Dipartimento di Neuroscienze, Farmaco e Salute Bambino Neurologia II Centro Riferimento Regionale Sclerosi Multipla National Institute of Neurological Disorders and Stroke Non – inferiorità di Azatioprina verso interferone beta nella Sclerosi Multipla: ricadute cliniche ed economiche per il servizio sanitario regionale Luca Massacesi Firenze, SIN Toscana 28 Novembre 2014 outline • Risultati del 1° RCT italiano in campo neurologico finanziato da fondi per la ricerca indipendente dell’AIFA • Comune percezione di efficacia e sicurezza azatioprina nella SM • Comparazione profili sicurezza • Costi Studio finanziato da AIFA tra 2007 e 2012 (bando 2006) 17 Novembre 2014 Valore aggiunto di ricerca indipendente • Valutazioni per nuove indicazioni di farmaci generici non sviluppati dai privati perché non più coperti da brevetto (di regola post-marketing) • Confronto tra farmaci (cosa non richiesta da normativa europea per nuove approvazioni) – – – – – Efficacia Sicurezza Tollerabilità Maneggevolezza Costi Azathioprine • generic medication (patent expired early in the ’90s) developed in the ’50s (Nobel Prize granted to the authors ) • allowed first successful human organ transplantations; •still used in kidney transplantation and in autoimmune diseases •inhibit cell prolipheration including T cell proliph.; • selective immunesuppressive activity recently discovered (AICD through B7 pathway suppression) Multicentric Aza vs IFN Non-inferiority (M.A.I.N.) TRIAL • Study design: – Non-inferiority – Randomized – Single blinded – pragmatic (drugs were prescribed) efficacia Effect of AZA and of IFNs on annualized Relapse Rate over 2 years 0,7 0,6 0,5 annualized relapse rate 0,4 0,3 AZA 0,2 IFN 0,1 6E-16 I° year -0,1 II° year I°+II° year Non-inferiority of efficacy on relapse rate ratio % pazienti con ricadute in 2 anni 100 90 80 70 60 50 40 30 20 10 0 aza 1 IFN 1 aza 2 IFN 2 0 ricadute > 0 ricadute aza 1+2 IFN 1+2 ODDS RATIOS OF BEING RELAPSE FREE AT 2 Y. 2,5 2 1,5 Odds Ratio 1 0,5 0 Cop1 IFNB1a im IFNB1b IFNB1a sc AZA(4) Proportion of relapse free patients Cochrane metanalisis of studies on Aza effect vs placebo in MS (Casetta et al., JNNP 2009) New T2 lesions (FLAIR) volume/2Y (AZA n=50; IFNs n=47) 600 500 400 mm3 300 200 100 0 AZA IFN Trattamento Differenza EDSS in due anni Disability 0,6 0,5 0,4 0,3 0,2 0,1 0 -0,1 -0,2 aza IFN ODDS RATIOS OF BEING RELAPSE FREE AT 2 Y. 2,5 2 1,5 Odds Ratio 1 0,5 0 Cop1 IFNB1a im IFNB1b IFNB1a sc AZA(4) Lesion and lymphocyte number time course Lymphocyte number x 10 3 Gd+ lesion volume (mm ) 3 22 ********* 20 18 16 14 12 600 500 400 300 200 100 0 0 1 2 3 basel i ne 4 5 6 1 2 3 4 i nducti on 5 6 7 8 9 10 11 12 treatment MONTHS • • • • • Metodological pitfalls of the AZA vs placebo RCTs Underpowered for the Iary end-point selected (disability); Relapse Rate (base of more recent trials success) IIary end-point ; Population included unfit for evaluating Relapse Rate (no selection of disease form); AZA underdosed Absence of brain MRI evaluation support. compliance Averse events related to Azathioprine therapy • Previously reported – Bone marrow suppression: • WBC • Lymphocytes • RBC – – – – – Gastrointestinal problems Abnomal liver function tests General malaise Hair loss Flou like syndrome: • Arthralgia/myalgia/fever – Infection susceptibility – Skin rash – Intolerance • Thiopurin methiltranferase deficiency – Neoplasm risk • Observed in our experience (n= 135; FU: 7 aa): – Abnomal liver function tests (reversible; 20%) – Bone marrow suppression (100%): • WBC • Lymphocytes • RBC – Gastrointestinal disturbances (10) – Skin rash (sun exposure; 2) – Intolerance (2) – Infections (1) eventi avversi Titolo asse linfopenia grado 2 nausea IFN aza flou like syndrome pazienti con… 0 10 20 30 40 % pazienti 50 60 70 sicurezza Frequenza neoplasie maligne in IBD trattati con Aza o con altro (f.u.: 13.5 aa; Fraser et al., 2002) 100% 80% 60% 1556 no 6 22 neo plasi e Aza altro 621 40% 20% 0% N e opl a s i e pa z i e nt i ( n= SM 1 1 9 1 ; ma l i g n e di Li one ne l l a da l C onf a v r e ux c oor t e 1 9 5 7 e t a l a l di 1 9 9 1 1 9 9 6 ) 100% 90% 80% 70% 60% 50% 263 905 40% 30% no* 20% c anc r o 10% 0% 14 10 Az a no t r a t t a me nt o Neoplasie maligne in pazienti con LES trattati con Azatioprina per almeno 6 mesi (n= 148) o con altre terapie (n= 210) tra il 1978 ed il 2002 (Nero et al., 2004) 100% 80% 60% 140 no 196 neoplasie 40% 20% 0% 8 14 Aza altro outcome Frequenza trattamenti con Aza fra pazienti SM che hanno sviluppato neoplasie maligne e controlli SM appaiati (Confavreux, 1996) 100% 90% 80% 9 35 70% 60% 2 50% altro 40% Aza < 1 mese Aza 30% 12 34 neoplasie no neopl. 20% 10% 0% Sopravvivenza al 2002 di pazienti SM trattati con Aza (2.5 mg/kg/die; n= 149) o placebo (n= 151) per tre anni dal 1983-4 (Taylor et al., 2004) 100% 90% 80% 70% 60% 115 111 137 50% 154 40% 30% no neopl. 20% 10% 34 40 neopl. mal. 0% Aza altro 12 7 Aza altro viventi trattamento deceduti Costi annuali SM Complessivi • ͠ 23.000 €/ anno/paziente EDSS < 5 • Prev. 100/100.000: 23.000 x 60.000= 1.380.000.000 Farmaci per forme RR • 300 M, Ia linea – Circa 9.500/paz./ anno • Interferoni beta • Copaxone • 140 M: IIa linea • ͠ 58.000 €/ anno paziente EDSS > 5 • Prev. 70/ 100.000: 58.000 x 40.000= 2.320.000.000 – circa 20500/paz./ anno • fingolimod • natalizumab • azatioprina 600/anno/ paziente Tot. Italia : 3.700.000.000/ anno Number needed to treat to have 1 patient relapse free for 2 y 14 12 10 8 NNT 6 4 2 0 Euros needed to pay in order to have 1 patient relapse free for 2 y. 500 400 300 Keuro 200 100 Cop1 IFNB1a IFNB1b IFNB1a sc AZA 0 Cop1 IFNB1a 476 258 IFNB1b IFNB1a sc 233 291 AZA 9 Grazie! [email protected] Indicazione ex 648: malattie autommuni a carattere neurologico ex lege 648 Ex lege 648, lista uso consolidato • Consenso scritto • Registro • Report AIFA periodico • Consenso scritto • registro Activity on brain Gd+ lesions number of new treatments and AZA mean Gd+ lesion number 3,5 3 2,5 58% (10) 84% (14) COP1 IFNB1b 58% (33) 49% (35) 63% (8) 64% (14) 2 1,5 1 0,5 0 IFNB1a 22x3 sc pretreatment pretreat. (new les.) IFNB1a 11x3 sc IFNB1a im AZA treatment treatment (new les.) MAIN trial •End point • Primary – Non-inferiority of the Aza efficacy on Relapse Rate vs IFNs • Secondary – New brain lesion number – EDSS • Intervention – Aza 3 mg/kg/day (target dose) – IFN: Avonex 38%; Betaferon 6%; Rebif22 45%; Rebif44 11% Follow up • 30 italian centers • Centralized randomization • 2 years FU • Clinical evaluation: – every 3 months and at relapses – treating and blinded evaluating neurologist • MRI – 25 centers – baseline, month 