Romano Silvia, Ferraldeschi Michela, Bagnato Francesca, Mechelli Rosella, Morena Emanuele, Caldano Marzia, Buscarinu Maria Chiara, Fornasiero Arianna, Frontoni Marco, Nociti Viviana, Mirabella Massimiliano, Mayer Flavia, Bertolotto Antonio, Pozzilli Carlo, Vanacore Nicola, Salvetti Marco, Ristori Giovanni
Neurosciences, Mental Health, and Sensory Organs (NESMOS) Department, Center for Experimental Neurological Therapies, S. Andrea Hospital-site, "Sapienza" University of Rome, Rome, Italy.
Department of Neurology and Psychiatry, "Sapienza" University of Rome, Rome, Italy.
Front Neurol. 2019 Jul 16;10:695. doi: 10.3389/fneur.2019.00695. eCollection 2019.
To compare a schedule with cyclic withdrawal (CW) of interferon beta (IFN-b) 1b, respect to the full regimen (FR), in relapsing-remitting MS (RR-MS). Participants were randomly assigned to CW or FR schedule and monthly monitored with brain MRI scans for 12 months (three of run-in and 9 of treatment). CW schedule included drug withdrawal for 1 month after two of treatment for a total of three quarters over the 9-month treatment period. The assessing neurologist and the expert neuroradiologists were blind. After the blind phase of the study all participants took their indicated disease modifying therapies in a prospectively planned, open-label extension phase (up to 120 months). Of 60 randomized subjects 56 (29 in FR and 27 in CW group) completed the single-blind phase: the two groups were comparable, except for a non-significant difference in the number of contrast-enhanced lesions (CEL) at the end of run-in. The two-sided 90% CI for the ratio between median number of cumulative CEL was 0.29-1.07, allowing to significantly reject the null hypothesis of a ratio ≥1.2 and to meet the primary end-point of non-inferiority (the threshold and the ratio between median were chosen according to the non-normal distribution of the data). The differences (CW vs. FR) were also non-significant for secondary end points: mean cumulative number of T2-weighted new and enlarging lesions (3.48 ± 5.34 vs. 3.86 ± 6.76); mean number and volume (cm) of black holes (1.24 ± 1.61 vs. 2.71 ± 4.56; 489.11 ± 1488.12 vs. 204.48 ± 396.98); number of patients with at least an active scan (21 vs. 22); mean relapse rate (0.52 ± 0.89 vs. 0.34 ± 0.66), relapse risk ratio adjusted for baseline variables (2.15 [0.64-7.18]), EDSS score (1.0 [1-1.56] vs. 1.5 [1-1.78]), proportion of patients with antibodies anti-IFN (5 [21%] vs. 8 [36%]). Fifty-four patients (27 for each study arm) completed the open-label phase. The annualized RR, EDSS, proportion of patients shifting to progressive disease and hazard ratio of shifting, adjusting for baseline covariates, were comparable between the two study groups. A calendar with CW was non-inferior than FR at the beginning of IFN-b therapy, and may not affect the long-term outcome. www.ClinicalTrials.gov, identifier: NCT00270816.
在复发缓解型多发性硬化症（RR-MS）中，比较干扰素β（IFN-b）1b的循环撤药（CW）方案与全疗程（FR）方案。参与者被随机分配至CW或FR方案，并每月进行脑部MRI扫描监测12个月（3个月导入期和9个月治疗期）。CW方案包括在9个月治疗期内，每两个治疗周期后停药1个月，共三个周期。评估神经科医生和神经放射学专家均为盲态。在研究的盲态阶段结束后，所有参与者在一个前瞻性计划的开放标签延长期（长达120个月）接受其指定的疾病修正治疗。60名随机分组的受试者中，56名（FR组29名，CW组27名）完成了单盲阶段：两组具有可比性，除导入期结束时对比增强病灶（CEL）数量存在非显著性差异。累积CEL中位数之比的双侧90%置信区间为0.29 - 1.07，可显著拒绝比值≥1.2的零假设，并达到非劣效性的主要终点（根据数据的非正态分布选择阈值和中位数之比）。次要终点方面，差异（CW组与FR组）也无显著性：T2加权新发病灶和扩大病灶的平均累积数量（3.48 ± 5.34对3.86 ± 6.76）；黑洞的平均数量和体积（cm）（1.24 ± 1.61对2.71 ± 4.56；489.11 ± 1488.12对204.48 ± 396.98）；至少有一次活跃扫描的患者数量（分别为21名和22名）；平均复发率（0.52 ± 0.89对0.34 ± 0.66），根据基线变量调整后的复发风险比（2.15 [0.64 - 7.18]），扩展残疾状态量表（EDSS）评分（1.0 [1 - 1.56]对1.5 [1 - 1.78]），抗IFN抗体阳性患者比例（5名[21%]对8名[36%]）。54名患者（每个研究组27名）完成了开放标签阶段。调整基线协变量后，两个研究组的年化复发率、EDSS、进展为进展型疾病的患者比例以及进展风险比具有可比性。IFN-b治疗开始时，CW方案不劣于FR方案，且可能不影响长期预后。ClinicalTrials.gov网站，标识符：NCT00270816。
