Effectiveness of Etanercept for Idiopathic Pneumonia Syndrome Following Stem Cell Transplantation (BMT CTN 0403)

Tracking Information
First Submitted Date ICMJE	January 9, 2007
First Posted Date ICMJE	January 11, 2007
Results First Submitted Date	January 28, 2016
Results First Posted Date	May 16, 2016
Last Update Posted Date	September 25, 2017
Study Start Date ICMJE	August 2007
Actual Primary Completion Date	June 2010 (Final data collection date for primary outcome measure)
Current Primary Outcome Measures ICMJE; (submitted: April 8, 2016)	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.
Original Primary Outcome Measures ICMJE; (submitted: January 9, 2007)	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)
Change History	Complete list of historical versions of study NCT00421174 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures ICMJE; (submitted: October 25, 2016)	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 ]
Original Secondary Outcome Measures ICMJE; (submitted: January 9, 2007)	Response to therapy at Day 56; Overall Mortality; Discontinuation of supplemental oxygen; Pro-inflammatory Markers of Pulmonary Disease, in Both BAL Fluid and Plasma
Current Other Outcome Measures ICMJE	Not Provided
Original Other Outcome Measures ICMJE	Not Provided
Descriptive Information
Brief Title ICMJE	Effectiveness of Etanercept for Idiopathic Pneumonia Syndrome Following Stem Cell Transplantation (BMT CTN 0403)
Official Title ICMJE	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)
Brief Summary	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).
Detailed Description	BACKGROUND: 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. DESIGN NARRATIVE: 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 ICMJE	Interventional
Study Phase	Phase 3
Study Design ICMJE	Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Double (Participant, Investigator); Primary Purpose: Treatment
Condition ICMJE	Pneumonia; Idiopathic Pneumonia Syndrome
Intervention ICMJE	Drug: Etanercept 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®; 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
Study Arms	Experimental: Etanercept Etanercept plus corticosteroids Intervention: Drug: Etanercept; Active Comparator: Placebo Placebo plus Corticosteroids Intervention: Drug: Placebo plus corticosteroid
Publications *	Yanik GA, Horowitz MM, Weisdorf DJ, Logan BR, Ho VT, Soiffer RJ, Carter SL, Wu J, Wingard JR, Difronzo NL, Ferrara JL, Giralt S, Madtes DK, Drexler R, White ES, Cooke KR. Randomized, double-blind, placebo-controlled trial of soluble tumor necrosis factor receptor: enbrel (etanercept) for the treatment of idiopathic pneumonia syndrome after allogeneic stem cell transplantation: blood and marrow transplant clinical trials network protocol. Biol Blood Marrow Transplant. 2014 Jun;20(6):858-64. doi: 10.1016/j.bbmt.2014.02.026. Epub 2014 Mar 7.
* Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
Recruitment Information
Recruitment Status ICMJE	Completed
Actual Enrollment ICMJE; (submitted: October 30, 2013)	37
Original Enrollment ICMJE; (submitted: January 9, 2007)	120
Actual Study Completion Date	July 2013
Actual Primary Completion Date	June 2010 (Final data collection date for primary outcome measure)
Eligibility Criteria ICMJE	Inclusion Criteria: 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) Exclusion Criteria: 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
Sex/Gender	Sexes Eligible for Study: All
Ages	18 Years and older (Adult, Senior)
Accepts Healthy Volunteers	No
Contacts ICMJE	Contact information is only displayed when the study is recruiting subjects
Listed Location Countries ICMJE	United States
Removed Location Countries
Administrative Information
NCT Number ICMJE	NCT00421174
Other Study ID Numbers ICMJE	BMTCTN0403; BMT CTN 0403 ( Other Identifier: Blood and Marrow Transplant Clinicial Trials Network ); U01HL069294-05 ( U.S. NIH Grant/Contract ); 465 ( Other Identifier: BMT CTN )
Has Data Monitoring Committee	Yes
U.S. FDA-regulated Product	Not Provided
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). Supporting Materials: Study Protocol Supporting Materials: Informed Consent Form (ICF) Time Frame: Within 6 months of official study closure at participating sites. Access Criteria: Available to the public URL: https://biolincc.nhlbi.nih.gov/home/
Responsible Party	National Heart, Lung, and Blood Institute (NHLBI)
Study Sponsor ICMJE	National Heart, Lung, and Blood Institute (NHLBI)
Collaborators ICMJE	Blood and Marrow Transplant Clinical Trials Network; National Cancer Institute (NCI); National Marrow Donor Program
Investigators ICMJE	Study Director: Mary Horowitz, MD Center for International Blood and Marrow Transplant Research
PRS Account	National Heart, Lung, and Blood Institute (NHLBI)
Verification Date	August 2017
ICMJE Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP