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Selective serotonin-reuptake inhibitors (SSRIs), commonly administered for depression and anxiety in patients with multiple sclerosis, are associated with QT interval prolongation. Fingolimod (FTY720; Gilenya(®), Novartis Pharma AG) is a first-in-class sphingosine 1-phosphate receptor modulator approved for relapsing forms of multiple sclerosis. Fingolimod first-dose administration is associated with a transient, generally asymptomatic, slowing of heart rate, which may also prolong QT interval. This posthoc analysis compared cardiac outcomes in over 3300 patients with relapsing multiple sclerosis who were or were not receiving SSRIs during fingolimod treatment initiation, including a subset of patients receiving citalopram or escitalopram. Vital signs were recorded hourly for 6h, and electrocardiograms were obtained pre-dose and 6 h post-dose. Changes in mean hourly heart rate from baseline (pre-dose) to 6 h post-dose were similar among patients not receiving SSRIs (fingolimod 0.5 mg, -7.5 bpm; placebo, 0.0 bpm) and those receiving SSRIs (fingolimod 0.5 mg, -6.6 bpm; placebo, 0.3 bpm). In patients treated with fingolimod 0.5 mg, the mean change in corrected QT interval from baseline to 6 h after treatment initiation was under 10 ms, and few patients had absolute corrected QT intervals of over 450 ms (men) or 470 ms (women), calculated according to Bazett׳s or Fridericia׳s correction methods, irrespective of whether or not they were receiving an SSRI; similar findings were reported in the placebo group. Co-administration of SSRIs and fingolimod was not associated with an increased incidence of any electrocardiogram findings compared with fingolimod therapy alone, and the majority of patients receiving fingolimod (83-86%) were discharged from first-dose monitoring at 6 h irrespective of whether they were also receiving SSRIs. These analyses provide reassurance that concomitant use of SSRIs does not affect cardiac outcomes associated with fingolimod treatment initiation.

Introduction No head-to-head trials have compared the efficacy of the oral therapies, fingolimod, dimethyl fumarate and teriflunomide, in multiple sclerosis. Statistical modeling approaches, which control for differences in patient characteristics, can improve indirect comparisons of the efficacy of these therapies. Methods No evidence of disease activity (NEDA) was evaluated as the proportion of patients free from relapses and 3-month confirmed disability progression (clinical composite), free from gadolinium-enhancing T1 lesions and new or newly enlarged T2 lesions (magnetic resonance imaging composite), or free from all disease measures (overall composite). For each measure, the efficacy of fingolimod was estimated by analyzing individual patient data from fingolimod phase 3 trials using methodologies from studies of other oral therapies. These data were then used to build binomial regression models, which adjusted for differences in baseline characteristics between the studies. Models predicted the indirect relative risk of achieving NEDA status for fingolimod versus dimethyl fumarate or teriflunomide in an average patient from their respective phase 3 trials. Results The estimated relative risks of achieving NEDA status for fingolimod versus placebo in a pooled fingolimod trial population were numerically greater (i.e., fingolimod more efficacious) than the estimated relative risks for dimethyl fumarate or teriflunomide versus placebo in each respective trial population. In indirect comparisons, the predicted relative risks for all composite measures were better for fingolimod than comparator when tested against the trial populations of those treated with dimethyl fumarate (relative risk, clinical: 1.21 [95% confidence interval 1.06–1.39]; overall: 1.67 [1.08–2.57]), teriflunomide 7 mg (clinical: 1.22 [1.02–1.46]; overall: 2.01 [1.38–2.93]) and teriflunomide 14 mg (clinical: 1.14 [0.96–1.36]; overall: 1.61 [1.12–2.31]). Conclusion Our modeling approach suggests that fingolimod therapy results in a higher probability of NEDA than dimethyl fumarate and teriflunomide therapy when phase 3 trial data are indirectly compared and differences between trials are adjusted for. Electronic supplementary material The online version of this article (doi:10.1007/s12325-014-0167-z) contains supplementary material, which is available to authorized users.

New diagnoses of HIV infection were reported confidentially to the Public Health Laboratory Service AIDS Centre under a national voluntary surveillance scheme. Two sets of data drawn from the national data sets were made available to us for analysis, the first in 1991 and the second in 1994, by which time the replication of reports had been reduced. The data used in the analyses consisted of the numbers of replications of the reported full date of birth in the individual records (one, two, three and so on), for each year of birth. This paper uses a nonparametric maximum likelihood estimation method for quantifying the amount of replication in the data. The estimated amount of replication was 3.37% (95% confidence interval (0.98%, 11.83%)) in the 1991 data set and 0.58% (95% confidence interval (0%, 2.64%)) in the 1994 data set.

Objective Investigate relationships between Brain Volume (BV) loss and clinical and MRI outcomes observed in three phase 3 fingolimod trials. Method Percentage BV change (PBVC) was measured in the core-phases and extensions of FREEDOMS, FREEDOMS II and TRANSFORMS using ‘Structural Image Evaluation Normalization, of Atrophy’. During the core-phases, correlations were assessed between PBVC and: cumulative Gd+-lesion count (LC); T2-lesion volume change (LVC);new/enlarging T2-LC; T1-hypointense LVC; number of confirmed relapses; EDSS score change; and MSFC score change. Proportions of patients with 3- or 6-month confirmed disability progression (CDP) and correlations between PBVC and EDSS were determined. Results In FREEDOMS, FREEDOMS II and TRANSFORMS, PBVC consistently correlated best with cumulative Gd+-LC(p Conclusion BV loss was greatest in patients who relapsed or who developed new Gd+ or T2-lesions. By reducing BV loss, fingolimod may slow disability progression.