. 2024 Jan 11;13(2):283–322. doi: 10.1007/s40120-023-00565-7

Table 1.

Efficacy of IFN-β-1a sc: clinical studies

Study and timing	Design	Study population	Titration and dosing	Outcomes
RRMS
PRISMS [41] 1994–1997	Double-blind, placebo-controlled, phase 3	560 patients with clinically definite or laboratory-supported definite MS of ≥ 1 year duration Kurtzke EDSS scores of 0–5.0 ≥ 2 relapses in the preceding 2 years	Titration: Dose was gradually increased over 4–8 weeks Dosing: IFN-β-1a sc 22 μg tiw IFN-β-1a sc 44 μg tiw Placebo tiw	Primary outcome: Relapse count over the course of the study Relapse rate was significantly lower at 2 years with both doses of IFN-β-1a than with placebo Mean number per patient 1.82 and 1.73 for the 22-µg and 44-µg treatment groups, respectively vs 2.56 for the placebo group, (p < 0.005 for both) Risk reductions of 27% [95% CI 14–39] and 33% [21–44] for the 22-µg and 44-µg treatment groups, respectively, vs the placebo group Median time to first relapse was delayed by 3 months in the 22-μg group and 5 months in the 44-μg group vs the placebo group Time to EDSS progression was 21.3, 18.5, and 11.9 months in the IFN 22-μg, 44-μg, and placebo groups, respectively (p < 0.05 vs placebo for both treatment groups) In patients with high baseline EDSS (> 3.5): • Time to confirmed progression was significantly longer only in the 44-μg group compared to the placebo group (7.5, 21.3, and 7.3 months in the, IFN 22-μg, 44-μg, and placebo groups, respectively, p < 0.05 vs placebo for the 44-μg group) Median MRI lesion volume decreased by 1.2% in the 22-µg group and 3.8% in the 44-µg group and increased by 10.9% in the placebo group (p < 0.0001 compared with the placebo group for both IFN doses) T2 new or enlarging lesion number (determined by proton density T2-weighted scans) was reduced by 67% for the 22-µg group and 78% in the 44-µg group compared to the placebo group (p < 0.0001), with a dose effect in favor of the 44-µg tiw group (p = 0.0003)
OWIMS [42] 1995–1996	Double-blind, placebo-controlled, phase 3	293 patients with clinically definite or laboratory-supported definite RRMS of ≥ 1 year duration Kurtzke EDSS scores of 0–5.0 ≥ 1 relapse in the prior 24 months but not in the 8 weeks before entry ≥ 3 lesions consistent with MS	Dosing: IFN-β-1a sc 22 μg qw IFN-β-1a sc 44 μg qw Placebo qw	Primary outcome: Number of CUA lesions at 24 weeks Median CUA lesions of 0.71/scan with placebo, 0.5/scan with 22 μg qw (not significant), and 0.33/scan with 44 μg qw (p = 0.002) T2 new lesion count/scan (mean/median) at 48 weeks was 3.2/1.5 for placebo, 2.4/1.0 for 22 μg (p = 0.03), and 1.5/1.0 for 44 μg (p = 0.0005) BOD at 48 weeks showed a median increase of 5.9% for the placebo group compared with a decrease of 2% in the 22-μg qw group (p = 0.0018) and 1.4% in the 44-μg qw group (p = 0.0058)
EVIDENCE [43, 55] 1999–2002	Randomized, controlled, assessor-blinded	677 patients with relapsing MS EDSS scores of 0–5.5 ≥ 2 exacerbations in the preceding 2 years	Titration: In patients randomized to high-dose tiw treatment, the dose was increased over 4 weeks, with patients receiving 8.8 μg tiw for the first 2 weeks and 22 μg tiw for the next 2 weeks Dosing: IFN-β-1a sc 44 μg tiw IFN-β-1a im 30 μg qw	Primary clinical endpoint: Proportion of patients who remained free from relapses The proportion of patients who remained relapse-free was significantly greater in the high-dose tiw treatment group vs the low-dose qw treatment group (adjusted odds ratio 1.5; 95% CI 1.1–2.0; p = 0.023) After 24 weeks, 74.9% of the IFN-β-1a sc 44-µg tiw group and 63.3% of the IFN-β-1a im 30-µg qw group remained free from relapses (p = 0.0005) At the end of the 64-week comparative phase • A higher proportion of