A Phase II Study Comparing Low- and High-Dose Alemtuzumab and High-Dose Rebif® in Patients With Early, Active Relapsing-Remitting Multiple Sclerosis

• Sponsor: Genzyme, a Sanofi Company (Industry)
• Overall Status: Completed
• CT.gov ID: NCT00050778
• Collaborator: Bayer (Industry)
• Enrollment: 334
• Locations: 49
• Arms: 3
• Duration (Months): 85
• Patients Per Site: 6.8
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

This was a Phase II, randomized, open-label, rater-blinded, three-arm study comparing two different doses of alemtuzumab (Lemtrada™) and one dose of subcutaneous (SC) interferon beta-1a (Rebif®) in participants with early, active relapsing-remitting multiple sclerosis (MS) who had not been previously treated with MS therapies other than steroids. The study was conducted for an initial period of 3 years and a follow-up to 5 years or more.

Condition or Disease	Intervention/Treatment	Phase
Multiple Sclerosis, Relapsing-Remitting	Biological: Interferon beta-1a; Biological: Alemtuzumab 12 mg; Biological: Alemtuzumab 24 mg	Phase 2

Detailed Description

The aims of MS therapy are to prevent the progression of disease and accumulation of long-term disability. The hypothesis underlying this study was that aggressive treatment of inflammation in the brain early in the course of MS would protect the participant from disease progression and accumulating disability.

This protocol compared two different doses of alemtuzumab and high-dose, high frequency of SC interferon beta-1a to evaluate the safety profiles of the respective treatments and to evaluate efficacy in terms of:

• Slowing the sustained accumulation of disability in participant with MS;

• Reducing the frequency of relapses experienced by participant with MS; and

• Reducing the harmful effects of MS on the brain, as assessed by magnetic resonance imaging (MRI)

Participants who received alemtuzumab during the initial 36-month treatment period may have been eligible for re-treatment with alemtuzumab in the extension study CAMMS03409 (NCT00930553) to evaluate:

• How long the effects of prior alemtuzumab treatment lasted;

• If additional treatments with alemtuzumab continued to reduce the effects of MS; and

• What kind of side effects participants experienced upon retreatment with alemtuzumab

Study Design

• Study Type: Interventional
• Actual Enrollment: 334 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Single (Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: A Phase II, Randomized, Open-Label, Three-Arm Study Comparing Low- and High-Dose Alemtuzumab and High-Dose Subcutaneous Interferon Beta-1a (Rebif®) in Patients With Early, Active Relapsing-Remitting Multiple Sclerosis
• Study Start Date: Dec 1, 2002
• Actual Primary Completion Date: Sep 1, 2007
• Actual Study Completion Date: Jan 1, 2010

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Interferon Beta-1a	Biological: Interferon beta-1a; Interferon beta-1a 44 microgram (mcg) subcutaneously 3-times weekly for 36 months.; Other Names: Rebif®
Experimental: Alemtuzumab 12 mg	Biological: Alemtuzumab 12 mg; Alemtuzumab 12 milligram per day (mg/day) was given by intravenous infusion on 5 consecutive days during the first month and on 3 consecutive days at months 12 and 24 (the latter at the treating physicians' discretion if the cluster of differentiation 4+ [CD4+] T-cell count was >=100*10^6 cells per liter).; Other Names: Lemtrada
Experimental: Alemtuzumab 24 mg	Biological: Alemtuzumab 24 mg; Alemtuzumab 24 mg/day was given by intravenous infusion on 5 consecutive days during the first month and on 3 consecutive days at months 12 and 24 (the latter at the treating physicians' discretion if the CD4+ T-cell count was >=100*10^6 cells per liter).; Other Names: Lemtrada

Outcome Measures

Primary Outcome Measures

1. Probability of Participants With Sustained Accumulation of Disability (SAD) [Up to 3 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 Baseline score of 1.0 or more; and the increase persisted for at least next the 2 scheduled assessments, that is, 6 consecutive months. The 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. Probability of participants with SAD, estimated by Kaplan-Meier (KM) method, was reported.

2. Annualized Relapse Rate [Up to 3 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 using a Poisson regression model with observed number of relapses as a dependent variable, the log total amount of follow-up from date of randomization for each participant as an offset variable and treatment group indicator as a covariate.

Secondary Outcome Measures

1. Probability of Participants Who Were Relapse Free at 3 Years After Initial Treatment [Year 3]

   Participants were considered relapse free at Year 3 if they did not experience a relapse between randomization and study completion at 36 months. Participants who discontinued early were considered relapse free if they did not experience a relapse prior to discontinuation. Probability of participants who were relapse free at Year 3, estimated using the KM method, was reported.

2. Percent Change From Baseline in T1 Cerebral Volume at Year 3 [Baseline, Year 3]

   Magnetic resonance imaging (MRI) T1 was used to determine rate of cerebral atrophy (decrease in cerebral/brain volume). Partial brain volumes were measured using the technique of Losseff et al. (1996). Percent change in cerebral volume at Year 3 was calculated from MRI-T1-weighted scans as: 100*([brain volume at Year 3] minus [brain volume at Baseline]) divided by [brain volume at Baseline]).

3. Percent Change From Baseline in MRI T2 Lesion Volume at Year 3 [Baseline, Year 3]

   Percent change in lesion volume at Year 3 was calculated from MRI-T2-weighted scans as: 100*([lesion volume at Year 3] minus [lesion volume at Baseline]) divided by [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:

• Signed informed consent form (ICF)

• Male or non-pregnant, non-lactating female participants, 18 to 50 years of age (inclusive) as of signing the ICF

• Diagnosis of MS per McDonald's update of the Poser criteria, including cranial MRI consistent with those criteria (McDonald, 2001, Ann Neurol)

• Onset of first MS symptoms within 3 years prior to Screening as of signing the ICF

• Expanded Disability Status Scale (EDSS) score 0.0 to 3.0 (inclusive) at the screening and Baseline visits

• At least 2 completed clinical episodes of MS in the 2 years prior to study entry (that is, the initial event if within 2 years of study entry plus at least 1 relapse, or at least 2 relapses if the initial event was between 2 and 3 years prior to study entry)

• In addition to the clinical criteria, at least 1 enhancing lesion on any 1 of up to 4 screening gadolinium-enhanced MRI brain scans during a maximum 3-month run-in period (inclusive of the Month 0 Baseline scan)

Exclusion Criteria:

• Previous immunotherapy for MS other than steroids, including treatment with interferons, intravenous immunoglobulin (IVIG), glatiramer acetate, and mitoxantrone

• Personal history of thyroid autoimmune disease

• Personal history of clinically significant autoimmune disease (for example, inflammatory bowel disease, diabetes, lupus, severe asthma)

• History of thyroid carcinoma (previous thyroid adenoma was acceptable and was not considered an exclusion criterion)

• History of malignancy (except for basal cell skin carcinoma if disease-free for at least 5 years)

• Any disability acquired from trauma or another illness that, in the opinion of the Investigator, interfered with evaluation of disability due to MS

• Previous treatment with alemtuzumab

• History of anaphylaxis following exposure to humanized monoclonal antibodies

• Inability to undergo MRI with gadolinium administration

• Female participants of childbearing potential with a positive serum pregnancy test at screening or Baseline

• Male and female participants who did not agree to use effective contraceptive method(s) during the study

• Impaired renal function (that is, serum creatinine greater than or equal to 2 times the upper limit of normal [ULN])

• Untreated, major depressive disorder

• Epileptic seizures that were not adequately controlled by treatment

• Suicidal ideation

• Major systemic disease or other illness that, in the opinion of the Investigator, have compromised participant safety or interfered with the interpretation of study results

• Abnormal CD4 count or significantly abnormal thyroid function; presence of anti-thyroid stimulating hormone (TSH) receptor antibodies; known seropositivity for human immunodeficiency (HIV)

