Este estudio evaluó la seguridad, tolerabilidad y eficacia de 2 dosis de fingolimod oral,
versus interferón β-1a para reducir la frecuencia de las recaídas en pacientes con
recaída-remisión de esclerosis múltiple.
ANTECEDENTES: Fingolimod (FTY720), un modulador de la esfingosina-1-fosfato-receptor que impide la salida de linfocitos de los ganglios linfáticos, mostró una eficacia clínica y la mejora en la formación de imágenes en un estudio de fase 2 con pacientes con esclerosis múltiple.
MÉTODOS: En este 12-meses, doble ciego, doble simulación, se asignó aleatoriamente a 1.292 pacientes con esclerosis múltiple remitente-recurrente que tenía una historia reciente de al menos una recaída para recibir fingolimod oral en una dosis diaria de cualquiera de 1,25 o 0,5 mg intramuscular o interferón beta-1a (una terapia establecida para la esclerosis múltiple) a una dosis semanal de 30 microg. El criterio principal de valoración fue la tasa anual de recaídas. Criterios de valoración secundarios clave fueron el número de lesiones nuevas o ampliadas en T (2) imágenes por resonancia magnética-ponderada (IRM) a los 12 meses y la progresión de la discapacidad que se mantuvo durante al menos 3 meses.
RESULTADOS: Un total de 1.153 pacientes (89%) completaron el estudio. La tasa anual de recaídas fue significativamente menor en los dos grupos que recibieron fingolimod - 0,20 (95% intervalo de confianza [IC], 0,16-0,26) en el grupo de 1,25 mg y 0,16 (IC del 95%, desde 0,12 hasta 0,21) en el 0,5 mg grupo - que en el grupo de interferón (0,33; IC del 95%, 0,26-0,42; p <0,001 para ambas comparaciones). Hallazgos de la RM apoyaron los resultados primarios. No se observaron diferencias significativas entre los grupos de estudio con respecto a la progresión de la discapacidad. Dos infecciones fatales ocurrieron en el grupo que recibió la dosis de 1,25 mg de fingolimod: diseminada varicela zoster primaria y la encefalitis del herpes simplex. Otros acontecimientos adversos entre los pacientes que recibieron fingolimod fueron las infecciones fatales herpesvirus, bradicardia y bloqueo auriculoventricular, hipertensión, edema macular, cáncer de piel, y los niveles de enzimas hepáticas elevadas.
Conclusiones: Este estudio mostró la eficacia superior de fingolimod oral con respecto a las tasas de recaída y los resultados de resonancia magnética en pacientes con esclerosis múltiple, en comparación con interferón beta-1a intramuscular. Se necesitan estudios más largos para evaluar la seguridad y eficacia del tratamiento más allá de 1 año. (Número ClinicalTrials.gov, NCT00340834).
BACKGROUND: In a 12-month phase 3 study in patients with relapsing-remitting multiple sclerosis (RRMS), TRANSFORMS, fingolimod showed greater efficacy on relapse rates and MRI outcomes compared with interferon beta-1a. We had two aims in our extension: to compare year 2 with year 1 in the switched patients to assess the effect of a change from interferon beta-1a to fingolimod, and to compare over 24 months the treatment groups as originally randomised to assess the effect of delaying the start of treatment with fingolimod.
METHODS: Patients randomly assigned to receive 0.5 mg or 1.25 mg daily oral fingolimod in the core study continued with the same treatment in our extension; patients who originally received 30 μg weekly intramuscular interferon beta-1a were randomly reassigned (1:1) to receive either 0.5 mg or 1.25 mg fingolimod. The initial randomisation and dose of fingolimod assigned for the extension remained masked to the patients and investigators. As in the core study, re-randomisation was done centrally in blocks of six and stratified according to site. Our efficacy endpoints were annualised relapse rate (ARR), disability progression, and MRI outcomes. Our within-group analyses were based on the intention-to-treat and safety populations that entered our extension study. Our between-group analyses were based on the intention-to-treat and safety populations from the core study. This study is registered with ClinicalTrials.gov, number NCT00340834.
