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

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ClinicalTrials.gov Identifier: NCT00050778
Recruitment Status : Completed
First Posted : December 23, 2002
Results First Posted : August 25, 2009
Last Update Posted : January 8, 2015
Sponsor:
Collaborator:
Bayer
Information provided by (Responsible Party):
Sanofi ( Genzyme, a Sanofi Company )

Tracking Information
First Submitted Date  ICMJE December 19, 2002
First Posted Date  ICMJE December 23, 2002
Results First Submitted Date  ICMJE November 3, 2008
Results First Posted Date  ICMJE August 25, 2009
Last Update Posted Date January 8, 2015
Study Start Date  ICMJE December 2002
Actual Primary Completion Date September 2007   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: January 6, 2015)
  • Probability of Participants With Sustained Accumulation of Disability (SAD) [ Time Frame: 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.
  • Annualized Relapse Rate [ Time Frame: 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.
Original Primary Outcome Measures  ICMJE Not Provided
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: January 6, 2015)
  • Probability of Participants Who Were Relapse Free at 3 Years After Initial Treatment [ Time Frame: 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 T1 Cerebral Volume at Year 3 [ Time Frame: 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]).
  • Percent Change From Baseline in MRI T2 Lesion Volume at Year 3 [ Time Frame: 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]).
Original Secondary Outcome Measures  ICMJE Not Provided
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE A Phase II Study Comparing Low- and High-Dose Alemtuzumab and High-Dose Rebif® in Patients With Early, Active Relapsing-Remitting Multiple Sclerosis
Official Title  ICMJE 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
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
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single (Outcomes Assessor)
Primary Purpose: Treatment
Condition  ICMJE Multiple Sclerosis, Relapsing-Remitting
Intervention  ICMJE
  • Biological: Interferon beta-1a
    Interferon beta-1a 44 microgram (mcg) subcutaneously 3-times weekly for 36 months.
    Other Name: Rebif®
  • 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
  • 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
Study Arms  ICMJE
  • Active Comparator: Interferon Beta-1a
    Intervention: Biological: Interferon beta-1a
  • Experimental: Alemtuzumab 12 mg
    Intervention: Biological: Alemtuzumab 12 mg
  • Experimental: Alemtuzumab 24 mg
    Intervention: Biological: Alemtuzumab 24 mg
Publications *

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: September 14, 2005)
334
Original Enrollment  ICMJE
 (submitted: June 23, 2005)
180
Actual Study Completion Date  ICMJE January 2010
Actual Primary Completion Date September 2007   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years to 50 Years   (Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Croatia,   Poland,   Russian Federation,   United Kingdom,   United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT00050778
Other Study ID Numbers  ICMJE CAMMS223
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Sanofi ( Genzyme, a Sanofi Company )
Study Sponsor  ICMJE Genzyme, a Sanofi Company
Collaborators  ICMJE Bayer
Investigators  ICMJE
Study Director: Medical Monitor Genzyme, a Sanofi Company
PRS Account Sanofi
Verification Date January 2015

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP