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Fingolimod safety and efficacy data in relapsing-remitting multiple sclerosis (RRMS) are available up to 5 years, from an extension of a randomized, placebo-controlled, double-blind, phase 2 study, at a dose higher (5.0/1.25 mg) than the approved dose of 0.5 mg. The objective of the study is to present the end-of-study data (>7 years) from the open-label extension of the phase 2 study. In the core phase (6 months), patients (N = 281) were randomized to placebo or fingolimod 1.25/5 mg. In the extension, placebo patients were randomized to fingolimod 1.25/5 mg. All patients received open-label 1.25 mg fingolimod after month 24 and 0.5 mg after month 60. Clinical visits were performed every 3 months, expanded disability status scale (EDSS) every 6 months and magnetic resonance imaging (MRI) annually. 122 (48.8%) patients completed the extension study; overall fingolimod exposure was 1230.7 patient-years. The most common (>10%) reasons for study discontinuation were adverse events (19.6%) and consent withdrawal (16.4%). Fingolimod treatment for >7 years was associated with sustained low clinical and MRI disease activity. Over 60% of patients remained relapse free and about 80% were free from any MRI activity. Overall annualized relapse rate was 0.18. Long-term fingolimod treatment was not associated with new safety concerns. Long-term fingolimod was well tolerated and associated with a sustained low level of disease activity.

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.

Background: Patients with multiple sclerosis (MS) lose brain volume (BV) faster than healthy individuals. Objective: Our purpose, within the 12-month phase 3 TRANSFORMS study, was to examine the effect of treatment on BV loss in patient subgroups, establish correlations between baseline normalized BV (NBV) and baseline disease parameters, to identify variables predictive of baseline NBV and on-study percentage BV change (PBVC), and to establish correlations between on-study PBVC and on-study efficacy outcomes. Methods: Patients received fingolimod 0.5 mg or 1.25 mg, or intramuscular (IM) interferon β-1a (IFNβ-1a) for 12 months. The effect of treatment on PBVC was examined in patient demographic, disease and magnetic resonance imaging (MRI) characteristic subgroups. Pearson’s correlation analyses and a stepwise linear regression model were used to identify variables predictive of NBV and PBVC. Results: Fingolimod reduced BV loss over 12 months versus IFNβ-1a IM in all patient subgroups assessed, including individuals with or without gadolinium (Gd)-enhancing lesions at baseline. Baseline T1 hypointense lesion volume had the strongest correlation with baseline NBV. Baseline Gd-enhancing T1 lesion count was most predictive of change in PBVC over 12 months. Conclusions: Our results improve understanding of the contributions of different baseline demographic, clinical and MRI characteristics to NBV, including factors that may be predictive of future BV loss

Background: Epidemiologic studies have identified several demographic factors, including gender, that may influence the progression from mild cognitive impairment (MCI) to Alzheimer's disease (AD). Objective: This analysis aimed to develop a sensitive model for detecting treatment benefits in patients with MCI by controlling for factors that predict progression to AD. The study used this statistical modeling to investigate the effect of gender on treatment response in patients with MCI. Methods: This post hoc analysis used data from the InDDEx (Investigation in Delay to Diagnosis of Alzheimer's disease with Exelon) study, a long-term (3- to 4-year), multicenter, randomized, double-blind, placebo-controlled trial of rivastigmine 3- to 12-mg/d capsules in 1018 patients with MCI. Baseline variables that were significantly associated with progression to AD within the InDDEx study population were identified. A Cox proportional hazards multivariate regression model that adjusted for these predictive factors was applied to the overall study population and to the gender subgroups. Results: Of 31 baseline variables analyzed, 13 were found to be significantly associated with progression to AD in the overall population. After adjustment using the Cox proportional hazards regression model, rivastigmine was associated with a significantly lower risk for progression to AD compared with placebo in the overall population (1016 patients; hazard ratio [HR] = 0.747; P = 0.045). This effect of rivastigmine was evident in women (530 patients; HR = 0.676; P = 0.046) but not in men. Conclusions: In these patients with MCI, a significant decrease in the risk for progression to AD was found with rivastigmine over 3 to 4 years. The proportion of women whose disease progressed to AD was significantly lower in the rivastigmine group than the placebo group (P = 0.046). This effect was not found in men. These data suggest that prospectively adjusting for predictive factors could lead to a more accurate estimation of treatment benefits in future studies of MCI.

