Clinical trial NCT00050778: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Multiple Sclerosis, Relapsing-Remitting
Keywords: Multiple Sclerosis
Active Relapsing-Remitting Multiple Sclerosis
Lead sponsor: Sanofi
Sponsor class: INDUSTRY
Collaborators: name: Bayer
First posted: 2002-12-23
Enrollment: 334
Sex: ALL
Minimum age (years): 18
Maximum age (years): 50
Standard ages: ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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

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

Primary outcomes:
measure: Probability of Participants With Sustained Accumulation of Disability (SAD)
timeFrame: Up to 3 years
measure: Annualized Relapse Rate
timeFrame: Up to 3 years
Secondary outcomes:
measure: Probability of Participants Who Were Relapse Free at 3 Years After Initial Treatment
timeFrame: Year 3
measure: Percent Change From Baseline in T1 Cerebral Volume at Year 3
timeFrame: Baseline, Year 3
measure: Percent Change From Baseline in MRI T2 Lesion Volume at Year 3
timeFrame: Baseline, Year 3
Other outcomes:
Locations:
city: Scottsdale
country: United States
facility: Mayo Clinic Scottsdale Arizona
state: Arizona
city: Little Rock
country: United States
facility: Clinical Trials, Inc
state: Arkansas
city: Berkeley
country: United States
facility: East Bay Physicians Medical Group
state: California
city: Irvine
country: United States
facility: Nerve Pro Research
state: California
city: Pasadena
country: United States
facility: Neuro-Therapeutics, Inc.
state: California
city: Walnut Creek
country: United States
facility: Neurological Research Institute of the East Bay
state: California
city: Denver
country: United States
facility: Neurologic Research Institute/Mile High Research Center
state: Colorado
city: Orlando
country: United States
facility: Neurological Service of Orlando
state: Florida
city: Pompano Beach
country: United States
facility: Neurological Associates/ Research Dept.
state: Florida
city: Sunrise
country: United States
facility: Neurology Clinical Research, Inc.
state: Florida
city: Tampa
country: United States
facility: Axiom Clinical Research of Florida
state: Florida
city: Columbus
country: United States
facility: Medical Research and Health Education
state: Georgia
city: Northbrook
country: United States
facility: Consultants in Neurology, Ltd
state: Illinois
city: Fort Wayne
country: United States
facility: Fort Wayne Neurological Center
state: Indiana
city: Lexington
country: United States
facility: Associate in Neurology
state: Kentucky
city: Baltimore
country: United States
facility: University of Maryland -Maryland Center for MS
state: Maryland
city: Detroit
country: United States
facility: Wayne State University Department of Neurology
state: Michigan
city: Farmington Hills
country: United States
facility: Michigan Institute for Neurological Disorders
state: Michigan
city: Grand Rapids
country: United States
facility: Michigan Medical P.C. Neurology
state: Michigan
city: Rochester
country: United States
facility: Mayo Clinic Rochester Department of Neurology
state: Minnesota
city: Las Vegas
country: United States
facility: Nevada Neurological Consultants, Ltd.
state: Nevada
city: Stony Brook
country: United States
facility: University Hospital an Medical Center
state: New York
city: Winston-Salem
country: United States
facility: ALL-Trials Clinical Research, LLC
state: North Carolina
city: Tulsa
country: United States
facility: Neurological Associates of Tulsa, Inc
state: Oklahoma
city: Allentown
country: United States
facility: Neurosciencies and Pain Research
state: Pennsylvania
city: Knoxville
country: United States
facility: Neurology, PC
state: Tennessee
city: Houston
country: United States
facility: Baylor College of Medicine
state: Texas
city: Richardson
country: United States
facility: Dallas Neurological Associate
state: Texas
city: Round Rock
country: United States
facility: Central Texas Neurology Consultants PA
state: Texas
city: San Antonio
country: United States
facility: Integra Clinical Research, LLC
state: Texas
city: San Antonio
country: United States
facility: Neurology Center of San Antonio
state: Texas
city: Osijek
country: Croatia
facility: Department of Neurology, University Hospital "Osijek"
city: Rijeka
country: Croatia
facility: Department of Neurology, Clinical Hospital Centre "Rijeka"
city: Zagreb
country: Croatia
facility: Department of Neurology, Clinical Hospital Centre "Zagreb"
city: Zagreb
country: Croatia
facility: Department of Neurology, General Hospital "Sveti Duh"
city: Zagreb
country: Croatia
facility: Department of Neurology, University Hopsital "Sestre Milosrdnice"
city: Krakow
country: Poland
facility: Centrum Neurologii Klinicznej
city: Lodz
country: Poland
facility: Samodzielny Publiczny Zakład Opieki Zdrowotnej
city: Lublin
country: Poland
facility: Klinika Neurologii
city: Poznan
country: Poland
facility: Oddzial Kliniczny Neurologii
city: Warszawa
country: Poland
facility: Instytut Psychiatrii i Neurologii
city: Warszawa
country: Poland
facility: Katedra i Klinika Neurologii
city: Moscow
country: Russian Federation
facility: Russian State Medical University
city: Moscow
country: Russian Federation
facility: Neurology Scientific Center RAMS
city: Moscow
country: Russian Federation
facility: Moscow City Hospital #11
city: Moscow
country: Russian Federation
facility: Moscow City Hospital #61
city: St. Petersburg
country: Russian Federation
facility: Institute of Human brain RAS
city: St. Petersburg
country: Russian Federation
facility: St. Petersburg State Pavlov Medical University
city: Cambridge
country: United Kingdom
facility: Addenbrooke's Hospital
state: England
Study officials:
affiliation: Genzyme, a Sanofi Company
name: Medical Monitor
role: STUDY_DIRECTOR
References:
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.