Arthritis Care & Research Vol. 63, No. 1, January 2011, pp 128 134 DOI 10.1002/acr.20331 2011, American College of Rheumatology ORIGINAL ARTICLE American College of Rheumatology Hybrid Analysis of Certolizumab Pegol Plus Methotrexate in Patients With Active Rheumatoid Arthritis: Data From a 52-Week Phase III Trial R. F. VAN VOLLENHOVEN, 1 D. FELSON, 2 V. STRAND, 3 M. E. WEINBLATT, 4 K. LUIJTENS, 5 AND E. C. KEYSTONE 6 Objective. The American College of Rheumatology (ACR) hybrid (a modified mean percent response to treatment) was officially recommended by the ACR as a revision to 20%, 50%, and 70% response criteria (ACR20/50/70) scores, but has not been tested in clinical trials. We performed a post hoc analysis of a phase III study of certolizumab pegol (Rheumatoid Arthritis Prevention of Structural Damage 1 [RAPID 1]) using the ACR hybrid. Methods. Patients with active rheumatoid arthritis were randomized to certolizumab pegol (200 or 400 every other week) plus methotrexate or placebo plus methotrexate. ACR s were compared with ACR20/50/70 outcomes. Results. Differences between active treatment and placebo were significant throughout the study using the ACR20 and ACR hybrid outcomes. In the certolizumab pegol 200 group, the median ACR at week 52 (last observation carried forward) was 49.99. A total of 258 (65.8%) of 392 and 172 (43.9%) of 392 patients had ACR20 and ACR50 responses, respectively. An additional 55 patients (14.0%) and 59 patients (15.1%) had mean improvements in ACR core measures of >20% and >50%, respectively, and therefore had positive ACR s, despite lacking ACR20 and ACR50 responses, respectively. In the placebo group, median ACR s were <10 at most time points; unlike other measures, the ACR hybrid measure indicated worsening scores for many patients. Conclusion. ACR hybrid analysis had greater sensitivity than traditional ACR20/50/70 criteria, demonstrating improvements in ACR20 nonresponders treated with certolizumab pegol. Negligible benefit was observed with placebo using ACR hybrid analysis. INTRODUCTION American College of Rheumatology (ACR) 20%, 50%, and 70% response criteria (ACR20/50/70), as well as the European League Against Rheumatism (EULAR) criteria and Disease Activity Score 28-joint count (DAS28), have standardized the evaluation and reporting of response in clinical trials of rheumatoid arthritis (RA) (1,2). However, these measures have limitations. The DAS28 does not give an indication of the proportion of patients who improve - ClinicalTrials.gov identifier: NCT00152386. Supported by UCB, which sponsored the clinical trial from which these analyses were performed. Dr. Felson s work was supported by the NIH (grant AR47785) and by the American College of Rheumatology (ACR) for development of the ACR hybrid. Dr. Keystone s work was supported by Abbott Laboratories, Aen, Inc., AstraZeneca Pharmaceuticals LP, Bristol-Myers Squibb, Centocor, Inc., F. Hoffman- LaRoche, Inc., Novartis Pharmaceuticals Schering-Plough Corporation, UCB, and Wyeth Pharmaceuticals. with treatment, whereas the ACR20/50/70 and EULAR criteria are dichotomous (i.e., yes/no) and trichotomous measures of individual response, respectively, that may not be as sensitive to change as continuous measures of improvement (3). Therefore, the ACR was recently proposed and approved by the ACR as a revision to ACR20/50/70 scores (3). The ACR is designed to combine ACR20/50/70 scores with the mean percent change from baseline in all 7 ACR core set components, allowing for detection of smaller differences between active treatments while preserving ACR20/50/70 1 R. F. van Vollenhoven, MD, PhD: Karolinska Institute, Stockholm, Sweden; 2 D. Felson, MD: Boston University, Boston, Massachusetts; 3 V. Strand, MD: Stanford University, Palo Alto, California; 4 M. E. Weinblatt, MD: Brigham and Women s Hospital, Harvard Medical School, Boston, Massachusetts; 5 K. Luijtens, PhD: UCB, Brussels, Belgium; 6 E. C. Keystone, MD: University of Toronto, Toronto, Ontario, Canada. 128
