Repatriation General Hospital	Concord		Australia
46	Westmead Hospital	Westmead		Australia
47	Hospital da Restauracao, Av Governador Agamenon Magalhaes	Recife	Pernambuco	Brazil
48	Hospital Sao Lucas PUC-RS	Porto Alegre	RS	Brazil
49	Hospital de Clínicas USP	Sao Paulo	SP	Brazil
50	University of Calgary and Foothills Medical Cenre	Calgary	Alberta	Canada
51	UBC Hospital	Vancouver	British Columbia	Canada
52	The Ottawa Hospital, General Campus	Ottawa	Ontario	Canada
53	Clinique Nuero-outaouais	Gatineau	Quebec	Canada
54	Clinique Neuro rive-sud, Recherche Sepmus, Inc.	Greenfield park	Quebec	Canada
55	Clinical Hospital Centre Rijeka	Rijeka		Croatia
56	General Hospital Varazdin	Varazdin		Croatia
57	Clinical Hospital Centre "Sestre Milosrdnice"	Zagreb		Croatia
58	Clinical Hospital Centre Zagreb	Zagreb		Croatia
59	General Hospital "Sveti Duh"	Zagreb		Croatia
60	Department of Neurology, 1st Faculty of Medicine and General Teaching Hospital	Praha 2		Czech Republic
61	Krajska zdravotni a.s., Hospital Teplice	Teplice		Czech Republic
62	Hopital Purpan	Toulouse		France
63	Judisches Krankenhaus Berlin	Berlin		Germany
64	Universitätsklinik Carl Gustav Carus Dresden	Dresden		Germany
65	Klinikum der Goethe Universität Frankfurt	Frankfurt		Germany
66	Medizinische Hochschule Hannover	Hannover		Germany
67	Oberhavelkliniken Hennigsdorf	Hennigsdorf		Germany
68	Asklepios Klinikum Brandenburg	Teupitz		Germany
69	Hospital Angeles del Pedregal, Camino de Santa Teresa	Mexico City		Mexico
70	Hospital Medica Sur CIF-BIOTEC	Mexico City		Mexico
71	Clinical Neurology Centre Sp. z o.o. (Ltd)	Cracow		Poland
72	Independent Public Healthcare Facility, Norbert Barlicki University Hospital No. 1 of the Medical University of Lodz	Lodz		Poland
73	Independent Public Teaching Hospital No. 4 in Lublin	Lublin		Poland
74	Heliodor Swiecicki Teaching Hospital of the Poznan University of Medical Sciences	Poznan		Poland
75	Research Medical Complex "Your Health" Ltd	Kazan		Russian Federation
76	Moscow City Hospital #11	Moscow		Russian Federation
77	Moscow State Medical Institution City Clinical Hospital #11	Moscow		Russian Federation
78	Scientific Neurology Center RAMS	Moscow		Russian Federation
79	Municipal City Hospital #33	Nizhniy Novgorod		Russian Federation
80	Federal State Institution Siberian Rettitorial Medical Center under Federal Medical-Biological Agency of Russia	Novosibirsk		Russian Federation
81	City Clinical Hospital #2	Pyatigorsk		Russian Federation
82	Samara Regional Clinical Hospital n.a. Kalinin	Samara		Russian Federation
83	Institute of Human Brain RAS	St. Petersburg		Russian Federation
84	Nikolaevskaya Hospital	St. Petersburg		Russian Federation
85	St. Petersburg Pavlov State Medical University	St. Petersburg		Russian Federation
86	State Medical Institution: Republican Clinical Hospital n.a. G.G. Kuvatov	Ufa		Russian Federation
87	Clinical Centre Serbia, Institute for Neurology	Belgrade		Serbia
88	Military Medical Academy	Belgrade		Serbia
89	Clinical centre Kragujevac	Kragujevac		Serbia
90	Clinical Center Nis, Clinic for neurology	Nis		Serbia
91	Clinical Centre of Vojvodina, Clinic for neurology	Novi Sad		Serbia
92	Sahlgrenska University Hospital	Goteborg		Sweden
93	Chernihiv Regional Hospital	Chernihiv		Ukraine
94	Institute of Neurology, Psychiatry and Narcology under the Academy of Medical Sciences of Ukraine, Department of Neuroinfection and Multiple Sclerosis	Kharkiv		Ukraine
95	Hospoital of the Directorate of the Medical Corps within the Ukrainian Security Service, Neurology Department	Kyiv		Ukraine
96	Kyiv Municipal Clinical Hospital #4	Kyiv		Ukraine
97	Danylo Halytsky Lviv National Medical University	Lviv		Ukraine
98	Department Of Neurosciences, Addenbrookes Hospital	Cambridge	England	United Kingdom
99	Centre for Neuroscience & Trauma, Blizard Institute of Cell and Molecular Science, Barts and The London School of Medicine and Dentistry	London	England	United Kingdom
100	University Hospital of Wales	Cardiff	Wales	United Kingdom
101	Royal Hallamshire Hospital	Sheffield		United Kingdom

