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

Overview

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.

Interventions

• Drug Alvesco Inhalant Product
  Inhaled Alvesco will be administered daily for 14 days at escalating doses of 80mcg and 160mcg.

Primary outcome measures

• Number of hyperglycemia events (blood glucose >150mg/dL) during treatment. [Time frame: Through study completion, an average of 4 months.]
• Average change in z-scores for weight, length, and head circumference. [Time frame: Through the time of discharge, an average of 4 months.]
• Number of high systolic blood pressure events defined as >95% centile for gestational age and day of life. [Time frame: Through the time of discharge, an average of 4 months.]
• Number of infants who do not pass the Adrenocorticotrophic Hormone (ACTH) stimulation test. [Time frame: 6 weeks or later after last postnatal steroid course, prior to discharge]
• Number of episodes of bronchospasm related to inhaled ciclesonide administration. [Time frame: The entire duration of the study drug treatment (14 days).]
• Number of infants who develop oral thrush that require treatment. [Time frame: The duration of study drug treatment (14 days).]
• Compare rates of BPD and severe BPD between cases and controls. [Time frame: BPD and severe BPD are ascertained at 36 weeks post-menstrual age.]
• Systemic Absorption of inhaled Ciclesonide [Time frame: Day 1, 3, 7, 15 of study (during drug administration).]

Secondary outcome measures (2)

• Compare rates of extubation success between infants exposed to study drug and controls receiving standard NICU clinical care [Time frame: 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.]
• Assess changes in lung injury and need in mechanical ventilation support. [Time frame: Baseline, and daily from study drug initiation to 1 week after study drug cessation.]

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 35.
• Infants have not received dexamethasone for 120 hours
• If receiving hydrocortisone, then receiving ≤ 1mg/kg/day

Exclusion criteria

• Infants with major congenital lung or other organ anomalies, life-threatening illness, active sepsis or NEC, and grade IV hemorrhage will be excluded.
• Infants receiving DEX therapy will be excluded.
• We will exclude infants who have had ≥ 1 glucose level > 150mg in the 24 hours prior to study entry or those on insulin therapy to treat hyperglycemia. We will exclude infants who have hypertension (>95% centile for gestational age) in the 48 hours prior to study entry.
• For small for gestational age, we will exclude infants with a birthweight < 5% centile for gestational age.
• Infants with history of recent pulmonary hemorrhage (within 72 hours of study entry) will also be excluded.
• Infants receiving or have received any dexamethasone in the prior 120 hours.
• Infants receiving >1mg/kg/day of hydrocortisone.
• Infants receiving any other inhaled or systemic steroid.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Non-randomized

Model

Parallel assignment

Masking

Open label

Primary purpose

Prevention

Study locations

United States · 1 center

• Children's Mercy Kansas City — Kansas City

Identifiers

NCT: NCT06589245 · STUDY00003195 · R21HD116421

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