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Immunomodulators and immunosuppressants for multiple sclerosis: a network meta-analysis

  1. Graziella Filippini1,*,
  2. Cinzia Del Giovane2,
  3. Laura Vacchi3,
  4. Roberto D'Amico2,
  5. Carlo Di Pietrantonj4,
  6. Deirdre Beecher5,
  7. Georgia Salanti6

Editorial Group: Cochrane Multiple Sclerosis and Rare Diseases of the Central Nervous System Group

Published Online: 6 JUN 2013

Assessed as up-to-date: 10 FEB 2012

DOI: 10.1002/14651858.CD008933.pub2


How to Cite

Filippini G, Del Giovane C, Vacchi L, D'Amico R, Di Pietrantonj C, Beecher D, Salanti G. Immunomodulators and immunosuppressants for multiple sclerosis: a network meta-analysis. Cochrane Database of Systematic Reviews 2013, Issue 6. Art. No.: CD008933. DOI: 10.1002/14651858.CD008933.pub2.

Author Information

  1. 1

    Fondazione I.R.C.C.S. Istituto Neurologico Carlo Besta, Neuroepidemiology Unit, Milano, Italy

  2. 2

    University of Modena and Reggio Emilia, Statistics Unit, Department of Clinical and Diagnostic Medicine and Public Health, Modena, Italy

  3. 3

    Scientific Institute and University Ospedale San Raffaele, Institute of Experimental Neurology (INSPE), Milano, Italy

  4. 4

    Azienda Sanitaria Locale ASL AL, Servizio Regionale di Riferimento per l'Epidemiologia, SSEpi-SeREMI - Cochrane Vaccines Field, Alessandria, Piemonte, Italy

  5. 5

    London School of Hygiene & Tropical Medicine, Cochrane Injuries Group, London, UK

  6. 6

    University of Ioannina School of Medicine, Department of Hygiene and Epidemiology, Ioannina, Greece

*Graziella Filippini, Neuroepidemiology Unit, Fondazione I.R.C.C.S. Istituto Neurologico Carlo Besta, via Celoria, 11, Milano, 20133, Italy. gfilippini@istituto-besta.it.

Publication History

  1. Publication Status: New
  2. Published Online: 6 JUN 2013

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Characteristics of included studies [ordered by study ID]
Achiron 1998

MethodsRCT


ParticipantsAge: 19-60 years; definite RRMS; mean disease duration 4 years; mean EDSS 3.0


InterventionsLoading dose of intravenous immunoglobulins 0.4 g/kg/body weight per day for 5 consecutive days followed by additional booster doses of intravenous immunoglobulins 0.4 g/kg/body weight once daily every 2 months for 2 years (n 20).

placebo consisting of 0.9% saline administered with the same schedule as the active treatment (n 20).


OutcomesRelapses at 12 and 24 months. Progression at 24 months


NotesFunding: Miles Inc. Cutter Biological, Bayer and Promedico


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskPatients were assigned to receive immunoglobulin or placebo by a block-stratified randomisation procedure, performed at the pharmacy.

Allocation concealment (selection bias)Low riskAllocation made in pharmacy. Bottle of immunoglobulin or placebo were wrapped in sealed opaque bags and brought to the patients' rooms. Use also of an opaque plastic bag for fluid.

Blinding of participants and personnel (performance bias)
All outcomes
Low risk"All patients and evaluators were blinded to treatment...the bottles of immunoglobulin or placebo were wrapped in sealed opaque bags and brought to the patients' rooms. The entire IV set was covered by an opaque plastic bag to ensure that any possible fluid turbidity or frothing would not be evident to the investigators or patients". Page 399

Blinding of outcome assessment (detection bias)
All outcomes
Low risk"All patients and evaluators were blinded to treatment". Page 399

Incomplete outcome data (attrition bias)
All outcomes
Low risk"Two patients discontinued treatment after the first year (one in each group)." Page 400. The intention-to-treat analysis was performed including the 2 withdrawals.

Selective reporting (reporting bias)Low riskThe published reports included all expected efficacy outcomes.

Other biasHigh riskSustained disability progression confirmed at 3 months' follow-up.

AFFIRM 2006

MethodsRCT


ParticipantsAge: 18-50 years; clinical definite RRMS; disease duration 0-33 years; EDSS 0-5.0; ≥ 1 relapses in the year before randomisation.


InterventionsNatalizumab 300 mg by intravenous infusion every 4 weeks for up to 116 weeks (n. 627).

Placebo (unspecified) (n. 315)


OutcomesRelapses at 12 and 24 months. Progression at 24 months.


NotesFunding: Biogen Idec, Inc. and Elan Pharmaceutical.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low risk"Patients were randomly assigned to treatment that was stratified according to study site in blocks of three (two active, one placebo) with the use of a computer-generated block randomization schedule." Page 900

Allocation concealment (selection bias)Low risk"A multidigit identification number, implemented by an interactive voice-response system was used." Page 900

Blinding of participants and personnel (performance bias)
All outcomes
Low risk"All study personnel, patients, sponsor personnel involved in the conduct of the study, and the investigator advisory committee were unaware of treatment assignments throughout the study (Page 900)... Treating neurologists were responsible for all aspects of patient care, including the management of adverse events and the treatment of relapsing disease." Page 901

Blinding of outcome assessment (detection bias)
All outcomes
Low risk"Examining neurologists performed objective evaluation with use of the EDSS and neurologic examination during all study visits; they were not in contact with patients in any other capacity, so as to reduce the possibility of being unblinded by side effects or laboratory assessments." Page 901

Incomplete outcome data (attrition bias)
All outcomes
Low risk"8% of patients in the natalizumabgroup and 10% of those in the placebo group withdrew from the study". Pages 902-903

Selective reporting (reporting bias)High riskThe number of patients who progressed at 2 years were not available.

Other biasHigh riskData analysis performed by Biogen Idec and Elan Pharmaceuticals. Sustained disability progression confirmed at 3 months' follow-up. Relapses assessed also as adverse events. The number of lost to follow-up at 1 year were not available.

Andersen 2004

MethodsRCT


ParticipantsAge: 18-65 years; clinical definite SPMS defined as ≥ 1 EDSS point increase in 4 years before randomisation, with or without superimposed exacerbations; EDSS < 7.0.


InterventionsIFNß-1a (Rebif) 22 μg subcutaneously weekly for 36 months (n.188)

Placebo (unspecified) (n. 183)


OutcomesRelapses at 36 months. Progression at 36 months


NotesFunding: Serono International, Geneva, Switzerland


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskNot described

Allocation concealment (selection bias)Unclear risk"equal allocation." Page 707

Blinding of participants and personnel (performance bias)
All outcomes
Unclear risk"Patients were instructed to cover injection sites." Page 707

Blinding of outcome assessment (detection bias)
All outcomes
Unclear risk"Neurologists blinded to dose assignment were responsible for neurological assessments". Page 707

Incomplete outcome data (attrition bias)
All outcomes
High riskThe study had ended prematurely due to negative results from SPECTRIMS study. Only 83% of randomised patients completed about 3 years. Losses to follow-up not included in analysis: treatment  21%; placebo 16%. More AE and patients' decision in the treated group. The median time on treatment was 35.2 months (mean 32.0) for placebo and 35.0 months (mean 31.1) for IFNß-1a

Selective reporting (reporting bias)Low riskThe published reports included all expected efficacy outcomes

Other biasLow riskThe study appears to be free of other sources of bias

BEYOND 2009

MethodsRCT


ParticipantsAge: 18-55 years; clinical or laboratory-supported definite RRMS; EDSS 0-5; disease duration 3-8 years; ≥ 1 relapses in the year before randomisation.


InterventionsIFNß-1b 250 μg subcutaneous every other day (n. 897)

IFNß-1b 500 μg subcutaneous every other day (n. 899)

glatiramer acetate 20 mg subcutaneous every day (n. 448)


OutcomesRelapses at 24 months. Progression at 24 months


NotesFunding: Bayer HealthCare Pharmaceuticals


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low risk"Use of SAS-based block randomisation with regional stratification". Page 890

Allocation concealment (selection bias)Low risk"Patients were randomly assigned in a 2:2:1 ratio ... by the central randomisation group..." Page 890

Blinding of participants and personnel (performance bias)
All outcomes
High risk"Physicians and patients were double-blind to comparisons between the two doses of IFNß-1b... Ibuprofen or acetaminophen were given at the same time as random assignment to IFNß-1b, at least during the first 3 months, to
reduce flu-like symptoms. The treating physicians and the
patients were therefore aware of treatment assignments"
. Page 891

Blinding of outcome assessment (detection bias)
All outcomes
Low risk" The masked evaluating physicians did all neurological assessments and ascertained functional system and EDSS scores...The evaluating physicians were not involved in the care of patients and had no access to patient files or previous
assessments. ... Patients covered their injection sites during neurological examination and did not discuss any adverse events with the evaluating physician
". Page 891-2

Incomplete outcome data (attrition bias)
All outcomes
High riskLosses to follow-up not included in analysis: 500 μg IFNß-1b 13%; 250 μg IFNß-1b 20%; glatiramer acetate 16%

Selective reporting (reporting bias)Low riskThe published reports included all expected efficacy outcomes.

Other biasHigh riskSustained disability progression confirmed at 3 months' follow-up.

Bornstein 1987

MethodsRCT


ParticipantsAge: 20-35 years; definite RRMS; EDSS 0–6.0; disease duration ≥ 1 year; at least 2 relapses in the 2 years before randomisation.


InterventionsGlatiramer acetate 20 mg subcutaneous every day (n. 25)

Placebo bacteriostatic saline subcutaneous every day (n. 25)


OutcomesRelapses at 12 and 24 months. Progression at 24 months


NotesFunding: Grants from the NINCDS and the NIH, Bethesda, Md.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)High risk"The random assignment of the first patient of a pair determined the assignment of both". Page 409

Allocation concealment (selection bias)High riskAn open allocation schedule was used: "Treatment assignments were made known to the clinical assistant responsible for the production, labelling and distribution of medication". Page 409

Blinding of participants and personnel (performance bias)
All outcomes
High risk"The patient's self evaluation of ... side effects were reported to the clinical assistant, how was not blinded to the treatment". Page 409

Blinding of outcome assessment (detection bias)
All outcomes
Low risk"A neurologist unaware of the patient's treatment group completed a neurologic examination and status evaluation". Page 409

Incomplete outcome data (attrition bias)
All outcomes
Low riskLosses to follow-up excluded from the study analysis: 2 of 25 placebo patients

Selective reporting (reporting bias)Low riskThe published reports included all expected efficacy outcomes and those outcomes that were pre-specified in the methods section

Other biasHigh riskSustained disability progression was confirmed at 3 months' follow-up.

Bornstein 1991

MethodsRCT


ParticipantsAge: 20-60 years; progressive MS; EDSS 2–6.5; progression ≥ 18 months; ≤ 2 relapses in the 2 years before randomisation


Interventionsglatiramer acetate 30 mg subcutaneous twice a day (n. 51)

placebo, saline alone, subcutaneous twice a day (n. 55)


OutcomesProgression at 24 months


NotesFunding: Grants from the NINCDS and the NIH, Bethesda, Md.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low risk"... by randomized block design with two baseline EDSS strata < 5.0 and 5.0 or greater" Page 534

Allocation concealment (selection bias)Unclear risk"The investigator notified the statistical center, which assigned a randomization code number. Shipment of glatiramer acetateto the patients at their individual centers were totally at random and were dictated by the patients' date of entry into the trial. Only the statistician and the clinical assistant at Albert Einstein College of Medicine, who distributed medication, were aware of patients assignments". Page 534

Blinding of participants and personnel (performance bias)
All outcomes
Unclear risk"Side effects were reported to a clinical assistant". Page 534

Blinding of outcome assessment (detection bias)
All outcomes
Low risk"The blinded neurologist performed a complete neurological examination... Side effects were not discussed with the study neurologist... Another blinded neurologist was available to examine patients with severe or unusual side effects." Page 534

Incomplete outcome data (attrition bias)
All outcomes
Low riskNo losses to follow-up and 20 withdrawals were included in the data analyses. Page 536

Selective reporting (reporting bias)Low riskThe published reports included all expected efficacy outcomes and those outcomes that were pre-specified in the methods section.

Other biasHigh riskSustained disability progression was confirmed at 3 months' follow-up.

BPSM 1995

MethodsRCT


ParticipantsMean age: 35 years; clinical definite RRMS; EDSS < 5.5; disease duration: not reported; no relapses in the previous 45 days before randomisation.


InterventionsIntravenous methylprednisolone 2 g in saline solution for 12 hours, every 45-60 days for two years or until relapse (n. 17)

Placebo i.v. saline solution at the same schedule (n. 19)


OutcomesRelapses at 12 and 24 months


NotesFunding: None


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear risk"The method of randomisation was centralised" (Cochrane review)

Allocation concealment (selection bias)Low risk"Allocation were generated by computer by personnel not involved in patients management" (Cochrane review)

Blinding of participants and personnel (performance bias)
All outcomes
Unclear risk"the study was double blind" (Cochrane review)

Blinding of outcome assessment (detection bias)
All outcomes
Unclear risk"the study was double blind" (Cochrane review)

Incomplete outcome data (attrition bias)
All outcomes
High risk"There were 10 patients (7 treated) lost to follow-up (28% overall). Moreover, patients experiencing an exacerbation were not followed up although a two year follow-up was planned". (Cochrane review)

Selective reporting (reporting bias)High risk"Patients were not followed-up after the first exacerbation, contrary to what was planned. Since patients not experiencing a relapse in the two years of the study were just 2, we did not have any data on disability progression for the majority of the patients". (Cochrane review)

Other biasHigh risk"Prematurely interrupted at 36 out of 72 planned patients for organisational reasons and lack of funding". (Cochrane review)

British and Dutch 1988

MethodsRCT


ParticipantsAge: 30-65 years; definite RRMS, SPMS or PPMS; disease duration 5-15 years; EDSS 2.5–6.5; ≤ 1 relapses in the 2 years before randomisation.


InterventionsAzathioprine 2.5 mg/Kg body weight oral daily (n. 174)

Placebo (n. 180)


OutcomesRelapses at 12, 24 and 36 months


NotesFunding: Wellcome Company


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskThe randomisation sequence was generated for each centre by the trial statistician "by randomized block design". Page 534

Allocation concealment (selection bias)Low risk"The investigator notified the statistical center, which assigned a randomization code number" Page 534. The packs of trial tablets were issued to individual pharmacies labelled with a code. The treatment and placebo tablets were identical.

Blinding of participants and personnel (performance bias)
All outcomes
Low riskPatients were blind to treatment.

Blinding of outcome assessment (detection bias)
All outcomes
Low riskA masked assessor recorded the number of relapses, the ambulatory index and the Kurtzke scale.

Incomplete outcome data (attrition bias)
All outcomes
Low riskLosses to follow-up not included in the study analysis (at the end of the study): Treatment arm 8%; placebo 6%.

Selective reporting (reporting bias)High riskProportion of participants who progressed at 2 years was not available.

Other biasHigh riskSustained disability progression confirmed at 3 months' follow-up.

CCMSSG 1991

MethodsRCT


ParticipantsMean age: 32 years; clinically or laboratory-supported SPMS, PPMS or PRMS; ≥ 1.0 EDSS in the year before randomisation; mean disease duration 10 years; mean EDSS 5.8 (0.6).


