PROACTIVE: Preventing Acute Chest Syndrome by Transfusion Feasibility Study

• Sponsor: HealthCore-NERI (Other)
• Overall Status: Completed
• CT.gov ID: NCT00951808
• Collaborator: National Heart, Lung, and Blood Institute (NHLBI) (NIH)
• Enrollment: 237
• Locations: 24
• Arms: 3
• Duration (Months): 12
• Patients Per Site: 9.9
• Patients Per Site Per Month: 0.8

Study Details

Study Description

Brief Summary

Acute chest syndrome (ACS) is similar to severe pneumonia and is a common cause of hospitalizations for people with sickle cell disease (SCD). Blood transfusions are one treatment option for ACS. High levels of an enzyme called secretory phospholipase A2 (sPLA2) may be present in people before they develop ACS. This study will determine how well sPLA2 levels can predict the onset of ACS and whether identifying high sPLA2 levels allows enough time to prevent ACS with blood transfusions. Results from this study will help to determine the feasibility of conducting a larger study that would further examine the use of sPLA2 levels and blood transfusions to prevent ACS in people with SCD.

Condition or Disease	Intervention/Treatment	Phase
Sickle Cell Disease	Biological: Single blood transfusion; Behavioral: Standard care	N/A

Detailed Description

SCD is an inherited blood disorder, and symptoms include anemia, infections, organ damage, and intense episodes of pain, which are called "sickle cell crises." ACS, characterized by fever, respiratory distress, and lung tissue damage, is the second most common cause of hospitalization and the leading cause of death among people with SCD. Most people with SCD will experience at least one episode of ACS, and repeated episodes can result in progressive lung disease. ACS can appear suddenly and often requires immediate hospitalization and treatment, which can include blood transfusions. People with elevated blood levels of sPLA2 may be at risk for developing ACS, and this enzyme is often detectable before the onset of ACS symptoms. The purpose of this study is to examine the use of sPLA2 as a predictor of ACS and to determine whether subsequent blood transfusions can be administered early enough to prevent the onset of ACS in people with SCD who are at risk for ACS. Study researchers will also assess the feasibility of conducting a larger study that would further examine the effectiveness of using sPLA2 levels and blood transfusions to prevent ACS.

This study will involve two parts. In the first part of the study, participants with SCD who are admitted to the hospital with an acute sickle cell pain event will be randomly assigned to receive either a single blood transfusion or standard care for ACS and no blood transfusion. All participants will be closely monitored while in the hospital for the development of ACS, and study researchers will review participants' medical records. All participants will undergo daily blood collections, which will include testing for sPLA2 levels, and at least two chest x-rays. Twenty-eight days after hospital discharge, all participants will attend a follow-up study visit for blood collection, again to determine sPLA2 levels.

In the second part of the study, participants who are not eligible or who do not choose to participate in the first part of the study will be enrolled into an observational group. These participants will receive standard care for ACS, but will not receive a blood transfusion. They will undergo daily blood collection during their hospital stay and at least one chest x-ray. While participants are in the hospital and 28 days after discharge, study researchers will review participants' medical records.

Study Design

• Study Type: Interventional
• Actual Enrollment: 237 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Preventing Acute Chest Syndrome by Transfusion Feasibility Study( PROACTIVE Feasibility Study)
• Study Start Date: Jul 1, 2009
• Actual Primary Completion Date: Jun 1, 2010
• Actual Study Completion Date: Jul 1, 2010

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Blood Transfusion Trial Cohort Twenty participants will receive a blood transfusion while in the hospital.	Biological: Single blood transfusion; Participants will receive a single transfusion of 7-13cc/kg packed red blood cells (RBCs) while in the hospital.; Other Names: transfusion
Active Comparator: Standard Care Trial Cohort Twenty participants will not receive a blood transfusion and will receive standard care.	Behavioral: Standard care; Participants will receive standard care for ACS while in the hospital.; Other Names: standard of care
Active Comparator: Standard Care Observational Cohort Approximately 300 participants who are ineligible for or decline the blood transfusion part of the study will participate in the observational portion of the study and receive standard care.	Behavioral: Standard care; Participants will receive standard care for ACS while in the hospital.; Other Names: standard of care

Outcome Measures

Primary Outcome Measures

1. Acute Chest Syndrome [Chest x-rays (CXR) were ordered for trial eligibility, as a result of clinical indications, or at discharge or 72 hours if no prior CXR.]

