Additional file 3 – Summary of data extracted from included randomised controlled trials
Table A3a – Baseline characteristics of trial populations
Table A3b – Summary of individual trial outcomes
Table A3a: Baseline characteristics of trial populations /Study Author
(Study Acronym) / Year / Study Intervention and dosage / Mean Age (years) / Female (%) / Mean Disease Duration (years) § / Mean Number of relapses in the past two years* / Mean EDSS score / Prior treatment (%) /
IFNβ MS Study Group 1 † / 1993 / placebo / 35.60 / 70.45% / 4.30 / 3.50 / 2.90 / 0.00%
IFN β-1b 250mcg SC every second day
Johnson et al2 / 1995 / placebo / 34.45 / 73.31% / 6.95 / 2.90 / 2.60 / N/R
glatiramer acetate 20mg SC once daily
Jacobs et al (MSCRG) 3 / 1996 / placebo / 36.80 / 73.57% / 6.50 / 1.83* / 2.35 / N/R
IFN β-1a 30mcg IM once daily
PRISMS Study Group (PRISMS) 4 / 1998 / placebo / 35.00 / 69.34% / 5.36 / 3.00 / 2.47 / 0.00%
IFN β-1a 22mcg SC three times weekly
IFN β-1a 44mcg SC three times weekly
Comi et al5 / 2001 / placebo / 34.45 / N/R / 8.10 / 2.65 / 2.35 / N/R
glatiramer acetate 20mg SC once daily
Durelli et al (INCOMIN) 6 / 2002 / IFN β-1a 30mcg IM once daily / 36.89 / 65.57% / 6.29 / 2.90 / 1.97 / 0.00%
IFN β-1b 250mcg SC every second day
Panitch et al (EVIDENCE) 7 / 2002 / IFN β-1a 30mcg IM / 37.85 / 74.75% / 6.60 / 2.60 / 2.30 / N/R
IFN β-1a 44mcg SC three times weekly
Etemadifar et al 8 / 2006 / IFN β-1a 30mcg IM once daily / 31.80 / 75.56% / 3.20 / 3.36* / 1.97 / N/R
IFN β-1a 44mcg SC three times weekly
IFN β-1b 250mcg SC every second day
Polman et al (AFFIRM) 9 / 2006 / placebo / 35.97 / 70.33% / 5.33 / 2.32* / 2.30 / 8.39%
Natalizumab 300mcg IV once monthly
Mikol et al (REGARD) 10 / 2008 / glatiramer acetate 20mg SC once daily / 36.75 / 70.52% / 6.24 / N/R / 2.34 / 0.00%
IFN β-1a 44mcg SC three times weekly
International Campath-1H in Multiple Sclerosis trial Investigators (CAMMS223)11 † / 2008 / IFN β-1a 44mcg SC three times weekly / 32.35 / 64.15% / 1.50 / N/R / 1.90 / 100.00%
alemtuzumab 12mg IV once daily for five days/three days at 0 months/12 months
O'Connor et al
(BEYOND) 12 † / 2009 / glatiramer acetate 20mg SC once daily / 35.60 / 69.33% / 5.23 / 2.44* / 2.33 / 0.00%
IFN β-1b 250mcg SC every second day
Kappos et al
(FREEDOMS) 13 † / 2010 / placebo / 36.90 / 70.44% / 8.05 / 2.15 / 2.40 / 41.51%
fingolimod 0.5mg oral once daily
Cohen et al
(TRANSFORMS)14 † / 2010 / IFN β-1a 30mcg IM once daily / 36.35 / 66.60% / 7.45 / 2.30 / 2.21 / 55.75%
fingolimod 0.5mg oral once daily
O'Connor et al
(TEMSO) 15 / 2011 / placebo / 38.10 / 73.42% / 8.65 / 2.20 / 2.68 / 26.59%
teriflunomide 14mg oral once daily
Kappos et al 16 † / 2011 / Placebo / 38.05 / 63.00% / 5.05 / N/R / 3.15 / 30.50%
IFN β-1a 30mcg IM once daily
Saida et al17 † / 2012 / placebo / 35.00 / 69.30% / 8.20 / 2.50 / 2.20 / N/R
fingolimod 0.5mg oral once daily
Gold et al
(DEFINE) 18 † / 2012 / placebo / 38.30 / 73.50% / 8.35 / 1.98 / 2.44 / 40.00%
BG-12 240mg oral twice daily
Fox et al
(CONFIRM) 19 † / 2012 / placebo / 37.14 / 69.32% / 7.64 / 2.14* / 2.60 / 29.34%
glatiramer acetate 20mg SC once daily
BG-12 240mg oral twice daily
Cohen et al
(CARE-MS1) 20 / 2012 / IFN β-1a 44mcg SC three times weekly / 33.07 / 65.00% / 2.07 / 2.50 / 2.00 / 0.00%
alemtuzumab 12mg IV once daily for five days/three days at 0 months/12 months
Coles et al
(CARE-MS2) 21 / 2012 / IFN β-1a 44mcg SC three times weekly / 35.12 / 65.68% / 4.56 / 2.74 / 2.70 / 100.00%
alemtuzumab 12mg IV once daily for five days/three days at 0 months/12 months
Khan et al22 †
(GALA) / 2013 / placebo / 37.63 / 67.97% / 7.67 / 1.90 / 2.77 / 13.63%
glatiramer acetate 40mg SC once weekly
Vermersch et al
(TENERE) 23 † / 2013 / IFN β-1a 44mcg SC three times weekly / 36.90 / 69.33% / 7.16 / 1.70 / 2.15 / 17.65%
teriflunomide 14mg oral once daily
Lublin et al 24 †
(CombiRx) / 2013 / IFN β-1a 30mcg IM once daily / 38.31 / 70.32% / 1.20 / 2.52* / 1.95 / N/R
glatiramer acetate 20mg SC once daily
Vollmer et al 25 †
(BRAVO) / 2014 / placebo / 38.00 / 70.00% / 5.01 / 2.00* / 2.50 / 34.47%
IFN β-1a 30mcg IM once daily
Confavreux et al 26 †
(TOWER) / 2014 / placebo / 38.15 / 69.81% / 7.90 / 2.10 / 2.70 / 34.31%
Teriflunomide 14mg oral once daily
Calabresi et al†
(ADVANCE) 27 / 2014 / placebo / 36.60 / 71.49% / 6.60 / 2.42 / 2.46 / 17.00%
peg-IFN β-1a 125mcg every two weeks
Calabrese et al 28 †
(FREEDOMS II) / 2014 / placebo / 40.35 / 78.99% / 10.50 / 2.20 / 2.40 / 73.50%
fingolimod 0.5mg oral once daily
Mean
(SD) / 36.32 (1.96) / 70.04% (3.67%) / 6.13
(2.24) / 2.43
(0.45) / 2.40 (0.30) / 29.65% (30.90%)
Abbreviations: IFN-β=interferon beta, IM=intramuscular, IV=intravenous, peg=pegylated, SC=subcutaneous, ARR=annualised relapse rate, N/R = Not reported. EDSS=expanded disability status scale
† Interventions which were not among the treatment strategies of interest and which did not otherwise contribute to the network of evidence were excluded from the analysis. These include IFN β-1b SC 50mcg1 , IFN β-1b SC 500mcg12 , alemtuzumab 24mg 11 , fingolimod 1.25 mg (FREEDOMS, TRANSFORMS13 14 17 28 , ocrelizumab 16 , teriflunomide 7mg 15 23 26 , dimethyl fumarate 240mg three times daily 18 19 , glatiramer acetate/IFN β-30mcg IM combination 24, laquinimod 25 and pegylated IFN β-1a 125mcg every four weeks27
§ Duration of disease definition varied between trials. Reported as time from first symptoms 13-19 23 25 26 28 22 27, time from first episode/relapse 10 11 20 21, time from diagnosis 1, unspecified 2-9 12 24.
* Where not reported in RCTs the number of relapses in the previous two years was inferred using the relationship between the number of relapses in the previous year and the number of relapses in the previous two years from other studies where both were reported.
Table A3b: Summary of participants and outcomes of included trials /
Study Author
(Study Acronym) / Year / Study Intervention and dosage / Timepoint (weeks) / Number of Participants / Total Patient Years of follow-up* / Total number of Relapses* / ARR* / Proportion free of Disability Progression§ /
3-month / 6-month /
IFNβ MS Study Group 1 † / 1993 / placebo / 104 / 123 / 209 / 266 / 1.27 / 0.73 / N/R
IFN β-1b 250mcg SC every second day / 124 / 206 / 173 / 0.84 / 0.80 / N/R
Johnson et al2 / 1995 / placebo / 104 / 126 / 250 / 210 / 0.84 / 0.75 / N/R
glatiramer acetate 20mg SC once daily / 125 / 273 / 161 / 0.59 / 0.78 / N/R
Jacobs et al
(MSCRG) 3 / 1996 / placebo / 104 / 143 / 304 / 250 / 0.82 / N/R / 0.65
IFN β-1a 30mcg IM once daily / 158 / 327 / 219 / 0.67 / N/R / 0.78
PRISMS Study Group (PRISMS) 4 / 1998 / placebo / 104 / 187 / 363 / 477 / 1.32 / 0.63¶ / 0.75
IFN β-1a 22mcg SC three times weekly / 189 / 365 / 343 / 0.94 / 0.70¶ / N/R
IFN β-1a 44mcg SC three times weekly / 184 / 362 / 317 / 0.88 / 0.74¶ / 0.81
Comi et al5 / 2001 / placebo / 39 / 120 / 75 / 91 / 1.21 / N/R / N/R
glatiramer acetate 20mg SC once daily / 119 / 75 / 61 / 0.81 / N/R / N/R
Durelli et al
(INCOMIN) 6 / 2002 / IFN β-1a 30mcg IM once daily / 104 / 92 / 180 / 126 / 0.70 / N/R / 0.70
IFN β-1b 250mcg SC every second day / 96 / 189 / 95 / 0.50 / N/R / 0.87
Panitch et al
(EVIDENCE) 7 / 2002 / IFN β-1a 30mcg IM / 48 / 338 / 304 / 216 / 0.71 / 0.86 / 0.92
IFN β-1a 44mcg SC three times weekly / 339 / 306 / 183 / 0.60 / 0.87 / 0.94
Etemadifar et al 8 / 2006 / IFN β-1a 30mcg IM once daily / 104 / 30 / 60 / 72 / 1.2 / N/R / N/R
IFN β-1a 44mcg SC three times weekly / 30 / 60 / 36 / 0.6 / N/R / N/R
IFN β-1b 250mcg SC every second day / 30 / 60 / 42 / 0.7 / N/R / N/R
Polman et al
(AFFIRM) 9 / 2006 / placebo / 104 / 315 / 738 / 539 / 0.73 / 0.71 / 0.77
Natalizumab 300mcg IV once monthly / 627 / 1338 / 308 / 0.23 / 0.83 / 0.89
Mikol et al
(REGARD) 10 / 2008 / glatiramer acetate 20mg SC once daily / 96 / 386 / 689 / 200 / 0.29 / N/R / 0.91
IFN β-1a 44mcg SC three times weekly / 378 / 688 / 206 / 0.30 / N/R / 0.88
International Campath-1H in Multiple Sclerosis trial Investigators (CAMMS223)11 † / 2008 / IFN β-1a 44mcg SC three times weekly / 104 / 111 / 247 / 89 / 0.36 / 0.67 / 0.74
alemtuzumab 12mg IV once daily for five days/three days at 0 months/12 months / 112 / 309 / 34 / 0.11 / 0.84 / 0.92
O'Connor et al
(BEYOND) 12 † / 2009 / glatiramer acetate 20mg SC once daily / 104 / 448 / 1126 / 383 / 0.34 / 0.20 / N/R
IFN β-1b 250mcg SC every second day / 897 / 2299 / 828 / 0.36 / 0.21 / N/R
Kappos et al
(FREEDOMS) 13 † / 2010 / placebo / 103 / 418 / 515 / 206 / 0.40 / 0.76 / 0.81
fingolimod 0.5mg oral once daily / 425 / 561 / 101 / 0.18 / 0.82 / 0.88
Cohen et al
(TRANSFORMS) 14 † / 2010 / IFN β-1a 30mcg IM once daily / 52 / 431 / 542 / 179 / 0.33 / 0.92 / N/R
fingolimod 0.5mg oral once daily / 429 / 556 / 89 / 0.16 / 0.94 / N/R
O'Connor et al
(TEMSO) 15 † / 2011 / placebo / 108 / 363 / 676 / 365 / 0.54 / 0.73 / N/R
teriflunomide 14mg oral once daily / 358 / 664 / 246 / 0.37 / 0.80 / N/R
Kappos et al 16 † / 2011 / Placebo / 24 / 54 / 25 / 16 / 0.64 / N/R / N/R
IFN β-1a 30mcg IM once daily / 54 / 24 / 9 / 0.36 / N/R / N/R
Saida et al17 † / 2012 / placebo / 26 / 57 / 27 / 27 / 0.99 / N/R / N/R
fingolimod 0.5mg oral once daily / 57 / 26 / 13 / 0.50 / N/R / N/R
Gold et al
(DEFINE) 18 † / 2012 / placebo / 96 / 408 / 656 / 239 / 0.36 / 0.84 / 0.83
BG-12 240mg oral twice daily / 410 / 660 / 113 / 0.17 / 0.82 / 0.87
Fox et al
(CONFIRM) 19 † / 2012 / placebo / 96 / 363 / 599 / 240 / 0.40 / 0.87 / 0.88
glatiramer acetate 20mg SC once daily / 350 / 594 / 170 / 0.29 / 0.83 / 0.89
BG-12 240mg oral twice daily / 359 / 581 / 130 / 0.22 / 0.87 / 0.92
Cohen et al
(CARE-MS1) 20 / 2012 / IFN β-1a 44mcg SC three times weekly / 104 / 187 / 313 / 122 / 0.39 / N/R / 0.89
alemtuzumab 12mg IV once daily for five days/three days at 0 months/12 months / 376 / 661 / 119 / 0.18 / N/R / 0.92
Coles et al
(CARE-MS2) 21 / 2012 / IFN β-1a 44mcg SC three times weekly / 104 / 202 / 387 / 201 / 0.52 / N/R / 0.79
alemtuzumab 12mg IV once daily for five days/three days at 0 months/12 months / 426 / 908 / 236 / 0.26 / N/R / 0.87
Khan et al22 †
(GALA) / 2013 / placebo / 52 / 461 / 461 / 233 / 0.51 / N/R / N/R
glatiramer acetate 40mg SC once weekly / 943 / 941 / 312 / 0.33 / N/R / N/R
Vermersch et al
(TENERE) 23 † / 2013 / IFN β-1a 44mcg SC three times weekly / 62‡ / 104 / 120 / 26 / 0.22 / N/R / N/R
teriflunomide 14mg oral once daily / 111 / 137 / 36 / 0.26 / N/R / N/R
Lublin et al 24 †
(CombiRx) / 2013 / IFN β-1a 30mcg IM once daily / 140 / 250 / 604 / 97 / 0.16 / N/R / 0.78
glatiramer acetate 20mg SC once daily / 259 / 651 / 70 / 0.11 / N/R / 0.75
Vollmer et al 25 †
(BRAVO) / 2014 / placebo / 104 / 450 / 892 / 303 / 0.34 / 0.87 / 0.90
IFN β-1a 30mcg IM once daily / 447 / 892 / 232 / 0.26 / 0.89 / 0.92
Confavreux et al 26 †
(TOWER) / 2014 / placebo / 108 / 388 / 591 / 296 / 0.50 / 0.86 / N/R
Teriflunomide 14mg oral once daily / 370 / 555 / 177 / 0.32 / 0.92 / N/R
Calabresi et al†
(ADVANCE) 27 / 2014 / placebo / 48 / 500 / 456 / 181 / 0.40 / 0.895 / 0.92
peg-IFN β-1a 125mcg every two weeks / 512 / 453 / 116 / 0.27 / 0.932 / 0.96
Calabrese et al 28 †
(FREEDOMS II) / 2014 / placebo / 104 / 355 / 689 / 276 / 0.40 / 0.71 / 0.82
fingolimod 0.5mg oral once daily / 358 / 703 / 148 / 0.21 / 0.75 / 0.86
Abbreviations: IFN-β=interferon beta, IM=intramuscular, IV=intravenous, peg=pegylated, SC=subcutaneous, ARR=annualised relapse rate, N/R = Not reported
† Interventions which were not among the treatment strategies of interest and which did not otherwise contribute to the network of evidence were excluded from the analysis. These include IFN β-1b SC 50mcg1 , IFN β-1b SC 500mcg12 , alemtuzumab 24mg 11 , fingolimod 1.25 mg (FREEDOMS, TRANSFORMS13 14 17 28 , ocrelizumab 16 , teriflunomide 7mg 15 23 26 , dimethyl fumarate 240mg three times daily 18 19 , glatiramer acetate/IFN β-30mcg IM combination 24 , laquinimod 25 and pegylated IFN β-1a 125mcg every four weeks27
*Where ARR and/or total patient years of follow-up (TPY) were not reported, results were derived from total number of patients recruited, total number of relapses, mean number of relapses per person and total patient years of follow-up, where reported. Where TPY was not reported, it was calculated in a number of ways depending on the available data: median of patient-years of other outcomes within the same trial; number of patients*mean follow-up duration of the trial; (number of patients not withdrawn*planned follow-up duration)+(number of patients withdrawn*planned follow-up duration/2); number of patients*planned follow-up duration.
§ Sustained disability progression confirmed after three months or six months
¶ Proportion estimated from KM survival curve
‡Median exposure was 60.1 weeks in IFN β arm and 64.2 weeks in teriflunomide arm
References
1. Duquette P, Girard M, Despault L, DuBois R, Knobler RL, Lublin FD, et al. Interferon beta-1b is effective in relapsing-remitting multiple sclerosis. I. Clinical results of a multicenter, randomized, double-blind, placebo- controlled trial. Neurology 1993;43(4 I):655-61.
2. Johnson KP, Brooks BR, Cohen JA, Ford CC, Goldstein J, Lisak RP, et al. Copolymer 1 reduces relapse rate and improves disability in relapsing- remitting multiple sclerosis: Results of a phase III multicenter, double- blind, placebo-controlled trial. Neurology 1995;45(7):1268-76.