Pharmacological Approaches to Delaying Disability Progression in Patients with Multiple Sclerosis

Abstract

In individuals with multiple sclerosis, physical and cognitive disability progression are clinical and pathophysiological hallmarks of the disease. Despite shortcomings, particularly in capturing cognitive deficits, the Expanded Disability Status Scale is the assessment of disability progression most widely used in clinical trials. Here, we review treatment effects on disability that have been reported in large clinical trials of disease-modifying treatment, both among patients with relapsing–remitting disease and among those with progressive disease. However, direct comparisons are confounded to some degree by the lack of consistency in assessment of disability progression across trials. Confirmed disability progression (CDP) is a more robust measure when performed over a 6-month than a 3-month interval, and reduction in the risk of 6-month CDP in phase III trials provides good evidence for the beneficial effects on disability of several high-efficacy treatments for relapsing–remitting disease. It is also becoming increasingly clear that therapies effective in relapsing–remitting disease have little impact on the course of progressive disease. Given that the pathophysiological mechanisms, which lead to the long-term accrual of physical and cognitive deficits, are evident at the earliest stages of disease, it remains a matter of debate whether the most effective therapies are administered early enough to afford patients the best long-term outcomes.

Key Points

Several high-efficacy immune therapies can reduce the risk of disability progression in relapsing–remitting multiple sclerosis.

A standard definition of disability progression would facilitate comparative evaluation of therapies.

In relapsing multiple sclerosis, and potentially in certain progressive phenotypes, the best outcomes may be afforded by early treatment with the most effective immune therapies.

Introduction

Disability progression is a key clinical outcome in patients with multiple sclerosis (MS) that was originally assessed using the Disability Status Scale (DSS) [1]. The DSS was superseded by an expanded version of the scale [Expanded DSS (EDSS)], with which worsening disability can be scored in 0.5-point increments from 0 (normal neurological status) to 10 (death due to MS) [2]. Without treatment, patients with MS accrue moderate levels of disability (DSS score of 3) on average within 8 years of diagnosis, and need assistance walking (DSS score of 6) within 15 years of diagnosis [3]. Compounded by the unpredictable and debilitating nature of relapses experienced by many patients early in the disease course, even moderate levels of disability can be highly disruptive to normal living. A retrospective analysis of the Danish MS patient registry found that the median time from onset of MS to retirement (receipt of an early pension) was 10 years, compared with 24 years among matched control individuals [4]. A study of patients in nine European countries found an unemployment rate of 50 % among patients of working age with an EDSS score of 3.0, and also found a steady decline in utility score [calculated from the 5-dimension European Quality of Life (EuroQol) questionnaire] with increasing EDSS score [5].

The EDSS focuses mainly on motor function and ambulation, but captures cognitive decline poorly and has several other shortcomings [6]: ambiguity in the original rules for scoring affects reproducibility among raters, especially in the range 0–4.0 [7–10]; the scale is non-linear (i.e. the clinical importance of a 1-point increase varies depending on initial score) and a patient’s rate of progression through the scale also depends on baseline score [11]. This situation prompted development of the MS Functional Composite (MSFC), which assesses disability progression based on dexterity (Nine-Hole Peg Test), ambulation (Timed 25-Foot Walk Test) and cognitive function [Paced Auditory Serial Addition Test (PASAT)] [12, 13]. The MSFC has advantages over the EDSS, and is included as an endpoint in many studies, but it also has limitations: z scores (the summary score from the three components) are difficult to interpret; learning effects can skew PASAT on repeated use; and assessment of visual impairment is excluded [14].

Here, we review evidence for the potential of disease-modifying treatments (DMTs) to delay disability progression in patients with MS. We summarize disability data from all completed phase III trials of both approved and experimental therapies in patients with all forms of MS, grouping treatments by route of administration. Disability data from phase II trials are also reported, and a number of failed or inconclusive trials are listed, although these have been reviewed extensively elsewhere [15, 16]. The EDSS is the assessment most commonly used in MS trials (relatively few report changes in MSFC score), therefore we focus on measures related to EDSS score, such as confirmed disability progression (CDP), which is usually based on changes in the score sustained over 3 or 6 months; of these, 6-month CDP is the more robust indicator of permanent disability progression [17, 18]. Generally, CDP is defined as a 1.0-point increase if the EDSS score is less than 5.5 at baseline (sometimes a 1.5-point increase if EDSS score is 0), and as a 0.5-point increase if the baseline EDSS score is at least 5.5, but variations in these criteria are noted.

Reflecting the current treatment landscape, the majority of trials are in patients with relapsing–remitting MS (RRMS), rather than clinically isolated syndrome (CIS), primary progressive MS (PPMS) or secondary progressive MS (SPMS), and although used in the trials discussed here, some of this nomenclature has been recently superseded [19]. Trials are therefore grouped as pertaining to relapsing–remitting or to progressive disease.

Therapies in Patients with Relapsing–Remitting MS

Summary trial information and baseline characteristics are shown in Table 1 and disability outcomes from each trial are provided in Table 2.

Table 1.

Baseline characteristics of patients with relapsing forms of MS in phase II and III trials that report disability outcomes