   First occurence of positive infiltrate on chest x-ray

Eligibility Criteria

Criteria

• Ages Eligible for Study: 2 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria for the Observational and Trial Cohorts:

• Hemoglobin diagnosis of SS (two copies of the hemoglobin S gene), SC (one copy of the hemoglobin S gene and one copy of the hemoglobin C gene), or S-β thalassemia (β+ or β0)

• No clinically apparent ACS

• No prior participation in either part of the study

Inclusion Criteria for the Trial Cohort, in addition to the above criteria:

• sPLA2 level greater than 100 ng/mL within the same 24-hour window that coincides with fever and chest radiograph negative for new pulmonary infiltrate within the last 12 hours of the 24-hour window

• Fever greater than 38.0º C within the same 24-hour window that coincides with elevated sPLA2 level (greater than 100 ng/mL) and chest radiograph negative for new pulmonary infiltrate within the last 12 hours of the 24-hour window

• Chest radiograph negative for new pulmonary infiltrate within the last 12 hours of the 24-hour window of an abnormal sPLA2 level and fever

• Hemoglobin levels equal or less than 10 g/dL at time of study entry

• Informed consent of parent(s) or legal guardian; informed consent or assent of participant as applicable

Exclusion Criteria for Observational and Trial Cohorts:

• Existing diagnosis of a new pulmonary infiltrate diagnosed by chest radiography (pleural effusion not obscuring lung parenchyma will not exclude the person from the study)

• Any coexisting medical condition for which the physician feels that a transfusion may be needed within 24 hours (e.g., severe anemia, stroke)

• Red Blood Cell (RBC) transfusion in the 60 days before study entry

• Unwillingness to sign consent form, or if a minor, unwillingness of parent/guardian to sign consent form

• Treatment with any investigational drug or device in the 30 days before study entry (hydroxyurea is allowable)

• History of alloimmunization that would prevent the participant from receiving blood within 8 hours of eligibility for study entry or history of a life-threatening transfusion reaction

• Objection to transfusion for religious or other reasons from either the participant or guardian

• History of treatment with systemic steroids within 1 week of study entry (inhaled steroids are acceptable)

• Pregnant

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Children's Hospital and Research Center	Oakland	California	United States
2	A.I. duPont Hospital for Children	Wilmington	Delaware	United States
3	Children's National Medical Center	Washington	District of Columbia	United States
4	Howard University Hospital	Washington	District of Columbia	United States
5	Emory University School of Medicine	Atlanta	Georgia	United States
6	Medical College of Georgia	Augusta	Georgia	United States
7	Children's Memorial Hospital	Chicago	Illinois	United States
8	University of Illinois Sickle Cell Center	Chicago	Illinois	United States
9	Kosair Children's Hospital	Louisville	Kentucky	United States
10	Johns Hopkins	Baltimore	Maryland	United States
11	Boston Medical Center	Boston,	Massachusetts	United States
12	Brigham & Women's Hospital	Boston,	Massachusetts	United States
13	Children's Hospital Boston	Boston	Massachusetts	United States
14	University of Mississippi Medical Center	Jackson	Mississippi	United States
15	Interfaith Medical Center	Brooklyn	New York	United States
16	New York Methodist Hospital	Brooklyn	New York	United States
17	The University of North Carolina at Chapel Hill	Chapel Hill	North Carolina	United States
18	Duke University Medical Center	Durham	North Carolina	United States
19	Cincinnati Children's Hospital Medical Center	Cincinnati	Ohio	United States
20	Nationwide Children's Hospital	Columbus	Ohio	United States
21	Ohio State University	Columbus	Ohio	United States
22	Children's Hospital of Philadelphia	Philadelphia	Pennsylvania	United States
23	St. Christopher's Hospital for Children	Philadelphia	Pennsylvania	United States
24	Virginia Commonwealth University Health Systems	Richmond	Virginia	United States

Sponsors and Collaborators

• HealthCore-NERI
• National Heart, Lung, and Blood Institute (NHLBI)

Investigators

• Principal Investigator: Sonja McKinlay, PhD, HealthCore-NERI
• Study Director: Margaret C. Bell, MPH, MS, HealthCore-NERI

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: HealthCore-NERI
• ClinicalTrials.gov Identifier: NCT00951808
• Other Study ID Numbers: 668; U10HL083721
• First Posted: Aug 4, 2009
• Last Update Posted: Apr 24, 2013
• Last Verified: Apr 1, 2013

• Keywords provided by HealthCore-NERI: Anemia, Sickle Cell; Acute Chest Syndrome; Secretory phospholipase A2(sPLA2)
• Additional relevant MeSH terms: Acute Chest Syndrome; Anemia, Sickle Cell

Study Results

Participant Flow

Recruitment Details	In the period June 2009 - June 2010, 237 subjects from 25 sites were enrolled in the feasibility study. Of 237 enrolled, only 10 were randomized (six subjects in the Standard Care Arm and four subjects in the Transfusion Arm). The randomization trial has been terminated due to the lack of enrollment.

