Blood and Marrow Transplant Clinical Trials Network (BMT CTN) 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 (0403)
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August 2007 to July 2013
October 29, 2018
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To determine the response and survival rate of patients with idiopathic pneumonia syndrome (IPS) post allogeneic hematopoietic cell transplantation (HCT), following treatment with etanercept plus corticosteroids compared to placebo plus corticosteroids.
Idiopathic pneumonia syndrome (IPS) is a diffuse, noninfectious lung injury that occurs acutely after allogeneic hematopoietic cell transplantation (HCT) in nearly 50% of transplant recipients. The diagnosis of IPS is made by the presence of multilobar infiltrates on chest radiograph and clinical signs and symptoms of respiratory distress (hypoxemia, dyspnea, rales) without infectious etiology, as determined by a negative bronchoalveolar lavage (BAL).
IPS-related mortality has been historically high (>50%) despite treatment with high-dose systemic corticosteroids and supportive care measures which include supplemental oxygen and diuretics. More recently, studies suggest that including a tumor necrosis factor (TNF) inhibitor such as etanercept (Enbrel) with existing treatment measures results in better outcomes and survival rates.
Thirty-four people participated in this study. Participants were eligible if they were at least 18 years old and had received an allogeneic bone marrow, cord blood, or peripheral blood stem cell transplant within 180 days of enrollment. There were no restrictions on underlying disease, donor source, degree of HLA match, or conditioning regimen. There were also no restrictions based on hematologic, renal, or hepatic dysfunction. Participants with noninfectious, diffuse alveolar hemorrhage were also considered eligible for study inclusion because the condition is considered to be a subset of IPS. Eligible participants were required to meet National Institutes of Health Consensus criteria for IPS before study entry based on clinical findings, radiographic features, and BAL fluid analysis.
Participants with active infections, cytomegalovirus (CMV) viremia or CMV disease, a prior history of active tuberculosis, or chronic active hepatitis B or C infections were excluded from study entry. Those with pulmonary edema secondary to iatrogenic fluid overload or cardiac dysfunction, as evidenced by echocardiogram or clinical findings, were also ineligible. If a participant had received >2 mg/kg/day methylprednisolone equivalent for >48 hours within 7 days of study entry or required mechanical ventilation for >168 continuous hours before study entry, they were excluded.
This was randomized, double-blind, placebo-controlled trial where participants either received etanercept or a placebo. At study entry, all patients had a bronchoscopy with a bronchoalveolar lavage. Of the thirty-four enrolled participants, 16 were placed in the etanercept group and 18 were placed in the placebo group. Patients were to receive a total of 8 etanercept or placebo doses over a 24-day period. Etanercept was administered at .4 mg/kg/dose (maximum dose 25 mg), with the initial etanercept dose given as a 30-minute i.v. infusion in 100 mL of .9 normal saline to expedite the attainment of maximal plasma levels. Subsequent etanercept doses were given subcutaneously, twice weekly, for a total of 7 subcutaneous doses. Placebo doses were administered in a similar route and dilution.
In addition to receiving either etanercept or a placebo, participants were given corticosteroids at 2 mg/kg/day methylprednisolone (or corticosteroid equivalent), with dosing based on actual body weight. Patients already receiving corticosteroids at study entry remained on corticosteroids, with their dosing adjusted to 2 mg/kg/day methylprednisolone equivalent on the day of enrollment.
The primary study endpoint was response to study therapy, with response defined as survival to day 28 of study and discontinuation of all supplemental oxygen support for >72 consecutive hours by day 28 of study. The secondary objective was to evaluate response to therapy at Day 56.
There was no difference in response between therapy arms, at day 28 and day 56. Only half of participants in the etanercept arm completed all 8 etanercept doses, and 6 participants received 2 doses. Ten of 18 patients on the placebo arm received all 8 placebo doses, with only 1 patient receiving ≥ 2 placebo doses before study discontinuation.
The study was closed early by the Data and Safety Monitoring Board because of poor accrual.
Yanik GA, Horowitz MM, Weisdorf DJ, et al. 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. Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation. 2014;20(6):858-864. doi:10.1016/j.bbmt.2014.02.026.
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Resources AvailableStudy Datasets Only
- Data Dictionary (PDF - 408.1 KB)
- Protocol (PDF - 2.4 MB)
- Randomization Case Report Forms (PDF - 863.8 KB)
- Screening Case Report Forms (PDF - 899.3 KB)
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