Shannon Ritter

Long-term effects of fingolimod in multiple sclerosis: The randomized FREEDOMS extension trial

Objective: To assess long-term safety and efficacy of fingolimod in patients with relapsing-remitting multiple sclerosis (RRMS). Methods: Patients completing FTY720 Research Evaluating Effects of Daily Oral Therapy in MS (FREEDOMS) were eligible for this dose-blinded, parallel-group extension study, continuing fingolimod 0.5 mg/day or 1.25 mg/day, or switching from placebo to either dose, randomized 1:1. Efficacy variables included annualized relapse rate (ARR), brain volume loss (BVL), and confirmed disability progression (CDP). Between-group analyses were conducted in the intent-to-treat (ITT) population from FREEDOMS baseline to end of study. Within-group analyses compared years 0–2 (FREEDOMS) and years 2–4 (extension) in the extension ITT population. Results: Of 1,272 patients (FREEDOMS ITT population), 1,033 were eligible, and 920 enrolled in the extension study (continuous-fingolimod: 0.5 mg [n = 331], 1.25 mg [n = 289]; placebo–fingolimod: 0.5 mg [n = 155], 1.25 mg [n = 145]); 916 formed the extension ITT population (n = 330; n = 287; n = 154; n = 145) and 773 (84%) completed. In the continuous-fingolimod groups, ARR was lower (p < 0.0001), BVL was reduced (p < 0.05), and proportionately more patients were free from 3-month CDP (p < 0.05) than in a group comprising all placebo–fingolimod patients. Within each placebo–fingolimod group, ARR was lower (p < 0.001, both) and BVL was reduced after switching (p < 0.01, placebo–fingolimod 0.5 mg). Rates and types of adverse events were similar across groups; no new safety issues were reported. Conclusion: Efficacy benefits of fingolimod during FREEDOMS were sustained during the extension; ARR and BVL were reduced after switching. Classification of evidence: This study provides Class IV evidence that long-term fingolimod treatment is well-tolerated and reduces relapse rates, disability progression, and MRI effects in patients with RRMS.

Fingolimod in relapsing multiple sclerosis: An integrated analysis of safety findings

BACKGROUND Fingolimod 0.5mg once daily is the first approved oral therapy for relapsing multiple sclerosis (MS). OBJECTIVE To report integrated long-term safety data from phase 2/3 fingolimod studies. METHODS Descriptive safety data are reported from the FTY720 Research Evaluating Effects of Daily Oral Therapy in Multiple Sclerosis (FREEDOMS) study, a 24-month, randomized, double-blind study comparing fingolimod 0.5mg and 1.25mg with placebo, and an All Studies group (patients who received fingolimod 0.5mg (n=1640) or 1.25-0.5mg (n=1776) in phase 2/3 studies and associated extensions). Relevant post-marketing experience, up to December 2011, is included. RESULTS The incidence of adverse events (AEs) and serious AEs (SAEs) was similar with fingolimod and placebo in FREEDOMS. In the All Studies group, fingolimod 0.5mg was associated with transient, rarely symptomatic (0.5%), bradycardia and second-degree atrioventricular block on treatment initiation, minor blood pressure increases, frequent (9%) but generally asymptomatic liver enzyme elevations, and macular oedema (0.4%). The incidences of infections (including serious and herpes infections), malignancies, SAEs and treatment discontinuations due to AEs were similar with fingolimod 0.5mg and placebo. CONCLUSION The safety profile of fingolimod has been well characterized in this large combined trial population. Although infrequent SAEs can occur, there is no increased risk of infections, malignancies or serious cardiovascular events versus placebo.

Long-term (up to 4.5 years) treatment with fingolimod in multiple sclerosis: results from the extension of the randomised TRANSFORMS study

