Open-label observation of addition of etanercept versus a conventional disease-modifying antirheumatic drug in subjects with active rheumatoid arthritis despite methotrexate therapy in the Latin American region.

ORIGINAL ARTICLE

Open-Label Observation of Addition of Etanercept Versus a Conventional Disease-Modifying Antirheumatic Drug in Subjects With Active Rheumatoid Arthritis Despite Methotrexate Therapy in the Latin American Region Daniel A. Machado, MD,* Renato M. Guzman, MD,Þþ Ricardo M. Xavier, MD,§ J. Abraham Simon, MD,||¶ Linda Mele, MA,# Ronald Pedersen, MS,# Tahmina Ferdousi, PhD,** Andrew S. Koenig, DO,# Sameer Kotak, MS, MBA,# and Bonnie Vlahos, MBA, BSN, RN#

Background: Previous global studies examined etanercept (ETN) + methotrexate (MTX) for treatment of rheumatoid arthritis (RA), but included few subjects from Latin America. Objective: The objective of this study was to compare the safety and efficacy of ETN + MTX versus a standard-of-care disease-modifying antirheumatic drug (DMARD) + MTX in Latin American subjects with moderate to severe active RA despite MTX therapy. Methods: This open-label, active-comparator study (NCT00848354) randomized subjects 2:1 to ETN 50 mg/wk + MTX or investigatorselected DMARD (sulfasalazine or hydroxychloroquine) + MTX (ETN + MTX, n = 281; DMARD + MTX, n = 142). The primary end point was the proportion achieving American College of Rheumatology (ACR) 50 at week 24. Secondary end points included ACR20/70, disease activity score (DAS) 28 measures, and mean change in modified total Sharp score. Patient-reported outcomes were the Health Assessment Questionnaire, 36-item Short-Form, Hospital Anxiety and Depression Scale, Work Productivity and Activity Impairment: RA (WPAI:RA), and Caregiver Burden and Resource Utilization. Statistical analyses were stratified by country; W2 test and analysis of covariance were used. Adverse events were monitored. Results: More subjects achieved ACR50 at week 24 with ETN + MTX versus DMARD + MTX (62% vs 23%, respectively), in addition to secondary end points (P G 0.0001 for all); mean change in modified total Sharp score was lower for the ETN + MTX group (0.4 vs 1.4, respectively; P = 0.0270). Improvements in patient-reported outcomes favored ETN + MTX for Health Assessment Questionnaire, 36-item Short-Form, Hospital Anxiety and Depression Scale for depression, WPAI:RA, and Caregiver Burden and Resource Utilization emergency department visits for RA (P G 0.01). Overall, adverse events were similar between the groups (69% vs 68%,); serious adverse events were also similar (4% vs 1%). The rate of overall infections was higher with ETN + MTX (38%) than DMARD + MTX (22%, P e 0.001).

From *CAICI Instituto, Rosario, Santa Fe, Argentina; †IDEARG and ‡Saludcoop Clıńica, Bogota´, Colombia; §Hospital de Clıńicas de Porto Alegre, Porto Alegre, Brazil; ||BIOCEM and ¶Universidad Marista de Me´rida, Me´rida, Yucatań, Mexico; #Pfizer Inc and**Formerly of Pfizer Inc, Collegeville, PA. The Latin American RA study was designed and funded by Wyeth, which was acquired by Pfizer Inc in October 2009. Medical writing support was provided by Patricia McChesney, PhD, CMPP, of Engage Scientific Solutions and was funded by Pfizer Inc. D.A.M., R.M.X., and J.A.S. have received compensation for advisory boards and speaker fees from Pfizer Inc. R.M.G. has received consulting fees from Pfizer Inc. L.M., R.P., T.F., A.S.K., S.K., and B.V. were employees of Pfizer Inc during this study and manuscript preparation. Correspondence: Daniel A. Machado, MD, CAICI Instituto, Mendoza 2612, Rosario, Santa Fe, S2000 Argentina. E-mail: [email protected]. Copyright * 2013 by Lippincott Williams & Wilkins ISSN: 1076-1608/14/2001Y0025 DOI: 10.1097/RHU.0000000000000055

JCR: Journal of Clinical Rheumatology

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Conclusions: Consistent with published global data among RA patients with inadequate response to MTX, adding ETN to MTX demonstrated better efficacy than adding one other conventional DMARD to MTX. No new safety issues were observed. ETN + MTX provided favorable benefit-risk profile among RA patients from LA region. Key Words: Latin America, rheumatoid arthritis, etanercept, methotrexate, antirheumatic drugs (J Clin Rheumatol 2014;20: 25Y33)

