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)