Clinical trial NCT06589245: Inhaled Ciclesonide Study in Preterm Infants
Official title: The Safety and Toxicity of Inhaled Ciclesonide (i.e., Alvesco) in Preterm Infants at Risk for Developing Bronchopulmonary Dysplasia
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE1
Conditions: Bronchopulmonary Dysplasia
Lead sponsor: Children's Mercy Hospital Kansas City
Sponsor class: OTHER
Collaborators: name: University of Pittsburgh
name: Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
First posted: 2024-09-19
Enrollment: 30
Sex: ALL
Minimum age (years): 8
Maximum age (years): 28
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Intervention model description: An open label dose escalation
Primary purpose: PREVENTION

Brief summary: Our overall objective is to conduct a safety study with inhaled ciclesonide to evaluate known glucocorticoids (sGC)-related acute and intermediate toxic effects while measuring for the first time in neonates its systemic absorption and potential bioactivity (i.e. activation of primary target, the GR, in blood cells).

Detailed description: Preterm infants born before 30 weeks gestation are at increased risk of developing bronchopulmonary dysplasia (BPD), a leading cause of death and long-term pulmonary insufficiency. Both hydrocortisone and synthetic glucocorticoids (sGC) are commonly used to prevent BPD in premature infants. Clinical trials have shown that hydrocortisone targeted to infants with emerging lung disease does not prevent BPD, while inhaled sGC therapy has shown mixed efficacy in clinical trials. Dexamethasone (DEX) has been shown in clinical trials to reduce BPD rates in premature infants but is associated with short term and long-term adverse effects including cerebral palsy. There is an unmet need for efficacious Glucocorticoid (GC) therapy in premature infants to prevent BPD without encumbering serious adverse events. To address this challenge, our group has been investigating ciclesonide (CIC), a sGC pro-drug that in the inhaled form is FDA approved for use in asthma and allergic rhinitis in older children. Our published and ongoing work has shown that DEX and CIC regulate GR transcriptional targets and several genes implicated in lung protective effects in neonatal rats. Remarkably, CIC does not suppress somatic growth nor IGF-1 levels, induce hyperglycemia, or cause neuroanatomical changes in the cerebral cortex of neonatal rats, which are known pathologies caused by DEX in premature infants. Furthermore, ongoing studies reveal that CIC is as efficacious as DEX in preventing lung injury in a hyperoxia-model of experimental BPD. This study tests the hypothesis that CIC will have minimal systemic absorption and a favorable safety profile in premature infants at risk of developing BPD.

The fear of long-term neurological adverse effects has limited optimal use of sGC therapy to prevent BPD. This application is significant as it proposes to repurpose CIC, an existing sGC, for novel therapeutic use in preterm infants to prevent BPD. CIC is already FDA-approved for use in children \>5 years for allergic rhinitis and asthma, and can be used on a compassionate basis down to 2 years of age. The investigators believe our study is impactful and translationally relevant as it addresses an unmet need for efficacious GC therapy to prevent BPD in premature infants without encumbering the neurological and somatic adverse effects. Successful testing of our hypothesis will pave the way for a large, multicenter randomized control trial of CIC therapy in premature infants to prevent BPD.

Eligibility criteria: Inclusion Criteria:

* Viable Infants born between 23 0/7 - 29 6/7 gestation
* Requiring invasive (through an endotracheal tube) mechanical ventilation
* Between day of life 8 to 28.

Exclusion Criteria:

* Infants with congenital anomalies
* Infants with life-threatening illness
* Infants with active Sepsis or necrotizing enterocolitis (NEC)
* Grade IV interventricular hemorrhage
* Hyperglycemia or hypertension at the time of study drug administration

Primary outcomes:
measure: Number of hyperglycemia events (blood glucose >150mg/dL) during treatment.
timeFrame: Through study completion, an average of 4 months.
measure: Average change in z-scores for weight, length, and head circumference.
timeFrame: Through the time of discharge, an average of 4 months.
measure: Number of high systolic blood pressure events defined as >95% centile for gestational age and day of life.
timeFrame: Through the time of discharge, an average of 4 months.
measure: Number of infants who do not pass the Adrenocorticotrophic Hormone (ACTH) stimulation test.
timeFrame: 6 weeks or later after last postnatal steroid course, prior to discharge
measure: Number of episodes of bronchospasm related to inhaled ciclesonide administration.
timeFrame: The entire duration of the study drug treatment (14 days).
measure: Number of infants who develop oral thrush that require treatment.
timeFrame: The duration of study drug treatment (14 days).
measure: Compare rates of BPD and severe BPD between cases and controls.
timeFrame: BPD and severe BPD are ascertained at 36 weeks post-menstrual age.
measure: Systemic Absorption of inhaled Ciclesonide
timeFrame: Day 1, 3, 7, 15 of study (during drug administration).
Secondary outcomes:
measure: Compare rates of extubation success between infants exposed to study drug and controls receiving standard NICU clinical care
timeFrame: Extubation rates will be calculated from the day of study drug initiation to 7 days after cessation of study drug, i.e., a 21 day window.
measure: Assess changes in lung injury and need in mechanical ventilation support.
timeFrame: Baseline, and daily from study drug initiation to 1 week after study drug cessation.
Other outcomes:
Locations:
city: Kansas City
country: United States
facility: Children's Mercy Kansas City
state: Missouri
Study officials:
affiliation: Children's Mercy Hospital Kansas City
name: Venkatesh Sampath, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Physician-Scientist
name: Venkatesh Sampath, MD
role: PRINCIPAL_INVESTIGATOR
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