Delayed Cord Clamping With Oxygen In Extremely Low Gestation Infants (DOXIE)

• ClinicalTrials.gov Identifier: NCT04413097
• Recruitment Status: Recruiting
• First Posted: June 2, 2020
• Last Update Posted: March 25, 2022
• Sponsor: Sharp HealthCare
• Collaborators: Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD); Sharp Mary Birch Hospital for Women & Newborns
• Information provided by (Responsible Party): Anup Katheria, M.D., Sharp HealthCare

Study Description

Brief Summary:

This study is being conducted to compare the incidence of preterm infants (up to 28+6 weeks GA) who achieve a peripheral oxygen saturation of 80 percent by 5 minutes of life (MOL) given mask CPAP/PPV with an FiO2 of 1.0 during DCC for 90 seconds (HI Group) to infants given mask CPAP/PPV with an FiO2 of .30 during DCC for 90 seconds (LO Group).

Condition or disease	Intervention/treatment	Phase
IVH- Intraventricular Hemorrhage; Extreme Prematurity; Hypoxia Neonatal; Hyperoxia; Respiratory Insufficiency	Procedure: Delayed Cord Clamping with Low Oxygen concentration; Procedure: Delayed Cord Clamping with High Oxygen concentration	Not Applicable

Detailed Description:

Prenatal consent will be obtained on infant's with estimated gestational age up to 28+6 weeks. Shortly before delivery, infant's will be randomly assigned to receive either Low oxygen concentration (FiO2 .30) OR High oxygen concentration (FiO2 1.0) during 90 seconds of delayed cord clamping.

Randomization and intervention will remain blinded to the clinical care team during the entire study period. The research team member will open a randomization card when notified of a subject's impending birth, review the protocol with the obstetric provider performing the procedure, set-up the sterile stabilization bed, and note the time it takes from delivery until the clamping and cutting of the umbilical cord in both groups.

The research team member will set the oxygen blender as indicated by the randomization card and cover the blender to blind the FiO2 setting. The research team member will not be involved in the clinical care of the infant. The oxygen blender will be concealed from the clinical care team to ensure resuscitation maneuvers will not be biased.

Data will be submitted to the statistician, who will remain blinded to the intervention for the duration of the study.

At delivery, the infant will be placed on a platform that allows the infant to be close to the mother and the umbilical cord to remain intact for DCC. These beds are equipped with an oxygen blender, humidifier, t-piece resuscitator with mask, necessary to provide CPAP/PPV.

If an infant is randomized to the DCC and Low Oxygen concentration (DCC LO group), the following procedure will ensue:

During delayed cord clamping, the infant will be gently stimulated by drying the infant with a sterile towel and provide CPAP by 30 seconds of life. During delayed cord clamping, breathing assistance with CPAP of 5 cm H20 and a FiO2 0.3 will be provided.

If an infant is randomized to the DCC and High Oxygen concentration (DCC HI group), the following procedure will ensue:

During delayed cord clamping, the infant will be gently stimulated by drying the infant with a sterile towel and provide CPAP by 30 seconds of life. During delayed cord clamping, breathing assistance with CPAP of 5 cm H20 and a FiO2 1.0 will be provided.

Patency of the airway in both groups will be assessed by a Colorimetric CO2 detector. Lack of color change will indicate that the airway is not patent (obstructed), the pressure is not sufficient to expand the lungs, there was excessive air leak, or there was no or inadequate pulmonary blood flow. If there is no color change, the neonatal provider will reposition and reattempt to open the airway, if no improvement they will initiate PPV (starting PIP of 20 cm H20) by 60 seconds of life. Cord clamping will occur at 90 seconds or greater and the infant will be transferred to a standard neonatal warmer and resuscitated per NRP guidelines.

Additionally, when available heart rate data will be collected using a non-invasive dry-electrode monitor, (NeoBeat, Laerdal Medical, Stavanger, Norway) and applied over the infant's chest or abdomen to provide continuous display of heart rate during 90 seconds of DCC.

Pulse oximetry, ECG sensors and Near-Infrared Spectroscopy (NIRS) sensors will be applied after cord clamping. The NIRS sensor will be placed on the infant's forehead. Cerebral StO2, SpO2, blood pressure (once in the NICU) and Heart rate will be recorded every two seconds and linked with other variables. These variables will continue to be recorded for the first 24 hours of life.

