A Randomised Controlled Trial to Compare Ocrelizumab or Alemtuzumab With Autologous Hematopoietic Stem Cell Transplantation (aHSCT) in High Inflammatory Multiple Sclerosis (COAST)
试验速览
- 阶段
- 2 期
- 状态
- 终止
- 入组人数
- 1
- 试验地点
- 2
- 主要终点
- Time to treatment failure as assessed by failure of NEDA (no evidence of disease activity)
研究概览
简要总结
A multicentre controlled phase II trial to compare the efficacy and safety of ocrelizumab or alemtuzumab and autologous Hematopoietic Stem Cell Transplantation (aHSCT). Active relapsing-remitting MS-Patients will be included and randomised to ocrelizumab or alemtuzumab versus aHSCT. Primary endpoint will be the time to treatment failure as assessed by failure of NEDA (no evidence of disease activity) as represented by: no expanded disability status scale (EDSS) progression, no relapse, no new T2 lesion and no Gd-enhancing lesion.
This trial offers the opportunity to gain further information about efficacy and safety of all treatments and will give new insights into the immunology of highly active RRMS.
详细描述
A rater-blinded multicentre randomised controlled phase II trial to compare the efficacy and safety of ocrelizumab or alemtuzumab and aHSCT. Active RRMS-Patients will be included and randomised to ocrelizumab or alemtuzumab versus aHSCT. Primary endpoint will be the time to treatment failure as assessed by failure of NEDA (no evidence of disease activity) as represented by: no expanded disability status scale (EDSS) progression, no relapse, no new T2 lesion and no Gd-enhancing lesion.
aHSCT appears highly efficacious in reducing inflammatory disease activity and relapses in active relapsing-remitting MS. Cohort data show a long-term stagnation of inflammatory disease activity for up to 10 years and more after aHSCT. However, efficacy data from randomised controlled trials comparing aHSCT with approved treatments are still lacking.
The best available data concerning disease activity in MS patients with a documented treatment failure are from the CARE-MS II trial. The rate of patients without clinical or radiological disease activity after 2 years was 32% with alemtuzumab. aHSCT trial data on absence of disease activity show NEDA rates between 70 and 90% after 2 years. Here we assume 40% and 80% after 2 years for the ocrelizumab/alemtuzumab and aHSCT groups, respectively.
For all three treatments, a potential long-term benefit has to be balanced with potentially harmful treatment related risks. A randomised controlled trial offers the opportunity to gain further information about efficacy and safety of all treatments and will give new insights into the immunology of high active RRMS.
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
- None
入排标准
- 年龄范围
- 18 Years 至 55 Years（Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- 未提供
排除标准
- •Secondary or primary progressive MS
- •Pregnancy, or other medical condition incompatible with aHSCT
- •Any treatment or medical condition that, according to the haematologist / transplant specialist precludes the use of aHSCT
- •John Cunningham virus (JCV) antibody index of > 1.5 in previ-ously natalizumab-treated patients, if a negative CSF JCV-PCR prior to screening is not available
- •Relapse during 30 days before initiation of treatment. If a relapse occurs during this period and eligibility criteria are otherwise ful-filled, start of treatment will be delayed until at least 30 days after receiving steroids.
- •Concurrent clinically significant (as determined by the investiga-tors and haematologist / transplant specialist) cardiac, immuno-logical, pulmonary, neurological, renal or other major disease such as:
- •Prominent cardial disease (Left ventricular ejection frac-tion (LVEF) < 40%, myocardial infarction or ischemia, un-controlled arrhythmias, pericardial effusion > 1 cm)
- •Cerebrovascular disease
- •Renal disease (creatinine clearance < 30 ml/min/m2)
- •Respiratory disease (DLCO < 40% predicted)
- •Active bleeding or clotting disease
- •History of human immunodeficiency virus (HIV) or posi-tive HIV antibody testing
- •Any uncontrolled acute or chronic infection, including HIV, hepatitis B surface antigen positivity and hepatitis C PCR positivity
- •Cancer except in situ cervix or cutaneous
- •Unwillingness or inability to comply with the requirements of this protocol including the presence of any condition (physical, men-tal, or social) that is likely to affect the patient returning for follow-up visits on schedule. Unwillingness to use contraception.
- •Previous participation in this study, previous treatment with aHSCT or already both comparators
- •Ongoing immunotherapy. Treatment with interferon or glati-rameracetate will need no wash-out. Treatment pause before oc-relizumab/alemtuzumab or aHSCT will be:
- •for dimethylfumarate and fingolimod: 8 weeks
- •for natalizumab: 8 weeks
- •for ocrelizumab: 12 weeks
- •for alemtuzumab: 12 months
- •for teriflunomide: 4 weeks after elimination with cholesty-ramine
- •for cladribine: 24 weeks
- •Patients with cognitive impairments who are unable to provide written, informed consent prior to any testing under this protocol, including screening and baseline investigations that are not con-sidered part of routine patient care.
研究组 & 干预措施
Intervention (aHSCT)
Autologous Hematopoietic Stem Cell Transplantation. Mobilisation will be performed with 2 g/m2 cyclophosphamide and 10 μg/kg G-CSF from day 5 until apheresis is completed. Conditioning will be 200 mg/kg cyclo-phosphamide and Anti-T-lymphocyteglobuline (Grafalon®, Neovii) with cu-mulative doses of 20 mg/kg given on day +1 (10 mg/kg) and day +2 (10 mg/kg).
干预措施: Autologous Hematopoietic Stem Cell Transplantation (Drug)
Control
In the control arm patient and physician will decide which treatment to choose. Patients will be either treated with ocrelizumab according to the SmPC (600 mg every 6 months continuously) or with alemtuzumab according to the SmPC (12 mg/day for 5 consecutive days and again after 365 days for 3 days).
干预措施: Ocrelizumab (Drug)
Control
In the control arm patient and physician will decide which treatment to choose. Patients will be either treated with ocrelizumab according to the SmPC (600 mg every 6 months continuously) or with alemtuzumab according to the SmPC (12 mg/day for 5 consecutive days and again after 365 days for 3 days).
干预措施: Alemtuzumab (Drug)
结局指标
主要结局
Time to treatment failure as assessed by failure of NEDA (no evidence of disease activity)
时间窗: through study completion, on average at least 2 years
Time to treatment failure as assessed by failure of NEDA (no evidence of disease activity) during follow-up as defined by: * 3 months confirmed EDSS (Expanded disability status scale) progression * confirmed relapse * new/enlarging T2-hyperintense lesion on MRI (Magnetic resonance imaging) * any Gd-enhancing lesion on MRI
次要结局
- Efficacy of treatment defined by the annualized relapse rate(through study completion, on average at least 2 years)
- Efficacy of treatment defined by the number of Gd-enhancing lesions(through study completion, on average at least 2 years)
- Efficacy of treatment defined by the Percentage Brain Volume Change (PBVC)(through study completion, on average at least 2 years)
- Efficacy of treatment defined by grey and white matter atrophy(through study completion, on average at least 2 years)
- Efficacy of treatment defined by EDSS(through study completion, on average at least 2 years)
- Efficacy of treatment defined by multiple sclerosis functional composite (MSFC) change(through study completion, on average at least 2 years)
- Efficacy of treatment defined by the number of new T2 lesions(through study completion, on average at least 2 years)
- Efficacy of treatment defined by Hamburg quality of life scale in MS (HAQUAMS)(through study completion, on average at least 2 years)
- Rate of AE / SAE including NCI grade 3 and 4 non-haematological toxicities(through study completion, on average at least 2 years)