Arm/Group Title	Blood Transfusion Trial Cohort	Standard Care Trial Cohort	Standard Care Observational Cohort
Arm/Group Description	Subjects received a transfusion within 6 hours of randomization.	Subjects received standard care (regular care for acute chest syndrome (ACS)) without a clinically indicated transfusion.	Subjects who are ineligible for or who decline the blood transfusion part of the study participated in the observational portion of the study and received standard care (regular care for acute chest syndrome (ACS)).
Period Title: Overall Study
STARTED	4	6	227
COMPLETED	4	6	223
NOT COMPLETED	0	0	4

Baseline Characteristics

Arm/Group Title	All Participants
Arm/Group Description	237 subjects enrolled in the feasibility study.
Overall Participants	237
Age (Count of Participants)
<=18 years	122 51.5%
Between 18 and 65 years	114 48.1%
>=65 years	1 0.4%
Sex: Female, Male (Count of Participants)
Female	119 50.2%
Male	118 49.8%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	7 3%
Not Hispanic or Latino	230 97%
Unknown or Not Reported	0 0%
Race/Ethnicity, Customized (participants) [Number]
White	3 1.3%
Black or African American	230 97%
More than one race	1 0.4%
Other	3 1.3%
Maximum secretory phospholipase A2 (sPLA2) value (participants) [Number]
>0 - 25 ng/ml	106 44.7%
>25 - 50 ng/ml	34 14.3%
>50 - 100 ng/ml	22 9.3%
>100 - 200 ng/ml	13 5.5%
>200 - 800 ng/ml	28 11.8%
Not applicable	34 14.3%

Outcome Measures

1. Primary Outcome

Title	Acute Chest Syndrome
Description	First occurence of positive infiltrate on chest x-ray
Time Frame	Chest x-rays (CXR) were ordered for trial eligibility, as a result of clinical indications, or at discharge or 72 hours if no prior CXR.

Outcome Measure Data

Analysis Population Description

Of 237 enrolled subjects, 27 subjects who received a transfusion and 7 subjects who had insufficient sPLA2 measurements were excluded. Therefore, two hundred and three (203) subjects were included in the analysis. Results were not reported by Arm due to the lack of enrollment.

Arm/Group Title	Adults	Children	Overall
Arm/Group Description	Age >= 18	Age < 18	Both adults and children
Measure Participants	96	107	203
Yes	11 4.6%	11 NaN	22 NaN
No	85 35.9%	96 NaN	181 NaN

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Adults, Children, Overall
	Comments	The optimal threshold level (TL), determined via receiver operating characteristic (ROC) curve analysis, maximizes the difference between the true positive rate (TPR) and the false positive rate (FPR). Since there is no corresponding analytic standard deviation (SD) for this value, we computed a robust SD based upon the interquartile range (IQR)/1.35 from a bootstrap sample of optimal TLs.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	optimal threshold level of sPLA2
	Estimated Value	48
	Confidence Interval	(2-Sided) 95%; 38 to 58
	Parameter Dispersion	Type: Standard Deviation; Value: 5
	Estimation Comments	The optimal threshold level (TL) was determined to be the same for all analysis groups.

Adverse Events

Adverse Event Reporting Description	According to the protocol, adverse events (AEs) were only reportable for subjects who received a trial-indicated transfusion (blood transfusion trial cohort). Due to the early termination and low enrollment for the randomization trial, we are not reporting results for this cohort. Therefore, there are no AEs to report.
Arm/Group Title	Blood Transfusion Trial Cohort
Arm/Group Description	Subjects received a transfusion within 6 hours of randomization.
All Cause Mortality
	Blood Transfusion Trial Cohort
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	Blood Transfusion Trial Cohort
	Affected / at Risk (%)	# Events
Total	0/0 (NaN)
Other (Not Including Serious) Adverse Events
	Blood Transfusion Trial Cohort
	Affected / at Risk (%)	# Events
Total	0/0 (NaN)

Limitations/Caveats

The feasibility study has been completed, but the randomization trial has been terminated early due to the lack of enrollment. Therefore, the results were reported with the subjects who completed the feasibility study and were not reported by Arm.

More Information

Certain Agreements

All Principal Investigators ARE 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.