Optical coherence tomography in multiple sclerosis: A 3-year prospective multicenter study.

OBJECTIVE: To evaluate changes over 3 years in the thickness of inner retinal layers including the peripapillary retinal nerve fiber layer (pRNFL), and combined macular ganglion cell and inner plexiform layers (mGCIPL), in individuals with relapsing-remitting multiple sclerosis (RRMS) versus healthy controls; to determine whether optical coherence tomography (OCT) is sufficiently sensitive and reproducible to detect small degrees of neuroaxonal loss over time that correlate with changes in brain volume and disability progression as measured by the Expanded Disability Status Scale (EDSS). METHODS: Individuals with RRMS from 28 centers (n = 333) were matched with 64 healthy participants. OCT scans were performed on Heidelberg Spectralis machines (at baseline; 1 month; 6 months; 6-monthly thereafter). RESULTS: OCT measurements were highly reproducible between baseline and 1 month (intraclass correlation coefficient >0.98). Significant inner retinal layer thinning was observed in individuals with multiple sclerosis (MS) compared with controls regardless of previous MS-associated optic neuritis--group differences (95% CI) over 3 years: pRNFL: -1.86 (-2.54, -1.17) µm; mGCIPL: -2.03 (-2.78, -1.28) µm (both p < 0.0001; effect sizes 0.39 and 0.34). Greater inner retinal layer atrophy was observed in individuals diagnosed with RRMS <3 years versus >5 years (pRNFL: p < 0.05; mGCIPL: p < 0.01). Brain volume decreased by 1.3% in individuals with MS over 3 years compared to 0.5% in control subjects (effect size 0.76). mGCIPL atrophy correlated with brain atrophy (p < 0.0001). There was no correlation of OCT data with disability progression. INTERPRETATION: OCT has potential to estimate rates of neurodegeneration in the retina and brain. The effect size for OCT, smaller than for magnetic resonance imaging based on Heidelberg Spectralis data acquired in this study, was increased in early disease.

Oral fingolimod for chronic inflammatory demyelinating polyradiculoneuropathy (FORCIDP Trial): a double-blind, multicentre, randomised controlled trial.

BACKGROUND: Fingolimod is approved for the treatment of relapsing-remitting multiple sclerosis and was effective in experimental autoimmune neuritis in rats, a possible model for chronic inflammatory demyelinating polyradiculoneuropathy (CIDP). We aimed to evaluate the efficacy of fingolimod in delaying disability progression in patients with CIDP who withdrew from currently effective treatments (intravenous immunoglobulin [IVIg] or corticosteroids). METHODS: This double-blind, multicentre, randomised, placebo-controlled, parallel-group, event-driven study was done at 48 neurology centres in Australia, Canada, Israel, Japan, the USA, and nine countries in Europe. Participants with CIDP who were receiving IVIg or corticosteroids were randomly assigned (1:1) to once-daily oral fingolimod 0·5 mg or placebo. Owing to the event-driven design, treatment duration was flexible and could be up to 4·5 years. Randomisation was done with an automated interactive voice response-web response system and was stratified by Inflammatory Neuropathy Cause and Treatment (INCAT) disability scale scores. Previous IVIg treatment was discontinued after one final course ending the day before the first dose of fingolimod or placebo was given, whereas corticosteroids were tapered off over 8 weeks after randomisation. The primary endpoint was time to first confirmed worsening (≥1 point increase on the adjusted INCAT disability scale score versus baseline) and was assessed in the full analysis set, which consisted of all patients who underwent randomisation and had at least one efficacy assessment for the primary analysis. The survival distribution functions of time to first worsening were estimated within each treatment group according to the Kaplan-Meier survival distribution function and compared with a stratified log-rank test. The trial is registered with ClinicalTrials.gov, number NCT01625182. FINDINGS: Of 106 participants randomly assigned between Jan 24, 2013, and March 10, 2016, 54 received fingolimod (41 who had been receiving IVIg and 13 who had been receiving corticosteroids) and 52 received placebo (41 who had been receiving IVIg and 11 who had been receiving corticosteroids). The trial ended for futility as recommended by an independent data monitoring committee after an interim analysis when 44 confirmed worsening events had occurred. At the end of the study, the survival estimate of the proportion of participants free from confirmed worsening was not significantly different between the fingolimod group (42%, 95% CI 23-60) and the placebo group (43%, 28-59; p=0·91). Adverse events occurred in 41 (76%) participants receiving fingolimod and 44 (85%) on placebo, and serious adverse events occurred in nine (17%) and four (8%) patients, respectively. The most common adverse events with fingolimod were headache (12 [22%] patients), hypertension (ten [19%]), and extremity pain (seven [13%]). Adverse events leading to study discontinuation occurred in seven (13%) participants on fingolimod and none on placebo. INTERPRETATION: Fingolimod 0·5 mg once-daily was not better than placebo for the treatment of CIDP. Future trial designs should take account of the possibility that if IVIg is stopped abruptly, some patients might relapse soon afterwards whereas others might remain in remission. FUNDING: Novartis Pharma.