Sponsors and Collaborators

• Genzyme, a Sanofi Company
• Bayer

Investigators

• Study Director: Medical Monitor, Genzyme, a Sanofi Company

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/003718/WC500150521.pdf

Publications

• Cohen JA, Coles AJ, Arnold DL, Confavreux C, Fox EJ, Hartung HP, Havrdova E, Selmaj KW, Weiner HL, Fisher E, Brinar VV, Giovannoni G, Stojanovic M, Ertik BI, Lake SL, Margolin DH, Panzara MA, Compston DA; CARE-MS I investigators. Alemtuzumab versus interferon beta 1a as first-line treatment for patients with relapsing-remitting multiple sclerosis: a randomised controlled phase 3 trial. Lancet. 2012 Nov 24;380(9856):1819-28. doi: 10.1016/S0140-6736(12)61769-3. Epub 2012 Nov 1.

• Responsible Party: Genzyme, a Sanofi Company
• ClinicalTrials.gov Identifier: NCT00530348
• Other Study ID Numbers: CAMMS323; ISRCTN21534255; ACTRN12608000435381; CARE-MS I; 2007-001161-14
• First Posted: Sep 17, 2007
• Last Update Posted: Nov 24, 2014
• Last Verified: Nov 1, 2014

• Keywords provided by Genzyme, a Sanofi Company: Multiple Sclerosis
• Additional relevant MeSH terms: Multiple Sclerosis; Multiple Sclerosis, Relapsing-Remitting; Sclerosis; Interferons; Interferon-beta; Interferon beta-1a; Alemtuzumab

Study Results

Participant Flow

Recruitment Details	Participants were screened at 101 investigational sites in Argentina, Australia, Brazil, Canada, Croatia, the Czech Republic, France, Germany, Mexico, Poland, Russia, Serbia, Sweden, Ukraine, the United Kingdom (UK), and the United States (US) between August 28, 2007 and April 27, 2011.

Arm/Group Title	Interferon Beta-1a	Alemtuzumab
Arm/Group Description	Interferon beta-1a (Rebif®) 44 microgram (mcg) subcutaneously 3-times weekly for 24 months. Dose adjustment was done as per Investigator's discretion.	Alemtuzumab (Lemtrada™) 12 milligram (mg) per day intravenous (IV) infusion on 5 consecutive days at Month 0, followed by alemtuzumab 12 mg per day IV infusion on 3 consecutive days at Month 12.
Period Title: Overall Study
STARTED	195	386
Treated	187	376
COMPLETED	173	367
NOT COMPLETED	22	19

