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Rheumatology Advance Access originally published online on April 29, 2007
Rheumatology 2007 46(7):1122-1125; doi:10.1093/rheumatology/kem033
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© The Author 2007. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

A placebo-controlled, randomized, double-blinded study evaluating the safety of etanercept in patients with rheumatoid arthritis and concomitant comorbid diseases

Michael H. Weisman, Harold E. Paulus1, Francis X. Burch2, Alan J. Kivitz3, Joshua Fierer4, Meleana Dunn5, David R. Kerr6, Wayne Tsuji5 and Scott W. Baumgartner5

Division of Rheumatology, Cedars-Sinai Medical Center, Los Angeles, CA, 1Department of Medicine, UCLA School of Medicine, Los Angeles, CA, 2Radiant Research, San Antonio, TX, 3Altoona Arthritis & Osteo Center, Duncansville, PA, 4University of California, San Diego, San Diego, CA, 5Amgen Inc., Thousand Oaks, CA and 6Axio Research, Seattle, WA, USA.

Correspondence to: Michael H. Weisman, Division of Rheumatology, Cedars Sinai Medical Center, 8700 Beverly Blvd, Suite B131, Los Angeles, CA 90048, USA. E-mail: michael.weisman{at}cshs.org


   Abstract
Top
 Abstract
Introduction
 Patients and methods
 Results
 Discussion
 Acknowledgement
 References
 
Objective. To evaluate the safety of etanercept in patients with rheumatoid arthritis (RA) and concomitant comorbidities.

Methods. The safety of etanercept (25 mg twice weekly) in RA patients with at least one comorbidity (i.e. diabetes mellitus, chronic pulmonary disease, recent pneumonia, recurrent infections) was evaluated in a 16-week placebo-controlled, randomized, double-blinded study. The primary endpoint was the incidence of medically important infections (MIIs; defined as those resulting in hospitalization or treatment with intravenous antibiotics).

Results. Data from 535 patients were analysed; the study was terminated early because of slow enrolment and lower than predicted incidence of infections. Serious adverse events (5.9% placebo, 8.6% etanercept) were most commonly observed in the cardiovascular system. Six patients (1 placebo; 5 etanercept) died during the study; four deaths were attributed to cardiovascular events. The numerically higher mortality in the etanercept group was not statistically significant [relative risk (95% CI) = 5.06 (0.59, 42.99)] but remains unexplained. No etanercept-related increase in the incidence of MIIs (3.7% placebo, 3.0% etanercept) or overall infections was observed in the total study population or in subgroups of patients who were ≥65 yrs of age, had diabetes or had chronic pulmonary disease.

Conclusions. Etanercept was generally well tolerated by RA patients with comorbidities. Serious adverse events and deaths occurred more frequently in the etanercept group but event numbers were small and CIs were broad, preventing reliable conclusions from being drawn. Although the study had limited statistical power, the incidence of MIIs in these patients was not increased by etanercept treatment.

KEY WORDS: Tumour necrosis factor, Comorbidity, Infection, Cardiovascular disease, Risk factors


   Introduction
Top
 Abstract
 Introduction
Patients and methods
 Results
 Discussion
 Acknowledgement
 References
 
Etanercept (Enbrel®) is a soluble tumour necrosis factor (TNF) receptor used to treat rheumatoid arthritis (RA) and other rheumatic diseases. Although the safety of etanercept has been demonstrated in numerous clinical studies, the relationship between treatment with a TNF antagonist and infection is an area of particular interest. Patients with RA are more susceptible to infections than the general population and the risk is further exacerbated by comorbidities [1, 2]. As a post-marketing commitment to the Food and Drug Administration (FDA), the safety of etanercept was evaluated in RA patients with comorbidities. Enrolment of only patients with comorbidities differentiates this study from prior etanercept studies and the resultant safety data should better represent a ‘real-world’ RA population.