Impact of fingolimod therapy on magnetic resonance imaging outcomes in patients with multiple sclerosis.

OBJECTIVE: To assess the impact of fingolimod (FTY720) therapy on magnetic resonance imaging measures of inflammatory activity and tissue damage in patients participating in a 2-year, placebo-controlled, phase 3 study. DESIGN: Patients with active relapsing-remitting multiple sclerosis were randomized to receive fingolimod, 0.5 mg; fingolimod, 1.25 mg; or placebo for 2 years. Standardized magnetic resonance imaging scans were obtained at months 0, 6, 12, and 24 and centrally evaluated for number and volume of T1 gadolinium-enhancing, T2 hyperintense, and T1 hypointense lesions and for percentage of brain volume change. Findings were compared across subgroups by treatment and baseline characteristics. SETTING: Worldwide, multicenter clinical trial. PATIENTS: Patients were part of the fingolimod FTY720 Research Evaluating Effects of Daily Oral Therapy in Multiple Sclerosis (FREEDOMS) clinical trial for relapsing-remitting multiple sclerosis (N=1272). MAIN OUTCOME MEASURES: We measured the effect of therapy on acute inflammatory activity, burden of disease, and irreversible loss of brain volume. RESULTS: Fingolimod therapy resulted in rapid and sustained reductions in inflammatory lesion activity as assessed by gadolinium-enhancing and new/newly enlarged T2 lesions after 6, 12, and 24 months of therapy (P.001, all comparisons vs placebo). Changes in T2 hyperintense and T1 hypointense lesion volume also significantly favored fingolimod (P.05, all comparisons). Fingolimod, 0.5 mg (licensed dose), significantly reduced brain volume loss during months 0 to 6, 0 to 12, 12 to 24, and 0 to 24 (P.05, all comparisons) vs placebo, and subgroup analyses confirmed these effects over 2 years irrespective of the presence/absence of gadolinium-enhancing lesions, T2 lesion load, previous treatment status, or level of disability. CONCLUSION: These results, coupled with the significant reductions in relapse rates and disability progression reported previously, support the positive impact on long-term disease evolution. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00289978

Relapse and disability outcomes in patients with multiple sclerosis treated with fingolimod: subgroup analyses of the double-blind, randomised, placebo-controlled FREEDOMS study.