• Intolerance of pulsed corticosteroids, especially a history of steroid psychosis

• Presence of a monoclonal paraprotein

• Participants who had any form of MS other than relapsing-remitting

• Participants currently participating in a clinical study of an experimental or unapproved/unlicensed therapy

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Mayo Clinic Scottsdale Arizona	Scottsdale	Arizona	United States	85259
2	Clinical Trials, Inc	Little Rock	Arkansas	United States	72205
3	East Bay Physicians Medical Group	Berkeley	California	United States	94705
4	Nerve Pro Research	Irvine	California	United States	92618
5	Neuro-Therapeutics, Inc.	Pasadena	California	United States	91105
6	Neurological Research Institute of the East Bay	Walnut Creek	California	United States	938-1343
7	Neurologic Research Institute/Mile High Research Center	Denver	Colorado	United States	80218
8	Neurological Service of Orlando	Orlando	Florida	United States	32806
9	Neurological Associates/ Research Dept.	Pompano Beach	Florida	United States	33060
10	Neurology Clinical Research, Inc.	Sunrise	Florida	United States	3335-6637
11	Axiom Clinical Research of Florida	Tampa	Florida	United States	33609
12	Medical Research and Health Education	Columbus	Georgia	United States	31909
13	Consultants in Neurology, Ltd	Northbrook	Illinois	United States	60062
14	Fort Wayne Neurological Center	Fort Wayne	Indiana	United States	46805
15	Associate in Neurology	Lexington	Kentucky	United States	40503
16	University of Maryland -Maryland Center for MS	Baltimore	Maryland	United States	21201
17	Wayne State University Department of Neurology	Detroit	Michigan	United States	48201
18	Michigan Institute for Neurological Disorders	Farmington Hills	Michigan	United States	48334
19	Michigan Medical P.C. Neurology	Grand Rapids	Michigan	United States	49525
20	Mayo Clinic Rochester Department of Neurology	Rochester	Minnesota	United States	55905
21	Nevada Neurological Consultants, Ltd.	Las Vegas	Nevada	United States	89102
22	University Hospital an Medical Center	Stony Brook	New York	United States	11794
23	ALL-Trials Clinical Research, LLC	Winston-Salem	North Carolina	United States	27103
24	Neurological Associates of Tulsa, Inc	Tulsa	Oklahoma	United States	74137
25	Neurosciencies and Pain Research	Allentown	Pennsylvania	United States	18103-6296
26	Neurology, PC	Knoxville	Tennessee	United States	37934
27	Baylor College of Medicine	Houston	Texas	United States
28	Dallas Neurological Associate	Richardson	Texas	United States	75080
29	Central Texas Neurology Consultants PA	Round Rock	Texas	United States	78681
30	Integra Clinical Research, LLC	San Antonio	Texas	United States	78231
31	Neurology Center of San Antonio	San Antonio	Texas	United States	78258
32	Department of Neurology, University Hospital "Osijek"	Osijek		Croatia
33	Department of Neurology, Clinical Hospital Centre "Rijeka"	Rijeka		Croatia
34	Department of Neurology, Clinical Hospital Centre "Zagreb"	Zagreb		Croatia
35	Department of Neurology, General Hospital "Sveti Duh"	Zagreb		Croatia
36	Department of Neurology, University Hopsital "Sestre Milosrdnice"	Zagreb		Croatia
37	Centrum Neurologii Klinicznej	Krakow		Poland
38	Samodzielny Publiczny Zakład Opieki Zdrowotnej	Lodz		Poland
39	Klinika Neurologii	Lublin		Poland
40	Oddzial Kliniczny Neurologii	Poznan		Poland
41	Instytut Psychiatrii i Neurologii	Warszawa		Poland
42	Katedra i Klinika Neurologii	Warszawa		Poland
43	Russian State Medical University	Moscow		Russian Federation	117437
44	Neurology Scientific Center RAMS	Moscow		Russian Federation	125367
45	Moscow City Hospital #11	Moscow		Russian Federation
46	Moscow City Hospital #61	Moscow		Russian Federation
47	Institute of Human brain RAS	St. Petersburg		Russian Federation	197376
48	St. Petersburg State Pavlov Medical University	St. Petersburg		Russian Federation
49	Addenbrooke's Hospital	Cambridge	England	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

• Coles AJ, Cox A, Le Page E, Jones J, Trip SA, Deans J, Seaman S, Miller DH, Hale G, Waldmann H, Compston DA. The window of therapeutic opportunity in multiple sclerosis: evidence from monoclonal antibody therapy. J Neurol. 2006 Jan;253(1):98-108. Epub 2005 Jul 27.

• Responsible Party: Genzyme, a Sanofi Company
• ClinicalTrials.gov Identifier: NCT00050778
• Other Study ID Numbers: CAMMS223
• First Posted: Dec 23, 2002
• Last Update Posted: Jan 8, 2015
• Last Verified: Jan 1, 2015

• Keywords provided by Genzyme, a Sanofi Company: Multiple Sclerosis; Active Relapsing-Remitting 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	The study was conducted at 49 investigational sites in the United States, United Kingdom, and Eastern Europe between December 04, 2002 and January 12, 2010.

Arm/Group Title	Interferon Beta-1a	Alemtuzumab 12 mg	Alemtuzumab 24 mg
Arm/Group Description	Interferon beta-1a (Rebif®) 44 micrograms (mcg) subcutaneously 3-times weekly for 36 months.	Alemtuzumab (Lemtrada™) 12 milligram per day (mg/day) was given by intravenous infusion on 5 consecutive days during the first month and on 3 consecutive days at months 12 and 24 (the latter at the treating physicians' discretion if the cluster of differentiation 4+ [CD4+] T-cell count was >=100*10^6 cells per liter).	Alemtuzumab 24 mg/day was given by intravenous infusion on 5 consecutive days during the first month and on 3 consecutive days at months 12 and 24 (the latter at the treating physicians' discretion if the CD4+ T-cell count was >=100*10^6 cells per liter).
Period Title: Overall Study
STARTED	111	113	110
Treated	107	108	108
COMPLETED	66	92	92
NOT COMPLETED	45	21	18

Baseline Characteristics

Arm/Group Title	Interferon Beta-1a	Alemtuzumab 12 mg	Alemtuzumab 24 mg	Total
Arm/Group Description	Interferon beta-1a 44 mcg subcutaneously 3-times weekly for 36 months.	Alemtuzumab 12 mg/day was given by intravenous infusion on 5 consecutive days during the first month and on 3 consecutive days at months 12 and 24 (the latter at the treating physicians' discretion if the CD4+ T-cell count was >=100*10^6 cells per liter).	Alemtuzumab 24 mg/day was given by intravenous infusion on 5 consecutive days during the first month and on 3 consecutive days at months 12 and 24 (the latter at the treating physicians' discretion if the CD4+ T-cell count was >=100*10^6 cells per liter).	Total of all reporting groups
Overall Participants	111	112	110	333
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	32.8 (8.82)	31.9 (8.01)	32.2 (8.76)	32.3 (8.52)
Sex: Female, Male (Count of Participants)
Female	71 64%	72 64.3%	71 64.5%	214 64.3%
Male	40 36%	40 35.7%	39 35.5%	119 35.7%
Time Since First Relapse (years) [Median (Full Range) ]
Median (Full Range) [years]	1.4	1.3	1.2	1.3
Number of Relapse Episodes in the Preceding 2 Years (participants) [Number]
0 Relapse	0 0%	2 1.8%	1 0.9%	3 0.9%
1 Relapse	8 7.2%	5 4.5%	13 11.8%	26 7.8%
2 Relapses	73 65.8%	58 51.8%	56 50.9%	187 56.2%
Greater than or equal to 3 Relapses	30 27%	47 42%	40 36.4%	117 35.1%
Total Number of Relapses (relapses) [Number]
Number [relapses]	293	301	290	884
Expanded Disability Status Scale (EDSS) Score (units on a scale) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [units on a scale]	1.9 (0.81)	2.0 (0.73)	2.0 (0.73)	1.9 (0.76)
Time Constant 1 (T1) Cerebral Volume (cubic centimeter) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [cubic centimeter]	317.5 (24.70)	320.8 (27.15)	320.5 (24.99)	319.6 (25.61)
Time Constant 2 (T2) Lesion Volume (cubic centimeter) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [cubic centimeter]	15.8 (15.23)	17.2 (23.84)	17.8 (17.45)	17.0 (19.19)

Outcome Measures

1. Primary Outcome

Title	Probability 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 Baseline score of 1.0 or more; and the increase persisted for at least next the 2 scheduled assessments, that is, 6 consecutive months. The 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. Probability of participants with SAD, estimated by Kaplan-Meier (KM) method, was reported.
Time Frame	Up to 3 years

Outcome Measure Data

Analysis Population Description

Full Analysis Set (FAS) population included all randomized participants who had correct diagnosis of MS at entry.

