Premature Infants Receiving Milking or Delayed Cord Clamping: PREMOD2 (PREMOD2)

• ClinicalTrials.gov Identifier: NCT03019367
• Recruitment Status: Completed
• First Posted: January 12, 2017
• Last Update Posted: November 23, 2022
• Sponsor: Sharp HealthCare
• Collaborators: Sharp Mary Birch Hospital for Women & Newborns; Loma Linda University; University of Pittsburgh; Providence Hospital; University of Alabama at Birmingham; University of Alberta; University College Cork; University of Ulm; Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD); Christiana Care Health Services; Sharp Grossmont Hospital; University of Utah; University of Mississippi Medical Center; PIH Health Good Samaritan Hospital; University of California, Irvine; Children's Hospital Medical Center, Cincinnati; John H. Stroger Hospital; St. Louis University; LAC+USC Medical Center
• Information provided by (Responsible Party): Anup Katheria, M.D., Sharp HealthCare

Tracking Information

• First Submitted Date: November 21, 2016
• First Posted Date: January 12, 2017
• Last Update Posted Date: November 23, 2022
• Actual Study Start Date: June 6, 2017
• Actual Primary Completion Date: September 16, 2022 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: January 2, 2019)

Incidence of severe IVH or death [ Time Frame: Through study completion at death or discharge, up to 6 months corrected gestational age (CGA) ]

Severe intraventricular hemorrhage of grade 3 or 4 or death

• Original Primary Outcome Measures (submitted: January 10, 2017): Incidence of severe IVH or death [ Time Frame: Through study completion at death or discharge, up to 6 months corrected gestational age (CGA) ]

Current Secondary Outcome Measures (submitted: March 19, 2018)

• All Grade IVH [ Time Frame: Through study completion at discharge, up to 6 months corrected gestational age (CGA) ]
  Any intraventricular hemorrhage (grades 1-4)
• Severe IVH (Grade 3 or 4) [ Time Frame: Through study completion at discharge, up to 6 months corrected gestational age (CGA) ]
  Severe intraventricular hemorrhage (bleeding in the brain parenchyma and/or ventricular dilation)
• Hemoglobin/Hematocrit at 4 hours [ Time Frame: 4 +/- 2 hours of life ]
  hemoglobin/hematocrit
• Incidence of Severe IVH or death in infants <28 weeks gestation [ Time Frame: Through study completion at discharge, up to 6 months corrected gestational age (CGA) ]
  Severe intraventricular hemorrhage (grade 3 or 4) in infants born under 28 weeks gestational age
• Delivery room interventions [ Time Frame: In the first 10 minutes of life ]
  Resuscitation interventions including positive pressure ventilation, continuous positive airway pressure, intubation, chest compressions and medications
• Blood pressures in the first 24 hours of life [ Time Frame: In the first 24 hours of life ]
  Blood pressure on admission, 6, 12, 18 and 24 hours of life

Original Secondary Outcome Measures (submitted: January 10, 2017)

• Incidence of death or neurodevelopmental impairment at 22-26 months corrected gestational age [ Time Frame: Through follow up completion at 26 months corrected gestational age ]
• All Grade Intraventricular Hemorrhage [ Time Frame: Through study completion at discharge, up to 6 months corrected gestational age (CGA) ]
• Severe IVH (Grade 3 or 4) [ Time Frame: Through study completion at discharge, up to 6 months corrected gestational age (CGA) ]
• Hemoglobin/Hematocrit at 4 hours [ Time Frame: 4 +/- 2 hours of life ]
• Incidence of Severe IVH or death in infants <28 weeks gestation [ Time Frame: Through study completion at discharge, up to 6 months corrected gestational age (CGA) ]
• Cerebral StO2 during Resuscitation [ Time Frame: In the first 10 minutes of life ]
• Cerebral StO2 in the NICU [ Time Frame: In the first 72 hours of life ]

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Premature Infants Receiving Milking or Delayed Cord Clamping: PREMOD2
• Official Title: Premature Infants Receiving Milking or Delayed Cord Clamping: Randomized Controlled Multicenter Non-inferiority Trial

Brief Summary

This study is being done to find out whether umbilical cord milking (UCM) is at least as good as or better than delayed cord clamping (DCC) to reduce bleeding in the brain or prevent death in premature newborns. The investigators will study short and long term outcomes of infants delivered before 32 weeks gestation that receive either UCM or DCC.

* The trial was stopped by the DSMB for safety in the small strata. They subsequently allowed for continuation of the trial in infants 29-32+6 wk GA.

Detailed Description

Aim 1. Compare the incidence of severe intraventricular hemorrhage (IVH) and/or death in premature newborns <33 weeks gestational age (GA) delivered by C/S receiving UCM to those receiving DCC.

Hypothesis1: First demonstrate infants in the UCM group are not inferior to the DCC group (reject H10).

Hypothesis2: If H1 is true, demonstrate lower incidence of severe IVH and/or death in UCM infants compared to DCC.

Aim 2. Compare the safety and efficacy profiles of premature newborns <33 weeks GA delivered by C/S receiving UCM vs. DCC during their hospitalization.