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 140 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Masking Description: Once consent is obtained and the research staff is notified of a subject's impending birth, our research team member will open a randomization card and set the oxygen blender on the special bed to either an FiO2 of .30 or 1.0 and cover the blender. The research team member will not be involved in the clinical care for the infant and will blind the clinical care team from the randomized assignment.
• Primary Purpose: Prevention
• Official Title: Delayed Cord Clamping With Oxygen In Extremely Low Gestation Infants
• Actual Study Start Date: November 17, 2021
• Estimated Primary Completion Date: December 1, 2023
• Estimated Study Completion Date: June 1, 2026

Arms and Interventions

Arm	Intervention/treatment
Active Comparator: DCC and Low Oxygen Concentration; During 90 seconds of delayed cord clamping, the infant will receive gentle stimulation and start CPAP by 30 seconds of life at an FiO2 .30, with CPAP of 5 cmH20. If the infant is apneic or there is no Pedicap color change the team will begin positive pressure ventilation (starting PIP of 20 cmH20) by 60 seconds of life. The infant will remain on this support up until the umbilical cord is clamped at 90 seconds or greater. Once the cord is clamped the infant resuscitation will continue according to unit protocol.	Procedure: Delayed Cord Clamping with Low Oxygen concentration; During delayed umbilical cord clamping of 90 seconds, breathing assistance with CPAP/PPV and low oxygen concentration (FiO2 0.30) will be provided.; Other Names: DCC with Low Oxygen concentration; DCC LO group
Experimental: DCC and High Oxygen Concentration; During 90 seconds of delayed cord clamping, the infant will receive gentle stimulation and start CPAP by 30 seconds of life at an FiO2 1.0, with CPAP of 5 cmH20. If the infant is apneic or there is no Pedicap color change the team will begin positive pressure ventilation (starting PIP of 20 cmH20) by 60 seconds of life. The infant will remain on this support up until the umbilical cord is clamped at 90 seconds or greater. Once the cord is clamped the infant resuscitation will continue according to unit protocol.	Procedure: Delayed Cord Clamping with High Oxygen concentration; During delayed umbilical cord clamping of 90 seconds, breathing assistance with CPAP/PPV and high oxygen concentration (FiO2 1.0) will be provided.; Other Names: DCC with High Oxygen concentration; DCC HI group

Outcome Measures

Primary Outcome Measures :

1. Incidence of preterm infants (up to 28 +6 weeks) who achieve a peripheral oxygen saturation of 80 percent by 5 minutes of life [ Time Frame: at 5 minutes of life ]
   To compare the incidence of preterm infants (up to 28+6 weeks GA) who achieve a peripheral oxygen saturation of 80 percent by 5 MOL given mask CPAP/PPV with an FiO2 of 1.0 during DCC for 90 seconds (HI Group) to infants given mask CPAP/PPV with an FiO2 of .30 during DCC for 90 seconds (LO Group).

Secondary Outcome Measures :

1. All Grade IVH [ Time Frame: Through study completion at hospital discharge, up to 6 months corrected gestational age (CGA) ]
   Any Intraventricular Hemorrhage (grades 1-4)
2. Frequency of Grade III and IV intraventricular hemorrhage [ Time Frame: Through study completion at hospital discharge, up to 6 months corrected gestational age (CGA) ]
   Intraventricular hemorrhages (grades 3-4) (bleeding in the brain parenchyma and/or ventricular dilation
3. Resuscitation interventions [ Time Frame: In the first 10 minutes of life ]
   Resuscitation interventions including intubation, chest compressions, medications
4. Changes in heart rate (BPM) in the first 10 minutes of life [ Time Frame: In the first 10 minutes of life ]
   Changes in heart rate (BPM) in the first 10 minutes of life

Other Outcome Measures:

