A Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Preliminary Efficacy of RLS-0071 in Newborns With Moderate or Severe Hypoxic-Ischemic Encephalopathy Undergoing Therapeutic Hypothermia (STAR)

A Phase 2, Two-Stage, Randomized, Double-Blind, Placebo-Controlled, Multiple-Ascending Dose Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Preliminary Efficacy of RLS-0071 in Newborns With Moderate or Severe Hypoxic-Ischemic Encephalopathy Undergoing Therapeutic Hypothermia With Long-Term Follow-Up

Hypoxic-ischemic encephalopathy (HIE) affects approximately 4,000 to 12,000 persons annually in the United States. Mortality from HIE has been reported up to 60%, with at least 25% of survivors left with significant neurocognitive disability. Despite this vital unmet medical need, no pharmacological adjunct or alternative therapy has proven beneficial in improving outcomes in neonatal HIE.

RLS-0071 is a novel peptide being developed for the treatment of neonatal HIE. This study is designed to evaluate the safety and tolerability of RLS-0071 in the treatment of newborns with moderate or severe HIE.

Study Overview

• Status: Recruiting
• Conditions: Hypoxic-Ischemic Encephalopathy
• Intervention / Treatment: Drug: RLS-0071; Drug: Placebo

Detailed Description

This is a Phase 2, two-stage, multisite, randomized, double-blind, placebo-controlled, multiple-ascending dose study of RLS-0071 to assess the safety, tolerability, pharmacokinetics (PK), and preliminary efficacy in newborns with moderate or severe HIE undergoing therapeutic hypothermia.

In Stage 1, participants will receive either ascending doses of RLS-0071 or a matched volume of placebo for 72 hours in addition to standard of care treatment, including therapeutic hypothermia. During and after the dosing period, participants will be monitored and assessed for safety evaluations through Day 14. After completion of Stage 1, participants will transition to Stage 2 of the study for long-term observation until participants reach 24 months of age.

The first cohort subsets, consisting of Cohort 1a (moderate HIE) and 1b (severe HIE), will receive a dose of 3 mg/kg RLS-0071 or a matched volume of placebo every 8 hours (q8h). A Data Safety Monitoring Board (DSMB) will review available clinical safety and PK data from Cohort 1 subsets with completed study intervention, and make a recommendation on whether to escalate the dose for moderate and severe HIE cohorts. The Sponsor will consider the DSMB recommendation to make their decision on dose escalation in addition to their own evaluation of all available safety and PK data. If the decision is made to escalate, Cohort 2 subsets (2a [moderate] and 2b [severe]) will be recruited to receive an escalated dose of RLS-0071 (10 mg/kg) or a matched volume of placebo. Following the completion of study intervention for each Cohort 2 subset (2a [moderate] or 2b [severe]), the DSMB will review available safety and PK data and make a recommendation whether to expand enrollment for Cohort 2+ (2a+ [moderate] or 2b+ [severe]) at 10 mg/kg RLS-0071 or a matched volume of placebo.

• Study Type: Interventional
• Enrollment (Estimated): 70
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Lori Upham; Phone Number: 757-901-0331; Email: Lupham@realtals.com

