Erythropoietin to Prevent Unnecessary Transfusions In Patients With Cyanotic CHD - A Prospective Control Trial

• Sponsor: University of California, San Diego (Other)
• Overall Status: Terminated
• CT.gov ID: NCT02564796
• Collaborator: (none)
• Enrollment: 4
• Location: 1
• Arms: 2
• Actual Duration (Months): 43
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

Cyanotic congenital cardiac patients require higher hemoglobin concentrations (red blood cell levels) for optimal oxygen delivery to the body. Prophylactic erythropoietin (EPO) and iron can prevent and/or decrease the amount of blood transfusions needed in this population. We seek to investigate if EPO and iron make a clinically significant difference in the number of transfusions given to these patients and the morbidity associated with it.

Condition or Disease	Intervention/Treatment	Phase
Cyanotic Congenital Heart Disease; Anemia; Cyanosis; Congenital Heart Disease	Drug: Epoetin Alfa and Iron; Drug: Iron	Phase 2

Detailed Description

Congenital heart disease occurs in about 1% of all live births. Cyanotic cardiac lesions in particular are at risk for significant mortality and morbidity because of their reduced ability to provide adequate oxygenation to the body and the brain. Many experts believe that to have adequate oxygen carrying capacity that these infants should ideally have a hemoglobin level greater than 13 g/dL. Many of these patients require blood transfusions prior to surgery to provide adequate oxygenation. The cause for this is likely multifactorial including normal neonatal physiology, frequent lab draws, and co-morbidities. Although rare, the morbidity due to transfusions can be devastating to this population including transmitted infections, transfusion reactions, extra hospitalizations, and antigen sensitization that would complicate heart transplant if needed.

There are centers in the United States that have developed protocols using erythropoietin to minimize blood product transfusions before and after surgery, also referred to as "bloodless surgery". There have been retrospective studies evaluating the success of these protocols, but there are no randomized controlled prospective studies that the investigators have studying the effects of erythropoietin effects in patients with cyanotic heart disease in regards to transfusion prevention.

Congenital cyanotic cardiac patients require higher hemoglobin concentrations for optimal oxygen delivery. Prophylactic erythropoietin can prevent and/or decrease the amount of blood transfusions needed prior to surgery. The researchers seek to investigate if erythropoietin makes a clinically significant difference in the number of transfusions given to these patients and the morbidity associated with it.

Study Design

• Study Type: Interventional
• Actual Enrollment: 4 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Single (Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: Erythropoietin to Prevent Unnecessary Transfusions In Patients With Cyanotic Congenital Heart Disease - A Prospective Randomized Control Trial
• Actual Study Start Date: Nov 1, 2016
• Actual Primary Completion Date: Jun 1, 2020
• Actual Study Completion Date: Jun 1, 2020

Arms and Interventions

Arm	Intervention/Treatment
Placebo Comparator: Control Group II (non-treatment group): Patients in the treatment group will not receive any extra intervention outside of standard of care. They will receive iron supplementation for 6 weeks starting before 8 weeks of age, 1 week after their first procedure (surgery or heart catheterization). They will be followed for 14 weeks.	Drug: Iron; Patients in the treatment group will not receive any extra intervention outside of standard of care. They will receive iron supplementation for 6 weeks starting before 8 weeks of age, 1 week after their first procedure (surgery or heart catheterization). They will be followed for 14 weeks.; Other Names: No other name
Experimental: Epoetin alfa and iron supplements Group I (treatment group): Patients in the treatment group will receive weekly EPO injections and iron supplementation for 6 weeks starting before 8 weeks of age, 1 week after their first procedure (surgery or heart catheterization) They will be followed for 14 weeks.	Drug: Epoetin Alfa and Iron; Patients in the treatment group will receive weekly EPO injections and iron supplementation for 6 weeks starting before 8 weeks of age, 1 week after their first procedure (surgery or heart catheterization) They will be followed for 14 weeks.; Other Names: No other name

Outcome Measures

Primary Outcome Measures

1. Number of Transfusions Needed [First 4 months of life]

   Prophylactic erythropoietin can prevent and/or decrease the amount of blood transfusions needed prior to surgery. We seek to investigate if erythropoietin makes a clinically significant difference in the number of transfusions given to these patients and the morbidity associated with it during the period in which the subjects will be active in the study (from baseline to 14 weeks post initial injection). The primary aim will be assessed when all subjects have completed week 14 or discontinue early.

