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

Study Overview
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Brief Summary
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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
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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.

Official Title
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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)

Conditions
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Pneumonia, Idiopathic Pneumonia Syndrome

Intervention / Treatment
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* Drug: Etanercept
* Drug: Placebo plus corticosteroid


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Etanercept<br>Etanercept plus corticosteroids | Drug: Etanercept<br>* 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.<br>* Other names: Enbrel®;|
| Active Comparator: Placebo<br>Placebo plus Corticosteroids | Drug: Placebo plus corticosteroid<br>* 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.<br>* Other names: Methylprednisolone;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Response Rate | 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. | Day 28 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Response to Therapy | 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. | Day 56 | 
| Discontinuation of Supplemental Oxygen | The time required to discontinue supplemental oxygen will be measured in the number of days from study entry. | Day 56 | 
| Corticosteroid Dose | Patients were treated with systemic corticosteroids with methylprednisolone at 2 mg/kg/day on day 0, with taper allowed after day 7. | Day 14 and 28 | 
| Overall Survival | Percentage of patients that survived after one year | Year 1 | 
| Incidence of Infection |  | Day 56 | 
| Incidence of Toxicity |  | Day 56 | 
| Incidence of Graft-vs-Host-Disease (GVHD) |  | Year 1 | 
| Incidence of Relapse | Percentage of patients who experience relapse. Deaths without relapse are considered as a competing risk. | Year 1 | 
| Overall Mortality |  | Year 2 | 
| Dermatologic Reaction |  | Day 28 | 
| Pro-inflammatory Markers of Pulmonary Disease, in Both BAL Fluid and Plasma |  | Day 28 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Etanercept, IPS