patients in the IFN-β-1a sc 44-µg tiw group remained free from relapses compared with the IFN-β-1a im 30-µg qw group (p = 0.023) • ARR was 17% lower (p = 0.033) in the IFN-β-1a sc 44-µg tiw group vs the IFN-β-1a im 30-µg qw group • Time to first relapse was longer (hazard ratio [HR] 0.70; p = 0.002) in the IFN-β-1a sc 44-µg tiw group compared with the IFN-β-1a im 30-µg qw group at the end of the comparative phase During the second phase The group that changed from qw im to tiw sc dosing had • A 50% reduction in mean relapse rates (p < 0.001) • Significant reductions in MRI activity vs the comparative phase of the study The group that had remained with tiw sc dosing from the comparison phase had • A 26% reduction in mean relapse rates (p < 0.028)
REGARD [44] 2004–2006	Multicenter, randomized, parallel, open-label	764 patients with RRMS EDSS scores of 0–5.5 ≥ 1 attack in the previous 12 months Clinically stable or neurologically improving during the 4 weeks before randomization	Titration: Patients who received IFN-β-1a had a standard dose titration for the first 4 weeks Dosing: IFN-β-1a sc 44 μg tiw Glatiramer acetate sc 20 mg od	Primary outcome measure: Time to first relapse over 96 weeks No significant difference in time to first relapse between the treatment groups (HR 0.94; 95% CI 0.74–1.21; p = 0.64) No significant differences between groups were observed in • Numbers of T2 active lesions (defined as new or enlarging T2 lesions), • Proportions of scans with T2 active lesions, change in T2 lesion volume There were significantly fewer Gd+ lesions with IFN-β-1a compared with GA (0.24 vs 0.41 lesions per patient per scan, 95% CI − 0.4 to 0.1; p = 0.0002)
IMPROVE (Investigating MRI Parameters with Rebif® imprOVEd formulation) [45] NCT00441103 2006–2009	Randomized, double-blind (16 weeks) and rater-blind (24 weeks) phases	180 patients with RRMS EDSS scores of 0–5.5 Active disease ≥ 1 clinical event and ≥ 1 Gd+ MRI lesion within the previous 6 months	Dosing: New formulation of IFN-β-1a sc 44 μg tiw	Primary endpoint: The number of CUA MRI brain lesions at week 16 At week 16, the mean number of CUA lesions was lower with IFN-β-1a sc 44 μg tiw vs placebo (p < 0.001; 69% fewer lesions) No CUA lesions were observed in 53.3% of patients receiving IFN-β-1a vs 16.7% of those receiving placebo
Extension studies
PRISMS-4 [46] 1997–1999	Long-term, double-blind extension	533 patients with RRMS who had participated in the PRISMS study	Dosing: IFN-β-1a sc 22 μg tiw IFN-β-1a sc 44 μg tiw Crossover: Placebo, followed by IFN-β-1a sc 22 μg tiw Placebo, followed by IFN-β-1a sc 44 μg tiw	Primary outcome: Relapse count per patient over 4 years Relapse rates for 4 years were • Crossover (placebo/IFN-β-1a sc): 1.02 • IFN-β-1a sc 22 μg tiw: 0.80 (p < 0.001 vs crossover) • IFN-β-1a sc 44 μg tiw: 0.72 (p < 0.001 vs crossover)
PRISMS-7/8 [59]	Long-term open-label follow-up of a double-blind initial study	382 patients with RRMS who had participated in the PRISMS study	Dosing: IFN-β-1a sc 22 μg tiw IFN-β-1a sc 44 μg tiw	Compared with patients in the late treatment group, patients originally randomized to IFN-β-1a 44 μg sc tiw demonstrated • Less EDSS progression • Lower relapse rates • Less T2 burden of disease
PRISMS-15 [60]		290 patients with RRMS who had participated in the PRISMS study	Dosing: IFN-β-1a sc 22 μg tiw IFN-β-1a sc 44 μg tiw	Higher cumulative dose exposure and longer treatment times (i.e., the highest dose quartile) were associated with better outcomes compared with the lowest dose quartile as measured by: • Annualized relapse rate (0.37 and 0.50, respectively) • Number of relapses (5.8 and 7.8) • 3-month confirmed EDSS progression (38% vs 50%) • Mean change in EDSS score (1.15 and 2.53) • Conversion to SPMS (20.8% and 52.1%)