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.

We present here results at 60 months (M), from the extension component of a phase 2, randomized, placebo-controlled, double-blind, six-month study evaluating oral fingolimod (1.25 mg or 5 mg daily) in relapsing multiple sclerosis. Placebo patients from the core study were re-randomized to fingolimod 1.25 mg or 5 mg in the extension. All patients received 1.25 mg fingolimod after the M24 visit. A total of 140/281 (49.8%) patients completed M60. Fingolimod treatment was associated with a low annualized relapse rate (0.2 relapses/ year), low MRI activity, and a modest rate of disability progression in those treated for five years. No new safety issues were reported.

Introduction. Sotrastaurin is an immunosuppressant that inhibits protein kinase C and blocks T-lymphocyte activation. The authors determined the effect of combining sotrastaurin with the calcineurin inhibitor cyclosporine on the pharmacokinetics and biomarker responses to both drugs. Methods. This was a randomized, 4-period, crossover study in 20 healthy subjects who received single oral doses of (1) sotrastaurin 100 mg, (2) cyclosporine 400 mg, (3) 100 mg sotrastaurin with 100 mg cyclosporine and (4) 100 mg sotrastaurin with 400 mg cyclosporine. Blood samples were collected to measure drug levels and biomarkers of T-lymphocyte activation (interleukin-2 and tumor necrosis factor producing T-cells and interleukin-2 messenger RNA levels) and of T-lymphocyte proliferation (thymidine uptake). Results. Sotrastaurin did not alter cyclosporine AUC; however, low-dose and high-dose cyclosporine increased sotrastaurin AUC by 1.2-fold [90% confidence interval, 1.1–1.4] and 1.8-fold [1.6–2.1], respectively. Adding high-dose cyclosporine to a low-therapeutic dose of sotrastaurin significantly enhanced the inhibition of cytokine production by 31% [95% confidence interval, 25–36%], of interleukin-2 messenger RNA levels by 13% [7–19%], and of thymidine uptake by 37% [32–42%] compared with sotrastaurin alone. Addition of low-dose cyclosporine elicited slightly lower enhancements in inhibition by 21% [14–28%], 6% [−4–16%], and 26% [21–30%], respectively, compared with sotrastaurin alone. Conclusions. Sotrastaurin did not alter the pharmacokinetics of cyclosporine, but cyclosporine increased sotrastaurin AUC up to 1.8-fold. The combined drugs elicited a significantly greater inhibition of T-cell activation and proliferation than sotrastaurin alone. Copyright © 2010 John Wiley & Sons, Ltd.

Sotrastaurin is an immunosuppressant that inhibits protein kinase C. In the prevention of acute rejection in organ transplantation, sotrastaurin might be combined with tacrolimus. A drug interaction study was performed in 18 healthy subjects who received single oral doses of sotrastaurin 400 mg, tacrolimus 7 mg, and the drug combination. Drug blood levels and lymphocyte activation and proliferation were measured. Tacrolimus did not alter the pharmacokinetics of sotrastaurin; however, sotrastaurin increased tacrolimus area under the concentration-time curve by 2.0-fold (90% confidence interval, 1.8-2.1). Production of interleukin-2 and tumor necrosis factor by T cells activated via calcium-independent pathways was inhibited by 75% ± 22% from baseline by sotrastaurin. Interleukin-2 messenger RNA levels were decreased by 90% ± 9% from baseline by sotrastaurin. Addition of tacrolimus to sotrastaurin had minimal or no effect on these biomarkers, consistent with tacrolimus' mechanism of action. Lymphocyte proliferation induced via calcium-dependent pathways was decreased from baseline by 82% ± 9% by sotrastaurin, 76% ± 11% by tacrolimus, and 96% ± 2% for the drug combination. How sotrastaurin and tacrolimus could be partnered in an immunosuppressive regimen will need to be established in the context of controlled clinical trials in organ transplant patients, taking into account the pharmacokinetic interaction on tacrolimus and the potentially enhanced immunosuppressive activity of this drug combination.