Assessing Effective Treatment for RA With ACR Hybrid Analysis 129 Table 1. ACR s (3)* ACR status <20 >20, <50 >50, <70 >70 Not ACR20 Mean % 19.99 19.99 19.99 ACR20 but not ACR50 20 Mean % 49.99 49.99 ACR50 but not ACR70 50 50 Mean % 69.99 ACR70 n/a 70 70 Mean % * To obtain the American College of Rheumatology (ACR) hybrid response score, take the ACR 20% response criteria (ACR20), ACR50, or ACR70 status of the patient (left column) and the mean percentage improvement in the core set measures; the ACR is then taken at the point of intersection in the table, e.g., the ACR for an ACR20 nonresponder is calculated from the mean percent change. If that mean is lower than 20%, the actual mean percent change is reported, but if that mean exceeds 20%, the highest score that patient can achieve is 19.99% ( banded to 20% ). n/a not applicable. responses as benchmarks to facilitate standardized reporting (4). The ACR therefore provides valuable information not only about whether one treatment is more efficacious than another, but also about how much each treatment group improves on average. The objective of the present post hoc analysis was to evaluate the use of the ACR hybrid measure relative to other measures of response, including ACR20/50/70 response rates and changes in the DAS28, in assessing the benefit of the PEGylated anti tumor necrosis factor agent, certolizumab pegol, when dosed at 200 or 400 every 2 weeks with methotrexate (MTX) in patients with active RA in the Rheumatoid Arthritis Prevention of Structural Damage 1 (RAPID 1) trial. Dr. van Vollenhoven has received consultant fees, speaking fees, and/or honoraria (less than $10,000) from UCB Pharma. Dr. Strand has received consultant fees (less than $10,000 each) from Abbott Immunology, Alder, Allergan, Almirall, Aen Corporation, AstraZeneca, Biogen Idec, CBio, Can-Fite, Centocor, Chelsea, Crescendo, Cypress Biosciences, Inc., Euro-Diagnostica, Fibrogen, Forest Laboratories, Genentech, GlaxoSmithKline, Human Genome Sciences, Idera, Incyte, Jazz Pharmaceuticals, Lexicon Genetics, Lilly, Logical Therapeutics, Lux Biosciences, MedImmune, Merck Sorono, Novartis, Novo Nordisk, Nuon, Ono Pharmaceuticals, Pfizer, Rigel, Roche, Sanofi- Aventis, Savient, Schering-Plough, SKK, UCB, and XDx, and serves on the advisory boards for Abbott, Aen, Biogen Idec, BMS, Can-Fite, Centocor, Chelsea, Crescendo, Cypress, Euro-Diagnostica, Fibrogen, Forest, Genentech, GSK, HGS, Idera, Incyte, Jazz, Lilly, NicOx, Novartis, Novo Nordisk, Pfizer, Rigel, Roche, Savient, Schering-Plough, and UCB. Dr. Weinblatt has received consultant fees (less than $10,000) from UCB. Dr. Keystone has received consultant fees and/or honoraria (less than $10,000 each) and/or has served on the advisory boards for Abbott Laboratories, Aen, Inc., Bristol-Myers Squibb, Centocor, Inc., F. Hoffman-LaRoche, Inc., Genentech, Inc., Schering-Plough Corporation, UCB, and Wyeth Pharmaceuticals. Address correspondence to R. F. van Vollenhoven, MD, PhD, Karolinska Institute, Stockholm, Sweden. E-mail: Ronald.van.Vollenhoven@ki.se. Submitted for publication April 3, 2009; accepted in revised form August 10, 2010. PATIENTS AND METHODS Patients. The design of the RAPID 1 trial has been published in detail previously (5). Briefly, patients with adultonset RA, defined by the ACR 1987 criteria (6 8), were randomized to 1 of 2 regimens of subcutaneous certolizumab pegol (400 at weeks 0, 2, and 4 followed by 200 or 400 ) plus MTX, or placebo plus MTX, every other week for 52 weeks. Patients who failed to achieve an ACR20 response at both weeks 12 and 14 were to be withdrawn from the study at week 16 and given the option to enter an open-label extension study of certolizumab pegol 400 every other week. Efficacy end points included ACR20/50/70 response rates and change from baseline in the DAS28 (erythrocyte sedimentation rate) (5). Calculation of ACR s. The ACR hybrid score was determined by calculating the mean percent change from baseline across the 7 ACR core set measures for each patient (limiting the maximum improvement or worsening of each core set item to 100%) and