BACKGROUND: Fingolimod 0·5 mg once daily is approved for treatment of relapsing multiple sclerosis (MS). In the phase 3, 2-year FREEDOMS (FTY720 Research Evaluating Effects of Daily Oral therapy in MS) study, fingolimod significantly reduced annualised relapse rates (ARRs) and the risk of confirmed disability progression compared with placebo. We aimed to investigate whether the beneficial treatment effect reported for the overall population is consistent in subgroups of patients with different baseline characteristics. METHODS: We did subgroup analyses of ARRs (primary outcome) and confirmed disability progression (a secondary outcome) over 24 months in the FREEDOMS study, a randomised, double-blind study that included 1272 patients with relapsing-remitting MS who were assigned 1:1:1 to fingolimod (0·5 mg or 1·25 mg) or placebo once daily for 24 months. Subgroups were predefined, predefined and slightly modified, or defined post hoc, by demographic factors (including sex and age), disease characteristics (including baseline disability scores, relapse rates, and lesion parameters), and response to previous therapy (including analyses in patients eligible for fingolimod treatment according to the European label). Data were analysed by intention to treat. The FREEDOMS study is registered with ClinicalTrials.gov, number NCT00289978. FINDINGS: Treatment with fingolimod 0·5 mg was associated with significantly lower ARRs versus placebo across all subgroups except for patients aged over 40 years. ARR ratios ranged from 0·76 (95% CI 0·54-1·09; p=0·13) in patients aged over 40 years to 0·29 (0·16-0·52; p<0·0001) in patients who had relapse activity despite receiving interferon beta during the year before study enrolment. Hazard ratios for confirmed disability progression over 24 months with fingolimod 0·5 mg versus placebo ranged from 0·85 (95% CI 0·53-1·36; p=0·50) in patients with a T2 lesion volume of 3300 mm(3) or less to 0·32 (0·14-0·73; p=0·0066) in patients with an EDSS over 3·5. In patients who relapsed and had lesion activity despite treatment with interferon beta in the previous year, the ARR ratio for fingolimod 0·5 mg versus placebo was 0·38 (95% CI 0·21-0·68, p=0·0011), and for treatment-naive patients with rapidly evolving severe disease it was 0·33 (0·18-0·62, p=0·0006). Hazard ratios for confirmed disability progression over 24 months were 0·68 (0·29-1·62; p=0·39) and 0·73 (0·25-2·07; p=0·55), respectively, in these groups. INTERPRETATION: Patients with relapsing-remitting MS with a wide spectrum of clinical and MRI features including subgroups specified by the European label can potentially benefit from treatment with 0·5 mg fingolimod. FUNDING: Novartis.

A placebo-controlled trial of oral fingolimod in relapsing multiple sclerosis.

BACKGROUND: Oral fingolimod, a sphingosine-1-phosphate-receptor modulator that prevents the egress of lymphocytes from lymph nodes, significantly improved relapse rates and end points measured on magnetic resonance imaging (MRI), as compared with either placebo or intramuscular interferon beta-1a, in phase 2 and 3 studies of multiple sclerosis. METHODS: In our 24-month, double-blind, randomized study, we enrolled patients who had relapsing-remitting multiple sclerosis, were 18 to 55 years of age, had a score of 0 to 5.5 on the Expanded Disability Status Scale (which ranges from 0 to 10, with higher scores indicating greater disability), and had had one or more relapses in the previous year or two or more in the previous 2 years. Patients received oral fingolimod at a dose of 0.5 mg or 1.25 mg daily or placebo. End points included the annualized relapse rate (the primary end point) and the time to disability progression (a secondary end point). RESULTS: A total of 1033 of the 1272 patients (81.2%) completed the study. The annualized relapse rate was 0.18 with 0.5 mg of fingolimod, 0.16 with 1.25 mg of fingolimod, and 0.40 with placebo (P<0.001 for either dose vs. placebo). Fingolimod at doses of 0.5 mg and 1.25 mg significantly reduced the risk of disability progression over the 24-month period (hazard ratio, 0.70 and 0.68, respectively; P=0.02 vs. placebo, for both comparisons). The cumulative probability of disability progression (confirmed after 3 months) was 17.7% with 0.5 mg of fingolimod, 16.6% with 1.25 mg of fingolimod, and 24.1% with placebo. Both fingolimod doses were superior to placebo with regard to MRI-related measures (number of new or enlarged lesions on T(2)-weighted images, gadolinium-enhancing lesions, and brain-volume loss; P<0.001 for all comparisons at 24 months). Causes of study discontinuation and adverse events related to fingolimod included bradycardia and atrioventricular conduction block at the time of fingolimod initiation, macular edema, elevated liver-enzyme levels, and mild hypertension. CONCLUSIONS: As compared with placebo, both doses of oral fingolimod improved the relapse rate, the risk of disability progression, and end points on MRI. These benefits will need to be weighed against possible long-term risks. (ClinicalTrials.gov number, NCT00289978.)