12 , month 24 Power and sample size q k n 2 sd • q= ∫0.8 = 0.84 • k= ∫α0.05 = -1.64 2 • Sample size is direct function of variability (sd), of predefined significance α (k) and of power (q), whereas is inverse function of Method: non- inferiority • Treatment S is noninferior when lower CI (one tail) of its effect vs control treatment T , falls within a predefined margin μ named “noninferiority margin” • M value: – arbitrary – clinically meaning ful – predefined Non -inferiority: established metodology Availability of data related to a number od RCT against placebo, consitent among them, allowing to reliably establish μ value M estimate Dati da RCT storici 8 7 numero eventi 6 5 4 3 2 1 0 Placebo Farmaco T effetto T-P IFN efficacy vs. placebo in reference studies TRIAL treatment Betaferon (ΒIFN 1b, 1993) n relapse n./2y PRISMS (ΒIFN 1a 44, 1997) PRISMS (ΒIFN 1 a 22, 1997) n n relapse n./2y relapse n./2y Β IFN 122 1.68 187 1.73 189 1,82 1.74 Placebo 155 2.54 184 2.56 184 2,56 2,55 delta 0,86 0,83 0,74 0.81 ratio 1,51 1,48 1,40 1,46 ARR IFN/Placebo= 1.46 Statistics Non-inferiority • AZA will be considered non-inferior to IFNs if the • 1.46, relapse rate ratio detected 95% C.I (one tail) of the in 2 pivotal historical trials ratio between relapse rates (PRISMS; Betaferon) between in the AZA group and in the the Placebo and the IFNbeta IFN group will be < 1.23 groups • non inferiority margin M established a priori as 50% of the excess to 1.0 (= 1.23) Eligibility Criteria Inclusion criteria Exclusion criteria • • • • • relapse or steroides in the 30 days previous to recruitment • AZA or other DMT in the previous 6 months • Pregnancy/ breastfeeding • Cognitive decline preventing informed consent RR MS 18-55 Y < 10 y disease duration EDSS betweeen 1-5.5 • > 2 relapses in the last 2 y Baseline characteristics of the population included Relapse rate Time to first relapse New T2 lesions (FLAIR)/2Y (AZA n=50; IFNs n=47) 2,2 2 1,8 1,6 1,4 Lesion 1,2 number 1 0,8 0,6 0,4 0,2 0 Aza IFN Non-inferiority of efficacy on new T2 lesion rate ratio Gd+ lesion number at baseline and at month 24 (ITT analysis; Aza n= 50, IFN n= 47) 3,8 3,6 3,4 3,2 3 2,8 2,6 2,4 p< 0.0005 p<0.0002 2,2 2 lesion number 1,8 1,6 1,4 -83% 1,2 1 -88% 0,8 0,6 0,4 0,2 0 Aza IFN Treatment baseline month24 • The mean number of relapses during one year the AZA group than in the IFNβ products group (0.28 vs 0.64, P<0.05). • 20 relapses (42.6 %) in the IFNβ products group and 11 (23.4 %) in the AZA group. • 63/ 94 patients (67 %) remained relapse-free during one year of follow-up; 27 (57.4 %) in the IFNβ products group and 36 (76.6 %) in the AZA group (P<0.05). Odds ratio 2.42 (95 % CI, 1.0, 5.9; P=0.048), indicating a relative increase of 142 % in the odds of remaining relapse free during the first year of therapy for patients receiving AZA compared with those receiving IFNβ products. Conclusions • Aza effect on Relapse Rate is at least as intensive as that of IFNs • Aza effect on Relapse Rate and Disability raise the hypothesis of supertiority vs IFNs • Aza effect in suppressing brain new lesions is similar to that of IFNs • Short term safety profile is different from IFNs but overall well tolerated Trials on Aza efficacy in MS carried out in the ’80s
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