1. Changes in Inspired fractional oxygen (FiO2) [ Time Frame: In the first 10 minutes of life ]
   Changes in Inspired fractional oxygen (FiO2)
2. Duration of Hypoxia [ Time Frame: The first 10 minutes of life in the delivery room ]
   Duration of Hypoxia (defined as oxygen saturation<25th percentile of target ranges defined by Dawson et al.) in the first 10 minutes after birth
3. Duration of Hyperoxia [ Time Frame: The first 10 minutes of life in the delivery room ]
   Duration of Hyperoxia (defined as oxygen saturation>95%) in the first 10 minutes after birth
4. Changes in Mean airway pressure, MAP (cm H20) [ Time Frame: In the first 10 minutes of life ]
   Changes in Mean airway pressure, MAP (cm H20)
5. Duration of Positive Pressure Ventilation [ Time Frame: The first 10 minutes of life in the delivery room ]
   Duration of positive pressure ventilation
6. Blood pressures in the first 24 hours of life [ Time Frame: In the first 24 hours of life ]
   Blood pressures every hour in the first 24 hours of life
7. Cerebral tissue oxygenation in the first 24 hours of life [ Time Frame: In the first 24 hours of life ]
   Cerebral tissue oxygenation in the first 24 hours of life
8. Average oxygen saturation in the first 5 minutes after birth [ Time Frame: at 5 minutes of life ]
   Oxygen saturation in the first 5 minutes after birth
9. Average Heart rate in the first 5 minutes after birth [ Time Frame: at 5 minutes of life ]
   Heart rate in the first 5 minutes after birth
10. Intubation in the Delivery room or Neonatal Intensive Care Unit (NICU) [ Time Frame: Birth through study completion at discharge, up to 6 months of corrected gestational age ]
    Intubation in the Delivery room or Neonatal Intensive Care Unit (NICU)
11. Lowest and Highest Hemoglobin and/or Hematocrit [ Time Frame: First 24 hours of life ]
    Hemoglobin and/or Hematocrit levels (before transfusion)
12. Mean arterial blood pressure [ Time Frame: First 24 hours of life ]
    Mean arterial blood pressure (collected hourly)
13. Medication for Low Blood Pressure [ Time Frame: First 24 hours of life ]
    Medication for Low Blood Pressure (e.g. hydrocortisone or pressors)
14. CRIB-II (Clinical Risk Index for Babies) [ Time Frame: First 12 hours of life ]
    CRIB-II (Clinical Risk Index for Babies)
15. Duration of mechanical ventilation and/or CPAP [ Time Frame: Through study completion at discharge, up to 6 months of corrected gestational age ]
    Number of days on mechanical ventilation and/or CPAP
16. Surfactant administration [ Time Frame: First 10 days after birth ]
    Surfactant administration
17. Number of RBC Transfusions since birth [ Time Frame: First 10 days after birth ]
    Number of RBC Transfusions since birth
18. Patent Ductus Arteriosus requiring pharmacological or surgical treatment [ Time Frame: Through study completion at discharge, up to 6 months of corrected gestational age ]
    Patent Ductus Arteriosus requiring pharmacological or surgical treatment
19. Spontaneous Intestinal Perforation (SIP) requiring surgery or peritoneal drain [ Time Frame: Through study completion at discharge, up to 6 months of corrected gestational age ]
    Spontaneous Intestinal Perforation (SIP) requiring surgery or peritoneal drain
20. Necrotizing Enterocolitis (Modified Bell's stage 2-3) [ Time Frame: Through study completion at discharge, up to 6 months of corrected gestational age ]
    Necrotizing Enterocolitis (Modified Bell's stage 2-3)
21. Bronchopulmonary Dysplasia (mode of respiratory support administered at 36 weeks postmenstrual age; as defined and categorized in; Jensen, Dysart, Gantz, et al: Defining Bronchopulmonary Dysplasia) http://www.ncbi.nlm.nih.gov/pmc/articles/pmc6775872/ [ Time Frame: Hospital course until 36 weeks PMA ]
    Bronchopulmonary Dysplasia (mode of respiratory support administered at 36 weeks postmenstrual age; as defined and categorized in; Jensen, Dysart, Gantz, et al: Defining Bronchopulmonary Dysplasia) http://www.ncbi.nlm.nih.gov/pmc/articles/pmc6775872/
22. Severe ROP (stage 3 or treated with laser or bevacizumab) prior to 36 weeks PMA [ Time Frame: Hospital course until 36 weeks PMA ]
    Severe ROP (stage 3 or treated with laser or bevacizumab) prior to 36 weeks PMA
23. Combined outcome of severe IVH and/or death [ Time Frame: Through study completion at death or discharge, up to 6 months of corrected gestational age ]
    Combined outcome of severe IVH and/or death
24. Death [ Time Frame: Through study completion at death or discharge, up to 6 months of corrected gestational age ]
    Death
25. SVC Flow [ Time Frame: 6 hours of life ]
    Superior Vena Cava flow by echocardiography
26. RVO [ Time Frame: 6 hours of life ]
    Right Ventricular output by echocardiography
27. Left Ventricular Output [ Time Frame: 6 hours of life ]
    Left Ventricular output by echocardiography
28. Cognitive Composite Score [ Time Frame: 24 months corrected age ]
    Composite Score (cognitive 45-155; higher scores are better) as assessed by the Bayley Scales of Infant and Toddler Development Fourth Edition
29. Language Composite Score [ Time Frame: 24 months corrected age ]
    Composite Score (language 45-155; higher scores are better) as assessed by the Bayley Scales of Infant and Toddler Development Fourth Edition
30. Motor Composite Score [ Time Frame: 24 months corrected age ]
    Composite Score (motor 45-155; higher scores are better) as assessed by the Bayley Scales of Infant and Toddler Development Fourth Edition
31. Cerebral Palsy [ Time Frame: 24 months corrected age ]
    As assessed by Gross Motor Function Classification System (GMFCS) Levels 1-5
32. Pulsatility Index [ Time Frame: 6 hours of life ]
    Pulsatility index calculated from Doppler of the Middle Cerebral Artery
33. Resistive Index [ Time Frame: 6 hours of life ]
    Resistive index calculated from Doppler of the Middle Cerebral Artery
34. Changes in cerebral oxygenation saturation, StO2 (%) [ Time Frame: In the first 10 minutes of life ]
    Changes in cerebral oxygenation saturation, StO2 (%)
35. Changes in SpO2 (%) in the first 10 minutes of life [ Time Frame: In the first 10 minutes of life ]
    Changes in SpO2 (%) in the first 10 minutes of life
36. Inhaled Nitric Oxide [ Time Frame: Hospital course until 36 weeks PMA ]
    Use of Inhaled Nitric Oxide for Respiratory failure or Pulmonary Hypertension

