Table 1.
Outcome measures selected for clinical trials in relapsing-remitting multiple sclerosis.
| Study name/group | Drug treatment | N | Publication year | Primary outcome | Secondary outcomes |
|---|---|---|---|---|---|
| Multiple sclerosis collaborative research group | Interferon beta-1a (avonex) | 301 | 1990 | Worsening in disability defined as deterioration by 1.0 point on EDSS | (i) Time to first relapse (ii) Number and volume of gadolinium enhancing lesions |
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| Interferon beta-1b multiple sclerosis study group | Interferon beta-1b (Betaseron) | 372 | 1993 | (i) Annualized relapse rate (ii) Proportion of relapse-free patients |
(i) Time to first relapse (ii) Relapse duration and severity by NRS score (iii) Change in EDSS and NRS scores from baseline (iv) Quantitative disease burden by MRI (% change in lesion area) (v) Disease activity as measured by MRI (annual rate of new or enlarging lesions) |
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| Copolymer 1 multiple sclerosis study group | Copolymer 1 (glatiramer acetate, Copaxone) | 251 | 1995 | Average number of relapses at 2 years | (i) Proportion of relapse free patients (ii) Time to first relapse (iii) Proportion without sustained disease progression as measured by the EDSS at 3 months (iv) Average change in EDSS and ambulation index |
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| PRISMS | Interferon beta 1a (Rebif) | 560 | 1998 | Number of relapses | (i) Times to first and second relapse (ii) Progression of disability as measured by sustained worsening of EDSS, ambulation index, or arm function index at 3 months (iii) Proportion of relapse-free patients (iv) MRI burden (proton density T2 MRI, Number of T2 active lesions) |
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| CHAMPS | Interferon beta 1a (Avonex) | 383 | 2000 | Conversion to CDMS | (i) Volume of T2 lesions (ii) Number of new or enlarging T2 lesions (iii) Number of gadolinium enhancing T1 lesions |
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| ETOMS | Interferon beta 1a (Rebif) | 309 | 2001 | Conversion to CDMS | (i) Change in the SNRS score (ii) Time to second relapse (iii) Number of new or enhancing T2 lesions (iv) Number of enhancing T1 lesions (v) Number of patients without MRI activity (no new or enlarging T2 lesions or enhancing lesions throughout the study) (vi) Yearly changes of hyperintense T2 lesion volume |
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| EVIDENCE | Interferon beta-1a (Rebif) | 677 | 2005 | (i) Annualized relapse rate; (ii) Proportion remaining relapse free at 2 years |
(i) Change in new, enlarged, or reappearing lesions (ii) Proportion of active scans per patient (new, enlarged, or reappearing lesions) |
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| BENEFIT | Interferon beta-1b (Betaseron) | 487 | 2006 | (i) Time to conversion to CDMS; (ii) Time to McDonald defined MS |
(i) Cumulative number of new or enhancing T2 lesions (ii) Change in T2 lesion volume (iii) Cumulative volume of gadolinium enhancing lesions (iv) Change in EDSS and MSFC scores |
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| CHAMPIONS | Interferon beta 1a (Avonex) | 203 | 2006 | Conversion to CDMS | (i) Number of confirmed relapses (ii) Disease course classification (iii) Neurological disability as measured by EDSS at 5 years (iv) Number of new or enlarging T2 lesions (v) Changes in T2 volume (vi) Percentage with gadolinium enhancing lesions |
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| AFFIRM | Natalizumab (Tysabri) | 856 | 2006 | (i) Annualized relapse rate; (ii) Progression of disability as measured by sustained worsening of EDSS at 12 weeks |
(i) Number of new or enlarging T2 lesions (Year 1) (ii) Number of gadolinium enhancing lesions (Year 1) (iii) Proportion of relapse free patients (Year 1) (iv) Annualized relapse rate (Year 2) (v) Volume of lesions (Year 2) (vi) Number of new hypointense lesions (Year 2) (vii) MSFC as measure of disability (Year 2) |
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| SENTINEL | Natalizumab and Interferon beta-1a (Tysabri and Avonex) | 1003 | 2006 | (i) Annualized relapse rate; (ii) Progression of disability as measured by sustained worsening of EDSS at 12 weeks |
(i) Number of new or enlarging T2 lesions (Year 1) (ii) Number of gadolinium enhancing lesions (Year 1) (iii) Proportion of relapse free patients (Year 1) (iv) Annualized relapse rate (Year 2) (v) Volume of lesions (Year 2) (vi) Number of new hypointense T1 lesions (Year 2) (vii) MSFC as measure of disability (Year 2) |
