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

Abstract

Background: In patients with relapsing-remitting multiple sclerosis (RRMS), subcutaneous (sc) interferon (IFN)β-1a and IFNβ-1b have been shown to reduce relapse rates. A formulation of IFNβ-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 IFNβ-1a versus IFNβ-1b in IFNβ-treatment-naïve patients with RRMS. The objectives of the extension phase were to evaluate long-term safety and tolerability of IFNβ-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 IFNβ-1a, titrated to 44 μg sc three times weekly (tiw) (n = 65), or IFNβ-1b, titrated to 250 μg sc every other day (n = 64) over 12 weeks. Following this, all patients received IFNβ-1a 44 μg 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 IFNβ-1a versus IFNβ-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 IFNβ-treatment-naïve patients with RRMS, both the serum-free formulation of IFNβ-1a and IFNβ-1b treatments were generally accompanied by low-level injection-site pain and were well tolerated.

Trial registration: ClinicalTrials.gov NCT00428584.

Figures

Figure 1

Titration schedules for subcutaneous IFNβ-1a and IFNβ-1b. The first 21 injections of full-dose IFNβ-1a and IFNβ-1b treatment were termed the “full-dose period”. IFN, interferon; qod, every other day; tiw, three times weekly.

Figure 2

Patient enrollment and disposition. IFN, interferon; ITT, intent-to-treat; qod, every other day; sc, subcutaneous; tiw, three times weekly.

Figure 3

Mean change in VAS diary pain score during full-dose treatment in the comparative phase (intent-to-treat population). The VAS ranged from 0 mm (no pain) to 100 mm (worst possible pain). The mean change was calculated from the mean of 21 full-dose injections for each patient. IFN, interferon; SD, standard deviation; VAS, visual analog scale.

Figure 4

Patients who reported as pain-free on the VAS diary in the comparative phase (intent-to-treat population). Pain-free was defined as a VAS diary pain score of 0 mm (on a scale from 0 [no pain] to 100 mm [worst possible pain]) for all 21 full-dose injections. IFN, interferon; VAS, visual analog scale.