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. 2016 Sep;22(10):1297-305.
doi: 10.1177/1352458515616701. Epub 2015 Nov 19.

Inclusion of brain volume loss in a revised measure of 'no evidence of disease activity' (NEDA-4) in relapsing-remitting multiple sclerosis

Ludwig Kappos  1 , Nicola De Stefano  2 , Mark S Freedman  3 , Bruce Ac Cree  4 , Ernst-Wilhelm Radue  5 , Till Sprenger  6 , Maria Pia Sormani  7 , Terence Smith  8 , Dieter A Häring  9 , Daniela Piani Meier  9 , Davorka Tomic  9
Affiliations

Inclusion of brain volume loss in a revised measure of 'no evidence of disease activity' (NEDA-4) in relapsing-remitting multiple sclerosis

Ludwig Kappos et al. Mult Scler. 2016 Sep.

Abstract

Background: 'No evidence of disease activity' (NEDA), defined as absence of magnetic resonance imaging activity (T2 and/or gadolinium-enhanced T1 lesions), relapses and disability progression ('NEDA-3'), is used as a comprehensive measure of treatment response in relapsing multiple sclerosis (RMS), but is weighted towards inflammatory activity. Accelerated brain volume loss (BVL) occurs in RMS and is an objective measure of disease worsening and progression.

Objective: To assess the contribution of individual components of NEDA-3 and the impact of adding BVL to NEDA-3 ('NEDA-4') METHODS: We analysed data pooled from two placebo-controlled phase 3 fingolimod trials in RMS and assessed NEDA-4 using different annual BVL mean rate thresholds (0.2%-1.2%).

Results: At 2 years, 31.0% (217/700) of patients receiving fingolimod 0.5 mg achieved NEDA-3 versus 9.9% (71/715) on placebo (odds ratio (OR) 4.07; p < 0.0001). Adding BVL (threshold of 0.4%), the respective proportions of patients achieving NEDA-4 were 19.7% (139/706) and 5.3% (38/721; OR 4.41; p < 0.0001). NEDA-4 status favoured fingolimod across all BVL thresholds tested (OR 4.01-4.41; p < 0.0001).

Conclusion: NEDA-4 has the potential to capture the impact of therapies on both inflammation and neurodegeneration, and deserves further evaluation across different compounds and in long-term studies.

Keywords: Atrophy; NEDA; brain; fingolimod; multiple sclerosis.

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Conflict of interest statement

Ludwig Kappos’s institution, University Hospital Basel, has in the last 3 years received the following fees which were used exclusively for research support: steering committee, advisory board and consultancy fees from Actelion, Addex, Bayer HealthCare, Biogen, Biotica, Genzyme, Lilly, Merck, Mitsubishi, Novartis, Ono Pharma, Pfizer, Receptos, Sanofi-Aventis, Santhera, Siemens, Teva, UCB and Xenoport; speaker fees from Bayer HealthCare, Biogen, Merck, Novartis, Sanofi-Aventis and Teva; support of educational activities from Bayer HealthCare, Biogen, CSL Behring, Genzyme, Merck, Novartis, Sanofi and Teva; royalties from Neurostatus Systems GmbH; grants from Bayer HealthCare, Biogen, European Union, Merck, Novartis, Roche, Roche Research Foundations, Swiss MS Society and Swiss National Research Foundation. Nicola De Stefano has received honoraria for consulting services, speaking and travel support from Biogen Idec, Genzyme, Merck Serono S.A., Novartis, Roche, Schering and Teva, serves on advisory boards for Biogen Idec, Merck Serono S.A. and Novartis, and has received research grant support from the Italian MS Society. Mark S Freedman has received compensation for consulting services or a sponsored speaker’s bureau from Actelion, Bayer HealthCare, Biogen Idec, Chugai, EMD Canada, Genzyme, Hoffman-La Roche, Merck Serono, Novartis, Sanofi-Aventis and Teva Canada Innovation, and is a member of a company advisory board, board of directors or other similar group for Actelion, Bayer HealthCare, Biogen Idec, Hoffman-La Roche, Merck Serono, Novartis, Opexa and Sanofi-Aventis. Bruce Cree has received honoraria for consultancy services from Abbvie, Biogen Idec, EMD Serono, Genzyme/Sanofi-Aventis, MedImmune, Novartis, Teva Neurosciences, and has received research support from Acorda, Avanir, Biogen Idec, EMD Serono, F Hoffman-La Roche, MedImmune, Novartis and Teva Neurosciences. Ernst-Wilhelm Radue has received honoraria for serving as a speaker at scientific meetings and/or as a consultant from Actelion, Basilea, Bayer Schering, Biogen Idec, Merck Serono and Novartis; he has also received financial support for research activities from Actelion, Basilea, Biogen Idec, Merck Serono and Novartis. Till Sprenger’s previous institution, the University Hospital Basel, has received compensation for his serving on scientific advisory boards or for speaking fees from Actelion, Allergan, ATI, Biogen Idec, Electrocore, Eli Lilly, Genzyme, Janssen, Mitsubishi Pharma, Novartis and Teva. These fees were used exclusively for funding of research. He received research grants from the Swiss MS Society, the Swiss National Science Foundation, EFIC-Grünenthal and Novartis Pharmaceuticals. Maria Pia Sormani has received compensation for consulting services and speaking activities from Actelion, Biogen Idec, Genzyme, Merck Serono, Novartis, Synthon and Teva. Terence Smith is an employee of Oxford PharmaGenesis and was funded by Novartis Pharma AG. Dieter Häring, Daniela Piani Meier and Davorka Tomic are employees of Novartis Pharma AG.