determining whether the patient achieved ACR20, ACR50, or ACR70 responses (3) (Table 1). If the mean percent change from baseline exceeded 20% in a patient who did not reach an ACR20 response, the change was set at an ACR hybrid score of 19.99; however, if the mean was lower than 20% and the patient fulfilled the ACR20 criteria, an ACR hybrid score of 20.00 was given. Likewise, if the mean percent change from baseline exceeded 50% (or 70%) in a patient who did not reach an ACR50 (or ACR70) response, the change was set at an ACR of 49.99 (or 69.99), and if the mean was lower than 50% (or 70%) and the patient fulfilled the ACR50 (or ACR70) criteria, ACR hybrid scores of 50.00 (or 70.00) were assigned. Statistical analyses. Efficacy analyses were conducted on the intent-to-treat (ITT) population, which included all randomized patients. The comparison of ACR20/50/70 scores for each active treatment group versus placebo was tested using a logistic regression analysis, with region and treatment as factors. In the overall ITT analysis, if a patient withdrew or used rescue medication, ACR20/50/70 scores were imputed as no response. The comparison of ACR
130 van Vollenhoven et al s for each active treatment group versus placebo was tested using analysis of covariance (ANCOVA) on the ranks, with region and treatment as factors. If a patient withdrew or used rescue medication, ACR hybrid scores were carried forward from that point onward. As a consequence, in the detailed analysis of ACR hybrid scores, ACR20/50/70 responses were also assessed using last observation carried forward analysis. Change from baseline in the DAS28 was compared between each active treatment group and placebo using ANCOVA, with region and treatment as factors and baseline as covariate. RESULTS Patient characteristics and disposition. The ITT population comprised 982 patients in RAPID 1 (certolizumab pegol 200 : n 393, certolizumab pegol 400 : n 390, placebo: n 199). Baseline patient demographics and disease activity were comparable across treatment groups, with all core set values indicating that patients had high baseline disease activity (5) (see Supplementary Table 1, available in the online version of this article at http://onlinelibrary.wiley.com/journal/10.1002/(issn) 2151-4658). Improvements in the signs and symptoms of RA. Certolizumab pegol 200 plus MTX conferred significantly greater benefit than placebo plus MTX according to ACR20 responder rates (dichotomous measure) (Figure 1A), ACR s (hybrid measure) (Figure 1B), and mean change from baseline in the DAS28 (continuous measure) (Figure 1C). By all 3 measures, responses to certolizumab pegol 200 plus MTX were significantly greater than placebo plus MTX by week 1, continued to improve through the first 12 weeks of treatment, and were sustained to study end (Figure 1). ACR20 response rates were similar in the certolizumab pegol 400 plus MTX group as previously reported (5), as were mean changes from baseline in the DAS28 and ACR s (data not shown). Comparison between ACR s and ACR20 response rates. ACR s were then compared with ACR20 response rates, and ACR s at weeks 1 and 52 were further analyzed. For simplicity, the remainder of this study focuses on comparisons between the placebo plus MTX and the certolizumab pegol 200 plus MTX groups. Response at week 1. At week 1, the ACR20 response rate was significantly higher in the certolizumab pegol treated patients compared with the placebo plus MTX treated patients (22.9% versus 5.6%; P 0.001 by logistic regression). Similarly, the median ACR s were also significantly higher in the certolizumab pegol group than in the placebo group (19.99 versus 2.76; P 0.001 by rank analysis). The significant improvement at week 1 with certolizumab pegol is further evidenced by the rightward shift in the distribution of ACR s in patients treated with certolizumab pegol 200 plus MTX versus those treated with placebo plus MTX (Figure 2A). Figure 1. Efficacy of certolizumab pegol 200 plus methotrexate (MTX) versus placebo plus MTX over time in the treatment of