Study to evaluate whether there is sustained remission and productivity in subjects with early rheumatoid arthritis started on etanercept plus methotrexate treatment.
Background During Phase 1 of the 52 wk open-label PRIZE study treatment of patients (pts) with early (mean 6 mos.) moderate-severe rheumatoid arthritis (RA), who were methotrexate (MTX)/biologic naïve, with 50 mg etanercept (ETN) + 10-25 mg MTX yielded a 70% remission rate with no significant radiographic progression.1 Pts achieving remission in Phase I were randomized to a double-blind 39-wk period of reduced (25mg) ETN + MTX or withdrawn (MTX alone or placebo, PBO) therapy (PRIZE Phase 2). Objectives To assess sustained remission (DAS28 and ACR/EULAR Boolean [AEB]), other clinical, radiographic, and safety outcomes in pts subsequently treated with reduced dose ETN or PBO after remission induction during PRIZE Phase 1. Methods Pts achieving DAS28 remission by wk 52 (≤3.2 at wk 39, <2.6 at wk 52) in Phase 1 (n=193) were randomized 1:1:1 to ETN25/MTX: MTX + PBO injection: PBO capsules + PBO injection at wk 52. Pts with DAS28>3.2 (> low disease activity, LDA) received corticosteroid boosts at wks 56 or 64; pts not achieving LDA at the next visit withdrew. Remission and other standard clinical outcomes were assessed. Odds ratios and significance were determined by logistic regression models. Results ETN/MTX resulted in a significantly higher proportion of pts in sustained and AEB remission than MTX alone or PBO. More ETN/MTX treated pts achieved DAS28 LDA than PBO. Over Phase 2 radiographic progression (mTSS >0.5) occurred in <12% of pts, with no significant difference between treatment arms; at Phase 1 baseline the mTSS scores were 8.06, 8.46 and 7.59 for ETN25/MTX, MTX and PBO, with changes of 0.44, -0.5 and 1.41 by last observations in Phase 2 (LOCF), indicating no clinically relevant radiographic progression in any of these treatment groups ETN/MTX treatment resulted in more pts achieving ACR50 and 70 than PBO. There were no unexpected safety findings Conclusions of the moderate-severe early RA pts achieving DAS28 remission during a 52 wk induction (50 mg ETN/MTX in PRIZE Phase 1), 63.5% maintained remission (DAS28<2.6 at wk 76 & 91 visits) with ETN25/MTX, 38.5% with MTX and 23% with PBO over 39 subsequent wks. There was no significant radiographic progression in any treatment group. There were no unexpected safety findings. (Table Presented).
Background Open-label etanercept (ETN) + methotrexate (MTX) therapy in early rheumatoid arthritis (RA) yielded high clinical remission and improvements in patient-reported outcomes (PROs) in PRIZE Phase 1 (moderate-severe RA ≤1yr; MTX and biologic naïve pts).1 PRIZE (121-wks, 3-phases) evaluates ETN/MTX efficacy/efficacy maintenance and PROs with reduced/withdrawn therapy in Phase 2. Objectives To assess PROs in PRIZE Phase 2, a 39-wk, 3-arm, double-blind comparison of therapy reduction after a 52 wk induction of 50 mg QW ETN/MTX (Phase 1). Methods Pts achieving DAS28 remission (≤3.2 at wk 39, <2.6 at wk 52) in Phase 1 (n=193) were randomized 1:1:1 for 25 mg ETN + MTX: MTX+PBO injection: PBO capsules + PBO injection. PROs assessed included the Health Assessment Questionnaire disability index (HAQ-DI); EuroQol-5 Dimensions utility score (EQ-5D); Short Form Health Survey P/MCS Physical/Mental Component Summary; Functional Assessment of Chronic Illness Therapy (FACIT-Fatigue); Work Productivity and Activity Impairment Questionnaire (WPAI:RA) and Work Instability Scale for Rheumatoid Arthritis (RA-WIS). Results With dose reductions/withdrawals in Phase 2, the maintenance of effect in PROs was greater at LOCF in the ETN25 + MTX treatment group compared with the PBO group for: HAQ-DI, EQ-5D utility, EQ-5D VAS, SF-36 MCS/PCS, FACIT, and WPAI sub-scales. Additionally, at Phase 2 LOCF clinically meaningful improvements, relative to start of trial, in HAQ-DI (≥0.22); EQ-5D utility (≥0.05) and VAS >82; SF-36 P/MCS (>5) and statistically significantly greater proportions of pts with low and low/medium risk RA-WIS score (≤9 and ≤17) were observed in favor of ETN + MTX vs PBO; the relative benefits of MTX vs PBO were less. Conclusions ETN25 + MTX had a favorable impact on PROs compared to PBO, with greater maintenance of therapeutic effect from baseline to LOCF. (Figure Presented).