Study Locations

• United States
  • Arkansas
    • Little Rock, Arkansas, United States, 72202
      • Recruiting
      • Study Site 016
  • California
    • Orange, California, United States, 92868
      • Recruiting
      • Study Site 013
    • San Diego, California, United States, 92037
      • Recruiting
      • Study Site 020
    • San Diego, California, United States, 92123
      • Recruiting
      • Study Site 019
  • Florida
    • Gainesville, Florida, United States, 32608
      • Recruiting
      • Study Site 001
    • Miami, Florida, United States, 33143
      • Recruiting
      • Study Site 018
    • Orlando, Florida, United States, 32803
      • Recruiting
      • Study Site 010
  • Indiana
    • Indianapolis, Indiana, United States, 46202
      • Recruiting
      • Study Site 014
  • Kentucky
    • Lexington, Kentucky, United States, 40536
      • Withdrawn
      • Study Site 012
  • Massachusetts
    • Boston, Massachusetts, United States, 02115
      • Recruiting
      • Study Site 002
  • Missouri
    • St Louis, Missouri, United States, 63110
      • Recruiting
      • Study Site 006
  • North Carolina
    • Durham, North Carolina, United States, 27710
      • Recruiting
      • Study Site 003
  • Ohio
    • Cleveland, Ohio, United States, 44195
      • Recruiting
      • Study Site 021
  • Texas
    • Fort Worth, Texas, United States, 76104
      • Recruiting
      • Study Site 022
  • West Virginia
    • Morgantown, West Virginia, United States, 26506
      • Recruiting
      • Study Site 005

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: No older than 9 hours (Child)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. ≥ 36 weeks gestation.
2. Sentinel event prior to delivery such as abruption, tight nuchal cord, uterine rupture, profound bradycardia, shoulder dystocia, or cord prolapse or other acute event likely attributable for newborn depression at delivery or an acute change in the fetal status with a clinical presentation consistent with an acute sentinel event with no clearly defined etiology.

3. Moderate or severe encephalopathy based on at least one risk of encephalopathy criterion (a) and one clinical signs of encephalopathy criterion (b):

   1. Risk of encephalopathy (either):

      • Blood gas drawn within 1 hour of birth, either arterial blood gas (ABG) or venous blood gas (VBG) (cord or infant) with pH ≤ 7.0 OR base deficit ≥ 16 mmol/L.

      OR

      • appearance, pulse, grimace, activity, and respiration (APGAR) score ≤ 5 at 10 minutes OR
      • The infant required assisted ventilation ≥ 10 minutes after birth (ie, endotracheal, mask ventilation, or continuous positive airway pressure [CPAP]).

   2. Clinical signs of encephalopathy (either/both):

      • Moderate/Severe encephalopathy on National Institute of Child Health and Human Development assessment.
      • Evidence of seizures (clinical and/or electroencephalogram).
4. Be eligible to receive therapeutic hypothermia.
5. Active whole-body cooling to be started prior to 6 hours of age (passive cooling is permitted prior to active whole body cooling).
6. Product of a singleton pregnancy.
7. Written informed consent obtained from parent or legal guardian.

Exclusion Criteria:

1. Inability to enroll in the study and initiate the first dose of RLS-0071 within 10 hours of life.
2. Known major congenital and/or chromosomal abnormality(ies).
3. Severe growth restriction (birth weight ≤ 1800 g).
4. Prenatal diagnosis of brain abnormality or hydrocephalus.
5. Patient's head circumference is < 30 cm.
6. 10-minute APGAR score < 2, if available.
7. Infants suspected of overwhelming sepsis or congenital infection based on the Investigator's clinical consideration at the time of enrollment.
8. Persistent severe hypotension unresponsive to inotropic support (requiring >2 inotropes, not inclusive of hydrocortisone).
9. Persistent severe hypoxia in the setting of 100% fraction of inspired oxygen (FiO₂) and unresponsive to nitric oxide or requiring extracorporeal membrane oxygenation (ECMO).
10. Severe disseminated intravascular coagulation with clinical bleeding.
11. Neonatal encephalopathy believed to be due to a cause other than perinatal hypoxia (ie, other than HIE).
12. Moribund infants for whom withdrawal of care being considered.
13. Suspected or confirmed fetal alcohol syndrome or suspected substance withdraw seizures.
14. Any other condition that the investigator may consider would make the patient ineligible for the study or place the patient at an unacceptable risk (Note: this criterion would include a clinically significant [eg, Grade 3 or 4] intracranial hemorrhage).