active rheumatoid arthritis in the intent-to-treat population of the Rheumatoid Arthritis Prevention of Structural Damage 1 trial. Responses were significantly greater in patients treated with certolizumab pegol 200 plus MTX versus placebo plus MTX (P 0.001 at weeks 1 52). A, American College of Rheumatology (ACR) 20% response criteria (ACR20) response rates (logistic regression, nonresponder imputation). B, Median ACR hybrid scores (analysis of covariance [ANCOVA] on the ranks, last observation carried forward [LOCF] imputation). C, Mean changes from baseline in the Disease Activity Score in 28 joints (DAS28; erythrocyte sedimentation rate [ESR]) (ANCOVA, LOCF imputation). Part A adapted, with permission, from ref. 1. The median ACR of 19.99 indicates that at least half of the patients treated with certolizumab pegol
Assessing Effective Treatment for RA With ACR Hybrid Analysis 131 Figure 2. Distribution of American College of Rheumatology (ACR) s (last observation carried forward imputation) over time in patients treated with certolizumab pegol 200 plus methotrexate (MTX) versus placebo plus MTX in the Rheumatoid Arthritis Prevention of Structural Damage 1 trial. The number of subjects in the analysis varies slightly from the intent-to-treat population numbers due to nonimputable missing data for each visit. A, Week 1 (certolizumab pegol 200 plus MTX group: n 385, placebo plus MTX group: n 194). B, Week 12 (certolizumab pegol 200 plus MTX group: n 391, placebo plus MTX group: n 196). C, Week 52 (certolizumab pegol 200 plus MTX group: n 392, placebo plus MTX group: n 196). plus MTX had at least a 20% mean improvement in core set measures at week 1 of treatment. Table 2, which indicates the number of patients in each ACR hybrid category (as defined in Table 1), shows that 197 (51.2%) of 385 certolizumab pegol treated patients had at least a 20% mean improvement at week 1. Of these, only 88 patients (less than half of those with a mean improvement of 20%) had a concurrent ACR20 response (Table 2). These results indicate that the ACR hybrid may be more sensitive than the ACR20 in detecting small improvements, such as those that occurred early on during treatment. In contrast, the median ACR of 2.76 in the placebo plus MTX group, together with the distribution of ACR s shown in Figure 2A, indicate that the majority of patients treated with MTX alone had a minimal mean improvement in, or a worsening of, ACR core set measures at week 1. At week 1, only 28 (14.4%) of 194 patients in the placebo plus MTX group had at least a 20% mean improvement in ACR core set measures, and of these, 11 had a concurrent ACR20 response (Table 2). Response over time (weeks 1 52). The median ACR hybrid score remained at 19.99 through week 4 for patients treated with certolizumab pegol plus MTX (Figure 1B), during which time the proportion of patients meeting the criteria for ACR20 response increased to 43.6% (Figure 1A). Most of the shift in the ACR was achieved after 12 weeks of treatment and was indicative of outcomes at 52 weeks. After 50% of the patients had achieved an ACR20 response, the median ACR hybrid score improved to 44.54 at week 12 (Figures 1B and 2) and remained stable at 49.99 thereafter from week 16 to week 52 (i.e., at least 50% of patients had a mean improvement in core measures of 50% at week 52). Similarly, the ACR20 response rate reached 63.8% at week 12 and also remained stable to week 52. The distribution of ACR s at weeks 12 and 52 demonstrates peaks at scores of 20, 50, and 70 for patients treated with certolizumab pegol plus MTX (Figures 2B and C). These peaks reflect the banding of ACR s according to the ACR20, ACR50, or ACR70 response achieved and the level of improvement in the ACR components (Table 1). Although each peak mostly included patients who had a mean improvement in the ACR core set measures greater than the 20%/50%/70% threshold, but who did not meet the formal threshold definition for an ACR20/50/70 response, respectively (e.g., did not have an ACR20 response, but had a mean improvement of 