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| REGARD | Interferon beta-1a and Glatiramer acetate (Rebif and Copaxone) | 764 | 2008 | Time to relapse at 96 weeks | (i) Number of new or enhancing lesions (ii) Number of gadolinium enhancing lesions (iii) Change in T2 lesion volume (iv) Change in whole brain volume (v) Other relapse outcomes (vi) Progression of disability as measured by sustained worsening of EDSS at 6 months |
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| BECOME | Interferon beta-1b and glatiramer acetate (Betaseron and Copaxone) | 75 | 2009 | Number of combined active lesions in the first year (total contrasting enhancing lesions plus new non-enhancing lesions that have appeared since most recent examination) | New lesions per subject in year 1 and 2 |
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| PreCISe | Glatiramer acetate (Copaxone) | 619 | 2009 | Time to conversion to CDMS | (i) Number of new T2 lesions (ii) Baseline-adjusted T2 lesions volume at last scan (iii) Brain atrophy- percentage change from baseline (iv) Proportion of patients converted to MS |
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| TRANSFORMS | Fingolimod (Gilenya) | 1153 | 2010 | Annualized relapse rate | (i) Number of new or enlarged T2 hypointense lesions at 1 year (ii) Time to confirmed disability progression as measured by EDSS at 3 months |
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| FREEDOMS | Fingolimod (Gilenya) | 1272 | 2010 | Annualized relapse rate accompanied by change in EDSS | (i) Time to confirmed disability progression as measured by EDSS at 3 months (ii) Time to first relapse and disability progression at 6 months (iii) Change in EDSS and MSFC at 2 years (iv) Number of patients with gadolinium enhancing lesions (v) Number with new or enlarging T2 weighted lesions (vi) Proportion of patients with gadolinium-enhancing lesions and T2-weighted lesions (vii) T2 and T1 lesion volume (viii) Change in brain volume at 2 years |
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| TEMSO | Teriflunomide (Aubagio) | 1088 | 2011 | Annualized relapse rate | (i) Progression of disability as measured by EDSS at 12 weeks (ii) Total lesion volume (iii) Volume of hypointense T1 lesions (iv) Number of gadolinium enhanced T1 lesions (v) Number of active lesions (new gadolinium enhancing on T1 images or new or enlarged lesions on T2) (vi) Brain parenchymal fraction |
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| DEFINE | BG-12 (dimethyl fumarate, Tecfidera) | 1237 | 2012 | Proportion of patients who had a relapse at 2 years | (i) Number of gadolinium enhancing lesions (ii) New or enlarged hyperintense T2 lesions (iii) Annualized relapse rate (iv) Time to progression of disability as measured by EDSS at 12 weeks |
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| CONFIRM | BG-12 and glatiramer acetate (Tecfidera, Copaxone) | 308 | 2012 | Annualized relapse rate at 2 years | (i) New or enlarging hyperintense lesions on T2 (ii) Number of hypointense T1 lesions (iii) Proportion of patients with relapse (iv) Time to disability progression as measured by EDSS at 2 years |
PRISMS: Prevention of Relapses and Disability by Interferon beta-1a Subcutaneously in Multiple Sclerosis Study; CHAMPS: Controlled High Risk Avonex Multiple Sclerosis Study; ETOMS: Early Treatment of Multiple Sclerosis Study Group; EVIDENCE: Evidence of Interferon Dose-Response: European North American Comparative Efficacy; BENEFIT: Betaferon in Newly Emerging Multiple Sclerosis for Initial Treatment; CHAMPIONS: Controlled High Risk Avonex Multiple Sclerosis Prevention Study In Ongoing Neurological Surveillance; AFFIRM: Natalizumab Safety and Efficacy in Relapsing Remitting Multiple Sclerosis; SENTINEL: The Safety and Efficacy of Natalizumab in Combination with Interferon Beta-1a in Patients with Relapsing Remitting Multiple Sclerosis; REGARD: Rebif versus Glatiramer Acetate in Relapsing MS Disease; BECOME: Betaseron versus Copaxone in Multiple Sclerosis with Triple-Dose Gadolinium and 3-Tesla MRI Endpoints; PreCISe: Effect of glatiramer acetate on conversion to clinically definite multiple sclerosis in patients with clinically isolated syndrome; TRANSFORMS: Trial Assessing Injectable Interferon versus FTY720 Oral in Relapsing-Remitting Multiple Sclerosis; FREEDOMS: FTY720 Research Evaluating Effects of Daily Oral Therapy in Multiple Sclerosis; TEMSO: Teriflunomide Multiple Sclerosis Oral; DEFINE: Determination of the Efficacy and Safety of Oral Fumarate in Relapsing-Remitting Multiple Sclerosis; CONFIRM: Comparator and an Oral Fumarate in Relapsing-Remitting Multiple Sclerosis.
EDSS: Extended Disability Status Scale; MSFC: Multiple Sclerosis Functional Composite; CDMS: Clinically Definite Multiple Sclerosis; SNRS: Scripp's Neurological Rating Scale; NRS: Neurological Rating Scale.