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Table 1 Characteristics of included studies

From: Comparative effectiveness of beta-interferons and glatiramer acetate for relapsing-remitting multiple sclerosis: systematic review and network meta-analysis of trials including recommended dosages

Study ID

MS type (diagnostic criteria)

Study details

Characteristics of participants at baseline

Intervention

Participants

ADVANCE 2014

RRMS (2005 McDonald criteria)

Country: USA, Belgium, Bulgaria, Canada, Chile, Colombia, Croatia, Czech Republic, Estonia, France, Georgia, Germany, Greece, India, Latvia, Mexico, Netherlands, New Zealand, Peru, Poland, Romania, Russian Federation, Serbia, Spain, Ukraine, United Kingdom.

No. of countries: 26

Centres: 183

Study period: June 2009 and November 2011.

Sponsor: Biogen Idec

Mean age: 36.5 (9.9)

Mean sex: 71% female

Race: 82% white

EDSS Score: 2.5

Relapse rate: 1.6 within the previous 12 months, 2.6 within the previous 36 months

Time from diagnosis of MS: 3.6 years

Other clinical features of MS: Time from first MS symptoms: 6.6 years

Arm 1: pegylated IFN β-1a 125 μg SC every 2 weeks (Plegridy)

Arm 2: Placebo

Randomised

512 arm 1

500 arm 2

AVANTAGE 2014

RRMS/CIS, diagnostic criteria unclear

Country: France

No. of countries: 1

Centres: 61

Study period: March 2006–April 2008, 3 months follow up

Sponsor: Bayer

Mean age: 38.7

Mean sex: 75% female

Race: NA

EDSS Score: 1.8 ± 1.3

Mean number of relapse rate: 2.1 ± 1.1

Time from diagnosis of MS: 3.3 (6.4) years

Other clinical features of MS: NA

Arm 1: IFN β-1b 250 μg SC every other day (Betaferon) via Betaject

Arm 2: IFN β-1b 250 μg SC every other day (Betaferon) via Betaject light

Arm 3: IFN β-1a 44 SC three times weekly (Rebif) via Rebiject II

Included:

73 arm 1

79 arm 2

68 arm 3

BECOME 2009

RRMS/CIS (likely McDonald 2001 or 2005)

Country: USA

No. of countries: 1

Centres: 2

Study period: Not specified, follow up over 2 years

Sponsor: Bayer Schering pharma

Mean age: 36

Mean sex: 69% females

Race: 52% white

Median EDSS Score: 2

Relapse rate: 1.8 and 1.9 ARR

Time from diagnosis of MS: between 0.9 and 1.2

Other clinical features of MS: 81% RRMS, 19% CIS; MSFC median 0.13

Arm 1: IFN β-1b 250 μg SC every other day (Betaferon)

Arm 2: GA 20 mg SC daily (Copaxone)

Randomised

36 arm 1

39 arm 2

BEYOND 2009

RRMS (McDonald 2005)

Country: Not specified

No. of countries: 26

Centres: 198

Study period: November, 2003, and June, 2005. Follow up between 2 and 3.5 years

Sponsor: Bayer

Mean age 35.6

Mean sex: 69.4% female

Race: 91.9% white

EDSS Score: 2.33

Relapse rate: 1.6 relapses in last year

Time from diagnosis of MS: 5.2 years

Other clinical features of MS:

3.6 relapses previously; 70.6% had two or more relapses in past 2 years

Arm 1: IFN β-1b 250 μg SC every other day (Betaferon)

Arm 2: GA 20 mg SC daily (Copaxone)

Randomised

897 arm 1

448 arm 2

Bornstein 1987

RRMS (Poser)

Country: USA

No. of countries: 1

Centres: Not specified

Study period: Not specified, follow up over 2 years

Sponsor: public (grant from the National Institute of Neurological and Communicative Disorders and Stroke and grant from the National Institutes of Health)

Mean age: 30.5

Mean sex: 42% male/58% female

Race: 96% white

EDSS Score: 3.11

Relapse rate: 3.85 over 2 years

Time from diagnosis of MS: 5.5 years duration of disease

Other clinical features of MS: NA

Arm 1: GA 20 mg SC daily (Copaxone)