20%), the peaks also included patients who met the criteria for an ACR20/50/70 response, but had a mean core set improvement of less than or equal to the respective threshold. For example, analysis of the distribution peak at the ACR of 20 at week 52 showed that 4 (6.8%) of 59 or 1 (3.7%) of 27 of the certolizumab pegol 200 or placebo-treated patients at the peak, respectively, were ACR20 responders with a mean improvement in ACR core set measures of 20% (i.e., an ACR of 20.00). In contrast, 55 (93.2%) of 59 or 26 (96.3%) of 27 of the certolizumab pegol 200 or placebo-treated patients, respectively, were ACR20 nonresponders, with a mean improvement in the ACR core set measures of 20% (i.e., an ACR of 19.99) at week 52, demonstrating that the ACR20 response rate may underestimate treatment benefit (Table 3). Of the 55 certolizumab pegol 200 treated patients with an ACR of 19.99, approximately half (49.1%) failed to achieve an ACR20 response because they failed to achieve an improvement of 20% in tender and/or swollen joint counts. Likewise, analysis of the distribution peaks at the ACR hybrid of approximately 50 showed that these peaks primarily consisted of patients with an ACR of 49.99, with 51 (85.0%) of 60 or 3 (75.0%) of 4 of the certolizumab pegol 200 or placebo-treated patients, respectively, having an average improvement in ACR core set measures of at least 50% without a concurrent ACR50 response at week 52 (Table 3). Of the 51 certolizumab pegol 200 treated patients with an ACR of 49.99, 43.1% had an improvement in tender joint count
132 van Vollenhoven et al Table 2. Number and percentage of patients within each ACR hybrid (LOCF) category at week 1 in the Rheumatoid Arthritis Prevention of Structural Damage 1 trial* <20 >20, <50 >50, <70 >70 ACR status Not ACR20, ACR Mean % Mean % 19.99 19.99 19.99 19.99 19.99 19.99 Patients, no. (%) 188 (48.8) 166 (85.6) 106 (27.5) 17 (8.8) 3 (0.8) 0 0 0 ACR20 but not ACR50, ACR 20 20 Mean % Mean % 49.99 49.99 49.99 49.99 Patients, no. (%) 0 0 48 (12.5) 5 (2.6) 21 (5.5) 2 (1.0) 2 (0.5) 0 ACR50 but not ACR70, ACR 50 50 50 50 Mean % Mean % 69.99 69.99 Patients, no. (%) 0 0 1 (0.3) 0 8 (2.1) 4 (2.1) 6 (1.6) 0 ACR70, ACR n/a n/a 70 70 70 70 Mean % Mean % Patients, no. (%) n/a n/a 0 0 1 (0.3) 0 1 (0.3) 0 * methotrexate (MTX) group: n 385, placebo MTX group: n 194 (the number of subjects in the analysis varies slightly from the intent-to-treat population numbers due to nonimputable missing data). ACR American College of Rheumatology; LOCF last observation carried forward; CZP certolizumab pegol; ACR20 ACR 20% response criteria; n/a not applicable. ACR status by LOCF analysis. and/or swollen joint count of 50% and so did not achieve an ACR50 response. Interestingly, median ACR s in patients treated with placebo plus MTX remained low ( 10) throughout the study (Figure 1B), with scores of 9.96 and 6.67 at weeks 12 and 52, respectively (Figures 2B and C), indicating that the mean response of placebo-treated patients on the ACR core set measures was minimal during the study. Furthermore, at week 52, 39.8% of placebotreated patients had an ACR of 0 and 15.3% had a 20% worsening in the mean ACR components (compared with 6.6% and 2.3%, respectively, of patients treated in the certolizumab pegol 200 plus MTX group). DISCUSSION ACR20/50/70 scores have provided a standardized response measure in RA clinical trials for more than 10 years, allowing for important comparisons of efficacy to be made between treatments and consistency in reporting of clinical trial results, and facilitating approval of 7 diseasemodifying antirheumatic drugs since 1998 (1). Until that time, the measures that were used to assess treatment efficacy typically assessed mean or median improvements. Although these continuous measures conferred sensitivity to distinguish between treatments, they only provided information on the average level of improvement for the population and did not indicate the percentage of patients Table 3. Number and percentage of patients within each ACR hybrid (LOCF) category at week 52 