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

• Sponsor: National Heart, Lung, and Blood Institute (NHLBI) (NIH)
• Overall Status: Completed
• CT.gov ID: NCT00421174
• Collaborator: Blood and Marrow Transplant Clinical Trials Network (Other), National Cancer Institute (NCI) (NIH), National Marrow Donor Program (Other)
• Enrollment: 37
• Locations: 12
• Arms: 2
• Duration (Months): 71
• Patients Per Site: 3.1
• Patients Per Site Per Month: 0

Study Details

Study Description

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).

Condition or Disease	Intervention/Treatment	Phase
Pneumonia; Idiopathic Pneumonia Syndrome	Drug: Etanercept; Drug: Placebo plus corticosteroid	Phase 3

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 Design

• Study Type: Interventional
• Actual Enrollment: 37 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Participant, 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 Idiopathic Pneumonia Syndrome Following Allogeneic Cell Transplantation (BMTCTN0403)
• Study Start Date: Aug 1, 2007
• Actual Primary Completion Date: Jun 1, 2010
• Actual Study Completion Date: Jul 1, 2013

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Etanercept 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.; Other Names: Enbrel®
Active Comparator: Placebo Placebo plus Corticosteroids	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 Names: Methylprednisolone

Outcome Measures

Primary Outcome Measures

1. Response Rate [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.

Secondary Outcome Measures

1. Response to Therapy [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.

2. Discontinuation of Supplemental Oxygen [Day 56]

   The "time required to discontinue supplemental oxygen" will be measured in the number of days from study entry.

3. Corticosteroid Dose [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.

4. Overall Survival [Year 1]

   Percentage of patients that survived after one year

5. Incidence of Infection [Day 56]

6. Incidence of Toxicity [Day 56]

7. Incidence of Graft-vs-Host-Disease (GVHD) [Year 1]

8. Incidence of Relapse [Year 1]

   Percentage of patients who experience relapse. Deaths without relapse are considered as a competing risk.

9. Overall Mortality [Year 2]

10. Dermatologic Reaction [Day 28]

11. Pro-inflammatory Markers of Pulmonary Disease, in Both BAL Fluid and Plasma [Day 28]

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of Florida College of Medicine (Shands)	Gainesville	Florida	United States	32610
2	Indiana University Medical Center	Indianapolis	Indiana	United States	46202
3	Johns Hopkins University	Baltimore	Maryland	United States	21218
4	DFCI/Partners Cancer Center	Boston	Massachusetts	United States	02118
5	University of Michigan Medical Center	Ann Arbor	Michigan	United States	48105
6	University of Minnesota	Minneapolis	Minnesota	United States	55455
7	Mayo Clinic	Rochester	Minnesota	United States	55905
8	University of Nebraska Medical Center	Omaha	Nebraska	United States	68198-7680
9	Memorial Sloan Kettering Cancer Center	New York	New York	United States	10174
10	University of Pennsylvania Cancer Center	Philadelphia	Pennsylvania	United States	19104
11	University of Texas/MD Anderson Cancer Center	Houston	Texas	United States	77030
12	Fred Hutchinson Cancer Research Center	Seattle	Washington	United States	98109

Sponsors and Collaborators

• National Heart, Lung, and Blood Institute (NHLBI)
• Blood and Marrow Transplant Clinical Trials Network
• National Cancer Institute (NCI)
• National Marrow Donor Program

Investigators

• Study Director: Mary Horowitz, MD, Center for International Blood and Marrow Transplant Research

Study Documents (Full-Text)

• Study Protocol, Statistical Analysis Plan, and Informed Consent Form - Jun 2, 2010

More Information

Additional Information:

• Blood and Marrow Transplant Clinical Trials Network Website
• National Marrow Donor Program

Publications

None provided.