Secondary Outcome Measures

1. Oxygen Saturation [First 4 months of life]

   Often, cyanotic congenital heart defect neonates have prolonged initial hospital stays due to the inability to maintain acceptable oxygen saturations, and transition to adequate oral intake for appropriate weight gain. If the hospital stay is found to be shortened after starting erythropoietin, this may be of clinical and financial significance.

2. Number of Hospitalizations [First 4 months of life]

   The number of hospital readmissions (related to failure to thrive or cyanosis) may imply the overall clinical stability of a patient. Because these infants are at high risk for mortality at home, there are multiple reasons why they may be admitted to the hospital including clinically significant anemia which requires blood transfusions, poor weight gain, difficulty feeding, inadequate oxygen saturations, and illnesses. Each admission is stressful to the patient and their families. Having a normal hemoglobin level may have a role in preventing several of these factors, especially regarding failure to thrive or cyanosis.

3. Weight Gain [First 4 months of life]

   The secondary outcome of weight gain is appropriate in the setting of infants as this variable has been used to monitor the ability to thrive and meet the body's metabolic demands. It is well established in pediatrics that the neonate and infant should gain 15-30 grams per day for optimal growth. Infants who are cyanotic already have a deficiency in meeting their metabolic demands due to a reduced oxygen carrying capacity. This is further complicated in the instance of anemia. Thus, infants may have an increased ability to optimize weight gain in the setting of normal, stable hemoglobin levels which may be achieved with erythropoietin.

4. Time to Initial Discharge [First 4 months of life]

   If the hospital stay is found to be shortened after starting erythropoietin, this may be of clinical and financial significance.

Eligibility Criteria

Criteria

• Ages Eligible for Study: N/A to 8 Weeks
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria

• Newborns less than 4 weeks old at diagnosis

• Gestational age >34 weeks

• Birth weight 2.2-4kg

• Cyanotic heart disease who have had a surgical shunt or a catheterization intervention that is equivalent to a shunt (patent ductus arteriosus stent, right ventricular outflow tract stent).

• Baseline hematocrit to be below <40%.

• Completes at least 1 injection in the study by 8 weeks of age.

Exclusion Criteria

• Infants diagnosed at greater than 4 weeks of age

• Gestation <34 weeks

• Birth weight <2.2 kg or >4kg

• Hematocrit >40%

• Newborns with acyanotic heart disease

• Infants with significant co-morbidities:

• Renal failure (Creatinine > 2 standard deviations above age adjusted norm)

• Hepatic failure (elevated AST/ALT levels > 2 standard deviations above age adjusted norm

• Hemolytic disease

• Hemoglobinopathies (Sickle-cell disease, Thalassemias)

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Rady Children's Hospital	San Diego	California	United States	92123

Sponsors and Collaborators

• University of California, San Diego

Investigators

• Principal Investigator: David K Werho, MD, University of California, San Diego/Rady Children's Hospital San Diego

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Jun 28, 2018
• Informed Consent Form - Nov 29, 2018

More Information

Publications

• Donato H. Erythropoietin: an update on the therapeutic use in newborn infants and children. Expert Opin Pharmacother. 2005 May;6(5):723-34. Review.
• Fearon JA, Weinthal J. The use of recombinant erythropoietin in the reduction of blood transfusion rates in craniosynostosis repair in infants and children. Plast Reconstr Surg. 2002 Jun;109(7):2190-6.
• Maier RF, Obladen M, Müller-Hansen I, Kattner E, Merz U, Arlettaz R, Groneck P, Hammer H, Kössel H, Verellen G, Stock GJ, Lacaze-Masmonteil T, Claris O, Wagner M, Matis J, Gilberg F; European Multicenter Erythropoietin Beta Study Group. Early treatment with erythropoietin beta ameliorates anemia and reduces transfusion requirements in infants with birth weights below 1000 g. J Pediatr. 2002 Jul;141(1):8-15.
• Richard S, Brion JP, Couck AM, Flament-Durand J. Accumulation of smooth endoplasmic reticulum in Alzheimer's disease: new morphological evidence of axoplasmic flow disturbances. J Submicrosc Cytol Pathol. 1989 Jul;21(3):461-7.

• Responsible Party: David Werho, MD, Assistant Clinical Professor, University of California, San Diego
• ClinicalTrials.gov Identifier: NCT02564796
• Other Study ID Numbers: 160871
• First Posted: Oct 1, 2015
• Last Update Posted: Dec 2, 2021
• Last Verified: Nov 1, 2021

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by David Werho, MD, Assistant Clinical Professor, University of California, San Diego: Erythropoetin; Cyanotic Heart Disease; Transfusion; Congenital Heart Disease
• Additional relevant MeSH terms: Heart Diseases; Heart Defects, Congenital; Cyanosis; Iron; Epoetin Alfa

Study Results

Participant Flow

Pre-assignment Detail	4 Patients who had been screened/consented for the study did not reach the minimum hematocrit threshold for enrollment and were therefore screen failures.