Arm/Group Title	Interferon Beta-1a	Alemtuzumab 12 mg	Alemtuzumab 24 mg	Alemtuzumab (Pooled)
Arm/Group Description	Interferon Beta-1a 44 mcg subcutaneously 3-times weekly for 36 months.	Alemtuzumab 12 mg/day was given by intravenous infusion on 5 consecutive days during the first month and on 3 consecutive days at months 12 and 24 (the latter at the treating physicians' discretion if the CD4+ T-cell count was >=100*10^6 cells per liter).	Alemtuzumab 24 mg/day was given by intravenous infusion on 5 consecutive days during the first month and on 3 consecutive days at months 12 and 24 (the latter at the treating physicians' discretion if the CD4+ T-cell count was >=100*10^6 cells per liter).	Included all participants who received alemtuzumab 12 mg/day or 24 mg/day by intravenous infusion on 5 consecutive days during first month and on 3 consecutive days at months 12 and 24 (the latter at the treating physicians' discretion if the CD4+ T-cell count was >=100*10^6 cells per liter).
Measure Participants	111	112	110	222
Number (95% Confidence Interval) [probability of participants with SAD]	0.27 0.2%	0.08 0.1%	0.09 0.1%	0.09 0%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Interferon Beta-1a, Alemtuzumab 12 mg
	Comments	Cox proportional hazards (PH) regression model using treatment group, Baseline EDSS group (grouped by less than or equal to 1.5 and greater than 1.5), and country (investigative center grouped by country) as covariates was used.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0006
	Comments	An alpha-sharing approach was used to adjust for multiple treatment group comparisons, endpoints, and two pre-planned interim analyses, including a Lan-Demets error-spending function. Pre-specified threshold for statistical significance was 0.0165.
	Method	Cox Proportional Hazards Regression
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.24
	Confidence Interval	(2-Sided) 95%; 0.110 to 0.545
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Interferon Beta-1a, Alemtuzumab 24 mg
	Comments	Cox PH regression model using treatment group, Baseline EDSS group (grouped by less than or equal to 1.5 and greater than 1.5), and country (investigative center grouped by country) as covariates was used.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0021
	Comments	An alpha-sharing approach was used to adjust for multiple treatment group comparisons, endpoints, and two pre-planned interim analyses, including a Lan-Demets error-spending function. Pre-specified threshold for statistical significance was 0.0165.
	Method	Cox Proportional Hazards Regression
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.31
	Confidence Interval	(2-Sided) 95%; 0.151 to 0.658
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Interferon Beta-1a, Alemtuzumab (Pooled)
	Comments	Cox PH regression model using treatment group, Baseline EDSS group (grouped by less than or equal to 1.5 and greater than 1.5), and country (investigative center grouped by country) as covariates was used.
	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	0.28
	Confidence Interval	(2-Sided) 95%; 0.152 to 0.515
	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 using a Poisson regression model with observed number of relapses as a dependent variable, the log total amount of follow-up from date of randomization for each participant as an offset variable and treatment group indicator as a covariate.
Time Frame	Up to 3 years

Outcome Measure Data

Analysis Population Description

FAS population included all randomized participants who had correct diagnosis of MS at entry.

Arm/Group Title	Interferon Beta-1a	Alemtuzumab 12 mg	Alemtuzumab 24 mg	Alemtuzumab (Pooled)
Arm/Group Description	Interferon Beta-1a 44 mcg subcutaneously 3-times weekly for 36 months.	Alemtuzumab 12 mg/day was given by intravenous infusion on 5 consecutive days during the first month and on 3 consecutive days at months 12 and 24 (the latter at the treating physicians' discretion if the CD4+ T-cell count was >=100*10^6 cells per liter).	Alemtuzumab 24 mg/day was given by intravenous infusion on 5 consecutive days during the first month and on 3 consecutive days at months 12 and 24 (the latter at the treating physicians' discretion if the CD4+ T-cell count was >=100*10^6 cells per liter).	Included all participants who received alemtuzumab 12 mg/day or 24 mg/day by intravenous infusion on 5 consecutive days during first month and on 3 consecutive days at months 12 and 24 (the latter at the treating physicians' discretion if the CD4+ T-cell count was >=100*10^6 cells per liter).
Measure Participants	111	112	110	222
Number (95% Confidence Interval) [relapses per participant per year]	0.37	0.12	0.09	0.11

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Interferon Beta-1a, Alemtuzumab 12 mg
	Comments	Treatment effects were estimated using an Anderson-Gill multiplicative intensity model with robust variance estimation. Covariates included treatment group, Baseline EDSS group (grouped by less than or equal to 1.5 and greater than 1.5), and country (investigative center grouped by country).
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments	An alpha-sharing approach was used to adjust for multiple treatment group comparisons, endpoints, and two pre-planned interim analyses, including a Lan-Demets error-spending function. Pre-specified threshold for statistical significance was 0.0040.
	Method	Andersen-Gill Model
	Comments
Method of Estimation	Estimation Parameter	Rate ratio
	Estimated Value	0.33
	Confidence Interval	(2-Sided) 95%; 0.196 to 0.552
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Interferon Beta-1a, Alemtuzumab 24 mg
	Comments	Treatment effects were estimated using an Anderson-Gill multiplicative intensity model with robust variance estimation. Covariates included treatment group, Baseline EDSS group (grouped by less than or equal to 1.5 and greater than 1.5), and country (investigative center grouped by country).
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments	An alpha-sharing approach was used to adjust for multiple treatment group comparisons, endpoints, and two pre-planned interim analyses, including a Lan-Demets error-spending function. Pre-specified threshold for statistical significance was 0.0040.
	Method	Andersen-Gill Model
	Comments
Method of Estimation	Estimation Parameter	Rate ratio
	Estimated Value	0.23
	Confidence Interval	(2-Sided) 95%; 0.126 to 0.431
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Interferon Beta-1a, Alemtuzumab (Pooled)
	Comments	Treatment effects were estimated using an Anderson-Gill multiplicative intensity model with robust variance estimation. Covariates included treatment group, Baseline EDSS group (grouped by less than or equal to 1.5 and greater than 1.5), and country (investigative center grouped by country).
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Andersen-Gill Model
	Comments
Method of Estimation	Estimation Parameter	Rate ratio
	Estimated Value	0.28
	Confidence Interval	(2-Sided) 95%; 0.176 to 0.441
	Parameter Dispersion	Type: Value:
	Estimation Comments

3. Secondary Outcome

Title	Probability of Participants Who Were Relapse Free at 3 Years After Initial Treatment
Description	Participants were considered relapse free at Year 3 if they did not experience a relapse between randomization and study completion at 36 months. Participants who discontinued early were considered relapse free if they did not experience a relapse prior to discontinuation. Probability of participants who were relapse free at Year 3, estimated using the KM method, was reported.
Time Frame	Year 3

Outcome Measure Data

Analysis Population Description

FAS population included all randomized participants who had correct diagnosis of MS at entry.

