Effects of teriflunomide treatment on cognitive performance and brain volume in patients with relapsing multiple sclerosis: Post hoc analysis of the TEMSO core and extension studies

Abstract

Background: In post hoc analyses of Teriflunomide Multiple Sclerosis Oral study (TEMSO; NCT00134563), teriflunomide 14 mg significantly reduced brain volume loss (BVL) versus placebo in patients with relapsing multiple sclerosis (MS).

Objective: In this post hoc analysis of TEMSO and its long-term extension (NCT00803049), we examined the relationship between teriflunomide's effects on BVL and cognition.

Methods: We analyzed data from 709 patients who received teriflunomide 14 mg in TEMSO or its extension. The change in cognitive performance, assessed using the Paced Auditory Serial Addition Test 3 (PASAT-3), was measured in subgroups stratified by BVL over 2 years (least BVL: ⩽ 0.52%; intermediate BVL: >0.52%-2.18%; most BVL: >2.18%). BVL, MRI lesions, and relapses over 2 years were evaluated as potential mediators of the effect of teriflunomide on cognition.

Results: Teriflunomide 14 mg significantly improved PASAT-3 Z-scores versus placebo through year 2. In the least- and intermediate-BVL groups, significant improvements in PASAT-3 Z-score were demonstrated versus the most-BVL group over 3 years in the extension. According to the mediation analysis, 44% of the teriflunomide effect on cognition was due to effects on BVL at year 2.

Conclusion: Teriflunomide improves cognition largely through its effects on BVL. Accelerated BVL earlier in the disease course may predict cognitive outcomes.

Clinicaltrials.gov identifier: NCT00134563, NCT00803049.

Keywords: TEMSO; Teriflunomide; brain volume loss; cognition; multiple sclerosis.

Conflict of interest statement

Declaration of conflicting interests: The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: TS: Grants from EFIC-Grünenthal, Novartis Pharmaceuticals Switzerland, the Swiss MS Society, and the Swiss National Research Foundation. Institution received payments for steering committee/consultation and speaking activities from Actelion, ATI, Biogen Idec, Electrocore, Eli Lilly, Janssen, Merck Serono, Mitsubishi Pharma, Novartis, Roche, Sanofi, and Teva. LK: Institution (University Hospital Basel) has received the following exclusively for research support: steering committee, advisory board, and consultancy fees (Actelion, Bayer HealthCare, Biogen, BMS, Genzyme, Janssen, Merck, Novartis, Roche, Sanofi, Santhera, and TG Therapeutics); speaker fees (Bayer HealthCare, Biogen, Merck, Novartis, Roche, and Sanofi); support of educational activities (Allergan, Bayer HealthCare, Biogen, CSL Behring, Desitin, Genzyme, Merck, Novartis, Pfizer, Roche, Sanofi, Shire, and Teva); license fees for Neurostatus products; and grants (Bayer HealthCare, Biogen, European Union, InnoSwiss, Merck, Novartis, Roche, Swiss MS Society, and Swiss National Research Foundation). MPS: Consulting fees from Biogen, Genzyme, Merck Serono, Novartis, Roche, Synthon, and Teva. AEM: Consulting fees from Accordant Health Services, Adamas, Biogen, Celgene, EMD Serono, Genentech/Roche, Mapi-Pharma, and Novartis; contracted research for Biogen, Genentech, MedDay, Novartis, Mallinckrodt, and Roche. EMP: Employee of Sanofi at the time of the analysis; currently employed by Jazz Pharmaceuticals, Cambridge, MA, USA. SC: Employee of Sanofi at the time of the analysis; currently employed by Steven Cavalier Consulting, LLC. JW: Employee of MIAC AG in Basel, Switzerland; served on scientific advisory boards for Actelion, Bayer, Biogen, Idorsia, Novartis, Roche, Sanofi, and Teva.

Figures

Figure 1.

TEMSO core and extension study design (a), and flow diagram based on treatment group and the number of patients from each treatment group in each BVL subgroup after stratification (b). BVL: brain volume loss; ITT: intent to treat; PASAT-3: Paced Auditory Serial Addition Test 3; R: randomization; SIENA: structural image evaluation using normalization of atrophy. †ITT population with valid scans at baseline and year 2. ‡Least BVL from core study baseline to week 108: ⩽0.52%. §Intermediate BVL from core study baseline to week 108: >0.52%–2.18%. ¶Most BVL from core study baseline to week 108: >2.18%.

Figure 2.

Change in PASAT-3 Z-score through the TEMSO core study in placebo and teriflunomide 14 mg patients (a), and through the TEMSO core study and its extension period in pooled teriflunomide 14 mg patients (b). CEL: contrast-enhancing lesion; EDSS: Expanded Disability Status Scale; LS: least squares; PASAT-3: Paced Auditory Serial Addition Test 3; SE: standard error. †Last visit of core study, up to week 96.p-Values were generated using analysis of covariance adjusted for age, baseline Z-score, baseline EDSS strata, baseline CEL status, treatment, and quartile category. Panel A analytic sample is all participants in the randomized population (randomized to placebo or teriflunomide 14 mg) with PASAT scores available at baseline and week 96. Panel B analytic sample is all participants after teriflunomide 14 mg initiation (either at baseline or in the extension) with PASAT scores available at the specific week reported.

Figure 3.

Change in PASAT-3 Z-score by BVL group through the TEMSO extension period. BVL: brain volume loss; CEL: contrast-enhancing lesion; EDSS: Expanded Disability Status Scale; LS: least squares; PASAT-3: Paced Auditory Serial Addition Test 3; SE: standard error. Least BVL: ⩽0.52%; intermediate BVL: >0.52%–2.18%; most BVL: >2.18%. p-Values were generated using analysis of covariance adjusted for age, baseline Z-score, baseline EDSS strata, baseline CEL status (yes/no), treatment, and quartile category. The analytic sample is all patients (placebo and both teriflunomide groups) with valid MRIs at baseline and week 108 (for categorizing BVL) who have PASAT scores at baseline and the specific week reported.

Figure 4.

Percentage of relative contributions of each surrogate individually (a) and combined (b). BVL: brain volume loss; CEL: contrast-enhancing lesion; PTE: proportion of treatment effect; T2w: T2 weighted. The analytic sample is patients with valid MRIs at baseline and week 108.