title: Comparing outcomes from clinical studies of oral disease-modifying therapies (dimethyl fumarate, fingolimod, and teriflunomide) in relapsing MS: Assessing absolute differences using a number needed to treat analysis.
abstract: Dimethyl fumarate (DMF), fingolimod, and teriflunomide are oral disease-modifying therapies (DMTs) indicated for the treatment of relapsing-remitting multiple sclerosis. Despite well-established limitations of cross-trial comparisons, DMTs are still frequently compared in terms of relative reductions in specific endpoints, most commonly annualized relapse rate. Consideration of absolute risk reduction and number needed to treat (NNT) provides an alternative approach to assess the magnitude of treatment effect and can provide valuable additional information on therapeutic gain. Using data from pivotal studies of DMF (DEFINE, NCT00420212; CONFIRM, NCT00451451), fingolimod (FREEDOMS, NCT00289978; FREEDOMS II, NCT00355134), and teriflunomide (TEMSO, NCT00134563; TOWER, NCT00751881), we calculated NNTs to prevent any relapse, more severe relapses (such as those leading to hospitalization or requiring intravenous corticosteroids), and disability worsening. Higher relative reductions were reported for DMF and fingolimod vs placebo on overall relapse and relapses requiring intravenous corticosteroids in both individual and pooled studies (pooled data unavailable for fingolimod). However, NNTs for each outcome were similar for DMF and teriflunomide, with marginally lower NNTs observed with fingolimod. By contrast, for relapses requiring hospitalization, relative reductions were higher and NNTs were substantially lower for teriflunomide compared with DMF. For fingolimod, there were inconsistent outcomes between the two studies for relapses requiring hospitalization; thus, comparative conclusions against DMF or teriflunomide cannot be clearly established. The risk of disability worsening was significantly reduced in both teriflunomide studies, but only in a single study for DMF (DEFINE) and fingolimod (FREEDOMS). NNTs to prevent one patient from experiencing disability worsening were similar in DEFINE, FREEDOMS, and TEMSO and TOWER but were higher in CONFIRM and FREEDOMS II. This NNT analysis demonstrates broadly comparable effects for DMF, fingolimod, and teriflunomide across key clinical outcomes. These observations are clinically relevant and may help to inform treatment decisions by providing additional information on therapeutic gain beyond informal assessments of relative reductions alone.
authors.affiliation: University of Ottawa and the Ottawa Hospital Research Institute, The Ottawa Hospital - General Campus, 501 Smyth Road, Ottawa, ON, Canada, K1H 8L6. Electronic address: mfreedman@toh.ca.
authors.forename: Mark S
authors.initials: MS
authors.lastname: Freedman
authors.affiliation: Department of Neurology-Neuroimmunology, Cemcat, Vall d'Hebron University Hospital, P. de la Vall d'Hebron, 119-129, Barcelona 08035, Spain.
authors.forename: Xavier
authors.initials: X
authors.lastname: Montalban
authors.affiliation: Icahn School of Medicine at Mount Sinai, The Corinne Goldsmith Dickinson Center for Multiple Sclerosis, 5 East 98th Street, New York 10029, USA.
authors.forename: Aaron E
authors.initials: AE
authors.lastname: Miller
authors.affiliation: Sanofi Genzyme, 1 Avenue Pierre Brossolette, Chilly-Mazarin 91385, France.
authors.forename: Catherine
authors.initials: C
authors.lastname: Dive-Pouletty
authors.affiliation: Sanofi Genzyme, 500 Kendall Street, Cambridge, MA 02142, USA.
authors.forename: Steven
authors.initials: S
authors.lastname: Hass
authors.affiliation: Sanofi Genzyme, 500 Kendall Street, Cambridge, MA 02142, USA.
authors.forename: Karthinathan
authors.initials: K
authors.lastname: Thangavelu
authors.affiliation: Comprehensive Multiple Sclerosis Center, Thomas Jefferson University Hospital, 900 Walnut Street, Ste. 200, Philadelphia, PA 19107, USA.
authors.forename: Thomas P
authors.initials: TP
authors.lastname: Leist
mesh_terms: D000284:Administration, Oral; D000305:Adrenal Cortex Hormones / Q000627:therapeutic use; D000328:Adult; D003437:Crotonates / Q000008:administration & dosage*; D000069462:Dimethyl Fumarate / Q000008:administration & dosage*; D004185:Disability Evaluation; D018450:Disease Progression; D019317:Evidence-Based Medicine / Q000379:methods; D005260:Female; D000068876:Fingolimod Hydrochloride / Q000008:administration & dosage*; D006760:Hospitalization; D006801:Humans; D006885:Hydroxybutyrates; D007166:Immunosuppressive Agents / Q000008:administration & dosage*; D008297:Male; D020529:Multiple Sclerosis, Relapsing-Remitting / Q000188:drug therapy*; D009570:Nitriles; D061366:Numbers Needed To Treat; D012008:Recurrence; D012720:Severity of Illness Index; D014052:Toluidines / Q000008:administration & dosage*; D016896:Treatment Outcome
chemical_list: D000305:Adrenal Cortex Hormones; D003437:Crotonates; D006885:Hydroxybutyrates; D007166:Immunosuppressive Agents; D009570:Nitriles; D014052:Toluidines; C527525:teriflunomide; D000069462:Dimethyl Fumarate; D000068876:Fingolimod Hydrochloride
keywords: Absolute risk; Dimethyl fumarate; Fingolimod; Multiple sclerosis; Number needed to treat; Teriflunomide