Arm/Group Title	Interferon Beta-1a	Alemtuzumab 12 mg	Alemtuzumab 24 mg	Alemtuzumab (Pooled)
Arm/Group Description	Interferon Beta-1a 44 mcg subcutaneously 3-times weekly for 36 months.	Alemtuzumab 12 mg/day was given by intravenous infusion on 5 consecutive days during the first month and on 3 consecutive days at months 12 and 24 (the latter at the treating physicians' discretion if the CD4+ T-cell count was >=100*10^6 cells per liter).	Alemtuzumab 24 mg/day was given by intravenous infusion on 5 consecutive days during the first month and on 3 consecutive days at months 12 and 24 (the latter at the treating physicians' discretion if the CD4+ T-cell count was >=100*10^6 cells per liter).	Included all participants who received alemtuzumab 12 mg/day or 24 mg/day by intravenous infusion on 5 consecutive days during first month and on 3 consecutive days at months 12 and 24 (the latter at the treating physicians' discretion if the CD4+ T-cell count was >=100*10^6 cells per liter).
Measure Participants	111	112	110	222
Number (95% Confidence Interval) [probability of participants]	0.50 0.5%	0.76 0.7%	0.84 0.8%	0.80 0.2%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Interferon Beta-1a, Alemtuzumab 12 mg
	Comments	Cox PH regression model with treatment group indicator, Baseline EDSS and country as covariates was used.
	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	Treatment effect
	Estimated Value	62.64
	Confidence Interval	() %; to
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Interferon Beta-1a, Alemtuzumab 24 mg
	Comments	Cox PH regression model with treatment group indicator, Baseline EDSS and country as covariates was used.
	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	Treatment effect
	Estimated Value	76.71
	Confidence Interval	() %; to
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Interferon Beta-1a, Alemtuzumab (Pooled)
	Comments	Cox PH regression model with treatment group indicator, Baseline EDSS and country as covariates was used.
	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	Treatment effect
	Estimated Value	70.13
	Confidence Interval	() %; to
	Parameter Dispersion	Type: Value:
	Estimation Comments

4. Secondary Outcome

Title	Percent Change From Baseline in T1 Cerebral Volume at Year 3
Description	Magnetic resonance imaging (MRI) T1 was used to determine rate of cerebral atrophy (decrease in cerebral/brain volume). Partial brain volumes were measured using the technique of Losseff et al. (1996). Percent change in cerebral volume at Year 3 was calculated from MRI-T1-weighted scans as: 100*([brain volume at Year 3] minus [brain volume at Baseline]) divided by [brain volume at Baseline]).
Time Frame	Baseline, Year 3

Outcome Measure Data

Analysis Population Description

Analysis population included participants in the FAS population (randomized with a correct diagnosis of MS) who had an evaluable scan for MRI-T1 brain volume at Baseline and Year 3.

Arm/Group Title	Interferon Beta-1a	Alemtuzumab 12 mg	Alemtuzumab 24 mg	Alemtuzumab (Pooled)
Arm/Group Description	Interferon Beta-1a 44 mcg subcutaneously 3-times weekly for 36 months.	Alemtuzumab 12 mg/day was given by intravenous infusion on 5 consecutive days during the first month and on 3 consecutive days at months 12 and 24 (the latter at the treating physicians' discretion if the CD4+ T-cell count was >=100*10^6 cells per liter).	Alemtuzumab 24 mg/day was given by intravenous infusion on 5 consecutive days during the first month and on 3 consecutive days at months 12 and 24 (the latter at the treating physicians' discretion if the CD4+ T-cell count was >=100*10^6 cells per liter).	Included all participants who received alemtuzumab 12 mg/day or 24 mg/day by intravenous infusion on 5 consecutive days during first month and on 3 consecutive days at months 12 and 24 (the latter at the treating physicians' discretion if the CD4+ T-cell count was >=100*10^6 cells per liter).
Measure Participants	67	83	90	173
Mean (Standard Deviation) [percent change]	-1.9 (4.48)	-0.8 (3.66)	-0.4 (4.27)	-0.6 (3.99)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Interferon Beta-1a, Alemtuzumab 12 mg
	Comments	Ranked analysis of covariance (ANCOVA) model using Baseline MRI-T1 brain volume, EDSS group, country, and treatment as covariates was used.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0885
	Comments
	Method	ANCOVA
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Interferon Beta-1a, Alemtuzumab 24 mg
	Comments	Ranked ANCOVA model using Baseline MRI-T1 brain volume, EDSS group, country, and treatment as covariates was used.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0195
	Comments
	Method	ANCOVA
	Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Interferon Beta-1a, Alemtuzumab (Pooled)
	Comments	Ranked ANCOVA model using Baseline MRI-T1 brain volume, EDSS group, country, and treatment as covariates was used.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0215
	Comments
	Method	ANCOVA
	Comments

5. Secondary Outcome

Title	Percent Change From Baseline in MRI T2 Lesion Volume at Year 3
Description	Percent change in lesion volume at Year 3 was calculated from MRI-T2-weighted scans as: 100*([lesion volume at Year 3] minus [lesion volume at Baseline]) divided by [lesion volume at Baseline]).
Time Frame	Baseline, Year 3

Outcome Measure Data

Analysis Population Description

Analysis population included participants in the FAS population (randomized with a correct diagnosis of MS) who had an evaluable scan for MRI-T2 lesion volume at Baseline and Year 3.

Arm/Group Title	Interferon Beta-1a	Alemtuzumab 12 mg	Alemtuzumab 24 mg	Alemtuzumab (Pooled)
Arm/Group Description	Interferon Beta-1a 44 mcg subcutaneously 3-times weekly for 36 months.	Alemtuzumab 12 mg/day was given by intravenous infusion on 5 consecutive days during the first month and on 3 consecutive days at months 12 and 24 (the latter at the treating physicians' discretion if the CD4+ T-cell count was >=100*10^6 cells per liter).	Alemtuzumab 24 mg/day was given by intravenous infusion on 5 consecutive days during the first month and on 3 consecutive days at months 12 and 24 (the latter at the treating physicians' discretion if the CD4+ T-cell count was >=100*10^6 cells per liter).	Included all participants who received alemtuzumab 12 mg/day or 24 mg/day by intravenous infusion on 5 consecutive days during first month and on 3 consecutive days at months 12 and 24 (the latter at the treating physicians' discretion if the CD4+ T-cell count was >=100*10^6 cells per liter).
Measure Participants	66	81	88	169
Mean (Standard Deviation) [percent change]	23.4 (134.3)	-11.4 (38.8)	-8.9 (41.1)	-10.1 (39.9)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Interferon Beta-1a, Alemtuzumab 12 mg
	Comments	Ranked ANCOVA model using Baseline MRI-T2 lesion volume, EDSS group, country, and treatment as covariates was used.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.3077
	Comments
	Method	ANCOVA
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Interferon Beta-1a, Alemtuzumab 24 mg
	Comments	Ranked ANCOVA model using Baseline MRI-T2 lesion volume, EDSS group, country, and treatment as covariates was used.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.3632
	Comments
	Method	ANCOVA
	Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Interferon Beta-1a, Alemtuzumab (Pooled)
	Comments	Ranked ANCOVA model using Baseline MRI-T2 lesion volume, EDSS group, country, and treatment as covariates was used.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.2758
	Comments
	Method	ANCOVA
	Comments