Baseline Characteristics

Arm/Group Title	Interferon Beta-1a	Alemtuzumab	Total
Arm/Group Description	Interferon beta-1a 44 mcg subcutaneously 3-times weekly for 24 months. Dose adjustment was done as per Investigator's discretion.	Alemtuzumab 12 mg per day IV infusion on 5 consecutive days at Month 0, followed by alemtuzumab 12 mg per day IV infusion on 3 consecutive days at Month 12.	Total of all reporting groups
Overall Participants	187	376	563
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	33.2 (8.48)	33.0 (8.03)	33.1 (8.18)
Sex: Female, Male (Count of Participants)
Female	122 65.2%	243 64.6%	365 64.8%
Male	65 34.8%	133 35.4%	198 35.2%
Time Since First Relapse (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	2.0 (1.32)	2.1 (1.36)	2.1 (1.35)
Number of Relapse Episodes in the Preceding 2 Years (participants) [Number]
1 Relapse	3 1.6%	12 3.2%	15 2.7%
2 Relapses	118 63.1%	215 57.2%	333 59.1%
Greater than or equal to 3 Relapses	66 35.3%	149 39.6%	215 38.2%
Expanded Disability Status Scale (EDSS) Score (units on a scale) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [units on a scale]	2.0 (0.79)	2.0 (0.81)	2.0 (0.81)

Outcome Measures

1. Primary Outcome

Title	Percentage of Participants With Sustained Accumulation of Disability (SAD)
Description	EDSS is an ordinal scale in half-point increments that quantifies disability in participants with MS. It assesses 7 functional systems (visual, brainstem, pyramidal, cerebellar, sensory, bowel/bladder and cerebral) as well as ambulation. EDSS total score: 0 (normal neurological examination) to 10 (death due to MS). As measured by EDSS score, SAD was defined as increase of at least 1.5 points for participants with Baseline score of 0 and increase of at least 1.0 point for participants with a Baseline score of 1.0 or more; and the increase persisted for at least next 2 scheduled assessments, that is, 6 consecutive months. Onset date of SAD was date of first EDSS assessment that began 6 month consecutive period of SAD. Participants who did not reach SAD endpoint were censored at their last visit. Percentage of participants with SAD, estimated by Kaplan-Meier (KM) method, was reported.
Time Frame	Up to 2 years

Outcome Measure Data

Analysis Population Description

FAS population included all randomized participants who received at least 1 dose of study drug.

Arm/Group Title	Interferon Beta-1a	Alemtuzumab
Arm/Group Description	Interferon beta-1a 44 mcg subcutaneously 3-times weekly for 24 months. Dose adjustment was done as per Investigator's discretion.	Alemtuzumab 12 mg per day IV infusion on 5 consecutive days at Month 0, followed by alemtuzumab 12 mg per day IV infusion on 3 consecutive days at Month 12.
Measure Participants	187	376
Number (95% Confidence Interval) [percentage of participants with SAD]	11.12 5.9%	8.00 2.1%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Interferon Beta-1a, Alemtuzumab
	Comments	Cox proportional hazards (PH) regression model with robust variance estimation using treatment group and geographic region as covariates was used.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.2173
	Comments	Hochberg method was used to adjust for the two co-primary outcomes.
	Method	Cox Proportional Hazards Regression
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.70
	Confidence Interval	(2-Sided) 95%; 0.40 to 1.23
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Primary Outcome

Title	Annualized Relapse Rate
Description	Relapse was defined as new neurological symptoms or worsening of previous neurological symptoms with an objective change on neurological examination, attributable to multiple sclerosis that lasted for at least 48 hours, that were present at normal body temperature, and that were preceded by at least 30 days of clinical stability. Annualized relapse rate was estimated through negative binomial regression with robust variance estimation and covariate adjustment for geographic region using observed number of relapses as dependent variable, the log total amount of follow-up from date of first study treatment for each participant as an offset variable, and treatment group and geographic region as model covariates.
Time Frame	Up to 2 years

Outcome Measure Data

Analysis Population Description

FAS population included all randomized participants who received at least 1 dose of study drug.

Arm/Group Title	Interferon Beta-1a	Alemtuzumab
Arm/Group Description	Interferon beta-1a 44 mcg subcutaneously 3-times weekly for 24 months. Dose adjustment was done as per Investigator's discretion.	Alemtuzumab 12 mg per day IV infusion on 5 consecutive days at Month 0, followed by alemtuzumab 12 mg per day IV infusion on 3 consecutive days at Month 12.
Measure Participants	187	376
Number (95% Confidence Interval) [relapses per participant per year]	0.39	0.18

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Interferon Beta-1a, Alemtuzumab
	Comments	Proportional means regression model with robust variance estimation and covariate adjustment for geographic region was used.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments	Hochberg method was used to adjust for the two co-primary outcomes.
	Method	Proportional means regression
	Comments
Method of Estimation	Estimation Parameter	Rate ratio
	Estimated Value	0.45
	Confidence Interval	(2-Sided) 95%; 0.32 to 0.63
	Parameter Dispersion	Type: Value:
	Estimation Comments

3. Secondary Outcome

Title	Percentage of Participants Who Were Relapse Free at Year 2
Description	Participants were considered relapse free at Year 2 if they did not experience a relapse from the date of first study treatment to study completion at 24 months. Percentage of participants who were relapse free at Year 2, estimated using the KM method, was reported.
Time Frame	Year 2

Outcome Measure Data

Analysis Population Description

FAS population included all randomized participants who received at least 1 dose of study drug.

Arm/Group Title	Interferon Beta-1a	Alemtuzumab
Arm/Group Description	Interferon beta-1a 44 mcg subcutaneously 3-times weekly for 24 months. Dose adjustment was done as per Investigator's discretion.	Alemtuzumab 12 mg per day IV infusion on 5 consecutive days at Month 0, followed by alemtuzumab 12 mg per day IV infusion on 3 consecutive days at Month 12.
Measure Participants	187	376
Number (95% Confidence Interval) [percentage of participants]	58.69 31.4%	77.59 20.6%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Interferon Beta-1a, Alemtuzumab
	Comments	Cox PH regression model with robust variance estimation, covariate adjustment for geographic region, was used. Secondary endpoints were analyzed sequentially as: Proportion of participants relapse free at Year 2, Change from baseline in EDSS, Percent change from Baseline in magnetic resonance imaging-T2 hyperintense lesion volume at Year 2, Acquisition of disability measured by multiple sclerosis functional composite. Each endpoint could only be formally tested if prior endpoint was significant.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Cox Proportional Hazards Regression
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.45
	Confidence Interval	(2-Sided) 95%; 0.33 to 0.61
	Parameter Dispersion	Type: Value:
	Estimation Comments

4. Secondary Outcome

Title	Change From Baseline in Expanded Disability Status Scale (EDSS) Score at Year 2
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). Change was calculated by subtracting Baseline value from value at Year 2.
Time Frame	Baseline, Year 2

Outcome Measure Data

Analysis Population Description

FAS population included all randomized participants who received at least 1 dose of study drug. Here, number of participants analyzed was subset of FAS who had EDSS assessment at both Baseline and end-of-study (Year 2).

Arm/Group Title	Interferon Beta-1a	Alemtuzumab
Arm/Group Description	Interferon beta-1a 44 mcg subcutaneously 3-times weekly for 24 months. Dose adjustment was done as per Investigator's discretion.	Alemtuzumab 12 mg per day IV infusion on 5 consecutive days at Month 0, followed by alemtuzumab 12 mg per day IV infusion on 3 consecutive days at Month 12.
Measure Participants	173	366
Mean (Standard Deviation) [units on a scale]	-0.2 (1.05)	-0.2 (0.87)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Interferon Beta-1a, Alemtuzumab
	Comments	The analysis was performed using Wei-Lachin method for non-parametric analysis of repeated measures. Secondary endpoints were analyzed sequentially as: Proportion of participants relapse free at Year 2, Change from baseline in EDSS, Percent change from Baseline in magnetic resonance imaging-T2 hyperintense lesion volume at Year 2, Acquisition of disability measured by multiple sclerosis functional composite. Each endpoint could only be formally tested if prior endpoint was significant.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.4188
	Comments
	Method	Wei-Lachin
	Comments

5. Secondary Outcome

Title	Change From Baseline in Multiple Sclerosis Functional Composite (MSFC) Score at Year 2
Description	MSFC is a multidimensional measure consisting of quantitative tests of ambulation (Timed 25-Foot Walk), manual dexterity (9-Hole Peg Test; 9HPT), and cognitive function (Paced Auditory Serial Addition Test; PASAT). The MSFC score was calculated as the mean of the Z-scores of the 3 components. A Z-score was calculated by subtracting the mean of the reference population from the test result, then dividing by the standard deviation of the reference population. Higher Z-scores reflected better neurological function and a positive change from Baseline indicates improvement. An increase in score indicated an improvement (Z-score range: -3 to +3). Acquisition of disability was measured by change from Baseline in MSFC score at Year 2.
Time Frame	Baseline, Year 2

Outcome Measure Data

Analysis Population Description

FAS population included all randomized participants who received at least 1 dose of study drug. Here, number of participants analyzed signifies subset of FAS who had MSFC score assessment at Baseline; 'n' signifies participants who had MSFC score assessment at Baseline (for Baseline) and at both Baseline and Year 2 (for change at Year 2).

Arm/Group Title	Interferon Beta-1a	Alemtuzumab
Arm/Group Description	Interferon beta-1a 44 mcg subcutaneously 3-times weekly for 24 months. Dose adjustment was done as per Investigator's discretion.	Alemtuzumab 12 mg per day IV infusion on 5 consecutive days at Month 0, followed by alemtuzumab 12 mg per day IV infusion on 3 consecutive days at Month 12.
Measure Participants	186	375
Baseline (n=186, 375)	0.05 (0.629)	-0.02 (0.695)
Change at Year 2 (n=172, 362)	0.07 (0.450)	0.15 (0.516)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Interferon Beta-1a, Alemtuzumab
	Comments	Change at Year 2: analysis was performed using Wei-Lachin method for non-parametric analysis of repeated measures. Secondary endpoints were analyzed sequentially as: Proportion of participants relapse free at Year 2, Change from baseline in EDSS, Percent change from Baseline in magnetic resonance imaging-T2 hyperintense lesion volume at Year 2, Acquisition of disability measured by MSFC. Each endpoint could only be formally tested if prior endpoint was significant.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0115
	Comments
	Method	Wei-Lachin
	Comments

6. Secondary Outcome

Title	Percent Change From Baseline in Magnetic Resonance Imaging Time Constant 2 (MRI-T2) Hyperintense Lesion Volume at Year 2
Description	Percent change in MS lesion volume as measured by MRI-T2 scan was calculated from MRI-T2-weighted scans as the following: (lesion volume at 2 years - lesion volume at Baseline)*100/ (lesion volume at Baseline).
Time Frame	Baseline, Year 2

Outcome Measure Data

Analysis Population Description

FAS population included all randomized participants who received at least 1 dose of study drug. Here, number of participants analyzed was subset of FAS who had assessment for T2 volume at both Baseline and end-of-study (Year 2).

Arm/Group Title	Interferon Beta-1a	Alemtuzumab
Arm/Group Description	Interferon beta-1a 44 mcg subcutaneously 3-times weekly for 24 months. Dose adjustment was done as per Investigator's discretion.	Alemtuzumab 12 mg per day IV infusion on 5 consecutive days at Month 0, followed by alemtuzumab 12 mg per day IV infusion on 3 consecutive days at Month 12.
Measure Participants	177	364
Mean (Standard Deviation) [percent change]	-6.68 (32.44)	-10.28 (22.58)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Interferon Beta-1a, Alemtuzumab
	Comments	Ranked ANCOVA models with covariate adjustment for geographic region and baseline T2 lesion volume was used. Secondary endpoints were analyzed sequentially as: Proportion of participants relapse free at Year 2, Change from baseline in EDSS, Percent change from Baseline in magnetic resonance imaging-T2 hyperintense lesion volume at Year 2, Acquisition of disability measured by multiple sclerosis functional composite. Each endpoint could only be formally tested if prior endpoint was significant.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.3080
	Comments
	Method	Ranked ANCOVA
	Comments

Adverse Events

Time Frame	First dose of study drug up to 2 years
Adverse Event Reporting Description	If a participant experienced both a serious and a non-serious event with the same adverse event term, the individual has been included in the numerator ("number of affected participants") of both adverse event tables. The analysis was performed on the safety population, defined as all participants who received any amount of study drug.
Arm/Group Title	Interferon Beta-1a		Alemtuzumab
Arm/Group Description	Interferon beta-1a 44 mcg subcutaneously 3-times weekly for 24 months. Dose adjustment was done as per Investigator's discretion.		Alemtuzumab 12 mg per day IV infusion on 5 consecutive days at Month 0, followed by alemtuzumab 12 mg per day IV infusion on 3 consecutive days at Month 12.
All Cause Mortality
	Interferon Beta-1a		Alemtuzumab
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Interferon Beta-1a		Alemtuzumab
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	27/187 (14.4%)		69/376 (18.4%)
Blood and lymphatic system disorders
Agranulocytosis	0/187 (0%)		2/376 (0.5%)
Autoimmune thrombocytopenia	0/187 (0%)		3/376 (0.8%)
Cardiac disorders
Atrial fibrillation	0/187 (0%)		2/376 (0.5%)
Bradycardia	0/187 (0%)		1/376 (0.3%)
Sinus bradycardia	0/187 (0%)		1/376 (0.3%)
Sinus tachycardia	0/187 (0%)		2/376 (0.5%)
Tachycardia	0/187 (0%)		1/376 (0.3%)
Endocrine disorders
Basedow's disease	0/187 (0%)		2/376 (0.5%)
Goitre	0/187 (0%)		1/376 (0.3%)
Hyperthyroidism	0/187 (0%)		1/376 (0.3%)
Thyrotoxic crisis	0/187 (0%)		1/376 (0.3%)
Gastrointestinal disorders
Colitis	1/187 (0.5%)		0/376 (0%)
Malocclusion	1/187 (0.5%)		0/376 (0%)
Nausea	0/187 (0%)		1/376 (0.3%)
Oesophagitis	1/187 (0.5%)		0/376 (0%)
General disorders
Chest discomfort	0/187 (0%)		1/376 (0.3%)
Non-cardiac chest pain	1/187 (0.5%)		0/376 (0%)
Pyrexia	0/187 (0%)		1/376 (0.3%)
Hepatobiliary disorders
Hepatitis toxic	1/187 (0.5%)		0/376 (0%)
Immune system disorders
Anaphylactic shock	0/187 (0%)		1/376 (0.3%)
Infections and infestations
Appendicitis	1/187 (0.5%)		2/376 (0.5%)
Disseminated tuberculosis	0/187 (0%)		1/376 (0.3%)
Hepatitis A	1/187 (0.5%)		0/376 (0%)
Herpes zoster	0/187 (0%)		1/376 (0.3%)
Meningitis herpes	0/187 (0%)		1/376 (0.3%)
Postoperative wound infection	0/187 (0%)		1/376 (0.3%)
Tooth infection	0/187 (0%)		1/376 (0.3%)
Uterine infection	0/187 (0%)		1/376 (0.3%)
Injury, poisoning and procedural complications
Abdominal wound dehiscence	0/187 (0%)		1/376 (0.3%)
Accidental overdose	1/187 (0.5%)		0/376 (0%)
Foot fracture	0/187 (0%)		2/376 (0.5%)
Forearm fracture	1/187 (0.5%)		0/376 (0%)
Hand fracture	1/187 (0.5%)		0/376 (0%)
Humerus fracture	1/187 (0.5%)		0/376 (0%)
Incorrect dose administered	0/187 (0%)		2/376 (0.5%)
Joint dislocation	0/187 (0%)		1/376 (0.3%)
Post procedural haemorrhage	1/187 (0.5%)		0/376 (0%)
Road traffic accident	0/187 (0%)		1/376 (0.3%)
