Subcutaneous interferon ß-1a in the treatment of clinically isolated syndromes: 3-year and 5-year results of the phase III dosing frequency-blind multicentre REFLEXION study.

OBJECTIVE: Early treatment following a first clinical demyelinating event (FCDE) delays further disease activity in patients with multiple sclerosis (MS). This study determined the effects of early versus delayed treatment (DT) with subcutaneous interferon (sc IFN) ß-1a 44 µg in patients with an FCDE up to 60 months postrandomisation. METHODS: Patients who completed the 24-month double-blind REFLEX (REbif FLEXible dosing in early MS) study entered an extension (REFLEXION, REbif FLEXible dosing in early MS extensION): patients initially randomised to sc IFN ß-1a and not reaching clinically definite MS (clinically definite MS, CDMS (second attack or sustained Expanded Disability Status Scale (EDSS) score increase)) continued original treatment (three times weekly (tiw) or once weekly (qw)); placebo patients switched to tiw (DT); patients with CDMS switched to tiw. Clinical, MRI and adverse event data up to month 60 are reported. RESULTS: 402/517 (77.8%) REFLEX patients entered REFLEXION (DT, n=133; tiw, n=127; qw, n=142). At month 60, cumulative probability of CDMS was: DT 44.6%; qw 40.7% (nominal p=0.084 vs DT); tiw 39.2% (nominal p=0.032 vs DT). Cumulative probability of McDonald MS conversion (CDMS or new MRI activity) at month 60 was also reduced for tiw versus DT (nominal p<0.001). At month 60, mean cumulative numbers of new T2, gadolinium-enhancing and T1 hypointense lesions were lower with sc IFN ß-1a qw (nominal p<0.05) and tiw versus DT (nominal p<0.001); T2 and T1 hypointense lesion volume change was lower for sc IFN ß-1a tiw versus DT (nominal p<0.01). Treatment was well tolerated; fewer patients receiving tiw versus qw were positive for neutralising or binding antibodies. CONCLUSIONS: Over 5 years in patients presenting with an FCDE, early sc IFN ß-1a tiw administration versus DT prolonged time to CDMS and McDonald MS, and reduced overall MRI activity. TRIAL REGISTRATION NUMBER: NCT00813709; Results.

Assessing the duration of EDSS improvement after a therapy start: A novel approach applied to the long-term extension of the PRISMS study.

BACKGROUND: In a chronic and progressive disease such as multiple sclerosis (MS), the improvement on Expanded Disability Status Scale (EDSS) can be a transient event. Therefore, estimating the prevalence of disability improvement over time, accounting both for improvement incidence and duration, is of interest. The aim of this study was to show the application of a simple estimator for the proportion of patients with sustained improvement over time using data from the long-term extension of the PRISMS trial. METHODS: A total of 534 relapsing-remitting MS (RRMS) patients from the PRISMS trial were included. Patients with a baseline EDSS of 0 were excluded. Patients were randomized to placebo (n = 178), subcutaneous interferon beta-1a (sc IFN ß-1a) 22 µg (n = 181) or sc IFN ß-1a 44 µg (n = 175). At Year 2, patients receiving placebo were re-randomized to sc IFN ß-1a 22 µg or 44 µg (delayed sc IFN ß-1a) while patients receiving sc IFN ß-1a 22 µg or 44 µg continued their initial regimen. Patients were followed up for over 7 years post-randomization. Disability improvement was defined as a 1-point decrease in EDSS from baseline confirmed at 6 months. Prevalence of improvement was estimated as difference of Kaplan-Meier (KM) estimators while the cumulative incidence of improvement was calculated using the standard KM curves. RESULTS: No significant differences in cumulative incidence of EDSS improvement at 3 years between delayed sc IFN ß-1a (20.3%) and sc IFN ß-1a 22 µg (20.8%; p = 0.49) or 44 µg (21.3%; p = 0.33). When taking duration of improvement into account, the proportion of patients showing an improved condition after 3 years was 10.1% with delayed sc IFN ß-1a, 11.3% with sc IFN ß-1a 22 µg (p = 0.17) and 15.4% with sc IFN ß-1a 44 µg (p = 0.037) that was substantially maintained over the long term. CONCLUSIONS: With the use of this new statistical methodology, it is possible to estimate the time to improvement as well as the duration of improvement, information that is better suited to describing a non-final outcome like disability improvement. In this case, early sc IFN ß-1a 44 µg initiation had a greater proportion of patients with a sustained disability improvement over a long period of follow-up as compared to patients who had initially been randomized to placebo. In contrast, no significant differences on the cumulative incidence of improvement were observed.

