Neonatal White Matter Injury Trial (WRAP) (WRAP)

An Open-label, Dose-escalation, Phase I/Ib Clinical Trial to Assess the Safety and Pharmacokinetics of Clemastine in Preterm Neonates With White Matter Injury (WRAP)

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.

Study Overview

• Status: Not yet recruiting
• Conditions: Periventricular Leukomalacia; White Matter Injury; Brain Injury, Fetus and Neonate; Periventricular White Matter Abnormalities; Neonatal Brain Injury
• Intervention / Treatment: Drug: Clemastine fumarate

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.

• Study Type: Interventional
• Enrollment (Estimated): 24
• Phase: Phase 1

Contacts and Locations

• Study Contact: Name: Audrey Hernando, BS; Phone Number: 415-502-2425; Email: audrey.hernando@ucsf.edu
• Study Contact Backup: Name: Lena Odell, BA; Email: elizabeth.odell@ucsf.edu

Study Locations

• United States
  • California
    • San Francisco, California, United States, 94158
      • University of California, San Francisco
      • Contact: Audrey Hernando; Phone Number: 415-502-2425; Email: audrey.hernando@ucsf.edu
      • Principal Investigator: Bridget Ostrem, MD, PhD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child
• Accepts Healthy Volunteers: No

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Sequential Assignment
• Masking: None (Open Label)

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Dose level 4	Drug: Clemastine fumarate; Clemastine fumarate oral suspension
Experimental: Dose level 1; Dose level 1 (0.01 mg/kg/day)	Drug: Clemastine fumarate; Clemastine fumarate oral suspension
Experimental: Dose level 2; Dose level 2 (0.03 mg/kg/day)	Drug: Clemastine fumarate; Clemastine fumarate oral suspension
Experimental: Dose level 3; Dose level 3 (0.05 mg/kg/day)	Drug: Clemastine fumarate; Clemastine fumarate oral suspension

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of subjects who experience dose limiting toxicity	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.	From study drug administration through 30 days after the last dose

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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	Oral clearance (CL/F)	From day 1 through day 15
Pharmacokinetics of Clemastine in Preterm Neonates	Area under the plasma concentration-time curve from over a 24 hour period (AUC24)	From day 1 through day 15
Pharmacokinetics of Clemastine in Preterm Neonates	Average concentration (Cavg)	From day 1 through day 15
Pharmacokinetics of Clemastine in Preterm Neonates	Observed concentration at 24 hours post-dose (C24h)	From day 1 through day 15
Pharmacokinetics of Clemastine in Preterm Neonates	Maximum observed plasma concentration (Cmax)	From day 1 through day 15
Pharmacokinetics of Clemastine in Preterm Neonates	Time of the maximum observed concentration in plasma (Tmax)	From day 1 through day 15

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Auditory brainstem response (ABR) at 0-6 months corrected age (CA)		0-6 months corrected age
Brain magnetic resonance imaging (MRI) at 2-3 months corrected age (CA)		2-3 months corrected age (CA)
General Movements Assessment (GMA) at 3-5 months corrected age (CA)	Motor Optimality Score: Minimum score is 5, Maximum score is 28; higher scores mean a better outcome. Categorical Classification: Qualitative outcome categorized as normal fidgety, abnormal fidgety, or absent fidgety; normal fidgety movements represent a better outcome.	3-5 months corrected age (CA)
Warner Initial Developmental Evaluation of Adaptive and Functional Skills (WIDEA-FS) assessment at 18 months corrected age (CA)	Total score: : Minimum 50, Maximum 200; higher scores mean a better outcome.	18 months corrected age (CA)
Bayley Scales of Infant and Toddler Development, 4th Edition (BSID-4) at 22-26 months corrected age (CA)	Standard score: Minimum 45, Maximum 155; higher scores mean a better outcome. Scaled score: Minimum 1, Maximum 19; higher scores mean a better outcome.	22-26 months corrected age (CA)
Gross Motor Function Classification System (GMFCS) score at 22-26 months corrected age (CA)	Scores range from Level I to Level V, where lower levels indicate a better outcome and higher levels indicate a worse outcome	22-26 months corrected age (CA)
Proportion of subjects with any evidence of neurodevelopmental impairment, defined by cerebral palsy (CP) diagnosis, GMFCS≥2 and/or BSID-4 score less than 85 on any scale and/or diagnosis of epilepsy and/or WIDEA-FS >2 SD below normal value for age.		16.9-18 months CA, 22-26 months CA

Collaborators and Investigators

• Sponsor: Bridget LaMonica Ostrem, M.D., Ph.D.
• Collaborators: National Institute of Neurological Disorders and Stroke (NINDS)
• Investigators: Principal Investigator: Bridget Ostrem, MD, PhD, University of California, San Francisco

Study record dates

Study Major Dates

• Study Start (Estimated): July 1, 2026
• Primary Completion (Estimated): March 1, 2028
• Study Completion (Estimated): July 1, 2031

Study Registration Dates

• First Submitted: June 9, 2026
• First Submitted That Met QC Criteria: June 30, 2026
• First Posted (Actual): July 7, 2026

Study Record Updates

• Last Update Posted (Actual): July 7, 2026
• Last Update Submitted That Met QC Criteria: June 30, 2026
• Last Verified: June 1, 2026

More Information

Terms related to this study

• Keywords: brain injury; prematurity; infant; neonate; neuroprotection; clemastine; white matter injury
• Additional Relevant MeSH Terms: Urogenital Diseases; Cerebrovascular Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Vascular Diseases; Cardiovascular Diseases; Wounds and Injuries; Female Urogenital Diseases and Pregnancy Complications; Obstetric Labor, Premature; Obstetric Labor Complications; Pregnancy Complications; Infant, Premature, Diseases; Infant, Newborn, Diseases; Craniocerebral Trauma; Trauma, Nervous System; Encephalomalacia; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Premature Birth; Brain Injuries; Leukomalacia, Periventricular; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Pyrrolidines; Clemastine
• Other Study ID Numbers: 26-45933; 1DP2NS148743-01 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No