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
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 发起方
- 入组人数
- 334
- 试验地点
- 82
- 主要终点
- Annualized Relapse Rate
研究概览
简要总结
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.
详细描述
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
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Single (Outcomes Assessor)
入排标准
- 年龄范围
- 18 Years 至 50 Years（Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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)
排除标准
- •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
结局指标
主要结局
Annualized Relapse Rate
时间窗: 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.
Probability of Participants With Sustained Accumulation of Disability (SAD)
时间窗: 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.
次要结局
- Percent Change From Baseline in T1 Cerebral Volume at Year 3(Baseline, Year 3)
- Probability of Participants Who Were Relapse Free at 3 Years After Initial Treatment(Year 3)
- Percent Change From Baseline in MRI T2 Lesion Volume at Year 3(Baseline, Year 3)