Arm 2: Placebo

Randomised

25 arm 1

25 arm 2

BRAVO 2014

RRMS (McDonald 2005)

Country: US, Bulgaria, Croatia, Czech Republic, Estonia, Georgia, Germany, Israel, Italy, Lithuania, Macedonia, Poland, Romania, Russia, Slovakia, South Africa, Spain, Ukraine and others not specified

No. of countries: 18

Centres: 140

Study period: April 2008 to June 2011. 24 months follow up

Sponsor: Teva Pharmaceutical Industries

Mean age: Median: 37.5 placebo, 38.5 IFN

Mean sex: 71.3% females in placebo arm, 68.7% females in IFN arm

Race: N/A

EDSS Score: Median: 2.5 placebo, 2.5 IFN

Median Relapse rate: previous year: 1.0 placebo, 1.0 IFN;

previous 2 years: 2.0 placebo, 2.0 IFN

Median Time from diagnosis of MS: 1.2 placebo, 1.4 IFN

Other clinical features of MS: NA

Arm 1: IFN β-1a 30 μg IM once weekly (Avonex)

Arm 2: Oral placebo once-daily with neurologist monitoring

Randomised

447 arm 1

450 arm 2

Calabrese 2012

RRMS (McDonald 2005)

Country: Italy

No. of countries: 1

Centres: 1

Study period: 1 Jan 2007–30 June 2008

Follow up over 2 years

Sponsor: grant from Merck Serono S.A

Mean age: 36.5 (9.9)

Mean sex: 70.2% of female/20.8% of male

Race: NA

EDSS Score: 2.1 (1.1)

Relapse rate: 1.2 (0.7)

Time from diagnosis of MS: 5.6 years (2.4)

Other clinical features of MS: None

Arm 1: IFN β-1a 44 SC three times weekly (Rebif)

Arm 2: IFN β-1a 30 μg IM once weekly (Avonex)

Arm 3: GA 20 mg SC daily (Copaxone)

Randomised

55 arm 1

55 arm 2

55 arm 3

CombiRx 2013

RRMS (McDonald 2001, Poser)

Country: United States, Canada

No. of countries: 2

Centres: 68

Study period: January 2005–April 2012. Minimally 36 months follow up

Sponsor: NIH, with materials provided by Biogen and Teva

Mean age 38.3

Mean sex: 70.3% female

Race: 87.6% white

EDSS Score: 2.0

Relapse rate: 1.7 relapses in last year, on average

Time from diagnosis of MS: 1.2

Other clinical features of MS:

NA

Arm 1: IFN β-1a 30 μg IM once weekly (Avonex)

Arm 2: GA 20 mg SC daily (Copaxone)

Randomised

250 arm 1

259 arm 2

CONFIRM 2012

RRMS (McDonald 2005)

Country: USA, Belarus, Belgium, Bosnia and Herzegovina, Bulgaria, Canada, Costa Rica, Croatia, Czech Republic, Estonia, France, Germany, Greece, India, Ireland, Israel, Latvia, Macedonia, Mexico, Republic of Moldova, New Zealand, Poland, Puerto Rico, Romania, Serbia, Slovakia, Spain, Ukraine

No. of countries: 28

Centres: 200

Study period: 2 year follow up

Sponsor: Biogen idec

Mean age 36.8

Mean sex: 70% female

Race: 84% white

EDSS Score: 2.6

Relapse rate: 1.4 in prior 12 months

Time from diagnosis of MS: 4.6 years

Other clinical features of MS:

any prior DMTs (%) = 29%

Arm 1: GA 20 mg SC daily (Copaxone)

Arm 2: 2 placebo capsules orally thrice daily

Randomised

360 arm 1

363 arm 2

Cop1 MSSG 1995

RRMS (Poser)

Country: USA

No. of countries: 1

Centres: 11

Study period: October, 1991, and May, 1992. 2 year follow up.

Sponsor: the FDA orphan drug program, the National multiple sclerosis society, and TEVA pharmaceutical

Mean age 34.4.

