Intranasal Human Milk for Intraventricular Hemorrhage

Intranasal Human Milk as Stem Cell Therapy in Preterm Infants With Intraventricular Hemorrhage

Intraventricular hemorrhage (IVH) is a leading cause of brain injury in infants born before term. Severe IVH, which occurs nearly exclusively in very preterm infants (born before 32 weeks gestation) who are already at risk of neurodevelopmental delays and cerebral palsy at baseline, results in a ~5 times higher risk of death or moderate-severe neurodevelopmental impairment, as well as short-term morbidities in the neonatal intensive care unit (NICU). Infants with grade I and II IVH, although less severe than the higher grades of IVH, also have a higher risk of death or moderate to severe neurodevelopmental impairment compared to infants with a normal head ultrasound. Outcomes are worsened by the fact that the brains of these preterm infants are not fully developed, so the progenitor cells that would later differentiate and mature are damaged, resulting in hypomyelination and gray matter loss that are associated with poor neurodevelopmental outcomes. There is no available therapy to treat the IVH or resultant brain injury, other than symptomatic management for resultant post-hemorrhagic hydrocephalus with lumbar punctures and temporary or permanent shunts, which have significant risks on their own.

This is a phase I trial to determine whether fresh intranasal human milk (HM) can be safely delivered as stem cell therapy to preterm IVH patients within a 3-hour window from HM expression and to identify signals which would indicate whether intranasal HM stimulates the repair of damaged brain tissue. Outcomes will be compared to HM fed historical IVH controls. Recruitment will take place in tertiary care NICUs in Toronto, which care for the highest proportion of very preterm infants with IVH in Canada. These NICUs have already adopted a common protocolized approach to manage severe IVH and post-hemorrhagic hydrocephalus with intensive monitoring, early symptomatic management, and detailed prospectively collected IVH data.

Study Overview

• Status: Active, not recruiting
• Conditions: Intraventricular Hemorrhage
• Intervention / Treatment: Other: Human breast milk

• Study Type: Interventional
• Enrollment (Actual): 37
• Phase: Not Applicable

Contacts and Locations

Study Locations

• Canada
  • Ontario
    • Toronto, Ontario, Canada, M5G 1X8
      • The Hospital for Sick Children
    • Toronto, Ontario, Canada, M5G 1X5
      • Mount Sinai Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: No older than 7 months (Child)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Preterm infants (<33 weeks gestation at birth, stratified < and ≥28 weeks) with any grade IVH/intraparenchymal hemorrhage/infarction on head ultrasound in the first 10 days of life. Diagnostic criteria will be based on the Papile definitions as used by the study sites/Toronto Centre for Neonatal Health for PHVD management, outlined in the document "Intraventricular Hemorrhage and Measurements of Lateral Ventricular Size from Head Ultrasound"

Exclusion Criteria:

1. Disorders associated with neurodevelopmental delays or impairment (i.e. Trisomy 21)
2. Moribund/critically ill infant or known lethal diagnosis with plans by medical team to redirect care
3. Choanal atresia or anomalies that would not allow intranasal treatment
4. Surgical condition (e.g. esophageal atresia) for which team feels intranasal HM is contraindicated
5. Enrolled in other intervention trials in which primary target is neurodevelopmental outcome
6. Parent with lactation contraindication(s) (i.e. HIV) or parent who declines lactation initiation
7. Lactating parent unable to provide fresh HM: unable/unwilling to pump at study site or unable to have fresh HM delivered by designee at least once/day for 3 days within 3 hours of pumping AND located (in hospital or home) >30km from study sites (for courier services)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Intranasal human breast milk; Human breast milk delivered intranasally to preterm infants (<33 weeks gestation at birth, stratified < and ≥28 weeks) with any grade IVH/intraparenchymal hemorrhage/infarction identified on head ultrasound in the first 10 days of life. Dosing: Escalating dose starting at 0.2mL into one nostril with repeat dose 10-15 minutes later 1-2x daily, depending on availability of fresh HM

Other: Human breast milk; Intranasal human breast milk

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of participants with treatment-related adverse events as described in the protocol	Increased respiratory support settings or increase in Fio2 by more than 10% for more than 1 hour after the intervention, need for PPV/bagging immediately (within 5 minutes) of administration, or need for escalation of respiratory modality (ie NC to CPAP or NIV to intubation) in the hour after administration.	1 year

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
The number of participants with IVH related long-term adverse neurodevelopmental outcomes compared with a cohort of HM-fed historical controls with IVH from 30 months prior to the intervention cohort.	Cerebral Palsy, Gross motor delay (in the absence of CP), Fine motor delay, Vision impairment (blindness or wears glasses), Hearing impairment (aided / cochlear implant), Cognitive delay, Speech and language delay	2 years
Interference of IHM administration with routine clinical care measured using post-intervention staff survey		1 year
Number of participants with any grade IVH unable to be recruited within 10 days of birth		1 year
Number of eligible patients unable to receive intranasal HM administration within 3 hours of HM collection		1 year

Other Outcome Measures

Outcome Measure	Time Frame
Number of stem cells in maternal milk provided by lactating parents of preterm infants	1 year
Number of stem cells measured in CSF of treated infants who have lumbar punctures for clinical indications.	1 year

Collaborators and Investigators

• Sponsor: The Hospital for Sick Children
• Collaborators: MOUNT SINAI HOSPITAL
• Investigators: Principal Investigator: Rebecca Hoban, MD, The Hospital for Sick Children

Study record dates

Study Major Dates

• Study Start (Actual): March 11, 2020
• Primary Completion (Actual): December 1, 2021
• Study Completion (Anticipated): December 1, 2023

Study Registration Dates

• First Submitted: December 20, 2019
• First Submitted That Met QC Criteria: January 9, 2020
• First Posted (Actual): January 13, 2020

Study Record Updates

• Last Update Posted (Actual): May 4, 2022
• Last Update Submitted That Met QC Criteria: May 3, 2022
• Last Verified: May 1, 2022

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Cardiovascular Diseases; Vascular Diseases; Cerebrovascular Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Intracranial Hemorrhages; Hemorrhage; Cerebral Hemorrhage
• Other Study ID Numbers: 1911

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No