FINDINGS: 1027 patients entered our extension and received the study drug, and 882 completed 24 months of treatment. Patients receiving continuous fingolimod showed persistent benefits in ARR (0.5 mg fingolimod [n=356], 0.12 [95% CI 0.08-0.17] in months 0-12 vs 0.11 [0.08-0.16] in months 13-24; 1.25 mg fingolimod [n=330], 0.15 [0.10-0.21] vs 0.11 [0.08-0.16]; however, in patients who initially received interferon beta-1a, ARR was lower after switching to fingolimod compared with the previous 12 months (interferon beta-1a to 0.5 mg fingolimod [n=167], 0.31 [95% CI 0.22-0.43] in months 0-12 vs 0.22 [0.15-0.31], in months 13-24 p=0.049; interferon beta-1a to 1.25 mg fingolimod [n=174], 0.29 [0.20-0.40] vs 0.18 [0.12-0.27], p=0.024). After switching to fingolimod, numbers of new or newly enlarging T2 and gadolinium (Gd)-enhancing T1 lesions were significantly reduced compared with the previous 12 months of interferon beta-1a therapy (p<0.0001 for T2 lesions at both doses; p=0.002 for T1 at 0.5 mg; p=0.011 for T1 at 1.25 mg), and the pattern of adverse events shifted towards that typical for fingolimod. Over 24 months, in continuous fingolimod groups compared with the group that switched from interferon beta-1a to fingolimod, we recorded lower ARRs (0.18 [95% CI 0.14-0.22] for 0.5 mg; 0.20 [0.16-0.25] for 1.25 mg; 0.33 [0.27-0.39] for the switch group; p<0.0001 for both comparisons), fewer new or newly enlarged T2 lesions (p=0.035 for 0.5 mg, p=0.068 for 1.25 mg), and fewer patients with Gd-enhancing T1 lesions (p=0.001 for 0.5 mg fingolimod vs switch group; p=0.002 for 1.25 mg fingolimod vs switch group). There was no benefit on disability progression.
INTERPRETATION: Switching from interferon beta-1a to fingolimod led to enhanced efficacy with no unexpected safety concerns. Compared with patients switched from interferon beta-1a to fingolimod, continuous treatment with fingolimod for 2 years provides a sustained treatment effect with improved clinical and MRI outcomes.
FUNDING: Novartis Pharma AG.
Revista»Abstract meeting of the 5th Joint Triennal Congress of the European and Americas Committees for the treatment and research in Multiple Sclerosis
In the 12-month phase 3 TRANSFORMS study, fingolimod showed greater efficacy than intramuscular interferon beta (IFNβ)-1a in patients with relapsing-remitting multiple sclerosis (RRMS). This study analyzed fingolimod efficacy compared with IFNβ-1a in patient subgroups from TRANSFORMS. Patients were randomized to receive fingolimod or weekly IM IFNβ-1a for 12 months. Analyses of efficacy included annualized relapse rate (ARR), and magnetic resonance imaging (MRI) measures [gadolinium (Gd)-enhancing T1 lesions, new/newly enlarged (active) T2 lesions, brain volume change]. Subgroups were defined based on demographics, disease characteristics (baseline EDSS score, relapse rate, and MRI parameters), and response to previous therapy. Fingolimod 0.5 mg reduced ARR over 12 months by 32-59 % relative to IFNβ-1a in all subgroups defined by demographic factors or baseline disease characteristics. Fingolimod also reduced the number of new Gd-enhancing lesions, active T2 lesions, and the rate of brain volume loss, versus IFNβ-1a in most (95 %) subgroups. In patients with high disease activity despite IFNβ treatment in the year before study, fingolimod 0.5 mg reduced ARR by 61 % relative to IFNβ-1a. Reductions in lesion counts and brain volume loss also favored fingolimod in these patients. In conclusion, consistently better efficacy was observed for fingolimod compared with IFNβ-1a across different subgroups of patients with RRMS.
BACKGROUND: Patients with multiple sclerosis (MS) lose brain volume (BV) faster than healthy individuals.
OBJECTIVE: Our purpose, within the 12-month phase 3 TRANSFORMS study, was to examine the effect of treatment on BV loss in patient subgroups, establish correlations between baseline normalized BV (NBV) and baseline disease parameters, to identify variables predictive of baseline NBV and on-study percentage BV change (PBVC), and to establish correlations between on-study PBVC and on-study efficacy outcomes.
METHODS: Patients received fingolimod 0.5 mg or 1.25 mg, or intramuscular (IM) interferon β-1a (IFNβ-1a) for 12 months. The effect of treatment on PBVC was examined in patient demographic, disease and magnetic resonance imaging (MRI) characteristic subgroups. Pearson's correlation analyses and a stepwise linear regression model were used to identify variables predictive of NBV and PBVC.
RESULTS: Fingolimod reduced BV loss over 12 months versus IFNβ-1a IM in all patient subgroups assessed, including individuals with or without gadolinium (Gd)-enhancing lesions at baseline. Baseline T1 hypointense lesion volume had the strongest correlation with baseline NBV. Baseline Gd-enhancing T1 lesion count was most predictive of change in PBVC over 12 months.
CONCLUSIONS: Our results improve understanding of the contributions of different baseline demographic, clinical and MRI characteristics to NBV, including factors that may be predictive of future BV loss.
Este estudio evaluó la seguridad, tolerabilidad y eficacia de 2 dosis de fingolimod oral, versus interferón β-1a para reducir la frecuencia de las recaídas en pacientes con recaída-remisión de esclerosis múltiple.
Diseño del estudio»Ensayo controlado aleatorizado (ECA)
País»Argentina,Australia,Austria,Belgium,Brazil,Canada,Egypt,France,Germany,Greece,Hungary,Italy,Korea, Republic of,Portugal,Spain,Switzerland,United Kingdom,United States