Hypothesis3: UCM group will have a decreased need for resuscitation interventions with no differences in bilirubin or polycythemia compared to DCC.

Hypothesis4: UCM group will have improved blood pressures in the first 24 hours of life compared to DCC.

Aim 3 (exploratory). To compare the outcomes of premature newborns <33 weeks GA delivered by C/S (Cesarean section) (from Aims 1 and 2) with those born by V/D (vaginal delivery) receiving UCM or DCC.

• Study Type: Interventional
• Study Phase: Not Applicable

Study Design

Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple (Care Provider, Investigator, Outcomes Assessor)
Masking Description:

It is not possible to blind the delivering obstetrician, however all other caregivers will be blinded. The procedure will be documented as "placental transfusion" in the delivery summary or admission-progress notes and all study assessments whether primary (head US) or secondary (neurodevelopmental exams) will be performed by blinded team members.

Primary Purpose: Prevention

Condition

• Intraventricular Haemorrhage Neonatal
• Death; Neonatal

Intervention

• Procedure: Umbilical cord milking UCM
  At delivery, the umbilical cord is grasped, and blood is pushed toward the infant 4 times before it is clamped. This procedure infuses a placental transfusion of blood into the preterm neonate and can be done in 15-20 seconds.
• Procedure: Delayed cord clamping DCC
  At delivery, delayed cord clamping will be performed by having the delivering obstetrician delay clamping of the umbilical cord for at least 60 seconds.

Study Arms

• Active Comparator: Umbilical cord milking UCM
  Milking the umbilical cord 4 times towards the infant at a speed of 20cm/2seconds.
  Intervention: Procedure: Umbilical cord milking UCM
• Active Comparator: Delayed cord clamping DCC
  Delayed clamping of the umbilical cord for at least 60 seconds.
  Intervention: Procedure: Delayed cord clamping DCC

Publications *

• Katheria AC, Allman P, Szychowski JM, Essers J, Carlo WA, Schmolzer GM, Dempsey E, Yanowitz T, Kaempf J, Vora F, Bhat S, Arnell K, Rich W, Varner M. Perinatal Outcomes of Subjects Enrolled in a Multicenter Trial with a Waiver of Antenatal Consent. Am J Perinatol. 2022 Jun;39(8):904-908. doi: 10.1055/s-0040-1719184. Epub 2020 Nov 3.
• Katheria A, Reister F, Essers J, Mendler M, Hummler H, Subramaniam A, Carlo W, Tita A, Truong G, Davis-Nelson S, Schmolzer G, Chari R, Kaempf J, Tomlinson M, Yanowitz T, Beck S, Simhan H, Dempsey E, O'Donoghue K, Bhat S, Hoffman M, Faksh A, Arnell K, Rich W, Finer N, Vaucher Y, Khanna P, Meyers M, Varner M, Allman P, Szychowski J, Cutter G. Association of Umbilical Cord Milking vs Delayed Umbilical Cord Clamping With Death or Severe Intraventricular Hemorrhage Among Preterm Infants. JAMA. 2019 Nov 19;322(19):1877-1886. doi: 10.1001/jama.2019.16004.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: November 22, 2022): 1201
• Original Estimated Enrollment (submitted: January 10, 2017): 1500
• Actual Study Completion Date: September 16, 2022
• Actual Primary Completion Date: September 16, 2022 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

• 23 to 32 +6 Gestational age (currently enrolling 29 to 32+6 weeks)
• Multiples without Twin-to-twin Transfusion Syndrome (TTTS)

Exclusion Criteria:

• Congenital anomalies
• Major cardiac defects
• Placental abruption or previa with hemorrhage
• Cord prolapse
• Hydrops
• Bleeding Accreta
• Monochorionic multiples with evidence of TTTS
• Fetal or maternal risk (i.e. compromise)
• Parents declined study
• Unlikely to return for 2 yr Follow Up

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 23 Weeks to 33 Weeks (Child)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Canada, Germany, Ireland, United States

Administrative Information

• NCT Number: NCT03019367
• Other Study ID Numbers: PREMOD2; 1R01HD088646-01A1 ( U.S. NIH Grant/Contract )
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

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

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 uses 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.

• Current Responsible Party: Anup Katheria, M.D., Sharp HealthCare
• Original Responsible Party: Sharp HealthCare
• Current Study Sponsor: Sharp HealthCare
• Original Study Sponsor: Same as current

Collaborators

• Sharp Mary Birch Hospital for Women & Newborns
• Loma Linda University
• University of Pittsburgh
• Providence Hospital
• University of Alabama at Birmingham
• University of Alberta
• University College Cork
• University of Ulm
• Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
• Christiana Care Health Services
• Sharp Grossmont Hospital
• University of Utah
• University of Mississippi Medical Center
• PIH Health Good Samaritan Hospital
• University of California, Irvine
• Children's Hospital Medical Center, Cincinnati
• John H. Stroger Hospital
• St. Louis University
• LAC+USC Medical Center

Investigators

• Principal Investigator: Anup C Katheria, MD; Sharp HealthCare

• PRS Account: Sharp HealthCare
• Verification Date: November 2022