Comparison of Alemtuzumab and Rebif® Efficacy in Multiple Sclerosis, Study One

Multiple Sclerosis, Relapsing-Remitting Clinical Trial

— CARE-MS I  

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00530348
• Other study ID #: CAMMS323
• Secondary ID: ISRCTN21534255AC
• Status: Completed
• Phase: Phase 3
• First received: September 13, 2007
• Last updated: November 17, 2014
• Start date: August 2007
• Est. completion date: April 2011

Study information

• Verified date: November 2014
• Source: Sanofi
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Food and Drug AdministrationBrazil: National Health Surveillance AgencyArgentina: Administracion Nacional de Medicamentos, Alimentos y Tecnologia MedicaAustralia: Department of Health and Ageing Therapeutic Goods AdministrationCanada: Health CanadaCroatia: Agency for Medicinal Product and Medical DevicesCzech Republic: State Institute for Drug ControlFrance: Afssaps - Agence française de sécurité sanitaire des produits de santé (Saint-Denis)Germany: Paul-Ehrlich-InstitutMexico: Federal Commission for Protection Against Health RisksPoland: Office for Registration of Medicinal Products, Medical Devices and Biocidal ProductsRussia: Ministry of Health of the Russian FederationSerbia and Montenegro: Agency for Drugs and Medicinal DevicesSweden: Medical Products AgencyUkraine: State Pharmacological Center - Ministry of HealthUnited Kingdom: Medicines and Healthcare Products Regulatory Agency
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 581
• Est. completion date: April 2011
• Est. primary completion date: April 2011
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years to 50 Years

Eligibility

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

Study Design

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Single Blind (Outcomes Assessor), Primary Purpose: Treatment

Related Conditions & MeSH terms

• Multiple Sclerosis
• Multiple Sclerosis, Relapsing-Remitting
• Sclerosis

Intervention

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.
• 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.