Objective The 12-month (M), phase 3, double-blind, randomised TRANSFORMS study demonstrated significant benefits of fingolimod 0.5 or 1.25 mg over interferon β-1a (IFNβ-1a) in patients with relapsing–remitting multiple sclerosis. We report the results of long-term (up to 4.5 years) extension of TRANSFORMS. Methods Patients randomised to fingolimod (0.5/1.25 mg) in the core phase continued the same dose (continuous-fingolimod) in the extension, whereas those on IFNβ-1a were re-randomised (1:1) to fingolimod (IFN-switch; IFN: 0.5/1.25 mg). Outcomes included annualised relapse rate (ARR), confirmed disability progression and MRI measures. Results are presented here for the continuous-fingolimod 0.5 mg and pooled IFN-switch groups. Results Of the 1027 patients who entered the extension, 772 (75.2%) completed the study. From baseline to the end of the study (EOS), ARR in patients on continuous-fingolimod 0.5 mg was significantly lower than in the IFN-switch group (M0–EOS: 0.17 vs 0.27). After switching to fingolimod (M0–12 vs M13–EOS), patients initially treated with IFN had a 50% reduction in ARR (0.40 vs 0.20), reduced MRI activity and a lower rate of brain volume loss. In a post hoc analysis, the proportion of IFN-switch patients with no evidence of disease activity increased by approximately 50% in the first year after switching to fingolimod treatment (44.3% to 66.0%). The safety profile was consistent with that observed in the core phase. Conclusions These results support a continued effect of long-term fingolimod therapy in maintaining a low rate of disease activity and sustained improved efficacy after switching from IFNβ-1a to fingolimod. Clinical trial registration No NCT00340834.

Efficacy of aliskiren/hydrochlorothiazide single-pill combinations in aliskiren non-responders.

Objectives. To evaluate the efficacy, safety and tolerability of a single-pill combination of the direct renin inhibitor aliskiren and hydrochlorothiazide (HCT) in patients with hypertension and an inadequate BP response to aliskiren monotherapy (mean sitting diastolic BP [msDBP] >90 and ≤110 mmHg following 4 weeks of aliskiren 300 mg). Methods. In this study, 880 patients with hypertension and an inadequate BP response to aliskiren monotherapy were randomized to once-daily, double-blind treatment with a single-pill combination of aliskiren/HCT 300/25 mg or 300/12.5 mg, or aliskiren 300 mg monotherapy. At the week 8 endpoint, least-squares mean changes in mean sitting systolic/diastolic BP (msSBP/DBP) from baseline were analyzed for the intent-to-treat population. Results. Aliskiren/HCT 300/25 mg and 300/12.5 mg provided significantly greater msSBP/DBP reductions from baseline (15.9/11.0 mmHg and 13.5/10.5 mmHg, respectively) than aliskiren 300 mg alone (8.0/7.4 mmHg; both p<0.001). Rates of BP control (<140/90 mmHg) were significantly higher with aliskiren/HCT 300/25 mg (60.2%) and 300/12.5 mg (57.9%) than with aliskiren 300 mg alone (40.9%; both p<0.001). Aliskiren/HCT single-pill combination treatment showed similar tolerability to aliskiren monotherapy. Conclusions. Aliskiren/HCT single-pill combinations provide clinically significant additional BP reductions and improved BP control rates over aliskiren alone in patients who are non-responsive to aliskiren 300 mg monotherapy.

Long-term safety and efficacy of aliskiren and valsartan combination with or without the addition of HCT in patients with hypertension

Abstract Objective: To assess the long-term safety and antihypertensive efficacy of aliskiren/valsartan 300/320 mg combination. Methods: This was a 54-week, multicenter, open-label study (core phase), followed by a 26-week extension phase. Efficacy variables were change in msDBP and msSBP from baseline to endpoint (54-week and 80-week). Safety was assessed by monitoring and recording adverse events (AEs). ClinicalTrials.gov Identifier: NCT00386607 Results: A total of 601 patients (msDBP ≥90 and <110 mmHg) entered the 54-week core study. Optional add-on HCT was allowed at week 10 onwards if BP was ≥140/90 mmHg at two consecutive visits. Of the 486 patients completed the core study, 180 patients entered the extension phase and received aliskiren/valsartan and add-on HCT (12.5 or 25 mg). Overall the combination of aliskiren/valsartan was well-tolerated and the majority of AEs were mild-to-moderate in severity. The incidence of SAEs was low (core phase: n = 22 [3.7%]; extension phase: n = 4 [2.2%]). Elevated serum potassium (>5.5 mmol/L at any time during the study) was observed in 21 (3.6%) patients. The majority of these elevations were transient and returned to normal in subsequent visits, and the discontinuation rate due to elevated serum potassium was low (0.3% [n = 2]). Decreased serum potassium levels (<3.5 mmol/L at any time during the study) was observed in 26 (4.4%) patients, mainly in patients receiving aliskiren/valsartan/HCT (n = 22; 7.1%). At the 54-week endpoint, a mean BP reduction of 20.5/13.4 mmHg from baseline (baseline BP: 152.9/97.0 mmHg) was observed and 66.9% (n = 398/595) of patients achieved BP control with aliskiren/valsartan with or without HCT. At the end of the extension phase (80-week endpoint), additional reduction in BP was obtained (overall, 28.8/18.3 mmHg) and 86.6% (n = 155/179) of patients achieved BP control with aliskiren/valsartan/HCT. A limitation is the absence of an active comparator group. Conclusion: Long-term treatment with the combination of aliskiren/valsartan with or without HCT provided clinically meaningful BP reductions and high rates of BP control and was well-tolerated. Trial registration: ClinicalTrials.gov identifier: NCT00386607.

