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

NCT ID: NCT00050778

Last Updated: 2015-01-08

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE2
• Total Enrollment: 334 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2002-12-31
• Study Completion Date: 2010-01-31

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

Conditions

Multiple Sclerosis, Relapsing-Remitting

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: SINGLE

Study Groups

Interferon Beta-1a

Group Type: ACTIVE_COMPARATOR

Interferon beta-1a

Intervention Type: BIOLOGICAL

Interferon beta-1a 44 microgram (mcg) subcutaneously 3-times weekly for 36 months.

Alemtuzumab 12 mg

Group Type: EXPERIMENTAL

Alemtuzumab 12 mg

Intervention Type: BIOLOGICAL

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).

Alemtuzumab 24 mg

Group Type: EXPERIMENTAL

Alemtuzumab 24 mg

Intervention Type: BIOLOGICAL

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).

Interventions

Interferon beta-1a

Interferon beta-1a 44 microgram (mcg) subcutaneously 3-times weekly for 36 months.

Intervention Type: 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).

Intervention Type: 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).

Intervention Type: BIOLOGICAL

Other Intervention Names

Rebif®; Lemtrada; Lemtrada

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

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 50 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Bayer

INDUSTRY

Sponsor Role: collaborator

Genzyme, a Sanofi Company

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Medical Monitor

Role: STUDY_DIRECTOR

Genzyme, a Sanofi Company

Locations

Mayo Clinic Scottsdale Arizona

Scottsdale, Arizona, United States

Clinical Trials, Inc

Little Rock, Arkansas, United States

East Bay Physicians Medical Group

Berkeley, California, United States

Nerve Pro Research

Irvine, California, United States

Neuro-Therapeutics, Inc.

Pasadena, California, United States

Neurological Research Institute of the East Bay

Walnut Creek, California, United States

Neurologic Research Institute/Mile High Research Center

Denver, Colorado, United States

Neurological Service of Orlando

Orlando, Florida, United States

Neurological Associates/ Research Dept.

Pompano Beach, Florida, United States

Neurology Clinical Research, Inc.

Sunrise, Florida, United States

Axiom Clinical Research of Florida

Tampa, 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

Wayne State University Department of Neurology

Detroit, Michigan, United States

Michigan Institute for Neurological Disorders

Farmington Hills, Michigan, United States

Michigan Medical P.C. Neurology

Grand Rapids, Michigan, United States

Mayo Clinic Rochester Department of Neurology

Rochester, Minnesota, United States

Nevada Neurological Consultants, Ltd.

Las Vegas, Nevada, United States

University Hospital an Medical Center

Stony Brook, New York, United States

ALL-Trials Clinical Research, LLC

Winston-Salem, North Carolina, 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

Baylor College of Medicine

Houston, Texas, United States

Dallas Neurological Associate

Richardson, Texas, United States

Central Texas Neurology Consultants PA

Round Rock, Texas, United States

Integra Clinical Research, LLC

San Antonio, Texas, United States

Neurology Center of San Antonio

San Antonio, Texas, United States

Department of Neurology, University Hospital "Osijek"

Osijek, , Croatia

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

Department of Neurology, University Hopsital "Sestre Milosrdnice"

Zagreb, , Croatia

Centrum Neurologii Klinicznej

Krakow, , Poland

Samodzielny Publiczny Zakład Opieki Zdrowotnej

Lodz, , Poland

Klinika Neurologii

Lublin, , Poland

Oddzial Kliniczny Neurologii

Poznan, , Poland

Instytut Psychiatrii i Neurologii

Warsaw, , Poland

Katedra i Klinika Neurologii

Warsaw, , Poland

Russian State Medical University

Moscow, , Russia

Neurology Scientific Center RAMS

Moscow, , Russia

Moscow City Hospital #11

Moscow, , Russia

Moscow City Hospital #61

Moscow, , Russia

Institute of Human brain RAS

Saint Petersburg, , Russia

St. Petersburg State Pavlov Medical University

Saint Petersburg, , Russia

Addenbrooke's Hospital

Cambridge, England, United Kingdom

Countries

United States; Croatia; Poland; Russia; United Kingdom

References

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.

Reference Type: BACKGROUND

PMID: 16044212 (View on PubMed)

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.

Reference Type: RESULT

PMID: 18946064 (View on PubMed)

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.

Reference Type: RESULT

PMID: 24170099 (View on PubMed)

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.

Reference Type: RESULT

PMID: 23459567 (View on PubMed)

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.

Reference Type: RESULT

PMID: 22442431 (View on PubMed)

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.

Reference Type: RESULT

PMID: 21397567 (View on PubMed)

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.

Reference Type: RESULT

PMID: 20659956 (View on PubMed)

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.

Reference Type: RESULT

PMID: 21960587 (View on PubMed)

Riera R, Torloni MR, Martimbianco ALC, Pacheco RL. Alemtuzumab for multiple sclerosis. Cochrane Database Syst Rev. 2023 Jun 5;6(6):CD011203. doi: 10.1002/14651858.CD011203.pub3.

Reference Type: DERIVED

PMID: 37272540 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 34882037 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 30144037 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 27000249 (View on PubMed)

Other Identifiers

CAMMS223

Identifier Type: -

Identifier Source: org_study_id