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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT04255147
Recruitment Status : Not yet recruiting
First Posted : February 5, 2020
Last Update Posted : April 10, 2020
Sponsor:
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

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.

Condition or disease Intervention/treatment Phase
Bronchopulmonary Dysplasia Biological: Allogeneic Umbilical Cord Tissue-Derived Mesenchymal Stromal Cells Phase 1

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.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 9 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Prevention
Official Title: Helping Underdeveloped Lungs With Cells (HULC): Mesenchymal Stromal Cells in Extreme Preterm Infants at Risk of Developing Bronchopulmonary Dysplasia - Phase 1 Study
Estimated Study Start Date : January 2021
Estimated Primary Completion Date : June 2022
Estimated Study Completion Date : December 2035

Resource links provided by the National Library of Medicine


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.




Primary Outcome Measures :
  1. 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.


Secondary Outcome Measures :
  1. 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

  2. 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

  3. FiO2 and Oxygen Index [ Time Frame: From enrollment until discharge, 40 weeks corrected gestational age, or death (whichever occurs first) ]
    Measures of gas exchange

  4. 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

  5. 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

  6. 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

  7. 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)

  8. 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

  9. Biological Measure of Clinical Improvement [ Time Frame: 72-96 hours following uc-MSC injection ]
    Markers of inflammation will be assessed in patient serum samples

  10. 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

  11. Feasibility: Cell Administration [ Time Frame: Day of life 7-21 ]
    Successful recruitment and administration of cells to nine patients in 18 months

  12. 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)

  13. Feasibility: Recruitment Timing [ Time Frame: Day of life 7-21 ]
    • Median time from screening to enrollment
    • Median time from screening to cell administration

  14. 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

  15. Bayley Scale of Infant and Toddler Development [ Time Frame: 18-24 months-of-age ]
    Assessment of cognitive, language, and motor development

  16. 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

  17. Animated Information Video [ Time Frame: Day of life 7-21 ]
    Characterize parental views of an animated MSC information video through brief semi-structured interviews



Information from the National Library of Medicine

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Ages Eligible for Study:   up to 21 Days   (Child)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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)

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04255147


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

Locations
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Canada, Ontario
The Ottawa Hospital - General Campus
Ottawa, Ontario, Canada, K1H 8L6
Sponsors and Collaborators
Ottawa Hospital Research Institute
Canadian Institutes of Health Research (CIHR)
Ontario Institute of Regenerative Medicine (OIRM)
Stem Cell Network
Investigators
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Principal Investigator: Bernard Thébaud, MD, PhD Ottawa Hospital Research Institute
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Responsible Party: Ottawa Hospital Research Institute
ClinicalTrials.gov Identifier: NCT04255147    
Other Study ID Numbers: HULC-1
First Posted: February 5, 2020    Key Record Dates
Last Update Posted: April 10, 2020
Last Verified: April 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided
Plan Description: Due to the small sample size, the sharing of individual data has privacy and confidentiality implications.

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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
Keywords provided by Ottawa Hospital Research Institute:
Phase I clinical trial
Stem cells
Mesenchymal stromal cell
Bronchopulmonary Dysplasia
Preterm birth
Cell therapy
Additional relevant MeSH terms:
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Bronchopulmonary Dysplasia
Hyperplasia
Pathologic Processes
Ventilator-Induced Lung Injury
Lung Injury
Lung Diseases
Respiratory Tract Diseases
Infant, Premature, Diseases
Infant, Newborn, Diseases