Azathioprine versus beta interferons for relapsing-remitting multiple sclerosis: a multicentre randomized non-inferiority trial

Abstract

For almost three decades in many countries azathioprine has been used to treat relapsing-remitting multiple sclerosis. However its efficacy was usually considered marginal and following approval of β interferons for this indication it was no longer recommended as first line treatment, even if presently no conclusive direct β interferon-azathioprine comparison exists. To compare azathioprine efficacy versus the currently available β interferons in relapsing-remitting multiple sclerosis, a multicenter, randomized, controlled, single-blinded, non-inferiority trial was conducted in 30 Italian multiple sclerosis centers. Eligible patients (relapsing-remitting course; ≥ 2 relapses in the last 2 years) were randomly assigned to azathioprine or β interferons. The primary outcome was annualized relapse rate ratio (RR) over 2 years. Key secondary outcome was number of new brain MRI lesions. Patients (n = 150) were randomized in 2 groups (77 azathioprine, 73 β interferons). At 2 years, clinical evaluation was completed in 127 patients (62 azathioprine, 65 β interferons). Annualized relapse rate was 0.26 (95% Confidence Interval, CI, 0.19-0.37) in the azathioprine and 0.39 (95% CI 0.30-0.51) in the interferon group. Non-inferiority analysis showed that azathioprine was at least as effective as β interferons (relapse RRAZA/IFN 0.67, one-sided 95% CI 0.96; p<0.01). MRI outcomes were analyzed in 97 patients (50 azathioprine and 47 β interferons). Annualized new T2 lesion rate was 0.76 (95% CI 0.61-0.95) in the azathioprine and 0.69 (95% CI 0.54-0.88) in the interferon group. Treatment discontinuations due to adverse events were higher (20.3% vs. 7.8%, p = 0.03) in the azathioprine than in the interferon group, and concentrated within the first months of treatment, whereas in the interferon group discontinuations occurred mainly during the second year. The results of this study indicate that efficacy of azathioprine is not inferior to that of β interferons for patients with relapsing-remitting multiple sclerosis. Considering also the convenience of the oral administration, and the low cost for health service providers, azathioprine may represent an alternative to interferon treatment, while the different side effect profiles of both medications have to be taken into account.

Trial registration: EudraCT 2006-004937-13.

Figure 1. Flow-chart: patient allocation and follow-up.

Abbreviations: AZA, azathioprine; IFN, interferon; ITT, intention to treat; PP, per-protocol. ¹One missing CRF at month 12.

Figure 2. Primary clinical outcome over 2 years: non-inferiority of effect of AZA vs. IFN, represented as annualized relapse rate ratio (RR_AZA/IFN) compared with the pre-established non-inferiority margin M ( = 1.23) and with a margin M₁ = 1.0.

One-sided 99% CI of the 0.67 ratio (upper-limit, U_L = 1.12), represents an effect of AZA vs. IFNs equivalent to at least 75% of the effect of IFNs vs. Placebo. One-sided 95% CI of the same ratio (U_L = 0.96), represents an effect of AZA vs. IFNs equivalent to at least 100% of the effect of IFNs vs. Placebo. Abbreviations: AZA, azathioprine; IFN, interferon; PY, person-years; RR, rate ratio.

Figure 3. Time to first relapse.

Beneath the plot patients at risk and number of events (in brackets) by treatment were reported for each interval of 6 months. Abbreviations: AZA, azathioprine; IFN, interferon.

Figure 4. Non-inferiority of the effect AZA vs. IFN on new T2 lesions over 2 years.

One-sided 99% CI (upper-limit, U_L = 1.63), and one-sided 95% CI (U_L = 1.45), of the effect of AZA vs. IFNs as for annualized new T2 lesion rate ratio (RR_AZA/IFN), compared with the pre-established non-inferiority margin (M = 1.84), representing an effect of AZA vs. IFNs equivalent to the 73% of the effect of IFNs vs placebo. Abbreviations: AZA, azathioprine; IFN, interferon; PY, person-years; RR, rate ratio.