Table 1.

Comparison of results of phase III clinical trials of different oral therapies for RRMS

Disease-modifying agent	Clinical trial name, number of patients	Results	Key adverse events
Fingolimod	FREEDOMS, 1,272 [28]	ARRfor 0.5 mg FIN and 1.25 mg FIN vs. PL (0.18 and 0.16 vs. 0.40, respectively; P < 0.001) Risk of disability progression for 0.5 mg FIN and 1.25 mg FIN vs. PL (HR 0.7 and 0.68, respectively; P = 0.02)	Cardiovascular events like bradycardia and AV block Severe infection (herpes simplex, varicella zoster) Macular edema
	TRANSFORMS, 1,292 [29, 30]	ARR for 0.5 mg and 1.25 FIN vs. IFNβ (0.16 and 0.20 vs. 0.33, respectively; P < 0.001) Reduced brain lesions on MRI for FIN vs. IFNβ No significant difference seen in disability progression
Teriflunomide	TEMSO, 1,088 [31]	Decreased ARR in TER 7 mg and TER 14 mg vs. PL (31.2% and 31.5%; P < 0.001) Decreased proportion of patients with disability progression in 7 mg TER and 14 mg TER vs.PL (21.7% and 20.2% vs. 27.3%, respectively) Improved MRI outcomes in TER groups vs. PL	Elevated liver enzymes Lymphocytopenia Opportunistic infections
	TOWER, 1,169 [32]	Decreased ARR in TER 7 mg vs.PL and TER 14 mg vs. PL (22.3%, P = 0.02 vs. 36.3 %, P < 0.0001, respectively) Decreased disability progression in 14 mg TER vs. PL
	TENERE, 324 [33]	Preliminary results: No statistical superiority of IFNβ over TER on risk of treatment failure (48.6%, 37.8%, and 42.3% in 7 mg, 14 mg, and IFNβ, respectively) ARR not statistically different in 14 mg TER and IFNβ group (0.259 vs. 0.216).ARR in 7 mg TER(0.410) higher than IFNβ (0.216)
Dimethyl fumarate	DEFINE, 1,237 [34]	Decrease in proportion of people with relapse in DMF 240 mg bid and tid vs. PL (27% and 26% vs. 46%, respectively; P < 0.001) ARR decreased in DMF 240 mg bid and tid vs. PL (0.17 and 0.19 vs. 0.36, respectively; P < 0.001) Decrease in percentage of patients with disease progression as compared to PL(16 % in DMF bid, P = 0.005; 18 % in tid DMF P = 0.01; 27 % in PL group) Reduced MRI measure of disease activity in DMF groups as compared to PL (P < 0.001)	Mild/Moderate infections Elevated liver enzymes Leukopenia
	CONFIRM, 1,430 [35]	ARR decreased for DMF 240 mg bid (0.22; P < 0.001), DMF 240 mg tid (0.20; P < 0.001), GA (0.29; P = 0.01) and 0.40 for PL Decrease in MRI based endpoints in DMF and GA patients vs. PL (P = 0.01) No differences in disability progression between DMF or GA vs. PL
Laquinimod	ALLEGRO, 1,106 [1]	Lower ARR in LAQ vs. PL (0.3 vs. 0.39; P = 0.02) Decrease in risk of disability progression in LAQ vs. PL (11.1% vs. 15.7%; P = 0.01) Decrease in MRI endpoints (P < 0.001)	Elevated liver enzymes Infections
	BRAVO, 1,331 [20]	After adjusted analysis, reduced ARR in LAQ vs. PL (21.3%; P = 0.026) Reduction in disability progression in LAQ vs. PL (33.5%;P = 0.044) Reduction in brain volume loss in LAQ vs. PL (27.5%; P < 0.0001)

Clinical trial acronyms: ALLEGRO, Placebo Controlled Trial of Oral Laquinimod for Multiple Sclerosis; BRAVO, Laquinimod Double Blind Placebo Controlled Study in RRMS Patients With a Rater Blinded Reference Arm of Interferon β-1a; CONFIRM, Comparator and an Oral Fumarate in RRMS; DEFINE, Determination of the Efficacy and Safety of Oral Fumarate in RRMS; FREEDOMS, A placebo-controlled trial of oral Fingolimod in Relapsing Multiple Sclerosis; TEMSO, The Teriflunomide Multiple Sclerosis Oral Trial; TENERE, A study comparing the effectiveness and safety of Teriflunomide and Interferon Beta-1a in Patients with Relapsing multiple sclerosis; TOWER, Teriflunomide efficacy and safety in patients with relapsing multiple sclerosis; TRANSFORMS, Trial Assessing Injectable Interferon versus FTY720 Oral in Relapsing-Remitting Multiple Sclerosis

ARR annualized relapse rate, AV atrioventricular, bid twice a day, DMF dimethyl fumarate, FIN fingolimod, GA Glatirameracetate, HR Hazard ratio, IFN interferon, LAQ laquinimod, MRI magnetic resonance imaging, PL placebo, TER teriflunomide, tid three times a day