Brain Injury, Fetus and Neonate, Neonatal Brain Injury, Periventricular Leukomalacia, Periventricular White Matter Abnormalities, White Matter Injury
Conditions
Keywords
infant, neonate, brain injury, clemastine, white matter injury, prematurity, neuroprotection
Brief summary
The researchers are investigating a new treatment for white matter injury, which is a common type of brain injury in premature babies. The drug, clemastine, is experimental. This means that the drug is not approved by the Food and Drug Administration (FDA) for the treatment of white matter injury. The main purpose of this study is to learn whether clemastine is safe to give to infants with white matter injury. The researchers also want to understand how much clemastine gets into an infant's body when the medication is taken by mouth, and how long it stays in the body.
Detailed description
Preterm white matter injury (WMI) is the most common type of brain injury in premature infants and is associated with adverse neurological outcomes, including motor and cognitive disability and seizures. Preterm WMI involves an arrest of differentiation in the oligodendroglial cell lineage and a failure of normal developmental myelination. No therapies exist that directly promote brain repair and myelination or can be given at the time that preterm WMI has been identified and is likely most amenable to treatment. The lack of available treatments inherently limits the possibility for functional recovery in affected infants. Clemastine is an antihistamine and antimuscarinic agent that was identified in a high-throughput screen of FDA-approved compounds that significantly promote myelination in vitro. Clemastine was subsequently shown to promote myelination and improve functional recovery in multiple animal models of WMI, including preterm WMI, and induces remyelination in adult patients with multiple sclerosis. Clemastine is therefore an ideal potential candidate treatment for preterm WMI. The investigators will be conducting a Phase I/Ib open label dose-escalation and dose expansion study to test the safety and pharmacokinetics of oral clemastine treatment in neonates with preterm WMI.
Interventions
Clemastine fumarate oral suspension
Sponsors
Bridget LaMonica Ostrem, M.D., Ph.D.
National Institute of Neurological Disorders and Stroke (NINDS)
Study design
Allocation
NON_RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
This is an open-label dose-escalation and dose-expansion study. The Phase I component will employ a conventional "3+3" design with a minimum of three and a maximum of six patients in each of up to three dose levels (Dose level 1, 2, and 3). This is an adaptive, PK-guided trial and a fourth dose will be added if needed to reach the target exposure for the final dose.
Eligibility
Sex/Gender
ALL
Age
3 Weeks to 20 Weeks
Healthy volunteers
No
Inclusion criteria
1. Born at ≤32 weeks gestational age based on prenatal ultrasound or last menstrual period (LMP). 2. Current age of between 35-41 weeks PMA. 3. Imaging evidence of white matter injury on any scan as defined by either brain MRI or cUS criteria: * Brain MRI with Grade Ib WMI or higher based on the Martinez-Biarge et al 2016 criteria. * cUS with Grade 3 or higher white matter abnormalities based on Miller et al 2003 criteria. 4. Currently hospitalized in a participating intensive care nursery.
Exclusion criteria
1. Known or suspected metabolic or chromosomal disorder or major congenital anomalies 2. Major intracranial hemorrhage within the last 1 week or intracranial hemorrhage of any age that is not controlled or continuing to cause significant mass effect or midline shift. 3. History of cardiac arrhythmia or current ongoing tachycardia with baseline heart rate \>10% age expected norms. 4. Hypotension requiring ongoing vasopressor or inotropic support. 5. Not able to receive enteral medications. 6. Clinically significant sedation due to critical illness or medications. 7. Concomitant use of any other putative neuroprotective or myelination promoting therapy as determined by the investigator. 8. Serum creatinine, aspartate aminotransferase (AST), or alanine aminotransferase (ALT) \>2x the upper limit of normal for age. 9. Family history of epilepsy due to a confirmed or suspected genetic cause. 10. History of confirmed seizure activity. 11. If ≥36 weeks postmenstrual age, required respiratory support greater than 2L/min, noninvasive positive airway pressure, or mechanical ventilation upon reaching 36 weeks postmenstrual age due to diagnosis of moderate or severe BPD. 12. If less than 36 weeks postmenstrual age, currently requiring respiratory support greater than 2L/min, noninvasive positive airway pressure, or mechanical ventilation, unless respiratory support is being given to promote lung development and not due to clinical need. 13. Major medical conditions, laboratory abnormalities, or concurrent treatments that, in opinion of the investigator, may affect interpretation of study results or patient safety.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of subjects who experience dose limiting toxicity | From study drug administration through 30 days after the last dose | The primary objective is to assess the safety of oral clemastine in preterm neonates with white matter injury (WMI) who have reached at least 35 weeks postmenstrual age (PMA), as measured by the number of subjects who experience dose limiting toxicity (DLT). PMA equals the gestational age (GA) at birth plus chronological age. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of patients who experience any adverse events related to the study drug | From study drug administration through 30 days after the last dose | — |
| Pharmacokinetics of Clemastine in Preterm Neonates | From day 1 through day 15 | Oral clearance (CL/F) |
Countries
United States
Contacts
CONTACTAudrey Hernando, BS
CONTACTLena Odell, BA
PRINCIPAL_INVESTIGATORBridget Ostrem, MD, PhD
University of California, San Francisco
Outcome results
None listed