TNF-alpha Antagonists for AECOPD: A Randomized, Double-Blind, Placebo-Controlled Pilot Trial
TNF-alpha Antagonists for AECOPD: A Randomized, Double-Blind, Placebo-Controlled Pilot Trial
The purpose of this study is to determine whether treatment with antibiotics plus a TNFalpha
 antagonist will provide more effective treatment for acute COPD exacerbation compared to the
 current standard treatment of antibiotics plus prednisone.
Acute exacerbations of COPD (AECOPD)are usually treated with steroids and antibiotics.
 Currently this conventional therapy has significant side effects including osteoporosis,
 cataracts,and suppression of the immune system. Studies have suggested that up to 24% of
 inpatients and 27% of outpatients fail this treatment by 4 weeks. During an acute
 exacerbation of COPD, the inflammatory process increases. Studies have shown the TNF-alpha
 cytokines appears to play a major role. Etanercept is a TNF alpha inhibitor. It inactivates
 TNF alpha cytokines by blocking their interaction with their cellular receptors. This study
 will compare the treatment of acute exacerbations of COPD with: 1) Levofloxacin 750 mg daily
 for 10 days + prednisone 40 mg daily for 10 days, or 2) Levofloxacin 750 mg daily for 10 days
 + etanercept 50 mg subcutaneous given on the day of randomization and one week later.
 Patients randomized to group 1 (the control group) will receive placebo subcutaneous
 injections, and patients randomized to group 2 (the experimental group) will receive placebo
 prednisone capsules.
Inclusion Criteria:

 Both inpatients and outpatients with acute COPD exacerbation will be selected for
 randomization. Patients will be considered to fulfill the diagnosis of AECOPD if they meet
 the following 5 criteria:

 1. Patients must have had a previous diagnosis of chronic bronchitis, emphysema or COPD
 established by a physician.

 2. Patients must have evidence of airflow obstruction on presentation, defined as an
 forced expiratory volume at one second (FEV1) equal to or less than 70% of predicted
 and a FEV1 / forced vital capacity (FVC) ratio less 70%.

 3. Patients must be > 35 years old.

 4. Patients must have a minimum history of 10 pack years smoking.

 5. Patients must be experiencing an acute exacerbation of COPD and must meet at least two
 of the following three clinical criteria for acute COPD exacerbation as defined by
 Anthonisen:

 -  increased chronic baseline dyspnea,

 -  increased sputum volume or increased sputum purulence

 The above complaints had to have necessitated the emergency department or physician visit.

 Exclusion Criteria:

 1. Respiratory failure necessitating admission to an intensive care unit or necessitating
 use of mechanical invasive or non-invasive (BIPAP) mechanical ventilation.

 2. Physician diagnosed asthma.

 3. Any patient who has used oral or injectable corticosteroids during the month preceding
 trial entry will be excluded,except for patients who have received a single dose of
 oral or injectable steroids (up to the equivalent of 125 mg of methylprednisolone) in
 the emergency department prior to randomization. (Note that standard clinical practice
 in emergency departments is to treat these patients with oral or intravenous steroids
 on presentation to the ED. Since it will be functionally impossible to randomize
 patients prior to initial ED treatment we will allow randomization of patients who
 have been given a single dose of steroid in the ED).

 4. History of chronic lung disease other than COPD. Patients with a history of
 bronchiectasis, cystic fibrosis, lung cancer and interstitial lung disease.

 5. Pneumonia or congestive heart failure or suspected malignancy on chest x-ray (CXR)
 prior to randomization.

 6. Patients with a history of infection, or suspected current infection, with
 mycobacteria tuberculosis, non-tuberculous mycobacteria, or fungal infection.

 7. Patients not able to perform an FEV1 assessment.

 8. Patients with known adverse reaction or intolerance to systemic steroids or TNF-alpha
 antagonists.

 9. Patients with a history of multiple sclerosis or demyelinating disease (etanercept is
 contraindicated in these patients).

 10. Inability to provide informed consent or comply with the study protocol due to
 cognitive impairment, language barrier, or distance > 100 kilometres from the study
 centre.

 11. Patients with a history of HIV or other immuno-compromising diseases.

 12. Patients with a known malignancy within the past 5 years (except for squamous or basal
 cell carcinoma of the skin that was treated with no evidence of recurrence).

 13. Patients who have serum white blood cell count (WBC) < 3,000 or platelet count <
 100,000 at time of randomization.

 14. Patients who are pregnant or nursing will be excluded. Females of child-bearing age
 will be required to have a negative serum or urine pregnancy test before
 randomization.

 15. Patients with suspected sepsis- ie. those with temperature > 38.5 degrees or serum
 WBC> 20 000 will be excluded.

 16. Patients who have a history or active infection with viral Hepatitis B or Hepatitis C.