   Patients and methods
Top
 Abstract
 Introduction
 Patients and methods
Results
 Discussion
 Acknowledgement
 References
 
Patients
Eligible patients were at least 18 yrs of age, met the American College of Rheumatology criteria for RA [3], and had at least one qualifying comorbidity: diabetes mellitus (only patients taking insulin and/or oral hypoglycaemic agents), chronic pulmonary disease (asthma or chronic obstructive pulmonary disease), or pneumonia or recurrent infections (bronchitis, sinusitis, or urinary tract infection) in the preceding year. Patients with recent myocardial infarction, uncontrolled hypertension or severe pulmonary disease requiring continual oxygen therapy were excluded. A protocol amendment later excluded patients with angina pectoris. Patients could not take other TNF antagonists before or during the study but could receive corticosteroids, non-steroidal anti-inflammatory drugs, disease modifying anti–rheumatic drugs (except azathioprine, cyclosporine and cyclophosphamide) and pain medications at the discretion of their physicians. Patients gave written informed consent before study-related procedures began.

Study design
This was a randomized, double-blind, placebo-controlled safety study. Randomization was stratified by diagnosis of diabetes (with or without another comorbidity) and the diabetic stratum was further stratified by treatment with oral hypoglycaemic agents or insulin (or both therapies). Patients in each stratum were randomized in a 1:1 ratio to subcutaneous injections of placebo or etanercept (25 mg) twice weekly for 16 weeks. Institutional review boards approved the study protocol, patient informed consent and associated materials. Evaluations were performed at baseline, weeks 8 and 16, and 30 days post–therapy. The primary endpoint was the incidence of medically important infections (MIIs; defined as infections resulting in hospitalization or treatment with intravenous antibiotics). An independent data safety monitoring board (DSMB) was established before study initiation to periodically review unblinded safety data, recommend protocol modifications and propose early study termination if persuasive evidence was observed for futility or for harm or benefit attributable to etanercept.

Statistical considerations
The planned sample size (1000 patients) was based on literature estimates of infections in the general population. If the incidence of MIIs in the placebo group was 10% and the true relative risk was 2.0 (i.e. incidence of 20% in the etanercept group), the study design provided 84% power to detect the difference between treatment groups. If the observed incidence was substantially lower, the power would decrease considerably. Enrolment began in April 2000 and proceeded more slowly than expected. During an interim review, the DSMB found no safety issues that warranted stopping the trial, but noted that the incidence of MIIs was markedly lower than anticipated (3% overall), providing only 43% power to detect a 2-fold increase in the etanercept group over the expected 10% placebo incidence. After consultation with the FDA, the sponsor closed the study after 3.5 yrs and analysed the available data descriptively.


   Results
Top
 Abstract
 Introduction
 Patients and methods
 Results
Discussion
 Acknowledgement
 References
 
Patient characteristics, exposure and disposition
Forty-eight sites in the United States enrolled and randomized 564 patients; 535 patients received at least one dose of blinded-study medication and were analysed. At baseline, the treatment groups were well balanced demographically, and the distribution of specific comorbidities was generally similar across groups (Table 1). Although patients with recent myocardial infarction or uncontrolled hypertension were excluded, 81% of the population had cardiovascular conditions. The slightly numerically greater baseline cardiovascular risk for the etanercept group was not statistically significant, but the study had limited statistical power. The proportions of patients aged ≥65 yrs were 34.6 and 36.5% for the placebo and etanercept groups, respectively. The most common concomitant medications used during the study were methotrexate (55.4% placebo, 48.5% etanercept), prednisone (51.3% placebo, 49.6% etanercept) and celecoxib (22.7% placebo, 21.4% etanercept).


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  		TABLE 1. Demographic characteristics and comorbid diseases at baseline

 
Patient compliance was high in both treatment groups. Ninety-eight percent of doses were self administered or received on schedule. Twice as many placebo patients discontinued study treatment prematurely (27.9% placebo, 13.9% etanercept) and the most common reason was lack of efficacy (13.8% placebo, 2.3% etanercept). Three etanercept patients discontinued treatment because of death; three additional patients (1 placebo, 2 etanercept) discontinued treatment for other reasons but died on study. Adverse events led to the withdrawal of 31 patients from treatment (6.7% placebo, 4.9% etanercept).