Effectiveness, Healthcare Resource Utilization and Adherence to Subcutaneous Interferon Beta-1a According to Age in Patients With Multiple Sclerosis: A Cohort Study Using a US Claims Database.

Background: It is thought that older patients with multiple sclerosis (MS) may present with a different clinical disease phenotype, and therefore respond to subcutaneous interferon beta-1a (sc IFN ß-1a) differently to younger patients. However, few real-world data are available concerning the effectiveness of sc IFN ß-1a according to age. Using data from US claims databases, this cohort analysis aimed to determine the differences in relapse rates, healthcare utilization, treatment adherence, and discontinuation according to pre-defined age groups. Methods: Patient data were pooled from the IBM® MarketScan® Commercial Claims Database and Medicare Supplemental Database. Patients with a confirmed MS diagnosis who initiated treatment with sc IFN ß-1a between July 01, 2010 and December 31, 2015, along with at least 6 months continuous enrolment in a healthcare plan, were followed from first prescription (index date) until date of discontinuation, treatment switch, or end of observation period (1 year after index date). Results: Of the 5,340 patients included in the analysis, there was a high proportion of patients free from relapse across all age groups (range: 94.1-95.4%), with a numerical decrease in the number of MRI performed by age (mean: 0.25, 18-30 years; 0.20, 31-40 years; 0.16, 41-50 years; 0.14, ≥51 years). Adherence (≥80%) was seen to increase with age (77.6%, 18-30 years; 79.6%, 31-40 years; 81.3%, 41-50 years; 84.0%, ≥51 years), at the same time as a non-significant decrease in discontinuation (incidence rate: 79.91, 73.01, 71.75, 68.71%). Conclusion: The effectiveness of sc IFN ß-1a does not appear reduced as a consequence of age in this real-world setting. Older patients had lower discontinuation rates and reduced disease activity, reflected in lower relapse rates and fewer MRI scans compared with younger patients.

MAGNIMS score predicts long-term clinical disease activity-free status and confirmed disability progression in patients treated with subcutaneous interferon beta-1a.

BACKGROUND: Subcutaneous (sc) interferon (IFN) ß-1a reduces relapse rates and delays disability progression in patients with MS. We examined the association of the year 1 Magnetic Resonance Imaging in MS (MAGNIMS) score with long-term clinical disease activity (CDA) -free status and confirmed disability progression in patients treated with sc IFN ß-1a in PRISMS. METHODS: Patients treated with sc IFN ß-1a three-times-weekly (22 or 44 µg; pooled data) were classified by MAGNIMS score (0, n = 129; 1, n = 108; 2, n = 130) at year 1. Hazard ratios (HR; 95% confidence intervals [CI]) for risk of CDA and confirmed Expanded Disability Status Score (EDSS) progression were calculated by MAGNIMS score for up to 15 years of follow-up. RESULTS: The risk of CDA was higher with a year 1 MAGNIMS score of 1 versus 0 (HR 1.82 [1.38-2.41]), 2 versus 0 (2.63 [2.01-3.45]) and 2 versus 1 (1.45 [1.11-1.89], all p < 0.0001). The same outcome was observed with the risk of confirmed EDSS progression (1 versus 0: 1.93 [1.23-3.02]; 2 versus 0: 2.95 [1.95-4.46]; 2 versus 1: 1.53 [1.05-2.23]; all p < 0.0001). CONCLUSION: In PRISMS, MAGNIMS score at Year 1 predicted risk of CDA and confirmed disability progression in sc IFN ß-1a-treated patients over up to 15 years. PRISMS-15 clinicaltrial.gov identifier: NCT01034644.

No evidence of disease activity status in patients treated with early vs. delayed subcutaneous interferon ß-1a.

