By Elena Moro
For April 2016 we have selected: Lublin F, Miller DH, Freedman MS, et al., on behalf of the INFORMS study investigators. Oral fingolimod in primary progressive multiple sclerosis (INFORMS): a phase 3, randomized, double-blind, placebo-controlled trial. Lancet Neurol, 27 Jan 2016; pii: S0140-6736(15)01314-8. doi: 10.1016/S0140-6736(15)01314-8.
Primary progressive multiple sclerosis (PPMS) represents around 10-15% of the clinical forms of MS. Several characteristics differentiate PPMS from the relapse-onset MS, the classical more frequent form: older age at onset, equal prevalence between sexes, less inflammatory component at the MRI, and quicker progression of disability. In relapse-onset MS, oral treatment with fingolimod has been effective in reducing frequency of relapses and MRI lesion activity, delaying disability progression, and limiting brain volume loss. Fingolimod is an oral sphingosine 1-phosphate receptor modulator with anti-inflammatory action (by preventing lymphocyte egress from lymphoid tissues), and possibly inhibition effect on neurodegeneration.
In this double-blind multicenter study (INFORMS), the investigators studied the effects of fingolimod on delaying the phase of confirmed disability progression (CDP) in patients with PPMS using the Expanded Disability Status Scale (EDSS) and two additional validated measure of disability, the 25’ Timed-Walk Test (25’TWT), and the Nine-Hole Peg Test (9-HPT). Patients were recruited from 148 centers in 18 countries, and randomly allocated to received placebo or fingolimod 1.25 mg/day (later reduced to 0.5 mg/day in another randomized group of patients, cohort 2). Clinical assessments were done at baseline, 2 weeks, 1 month, 2 months, 3 months, and every 3 months afterwards up to month 36. CDP was defined as the first occurrence of a progression according to at least one of three criteria: a. EDSS score increased by 1 point from a baseline EDSS score £ 5, or by 0.5 points from a baseline EDSS score ³5.5; b. increase of at least 20% from baseline in the 25’TWT; c. increase of at least 20% from baseline in time taken to complete the 9-HT. The effects of fingolimod on percent brain volume change (using SIENA applied to T1-weighted images), MRI parameters of inflammation activity, and patient’s reported outcomes were also assessed. The primary efficacy analysis included patients with 0.5 mg fingolimod and placebo. The Cox proportional hazard model was used to test for differences between fingolimod and placebo in the time to 3-month CDP, with region, age, baseline EDSS, baseline 25’TWT, and baseline 9-HT as covariates.
Of the 970 randomized patients, 147 were assigned to fingolimod 1.25 mg vs. 133 to placebo (cohort 1), and 336 to fingolimod 0.5 mg vs. 354 to placebo (cohort 2). There was no difference between fingolimod and placebo (hazard ratio 0.95, 95% CI 0.8-1.12) in the time to 3-month CDP, and no significant treatment effect in either cohort. No significant difference was found between fingolimod 0.5 mg and placebo in changes from baseline and the end time point of 36 months. There was no impact of any covariate on the results. However, fingolimod significantly reduced the number of new or newly enlarging T2 lesions, Gd-enhancing T1 lesions, and new T1 hypointense lesions. Incidence of adverse events was similar between groups. Side effects induced by fingolimod (lymphopenia, bradycardia, first-degree atrioventricular block) did not differ from previous published studies.
“Results coming from this large prospective study show that fingolimod is ineffective in decreasing the risk of progression of disability in patients with PPMS. The authors used a composite tool to assess disability, with each component bringing consistent results. Moreover, the study was adequately powered to detect a treatment effect and the follow-up was relatively long,” says Dr. Luisa Maria Villar, Head of the Immunology Department, Ramon y Cajal University Hospital, Madrid, Spain. “Interestingly, fingolimod decreased MRI measures of lesion activity in PPMS according to previous results obtained in relapse-onset MS, but not the rate of brain volume loss. Taking together, these findings suggest that PPMS patients with high inflammatory activity may be good candidates for treatment with drugs that proved to be efficacious in the relapsing remitting form, as it happened in the OLYMPUS trial (Rituximab). In the remaining PPMS patients, it seems that the mechanisms underlying brain volume loss are different, with a more aggressive neurodegenerative activity. Different therapeutic strategies are likely needed in patients with low inflammatory PPMS.”
The other nominees for the April paper of the month are:
- Henderson EJ, Lord SR, Brodie MA, et al. Rivastigmine for gait stability in patients with Parkinson’s disease (ReSPonD): a randomized, double-blind placebo-controlled, phase 2 trial. Lancet Neurol 2016; 15;249-58. In this monocenter study the authors studied the effects on gait of 12 mg/day of rivastigmine vs. placebo in a total of 130 parkinsonian patients. At the 32-week end point, the 55 patient with rivastigmine significantly improved step time variability during normal walking and during simple dual task while walking. The authors conclude that rivastigmine can improve gait stability and could reduce falls. No effect on freezing or quality of life outcomes was detected.
- Goyal M, Menon BK, van Zwam WH, et al., for the HERMES collaborators. Endovascular thrombectomy after large-vessels ischaemic stroke: a meta-analysis of individual patient data from five randomized trials. Lancet Neurol February 18, 2016, http://dx.doi.org/10.1016/ S0140-6736(16)00163-X. From the combined analysis of data coming from five previous trials comparing endovascular thrombectomy vs. placebo (634 vs. 653 patients, respectively), the former significantly reduced disability at 3-month follow-up. The benefit from thrombectomy was not dependent on age, randomization after more than 300 minutes after symptoms onset, and ineligibility for intravenous alteplase. Mortality and intracerebral hematomas risk was not different between groups.
- Kernan WN, Viscoli CM, Furie KL, et al., for the IRIS Trial Investigators. Pioglitazone after ischemic stroke or transient ischemic attack. N Engl J Med February 17, 2016; DOI: 10.1056/NEJMoa1506930. In this multicenter, double-blind trial, the authors investigated the effects of pioglitazone, a drug that improves insulin sensitivity, on reducing the risk of stroke or myocardial infarction in 3,876 patients who had had a recent ischemic stroke or TIA. At the 5-year time point, there was a significant decreased risk of stroke or myocardial infarct in the pioglitazone group, together with a lower risk of diabetes. However, the active groups had higher risk of fracture, edema, and weight gain.