To evaluate the synergistic effects of the apolipoprotein E (APOE) epsilon4 and butyrylcholinesterase K-variant (BCHE-K) alleles on progression to Alzheimer's disease (AD) in individuals with mild cognitive impairment (MCI).This was a post-hoc exploratory analysis from a 3-4-year, randomized, placebo-controlled study of rivastigmine in participants with MCI (InDDEx study). Participants who consented to genetic testing were included in the current analyses. The incidence of progression to AD, cognitive decline and changes in MRI brain volumes were investigated in participants from the placebo arm of the InDDEx study.Of the 1018 participants in the overall study, 464 were successfully genotyped for both APOE and butyrylcholinesterase. Of these, 68 (14.7%) carriedor =1 APOE epsilon4 andor =1 BCHE-K allele. The presence of APOE epsilon4 was associated with a significantly higher incidence of progression to AD whereas the presence of BCHE-K had no independent effect on progression. A synergistic effect of the combined presence of APOE epsilon4 and BCHE-K on the time to clinical diagnosis of AD and on MRI brain volumes was seen. Progression to AD and hippocampal volumetric loss was greatest in participants who carried both APOE epsilon4 and BCHE-K alleles and lowest in BCHE-K carriers without the APOE epsilon4 allele.In MCI, the risk of cognitive decline, hippocampal volumetric loss and progression to AD seems to be the greatest in individuals who carry at least one copy of both the BCHE-K and APOE epsilon4 alleles.

Summary Objective To assess the effect of rivastigmine in patients with mild cognitive impairment (MCI) on the time to clinical diagnosis of Alzheimer's disease (AD) and the rate of cognitive decline. Methods The study was a double-blind, randomised, placebo-controlled trial of up to 48 months. All patients had MCI operationally defined by having cognitive symptoms, a global clinical dementia rating stage of 0·5, a score of less than 9 on the New York University delayed paragraph recall test, and by not meeting the diagnostic criteria for AD. Primary efficacy variables were time to clinical diagnosis of AD, and change in performance on a cognitive test battery. This study is registered with the US National Institutes of Health clinical trials database (ClinicalTrials.gov), number NCT00000174. Findings Of 1018 study patients enrolled, 508 were randomly assigned to rivastigmine and 510 to placebo; 17·3% of patients on rivastigmine and 21·4% on placebo progressed to AD (hazard ratio 0·85 [95% CI 0·64–1·12]; p=0·225). There was no significant difference between the rivastigmine and placebo groups on the standardised Z score for the cognitive test battery measured as mean change from baseline to endpoint (−0·10 [95% CI −0·63 to 0·44], p=0·726). Serious adverse events were reported by 141 (27·9%) rivastigmine-treated patients and 155 (30·5%) patients on placebo; adverse events of all types were reported by 483 (95·6%) rivastigmine-treated patients and 472 (92·7%) placebo-treated patients. The predominant adverse events were cholinergic: the frequencies of nausea, vomiting, diarrhoea, and dizziness were two to four times higher in the rivastigmine group than in the placebo group. Interpretation There was no significant benefit of rivastigmine on the progression rate to AD or on cognitive function over 4 years. The overall rate of progression from MCI to AD in this randomised clinical trial was much lower than predicted. Rivastigmine treatment was not associated with any significant safety concerns.