BACKGROUND: Clinically isolated syndrome (CIS) is defined as a monophasic clinical episode highly suggestive of multiple sclerosis (MS). Regardless, studies have shown that treatment at this early stage of MS can delay a second event and prolong the transition to clinically diagnosed MS. The objective of this post-hoc analysis was to determine the effect of early CIS treatment with once weekly (qw) or three times weekly (tiw) subcutaneous interferon (scIFN) ß-1a vs. delayed treatment (DT) on the composite endpoint of no evidence of disease activity (NEDA)-3. METHODS: In REFLEX, patients with CIS were randomized to double-blind scIFN ß-1a 44 µg tiw, qw, or placebo for 24 months. Upon clinically-definite MS, patients switched to open-label scIFN ß-1a tiw. Patients who completed REFLEX entered an extension (REFLEXION). Patients initially randomized to placebo switched to tiw (DT); scIFN ß-1a patients continued their initial qw/tiw regimen for up to 60-months post-randomization. This post-hoc analysis was conducted in the integrated intent-to-treat REFLEX plus REFLEXION population (tiw, n = =171; qw, n = =175; DT, n = =171). All p values are nominal. CIS was defined using the McDonald 2010 criteria. RESULTS: Patients receiving early treatment (ET) with scIFN ß-1a tiw and qw were more likely to achieve NEDA-3 than DT at year 2 (tiw vs. DT: OR 4.26, 95% CI 2.02-8.98, p = =0.0001; qw vs. DT: OR 2.99, 95% CI 1.39-6.43, p = =0.005). Compared with DT, ET with scIFN ß-1a tiw was more likely to achieve NEDA-3 at year 3 (OR 3.73, 95% CI 1.63-8.55, p = =0.002) and year 5 (OR 12.96, 95% CI 1.66-101.04, p = =0.015). Between ET regimens, the odds of achieving NEDA-3 were not significantly improved by scIFN ß-1a 44 µg tiw at year 2 (OR 1.42, 95% CI 0.81-2.50, p = =0.22) but were at year 3 (OR 2.26, 95% CI 1.11-4.60, p = =0.024) and year 5 (OR 3.22, 95% CI 1.01-10.22, p = =0.048), indicating that the beneficial effects of more frequent scIFN ß-1a dosing become more apparent over time in patients with CIS. In the subgroup of patients with Gd+ lesions at baseline the odds for achieving NEDA-3 were higher for ET up to year 2 compared with DT (tiw: OR 10.21, 95% CI 1.23-84.82, p = =0.03; qw: OR 8.97, 95% CI 1.08-74.28, p = =0.04). In patients without Gd+ lesions at baseline, those receiving ET were more likely to achieve NEDA-3 at year 2 (OR 3.56, 95% CI 1.56-8.10, p = =0.003), year 3 (OR 2.54, 95% CI 1.05-6.18, p = =0.04) and year 5 (OR 9.63, 95% CI 1.19-77.79, p = =0.034) than patients who received DT. CONCLUSIONS: ET with scIFN ß-1a tiw was associated with a higher likelihood of achieving NEDA-3 not only at 2 but also at 3 and 5 years.

Randomized trial of daily high-dose vitamin D3 in patients with RRMS receiving subcutaneous interferon ß-1a.

OBJECTIVE: In the phase II, randomized, double-blind, placebo-controlled Supplementation of Vigantol Oil versus Placebo Add-on in Patients with Relapsing-Remitting Multiple Sclerosis (RRMS) Receiving Rebif Treatment (SOLAR) study (NCT01285401), we assessed the efficacy and safety of add-on vitamin D3 in patients with RRMS. METHODS: Eligible patients with RRMS treated with SC interferon-ß-1a (IFN-ß-1a) 44 µg 3 times weekly and serum 25(OH)D levels <150 nmol/L were included. From February 15, 2011, to May 11, 2015, 229 patients were included and randomized 1:1 to receive SC IFN-ß-1a plus placebo (n = 116) or SC IFN-ß-1a plus oral high-dose vitamin D3 14,007 IU/d (n = 113). The revised primary outcome was the proportion of patients with no evidence of disease activity (NEDA-3) at week 48. RESULTS: At 48 weeks, 36.3% of patients who received high-dose vitamin D3 had NEDA-3, without a statistically significant difference in NEDA-3 status between groups (placebo 35.3%; odds ratio 0.93; 95% confidence interval [CI] 0.53-1.63; p = 0.80). Compared with placebo, the high-dose vitamin D3 group had better MRI outcomes for combined unique active lesions (incidence rate ratio 0.68; 95% CI 0.52-0.89; p = 0.0045) and change from baseline in total volume of T2 lesions (difference in mean ranks: -0.074; p = 0.035). CONCLUSIONS: SOLAR did not establish a benefit for high-dose vitamin D3 as add-on to IFN-ß-1a, based on the primary outcome of NEDA-3, but findings from exploratory outcomes suggest protective effects on development of new MRI lesions in patients with RRMS. CLINICALTRIALSGOV IDENTIFIER: NCT01285401. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that for patients with RRMS treated with SC IFN-ß-1a, 48 weeks of cholecalciferol supplementation did not promote NEDA-3 status.

