Effectiveness of Etanercept for Idiopathic Pneumonia Syndrome Following Stem Cell Transplantation (BMT CTN 0403)
The study is designed as a Phase III, multi-center randomized, double-blind, placebo-controlled trial investigating the use of etanercept for the treatment of acute, non-infectious pulmonary dysfunction (IPS) occurring after allogeneic hematopoietic cell transplantation (HCT).
Idiopathic Pneumonia Syndrome
Drug: Placebo + corticosteroid
|Study Design:||Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Investigator)
Primary Purpose: Treatment
|Official Title:||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)|
- 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) [ Time Frame: Day 28 ] [ Designated as safety issue: No ]
- Response to therapy at Day 56 [ Time Frame: Day 56 ] [ Designated as safety issue: No ]
- Overall mortality [ Time Frame: Day 28, 56 and 1 year ] [ Designated as safety issue: Yes ]
- Discontinuation of supplemental oxygen [ Time Frame: Day 28 and 56 ] [ Designated as safety issue: No ]
- Pro-inflammatory markers of pulmonary disease, in both BAL fluid and plasma [ Time Frame: Day 28 ] [ Designated as safety issue: No ]
- Serious infection [ Time Frame: Day 28 ] [ Designated as safety issue: Yes ]
- Dermatologic reaction [ Time Frame: Day 28 ] [ Designated as safety issue: Yes ]
|Study Start Date:||August 2007|
|Estimated Study Completion Date:||July 2013|
|Estimated Primary Completion Date:||July 2012 (Final data collection date for primary outcome measure)|
Etanercept plus corticosteroids
Etanercept will be given eight doses of study drug over a 4-week period. The initial dose of etanercept will be administered intravenously on Day 0, with subsequent doses administered subcutaneously (SQ). Dosing will be administered twice weekly over 4 consecutive weeks. Additionally, patients in both arms will receive corticosteroids (2 mg/kg/day) Day 0 through Day 7, with subsequent taper as clinically indicated.
Active Comparator: 2
Drug: Placebo + corticosteroid
Patients will receive a total of eight doses of placebo over a 4-week period. The initial dose of 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.
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 undertaken.
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 entry.
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 cases.
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.
|United States, Florida|
|University of Florida College of Medicine (Shands)|
|Gainesville, Florida, United States, 32610|
|United States, Indiana|
|Indiana University Medical Center|
|Indianapolis, Indiana, United States, 46202|
|United States, Maryland|
|Johns Hopkins University|
|Baltimore, Maryland, United States, 21218|
|United States, Massachusetts|
|DFCI/Partners Cancer Center|
|Boston, Massachusetts, United States, 02118|
|United States, Michigan|
|University of Michigan Medical Center|
|Ann Arbor, Michigan, United States, 48105|
|United States, Minnesota|
|University of Minnesota|
|Minneapolis, Minnesota, United States, 55455|
|Rochester, Minnesota, United States, 55905|
|United States, Nebraska|
|University of Nebraska Medical Center|
|Omaha, Nebraska, United States, 68198-7680|
|United States, New York|
|Memorial Sloan Kettering Cancer Center|
|New York, New York, United States, 10174|
|United States, Pennsylvania|
|University of Pennsylvania Cancer Center|
|Philadelphia, Pennsylvania, United States, 19104|
|United States, Texas|
|University of Texas/MD Anderson Cancer Center|
|Houston, Texas, United States, 77030|
|United States, Washington|
|Fred Hutchinson Cancer Research Center|
|Seattle, Washington, United States, 98109|
|Principal Investigator:||John Wingard, MD||University of Florida College of Medicine (Shands)|
|Principal Investigator:||Jennifer Schwartz, MD||Indiana University School of Medicine|
|Principal Investigator:||Javier Bolanos-Meade, MD||Johns Hopkins University|
|Principal Investigator:||Vincent Ho, MD||DFCI/Partners Cancer Center|
|Study Chair:||Gregory Yanik, MD||University of Michigan|
|Principal Investigator:||Brian McClune, DO||University of Minnesota - Clinical and Translational Science Institute|
|Principal Investigator:||Bekele Afessa, MD||Mayo Clinic|
|Principal Investigator:||Gwynn Long, MD||Duke University|
|Principal Investigator:||Hillard Lazarus, MD||University Hospitals of Cleveland/Case Western|
|Principal Investigator:||Edward Stadtmann, MD||University of Pennsylvania|
|Principal Investigator:||Sergio Giralt, MD||M.D. Anderson Cancer Center|
|Principal Investigator:||David Madtes, MD||Fred Hutchinson Cancer Research Center|
|Principal Investigator:||Jan Jansen, MD, PhD||Indiana BMT at Beech Grove|
|Principal Investigator:||Hugo Castro-Malaspina, MD||Memorial Sloan-Kettering Cancer Center|
|Principal Investigator:||Brandon Hayes-Lattin, MD||Oregon Health and Science University|