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: RLS-0071; Doses of RLS-0071 to be administered every 8 hours (q8h), for a total of 10 doses over 72 hours.	Drug: RLS-0071; RLS-0071 (unit strength 10 mg/mL) will be administered by infusion for a dose level of 3 or 10 mg/kg. Planned infusion duration is 10 minutes for all dose levels.
Placebo Comparator: Placebo; Doses of sterile saline (sodium chloride, 0.9%) to be administered every 8 hours (q8h), for a total of 10 doses over 72 hours.	Drug: Placebo; Placebo control (commercial sterile saline) will be administered by infusion at a volume matched to RLS-0071 (3 or 10 mg/kg). Planned infusion duration is 10 minutes for all matched dose levels.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Frequency and severity of adverse events (AEs) and serious adverse events (SAEs) by treatment group at Day 14	Number of participants with AEs and SAEs graded between Grade 1 (mild in severity) and Grade 5 (death related to AE).	Day 1 to Day 14
Frequency of premature discontinuation by treatment group due to AEs at Day 14	Number of participants who prematurely discontinue from the study due to AEs	Day 1 to Day 14
Frequency and severity of events of special interest and SAEs by treatment group at 24 months	Number of participants with events of special interest and SAEs graded between Grade 1 (mild in severity) and Grade 5 (death related to AE). Events of special interest are: autoimmune disorder, persistent hypotension, persistent pulmonary hypertension, acute kidney injury, major venous thrombosis, severe intracranial hemorrhage, pulmonary hemorrhage, culture proven sepsis, necrotizing enterocolitis, severe thrombocytopenia, hepatic dysfunction, hyperbilirubinemia, coagulopathy, hypocalcemia, cerebral palsy, developmental or speech delay, learning disability, and visual or hearing impairment.	Day 1 to 24 months
Acute brain injury at Day 4, assessed through magnetic resonance imaging (MRI), using a standardized scoring system	Brain injury MRI score includes scoring extent of injury across 4 domains (Grey matter, White matter/cortex, Cerebellum, and Additional). A score of 0 indicates a normal brain MRI, whereas the maximum score of 57 indicates extensive bilateral injury.	Day 4
Acute brain injury at Day 12, assessed through magnetic resonance imaging (MRI), using a standardized scoring system	Brain injury MRI score includes scoring extent of injury across 4 domains (Grey matter, White matter/cortex, Cerebellum, and Additional). A score of 0 indicates a normal brain MRI, whereas the maximum score of 57 indicates extensive bilateral injury.	Day 12

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Composite of mortality and neurodevelopmental impairment (NDI) at 24 months		Day 1 to 24 months
Mortality at 3, 6, 12, 18, and 24 months	Number of participants alive at each timepoint	Day 1 to 3, 6, 12, 18, and 24 months
Neurocognitive developmental outcome assessed by Bayley-4 at 24 months of age	The Bayley Scales of Infant and Toddler Development (4th Edition) consists of 5 subdomains: the Cognitive, Language, Motor, Social-Emotional, and Adaptive Behavior scales. Cognitive, Language, and Motor domains include a total of 264 items, each ranked between 0-2 (where 0 is not present and 2 is mastery); the Social-Emotional and Adaptive Behavior domains are assessed through caregiver questionnaires.	24 months
Neurodevelopmental growth impact: Diagnosis of cerebral palsy at 24 months of age	Number of participants diagnosed with cerebral palsy	24 months
Neurodevelopmental growth impact: Grading of cerebral palsy by using the Gross Motor Function Classification System-Expanded and Revised (GMFCS-E&R) at 24 months of age	The GMFCS is a 5-level classification system for children and young people with cerebral palsy, where Level 1 indicates ability to walk without limitations and Level 5 indicates reliance on a manual wheelchair.	24 months
Number of participants diagnosed with mild, moderate, or severe visual impairment and hearing impairment		Day 1 to 24 months
Number of days of supplemental nutritional support required		Day 1 to 24 months
Quality of life assessment over the first 24 months of life	A quality of life questionnaire will be used to collect information regarding the care of the aging child over the first 24 months of life.	Day 4 to 24 months
Number of participants with clinically significant laboratory abnormalities, events of special interest, and SAEs at 3, 6, 12, and 18 months		Day 1 to 3, 6, 12, and 18 months
Seizure occurrence	Discrete number of seizures recorded	Day 1 to Day 14
Total seizure burden (total number of minutes seizing as measured by continuous electroencephalogram [EEG]) during hospitalization		Day 1 to Day 14
Electrical activity abnormality scoring as measured by EEG		Day 1 to Day 14
Impact on infant and family wellness, assessed by the Mother-to-Infant Bonding Scale (MIBS)	The MIBS is a 9-item questionnaire, with total scores ranging from 0 to 27. A high score indicates weaker mother-to-infant bonding.	3 and 12 months
Impact on infant and family wellness, assessed by the Parenting Stress Index, 4th Edition Short Form (PSI-4-SF)	The PSI-4 is a 36-item questionnaire focusing on three domains: Parental Distress, Parent-Child Dysfunctional Interaction, and Difficult Child, which combine to form a Total Stress scale. Scores are assessed following conversion into percentile ranks. Scores falling in the 90th or higher percentile indicate clinically significant parenting stress.	3, 12, and 24 months