Adherence to, and effectiveness of, subcutaneous interferon ß-1a administered by RebiSmart® in patients with relapsing multiple sclerosis: results of the 1-year, observational SMART study.

BACKGROUND: Patients with multiple sclerosis who have poor adherence to treatment have a higher risk of relapse than adherent patients. This study assessed adherence to, and effectiveness and convenience of, treatment with subcutaneous (sc) interferon (IFN) ß-1a (Rebif®, Merck Serono SA) 44 or 22 µg three times weekly in patients with relapsing multiple sclerosis (RMS) using the RebiSmart® electronic, multidose, autoinjector for 1 year. STUDY DESIGN: European, multicentre, observational study among neurologists: inclusion criteria included RMS, Expanded Disability Status Scale score ≤ 6, sc IFN ß-1a administered by RebiSmart for ≤ 6 weeks. The primary endpoint was cumulative adherence recorded by RebiSmart. RESULTS: The safety population included 912 patients, 77.4% (n = 823) of whom completed the Month-12 visit. Mean (± standard deviation) cumulative adherence was 97.1 ± 7.3% (n = 791). The most common reason for missed injection was 'forgot to inject' (37.0%). At Month 12/ED, 79.5% of patients were relapse-free. Of 353 patients who rated the convenience of the device, 68.3% found injecting 'very easy'. No unknown safety issues were detected. CONCLUSIONS: Patients with RMS self-injecting sc IFN ß-1a with RebiSmart had excellent adherence at Month 12/ED, which was associated with good clinical outcomes and no unexpected safety issues. Patients rated RebiSmart as convenient and easy to use.

The STAR Study: a real-world, international, observational study of the safety and tolerability of, and adherence to, serum-free subcutaneous interferon ß-1a in patients with relapsing multiple sclerosis.

BACKGROUND: Adverse reactions, particularly injection site reactions (ISRs), are common reasons for nonadherence to injectable multiple sclerosis (MS) treatments. Adherence to MS treatment is important to ensure good treatment outcomes. OBJECTIVE: The aim of this study was to assess the local tolerability of subcutaneous (SC) serum-free interferon (IFN) ß-1a in patients with relapsing MS over 1 year in a real-life, international setting. The study also assessed safety, disease activity, and adherence. METHODS: This was a prospective, international, multicenter, observational study of 251 patients with relapsing-remitting MS treated with SC serum-free IFN ß-1a 44 µg or 22 µg 3 times weekly for 12 months or until early discontinuation. The primary end point was the proportion of patients with ISRs. Secondary end points included proportion of patients with adverse events (AEs); annualized relapse rate (ARR); proportion of patients remaining relapse-free; and adherence to treatment. RESULTS: During the observation period, 27.5% (69 of 251) of patients experienced nonserious ISRs, which was consistent with the incidence reported in clinical studies. Five patients discontinued treatment and 2 patients suspended treatment because of ISRs. Mean age was 35.8 years; patients were predominantly white (94.8%), and two thirds (66.1%) were female. The overall incidence of AEs was 63.7% (160 of 251), and overall safety and tolerability were assessed as excellent, very good, or good in >85% of patients. More than 70% of patients remained relapse-free, and the mean ARR was 0.4. More than 90% of patients had very good or good adherence to treatment; a significantly greater proportion of these were relapse-free at 12 months compared with those with fair or poor adherence (77.6% vs 50.0%; P = 0.0107), and their ARR was significantly lower (0.3 vs 0.9; P = 0.0055). Patients with fair or poor adherence had 4.6 times higher odds of experiencing a relapse than those with very good or good adherence. CONCLUSIONS: The incidence of ISRs and the overall safety profile in this observational study, in an international population in a real-life setting, confirm the good local tolerability of SC serum-free IFN ß-1a reported in clinical studies. The association between good adherence and a lower ARR underlines the importance of good adherence. The good local and general tolerability of SC IFN ß-1a may help ensure a high level of adherence, which is associated with better clinical outcomes. ClinicalTrials.gov identifier: NCT01080027.