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

• 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: Genzyme, a Sanofi Company
• Collaborator: Bayer
• Information provided by (Responsible Party): Sanofi ( Genzyme, a Sanofi Company )

Tracking Information

• First Submitted Date: December 19, 2002
• First Posted Date: December 23, 2002
• Results First Submitted Date: November 3, 2008
• Results First Posted Date: August 25, 2009
• Last Update Posted Date: January 8, 2015
• Study Start Date: December 2002
• Actual Primary Completion Date: September 2007 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (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: Not Provided

Current Secondary Outcome Measures (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: Not Provided
• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: 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: 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: Interventional
• Study Phase: Phase 2
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Single (Outcomes Assessor); Primary Purpose: Treatment
• Condition: Multiple Sclerosis, Relapsing-Remitting

Intervention

• 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

• 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 *

• 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. doi: 10.1007/s00415-005-0934-5. Epub 2005 Jul 27.
• 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. doi: 10.1056/NEJMoa0802670.
• Daniels GH, Vladic A, Brinar V, Zavalishin I, Valente W, Oyuela P, Palmer J, Margolin DH, Hollenstein J. Alemtuzumab-related thyroid dysfunction in a phase 2 trial of patients with relapsing-remitting multiple sclerosis. J Clin Endocrinol Metab. 2014 Jan;99(1):80-9. doi: 10.1210/jc.2013-2201. Epub 2013 Dec 20.
• Graves J, Galetta SL, Palmer J, Margolin DH, Rizzo M, Bilbruck J, Balcer LJ. Alemtuzumab improves contrast sensitivity in patients with relapsing-remitting multiple sclerosis. Mult Scler. 2013 Sep;19(10):1302-9. doi: 10.1177/1352458513475722. Epub 2013 Mar 4.
• Coles AJ, Fox E, Vladic A, Gazda SK, Brinar V, Selmaj KW, Skoromets A, Stolyarov I, Bass A, Sullivan H, Margolin DH, Lake SL, Moran S, Palmer J, Smith MS, Compston DA. Alemtuzumab more effective than interferon beta-1a at 5-year follow-up of CAMMS223 clinical trial. Neurology. 2012 Apr 3;78(14):1069-78. doi: 10.1212/WNL.0b013e31824e8ee7. Epub 2012 Mar 21.
• Coles AJ, Fox E, Vladic A, Gazda SK, Brinar V, Selmaj KW, Bass AD, Wynn DR, Margolin DH, Lake SL, Moran S, Palmer J, Smith MS, Compston DA. Alemtuzumab versus interferon beta-1a in early relapsing-remitting multiple sclerosis: post-hoc and subset analyses of clinical efficacy outcomes. Lancet Neurol. 2011 Apr;10(4):338-48. doi: 10.1016/S1474-4422(11)70020-5.
• Jones JL, Anderson JM, Phuah CL, Fox EJ, Selmaj K, Margolin D, Lake SL, Palmer J, Thompson SJ, Wilkins A, Webber DJ, Compston DA, Coles AJ. Improvement in disability after alemtuzumab treatment of multiple sclerosis is associated with neuroprotective autoimmunity. Brain. 2010 Aug;133(Pt 8):2232-47. doi: 10.1093/brain/awq176. Epub 2010 Jul 21.
• Cuker A, Coles AJ, Sullivan H, Fox E, Goldberg M, Oyuela P, Purvis A, Beardsley DS, Margolin DH. A distinctive form of immune thrombocytopenia in a phase 2 study of alemtuzumab for the treatment of relapsing-remitting multiple sclerosis. Blood. 2011 Dec 8;118(24):6299-305. doi: 10.1182/blood-2011-08-371138. Epub 2011 Sep 29.
• Coles AJ, Jones JL, Vermersch P, Traboulsee A, Bass AD, Boster A, Chan A, Comi G, Fernandez O, Giovannoni G, Kubala Havrdova E, LaGanke C, Montalban X, Oreja-Guevara C, Piehl F, Wiendl H, Ziemssen T. Autoimmunity and long-term safety and efficacy of alemtuzumab for multiple sclerosis: Benefit/risk following review of trial and post-marketing data. Mult Scler. 2022 Apr;28(5):842-846. doi: 10.1177/13524585211061335. Epub 2021 Dec 9.
• Li Z, Richards S, Surks HK, Jacobs A, Panzara MA. Clinical pharmacology of alemtuzumab, an anti-CD52 immunomodulator, in multiple sclerosis. Clin Exp Immunol. 2018 Dec;194(3):295-314. doi: 10.1111/cei.13208. Epub 2018 Oct 1.
• Fox EJ, Wynn D, Coles AJ, Palmer J, Margolin DH; CAMMS223 Investigators. Alemtuzumab improves neurological functional systems in treatment-naive relapsing-remitting multiple sclerosis patients. J Neurol Sci. 2016 Apr 15;363:188-94. doi: 10.1016/j.jns.2016.02.025. Epub 2016 Feb 12.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: September 14, 2005): 334
• Original Enrollment (submitted: June 23, 2005): 180
• Actual Study Completion Date: January 2010
• Actual Primary Completion Date: September 2007 (Final data collection date for primary outcome measure)

Eligibility 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

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years to 50 Years (Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Croatia, Poland, Russian Federation, United Kingdom, United States

Administrative Information

• NCT Number: NCT00050778
• Other Study ID Numbers: CAMMS223
• Has Data Monitoring Committee: Yes
• U.S. FDA-regulated Product: Not Provided
• IPD Sharing Statement: Not Provided
• Current Responsible Party: Sanofi ( Genzyme, a Sanofi Company )
• Original Responsible Party: Not Provided
• Current Study Sponsor: Genzyme, a Sanofi Company
• Original Study Sponsor: Same as current
• Collaborators: Bayer

Investigators

• Study Director: Medical Monitor; Genzyme, a Sanofi Company

• PRS Account: Sanofi
• Verification Date: January 2015