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

This study has been completed.
Sponsor:
Collaborators:
Blood and Marrow Transplant Clinical Trials Network
Information provided by (Responsible Party):
National Heart, Lung, and Blood Institute (NHLBI)
ClinicalTrials.gov Identifier:
NCT00421174
First received: January 9, 2007
Last updated: October 30, 2013
Last verified: October 2013
  Purpose

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).


Condition Intervention Phase
Pneumonia
Idiopathic Pneumonia Syndrome
Drug: Etanercept
Drug: Placebo + corticosteroid
Phase 3

Study Type: Interventional
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)

Resource links provided by NLM:


Further study details as provided by National Heart, Lung, and Blood Institute (NHLBI):

Primary Outcome Measures:
  • 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 ]

Secondary Outcome Measures:
  • 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 ]

Enrollment: 37
Study Start Date: August 2007
Study Completion Date: July 2013
Primary Completion Date: June 2010 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: 1
Etanercept plus corticosteroids
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.
Active Comparator: 2
Corticosteroids
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.


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

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
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 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 RSV, adenovirus, parainfluenza, influenza A and B, and CMV
    4. Fungal and mycobacterial cultures
    5. Pneumocystis carinii pneumonia (PCP) assay, by 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/U01 HL069294-05 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
  Contacts and Locations
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, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00421174

Locations
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
Mayo Clinic
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
Sponsors and Collaborators
Blood and Marrow Transplant Clinical Trials Network
Investigators
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
  More Information

Additional Information:
No publications provided

Responsible Party: National Heart, Lung, and Blood Institute (NHLBI)
ClinicalTrials.gov Identifier: NCT00421174     History of Changes
Other Study ID Numbers: 465, BMT CTN 0403, 5U 01H1069294
Study First Received: January 9, 2007
Last Updated: October 30, 2013
Health Authority: United States: Food and Drug Administration

Keywords provided by National Heart, Lung, and Blood Institute (NHLBI):
Etanercept
IPS

Additional relevant MeSH terms:
Pneumonia
Syndrome
Lung Diseases
Respiratory Tract Diseases
Respiratory Tract Infections
Disease
Pathologic Processes
TNFR-Fc fusion protein
Anti-Inflammatory Agents, Non-Steroidal
Analgesics, Non-Narcotic
Analgesics
Sensory System Agents
Peripheral Nervous System Agents
Physiological Effects of Drugs
Pharmacologic Actions
Anti-Inflammatory Agents
Therapeutic Uses
Antirheumatic Agents
Gastrointestinal Agents
Immunologic Factors
Immunosuppressive Agents
Central Nervous System Agents

ClinicalTrials.gov processed this record on September 16, 2014