InterventionsCyclophosphamide 1 g intravenous three times weekly + 40 mg prednisone tapered for 16 days (total dose ≤ 9 gm) (n. 55)

Placebo (n. 56)


OutcomesProgression at 36 months


NotesFunding: BRISTOL Myers; Upjohn


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear risk"A randomisation sequence was generated separately for each centre. Patients were stratified by centre and EDSS score." Page 442

Allocation concealment (selection bias)Unclear riskNot described.

Blinding of participants and personnel (performance bias)
All outcomes
High risk"Patients with exacerbation or progression were seen by the monitoring neurologist... who was aware of the treatment allocation". Pages 442, 444

Blinding of outcome assessment (detection bias)
All outcomes
Low risk"The evaluating neurologist (not involved with the patients' ongoing care) was blinded". Page 444

Incomplete outcome data (attrition bias)
All outcomes
Low risk"Subjects who did not complete the allocated treatment were followed and their outcome was assigned to the group to which they were randomised (intention to treat analysis)". Page 443

Selective reporting (reporting bias)Low riskThe published reports included patients who progressed at 36 months.

Other biasHigh riskSustained disability progression confirmed at 3 months' follow-up

Comi 2001

MethodsRCT


ParticipantsAge: 18-50 years; clinical or laboratory-supported definite RRMS; EDSS 0–5.0; disease duration ≥ 1years; ≥ 1 relapses in the 2 years before randomisation.


InterventionsGlatiramer acetate 20 mg subcutaneous every day (n. 119)

Placebo (not described) (n. 120)


OutcomesRelapses at 9 months


NotesFunding: Teva Pharmaceutical


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low risk"The randomization list, stratified by centers, was computer-generated by the TEVA Statistical Data Management Department. Equal allocation of the two treatment groups was used". Page 291

Allocation concealment (selection bias)Unclear riskNot described

Blinding of participants and personnel (performance bias)
All outcomes
Unclear risk"A treating neurologist was responsible for the overall medical management of the patient including safety monitoring... All personnel were unaware of treatment allocation... both the treating neurologist and the patient were informed on the importance of not discussing safety issue with the examining neurologist" . Page 291

Blinding of outcome assessment (detection bias)
All outcomes
Unclear risk" An examining neurologist was responsible for all scheduled neurological examinations and exacerbation follow-up". Page 291

Incomplete outcome data (attrition bias)
All outcomes
Low risk"Analyses were based on an intention to treat dataset. The last
observation carried forward (LOCF) method was implemented to account for early discontinuation and missing data." 7 (6%) patients dropped out in each arm
". Page 292

Selective reporting (reporting bias)High riskProgression was not measured in the trial.

Other biasHigh riskTeva Pharmaceutical was involved in the trial.

Edan 1997

MethodsRCT


ParticipantsAge: 18-45 years; definite SPMS or PRMS; disease duration < 10 years; ≥ 2 relapses or ≥ 2 EDSS points increase in the year before randomisation; EDSS ≤ 6.0.


Interventions20 mg intravenously/month and methylprednisolone (1 g intravenously/month) (n. 21)

methylprednisolone alone (1 g intravenously/month) (n. 21)


OutcomesRelapses at 6 months.


NotesFunding: not reported


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskNot described

Allocation concealment (selection bias)Low risk"The allocation of the treatment was done after inclusion by a central randomisation service by fax". Page 113

Blinding of participants and personnel (performance bias)
All outcomes
High risk"In the present study, ... neither the patients nor the clinical investigators were blinded during the study. Blinding of patients was not possible in this trial, as obvious side effects of mitoxantrone were experienced in almost all cases. Blinding of the physician was made difficult by the fall in white cell count that always accompanies mitoxantrone treatment". Page 116

Blinding of outcome assessment (detection bias)
All outcomes
High risk"Blind clinical observers might have been appointed, but this could not be done for economic reasons". Page 116

Incomplete outcome data (attrition bias)
All outcomes
Low risk5 withdrawals "due to pronounced clinical worsening" (all in the methylprednisolone group) were included in analysis.

Selective reporting (reporting bias)Low riskThe published reports included all expected efficacy outcomes.

Other biasHigh riskSustained disability progression confirmed at 2 months' follow-up. It's unclear if this study was sponsored.

Ellison 1989

MethodsRCT


ParticipantsMean age: 32 years; definite SPMS or PPMS; disease duration 5-15 years; EDSS 2.5–6.5; ≤ 1 relapses in the 2 years before randomisation.


InterventionsAzathioprine 3 mg/kg body weight oral daily (n. 31)

Azathioprine 3 mg/kg body weight oral daily and methylprednisolone for 36 weeks (n. 34)

Placebo (n. 34)


OutcomesRelapses at 12, 24 and 36 months. Progression at 36 months


NotesFunding: Wellcome Company and Upjohn Company


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear risk"Patient sequence was the order of presenting the initial prescription to the pharmacy". Page 1019

Allocation concealment (selection bias)Unclear risk"The statistician told the examining neurologists that the treatments would be allocated by a randomisation process to blocks of 4 successive patients, but the assignment rules were not revealed". Page 1019

Blinding of participants and personnel (performance bias)
All outcomes
Low risk"Monitoring neurologist, study nurse, clinic coordinator, technician and patients were masked to the treatment assigned". Page 1019

Blinding of outcome assessment (detection bias)
All outcomes
Low risk"Observer neurologist was masked to the treatment assigned". Page 1019

Incomplete outcome data (attrition bias)
All outcomes
Low riskNo losses to follow-up at 1 year; 2 placebo and 1 methylprednisolone+ azathioprine arm at 2 years; 6 placebo, 5 azathioprine and 6 methylprednisolone+ azathioprine at 3 years.

Selective reporting (reporting bias)Low riskPrimary outcomes of interest were reported completely.

Other biasHigh riskSustained disability progression confirmed at 3 months' follow-up.

Etemadifar 2006

MethodsRCT


ParticipantsAge: 15-50 years; clinical or laboratory-supported definite RRMS; mean disease duration 3 years; EDSS ≤ 5.0; ≥ 2 relapses in the 2 years before randomisation.


InterventionsIFNß-1b 250 μg subcutaneous every other day for 24 months (n. 30)

IFNß-1a (Avonex) 30 μg intramuscular once a week for 24 months (n. 30)

IFNß-1a (Rebif) 44 μg subcutaneous three times a week for 24 months (n. 30)


OutcomesRelapses at 24 months


NotesFunding: not reported


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskPatients "were assigned randomly and equally to one of the three treatment groups". Page 284

Allocation concealment (selection bias)Unclear riskNot described.

Blinding of participants and personnel (performance bias)
All outcomes
High risk"The trial was single-blinded in that patients were aware". Page 284

Blinding of outcome assessment (detection bias)
All outcomes
Low risk"Physicians who assessed the outcome were unaware of the treatment type that the patient had received". Page 284

Incomplete outcome data (attrition bias)
All outcomes
Low riskAll randomised patients were included in the study analysis.

Selective reporting (reporting bias)High riskProgression at 2 years was not reported.

Other biasUnclear riskIt's unclear if this study was sponsored.

European Study Group 1998

Methods


ParticipantsAge: 18-55 years; clinical definite SPMS; ≥ 2 relapses or ≥ 1.0 EDSS points in the 2 years before randomisation; EDSS 3.0-6.5; mean disease duration 13 years.


InterventionsSubcutaneous injection every other day of IFN-1b 250 ug (8.0 million international units [MIU]), for 36 months (n. 360).

Placebo (unspecified) for 36 months (n. 358).


OutcomesRelapses at 36 months. Progression at 36 months


NotesFunding: Schering AG, Berlin


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low risk"Central randomisation schedule assigned placebo or IFNß-1b to blocks of six patients in a 1/1 ratio". Page 1492

Allocation concealment (selection bias)Low risk"Access to the code was strictly limited according to study protocol". Page 1492

Blinding of participants and personnel (performance bias)
All outcomes
Unclear risk"Separate treating and examining physicians were employed... IFNß-1b was indistinguishable from placebo". Page 1492

Blinding of outcome assessment (detection bias)
All outcomes
Unclear risk"Evaluating physicians received no potentially unmasking information from the treating physicians, and were allowed to speak to patients only as necessary to carry out neurological tests". Page 1492 It is unclear if the 3 years evaluation was double blind or open for the early study termination.

Incomplete outcome data (attrition bias)
All outcomes
High risk90 (25%) of 360 patients in the treatment group and 97 (27%) of 358 controls had not completed the scheduled 3 years' follow-up because the study had ended prematurely for benefit.

Selective reporting (reporting bias)Low riskThe published reports included all expected efficacy outcomes

Other biasHigh riskSchering AG, Berlin performed the statistical analysis.

EVIDENCE 2007

MethodsRCT


ParticipantsAge: 18-55 years; clinical or laboratory-supported definite RRMS; EDSS 0-5.5; median disease duration 4 years; ≥ 2 relapses in the 2 years before randomisation.


InterventionsIFNß-1a (Rebif) 44 μg subcutaneous three times a week (n. 339)

IFNß-1a (Avonex) 30 μg intramuscular once a week (n. 338)


OutcomesRelapses at 12 months


NotesFunding: Serono Inc.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low risk"Computer-generated scheme with block size of 6 followed by block size of 4". Page 2033

Allocation concealment (selection bias)Unclear riskNot described

Blinding of participants and personnel (performance bias)
All outcomes
High risk"Patients and a treating physician who was not involved in end point assessment were aware of treatment assignments". Page 2033

Blinding of outcome assessment (detection bias)
All outcomes
Low risk"Evaluating physicians who were blinded to the patients' treatment and symptoms performed all clinical exams". Page 2033

Incomplete outcome data (attrition bias)
All outcomes
Low riskLosses to follow-up not included in analysis: IFN-β1a (Avonex) 9.5%; IFN-β1a (rebif) 12%.

Selective reporting (reporting bias)High riskOnly relapses at 12 months were reported.

Other biasHigh riskData management and study analysis were done by Serono. Sustained disability progression confirmed at 3 months' follow-up.

Fazekas 1997

Methods


ParticipantsAge: 15-64 years; clinical definite RRMS; EDSS, range 1.0-6.0; disease duration, range: 5.7-8.6 years; ≥ 2 relapses in the 2 years before randomisation.


InterventionsImmunoglobulins 0.15–0.20 gm/kg body weight intravenously monthly (n. 75).

Placebo (n. 73).


OutcomesRelapses at 24 months.


NotesFunding: Sero-Merieux (Vienna, Austria)


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low risk"Centralised computer-generated randomisation schedule with stratification by centre, age, sex, and deterioration rate." Page 590

Allocation concealment (selection bias)Low risk"Randomly and centrally allocated". Page 590

Blinding of participants and personnel (performance bias)
All outcomes
High risk"Infusions of intravenous immunoglobulinsand placebo were identical in appearance and were stored in plastic bags for concealment during administration". Page 590

The treating physician was aware of treatment.

Blinding of outcome assessment (detection bias)
All outcomes
Low risk"The assessing physician was unaware of treatment assignment". Page 590

Incomplete outcome data (attrition bias)
All outcomes
High risk64 (85%) patients in the intravenous immunoglobulins group and 56 (75%) in the placebo group completed the trial.

Selective reporting (reporting bias)Low riskThe published reports included all expected efficacy outcomes.

Other biasUnclear riskDefinition of sustained disability progression was not clearly reported.

Fazekas 2008

MethodsRCT


ParticipantsAge: 15-64 years; clinical definite RRMS; mean EDSS 2.0; disease duration 1.3-1.6 years; ≥ 2 relapses in the 2 years before randomisation.


InterventionsImmunoglobulins 0.2 gm/kg body weight intravenously monthly (n. 45).

Immunoglobulins 0.4 gm/kg body weight intravenously monthly (n. 42).

Placebo (n. 41).


OutcomesRelapses at 12 months.


NotesFunding: Bayer HealthCare AG.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low risk"The random code number was computer generated by the Statistics and Data System Department of Bayer." Page 266

Allocation concealment (selection bias)Low risk"Randomisation performed by an unblinded pharmacist who assigned code numbers from sealed envelopes in a sequential manner". Page 266

Blinding of participants and personnel (performance bias)
All outcomes
Unclear riskNot clearly reported.

Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskEndpoints "assessed by an evaluating physician who was otherwise not involved in patient care"

Incomplete outcome data (attrition bias)
All outcomes
Unclear riskDropouts: intravenous immunoglobulins 0.2 g: 7/45 (15%); intravenous immunoglobulins 0.4 g: 4/42 (9%); placebo 4/41 (10%).

Selective reporting (reporting bias)High riskOnly relapses at 12 months were reported.

Other biasHigh riskBayer HealthCare AG supported the study.

Ghezzi 1989

MethodsRCT


ParticipantsAge not reported; definite RRMS or SPMS; disease duration 5-15 years; EDSS 2.5–6.5; ≤ 1 relapses in the 2 years before randomisation.


InterventionsAzathioprine 2.5 mg/Kg/body weight oral daily (n. 93)

Placebo (n. 92)


OutcomesRelapses 24 months. Progression at 24 months


NotesFunding: Not reported


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskNot described.

Allocation concealment (selection bias)Unclear riskNot described.

Blinding of participants and personnel (performance bias)
All outcomes
High riskNo blinding.

Blinding of outcome assessment (detection bias)
All outcomes
Low riskExamining neurologist blinded to treatment arm.

Incomplete outcome data (attrition bias)
All outcomes
High riskLosses to follow-up not included in the study analysis: treatment 26%; placebo 28%.

Selective reporting (reporting bias)Low riskThe published reports included all expected efficacy outcomes and those outcomes that were pre-specified in the methods section.

Other biasUnclear riskDefinition of sustained disability progression not clearly reported. It is unclear if the study was sponsored.

Goodkin 1991

MethodsRCT


ParticipantsMean age: 30 years; definite RRMS; disease duration 5-15 years; EDSS 2.5–6.5; ≤ 1 relapses in the 2 years before randomisation.


InterventionsAzathioprine 3.0 mg/Kg/body weight oral daily for 24 moths (n. 30)

Placebo for 24 months (n. 29)


OutcomesRelapses 12 and 24 months. Progression at 24 months


NotesFunding: Wellcome Company


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low risk"Randomised by the statistician using random number tables". Page 21

Allocation concealment (selection bias)Unclear riskNot described

Blinding of participants and personnel (performance bias)
All outcomes
Low riskPatients and personnel were blinded.

Blinding of outcome assessment (detection bias)
All outcomes
Low riskThe examining neurologist was blinded.

Incomplete outcome data (attrition bias)
All outcomes
Low risk7 (12%) people were lost to 2 years follow-up (3 azathioprine, 4 placebo)

Selective reporting (reporting bias)Low riskThe published reports included all expected efficacy outcomes.

Other biasUnclear riskDefinition of sustained disbility progression not clearly reported.

Goodkin 1995

MethodsRCT


ParticipantsAge: 21-60 years; definite PPMS or SPMS ; disease duration >1 years; EDSS 3.0–6.5; ≤ 1 relapses in the 2 years before randomisation.