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heumatoid arthritis (RA) is a chronic, progressive, systemic disease manifesting primarily as chronic and persistent inflammation and destruction of synovial joints. Its prevalence is È0.5% to 1.0% overall, with higher occurrence in women, as estimated from population studies.1Y3 Major advances in the management of RA have been made over the last couple of decades with optimized use of methotrexate (MTX), leflunomide, and biologic disease-modifying antirheumatic drugs (DMARDs),4,5 which is reflected by changes in the baseline characteristics of patients participating in clinical trials over the last 2 decades.6 While more recent global clinical trials of newer of therapies included patients from Latin American countries, the numbers are not large enough to conduct robust statistical analyses comparing the effectiveness with global populations. The Latin American nations include populations and cultures that are different from those in the Western developed countries, which traditionally have contributed the majority of patients to these clinical trials of biologic DMARDs. Health care standards and clinical practice differ from Western countries, and many patients with RA are poorly informed about their disease.7,8 Despite significant advances that local and regional rheumatology societies have made in recent years, clinicians who treat RA need information that is specific to the populations they treat and that is based on data from their region or country. In 2009, the Pan American League of Associations for Rheumatology and Grupo Latino Americano de Estudio de Artritis Reumatoide noted in their standard-of-care recommendations that about half of physicians surveyed used sequential monotherapy, and the other half used combination DMARD therapy to treat RA. The most popular DMARD combination was MTX + chloroquine or hydroxychloroquine (HCQ). The physician-based groups recommended a standard of care7 that consisted of at least 3 months on conventional DMARDs, including MTX (up to 25 mg/wk) and either sulfasalazine (SSZ), HCQ, leflunomide, azathioprine, or chloroquine, either as monotherapy or combinations of MTX + 1 or 2 DMARDs.8 Biologic DMARDs are recommended for patients with inadequate clinical

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Machado et al

response to standard of care (MTX + 1 or 2 DMARDs).8 In addition, individual nations and regions in Latin America have local guidelines. Previous global clinical studies have reported the safety and efficacy of etanercept (ETN) 50 mg once weekly, administered in combination with MTX or as monotherapy, in treatment of moderate to severe RA.9,10 Despite the global nature of published ETN trials, relatively few subjects from the Latin American region were enrolled (È5%). Other studies in the space of biologic versus DMARD have been conducted in very specific populations11 and only in limited geographies. This is a first step to provide safety and efficacy data for ETN + MTX treatment of RA in the Latin American region, which has unique cultural, educational, and socioeconomic circumstances as well as regional standards of health care and clinical practice. A similar study in patients with RA from Asian countries was recently reported.12 This open-label study was conducted exclusively in Latin America. Subjects with active RA who were experiencing suboptimal response to MTX monotherapy were randomized to receive either ETN + MTX or conventional nonbiologic DMARD + MTX. At their discretion, the investigator selected 1 of 2 DMARDs (SSZ or HCQ) to add to MTX (as recommended by Latin American guidelines at the time the study was planned).7,8 In addition, the dose of the DMARD was selected by the investigator to reflect standard of care and the local label. Part 1 of the study was 24 weeks. At the conclusion of part 1, subjects were given the opportunity to continue treatment for an additional 104 weeks (part 2). There is a paucity of long-term treatment data for ETN in the Latin American region in literature, and part 2 of this study will provide important safety and select efficacy outcomes. This interim report describes results of part 1. The objective of this study was to compare clinical benefit of adding ETN to MTX versus adding another nonbiologic DMARD (standard of care) to MTX among patients who had an inadequate response to MTX alone. The primary efficacy end point was the American College of Rheumatology (ACR) 50 response (50% improvement in ACR response criteria) at 24 weeks of treatment.

METHODS This was a randomized, 2-part, open-label, active-comparator, parallel-design, multicenter study (NCT00848354) conducted in 5 countries in Latin America. Randomization of subjects was performed using the eClinical Enrollment System. Part 1 of this study began in June 2009 and continued through March 2011. The study design for part 1 is shown in Figure 1. Subjects who had an inadequate response to MTX (MTX-IR) were randomized (2:1) to receive ETN (50 mg/wk) + MTX or conventional DMARD (SSZ or HCQ [investigator choice]) + MTX. Leflunomide was a standard-of-care DMARD in Latin America at the time of this study.7 However, some safety concerns had been raised regarding the combinations of leflunomide + MTX and leflunomide + tumor necrosis factor (TNF) inhibitors at the time this study protocol was being written5,13; thus, leflunomide was excluded from the investigator’s treatment options. Diseasemodifying antirheumatic drug and MTX doses could be titrated between baseline and week 4 (MTX minimum dose, 7.5 mg/wk; maximum dose, 25 mg/wk) and were required to be stable thereafter. In the event of a treatment-related adverse event (AE), the MTX dose could be lowered but was to be retitrated back to the pre-event dose if possible. Conventional DMARDs were titrated to an optimal dose at the discretion of the investigator to reflect standard of care and local label. All drugs were provided by the study sponsor at no cost to the investigators or