Figures

Figure 1.
Figure 1.
Proportion of patients by treatment group, exceeding different annual BVL thresholds in the pooled FREEDOMS/FREEDOMS II population. AR-BVL: annualized rate of brain volume loss; BVL: brain volume loss. Data were calculated using the pooled population full analysis set (N = 2355; fingolimod 0.5 mg, n = 783; placebo, n = 773) from patients with available MRI scans (fingolimod 0.5 mg, n = 623; placebo n = 580). p values were derived from a logistic regression model with treatment as the only factor.
Figure 2.
Figure 2.
Impact of different annual BVL thresholds on the proportions of patients achieving NEDA-4; in the pooled FREEDOMS/FREEDOMS II population. AR-BVL: annualized rate of brain volume loss; BVL: brain volume loss; CI: confidence interval; NEDA: no evidence of disease activity; OR: odds ratio. Data were calculated using the pooled population full analysis set (N = 2355; fingolimod 0.5 mg n = 783; placebo, n = 773) from patients with available MRI scans (AR-BVL 1.2%: fingolimod 0.5 mg, n = 699; placebo, n = 714; AR-BVL 0.6%: fingolimod 0.5 mg, n = 704; placebo, n = 715; AR-BVL 0.4%: fingolimod 0.5 mg, n = 706; placebo n = 721; AR-BVL 0.2%: fingolimod 0.5 mg, n = 712; n = 723, placebo). aORs were derived from logistic regression of NEDA-4 and treatment.
Figure 3.
Figure 3.
Relative contribution of the individual components of NEDA-4 on the proportion of patients achieving NEDA. BVL: brain volume loss; CDP: confirmed disability progression; CI: confidence interval; EDSS: Expanded Disability Status Scale; NEDA: no evidence of disease activity; OR: odds ratio. Data were calculated using the pooled population full analysis set (N = 2355; fingolimod 0.5 mg, n = 783; placebo, n = 773) from patients with available MRI scans (New T2 lesion activity: fingolimod 0.5 mg, n = 687; placebo, n = 677; New T2 lesion activity and Relapses: fingolimod 0.5 mg, n = 700; placebo, n = 712; NEDA-3: fingolimod 0.5 mg, n = 700; placebo, n = 715; NEDA-4: fingolimod 0.5 mg, n = 706; placebo, n = 721). ap value from logistic regression of NEDA and treatment; bDisability progression defined as an increase in EDSS score of 1.5 points if baseline EDSS score = 0 and of 1.0 point if baseline EDSS score ⩾1.
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