InterventionsMethotrexate 7.5 mg oral weekly for 24 months (n. 31)

Placebo for 24 months (n. 29)


OutcomesRelapses at 12 and 24 months. Progression at 24 months


NotesFunding: none


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear risk"The randomisation scheme was developed prior to the initiation of the study and was blocked in groups of 10". Page 32

Allocation concealment (selection bias)High risk"Treatment assignments were made by the unblinded study coordinator who appeared to be not responsible for patients' recruitment". Page 32

Blinding of participants and personnel (performance bias)
All outcomes
Unclear riskIt was not clearly reported

Blinding of outcome assessment (detection bias)
All outcomes
Low risk"The examining neurologist performed all neurological examinations without reference to earlier examinations and was not permitted to talk to the patient or treating physician about the general progress of the study, clinical events, or therapy provided to any study participants." Page 32

Incomplete outcome data (attrition bias)
All outcomes
Low riskLosses to follow-up not included in the study analysis: treatment 2/31; placebo 0/29

Selective reporting (reporting bias)Low riskThe published reports included all expected efficacy outcomes and those outcomes that were pre-specified in the methods section.

Other biasHigh risk"Sustained" disability progression was confirmed at ≥ 2 months of follow-up.

Hartung 2002

MethodsRCT


ParticipantsAge: 18-65 years; definite SPMS or PRMS; mean disease duration 10 years; ≥ 1.0 EDSS n the 18 months before randomisation; no clinical relapses or treatment with steroids for at least 8 weeks before enrolment; EDSS 3.0-6.0.


InterventionsMitoxantrone 5 mg/m² body surface area intravenously every 3 months (n. 66).

Mitoxantrone 12 mg/m² body surface area intravenously every 3 months (n. 63).

Placebo (n. 65).


OutcomesRelapses at 24 months. Progression at 24 months.


NotesFunding: Wyeth-Lederle Benelux and Germany


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low risk"Randomisation by a computer-generated schedule, block size of three". Page 2019

Allocation concealment (selection bias)Unclear riskNot described

Blinding of participants and personnel (performance bias)
All outcomes
High risk"A separate treating physician was aware of treatment assignment." Page 2019

Blinding of outcome assessment (detection bias)
All outcomes
Low risk"Neurologist who assessed outcome measures was unaware of treatment assignment (assessing physician)." Page 2019

Incomplete outcome data (attrition bias)
All outcomes
Low riskLosses to follow-up not included in the study analysis: treatment arms 3/63 (5%) and 2/66 (3%); placebo 1/65 (1.5%)

Selective reporting (reporting bias)Low riskThe published reports included all expected efficacy outcomes.

Other biasHigh riskWyeth-Lederle Benelux and Germany sponsored the trial and financially supported statistical analysis.

Hommes 2004

MethodsRCT


ParticipantsAge: 18-55 years; clinical definite SPMS; progression ≥ 1.0 EDSS points in the 2 years before randomisation; EDSS 3.0-6.5; disease duration ≥ 3 years.


InterventionsImmunoglobulins 1 gm/kg body weight intravenously monthly (n. 159).

Placebo (n. 159).


OutcomesRelapses at 12 and 24 months. Progression at 24 months.


NotesFunding: Bayer Corporation.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear risk"The randomisation was done centrally as block randomisation with stratification by centre." Page 1150

Allocation concealment (selection bias)Unclear risk"Concealment of treatment was guaranteed by use of an albumin solution identical in appearance to the study medication, with identical labelling and opaque plastic wrapping." Page 1150

Blinding of participants and personnel (performance bias)
All outcomes
Low risk"Concealment of treatment was guaranteed by use of an albumin solution
identical in appearance to the study medication, with identical labelling and opaque plastic wrapping...a treating neurologist or a study nurse administered the study drug.. Physicians and study nurses were unaware of treatment allocation."
Page 1150

Blinding of outcome assessment (detection bias)
All outcomes
Low risk"The clinical assessment of the patients was made by an evaluating neurologist, who was not allowed to discuss therapy or adverse effects with the patients." Page 1150

Incomplete outcome data (attrition bias)
All outcomes
Low risk"32 patients (10%) withdrew from the study.Thus, complete data for 27 months were available for 280 (90%) patients." Page 1152

Selective reporting (reporting bias)Low riskThe published reports included all expected efficacy outcomes.

Other biasHigh riskBayer Corporation was involved in every phase of the trial. Sustained disability progression confirmed at 3 months' follow-up.

IFNB MS Group 1993

MethodsRCT


ParticipantsAge: 18-50 years; clinical or laboratory-supported definite RRMS; EDSS ≤ 5.5; disease duration > 1 year; ≥ 2 relapses in the 2 years before randomisation; no relapses for at least 1 month before randomisation.


InterventionsIFNß -1b (Betaseron) 50 μg subcutaneously every other day (n. 125).

IFNß -1b (Betaseron) 250 μg subcutaneously every other day (n. 124).

Placebo (n. 123).


OutcomesRelapses at 24 months. Progression at 24 months.


NotesFunding: Triton Biosciences, Inc., Alameda, CA and Berlex Laboratories Inc.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskNot described

Allocation concealment (selection bias)Unclear riskNot described

Blinding of participants and personnel (performance bias)
All outcomes
Low risk"One treating neurologist who knew about side effects, reviewed laboratory findings for toxicity, and was responsible for overall care". Page S4

Blinding of outcome assessment (detection bias)
All outcomes
Low riskEndpoints were measured by "One examining neurologist who was not aware of drug side effects". Page S4

Incomplete outcome data (attrition bias)
All outcomes
Unclear riskWithdrawals and losses to follow-up were difficult to find, and different data were given in different articles about the same trial. Specifically, 2 years after randomisation, withdrawals plus losses to follow-up in the treated group were described as either 18 or 20 in the 1.6 million IU interferon group and as 24 or 25 in the 8 million IU group. Patients included into analysis in the treated group were described as either 184 or 205 in the 1.6 million IU interferon group and as 244 or 255 in the 8 million IU group.

Selective reporting (reporting bias)Low riskThe published reports included all expected efficacy outcomes and those outcomes that were pre-specified in the methods section.

Other biasHigh risk"Sustained" disability progression was confirmed at 3 months' follow-up. The role of the study sponsor was unclear.

IMPACT 2002

MethodsRCT


ParticipantsAge: 18-55 years; clinical definite SPMS; progression not reported; EDSS 3.5-6.5; mean disease duration 16 years.


InterventionsIFNß -1a (Avonex) 60 μg intramuscular injections weekly (n. 217)

Placebo (n. 219)


OutcomesRelapses at 24 months. Progression at 24 months.


NotesFunding: BIOGEN INC.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear risk"The contract research organization computer generated two minimization schemes, one for North America and one for Europe and Israel". Page 680

Allocation concealment (selection bias)Unclear riskNot described

Blinding of participants and personnel (performance bias)
All outcomes
Unclear risk"A treating nurse and neurologist were responsible for clinical management of the subjects". Page 680

Blinding of outcome assessment (detection bias)
All outcomes
Unclear risk"The examining neurologist was not involved with any other aspect of subject care, and neither had access to the results of prior examinations or to clinical information that might compromise blinding". Page 680

Incomplete outcome data (attrition bias)
All outcomes
High risk"Twenty-three (11%) subjects in the placebo group and 29 (13%)
subjects in the IFN-1a group failed to complete 24 months of follow-up.The between-group difference in reason for study discontinuation was subject request (six placebo subjects vs 16 IFN-1a subjects, p < 0.05)"
Page 682

Selective reporting (reporting bias)Low riskThe published reports included all expected efficacy outcomes.

Other biasHigh riskSustained disability progression confirmed at 3 months' follow-up. Unclear the role of Biogen Inc. The FDA letters of July 23, 1998, December 6, 1999, and March 8, 2000 informed Biogen that the primary study endpoint, the Multiple Sclerosis Functional Composite (MSFC), is not a validated efficacy outcome measure and therefore is not appropriate as a primary efficacy endpoint in this Phase 3 study (FDA 2001).

INCOMIN 2002

MethodsRCT


ParticipantsAge: 18-50 years; clinical definite RRMS; mean disease duration 6 years; EDSS 1.0-3.5; ≥ 2 relapses in the 2 years before randomisation; in remission at randomisation.


InterventionsIFNß -1b 250 μg subcutaneously every other day for 24 months (n. 96)

IFNß -1a (Avonex) 30 μg by weekly intramuscular injections for 24 months (n. 92)


OutcomesRelapses at 12 and 24 months. Progression at 24 months


NotesFunding: The Italian Ministry of Health and the Italian MS Society


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low risk"Randomisation followed computer-generated random sequences of digits that were different for each centre and for each sex, to achieve
centre and sex stratification
". Page 1454

Allocation concealment (selection bias)Low risk"The codes were randomly assigned to treatments by an independent team of statisticians unaware of the patient’s clinical characteristics". Page 1454

Blinding of participants and personnel (performance bias)
All outcomes
High riskAll clinical outcomes were assessed in an open-label manner”. Page 1454

Blinding of outcome assessment (detection bias)
All outcomes
High riskAll clinical outcomes were assessed in an open-label manner”. Page 1454

Incomplete outcome data (attrition bias)
All outcomes
Low riskLosses to follow-up not included in analysis: IFNß -1a 4/92 (4%); IFNß -1b 2/96 (2%).

Selective reporting (reporting bias)Low riskThe published reports included all expected efficacy outcomes.

Other biasLow riskThe study appears to be free of other sources of bias.

Johnson 1995

MethodsRCT


ParticipantsAge: 18-45 years; clinical or laboratory-supported definite RRMS; EDSS 0–5.0; ≥ 2 relapses in the 2 years before randomisation.


InterventionsGlatiramer acetate 20 mg subcutaneously every day (n. 125).

Placebo (n. 126)


OutcomesRelapses at 24 months. Progression at 24 months.


NotesFunding: Teva Pharmaceutical.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskNot described

Allocation concealment (selection bias)Unclear risk"A centralized randomization scheme was used". Page 1270

Blinding of participants and personnel (performance bias)
All outcomes
Unclear risk"Treating neurologists were blinded". Page 1270

Blinding of outcome assessment (detection bias)
All outcomes
Unclear risk"Examining neurologists were blinded". Page 1270

Incomplete outcome data (attrition bias)
All outcomes
Low riskWithdrawals: glatiramer acetate = 19 (15%); placebo = 17 (13%).They were included in the analyses.

Selective reporting (reporting bias)Low riskThe published reports included all expected efficacy outcomes.

Other biasHigh risk"Sustained" disability progression confirmed at 3 months' follow-up.

Knobler 1993

MethodsRCT


ParticipantsAge: 18-50 years; clinical definite RRMS; EDSS ≤ 5.5; disease duration ≥ 1 and ≤ 15 years; ≥ 2 relapses in the 2 years before randomisation; in remission at randomisation.


InterventionsIFNß -1b 25 μg subcutaneous three times weekly for three years (n. 6)

IFNß -1b 125 μg subcutaneous three times weekly for three years (n. 6)

IFNß -1b 250 μg subcutaneous three times weekly for three years (n. 6)

IFNß -1b 500 μg subcutaneous three times weekly for three years (n. 6)

Placebo for three years (n. 7)


OutcomesRelapses at 12 months


NotesFunding: Triton Biosciences, Inc., Alameda, CA and Berlex Laboratories Inc.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskNot described

Allocation concealment (selection bias)Unclear riskNot described

Blinding of participants and personnel (performance bias)
All outcomes
High risk"One treating neurologist not blinded". Page 335

Blinding of outcome assessment (detection bias)
All outcomes
Low risk"An examining neurologist blinded to treatment arms". Page 335

Incomplete outcome data (attrition bias)
All outcomes
Unclear riskWithdrawals and losses to follow-up not described

Selective reporting (reporting bias)High riskProgression was not reported.

Other biasUnclear riskThe role of the study sponsor was unclear.

Koch-Henriksen 2006

MethodsRCT


ParticipantsAge: 18-55 years; clinical definite RRMS; disease duration 0-35; ≥ 2 relapses within 2 years before randomisation; EDSS ≤ 5.5.


InterventionsIFNß -1b 250 μg subcutaneous every other day for 24 months. (n. 158)

IFNß -1a (Rebif) 22 μg subcutaneous weekly for 24 months (n. 143)


OutcomesProgression at 24 months


NotesFunding: not reported


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskNot described

Allocation concealment (selection bias)Low risk"A central computerized randomization schedule assigned patients to treatment". Page 1057

Blinding of participants and personnel (performance bias)
All outcomes
High riskOpen label trial. "Blinding was abandoned because it could not be maintained owing to the different administration schemes of the two study drugs". Page 1057

Blinding of outcome assessment (detection bias)
All outcomes
High riskOpen label trial. Page 1057

Incomplete outcome data (attrition bias)
All outcomes
High riskLosses to follow-up not included in analysis: IFNß -1b 28%; IFNß -1a 23%.

Selective reporting (reporting bias)High riskRelapses were not reported.

Other biasHigh riskSustained disability progression confirmed at 3 months' follow-up. Is is unclear if the study was sponsored.

Leary 2003

MethodsRCT


ParticipantsAge: 25-59 years; definite PPMS; disease duration 2-21 years; EDSS 2.0–7.0.


InterventionsIFNß-1a (Avonex) 30 μg intramuscular weekly for 24 months (n. 15)

IFNß-1a (Avonex) 60 μg intramuscular weekly for 24 months (n. 15)

Placebo for 24 months (n. 20)


OutcomesProgression at 24 months


NotesFunding: BIOGEN


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear risk"The randomization was carried out off-site by Biogen using a randomization block method."Page 44

Allocation concealment (selection bias)Low risk"The study drug was blinded off-site by Biogen and delivered to the study centre with the study numbers already allocated. Subjects were allocated by study number consecutively as they were entered into the study. A copy of the randomization codes was kept in pharmacy and by Biogen, but no codes were broken until the study and analysis was completed".

Blinding of participants and personnel (performance bias)
All outcomes
Unclear risk"All personnel at the study site (dispensing pharmacists, treating physicians and EDSS physicians) were blinded to the study drug." Page 44

Blinding of outcome assessment (detection bias)
All outcomes
Low risk"EDSS and clinical assessments were performed by an independent evaluating physician blinded to all clinical information." Page 44

Incomplete outcome data (attrition bias)
All outcomes
Low riskOnly one patient (arm IFN 60µg ) was lost to follow-up.

Selective reporting (reporting bias)High riskRelapses were not reported.

Other biasHigh risk"Sustained" disability progression was confirmed at 3 months' follow-up. Funding: Biogen, Multiple Sclerosis Society of Great Britain and Northern Ireland.

Lewanska 2002

MethodsRCT


ParticipantsAge: 18-55 years; clinical definite RRMS; EDSS 0-6.5; mean disease duration >2 years; ≥ 2 relapses in the 2 years before randomisation.


InterventionsIntravenous immunoglobulins 0.2 g/kg/body weight intravenous monthly for 12 months.(n. 17)

Intravenous immunoglobulins 0.4 g/kg/body weight intravenous monthly for 12 months (n. 16)

Placebo (saline) for 12 months (n. 18)


OutcomesRelapses at 12 months


NotesFunding: Supported by the KBN (State Research Committee)


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low risk"The generation of allocation sequence was based on random-number table." Page 566

Allocation concealment (selection bias)Unclear riskInfusions of intravenous immunoglobulins and placebo were stored in identical opaque plastic bags for concealment during administration. No more information about treatment allocation

Blinding of participants and personnel (performance bias)
All outcomes
Unclear risk"Infusions of intravenous immunoglobulinsand placebo were stored in identical opaque plastic bags for concealment." Page 566

Blinding of outcome assessment (detection bias)
All outcomes
Unclear risk"Evaluating physician was unaware of the actual treatment allocation...Monitoring and recording of relapses, con-
comitant treatment, side-effects or other medical events were documented throughout the study." Page 566

Incomplete outcome data (attrition bias)
All outcomes
Low risk49 patients completed the trial: 15/16 in the intravenous immunoglobulins 0.4 g/kg arm; 17/17 in the intravenous immunoglobulins 0.2 g/kg arm; 17/18 in the placebo arm.

Selective reporting (reporting bias)High riskProgression was not reported.

Other biasHigh riskSustained disability progression confirmed at 3 months' follow-up. Supported by the KBN (State Research
Committee).

Likosky 1991

MethodsRCT


ParticipantsAge: 18-60 years; SPMS, PPMS or PRMS; progression ≥ 1.0 EDSS in the year before randomisation; disease duration 1-29 years; EDSS 2.0-7.0.


Interventions"short course" of cyclophosphamide 500 mg administered intravenously five days per week; (n. 22)

Folic acid (1 mg) administered intravenously five days per week (n. 21)


OutcomesProgression at 24 months


NotesFunding: The Community Service Program of Kaiser Foundation Hospitals


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskNot described

Allocation concealment (selection bias)Unclear riskNot described

Blinding of participants and personnel (performance bias)
All outcomes
Unclear riskNot described

Blinding of outcome assessment (detection bias)
All outcomes
Low risk"Evaluating physicians were unaware of the treatment status of the patients they evaluated". Page 1056

Incomplete outcome data (attrition bias)
All outcomes
Low riskLosses to follow-up not included in the study analysis: treatment 3/22 (15%); placebo 3/21 (14%). Losses appear to be balanced between the groups.

Selective reporting (reporting bias)Low riskThe published report included expected efficacy outcome.

Other biasUnclear riskDefinition of sustained disability progression not clearly reported.

"The research was supported in part by the Community Service Program of Kaiser Foundation Hospitals. Evansville, Indiana, provided cyclophosphamide as Cytoxan." Page 1060

Milanese 1993

MethodsRCT


ParticipantsMean age: 30 years; definite RRMS, SPMS or PPMS; disease duration 5-15 years; EDSS 2.5–6.5; ≤ 1 relapses in the 2 years before randomisation.


InterventionsAzathioprine 2.5 mg/Kg/body weight oral daily for 3 years (n. 19)

Placebo (lactose) in identical form (50 mg tablets) for three years (n. 21)


OutcomesRelapses at 12, 24 and 36 months. Progression at 24 and 36 months.


NotesFunding: Wellcome Company.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear risk"Wellcome Italia provided the randomisation code". Page 295

Allocation concealment (selection bias)Unclear risk"Patients were allocated to azathioprineor placebo groups according to a list of random code numbers". Page 295

Blinding of participants and personnel (performance bias)
All outcomes
Unclear risk"azathioprineand placebo tablets in identical form were supplied by Wellcome Company". Page 295

Blinding of outcome assessment (detection bias)
All outcomes
Low risk"EDSS and relapses evaluated by the same blinded neurologist". Page 295

Incomplete outcome data (attrition bias)
All outcomes
High riskLosses to follow-up not included in the study analysis: azathioprine 26%; placebo 14%.

Selective reporting (reporting bias)Low riskThe published reports included all expected efficacy outcomes.

Other biasHigh riskSustained disability progression confirmed at 3 months' follow-up. Funding: Wellcome Company

Millefiorini 1997

MethodsRCT


ParticipantsAge: 18-45 years; clinical or laboratory-supported definite RRMS; disease duration 1-10 years; EDSS 2.0-5.0; ≥ 1 relapses in the 2 years before randomisation.


Interventions12 pulses of mitoxantrone 8 mg/m²/body surface every month for 1 year (total dosage of 96 mg/m2 of body surface over 1 year) (n. 27)

Placebo (n. 24)


OutcomesRelapses at 12 and 24 months, Progression at 24 months


NotesFunding: not reported


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskNot described

Allocation concealment (selection bias)Low risk"Central allocation and the intravenous bag and tubing were black to ensure no differences between the treatment groups." Page 154.

Blinding of participants and personnel (performance bias)
All outcomes
High riskTreating physicians were not blinded. Unclear blinding of patients.

Blinding of outcome assessment (detection bias)
All outcomes
High risk"The interaction of the EDSS physicians with the patient was strictly restricted to the neurological examination. The neurologist was not allowed to talk with the patient about adverse events, or any other issue which could potentially disclose the patient’s treatment...The assessment of exacerbations was monitored by treating physicians not blinded to study treatment.” Page 154, 157

Incomplete outcome data (attrition bias)
All outcomes
Low riskAll randomised patients were included in the analysis.

Selective reporting (reporting bias)Low riskThe published reports included all expected efficacy outcomes.

Other biasHigh riskSustained disability progression confirmed at 3 months' follow-up. It's unclear if this study was sponsored.

Miller 1961

MethodsRCT


ParticipantsMean age: 33 years; SPMS, or PRMS; mean disease duration 10-13 years; EDSS not reported.


InterventionsPrednisolone tablets 15 mg oral daily for 8 months then 10 mg/day for 10 months (n. 29)

Calcium aspirin 9 tablets (54 g) oral daily (n. 27)

Placebo corresponding number of "dummy" tablets (n. 30)


OutcomesProgression at 24 months


NotesNo funding.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskNot described

Allocation concealment (selection bias)Unclear riskNot described

Blinding of participants and personnel (performance bias)
All outcomes
Unclear riskNot clearly described

Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskNot clearly described

Incomplete outcome data (attrition bias)
All outcomes
High riskLosses to follow-up: prednisolone 3/29 (10%); "dummy" tablets 1/30 (3%); calcium aspirin 3/27 (11%).

Selective reporting (reporting bias)Low riskThe published report included the expected efficacy outcome.

Other biasUnclear riskDefinition of sustained disability progression not clearly reported.

Montalban 2009

MethodsRCT


ParticipantsAge: 18-65 years; definite PPMS or "transitional" MS; mean disease duration 11 years; EDSS 3.0–7.0.


InterventionsIFNß -1b 250 μg subcutaneously every other day for 2 years (n. 36)

Placebo for 2 years (n. 37)


OutcomesProgression at 24 months


NotesFunding: SCHERING ESPANA S.A


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low risk"...Using a randomisation list. This randomization was performed in blocks of 6 and for each treatment was assigned in a 1:1 ratio". Page 1196

Allocation concealment (selection bias)Unclear riskNot clearly described

Blinding of participants and personnel (performance bias)
All outcomes
Low risk"All personnel at the study site (dispensing pharmacists, treating physicians and participants) were blinded to the outcome assessment and study drug." Page 1197

Blinding of outcome assessment (detection bias)
All outcomes
Low risk"EDSS physicians were blinded to the outcome assessment and study drug." Page 1197

Incomplete outcome data (attrition bias)
All outcomes
Low risk3 patients dropped out the study: 1 in the IFNß -1b arm; 2 in the placebo arm.

Selective reporting (reporting bias)Low riskThe published report included the expected efficacy outcome.

Other biasHigh risk"An external company (MDS Pharma Services Espana) named and funded by the study sponsor produced the statistical analyses under supervision from the principal investigator".

MSCRG 1996

MethodsRCT


ParticipantsAge: 18–55 years; definite RRMS; EDSS 1–3.5; disease duration ≥ 1 year; ≥ 2 relapses in the 3 years before randomisation; no relapses for at least 2 months before randomisation.


InterventionsIFNß-1a (Avonex) 30 μg intramuscular weekly (n. 158).

Placebo (n. 143).


OutcomesRelapses at 12 and 24 months. Progression at 24 months.


NotesFunding: Biogen, Inc, Cambridge, MA


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear risk"Randomisation performed at statistical centre of Buffalo General Hospital, one of the participating centres (biased coin assignment used for sequence generation". Page 286

Allocation concealment (selection bias)Unclear risk"schedule sent to each clinical centre, included patients were sequentially assigned the next ID number from the schedule." Page 286

Blinding of participants and personnel (performance bias)
All outcomes
Low risk"Personnel and participants were blinded to treatment status." Page 286

Blinding of outcome assessment (detection bias)
All outcomes
Low risk"Evaluating physicians were blinded to treatment status." Page 286

Incomplete outcome data (attrition bias)
All outcomes
High riskThe study stopped early for benefit without a formal-stopping rule. 73 (46%) of 158 patients in the treatment group and 56 (39%) of 143 controls had not completed the scheduled 2 years of follow-up. At 2 years' follow-up primary outcomes were available for only 57% of randomised participants.

Selective reporting (reporting bias)Low riskExpected efficacy outcomes were reported.

Other biasHigh risk"Supported by National Institutes of Health, National Institute of Neurological Disorders and Stroke (NINDS) and Biogen, Inc, Cambridge, MA. Personnel of the study sponsor (Biogen) were involved in the conduct and data analysis". Page 293

NASP 2004

MethodsRCT


ParticipantsAge 18-65 years, clinically definite SPMS of at least 2 years’ duration; ≥ 1.0 EDSS increase in the 2 years before randomisation; ≥ 1.0 relapses followed by progressive deterioration sustained for at least 6 months; EDSS 3.0-6.5.


InterventionsIFNß -1b (Betaseron) 250 μg subcutaneously every other day (n. 317)

INFß -1b (Betaseron) 160 μg/m² body surface area (mean administered dose 220 μg) every other day (n. 314)

Placebo (n. 308)


OutcomesRelapses at 36 months. Progression at 36 months.


NotesFunding: Berlex Laboratories (Richmond, CA)


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low risk"The randomisation schedule was generated by the Biostatistics and Data Management Group of Berlex Laboratories (Richmond, CA) using an SAS program (Cary, NC)... Each block allocated 2 subjects to fixed-dose Betaseron, 2 to Body Surface Area (BSA)-adjusted Betaseron, 1 to fixed placebo, and 1 to BSA-adjusted placebo. Each site received an adequate number of blocks, based on projected subject recruitment, to ensure sequential subject numbering within each site." Page 1789

Allocation concealment (selection bias)Low risk"The biostatistician and supporting programmers were the only individuals with access to the randomisation codes" (FDA page 9). "The active study drug was indistinguishable from placebo in appearance, smell and color, and labels and packages for active study agent and placebo were indistinguishable" (FDA page 9)

Blinding of participants and personnel (performance bias)
All outcomes
Low risk"All sponsor personnel directly involved in the conduct of the study, investigators, and subjects remained blinded to subject treatment assignment throughout the study". (FDA page 9)

Blinding of outcome assessment (detection bias)
All outcomes
Low risk"Investigators remained blinded to subject treatment assignment throughout the study". (FDA page 9)

Incomplete outcome data (attrition bias)
All outcomes
High risk"The study had ended prematurely based on the results of a planned interim analysis indicating that "continuing the trial was unlikely to change the results". The study initiated in August 2, 1995, interrupted November 22, 1999. The last patient enrolled on April 1, 1997. The final patient visit occurred on November 15, 1999". (FDA report page 21). "Only 72% of randomised patients completed 33 months or more on study and could be included in analysis" (FDA 2001 page 26).

Selective reporting (reporting bias)Unclear riskThe published reports included relapses and progression at 36 months (no data at 24 months).

Other biasHigh riskFunding: Berlex Laboratories (Richmond, CA).

OWIMS 1999

MethodsRCT


ParticipantsAge: 18–50 years; clinical or laboratory-supported definite RRMS; EDSS 0–5.0; disease duration ≥ 1 year; ≥ 1 relapses in the 2 years before randomisation; no relapses for at least 2 months before randomisation.


InterventionsIFNß -1a (Rebif) 22 μg subcutaneous three times/week for 48 weeks (n. 95)

IFNß -1a (Rebif) 44 μg subcutaneous three times/week for 48 weeks (n. 98)

Placebo (human albumin and mannitol) for 48 weeks (n. 100)


OutcomesRelapses at 12 months


NotesFunding: Ares-Serono International SA, Geneva, Switzerland


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low risk"Randomisation performed at Corporate Biometrics Department of Ares-Serono (computer-generated list)." Page 680

Allocation concealment (selection bias)Unclear risk"Sealed envelopes were used but it was unclear whether envelopes were sequentailly numbered and opaque." Page 680

Blinding of participants and personnel (performance bias)
All outcomes
Low risk"Participants were blinded to treatment" Page 681

Blinding of outcome assessment (detection bias)
All outcomes
Low risk"The evaluating physician was responsible for neurologic assessments and remained unaware of adverse event profiles and any changes in safety assessments." Page 681

Incomplete outcome data (attrition bias)
All outcomes
High riskLosses to follow-up: treatment arms 13% and 8%; placebo arm 3%. Reason for missing data was likely related to outcome with imbalance in numbers across intervention groups.

Selective reporting (reporting bias)High riskOnly relapses at 12 months were reported.

Other biasHigh riskSponsored by Ares-Serono International SA, Geneva, Switzerland.

Pohlau 2007

Methods


ParticipantsAge: 18-65 years; SPMS, or PPMS; progression ≥ 0.5 EDSS point in the year before randomisation; disease duration > 2 years; EDSS 3.0-7.0.


InterventionsIVIg 0.4 gm/kg body weight intravenous monthly (n. 116).

Placebo (n. 115).


OutcomesProgression at 24 months.


NotesFundings: Novartis Pharma GmbH and ZLB Behring.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low risk"Randomisation was performed by the Biometric Department Novartis Germany using a scheme, which provided balanced blocks of patient numbers for both treatment groups and the two diagnostic layers." Page 1109

Allocation concealment (selection bias)Unclear riskNot clearly described. Only "randomly assigned" Page 1109

Blinding of participants and personnel (performance bias)
All outcomes
Unclear riskNot clearly described. Only "intravenous immunoglobulinsand placebo could not visually be distinguished." Page 1109

Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskNot described

Incomplete outcome data (attrition bias)
All outcomes
Unclear risk"113 patients (49%) completed the 112 weeks of the study, and 118 (51%) discontinued their participation prematurely." Page 1110 . Follow-up of the participants who discontinued participation was not reported.

Selective reporting (reporting bias)Low riskProgression at 24 months is the expected efficacy outcome.

Other biasHigh riskSustained disability progression confirmed at 16 weeks' follow-up. Supported by Novartis Pharma GmbH, Nürnberg, Germany and ZLB Behring, Bern Switzerland.

PRISMS 1998

MethodsRCT


ParticipantsAge: 28-41 years; clinical or laboratory-supported definite RRMS; EDSS 0–5.0; disease duration ≥ 1 year; at least 2 relapses in the 2 years before randomisation.


InterventionsIFNß -1a (Rebif) 22 μg subcutaneous three times/week for 2 years (n. 189)

IFNß -1a (Rebif) 44 μg subcutaneous three times/week for 2 years (n. 184)

Placebo (unspecified) for 2 years (n. 187)


OutcomesRelapses at 12 and 24 months. Progression at 24 months


NotesFundng: Ares-Serono International SA, Geneva, Switzerland


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low risk"Randomisation at Corporate Biometrics Department of Ares-Serono (computer-generated list, stratified by centre, equal allocation of the treatment groups by a block size of 6)." Page 1499

Allocation concealment (selection bias)Low risk"The study drug was packed accordingly to the randomisation list and delivered to the centres so that treatment allocation remained concealed". Page 1499

Blinding of participants and personnel (performance bias)
All outcomes
Low risk"All personnel involved in the study were unaware of treatment allocation". Page 1499

Blinding of outcome assessment (detection bias)
All outcomes
Low risk"All personnel involved in the study were unaware of treatment allocation. All injection sites were covered up at neurological examinations to ensure that masking was not compromised because of local reactions". Page 1499

Incomplete outcome data (attrition bias)
All outcomes
Low riskLosses to follow-up excluded from study analysis: treatment arms 6% and 3%; placebo arm 5%.