Trial name	Interventions	Baseline characteristics
		n	Age (years)	Women (%)	EDSS score	MSFC score	Disease durationa (years)
Oral therapies
FREEDOMS NCT00289978 [20]	Fingolimod 0.5 mg	425	36.6 (8.8)	69.6	2.3 (1.3)	NR	8.0 (6.6)
	Fingolimod 1.25 mg	429	37.4 (8.9)	68.8	2.4 (1.4)		8.4 (6.9)
	Placebo	418	37.2 (8.6)	71.3	2.5 (1.3)		8.1 (6.4)
FREEDOMS II NCT00355134 [21]	Fingolimod 0.5 mg	358	40.6 (8.4)	77	2.4 (1.3)	0.04 (0.7)	10.4 (8.0)
	Fingolimod 1.25 mg	370	40.9 (8.9)	76	2.5 (1.3)	0 (0.7)	10.8 (8.2)
	Placebo	355	40.1 (8.4)	81	2.4 (1.3)	−0.02 (0.8)	10.6 (7.9)
TRANSFORMS NCT00340834 [22]	Fingolimod 0.5 mg	431	36.7 (8.8)	65.4	2.24 (1.33)	NR	7.5 (6.2)
	Fingolimod 1.25 mg	426	35.8 (8.4)	68.8	2.21 (1.31)		7.3 (6.0)
	IFN beta-1a i.m. 30 µg/week	435	36.0 (8.3)	67.8	2.19 (1.26)		7.4 (6.3)
NCT00333138 [117]	Fingolimod 1.25 mg	93	38.0	75.3	2.7	NR	8.6
	Fingolimod 5.0 mg	92	38.3	70.7	2.5		9.5
	Placebo	92	37.1	66.3	2.6		8.4
NCT00537082 [118]	Fingolimod 0.5 mg	57	35.0 (9.0)	70.2	2.3 (1.9)	NR	8.2 (6.8)
	Fingolimod 1.25 mg	57	36.0 (9.3)	68.4	1.8 (1.7)		7.1 (5.3)
	Placebo	57	35.0 (8.9)	68.4	2.1 (1.7)		8.2 (7.3)
NCT00670449 [119]	Fingolimod 0.5 mg	47	34.9 (9.0)	70.2	2.4 (1.9)	NR	8.2 (6.6)
	Fingolimod 1.25 mg	46	35.7 (8.8)	67.4	1.9 (1.7)		7.6 (5.5)
	Placebo-fingolimod 0.5 mg	27	34.2 (9.1)	70.4	1.9 (1.6)		8.4 (8.1)
	Placebo-fingolimod 1.25 mg	23	35.5 (8.4)	60.9	2.4 (1.6)		8.4 (7.2)
TEMSO NCT00134563 [27]	Teriflunomide 7 mg	366	37.4 (9.0)	69.7	2.68 (1.34)	NR	8.8 (6.8)
	Teriflunomide 14 mg	359	37.8 (8.2)	71.0	2.67 (1.24)		8.7 (6.7)
	Placebo	363	38.4 (9.0)	75.8	2.68 (1.34)		8.6 (7.1)
TOWER NCT00751881 [28]	Teriflunomide 7 mg	408	37.4 (9.4)	74	2.71 (1.39)	NR	8.18 (6.75)
	Teriflunomide 14 mg	372	38.2 (9.4)	69	2.71 (1.35)		8.18 (6.73)
	Placebo	389	38.1 (9.1)	70	2.69 (1.36)		7.64 (6.70)
TOPIC NCT00622700 [29]	Teriflunomide 7 mg	205	31.6 (9.0)	63	1.50 (1.02)	NR	1.89 (0.56)b
	Teriflunomide 14 mg	216	32.8 (8.1)	71	1.80 (0.97)		1.80 (0.56)b
	Placebo	197	32.0 (8.4)	69	1.71 (1.00)		1.88 (0.52)b
NCT01487096 [120]	Teriflunomide 7 mg	61	40.1 (9.3)	75.4	2.5c	NR	10.3 (8.1)
	Teriflunomide 14 mg	57	40.1 (9.1)	78.9	2.0c		8.5 (7.1)
	Placebo	61	39.2 (8.7)	67.2	2.5c		8.6 (7.9)
NCT00475865 NCT00811395 [no publication]	Teriflunomide 7 mg + GA s.c.d	42	42.1 (7.8)	78.6	2.43 (1.23)	NR	8.82 (5.85)e
	Teriflunomide 14 mg + GA s.c.d	40	40.3 (7.5)	80.0	2.60 (1.28)		7.60 (6.03)e
	Placebo + GA s.c.d	41	41.8 (8.5)	78.0	2.54 (1.11)		7.61 (6.04)e
NCT00489489 NCT00811395 [121]	Teriflunomide 7 mg + IFNf	37	41.4 (6.8)	67.6	2.4 (1.4)	NR	8.35 (5.44)e
	Teriflunomide 14 mg + IFNf	38	39.6 (8.1)	65.8	2.5 (1.6)		7.97 (6.59)e
	Placebo + IFNf	41	39.2 (9.0)	75.6	2.6 (1.3)		8.78 (5.62)e
CONFIRM NCT00451451 [34]	DMF 240 mg twice/day	359	37.8 (9.4)	68	2.6 (1.2)	NR	4.9 (5.1)e
	DMF 240 mg three times/day	345	37.8 (9.4)	72	2.5 (1.2)		4.6 (5.2)e
	GA 20 mg s.c. once/day	350	36.7 (9.1)	71	2.6 (1.2)		4.4 (4.7)e
	Placebo	363	36.9 (9.2)	69	2.6 (1.2)		4.8 (5.0)e
DEFINE NCT00420212 [35]	DMF 240 mg twice/day	410	38.1 (9.1)	72	2.40 (1.29)	NR	5.6 (5.4)e
	DMF 240 mg three times/day	416	38.8 (8.8)	74	2.36 (1.19)		5.1 (5.3)e
	Placebo	408	38.5 (9.1)	75	2.48 (1.24)		5.8 (5.8)e
ALLEGRO NCT00509145 [37]	Laquinimod 0.6 mg/day	550	38.9 (9.2)	71.1	2.6 (1.3)	NR	8.7 (6.9)
	Placebo	556	38.5 (9.1)	66.2	2.6 (1.3)		8.7 (6.7)
BRAVO NCT00605215 [38]	Laquinimod 0.6 mg/day	434	36.7	65.0c	2.5c	NR	4.9c
	IFN beta-1a i.m. 30 µg/week	447	38.5	68.7c	2.5c		5.3c
	Placebo	450	37.5	71.3c	2.5c		4.7c
CLARITY NCT00213135 [39]	Cladribine 3.5 mg/kg	433	37.9 (10.3)	68.8	2.8 (1.2)	NR	7.9 (7.2)
	Cladribine 5.25 mg/kg	456	39.1 (9.9)	68.4	3.0 (1.4)		9.3 (7.6)
	Placebo	437	38.7 (9.9)	65.9	2.9 (1.3)		8.9 (7.4)
EudraCT code 2006-004937-13 [42]	Azathioprine 3 mg/kg/day	77	38.1 (8.9)	63.6	1.9 (0.9)	NR	6.8 (7.1)
	IFNf	73	36.6 (8.8)	68.5	1.9 (0.9)		5.7 (5.7)
TIME-MS NCT00223301 [122]	Mycophenolate mofetil 250 mg four times/day + IFN beta-1a i.m. 30 µg/week	12	36 (7.8)	75.0	1.75 (1.12)	NRg	≤2h
	Placebo + IFN beta-1a i.m. 30 μg/week	12	38 (10.6)	91.7	1.17 (1.01)		≤2h
SWABIMS NCT01111656 [123]	Atorvastatin 40 mg/day + IFN beta-1b s.c.d	13	32.15 (9.61)	76.9	1.88 (0.79)	0.42 (0.26)	1.45 (4.51)
	IFN beta-1b s.c.d (no add-on placebo)	14	36.93 (8.24)	64.3	1.75 (0.91)	0.24 (0.39)	1.21 (2.2)
OFAMS NCT00360906 [124]	EPA 1350 mg/day + DHA 850 mg/day	46	38.8 (8.4)	65	1.94 (0.78)	NR	5.4 (5.4)
	Placebo (all patients started IFN beta-1a s.c. 44 µg three times/week at 6 months)	45	38.3 (8.4)	64	1.86 (0.86)		5.8 (5.9)
NCT00395317 [125]	Firategrast 150 mg twice/day	49	37 (11)	67	2.7 (1.4)	NR	5.6 (6.6)
	Firategrast 600 mg twice/day	95	39 (10)	67	2.8 (1.2)		6.5 (6.3)
	Firategrast 900 mg or 1200 mg twice/dayi	100	41 (11)	68	2.9 (1.5)		5.7 (5.2)
	Placebo	99	39 (11)	76	2.7 (1.4)		5.5 (5.9)
Intravenous therapies
CARE-MS I NCT00530348 [45]	Alemtuzumab 12 mg/dayj	376	33.0 (8.0)	65	2.0 (0.8)	NR	2.1 (1.4)
	IFN beta-1a s.c. 44 µg three times/week	187	33.2 (8.5)	65	2.0 (0.8)		2.0 (1.3)
CARE-MS II NCT00548405 [46]	Alemtuzumab 12 mg/dayj	426	34.8 (8.36)	66	2.7 (1.26)	NR	4.5 (2.68)
	Alemtuzumab 24 mg/dayj	170	35.1 (8.40)	71	2.7 (1.17)		4.3 (2.77)
	IFN beta-1a s.c. 44 µg three times/week	202	35.8 (8.77)	65	2.7 (1.21)		4.7 (2.86)
CAMM223 NCT00050778 [126]	Alemtuzumab 12 mg/dayj	112	31.9 (8.0)	64.3	1.9 (0.74)	NR	1.3c,k
	Alemtuzumab 24 mg/dayj	110	32.2 (8.8)	64.5	2.0 (0.73)		1.2c,k
	IFN beta-1a s.c. 44 µg three times/week	111	32.8 (8.8)	64.0	1.9 (0.83)		1.4c,k
AFFIRM NCT00027300 [49]	Natalizumab 300 mg every 4 weeks	627	35.6 (8.5)	72	2.3 (1.2)	NR	5.0c
	Placebo	315	36.7 (7.8)	67	2.3 (1.2)		6.0c
SENTINEL NCT00030966 [50]	Natalizumab 300 mg every 4 weeks + IFN beta-1a i.m. 30 μg/week	589	38.8 (7.7)	75	2.4 (1.1)	NR	7.0c
	Placebo + IFN beta-1a i.m. 30 μg/week	582	39.1 (7.6)	72	2.5 (1.1)		8.0c
NCT00516893 [no publication]	Natalizumab 300 mg every 4 weeks	113	38.9 (8.64)	80.5	3.66 (1.817)	NR	NR
[no trial code] [53]	Mitoxantrone 8 mg/m2 once/month	27	30.9 (6.0)	63.0	3.6 (0.9)	NR	5.7 (3)
	Placebo	24	28.7 (6.5)	75.0	3.5 (1.2)		5.0 (3)
[no trial code] [52]	Mitoxantrone 20 mg once/month + methylprednisolone 1 g/month	21	31.4 (8.3)	71.4	4.4 (1.8)	NR	6.9 (3.6)
	Methylprednisolone 1 g/month	21	32.2 (8.1)	52.4	4.7 (1.5)		5.7 (4.0)
French–Italian Mitoxantrone IFN beta-1b Trial Group NCT00219908 [55]	Mitoxantrone 12 mg/m2 once/month + methylprednisolone 1 g/month	54	33.8 (7.7)	65.5	4.1 (1.1)	NR	7.0 (5.4)
	Methylprednisolone 1 g/month (treatment during months 0–6)l	55	32.2 (8.1)	66.7	3.8 (0.9)		5.6 (5.1)
Injectable therapies
GALA NCT01067521 [58]	GA s.c. 40 mg three times/week	943	37.4 (9.4)	68.0	2.8 (1.2)	NR	7.7 (6.7)
	Placebo	461	38.1 (9.2)	67.9	2.7 (1.2)		7.6 (6.4)
REGARD NCT00078338 [60]	IFN beta-1a s.c. 44 µg three times/week	386	36.7 (9.8)	69	2.35 (1.28)	NR	5.93 (6.25)k
	GA s.c. 20 mg/day	378	36.8 (9.5)	72	2.33 (1.31)		6.55 (7.10)k
CombiRx NCT00211887 [62]	IFN beta-1a i.m. 30 µg once/week +  GA s.c. 20 mg/day	499	37.1 (9.4)	74.6	1.9 (1.2)	0.03 (0.73)	1.1 (3.1)
	IFN beta-1a i.m. 30 µg once/week + placebo	250	37.6 (10.2)	69.2	2.0 (1.2)	−0.01 (0.75)	1.4 (4.0)
	GA s.c. 20 mg/day + placebo	259	39.0 (9.5)	71.4	1.9 (1.2)	−0.03 (0.73)	1.0 (2.9)
BEYOND NCT00099502 [61]	IFN beta-1b s.c. 250 µg e.o.d.	897	35.8	70	2.35	NR	5.3
	IFN beta-1b s.c. 500 µg e.o.d.	899	35.9	70	2.33		5.4
	GA s.c. 20 mg/day	448	35.2	68	2.28		5.1
MSCRG [no trial code] [73] PRISMS [no trial code] [75]	IFN beta-1a i.m. 30 µg once/week	158	36.7 (0.57)m	75	2.4 (0.06)m	NR	6.6 (0.46)m
	Placebo	143	36.9 (0.64)m	72	2.3 (0.07)m		6.4 (0.49)m
	IFN beta-1a s.c. 22 µg three times/week	189	34.8c	67	2.5 (1.2)	NR	5.4c
	IFN beta-1a s.c. 44 µg three times/week	184	35.6c	66	2.5 (1.3)		6.4c
	Placebo	187	34.6c	75	2.4 (1.2)		4.3c
EVIDENCE NCT00292266 [76]	IFN beta-1a s.c. 44 µg three times/week	339	38.3	74.9	2.3	NR	6.5
	IFN beta-1a i.m. 30 µg four times/week	338	37.4	74.6	2.3		6.7
ADVANCE NCT00906399 [83]	Pegylated IFN beta-1a 125 µg every 2 weeks	512	36.9 (9.8)	71	2.47 (1.26)	NR	6.9 (6.6)
	PEGylated IFN beta-1a 125 µg every 4 weeks	500	36.4 (9.9)	70	2.48 (1.24)		6.5 (6.1)
	Placebo	500	36.3 (9.7)	72	2.44 (1.18)		6.3 (6.3)
IFNB [no trial code] [80]	IFN beta-1b s.c. 50 μg (1.6 MIU) e.o.d.	125	35.3 (0.7)m	68.0	2.9 (0.1)k	NR	4.7 (0.4)e,m
	IFN beta-1b s.c. 250 μg (8 MIU) e.o.d.	124	35.2 (0.6)m	69.4	3.0 (0.1)k		4.7 (0.4)e,m
	Placebo	123	36.0 (0.6)m	71.5	2.8 (0.1)k		3.9 (0.3)e,m
INCOMIN [no trial code] [82]	IFN beta-1b s.c. 250 μg (8 MIU) e.o.d.	96	38.8 (7.1)	69	1.97 (0.7)	NR	5.9 (4.2)
	IFN beta-1a i.m. 30 µg (6 MIU) once/week	92	34.9 (7.9)	62	1.96 (0.7)		6.7 (5.4)
NCT00207727 [127]	Ustekinumab 27 mg every 4 weeks	50	37c	64	2c	NR	1.70c
	Ustekinumab 90 mg every 4 weeks	50	39c	66	2.5c		1.85c
	Ustekinumab 180 mg every 4 weeks	50	40.5c	72	2.5c		2.15c
	Ustekinumab 90 mg every 8 weeks	50	37c	74	2.75c		2.25c
	Placebo	49	34c	76	2.5c		1.90c

Data are shown as mean (SD) unless otherwise indicated

CIS clinically isolated syndrome, DHA docosahexaenoic acid, DMF dimethyl fumarate, EDSS expanded disability status scale, e.o.d. every other day, EPA eicosapentaenoic acid, GA glatiramer acetate, IFN interferon, i.m. intramuscular, MIU million international units, MS multiple sclerosis, MSFC MS functional composite, NR not reported, s.c. subcutaneous, SD standard deviation

^aDisease duration stated as (or presumed to be) years since first symptoms unless noted otherwise

^bDisease duration reported in months rather than years (all patients had CIS)

^cMedian values

^dDose NR

^eTime since diagnosis rather than time since first symptoms

^fIFN beta-1a (30 μg i.m. once weekly or 22 µg or 44 µg s.c. three times weekly) or IFN beta-1b 250 μg s.c. e.o.d

^gMSFC component scores are reported but not the composite z score [122]

^hOne of the eligibility criteria; mean disease duration not reported

ⁱHigher dose was administered in men, lower dose in women

^jInfused on 5 consecutive days at baseline and for 3 consecutive days at 12-month intervals

^kTime since first relapse

^lSpecified treatments continued until month 6; the control group also started IFN beta-1b s.c. e.o.d. at baseline and the mitoxantrone group started IFN beta-1b s.c. e.o.d. at month 9; both groups were treated until month 36

^mStandard error reported rather than SD

Table 2.