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FIGURE 1. Study design (part 1).

subjects. All investigators were trained on the study protocol by the study sponsor. Radiographic images of the hands, wrists, and forefeet were taken at baseline and at week 24 of treatment. The original films were digitized, and the subject data were masked; the digitized images were presented in random order to blinded radiologists for evaluation. Laboratory tests were analyzed at a central diagnostic center at the expense of the study sponsor. At the end of 24 weeks of treatment, subjects had the option to enter a second open-label 104-week continuation study (part 2). Main inclusion criteria for this study were diagnosis of RA according to ACR classification criteria,14 active RA despite MTX monotherapy (Q7.5 and e25 mg/wk) for at least 3 months as indicated by 6 or more swollen joints, 8 or more tender joints, and erythrocyte sedimentation rate of 28 mm/h or greater, and ages 18 years or older and younger than 70 years. Women of childbearing age were included if they used medically acceptable birth control. Subjects were excluded if they had previous treatment with ETN or other biologic agents, were treated with a concurrent DMARD at baseline or up to 3 months before screening (other than MTX), or were intolerant of MTX, SSZ, or HCQ. Subjects were excluded if they were taking more than 1 nonsteroidal antiinflammatory drug (NSAID) concurrent at screening (or their dose changed within 2 weeks before screening), treated with prednisone of more than 10 mg/d (or equivalent) at screening or had a dose change within 2 weeks before screening, or had current or recent (within 4 weeks) serious infections. In addition, subjects with latent or recent (within 2 years) active tuberculosis infection were not included. Tuberculosis screening was based on tuberculin purified protein derivative, a chest radiograph at screening or within the previous 12 months, and by examination of local records. Prior nonbiologic DMARDs other than MTX could not have been received within 3 months before screening. Concomitant medications allowed during the study included oral corticosteroids (e10 mg/d prednisone or equivalent), a maximum of 1 intra-articular corticosteroid injection, stable dose (from 2 weeks before screening) of a single NSAID, aspirin up to 325 mg/d if indicated for cardiovascular protection, folic acid, simple short-acting oral analgesics with no anti-inflammatory action, and approved medication for acute or chronic conditions. The primary efficacy end point was ACR50 response at week 24. Secondary efficacy end points included responses over time (weeks 2, 4, 8, 12, 16, 20, and 24) for ACR20, ACR50, and ACR70; disease activity score (DAS) 28 remission (G2.6); DAS28 low disease activity (G3.2); and European League Against Rheumatism (EULAR) responses, which were based on improvement * 2013 Lippincott Williams & Wilkins



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in DAS28 scores. Additional secondary end points included mean changes in DAS28 score; painful/tender joint count (TJC); swollen joint count (SJC); physician global assessment (PGA); subject global assessment (SGA); visual analog scales of general health, pain, and fatigue; and duration of morning stiffness. Radiographic efficacy end points included mean change in van der Heijde modified total Sharp score (mTSS) and components of erosions and joint space narrowing scores from baseline to week 24. The ACR/EULAR Boolean-based remission15 (defined as simultaneous achievement of total SJC e1, total TJC e1, C-reactive protein e1 mg/dL, and PGA e1 on a scale of 1Y10) was analyzed post hoc. Patient-reported outcomes (PROs) included the Health Assessment Questionnaire (HAQ), 36-item Short-Form (SF-36) Health Survey (a key secondary end point), Hospital Anxiety

LA RA Etanercept Study

and Depression Scale, Work Productivity and Activity Impairment: RA (WPAI:RA) questionnaire, and Caregiver Burden and Resource Utilization questionnaire. Adverse events were evaluated at each study visit. Adverse events and serious AEs were categorized by system organ class and the Medical Dictionary for Regulatory ActivitiesYpreferred terms. This study was conducted in compliance with the principles of the Declaration of Helsinki and the International Conference on Harmonization Good Clinical Practice guidelines. In addition, all local regulatory requirements were followed, including those for greater protection of the safety of trial participants. All subjects signed an informed consent form, which was reviewed and approved by an independent ethics committee or institutional review board.

