Consultants in Neurology Multiple Sclerosis Center, Northbrook, IL, USA.
Lancet Neurol. 2010 Apr;9(4):381-90. doi: 10.1016/S1474-4422(10)70033-8. Epub 2010 Feb 15.
Daclizumab, a humanised monoclonal antibody, reduced multiple sclerosis disease activity in previous non-randomised studies. We aimed to assess whether daclizumab reduces disease activity in patients with active relapsing multiple sclerosis who are receiving interferon beta treatment.
We did a phase 2, randomised, double-blind, placebo-controlled study at 51 centres in the USA, Canada, Germany, Italy, and Spain. Patients with active relapsing multiple sclerosis who were taking interferon beta were randomly assigned to receive add-on subcutaneous daclizumab 2 mg/kg every 2 weeks (interferon beta and high-dose daclizumab group), daclizumab 1 mg/kg every 4 weeks (interferon beta and low-dose daclizumab group), or interferon beta and placebo for 24 weeks. The randomisation scheme was generated by Facet Biotech. All patients and assessors were masked to treatment with the exception of Facet Biotech bioanalysts who prepared data for the data safety monitoring board or generated pharmacokinetic or pharmacodynamic data, a drug accountability auditor, and the site pharmacist. The primary endpoint was total number of new or enlarged gadolinium contrast-enhancing lesions measured on brain MRI scans every 4 weeks between weeks 8 and 24. Effects of daclizumab on prespecified subsets of lymphocytes and quantitative T-cell proliferative response were assessed in an exploratory pharmacodynamic substudy. Analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00109161.
From May, 2005, to March, 2006, 288 patients were assessed for eligibility, and 230 were randomly assigned to receive interferon beta and high-dose daclizumab (n=75), interferon beta and low-dose daclizumab (n=78), or interferon beta and placebo (n=77). The adjusted mean number of new or enlarged gadolinium contrast-enhancing lesions was 4.75 in the interferon beta and placebo group compared with 1.32 in the interferon beta and high-dose daclizumab group (difference 72%, 95% CI 34% to 88%; p=0.004) and 3.58 in the interferon beta and low-dose daclizumab group (25%, -76% to 68%; p=0.51). In the pharmacodynamic substudy, daclizumab was not associated with significant changes in absolute numbers of T cells, B cells, or natural killer cells, or T-cell proliferative response compared with interferon beta alone. The number of CD56(bright) natural killer cells was seven to eight times higher in both daclizumab groups than in the interferon beta and placebo group (interferon beta and low-dose daclizumab group p=0.002; interferon beta and high-dose daclizumab group p<0.0001). Common adverse events were equally distributed across groups.
Add-on daclizumab treatment reduced the number of new or enlarged gadolinium contrast-enhancing lesions compared with interferon beta alone and might reduce multiple sclerosis disease activity to a greater extent than interferon beta alone.
Facet Biotech and Biogen Idec.
达利珠单抗是一种人源化单克隆抗体，在先前的非随机研究中降低了多发性硬化症的疾病活动度。我们旨在评估达利珠单抗是否能降低正在接受干扰素β治疗的活动期复发多发性硬化症患者的疾病活动度。
我们在美国、加拿大、德国、意大利和西班牙的 51 个中心进行了一项 2 期、随机、双盲、安慰剂对照研究。正在接受干扰素β治疗的活动期复发多发性硬化症患者被随机分配接受添加用皮下注射达利珠单抗 2mg/kg，每 2 周 1 次（干扰素β和高剂量达利珠单抗组）、达利珠单抗 1mg/kg，每 4 周 1 次（干扰素β和低剂量达利珠单抗组）或干扰素β和安慰剂治疗 24 周。随机方案由 Facet Biotech 生成。所有患者和评估者均对治疗情况不知情，除了 Facet Biotech 生物分析员，他们为数据安全监测委员会准备数据或生成药代动力学或药效动力学数据、药物问责审计员和现场药剂师除外。主要终点是在第 8 周至 24 周的每 4 周期间，脑部 MRI 扫描上新或扩大的钆增强病变的总数。在探索性药效动力学亚研究中评估了达利珠单抗对预先指定的淋巴细胞亚群和定量 T 细胞增殖反应的影响。分析按意向治疗进行。该试验在 ClinicalTrials.gov 注册，编号为 NCT00109161。
从 2005 年 5 月至 2006 年 3 月，有 288 名患者接受了入选评估，有 230 名患者被随机分配接受干扰素β和高剂量达利珠单抗（n=75）、干扰素β和低剂量达利珠单抗（n=78）或干扰素β和安慰剂（n=77）治疗。与干扰素β和安慰剂组相比，干扰素β和高剂量达利珠单抗组新或扩大的钆增强病变的调整后平均数量为 4.75，干扰素β和低剂量达利珠单抗组为 3.58（差异 72%，95%CI 34%至 88%；p=0.004）。在药效动力学亚研究中，与单独使用干扰素β相比，达利珠单抗并未导致 T 细胞、B 细胞或自然杀伤细胞的绝对数量或 T 细胞增殖反应发生显著变化。与干扰素β和安慰剂组相比，两组达利珠单抗组的 CD56（bright）自然杀伤细胞数量均高出 7 至 8 倍（干扰素β和低剂量达利珠单抗组 p=0.002；干扰素β和高剂量达利珠单抗组 p<0.0001）。常见的不良反应在各组中分布均匀。
添加用达利珠单抗治疗与单独使用干扰素β相比，减少了新或扩大的钆增强病变的数量，并且可能比单独使用干扰素β更能降低多发性硬化症的疾病活动度。
Facet Biotech 和 Biogen Idec。
