Cellular Therapy for Extreme Preterm Infants at Risk of Developing Bronchopulmonary Dysplasia

Helping Underdeveloped Lungs With Cells (HULC): Mesenchymal Stromal Cells in Extreme Preterm Infants at Risk of Developing Bronchopulmonary Dysplasia - Phase 1 Study

Bronchopulmonary dysplasia (BPD) is a common and chronic lung disease that occurs in preterm infants following ventilator and oxygen therapy and is associated with long-term health consequences. Preclinical research shows that mesenchymal stromal cells (MSCs) can modify a number of pathophysiological processes that are central to the progression of BPD and thus present as a promising new treatment option. The main purpose of this Phase I study is to evaluate the safety of human umbilical cord tissue-derived MSCs in extremely preterm infants at risk of developing BPD.

Study Overview

• Status: Recruiting
• Conditions: Bronchopulmonary Dysplasia
• Intervention / Treatment: Biological: Allogeneic Umbilical Cord Tissue-Derived Mesenchymal Stromal Cells

Detailed Description

Complications of extreme preterm birth are the primary cause of mortality in children under the age of five. Bronchopulmonary dysplasia (BPD), the chronic lung disease that follows ventilator and oxygen therapy for acute respiratory failure, is the most common complication of extreme prematurity and contributes to life-long respiratory and neurological impairment. Currently, there is no effective treatment for BPD. The multi-factorial nature of BPD makes it challenging for traditional pharmacological therapies targeting a single pathway to have a major impact on outcome. Mesenchymal stromal cells (MSCs) may provide a promising new treatment avenue due to their pleiotropic effects that may prevent neonatal lung injury while promoting lung (and other organ) growth. A systematic review and meta-analysis of all preclinical studies testing MSCs in neonatal lung injury models provides strong evidence for the lung protective effect of MSCs. Additionally, studies in a large preclinical model of extreme prematurity and chronic lung injury suggest feasibility, safety and short-term hemodynamic benefit of intravenously delivered human umbilical cord tissue-derived MSCs (uc-MSC).

The aim of this study is to establish the safety, maximum feasible dose and feasibility of intravenously delivered allogeneic uc-MSCs in preterm infants at risk of developing BPD. This will be a Phase 1, open-label, single center, dose-escalating trial using a 3+3+3 design.

• Study Type: Interventional
• Enrollment (Estimated): 9
• Phase: Phase 1

Contacts and Locations

• Study Contact: Name: Study Coordinator; Phone Number: 6041 613-737-7600; Email: chorth@cheo.on.ca

Study Locations

• Canada
  • Ontario
    • Gloucester, Ontario, Canada, K1T 8L6
      • Recruiting
      • The Ottawa Hospital - General Campus
      • Contact: Chantal Horth; Phone Number: 6041 613-737-7600; Email: chorth@cheo.on.ca
      • Contact: Rebecca Grimwood; Phone Number: 2794 613-737-7600; Email: rgrimwood@cheo.on.ca
      • Principal Investigator: Bernard Thebaud, MD
    • Toronto, Ontario, Canada, M4N 3M5
      • Recruiting
      • Sunnybrook Health Sciences Centre
      • Contact: Afsheen Ayaz; Phone Number: 87994 416-480-6400; Email: afsheen.ayaz@sunnybrook.ca
      • Contact: Michael Dunn, Dr.; Email: michael.dunn@sunnybrook.ca

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 1 week to 3 weeks (Child)
• Accepts Healthy Volunteers: No

Description

A participant needs to meet all inclusion criteria between day of life 7-28 to be eligible:

Inclusion Criteria:

• Admission to The Ottawa Hospital (TOH) NICU - General Campus or Sunnybrook Health Sciences Centre NICU
• Gestational age at birth < 28 weeks
• Intubated on mechanical ventilation
• Fraction of inspired oxygen ≥ 30%
• Parents or substitute decision make must provide written informed consent

Exclusion Criteria:

• Severe congenital anomaly by antenatal ultrasound and physical examination
• Ongoing shock and severe sepsis (confirmed by positive blood or cerebrospinal fluid culture) as per attending physician
• Severe pulmonary hemorrhage
• Active pneumothorax (with chest tube in-situ)
• Hemodynamically significant PDA
• Participants with caregiver unable to speak English or French
• Patient i moribund, not expected to survive
• Planned to be extubated in the 24 hours after uc-MSC administration

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• 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: Mesenchymal Stromal Cell Therapy; Patients are enrolled into one of three escalating dose panels based on the time of enrolment. The first three patients will receive 1 million cells/kg of body weight, the next three patients will receive 3 million cells/kg of body weight, and the final three patients will receive 10 million cells/kg of body weight. Progression through the escalating dose panels is subject to review by an independent Data Safety Monitoring Committee.