FIGURE 2. CONSORT diagram. mITT indicates modified ITT; rITT, radiographic ITT. aThree randomized subjects in each group discontinued before receiving the study drug. bTwo subjects were excluded because of missing postrandomization efficacy data required to calculate ACR50 (primary end point). * 2013 Lippincott Williams & Wilkins

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Machado et al

Statistical Methods The study hypothesis was that the addition of ETN to MTX would yield superior responses compared with the addition of a conventional DMARD to MTX in subjects who had suboptimal responses to MTX alone as determined by achievement of ACR50 at 24 weeks. The modified intent-to-treat (ITT) population was used for all efficacy analyses and included all subjects who took at least 1 dose of test drug and completed 1 postrandomization visit, where data were collected to calculate the ACR50 for that time point. The radiographic ITT population was used for all radiographic analyses and included all subjects who took at least 1 dose of test drug and provided evaluable radiographic data at baseline and at week 24. ACR50 response proportions were compared between treatment groups using the Cochran-Mantel-Haenszel test. Analyses of mean change from baseline to week 24, including radiographic change, were conducted using analysis of covariance models, with baseline as covariate and factors for treatment and country as class variables. Within-group changes were summarized

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using 95% confidence intervals (CIs), and P values were calculated using paired t tests with > = 0.05. Secondary analyses involving response proportions at time points were analyzed using Fisher’s exact test; last-observation-carried-forward imputation was used for missing data. All subjects who took at least 1 dose of test drug were included in the safety analyses.

RESULTS This study was conducted in 30 centers in 5 countries, where 423 randomized subjects were treated with ETN + MTX (n = 281) and a conventional DMARD + MTX (n = 142; Fig. 2). The mean age of subjects was 48.5 (SD, 11.8) years, and the majority (89%) were female (Table 1). The mean disease duration at baseline was 8.3 (SD, 7.2) years. Before baseline, all subjects had been treated with MTX, and the majority (973%) had been treated with corticosteroids and NSAIDs. During the study, the mean dose of MTX chosen by the clinicians in the ETN + MTX group was 14.1 (SD, 3.8) mg/wk, and in the conventional DMARD + MTX group was 14.4 (SD, 3.9) mg/wk.

TABLE 1. Baseline Characteristics

Age, mean (SD), y Female, n (%) Ethnicityc White, n (%) Mestizos, n (%) African-Latin American, n (%) Other, n (%) Body mass index, mean (SD), kg/m2 Disease duration, mean (SD), y C-reactive protein, mean (SD), mg/L Rheumatoid factor positive, n (%) Cyclic citrullinated peptide antibody positive, n (%) ESR, mean (SD), mm/h Prior MTX use, n (%) Prior NSAID use, n (%) Prior corticosteroid use, n (%) DAS28 (ESR), mean (SD) TJC, mean (SD)d SJC, mean (SD)d SGA (1Y10), mean (SD) PGA (1Y10), mean (SD) Morning stiffness, mean (SD), min VAS general health (0Y100 mm), mean (SD) VAS pain (0Y100 mm), mean (SD) VAS fatigue (0Y100 mm), mean (SD) HADS-Anxiety, mean (SD) HADS-Depression, mean (SD) SF-36 Physical Health Scale, mean (SD) SF-36 Mental Health Scale, mean (SD) HAQ total score, mean (SD)

ETN + MTX (n = 281)

DMARD + MTX (n = 142)

P

48.4 (12.0) 248 (88.3)

48.6 (11.3) 128 (90.1)

0.876a 0.625b

134 60 39 48 26.4 7.9 20.7 242 245 43.2 281 231 207 6.6 25.1 18.2 7.1 6.7 186.1 60.0 65.6 55.9 8.9 8.0 30.2 40.0 1.6

(47.7) (21.4) (13.9) (17.1) (5.1) (7.0) (25.4) (86.1) (87.2) (16.6) (100) (82.2) (73.7) (0.7) (11.9) (8.4) (2.0) (1.6) (278.9) (21.5) (21.3) (26.1) (4.5) (3.9) (7.2) (11.1) (0.7)

65 34 23 20 27.4 9.0 20.8 119 120 42.8 142 122 102 6.7 26.2 19.3 7.1 6.7 156.3 61.5 64.9 58.9 9.2 7.9 30.1 40.0 1.6

(45.8) (23.9) (16.2) (14.1) (5.1) (7.5) (23.0) (83.8) (84.5) (16.4) (100) (85.9) (71.8) (0.7) (12.3) (10.1) (1.9) (1.6) (199.8) (20.6) (21.7) (24.9) (4.8) (4.0) (6.9) (10.2) (0.7)

