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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2. Primary:

Relapse [ 3 years ]

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Serious Adverse Events

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Other Adverse Events

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Time Frame	No text entered.
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Frequency Threshold

Threshold above which other adverse events are reported	≥ 10%

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.

Other Adverse Events

	Arm 1: Interferon Beta-1a (Rebif)	Arm 2: 12 mg Alemtuzumab	Arm 3: 24 mg Alemtuzumab	Alemtuzumab Arms (Arms 2 and 3) Pooled
Total, other (not including serious) adverse events
# participants affected	106	108	107	215
Cardiac disorders
Tachycardia ^†^A # participants affected / at risk # events	5/107 (4.67%) 5	12/108 (11.11%) 14	12/108 (11.11%) 19	24/216 (11.11%) 33
Eye disorders
Vision blurred ^†^A # participants affected / at risk # events	4/107 (3.74%) 5	8/108 (7.41%) 9	15/108 (13.89%) 18	23/216 (10.65%) 27
Gastrointestinal disorders
Nausea ^†^A # participants affected / at risk # events	15/107 (14.02%) 21	27/108 (25.00%) 36	41/108 (37.96%) 57	68/216 (31.48%) 93
Diarrhoea ^†^A # participants affected / at risk # events	7/107 (6.54%) 9	14/108 (12.96%) 19	18/108 (16.67%) 19	32/216 (14.81%) 38
Vomiting ^†^A # participants affected / at risk # events	7/107 (6.54%) 9	15/108 (13.89%) 21	17/108 (15.74%) 20	32/216 (14.81%) 41
Dyspepsia ^†^A # participants affected / at risk # events	8/107 (7.48%) 11	14/108 (12.96%) 17	12/108 (11.11%) 18	26/216 (12.04%) 35
General disorders
Fatigue ^†^A # participants affected / at risk # events	30/107 (28.04%) 38	43/108 (39.81%) 58	45/108 (41.67%) 79	88/216 (40.74%) 137
Pyrexia ^†^A # participants affected / at risk # events	11/107 (10.28%) 22	42/108 (38.89%) 61	42/108 (38.89%) 60	84/216 (38.89%) 121
Chills ^†^A # participants affected / at risk # events	8/107 (7.48%) 9	17/108 (15.74%) 25	20/108 (18.52%) 23	37/216 (17.13%) 48
Chest discomfort ^†^A # participants affected / at risk # events	3/107 (2.80%) 3	12/108 (11.11%) 14	17/108 (15.74%) 22	29/216 (13.43%) 36
Asthenia ^†^A # participants affected / at risk # events	5/107 (4.67%) 6	14/108 (12.96%) 19	11/108 (10.19%) 20	25/216 (11.57%) 39
Influenza like illness ^†^A # participants affected / at risk # events	29/107 (27.10%) 46	14/108 (12.96%) 15	10/108 (9.26%) 12	24/216 (11.11%) 27
Pain ^†^A # participants affected / at risk # events	5/107 (4.67%) 6	12/108 (11.11%) 18	12/108 (11.11%) 13	24/216 (11.11%) 31
Gait disturbance ^†^A # participants affected / at risk # events	13/107 (12.15%) 24	6/108 (5.56%) 7	4/108 (3.70%) 4	10/216 (4.63%) 11
Injection site erythema ^†^A # participants affected / at risk # events	28/107 (26.17%) 30	0/108 (0.00%) 0	1/108 (0.93%) 1	1/216 (0.46%) 1
Injection site pain ^†^A # participants affected / at risk # events	13/107 (12.15%) 14	1/108 (0.93%) 1	0/108 (0.00%) 0	1/216 (0.46%) 1
Injection site reaction ^†^A # participants affected / at risk # events	26/107 (24.30%) 32	1/108 (0.93%) 2	0/108 (0.00%) 0	1/216 (0.46%) 2
Infections and infestations
Upper respiratory tract infection ^†^A # participants affected / at risk # events	8/107 (7.48%) 13	17/108 (15.74%) 30	24/108 (22.22%) 35	41/216 (18.98%) 65
Nasopharyngitis ^†^A # participants affected / at risk # events	11/107 (10.28%) 19	14/108 (12.96%) 24	20/108 (18.52%) 29	34/216 (15.74%) 53
Sinusitis ^†^A # participants affected / at risk # events	7/107 (6.54%) 11	13/108 (12.04%) 26	14/108 (12.96%) 19	27/216 (12.50%) 45
Urinary tract infection ^†^A # participants affected / at risk # events	12/107 (11.21%) 16	7/108 (6.48%) 9	15/108 (13.89%) 26	22/216 (10.19%) 35
Injury, poisoning and procedural complications
Contusion ^†^A # participants affected / at risk # events	3/107 (2.80%) 3	4/108 (3.70%) 4	13/108 (12.04%) 20	17/216 (7.87%) 24
