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

Study Type:	Interventional
Study Design:	Randomized, Single Blind (Outcomes Assessor), Parallel Assignment
Condition:	Multiple Sclerosis, Relapsing-Remitting
Interventions:	Biological: interferon beta-1a (Rebif®) Biological: alemtuzumab

Participant Flow

Recruitment Details

Key information relevant to the recruitment process for the overall study, such as dates of the recruitment period and locations
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Pre-Assignment Details

Significant events and approaches for the overall study following participant enrollment, but prior to group assignment
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Reporting Groups

	Description
Arm/Group 1: Interferon Beta-1a (Rebif®)	44 micrograms (mcg) administered 3-times weekly by subcutaneous (SC) injections for 36 months
Arm/Group 2: 12 mg Alemtuzumab	12 milligrams (mg) per day administered through intravenous (IV) infusion, once a day for 5 consecutive days at Month 0 and 12 mg per day administered through IV, once a day for 3 consecutive days at Month 12; optional re-treatment at Month 24 depending on investigator discretion and laboratory assessments.
Arm/Group 3: 24 mg Alemtuzumab	24 mg per day administered through IV, once a day for 5 consecutive days at Month 0 and 24 mg per day administered through IV, once a day for 3 consecutive days at Month 12; optional re-treatment at Month 24 depending on investigator discretion and laboratory assessments.

Participant Flow: Overall Study

	Arm/Group 1: Interferon Beta-1a (Rebif®)	Arm/Group 2: 12 mg Alemtuzumab	Arm/Group 3: 24 mg Alemtuzumab
STARTED	111	113^[1]	110
COMPLETED	66	92	92
NOT COMPLETED	45	21	18
Adverse Event	13	2	1
Death	0	1	1
Lack of Efficacy	16	2	2
Lost to Follow-up	0	2	4
Physician Decision	3	1	2
Protocol Violation	2	0	1
Withdrawal by Subject	3	0	2
Not Dosed Due to Depression	1	0	0
Noncompliant	4	8	4
Not Dosed Due to Thyroid Abnormality	0	3	0
Not Dosed Due to Randomization Error	0	2	0
Other Reason	3	0	1

[1]	1 patient included in safety but excluded from efficacy analysis; initial MS diagnosis was incorrect

Baseline Characteristics

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Reporting Groups

	Description
Arm/Group 1: Interferon Beta-1a (Rebif®)	44 micrograms (mcg) administered 3-times weekly by subcutaneous (SC) injections for 36 months
Arm/Group 2: 12 mg Alemtuzumab	12 milligrams (mg) per day administered through intravenous (IV) infusion, once a day for 5 consecutive days at Month 0 and 12 mg per day administered through IV, once a day for 3 consecutive days at Month 12; optional re-treatment at Month 24 depending on investigator discretion and laboratory assessments.
Arm/Group 3: 24 mg Alemtuzumab	24 mg per day administered through IV, once a day for 5 consecutive days at Month 0 and 24 mg per day administered through IV, once a day for 3 consecutive days at Month 12; optional re-treatment at Month 24 depending on investigator discretion and laboratory assessments.

Baseline Measures

	Arm/Group 1: Interferon Beta-1a (Rebif®)	Arm/Group 2: 12 mg Alemtuzumab	Arm/Group 3: 24 mg Alemtuzumab	Total
Number of Participants [units: participants]	111	112	110	333
Age [units: years] Mean ± Standard Deviation	32.8 ± 8.8	31.9 ± 8.0	32.2 ± 8.8	32.3 ± 8.5
Gender, Customized [units: Number of Participants]
Male	40	40	39	119
Female	71	72	71	214

Outcome Measures

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1. Primary:

Sustained Accumulation of Disability (SAD), Confirmed Through 6 Months [ 3 years ]

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Measure Type	Primary
Measure Title	Sustained Accumulation of Disability (SAD), Confirmed Through 6 Months
Measure Description	As measured by the Expanded Disability Status Scale (EDSS) score, an increase of at least 1.5 points for patients with a baseline score of 0 and of at least 1.0 point for patients with a baseline score of 1.0 or more; increases were confirmed on 2 consecutive assessments over a 6-month period
Time Frame	3 years
Safety Issue	No

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
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Reporting Groups

	Description
Arm 1: Interferon Beta-1a (Rebif)	44 mcg administered 3-times weekly by SC injections for 36 months
Arm 2: 12 mg Alemtuzumab	12 mg per day administered through IV, once a day for 5 consecutive days at Month 0 and 12 mg per day administered through IV, once a day for 3 consecutive days at Month 12; optional re-treatment at Month 24 depending on investigator discretion and laboratory assessments.
Arm 3: 24 mg Alemtuzumab	24 mg per day administered through IV, once a day for 5 consecutive days at Month 0 and 24 mg per day administered through IV, once a day for 3 consecutive days at Month 12; optional re-treatment at Month 24 depending on investigator discretion and laboratory assessments.
Alemtuzumab Arms (Arms 2 and 3) Pooled	All patients receiving alemtuzumab.