0.748b

0.058a 0.165a 0.960a 0.561b 0.457b 0.831a N/A 0.406b 0.728b 0.345a 0.382a 0.234a 0.758a 0.947a 0.261a 0.502a 0.740a 0.251a 0.553a 0.781a 0.799a 0.984a 0.492a

a

One-way analysis of variance with treatment as factor. Fisher exact test (2-tailed). c Case report forms included Asian and Mulatto ethnicities, but no subjects chose these. d Values for tender and SJCs are prorated. ESR indicates erythrocyte sedimentation rate; HADS, Hospital Anxiety and Depression Scale; VAS, visual analog scale. b

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* 2013 Lippincott Williams & Wilkins



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Hydroxychloroquine was administered to 70 subjects, with mean dose of 2242.8 (SD, 681.3) mg/wk (320.4 [SD, 97.3] mg/d); SSZ was administered to 72 subjects, with mean dose of 12,021.0 (SD, 3,548.8) mg/wk (1717.3 [SD, 507.0] mg/d). Both DMARDs were dosed per the investigator’s discretion. The percentage of subjects who achieved an ACR50 response at week 24 (primary end point) was 62% for ETN + MTX treatment versus 23% for conventional DMARD + MTX treatment (P G 0.0001; 95% CI for the difference in proportions, 29.3Y48.3; Table 2). The percentage of subjects who achieved ACR20, ACR50, and ACR70 responses over time is shown in Figure 3. For each measure and at each time point, ETN + MTX yielded significantly better responses than did conventional DMARD + MTX except for ACR70 at week 2. Significantly more subjects achieved DAS28 remission (25.1%), Boolean remission (12.9%), EULAR good response (47.0%), and DAS28 low disease activity (47.0%) with ETN + MTX relative to DMARD + MTX (3.5%, 2.1%, 12.0%, and 12.0%, respectively; P G 0.005 for all). Differences were seen between treatment groups in change from baseline to week 24 over time in adjusted mean PGA and SGA scores, and TJC and SJC at all time points were significantly in favor of the ETN + MTX group (P G 0.0001). Improvement in morning stiffness was significant at all time points from baseline to week 24 (P G 0.001). Adjusted mean change in mTSS and joint space erosion were also significantly in favor of ETN + MTX (0.4 and 0.4, respectively) compared with DMARD + MTX (1.4 and 1.1, respectively; P G 0.05 for both; Table 2). Although not significant,


adjusted mean change in joint space narrowing also favored ETN + MTX (j0.1) over DMARD + MTX (0.2; P = 0.20) at week 24. Joint space narrowing was not significantly different between treatment groups at week 24. The percentage of subjects who achieved normal HAQ score (e0.5) was significantly higher with ETN + MTX treatment (43.7%) compared with DMARD + MTX treatment (27.5%; P = 0.0014; 95% CI, 6.4Y26.2; Table 3). The percentage of subjects with clinically meaningful improvement in HAQ score (90.22) from baseline favored ETN + MTX treatment versus DMARD + MTX treatment at weeks 8, 16, and 24 (Q80% vs e63%, respectively; P e 0.0001). Differences between treatment groups in change from baseline in adjusted mean SF-36 vitality domain, mental component, and physical component scores were significantly in favor of the ETN + MTX group (P e 0.02 for all time points). The percentage of subjects who achieved minimally clinical important difference of improvement in scores of more than 5 at week 24 for vitality domain, mental component, and physical component was significantly higher for the ETN + MTX group versus the DMARD + MTX group (44% vs 27%, 57% vs 44%, and 75% vs 57%, respectively; P G 0.05 for each). Improvements in subject satisfaction, physician satisfaction, and subject’s willingness to retake medications were in favor of ETN + MTX (P G 0.0001 for all). Significant differences between treatment groups were not seen in the Caregiver Burden and Resource Utilisation except for the mean number of emergency department visits for RA in the past 6 months, where ETN + MTX had

TABLE 2. Primary and Secondary Clinical and Radiographic End Points at Week 24 (LOCF, mITT Population)

ACR50 response, n (%) ACR20 response, n (%) ACR70 response, n (%) DAS28 (ESR), adjusted mean change (SE)c DAS28 (ESR) low disease activity (G3.2), n (%) DAS28 (ESR) remission (G2.6), n (%) EULAR moderate or good response,e n (%) EULAR good response,e n (%) ACR/EULAR Boolean remission, n (%) TJC, adjusted mean change (SE)c SJC, adjusted mean change (SE)c SGA, adjusted mean change (SE)c PGA, adjusted mean change (SE)c Duration of morning stiffness, adjusted mean change (SE)c mTSS, adjusted mean change (SE)c,f $mTSS e0, n (%)f Joint space narrowing, adjusted mean change (SE)c,f Joint space erosions, adjusted mean change (SE)c,f

ETN + MTX

DMARD + MTX

n = 279

n = 142

173 232 97 j3.20 131 70 256 131 36 j19.8 j15.1 j3.9 j4.8 j102.1 0.4 186 j0.1 0.4

(62.0) (83.2) (34.8) (0.09) (47.0) (25.1) (91.8) (47.0) (12.9) (0.6) (0.4) (0.2) (0.1) (8.1) (0.4) (75.3) (0.2) (0.2)

33 71 16 j1.70 17 5 92 17 3 j12.8 j8.6 j2.3 j2.4 j53.7 1.4 81 0.2 1.1

(23.2) (50.0) (11.3) (0.12) (12.0) (3.5) (64.8) (12.0) (2.1) (0.8) (0.6) (0.2) (0.2) (10.4) (0.5) (68.1) (0.3) (0.3)

P G0.0001a G0.0001b G0.0001b G0.0001d G0.0001b G0.0001b G0.0001b G0.0001b 0.0042b G0.0001c G0.0001c G0.0001c G0.0001c G0.0001c 0.0270e 0.1671b 0.1975d 0.0044d

a

Cochran-Mantel-Haenszel test. Fisher’s exact test. c ANCOVA model with baseline score, therapy, and country as variables. d P value derived from ANCOVA model: ranked mTSS changes score with baseline score, therapy, and country as variables. e DAS28-based EULAR response. f rITT population. ESR indicates erythrocyte sedimentation rate; LOCF, last observation carried forward; mITT, modified ITT; N/A, not available; rITT: radiographic ITT. b


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FIGURE 3. Percentage of subjects who achieved ACR20, ACR50, and ACR70 responses over time. *P G 0.0001 for treatment effects for all time points except ACR70 at weeks 2 and 4 (not statistically significant at week 2 and P G 0.05 at week 4).

fewer visits (P = 0.0039; Table 3). The number of subjects reporting their caregiver information at week 24 was substantially less than that at baseline, which made caregiver analyses difficult. Both treatment arms had significant improvement in the WPAI:RA relative to baseline, but few differences were seen between treatment arms. The change in percentage of overall work impairment caused by RA in the past 7 days was greater for ETN + MTX versus DMARD + MTX (P = 0.0188). Overall incidence of treatment-emergent AEs was similar between treatment groups (ETN + MTX, 69% vs DMARD + MTX, 68%; P = 1.000) from baseline through week 24 (Table 4). The incidence of serious AEs (excluding serious infections) was similar between ETN + MTX group (3.6%) and DMARD + MTX group (1.4%; P = 0.352). Overall, the most common AE was bronchitis, which occurred in a higher percentage of subjects treated with ETN + MTX than in subjects treated with DMARD + MTX (5.7% vs 2.1%, respectively; P = 0.134). In other common AEs, the proportions of subjects who had nausea, dyspepsia, and gastritis were significantly greater in the DMARD + MTX group than in the ETN + MTX group (P G 0.05

for each). The proportion of subjects who had at least 1 treatmentemergent infection was significantly greater in the ETN + MTX group (38.1% vs 21.8%, respectively; P G 0.001). Five subjects in the ETN + MTX group experienced serious infections; none of the subjects in the DMARD + MTX group experienced serious infections. There were no reports of opportunistic infections or tuberculosis in this study at week 24.

DISCUSSION The results of this open-label study among MTX-IR RA subjects from the Latin American region are consistent with double-blind placebo-controlled studies of ETN in MTX-IR RA subjects in the global population.9,10,12 In this study of subjects from the Latin American region with moderate to severe RA, despite MTX therapy, combination ETN + MTX therapy demonstrated superior efficacy over the Latin American standard of care,7,8 conventional physician-selected nonbiologic DMARD + MTX therapy in primary and secondary efficacy end points. Although infections were more common with ETN + MTX relative to a conventional DMARD + MTX, there were

TABLE 3. Subject-Reported Outcomes at Week 24 (LOCF, mITT Population) ETN + MTX HAQ total score, adjusted mean change (SE) VAS general health, 0Y100 mm, adjusted mean change (SE) VAS pain, 0Y100 mm, adjusted mean change (SE) VAS fatigue, 0Y100 mm, adjusted mean change (SE) HADS-Anxiety, adjusted mean change (SE) HADS-Depression, adjusted mean change (SE) SF-36 vitality domain, adjusted mean change (SE) SF-36 Physical Health Scale, adjusted mean change (SE) SF-36 Mental Health Scale, adjusted mean change (SE) CBRU no. emergency department visits for RA, adjusted mean change (SE) WPAI:RA percent overall work impairment due to RA in the past 7 d, adjusted mean change (SE)

DMARD + MTX

(n = 279)

(n = 142)

P

j0.9 (G0.1) j33.7 (1.6) j40.9 (1.6) j29.6 (1.6) j2.2 (0.3) j2.8 (0.2) 3.8 (0.3) 12.4 (0.7) 7.3 (0.7) j0.5 (G0.1)

j0.5 (0.1) j19.3 (2.0) j24.0 (2.1) j17.3 (2.1) j1.7 (0.3) j1.9 (0.3) 2.4 (0.4) 7.4 (0.8) 3.3 (1.0) j0.4 (G0.1)

G0.0001a G0.0001a G0.0001a G0.0001a 0.1624a 0.0077a 0.0003a G0.0001a 0.0002a 0.0039a

j33.4 (3.0)

j21.5 (4.4)

0.0188a

a ANCOVA with baseline score, therapy, and country as variables. CBRU indicates Caregiver Burden and Resource Utilization; HADS, Hospital Anxiety and Depression Scale; LOCF, last observation carried forward; mITT, modified ITT; VAS, visual analog scale.

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TABLE 4. Summary of Treatment-Emergent Adverse Events (Safety Population) ETN + MTX

DMARD + MTX

n = 281

n = 142

Pa

97 (68.3) 31 (21.8)

1.000 G0.001

2 (1.4)

0.352

9 (6.3)

0.828

39 (27.5) 9 (6.3) 9 (6.3) 13 (9.2) 9 (6.3)

0.001 0.020 0.047 0.006 0.209

36 (25.4) 3 (2.1) 6 (4.2) 12 (8.5) 10 (7.0)

0.005 0.134 0.813 0.215 1.000

21 (14.8) 10 (7.0) 10 (7.0) 9 (6.3)

0.003 0.144 0.034 0.650

5 (3.5)

0.006

Any AE, n (%) 193 (68.7) Treatment-emergent infection 107 (38.1) Q1, n (%) Serious AEs, n (%) 10 (3.6) Most common AEs (Q5%) Blood and lymphatic system 16 (5.7) disorders Gastrointestinal disorders 40 (14.2) Dyspepsia 5 (1.8) Gastritis 6 (2.1) Nausea 7 (2.5) General disorders and 29 (10.3) administration site AEs Infections and infestations 111 (39.5) Bronchitis 16 (5.7) Influenza 15 (5.3) Investigations 15 (5.3) Musculoskeletal and 19 (6.8) connective tissue disorders Nervous system disorders 16 (5.7) Headache 10 (3.6) Psychiatric disorders 7 (2.5) Respiratory, thoracic, and 14 (5.0) mediastinal disorders Skin and subcutaneous 32 (11.4) tissue disorders a

Fisher’s exact test (2-tailed).

no occurrences of opportunistic infections, and there were no unexpected safety issues; safety results were consistent with previous trials of ETN in RA.9,10 The objective of this study was to assess if the efficacy and safety data from the Latin American region, which is known to have cultural, socioeconomic, health care standards, and clinical practice differences from the Western developed world, are consistent with safety and efficacy data from global studies of ETN among MTX-IR RA subjects. At the time (2007Y2008) this study was being designed, the Latin American regional treatment guidelines recommended using at least 2 conventional DMARDs before prescribing a biologic DMARD.7,8 Thus, in this well-controlled but open-label study, observations were made to assess addition of ETN to MTX versus the Latin American standard of care (i.e., adding another conventional DMARD to MTX) in subjects who had an inadequate response to MTX. While the ACR/EULAR guidelines16Y18 include the use of triple DMARD (MTX, SSZ, HCQ) therapy as studies have shown that to be an effective therapy for RA,11,19,20 the studies of triple DMARD therapies were reported after the current protocol was already developed. The efficacy of a triple DMARD therapy (SSZ + HCQ + MTX) regimen has been reported for early RA subjects.20 This study, however, was conducted in a population that was different from the present study in MTX-IR subjects and did not include a comparison with a biologic DMARD. A recent noninferiority study compared the efficacy of ETN + MTX with * 2013 Lippincott Williams & Wilkins