• Responsible Party: National Heart, Lung, and Blood Institute (NHLBI)
• ClinicalTrials.gov Identifier: NCT00421174
• Other Study ID Numbers: BMTCTN0403; BMTCTN0403; U01HL069294-05; 465
• First Posted: Jan 11, 2007
• Last Update Posted: Nov 1, 2021
• Last Verified: Aug 1, 2017

• Individual Participant Data (IPD) Sharing Statement: Yes
• Plan to Share IPD: Yes
• Keywords provided by National Heart, Lung, and Blood Institute (NHLBI): Etanercept; IPS
• Additional relevant MeSH terms: Pneumonia; Syndrome; Methylprednisolone; Etanercept

Study Results

Participant Flow

Recruitment Details	Patients were enrolled from September 2007 to August 2011 from 12 different sites.

Arm/Group Title	Etanercept	Placebo
Arm/Group Description	Etanercept plus corticosteroids	Placebo plus Corticosteroids
Period Title: Overall Study
STARTED	18	19
COMPLETED	16	18
NOT COMPLETED	2	1

Baseline Characteristics

Arm/Group Title	Etanercept	Placebo	Total
Arm/Group Description	Etanercept plus corticosteroids	Placebo plus Corticosteroids	Total of all reporting groups
Overall Participants	16	18	34
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	47.7	46.4	46.6
Sex: Female, Male (Count of Participants)
Female	8 50%	10 55.6%	18 52.9%
Male	8 50%	8 44.4%	16 47.1%
Primary Disease (participants) [Number]
Acute Myelogenous Leukemia (AML)	1 6.3%	9 50%	10 29.4%
Myelodysplastic Syndrome (MDS)	2 12.5%	2 11.1%	4 11.8%
Acute Lymphoblastic Leukemia (ALL)	3 18.8%	4 22.2%	7 20.6%
Lymphoma	3 18.8%	0 0%	3 8.8%
Other	7 43.8%	3 16.7%	10 29.4%
Karnofsky Performance (participants) [Number]
70 - 90	3 18.8%	1 5.6%	4 11.8%
50 - 60	5 31.3%	5 27.8%	10 29.4%
< 50	5 31.3%	10 55.6%	15 44.1%
Unknown	3 18.8%	2 11.1%	5 14.7%
Conditioning Regimen (participants) [Number]
Myeloablative	9 56.3%	11 61.1%	20 58.8%
Non-myeloablative	7 43.8%	7 38.9%	14 41.2%
Recipient Cytomegalovirus Status (participants) [Number]
Positive	8 50%	10 55.6%	18 52.9%
Negative	8 50%	7 38.9%	15 44.1%
Unknown	0 0%	1 5.6%	1 2.9%
Total Bilirubin (mg/dl) [Median (Full Range) ]
Median (Full Range) [mg/dl]	1.2	0.9	1.0
Creatinine (mg/dl) [Median (Full Range) ]
Median (Full Range) [mg/dl]	1.3	1.4	1.3
Oxygen Support (participants) [Number]
Nasal cannula	10 62.5%	6 33.3%	16 47.1%
Face mask	3 18.8%	5 27.8%	8 23.5%
Mechanical ventilation	2 12.5%	6 33.3%	8 23.5%
Unknown	1 6.3%	1 5.6%	2 5.9%

Outcome Measures

1. Primary Outcome

Title	Response Rate
Description	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.
Time Frame	Day 28

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Etanercept	Placebo
Arm/Group Description	Etanercept plus corticosteroids	Placebo plus Corticosteroids
Measure Participants	16	18
Number (95% Confidence Interval) [percentage of participants]	62.5 390.6%	66.7 370.6%

2. Secondary Outcome

Title	Response to Therapy
Description	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.
Time Frame	Day 56

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Etanercept	Placebo
Arm/Group Description	Etanercept plus corticosteroids	Placebo plus Corticosteroids
Measure Participants	16	18
Number (95% Confidence Interval) [percentage of participants]	56.3 351.9%	50.0 277.8%

3. Secondary Outcome

Title	Discontinuation of Supplemental Oxygen
Description	The "time required to discontinue supplemental oxygen" will be measured in the number of days from study entry.
Time Frame	Day 56

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Etanercept	Placebo
Arm/Group Description	Etanercept plus corticosteroids	Placebo plus Corticosteroids
Measure Participants	16	18
Median (Full Range) [days]	9	7

