Phase IV study of retention on fingolimod versus injectable multiple sclerosis therapies: a randomized clinical trial

Abstract

Objective: In relapsing-remitting multiple sclerosis (RRMS), suboptimal adherence to injectable disease-modifying therapies (iDMTs; interferon β-1a/b, glatiramer acetate) is common, reducing their effectiveness. Patient retention on oral fingolimod and iDMTs was evaluated in PREFERMS, a randomized, parallel-group, active-controlled, open-label, 48-week study.

Methods: Patients were included if they had RRMS, were aged 18-65 years and had Expanded Disability Status Scale score up to 6, enrolled at 117 US study sites, were treatment naïve or had received only one iDMT class. Patients were randomized 1:1 (fingolimod 0.5 mg/day; preselected iDMT) by interactive voice-and-web-response system without blinding, followed up quarterly, and allowed one study-approved treatment switch after 12 weeks, or earlier for efficacy or safety reasons. The primary outcome was patient retention on randomized treatment over 48 weeks. Secondary endpoints included patient-reported outcomes, brain volume loss (BVL), and cognitive function.

Results: Analysis of 433/436 patients receiving fingolimod and 428/439 receiving iDMTs showed that patient retention rate was significantly higher with fingolimod than with iDMTs [352 (81.3%) versus 125 (29.2%); 95% confidence interval 46.4-57.8%; p < 0.0001]. The most common treatment switch was from iDMT to fingolimod for injection-related reasons. Patient satisfaction was greater and BVL less with fingolimod than with iDMTs, with no difference in cognitive function. Adverse events were consistent with established tolerability profiles for each treatment.

Conclusions: In RRMS, fingolimod was associated with better treatment retention, patient satisfaction and BVL outcomes than iDMTs. Patients may persist with iDMTs, but many may switch treatment if permitted. Treatment satisfaction fosters adherence, a prerequisite for optimal outcomes.

Keywords: adherence; disease-modifying therapy; fingolimod; glatiramer acetate; interferon; multiple sclerosis; randomized controlled trial; retention.

Figure 1.

CONSORT patient flow diagram for PREFERMS. *More than one reason for exclusion could be recorded for a patient. CONSORT, Consolidated Standards of Reporting Trials; iDMT, injectable disease-modifying therapy; PREFERMS, Prospective, Randomized, active-controlled, open-label study to Evaluate patient retention on Fingolimod versus approved first-line disease modifying therapies in adults with Relapsing remitting Multiple Sclerosis.

Figure 2.

Retention rates, patient satisfaction with treatment, and reasons for discontinuing randomized treatment in PREFERMS. (a) The primary outcome of retention rate in the two treatment groups as a Kaplan–Meier plot, statistically analyzed as a log-rank test adjusted for treatment. The data were also analyzed by a Cochran–Mantel–Haenszel test, a logistic regression and a Cox proportional hazard model, which were adjusted for treatment and treatment naïvety. The data were also measured by normal approximation performed using continuity correction. ****p < 0.0001 for all analyses. (b) Sensitivity analysis of the retention rate shown in panel (a) excluding patients who switched treatment for nonefficacy or safety reasons before week 12 in violation of the study protocol, and all patients switching treatment between days 77 and 110 in case any had enrolled with the intention of switching from iDMT to fingolimod as soon as it became permissible for any reason. (c) Patient-reported satisfaction as measured by the Medication Satisfaction Questionnaire at last assessment. The overall difference across categories between fingolimod 0.5 mg and iDMTs is significant (Cochran–Mantel–Haenszel test using modified ridit scores adjusted for treatment and treatment naïvety; p < 0.0001). (d) Primary reasons for discontinuing randomized treatment. Labels for each bar represent the number (percentage of the total number of patients discontinuing randomized treatment). *Injection-related reasons for discontinuation are listed on the left of the corresponding area of the graph. ^†Reasons for ‘Other’ stated in the fingolimod group include the following [n = 1 (0.35%), unless stated otherwise]: abnormal platelet counts; adverse drug reaction; AE of headache; AE of joint pain; AE of papilloma, hair loss, herpes simplex virus, and lymphopenia; anxiety; hypertension; lymphopenia [n = 2 (0.70%)]; mouth sores; possible diagnosis of macular edema; side effects; and tolerability. Reasons for ‘Other’ in the iDMT group include the following [n = 1 (0.35%), unless stated otherwise]: abdominal pain, chest pain, flushing; AE; AE of bilateral lower extremity edema; AE of headache; allergic reaction [n = 2 (0.70%)]; anxiety; anxiety and depression; anxiety and fatigue; arthralgia and myalgia; bruising; convenience; fatigue [n = 2 (0.70%)]; flu-like symptoms [n = 2 (0.70%)]; general body ache [n = 2 (0.70%)]; headache [n = 2 (0.70%)]; injection fatigue; injection pain [n = 8 (2.82%)]; injection reaction; intolerant; lack of efficacy; muscle aches; mood altering; needle phobia [n = 4 (1.41%)]; palpitations; panic and irritability; patient choice [n = 10 (3.52%)]; possible seizure exacerbation; rash; relapse [n = 3 (1.06%)]; stopped taking medication; and treatment dissatisfaction [n = 2 (0.70%)]. AE, adverse event; CI, confidence interval; iDMT, injectable disease-modifying treatment; MRI, magnetic resonance imaging; PREFERMS, Prospective, Randomized, active-controlled, open-label study to Evaluate patient retention on Fingolimod versus approved first-line disease modifying thErapies in adults with Relapsing remitting Multiple Sclerosis.

Figure 3.

ARR, key MRI measures, and volumetric brain changes at last assessment in PREFERMS. Bars show mean (SD) except in (a), where they represent mean (95% Cl), with values listed below each graph together with n for each group. Statistics in (a)–(e): negative binomial regression adjusted for treatment, number of relapses in previous 2 years, screening Expanded Disability Status Scale score, and treatment naïvety, using duration (years) as an offset variable. Statistics in (f)–(h) performed on annualized rates with a rank analysis of covariance, adjusted for treatment, treatment naïvety, corresponding baseline values, and age. All data from last assessment. **p < 0.01; ***p < 0.001; ****p < 0.0001 versus iDMTs. ARR, annualized relapse rate; CI, confidence interval; Gd+, gadolinium enhanced; iDMT, injectable disease-modifying therapy; MRI, magnetic resonance imaging; PREFERMS, Prospective, Randomized, active-controlled, open-label study to Evaluate patient retention on Fingolimod versus approved first-line disease modifying thErapies in adults with Relapsing remitting Multiple Sclerosis; SD, standard deviation.