ANTECEDENTES: Durante la Fase 1 de la 52 semanas de etiqueta abierta PREMIO tratamiento del estudio de pacientes (pts) con principios (media de 6 meses). Artritis reumatoide moderada a grave (AR), que eran el metotrexato (MTX) / biológico ingenuo, con 50 mg etanercept (ETN) + 10-25 mg MTX arrojó una tasa de remisión del 70% sin progression.1 radiográfica significativa Pts alcanzar la remisión en la Fase I fueron asignados al azar a un periodo doble ciego de 39 semanas de reducido (25 mg) ETN + MTX o retirado (MTX solo o placebo, PBO) terapia (PREMIO Fase 2). Evaluar remisión sostenida (DAS28 y ACR / EULAR Boolean [AEB]), otros, radiográfica y los resultados de seguridad clínica en pts posteriormente tratados con dosis reducida ETN o PBO después de la inducción de remisión en la Fase 1 PREMIO. MÉTODOS: Pts alcanzar la remisión DAS28 por sem 52 (≤3.2 en la semana 39, <2,6 en la semana 52) en la Fase 1 (n = 193) fueron aleatorizados 1: 1: 1 a ETN25 / MTX: MTX + PBO inyección: cápsulas PBO + inyección de PBO en la semana 52. Pts con DAS28> 3.2 (> baja actividad de la enfermedad, LDA) recibió corticosteroides aumenta en semanas 56 o 64; pts no alcanzar LDA en la próxima visita se retiró. Remisión y otros resultados clínicos estándar fueron evaluados. La odds ratio y el significado se determinaron mediante modelos de regresión logística. RESULTADOS: ETN / MTX resultó en una proporción significativamente mayor de pts en remisión sostenida y AEB que solo MTX o PBO. Más ETN / MTX tratados pts conseguidos LDA DAS28 de PBO. Durante la fase 2 la progresión radiográfica (MTSS> 0,5) se produjo en <12% de los puntos, sin diferencia significativa entre los grupos de tratamiento; en la Fase 1 de la línea de base de los puntajes MTSS fueron 8,06, 8,46 y 7,59 para ETN25 / MTX, MTX y PBO, con cambios de 0.44, -0.5 y 1.41 por últimas observaciones en la fase 2 (LOCF), indicando que no hay progresión radiográfica clínicamente relevante en cualquiera de estos grupos de tratamiento ETN tratamiento / MTX resultó en más puntos que alcanzaron ACR50 y 70 de PBO. No hubo hallazgos de seguridad inesperados. CONCLUSIONES: De los moderados-severos pts AR temprana alcanzan la remisión DAS28 durante una inducción de 52 semanas (50 mg ETN / MTX en PREMIO Fase 1), el 63,5% mantiene la remisión (DAS28 <2,6 en la semana 76 y 91 visitas) con ETN25 / MTX, 38,5% con MTX y 23% con PBO más de 39 semanas posteriores. No hubo progresión radiográfica significativa en cualquier grupo de tratamiento. No hubo hallazgos de seguridad inesperados.
BACKGROUND: We assessed the effects of reduction and withdrawal of treatment in patients with rheumatoid arthritis who had a remission while receiving etanercept-plus-methotrexate therapy.
