Most Trial Eligibility Criteria and Patient Baseline Characteristics Do Not Modify Treatment Effect in Trials Using Targeted Therapies for Rheumatoid Arthritis: A Meta-Epidemiological Study

<div><p>Objective</p><p>To determine if variations in trial eligibility criteria and patient baseline characteristics could be considered effect modifiers of the treatment response when testing targeted therapies (biological agents and targeted synthetic disease modifying antirheumatic drugs (DMARDs)) for rheumatoid arthritis (RA).</p><p>Methods</p><p>We conducted a meta-epidemiological study of all trials evaluating a targeted therapy approved by regulatory authorities for treating RA. The database search was completed on December 11^th 2013. Eligible trials reported ACR20 data at months 3–6 and used an add-on design. Odds ratios (ORs) were calculated from the response rates and compared among the trial eligibility criteria/patient baseline characteristics of interest. Comparisons are presented as the Ratio of Odds Ratios (ROR).</p><p>Results</p><p>Sixty-two trials (19,923 RA patients) were included in the primary analyses using ACR20 response. Overall, targeted therapies constituted an effective treatment (OR 3.96 95% confidence interval (CI) 3.41 to 4.60). The majority of the trial eligibility criteria and patient baseline characteristics did not modify treatment effect. The added benefit of targeted therapies was lower in trials including "DMARD-naïve" patients compared with trials including "DMARD inadequate responders" (ROR = 0.45, 95%CI 0.31 to 0.66) and trials including "targeted therapy inadequate responders" (0.50, 95%CI 0.29 to 0.87), test for interaction: p = 0.0002. Longer mean disease duration was associated with a higher likelihood of responding to treatment (β = 1.05, 95%CI 1.00 to 1.11 OR’s per year; p = 0.03). Analyses conducted using DAS28-remission as the outcome supported the above-mentioned findings.</p><p>Conclusion</p><p>Our results suggest that a highly selective inclusion is not associated with greater treatment effect, as might otherwise be expected. The added benefit of a targeted therapy was lower in trials including patients who were DMARD-naïve and trials including patients with shorter disease durations.</p></div

Results of the stratified meta-analyses for patient baseline characteristics modifying response (ACR20 and DAS28-remission state).

<p>BL, baseline; CRP, C-reactive protein; DAS28, disease activity score in 28 joints; HAQ-DI, health assessment questionnaire–disability index;MD Global, physicians global assessment (0–100); PT Global, patient global assessment (0–100); RF, rheumatoid factor; SJC, swollen joint count; TJC, tender joint count; VAS_pain, visual analogue scale for pain (0–100).</p><p>Results of the stratified meta-analyses for patient baseline characteristics modifying response (ACR20 and DAS28-remission state).</p

Study Designs, Demographic and Baseline Characteristics.

<p>Study Designs, Demographic and Baseline Characteristics.</p

Forest plot showing the effect (ACR20 response) of included trials, stratified by the included patients DMARD-history.

<p>Forest plot showing the effect (ACR20 response) of included trials, stratified by the included patients DMARD-history.</p

Daphne arisanensis Hayata

原著和名: アリサンコセウノキ科名: ジンチョウゲ科 = Thymelaeaceae採集地: 台湾 玉山山麓 (台湾省 玉山山麓)採集日: 1968/3/5採集者: 萩庭丈壽整理番号: JH048935国立科学博物館整理番号: TNS-VS-99893

Forest plot showing the effect (DAS28-remission) of included trials, stratified by the included patients DMARD-history.

<p>Forest plot showing the effect (DAS28-remission) of included trials, stratified by the included patients DMARD-history.</p

Flow Diagram of Patient Disposition in Each Study.

<p>The diagram shows the numbers of patients who were enrolled/randomized, received at least one infusion of ofatumumab, completed/discontinued, and included in analysis populations in each of the three studies. DB, double-blind treatment period; OL, open-label treatment period; FU, safety follow-up.</p

Results of the stratified meta-analyses for trial eligibility criteria modifying ACR20 response.

<p>CE, control event; CRP, C-reactive protein; DAS28, disease activity score in 28 joints; csDMARD, conventional synthetic disease modifying antirheumatic drug; IR, inadequate responders; MTX, metothrexate; OR, odds ratio; RF, rheumatoid factor; SJC, swollen joint count; TJC, tender joint count; TT, Targeted therapy.</p><p>Results of the stratified meta-analyses for trial eligibility criteria modifying ACR20 response.</p

Time to Retreatment in Weeks by Ofatumumab Treatment Course in Each Study.

<p>Time to Retreatment in Weeks by Ofatumumab Treatment Course in Each Study.</p

Median CD19+ B-cell Counts by Ofatumumab Treatment Course.

<p>Line plots show median B-cell CD19+ (GI/L) counts by week for each treatment course in OFA110635 (panel A) and OFA110634 (panel B). The data for OFA111752 were incomplete and have not been plotted. Inf. A, infusion A, was the first infusion of each treatment course; LLN, lower limit of normal = 0.11 GI/L; Trt, treatment.</p