Bartosik-Psujek Halina, Kaczyński Łukasz, Górecka Magdalena, Rolka Mirosław, Wójcik Rafał, Zięba Patrycja, Kaczor Marcin
Department of Neurology, Institute of Medical Sciences, Medical College of Rzeszow University, Warzywna 1A, 35-310 Rzeszów, Poland.
Aestimo s.c., Krakowska 36/3, 31-062 Kraków, Poland.
Mult Scler Relat Disord. 2021 Apr;49:102769. doi: 10.1016/j.msard.2021.102769. Epub 2021 Jan 16.
Assuming full control of the relapsing-remitting multiple sclerosis (RRMS) is the main target for practitioners. Disease control could be defined as no clinical relapse, absence of 3-month confirmed disability progression expressed on the Expanded Disability Status Scale (EDSS), as well as no disease activity on magnetic resonance imaging (MRI). NEDA-3 (no evidence of disease activity) is a composite endpoint used primarily in clinical trials, comprising these 3 measurements of disease activity. The aim of this study is to compare cladribine tablets (CT) with oral disease-modifying drugs (DMDs) - fingolimod (FTY), dimethyl fumarate (DMF), and teriflunomide (TERI) - with regard to NEDA-3 and its clinical (relapse and disability progression) and MRI (no new T1 Gd+ lesions or no new T2 lesions or no enlargement of existing lesions) components occurrence during a 24-month follow-up.
In June 2018, a systematic review of MEDLINE, Embase and Cochrane database was performed. Due to the lack of head-to-head trials directly comparing cladribine tablets to oral drugs of interest, an indirect network meta-analysis (NMA) was applied, with placebo as a common comparator. NMA was performed with Bayesian approach and Markov chain Monte Carlo (MCMC) method for estimating posterior distributions. Additional data used in the analysis were taken from conference abstracts or post hoc analyses of pooled data from the clinical studies.
Six randomised clinical trials (RCTs) presenting NEDA, with active treatment compared to placebo, were included in the NMA: CLARITY (CT), FREEDOMS and FREEDOMS II (FTY), CONFIRM and DEFINE (DMF) and TEMSO (TERI). The rate of NEDA-3 was significantly higher in cladribine tablets vs DMF: OR (odds ratio)=1.76 (95% CrI [credible intervals]: 1.02-3.03) and TERI: OR=2.78 (95% CrI: 1.60-4.83), but not vs FTY. For the MRI NEDA results were as follows - cladribine tablets vs DMF: OR=1.87 (95% CrI: 1.18-2.97); cladribine tablets vs TERI: OR=6.59 (95% CrI: 4.32-10.09); cladribine tablets vs FTY: OR=1.58 (95% CrI: 1.10-2.29). The comparison of clinical NEDA did not reach significance vs either DMF or TERI and evaluation vs FTY was not possible because of lack of data.
Cladribine in the form of tablets was significantly more effective in achieving NEDA-3 than DMF and TERI, but there was no significant difference vs FTY. Cladribine tablets was more effective than all oral comparators considering the MRI NEDA. For clinical NEDA, the superiority vs DMF and vs TERI was not confirmed, and vs FTY evaluation was not possible.
对复发缓解型多发性硬化症（RRMS）实现完全控制是临床医生的主要目标。疾病控制可定义为无临床复发、在扩展残疾状态量表（EDSS）上无3个月确诊的残疾进展，以及磁共振成像（MRI）上无疾病活动。无疾病活动证据3（NEDA-3）是主要用于临床试验的复合终点，包括这3项疾病活动测量指标。本研究的目的是比较克拉屈滨片（CT）与口服疾病修正药物（DMDs）——芬戈莫德（FTY）、富马酸二甲酯（DMF）和特立氟胺（TERI）——在24个月随访期间NEDA-3及其临床（复发和残疾进展）和MRI（无新的T1加权钆增强病变或无新的T2病变或现有病变无增大）组成部分的发生情况。
2018年6月，对MEDLINE、Embase和Cochrane数据库进行了系统评价。由于缺乏直接比较克拉屈滨片与感兴趣的口服药物的头对头试验，因此应用了间接网络荟萃分析（NMA），以安慰剂作为共同对照。采用贝叶斯方法和马尔可夫链蒙特卡罗（MCMC）方法进行NMA以估计后验分布。分析中使用的其他数据来自会议摘要或临床研究汇总数据的事后分析。
NMA纳入了6项呈现NEDA的随机临床试验（RCT），将活性治疗与安慰剂进行比较：CLARITY（CT）、FREEDOMS和FREEDOMS II（FTY）、CONFIRM和DEFINE（DMF）以及TEMSO（TERI）。克拉屈滨片的NEDA-3发生率显著高于DMF：比值比（OR）=1.76（95%可信区间[CrI]：1.02 - 3.03）和TERI：OR = 2.78（95% CrI：1.60 - 4.83），但与FTY相比无显著差异。对于MRI的NEDA结果如下——克拉屈滨片与DMF：OR = 1.87（95% CrI：1.18 - 2.97）；克拉屈滨片与TERI：OR = 6.59（95% CrI：4.32 - 10.09）；克拉屈滨片与FTY：OR = 1.58（95% CrI：1.10 - 2.29）。临床NEDA的比较与DMF或TERI相比均未达到显著差异，且由于缺乏数据无法与FTY进行评估。
片剂形式的克拉屈滨在实现NEDA-3方面比DMF和TERI显著更有效，但与FTY相比无显著差异。考虑到MRI的NEDA，克拉屈滨片比所有口服对照药物更有效。对于临床NEDA，未证实其优于DMF和TERI，且无法与FTY进行评估。