Measured Values

	Arm 1: Interferon Beta-1a (Rebif)	Arm 2: 12 mg Alemtuzumab	Arm 3: 24 mg Alemtuzumab	Alemtuzumab Arms (Arms 2 and 3) Pooled
Number of Participants Analyzed [units: participants]	111	112	110	222
Sustained Accumulation of Disability (SAD), Confirmed Through 6 Months [units: Participants]
Number of participants with SAD	24	8	10	18
Kaplan-Meier proportion of participants with SAD	.262	.085	.095	.090

Statistical Analysis 1 for Sustained Accumulation of Disability (SAD), Confirmed Through 6 Months

Groups ^[1]	Arm 1: Interferon Beta-1a (Rebif) vs. Alemtuzumab Arms (Arms 2 and 3) Pooled
Treatment Effect ^[2]	71
95% Confidence Interval	( 46 to 84 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Treatment effect represents the percent reduction in risk of SAD from alemtuzumab (pooled Arms 2 and 3) compared to interferon beta-1a (Arm 1) based on the proportional-hazards model. Proportion of patients with SAD estimated by Kaplan-Meier.
[2]	Other relevant estimation information:
	No text entered.

Statistical Analysis 2 for Sustained Accumulation of Disability (SAD), Confirmed Through 6 Months

Groups ^[1]	Arm 1: Interferon Beta-1a (Rebif) vs. Arm 2: 12 mg Alemtuzumab
Treatment Effect ^[2]	75
95% Confidence Interval	( 43 to 89 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Treatment effect represents the percent reduction in risk of SAD from alemtuzumab (Arm 2) compared to interferon beta-1a (Arm 1) based on the proportional-hazards model. Proportion of patients with SAD estimated by Kaplan-Meier.
[2]	Other relevant estimation information:
	No text entered.

Statistical Analysis 3 for Sustained Accumulation of Disability (SAD), Confirmed Through 6 Months

Groups ^[1]	Arm 1: Interferon Beta-1a (Rebif) vs. Arm 3: 24 mg Alemtuzumab
Treatment Effect ^[2]	67
95% Confidence Interval	( 31 to 84 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Treatment effect represents the percent reduction in risk of SAD from alemtuzumab (Arm 3) compared to interferon beta-1a (Arm 1) based on the proportional-hazards model. Proportion of patients with SAD estimated by Kaplan-Meier.
[2]	Other relevant estimation information:
	No text entered.

2. Primary:

Relapse [ 3 years ]

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Serious Adverse Events

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Other Adverse Events

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More Information

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Certain Agreements:

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

There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

The agreement is:

	The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 60 days. The sponsor cannot require changes to the communication and cannot extend the embargo.
	The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is more than 60 days but less than or equal to 180 days. The sponsor cannot require changes to the communication and cannot extend the embargo.
	Other disclosure agreement that restricts the right of the PI to discuss or publish trial results after the trial is completed. Restriction Description: In multi-site studies, PI can publish after Genzyme publishes or 18 months after study completion. PI gives Genzyme a draft 60 days before publication. Genzyme 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.

Limitations and Caveats

Limitations of the study, such as early termination leading to small numbers of participants analyzed and technical problems with measurement leading to unreliable or uninterpretable data
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Results Point of Contact:

Name/Title: Genzyme Medical Information
Organization: Genzyme Corporation
phone: 800-745-4447

Publications of Results:

CAMMS223 Trial Investigators; Coles AJ, Compston DA, Selmaj KW, Lake SL, Moran S, Margolin DH, Norris K, Tandon PK. Alemtuzumab vs. Interferon beta-1a in early multiple sclerosis. N Engl J Med. 2008 Oct 23;359(17):1786-801.

Other 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 Corporation ( Medical Monitor )
Study ID Numbers:	CAMMS223
Study First Received:	December 19, 2002
Results First Received:	November 3, 2008
Last Updated:	July 13, 2009
ClinicalTrials.gov Identifier:	NCT00050778 History of Changes
Health Authority:	United States: Food and Drug Administration; United Kingdom: Medicines and Healthcare Products Regulatory Agency; Croatia: Ministry of Health and Social Care; Poland: Office for Registration of Medicinal Products, Medical Devices and Biocidal Products; Russia: Ministry of Health and Social Development of the Russian Federation