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.
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
Allocation
NA
Purpose
PREVENTION
Masking
NONE
Enrollment
9
Cryopreserved allogeneic umbilical cord tissue-derived mesenchymal stromal cells are thawed and administered intravenously.
The Ottawa Hospital - General Campus
Gloucester, Ontario, Canada
Sunnybrook Health Sciences Centre
Toronto, Ontario, Canada
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.
Time frame: Up to 1 week following uc-MSC injection
Rate of Death
Rate of death until discharge or 40 weeks corrected gestational age, whichever comes first
Time frame: 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
Time frame: From enrollment until discharge or 40 weeks corrected gestational age (whichever occurs first)
FiO2 and Oxygen Index
Measures of gas exchange
Time frame: From enrollment until discharge, 40 weeks corrected gestational age, or death (whichever occurs first)
Need for Ventilatory Support
* Time to extubation * Duration of mechanical ventilation * Duration of non-invasive positive pressure respiratory support * Duration of supplemental oxygen
Time frame: From enrollment until discharge, 40 weeks corrected gestational age, or death (whichever occurs first)
Need for Postnatal Steroids
This is a yes/no measure
Time frame: 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
Time frame: 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)
Time frame: From enrollment until 36 weeks corrected gestational age
Changes in Pulmonary Hemodynamics
Targeted neonatal echocardiography to assess pulmonary hypertension using validated parameters
Time frame: 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
Time frame: 72-96 hours following uc-MSC injection
Biological Measure of Lung Improvement
Biomarkers of lung improvement will be assessed in patient tracheal aspirate samples
Time frame: 72-96 hours following uc-MSC injection
Feasibility: Cell Administration
Successful recruitment and administration of cells to nine patients in 18 months
Time frame: 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)
Time frame: Day of life 7-28
Feasibility: Recruitment Timing
* Median time from screening to enrollment * Median time from screening to cell administration
Time frame: 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
Time frame: 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
Time frame: 18-30 months-of-age
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
Time frame: Ten years following follow-up visit
Animated Information Video
Characterize parental views of an animated MSC information video through brief semi-structured interviews
Time frame: Day of life 7-28
This platform is for informational purposes only and does not constitute medical advice. Always consult a qualified healthcare professional.