Arm/Group Title	Control	Epoetin Alfa and Iron Supplements
Arm/Group Description	Group II (non-treatment group): Patients in the treatment group will not receive any extra intervention outside of standard of care. They will receive iron supplementation for 6 weeks starting before 8 weeks of age, 1 week after their first procedure (surgery or heart catheterization). They will be followed for 14 weeks. Iron: Patients in the treatment group will not receive any extra intervention outside of standard of care. They will receive iron supplementation for 6 weeks starting before 8 weeks of age, 1 week after their first procedure (surgery or heart catheterization). They will be followed for 14 weeks.	Group I (treatment group): Patients in the treatment group will receive weekly EPO injections and iron supplementation for 6 weeks starting before 8 weeks of age, 1 week after their first procedure (surgery or heart catheterization) They will be followed for 14 weeks. Epoetin Alfa and Iron: Patients in the treatment group will receive weekly EPO injections and iron supplementation for 6 weeks starting before 8 weeks of age, 1 week after their first procedure (surgery or heart catheterization) They will be followed for 14 weeks.
Period Title: Overall Study
STARTED	2	2
COMPLETED	0	0
NOT COMPLETED	2	2

Baseline Characteristics

Arm/Group Title	Control	Epoetin Alfa and Iron Supplements	Total
Arm/Group Description	Group II (non-treatment group): Patients in the treatment group will not receive any extra intervention outside of standard of care. They will receive iron supplementation for 6 weeks starting before 8 weeks of age, 1 week after their first procedure (surgery or heart catheterization). They will be followed for 14 weeks. Iron: Patients in the treatment group will not receive any extra intervention outside of standard of care. They will receive iron supplementation for 6 weeks starting before 8 weeks of age, 1 week after their first procedure (surgery or heart catheterization). They will be followed for 14 weeks.	Group I (treatment group): Patients in the treatment group will receive weekly EPO injections and iron supplementation for 6 weeks starting before 8 weeks of age, 1 week after their first procedure (surgery or heart catheterization) They will be followed for 14 weeks. Epoetin Alfa and Iron: Patients in the treatment group will receive weekly EPO injections and iron supplementation for 6 weeks starting before 8 weeks of age, 1 week after their first procedure (surgery or heart catheterization) They will be followed for 14 weeks.	Total of all reporting groups
Overall Participants	2	2	4
Age (Count of Participants)
<=18 years	2 100%	2 100%	4 100%
Between 18 and 65 years	0 0%	0 0%	0 0%
>=65 years	0 0%	0 0%	0 0%
Sex: Female, Male (Count of Participants)
Female	1 50%	0 0%	1 25%
Male	1 50%	2 100%	3 75%
Race and Ethnicity Not Collected (Count of Participants)
Count of Participants [Participants]	0 0%
Region of Enrollment (Count of Participants)
United States	2 100%	2 100%	4 100%

Outcome Measures

1. Primary Outcome

Title	Number of Transfusions Needed
Description	Prophylactic erythropoietin can prevent and/or decrease the amount of blood transfusions needed prior to surgery. We seek to investigate if erythropoietin makes a clinically significant difference in the number of transfusions given to these patients and the morbidity associated with it during the period in which the subjects will be active in the study (from baseline to 14 weeks post initial injection). The primary aim will be assessed when all subjects have completed week 14 or discontinue early.
Time Frame	First 4 months of life

Outcome Measure Data

Analysis Population Description

The principal investigator discussed the study's future with the sub-investigators on the study and came to the conclusion to close the study due to low enrollment while also considering the financial costs to continue to run the study.

Arm/Group Title	Control	Epoetin Alfa and Iron Supplements
Arm/Group Description	Group II (non-treatment group): Patients in the treatment group will not receive any extra intervention outside of standard of care. They will receive iron supplementation for 6 weeks starting before 8 weeks of age, 1 week after their first procedure (surgery or heart catheterization). They will be followed for 14 weeks. Iron: Patients in the treatment group will not receive any extra intervention outside of standard of care. They will receive iron supplementation for 6 weeks starting before 8 weeks of age, 1 week after their first procedure (surgery or heart catheterization). They will be followed for 14 weeks.	Group I (treatment group): Patients in the treatment group will receive weekly EPO injections and iron supplementation for 6 weeks starting before 8 weeks of age, 1 week after their first procedure (surgery or heart catheterization) They will be followed for 14 weeks. Epoetin Alfa and Iron: Patients in the treatment group will receive weekly EPO injections and iron supplementation for 6 weeks starting before 8 weeks of age, 1 week after their first procedure (surgery or heart catheterization) They will be followed for 14 weeks.
Measure Participants	0	0

