Comparative injection-site pain and tolerability of subcutaneous serum-free formulation of interferonβ-1a versus subcutaneous interferonβ-1b: results of the randomized, multicenter, Phase IIIb REFORMS study

Barry Singer 0 Daniel Bandari 2 Mark Cascione 1 Christopher LaGanke 5 John Huddlestone 4 Randy Bennett 3 Fernando Dangond 3 on behalf of the REFORMS Study Group 0 Missouri Baptist Medical Center , St. Louis, MO , USA 1 Tampa Neurology Associates , South Tampa MS Center, Tampa, FL , USA 2 Multiple Sclerosis Center of Southern California and Research Group , Newport Beach, CA , USA 3 EMD Serono, Inc., One Technology Place , Rockland, MA , USA 4 MultiCare Neuroscience Center of Washington , Tacoma, WA , USA 5 North Central Neurology Associates , Cullman, AL , USA Background: In patients with relapsing-remitting multiple sclerosis (RRMS), subcutaneous (sc) interferon (IFN)-1a and IFN-1b have been shown to reduce relapse rates. A formulation of IFN-1a has been produced without fetal bovine serum and without human serum albumin as an excipient (not currently approved for use in the US). The objectives of this study were to evaluate tolerability, injection-site redness, subject-reported satisfaction with therapy, and clinical safety and efficacy of the serum-free formulation of IFN-1a versus IFN-1b in IFN-treatment-nave patients with RRMS. The objectives of the extension phase were to evaluate long-term safety and tolerability of IFN-1a. Methods: This randomized, parallel-group, open-label study was conducted at 27 clinical sites in the US. Eligible patients aged 18-60 years were randomized to receive either IFN-1a, titrated to 44 g sc three times weekly (tiw) (n = 65), or IFN-1b, titrated to 250 g sc every other day (n = 64) over 12 weeks. Following this, all patients received IFN-1a 44 g tiw for 82-112 weeks. Primary endpoint was mean change in patient-reported pain, as assessed by visual analog scale (VAS) diary pain score (from 0 mm [no pain] to 100 mm [worst possible pain]) at the injection site, from pre-injection to 30 min post-injection over the first 21 full-dose injections. Secondary assessments included proportion of patients pain-free as recorded by VAS diary and the Short-Form McGill Pain questionnaire VAS. Results: A total of 129 patients were included in the intent-to-treat analysis. Mean (standard deviation) change in VAS diary pain score was not significantly different between groups, although numerically lower with IFN-1a versus IFN-1b from pre-injection to immediately post-injection (1.46 [2.93] vs. 4.63 [10.57] mm), 10 min post-injection (0.70 [1.89] vs. 1.89 [5.75] mm), and 30 min post-injection (0.67 [2.32] vs. 1.14 [4.94] mm). Proportion of patients pain-free at all time periods post-injection was also not significantly different between groups. Adverse events were consistent with the known safety profiles of these treatments. Conclusions: In IFN-treatment-nave patients with RRMS, both the serum-free formulation of IFN-1a and IFN-1b treatments were generally accompanied by low-level injection-site pain and were well tolerated. (Continued on next page) - (Continued from previous page) Trial registration: ClinicalTrials.gov NCT00428584 Background Clinical studies of subcutaneous (sc) interferon (IFN)-1a and IFN-1b have shown that these disease-modifying drugs reduce relapse rates in patients with relapsing remitting multiple sclerosis (RRMS) [1-4]. At the doses approved for the treatment of RRMS, both IFN-1a and IFN-1b have established long-term safety and tolerability profiles [5,6]. However, injections with these drugs are commonly associated with injection-site reactions (ISRs), injection-site pain, and flu-like symptoms (FLS), which can lead to poor adherence to treatment in some patients [7,8]. A formulation of IFN-1a has been developed without fetal bovine serum and without human serum albumin as an excipient, although this formulation is not currently approved for use within the US. In a 96-week study in patients with relapsing MS, the serum-free formulation of IFN-1a was associated with a lower prevalence of ISRs than had been seen in two earlier studies with the original IFN-1a formulation [9-11]. No randomized clinical study has yet compared the injection-site pain and tolerability profile of the serum-free formulation IFN-1a with that of another disease-modifying drug. The primary objective of this study was to compare the tolerability of the serum-free formulation of IFN1a, 44 g sc three times weekly (tiw), with IFN-1b, 250 g sc every other day (qod), as measured by the mean change in subject-reported injection-site pain from pre-injection to 30 min post-injection in IFNtreatment-nave patients with RRMS during a 12-week period (comparative phase). During the extension phase, the primary objective was to evaluate long-term safety and tolerability of IFN-1a sc tiw. Secondary efficacy endpoints included: the mean difference in injection-site pain from pre-injection to immediately post-injection and to 10 min post-injection, the proportion of pain-free patients, number and severity of relapses, assessments of the treatment of side effects, patient-rated treatment satisfaction, and rater-blinded assessment of injection-site redness. Safety endpoints included analysis of adverse events (AEs), laboratory tests, physical examinations, vital signs, and concomitant medications. NCT00428584) was a randomized, multicenter, 2-arm, Phase IIIb study conducted at 27 clinical sites in the US. The study consisted of a 12-week randomized comparative phase, which was followed by a safety-extension phase of up to 112 weeks (range 82112 weeks). The study was open-label, except for blinded assessments of ISRs. The initial central Institutional Review Board (IRB) submission was approved by Coast IRB, Colorado Springs, Colorado and, later, Schulman Associates IRB, Cincinnati, Ohio. For those sites that were not permitted to use a central IRB for study approval, submissions were made to the local IRB. This study was performed in accordance with the study protocol, the Declaration of Helsinki, the International Conference on Harmonization (ICH) Harmonized Tripartite Guideline for Good Clinical Practice (GCP), and all applicable regulatory requirements. Patients provided written informed consent for participation in the study. Eligible patients were 1860 years of age, had a primary diagnosis of RRMS as defined by the Poser or 2005 revised McDonald criteria [12,13], and had not previously received IFN treatment. Patients were not eligible if they had used any other approved disease-modifying treatment for MS (e.g. glatiramer acetate) or any cytokine or anti-cytokine treatment within 3 months before study initiation, used any immunomodulatory or immunosuppressive treatment within 12 months before study initiation, used any investigational drug or experimental procedure within 12 weeks before screening, received oral or systemic corticosteroids or adrenocorticotropic hormone within 30 days of study initiation, or used other injectable medications on a regular basis during the week before screening. Other exclusion criteria included having an alternative diagnosis (...truncated)