Selective reporting (reporting bias)Low riskThe published report included all expected efficacy outcomes.

Other biasHigh risk"Sustained" disability progression was confirmed at 3 months' follow-up. Ares-Serono was involved in the trial.

REGARD 2008

MethodsRCT


ParticipantsMean age: 37 years; clinical or laboratory-supported definite RRMS; EDSS 0-5.5; mean disease duration 6 years; ≥ 1 relapses in the year before randomisation.


InterventionsIFNß -1a (Rebif) 44 μg subcutaneous three times/week for 96 weeks (n. 386)

Glatiramer acetate 20 mg subcutaneous every day for 96 weeks (n. 378)


OutcomesRelapses at 24 months. Progression at 24 months


NotesFunding: EMD Serono and Pfizer


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low risk"Computer-generated randomisation list stratified by centre". Page 904

Allocation concealment (selection bias)Unclear riskNot described

Blinding of participants and personnel (performance bias)
All outcomes
High risk"Neither the patients nor the treating physicians were blinded to treatment." Page 904

Blinding of outcome assessment (detection bias)
All outcomes
Low risk"The physicians who assessed patients ...were blinded to treatment and communicated with the patients only as needed to complete the EDSS, Kurtzke functional scale (KFS), and relapse assessments. Patients were asked not to discuss their treatment with the assessing physician and they covered their injection sites." Page 904

Incomplete outcome data (attrition bias)
All outcomes
Low riskLosses to follow-up: IFNß -1a 20/386 (5%); glatiramer acetate 5/378 (1%).

Selective reporting (reporting bias)Low riskThe published report included all expected efficacy outcomes.

Other biasHigh risk"The study protocol was drafted and developed by the study sponsors, EMD Serono and Pfizer, in conjunction with the investigator steering committee. Data management and analysis were done by the study sponsors." Page 907

SENTINEL 2006

MethodsRCT


ParticipantsAge: 18-55 years; clinical definite RRMS; disease duration 1-34 years; EDSS 0-5.0; ≥ 1 relapses in the year before randomisation.


InterventionsNatalizumab 300 mg intravenous monthly and IFNß-1a (Avonex) 30 μg intramuscular weekly for 116 weeks.(n. 589)

Placebo and IFNß-1a (Avonex) 30 μg intramuscular weekly for 116 weeks.(n. 582)


OutcomesRelapses at 12 and 24 months. Progression at 24 months


NotesFunding: Biogen Idec, Inc. and Elan Pharmaceutical


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low risk"Randomization was stratified according to study site in blocks of four (two active and two placebo) with the use of a computer-generated schedule and a multidigit identification number". Page 912

Allocation concealment (selection bias)Low risk"An interactive voice-response system was used". Page 912

Blinding of participants and personnel (performance bias)
All outcomes
Low risk"All study personnel, patients, sponsor personnel involved in the conduct of the study, and members of the investigator advi-
sory committee were blinded to the treatment assignments throughout the study.
" Page 912 "The treating neurologists were responsible for all patient care, including the management of adverse events and relapses of multiple sclerosis". Page 913

Blinding of outcome assessment (detection bias)
All outcomes
Unclear risk"Examining neurologists performed the EDSS and neurologic examinations but were otherwise not involved in the patients’ medical care." Page 913

Incomplete outcome data (attrition bias)
All outcomes
Low risk516/589 (88%) in the natalizumab + IFNß-1a group and 487/582 (84%) in the placebo+ IFNß-1a group completed the 120-week study.

Selective reporting (reporting bias)Low riskThe published report included all expected efficacy outcomes.

Other biasHigh riskSustained disability progression confirmed at 3 months' follow-up.

The study protocol was developed by the investigator advisory committee and the sponsors (Biogen Idec and Elan Pharmaceuticals). Data were analyzed by the sponsor. Relapses were assessed also as adverse events.

SPECTRIMS 2001

MethodsRCT


ParticipantsAge: 18-55 years; clinical definite SPMS; progression ≥ 1 EDSS over the previous 2 years, with or without superimposed relapses before randomisation; EDSS 3.0-6.5; mean disease duration 14 years.


InterventionsIFNß -1a (Rebif) 22 μg subcutaneous three times/week for 3 years (n. 209)

IFNß -1a (Rebif) 44 μg subcutaneous three times/week for 3 years (n. 204)

Placebo (unspecified) for 3 years (n. 205)


OutcomesProgression at 24 and 36 months


NotesFunding: Serono International, Geneva, Switzerland


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low risk"Computer generated randomisation list provided by Serono, stratified by center; treatments were equally allocated with a block size of six". Page 1497

Allocation concealment (selection bias)Unclear risk"The block size was not revealed to the investigators. The manufacturer labelled containers of study medication with patient identification numbers based on the randomisation list, and patients received the medication labelled with their numbers." Page 1497

Blinding of participants and personnel (performance bias)
All outcomes
Unclear risk"A treating physician supervised drug administration, monitored safety, and managed adverse events". Page 1497

Blinding of outcome assessment (detection bias)
All outcomes
Low risk"A separate evaluating physician conducted neurologic assessments and followed-up exacerbations. Patients were instructed to cover injection sites and to discuss only neurologic matters during neurologic evaluations. Clinical and neurologic data
were recorded in separate binders." Page 1497

Incomplete outcome data (attrition bias)
All outcomes
Low risk195/209 (93%) in the IFNß -1a 22 μg group, 190/204 (93%) in the IFNß -1a 44 μg group and 186/205 (91%) in the placebo group completed 3 years' follow-up.

Selective reporting (reporting bias)Low riskThe published report included all expected efficacy outcomes.

Other biasHigh riskSustained disability progression confirmed at 3 months' follow-up. Serono Biometrics (Geneva) performed statistical analysis.

Wolinsky 2007

MethodsRCT


ParticipantsAge: 30-65 years; definite chronic progressive MS; EDSS 3.0–6.5; progression ≥ 6 months; ≤ 2 relapses in the 2 years before randomisation.


InterventionsGlatiramer acetate 20 mg subcutaneous every day for 3 years (n. 627)

Placebo (unspecified) for 3 years (n. 316)


OutcomesProgression at 24 months


NotesFunding: Teva Pharmaceutical


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskNot described

Allocation concealment (selection bias)Unclear riskNot described

Blinding of participants and personnel (performance bias)
All outcomes
Unclear risk"All patients were attended by a treating neurologist and an examining neurologist who were blinded to treatment. The treating neurologist supervised drug administration, recorded and treated adverse events, and coordinated MRI testing." Page 16

Blinding of outcome assessment (detection bias)
All outcomes
Unclear risk"... examining neurologist was blinded to treatment." Page 16

Incomplete outcome data (attrition bias)
All outcomes
Unclear riskStudy stopped early for futility. 376/627 (60%) of participants in the glatiramer acetate group and 186/315 (59%) in the placebo group had received study drugs for 24 months. Insufficient information to judge whether withdrawals and lost to follow-up were included in data analysis.

Selective reporting (reporting bias)Unclear riskProgression at 24 months was reported.

Other biasHigh riskSustained disability progression confirmed at 3 months' follow-up. Funding: Teva Pharmaceutical.

 
Characteristics of excluded studies [ordered by study ID]

StudyReason for exclusion

Arnason 1999Study on TNF neutralization (Lenercept).

Barkhof 2003ETOMS trial MRI subgroup analysis.

Baum 2006Study evaluating two formulations of interferon b (IFNbeta-1b-G or the refrigeration-free formulation (IFNbeta-1b-M) without a control group.

BENEFIT 2006Study on interferon beta 1b for clinically isolated syndromes (CIS).

Boiko 2001Trial on short course of antibodies to IFN gamma or antibodies to tumour necrosis factor alpha.

Burton 2009A Cochrane review on oral versus Intravenous steroids for treatment of relapses in multiple sclerosis.

CHAMPS 2000Study on interferon beta 1a for clinically isolated syndromes (CIS).

Christodoulou 2006Study on donepezil.

Clanet 2002A dose-comparison study of interferon beta-1a without a control group.

Durelli 1994Study on interferon alfa for multiple sclerosis.

ETOMS 2001Study on interferon beta 1a for clinically isolated syndromes (CIS).

Fernandez 2002Prospective study evaluating combination therapy with interferon beta 1b and azathioprine in MS.

Filippi 2004ETOMS trial MRI subgroup analysis.

Filippi 2006Study on oral glatiramer acetate for multiple sclerosis.

GLANCE 2009Active treatment with natalizumab was confounded by glatiramer acetate.

Goodkin 2000Study on complex of human leukocyte antigen-DR2 with myelin basic protein84-102.

Hauser 1983Active treatment with cyclophosphamide was confounded by other treatments.

Hoogervorst 2002A phase II study evaluating the safety, tolerability and MRI effects of oral interferon beta-1a.

Labetouelle 2001Review about CHAMPS study.

Liu 2010A Cochrane review on daclizumab for multiple sclerosis.

Myhr 1999Study on interferon alfa for multiple sclerosis.

Patti 1999Study on natural interferon beta derived from human fibroblasts (Ares-Serono@).

Rio 2007Open label, non-randomised, observational study.

Skurkovich 2001A trial comparing antibodies to TNF-a, to IFN-γ and placebo.

Steultjens 2003A Cochrane review on occupational therapy for multiple sclerosis.

Tejani 2010A Cochrane review on carnitine for fatigue in multiple sclerosis.

Tubridy 1999Study on natalizumab with a dosage of 3 mg/kg.

Van de Wyngaert 2001Study on mitoxantrone in which participants' inclusion criteria were not described.

Wender 1988Active treatment with cyclophosphamide was confounded by other treatments.

Zavalishin 2003Multicentre non-randomised study evaluating the effect of interferon alfa.

Zivadinov 2001A dose-comparison trial of long-term corticosteroids without a control group.

 
Comparison 1. Comparisons for relapse over 12 months

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Relapse over 12 months in MS of all types21Odds Ratio (IV, Random, 95% CI)Subtotals only

    1.1 IFNß-1b (Betaseron) versus placebo
125Odds Ratio (IV, Random, 95% CI)0.6 [0.10, 3.49]

    1.2 IFNß-1a (Avonex) versus placebo
1301Odds Ratio (IV, Random, 95% CI)0.72 [0.45, 1.14]

    1.3 IFNß-1a (Rebif) versus placebo
2853Odds Ratio (IV, Random, 95% CI)0.66 [0.25, 1.78]

    1.4 Glatiramer acetate versus placebo
2289Odds Ratio (IV, Random, 95% CI)0.34 [0.06, 2.05]

    1.5 Natalizumab versus placebo
1942Odds Ratio (IV, Random, 95% CI)0.38 [0.28, 0.51]

    1.6 Mitoxantrone versus placebo
151Odds Ratio (IV, Random, 95% CI)0.14 [0.04, 0.48]

    1.7 Azathioprine versus placebo
4547Odds Ratio (IV, Random, 95% CI)0.63 [0.44, 0.89]

    1.8 Immunoglobulins versus placebo
4537Odds Ratio (IV, Random, 95% CI)0.56 [0.20, 1.60]

    1.9 Corticosteroids versus placebo
136Odds Ratio (IV, Random, 95% CI)0.46 [0.12, 1.84]

    1.10 IFNß-1a (Avonex) versus IFNß-1b (Betaseron)
1188Odds Ratio (IV, Random, 95% CI)1.53 [0.86, 2.72]

    1.11 IFNß-1a (Rebif) versus IFNß-1a (Avonex)
1677Odds Ratio (IV, Random, 95% CI)0.79 [0.58, 1.07]

    1.12 Natalizumab versus IFNß-1a (Avonex)
11171Odds Ratio (IV, Random, 95% CI)0.40 [0.32, 0.51]

    1.13 Corticosteroids versus Mitoxantrone
142Odds Ratio (IV, Random, 95% CI)4.0 [1.11, 14.43]

 2 Relapse over 12 months in relapsing-remitting MS164806Odds Ratio (M-H, Fixed, 95% CI)0.55 [0.49, 0.62]

    2.1 IFNß-1b (Betaseron) versus placebo
125Odds Ratio (M-H, Fixed, 95% CI)0.6 [0.10, 3.49]

    2.2 IFNß-1a (Avonex) versus placebo
1301Odds Ratio (M-H, Fixed, 95% CI)0.72 [0.45, 1.14]

    2.3 IFNß-1a (Rebif) versus placebo
2853Odds Ratio (M-H, Fixed, 95% CI)0.59 [0.43, 0.81]

    2.4 Glatiramer acetate versus placebo
2289Odds Ratio (M-H, Fixed, 95% CI)0.59 [0.37, 0.93]

    2.5 Natalizumab versus placebo
1942Odds Ratio (M-H, Fixed, 95% CI)0.38 [0.28, 0.51]

    2.6 Mitoxantrone versus placebo
151Odds Ratio (M-H, Fixed, 95% CI)0.14 [0.04, 0.48]

    2.7 Azathioprine versus placebo
154Odds Ratio (M-H, Fixed, 95% CI)0.77 [0.25, 2.38]

    2.8 Immunoglobulins versus placebo
3219Odds Ratio (M-H, Fixed, 95% CI)0.67 [0.38, 1.21]

    2.9 Corticosteroids versus placebo
136Odds Ratio (M-H, Fixed, 95% CI)0.46 [0.12, 1.84]

    2.10 IFNß-1a (Avonex) versus IFNß-1b (Betaseron)
1188Odds Ratio (M-H, Fixed, 95% CI)1.53 [0.86, 2.72]

    2.11 IFNß-1a (Rebif) versus IFNß-1a (Avonex)
1677Odds Ratio (M-H, Fixed, 95% CI)0.79 [0.58, 1.07]

    2.12 Natalizumab versus IFNß-1a (Avonex)
11171Odds Ratio (M-H, Fixed, 95% CI)0.40 [0.32, 0.51]

 3 Relapse over 12 months in progressive MS3459Odds Ratio (M-H, Fixed, 95% CI)1.04 [0.70, 1.54]

    3.1 Azathioprine versus placebo
199Odds Ratio (M-H, Fixed, 95% CI)0.43 [0.16, 1.12]

    3.2 Immunoglobulins versus placebo
1318Odds Ratio (M-H, Fixed, 95% CI)1.06 [0.66, 1.68]

    3.3 Corticosteroids versus Mitoxantrone
142Odds Ratio (M-H, Fixed, 95% CI)4.0 [1.11, 14.43]

 
Comparison 2. Comparisons for relapse over 24 months

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Relapse over 24 months in MS of all types25Odds Ratio (IV, Random, 95% CI)Subtotals only

