A Randomized Double-Blind, Placebo-Controlled Trial of Soluble Tumor Necrosis Factor Receptor: Enbrel (Etanercept) for the Treatment of Acute Non-Infectious Pulmonary Dysfunction (Idiopathic Pneumonia Syndrome) Following Allogeneic Cell Transplantation (BMT CTN #0403)
Over the last two decades, allogeneic hematopoietic cell transplantation (HCT) has emerged
as an important treatment for a number of malignant and non-malignant disorders.
Unfortunately, several complications, including graft-versus-host disease (GVHD) and
pulmonary dysfunction, limit the utility of this aggressive form of therapy. Infectious and
non-infectious lung complications occur in 25% to 55% of HCT recipients and account for up
to 50% of transplant-related mortality. In about half of affected patients, no infectious
organisms are identified in the lungs. Two major types of non-infectious pulmonary injury
are recognized: acute idiopathic pneumonia syndrome (IPS) and sub-acute lung injury
(obstructive airway disease or bronchiolitis obliterans [BrOb] and restrictive lung
disease). The current study will examine the use of etanercept in patients with IPS.
Eligible patients will be randomized to receive one of two arms of therapy: (A) etanercept
plus corticosteroids, or (B) placebo plus corticosteroids. Patients will receive a total of
eight doses of etanercept (or placebo) over a 4-week period. The initial dose of etanercept
(or placebo) will be administered intravenously on Day 0, with subsequent doses administered
subcutaneously (SQ). Dosing will be administered twice weekly over 4 consecutive weeks.
The placebo will be the inert diluent used for the etanercept formulation.
Additionally, patients in both arms will receive corticosteroids (2 mg/kg/day) Day 0 through
Day 7, with subsequent taper as clinically indicated. Chest radiographs shall be obtained
weekly through Day 28. Plasma cytokine profiles will be obtained on Days 0, 7, and 28.
For patients < 30 days post-transplant: If the patient's clinical condition is such that a
broncho-alveolar lavage (BAL) is deemed "not possible to be performed" by the treating
physician (or pulmonologist), then the "on study" BAL may be waived. In such circumstances,
the patient may register and be randomized to study therapy without the BAL being
For patients not on mechanical ventilation: If a BAL is not done, appropriate virology
studies on a nasal swab (or nasal washing) are required as a minimum procedure to study
For patients on mechanical ventilation: Microbiologic studies of a deep endotracheal
aspirate are allowed in lieu of a formal bronchoscopy procedure. However, no
protocol-specified biologic studies (see Section 4.4) will be done on these specimens.
For patients 31-180 days post-transplant: An "on study" bronchoscopy is required in all
If, at any point following initiation of study drug therapy, previously obtained BAL fluid
cultures or other BAL fluid analysis become positive for an infectious pathogen, study drug
therapy shall be discontinued at that point, and not re-instituted. The patient will
discontinue study drug therapy, but will still be followed for outcome.
The primary study endpoint is response at Day 28. Patients who discontinue study drug
therapy for any reason will still be followed for primary and secondary study endpoints.
Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Investigator), Primary Purpose: Treatment
Day 28 response rate (response will be defined as (a) survival to Day 28 of study, plus (b) discontinuation of all supplemental oxygen support for more than 72 consecutive hours by Day 28)
John Wingard, MD
University of Florida College of Medicine (Shands)
United States: Food and Drug Administration
|Johns Hopkins University||Baltimore, Maryland 21205|
|Memorial Sloan Kettering Cancer Center||New York, New York 10021|
|Mayo Clinic||Rochester, Minnesota 55905|
|Fred Hutchinson Cancer Research Center||Seattle, Washington 98109|
|University of Pennsylvania Cancer Center||Philadelphia, Pennsylvania 19104|
|University of Nebraska Medical Center||Omaha, Nebraska 68198-3330|
|University of Minnesota||Minneapolis, Minnesota 55455|
|University of Michigan Medical Center||Ann Arbor, Michigan 48104-0914|
|Indiana University Medical Center||Indianapolis, Indiana 46202|
|University of Florida College of Medicine (Shands)||Gainesville, Florida 32610|
|DFCI/Partners Cancer Center||Boston, Massachusetts 02118|
|University of Texas/MD Anderson Cancer Center||Houston, Texas 77030|