Adverse Events

Time Frame	First dose of study drug up to last follow-up (80.6 months)
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 12 mg		Alemtuzumab 24 mg		Alemtuzumab (Pooled)
Arm/Group Description	Interferon Beta-1a 44 mcg subcutaneously 3-times weekly for 36 months.		Alemtuzumab 12 mg/day was given by intravenous infusion on 5 consecutive days during the first month and on 3 consecutive days at months 12 and 24 (the latter at the treating physicians' discretion if the CD4+ T-cell count was >=100*10^6 cells per liter).		Alemtuzumab 24 mg/day was given by intravenous infusion on 5 consecutive days during the first month and on 3 consecutive days at months 12 and 24 (the latter at the treating physicians' discretion if the CD4+ T-cell count was >=100*10^6 cells per liter).		Included all participants who received alemtuzumab 12 mg/day or 24 mg/day by intravenous infusion on 5 consecutive days during first month and on 3 consecutive days at months 12 and 24 (the latter at the treating physicians' discretion if the CD4+ T-cell count was >=100*10^6 cells per liter).
All Cause Mortality
	Interferon Beta-1a		Alemtuzumab 12 mg		Alemtuzumab 24 mg		Alemtuzumab (Pooled)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	Interferon Beta-1a		Alemtuzumab 12 mg		Alemtuzumab 24 mg		Alemtuzumab (Pooled)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	29/107 (27.1%)		30/108 (27.8%)		33/108 (30.6%)		63/216 (29.2%)
Blood and lymphatic system disorders
Autoimmune thrombocytopenia	0/107 (0%)		1/108 (0.9%)		1/108 (0.9%)		2/216 (0.9%)
Idiopathic thrombocytopenic purpura	0/107 (0%)		0/108 (0%)		2/108 (1.9%)		2/216 (0.9%)
Neutropenia	0/107 (0%)		1/108 (0.9%)		0/108 (0%)		1/216 (0.5%)
Thrombocytopenia	0/107 (0%)		0/108 (0%)		1/108 (0.9%)		1/216 (0.5%)
Cardiac disorders
Acute myocardial infarction	0/107 (0%)		1/108 (0.9%)		0/108 (0%)		1/216 (0.5%)
Angina pectoris	1/107 (0.9%)		0/108 (0%)		1/108 (0.9%)		1/216 (0.5%)
Arrhythmia	1/107 (0.9%)		0/108 (0%)		0/108 (0%)		0/216 (0%)
Atrial fibrillation	0/107 (0%)		1/108 (0.9%)		0/108 (0%)		1/216 (0.5%)
Bradycardia	0/107 (0%)		0/108 (0%)		1/108 (0.9%)		1/216 (0.5%)
Cardiovascular disorder	0/107 (0%)		1/108 (0.9%)		0/108 (0%)		1/216 (0.5%)
Myocardial infarction	3/107 (2.8%)		0/108 (0%)		0/108 (0%)		0/216 (0%)
Pericarditis	0/107 (0%)		0/108 (0%)		1/108 (0.9%)		1/216 (0.5%)
Endocrine disorders
Autoimmune thyroiditis	0/107 (0%)		1/108 (0.9%)		0/108 (0%)		1/216 (0.5%)
Basedow's disease	0/107 (0%)		0/108 (0%)		2/108 (1.9%)		2/216 (0.9%)
Thyroiditis subacute	0/107 (0%)		0/108 (0%)		1/108 (0.9%)		1/216 (0.5%)
Eye disorders
Cataract	1/107 (0.9%)		0/108 (0%)		0/108 (0%)		0/216 (0%)
Diplopia	1/107 (0.9%)		0/108 (0%)		0/108 (0%)		0/216 (0%)
Exophthalmos	0/107 (0%)		1/108 (0.9%)		0/108 (0%)		1/216 (0.5%)
Vision blurred	0/107 (0%)		0/108 (0%)		1/108 (0.9%)		1/216 (0.5%)
Visual acuity reduced	0/107 (0%)		1/108 (0.9%)		0/108 (0%)		1/216 (0.5%)
Gastrointestinal disorders
Abdominal hernia	0/107 (0%)		1/108 (0.9%)		0/108 (0%)		1/216 (0.5%)
Dyspepsia	0/107 (0%)		0/108 (0%)		1/108 (0.9%)		1/216 (0.5%)
Enterocutaneous fistula	1/107 (0.9%)		0/108 (0%)		0/108 (0%)		0/216 (0%)
Erosive oesophagitis	0/107 (0%)		1/108 (0.9%)		0/108 (0%)		1/216 (0.5%)
Gastric ulcer	0/107 (0%)		0/108 (0%)		1/108 (0.9%)		1/216 (0.5%)
Gastritis	0/107 (0%)		0/108 (0%)		2/108 (1.9%)		2/216 (0.9%)
Gastroduodenitis	0/107 (0%)		1/108 (0.9%)		0/108 (0%)		1/216 (0.5%)
Hypoaesthesia oral	1/107 (0.9%)		0/108 (0%)		0/108 (0%)		0/216 (0%)
Ileus	0/107 (0%)		1/108 (0.9%)		0/108 (0%)		1/216 (0.5%)
Ileus paralytic	1/107 (0.9%)		0/108 (0%)		0/108 (0%)		0/216 (0%)
Nausea	1/107 (0.9%)		0/108 (0%)		1/108 (0.9%)		1/216 (0.5%)
Paraesthesia oral	1/107 (0.9%)		0/108 (0%)		0/108 (0%)		0/216 (0%)
Peritonitis	0/107 (0%)		1/108 (0.9%)		0/108 (0%)		1/216 (0.5%)
Salivary gland calculus	0/107 (0%)		0/108 (0%)		1/108 (0.9%)		1/216 (0.5%)
Vomiting	1/107 (0.9%)		0/108 (0%)		1/108 (0.9%)		1/216 (0.5%)
General disorders
Adverse drug reaction	0/107 (0%)		0/108 (0%)		1/108 (0.9%)		1/216 (0.5%)
Asthenia	0/107 (0%)		1/108 (0.9%)		0/108 (0%)		1/216 (0.5%)
Chest discomfort	0/107 (0%)		0/108 (0%)		1/108 (0.9%)		1/216 (0.5%)
Death	1/107 (0.9%)		0/108 (0%)		0/108 (0%)		0/216 (0%)
Fatigue	1/107 (0.9%)		0/108 (0%)		0/108 (0%)		0/216 (0%)
Gait disturbance	1/107 (0.9%)		0/108 (0%)		0/108 (0%)		0/216 (0%)
Infusion related reaction	0/107 (0%)		1/108 (0.9%)		0/108 (0%)		1/216 (0.5%)
Pyrexia	0/107 (0%)		0/108 (0%)		1/108 (0.9%)		1/216 (0.5%)
Hepatobiliary disorders
Hepatic failure	1/107 (0.9%)		0/108 (0%)		0/108 (0%)		0/216 (0%)
Infections and infestations
Appendicitis	1/107 (0.9%)		0/108 (0%)		0/108 (0%)		0/216 (0%)
Bronchitis	0/107 (0%)		0/108 (0%)		1/108 (0.9%)		1/216 (0.5%)
Catheter bacteraemia	1/107 (0.9%)		0/108 (0%)		0/108 (0%)		0/216 (0%)
Cellulitis of male external genital organ	0/107 (0%)		0/108 (0%)		1/108 (0.9%)		1/216 (0.5%)
Cervicitis	0/107 (0%)		1/108 (0.9%)		0/108 (0%)		1/216 (0.5%)
Gastroenteritis	0/107 (0%)		1/108 (0.9%)		1/108 (0.9%)		2/216 (0.9%)
Herpes ophthalmic	0/107 (0%)		0/108 (0%)		1/108 (0.9%)		1/216 (0.5%)
Herpes zoster	0/107 (0%)		0/108 (0%)		1/108 (0.9%)		1/216 (0.5%)
Meningitis listeria	0/107 (0%)		0/108 (0%)		1/108 (0.9%)		1/216 (0.5%)
Meningitis viral	0/107 (0%)		0/108 (0%)		1/108 (0.9%)		1/216 (0.5%)
Sepsis	0/107 (0%)		1/108 (0.9%)		0/108 (0%)		1/216 (0.5%)
Sinusitis	1/107 (0.9%)		1/108 (0.9%)		0/108 (0%)		1/216 (0.5%)
Subcutaneous abscess	0/107 (0%)		1/108 (0.9%)		0/108 (0%)		1/216 (0.5%)
Urinary tract infection	0/107 (0%)		0/108 (0%)		2/108 (1.9%)		2/216 (0.9%)
Varicella	0/107 (0%)		1/108 (0.9%)		0/108 (0%)		1/216 (0.5%)
Viral infection	0/107 (0%)		1/108 (0.9%)		0/108 (0%)		1/216 (0.5%)
Injury, poisoning and procedural complications
Alcohol poisoning	1/107 (0.9%)		0/108 (0%)		0/108 (0%)		0/216 (0%)
Fibula fracture	1/107 (0.9%)		0/108 (0%)		0/108 (0%)		0/216 (0%)
Joint injury	0/107 (0%)		0/108 (0%)		1/108 (0.9%)		1/216 (0.5%)
Limb traumatic amputation	0/107 (0%)		1/108 (0.9%)		0/108 (0%)		1/216 (0.5%)
Procedural pain	1/107 (0.9%)		0/108 (0%)		0/108 (0%)		0/216 (0%)
Rib fracture	1/107 (0.9%)		0/108 (0%)		0/108 (0%)		0/216 (0%)
Tibia fracture	1/107 (0.9%)		0/108 (0%)		1/108 (0.9%)		1/216 (0.5%)
Traumatic brain injury	1/107 (0.9%)		0/108 (0%)		0/108 (0%)		0/216 (0%)
Traumatic lung injury	1/107 (0.9%)		0/108 (0%)		0/108 (0%)		0/216 (0%)
Investigations
Alanine aminotransferase increased	0/107 (0%)		0/108 (0%)		1/108 (0.9%)		1/216 (0.5%)
Aspartate aminotransferase increased	0/107 (0%)		0/108 (0%)		1/108 (0.9%)		1/216 (0.5%)
Hepatic enzyme increased	1/107 (0.9%)		0/108 (0%)		0/108 (0%)		0/216 (0%)
Transaminases increased	0/107 (0%)		0/108 (0%)		1/108 (0.9%)		1/216 (0.5%)
Metabolism and nutrition disorders
Dehydration	1/107 (0.9%)		0/108 (0%)		0/108 (0%)		0/216 (0%)
Musculoskeletal and connective tissue disorders
Back pain	0/107 (0%)		0/108 (0%)		1/108 (0.9%)		1/216 (0.5%)
Intervertebral disc protrusion	1/107 (0.9%)		0/108 (0%)		0/108 (0%)		0/216 (0%)
Muscular weakness	2/107 (1.9%)		2/108 (1.9%)		1/108 (0.9%)		3/216 (1.4%)
Osteoarthritis	1/107 (0.9%)		0/108 (0%)		0/108 (0%)		0/216 (0%)
Pain in extremity	0/107 (0%)		0/108 (0%)		1/108 (0.9%)		1/216 (0.5%)
Polyarthritis	0/107 (0%)		0/108 (0%)		1/108 (0.9%)		1/216 (0.5%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Acoustic neuroma	0/107 (0%)		1/108 (0.9%)		0/108 (0%)		1/216 (0.5%)
Angiomyolipoma	0/107 (0%)		1/108 (0.9%)		0/108 (0%)		1/216 (0.5%)
Basal cell carcinoma	0/107 (0%)		0/108 (0%)		1/108 (0.9%)		1/216 (0.5%)
Breast cancer	0/107 (0%)		0/108 (0%)		1/108 (0.9%)		1/216 (0.5%)
Cervix carcinoma	0/107 (0%)		0/108 (0%)		1/108 (0.9%)		1/216 (0.5%)
Colon cancer	1/107 (0.9%)		0/108 (0%)		0/108 (0%)		0/216 (0%)
Glomus tumour	0/107 (0%)		1/108 (0.9%)		0/108 (0%)		1/216 (0.5%)
Thyroid cancer	0/107 (0%)		0/108 (0%)		1/108 (0.9%)		1/216 (0.5%)
Uterine leiomyoma	0/107 (0%)		1/108 (0.9%)		0/108 (0%)		1/216 (0.5%)
Nervous system disorders
Ataxia	2/107 (1.9%)		0/108 (0%)		1/108 (0.9%)		1/216 (0.5%)
Balance disorder	0/107 (0%)		0/108 (0%)		2/108 (1.9%)		2/216 (0.9%)
Carpal tunnel syndrome	1/107 (0.9%)		0/108 (0%)		0/108 (0%)		0/216 (0%)
Cerebellar ataxia	1/107 (0.9%)		0/108 (0%)		0/108 (0%)		0/216 (0%)
Cerebral haemorrhage	0/107 (0%)		0/108 (0%)		1/108 (0.9%)		1/216 (0.5%)
Cerebrovascular accident	0/107 (0%)		1/108 (0.9%)		0/108 (0%)		1/216 (0.5%)
Dizziness	1/107 (0.9%)		0/108 (0%)		0/108 (0%)		0/216 (0%)
Headache	0/107 (0%)		0/108 (0%)		1/108 (0.9%)		1/216 (0.5%)
Hemiparesis	0/107 (0%)		1/108 (0.9%)		1/108 (0.9%)		2/216 (0.9%)
Hypoaesthesia	1/107 (0.9%)		0/108 (0%)		1/108 (0.9%)		1/216 (0.5%)
Multiple sclerosis relapse	14/107 (13.1%)		5/108 (4.6%)		9/108 (8.3%)		14/216 (6.5%)
Myelitis	0/107 (0%)		1/108 (0.9%)		0/108 (0%)		1/216 (0.5%)
Paraesthesia	1/107 (0.9%)		0/108 (0%)		0/108 (0%)		0/216 (0%)
Paraparesis	0/107 (0%)		0/108 (0%)		1/108 (0.9%)		1/216 (0.5%)
Paresis	0/107 (0%)		1/108 (0.9%)		0/108 (0%)		1/216 (0.5%)
Sensory disturbance	1/107 (0.9%)		0/108 (0%)		0/108 (0%)		0/216 (0%)
Sensory loss	0/107 (0%)		1/108 (0.9%)		0/108 (0%)		1/216 (0.5%)
Syncope	0/107 (0%)		1/108 (0.9%)		0/108 (0%)		1/216 (0.5%)
Pregnancy, puerperium and perinatal conditions
Abortion	0/107 (0%)		1/108 (0.9%)		0/108 (0%)		1/216 (0.5%)
Abortion missed	0/107 (0%)		1/108 (0.9%)		1/108 (0.9%)		2/216 (0.9%)
Abortion spontaneous	0/107 (0%)		0/108 (0%)		2/108 (1.9%)		2/216 (0.9%)
Abortion threatened	0/107 (0%)		0/108 (0%)		1/108 (0.9%)		1/216 (0.5%)
Psychiatric disorders
Anxiety	1/107 (0.9%)		0/108 (0%)		0/108 (0%)		0/216 (0%)
Bipolar disorder	0/107 (0%)		1/108 (0.9%)		0/108 (0%)		1/216 (0.5%)
Suicide attempt	0/107 (0%)		0/108 (0%)		1/108 (0.9%)		1/216 (0.5%)
Renal and urinary disorders
Goodpasture's syndrome	0/107 (0%)		1/108 (0.9%)		0/108 (0%)		1/216 (0.5%)
Micturition urgency	0/107 (0%)		1/108 (0.9%)		0/108 (0%)		1/216 (0.5%)