Biological: Allogeneic Umbilical Cord Tissue-Derived Mesenchymal Stromal Cells; Cryopreserved allogeneic umbilical cord tissue-derived mesenchymal stromal cells are thawed and administered intravenously.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Occurrence and rate of dose limiting toxicity	Dose limiting toxicity consists of the following events: Death occurring within 24 hours of injection;; Pulmonary embolism defined as acute increase in right ventricular afterload (identified by serial targeted neonatal echocardiography) and signs of acute increased dead space ventilation (respiratory distress, increased PaCO2, increased minute ventilation) occurring within 24 hours of injection;; Hypersensitivity / anaphylactic to uc-MSCs defined as any severe systemic inflammatory response syndrome with negative blood culture not consistent with the overall clinical course of the infant occurring within 72 hours of injection;; Any other serious adverse event not expected in this patient population for which there is no alternative explanation but the administration of uc-MSCs, occurring within 1 week of injection.	Up to 1 week following uc-MSC injection

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Need for Ventilatory Support	Time to extubation; Duration of mechanical ventilation; Duration of non-invasive positive pressure respiratory support; Duration of supplemental oxygen	From enrollment until discharge, 40 weeks corrected gestational age, or death (whichever occurs first)
Rate of Death	Rate of death until discharge or 40 weeks corrected gestational age, whichever comes first	From enrollment until discharge or 40 weeks corrected gestational age (whichever occurs first)
Occurrence of Other Severe Complications of Prematurity	Blood culture-proven sepsis; Patent ductus arteriosus (treated medically or surgically); Necrotizing enterocolitis; Isolated intestinal perforation; Retinopathy of prematurity requiring treatment; Severe intraventricular hemorrhage (≥ grade 3); Cystic periventricular leukomalacia	From enrollment until discharge or 40 weeks corrected gestational age (whichever occurs first)
FiO2 and Oxygen Index	Measures of gas exchange	From enrollment until discharge, 40 weeks corrected gestational age, or death (whichever occurs first)
Need for Postnatal Steroids	This is a yes/no measure	From enrollment until discharge, 40 weeks corrected gestational age, or death (whichever occurs first)
Incidence and Severity of BPD	Measured as mild, moderate, or severe	From enrollment until discharge, 40 weeks corrected gestational age, or death (whichever occurs first)
Rate of Survival Without (moderate or severe) BPD	Measured according to the physiological definition of BPD (BPD at 36 weeks corrected age)	From enrollment until 36 weeks corrected gestational age
Changes in Pulmonary Hemodynamics	Targeted neonatal echocardiography to assess pulmonary hypertension using validated parameters	At enrollment, 48 hours following uc-MSC injection, 28 days of life, and 36 weeks corrected gestational age
Biological Measure of Clinical Improvement	Markers of inflammation will be assessed in patient serum samples	72-96 hours following uc-MSC injection
Biological Measure of Lung Improvement	Biomarkers of lung improvement will be assessed in patient tracheal aspirate samples	72-96 hours following uc-MSC injection
Long-term Safety Follow-Up	Participant's overall health will be assessed through a questionnaire administered over the phone, once a year for 10 years	Ten years following follow-up visit
Feasibility: Cell Administration	Successful recruitment and administration of cells to nine patients in 18 months	Day of life 7-28
Feasibility: Recruitment Efficiency	Proportion of potentially eligible patients that are successfully screened; Proportion of participants successfully screened who do not enroll (reason for failure to enroll will be recorded)	Day of life 7-28
Feasibility: Recruitment Timing	Median time from screening to enrollment; Median time from screening to cell administration	Day of life 7-28
Feasibility: Participant Retainment	Proportion of patients that do not complete cell infusion; Proportion of patients enrolled that do not undergo scheduled follow-up	From enrollment until follow-up at 18-30 months-of-age
Bayley Scale of Infant and Toddler Development	Assessment of cognitive, language, and motor development	18-30 months-of-age
Animated Information Video	Characterize parental views of an animated MSC information video through brief semi-structured interviews	Day of life 7-28

Collaborators and Investigators

• Sponsor: Ottawa Hospital Research Institute
• Collaborators: Canadian Institutes of Health Research (CIHR); Stem Cell Network; Ontario Institute of Regenerative Medicine (OIRM)
• Investigators: Principal Investigator: Bernard Thébaud, MD, PhD, Ottawa Hospital Research Institute

Study record dates

Study Major Dates

• Study Start (Actual): October 17, 2022
• Primary Completion (Estimated): December 31, 2023
• Study Completion (Estimated): December 1, 2035

Study Registration Dates

• First Submitted: January 14, 2020
• First Submitted That Met QC Criteria: February 3, 2020
• First Posted (Actual): February 5, 2020

Study Record Updates

• Last Update Posted (Actual): November 1, 2023
• Last Update Submitted That Met QC Criteria: October 30, 2023
• Last Verified: October 1, 2023

More Information

Terms related to this study

• Keywords: Stem cells; Cell therapy; Phase I clinical trial; Preterm birth; Bronchopulmonary Dysplasia; Mesenchymal stromal cell
• Additional Relevant MeSH Terms: Pathologic Processes; Respiratory Tract Diseases; Lung Diseases; Infant, Newborn, Diseases; Lung Injury; Infant, Premature, Diseases; Ventilator-Induced Lung Injury; Hyperplasia; Bronchopulmonary Dysplasia
• Other Study ID Numbers: HULC-1

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO
• IPD Plan Description: Due to the small sample size, the sharing of individual data has privacy and confidentiality implications.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No