    1.1 IFNß-1b (Betaseron) versus placebo
1372Odds Ratio (IV, Random, 95% CI)0.55 [0.31, 0.99]

    1.2 IFNß-1a (Avonex) versus placebo
2737Odds Ratio (IV, Random, 95% CI)0.76 [0.56, 1.05]

    1.3 IFNß-1a (Rebif) versus placebo
1560Odds Ratio (IV, Random, 95% CI)0.45 [0.28, 0.71]

    1.4 Glatiramer acetate versus placebo
2301Odds Ratio (IV, Random, 95% CI)0.49 [0.18, 1.36]

    1.5 Natalizumab versus placebo
1942Odds Ratio (IV, Random, 95% CI)0.32 [0.24, 0.43]

    1.6 Mitoxantrone versus placebo
2245Odds Ratio (IV, Random, 95% CI)0.35 [0.09, 1.42]

    1.7 Azathioprine versus placebo
5737Odds Ratio (IV, Random, 95% CI)0.64 [0.44, 0.94]

    1.8 Immunoglobulins versus placebo
4705Odds Ratio (IV, Random, 95% CI)0.70 [0.40, 1.22]

    1.9 Corticosteroids versus placebo
136Odds Ratio (IV, Random, 95% CI)1.13 [0.06, 19.50]

    1.10 Methotrexate versus placebo
160Odds Ratio (IV, Random, 95% CI)1.15 [0.31, 4.28]

    1.11 IFNß-1a (Avonex) versus IFNß-1b (Betaseron)
2248Odds Ratio (IV, Random, 95% CI)2.26 [1.33, 3.83]

    1.12 IFNß-1a (Rebif) versus IFNß-1a (Avonex)
160Odds Ratio (IV, Random, 95% CI)0.19 [0.06, 0.60]

    1.13 Natalizumab versus IFNß-1a (Avonex)
11171Odds Ratio (IV, Random, 95% CI)0.28 [0.22, 0.36]

    1.14 IFNß-1a (Rebif) versus Interferon beta 1b
160Odds Ratio (IV, Random, 95% CI)0.58 [0.21, 1.62]

    1.15 Glatiramer acetate versus IFNß-1b (Betaseron)
12244Odds Ratio (IV, Random, 95% CI)1.05 [0.85, 1.29]

    1.16 Glatiramer acetate versus IFNß-1a (Rebif)
1764Odds Ratio (IV, Random, 95% CI)0.93 [0.69, 1.25]

 2 Relapse over 24 months in relapsing-remitting MS16Odds Ratio (IV, Random, 95% CI)Subtotals only

    2.1 IFNß-1b (Betaseron) versus placebo
1372Odds Ratio (IV, Random, 95% CI)0.55 [0.31, 0.99]

    2.2 IFNß-1a (Avonex) versus placebo
1301Odds Ratio (IV, Random, 95% CI)0.83 [0.46, 1.49]

    2.3 IFNß-1a (Rebif) versus placebo
1560Odds Ratio (IV, Random, 95% CI)0.45 [0.28, 0.71]

    2.4 Glatiramer acetate versus placebo
2301Odds Ratio (IV, Random, 95% CI)0.49 [0.18, 1.36]

    2.5 Natalizumab versus placebo
1942Odds Ratio (IV, Random, 95% CI)0.32 [0.24, 0.43]

    2.6 Mitoxantrone versus placebo
151Odds Ratio (IV, Random, 95% CI)0.15 [0.04, 0.54]

    2.7 Azathioprine versus placebo
159Odds Ratio (IV, Random, 95% CI)0.36 [0.11, 1.21]

    2.8 Immunoglobulins versus placebo
2190Odds Ratio (IV, Random, 95% CI)0.22 [0.03, 1.90]

    2.9 Corticosteroids versus placebo
136Odds Ratio (IV, Random, 95% CI)1.13 [0.06, 19.50]

    2.10 IFNß-1a (Avonex) versus IFNß-1b (Betaseron)
2248Odds Ratio (IV, Random, 95% CI)2.26 [1.33, 3.83]

    2.11 IFNß-1a (Rebif) versus IFNß-1a (Avonex)
160Odds Ratio (IV, Random, 95% CI)0.19 [0.06, 0.60]

    2.12 Natalizumab versus IFNß-1a (Avonex)
11171Odds Ratio (IV, Random, 95% CI)0.28 [0.22, 0.36]

    2.13 IFNß-1a (Rebif) versus IFNß-1b (Betaseron)
160Odds Ratio (IV, Random, 95% CI)0.58 [0.21, 1.62]

    2.14 Glatiramer acetate versus IFNß-1b (Betaseron)
12244Odds Ratio (IV, Random, 95% CI)1.05 [0.85, 1.29]

    2.15 Glatiramer acetate versus IFNß-1a (Rebif)
1764Odds Ratio (IV, Random, 95% CI)0.93 [0.69, 1.25]

 3 Relapse over 24 months in progressive MS6Odds Ratio (IV, Random, 95% CI)Subtotals only

    3.1 IFNß-1a (Avonex) versus placebo
1436Odds Ratio (IV, Random, 95% CI)0.74 [0.51, 1.08]

    3.2 Mitoxantrone versus placebo
1194Odds Ratio (IV, Random, 95% CI)0.65 [0.35, 1.20]

    3.3 Azathioprine versus placebo
199Odds Ratio (IV, Random, 95% CI)0.56 [0.24, 1.33]

    3.4 Immunoglobulins versus placebo
2515Odds Ratio (IV, Random, 95% CI)0.93 [0.66, 1.32]

    3.5 Methotrexate versus placebo
160Odds Ratio (IV, Random, 95% CI)1.15 [0.31, 4.28]

 
Comparison 3. Comparisons for relapse over 36 months

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Relapse over 36 months in MS of all types6Odds Ratio (IV, Random, 95% CI)Subtotals only

    1.1 IFNß-1b (Betaseron) versus placebo
21657Odds Ratio (IV, Random, 95% CI)0.71 [0.56, 0.90]

    1.2 IFNß-1a (Rebif) versus placebo
1371Odds Ratio (IV, Random, 95% CI)1.28 [0.85, 1.93]

    1.3 Azathioprine versus placebo
3493Odds Ratio (IV, Random, 95% CI)0.45 [0.27, 0.76]

 
Comparison 4. Comparisons for disability progression over 24 months

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Disability progression over 24 months in MS of all types30Odds Ratio (IV, Random, 95% CI)Subtotals only

    1.1 IFNß-1b (Betaseron) versus placebo
2445Odds Ratio (IV, Random, 95% CI)0.89 [0.59, 1.36]

    1.2 IFNß-1a (Avonex) versus placebo
3787Odds Ratio (IV, Random, 95% CI)0.94 [0.71, 1.25]

    1.3 IFNß-1a (Rebif) versus placebo
21178Odds Ratio (IV, Random, 95% CI)0.71 [0.56, 0.92]

    1.4 Glatiramer acetate versus placebo
41350Odds Ratio (IV, Random, 95% CI)0.76 [0.49, 1.17]

    1.5 Natalizumab versus placebo
1942Odds Ratio (IV, Random, 95% CI)0.56 [0.42, 0.74]

    1.6 Mitoxantrone versus placebo
2245Odds Ratio (IV, Random, 95% CI)0.34 [0.08, 1.44]

    1.7 Azathioprine versus placebo
3284Odds Ratio (IV, Random, 95% CI)0.77 [0.48, 1.24]

    1.8 Immunoglobulins versus placebo
4739Odds Ratio (IV, Random, 95% CI)0.78 [0.48, 1.25]

    1.9 Cyclophosphamide versus placebo
144Odds Ratio (IV, Random, 95% CI)0.80 [0.22, 2.94]

    1.10 Corticosteroids versus placebo
186Odds Ratio (IV, Random, 95% CI)1.58 [0.64, 3.87]

    1.11 Methotrexate versus placebo
160Odds Ratio (IV, Random, 95% CI)0.67 [0.24, 1.87]

    1.12 IFNß-1a (Avonex) versus IFNß-1b (Betaseron)
1188Odds Ratio (IV, Random, 95% CI)2.88 [1.43, 5.79]

    1.13 IFNß-1a (Rebif) versus IFNß-1b (Betaseron)
1301Odds Ratio (IV, Random, 95% CI)0.98 [0.62, 1.54]

    1.14 Natalizumab versus IFNß-1a (Avonex)
11171Odds Ratio (IV, Random, 95% CI)0.62 [0.49, 0.78]

    1.15 Glatiramer acetate versus IFNß-1b (Betaseron)
12244Odds Ratio (IV, Random, 95% CI)0.86 [0.69, 1.06]

    1.16 Glatiramer acetate versus IFNß-1a (Rebif)
1764Odds Ratio (IV, Random, 95% CI)0.53 [0.34, 0.83]

    1.17 Corticosteroids versus Mitoxantrone
142Odds Ratio (IV, Random, 95% CI)8.00 [0.87, 73.68]

 2 Disability progression over 24 months in relapse-remitting MS15Odds Ratio (IV, Random, 95% CI)Subtotals only

    2.1 IFNß-1b (Betaseron) versus placebo
1372Odds Ratio (IV, Random, 95% CI)0.96 [0.61, 1.52]

    2.2 IFNß-1a (Avonex) versus placebo
1301Odds Ratio (IV, Random, 95% CI)0.93 [0.59, 1.47]

    2.3 IFNß-1a (Rebif) versus placebo
1560Odds Ratio (IV, Random, 95% CI)0.65 [0.45, 0.93]

    2.4 Glatiramer acetate versus placebo
2301Odds Ratio (IV, Random, 95% CI)0.50 [0.14, 1.74]

    2.5 Natalizumab versus placebo
1942Odds Ratio (IV, Random, 95% CI)0.56 [0.42, 0.74]

    2.6 Mitoxantrone versus placebo
151Odds Ratio (IV, Random, 95% CI)0.13 [0.03, 0.70]

    2.7 Azathioprine versus placebo
159Odds Ratio (IV, Random, 95% CI)0.52 [0.17, 1.54]

    2.8 Immunoglobulins versus placebo
2190Odds Ratio (IV, Random, 95% CI)0.62 [0.30, 1.29]

    2.9 IFNß-1a (Avonex) versus IFNß-1b (Betaseron)
1188Odds Ratio (IV, Random, 95% CI)2.88 [1.43, 5.79]

    2.10 IFNß-1a (Rebif) versus IFNß-1b (Betaseron)
1301Odds Ratio (IV, Random, 95% CI)0.98 [0.62, 1.54]

    2.11 Natalizumab versus IFNß-1a (Avonex)
11171Odds Ratio (IV, Random, 95% CI)0.62 [0.49, 0.78]

    2.12 Glatiramer acetate versus IFNß-1b (Betaseron)
12244Odds Ratio (IV, Random, 95% CI)0.86 [0.69, 1.06]

    2.13 Glatiramer acetate versus IFNß-1a (Rebif)
1764Odds Ratio (IV, Random, 95% CI)0.53 [0.34, 0.83]

 3 Disability progression over 24 months in progressive MS13Odds Ratio (IV, Random, 95% CI)Subtotals only

    3.1 IFNß-1b (Betaseron) versus placebo
173Odds Ratio (IV, Random, 95% CI)0.62 [0.22, 1.69]

    3.2 IFNß-1a (Avonex) versus placebo
2486Odds Ratio (IV, Random, 95% CI)0.95 [0.66, 1.36]

    3.3 IFNß-1a (Rebif) versus placebo
1618Odds Ratio (IV, Random, 95% CI)0.78 [0.55, 1.10]

    3.4 Glatiramer acetate versus placebo
21049Odds Ratio (IV, Random, 95% CI)0.94 [0.73, 1.23]

    3.5 Mitoxantrone versus placebo
1194Odds Ratio (IV, Random, 95% CI)0.61 [0.27, 1.34]

    3.6 Immunoglobulins versus placebo
2549Odds Ratio (IV, Random, 95% CI)0.83 [0.39, 1.74]

    3.7 Cyclophosphamide versus placebo
144Odds Ratio (IV, Random, 95% CI)0.80 [0.22, 2.94]

    3.8 Corticosteroids versus placebo
186Odds Ratio (IV, Random, 95% CI)1.58 [0.64, 3.87]

    3.9 Methotrexate versus placebo
160Odds Ratio (IV, Random, 95% CI)0.67 [0.24, 1.87]

    3.10 Corticosteroids versus Mitoxantrone
142Odds Ratio (IV, Random, 95% CI)8.00 [0.87, 73.68]

 
Comparison 5. Comparisons for disability progression over 36 months

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Disability progression over 36 months in progressive MS7Odds Ratio (IV, Random, 95% CI)Subtotals only

    1.1 IFNß-1b (Betaseron) versus placebo
21657Odds Ratio (IV, Random, 95% CI)0.87 [0.57, 1.33]

    1.2 IFNß-1a (Rebif) versus placebo
2989Odds Ratio (IV, Random, 95% CI)1.10 [0.68, 1.80]

    1.3 Azathioprine versus placebo
2139Odds Ratio (IV, Random, 95% CI)0.47 [0.19, 1.17]

    1.4 Cyclophosphamide versus placebo
1111Odds Ratio (IV, Random, 95% CI)1.60 [0.76, 3.39]

 
Comparison 6. Comparison for adverse events

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Serious adverse events145785Odds Ratio (M-H, Random, 95% CI)1.14 [0.96, 1.35]

    1.1 Interferons versus placebo
51866Odds Ratio (M-H, Random, 95% CI)1.05 [0.80, 1.39]

    1.2 Glatiramer acetate versus placebo
31046Odds Ratio (M-H, Random, 95% CI)1.71 [0.87, 3.39]

    1.3 Natalizumab versus placebo
22110Odds Ratio (M-H, Random, 95% CI)1.14 [0.87, 1.50]

    1.4 Mitoxantrone versus placebo
1131Odds Ratio (M-H, Random, 95% CI)2.58 [0.48, 13.81]

    1.5 Intravenous immunoglobulins versus placebo
3632Odds Ratio (M-H, Random, 95% CI)2.28 [0.54, 9.74]

 2 Withdrawals due to adverse events268332Odds Ratio (M-H, Random, 95% CI)2.41 [1.92, 3.03]

    2.1 Interferons versus placebo
103711Odds Ratio (M-H, Random, 95% CI)3.08 [2.23, 4.26]

    2.2 Glatiramer acetate versus placebo
41096Odds Ratio (M-H, Random, 95% CI)3.48 [1.55, 7.84]

    2.3 Natalizumab versus placebo
22110Odds Ratio (M-H, Random, 95% CI)1.36 [0.99, 1.85]

    2.4 Azathioprine versus placebo
4513Odds Ratio (M-H, Random, 95% CI)6.35 [2.50, 16.11]

    2.5 Mitoxantrone versus placebo
1131Odds Ratio (M-H, Random, 95% CI)3.15 [0.61, 16.22]

    2.6 Intravenous immunoglobulins versus placebo
5771Odds Ratio (M-H, Random, 95% CI)1.99 [1.07, 3.71]

 
Summary of findings for the main comparison. Summary of findings table

Immunomodulators and immunosuppressants for multiple sclerosis

InterventionComparison

intervention
Illustrative comparative risks*Relative effect
(95% CI)
No of Participants
(studies)
Quality of the evidence
(GRADE)

Assumed risk with comparatorCorresponding risk

with intervention

(95% CI)