Nephrolithiasis	0/107 (0%)		1/108 (0.9%)		0/108 (0%)		1/216 (0.5%)
Urinary incontinence	0/107 (0%)		0/108 (0%)		2/108 (1.9%)		2/216 (0.9%)
Urinary retention	1/107 (0.9%)		0/108 (0%)		0/108 (0%)		0/216 (0%)
Reproductive system and breast disorders
Dysmenorrhoea	0/107 (0%)		0/108 (0%)		1/108 (0.9%)		1/216 (0.5%)
Ectropion of cervix	1/107 (0.9%)		0/108 (0%)		0/108 (0%)		0/216 (0%)
Endometriosis	1/107 (0.9%)		0/108 (0%)		0/108 (0%)		0/216 (0%)
Menometrorrhagia	0/107 (0%)		0/108 (0%)		1/108 (0.9%)		1/216 (0.5%)
Menorrhagia	1/107 (0.9%)		0/108 (0%)		0/108 (0%)		0/216 (0%)
Metrorrhagia	1/107 (0.9%)		0/108 (0%)		0/108 (0%)		0/216 (0%)
Ovarian cyst	0/107 (0%)		1/108 (0.9%)		0/108 (0%)		1/216 (0.5%)
Ovarian cyst ruptured	1/107 (0.9%)		0/108 (0%)		0/108 (0%)		0/216 (0%)
Ovarian disorder	1/107 (0.9%)		0/108 (0%)		0/108 (0%)		0/216 (0%)
Pelvic pain	1/107 (0.9%)		0/108 (0%)		0/108 (0%)		0/216 (0%)
Uterine polyp	1/107 (0.9%)		0/108 (0%)		0/108 (0%)		0/216 (0%)
Respiratory, thoracic and mediastinal disorders
Asthma	0/107 (0%)		0/108 (0%)		2/108 (1.9%)		2/216 (0.9%)
Dyspnoea	1/107 (0.9%)		0/108 (0%)		0/108 (0%)		0/216 (0%)
Epistaxis	0/107 (0%)		1/108 (0.9%)		0/108 (0%)		1/216 (0.5%)
Haemothorax	1/107 (0.9%)		0/108 (0%)		0/108 (0%)		0/216 (0%)
Pleural effusion	1/107 (0.9%)		0/108 (0%)		0/108 (0%)		0/216 (0%)
Pulmonary embolism	1/107 (0.9%)		0/108 (0%)		1/108 (0.9%)		1/216 (0.5%)
Skin and subcutaneous tissue disorders
Hyperhidrosis	1/107 (0.9%)		0/108 (0%)		0/108 (0%)		0/216 (0%)
Vascular disorders
Hypertension	0/107 (0%)		1/108 (0.9%)		0/108 (0%)		1/216 (0.5%)
Hypotension	0/107 (0%)		1/108 (0.9%)		0/108 (0%)		1/216 (0.5%)
Other (Not Including Serious) Adverse Events
	Interferon Beta-1a		Alemtuzumab 12 mg		Alemtuzumab 24 mg		Alemtuzumab (Pooled)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	106/107 (99.1%)		108/108 (100%)		108/108 (100%)		216/216 (100%)
Blood and lymphatic system disorders
Neutropenia	1/107 (0.9%)		6/108 (5.6%)		4/108 (3.7%)		10/216 (4.6%)
Cardiac disorders
Palpitations	3/107 (2.8%)		6/108 (5.6%)		8/108 (7.4%)		14/216 (6.5%)
Tachycardia	6/107 (5.6%)		13/108 (12%)		13/108 (12%)		26/216 (12%)
Ear and labyrinth disorders
Vertigo	10/107 (9.3%)		12/108 (11.1%)		11/108 (10.2%)		23/216 (10.6%)
Endocrine disorders
Basedow's disease	1/107 (0.9%)		12/108 (11.1%)		6/108 (5.6%)		18/216 (8.3%)
Hyperthyroidism	1/107 (0.9%)		11/108 (10.2%)		13/108 (12%)		24/216 (11.1%)
Hypothyroidism	1/107 (0.9%)		11/108 (10.2%)		11/108 (10.2%)		22/216 (10.2%)
Eye disorders
Diplopia	7/107 (6.5%)		3/108 (2.8%)		6/108 (5.6%)		9/216 (4.2%)
Vision blurred	4/107 (3.7%)		9/108 (8.3%)		16/108 (14.8%)		25/216 (11.6%)
Visual acuity reduced	6/107 (5.6%)		4/108 (3.7%)		2/108 (1.9%)		6/216 (2.8%)
Gastrointestinal disorders
Abdominal pain	7/107 (6.5%)		6/108 (5.6%)		5/108 (4.6%)		11/216 (5.1%)
Abdominal pain upper	6/107 (5.6%)		2/108 (1.9%)		4/108 (3.7%)		6/216 (2.8%)
Constipation	9/107 (8.4%)		9/108 (8.3%)		6/108 (5.6%)		15/216 (6.9%)
Diarrhoea	7/107 (6.5%)		17/108 (15.7%)		17/108 (15.7%)		34/216 (15.7%)
Dyspepsia	9/107 (8.4%)		16/108 (14.8%)		13/108 (12%)		29/216 (13.4%)
Gastrooesophageal reflux disease	0/107 (0%)		6/108 (5.6%)		7/108 (6.5%)		13/216 (6%)
Nausea	17/107 (15.9%)		32/108 (29.6%)		45/108 (41.7%)		77/216 (35.6%)
Stomatitis	1/107 (0.9%)		2/108 (1.9%)		9/108 (8.3%)		11/216 (5.1%)
Toothache	1/107 (0.9%)		1/108 (0.9%)		6/108 (5.6%)		7/216 (3.2%)
Vomiting	9/107 (8.4%)		18/108 (16.7%)		19/108 (17.6%)		37/216 (17.1%)
General disorders
Asthenia	5/107 (4.7%)		18/108 (16.7%)		12/108 (11.1%)		30/216 (13.9%)
Chest discomfort	3/107 (2.8%)		12/108 (11.1%)		18/108 (16.7%)		30/216 (13.9%)
Chills	8/107 (7.5%)		19/108 (17.6%)		21/108 (19.4%)		40/216 (18.5%)
Fatigue	31/107 (29%)		47/108 (43.5%)		44/108 (40.7%)		91/216 (42.1%)
Gait disturbance	13/107 (12.1%)		6/108 (5.6%)		5/108 (4.6%)		11/216 (5.1%)
Hyperthermia	1/107 (0.9%)		7/108 (6.5%)		5/108 (4.6%)		12/216 (5.6%)
Influenza like illness	32/107 (29.9%)		21/108 (19.4%)		15/108 (13.9%)		36/216 (16.7%)
Injection site erythema	35/107 (32.7%)		1/108 (0.9%)		0/108 (0%)		1/216 (0.5%)
Injection site pain	18/107 (16.8%)		3/108 (2.8%)		0/108 (0%)		3/216 (1.4%)
Injection site reaction	12/107 (11.2%)		1/108 (0.9%)		0/108 (0%)		1/216 (0.5%)
Oedema peripheral	4/107 (3.7%)		6/108 (5.6%)		3/108 (2.8%)		9/216 (4.2%)
Pain	6/107 (5.6%)		13/108 (12%)		14/108 (13%)		27/216 (12.5%)
Pyrexia	11/107 (10.3%)		47/108 (43.5%)		47/108 (43.5%)		94/216 (43.5%)
Infections and infestations
Bronchitis	3/107 (2.8%)		11/108 (10.2%)		14/108 (13%)		25/216 (11.6%)
Herpes zoster	1/107 (0.9%)		4/108 (3.7%)		8/108 (7.4%)		12/216 (5.6%)
Influenza	4/107 (3.7%)		10/108 (9.3%)		3/108 (2.8%)		13/216 (6%)
Nasopharyngitis	14/107 (13.1%)		17/108 (15.7%)		26/108 (24.1%)		43/216 (19.9%)
Oral herpes	1/107 (0.9%)		7/108 (6.5%)		8/108 (7.4%)		15/216 (6.9%)
Pharyngitis	4/107 (3.7%)		3/108 (2.8%)		9/108 (8.3%)		12/216 (5.6%)
Rhinitis	3/107 (2.8%)		9/108 (8.3%)		9/108 (8.3%)		18/216 (8.3%)