Mean sex: 73% female

Race: 94% white

EDSS Score: 2.6

Relapse rate: 2.9 prior 2-year rate

MS duration:6.9 years

Other clinical features of MS:

ambulation index = 1.1

Arm 1: GA 20 mg SC daily (Copaxone)

Arm 2: Placebo

Randomised

125 arm 1

126 arm 2

ECGASG 2001

RRMS (Poser)

Country: Canada

No. of countries: 7

Centres: 29

Study period: Enrollment started in February 1997 and concluded in November 1997. 9 month follow up

Sponsor: Teva Pharmaceutical Industries

Mean age 34

Mean sex: NA

Race: NA

EDSS Score: 2.4

Relapse rate: 2.65

Disease duration (years): 8.1

Other clinical features of MS:

ambulation index = 1.15

Arm 1: GA 20 mg SC daily (Copaxone)

Arm 2: Placebo SC injections

Randomised

119 arm 1

120 arm 2

Etemadifar 2006

RRMS (Poser)

Country: Iran

No. of countries: 1

Centres: 1

Study period: September 2002 and September 2004. 24 month follow up

Sponsor: Not specified

Mean age 28.5

Mean sex: 76% female

Race: NA

EDSS Score: 2.0

Relapse rate 1 year prior: 2.2

Time from diagnosis of MS: 3.2 years

Other clinical features of MS: None

Arm 1: IFN β-1b 250 μg SC every other day (Betaferon)

Arm 2: IFN β-1a 30 μg IM once weekly (Avonex)

Arm 3: IFN β-1a 44 SC three times weekly (Rebif)

Randomised

30 arm 1

30 arm 2

30 arm 3

EVIDENCE 2007

RRMS (Poser)

Country: USA, France, UK, Norway, Austria, Germany, France, Finland, Sweden, Canada

No. of countries: 10

Centres: 56

Study period: Unclear. Minimally 48 weeks follow up, average 64.2

Sponsor: Serono

Mean age 37.9

Mean sex: 74.8% female

Race: 91.0% Caucasian

EDSS Score: 2.3

Median: 2.0

Relapse rate: 2.6 Median 2.0 relapses in last 2 years

Duration of MS: 6.6. Median: 4.0–4.1 years

Other clinical features of MS:

Time since last relapse (months): Median 3.9 to 4.4; mean 5.1

Arm 1: IFN β-1a 44 SC three times weekly (Rebif)

Arm 2: IFN β-1a 30 μg IM once weekly (Avonex)

Randomised

339 arm 1

338 arm 2

GALA 2013

RRMS (McDonald 2005)

Country: United States, Bulgaria, Croatia, Germany, Poland, Romania, and Ukraine and others

No. of countries: 17

Centres: 142

Study period: Not specified. 12 months follow up.

Sponsor: TEVA pharmaceutical industries

Mean age 37.6

Mean sex: 68% female

Race: 98% Caucasian

EDSS Score: 2.7

Relapse rate: 1.3 in the prior 12 months, 1.9 in the prior 24 months

Time from diagnosis of MS: NA

Other clinical features of MS:

Time from onset of first symptoms of MS = 7.7 years

Arm 1: GA 40 mg SC three times weekly (Copaxone)

Arm 2: SC placebo injections

Randomised

943 arm 1

461 arm 2

GATE 2015

RRMS (McDonald 2010)

Country: USA, Belarus, Bosnia and Herzegovina, Bulgaria, Croatia, Czech Republic, Estonia, Georgia, Germany, Italy, Mexico, Republic of Moldova, Poland, Romania, Russian Federation, Serbia, South Africa, Ukraine, United Kingdom

No. of countries: 20

Centres: 118

Study period: Recruited between December 7, 2011, and March 21, 2013; last follow-up December 2, 2013. Follow up 9 months (double-blind follow-up) + additional 15 months (open-label)

Sponsor: Synthon BV

Mean age 33.1

Mean sex: 66.4% female

Race: NA

EDSS Score: 2.7

Relapse rate: 1.9 in prior 2 years

Time from diagnosis of MS: NA

Other clinical features of MS:

• Time to onset of first symptoms to randomisation (years): 5.9

• No history of prior disease treatment: 16.1%

Arm 1: GA 20 mg SC daily (Copaxone)

Arm 2: Placebo

Randomised

357 arm 1

84 arm 2

IFNB MSSG 1995

RRMS (Poser)

Country: USA and Canada

No. of countries: 2

Centres: 11

Study period: after 2 years of follow-up, all subjects were given the option of continuing treatment in a double-blind fashion, extending the total treatment period to 5.5 years for some patients

Sponsor: Triton Biosciences, Berlex Laboratories

Mean age 35.6

Mean sex: 70% female

Race: 94% white

EDSS Score: 2.9

Relapse rate: 3.5 in prior 2 years

Time from diagnosis of MS:4.3 years

Other clinical features of MS:

Baseline Scripps neurological rating scale: 80.8

Arm 1: IFN β-1b 250 μg SC every other day (Betaferon)

Arm 2: SC injections placebo

Randomised

124 arm 1

123 arm 2

IMPROVE 2012

RRMS (McDonald 2005)

Country: Italy, Germany, Serbia, Canada, Bulgaria, Estonia, Lithuania, Romania, Russia, Spain

No. of countries: 10

Centres: 5

Study period: December 2006 to February 2009.

Follow up 16 weeks for the double-blind phase, then 24 weeks where all patients received interferon beta 1-a, at last 4 weeks of safety period observation

Sponsor: Merck Serono S.A.

Mean age NA

Mean sex: NA

Race: NA

EDSS Score: NA

Relapse rate: NA

Time from diagnosis of MS: NA

Other clinical features of MS: NA

Arm 1: IFN β-1a 44 SC three times weekly (Rebif)

Arm 2: SC injections of placebo

Randomised

120 arm 1

60 arm 2

INCOMIN 2002

RRMS (Poser)

Country: Italy

No. of countries: 1

Centres: 15

Study period: October, 1997, and June, 1999. 2 year follow up

Sponsor: Istituto Superiore di Sanita’ of the Italian Ministry of Health and the Italian MS Society

Mean age 36.9

Mean sex: 65% female

Race: NA

EDSS Score: 1.97

Relapse rate 2 years prior: 1.45

Time from diagnosis of MS: 6.3 years

Other clinical features of MS: None

Arm 1: IFN β-1b 250 μg SC every other day (Betaferon)

Arm 2: IFN β-1a 30 μg IM once weekly (Avonex)

Randomised

92 arm 1

96 arm 2

Kappos 2011

RRMS (McDonald 2001)

Country: Belgium, Bulgaria, Canada, Czech Republic, Denmark, France, Germany, Italy, Mexico, Romania, Russian Federation, Serbia, Slovakia, Spain, Switzerland, Ukraine, United Kingdom, USA and others

No. of countries: 20

Centres: 79

Study period: Not specified. Up to 96 weeks follow up.

Sponsor: F Hoffmann-La Roche Ltd., Biogen Idec Inc

Mean age 37.5

Mean sex: 65% female

Race: 96% white

EDSS Score: 3.3

Relapse rate: NA

Time from diagnosis of MS: median only

Other clinical features of MS: NA

Arm 1: IFN β-1a 30 μg IM once weekly (Avonex)

Arm 2: placebo injection every other week

Randomised

55 arm 1

54 arm 2

Knobler 1993

RRMS (Poser)

Country: USA

No. of countries: 1

Centres: 3

Study period: June and October 1986. Follow up 3 years (24 weeks of initial follow-up for the 5 groups then all the patients that had received 0.8 mU, 4MU and 16MU for 24 weeks received a dose of 8MU from week 24 to 3 years)

Sponsor: Triton Biosciences, Inc. and Berlex Laboratories, Inc

Mean age 35.6

Mean sex: 48% female

Race: NA

EDSS Score: 3.1

Mean exacerbation in prior 2 years: 2.84

Time from diagnosis of MS: 6.6 years

Other clinical features of MS:

mean Scripps Neurological Rating Scale (NRS): 76.6

Arm 1: IFN β-1b 250 μg SC every other day (Betaferon)

Arm 2: Subcutaneous injection of placebo (1 mL like Betaseron 8 MU)

Randomised

6 arm 1

7 arm 2

MSCRG 1996

RRMS (Poser)

Country: USA

No. of countries: 1

Centres: 4

Study period: November, 1990 to early 1993

2 years follow up for all-patients + 2 additional years for patients completing dosing before the end of the first period of follow-up.