Adverse events
The incidence of adverse events was similar in the treatment groups overall and regardless of the presence or absence of diabetes or of chronic pulmonary disease. The incidence of serious adverse events (e.g. events that necessitate hospitalization, are life threatening, or result in significant disability or death) was 5.9% in the placebo group and 8.6% in the etanercept group. No single event occurred in more than three patients per group. When adjusted for time on study, serious adverse event rates were 0.24 and 0.34 events per patient-year for the placebo and etanercept groups, respectively. Etanercept was associated with small increases in the incidence of serious adverse events in patients with diabetes and chronic pulmonary disease (Table 2), but the increases were not attributable to any single event and the relative risk (RR) was not significantly elevated in either comorbidity group [diabetes RR (95% CI) = 1.34 (0.59, 3.08); chronic pulmonary disease RR (95% CI) = 1.58 (0.65, 3.87)]. Five malignancies were reported during the study [three placebo (carcinoma not otherwise specified, lung carcinoma and skin cancer); two etanercept (both skin cancer)]. Serious cardiovascular adverse events (e.g. heart failure, coronary artery disease, myocardial infarction, cerebrovascular events) occurred more often in the etanercept group (2.6% placebo, 4.9% etanercept). All but one patient with serious cardiovascular events had multiple risk factors; clinical review of the data did not suggest a clinically relevant difference between treatment groups.


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  		TABLE 2. Incidence of medically important infections and serious adverse events

 
Six patients died on study [one placebo (cardiac arrest); five etanercept (cardiac arrest, cardiomyopathy, coronary artery disease, respiratory failure and subarachnoid haemorrhage)]. All six patients had cardiovascular risk factors, four had a history of methotrexate therapy (two ongoing), four had previously received prednisone and one was receiving celecoxib. The relative risk of death for the etanercept group did not reach statistical significance [RR (95% CI) = 5.06 (0.59–42.99)]. An additional post-study death occurred in a patient who died from community-acquired pneumonitis 43 days after the final dose of etanercept. All deaths occurred in patients older than 60 yrs of age (range 61–84 yrs). No death was attributed to study treatment by the investigators.

Infections
Overall, 42% of patients experienced at least one infection during the study (43.5% placebo, 39.8% etanercept) and the incidence of infection was similar between subgroups (i.e. presence or absence of diabetes or of chronic pulmonary disease). No unusual or opportunistic infections were observed.

MIIs were infrequent (3.7% placebo, 3.0% etanercept) and the risk was not elevated in the etanercept group [RR (95% CI) = 0.81 (0.32, 2.02)]. The rates of MIIs were 0.115 and 0.111 events per patient-year for placebo and etanercept, respectively. Pneumonia was the most common type of MII, occurring in eight patients (three placebo, five etanercept), seven of whom had chronic pulmonary diseases. Bronchitis was observed in three patients (two placebo, one etanercept). Events observed in two patients each were gastroenteritis (one placebo, one etanercept), sepsis (zero placebo, two etanercept) and urinary tract infection (one placebo, one etanercept). Events observed in single patients were colitis (etanercept) and abscess, cellulitis and pyogenic arthritis (placebo). Seven patients (2.6%) in each treatment group were hospitalized for treatment of MIIs.

Subgroup analyses revealed no treatment-related patterns in MIIs (Table 2). The overall incidence of MIIs in diabetic patients was similar to that in non-diabetic patients and the relative risk in etanercept-treated patients was not elevated in the diabetes subgroup [RR (95% CI) = 0.61 (0.15, 2.48)]. MIIs occurred slightly more often in patients with chronic pulmonary disease compared with patients without, but the risk was not elevated for etanercept-treated patients [RR (95% CI) = 0.77 (0.24, 2.45)]. Although MIIs were more common in patients ≥65 yrs of age (7.5% placebo, 7.2% etanercept) than in younger patients (1.7% placebo, 0.6% etanercept), the incidence in each age group was similar between treatment groups.


   Discussion
Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
Acknowledgement
 References
 
This study was designed to evaluate the effect of etanercept treatment on MIIs and other adverse events in RA patients with comorbidities, a population considered to be at high risk. The study population also included many patients at least 65 yrs of age, a group in which infections occur more frequently than in younger adults [4]. Early termination of the study limited its statistical power. Accordingly, the inferences that can be derived and the ability to distinguish differences between treatment groups are limited, particularly for infrequent events.