2. Secondary Outcome

Title	Oxygen Saturation
Description	Often, cyanotic congenital heart defect neonates have prolonged initial hospital stays due to the inability to maintain acceptable oxygen saturations, and transition to adequate oral intake for appropriate weight gain. If the hospital stay is found to be shortened after starting erythropoietin, this may be of clinical and financial significance.
Time Frame	First 4 months of life

Outcome Measure Data

Analysis Population Description

The principal investigator discussed the study's future with the sub-investigators on the study and came to the conclusion to close the study due to low enrollment while also considering the financial costs to continue to run the study.

Arm/Group Title	Control	Epoetin Alfa and Iron Supplements
Arm/Group Description	Group II (non-treatment group): Patients in the treatment group will not receive any extra intervention outside of standard of care. They will receive iron supplementation for 6 weeks starting before 8 weeks of age, 1 week after their first procedure (surgery or heart catheterization). They will be followed for 14 weeks. Iron: Patients in the treatment group will not receive any extra intervention outside of standard of care. They will receive iron supplementation for 6 weeks starting before 8 weeks of age, 1 week after their first procedure (surgery or heart catheterization). They will be followed for 14 weeks.	Group I (treatment group): Patients in the treatment group will receive weekly EPO injections and iron supplementation for 6 weeks starting before 8 weeks of age, 1 week after their first procedure (surgery or heart catheterization) They will be followed for 14 weeks. Epoetin Alfa and Iron: Patients in the treatment group will receive weekly EPO injections and iron supplementation for 6 weeks starting before 8 weeks of age, 1 week after their first procedure (surgery or heart catheterization) They will be followed for 14 weeks.
Measure Participants	0	0

3. Secondary Outcome

Title	Number of Hospitalizations
Description	The number of hospital readmissions (related to failure to thrive or cyanosis) may imply the overall clinical stability of a patient. Because these infants are at high risk for mortality at home, there are multiple reasons why they may be admitted to the hospital including clinically significant anemia which requires blood transfusions, poor weight gain, difficulty feeding, inadequate oxygen saturations, and illnesses. Each admission is stressful to the patient and their families. Having a normal hemoglobin level may have a role in preventing several of these factors, especially regarding failure to thrive or cyanosis.
Time Frame	First 4 months of life

Outcome Measure Data

Analysis Population Description

The principal investigator discussed the study's future with the sub-investigators on the study and came to the conclusion to close the study due to low enrollment while also considering the financial costs to continue to run the study.

Arm/Group Title	Control	Epoetin Alfa and Iron Supplements
Arm/Group Description	Group II (non-treatment group): Patients in the treatment group will not receive any extra intervention outside of standard of care. They will receive iron supplementation for 6 weeks starting before 8 weeks of age, 1 week after their first procedure (surgery or heart catheterization). They will be followed for 14 weeks. Iron: Patients in the treatment group will not receive any extra intervention outside of standard of care. They will receive iron supplementation for 6 weeks starting before 8 weeks of age, 1 week after their first procedure (surgery or heart catheterization). They will be followed for 14 weeks.	Group I (treatment group): Patients in the treatment group will receive weekly EPO injections and iron supplementation for 6 weeks starting before 8 weeks of age, 1 week after their first procedure (surgery or heart catheterization) They will be followed for 14 weeks. Epoetin Alfa and Iron: Patients in the treatment group will receive weekly EPO injections and iron supplementation for 6 weeks starting before 8 weeks of age, 1 week after their first procedure (surgery or heart catheterization) They will be followed for 14 weeks.
Measure Participants	0	0

4. Secondary Outcome

Title	Weight Gain
Description	The secondary outcome of weight gain is appropriate in the setting of infants as this variable has been used to monitor the ability to thrive and meet the body's metabolic demands. It is well established in pediatrics that the neonate and infant should gain 15-30 grams per day for optimal growth. Infants who are cyanotic already have a deficiency in meeting their metabolic demands due to a reduced oxygen carrying capacity. This is further complicated in the instance of anemia. Thus, infants may have an increased ability to optimize weight gain in the setting of normal, stable hemoglobin levels which may be achieved with erythropoietin.
Time Frame	First 4 months of life

Outcome Measure Data

Analysis Population Description

The principal investigator discussed the study's future with the sub-investigators on the study and came to the conclusion to close the study due to low enrollment while also considering the financial costs to continue to run the study.

