Outcome Measures in Relapsing-Remitting Multiple Sclerosis: Capturing Disability and Disease Progression in Clinical Trials

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
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)
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
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)
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
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
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)
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
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
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)
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)
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
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
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
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
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
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
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
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.