in the Rheumatoid Arthritis Prevention of Structural Damage 1 trial* <20 >20, <50 >50, <70 >70 ACR status Not ACR20, ACR Mean % Mean % 19.99 19.99 19.99 19.99 19.99 19.99 Patients, no. (%) 79 (20.2) 128 (65.3) 47 (12.0) 26 (13.3) 6 (1.5) 0 2 (0.5) 0 ACR20 but not ACR50, ACR 20 20 Mean % Mean % 49.99 49.99 49.99 49.99 Patients, no. (%) 4 (1.0) 1 (0.5) 31 (7.9) 19 (9.7) 46 (11.7) 3 (1.5) 5 (1.3) 0 ACR50 but not ACR70, ACR 50 50 50 50 Mean % Mean % 69.99 69.99 Patients, no. (%) 0 0 9 (2.3) 1 (0.5) 48 (12.2) 9 (4.6) 17 (4.3) 2 (1.0) ACR70, ACR n/a n/a 70 70 70 70 Mean % Mean % Patients, no. (%) n/a n/a 0 0 9 (2.3) 3 (1.5) 89 (22.7) 4 (2.0) * methotrexate (MTX) group: n 392, placebo MTX group: n 196 (the number of subjects in the analysis varies slightly from the intent-to-treat population numbers due to nonimputable missing data). ACR American College of Rheumatology; LOCF last observation carried forward; CZP certolizumab pegol; ACR20 ACR 20% response criteria; n/a not applicable. ACR status by LOCF analysis.
Assessing Effective Treatment for RA With ACR Hybrid Analysis 133 who improved (1). Although the ACR20/50/70 scores address the question as to the proportion of patients that respond, they are dichotomous (indicating whether a treatment response is present or absent), so they may likely underestimate response and may have limited sensitivity to change and ability to gauge differences between treatments. In response to these limitations, the ACR hybrid was developed. The ACR combines conventional ACR20/50/70 scores with the mean percent improvement in all 7 ACR core set components. Importantly, this new measure is linked to ACR20/50/70 scores to allow for continuity of standardized reporting (i.e., the median ACR indicates whether at least 50% of patients achieved an ACR20, ACR50, or ACR70 response or no response), but also indicates the average response of the population (like the DAS28). Taken together, the ACR hybrid gives the percent improvement from baseline on a continuous scale of change and facilitates the detection of modest differences between therapies in RA clinical trials (3). Our analysis demonstrated that the ACR hybrid provided complementary results to DAS28 change from baseline and to the conventional ACR20, with all measures showing that certolizumab pegol treated patients had significantly greater improvements than placebo-treated patients from week 1 through study end. The majority of improvement in ACR s was achieved before 12 weeks and was maintained up to week 52, indicating that assessment at week 12 can be used as an indicator of outcome after 1 year. Comparison between the ACR hybrid scores and the ACR response rates suggests that the latter measure may underestimate differences between active treatment and placebo. One limitation of the ACR hybrid is that, because of its use of ACR20, ACR50, and ACR70 thresholds, there are clusters of scores at each of these thresholds rather than a continuum of scores. For example, the median value will be 49.99 until at least 50% of patients achieve an ACR50 response. This limitation can be overcome by presentation of the data in histograms, which provide considerably more information than the ACR response rates, showing the distribution of response across the population as well as indicating the proportion of patients that improve. Analysis of the distribution of the peaks at ACR s of 20, 50, and 70 showed that a proportion of patients receiving active treatment who did not have an ACR response still had improvements in ACR core set measures. The majority of certolizumab pegol treated patients in these peaks had scores of 19.99, 49.99, or 69.99 versus 20, 50, or 70, meaning that they achieved an average improvement in ACR core set measures of at least 20%, 50%, or 70%, respectively, while not achieving actual ACR20, ACR50, or ACR70 responses, respectively. In these patients, this failure to achieve ACR20/50/70 responses was frequently due to a lack of improvement in the swollen and/or tender joint count. The ACR hybrid measure also incorporates