4. Secondary Outcome

Title	Corticosteroid Dose
Description	Patients were treated with systemic corticosteroids with methylprednisolone at 2 mg/kg/day on day 0, with taper allowed after day 7.
Time Frame	Day 14 and 28

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Etanercept	Placebo
Arm/Group Description	Etanercept plus corticosteroids	Placebo plus Corticosteroids
Measure Participants	16	18
Day 14	0.94	1.00
Day 28	0.57	0.49

5. Secondary Outcome

Title	Overall Survival
Description	Percentage of patients that survived after one year
Time Frame	Year 1

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Etanercept	Placebo
Arm/Group Description	Etanercept plus corticosteroids	Placebo plus Corticosteroids
Measure Participants	16	18
Number (95% Confidence Interval) [percentage of participants]	18.8 117.5%	16.7 92.8%

6. Secondary Outcome

Title	Incidence of Infection
Time Frame	Day 56

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Etanercept	Placebo
Arm/Group Description	Etanercept plus corticosteroids	Placebo plus Corticosteroids
Measure Participants	16	18
Measure Total number of infections	20	33
Bacterial infection	9	21
Viral infection	7	10
Fungal infection	4	2

7. Secondary Outcome

Title	Incidence of Toxicity
Time Frame	Day 56

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Etanercept	Placebo
Arm/Group Description	Etanercept plus corticosteroids	Placebo plus Corticosteroids
Measure Participants	16	18
Measure Total number of toxicities	14	25
Renal	4	3
Hepatic	7	14
Cardiac	1	2
Central nervous system	2	6

8. Secondary Outcome

Title	Incidence of Graft-vs-Host-Disease (GVHD)
Time Frame	Year 1

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Etanercept	Placebo
Arm/Group Description	Etanercept plus corticosteroids	Placebo plus Corticosteroids
Measure Participants	16	18
Acute GVHD	31.2 195%	44.4 246.7%
GVHD	25.0 156.3%	27.8 154.4%
Chronic GVHD	12.5 78.1%	0 0%

9. Secondary Outcome

Title	Incidence of Relapse
Description	Percentage of patients who experience relapse. Deaths without relapse are considered as a competing risk.
Time Frame	Year 1

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Etanercept	Placebo
Arm/Group Description	Etanercept plus corticosteroids	Placebo plus Corticosteroids
Measure Participants	16	18
Count of Participants [Participants]	3 18.8%	2 11.1%

10. Secondary Outcome

Title	Overall Mortality
Time Frame	Year 2

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Etanercept	Placebo
Arm/Group Description	Etanercept plus corticosteroids	Placebo plus Corticosteroids
Measure Participants	16	18
Number [participants]	13 81.3%	15 83.3%

11. Secondary Outcome

Title	Dermatologic Reaction
Time Frame	Day 28

Outcome Measure Data

Analysis Population Description

No data collected

Arm/Group Title	Etanercept	Placebo
Arm/Group Description	Etanercept plus corticosteroids	Placebo plus Corticosteroids
Measure Participants	0	0

12. Secondary Outcome

Title	Pro-inflammatory Markers of Pulmonary Disease, in Both BAL Fluid and Plasma
Time Frame	Day 28

Outcome Measure Data

Analysis Population Description

No data collected

Arm/Group Title	Etanercept	Placebo
Arm/Group Description	Etanercept plus corticosteroids	Placebo plus Corticosteroids
Measure Participants	0	0

Adverse Events

Time Frame	1-year post transplant
Adverse Event Reporting Description	Serious adverse events are defined as events associated with death, life-threatening event, disability, congenital anomaly, required intervention to prevent permanent impairment or damage, hospitalization or other serious adverse event. Only unexpected adverse events are reported here.
Arm/Group Title	Etanercept		Placebo
Arm/Group Description	Etanercept plus corticosteroids		Placebo plus Corticosteroids
All Cause Mortality
	Etanercept		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Etanercept		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/16 (0%)		1/18 (5.6%)
Respiratory, thoracic and mediastinal disorders
Pulmonary alveolar haemorrhage	0/16 (0%)		1/18 (5.6%)
Other (Not Including Serious) Adverse Events
	Etanercept		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/16 (0%)		0/18 (0%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.