Ophthalmic evaluations in clinical studies of fingolimod (FTY720) in multiple sclerosis.

PURPOSE: To report outcomes of ophthalmic evaluations in clinical studies of patients receiving fingolimod (Gilenya; Novartis Pharma AG, Basel, Switzerland) for multiple sclerosis (MS). DESIGN: Analysis done on pooled safety data (N = 2615, all studies group) from 3 double-masked, randomized, parallel-group clinical trials (phase 2 core and extension >5 years, and phase 3 FREEDOMS and TRANSFORMS core and extension studies). PARTICIPANTS: Patients aged 18 to 55 years (18-60 years in phase 2 study) diagnosed with relapsing-remitting MS were included. Patients with diabetes mellitus or macular edema (ME) at screening were excluded. INTERVENTION: Participants received fingolimod (0.5/1.25 mg), placebo, or interferon beta for the respective study durations. Ophthalmic examination included detailed eye history (at screening), visual acuity (VA) assessment, dilated ophthalmoscopy, optical coherence tomography (OCT), and fluorescein angiography (FA). MAIN OUTCOME MEASURES: Extensive ophthalmic monitoring was performed for all patients. While being studied, patients with abnormal findings on dilated ophthalmoscopy and OCT compatible with ME were further studied by FA. All locally diagnosed ME cases were centrally reviewed by the retina specialist (M.A.Z.) on the Data and Safety Monitoring Board. RESULTS: Among 2615 patients assessed, 19 confirmed ME cases were observed in fingolimod-treated groups (0.5 mg: n = 4, 0.3%; 1.25 mg: n = 15, 1.2%). Most patients (n = 13, 68%) presented with blurred vision, decreased VA, or eye pain. Macular edema was diagnosed within 3 to 4 months of treatment initiation in most cases (n = 13, 68%); 2 patients had late onset (>12 months) ME. Of the 19 patients with ME, 5 (26%), all treated with fingolimod 1.25 mg, had a history of uveitis compared with 26 (1%) in the all studies group. In most cases (n = 16, 84%), ME resolved after discontinuing the study drug. Eleven patients required topical anti-inflammatory medications. No patient had further vision deterioration. CONCLUSIONS: Fingolimod 0.5 mg is associated with a low incidence of ME in MS studies. Patients with a history of uveitis may be at an increased risk of developing ME. An ophthalmic examination before initiating fingolimod therapy and regular follow-up eye examinations during fingolimod therapy are recommended.

Assessing Clinical Equivalence in Oncology Biosimilar Trials With Time-to-Event Outcomes.

A typical biosimilar study in oncology uses the overall response evaluated at a specific time point as the primary endpoint, which is generally acceptable regulatorily, to assess clinical equivalence between a biosimilar and its reference product. The standard primary endpoint for evaluating an anticancer therapy, progression-free or overall survival would be a secondary endpoint in a biosimilar trial. With a conventional analytic procedure via, for example, hazard ratio to quantify the group difference, it is difficult and challenging to assess clinical equivalence with respect to progression-free or overall survival because the study generally has a limited number of clinical events observed in the study. In this article, we show that an alternative procedure based on the restricted mean survival time, which has been discussed extensively for design and analysis of a general equivalence study, is readily applicable to a biosimilar trial. Unlike the hazard ratio, this procedure provides a clinically interpretable estimate for assessing equivalence. Using the restricted mean survival time as a summary measure of the survival curve will enhance better treatment decision making in adopting a biosimilar product over the reference product.

[Evaluation of bubble oxygen inhalators' performances and an investigation on their solutions for improvement].

This paper analyses the defects of bubble oxygen inhalators currently used, and investigates into their solutions for improvement.

First-dose effects of fingolimod: Pooled safety data from three phase 3 studies.

Fingolimod treatment initiation is associated with a transient slowing of heart rate and atrioventricular conduction. This report presents first-dose fingolimod effects (0.5mg or 1.25mg) on cardiac parameters using phase 3 FREEDOMS, FREEDOMS II and TRANSFORMS pooled study data (n=3635 patients). Vital signs were recorded hourly for ≥6h; 12-lead electrocardiogram (ECG) was obtained at baseline and at 6h post-dose. Clinical events were graded at the first-dose administrator׳s discretion. At screening, on day 1 and at month 3, 1073 patients underwent 24-h ambulatory electrocardiogram monitoring. A transient decrease in mean measured heart rate occurred 4-5h after the first dose, with a maximum reduction of 8 (fingolimod 0.5mg) and 11 beats per minute (fingolimod 1.25mg) below baseline. Symptomatic bradycardia at treatment initiation was reported in 0.6% (fingolimod 0.5mg) and 2.1% (fingolimod 1.25mg) of patients; events were typically mild or moderate in severity, and most resolved spontaneously. Atrioventricular (AV) conduction delays were observed in a few patients (Wenckebach (Mobitz type I) second-degree AV block, fingolimod 0.5mg, 0.2%; 1.25mg, 1%: 2:1 AV block fingolimod, 0.5mg, 0%; 1.25mg, 0.2% on ECG 6-h post-dose). These were usually well tolerated and first occurred within 6h of dosing. Consistent with its effects on atrial myocytes, fingolimod treatment initiation induced a transient slowing of heart rate and AV conduction. However, symptomatic bradycardia and second-degree AV block were uncommon and did not require intervention.