Phase II and III trials reporting disability outcomes in patients with relapsing forms of multiple sclerosis (MS)

Trial name	Interventions	Study outcomes
		F/U, months	3-month CDP HR (95 % CI) versus controla	6-month CDP HR (95 % CI) versus controla	Mean (SD) change in EDSS score from BL	Mean (SD) change in MSFC score from BL	Increase in EDSS for CDPb
Oral therapies
FREEDOMS NCT00289978 [20]	Fingolimod 0.5 mg	24	0.70 (0.52, 0.96)*	0.63 (0.44, 0.90)*	0.00 (0.88)**	0.03 (0.39)*	≥0.5 if BL >5.5
	Fingolimod 1.25 mg		0.68 (0.50, 0.93)*	0.60 (0.41, 0.86)**	−0.03 (0.88)**	0.01 (0.40)*
	Placebo		–	–	0.13 (0.94)	−0.06 (0.57)
FREEDOMS II NCT00355134 [21]	Fingolimod 0.5 mg	24	0.83 (0.61, 1.12)	0.72 (0.48, 1.07)	0.046 (1.02)	0.00 (0.60)*	≥0.5 if BL ≥5.0
	Fingolimod 1.25 mg		0.72 (0.53, 0.99)*	0.72 (0.48, 1.08)	−0.084 (1.13)	−0.08 (0.92)*
	Placebo		–	–	0.055 (1.20)	−0.07 (0.54)
TRANSFORMS NCT00340834 [22, 24]	Fingolimod 0.5 mg	12	0.71 (0.42, 1.21)	NR	−0.08 (0.79)	0.04 (0.42)*	≥0.5 if BL ≥5.5
	Fingolimod 1.25 mg		–		−0.11 (0.90)*	0.08 (0.46)***
	IFN beta-1a i.m. 30 µg/week		–		0.01 (0.78)	−0.03 (0.48)
NCT00333138 [117]	Fingolimod 1.25 mg	6	NR	NR	10 %*c	NR	NA
	Fingolimod 5.0 mg				15 %c
	Placebo				20 %c
NCT00537082 [118]	Fingolimod 0.5 mg	6	NR	NR	NS vs control	NR	NA
	Fingolimod 1.25 mg				NS vs control
	Placebo				–
NCT00670449 [119]	Fingolimod 0.5 mg	12	NR	NR	−0.02 (0.46)	NR	NA
	Fingolimod 1.25 mg				−0.02 (0.83)
	Placebo-fingolimod 0.5 mg				−0.32 (0.66)
	Placebo-fingolimod 1.25 mg				−0.11 (0.95)
TEMSO NCT00134563 [27, 30]	Teriflunomide 7 mg	24	0.76 (0.56, 1.05)	0.75 (0.51, 1.11)	NR	NS; values NR	≥0.5 if BL ≥5.5
	Teriflunomide 14 mg		0.70 (0.51, 0.97)*	0.75 (0.50, 1.11)
	Placebo		–	–
TOWER NCT00751881 [25, 28]	Teriflunomide 7 mg	24	0.95 (0.68, 1.35)	1.05 (0.69, 1.61)	0.04 (0.05)	NR	≥0.5 if BL >5.5
	Teriflunomide 14 mg		0.68 (0.47, 1.00)*	0.84 (0.53, 1.33)	–0.05 (0.05)*
	Placebo		–	–	0.09 (0.05)
TOPIC NCT00622700 [29]	Teriflunomide 7 mg	24	0.978 (0.521, 1.835)	NR	–0.250 (0.937)*	NR	≥0.5 if BL >5.5
	Teriflunomide 14 mg		0.701 (0.360, 1.366)		–0.265 (0.849)*
	Placebo		–		–0.056 (0.955)
NCT01487096 [30, 120]	Teriflunomide 7 mg	9	NR	NR	NR	NS; values NR	≥0.5 if BL ≥5.5
	Teriflunomide 14 mg		7.4 %*
	Placebo		21.3 %
NCT00475865 NCT00811395 [no publication]	Teriflunomide 7 mg + GA s.c.d	12	2.4 %	NR	NR	NR	≥0.5 if BL >5.5
	Teriflunomide 14 mg + GA s.c.d		10.0 %
	Placebo + GA s.c.d		9.8 %
NCT00489489 NCT00811395 [121]	Teriflunomide 7 mg + IFNe	12	8.1 %f	NR	NR	NR	≥0.5 if BL >5.5
	Teriflunomide 14 mg + IFNe		5.3 %f
	Placebo + IFNe		0.0 %f
CONFIRM NCT00451451 [34, 36]	DMF 240 mg twice/day	24	0.79 (0.52, 1.19)	0.62 (0.37, 1.03)	NR	NR	≥1.5 if BL = 0
	DMF 240 mg three times/day		0.76 (0.50, 1.16)	0.67 (0.40, 1.11)
	GA 20 mg s.c. once/day		0.93 (0.63, 1.37)	0.87 (0.55, 1.38)
	Placebo		–
DEFINE NCT00420212 [35, 36]	DMF 240 mg twice/day	24	0.62 (0.44, 0.87)**	0.77 (0.52, 1.14)	NR	NR	≥1.5 if BL = 0
	DMF 240 mg three times/day		0.66 (0.48, 0.92)*	0.69 (0.46, 1.04)
	Placebo		–	–
ALLEGRO NCT00509145 [37]	Laquinimod 0.6 mg/day	24	0.64 (0.45, 0.91)*	0.51 (0.34, 0.79)**	NR	NS; values NR	≥0.5 if BL ≥5.5
	Placebo		–	–
BRAVO NCT00605215 [38]	Laquinimod 0.6 mg/day	24	0.69 (0.46, 1.02)	0.61 (0.38, 0.98)*	NR	NS; values NR	≥0.5 pts if BL ≥5.5
	IFN beta-1a i.m. 30 µg/week		0.74 (0.51, 1.09)	0.73 (0.47, 1.14)
	Placebo		–	–
CLARITY NCT00213135 [39]	Cladribine 3.5 mg/kg	24	0.67 (0.48, 0.93)*	NR	NR	NR	≥1.5 if BL = 0
	Cladribine 5.25 mg/kg		0.69 (0.49, 0.96)*
	Placebo		–
EudraCT code 2006-004937-13 [42]	Azathioprine 3 mg/kg/day	24	NR	1.8 %	−0.08 (−0.31, 0.16)g	NR
	IFNf			8.0 %	0.22 (−0.03, 0.47)g
TIME-MS NCT00223301 [122]	Mycophenolate mofetil 250 mg four times/day + IFN beta-1a i.m. 30 µg/week Placebo + IFN beta-1a i.m. 30 μg/week	12	NR	NR	NS; values NR	NR	NA
SWABIMS NCT01111656 [123]	Atorvastatin 40 mg/day + IFN beta-1b s.c.d	24	NR	NR	0.154 (1.2142)	−0.3 (0.62)	NA
	IFN beta-1b s.c.d (no add-on placebo)				−0.036 (1.1174)	−0.4 (0.53)
OFAMS NCT00360906 [124]	EPA 1350 mg/day + DHA 850 mg/day	6/24	NR	NR	13 %/30 %	NS	NA
	Placebo (all patients started IFN beta-1a s.c. 44 µg three times/week at 6 months)				10 %/30 %
NCT00395317 [125]	Firategrast 150 mg twice/day	6	NR	NR	NR (‘remained stable’)	NR (‘no clinically meaningful differences’)	NA
	Firategrast 600 mg twice/day
	Firategrast 900 mg or 1200 mg twice/dayh
	Placebo
Intravenous therapies
CARE-MS I NCT00530348 [45]	Alemtuzumab 12 mg/dayi	24	NR	0.70 (0.40, 1.23)	−0.14 (−0.25, −0.02)g	0.15 (0.52)*	≥1.5 if BL = 0
	IFN beta-1a s.c. 44 µg three times/week			–	−0.14 (−0.29, 0.01)g	0.07 (0.45)
CARE-MS II NCT00548405 [46]	Alemtuzumab 12 mg/dayi	24	NR	0.58 (0.38, 0.87)**	−0.17 (−0.29, −0.05)g***	0.08 (0.04, 0.12)g**	≥1.5 if BL = 0
	Alemtuzumab 24 mg/dayi			NR	NR	NR
	IFN beta-1a s.c. 44 µg three times/week			–	0.24 (0.07, 0.41)g	−0.04 (−0.10, 0.02)g
CAMM223 NCT00050778 [126]	Alemtuzumab 12 mg/dayi	36	0.42 (0.23, 0.77)**	0.25 (0.11, 0.57)***	−0.32 (−0.55, −0.10)g**	NR	≥1.5 if BL = 0
	Alemtuzumab 24 mg/dayi		0.30 (0.15, 0.59)***	0.33 (0.16, 0.69)**	−0.45 (−0.68, −0.22)g***
	IFN beta-1a s.c. 44 µg three times/week		–	–	0.38 (0.13, 0.63)g**
AFFIRM NCT00027300 [48, 49, 128]	Natalizumab 300 mg every 4 weeks	24	0.58 (0.43, 0.77)***	0.46 (0.33, 0.64)***	NR	Significant; values NR	≥1.5 if BL = 0
	Placebo		–	–
SENTINEL NCT00030966 [50]	Natalizumab 300 mg every 4 weeks + IFN beta-1a i.m. 30 μg/week	24	0.76 (0.61, 0.96)*	15 %j	NR	NR	≥1.5 if BL = 0
	Placebo + IFN beta-1a i.m. 30 μg/week		–	18 %j
NCT00516893 [no publication]	Natalizumab 300 mg every 4 weeks	9	NR	NR	−0.19 (0.982)	NR	NA
[no trial code] [53]	Mitoxantrone 8 mg/m2 once/month	24	NR	NR	7 %*g	NR	NA
	Placebo				37 %g
[no trial code] [52]	Mitoxantrone 12 mg/m2 once/month + methylprednisolone 1 g/month	6	NR	NR	−1.1 (1.1)*	NR	NA
	Methylprednisolone 1 g/month				−0.1 (1.1)
French–Italian Mitoxantrone IFN beta-1b Trial Group NCT00219908 [55]	Mitoxantrone 12 mg/m2 once/month + methylprednisolone 1 g/month	36	9.1 %	NR	−0.45 (1.19)	NR
	Methylprednisolone 1 g/month (treatment during months 0–6)k		25.9 %		−0.06 (1.39)
Injectable therapies
GALA NCT01067521 [58]	GA s.c. 40 mg three times/week	12	NR	NR	4.5 %c	NR	NA
	Placebo				3.7 %c
REGARD NCT00078338 [60]	IFN beta-1a s.c. 44 µg three times/week	24	NR	11.7 %	NR	NR	≥1.5 if BL = 0; ≥0.5 if BL ≥5.0
	GA s.c. 20 mg/day			8.7 %
CombiRx NCT00211887 [62]	IFN beta-1a i.m. 30 µg once/week + GA s.c. 20 mg/day	36	NR	23.9 %	NR	0.1 (0.5)	≥0.5 if BL ≥5.5
	IFN beta-1a i.m. 30 µg once/week + placebo			21.6 %		0.1 (0.5)
	GA s.c. 20 mg/day + placebo			24.8 %		0.2 (0.5)
BEYOND NCT00099502 [61]	IFN beta-1b s.c. 250 µg e.o.d.	24	21 %	NR	NR	NR
	IFN beta-1b s.c. 500 µg e.o.d.		22 %
	GA s.c. 20 mg/day		20 %
MSCRG [no trial code] [73]	IFN beta-1a i.m. 30 µg once/week	24	NR	21.9 %*	0.02 (0.14)*l	NR
	Placebo			34.9 %	0.61 (0.18)l
PRISMS [no trial code] [75]	IFN beta-1a s.c. 22 µg three times/week	24	0.68 (0.48, 0.98)*	NR	0.23 (1.3)*	NR
	IFN beta-1a s.c. 44 µg three times/week		0.62 (0.43, 0.91)*		0.24 (1.1)*
	Placebo		–		0.48 (1.3)
EVIDENCE NCT00292266 [76]	IFN beta-1a s.c. 44 µg three times/week	12	0.87 (0.58,1.31)	0.70 (0.39, 1.25)	NR	NR
	IFN beta-1a i.m. 30 µg four times/week		–	–
ADVANCE NCT00906399 [83]	Pegylated IFN beta-1a 125 µg every 2 weeks	12	0.62 (0.40, 0.97)*	NR	NR	NR	≥1.5 if BL = 0
	PEGylated IFN beta-1a 125 µg every 4 weeks		0.62 (0.40, 0.97)*
	Placebo		–
IFNB [no trial code] [80]	IFN beta-1b s.c. 50 μg (1.6 MIU) e.o.d.	24	28 %	NR	NR	NR
	IFN beta-1b s.c. 250 μg (8 MIU) e.o.d.		20 %
	Placebo		28 %
INCOMIN [no trial code] [82]	IFN beta-1b s.c. 250 μg (8 MIU) e.o.d.	24	NR	0.44 (0.25, 0.80)**	2.1 (1.0)** 2.5 (1.1)	NR
	IFN beta-1a i.m. 30 µg (6 MIU) once/week			–
NCT00207727 [127]	Ustekinumab 27 mg every 4 weeks	6	NR	NR	0 (−0.5, 0)m	NR	NA
	Ustekinumab 90 mg every 4 weeks				0 (−0.5, 0.5)m
	Ustekinumab 180 mg every 4 weeks				0 (NR)m
	Ustekinumab 90 mg every 8 weeks				0 (0, 0.5)m
	Placebo				0 (−0.5, 0)m

BL baseline, CDP confirmed disease progression, CI confidence interval, DHA docosahexaenoic acid, DMF dimethyl fumarate, EDSS Expanded Disability Status Scale, e.o.d. every other day, EPA eicosapentaenoic acid, F/U follow-up, GA glatiramer acetate, HR hazard ratio, IFN interferon, i.m. intramuscular, IQR interquartile range, MIU million international units, MS multiple sclerosis, MSFC MS functional composite, NA not applicable, NR not reported, NS not significant, Pts points, s.c. subcutaneous, SD standard deviation

* p < 0.05; ** p < 0.01; *** p < 0.001 vs. control

^aThe percentage of patients with CDP is shown when HRs are not reported

^bIf no criteria are specified, the definition of CDP was a confirmed 1.0-point increase in EDSS score from baseline; criteria that are specified indicate increases in EDSS score that were used in conjunction with this definition

^cProportion of patients with at least a 1.0-point increase in EDSS from baseline

^dDose NR

^eIFN beta-1a (30 μg i.m. once weekly or 22 µg or 44 µg s.c. three times weekly) or IFN beta-1b 250 μg s.c. e.o.d

^fData posted under NCT00811395 on ClinicalTrials.gov

^gMean (95 % CI)

^hHigher dose was administered in men, lower dose in women

ⁱInfused on 5 consecutive days at baseline and for 3 consecutive days at month 12

^jEstimates of the cumulative probability of progression at 2 years [50]

^kSpecified treatments continued until month 6; the control group also started IFN beta-1b s.c. e.o.d. at baseline and the mitoxantrone group started IFN beta-1b s.c. e.o.d. at month 9; both groups were treated until month 36

^lStandard error of the mean

^mMedian (IQR)

Approved Oral Therapies

Fingolimod

Fingolimod (Gilenya^®, Novartis) was the first oral therapy used in the treatment of patients with RRMS, and has shown evidence of reducing disability progression in phase III trials [20–22]. It is approved in the USA for treating patients with relapsing forms of MS [23], and in the EU either as first-line therapy in patients with rapidly evolving severe RRMS or as second-line treatment in patients with RRMS and high disease activity despite treatment with at least one DMT [24]. Compared with placebo, fingolimod 0.5 mg (approved daily dose) reduced the respective risk of 3-month and 6-month CDP by 30 and 37 %, respectively, in FREEDOMS (p < 0.05, both) [20], but had a non-significant effect on CDP in FREEDOMS II [21]. The finding in FREEDOMS II was attributed to high variability in disability progression among patients with baseline EDSS scores of 0, and an exploratory analysis that excluded these patients found a significant reduction in the risk of 3-month CDP with fingolimod 0.5 mg versus placebo [hazard ratio (HR), 0.70; 95 % confidence interval (CI): 0.50, 0.98; p = 0.040]. Proportionately more patients had 3-month CDP in FREEDOMS II than in FREEDOMS, and the proportions with 6-month CDP were similar in both studies. A relatively small proportion of patients had 3-month CDP in the 1-year TRANSFORMS trial, and neither the 29 % reduction in risk of 3-month CDP with fingolimod 0.5 mg versus intramuscular interferon (IFN) beta-1a, nor the between-group difference in EDSS score reached significance [22, 24]. However, changes in MSFC scores were beneficial on fingolimod 0.5 mg compared with controls in all three trials [20–22].

Teriflunomide

Teriflunomide (Aubagio^®, Genzyme) was the second oral drug approved in both the EU and the USA for use in adults with RRMS [25, 26]. Two pivotal placebo-controlled, phase III trials of teriflunomide have been conducted in patients with RRMS (TEMSO [27] and TOWER [28]) and another trial in CIS (TOPIC [29]). In the 2-year TEMSO trial, patients receiving teriflunomide 14 mg had a 30 % reduction in risk of 3-month CDP compared with those receiving placebo (p < 0.05) [27], and at the 14-mg dose in TOWER there was a 32 % risk reduction in time to sustained disability progression (a key secondary endpoint based on 3-month CDP; p < 0.05). Reductions in the risk of 6-month CDP failed to reach significance in either study [25] and no significant changes in MSFC were reported in TEMSO [30]. At 12 months in TOWER there was a small decrease from baseline EDSS score in the 14-mg group (p < 0.05) compared with the placebo group [28], and in TOPIC there was a significantly greater reduction in EDSS scores at 24 months with teriflunomide 14 mg compared with placebo (p < 0.05) [29]. Reductions in 3-month CDP, however, were not significant in the TOPIC study [29], which used the same CDP criteria as TEMSO. A fourth phase III trial, TENERE, which compared teriflunomide with subcutaneous IFN beta-1a, assessed a composite endpoint of time to disease relapse or treatment discontinuation, rather than evaluating disability as a separate endpoint [31]. Accrual of at least a 0.5-point increase in EDSS score, however, was one possible criterion for disease relapse. No differences were reported for the composite endpoint comparing teriflunomide with subcutaneous IFN beta-1a.

Dimethyl Fumarate

Dimethyl fumarate (DMF; BG-12; BG00012; Tecfidera^®, Biogen Idec) is approved in the EU and USA for the treatment of adult patients with RRMS [32, 33]. Two 2-year, placebo-controlled phase III trials (CONFIRM [34] and DEFINE [35]) have been reported; CONFIRM also included a reference group randomized to subcutaneous glatiramer acetate (GA). In CONFIRM, reduction in risk of 3-month CDP was not significant compared with placebo, regardless of whether DMF was administered twice or three times a day [34]. In the DEFINE trial, a 38 % reduction in risk of 3-month CDP was noted for the approved regimen of 240 mg twice a day (p < 0.01) [35]; neither trial reported a reduction in the risk of 6-month CDP [32, 36]. Both trials used slightly more stringent criteria for CDP than were generally used elsewhere (a 1.0-point increase, or a 1.5-point increase if EDSS score is 0 at baseline) [34, 35]. Improvements in MSFC score were observed in both trials but were not statistically significant [36].

Oral Therapies Not Currently Approved

Laquinimod

Laquinimod (Nerventra^®, Teva), an oral immunomodulator as yet unapproved for use in patients with MS, has been compared with placebo for the treatment of RRMS in the 2-year, phase III placebo-controlled ALLEGRO [37] and BRAVO [38] trials; BRAVO also included a comparator group receiving intramuscular IFN beta-1a. Significant reductions in the risk of 6-month CDP among patients receiving laquinimod 0.6 mg/day compared with placebo were reported in both ALLEGRO (49 %; p < 0.01) and BRAVO (39 %; p < 0.05), and the risk of 3-month CDP was also reduced in ALLEGRO (36 %, p < 0.05). In BRAVO there was a non-significant 31 % reduction in 3-month CDP; changes in MSFC scores from baseline were non-significant versus placebo in both studies [37, 38].

Cladribine

Cladribine (Movectro^®, Merck Serono), an oral therapy approved for treatment of patients with hairy cell leukemia, was evaluated in patients with MS in the phase III CLARITY [39] and ORACLE MS [40] trials; however, clinical development was suspended in 2011 pursuant to safety concerns [41] and ORACLE MS terminated before disability outcomes were assessed [40]. The 2-year CLARITY trial used the same 3-month CDP criteria as did the phase III trials of DMF (a 1.0-point increase in EDSS score from baseline, or a 1.5-point increase if EDSS score is 0). At both doses of cladribine tested, the risk of 3-month CDP was approximately 50 % lower than with placebo (p < 0.05, both) [39].

Azathioprine

Azathioprine has been used to treat patients with MS for over 30 years, but its use was largely superseded by the advent of IFN beta-based therapies; however, a recent trial demonstrated its non-inferiority to IFN beta in patients with RRMS, including the finding that there was no significant between-group difference in the proportion of patients with 6-month CDP [42].

Approved Intravenous Therapies

Alemtuzumab

Alemtuzumab [Lemtrada^®, Genzyme (Sanofi)] is an anti-CD52 monoclonal antibody (mAb) originally indicated for second-line therapy in patients with B-cell chronic lymphocytic leukemia, that was re-licensed in the EU (2013) and in the USA (2014) for intravenous treatment of relapsing forms of MS, with active disease defined by clinical or imaging features [43, 44]. At the approved dose of 12 mg/day for 5 days, alemtuzumab was compared with subcutaneous IFN beta-1a in the 2-year, phase III CARE-MS I [45] and CARE-MS II [46] trials (some patients were also randomized to alemtuzumab 24 mg/day in CARE-MS II, but this was discontinued following a protocol amendment designed to accelerate recruitment into the other treatment groups). Disability was a co-primary endpoint in both trials, defined as 6-month CDP with a 1.0-point increase in EDSS score from baseline, or a 1.5-point increase if EDSS score was 0. Compared with subcutaneous IFN beta-1a, a 42 % reduction in risk of CDP was seen among patients receiving alemtuzumab in CARE-MS II (p < 0.01) [46], but the 30 % reduction seen in CARE-MS I was not significant [45]. In CARE-MS II, the improvement in mean EDSS score (p < 0.001) was significant compared with that observed with subcutaneous IFN beta-1a [46], but there was no between-group difference in EDSS score in CARE-MS I [45]. Patients eligible for CARE-MS I were treatment-naïve, unlike those eligible for CARE-MS II, who had disease breakthrough on first-line IFN beta or GA. Also in CARE-MS I, a lower proportion of patients in the subcutaneous IFN beta-1a control group had 6-month CDP (11 %) [45] than in CARE-MS II (21 %) [46]. Changes in MSFC scores in both studies were significant when considered in isolation, but not when considered in the context of a pre-specified hierarchical analysis of secondary endpoints.

Natalizumab

Natalizumab (Tysabri^®, Biogen Idec) is a humanized anti-α4 integrin mAb approved in the USA for the treatment of relapsing forms of MS and in the EU for the treatment of rapidly evolving severe RRMS and highly active RRMS among patients with disease breakthrough on IFN beta or GA [47, 48]. Administered intravenously at the approved dose of 300 mg every 4 weeks, natalizumab has been tested in two 2-year, phase III trials: AFFIRM [49], which was placebo-controlled; and SENTINEL [50], in which all patients continued intramuscular IFN beta-1a after randomization to natalizumab or placebo. The rate of 3-month CDP (defined as a 1.0-point increase in EDSS score from baseline, or a 1.5-point increase if EDSS score was 0) was the co-primary endpoint in both studies. Risk reductions of 42 % (AFFIRM; p < 0.001) and of 24 % (SENTINEL; p < 0.05) were demonstrated; and a 54 % reduction in the risk of 6-month CDP (p < 0.001) was reported in AFFIRM [48–50].

Mitoxantrone

Mitoxantrone (Novantrone^®, EMD Serono) is an antineoplastic type II topoisomerase inhibitor used to treat patients with worsening or aggressive RRMS. Not currently approved throughout the EU, it is a therapy option in Germany and is approved for use in the USA [51]. Controlled trials of mitoxantrone involving patients with RRMS or worsening RRMS include: a 6-month study in which patients received methylprednisolone with or without mitoxantrone [52]; a 1-year placebo-controlled trial with a 1-year follow-up [53]; the 2-year placebo-controlled MIMS trial [54] ( please also see Sect. 3.1.1); and, more recently, a 3-year study by the French–Italian Mitoxantrone IFN beta-1b Trial Group [55], which randomized patients either to mitoxantrone and intravenous methylprednisolone monthly for 6 months followed by subcutaneous IFN beta-1b for 27 months, or to subcutaneous IFN beta-1b for 3 years combined with monthly methylprednisolone for the first 6 months. Compared with controls, mitoxantrone treatment reduced the proportion of patients with at least a 1.0-point increase in EDSS score from baseline in the 6-month study (p < 0.01), and reduced the risk of 3-month CDP (defined as a 1.0-point increase in EDSS score) by 30 % (p < 0.05) at 2 years [53], and by 65 % at 3 years [55].

Approved Injectable Therapies

Glatiramer Acetate

Approved in the USA and EU in patients with CIS and RRMS [56, 57], GA (Copaxone^®, Teva) has been evaluated in six phase III trials [34, 58–62]. It was compared with placebo in two trials (GALA in patients with RRMS [58] and PreCISe in individuals with CIS [59]), with subcutaneous IFN beta-1a in REGARD [60], was an active comparator in two trials in patients with RRMS (the placebo-controlled CONFIRM trial of DMF [34] and the BEYOND trial of subcutaneous IFN beta-1b [61]), and was evaluated in combination with intramuscular IFN beta-1a in a placebo-controlled trial in patients with RRMS (CombiRx [62]). No large trials have reported an effect of GA on CDP relative to control treatment.

IFN beta

The three IFN beta-based therapies are the most long-standing approved DMTs for patients with RRMS and CIS, subcutaneous IFN beta-1b originally being licensed in the USA in 1993 [63] then in the EU in 1995 [64]. Intramuscular IFN beta-1a (Avonex^®, Biogen Idec [65, 66]), subcutaneous IFN beta-1a (Rebif^®, Merck Serono [67, 68]) and subcutaneous IFN beta-1b (Extavia^®, Novartis [69, 70]; Betaferon^®, Bayer [71, 72]) have been included in at least 18 phase III trials, either as the focus of investigation [61, 62, 73–82] or as reference compounds [22, 31, 38, 45, 46, 50, 55]. In the 2-year MSCRG study, proportionately fewer patients with RRMS had 6-month CDP on intramuscular IFN beta-1a than on placebo, and time to 6-month CDP was greater than with placebo (p = 0.02) [73]; disability endpoints were not reported in CHAMPS in patients with CIS [74]. In the PRISMS trial, there was a smaller increase in EDSS score over 2 years in both subcutaneous IFN beta-1a dose groups than in the placebo group [75], and subcutaneous IFN beta-1a was associated with non-significant reductions in the risk of 3-month and 6-month CDP compared with intramuscular IFN beta-1a in EVIDENCE [76, 77]; disability endpoints were not reported in IMPROVE [78] or among patients with CIS in REFLEX [79]. In the ADVANCE study [83] of subcutaneous pegylated IFN beta-1a (Plegridy^®, Biogen Idec [84]), there was a 38 % lower risk of 6-month CDP (p < 0.05) among patients treated every 2 weeks for 2 years compared with those who received placebo in year 1 followed by treatment every 2 weeks in year 2 [85]. Finally, with subcutaneous IFN beta-1b there was a non-significant reduction in 3-month CDP compared with placebo in the IFNB study in patients with RRMS [80]. Generally, there were no between-group differences in disability measures at the 8-year follow-up [86] of the BENEFIT study [81], which examined the impact of delaying treatment initiation by 1 year in patients with CIS. The exception was that throughout the study period, the early-treatment group scored higher than the delayed-treatment group on PASAT (p < 0.05). There were no between-group differences in the proportions of patients with 3-month CDP in the BEYOND study of subcutaneous IFN beta-1b and GA [61]. These findings are somewhat contradicted by the 2-year INCOMIN study [82], in which the risk of 6-month CDP was 56 % lower with subcutaneous IFN beta-1b than with intramuscular IFN beta-1a (p < 0.01).

Injectable Therapies Not Currently Approved

Daclizumab High-Yield Process

The randomized DECIDE trial compared subcutaneous daclizumab high-yield process (DAC HYP; Biogen Idec and Abbvie) with intramuscular IFN beta-1a administered over 96–144 weeks, in patients with RRMS [87]. Provisional results ahead of publication indicated no significant between-group difference in 3-month CDP [88].

Therapies in Patients with Progressive Forms of MS

Summary trial information and baseline characteristics are shown in Table 3 and disability outcomes from each trial are provided in Table 4.

Table 3.

Baseline characteristics of patients with progressive forms of multiple sclerosis (MS) in phase II and III trials

Trial name	MS type	Interventions	Baseline characteristics
			n	Age (years)	Women (%)	EDSS score	MSFC score	Disease durationa (years)
Oral therapies
MS-STAT NCT00647348 [129]	SPMS	Simvastatin 80 mg/day	70	51.5 (7.0)	70	5.76 (0.84)	−0.03 (0.92)	22.1 (8.3)
		Placebo	70	51.1 (6.8)	69	5.87 (0.78)	−0.29 (1.48)	20.3 (8.8)
NCT01450488 [130]	PPMS and	Masitinib 3 or 6 mg/kg/day	27	49 (9)	52	4.9 (1.2)	−0.1 (0.7)	9.5 (7.3)
	Rf-SPMS	Placebo	8	47 (7)	50	5.0 (1.1)	0.3 (0.8)	8.8 (8.4)
Intravenous therapies
Cladribine Clinical and MRI Study Groups [no trial code] [90]	PPMS and SPMS	Cladribine 0.7 mg/kg	53	44.6	58	5.6	NR	10.9
		Cladribine 2.1 mg/kg	52	43.8	50	5.6		10.6
		Placebo	54	44.2	63	5.6		12.3
[no trial code] [89]	CPMS	Cladribine 2.8 mg/kg	27	43.4	66.7	NR	NR	12.7
		Placebo	24	42.5	66.7			10.5
OLYMPUS NCT00087529 [91]	PPMS	Rituximab 1000 mg	292	50.1 (9.0)	47.9	4.8 (1.4)	8.35b	9.2 (6.4)
		Placebo	147	49.6 (8.7)	55.1	4.7 (1.4)	7.38b	9.0 (6.8)
[no trial code] [93]	PPMS	IVIG 0.4 g/kg/month	17	47.8 (8.7)	41	5.4 (1.2)	NR	7.2 (4.3)
		Placebo	17	48.1 (10.5)	35	5.8 (1.0)		9.7 (8.9)
	SPMS	IVIG 0.4 g/kg/month	99	47.8 (9.8)	62	5.6 (1.1)	NR	15.7 (9.0)
		Placebo	98	48.1 (9.1)	63	5.5 (1.2)		16.4 (9.3)
MIMS [no trial code] [54]	SPMS and PRMS	Mitoxantrone 5 mg/m2 every 3 months	66	39.92 (8.06)	61	4.64 (1.01)	NR	9.03 (6.18)
		Mitoxantrone 12 mg/m2 every 3 months	63	39.94 (6.85)	47	4.45 (1.05)		9.63 (6.94)
		Placebo	65	40.02 (7.88)	48	4.69 (0.97)		10.27 (6.86)
MAESTRO-01 NCT00869726 [92]	SPMS	MBP8298 500 mg every 6 months (haplotype DR2+ or 4+)	261	49.5	65.9	5.56 (1.02)	NR	9.24 (5.28)c
		Placebo (haplotype DR2+ or 4+)	252	50.0	62.7	5.55 (1.07)		9.19 (5.18)c
		MBP8298 500 mg every 6 months (haplotype DR2−/4−)	46	50.0	65.2	5.48 (1.04)		10.45 (6.09)c
		Placebo (haplotype DR2−/4−)	53	51.6	56.6	5.40 (1.12)		8.51 (5.30)c
Injectable therapies
PROMiSe [no trial code] [102]	PPMS	GA s.c. 20 mg/day	627	50.4 (8.4)	52.8	4.9 (1.2)	NR	11.0 (7.3)
		Placebo	316	50.2 (8.1)	48.1	4.9 (1.2)		10.7 (7.7)
[no trial code] [100]	PPMS	IFN beta-1a i.m. 30 µg/week	15	46.5	33.3	5.5d	NR	8d
		IFN beta-1a i.m. 60 µg/week	15	47	53.3	5.5d		8d
		Placebo	20	43	25	4.5d		8d
[no trial code] [97]	PPMS	IFN beta-1b s.c. 250 μg (8 MIU) e.o.d.	36	48.8 (7.5)	39	5.3 (1.2)	−0.006 (0.734)	11.3 (6.4)
		Placebo	37	48.6 (8.7)	60	5.2 (1.2)		11.4 (6.8)
[no trial code] [99]	SPMS	IFN beta-1a s.c. 22 μg once/week	186	45.1	60	4.7	NR	14.2
		Placebo	178	46.4	60	5.0		14.4
SPECTRIMS [no trial code] [98]	SPMS	IFN beta-1a s.c. 22 μg three times/week	209	43.1 (7.2)	62	5.5 (1.1)	NR	13.3 (7.4)
		IFN beta-1a s.c. 44 μg three times/week	204	42.6 (7.3)	67	5.3 (1.1)		12.9 (6.9)
		Placebo	205	42.7 (6.8)	60	5.4 (1.1)		13.7 (7.2)
European trial [no trial code] [94]	SPMS	IFN beta-1b s.c. 250 μg (8 MIU) e.o.d.	360	41.1 (7.2)	58.1	5.1 (1.1)	NR	12.8 (6.6)
		Placebo	358	40.9 (7.2)	64.2	5.2 (1.1)		13.4 (7.5)
North American trial [no trial code] [95]	SPMS	IFN beta-1b s.c. 250 μg (8 MIU) e.o.d.	317	46.1 (0.45)	66	5.2 (0.06)	NR	14.6 (0.44)
		IFN beta-1b s.c. 5 MIU/m2 e.o.d.	314	46.8 (0.47)	61	5.1 (0.07)		14.5 (0.49)
		Placebo	308	47.6 (0.46)	60	5.1 (0.07)		14.9 (0.48)

Data are reported as mean (SD) unless otherwise indicated

CPMS chronic progressive MS, EDSS Expanded Disability Status Scale, e.o.d. every other day, GA glatiramer acetate, IFN interferon, i.m. intramuscular, IVIG intravenous immunoglobulin, MIU million international units, MRI magnetic resonance imaging, MS multiple sclerosis, MSFC MS functional composite, NR not reported, PPMS primary progressive MS, PRMS progressive relapsing MS, Rf-SPMS relapse-free secondary progressive MS, s.c. subcutaneous, SD standard deviation, SPMS secondary progressive MS

^aDisease duration stated as (or presumed to be) years since first symptoms unless noted otherwise

^bTimed 25-Foot Walk Test component only

^cTime since diagnosis

^dMedian values

Table 4.

Disability outcomes of patients with progressive forms of multiple sclerosis (MS) in phase II and III trials

Trial name		Interventions	Study outcomes
			F/U, months	3-month CDP HR (95 % CI) versus controla	6-month CDP HR (95 % CI) versus controla	Mean (SD) change in EDSS score from BL	Mean (SD) change in MSFC score from BL	Increase in EDSS for CDPb
Oral therapies
MS-STAT NCT00647348  [129]		Simvastatin 80 mg/day	24	NR	NR	−0.254 (−0.464, −0.069)*c	0.289 (−0.333, 0.961)c	NA
		Placebo
NCT01450488 [130]		Masitinib 3 or 6 mg/kg/day total	12	NR	NR	0 (0.5)	103 % (189 %)	NA
		Placebo				0.3 (1.0)	−60 % (190 %)
Intravenous therapies
Cladribine Clinical and MRI Study Groups [no trial code] [90]		Cladribine 0.7 mg/kg	12	NR	NR	NS; values NR	NR	≥0.5 if BL ≥5.5
		Cladribine 2.1 mg/kg
		Placebo
[no trial code] [89]		Cladribine 2.8 mg/kg	24	NR	NR	Figure only; values NR	NR	NA
		Placebo
OLYMPUS NCT00087529 [91]		Rituximab 1000 mg	24	30.2 %	NR	0.33 (1.0)	−0.05	≥0.5 if BL >5.5
		Placebo		38.5 %		0.45 (1.0)	−0.04
[no trial code] [93]	PPMS	IVIG 0.4 g/kg/month	24	29 %*	NR	−0.39	NR	≥0.5 if BL ≥5.0
		Placebo		71 %		−0.03
	SPMS	IVIG 0.4 g/kg/month	24	52 %	NR	NR	NR	≥0.5 if BL ≥5.0
		Placebo		61 %
MIMS [no trial code] [54]		Mitoxantrone 5 mg/m2 every 3 months	24	14 %	NR	–	NR
		Mitoxantrone 12 mg/m2 every 3 months		8 %		−0.13 (0.90)*
		Placebo		22 %		0.23 (1.01)
MAESTRO-01 NCT00869726 [92]		Dirucotide 500 mg every 6 months (haplotype DR2+ or 4+)	24	NR	30.7 %	0.22 (0.06)	−0.28	≥0.5 if BL ≥5.5
		Placebo (haplotype DR2+ or 4+)			27.8 %	0.17 (0.06)	−0.46
		Dirucotide 500 mg every 6 months (haplotype DR2−/4−)			28.3 %	0.32 (0.14)	−0.55
		Placebo (haplotype DR2−/4−)			35.8 %	0.45 (0.13)	−0.49
Injectable therapies
PROMiSe [no trial code] [102]		GA s.c. 20 mg/day	36	39.6 %	NR	0.58 (1.00)	NS; values NR	≥0.5 if BL ≥5.5
		Placebo		45.2 %		0.61 (1.13)
[no trial code] [100]		IFN beta-1a i.m. 30 µg/week IFN beta-1a i.m. 60 µg/week	24	NS; values NR	NR	NR	NR	≥0.5 if BL ≥5.5
		Placebo
[no trial code] [97]		IFN beta-1b s.c. 8 MIU e.o.d.	24	33.3 %	22.2 %	NSc; values NR	NSc; values NR	≥0.5 if BL >5.5
		Placebo		40.5 %	32.4 %
[no trial code] [99]		IFN beta-1a s.c. 22 μg once/week	36	NR	41 %	Figure only	NR	≥0.5 if BL ≥5.5
		Placebo			38 %
SPECTRIMS [no trial code] [98]		IFN beta-1a s.c. 22 μg three times/week	36	With relapses pre-study:	NR	NR	NR	≥0.5 if BL ≥5.5
		IFN beta-1a s.c. 44 μg three times/week		0.52 (0.29, 0.93)*
		Placebo		Without relapses: 1.07 (0.64, 1.78) –
European trial [no trial code] [94]		IFN beta-1b s.c. 250 μg (8 MIU) e.o.d.	33	38.9 %	NR	0.47*	NR	≥0.5 if BL ≥6.0
		Placebo		49.8 %		0.60
North American trial [no trial code] [95]		IFN beta-1b s.c. 250 μg (8 MIU) e.o.d.	36	NR	NS; values NR	0.53	NR	≥0.5 if BL ≥6.0
		IFN beta-1b s.c. 160 μg (5 MIU)/m2 e.o.d.				0.72
		Placebo				0.62

BL baseline, CDP confirmed disease progression, CI confidence interval, EDSS Expanded Disability Status Scale, e.o.d. every other day, F/U follow-up, GA glatiramer acetate, HR hazard ratio, IFN interferon, i.m. intramuscular, IVIG intravenous immunoglobulin, MIU million international units, MRI magnetic resonance imaging, MS multiple sclerosis, MSFC MS functional composite, PPMS primary progressive MS, NR not reported, pts points, s.c. subcutaneous, SD standard deviation, SPMS secondary progressive MS

* p < 0.05; ** p < 0.01; *** p < 0.001 vs. control

^aThe percentage of patients with CDP is shown when hazard ratios are not reported

^bIf no criteria are specified, the definition of CDP was a confirmed 1.0-point increase in EDSS score from baseline; criteria that are specified indicate increases in EDSS score that were used in conjunction with this definition

^cMean between-group difference (95 % CI)

Approved Intravenous Therapies

Mitoxantrone

Approved in Germany and the USA for the treatment of patients with SPMS and progressive relapsing MS [51], mitoxantrone 12 mg/m² was associated with a small reduction in EDSS score from baseline in the 2-year placebo-controlled MIMS trial. Although interpretation is somewhat confounded by the fact that the trial was conducted in a mixed population of patients with progressive relapsing MS or SPMS, this reduction in EDSS score represented a significant treatment benefit compared with placebo (p = 0.0194). Time to 3-month and to 6-month CDP (increase in EDSS score of ≥1 point) was also greater in these patients than in those receiving placebo (p = 0.03, both) [54].

Intravenous Therapies Not Currently Approved

Cladribine

Intravenous cladribine has been evaluated in two phase III placebo-controlled trials in patients with progressive MS, but neither study reported values for 3-month or 6-month CDP [89, 90]. Evidence for an effect on disability progression was presented in the earlier, smaller trial (n = 48) [89], but no effect (based on changes in EDSS score) was seen in the subsequent larger trial of patients with PPMS (n = 48) or SPMS (n = 111) [90].

Rituximab

The OLYMPUS trial of intravenous rituximab in patients with PPMS found no effect of treatment on time to 3-month CDP. A significant delay in time to 3-month CDP was identified in planned subgroup analyses of patients with gadolinium-enhanced lesions on magnetic resonance imaging (MRI) at baseline (HR 0.41; p = 0.007) and in patients aged younger than 51 years (HR 0.52; p = 0.010), and the effect was augmented in the subgroup with both characteristics (HR 0.33; p = 0.009) [91].

Dirucotide (MBP8298)

The 2-year MAESTRO-01 trial examined the efficacy of dirucotide (MBP8298; Eli Lilly) in patients with SPMS and with human leukocyte antigen (HLA) haplotypes DR2⁺ or DR4⁺ [92]. No effect of treatment on disability progression was seen in MAESTRO-01, leading to the termination of phase III trials MAESTRO-02 and MAESTRO-03.

