Cladribine tablets versus other disease-modifying oral drugs in achieving no evidence of disease activity (NEDA) in multiple sclerosis-A systematic review and network meta-analysis

Abstract

Introduction: 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.

Methods: 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.

Results: 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.

Conclusions: 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.

Keywords: Cladribine tablets; Multiple sclerosis; NEDA; Network meta-analysis; Systematic review.