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

• ClinicalTrials.gov Identifier: NCT04255147
• Recruitment Status: Recruiting
• First Posted: February 5, 2020
• Last Update Posted: April 3, 2023
• Sponsor: Ottawa Hospital Research Institute
• Collaborators: Canadian Institutes of Health Research (CIHR); Ontario Institute of Regenerative Medicine (OIRM); Stem Cell Network
• Information provided by (Responsible Party): Ottawa Hospital Research Institute

Tracking Information

• First Submitted Date: January 14, 2020
• First Posted Date: February 5, 2020
• Last Update Posted Date: April 3, 2023
• Actual Study Start Date: October 17, 2022
• Estimated Primary Completion Date: September 30, 2023 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: February 3, 2020)

Occurrence and rate of dose limiting toxicity [ Time Frame: Up to 1 week following uc-MSC injection ]

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.

• Original Primary Outcome Measures: Same as current

Current Secondary Outcome Measures (submitted: April 8, 2020)

• Rate of Death [ Time Frame: From enrollment until discharge or 40 weeks corrected gestational age (whichever occurs first) ]
  Rate of death until discharge or 40 weeks corrected gestational age, whichever comes first
• Occurrence of Other Severe Complications of Prematurity [ Time Frame: From enrollment until discharge or 40 weeks corrected gestational age (whichever occurs first) ]
  • 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
• FiO2 and Oxygen Index [ Time Frame: From enrollment until discharge, 40 weeks corrected gestational age, or death (whichever occurs first) ]
  Measures of gas exchange
• Need for Ventilatory Support [ Time Frame: From enrollment until discharge, 40 weeks corrected gestational age, or death (whichever occurs first) ]
  • Time to extubation
  • Duration of mechanical ventilation
  • Duration of non-invasive positive pressure respiratory support
  • Duration of supplemental oxygen
• Need for Postnatal Steroids [ Time Frame: From enrollment until discharge, 40 weeks corrected gestational age, or death (whichever occurs first) ]
  This is a yes/no measure
• Incidence and Severity of BPD [ Time Frame: From enrollment until discharge, 40 weeks corrected gestational age, or death (whichever occurs first) ]
  Measured as mild, moderate, or severe
• Rate of Survival Without (moderate or severe) BPD [ Time Frame: From enrollment until 36 weeks corrected gestational age ]
  Measured according to the physiological definition of BPD (BPD at 36 weeks corrected age)
• Changes in Pulmonary Hemodynamics [ Time Frame: At enrollment, 48 hours following uc-MSC injection, 28 days of life, and 36 weeks corrected gestational age ]
  Targeted neonatal echocardiography to assess pulmonary hypertension using validated parameters
• Biological Measure of Clinical Improvement [ Time Frame: 72-96 hours following uc-MSC injection ]
  Markers of inflammation will be assessed in patient serum samples
• Biological Measure of Lung Improvement [ Time Frame: 72-96 hours following uc-MSC injection ]
  Biomarkers of lung improvement will be assessed in patient tracheal aspirate samples
• Feasibility: Cell Administration [ Time Frame: Day of life 7-21 ]
  Successful recruitment and administration of cells to nine patients in 18 months
• Feasibility: Recruitment Efficiency [ Time Frame: Day of life 7-21 ]
  • 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)
• Feasibility: Recruitment Timing [ Time Frame: Day of life 7-21 ]
  • Median time from screening to enrollment
  • Median time from screening to cell administration
• Feasibility: Participant Retainment [ Time Frame: From enrollment until follow-up at 18-24 months-of-age ]
  • Proportion of patients that do not complete cell infusion
  • Proportion of patients enrolled that do not undergo scheduled follow-up
• Bayley Scale of Infant and Toddler Development [ Time Frame: 18-24 months-of-age ]
  Assessment of cognitive, language, and motor development
• Long-term Safety Follow-Up [ Time Frame: Ten years following follow-up visit ]
  Participant's overall health will be assessed through a questionnaire administered over the phone, once a year for 10 years
• Animated Information Video [ Time Frame: Day of life 7-21 ]
  Characterize parental views of an animated MSC information video through brief semi-structured interviews

Original Secondary Outcome Measures (submitted: February 3, 2020)