Intravenous Immunoglobulin

A randomized, 2-year, placebo-controlled trial of intravenous immunoglobulin (IVIG) in a mixed population of patients with PPMS (n = 34) or SPMS (n = 197) found that time to sustained disability progression was 12 weeks longer among patients receiving treatment than in those taking placebo (p = 0.0406) [93].

Approved Injectable Therapies

IFN Beta

Among the IFN beta-based therapies, only subcutaneous IFN beta-1b has received approval in the EU for treatment of progressive disease, specifically in relapsing forms of SPMS [70, 72]. Placebo-controlled trials of subcutaneous IFN beta-1b in Europe [94] and in North America [95] among patients with SPMS yielded different findings. There was a significant increase in time to 3-month CDP with treatment in the European trial compared with placebo (p = 0.0008) [94], but no effect on 6-month CDP was reported in the North American trial [95]. However, a post hoc meta-analysis of the two trial populations found an overall reduction in the risk of 6-month CDP (HR, 0.79; 95 % CI: 0.66, 0.93; p = 0.0076) [96]. Unfortunately, no such benefit was seen among patients with PPMS in a subsequent 2-year placebo controlled trial of subcutaneous IFN beta-1b [97]. Subcutaneous IFN beta-1a is a treatment option in Germany for relapsing forms of SPMS, although no effect on disability measures was reported in either of two 3-year placebo-controlled trials in patients with SPMS (SPECTRIMS [98]; the Nordic SPMS trial [99]); no phase III trials of subcutaneous IFN beta-1a in patients with PPMS have been reported.

Injectable Therapies Not Currently Approved

Intramuscular IFN Beta-1a

No improvement in time to 3-month CDP with intramuscular IFN beta-1a was seen among patients with PPMS [100], or among patients with SPMS in the 2-year IMPACT trial [101]. However, a significant improvement in MSFC scores (the primary endpoint) was seen at 2 years with intramuscular IFN beta-1a compared with placebo (p = 0.033).

Glatiramer Acetate

The placebo-controlled PROMiSe trial of GA in patients with PPMS was terminated when an interim analysis revealed no treatment effect on time to 3-month CDP, the primary outcome [102].

Discussion

The goal of DMT in patients with MS is to prevent the accrual of physical and cognitive deficits associated with disease worsening. Here, we have collected evidence of the effects of MS DMTs, with the aim of identifying those which offer the greatest benefit in mitigating disability progression. In addition to summarizing reported trial data (Tables 1, 2, 3, 4), we have listed for completeness any ongoing trials of MS DMTs and any trials that have been withdrawn or stopped (Table 5).

Table 5.

Trials of multiple sclerosis (MS) therapies that are active but no longer recruiting, or that have been withdrawn, suspended or terminated. Trials are only listed if disability endpoints were specified

Trial name	Intervention(s)	Patient group	Comment
Active trials—oral therapies
CHOLINE NCT01198132	Cholecalciferol as add-on to subcutaneous IFN beta-1a	RRMS
CONTAIN NCT01514370	Curcumin as add-on to subcutaneous IFN beta-1a	Early active RMS
NCT00835770	Dimethyl fumarate	RRMS	Combined extension to CONFIRM and DEFINE
INFORMS NCT00731692	Fingolimod	PPMS
NCT01047319	Laquinimod	RMS	BRAVO extension
NCT01188811	Lipoic acid	SPMS
MS-SPI NCT02220933	MD1003	Spinal PMS
SUPREMES NCT00799890	Sunphenon	PPMS SPMS
NCT00803049	Teriflunomide	RRMS	TEMSO extension
NCT00228163	Teriflunomide	RMS	Phase II 10-year follow-up
SOLAR NCT01285401	VigantOL® oil as add-on to subcutaneous IFN beta-1a	RRMS
Active trials—intravenous therapies
ACCLAIM NCT01116427	Abatacept	RRMS
NCT01433250	AIN457 (secukinumab)	RRMS	Phase II
NCT00930553	Alemtuzumab	RRMS	Extension to CAMMS223, CARE-MS I and CARE-MS II
SYNERGY NCT01864148	BIIB033 (anti-LINGO-1) with intramuscular IFN beta-1a	RMS
ASCEND NCT01416181	Natalizumab	SPMS
NCT01416155	Natalizumab	RRMS	Phase II Japanese study extension
NCT01412333 NCT01247324	Ocrelizumab ± subcutaneous IFN beta-1a	RRMS
NCT01194570	Ocrelizumab + methylprednisolone	PPMS
GATEWAY II NCT01569451	Rituximab then subcutaneous GA	CIS RMS
Active trials—injectable therapies
DECIDE NCT01064401	Subcutaneous daclizumab + IFN beta-1a	RRMS	Pivotal phase III trial
SELECTED NCT01051349	Subcutaneous daclizumab	RRMS	SELECT extension
ATTAIN NCT01332019	Subcutaneous pegylated IFN beta-1a	RRMS	Phase III ADVANCE extension
Withdrawn trials—oral therapies
NCT00296205	High-dose cyclophosphamide	SPMS PPMS PRMS	Principal investigator changed institution
NCT00104143	A4i antagonist	RMS	Withdrawn before enrollment
NCT00429442	Simvastatin as add-on to GA	RMS	Withdrawn before enrollment
Suspended trials—intravenous therapies
NCT00939549	High-dose cyclophosphamide then subcutaneous GA	RRMS	Suspended for revisions to protocol
NCT01039103	Nanocort in acute exacerbation	RRMS	No reason given
Terminated trials—oral therapies
TERACLES NCT01252355	Teriflunomide	RRMS	Sponsor decision, not linked to safety
TOFINGO NCT01499667	Fingolimod	RRMS	Determination of natalizumab washout period no longer relevant
RECYCLINE NCT01134627	Minocycline	RRMS	No reason recorded
NCT00418145	Oral (vs intravenous) steroids	RMS	Low enrollment
NCT01516554	Oral testosterone for fatigue	RRMS	No reason recorded
NCT01037907	BGC20-0134	RRMS	Lack of efficacy
FLORIMS NCT00623415	Flupirtine	RRMS
Memantine-MS NCT00638833	Memantine	All MS types	Unexpected, reversible, mild-to-moderate neurological impairment
Terminated trials—intravenous therapies
NCT00146159	Mitoxantrone	SPMS	No reason recorded
NCT00219908	Mitoxantrone	Early active RRMS	No reason recorded
MAESTRO-02 NCT00870155	MBP8298	SPMS	Negative efficacy in MAESTRO-01
MAESTRO-03 NCT00468611	MBP8298	SPMS	Negative efficacy in MAESTRO-01
STRATA NCT00297232	Natalizumab	RMS	No reason recorded
Terminated trials—injectable therapies
RECLAIM NCT00947895	ACTH	RRMS	Study halted after 1 year for data analysis
ATAMS extension NCT00853762	Atacicept		Increased MS disease activity in ATAMS
NCT00313976	Subcutaneous IFN beta-1b (double dose)	SPMS	No reason recorded
SURPASS NCT01058005	Subcutaneous IFN beta-1a + subcutaneous GA + natalizumab	RRMS	Terminated by sponsor because of low enrollment
NCT00784836	Subcutaneous IFN beta-1a (Avonex®)	RRMS	Terminated by sponsor for reasons unrelated to safety

ACTH adrenocorticotrophic hormone, CIS clinically isolated syndrome, GA glatiramer acetate, IFN interferon, MS multiple sclerosis, PPMS primary progressive MS, PRMS progressive relapsing MS, RMS relapsing MS, RRMS relapsing–remitting MS, SPMS secondary progressive MS

There are difficulties when trying to compare the efficacy of different DMTs in relation to disability outcomes. Definitions of CDP vary across trials, both in the magnitude of the change in EDSS score that constitutes progression, and in the time over which this change must be sustained. A 1.5-point change from a baseline EDSS score of zero is a more robust measure of permanent disease worsening than a 1.0-point change, because recovery from a relapse is likely in the early stages of MS. Given that recovery is also likely if assessments are made over 3 months [18], the European Medicines Agency has recommended that assessments of disability should be made at least 6 months apart [17]; however, this recommendation was made subsequent to the time when the trials reviewed here were planned.

These challenges notwithstanding, trials of fingolimod, alemtuzumab, natalizumab laquinimod and subcutaneous IFN beta-1b in patients with RRMS have demonstrated significant reductions in the risk of 6-month CDP, effect sizes being in the range 40–60 % [20, 37, 38, 46, 49, 82]. A similar effect size is also implied by the proportions of patients free from 6-month CDP reported for intramuscular IFN beta-1a [73]. Patient demography at baseline was broadly similar in the phase III trials that demonstrated these treatment effects (Table 1), although the period since symptom onset was shortest in the alemtuzumab trials. Laquinimod is unusual among this group, in that its impact on disability was significant but its effect on relapse rates was modest [37, 38].

Evidence for mitigation of disease worsening in progressive forms of MS remains sparse, particularly in patients with PPMS. Treatment effects have been reported for mitoxantrone in a mixed population of patients with progressive disease [54], and for subcutaneous IFN beta-1b in individuals with SPMS [94, 96] but the general lack of reported values for risk reduction in trials in patients with progressive MS tends to confound comparisons. Details of the phase III INFORMS trial of fingolimod in PPMS are awaited, but it is known that the primary endpoint was not met [103].

Considerable advances have been made in the last 5 years in the treatment of relapsing MS, but the immunomodulatory nature of the majority of DMTs means that they may have little influence on the pathophysiological mechanisms associated with progressive disease [104]. Although inflammation is known to occur [105], it remains unclear whether it precedes or follows neurodegenerative tissue injury. However, there is some evidence that targeting inflammatory activity may be beneficial in certain patients with progressive disease. In subgroup analyses of the OLYMPUS trial of rituximab in PPMS [91], there was a significant effect of treatment on 3-month CDP among patients with gadolinium-enhanced MRI lesions at baseline. This treatment effect was driven by the fact that disability progression was faster among patients who received placebo in this subgroup (patients with disease now classified as ‘active and with progression’ [13]), than among those on placebo who were free from inflammatory activity at baseline (‘not active but with progression’ [13]). Age, but not disease duration, also affected outcomes in OLYMPUS: the effect of treatment on 3-month CDP was seen in patients younger than 51 years of age, but not in older patients [91]. These findings tend to support the use of the most effective immunomodulatory therapies early in the disease course among young patients whose MS is both active and progressive. The lack of effect among older patients may be symptomatic of age-related functional changes in immunity, or may be because recovery mechanisms are overwhelmed once a certain level of CNS damage has been accumulated by the combined effects of disease progression and aging. Either scenario adds another layer of complexity to the problem of identifying effective treatments in progressive MS.

Figure 1 illustrates schematically how different factors might combine in different MS disease types; analogous schemes have been proposed previously [106, 107]. The relapsing–remitting disease course is initially driven by inflammation, characterized by relapses, focal demyelinated lesions and axonal loss in the central nervous system (CNS), the effects of which are to some degree mitigated by neuronal plasticity and repair mechanisms [108, 109]. Coinciding with this, diffuse neurodegenerative damage in normal-appearing white and grey matter (‘underlying progression’) becomes increasingly apparent as inflammatory focal disease recedes [105, 109]. In addition to permanent focal CNS damage, this diffuse neurodegeneration contributes to the long-term brain atrophy characteristic of disease progression.

