Efficacy of fingolimod and interferon beta-1b on cognitive, MRI, and clinical outcomes in relapsing-remitting multiple sclerosis: an 18-month, open-label, rater-blinded, randomised, multicentre study (the GOLDEN study)

Abstract

Cognitive impairment (CI) affects 40-65% of multiple sclerosis (MS) patients. This study attempted evaluating the effects of fingolimod and interferon beta-1b (IFN β-1b) on CI progression, magnetic resonance imaging (MRI) and clinical outcomes in relapsing-remitting MS (RRMS) patients over 18 months. The GOLDEN study was a pilot study including RRMS patients with CI randomised (2:1) to fingolimod (0.5 mg daily)/IFN β-1b (250 µg every other day). CI was assessed via Rao's Brief Repeatable Battery and Delis-Kaplan Executive Function System test. MRI parameters, Expanded Disability Status Scale scores and relapses were measured. Overall, 157 patients were randomised, of whom 30 discontinued the study (fingolimod, 8.49%; IFN β-1b, 41.18%; p ≤ 0.0001). Patients randomised to fingolimod had more severe clinical and MRI disease characteristics at baseline compared with IFN β-1b. At Month (M) 18, both treatment groups showed improvements in all cognitive parameters. At M18, relapse rate, total number and volume of T2/T1 gadolinium-enhancing lesions were higher with IFN β-1b, as well as the percentage brain volume change during the study. Safety and tolerability of both treatments were similar to previous studies. Both treatments showed improvements in cognitive parameters. Fingolimod demonstrated significantly better effects on MRI parameters and relapse rate. Imbalance in baseline characteristics and the drop-out pattern may have favoured IFN β-1b. A longer duration trial may be needed to observe the complete expression of differential effects on CI scales reflecting the between-groups differences on MRI. Although limited in size, the GOLDEN study confirms the favourable benefit-risk profile of fingolimod reported in previous studies.

Keywords: Brain atrophy; Brief repeatable battery test; Cognitive impairment; Delis–Kaplan executive function test; Fingolimod; Interferon beta-1b.

Fig. 1

Study design. BRB Rao’s brief repeatable battery, DKEFS Delis–Kaplan executive function system, eod every other day, MADRS Montgomery–Asberg Depression Rating Scale, MRI magnetic resonance imaging

Fig. 2

Patient disposition. AE adverse event, IFN β-1b interferon beta-1b, RRMS relapsing–remitting multiple sclerosis

Fig. 3

SDMT and PASAT scores at screening for patients who completed the treatment versus those who dropped out of the study (safety population). IFN β-1b interferon beta-1b, PASAT paced auditory serial addition test, SDMT symbol digit modalities test. The figure represents mean values of PASAT and SDMT raw scores. The p value was calculated using the t test for SDMT and PASAT-2 in IFN group and PASAT-3 in fingolimod group; otherwise, the Wilcoxon two-sample test was used

Fig. 4

Cognitive impairment test results a Rao’s BRB test: ANCOVA LS mean changes Month 18 versus screening (FAS population) *p < 0.05; **p < 0.01; ***p < 0.001. ANCOVA analysis of covariance, BRB brief repeatable battery, FAS full analysis set, IFN β-1b interferon beta-1b, LS least squares, M month, PASAT paced auditory serial addition test, SDMT symbol digit modalities test, SE standard error, SPART 10/36 spatial recall test, SPART-d 10/36 spatial recall test-delayed recall, SRT-LTS selective reminding test-long-term storage, SRT-CLTR selective reminding test-consistent long-term retrieval, SRT-d selective reminding test-delayed recall, WLG Word List Generation, b DKEFS-sorting test: ANCOVA model estimated mean (LSmean) changes at Month 18 versus screening (FAS population). *p < 0.05; **p < 0.01. Note: Condition 1—free sorting: fingolimod 66, IFN β-1b 27. Condition 1—free sorting description: fingolimod 65, IFN β-1b 27. Condition 2–sort recognition: fingolimod 50, IFN β-1b 21. ANCOVA analysis of covariance, DKEFS Delis–Kaplan executive function test, FAS full analysis set, IFN β-1b interferon beta-1b, LS least squares, M month

Fig. 5

MRI measures. a Total T2 lesion volume (mm³), b number of T1 Gd+ lesions, c volume of T1 Gd+ lesions (mm³), and d brain volume (mL). p values for the changes were calculated using an ANCOVA model, except for the number of T1 Gd+ lesions, which was computed by using a negative binomial regression model. At baseline, the p values were calculated using the Wilcoxon two-sample test, except for the brain volume, which was calculated using the t test. *p < 0.05 within group. ANCOVA analysis of covariance, Gd+ gadolinium enhancing, IFN β-1b interferon beta-1b, M month, MRI magnetic resonance imaging

Fig. 6

MS relapse rate (safety population). IFN β-1b interferon beta-1b, MS multiple sclerosis