Skin laceration	0/187 (0%)		1/376 (0.3%)
Investigations
Thyroxine free increased	0/187 (0%)		1/376 (0.3%)
Tri-iodothyronine free increased	0/187 (0%)		1/376 (0.3%)
Metabolism and nutrition disorders
Feeding disorder neonatal	0/187 (0%)		1/376 (0.3%)
Musculoskeletal and connective tissue disorders
Myalgia	0/187 (0%)		1/376 (0.3%)
Osteitis	1/187 (0.5%)		0/376 (0%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Bladder papilloma	0/187 (0%)		1/376 (0.3%)
Thyroid cancer	0/187 (0%)		2/376 (0.5%)
Uterine leiomyoma	0/187 (0%)		1/376 (0.3%)
Nervous system disorders
Brain stem syndrome	0/187 (0%)		1/376 (0.3%)
Cerebrovascular insufficiency	0/187 (0%)		1/376 (0.3%)
Headache	0/187 (0%)		2/376 (0.5%)
Hypoxic-ischaemic encephalopathy	0/187 (0%)		1/376 (0.3%)
Migraine	0/187 (0%)		1/376 (0.3%)
Multiple sclerosis	0/187 (0%)		1/376 (0.3%)
Multiple sclerosis relapse	13/187 (7%)		19/376 (5.1%)
Syncope	0/187 (0%)		2/376 (0.5%)
Psychiatric disorders
Insomnia	0/187 (0%)		1/376 (0.3%)
Major depression	0/187 (0%)		1/376 (0.3%)
Mood altered	1/187 (0.5%)		0/376 (0%)
Suicide attempt	0/187 (0%)		1/376 (0.3%)
Renal and urinary disorders
Nephrolithiasis	0/187 (0%)		1/376 (0.3%)
Reproductive system and breast disorders
Menometrorrhagia	0/187 (0%)		2/376 (0.5%)
Menorrhagia	0/187 (0%)		1/376 (0.3%)
Ovarian cyst	0/187 (0%)		1/376 (0.3%)
Ovarian haemorrhage	1/187 (0.5%)		0/376 (0%)
Uterine polyp	0/187 (0%)		1/376 (0.3%)
Respiratory, thoracic and mediastinal disorders
Chronic obstructive pulmonary disease	1/187 (0.5%)		0/376 (0%)
Pleurisy	0/187 (0%)		1/376 (0.3%)
Pneumonitis	0/187 (0%)		1/376 (0.3%)
Sleep apnoea syndrome	0/187 (0%)		1/376 (0.3%)
Throat tightness	0/187 (0%)		1/376 (0.3%)
Skin and subcutaneous tissue disorders
Angioedema	0/187 (0%)		1/376 (0.3%)
Increased tendency to bruise	0/187 (0%)		1/376 (0.3%)
Urticaria	0/187 (0%)		2/376 (0.5%)
Social circumstances
Physical assault	0/187 (0%)		1/376 (0.3%)
Vascular disorders
Hypotension	0/187 (0%)		2/376 (0.5%)
Other (Not Including Serious) Adverse Events
	Interferon Beta-1a		Alemtuzumab
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	168/187 (89.8%)		360/376 (95.7%)
Blood and lymphatic system disorders
Anaemia	11/187 (5.9%)		8/376 (2.1%)
Leukopenia	10/187 (5.3%)		11/376 (2.9%)
Lymphopenia	8/187 (4.3%)		26/376 (6.9%)
Neutropenia	12/187 (6.4%)		7/376 (1.9%)
Cardiac disorders
Tachycardia	3/187 (1.6%)		34/376 (9%)
Gastrointestinal disorders
Abdominal pain	5/187 (2.7%)		21/376 (5.6%)
Abdominal pain upper	0/187 (0%)		22/376 (5.9%)
Diarrhoea	6/187 (3.2%)		36/376 (9.6%)
Dyspepsia	8/187 (4.3%)		33/376 (8.8%)
Nausea	14/187 (7.5%)		65/376 (17.3%)
Vomiting	4/187 (2.1%)		42/376 (11.2%)
General disorders
Chest discomfort	6/187 (3.2%)		25/376 (6.6%)
Chills	3/187 (1.6%)		38/376 (10.1%)
Fatigue	23/187 (12.3%)		68/376 (18.1%)
Influenza like illness	59/187 (31.6%)		19/376 (5.1%)
Injection site erythema	56/187 (29.9%)		0/376 (0%)
Injection site haematoma	12/187 (6.4%)		1/376 (0.3%)
Injection site pain	10/187 (5.3%)		0/376 (0%)
Injection site reaction	14/187 (7.5%)		0/376 (0%)
Pain	5/187 (2.7%)		23/376 (6.1%)
Pyrexia	18/187 (9.6%)		138/376 (36.7%)
Infections and infestations
Bronchitis	4/187 (2.1%)		23/376 (6.1%)
Influenza	11/187 (5.9%)		28/376 (7.4%)
Nasopharyngitis	25/187 (13.4%)		74/376 (19.7%)
Oral herpes	2/187 (1.1%)		40/376 (10.6%)
Rhinitis	6/187 (3.2%)		20/376 (5.3%)
Sinusitis	9/187 (4.8%)		30/376 (8%)
Upper respiratory tract infection	25/187 (13.4%)		57/376 (15.2%)
Urinary tract infection	8/187 (4.3%)		64/376 (17%)
Injury, poisoning and procedural complications
Contusion	11/187 (5.9%)		38/376 (10.1%)
Investigations
Alanine aminotransferase increased	19/187 (10.2%)		2/376 (0.5%)
Aspartate aminotransferase increased	17/187 (9.1%)		3/376 (0.8%)
B-lymphocyte count decreased	0/187 (0%)		19/376 (5.1%)
Blood urine present	6/187 (3.2%)		20/376 (5.3%)
CD4 lymphocytes decreased	4/187 (2.1%)		26/376 (6.9%)
CD8 lymphocytes decreased	5/187 (2.7%)		26/376 (6.9%)
T-lymphocyte count decreased	5/187 (2.7%)		22/376 (5.9%)
Musculoskeletal and connective tissue disorders
Arthralgia	10/187 (5.3%)		41/376 (10.9%)
Back pain	13/187 (7%)		48/376 (12.8%)
Muscle spasms	6/187 (3.2%)		20/376 (5.3%)
Muscular weakness	11/187 (5.9%)		29/376 (7.7%)
Neck pain	2/187 (1.1%)		21/376 (5.6%)
Pain in extremity	15/187 (8%)		35/376 (9.3%)
Nervous system disorders
Dizziness	8/187 (4.3%)		33/376 (8.8%)
Dysgeusia	19/187 (10.2%)		39/376 (10.4%)
Headache	52/187 (27.8%)		189/376 (50.3%)
Hypoaesthesia	19/187 (10.2%)		28/376 (7.4%)
Migraine	11/187 (5.9%)		15/376 (4%)
Multiple sclerosis relapse	64/187 (34.2%)		65/376 (17.3%)
Paraesthesia	13/187 (7%)		32/376 (8.5%)
Psychiatric disorders
Anxiety	10/187 (5.3%)		24/376 (6.4%)
Depression	14/187 (7.5%)		28/376 (7.4%)
Insomnia	31/187 (16.6%)		56/376 (14.9%)
Reproductive system and breast disorders
Menorrhagia	2/187 (1.1%)		24/376 (6.4%)
Respiratory, thoracic and mediastinal disorders
Cough	10/187 (5.3%)		39/376 (10.4%)
Dyspnoea	4/187 (2.1%)		32/376 (8.5%)
Oropharyngeal pain	11/187 (5.9%)		42/376 (11.2%)
Skin and subcutaneous tissue disorders
Erythema	6/187 (3.2%)		20/376 (5.3%)
Pruritus	3/187 (1.6%)		52/376 (13.8%)
Rash	9/187 (4.8%)		174/376 (46.3%)
Rash generalised	2/187 (1.1%)		28/376 (7.4%)
Urticaria	5/187 (2.7%)		50/376 (13.3%)
Vascular disorders
Flushing	10/187 (5.3%)		44/376 (11.7%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

PI can publish after sponsor published, after a defined period of time after study completion, and/or with written sponsor approval. Generally PI gives sponsor a draft 60 days before publication. Sponsor can ask that confidential information be removed, and can further defer publication upon notifying PI that it will file a patent application on inventions contained in the draft.