Clinical trial NCT00421174: Effectiveness of Etanercept for Idiopathic Pneumonia Syndrome Following Stem Cell Transplantation (BMT CTN 0403)
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 type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Pneumonia
Idiopathic Pneumonia Syndrome
Keywords: Etanercept
IPS
Lead sponsor: National Heart, Lung, and Blood Institute (NHLBI)
Sponsor class: NIH
Collaborators: name: Blood and Marrow Transplant Clinical Trials Network
name: National Cancer Institute (NCI)
name: National Marrow Donor Program
First posted: 2007-01-11
Enrollment: 37
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

Eligibility criteria: 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:

  1. Acid fast bacilli stain (AFB)
  2. Bacterial culture (a quantitative culture of at least 10(4) CFU/mL is considered positive)
  3. Viral cultures for respiratory pathogens, including Respiratory syncytial virus (RSV), adenovirus, parainfluenza, influenza A and B, and Cytomegalovirus (CMV)
  4. Fungal and mycobacterial cultures
  5. 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

Primary outcomes:
measure: Response Rate
timeFrame: Day 28
Secondary outcomes:
measure: Response to Therapy
timeFrame: Day 56
measure: Discontinuation of Supplemental Oxygen
timeFrame: Day 56
measure: Corticosteroid Dose
timeFrame: Day 14 and 28
measure: Overall Survival
timeFrame: Year 1
measure: Incidence of Infection
timeFrame: Day 56
measure: Incidence of Toxicity
timeFrame: Day 56
measure: Incidence of Graft-vs-Host-Disease (GVHD)
timeFrame: Year 1
measure: Incidence of Relapse
timeFrame: Year 1
measure: Overall Mortality
timeFrame: Year 2
measure: Dermatologic Reaction
timeFrame: Day 28
measure: Pro-inflammatory Markers of Pulmonary Disease, in Both BAL Fluid and Plasma
timeFrame: Day 28
Other outcomes:
Locations:
city: Gainesville
country: United States
facility: University of Florida College of Medicine (Shands)
state: Florida
city: Indianapolis
country: United States
facility: Indiana University Medical Center
state: Indiana
city: Baltimore
country: United States
facility: Johns Hopkins University
state: Maryland
city: Boston
country: United States
facility: DFCI/Partners Cancer Center
state: Massachusetts
city: Ann Arbor
country: United States
facility: University of Michigan Medical Center
state: Michigan
city: Minneapolis
country: United States
facility: University of Minnesota
state: Minnesota
city: Rochester
country: United States
facility: Mayo Clinic
state: Minnesota
city: Omaha
country: United States
facility: University of Nebraska Medical Center
state: Nebraska
city: New York
country: United States
facility: Memorial Sloan Kettering Cancer Center
state: New York
city: Philadelphia
country: United States
facility: University of Pennsylvania Cancer Center
state: Pennsylvania
city: Houston
country: United States
facility: University of Texas/MD Anderson Cancer Center
state: Texas
city: Seattle
country: United States
facility: Fred Hutchinson Cancer Research Center
state: Washington
Study officials:
affiliation: Center for International Blood and Marrow Transplant Research
name: Mary Horowitz, MD
role: STUDY_DIRECTOR
References:
citation: 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.