Effectiveness of Etanercept for Idiopathic Pneumonia Syndrome Following Stem Cell Transplantation (BMT CTN 0403)
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|ClinicalTrials.gov Identifier: NCT00421174|
Recruitment Status : Completed
First Posted : January 11, 2007
Results First Posted : May 16, 2016
Last Update Posted : November 1, 2021
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|Condition or disease||Intervention/treatment||Phase|
|Pneumonia Idiopathic Pneumonia Syndrome||Drug: Etanercept Drug: Placebo plus corticosteroid||Phase 3|
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.
|Study Type :||Interventional (Clinical Trial)|
|Actual Enrollment :||37 participants|
|Intervention Model:||Parallel Assignment|
|Masking:||Double (Participant, Investigator)|
|Official Title:||A Randomized Double-Blind, Placebo-Controlled Trial of Soluble Tumor Necrosis Factor Receptor: Enbrel (Etanercept) for the Treatment of Acute Idiopathic Pneumonia Syndrome Following Allogeneic Cell Transplantation (BMTCTN0403)|
|Study Start Date :||August 2007|
|Actual Primary Completion Date :||June 2010|
|Actual Study Completion Date :||July 2013|
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.
Other Name: Enbrel®
Active Comparator: Placebo
Placebo plus Corticosteroids
Drug: Placebo plus 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.
Other Name: Methylprednisolone
- Response Rate [ Time Frame: Day 28 ]Response will be defined as survival to Day 28 of study, plus discontinuation of all supplemental oxygen support for more than 72 consecutive hours by Day 28.
- Response to Therapy [ Time Frame: Day 56 ]Response will be defined as the ability to survive to Day 56 of study, plus the ability to completely discontinue all supplemental oxygen support for > 72 consecutive hours during this time period.
- Discontinuation of Supplemental Oxygen [ Time Frame: Day 56 ]The "time required to discontinue supplemental oxygen" will be measured in the number of days from study entry.
- Corticosteroid Dose [ Time Frame: Day 14 and 28 ]Patients were treated with systemic corticosteroids with methylprednisolone at 2 mg/kg/day on day 0, with taper allowed after day 7.
- Overall Survival [ Time Frame: Year 1 ]Percentage of patients that survived after one year
- Incidence of Infection [ Time Frame: Day 56 ]
- Incidence of Toxicity [ Time Frame: Day 56 ]
- Incidence of Graft-vs-Host-Disease (GVHD) [ Time Frame: Year 1 ]
- Incidence of Relapse [ Time Frame: Year 1 ]Percentage of patients who experience relapse. Deaths without relapse are considered as a competing risk.
- Overall Mortality [ Time Frame: Year 2 ]
- Dermatologic Reaction [ Time Frame: Day 28 ]
- Pro-inflammatory Markers of Pulmonary Disease, in Both BAL Fluid and Plasma [ Time Frame: Day 28 ]
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.
|Ages Eligible for Study:||18 Years and older (Adult, Older Adult)|
|Sexes Eligible for Study:||All|
|Accepts Healthy Volunteers:||No|
Patients fulfilling the following criteria will be eligible for registration in this study:
- Recipient of an allogeneic bone marrow, cord blood, or peripheral blood stem cell transplant. There are no restrictions based upon underlying disease, donor source, degree of human leukocyte antigen (HLA) match, intensity of the pre-transplant conditioning regimen, or the use of a prior donor leukocyte infusion
- Evidence of acute lung injury, based upon the presence of bilateral pulmonary infiltrates (on chest radiograph) and a supplemental oxygen requirement
- No more than 180 days post transplant
Patients fulfilling the following criteria will be eligible for random assignment in this study:
- BAL fluid negative for pathogenic microorganisms as assessed by gram stain and fungal stain
BAL fluid negative for pathogenic microorganisms, or test result pending, as assessed by the following tests:
- Acid fast bacilli stain (AFB)
- Bacterial culture (a quantitative culture of at least 10(4) CFU/mL is considered positive)
- Viral cultures for respiratory pathogens, including Respiratory syncytial virus (RSV), adenovirus, parainfluenza, influenza A and B, and Cytomegalovirus (CMV)
- Fungal and mycobacterial cultures
- Pneumocystis carinii pneumonia (PCP) assay, by polymerase chain reaction (PCR), direct fluorescent antibody (DFA) stain, or cytology (per institutional guidelines)
- Sepsis syndrome or hypotension in which inotropic support (excluding dopamine of no more than 5 mcg/kg/minute) is required
- Bacteremia within 48 hours prior to study registration
- Documented invasive fungal or systemic viral infection (excluding asymptomatic viruria) within 14 days prior to study registration
- Evidence of CMV infection, based upon an abnormal PCR assay, antigenemia assay, or shell vial culture within 14 days of study registration
- On mechanical ventilation for more than 48 hours at study registration
- Evidence of congestive heart failure by clinical assessment
- Participating in other investigational studies (Phase I, II, or III) for the treatment of acute GVHD within 7 days of study registration (patients enrolled in BMT CTN 0302 are ineligible for study entry)
- Received etanercept within 14 days prior to study registration
- Pregnant or breastfeeding
- On more than 2 mg/kg/day of methylprednisolone equivalent for more than 48 hours, within 7 days prior to study registration
- Known hypersensitivity to etanercept
- History of active tuberculosis (TB) infection
- History of chronic active hepatitis B or hepatitis C infection
- Patients who have undergone a BAL within 72 hours of study registration are ineligible if the BAL fluid is known to be positive for pathogenic microorganisms
- Patients who have relapsed or have developed progressive disease post-transplant
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT00421174
|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|
|Study Director:||Mary Horowitz, MD||Center for International Blood and Marrow Transplant Research|
Documents provided by National Heart, Lung, and Blood Institute (NHLBI):
Publications of Results:
|Responsible Party:||National Heart, Lung, and Blood Institute (NHLBI)|
|Other Study ID Numbers:||
BMTCTN0403 ( Other Identifier: Blood and Marrow Transplant Clinicial Trials Network )
U01HL069294-05 ( U.S. NIH Grant/Contract )
465 ( Other Identifier: BMT CTN )
|First Posted:||January 11, 2007 Key Record Dates|
|Results First Posted:||May 16, 2016|
|Last Update Posted:||November 1, 2021|
|Last Verified:||August 2017|
|Individual Participant Data (IPD) Sharing Statement:|
|Plan to Share IPD:||Yes|
|Plan Description:||Results will be published in a manuscript and supporting information submitted to NIH BioLINCC (including data dictionaries, case report forms, data submission documentation, documentation for outcomes dataset, etc where indicated).|
Informed Consent Form (ICF)
|Time Frame:||Within 6 months of official study closure at participating sites.|
|Access Criteria:||Available to the public|
Respiratory Tract Infections
Respiratory Tract Diseases
Peripheral Nervous System Agents
Physiological Effects of Drugs
Hormones, Hormone Substitutes, and Hormone Antagonists
Anti-Inflammatory Agents, Non-Steroidal
Sensory System Agents