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

Multiple Sclerosis, Relapsing-Remitting Clinical Trial

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00050778
• Other study ID #: CAMMS223
• Status: Completed
• Phase: Phase 2
• First received: December 19, 2002
• Last updated: January 6, 2015
• Start date: December 2002
• Est. completion date: January 2010

Study information

• Verified date: January 2015
• Source: Sanofi
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Food and Drug AdministrationUnited Kingdom: Medicines and Healthcare Products Regulatory AgencyCroatia: Ministry of Health and Social CarePoland: Office for Registration of Medicinal Products, Medical Devices and Biocidal ProductsRussia: Ministry of Health of the Russian Federation
• Study type: Interventional

Clinical Trial 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.

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

Recruitment information / eligibility

• Status: Completed
• Enrollment: 334
• Est. completion date: January 2010
• Est. primary completion date: September 2007
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years to 50 Years

Eligibility

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

Study Design

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Single Blind (Outcomes Assessor), Primary Purpose: Treatment

Related Conditions & MeSH terms

• Multiple Sclerosis
• Multiple Sclerosis, Relapsing-Remitting
• Sclerosis

Intervention

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

Locations

Country	Name	City	State
Croatia	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
Poland	Centrum Neurologii Klinicznej	Krakow
Poland	Samodzielny Publiczny Zaklad Opieki Zdrowotnej	Lodz
Poland	Klinika Neurologii	Lublin
Poland	Oddzial Kliniczny Neurologii	Poznan
Poland	Instytut Psychiatrii i Neurologii	Warszawa
Poland	Katedra i Klinika Neurologii	Warszawa
Russian Federation	Moscow City Hospital #11	Moscow
Russian Federation	Moscow City Hospital #61	Moscow
Russian Federation	Neurology Scientific Center RAMS	Moscow
Russian Federation	Russian State Medical University	Moscow
Russian Federation	Institute of Human brain RAS	St. Petersburg
Russian Federation	St. Petersburg State Pavlov Medical University	St. Petersburg
United Kingdom	Addenbrooke's Hospital	Cambridge	England
United States	Neurosciencies and Pain Research	Allentown	Pennsylvania
United States	University of Maryland -Maryland Center for MS	Baltimore	Maryland
United States	East Bay Physicians Medical Group	Berkeley	California
United States	Medical Research and Health Education	Columbus	Georgia
United States	Neurologic Research Institute/Mile High Research Center	Denver	Colorado
United States	Wayne State University Department of Neurology	Detroit	Michigan
United States	Michigan Institute for Neurological Disorders	Farmington Hills	Michigan
United States	Fort Wayne Neurological Center	Fort Wayne	Indiana
United States	Michigan Medical P.C. Neurology	Grand Rapids	Michigan
United States	Baylor College of Medicine	Houston	Texas
United States	Nerve Pro Research	Irvine	California
United States	Neurology, PC	Knoxville	Tennessee
United States	Nevada Neurological Consultants, Ltd.	Las Vegas	Nevada
United States	Associate in Neurology	Lexington	Kentucky
United States	Clinical Trials, Inc	Little Rock	Arkansas
United States	Consultants in Neurology, Ltd	Northbrook	Illinois
United States	Neurological Service of Orlando	Orlando	Florida
United States	Neuro-Therapeutics, Inc.	Pasadena	California
United States	Neurological Associates/ Research Dept.	Pompano Beach	Florida
United States	Dallas Neurological Associate	Richardson	Texas
United States	Mayo Clinic Rochester Department of Neurology	Rochester	Minnesota
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	Mayo Clinic Scottsdale Arizona	Scottsdale	Arizona
United States	University Hospital an Medical Center	Stony Brook	New York
United States	Neurology Clinical Research, Inc.	Sunrise	Florida
United States	Axiom Clinical Research of Florida	Tampa	Florida
United States	Neurological Associates of Tulsa, Inc	Tulsa	Oklahoma
United States	Neurological Research Institute of the East Bay	Walnut Creek	California
United States	ALL-Trials Clinical Research, LLC	Winston-Salem	North Carolina

Sponsors (2)

Lead Sponsor	Collaborator
Genzyme, a Sanofi Company	Bayer

Countries where clinical trial is conducted

United States,  Croatia,  Poland,  Russian Federation,  United Kingdom, 

References & Publications (8)

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. — View 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. Epub 2005 Jul 27. — View 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 ß-1a in early relapsing-remitting multiple sclerosis: post-hoc and subset analyses of — View 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 ß-1a at 5-year follow-up of CAMMS223 clinica — View 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 — View 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; — View 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 Ma — View 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 auto — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Probability of Participants With Sustained Accumulation of Disability (SAD)	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.	Up to 3 years	No
Primary	Annualized Relapse Rate	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.	Up to 3 years	No
Secondary	Probability of Participants Who Were Relapse Free at 3 Years After Initial Treatment	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.	Year 3	No
Secondary	Percent Change From Baseline in T1 Cerebral Volume at 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]).	Baseline, Year 3	No
Secondary	Percent Change From Baseline in MRI T2 Lesion Volume at 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]).	Baseline, Year 3	No

External Links

•   http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/003718/WC500150521.pdf