CHANCE OF DISABILITY GETTING WORSE OVER 24 MONTHS

IFNß-1b (Betaseron)placeboMS of all types

34 per 10032 per 100
(24 to 42)
OR 0.89

(0.59 to 1.36)
445
(2 studies)
⊕⊝⊝⊝

very low1,2,3

RRMS

34 per 10033 per 100
(24 to 44)
OR 0.96

(0.61 to 1.52)
372
(1 study)
⊕⊝⊝⊝

very low1,2,3

SPMS/PRMS/PPMS

35 per 10025 per 100
(11 to 48)
OR 0.62

(0.22 to 1.69)
73
(1 study)
⊕⊝⊝⊝

very low1,2,3

IFNß-1a (Avonex)placeboMS of all types

48 per 10046 per 100
(39 to 53)
OR 0.94

(0.71 to 1.25)
787
(3 studies)
⊕⊝⊝⊝

very low1,2,3

RRMS

59 per 10058 per 100
(46 to 68)
OR 0.93

(0.59 to 1.47)
301
(1 study)
⊕⊝⊝⊝

very low1,2,3

SPMS/PRMS/PPMS

41 per 10039 per 100
(31 to 48)
OR 0.95

(0.66 to 1.36)
486
(2 studies)
⊕⊝⊝⊝

very low1,2,3

IFNß-1a (Rebif)placeboMS of all types

53 per 10044 per 100
(39 to 51)
OR 0.71
(0.56 to 0.92)
1178
(2 studies)
⊕⊕⊕⊝

moderate1

RRMS

42 per 10032 per 100
(25 to 40)
OR 0.65
(0.45 to 0.93)
560
(1 study)
⊕⊕⊕⊝

moderate1

SPMS/PRMS/PPMS

62 per 10056 per 100
(48 to 65)
OR 0.78
(0.55 to 1.10)
618
(1 study)
⊕⊝⊝⊝

very low1,2,3

Glatiramer acetateplaceboMS of all types

39 per 10033 per 100
(24 to 43)
OR 0.76
(0.49 to 1.17)
1350
(4 studies)
⊕⊝⊝⊝

very low1,2,4,5

RRMS

29 per 10017 per 100
(5 to 42)
OR 0.50
(0.14 to 1.74)
301
(2 studies)
⊕⊝⊝⊝

very low1,2,3,4,5

SPMS/PRMS/PPMS

44 per 10042 per 100
(36 to 49)
OR 0.94
(0.73 to 1.23)
1049
(2 studies)
⊕⊝⊝⊝

very low1,2,3

MethotrexateplaceboSPMS/PPMS

52 per 10042 per 100
(20 to 67)
OR 0.67
(0.24 to 1.87)
60
(1 study)
⊕⊝⊝⊝

very low1,2,3

AzathioprineplaceboMS of all types

54 per 10047 per 100
(36 to 59)
OR 0.77
(0.48 to 1.24)
284
(3 studies)
⊕⊝⊝⊝

very low1,2,3

RRMS

41 per 10027 per 100
(11 to 52)
OR 0.52
(0.17 to 1.54)
59
(1 study)
⊕⊝⊝⊝

very low1,2,3

MitoxantroneplaceboMS of all types

25 per 10010 per 100
(3 to 32)
OR 0.34
(0.08 to 1.44)
245
(2 studies)
⊕⊝⊝⊝

very low1,2,5,6

RRMS

38 per 1007 per 100
(2 to 30)
OR 0.13
(0.03 to 0.70)
51
(1 study)
⊕⊕⊝⊝

low1,6

SPMS/PRMS/PPMS

20 per 10013 per 100
(6 to 25)
OR 0.61
(0.27 to 1.34)
194

(1 study)
⊕⊕⊝⊝
low2,3

CyclophosphamideplaceboSPMS/PRMS/PPMS

73 per 10068 per 100
(37 to 89)
OR 0.80
(0.22 to 2.94)
44
(1 study)
⊕⊝⊝⊝
very low1,2,3

ImmunoglobulinsplaceboMS of all types

44 per 10038 per 100
(28 to 50)
OR 0.78
(0.48 to 1.25)
739
(4 studies)
⊕⊝⊝⊝
very low1,2,3

RRMS

23 per 10016 per 100
(8 to 28)
OR 0.62
(0.30 to 1.29)
190
(2 studies)
⊕⊝⊝⊝
very low1,2,3

SPMS/PRMS/PPMS

52 per 10047 per 100
(30 to 65)
OR 0.83
(0.39 to 1.74)
549

(2 studies)
⊕⊝⊝⊝

very low1,2,3

CorticosteroidsplaceboSPMS/PRMS/PPMS

44 per 10052 per 100
(30 to 58)
OR 1.37
(0.56 to 1.74)
86

(1 study)
⊕⊝⊝⊝

very low1,2,3

NatalizumabplaceboRRMS

47 per 10033 per 100
(27 to 39)
OR 0.56
(0.42 to 0.74)
942
(1 study)
⊕⊕⊕⊝

moderate1

NatalizumabIFNß-1a (Avonex)RRMS    




57 per 10046 per 100
(40 to 51)
OR 0.62
(0.49 to 0.78)
1171
(1 study)
⊕⊕⊕⊝

moderate1

IFNß-1b (Betaseron)IFNß-1a (Avonex)RRMS

35 per 10016 per 100
(8 to 27)
OR 0.35
(0.17 to 0.70)
188
(1 study)
⊕⊕⊕⊝

moderate7

IFNß-1b (Betaseron)IFNß-1a (Rebif)RRMS

48 per 10049 per 100
(34 to 56)
OR 1.02
(0.54 to 1.38)
301
(1 study)
⊕⊝⊝⊝

very low1,2,3,8

Glatiramer acetateIFNß-1b (Betaseron)RRMS

41 per 10037 per 100
(32 to 42)
OR 0.86 (0.69 to 1.06)2244
(1 study)
⊕⊕⊝⊝
low1,2

Glatiramer acetateIFNß-1a (Rebif)RRMS

16 per 1009 per 100
(6 to 14)
OR 0.53
(0.34 to 0.83)
764
(1 study)
⊕⊕⊝⊝
low1,3

CHANCE OF DISABILITY GETTING WORSE OVER 36 MONTHS

IFNß-1b (Betaseron)placeboSPMS

68 per 10065 per 100
(55 to 74)
OR 0.87
(0.57 to 1.33)
1657
(2 studies)
⊕⊝⊝⊝
very low2,3,5

IFNß-1a (Rebif)placeboSPMS

63 per 10066 per 100
(54 to 76)
OR 1.10
(0.68 to 1.80)
989
(2 studies)
⊕⊝⊝⊝
very low1,2,3,5

AzathioprineplaceboSPMS/PRMS/PPMS

67 per 10049 per 100
(28 to 71)
OR 0.47
(0.19 to 1.17)
139
(2 studies)
⊕⊝⊝⊝

very low1,2,3

CyclophosphamideplaceboSPMS/PRMS/PPMS

41 per 10053 per 100
(35 to 70)
OR 1.60
(0.76 to 3.39)
111
(1 study)
⊕⊝⊝⊝

very low1,2,3

CHANCE OF EXPERIENCING ONE OR MORE RELAPSES OVER 12 MONTHS

IFNß-1b (Betaseron)placeboRRMS

57 per 10044 per 100
(12 to 82)
OR 0.60

(0.10 to 3.49)
25
(1 study)
⊕⊕⊝⊝
low2,3

IFNß-1a (Avonex)placeboRRMS

64 per 10056 per 100
(44 to 67)
OR 0.72

(0.45 to 1.14)
301
(1 study)
⊕⊕⊝⊝
low2,3

IFNß-1a (Rebif)placeboRRMS

74 per 10066 per 100
(42 to 84)
OR 0.66

(0.25 to 1.78)
853
(2 studies)
⊕⊕⊝⊝
low2,5

Glatiramer acetateplaceboRRMS

55 per 10030 per 100
(7 to 72)
OR 0.34

(0.06 to 2.05)
289
(2 studies)
⊕⊝⊝⊝
very low2,3,4,5

AzathioprineplaceboMS of all types

57 per 10045 per 100

(36 to 54)
OR 0.63

(0.44 to 0.89)
547
(4 studies)
⊕⊕⊕⊕
high

RRMS

68 per 10062 per 100

(35 to 83)
OR 0.77

(0.25 to 2.38)
54
(1 study)
⊕⊕⊝⊝
low2,3

SPMS/PRMS/PPMS

32 per 10017 per 100

(7 to 35)
OR 0.43

(0.16 to 1.12)
99
(1 study)
⊕⊕⊝⊝
low2,3

MitoxantroneplaceboRRMS

75 per 10030 per 100

(11 to 59)
OR 0.14

(0.04 to 0.48)
51
(1 study)
⊕⊕⊕⊝

moderate6

ImmunoglobulinsplaceboMS of all types

42 per 10029 per 100

(13 to 54)
OR 0.56

(0.20 to 1.60)
537
(4 studies)
⊕⊝⊝⊝
very low2,3,5

RRMS

61 per 10055 per 100

(43 to 56)
OR 0.67

(0.38 to 1.21)
219
(3 studies)
⊕⊝⊝⊝
very low2,3,5

SPMS/PRMS/PPMS

35 per 10033 per 100

(24 to 44)
OR 0.95

(0.59 to 1.50)
318
(1 study)
⊕⊕⊝⊝
low2,3

CorticosteroidsplaceboRRMS

71 per 10052 per 100

(22 to 82)
OR 0.46

(0.12 to 1.84)
36
(1 study)
⊕⊕⊝⊝
low2,3

NatalizumabplaceboRRMS

40 per 10020 per 100

(16 to 25)
OR 0.38

(0.28 to 0.51)
942
(1 study)
⊕⊕⊕⊕
high

NatalizumabIFNß-1a (Avonex)RRMS

49 per 10028 per 100

(24 to 33)
OR 0.40

(0.32 to 0.51)
1171
(1 study)
⊕⊕⊕⊕
high

IFNß-1b (Betaseron)IFNß-1a (Avonex)RRMS

52 per 10041 per 100

(29 to 56)
OR 0.65

(0.37 to 1.16)
188
(1 study)
⊕⊝⊝⊝
very low2,3,7

IFNß-1a (Rebif)IFNß-1a (Avonex)RRMS

61 per 10056 per 100

(48 to 63)
OR 0.79

(0.58 to 1.07)
677
(1 study)
⊕⊕⊝⊝
low2,3

CHANCE OF EXPERIENCING ONE OR MORE RELAPSES OVER 24 MONTHS

IFNß-1b (Betaseron)placeboRRMS

85 per 10076 per 100
(64 to 85)
OR 0.55 (0.31 to 0.99)372
(1 study)
⊕⊕⊕⊝
moderate3

IFNß-1a (Avonex)placeboMS of all types

61 per 10055 per 100
(47 to 62)
OR 0.76 (0.56 to 1.05)737
(2 studies)
⊕⊕⊝⊝
low2,3

RRMS

83 per 10080 per 100
(70 to 88)
OR 0.83 (0.46 to 1.49)301
(1 study)
⊕⊕⊝⊝
low2,3

SPMS

47 per 10040 per 100
(31 to 49)
OR 0.74 (0.51 to 1.08)436
(1 study)
⊕⊕⊝⊝
low2,3

IFNß-1a (Rebif)placeboRRMS

85 per 10072 per 100
(61 to 80)
OR 0.45 (0.28 to 0.71)560
(1 study)
⊕⊕⊕⊕
high

Glatiramer acetateplaceboRRMS

74 per 10058 per 100

(33 to 79)
OR 0.49 (0.18 to 1.36)301
(2 studies)
⊕⊝⊝⊝

very low2,3,4,5

MethotrexateplaceboSPMS/PPMS

17 per 10019 per 100

(6 to 47)
OR 1.15 (0.31 to 4.28)60
(1 study)
⊕⊝⊝⊝

very low2,3,9

AzathioprineplaceboMS of all types

68 per 10058 per 100

(48 to 67)
OR 0.64 (0.44 to 0.94)737
(5 studies)
⊕⊕⊕⊕
high

RRMS

83 per 10063 per 100

(35 to 85)
OR 0.36 (0.11 to 1.21)59
(1 study)
⊕⊕⊝⊝
low2,3

SPMS/PRMS/PPMS

52 per 10048 per 100

(33 to 64)
OR 0.85 (0.45 to 1.64)284
(2 studies)
⊕⊕⊝⊝
low2,3

MitoxantroneplaceboMS of all types

69 per 10043 per 100

(16 to 76)
OR 0.35 (0.09 to 1.42)245
(2 studies)
⊕⊝⊝⊝

very low2,3,5,6

RRMS

79 per 10036 per 100

(13 to 67)
OR 0.15 (0.04 to 0.54)51
(1 study)
⊕⊕⊕⊝

moderate6

SPMS/PRMS

65 per 10054 per 100

(40 to 69)
OR 0.65 (0.35 to 1.20)194
(1 study)
⊕⊕⊝⊝
low2,3

ImmunoglobulinsplaceboMS of all types

53 per 10044 per 100

(31 to 58)
OR 0.70 (0.40 to 1.22)705
(4 studies)
⊕⊝⊝⊝
very low2,3,5

RRMS

73 per 10037 per 100

(7 to 83)
OR 0.22 (0.03 to 1.90)190
(2 studies)
⊕⊕⊝⊝
low2,5

SPMS

46 per 10044 per 100

(36 to 53)
OR 0.93 (0.66 to 1.32)515
(2 studies)
⊕⊕⊝⊝
low2,3

CorticosteroidsplaceboRRMS

95 per 10094 per 100

(47 to 100)
OR 0.89 (0.05 to 15.40)36
(1 study)
⊕⊕⊝⊝
low2,3

NatalizumabplaceboRRMS

63 per 10036 per 100

(29 to 43)
OR 0.32 (0.24 to 0.43)942
(1 study)
⊕⊕⊕⊕
high

NatalizumabIFNß-1a (Avonex)RRMS

79 per 10051 per 100

(45 to 58)
OR 0.28 (0.22 to 0.36)1171
(1 study)
⊕⊕⊕⊕
high

IFNß-1b (Betaseron)IFNß-1a (Avonex)RRMS

71 per 10052 per 100

(39 to 65)
OR 0.44 (0.26 to 0.75)248
(2 studies)
⊕⊕⊕⊝

moderate7

IFNß-1b (Betaseron) Glatiramer acetateRRMS

58 per 10057 per 100

(52 to 62)
OR 0.96 (0.78 to 1.18)2244
(1 study)
⊕⊕⊝⊝
low2,3

Glatiramer acetateIFNß-1a (Rebif)RRMS

37 per 10035 per 100

(29 to 42)
OR 0.93 (0.69 to 1.25)764
(1 study)
⊕⊕⊝⊝
low2,3

IFNß-1a

Rebif
IFNß-1b (Betaseron) RRMS

57 per 10043 per 100

(22 to 68)
OR 0.58 (0.21 to 1.62)60
(1 study)
⊕⊕⊝⊝
low2,3

IFNß-1a (Rebif)IFNß-1a

Avonex
RRMS

80 per 10043 per 100

(19 to 71)
OR 0.19 (0.06 to 0.60)60
(1 study)
⊕⊕⊕⊕
high

CHANCE OF EXPERIENCING ONE OR MORE RELAPSES OVER 36 MONTHS

IFNß-1b (Betaseron) placeboSPMS

78 per 10071 per 100

(66 to 76)
OR 0.71 (0.56 to 0.90)1657
(2 studies)
⊕⊕⊕⊕
high

IFNß-1a (Rebif)placeboSPMS     

60 per 10064 per 100

(55 to 69)
OR 1.22 (0.82 to 1.48)371
(1 study)
⊕⊕⊝⊝

low2,3

AzathioprineplaceboSPMS     

81 per 10066 per 100

(54 to 77)
OR 0.45 (0.27 to 0.76)493
(3 studies)
⊕⊕⊕⊕
high

*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: Confidence interval; OR: Odds ratio;NNT: number needed to treat. RRMS: participants with a relapsing remitting form of MS; SPMS/PRMS/PPMS: participants with a secondary progressive or progressive relapsing or primary progressive form of MS.