Arm/Group Title	Control	Epoetin Alfa and Iron Supplements
Arm/Group Description	Group II (non-treatment group): Patients in the treatment group will not receive any extra intervention outside of standard of care. They will receive iron supplementation for 6 weeks starting before 8 weeks of age, 1 week after their first procedure (surgery or heart catheterization). They will be followed for 14 weeks. Iron: Patients in the treatment group will not receive any extra intervention outside of standard of care. They will receive iron supplementation for 6 weeks starting before 8 weeks of age, 1 week after their first procedure (surgery or heart catheterization). They will be followed for 14 weeks.	Group I (treatment group): Patients in the treatment group will receive weekly EPO injections and iron supplementation for 6 weeks starting before 8 weeks of age, 1 week after their first procedure (surgery or heart catheterization) They will be followed for 14 weeks. Epoetin Alfa and Iron: Patients in the treatment group will receive weekly EPO injections and iron supplementation for 6 weeks starting before 8 weeks of age, 1 week after their first procedure (surgery or heart catheterization) They will be followed for 14 weeks.
Measure Participants	0	0

5. Secondary Outcome

Title	Time to Initial Discharge
Description	If the hospital stay is found to be shortened after starting erythropoietin, this may be of clinical and financial significance.
Time Frame	First 4 months of life

Outcome Measure Data

Analysis Population Description

The principal investigator discussed the study's future with the sub-investigators on the study and came to the conclusion to close the study due to low enrollment while also considering the financial costs to continue to run the study.

Arm/Group Title	Control	Epoetin Alfa and Iron Supplements
Arm/Group Description	Group II (non-treatment group): Patients in the treatment group will not receive any extra intervention outside of standard of care. They will receive iron supplementation for 6 weeks starting before 8 weeks of age, 1 week after their first procedure (surgery or heart catheterization). They will be followed for 14 weeks. Iron: Patients in the treatment group will not receive any extra intervention outside of standard of care. They will receive iron supplementation for 6 weeks starting before 8 weeks of age, 1 week after their first procedure (surgery or heart catheterization). They will be followed for 14 weeks.	Group I (treatment group): Patients in the treatment group will receive weekly EPO injections and iron supplementation for 6 weeks starting before 8 weeks of age, 1 week after their first procedure (surgery or heart catheterization) They will be followed for 14 weeks. Epoetin Alfa and Iron: Patients in the treatment group will receive weekly EPO injections and iron supplementation for 6 weeks starting before 8 weeks of age, 1 week after their first procedure (surgery or heart catheterization) They will be followed for 14 weeks.
Measure Participants	0	0

Adverse Events

Arm/Group Title	Control		Epoetin Alfa and Iron Supplements
Arm/Group Description	Group II (non-treatment group): Patients in the treatment group will not receive any extra intervention outside of standard of care. They will receive iron supplementation for 6 weeks starting before 8 weeks of age, 1 week after their first procedure (surgery or heart catheterization). They will be followed for 14 weeks. Iron: Patients in the treatment group will not receive any extra intervention outside of standard of care. They will receive iron supplementation for 6 weeks starting before 8 weeks of age, 1 week after their first procedure (surgery or heart catheterization). They will be followed for 14 weeks.		Group I (treatment group): Patients in the treatment group will receive weekly EPO injections and iron supplementation for 6 weeks starting before 8 weeks of age, 1 week after their first procedure (surgery or heart catheterization) They will be followed for 14 weeks. Epoetin Alfa and Iron: Patients in the treatment group will receive weekly EPO injections and iron supplementation for 6 weeks starting before 8 weeks of age, 1 week after their first procedure (surgery or heart catheterization) They will be followed for 14 weeks.
All Cause Mortality
	Control		Epoetin Alfa and Iron Supplements
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/0 (NaN)		0/0 (NaN)
Serious Adverse Events
	Control		Epoetin Alfa and Iron Supplements
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/0 (NaN)		0/0 (NaN)
Other (Not Including Serious) Adverse Events
	Control		Epoetin Alfa and Iron Supplements
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/0 (NaN)		0/0 (NaN)

Limitations/Caveats

The principal investigator discussed the study's future with the sub-investigators on the study and came to the conclusion to terminate the study early due to low enrollment while also considering the financial costs to continue to run the study. It would be highly improbable to be able to enroll 54 more patients with the amount of funding left in the grant. No subjects were analyzed.

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.