The incidence of serious adverse events in etanercept-treated patients (8.6%) was slightly higher than that reported in the product label (5%) [5], presumably due to the selection of patients with comorbidities. Serious adverse events occurred most often in the cardiovascular system in both treatment groups; interpretation of the difference between groups is confounded by the slightly higher baseline cardiovascular risk in the etanercept group. Four deaths (one placebo, three etanercept) were attributed to cardiovascular events, consistent with the reported association of RA with cardiovascular abnormalities and mortality [1, 2, 6, 7].

The observed imbalance in on-study mortality (six patients died, five taking etanercept) was not statistically significant and the deaths should be interpreted in the context of excess mortality expected in these patients, 81% of whom had one or more cardiovascular conditions. Mortality among RA patients is generally considered to be elevated about 2-fold compared with the general population [2, 6, 8] and estimates of the relative risks associated with cardiovascular, pulmonary and diabetic disease range from 1.5 to over 5.0 [9–13]. If the true mortality in this high-risk population is assumed to be three times that of the general population, mortality for all patients is consistent with expectations [standardized mortality ratio (SMR) = 0.93 (95% CI: 0.34–2.02)] and the SMR for etanercept-treated patients is 1.50 (95% CI: 0.49–3.50). Mortality in the placebo group was unexpectedly low, but the CI was wide, reflecting the study's limited statistical power.

As expected for this study population, the overall incidences of infections (39.8%) and infections requiring hospitalization (2.6%) in the etanercept group were slightly higher than those reported in the product label (35% and 1%, respectively). MIIs were infrequent, and the incidences (3.7% placebo, 3.0% etanercept) and rates (0.115 and 0.111 events per patient-year for placebo and etanercept, respectively) were comparable between groups. These rates are slightly higher than those previously reported for etanercept trials in RA (0.04 and 0.09 events per patient-year for patients <65 and ≥65 yrs, respectively) [4] and for MII rates in patients with less comorbidity (0.051 etanercept, 0.055 infliximab and 0.052 adalimumab) [14]. Similarly, rates of infections resulting in hospitalization for RA patients in the pre-TNF antagonist era range from 0.03 to 0.12 events per patient-year [15–18]. In both treatment groups, MIIs occurred more often in patients aged ≥65 yrs than in younger patients and more frequently in patients with chronic pulmonary disease than in patients without; the incidence of MIIs in patients with diabetes was not elevated in this study. However, no treatment-related patterns were detected in these subgroup analyses.

The safety profile of etanercept in this study was generally consistent with previous observations and with the concept that etanercept does not increase the risk of infection in RA patients with comorbidities. Serious adverse events and deaths occurred more frequently in the etanercept group, but event numbers were small and CIs were broad, preventing reliable conclusions from being drawn regarding the significance of the events.

Formula


   Acknowledgement
Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 Acknowledgement
References
 
The authors would like to thank Roberta Connelly and Cheri Osteen for their assistance in the drafting of this manuscript.

This research was funded by Immunex Corporation, a wholly owned subsidiary of Amgen Inc., and by Wyeth Pharmaceuticals. Dr Weisman has received research support and honoraria from Amgen. For this study, Dr Baumgartner, Dr Burch and Dr Kivitz received research support from Amgen, Mr Kerr served as a consultant for Amgen and Dr Paulus, Dr Fierer and Dr Weisman were members of the Data Safety Monitoring Board. Ms Dunn, Dr Tsuji and Dr Baumgartner currently are employees of Amgen.


   References
Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 Acknowledgement
 References
 

  1. Doran MF, Crowson CS, Pond GR, O'Fallon WM, Gabriel SE. Predictors of infection in rheumatoid arthritis. Arthritis Rheum (2002) 46:2294–300.[CrossRef][ISI][Medline]
  2. Wolfe F, Mitchell DM, Sibley JT, et al. The mortality of rheumatoid arthritis. Arthritis Rheum (1994) 37:481–94.[ISI][Medline]
  3. Arnett FC, Edworthy SM, Bloch DA, et al. The American Rheumatism Association 1987 revised criteria for the classification of rheumatoid arthritis. Arthritis Rheum (1988) 31:315–24.[ISI][Medline]
  4. Fleischmann RM, Baumgartner SW, Tindall EA, et al. Response to etanercept (Enbrel) in elderly patients with rheumatoid arthritis: a retrospective analysis of clinical trial results. J Rheumatol (2003) 30:691–6.[ISI][Medline]
  5. Enbrel®. etanercept. (2006) Thousand Oaks, CA: Immunex Corporation, marketed by Amgen and Wyeth Pharmaceuticals.
  6. Symmons DP, Jones MA, Scott DL, Prior P. Longterm mortality outcome in patients with rheumatoid arthritis: early presenters continue to do well. J Rheumatol (1998) 25:1072–7.[ISI][Medline]
  7. Nicola PJ, Maradit-Kremers H, Roger VL, et al. The risk of congestive heart failure in rheumatoid arthritis: a population-based study over 46 years. Arthritis Rheum (2005) 52:412–20.[CrossRef][ISI][Medline]
  8. Goodson N, Marks J, Lunt M, Symmons D. Cardiovascular admissions and mortality in an inception cohort of patients with rheumatoid arthritis with onset in the 1980s and 1990s. Ann Rheum Dis (2005) 64:1595–601.[Abstract/Free Full Text]
  9. Kannel WB, Wilson PW, D’Agostino RB, Cobb J. Sudden coronary death in women. Am Heart J (1998) 136:205–12.[CrossRef][ISI][Medline]
  10. Garcia-Aymerich J, Sunyer J, Domingo-Salvany A, et al. Differences in mortality between patients attending the emergency room services for asthma and chronic obstructive pulmonary disease. Respir Med (1999) 93:822–6.[CrossRef][ISI][Medline]
  11. Roper NA, Bilous RW, Kelly WF, Unwin NC, Connolly VM. Excess mortality in a population with diabetes and the impact of material deprivation: longitudinal, population based study. Br Med J (2001) 322:1389–93.[Abstract/Free Full Text]
  12. Bertoni AG, Krop JS, Anderson GF, Brancati FL. Diabetes-related morbidity and mortality in a national sample of U.S. elders. Diabetes Care (2002) 25:471–5.[Abstract/Free Full Text]
  13. Bjornadal L, Baecklund E, Yin L, Granath F, Klareskog L, Ekbom A. Decreasing mortality in patients with rheumatoid arthritis: results from a large population based cohort in Sweden, 1964–95. J Rheumatol (2002) 29:906–12.[ISI][Medline]
  14. Dixon WG, Watson K, Lunt M, Hyrich KL, Silman AJ, Symmons DP. Rates of serious infection, including site-specific and bacterial intracellular infection, in rheumatoid arthritis patients receiving anti-tumor necrosis factor therapy: results from the British Society for Rheumatology Biologics Register. Arthritis Rheum (2006) 54:2368–76.[CrossRef][ISI][Medline]
  15. Doran MF, Crowson CS, O'Fallon WM, Gabriel SE. Predictors of serious infections in rheumatoid arthritis (RA) [abstract]. Arthritis Rheum (2000) 43:S134.
  16. Jeurissen ME, Boerbooms AM, van de Putte LB, et al. Methotrexate versus azathioprine in the treatment of rheumatoid arthritis. A forty-eight-week randomized, double-blind trial. Arthritis Rheum (1991) 34:961–72.[ISI][Medline]
  17. Schnabel A, Herlyn K, Burchardi C, Reinhold-Keller E, Gross WL. Long-term tolerability of methotrexate at doses exceeding 15 mg per week in rheumatoid arthritis. Rheumatol Int (1996) 15:195–200.[CrossRef][ISI][Medline]
  18. Singh G, Ramey DR, Rausch PL, Schettler JD. Serious infections in rheumatoid arthritis: relationship to immunosuppressive use [abstract]. Arthritis Rheum (1999) 42:S242.
Submitted 26 August 2006; revised version accepted 24 January 2007.
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