Sinusitis	9/107 (8.4%)		13/108 (12%)		18/108 (16.7%)		31/216 (14.4%)
Upper respiratory tract infection	10/107 (9.3%)		21/108 (19.4%)		28/108 (25.9%)		49/216 (22.7%)
Urinary tract infection	11/107 (10.3%)		11/108 (10.2%)		17/108 (15.7%)		28/216 (13%)
Viral infection	6/107 (5.6%)		4/108 (3.7%)		2/108 (1.9%)		6/216 (2.8%)
Injury, poisoning and procedural complications
Contusion	3/107 (2.8%)		6/108 (5.6%)		15/108 (13.9%)		21/216 (9.7%)
Investigations
Alanine aminotransferase increased	9/107 (8.4%)		0/108 (0%)		0/108 (0%)		0/216 (0%)
Aspartate aminotransferase increased	6/107 (5.6%)		0/108 (0%)		0/108 (0%)		0/216 (0%)
Body temperature increased	0/107 (0%)		1/108 (0.9%)		6/108 (5.6%)		7/216 (3.2%)
Weight decreased	2/107 (1.9%)		7/108 (6.5%)		9/108 (8.3%)		16/216 (7.4%)
Weight increased	7/107 (6.5%)		9/108 (8.3%)		11/108 (10.2%)		20/216 (9.3%)
Musculoskeletal and connective tissue disorders
Arthralgia	10/107 (9.3%)		21/108 (19.4%)		11/108 (10.2%)		32/216 (14.8%)
Back pain	11/107 (10.3%)		17/108 (15.7%)		27/108 (25%)		44/216 (20.4%)
Muscle spasms	11/107 (10.3%)		19/108 (17.6%)		20/108 (18.5%)		39/216 (18.1%)
Muscle tightness	0/107 (0%)		7/108 (6.5%)		2/108 (1.9%)		9/216 (4.2%)
Muscular weakness	30/107 (28%)		17/108 (15.7%)		20/108 (18.5%)		37/216 (17.1%)
Musculoskeletal pain	9/107 (8.4%)		10/108 (9.3%)		5/108 (4.6%)		15/216 (6.9%)
Myalgia	9/107 (8.4%)		11/108 (10.2%)		12/108 (11.1%)		23/216 (10.6%)
Neck pain	5/107 (4.7%)		8/108 (7.4%)		7/108 (6.5%)		15/216 (6.9%)
Pain in extremity	16/107 (15%)		25/108 (23.1%)		32/108 (29.6%)		57/216 (26.4%)
Nervous system disorders
Ataxia	13/107 (12.1%)		5/108 (4.6%)		3/108 (2.8%)		8/216 (3.7%)
Balance disorder	5/107 (4.7%)		7/108 (6.5%)		5/108 (4.6%)		12/216 (5.6%)
Burning sensation	5/107 (4.7%)		2/108 (1.9%)		8/108 (7.4%)		10/216 (4.6%)
Coordination abnormal	6/107 (5.6%)		6/108 (5.6%)		4/108 (3.7%)		10/216 (4.6%)
Dizziness	11/107 (10.3%)		13/108 (12%)		29/108 (26.9%)		42/216 (19.4%)
Dysgeusia	22/107 (20.6%)		18/108 (16.7%)		19/108 (17.6%)		37/216 (17.1%)
Headache	26/107 (24.3%)		72/108 (66.7%)		85/108 (78.7%)		157/216 (72.7%)
Hypoaesthesia	24/107 (22.4%)		29/108 (26.9%)		26/108 (24.1%)		55/216 (25.5%)
Migraine	4/107 (3.7%)		9/108 (8.3%)		6/108 (5.6%)		15/216 (6.9%)
Multiple sclerosis	5/107 (4.7%)		8/108 (7.4%)		6/108 (5.6%)		14/216 (6.5%)
Multiple sclerosis relapse	40/107 (37.4%)		27/108 (25%)		21/108 (19.4%)		48/216 (22.2%)
Muscle spasticity	8/107 (7.5%)		4/108 (3.7%)		0/108 (0%)		4/216 (1.9%)
Paraesthesia	18/107 (16.8%)		36/108 (33.3%)		22/108 (20.4%)		58/216 (26.9%)
Sensory disturbance	8/107 (7.5%)		7/108 (6.5%)		7/108 (6.5%)		14/216 (6.5%)
Tremor	5/107 (4.7%)		7/108 (6.5%)		6/108 (5.6%)		13/216 (6%)
Pregnancy, puerperium and perinatal conditions
Pregnancy	9/107 (8.4%)		11/108 (10.2%)		6/108 (5.6%)		17/216 (7.9%)
Psychiatric disorders
Anxiety	10/107 (9.3%)		12/108 (11.1%)		20/108 (18.5%)		32/216 (14.8%)
Depression	20/107 (18.7%)		19/108 (17.6%)		18/108 (16.7%)		37/216 (17.1%)
Insomnia	17/107 (15.9%)		36/108 (33.3%)		29/108 (26.9%)		65/216 (30.1%)
Renal and urinary disorders
Micturition urgency	6/107 (5.6%)		1/108 (0.9%)		6/108 (5.6%)		7/216 (3.2%)
Pollakiuria	6/107 (5.6%)		4/108 (3.7%)		6/108 (5.6%)		10/216 (4.6%)
Urinary incontinence	6/107 (5.6%)		6/108 (5.6%)		3/108 (2.8%)		9/216 (4.2%)
Urinary retention	6/107 (5.6%)		0/108 (0%)		2/108 (1.9%)		2/216 (0.9%)
Respiratory, thoracic and mediastinal disorders
Cough	4/107 (3.7%)		12/108 (11.1%)		12/108 (11.1%)		24/216 (11.1%)
Dyspnoea	3/107 (2.8%)		17/108 (15.7%)		18/108 (16.7%)		35/216 (16.2%)
Epistaxis	1/107 (0.9%)		7/108 (6.5%)		6/108 (5.6%)		13/216 (6%)
Oropharyngeal pain	4/107 (3.7%)		16/108 (14.8%)		14/108 (13%)		30/216 (13.9%)
Skin and subcutaneous tissue disorders
Alopecia	1/107 (0.9%)		6/108 (5.6%)		7/108 (6.5%)		13/216 (6%)
Erythema	5/107 (4.7%)		10/108 (9.3%)		8/108 (7.4%)		18/216 (8.3%)
Hypoaesthesia facial	2/107 (1.9%)		6/108 (5.6%)		5/108 (4.6%)		11/216 (5.1%)
Pruritus	4/107 (3.7%)		36/108 (33.3%)		28/108 (25.9%)		64/216 (29.6%)
Rash	8/107 (7.5%)		78/108 (72.2%)		82/108 (75.9%)		160/216 (74.1%)
Rash generalised	0/107 (0%)		13/108 (12%)		7/108 (6.5%)		20/216 (9.3%)
Rash pruritic	0/107 (0%)		6/108 (5.6%)		4/108 (3.7%)		10/216 (4.6%)
Urticaria	3/107 (2.8%)		31/108 (28.7%)		38/108 (35.2%)		69/216 (31.9%)
Vascular disorders
Flushing	6/107 (5.6%)		12/108 (11.1%)		8/108 (7.4%)		20/216 (9.3%)
Hypertension	8/107 (7.5%)		6/108 (5.6%)		3/108 (2.8%)		9/216 (4.2%)

Limitations/Caveats

[Not Specified]

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

In multi-site studies, PI can publish after sponsor publishes or 18 months after study completion. PI gives sponsor a draft 60 days before publication. Sponsor can ask that confidential information be removed, and can defer publication another 60 days upon notifying PI that it will file a patent application on inventions contained in the draft.