triple DMARD therapy in a population who had an inadequate response to MTX alone21; the authors found that triple DMARD was not inferior to ETN + MTX with respect to clinical and radiographic outcomes in subjects with active RA in North America. A noted limitation of this study by the authors was that the evaluable subject population was well below the estimate needed for 90% power to detect differences between the treatment regimens. Another study (TEAR) of triple DMARD therapy also among early RA subjects but including a comparison with ETN was reported by Moreland et al.11 The triple DMARD therapy seemed to have similar efficacy as ETN in controlling signs and symptoms; however, ETN was more effective in inhibiting radiographic structural damage progression as was seen in this current study as well. Several studies of biologic antiTNF have shown similar efficacy of anti-TNF agents and MTX in early RA subjects as measured by ACR and DAS28 response criteria.22Y24 The current study, where ETN + MTX seems to have better efficacy than the DMARD + MTX combination, was conducted in an MTX-IR population. As mentioned above, our study followed a standard of care in Latin America, used a combination of 2 DMARDs rather than 3, and was also an openlabel study, which can impact the results observed. However, the radiographic endpoint (a more objective endpoint that should not be affected by the open-label nature of the study) was statistically significantly better with ETN + MTX combination than the conventional DMARD regimen. Thus, the main benefit of ETN usage in Latin America is among MTX-IR population and in the better inhibition of structural damage progression, which is consistent with data from global studies of biologic anti-TNF agents in an MTX-IR population.9,25,26 A goal for diagnosing and treating RA is to use evidencebased medicine to make clinical decisions. In the Latin American region, few data are available that reflect real-world clinical conditions. Local treatment recommendations suggest checking treatment response every 3 to 6 months and adjusting therapeutic regimen accordingly.7,8 In this study, we attempted to combine elements of real-world practice (by allowing the investigators to select standard-of-care conventional DMARD therapy) and a randomized controlled trial by adding rigor of scheduled visits with specific data collection that may not be normally done in observational studies. While we acknowledge limitations that this study design may have, we wanted to gather sufficient data to help physicians judge how patients may fare with a given treatment regimen. Limitations of these data include the open-label design, which may introduce bias into assessments made by investigators. In addition, subjects had to qualify for study entry by fixed criteria, which may limit application of data or conclusions in routine clinical management of the general RA population. Furthermore, the study environment may have allowed some subjects to receive medication that may not have been covered by a payer and thus been financially unavailable in daily clinical practice. This study did not enroll a sufficient number of subjects to adequately power subanalyses of efficacy of DMARD treatment across different dose ranges. Subjects with an inadequate response to treatment may have discontinued open-label study, and the controlled period follow-up time was limited to 24 weeks for part 1 of this study. Finally, geographic representation is incomplete, considering the significant heterogeneity across regions and countries; it was not possible to include all regions and all ethnic groups of Latin America; consequently, general conclusions may be limited for this diverse population. Populations of the Latin American region are heterogeneous, which may have epidemiologic and clinical relevance to diagnosis and treatment of RA.8 Further work is needed in the www.jclinrheum.com


31


Machado et al

Latin American region to better clarify and understand the population response to this and other therapies. While early treatment of RA is widely recommended,7 length of time between onset of symptoms and diagnosis or treatment can be 2 to 6 years in the Latin American region.27 Future research on barriers for early diagnosis and treatment of RA is needed in Latin American nations. Data from this study will be helpful for evidence-based decision making and for spurring discussion about treatment of RA in local clinics. The extensive use of PROs and qualityof-life measures provided further evidence to support early treatment of RA, which may reduce the health-related economic impact of this chronic disease. In conclusion, these data are consistent with previous global studies of the addition of biologics or single conventional DMARDs in subjects with an inadequate response to MTX monotherapy.

KEY POINTS This was a randomized open-label trial that looked at physician-selected standard-of-care treatment (adding a 1 conventional nonbiologic DMARD to MTX) versus adding a biologic DMARD (ETN) to MTX for moderately to severely active RA despite MTX therapy, conducted exclusively in Latin America. The study data showed that ETN + MTX therapy demonstrated superior efficacy over the conventional nonbiologic DMARD + MTX for clinical endpoints, radiographic nonprogression, and PROs, similar to previously published global, randomized, double-blind, controlled trials. ACKNOWLEDGMENTS The authors thank Dr Mahboob U. Rahman of Pfizer Inc for providing guidance and a critical review of their manuscript. The authors also thank the investigators of this study.

Argentina

Colombia

Juan Carlos Barreira Carlos Baruzzo Alberto Berman Maria Celina de la Vega Ruth Celina Moriondo de Pizzolato Javier Duhau Julio Hofman Eleonora Lucero Daniel Augusto Machado Osvaldo Daniel Messina Jose Luis Christian Moreno Eduardo Fabian Mysler Horacio Venarotti Chile Pedro Miranda Oscar Neira

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Monique R. Chalem Mario Enrique Diaz William Jose Otero Escalante Elias Gonzalo Forero Edwin Antonio Jauregui John Dario Londono Jose Fernando Molina Juan Jose Jaller Raad Diego Luis Saaibi Solano Edgardo David Tobias

Mexico Federico Galvan Jesus Abraham Simon Cesar Pacheco-Tena Panama Generoso Guerra Antonio Cachafeiro Vilar

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