title: No evidence of disease activity: indirect comparisons of oral therapies for the treatment of relapsing-remitting multiple sclerosis.
abstract: BACKGROUND
  No head-to-head trials have compared the efficacy of the oral therapies, fingolimod, dimethyl fumarate and teriflunomide, in multiple sclerosis. Statistical modeling approaches, which control for differences in patient characteristics, can improve indirect comparisons of the efficacy of these therapies.
  
  
  METHODS
  No evidence of disease activity (NEDA) was evaluated as the proportion of patients free from relapses and 3-month confirmed disability progression (clinical composite), free from gadolinium-enhancing T1 lesions and new or newly enlarged T2 lesions (magnetic resonance imaging composite), or free from all disease measures (overall composite). For each measure, the efficacy of fingolimod was estimated by analyzing individual patient data from fingolimod phase 3 trials using methodologies from studies of other oral therapies. These data were then used to build binomial regression models, which adjusted for differences in baseline characteristics between the studies. Models predicted the indirect relative risk of achieving NEDA status for fingolimod versus dimethyl fumarate or teriflunomide in an average patient from their respective phase 3 trials.
  
  
  RESULTS
  The estimated relative risks of achieving NEDA status for fingolimod versus placebo in a pooled fingolimod trial population were numerically greater (i.e., fingolimod more efficacious) than the estimated relative risks for dimethyl fumarate or teriflunomide versus placebo in each respective trial population. In indirect comparisons, the predicted relative risks for all composite measures were better for fingolimod than comparator when tested against the trial populations of those treated with dimethyl fumarate (relative risk, clinical: 1.21 [95% confidence interval 1.06-1.39]; overall: 1.67 [1.08-2.57]), teriflunomide 7 mg (clinical: 1.22 [1.02-1.46]; overall: 2.01 [1.38-2.93]) and teriflunomide 14 mg (clinical: 1.14 [0.96-1.36]; overall: 1.61 [1.12-2.31]).
  
  
  CONCLUSIONS
  Our modeling approach suggests that fingolimod therapy results in a higher probability of NEDA than dimethyl fumarate and teriflunomide therapy when phase 3 trial data are indirectly compared and differences between trials are adjusted for.
authors.affiliation: Novartis Pharma AG, Postfach, 4002, Basel, Switzerland, richard.nixon@novartis.com.
authors.forename: Richard
authors.initials: R
authors.lastname: Nixon
authors.forename: Niklas
authors.initials: N
authors.lastname: Bergvall
authors.forename: Davorka
authors.initials: D
authors.lastname: Tomic
authors.forename: Nikolaos
authors.initials: N
authors.lastname: Sfikas
authors.forename: Gary
authors.initials: G
authors.lastname: Cutter
authors.forename: Gavin
authors.initials: G
authors.lastname: Giovannoni
mesh_terms: D000284:Administration, Oral; D000328:Adult; D003437:Crotonates / Q000627:therapeutic use*; D000069462:Dimethyl Fumarate / Q000627:therapeutic use*; D004185:Disability Evaluation; D018450:Disease Progression; D005260:Female; D000068876:Fingolimod Hydrochloride / Q000627:therapeutic use*; D006801:Humans; D006885:Hydroxybutyrates; D007166:Immunosuppressive Agents / Q000627:therapeutic use; D008279:Magnetic Resonance Imaging; D008297:Male; D015233:Models, Statistical; D020529:Multiple Sclerosis, Relapsing-Remitting / Q000175:diagnosis / Q000188:drug therapy / Q000503:physiopathology; D009570:Nitriles; D017063:Outcome Assessment, Health Care; D062072:Patient Acuity; D016032:Randomized Controlled Trials as Topic; D012008:Recurrence; D014052:Toluidines / Q000627:therapeutic use*
chemical_list: D003437:Crotonates; D006885:Hydroxybutyrates; D007166:Immunosuppressive Agents; D009570:Nitriles; D014052:Toluidines; C527525:teriflunomide; D000069462:Dimethyl Fumarate; D000068876:Fingolimod Hydrochloride