Temporal profile of lymphocyte counts and relationship with infections with fingolimod therapy in paediatric patients with multiple sclerosis: Results from the PARADIGMS study.

BACKGROUND: Reduction in absolute lymphocyte count (ALC) is expected with fingolimod treatment. OBJECTIVE: To evaluate the effect of fingolimod 0.5 mg versus intramuscular interferon ß-1a (30 µg) on ALC and its relationship with infections in paediatric-onset multiple sclerosis (POMS) up to 4 years. METHODS: We assessed ALC at baseline, monthly till 3 months, and every 3 months (core phase) and with variable periodicity (extension phase) of Phase 3 PARADIGMS study (N = 215). Incidence rates (IRs) of infection-related adverse events (infAEs)/100 patient-years were analysed by on-study nadir ALC. RESULTS: With fingolimod, ALC rapidly reduced to 29.9%-34.4% of baseline values within 2 weeks and remained stable thereafter; no relevant changes observed with interferon. IRs of infAEs were 67.6 with fingolimod and 61.8 with interferon; IR ratios with respect to interferon, overall: 1.09, by nadir ALC 0.2-0.4 × 109/L: 1.13 and >0.4 × 109/L: 0.91. Three patients had a single episode of ALC <0.2 × 109/L (core phase). No opportunistic infections were observed and infection risk did not increase during the extension phase. CONCLUSION: In paediatric patients, the overall incidence of infections was comparable between fingolimod and interferon. No association was observed between nadir ALC and infections in POMS, although sample size may have been too small to rule an association.

Correction to: Long-Term Effect of Immediate Versus Delayed Fingolimod Treatment in Young Adult Patients with Relapsing-Remitting Multiple Sclerosis: Pooled Analysis from the FREEDOMS/FREEDOMSII Trials.

Figures 1a, 1b and 3 were published incorrectly in the original version. The corrected images are given as follows.

Long-Term Effect of Immediate Versus Delayed Fingolimod Treatment in Young Adult Patients with Relapsing-Remitting Multiple Sclerosis: Pooled Analysis from the FREEDOMS/FREEDOMS II Trials.

INTRODUCTION: Fingolimod has demonstrated clinical and MRI benefits versus placebo/interferon ß-1a in young adults with multiple sclerosis (MS). Here we report the long-term effects of fingolimod 0.5 mg on clinical and MRI outcomes in young adults with MS aged ≤ 30 years followed up for up to 8 years (96 months). METHODS: This post hoc analysis of pooled FREEDOMS/FREEDOMS II studies included patients who either received fingolimod 0.5 mg from randomization (immediate; N = 163) or switched from placebo to fingolimod at month (M) 24 (delayed; N = 147). The 6-month confirmed disability improvement [6m-CDI: based on Expanded Disability Status Scale (EDSS)], 6m-CDI-plus (6m-CDI+; EDSS, 9-Hole Peg Test, Timed 25-Foot Walk Test), 6-month confirmed disability progression (6m-CDP), time to EDSS score ≥ 4, annualized relapse rates (ARRs), new/newly enlarging T2 (neT2) lesions, and annual rate of brain volume loss (BVL) were analyzed from baseline to M24, M48, and M96. Cox regression and negative binomial regression models were used to analyze measured outcomes. RESULTS: At baseline, more than two-thirds of young adult patients were treatment naïve, had more than two relapses in the previous 2 years, and EDSS score < 2. From M0 to M96, a significantly higher proportion of young adult patients in the immediate group (vs. delayed group) achieved 6m-CDI (58.2% vs. 30.5%, p = 0.0206) and 6m-CDI+ (70.6% vs. 42.3%, p = 0.0149); significantly fewer patients reached 6m-CDP (20.1% vs. 34.7%, p = 0.0058) and EDSS ≥ 4 (24.1% vs. 34.1%, p = 0.0041). Up to M96, young adults in the immediate versus delayed group had lower ARRs (0.16 vs. 0.38, p < 0.0001) and a higher proportion of patients were free of neT2 lesions at M48 (31.0% vs. 5.0%, p = 0.0011). CONCLUSION: In young adult patients with MS, immediate versus delayed fingolimod treatment was associated with improved disease outcomes and greater long-term benefits in both disease activity and disability progression. FUNDING: Novartis Pharma AG.

Clinical review: impact of statin substitution policies on patient outcomes.

BACKGROUND: The increasing awareness of cost issues in health care has led to the increasing use of policy-driven substitution of branded for generic medications, particularly relative to statin treatment for cardiovascular diseases. While there are potential short-term health care savings, the consequences for primary care are under-researched. Our objective was to review data on intensive statin therapy and generic substitution in patients at high cardiovascular risk. RESULTS: Current treatment guidelines for the prevention of cardiovascular disease are consistent in their recommendations regarding statin therapy and treatment targets. Clinical trials demonstrate that to reduce cardiovascular events, a statin is more effective than placebo, intensive statin therapy is more effective than moderate statin therapy in patients with established coronary disease, and in patients receiving intensive statin therapy the lowest risk is associated with the lowest low-density lipoprotein levels. However, in clinical practice, patients at high cardiovascular risk are prone to be undertreated. Observational studies suggest that mandatory statin substitution may increase the gap between achieved and recommended therapeutic targets. CONCLUSIONS: Substitution of generic statins may be cost-saving, particularly at the primary prevention level. However, statin substitution policies have not been adequately studied on a population level. Data raise concern that mandated statin substitution may lead to unfavourable treatment choices at the level of the individual high-risk patient.