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


BACKGROUND
EudraCT 2006-004937-13.
Dipartimento di Neuroscienze, Psicologia, Farmaco e Salute del Bambino Università di Firenze, Firenze, Italy; Neurologia 2, Azienda Ospedaliero-Universitaria Careggi, Firenze, Italy.
Luca
L
Massacesi
Fondazione IRCCS Istituto Neurologico Carlo Besta, Milano, Italy.
Irene
I
Tramacere
Dipartimento di Neuroscienze, Sezione di Farmacologia, Università Politecnica delle Marche, Ancona, Italy.
Salvatore
S
Amoroso
Associazione Italiana Sclerosi Multipla (AISM), Fondazione Italiana Sclerosi Multipla (FISM), Genova, Italy.
Mario A
MA
Battaglia
Dipartimento Universitario di Neurologia, Azienda Ospedaliera Universitaria Integrata di Verona, Verona, Italy.
Maria Donata
MD
Benedetti
Fondazione IRCCS Istituto Neurologico Carlo Besta, Milano, Italy.
Graziella
G
Filippini
Unità di Neurologia - Multiple Sclerosis Center, I.R.C.C.S. Santa Maria Nascente Fondazione Don Gnocchi, Milano, Italy.
Loredana
L
La Mantia
Neurologia 2, Azienda Ospedaliero-Universitaria Careggi, Firenze, Italy.
Anna
A
Repice
Fondazione IRCCS Istituto Neurologico Carlo Besta, Milano, Italy.
Alessandra
A
Solari
Clinica Neurologica, Università di Napoli, Napoli, Italy.
Gioacchino
G
Tedeschi
Fondazione IRCCS Istituto Neurologico Carlo Besta, Milano, Italy.
Clara
C
Milanese
D000328:Adult; D001379:Azathioprine / Q000627:therapeutic use*; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007155:Immunologic Factors / Q000627:therapeutic use; D007166:Immunosuppressive Agents / Q000627:therapeutic use; D016899:Interferon-beta / Q000627:therapeutic use*; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D020529:Multiple Sclerosis, Relapsing-Remitting / Q000188:drug therapy* / Q000473:pathology; D011379:Prognosis; D012008:Recurrence; D016037:Single-Blind Method; D055815:Young Adult
D007155:Immunologic Factors; D007166:Immunosuppressive Agents; D016899:Interferon-beta; D001379:Azathioprine