Drug Holiday of Interferon Beta 1b in Multiple Sclerosis: A Pilot, Randomized, Single Blind Study of Non-inferiority

Silvia Romano, Michela Ferraldeschi, Francesca Bagnato, Rosella Mechelli, Emanuele Morena, Marzia Caldano, Maria Chiara Buscarinu, Arianna Fornasiero, Marco Frontoni, Viviana Nociti, Massimiliano Mirabella, Flavia Mayer, Antonio Bertolotto, Carlo Pozzilli, Nicola Vanacore, Marco Salvetti, Giovanni Ristori, Silvia Romano, Michela Ferraldeschi, Francesca Bagnato, Rosella Mechelli, Emanuele Morena, Marzia Caldano, Maria Chiara Buscarinu, Arianna Fornasiero, Marco Frontoni, Viviana Nociti, Massimiliano Mirabella, Flavia Mayer, Antonio Bertolotto, Carlo Pozzilli, Nicola Vanacore, Marco Salvetti, Giovanni Ristori

Abstract

Introduction: To compare a schedule with cyclic withdrawal (CW) of interferon beta (IFN-b) 1b, respect to the full regimen (FR), in relapsing-remitting MS (RR-MS). Methods: Participants were randomly assigned to CW or FR schedule and monthly monitored with brain MRI scans for 12 months (three of run-in and 9 of treatment). CW schedule included drug withdrawal for 1 month after two of treatment for a total of three quarters over the 9-month treatment period. The assessing neurologist and the expert neuroradiologists were blind. After the blind phase of the study all participants took their indicated disease modifying therapies in a prospectively planned, open-label extension phase (up to 120 months). Results: Of 60 randomized subjects 56 (29 in FR and 27 in CW group) completed the single-blind phase: the two groups were comparable, except for a non-significant difference in the number of contrast-enhanced lesions (CEL) at the end of run-in. The two-sided 90% CI for the ratio between median number of cumulative CEL was 0.29-1.07, allowing to significantly reject the null hypothesis of a ratio ≥1.2 and to meet the primary end-point of non-inferiority (the threshold and the ratio between median were chosen according to the non-normal distribution of the data). The differences (CW vs. FR) were also non-significant for secondary end points: mean cumulative number of T2-weighted new and enlarging lesions (3.48 ± 5.34 vs. 3.86 ± 6.76); mean number and volume (cm3) of black holes (1.24 ± 1.61 vs. 2.71 ± 4.56; 489.11 ± 1488.12 vs. 204.48 ± 396.98); number of patients with at least an active scan (21 vs. 22); mean relapse rate (0.52 ± 0.89 vs. 0.34 ± 0.66), relapse risk ratio adjusted for baseline variables (2.15 [0.64-7.18]), EDSS score (1.0 [1-1.56] vs. 1.5 [1-1.78]), proportion of patients with antibodies anti-IFN (5 [21%] vs. 8 [36%]). Fifty-four patients (27 for each study arm) completed the open-label phase. The annualized RR, EDSS, proportion of patients shifting to progressive disease and hazard ratio of shifting, adjusting for baseline covariates, were comparable between the two study groups. Conclusions: A calendar with CW was non-inferior than FR at the beginning of IFN-b therapy, and may not affect the long-term outcome. Clinical Trial Registration: www.ClinicalTrials.gov, identifier: NCT00270816.

Keywords: black holes; contrast-enhanced lesions; cyclic withdrawal; interferon beta 1b; non-inferiority; relapsing-remitting multiple sclerosis.

Figures

Figure 1
Figure 1
CONSORT flow diagram.
Figure 2
Figure 2
Two-sided 90%CI for the ratio between median number of cumulative Gd-enhancing lesions at MRI observed in the two regimens. Maximum ratio of 1.2 lesions was set for the one-tailed test with a significance level of 0.05. At month 12 median of the cumulative number of Gd-enhancing lesions at MRI was 1 (0–9) in CW vs. 3 (0–10) in FR patients.

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