Investigations
Weight increased ^†^A # participants affected / at risk # events	7/107 (6.54%) 7	8/108 (7.41%) 8	11/108 (10.19%) 12	19/216 (8.80%) 20
Body temperature increased ^†^A # participants affected / at risk # events	0/107 (0.00%) 0	4/108 (3.70%) 5	11/108 (10.19%) 14	15/216 (6.94%) 19
Musculoskeletal and connective tissue disorders
Pain in extremity ^†^A # participants affected / at risk # events	14/107 (13.08%) 21	23/108 (21.30%) 37	29/108 (26.85%) 44	52/216 (24.07%) 81
Muscle spasms ^†^A # participants affected / at risk # events	10/107 (9.35%) 13	17/108 (15.74%) 25	18/108 (16.67%) 26	35/216 (16.20%) 51
Back pain ^†^A # participants affected / at risk # events	10/107 (9.35%) 12	14/108 (12.96%) 23	19/108 (17.59%) 25	33/216 (15.28%) 48
Arthralgia ^†^A # participants affected / at risk # events	11/107 (10.28%) 15	18/108 (16.67%) 31	10/108 (9.26%) 12	28/216 (12.96%) 43
Muscular weakness ^†^A # participants affected / at risk # events	27/107 (25.23%) 46	12/108 (11.11%) 26	16/108 (14.81%) 24	28/216 (12.96%) 50
Myalgia ^†^A # participants affected / at risk # events	8/107 (7.48%) 8	10/108 (9.26%) 13	12/108 (11.11%) 12	22/216 (10.19%) 25
Nervous system disorders
Headache ^†^A # participants affected / at risk # events	27/107 (25.23%) 39	66/108 (61.11%) 146	82/108 (75.93%) 164	148/216 (68.52%) 310
Paraesthesia ^†^A # participants affected / at risk # events	18/107 (16.82%) 28	36/108 (33.33%) 59	17/108 (15.74%) 25	53/216 (24.54%) 84
Hypoaesthesia ^†^A # participants affected / at risk # events	21/107 (19.63%) 37	27/108 (25.00%) 64	19/108 (17.59%) 28	46/216 (21.30%) 92
Dizziness ^†^A # participants affected / at risk # events	11/107 (10.28%) 14	11/108 (10.19%) 13	26/108 (24.07%) 29	37/216 (17.13%) 42
Dysgeusia ^†^A # participants affected / at risk # events	22/107 (20.56%) 49	18/108 (16.67%) 52	19/108 (17.59%) 54	37/216 (17.13%) 106
Multiple sclerosis relapse ^†^A # participants affected / at risk # events	24/107 (22.43%) 51	20/108 (18.52%) 30	9/108 (8.33%) 15	29/216 (13.43%) 45
Multiple sclerosis ^†^A # participants affected / at risk # events	11/107 (10.28%) 14	6/108 (5.56%) 6	7/108 (6.48%) 7	13/216 (6.02%) 13
Coordination abnormal ^†^A # participants affected / at risk # events	12/107 (11.21%) 13	5/108 (4.63%) 6	1/108 (0.93%) 1	6/216 (2.78%) 7
Psychiatric disorders
Insomnia ^†^A # participants affected / at risk # events	16/107 (14.95%) 20	32/108 (29.63%) 44	24/108 (22.22%) 33	56/216 (25.93%) 77
Depression ^†^A # participants affected / at risk # events	19/107 (17.76%) 24	14/108 (12.96%) 16	17/108 (15.74%) 18	31/216 (14.35%) 34
Anxiety ^†^A # participants affected / at risk # events	10/107 (9.35%) 13	11/108 (10.19%) 14	17/108 (15.74%) 22	28/216 (12.96%) 36
Respiratory, thoracic and mediastinal disorders
Dyspnoea ^†^A # participants affected / at risk # events	3/107 (2.80%) 3	17/108 (15.74%) 23	16/108 (14.81%) 20	33/216 (15.28%) 43
Pharyngolaryngeal pain ^†^A # participants affected / at risk # events	3/107 (2.80%) 6	15/108 (13.89%) 20	12/108 (11.11%) 14	27/216 (12.50%) 34
Cough ^†^A # participants affected / at risk # events	4/107 (3.74%) 4	10/108 (9.26%) 11	11/108 (10.19%) 13	21/216 (9.72%) 24
Skin and subcutaneous tissue disorders
Rash ^†^A # participants affected / at risk # events	7/107 (6.54%) 8	79/108 (73.15%) 158	80/108 (74.07%) 188	159/216 (73.61%) 346
Urticaria ^†^A # participants affected / at risk # events	2/107 (1.87%) 2	28/108 (25.93%) 46	37/108 (34.26%) 78	65/216 (30.09%) 124
Pruritus ^†^A # participants affected / at risk # events	4/107 (3.74%) 4	32/108 (29.63%) 55	27/108 (25.00%) 42	59/216 (27.31%) 97
Rash generalised ^†^A # participants affected / at risk # events	0/107 (0.00%) 0	12/108 (11.11%) 23	6/108 (5.56%) 10	18/216 (8.33%) 33

^†	Indicates events were collected by systematic assessment.
^A	Term from vocabulary, MedDRA

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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