Active comparator
CARE-MS I [47] NCT00530348 Enrollment: 2007–2009	Randomized rater-masked, controlled phase 3 trial	581 patients with RRMS with disease duration ≤ 5 years ≥ 2 relapses in the previous 2 years and ≥ 1 in the previous year EDSS score ≤ 3.0 Cranial abnormalities on MRI attributable to MS	Dosing: IFN-β-1a sc 44 μg tiw Alemtuzumab 12 mg iv od (od for 5 days at baseline and od for 3 days at 12 months)	Co-primary endpoints: Relapse rate and time to 6-month sustained accumulation of disability 75 (40%) patients in the IFN-β-1a sc 44-μg tiw group relapsed (122 events) compared with 82 (22%) patients in the alemtuzumab group (119 events; rate ratio 0.45; 95% CI 0.32–0.63; p < 0.0001) 20 (11%) of the IFN-β-1a sc 44-μg tiw group had sustained accumulation of disability vs 30 (8%) in the alemtuzumab group (HR 0.70; 95% CI 0.40–1.23; p = 0.22)
CARE-MS II [47] NCT00548405 Enrollment: 2007–2009	Rater-masked, randomised controlled phase 3	581 patients with RRMS with disease duration ≤ 10 years ≥ 2 relapses in the previous 2 years and ≥ 1 in the previous year ≥ 1 relapse on IFN-β or glatiramer after ≥ 6 months of treatment EDSS score ≤ 5.0 Cranial and spinal MRI lesions fulfilling protocol-defined criteria	Dosing: IFN-β-1a sc 44 μg tiw Alemtuzumab 12 mg iv od (od for 5 days at baseline and od for 3 days at 12 months) Alemtuzumab 24 mg iv od—the 24 mg od group was discontinued to aid recruitment, but data were included for safety assessments	Co-primary endpoints: Relapse rate and time to 6-month sustained accumulation of disability Relapse rate was lower with alemtuzumab 12 mg vs IFN-β-1a 104 (51%) patients in the IFN-β-1a group relapsed (201 events) compared with 147 (35%) patients in the alemtuzumab group (236 events; rate ratio 0.51; 95% CI 0.39–0.65; p < 0.0001) Risk of sustained accumulation of disability was lower with alemtuzumab 12 mg vs IFN-β-1a 40 (20%) patients in the IFN-β-1a group had sustained accumulation of disability compared with 54 (13%) in the alemtuzumab group (HR 0.58; 95% CI 0.38–0.87; p = 0.008)
TENERE (TErifluNomidE and REbif^®) [48] NCT00883337 2009–2011	Rater-blinded phase 3	324 patients with RRMS Relapsing clinical course with or without progression EDSS score ≤ 5.5 Relapse-free for 30 days prior to randomization	Dosing: IFN-β-1a sc 44 μg tiw Orally administered teriflunomide 7 mg Orally administered teriflunomide 14 mg	Primary composite endpoint: Time to failure, defined as first occurrence of confirmed relapse or permanent treatment discontinuation for any cause No difference in time to failure was observed between either dose of teriflunomide and IFN-β-1a
OPERA I/II NCT01247324/NCT01412333 Randomization: 2011–2013	Two identical phase 3, double-blind, Double-dummy, active-controlled, randomized trials	1656 patients with relapsing MS n = 821 in OPERA I n = 835 in OPERA II EDSS score ≤ 5.5 ≥ 2 relapses in the previous 2 years or ≥ 1 in the previous year MRI showing abnormalities consistent with MS No neurologic worsening for ≥ 30 days before both screening and baseline	Dosing: Ocrelizumab at a dose of 600 mg iv every 24 weeks IFN-β-1a sc at a dose of 44 μg tiw for 96 weeks	Primary endpoint: Annualized relapse rate at 96 weeks ARR was lower with ocrelizumab than with IFN-β-1a in OPERA I (0.16 vs 0.29; 46% lower rate with ocrelizumab; p < 0.001) and OPERA II (0.16 vs 0.29; 47% lower rate; p < 0.001 for both trials) In pooled analyses • The percentage of patients with confirmed disability progression at 12 weeks was lower for ocrelizumab: 9.1% for ocrelizumab vs 13.6% for IFN-β-1a, p < 0.001 • The percentage of patients with confirmed disability progression at 24 weeks was lower for ocrelizumab: 6.9% for ocrelizumab vs 10.5% for IFN-β-1a, p = 0.003
