Department of NEUROFARBA, University of Florence, Florence, Italy; Department of Neurology 2 and Tuscan Region Multiple Sclerosis Referral Centre, Careggi University Hospital, Florence, Italy.
Department of Statistics Informatics and Applications "Giuseppe Parenti", University of Florence, Florence, Italy; Florence Centre for Data Science, Florence, Italy.
Mult Scler Relat Disord. 2024 Nov;91:105852. doi: 10.1016/j.msard.2024.105852. Epub 2024 Aug 27.
The non-inferiority of the efficacy of subcutaneous (SC) vs intravenous (IV) administration of natalizumab (NTZ) once every 4 weeks in relapsing-remitting multiple sclerosis (RRMS) was recently demonstrated on the primary outcome of the REFINE study, i.e. MRI "combined unique active lesions number" (CUAL). To provide further evidence on the comparative efficacy of the two NTZ formulations, the effect of NTZ-SC vs NTZ-IV on annualized relapse rate (ARR) was investigated re-analysing the REFINE dataset.
Post-hoc analysis of the REFINE study dataset aimed at exploring the non-inferiority of the efficacy of NTZ-SC vs NTZ-IV on ARR, i.e. the main secondary outcome of the REFINE study. Robustness of the non-inferiority analysis on CUAL with respect to the presence of cases from the SC arm who received a rescue treatment, including NTZ-IV, was also assessed by sensitivity analyses. Three non-inferiority margins were selected, corresponding to 25 %, 33 %, and 50 % fractions of the effect size of NTZ-IV vs placebo observed in the AFFIRM study on ARR (i.e. 0.125, 0.170, and 0.250).
Ninety-nine RRMS patients were included. The mean difference in the effect of NTZ-SC vs NTZ-IV on ARR was close to 0. The lower bound of the 95 % confidence interval (worst case scenario) was -0.119, corresponding to 25 % (p = 0.025) of the effect of NTZ-IV vs placebo on ARR. Sensitivity analyses confirmed the results of the primary non-inferiority analysis on the outcome CUAL.
NTZ-SC resulted not inferior to NTZ-IV on ARR for all the non-inferiority margins. The non-inferiority analysis of the efficacy of NTZ-SC vs NTZ-IV on CUAL was demonstrated to be robust with respect to rescued patients.
最近的 REFINE 研究表明，在原发性结局 MRI“联合独特活跃病变数”（CUAL）上，每四周皮下（SC）注射和静脉（IV）注射那他珠单抗（NTZ）的疗效无差异，即每四周皮下（SC）注射和静脉（IV）注射 NTZ 的疗效无差异。为了进一步提供两种 NTZ 制剂疗效比较的证据，我们重新分析了 REFINE 数据集，以研究 NTZ-SC 与 NTZ-IV 对年复发率（ARR）的影响。
对 REFINE 研究数据集进行事后分析，旨在探索 NTZ-SC 与 NTZ-IV 在 ARR 上的疗效非劣效性，即 REFINE 研究的主要次要结局。还通过敏感性分析评估了 CUAL 非劣效性分析的稳健性，以及 SC 臂中接受包括 NTZ-IV 在内的抢救治疗的病例的存在。选择了三个非劣效性边界，分别对应于ARR 中 NTZ-IV 与安慰剂相比的效应大小的 25%、33%和 50%，即 AFFIRM 研究中ARR 的 0.125、0.170 和 0.250。
共纳入 99 例 RRMS 患者。NTZ-SC 与 NTZ-IV 对 ARR 的影响差异接近 0。95%置信区间（最坏情况）的下限为-0.119，对应于 NTZ-IV 与安慰剂相比 ARR 的 25%（p=0.025）。敏感性分析证实了 CUAL 主要非劣效性分析的结果。
在所有非劣效性边界上，NTZ-SC 在 ARR 上的疗效均不劣于 NTZ-IV。证明了 NTZ-SC 与 NTZ-IV 对 CUAL 的疗效非劣效性分析对接受抢救治疗的患者具有稳健性。
