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

This study has been completed.
Sponsor:
Collaborator:
Bayer
Information provided by (Responsible Party):
Sanofi ( Genzyme, a Sanofi Company )
ClinicalTrials.gov Identifier:
NCT00050778
First received: December 19, 2002
Last updated: January 6, 2015
Last verified: January 2015
  Purpose

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 Intervention Phase
Multiple Sclerosis, Relapsing-Remitting
Biological: Interferon beta-1a
Biological: Alemtuzumab 12 mg
Biological: Alemtuzumab 24 mg
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Single Blind (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

Resource links provided by NLM:


Further study details as provided by Sanofi:

Primary Outcome Measures:
  • Probability of Participants With Sustained Accumulation of Disability (SAD) [ Time Frame: Up to 3 years ] [ Designated as safety issue: No ]
    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.

  • Annualized Relapse Rate [ Time Frame: Up to 3 years ] [ Designated as safety issue: No ]
    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:
  • Probability of Participants Who Were Relapse Free at 3 Years After Initial Treatment [ Time Frame: Year 3 ] [ Designated as safety issue: No ]
    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 T1 Cerebral Volume at Year 3 [ Time Frame: Baseline, Year 3 ] [ Designated as safety issue: No ]
    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]).

  • Percent Change From Baseline in MRI T2 Lesion Volume at Year 3 [ Time Frame: Baseline, Year 3 ] [ Designated as safety issue: No ]
    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]).


Enrollment: 334
Study Start Date: December 2002
Study Completion Date: January 2010
Primary Completion Date: September 2007 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Active Comparator: Interferon Beta-1a Biological: Interferon beta-1a
Interferon beta-1a 44 microgram (mcg) subcutaneously 3-times weekly for 36 months.
Other Name: 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 Name: 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 Name: Lemtrada

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
  Eligibility

Ages Eligible for Study:   18 Years to 50 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

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
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00050778

  Show 49 Study Locations
Sponsors and Collaborators
Genzyme, a Sanofi Company
Bayer
Investigators
Study Director: Medical Monitor Genzyme, a Sanofi Company
  More Information

Additional Information:
Publications:

Responsible Party: Sanofi ( Genzyme, a Sanofi Company )
ClinicalTrials.gov Identifier: NCT00050778     History of Changes
Other Study ID Numbers: CAMMS223
Study First Received: December 19, 2002
Results First Received: November 3, 2008
Last Updated: January 6, 2015
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 of the Russian Federation

Keywords provided by Sanofi:
Multiple Sclerosis
Active Relapsing-Remitting Multiple Sclerosis

Additional relevant MeSH terms:
Multiple Sclerosis, Relapsing-Remitting
Multiple Sclerosis
Sclerosis
Autoimmune Diseases
Autoimmune Diseases of the Nervous System
Demyelinating Autoimmune Diseases, CNS
Demyelinating Diseases
Immune System Diseases
Nervous System Diseases
Pathologic Processes
Alemtuzumab
Interferon beta 1a
Interferon-beta
Interferons
Adjuvants, Immunologic
Anti-Infective Agents
Antineoplastic Agents
Antiviral Agents
Immunologic Factors
Pharmacologic Actions
Physiological Effects of Drugs
Therapeutic Uses

ClinicalTrials.gov processed this record on May 29, 2015