worsening of disease activity, so it may provide a better assessment of the overall average change in disease activity during the course of a clinical trial. This is particularly important for patients who receive placebo in clinical trials because they are more likely to show worsening, or at least inconsistent changes, from one core set measure to another, whereas patients receiving active treatment often experience improvement (9). -treated patients are therefore likely to have worse (or even negative) ACR s compared with patients receiving active treatment, thereby permitting easy discrimination of effective treatment from placebo. Consistent with this, our ACR hybrid analysis found that 15% of patients in the placebo group had a worsening in ACR core components of 20% at the end of the study and the average clinical response to placebo plus MTX was negligible throughout (40% of placebo-treated patients had an ACR of 0). The mean change from baseline in the DAS28 measure also demonstrated that the response to placebo and MTX was low; however, unlike the ACR hybrid, mean change data give no indication of the proportion of patients who achieved an average response. In contrast, the ACR20 responder rates to placebo ranged from 10% to 20%, consistent with placebo response rates in other RA clinical trials (5,10 16). Our results should be considered an impetus for future prospective studies that employ the ACR as a primary end point. These clinical trials may require fewer patients for measurement of efficacy due to the increased sensitivity of the ACR hybrid. The observation that patients randomized to placebo plus MTX experienced, on average, a negligible benefit (and that some placebo-treated patients had disease worsening) throughout the trial reinforces concerns about extended placebo treatment in RA clinical trials and supports the use of an early rescue arm as used in RAPID 1. In conclusion, post hoc analysis of RAPID 1 using the ACR confirms the value of this response criterion in clinical studies and reinforces the validity of traditional ACR20/50/70 scores. ACKNOWLEDGMENTS We would like to thank Lucian Ionescu, Owen Davies, and Lee Gervitz, employees of UCB, for critically reviewing the manuscript. We would also like to acknowledge the medical writing assistance and editorial services of Karen Munro and Linda Wychowski from PAREXEL, which was funded by UCB. AUTHOR CONTRIBUTIONS All authors were involved in drafting the article or revising it critically for important intellectual content, and all authors approved the final version to be submitted for publication. Dr. van Vollenhoven had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Study conception and design. Van Vollenhoven, Felson, Strand, Weinblatt, Keystone. Acquisition of data. Van Vollenhoven, Strand. Analysis and interpretation of data. Van Vollenhoven, Felson, Strand, Weinblatt, Luijtens, Keystone. ROLE OF THE STUDY SPONSOR UCB contributed to the study design and to the collection, analysis, and interpretation of the data. The trial on which the
134 van Vollenhoven et al current analysis was based (the Rheumatoid Arthritis Prevention of Structural Damage 1 trial) was a phase III clinical trial fully supported by the sponsor, and the data from this trial are owned by the sponsor. The first author of this paper (RFvV) approached the sponsor with the suggestion to perform the current analysis (which was not part of the original study plan, as the American College of Rheumatology hybrid was not yet known at that time) and was given the opportunity to undertake this with the other coauthors, some of whom are employees of the sponsor and others who are academicians. At that time it was also agreed to publish the results of the analysis, and no further approval was needed thereafter. REFERENCES 1. Felson DT, Anderson JJ, Boers M, Bombardier C, Furst D, Goldsmith C, et al. American College of Rheumatology preliminary definition of improvement in rheumatoid arthritis. Arthritis Rheum 1995;38:727 35. 