Neonatal White Matter Injury Trial (WRAP)
Purpose
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.
Conditions
- White Matter Injury
- Brain Injury, Fetus and Neonate
- Neonatal Brain Injury
- Periventricular Leukomalacia
- Periventricular White Matter Abnormalities
Eligibility
- Eligible Ages
- Between 3 Weeks and 20 Weeks
- Eligible Sex
- All
- Accepts Healthy Volunteers
- No
Inclusion Criteria
- 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
- 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.
Study Design
- Phase
- Phase 1
- Study Type
- Interventional
- Allocation
- Non-Randomized
- Intervention Model
- Sequential Assignment
- 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.
- Primary Purpose
- Treatment
- Masking
- None (Open Label)
Arm Groups
| Arm | Description | Assigned Intervention |
|---|---|---|
|
Experimental Dose level 1 |
Dose level 1 (0.01 mg/kg/day) |
|
|
Experimental Dose level 2 |
Dose level 2 (0.03 mg/kg/day) |
|
|
Experimental Dose level 3 |
Dose level 3 (0.05 mg/kg/day) |
|
|
Experimental Dose level 4 |
|
Recruiting Locations
San Francisco, California 94158
More Details
- Status
- Recruiting
- Sponsor
- Bridget LaMonica Ostrem, M.D., Ph.D.
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.