Other MS settings
ETOMS [66] 1995 and 1997	Double-blind, placebo-controlled, randomized study	278 patients who had a first episode of neurological dysfunction suggesting MS At least 1 abnormality evident during neurological examination A positive brain MRI scan (≥ 4 white matter lesions on T2-weighted scans, or ≥ 3 white matter lesions, if ≥ 1 was infratentorial or Gd +)	Dosing: Low dose of 22 µg IFN-β-1a sc qw Placebo	Primary outcome measure: conversion to CDMS, defined by the occurrence of a second exacerbation The time at which 30% of patients had converted to CDMS was longer in patients treated with IFN-β-1a (569 days) vs placebo (252 days, p = 0.034) Fewer participants in the IFN group developed CDMS compared with the placebo group (52/154 [34%] vs 69/154 [45%]; p = 0.047)
REFLEX [49] NCT00404352 2006–2010	Randomized, controlled, double-blind, phase 3 trial	517 participants with a first clinical demyelinating event suggestive of MS ≥ 2 clinically silent T2 lesion	Dosing: Serum-free formulation of IFN-β-1a sc 44 μg tiw (n = 171) Serum-free formulation of IFN-β-1a sc 44 μg qw (n = 175) Placebo (n = 171)	Primary endpoint: Time to a diagnosis of MS as defined by the 2005 McDonald criteria Two-year cumulative probability of a diagnosis of McDonald MS was significantly lower in patients treated with IFN-β-1a sc tiw (62.5%; p < 0.0001; HR 0.49; 95% CI 0.38–0.64; or qw (75.5%, p = 0.008, HR 0.69; 0.54–0.87) vs placebo (85.8%) Risk of conversion to a diagnosis of MS was significantly lower in the IFN-β-1a sc tiw group compared with the qw group (p = 0.0087; HR 0.71; [0.54–0.91]) compared with the placebo group Two-year rates of conversion to clinically definite MS were lower for both IFN-β-1a sc tiw (20.6%; p = 0.0004; HR 0.48 [0.31–0.73]) and qw (21.6%; p = 0.0023; HR 0.53 [0.35–0.79]) than for placebo (37.5%)
REFLEXION [50]	Extension study	Participants who completed the 24-month double-blind REFLEX study	Dosing: Participants who received IFN-β-1a sc in the REFLEX study and did not reach a diagnosis of clinically definite MS continued original treatment Delayed treatment group: participants who received placebo in the REFLEX study who did not reach a diagnosis of clinically definite MS were switched to IFN-β-1a sc 44 μg tiw Participants with clinically definite MS received IFN-β-1a sc 44 μg tiw	Primary endpoint: Time to a diagnosis of MS as defined by the 2005 McDonald criteria Two-year cumulative probability of a diagnosis of McDonald MS was significantly lower for the IFN-β-1a sc 44-μg tiw group compared with the DT group (44.6% for DT, 40.7% for IFN-β-1a sc 44 μg qw [nominal p = 0.084 vs DT], 39.2% for IFN-β-1a sc 44 μg tiw [nominal p = 0.032 vs DT]) The cumulative probability of meeting McDonald MS 2005 criteria was lower in the IFN-β-1a sc 44-μg tiw group compared with the DT group Mean cumulative numbers of new T2, Gd+, and T1 hypointense lesions as well as T2 and T1 hypointense lesion volume changes were lower in the IFN-β-1a sc 44-μg tiw group compared with the DT group (nominal p < 0.05 for all)
SPECTRIMS [51]	Randomized, placebo-controlled trial	Patients with clinically definite SPMS, with or without exacerbations, following an initial relapsing–remitting course Baseline EDSS of 3.0–6.5 Pyramidal functional score ≥ 2	Dosing: IFN-β-1a sc 22 μg tiw IFN-β-1a sc 44 μg tiw Placebo	Primary endpoint: Time to confirmed progression in disability Time to confirmed progression in disability was not different between the IFN-β-1a sc group and placebo group Relapse rates were reduced for both IFN-β-1a sc dose groups (p < 0.001 for both) Exploratory subanalyses suggested a greater benefit of treatment with IFN-β-1a sc in patients with ≥ 1 exacerbation in the 2 years before the study