Eligibility Criteria

• Ages Eligible for Study: 22 Weeks to 28 Weeks (Child)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

• up to 28+6 weeks Gestational age
• Single and Multiple pregnancy
• All modes of delivery (vaginally or caesarean section)

Exclusion Criteria:

• Parents decline consent
• Congenital anomalies of the newborn
• Bleeding Accreta
• Monochorionic multiples with evidence of TTTS
• Fetal or maternal risk (i.e. compromise)
• Preterm Premature Rupture of Membranes prior to 20 weeks gestation

Contacts and Locations

Contacts

Contact: Anup Katheria, MD; 858-939-4170; anup.katheria@sharp.com

Contact: Felix Ines, RCP-RRT; 858-939-4136; felix.ines@sharp.com

Locations

United States, California

University of California Davis; Recruiting

Davis, California, United States, 95618

Contact: Payam Vali, MD 916-734-8672 pvali@ucdavis.edu

Sharp Mary Birch Hospital for Women and Newborns; Recruiting

San Diego, California, United States, 92123

Contact: Anup C Katheria, MD 858-939-4198 anup.katheria@sharp.com

Contact: Felix Ines, RCP-RRT 858-939-4136 felix.ines@sharp.com

Sponsors and Collaborators

Sharp HealthCare

Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)

Sharp Mary Birch Hospital for Women & Newborns

Investigators

• Principal Investigator: Anup Katheria, MD; Sharp HealthCare

More Information

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Wang CL, Anderson C, Leone TA, Rich W, Govindaswami B, Finer NN. Resuscitation of preterm neonates by using room air or 100% oxygen. Pediatrics. 2008 Jun;121(6):1083-9. doi: 10.1542/peds.2007-1460.

Katheria AC, Harbert MJ, Nagaraj SB, Arnell K, Poeltler DM, Brown MK, Rich W, Hassen KO, Finer N. The Neu-Prem Trial: Neuromonitoring of Brains of Infants Born Preterm During Resuscitation-A Prospective Observational Cohort Study. J Pediatr. 2018 Jul;198:209-213.e3. doi: 10.1016/j.jpeds.2018.02.065. Epub 2018 Apr 18.

Katheria AC, Leone TA, Woelkers D, Garey DM, Rich W, Finer NN. The effects of umbilical cord milking on hemodynamics and neonatal outcomes in premature neonates. J Pediatr. 2014 May;164(5):1045-1050.e1. doi: 10.1016/j.jpeds.2014.01.024. Epub 2014 Feb 20.

Katheria AC, Truong G, Cousins L, Oshiro B, Finer NN. Umbilical Cord Milking Versus Delayed Cord Clamping in Preterm Infants. Pediatrics. 2015 Jul;136(1):61-9. doi: 10.1542/peds.2015-0368.

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• Responsible Party: Anup Katheria, M.D., Director of Neonatal Research Institute, Sharp HealthCare
• ClinicalTrials.gov Identifier: NCT04413097
• Other Study ID Numbers: DOXIE
• First Posted: June 2, 2020
• Last Update Posted: March 25, 2022
• Last Verified: March 2022

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Yes
• Plan Description: Data will be made available per NICHD requirements (National Institute of Child Health and Human Development)
• Supporting Materials: Statistical Analysis Plan (SAP)
• Time Frame: 2 years after primary publication
• Access Criteria: An archived dataset with documentation will be made available for additional users by outside investigators, in collaboration with the study investigators. We will work with NICHD program staff to develop a broad data sharing plan over time.

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Anup Katheria, M.D., Sharp HealthCare:

Delayed Cord Clamping; IVH- Intraventricular Hemorrhage; Hyperoxia in Neonates; Hypoxia Neonatal; Continuous Positive Airway Pressure (CPAP)

Additional relevant MeSH terms:

Respiratory Insufficiency; Pulmonary Valve Insufficiency; Hemorrhage; Hypoxia; Hyperoxia; Pathologic Processes; Signs and Symptoms, Respiratory; Respiration Disorders; Respiratory Tract Diseases; Heart Valve Diseases; Heart Diseases; Cardiovascular Diseases