Fig. 1.

Schematic representation of the relationship between disability progression and the underlying pathological and rescue processes during a the typical relapsing–remitting disease course, which can ultimately transition into progressive disease, and b the purely progressive disease course. Disease worsening in patients with relapsing MS is a consequence of incomplete recovery from what is mostly focal inflammatory disease; disease progression is attributable to chronic diffuse neurodegenerative damage, a portion of which is caused by permanent focal damage. The colored boxes indicate typical eligibility criteria, as a range of EDSS scores, for recruitment into phase III trials. CIS clinically isolated syndrome, EDSS Expanded Disability Status Scale, MRI magnetic resonance imaging, MS multiple sclerosis, PPMS primary progressive MS, R–SPMS relapsing secondary progressive MS, RR relapsing–remitting, RRMS relapsing–remitting MS, SPMS secondary progressive MS

Brain atrophy begins early in patients with MS [110], is one of the best predictors of long-term disability [111, 112] and correlates with worsening disability [113]. Analyses conducted post hoc in a population of patients with relapsing MS pooled from the three phase III trials of fingolimod [20–22] revealed a strengthening correlation between loss of brain volume and increase in EDSS score over 4 years [113]. During this period, the correlation between these parameters was also generally stronger in the group of patients with 6-month CDP than in the overall analysis population; consistent with these findings, the average increase in EDSS score over 4 years was greatest in the quartile of patients with the most brain volume loss. In the same set of analyses, significant correlations were also seen between brain volume at baseline and both EDSS score and T2 lesion volume, the former correlation supporting an association between loss of brain volume and accrual of disability before enrolment, and the latter correlation supporting an association between accumulated inflammatory focal CNS damage and brain atrophy [113]. These relationships between CNS damage and disability progression emphasise the need to initiate treatment to arrest focal inflammatory and diffuse neurodegenerative processes as early as possible. Although there are both procedural and methodological challenges in conducting routine monitoring of brain volume in patients with MS, these challenges should be tackled because treatment to reduce brain volume loss has been shown to correlate with beneficial effects on disability [114]. The effect of different MS DMTs on brain atrophy is reviewed elsewhere [115].

The evolution of the pathophysiology of MS during the disease course serves to emphasise the difficulty in comparing treatment effects, and confounds long-term extrapolation of effects seen during a 2- or 3-year clinical trial. Furthermore, changes in EDSS score tend to be modest over such a period, and long-term follow-up data, which might corroborate short-term effects on disability, are currently unavailable for many DMTs; the outcomes of several ongoing phase III trial extensions will be interesting. Beyond clinical trials, statistical modelling of real-world data offers a further means to assess the benefits of different treatments. Although still relatively short-term, a recent MS registry analysis of 3326 propensity-matched patients with a median follow-up time of 3.7 years found no difference among IFN beta therapies and GA in terms of 12-month CDP [116].

Despite great progress in the treatment of patients with relapsing MS, there remains an urgent need for drugs that modify the progressive disease course. From the patient’s perspective, physical and cognitive deterioration is probably the greatest concern. It is therefore important that clinical and paraclinical measures that accurately predict and track disease worsening and progression continue to be optimized and standardized to inform prescribing decisions.

Conclusions

In relapsing MS, increased numbers of approved DMTs give clinicians much greater scope than was possible only 5 years ago to select therapy options that their patients tolerate and which are likely to slow disability progression. Treatment options for patients with progressive MS remain scant, but immunomodulatory therapies may be effective in certain patient phenotypes. Challenges remain in standardizing how the efficacy of new and existing treatments is assessed, and assessment of subclinical disease as well as of relapses and disability progression should become part of routine disease monitoring. For the best outcomes in relapsing MS, evidence is accumulating that the most effective treatments should be used early in the disease course to reduce inflammatory disease, slow the accumulation of CNS damage and atrophy, and thereby delay the accrual of disability.

Glossary of Trials Listed

ACCLAIM

A Cooperative Clinical Study of Abatacept in Multiple Sclerosis

ADVANCE

Efficacy and Safety Study of Peginterferon Beta-1a in Participants with Relapsing Multiple Sclerosis

AFFIRM

Natalizumab Safety and Efficacy in Relapsing Remitting Multiple Sclerosis

ALLEGRO

Assessment of Oral Laquinimod in Preventing Progression in Multiple Sclerosis

ASCEND

A Clinical Study of the Efficacy of Natalizumab on Reducing Disability Progression in Participants with Secondary Progressive Multiple Sclerosis

ATAMS

Atacicept in Multiple Sclerosis, Phase II

ATTAIN

Long-Term Safety and Efficacy Study of BIIB017 (PEGylated Interferon Beta-1a)

BENEFIT

Betaferon/Betaseron in Newly Emerging Multiple Sclerosis for Initial Treatment

BEYOND

Betaferon/Betaseron Efficacy Yielding Outcomes of a New Dose in Multiple Sclerosis (MS) Patients

BRAVO

Benefit–Risk Assessment of Avonex and Laquinimod

CARE-MS

Comparison of Alemtuzumab and Rebif Efficacy in Multiple Sclerosis

CHAMPS

Controlled High-Risk Subjects Avonex Multiple Sclerosis Prevention Study

CHOLINE

A Multicentre Study of the Efficacy and Safety of Supplementary Treatment with Cholecalciferol in Patients with Relapsing Multiple Sclerosis Treated with Subcutaneous Interferon Beta-1a 44 µg 3 Times Weekly

CLARITY

Cladribine Tablets Treating Multiple Sclerosis Orally

CombiRx

Combination Therapy in Patients with Relapsing–Remitting Multiple Sclerosis

CONFIRM

Comparator and an Oral Fumarate in Relapsing–Remitting Multiple Sclerosis

CONTAIN

Dietary Supplement of Curcumin in Subjects with Active Relapsing Multiple Sclerosis Treated with Subcutaneous Interferon Beta 1a

DECIDE

Efficacy and Safety of BIIB019 (Daclizumab High Yield Process) Versus Interferon β 1a in Participants with Relapsing–Remitting Multiple Sclerosis

DEFINE

Determination of the Efficacy and Safety of Oral Fumarate in Relapsing–Remitting Multiple Sclerosis

EVIDENCE

Evidence of Interferon Dose-Response European North American Comparative Efficacy

FLORIMS

Flupirtine as Oral Treatment in Multiple Sclerosis

FREEDOMS

FTY720 Research Evaluating Effects of Daily Oral Therapy in Multiple Sclerosis

GALA

Glatiramer Acetate Low-frequency Administration

GATEWAY II

Comparison of Rituximab Induction Therapy Followed by Glatiramer Acetate Therapy to Glatiramer Acetate Monotherapy for MS

IFNB

Interferon Beta-1b Study

IMPACT

International MS Secondary Progressive Avonex Controlled Trial

IMPROVE

Investigating MRI Parameters with Rebif^® Improved Formulation

INCOMIN

Independent Comparison of Interferons

INFORMS

Investigating FTY720 Oral in Primary Progressive MS

MAESTRO

A Study for Patients with Secondary Progressive Multiple Sclerosis

Memantine-MS

Memantine Therapy for Multiple Sclerosis

MIMS

Mitoxantrone in Multiple Sclerosis Study

MS-SPI

Effect of MD1003 in Spinal Progressive Multiple Sclerosis

MS-STAT

Investigation of Simvastatin in Secondary Progressive Multiple Sclerosis

OFAMS

ω-3 Fatty Acid Treatment in Multiple Sclerosis

OLYMPUS

A Study to Evaluate the Safety and Efficacy of Rituximab in Adults with Primary Progressive Multiple Sclerosis

ORACLE MS

Oral cladribine for early MS

PreCISe

Early Glatiramer Acetate Treatment in Delaying Conversion to Clinically Definite Multiple Sclerosis in Subjects Presenting with a Clinically Isolated Syndrome

PROMiSe

Glatiramer Acetate in Primary Progressive Multiple Sclerosis

PRISMS

Prevention of Relapses and Disability by Interferon Beta-1a Subcutaneously in Multiple Sclerosis

RECLAIM

Efficacy Study of Adrenocorticotropin Hormone to Treat Multiple Sclerosis (MS) Relapses After Sub-responding to an Initial 3 Day Course of Intravenous (IV) Methylprednisolone

RECYCLINE

Minocycline as Add-on to Interferon Beta-1a [IFN Beta-1a] (Rebif^®) in Relapsing–Remitting Multiple Sclerosis

REFLEX

Rebif Flexible dosing in early MS

REGARD

Rebif vs Glatiramer Acetate in Relapsing MS Disease

SELECTED

Safety and Efficacy Extension Study of Daclizumab High Yield Process (DAC HYP) (BIIB019) in Participants Who Have Completed Study 205MS202 (NCT00870740) to Treat Relapsing Remitting Multiple Sclerosis

SENTINEL

Safety and Efficacy of Natalizumab in Combination with Interferon Beta-1a in Patients with Relapsing–Remitting Multiple Sclerosis

SOLAR

Supplementation of VigantOL^® Oil Versus Placebo as Add-on in Patients with Relapsing Remitting Multiple Sclerosis Receiving Rebif^® Treatment

SPECTRIMS

Secondary Progressive Efficacy Clinical Trial of Recombinant Interferon-beta-1a in MS

STRATA

Natalizumab (Tysabri) Re-Initiation of Dosing

SUPREMES

Sunphenon in Progressive Forms of Multiple Sclerosis

SURPASS

Study Evaluating Rebif, Copaxone, and Tysabri for Active Multiple Sclerosis

SWABIMS

Swiss Atorvastatin and Interferon Beta-1b trial In Multiple Sclerosis

SYNERGY

Study to Assess the Efficacy, Safety, Tolerability, and Pharmacokinetics of BIIB033 in Participants with Relapsing Forms of Multiple Sclerosis When Used Concurrently with Avonex

TEMSO

Teriflunomide Multiple Sclerosis Oral

TENERE

Teriflunomide and Rebif^®

TERACLES

Efficacy and Safety of Teriflunomide in Patients with Relapsing Multiple Sclerosis and Treated with Interferon-beta

TIME-MS

Safety Study of Combination Therapy with Intramuscular Avonex and Oral Cellcept in Patients with Multiple Sclerosis

TOFINGO

Disease Control and Safety in Patients with Relapsing Remitting Multiple Sclerosis (RRMS) Switching From Natalizumab to Fingolimod

TOPIC

Oral Teriflunomide for Patients with a First Clinical Episode Suggestive of Multiple Sclerosis

TOWER

Teriflunomide Oral in People with Relapsing Multiple Sclerosis

TRANSFORMS

Trial Assessing Injectable Interferon versus FTY720 Oral in Relapsing–Remitting Multiple Sclerosis