Study and timing

Design

Study population

Titration and dosing

Outcomes

RRMS

PRISMS [41]

1994–1997

Double-blind, placebo-controlled, phase 3

560 patients with clinically definite or laboratory-supported definite MS of ≥ 1 year duration

Kurtzke EDSS scores of 0–5.0

≥ 2 relapses in the preceding 2 years

Titration:

Dose was gradually increased over 4–8 weeks

Dosing:

IFN-β-1a sc 22 μg tiw

IFN-β-1a sc 44 μg tiw

Placebo tiw

Primary outcome:

Relapse count over the course of the study

Relapse rate was significantly lower at 2 years with both doses of IFN-β-1a than with placebo

Mean number per patient 1.82 and 1.73 for the 22-µg and 44-µg treatment groups, respectively vs 2.56 for the placebo group, (p < 0.005 for both)

Risk reductions of 27% [95% CI 14–39] and 33% [21–44] for the 22-µg and 44-µg treatment groups, respectively, vs the placebo group

Median time to first relapse was delayed by 3 months in the 22-μg group and 5 months in the 44-μg group vs the placebo group

Time to EDSS progression was 21.3, 18.5, and 11.9 months in the IFN 22-μg, 44-μg, and placebo groups, respectively (p < 0.05 vs placebo for both treatment groups)

In patients with high baseline EDSS (> 3.5):

• Time to confirmed progression was significantly longer only in the 44-μg group compared to the placebo group (7.5, 21.3, and 7.3 months in the, IFN 22-μg, 44-μg, and placebo groups, respectively, p < 0.05 vs placebo for the 44-μg group)

Median MRI lesion volume decreased by 1.2% in the 22-µg group and 3.8% in the 44-µg group and increased by 10.9% in the placebo group (p < 0.0001 compared with the placebo group for both IFN doses)

T2 new or enlarging lesion number (determined by proton density T2-weighted scans) was reduced by 67% for the 22-µg group and 78% in the 44-µg group compared to the placebo group (p < 0.0001), with a dose effect in favor of the 44-µg tiw group (p = 0.0003)

OWIMS [42]

1995–1996

Double-blind, placebo-controlled, phase 3

293 patients with clinically definite or laboratory-supported definite RRMS of ≥ 1 year duration

Kurtzke EDSS scores of 0–5.0

≥ 1 relapse in the prior 24 months but not in the 8 weeks before entry

≥ 3 lesions consistent with MS

Dosing:

IFN-β-1a sc 22 μg qw

IFN-β-1a sc 44 μg qw

Placebo qw

Primary outcome:

Number of CUA lesions at 24 weeks

Median CUA lesions of 0.71/scan with placebo, 0.5/scan with 22 μg qw (not significant), and 0.33/scan with 44 μg qw (p = 0.002)

T2 new lesion count/scan (mean/median) at 48 weeks was 3.2/1.5 for placebo, 2.4/1.0 for 22 μg (p = 0.03), and 1.5/1.0 for 44 μg (p = 0.0005)

BOD at 48 weeks showed a median increase of 5.9% for the placebo group compared with a decrease of 2% in the 22-μg qw group (p = 0.0018) and 1.4% in the 44-μg qw group (p = 0.0058)

EVIDENCE [43, 55]

1999–2002

Randomized, controlled, assessor-blinded

677 patients with relapsing MS

EDSS scores of 0–5.5

≥ 2 exacerbations in the preceding 2 years

Titration:

In patients randomized to high-dose tiw treatment, the dose was increased over 4 weeks, with patients receiving 8.8 μg tiw for the first 2 weeks and 22 μg tiw for the next 2 weeks

Dosing:

IFN-β-1a sc 44 μg tiw

IFN-β-1a im 30 μg qw

Primary clinical endpoint:

Proportion of patients who remained free from relapses

The proportion of patients who remained relapse-free was significantly greater in the high-dose tiw treatment group vs the low-dose qw treatment group (adjusted odds ratio 1.5; 95% CI 1.1–2.0; p = 0.023)

After 24 weeks, 74.9% of the IFN-β-1a sc 44-µg tiw group and 63.3% of the IFN-β-1a im 30-µg qw group remained free from relapses (p = 0.0005)

At the end of the 64-week comparative phase

• A higher proportion of patients in the IFN-β-1a sc 44-µg tiw group remained free from relapses compared with the IFN-β-1a im 30-µg qw group (p = 0.023)

• ARR was 17% lower (p = 0.033) in the IFN-β-1a sc 44-µg tiw group vs the IFN-β-1a im 30-µg qw group

• Time to first relapse was longer (hazard ratio [HR] 0.70; p = 0.002) in the IFN-β-1a sc 44-µg tiw group compared with the IFN-β-1a im 30-µg qw group at the end of the comparative phase