METHODS: Patients with early active disease who had not previously received methotrexate or biologic therapy received 50 mg of etanercept plus methotrexate weekly for 52 weeks (open-label phase). We then randomly assigned patients who had qualifying responses at weeks 39 and 52 to receive 25 mg of etanercept plus methotrexate (combination-therapy group), methotrexate alone, or placebo for 39 weeks (double-blind phase). Patients who had qualifying responses at week 39 of the double-blind phase had all treatment withdrawn at that time and were followed to week 65 (treatment-withdrawal phase). The primary end point was the proportion of patients with sustained remission in the double-blind phase.
RESULTS: Of 306 patients enrolled, 193 underwent randomization in the double-blind phase; 131 qualified for the treatment-withdrawal phase. More patients in the combination-therapy group than in the methotrexate-alone group or the placebo group met the criterion for the primary end point (40 of 63 [63%] vs. 26 of 65 [40%] and 15 of 65 [23%], respectively; P=0.009 for combination therapy vs. methotrexate alone; P<0.001 for combination therapy vs. placebo). At 65 weeks, 28 patients (44%) who had received combination therapy, 19 (29%) who had received methotrexate alone, and 15 (23%) who had received placebo were in remission (P=0.10 for combination therapy vs. methotrexate alone; P=0.02 for combination therapy vs. placebo; P=0.55 for methotrexate alone vs. placebo). No significant between-group differences were observed in radiographic progression of disease. Serious adverse events were reported in 3 patients (5%) in the combination-therapy group, 2 (3%) in the methotrexate-alone group, and 2 (3%) in the placebo group.
CONCLUSIONS: In patients with early rheumatoid arthritis who had a remission while receiving full-dose etanercept-plus-methotrexate therapy, continuing combination therapy at a reduced dose resulted in better disease control than switching to methotrexate alone or placebo, but no significant difference was observed in radiographic progression. (Funded by Pfizer; ClinicalTrials.gov number, NCT00913458.).
Background: Previous results have demonstrated that etanercept 50mg (ETN50) plus methotrexate (MTX) can reduce work loss in patients with early rheumatoid arthritis (RA). Objectives: To assess the impact on work productivity of reducing and withdrawing etanercept in patients who had reached remission. Methods: Phase I of the PRIZE trial recruited patients with early, moderate-tosevere RA to an open-label ETN50+MTX for 52 weeks. Phase II was a 39-week, randomized, and double-blind comparison of dose reduction to ETN25+MTX, MTX or Placebo in subjects who had achieved response during Phase I. Phase III was a 26-week observational phase in which Phase II responders progressively stopped treatment. The Valuation of Lost Productivity (VOLP), a validated instrument developed to estimate productivity impacts from a societal perspective, was completed approximately every 13 weeks. One of the main VOLP outcomes, the 3-month paid work productivity loss, was calculated as the sum of lost work hours attributable to absenteeism, presenteeism (reduced productivity while at work) and employment status changes. Patients included in the Phase II analysis were employed at week 52 with ≥1 follow-up during Phase II. Those included in Phase I and III were the Phase II study patients who were also employed at baseline with ≥1 follow-up during Phase I and who were also employed at week 91 with ≥1 follow-up during Phase III, respectively. Results: A total of 116, 120 and 55 subjects were included in our Phases I, II and III analyses, respectively. At week 52, the 3-month paid work productivity loss was 21.8 hours, 12.8 hours and 14.0 hours, respectively. The productivity loss increased at week 64 from week 52 and dropped at week 76 for all treatment groups. Nonetheless, the productivity loss continued rising after week 76 for the Placebo group (71.9 hours at week 91) but not for the other two groups (21.9 hours for ETX25+MTX and 27.6 hours for MTX). However, the loss differences between groups were not statistical significant. In contrast, for patients who were also employed at baseline, the 3-month paid work productivity loss dropped sharply from 93.1 hours at baseline to 14.0 hours at week 39 and then flattened at week 52 (15.8 hours) during Phase I. All patients who remained in the study, regardless of the treatment group, maintained their paid work productivity loss during Phase III the same as their loss at the end of Phase II. In addition, the changing trend of the employment rate was similar for the ETN25+MTX and MTX groups. The employment rate dropped more sharply during Phases II and III for the Placebo group than the other two treatment groups. Conclusions: The work productivity gain in Phase I as a result of ETN50+MTX was marginally lost in the dose reduction treatment groups, ETN25+MTX and MTX, but substantially lost in the Placebo group during Phase II of the trial. Patients who still remained in the study maintained their paid work productivity during Phase III. The patients in the ETN25+MTX and MTX groups were more able to maintain their employment than those in the Placebo group. (Figure Presented).