GRADE Working Group grades of evidence
High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: We are very uncertain about the estimate.

Control event rates based on the number of events in the included studies.

1 Disability getting worse confirmed at 3 months' follow-up.
2 The 95% confidence interval around the pooled effect included both no effect and appreciable benefit or harm.

3 The optimal information size (OIS) criterion was not met (small sample size, very few events).
4 Out of two studies, one (Bornstein 1987) had inadequate allocation concealment.

5 Widely differing estimates of the treatment effect (i.e. heterogeneity in results) across the studies.

6 The study (Millefiorini 1997) reported no blinding of outcome assessment.

7 The INCOMIN (INCOMIN 2002) study reported no blinding of personnel, participants and outcome assessment.

8 The Koch-Henriksen (Koch-Henriksen 2006) study reported no blinding of personnel, participants and outcome assessment.

9The study (Goodkin 1995) had inadequate allocation concealment.

 
Table 1. Number of participants in each treatment group

Type of treatmentRCTs

N
RRMS

N = 9096
Progressive MS

N = 7726
RRMS and

progressive MS

combined

N = 579
All MS

N = 17401

Azathioprine53065286381

Cyclophosphamide2077 77

Corticosteroids31950 69

Glatiramer acetate71095678 1773

IFNß-1b (Betaseron)923471027 3374

IFNß-1a (Avonex)712002647 3847 

IFNß-1a (Rebif)81464601 2065

IV immunoglobulins6215275 490

Methotrexate1031 31

Mitoxantrone327150 177

Natalizumab212160 1216

placebo36148321252933901

 
Table 2. Methods of adverse events monitoring

Study Risk of

bias 
Did the researchers actively monitor for adverse events (AEs) (low risk of bias) or did they simply provide spontaneous reporting of AEs that arose (high risk of bias)?Risk of biasDid the authors define serious AEs (SAEs) according to an accepted international classification and report the number of SAEs?

Achiron 1998UnclearNot reportedHighSAEs not reported

AFFIRM 2006Low"Treating neurologists were responsible for all aspects of patient care, including the management of adverse events". Participants"visited the clinic every 12 weeks for ... blood chemical and hematologic analyses, evaluation of adverse events..."UnclearInsufficient information on SAEs
definition

Andersen 2004Low"Adverse events and concomitant medications were recorded throughout the study, and clinical laboratory evaluation was performed at months 1, 3, and 6, and then at 6 monthly evaluation visits or as needed"UnclearInsufficient information on SAEs
definition

BEYOND 2009Low"Clinic visits were scheduled every 3 months to assess ... safety, and tolerability. The occurrence of new neurological symptoms and adverse events was assessed by telephone, 6 weeks after each visit"LowCategorisation of SAEs conformed to ICH guidelines (International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use)

Bornstein 1987High"Self-evaluation reported to a clinical assistant"HighSAEs not reported

Bornstein 1991High"Self-reporting reported to a clinical assistant"HighSAEs not reported

BPSM 1995 UnclearNot reportedUnclearInsufficient information on SAEs
definition

British and Dutch 1988Unclear"The occurrence of side effects was notified to the trial centre every 3 months"HighSAEs not reported

CCMSSG 1991 Unclear"The external safety monitoring committee monitored the progress of the trial every 6 months (severe adverse experiences, deaths, clinical status)"HighSAEs not reported

Comi 2001 Unclear"The treating physician monitored safety..."UnclearInsufficient information on SAEs
definition

Edan 1997UnclearNot reportedUnclearInsufficient information on SAEs
definition

Ellison 1989LowParticipants"were instructed to call the clinic anytime they suspected an adverse events and then actively monitored by neurologist"HighSAEs not reported

Etemadifar 2006High"Given the lack of safety assessment of this trial, it is important to recall that the safety of IFN-b products in the treatment of RRMS had already been established for the three drugs in previous studies"HighSAEs not reported

European Study Group 1998Low"Safety assessments included adverse events, vital signs, physical examinations, and concomitant medication. An independent advisory committee reviewed the results of regular interim safety analyses done after all participantshad been in the study for at least 24 months"HighSAEs not reported

EVIDENCE 2007High"Adverse events were determined by spontaneous reporting and monthly laboratory testing during the comparative phase"UnclearInsufficient information on SAEs
definition

Fazekas 1997LowParticipants"asked about safety monthly..."HighSAEs not reported

Fazekas 2008 UnclearNot reportedUnclearInsufficient information on SAEs
definition

Ghezzi 1989 UnclearNot reportedHighSAEs not reported

Goodkin 1991High"Side effect were reported to the treating neurologist every 6 months"HighSAEs not reported

Goodkin 1995Low"All participantsmaintained a daily diary of undesirable events… The adverse event diary was checked every 3 months by the study nurse during a clinical visit"HighSAEs not reported

Hartung 2002 UnclearNot reportedUnclearInsufficient information on SAEs
definition

Hommes 2004  Unclear"Several safety laboratory tests were done..."UnclearInsufficient information on SAEs
definition

IFNB MS Group 1993Low"Treating neurologist reviewed side effects, laboratory findings for toxicity ..."HighSAEs not reported 

IMPACT 2002Unclear"An independent external Data and Safety Monitoring Committee reviewed safety data at three time points during the trial and performed a preplanned interim analysis after all subjects had been followed for 15 months"HighSAEs not reported

INCOMIN 2002Low"Safety assessments included adverse events, vital signs, physical examination, and concomitant medications. Participantsunderwent haematology and biochemical tests, including liver-function tests, every 2 weeks for the first 8 weeks, and then every 3 months"HighSAEs not reported

Johnson 1995Low"The evaluating physician monitored safety every 3 month..."UnclearInsufficient information on SAEs
definition

Knobler 1993UnclearNot reportedHighSAEs not reported 

Koch-Henriksen 2006LowParticipants"were interviewed about side effects and had routine blood tests including hematology and liver function tests every 3 months and thyroid tests and neutralizing antibodies every 6 months"HighSAEs not reported

Leary 2003 Low"AEs were monitored throughout the study..."HighSAEs not reported

Lewanska 2002 Unclear"Laboratory safety examinations were made at the beginning and at the end of the study period"UnclearInsufficient information on SAEs
definition

Likosky 1991 UnclearNot reportedHighSAEs not reported

Milanese 1993UnclearNot reportedHighSAEs not reported

Millefiorini 1997Low"The safety of the treatment was assessed on the basis of adverse events volunteered by the patient either spontaneously or on questioning and monitoring of the main laboratory parameters"UnclearInsufficient information on SAEs
definition

Miller 1961 Low"An independent observer unconnected with the trial, observed every 3 months the prednisolone participantsto detect toxic effects"HighSAEs not reported

Montalban 2009Low"Safety issues during the study were monitored by an independent Safety Committee. Participantswere asked to report any adverse event,... the presence of adverse events and intercurrent illnesses was assessed at all visits"HighSAEs not reported

MSCRG 1996Low"According to the FDA phase III requirements..."UnclearInsufficient information on SAEs
definition

NASP 2004Unclear"As required by protocol, an Independent Data and Safety Monitoring Board (IDSMB) reviewed interim safety data every 6 months"UnclearInsufficient information on SAEs
definition

OWIMS 1999Unclear"The treating physician recorded and treated AEs..."UnclearInsufficient information on SAEs
definition

Pohlau 2007Low"Safety and tolerability of the treatment were assessed by recording adverse events, vital signs and by laboratory findings. All adverse events and clinical symptoms related to the disease or the study medication were recorded every 4 weeks"UnclearInsufficient information on SAEs
definition

PRISMS 1998Unclear"The treating physician treated AEs..."UnclearInsufficient information on SAEs
definition

REGARD 2008Unclear"Adverse events (including pregnancy), withdrawals owing to adverse events, serious adverse events, and laboratory results were obtained for safety comparisons"UnclearInsufficient information on SAEs
definition

SENTINEL 2006LowThe treating neurologists were responsible for all patient care, including the management of adverse events and relapses of multiple sclerosis. Clinical visits every 12 weeks included (…) assessment of any adverse events. Participantswere also seen by a treating neurologist during unscheduled visits within 72 hours after the development of new symptoms so that they could be assessed for possible relapses or adverse events"UnclearInsufficient information on SAEs
definition

SPECTRIMS 2001 Low"A treating physician supervised drug administration, monitored safety, and managed adverse events"HighSAEs not reported

Wolinsky 2007Low"The treating neurologist supervised drug administration, recorded and treated adverse events"UnclearInsufficient information on SAEs
definition

 
Table 3. Model fit and parsimony measures for all the primary outcomes

 Posterior Residual

Deviance

(consistency model)
Data

Points
DIC

(consistency model)
DIC

(inconsistency model)

Recurrence of relapses over 12 months45428384

Recurrence of relapses over 24 months6051104106

Relapses over 36 months12122222

Disability progression over 24 months6060109112

Disability progression over 36 months14142828

Acceptability54578586

 
Table 4. Network meta-analysis: summary results for recurrence of relapses at any time point, posterior ORs and their 95% credible intervals of all active interventions versus placebo and SUCRA values

 Recurrence of relapses

over 12 months
Recurrence of relapses

over 24 months
Recurrence of relapses

over 36 months




 Median OR

(95%CrI)
SUCRAMedian OR

(95%CrI)
SUCRAMedian OR

(95%CrI)
SUCRA

Natalizumab0.35

(0.12 to 1.06)
72%0.29

(0.17 to 0.51)
92%--

IFNß-1a (Rebif)0.65

(0.27 to 1.59)
40%0.44

(0.24 to 0.70)
73%1.28

(0.40 to 4.05)
13%

Mitoxantrone0.12

(0.03 to 0.55)
95%0.43

(0.20 to 0.87)
71%--

Glatiramer acetate0.40

(0.11 to 1.15)
65%0.48

(0.38 to 0.75)
66%--

IFNß-1b (Betaseron)0.54

(0.14 to 2.15)
50%0.48

(0.29 to 0.78)
65%0.69

(0.29 to 1.47)
64%

Azathioprine0.63

(0.27 to 1.45)
42%0.63

(0.39 to 0.97)
46%0.43

(0.17 to 0.88)
94%

Immunoglobulins0.61

(0.22 to 1.31)
44%0.69

(0.40 to 1.04)
41%--

Corticosteroids0.48

(0.10 to 2.29)
53%1.13

(0.03 to 47.93)
36%--

Methotrexate--1.16

(0.27 to 5.35)
23%--

IFNß-1a (Avonex)0.81

(0.33 to 1.99)
26%0.96

(0.64 to 1.50)
19%--

 SUCRA: Surface below the Cumulative Ranking Curve. The larger the SUCRA value for a treatment, the higher its rank among the available treatment options.
 
Table 5. Network meta-analysis: summary results for disability progression at any time point, posterior ORs and their 95% credible intervals of all active intervnetions versus placebo and SUCRA values

 Disability progression over 24 monthsDisability progression over 36 months



 Median OR (95%CrI)SUCRAMedian OR (95%CrI)SUCRA

Mitoxantrone0.42 (0.20 to 0.87)89%--

Natalizumab0.61 (0.41 to 0.91)74%--

Glatiramer acetate0.67 (0.49 to 0.88)67%--

Methotrexate0.67 (0.22 to 2.04)58%--

Immunoglobulins0.79 (0.53 to 1.17)58%--

IFNß-1b (Betaseron)0.74 (0.54 to 1.00)54%0.87 (0.35 to 2.09)59%

Azathioprine0.75 (0.42 to 1.30)54%0.45 (0.13 to 1.31)92%

Cyclophosphamide0.79 (0.19 to 3.27)49%1.62 (0.40 to 6.56)18%

IFNß-1a (Rebif)0.79 (0.60 to 1.04)47%1.10 (0.45 to 2.79)36%

IFNß-1a (Avonex)1.06 (0.78 to 1.51)18%--

Corticosteroids1.58 (0.58 to 4.35)11%--

 SUCRA: Surface below the Cumulative Ranking Curve. The larger the SUCRA value for a treatment, the higher its rank among the available treatment options.
 
Table 6. Network meta-analysis: summary results for patients with RRMS for recurrence of relapses over 12 and 24 months and disability progression over 24 months, posterior ORs (95% credible intervals) of all active interventions versus placebo and SUCRA values

 Recurrence of relapses

over 12 months
Recurrence of relapses

over 24 months
Disability progression

over 24 months




 Median OR (95%CrI)SUCRAMedian OR (95%CrI)SUCRAMedian OR (95%CrI)SUCRA

Mitoxantrone0.13 (0.01 to 1.32)85%0.14 (0.03 to 0.55)92%0.11 (0.01 to 0.65)96%

Natalizumab0.35 (0.07 to 1.67)65%0.31 (0.19 to 0.55)75%0.62 (0.33 to 1.24)55%

Immunoglobulins0.36 (0.08 to 1.28)63%0.34 (0.13 to 0.69)70%0.63 (0.24 to 1.67)52%

Azathioprine0.76 (0.08 to 7.40)36%0.34 (0.08 to 1.30)65%0.51 (0.13 to 1.95)61%

IFNß-1a (Rebif)0.65 (0.19 to 2.29)46%0.46 (0.25 to 0.71)53%0.74 (0.40 to 1.32)40%

Glatiramer acetate0.36 (0.07 to 1.54)63%0.50 (0.29 to 0.71)46%0.52 (0.28 to 0.88)70%

IFNß-1b (Betaseron)0.54 (0.09 to 3.33)47%0.50 (0.31 to 0.82)45%0.67 (0.38 to 1.13)50%

Corticosteroids0.44 (0.04 to 4.86)54%1.17 (0.02 to 50.83)31%--

IFNß-1a (Avonex)0.81 (0.23 to 2.90)29%1.10 (0.69 to 1.82)10%1.11 (0.64 to 2.16)10%

 SUCRA: Surface below the Cumulative Ranking Curve. The larger the SUCRA value for a treatment, the higher its rank among the available treatment options.
 
Table 7. Network meta-analysis: summary results for patients who dropped out (withdrawals or lost to follow-up) due to adverse events (posterior ORs and 95% credible intervals of all active interventions versus placebo and SUCRA values)

 Median OR (95%CrI)SUCRA

Cyclophosphamide0.51 (0.08 to 2.75)82%

Mitoxantrone0.70 (0.31 to 1.56)81%

Glatiramer acetate0.93 (0.69 to 1.25)70%

IFNß-1b (Betaseron)0.94 (0.72 to 1.22)69%

Natalizumab1.04 (0.52 to 2.17)57%

Azathioprine1.34 (0.39 to 4.82)43%

Immunoglobulins1.23 (0.82 to 1.84)40%

IFNß-1a (Rebif)1.23 (0.85 to 1.74)39%

IFNß-1a (Avonex)1.37(0.86 to 2.25)32%

Corticosteroids2.95 (0.62 to 17.66)17%

Methotrexate4.37 (0.86 to 37.96)8%

 SUCRA: Surface below the Cumulative Ranking Curve. The larger the SUCRA value for a treatment, the higher its rank among the available treatment options.