A comparison of multiple sclerosis disease activity after discontinuation of fingolimod and placebo

Background Cases of higher-than-expected disease activity have been reported following fingolimod discontinuation. Objective The objective of this paper is to assess the risk of substantially higher-than-expected disease activity post-study drug discontinuation (SDD) at the individual patient level using data from the Phase III, placebo-controlled FREEDOMS and FREEDOMS II trials. Methods Baseline gadolinium-enhancing T1-lesion volumes were used to statistically model the expected level of MRI disease activity post-SDD. Patients exceeding this level were classed as “MRI outliers.” Patients with an unusually high increase in Expanded Disability Status Scale score, hospitalization for relapse, severe relapse, or relapse with incomplete recovery post-SDD were classed as “clinical outliers.” Results In FREEDOMS, the number of MRI outliers post-SDD was 2/69 (2.9%), 1/65 (1.5%) and 7/83 (8.4%) for the placebo, fingolimod 0.5 mg, and fingolimod 1.25 mg groups, respectively. In FREEDOMS II, the corresponding numbers were 4/72 (5.6%), 6/79 (7.6%) and 3/73 (4.1%). The number of clinical outliers across both trials was low. No consistent evidence of placebo vs fingolimod, dose-related or inter-trial patterns was discernable. Conclusion The low number of clinical and MRI outliers and lack of any discernible pattern within and between trials, including between placebo and fingolimod, argues against a systematic risk of higher-than-expected recurrence of disease activity following discontinuation of fingolimod.

EFFECT OF FINGOLIMOD VS. IFN-BETA1A ON NO EVIDENCE OF DISEASE ACTIVITY

Introduction To compare effects of fingolimod vs. interferon beta-1a (IFN) in achieving no evidence of disease activity (NEDA-4) in patients with relapsing-remitting multiple sclerosis (RRMS) in the TRANSFORMS study. Adding Brain Volume Loss (BVL) to NEDA results in a more comprehensive and balanced measure of focal and diffuse damage. Methods In this post-hoc analysis, we used data from the fingolimod 0.5 mg daily (n=431) and IFN 30 µg weekly (n=435) groups. NEDA-4 was defined as absence of confirmed relapses, new/enlarging T2 lesions, 6-month confirmed disability progression (CDP) and BVL (annual percent brain volume change [PBVC] of >−0.4%). 3-month CDP and additional PBVC cut-offs representing mean BVL rates in healthy adults (0.2%), MS patients (0.6%), or accelerated BVL (1.2%) were also tested. Odds ratios (OR) were calculated for differences between fingolimod- and IFN-treated groups. Results Significantly more fingolimod (n=425) than IFN-treated patients (n=418) achieved NEDA-4 status: 27.9% vs. 16.7% (OR:1.93; 95% CI: 1.36–2.73; p=0.0002). Results were similar for other PBVC cut-offs: (>–0.2%): 20.2% vs 11.5%; 1.94; 1.30–2.90, p=0.0011; (>–0.6%): 34.6% vs 20.4%; 2.06; 1.49–2.86, p<0.0001; (>–1.2%): 40.8% vs 26.4%; 1.92; 1.42–2.60; p<0.0001. Conclusion Fingolimod-treated patients had twice the odds of achieving NEDA-4 status over 1 year as patients treated with IFN.