Durability of no evidence of disease activity-3 (NEDA-3) in patients receiving cladribine tablets: The CLARITY extension study.

BACKGROUND: No evidence of disease activity (NEDA-3) is a patient-centric outcome increasingly used as the goal of multiple sclerosis treatment. OBJECTIVE: Determine treatment durability of cladribine tablets beyond 2 years considering the variable bridging interval of 0.1-116.0 weeks between CLARITY and CLARITY Extension. METHODS: Between CLARITY and CLARITY Extension, patients transitioned from cladribine tablets 3.5 mg/kg to placebo (CP3.5 group, n = 98) or continued further treatment with cladribine tablets 3.5 mg/kg (CC7.0 group, n = 186). Treatment assignment was randomized and blinded in both CLARITY and CLARITY Extension. RESULTS: The 2-year NEDA-3 in CLARITY Extension (encompassing both years of CLARITY Extension) was 29.6% in the CP3.5 group and 32.8% in the CC7.0 group. There was no evidence that treatment effect differed with varying bridging intervals. For patients in the CP3.5 group with a bridging interval of ⩽48 weeks, 1 year NEDA-3 (the first year of CLARITY Extension) was 44.4% (28/63) compared with 31.4% (11/35) in patients with a bridging interval of >48 weeks. CONCLUSION: Treatment with cladribine tablets in CLARITY, followed by either placebo or cladribine tablets in CLARITY Extension, produced sustained benefits for NEDA-3 and its constituent elements for a follow up period up to 6 years from CLARITY baseline.

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.

Factors influencing long-term outcomes in relapsing-remitting multiple sclerosis: PRISMS-15.

AIM: An exploratory study of the relationship between cumulative exposure to subcutaneous (sc) interferon (IFN) ß-1a treatment and other possible prognostic factors with long-term clinical outcomes in relapsing-remitting multiple sclerosis (RRMS). METHODS: Patients in the original PRISMS study were invited to a single follow-up visit 15 years after initial randomisation (PRISMS-15). Outcomes over 15 years were compared in the lowest and highest quartile of the cumulative sc IFN ß-1a dose groups, and according to total time receiving sc IFN ß-1a as a continuous variable per 5 years of treatment. Potential prognostic factors for outcomes were analysed. RESULTS: Of 560 patients randomised in PRISMS, 291 returned for PRISMS-15 and 290 (51.8%) were analysed. Higher cumulative dose exposure and longer treatment time appeared to be associated with better outcomes on: annualised relapse rate, number of relapses, time to Expanded Disability Status Scale (EDSS) progression, change in EDSS, proportions of patients with EDSS ≥ 4 or ≥ 6, ≤ 5 relapses and EDSS <4 or <6, and time to conversion to secondary-progressive MS (SPMS). Higher dose exposure was associated with lower proportions of patients with EDSS progression and conversion to SPMS, and longer time on treatment with lower risk of first relapse. Change in EDSS from baseline to 24 months was a strong predictor of evaluated clinical outcomes over 15 years. CONCLUSIONS: These findings suggest that higher cumulative exposure to sc IFN ß-1a may be associated with better clinical outcomes, and early change in EDSS score may have prognostic value, over many years, in RRMS.

Rapid benefits of a new formulation of subcutaneous interferon beta-1a in relapsing-remitting multiple sclerosis.

This study evaluated the efficacy of a new formulation of subcutaneous (sc) interferon (IFN)-beta1a in relapsing-remitting multiple sclerosis (RRMS). Patients (n = 180) were randomized (2 : 1) to IFN-beta1a or placebo for 16 weeks; all patients then received IFN-beta1a for 24 weeks. Monthly brain MRI was performed. At week 16, the mean number of combined unique active (CUA) lesions was lower with IFN-beta1a than with placebo (p < 0.001; 69% fewer lesions). The mean cumulative number of CUA lesions was already lower with IFN-beta1a by week 4 (post hoc analysis; p = 0.015). The new formulation of sc IFN-beta1a has rapid beneficial effects on MRI outcomes in RRMS.

Efficacy and safety of subcutaneous interferon ß-1a in relapsing-remitting multiple sclerosis: further outcomes from the IMPROVE study.

BACKGROUND: The IMPROVE study demonstrated that the fetal bovine serum (FBS)- and human serum albumin (HSA)-free formulation of subcutaneous (sc) interferon (IFN) beta-1a had beneficial effects on the numbers of combined unique active magnetic resonance imaging (MRI) lesions in relapsing-remitting multiple sclerosis (RRMS). Here we report additional MRI endpoints (including post hoc analyses), and clinical efficacy, safety, and immunogenicity outcomes. METHODS: Patients with active RRMS were randomized (2:1) to IFN beta-1a, 44 mcg sc three times weekly (tiw) (n=120), or placebo (n=60), for 16 weeks (double-blind phase). All patients then received IFN beta-1a, 44 mcg sc tiw, for 24 weeks (rater-blind phase). Patients underwent MRI brain scans every 4 weeks. RESULTS: Compared with placebo, there was a 68% reduction in the mean cumulative number of new gadolinium-enhancing lesions with IFN beta-1a as early as week 4 (p<0.001), and a 53% reduction in the mean cumulative number of new T2 lesions as early as week 8 (p=0.025; post hoc analyses). During the 16-week double-blind phase, the relapse rate was 0.14 (95% confidence interval [CI] 0.09-0.23) with IFN beta-1a and 0.33 (95% CI 0.22-0.52) with placebo (p=0.010). Safety outcomes were consistent with those expected with IFN-beta treatment. CONCLUSIONS: The FBS/HSA-free formulation of sc IFN beta-1a has a beneficial impact on MRI and efficacy outcomes as early as 4 weeks after treatment initiation in patients with RRMS and has a safety profile consistent with previous trials of sc IFN beta-1a.