OBJECTIVE: To assess changes in work productivity in patients who have achieved response using etanercept (ETN) 50 mg+methotrexate (MTX) (phase I) are randomised to ETN 25 mg+MTX versus MTX versus placebo (phase II) and then withdrawn from treatment (phase III).
METHODS: Patients included in the analysis were in employment entering phase II of the PRIZE trial and had one or more follow-ups. Phase II was a 39-week, randomised and double-blind comparison of the 3 dose-reduction treatments. Phase III was a 26-week observational study where treatment was withdrawn. The Valuation of Lost Productivity was completed approximately every 13 weeks to estimate productivity impacts from a societal perspective.
RESULTS: A total of 120 participants were included in our analyses. During phase II, ETN25+MTX or MTX improved paid work productivity by over 100 hours compared with placebo, amounting to a gain of €1752 or €1503, respectively. ETN25+MTX compared with placebo gains €1862 in total paid/unpaid productivity. At week 52, the 3-month paid work productivity loss was 21.8, 12.8 and 14.0 hours, respectively. The productivity loss increased at week 64 from week 52, dropped at week 76 for all treatment groups and then continued rising after week 76 for the placebo group (71.9 hours at week 91) but not for the other 2 groups (21.9 hours for ETX25+MTX and 27.6 hours for MTX).
CONCLUSIONS: The work productivity gain in phase I as a result of ETN50+MTX was marginally lost in the dose-reduction treatment groups, ETN25+MTX and MTX, but substantially lost in the placebo group during phase II.
TRIAL REGISTRATION NUMBER: NCT00913458; Results.
Objective: To explore the influence of early treatment response to etanercept-methotrexate therapy on sustained remission after tapering/withdrawal of etanercept in methotrexate/biologic-naïve patients with early rheumatoid arthritis in the PRIZE study (ClinicalTrials.gov: NCT00913458). Method: In the initial 52-week open-label phase, enrolled patients received once-weekly etanercept 50 mg plus methotrexate. Patients who achieved DAS28 ≤3.2 at week 39 and <2.6 at week 52 were randomized to etanercept 25 mg plus methotrexate, methotrexate monotherapy, or placebo once weekly for 39 weeks in the double-blind phase. The relationships between responses in the open-label phase and sustained remission (DAS28 <2.6 at weeks 76 and 91, without glucocorticoid rescue therapy from weeks 52 to 64) in the double-blind phase were analyzed. Results: In the open-label phase, 70% of patients achieved DAS28 remission at week 52. In the double-blind phase, 63%, 40%, and 23% of patients had sustained DAS28 remission in the reduced-dose combination-therapy, methotrexate-monotherapy, and placebo groups, respectively. In patients receiving reduced-dose combination therapy, sustained remission was more likely in those who achieved DAS28 remission (p = 0.005) or low disease activity (p=0.044) in a shorter time, and who had a lower DAS28 (p = 0.016) or achieved ACR/EULAR Boolean remission (p < 0.05) at the end of the open-label phase. In patients receiving methotrexate monotherapy, sustained remission was associated with a lower acute-phase response (C-reactive protein, p = 0.007; erythrocyte sedimentation rate, p = 0.016) at the end of the open-label phase. Conclusion: Fast response and suppression of inflammation with etanercept-methotrexate therapy may predict successful etanercept tapering/withdrawal in patients with early rheumatoid arthritis.
Study to evaluate whether there is sustained remission and productivity in subjects with early rheumatoid arthritis started on etanercept plus methotrexate treatment.