Locations

Country	Name	City	State
Argentina	DIABAID	Buenos Aires
Australia	The Wesley Research Institute	Auchenflower	Queensland
Australia	Concord Repatriation General Hospital	Concord
Australia	St Vincent's Hospital	Fitzroy	Victoria
Australia	Austin Health	Heidelberg	Victoria
Australia	Royal Hobart Hospital	Hobart	Tasmania
Australia	Royal Melbourne Hospital, Department of Neurology, Ward 4 East	Parkville	Victoria
Australia	Griffith University School of Medicine	Southport	Queensland
Australia	Westmead Hospital	Westmead
Australia	The Queen Elizabeth Hospital	Woodville South	South Australia
Brazil	Hospital Sao Lucas PUC-RS	Porto Alegre	RS
Brazil	Hospital da Restauracao, Av Governador Agamenon Magalhaes	Recife	Pernambuco
Brazil	Hospital de Clínicas USP	Sao Paulo	SP
Canada	University of Calgary and Foothills Medical Cenre	Calgary	Alberta
Canada	Clinique Nuero-outaouais	Gatineau	Quebec
Canada	Clinique Neuro rive-sud, Recherche Sepmus, Inc.	Greenfield park	Quebec
Canada	The Ottawa Hospital, General Campus	Ottawa	Ontario
Canada	UBC Hospital	Vancouver	British Columbia
Croatia	Clinical Hospital Centre Rijeka	Rijeka
Croatia	General Hospital Varazdin	Varazdin
Croatia	Clinical Hospital Centre "Sestre Milosrdnice"	Zagreb
Croatia	Clinical Hospital Centre Zagreb	Zagreb
Croatia	General Hospital "Sveti Duh"	Zagreb
Czech Republic	Department of Neurology, 1st Faculty of Medicine and General Teaching Hospital	Praha 2
Czech Republic	Krajska zdravotni a.s., Hospital Teplice	Teplice
France	Hopital Purpan	Toulouse
Germany	Judisches Krankenhaus Berlin	Berlin
Germany	Universitätsklinik Carl Gustav Carus Dresden	Dresden
Germany	Klinikum der Goethe Universität Frankfurt	Frankfurt
Germany	Medizinische Hochschule Hannover	Hannover
Germany	Oberhavelkliniken Hennigsdorf	Hennigsdorf
Germany	Asklepios Klinikum Brandenburg	Teupitz
Mexico	Hospital Angeles del Pedregal, Camino de Santa Teresa	Mexico City
Mexico	Hospital Medica Sur CIF-BIOTEC	Mexico City
Poland	Clinical Neurology Centre Sp. z o.o. (Ltd)	Cracow
Poland	Independent Public Healthcare Facility, Norbert Barlicki University Hospital No. 1 of the Medical University of Lodz	Lodz
Poland	Independent Public Teaching Hospital No. 4 in Lublin	Lublin
Poland	Heliodor Swiecicki Teaching Hospital of the Poznan University of Medical Sciences	Poznan
Russian Federation	Research Medical Complex "Your Health" Ltd	Kazan
Russian Federation	Moscow City Hospital #11	Moscow
Russian Federation	Moscow State Medical Institution City Clinical Hospital #11	Moscow
Russian Federation	Scientific Neurology Center RAMS	Moscow
Russian Federation	Municipal City Hospital #33	Nizhniy Novgorod
Russian Federation	Federal State Institution Siberian Rettitorial Medical Center under Federal Medical-Biological Agency of Russia	Novosibirsk
Russian Federation	City Clinical Hospital #2	Pyatigorsk
Russian Federation	Samara Regional Clinical Hospital n.a. Kalinin	Samara
Russian Federation	Institute of Human Brain RAS	St. Petersburg
Russian Federation	Nikolaevskaya Hospital	St. Petersburg
Russian Federation	St. Petersburg Pavlov State Medical University	St. Petersburg
Russian Federation	State Medical Institution: Republican Clinical Hospital n.a. G.G. Kuvatov	Ufa
Serbia	Clinical Centre Serbia, Institute for Neurology	Belgrade
Serbia	Military Medical Academy	Belgrade
Serbia	Clinical centre Kragujevac	Kragujevac
Serbia	Clinical Center Nis, Clinic for neurology	Nis
Serbia	Clinical Centre of Vojvodina, Clinic for neurology	Novi Sad
Sweden	Sahlgrenska University Hospital	Goteborg
Ukraine	Chernihiv Regional Hospital	Chernihiv
Ukraine	Institute of Neurology, Psychiatry and Narcology under the Academy of Medical Sciences of Ukraine, Department of Neuroinfection and Multiple Sclerosis	Kharkiv
Ukraine	Hospoital of the Directorate of the Medical Corps within the Ukrainian Security Service, Neurology Department	Kyiv
Ukraine	Kyiv Municipal Clinical Hospital #4	Kyiv
Ukraine	Danylo Halytsky Lviv National Medical University	Lviv
United Kingdom	Department Of Neurosciences, Addenbrookes Hospital	Cambridge	England
United Kingdom	University Hospital of Wales	Cardiff	Wales
United Kingdom	Centre for Neuroscience & Trauma, Blizard Institute of Cell and Molecular Science, Barts and The London School of Medicine and Dentistry	London	England
United Kingdom	Royal Hallamshire Hospital	Sheffield
United States	University of New Mexico, Health Sciences Center, MS Specialty Clinic	Albuquerque	New Mexico
United States	Lehigh Valley Hospital Neurosciences and Pain Research	Allentown	Pennsylvania
United States	University of Michigan Health System	Ann Arbor	Michigan
United States	Carolinas Medical Center (CMC), Neurosciences & Spine Institute (NSSI)	Charlotte	North Carolina
United States	The Ohio State University Medical Center, Multiple Sclerosis Center	Columbus	Ohio
United States	North Central Neurology Associates, P.C.	Cullman	Alabama
United States	Wayne State University	Detroit	Michigan
United States	Advanced Neurosciences Research	Fort Collins	Colorado
United States	Fort Wayne Neurological Center	Fort Wayne	Indiana
United States	Advanced Neurosciences Institute	Franklin	Tennessee
United States	Biomedical Research Alliance of NY, LLC	Franklin	Tennessee
United States	Baylor College of Medicine, Maxine Mesinger MS Clinic	Houston	Texas
United States	Idaho Falls Multiple Sclerosis Center, PLLC	Idaho Falls	Idaho
United States	University of Kansas Medical Center	Kansas City	Kansas
United States	Hope Neurology PC	Knoxville	Tennessee
United States	University of Nevada School of Medicine	Las Vegas	Nevada
United States	Empire Neurology	Latham	New York
United States	Dartmouth-Hitchcock Medical Center	Lebanon	New Hampshire
United States	MidAmerican Neuroscience Institute	Lenexa	Kansas
United States	Associates in Neurology, PSC	Lexington	Kentucky
United States	University of Louisville Research Foundation	Louisville	Kentucky
United States	Consultants in Neurology, Ltd.	Northbrook	Illinois
United States	MS Center of Oklahoma	Oklahoma City	Oklahoma
United States	Comprehensive Multiple Sclerosis Care Center at South Shore Neurologic Associates, P.C.	Patchogue	New York
United States	Barrow Neurological Institute, St. Joseph's Hospital & Medical Center	Phoenix	Arizona
United States	Neurological Associates	Pompano Beach	Florida
United States	University of Rochester Medical Center	Rochester	New York
United States	Central Texas Neurology	Round Rock	Texas
United States	Integra Clinical Research	San Antonio	Texas
United States	Neurology Center of San Antonio	San Antonio	Texas
United States	Mayo Clinic Arizona	Scottsdale	Arizona
United States	Louisiana State University Health Sciences Center	Shreveport	Louisiana
United States	Axiom Clinical Research of Florida	Tampa	Florida
United States	Northwest NeuroSpecialists, PLLC	Tucson	Arizona
United States	Oak Clinic for Multiple Sclerosis	Uniontown	Ohio
United States	UMass Memorial Medical Center	Worcester	Massachusetts

Sponsors (2)

Lead Sponsor	Collaborator
Genzyme, a Sanofi Company	Bayer

Countries where clinical trial is conducted

United States,  Argentina,  Australia,  Brazil,  Canada,  Croatia,  Czech Republic,  France,  Germany,  Mexico,  Poland,  Russian Federation,  Serbia,  Sweden,  Ukraine,  United Kingdom, 

References & Publications (1)

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. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Percentage of Participants With Sustained Accumulation of Disability (SAD)	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.	Up to 2 years	No
Primary	Annualized Relapse Rate	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.	Up to 2 years	No
Secondary	Percentage of Participants Who Were Relapse Free at 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.	Year 2	No
Secondary	Change From Baseline in Expanded Disability Status Scale (EDSS) Score at 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.	Baseline, Year 2	No
Secondary	Change From Baseline in Multiple Sclerosis Functional Composite (MSFC) Score at 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.	Baseline, Year 2	No
Secondary	Percent Change From Baseline in Magnetic Resonance Imaging Time Constant 2 (MRI-T2) Hyperintense Lesion Volume at 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).	Baseline, Year 2	No

External Links

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