A Phase II Study Comparing Low- and High-Dose Alemtuzumab and High-Dose Rebif® in Patients With Early, Active Relapsing-Remitting Multiple Sclerosis
- Conditions
- Multiple Sclerosis, Relapsing-Remitting
- Interventions
- Biological: Alemtuzumab 12 mgBiological: Interferon beta-1aBiological: Alemtuzumab 24 mg
- Registration Number
- NCT00050778
- Lead Sponsor
- Genzyme, a Sanofi Company
- 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.
- 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
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 334
- 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)
- 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
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Alemtuzumab 12 mg Alemtuzumab 12 mg - Interferon Beta-1a Interferon beta-1a - Alemtuzumab 24 mg Alemtuzumab 24 mg -
- Primary Outcome Measures
Name Time Method 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.
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.
- Secondary Outcome Measures
Name Time Method 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 \[brain volume at Baseline\]).
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.
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 \[lesion volume at Baseline\]).
Trial Locations
- Locations (49)
Neurology Scientific Center RAMS
🇷🇺Moscow, Russian Federation
Katedra i Klinika Neurologii
🇵🇱Warszawa, Poland
Department of Neurology, Clinical Hospital Centre "Rijeka"
🇭🇷Rijeka, Croatia
Department of Neurology, Clinical Hospital Centre "Zagreb"
🇭🇷Zagreb, Croatia
Department of Neurology, General Hospital "Sveti Duh"
🇭🇷Zagreb, Croatia
Instytut Psychiatrii i Neurologii
🇵🇱Warszawa, Poland
Department of Neurology, University Hospital "Osijek"
🇭🇷Osijek, Croatia
Moscow City Hospital #11
🇷🇺Moscow, Russian Federation
Centrum Neurologii Klinicznej
🇵🇱Krakow, Poland
Department of Neurology, University Hopsital "Sestre Milosrdnice"
🇭🇷Zagreb, Croatia
Russian State Medical University
🇷🇺Moscow, Russian Federation
Samodzielny Publiczny Zakład Opieki Zdrowotnej
🇵🇱Lodz, Poland
Oddzial Kliniczny Neurologii
🇵🇱Poznan, Poland
Baylor College of Medicine
🇺🇸Houston, Texas, United States
Integra Clinical Research, LLC
🇺🇸San Antonio, Texas, United States
Neurology Center of San Antonio
🇺🇸San Antonio, Texas, United States
Moscow City Hospital #61
🇷🇺Moscow, Russian Federation
Addenbrooke's Hospital
🇬🇧Cambridge, England, United Kingdom
Klinika Neurologii
🇵🇱Lublin, Poland
Institute of Human brain RAS
🇷🇺St. Petersburg, Russian Federation
St. Petersburg State Pavlov Medical University
🇷🇺St. Petersburg, Russian Federation
Mayo Clinic Scottsdale Arizona
🇺🇸Scottsdale, Arizona, United States
Clinical Trials, Inc
🇺🇸Little Rock, Arkansas, United States
Nerve Pro Research
🇺🇸Irvine, California, United States
East Bay Physicians Medical Group
🇺🇸Berkeley, California, United States
Neuro-Therapeutics, Inc.
🇺🇸Pasadena, California, United States
Neurological Research Institute of the East Bay
🇺🇸Walnut Creek, California, United States
Neurological Associates/ Research Dept.
🇺🇸Pompano Beach, Florida, United States
Neurology Clinical Research, Inc.
🇺🇸Sunrise, Florida, United States
Medical Research and Health Education
🇺🇸Columbus, Georgia, United States
Consultants in Neurology, Ltd
🇺🇸Northbrook, Illinois, United States
Fort Wayne Neurological Center
🇺🇸Fort Wayne, Indiana, United States
Associate in Neurology
🇺🇸Lexington, Kentucky, United States
University of Maryland -Maryland Center for MS
🇺🇸Baltimore, Maryland, United States
Michigan Institute for Neurological Disorders
🇺🇸Farmington Hills, Michigan, United States
Michigan Medical P.C. Neurology
🇺🇸Grand Rapids, Michigan, United States
Nevada Neurological Consultants, Ltd.
🇺🇸Las Vegas, Nevada, United States
University Hospital an Medical Center
🇺🇸Stony Brook, New York, United States
Neurological Associates of Tulsa, Inc
🇺🇸Tulsa, Oklahoma, United States
Neurosciencies and Pain Research
🇺🇸Allentown, Pennsylvania, United States
Neurology, PC
🇺🇸Knoxville, Tennessee, United States
Dallas Neurological Associate
🇺🇸Richardson, Texas, United States
Central Texas Neurology Consultants PA
🇺🇸Round Rock, Texas, United States
Neurologic Research Institute/Mile High Research Center
🇺🇸Denver, Colorado, United States
Axiom Clinical Research of Florida
🇺🇸Tampa, Florida, United States
Neurological Service of Orlando
🇺🇸Orlando, Florida, United States
Wayne State University Department of Neurology
🇺🇸Detroit, Michigan, United States
Mayo Clinic Rochester Department of Neurology
🇺🇸Rochester, Minnesota, United States
ALL-Trials Clinical Research, LLC
🇺🇸Winston-Salem, North Carolina, United States