• Rate of Death [ Time Frame: From enrollment until discharge or 40 weeks corrected gestational age (whichever occurs first) ]
  Rate of death until discharge or 40 weeks corrected gestational age, whichever comes first
• Occurrence of Other Severe Complications of Prematurity [ Time Frame: From enrollment until discharge or 40 weeks corrected gestational age (whichever occurs first) ]
  • 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
• FiO2 and Oxygen Index [ Time Frame: From enrollment until discharge, 40 weeks corrected gestational age, or death (whichever occurs first) ]
  Measures of gas exchange
• Need for Ventilatory Support [ Time Frame: From enrollment until discharge, 40 weeks corrected gestational age, or death (whichever occurs first) ]
  • Time to extubation
  • Duration of mechanical ventilation
  • Duration of non-invasive positive pressure respiratory support
  • Duration of supplemental oxygen
• Need for Postnatal Steroids [ Time Frame: From enrollment until discharge, 40 weeks corrected gestational age, or death (whichever occurs first) ]
  This is a yes/no measure
• Incidence and Severity of BPD [ Time Frame: From enrollment until discharge, 40 weeks corrected gestational age, or death (whichever occurs first) ]
  Measured as mild, moderate, or severe
• Rate of Survival Without (moderate or severe) BPD [ Time Frame: From enrollment until 36 weeks corrected gestational age ]
  Measured according to the physiological definition of BPD (BPD at 36 weeks corrected age)
• Changes in Pulmonary Hemodynamics [ Time Frame: At enrollment, 48 hours following uc-MSC injection, 28 days of life, and 36 weeks corrected gestational age ]
  Targeted neonatal echocardiography to assess pulmonary hypertension using validated parameters
• Biological Measure of Lung Improvement [ Time Frame: 72-96 hours following uc-MSC injection ]
  Markers of inflammation will be assessed, including IL-1, IL-1RA, IL-6, IL-8, IL-10, TNF-α, IFN-γ, MCP-1, IP- 10, RANTES
• Feasibility: Cell Administration [ Time Frame: Day of life 7-21 ]
  Successful recruitment and administration of cells to nine patients in 18 months
• Feasibility: Recruitment Efficiency [ Time Frame: Day of life 7-21 ]
  • 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)
• Feasibility: Recruitment Timing [ Time Frame: Day of life 7-21 ]
  • Median time from screening to enrollment
  • Median time from screening to cell administration
• Feasibility: Participant Retainment [ Time Frame: From enrollment until follow-up at 18-24 months-of-age ]
  • Proportion of patients that do not complete cell infusion
  • Proportion of patients enrolled that do not undergo scheduled follow-up
• Ages & Stages Questionnaire [ Time Frame: 18-24 months-of-age ]
  Assessment of communication, gross motor, fine motor, problem solving, and personal social skills
• Bayley Scale of Infant and Toddler Development [ Time Frame: 18-24 months-of-age ]
  Assessment of cognitive, language, and motor development
• Long-term Safety Follow-Up [ Time Frame: Ten years following follow-up visit ]
  Participant's overall health will be assessed through a questionnaire administered over the phone, once a year for 10 years
• Animated Information Video [ Time Frame: Day of life 7-21 ]
  Characterize parental views of an animated MSC information video through brief semi-structured interviews

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

Descriptive Information

• Brief Title: Cellular Therapy for Extreme Preterm Infants at Risk of Developing Bronchopulmonary Dysplasia
• Official Title: Helping Underdeveloped Lungs With Cells (HULC): Mesenchymal Stromal Cells in Extreme Preterm Infants at Risk of Developing Bronchopulmonary Dysplasia - Phase 1 Study
• Brief Summary: 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.

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
• Study Phase: Phase 1
• Study Design: Allocation: N/A; Intervention Model: Single Group Assignment; Masking: None (Open Label); Primary Purpose: Prevention
• Condition: Bronchopulmonary Dysplasia

Intervention

Biological: Allogeneic Umbilical Cord Tissue-Derived Mesenchymal Stromal Cells

Cryopreserved allogeneic umbilical cord tissue-derived mesenchymal stromal cells are thawed and administered intravenously.

Study Arms

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.

Intervention: Biological: Allogeneic Umbilical Cord Tissue-Derived Mesenchymal Stromal Cells

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Recruiting
• Estimated Enrollment (submitted: February 3, 2020): 9
• Original Estimated Enrollment: Same as current
• Estimated Study Completion Date: December 2035
• Estimated Primary Completion Date: September 30, 2023 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

• Admission to The Ottawa Hospital General Campus Neonatal Intensive Care Unit
• Gestational age at birth < 28 weeks
• Day of life 7-21
• Intubated on mechanical ventilation
• Fraction of inspired oxygen ≥ 35%
• Parents or surrogates must provide written informed consent

Exclusion Criteria:

• Severe congenital anomaly by antenatal ultrasound and physical examination
• Ongoing shock and severe sepsis
• Active pulmonary hemorrhage
• Active pneumothorax (with chest tube in-situ)

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 7 Days to 21 Days (Child)
• Accepts Healthy Volunteers: No

Contacts

Contact: Study Coordinator; 613-737-7600 ext 6041; chorth@cheo.on.ca

• Listed Location Countries: Canada

Administrative Information

• NCT Number: NCT04255147
• Other Study ID Numbers: HULC-1
• 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
• Product Manufactured in and Exported from the U.S.: No

IPD Sharing Statement

• Plan to Share IPD: No
• Plan Description: Due to the small sample size, the sharing of individual data has privacy and confidentiality implications.

• Current Responsible Party: Ottawa Hospital Research Institute
• Original Responsible Party: Same as current
• Current Study Sponsor: Ottawa Hospital Research Institute
• Original Study Sponsor: Same as current

Collaborators

• Canadian Institutes of Health Research (CIHR)
• Ontario Institute of Regenerative Medicine (OIRM)
• Stem Cell Network

Investigators

• Principal Investigator: Bernard Thébaud, MD, PhD; Ottawa Hospital Research Institute

• PRS Account: Ottawa Hospital Research Institute
• Verification Date: March 2023