Sponsor: National Institutes of Health, National Institute of Neurological Disorders and Stroke (NINDS) grant R01–26321 and Biogen, Inc.

Mean age 36.8

Mean sex: 73.7% female

Race: 93% white

EDSS Score: 2.4

Relapse rate: 1.2

MS duration (years): 6.5

Other clinical features of MS: None

Arm 1: IFN β-1a 30 μg IM once weekly (Avonex)

Arm 2: Placebo

Randomised

158 arm 1

143 arm 2

PRISMS 1998

RRMS (Poser)

Country: Australia, Belgium, Canada, Finland, Germany, Netherlands, Sweden, Switzerland, UK

No. of countries: 9

Centres: 22

Study period: May 1994 to February 1995 with 2 years follow up.

Sponsor: Ares- Serono

Mean age Median: 34.9

Mean sex: 69% female

Race: NA

EDSS Score: 2.5 (SD 1.2)

Relapse rate: 3.0 (SD 1.2)

Time from diagnosis of MS: Median: 5.3 years)

Other clinical features of MS: NA

Arm 1: IFN β-1a 22 μg SC three times weekly (Rebif)

Arm 2: IFN β-1a 44 SC three times weekly (Rebif)

Arm 3: Placebo

Randomised

189 arm 1

184 arm 2

187 arm 3

REFORMS 2012

RRMS (McDonald 2005, Poser)

Country: USA

No. of countries: 1

Centres: 27

Study period: December 2006–November 2007. 12 weeks follow up

Sponsor: EMD Serono, Pfizer

Mean age 40.52 (SD 9.65)

Mean sex: 70% female

Race: 87.6% white

EDSS Score: NA

Relapse rate: 1.33 (SD 0.49) (of those with relapses)

Time from diagnosis of MS: 1.47 yrs. (3.31)

Other clinical features of MS:

Percentage with no relapse in last 12 months: 24 (18.6%)

Time since onset: 5.12 yrs. (6.68)

Percentage diagnosed with Poser criteria: 36 (27.9%)

Time since last relapse, of those with last-year relapses: 3.76 mos (2.93)

Steroid treatment episodes: 0.50 (0.55)

Percentage needing more than one course of steroids: 49 (38.0%)

Arm 1: IFN β-1a 44 SC three times weekly (Rebif)

Arm 2: IFN β-1b 250 μg SC every other day (Betaferon)

Randomised

65 arm 1

64 arm 2

REGARD 2008

RRMS (McDonald 2001)

Country: Argentina, Austria, Brazil, Canada, France, Germany, Ireland, Italy, Netherlands, Russia, Spain, Switzerland, UK, and USA

No. of countries: 14

Centres: 80

Study period: February and December 2004, with 96 weeks follow up

Sponsor: EMD Serono, Pfizer

Mean age 36.8

Mean sex: 29.5% male

Race: 93.6% white

EDSS Score: 2.34

Relapse rate: Presented as distribution of relapses; months since last relapse about 5 on average

Time from diagnosis of MS: Years since first relapse: 6.2

Other clinical features of MS:

Receiving steroid treatment in last 6 months: 43.7%

Arm 1: IFN β-1a 44 SC three times weekly (Rebif)

Arm 2: GA 20 mg SC daily (Copaxone)

Randomised

386 arm 1

378 arm 2

  1. RRMS relapsing remitting MS, SPMS secondary progressive MS, CIS clinically isolated syndrome, IFN interferon, GA glatiramer acetate, IM intramuscular, SC subcutaneous, NA not available, EDSS Expanded Disability Status Score