During the second phase

The group that changed from qw im to tiw sc dosing had

• A 50% reduction in mean relapse rates (p < 0.001)

• Significant reductions in MRI activity vs the comparative phase of the study

The group that had remained with tiw sc dosing from the comparison phase had

• A 26% reduction in mean relapse rates (p < 0.028)

REGARD [44]

2004–2006

Multicenter, randomized, parallel, open-label

764 patients with RRMS

EDSS scores of 0–5.5

≥ 1 attack in the previous 12 months

Clinically stable or neurologically improving during the 4 weeks before randomization

Titration:

Patients who received IFN-β-1a had a standard dose titration for the first 4 weeks

Dosing:

IFN-β-1a sc 44 μg tiw

Glatiramer acetate sc 20 mg od

Primary outcome measure:

Time to first relapse over 96 weeks

No significant difference in time to first relapse between the treatment groups (HR 0.94; 95% CI 0.74–1.21; p = 0.64)

No significant differences between groups were observed in

• Numbers of T2 active lesions (defined as new or enlarging T2 lesions),

• Proportions of scans with T2 active lesions, change in T2 lesion volume

There were significantly fewer Gd+ lesions with IFN-β-1a compared with GA (0.24 vs 0.41 lesions per patient per scan, 95% CI − 0.4 to 0.1; p = 0.0002)

IMPROVE (Investigating MRI Parameters with Rebif® imprOVEd formulation) [45]

NCT00441103

2006–2009

Randomized, double-blind (16 weeks) and rater-blind (24 weeks) phases

180 patients with RRMS

EDSS scores of 0–5.5

Active disease ≥ 1 clinical event and ≥ 1 Gd+ MRI lesion within the previous 6 months

Dosing:

New formulation of IFN-β-1a sc 44 μg tiw

Primary endpoint:

The number of CUA MRI brain lesions at week 16

At week 16, the mean number of CUA lesions was lower with IFN-β-1a sc 44 μg tiw vs placebo (p < 0.001; 69% fewer lesions)

No CUA lesions were observed in 53.3% of patients receiving IFN-β-1a vs 16.7% of those receiving placebo

Extension studies

PRISMS-4 [46]

1997–1999

Long-term, double-blind extension

533 patients with RRMS who had participated in the PRISMS study

Dosing:

IFN-β-1a sc 22 μg tiw

IFN-β-1a sc 44 μg tiw

Crossover:

Placebo, followed by IFN-β-1a sc 22 μg tiw

Placebo, followed by IFN-β-1a sc 44 μg tiw

Primary outcome:

Relapse count per patient over 4 years

Relapse rates for 4 years were

• Crossover (placebo/IFN-β-1a sc): 1.02

• IFN-β-1a sc 22 μg tiw: 0.80 (p < 0.001 vs crossover)

• IFN-β-1a sc 44 μg tiw: 0.72 (p < 0.001 vs crossover)

PRISMS-7/8 [59]

Long-term open-label follow-up of a double-blind initial study

382 patients with RRMS who had participated in the PRISMS study

Dosing:

IFN-β-1a sc 22 μg tiw

IFN-β-1a sc 44 μg tiw

Compared with patients in the late treatment group, patients originally randomized to IFN-β-1a 44 μg sc tiw demonstrated

• Less EDSS progression

• Lower relapse rates

• Less T2 burden of disease

PRISMS-15 [60]

290 patients with RRMS who had participated in the PRISMS study

Dosing:

IFN-β-1a sc 22 μg tiw

IFN-β-1a sc 44 μg tiw

Higher cumulative dose exposure and longer treatment times (i.e., the highest dose quartile) were associated with better outcomes compared with the lowest dose quartile as measured by:

• Annualized relapse rate (0.37 and 0.50, respectively)

• Number of relapses (5.8 and 7.8)

• 3-month confirmed EDSS progression (38% vs 50%)

• Mean change in EDSS score (1.15 and 2.53)

• Conversion to SPMS (20.8% and 52.1%)

Active comparator

CARE-MS I [47]

NCT00530348

Enrollment: 2007–2009

Randomized rater-masked, controlled phase 3 trial

581 patients with RRMS with disease duration ≤ 5 years

≥ 2 relapses in the previous 2 years and ≥ 1 in the previous year

EDSS score ≤ 3.0

Cranial abnormalities on MRI attributable to MS

Dosing:

IFN-β-1a sc 44 μg tiw

Alemtuzumab 12 mg iv od (od for 5 days at baseline and od for 3 days at 12 months)

Co-primary endpoints:

Relapse rate and time to 6-month sustained accumulation of disability

75 (40%) patients in the IFN-β-1a sc 44-μg tiw group relapsed (122 events) compared with 82 (22%) patients in the alemtuzumab group (119 events; rate ratio 0.45; 95% CI 0.32–0.63; p < 0.0001)

20 (11%) of the IFN-β-1a sc 44-μg tiw group had sustained accumulation of disability vs 30 (8%) in the alemtuzumab group (HR 0.70; 95% CI 0.40–1.23; p = 0.22)

CARE-MS II [47]

NCT00548405

Enrollment: 2007–2009

Rater-masked, randomised controlled phase 3

581 patients with RRMS with disease duration ≤ 10 years

≥ 2 relapses in the previous 2 years and ≥ 1 in the previous year

≥ 1 relapse on IFN-β or glatiramer after ≥ 6 months of treatment

EDSS score ≤ 5.0

Cranial and spinal MRI lesions fulfilling protocol-defined criteria

Dosing:

IFN-β-1a sc 44 μg tiw

Alemtuzumab 12 mg iv od (od for 5 days at baseline and od for 3 days at 12 months)

Alemtuzumab 24 mg iv od—the 24 mg od group was discontinued to aid recruitment, but data were included for safety assessments

Co-primary endpoints:

Relapse rate and time to 6-month sustained accumulation of disability

Relapse rate was lower with alemtuzumab 12 mg vs IFN-β-1a

104 (51%) patients in the IFN-β-1a group relapsed (201 events) compared with 147 (35%) patients in the alemtuzumab group (236 events; rate ratio 0.51; 95% CI 0.39–0.65; p < 0.0001)

Risk of sustained accumulation of disability was lower with alemtuzumab 12 mg vs IFN-β-1a

40 (20%) patients in the IFN-β-1a group had sustained accumulation of disability compared with 54 (13%) in the alemtuzumab group (HR 0.58; 95% CI 0.38–0.87; p = 0.008)

TENERE (TErifluNomidE and REbif^®) [48]

NCT00883337

2009–2011

Rater-blinded phase 3

324 patients with RRMS

Relapsing clinical course with or without progression

EDSS score ≤ 5.5

Relapse-free for 30 days prior to randomization

Dosing:

IFN-β-1a sc 44 μg tiw

Orally administered teriflunomide 7 mg

Orally administered teriflunomide 14 mg

Primary composite endpoint:

Time to failure, defined as first occurrence of confirmed relapse or permanent treatment discontinuation for any cause

No difference in time to failure was observed between either dose of teriflunomide and IFN-β-1a

OPERA I/II

NCT01247324/NCT01412333

Randomization: 2011–2013

Two identical phase 3, double-blind,

Double-dummy, active-controlled, randomized trials

1656 patients with relapsing MS

n = 821 in OPERA I

n = 835 in OPERA II

EDSS score ≤ 5.5

≥ 2 relapses in the previous 2 years or ≥ 1 in the previous year

MRI showing abnormalities consistent with MS

No neurologic worsening for ≥ 30 days before both screening and baseline

Dosing:

Ocrelizumab at a dose of 600 mg iv every 24 weeks

IFN-β-1a sc at a dose of 44 μg tiw for 96 weeks

Primary endpoint:

Annualized relapse rate at 96 weeks

ARR was lower with ocrelizumab than with IFN-β-1a in OPERA I (0.16 vs 0.29; 46% lower rate with ocrelizumab; p < 0.001) and OPERA II (0.16 vs 0.29; 47% lower rate; p < 0.001 for both trials)

In pooled analyses

• The percentage of patients with confirmed disability progression at 12 weeks was lower for ocrelizumab: 9.1% for ocrelizumab vs 13.6% for IFN-β-1a, p < 0.001

• The percentage of patients with confirmed disability progression at 24 weeks was lower for ocrelizumab: 6.9% for ocrelizumab vs 10.5% for IFN-β-1a, p = 0.003

Other MS settings

ETOMS [66]

1995 and 1997

Double-blind, placebo-controlled, randomized study

278 patients who had a first episode of neurological dysfunction suggesting MS

At least 1 abnormality evident during neurological examination

A positive brain MRI scan (≥ 4 white matter lesions on T2-weighted scans, or ≥ 3 white matter lesions, if ≥ 1 was infratentorial or Gd +)