2. Van Gestel AM, Prevoo ML, van t Hof MA, van Rijswijk MH, van de Putte LB, van Riel PL. Development and validation of the European League Against Rheumatism response criteria for rheumatoid arthritis: comparison with the preliminary American College of Rheumatology and the World Health Organization/International League Against Rheumatism criteria. Arthritis Rheum 1996;39:34 40. 3. American College of Rheumatology Committee to Reevaluate Improvement Criteria. A proposed revision to the ACR20: the hybrid measure of American College of Rheumatology response. Arthritis Rheum 2007;57:193 202. 4. Smolen JS, Aletaha D. Activity assessments in rheumatoid arthritis. Curr Opin Rheumatol 2008;20:306 13. 5. Keystone E, van der Heijde D, Mason D, Landewe R, van Vollenhoven R, Combe B, et al. Certolizumab pegol plus methotrexate is significantly more effective than placebo plus methotrexate in active rheumatoid arthritis: findings of a fiftytwo week, phase III, multicenter, randomized, double-blind, placebo-controlled, parallel-group study. Arthritis Rheum 2008;58:3319 29. 6. Arnett FC, Edworthy SM, Bloch DA, McShane DJ, Fries JF, Cooper NS, et al. The American Rheumatism Association 1987 revised criteria for the classification of rheumatoid arthritis. Arthritis Rheum 1988;31:315 24. 7. Hochberg MC, Chang RW, Dwosh I, Lindsey S, Pincus T, Wolfe F. The American College of Rheumatology 1991 revised criteria for the classification of global functional status in rheumatoid arthritis. Arthritis Rheum 1992;35:498 502. 8. Felson DT, Anderson JJ, Boers M, Bombardier C, Chernoff M, Fried B, et al. The American College of Rheumatology preliminary core set of disease activity measures for rheumatoid arthritis clinical trials. Arthritis Rheum 1993;36:729 40. 9. Anderson JJ, Bolognese JA, Felson DT. Comparison of rheumatoid arthritis clinical trial outcome measures: a simulation study. Arthritis Rheum 2003;48:3031 8. 10. Weinblatt ME, Keystone EC, Furst DE, Moreland LW, Weisman MH, Birbara CA, et al. Adalimumab, a fully human anti tumor necrosis factor monoclonal antibody, for the treatment of rheumatoid arthritis in patients taking concomitant methotrexate: the ARMADA trial. Arthritis Rheum 2003; 48:35 45. 11. Maini RN, Breedveld FC, Kalden JR, Smolen JS, Furst D, Weisman MH, et al, for the Anti Tumor Necrosis Factor Trial in Rheumatoid Arthritis with Concomitant Therapy Study Group. Sustained improvement over two years in physical function, structural damage, and signs and symptoms among patients with rheumatoid arthritis treated with infliximab and methotrexate. Arthritis Rheum 2004;50:1051 65. 12. Maini R, St Clair EW, Breedveld F, Furst D, Kalden J, Weisman M, et al, and the ATTRACT Study Group. Infliximab (chimeric anti-tumour necrosis factor monoclonal antibody) versus placebo in rheumatoid arthritis patients receiving concomitant methotrexate: a randomised phase III trial. Lancet 1999;354:1932 9. 13. Weinblatt ME, Kremer JM, Bankhurst AD, Bulpitt KJ, Fleischmann RM, Fox RI, et al. A trial of etanercept, a recombinant tumor necrosis factor receptor:fc fusion protein, in patients with rheumatoid arthritis receiving methotrexate. N Engl J Med 1999;340:253 9. 14. Keystone EC, Kavanaugh AF, Sharp JT, Tannenbaum H, Hua Y, Teoh LS, et al. Radiographic, clinical, and functional outcomes of treatment with adalimumab (a human anti tumor necrosis factor monoclonal antibody) in patients with active rheumatoid arthritis receiving concomitant methotrexate therapy: a randomized, placebo-controlled, 52-week trial. Arthritis Rheum 2004;50:1400 11. 15. Lipsky PE, van der Heijde DM, St Clair EW, Furst DE, Breedveld FC, Kalden JR, et al, and the Anti Tumor Necrosis Factor Trial in Rheumatoid Arthritis with Concomitant Therapy Study Group. Infliximab and methotrexate in the treatment of rheumatoid arthritis. N Engl J Med 2000;343:1594 602. 16. Smolen JS, Landewe R, Mease P, Brzezicki J, Mason D, Luijtens K, et al. Efficacy and safety of certolizumab pegol plus methotrexate in active rheumatoid arthritis: the RAPID 2 study. A randomised controlled trial. Ann Rheum Dis 2009; 68:797 804.