Dosing:

Low dose of 22 µg IFN-β-1a sc qw

Placebo

Primary outcome measure: conversion to CDMS, defined by the occurrence of a second exacerbation

The time at which 30% of patients had converted to CDMS was longer in patients treated with IFN-β-1a (569 days) vs placebo (252 days, p = 0.034)

Fewer participants in the IFN group developed CDMS compared with the placebo group (52/154 [34%] vs 69/154 [45%]; p = 0.047)

REFLEX [49]

NCT00404352

2006–2010

Randomized, controlled, double-blind, phase 3 trial

517 participants with a first clinical demyelinating event suggestive of MS

≥ 2 clinically silent T2 lesion

Dosing:

Serum-free formulation of IFN-β-1a sc 44 μg tiw (n = 171)

Serum-free formulation of IFN-β-1a sc 44 μg qw (n = 175)

Placebo (n = 171)

Primary endpoint:

Time to a diagnosis of MS as defined by the 2005 McDonald criteria

Two-year cumulative probability of a diagnosis of McDonald MS was significantly lower in patients treated with IFN-β-1a sc tiw (62.5%; p < 0.0001; HR 0.49; 95% CI 0.38–0.64; or qw (75.5%, p = 0.008, HR 0.69; 0.54–0.87) vs placebo (85.8%)

Risk of conversion to a diagnosis of MS was significantly lower in the IFN-β-1a sc tiw group compared with the qw group (p = 0.0087; HR 0.71; [0.54–0.91]) compared with the placebo group

Two-year rates of conversion to clinically definite MS were lower for both IFN-β-1a sc tiw (20.6%; p = 0.0004; HR 0.48 [0.31–0.73]) and qw (21.6%; p = 0.0023; HR 0.53 [0.35–0.79]) than for placebo (37.5%)

REFLEXION [50]

Extension study

Participants who completed the 24-month double-blind REFLEX study

Dosing:

Participants who received IFN-β-1a sc in the REFLEX study and did not reach a diagnosis of clinically definite MS continued original treatment

Delayed treatment group: participants who received placebo in the REFLEX study who did not reach a diagnosis of clinically definite MS were switched to IFN-β-1a sc 44 μg tiw

Participants with clinically definite MS received IFN-β-1a sc 44 μg tiw

Primary endpoint:

Time to a diagnosis of MS as defined by the 2005 McDonald criteria

Two-year cumulative probability of a diagnosis of McDonald MS was significantly lower for the IFN-β-1a sc 44-μg tiw group compared with the DT group (44.6% for DT, 40.7% for IFN-β-1a sc 44 μg qw [nominal p = 0.084 vs DT], 39.2% for IFN-β-1a sc 44 μg tiw [nominal p = 0.032 vs DT])

The cumulative probability of meeting McDonald MS 2005 criteria was lower in the IFN-β-1a sc 44-μg tiw group compared with the DT group

Mean cumulative numbers of new T2, Gd+, and T1 hypointense lesions as well as T2 and T1 hypointense lesion volume changes were lower in the IFN-β-1a sc 44-μg tiw group compared with the DT group (nominal p < 0.05 for all)

SPECTRIMS [51]

Randomized, placebo-controlled trial

Patients with clinically definite SPMS, with or without exacerbations, following an initial relapsing–remitting course

Baseline EDSS of 3.0–6.5

Pyramidal functional score ≥ 2

Dosing:

IFN-β-1a sc 22 μg tiw

IFN-β-1a sc 44 μg tiw

Placebo

Primary endpoint:

Time to confirmed progression in disability

Time to confirmed progression in disability was not different between the IFN-β-1a sc group and placebo group

Relapse rates were reduced for both IFN-β-1a sc dose groups (p < 0.001 for both)

Exploratory subanalyses suggested a greater benefit of treatment with IFN-β-1a sc in patients with ≥ 1 exacerbation in the 2 years before the study

ARR annualized relapse rate, BOD burden of disease, CDMS clinically definite MS, CI confidence interval, CUA combined unique active, DT delayed treatment, EDSS Expanded Disability Status Scale, Gd+ gadolinium-enhancing, HR hazard ratio, IFN interferon, im intramuscular, iv intravenous, MRI magnetic resonance imaging, MS multiple sclerosis, od once per day, qw once per week, RRMS relapsing–remitting MS, sc subcutaneous, SPMS secondary progressive MS, tiw three times per week