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
PK parameters of RLS-0071 at multiple-ascending doses: Cmax	Maximum serum concentration observed (Cmax) of RLS-0071	Day 1 to Day 5
PK parameters of RLS-0071 at multiple-ascending doses: Ctrough	Concentration observed prior to subsequent or final dosing (Ctrough) of RLS-0071	Day 1 to Day 5
PK parameters of RLS-0071 at multiple-ascending doses: Area under the curve	Area under the curve (AUC) of RLS-0071 concentration in serum	Day 1 to Day 5
Number of participants diagnosed with epilepsy during the first 2 years of life		Day 1 to 24 months
Number of participants requiring anti-seizure medications during the first 2 years of life		Day 1 to 24 months
Brain injury MRI score at Day 4 and Day 12 for the white matter injury domain	Brain injury MRI score white matter domain includes the following items scored: cortex, cerebral white matter, optic radiations, corpus callosum, punctate white matter lesions, and parenchymal hemorrhage. The maximum white matter subscore is 21, indicating extensive bilateral injury.	Day 4 and Day 12
Brain injury MRI score at Day 4 and Day 12 for the grey matter injury domain	Brain injury MRI score grey matter domain includes the following items scored: thalamus, basal ganglia, posterior limb of the internal capsule, brainstem, perirolandic cortex, and hippocampus. The maximum white matter subscore is 23, indicating extensive bilateral injury.	Day 4 and Day 12
Number of days of mechanical ventilatory support required	Duration until ability to breathe without assistance	Day 1 to Day 14 (or until discharge from hospital, if later)
Number of participants with pulmonary hypertension		Day 1 to 24 months
Number of days spent in the Neonatal Intensive Care Unit and number of days spent in the hospital		Day 1 to Day 14 (or until discharge from hospital, if later)
Severity of organ reperfusion injury as measured by clinical laboratory assessments: liver enzymes		Day 1 to Day 14
Severity of organ reperfusion injury as measured by clinical laboratory assessments: serum creatinine		Day 1 to Day 14
Severity of organ reperfusion injury as measured by synthetic liver function		Day 1 to Day 14

Collaborators and Investigators

• Sponsor: ReAlta Life Sciences, Inc.
• Collaborators: Premier Research

Study record dates

Study Major Dates

• Study Start (Actual): July 27, 2023
• Primary Completion (Estimated): December 1, 2026
• Study Completion (Estimated): December 1, 2028

Study Registration Dates

• First Submitted: March 3, 2023
• First Submitted That Met QC Criteria: March 17, 2023
• First Posted (Actual): March 21, 2023

Study Record Updates

• Last Update Posted (Actual): April 13, 2026
• Last Update Submitted That Met QC Criteria: April 7, 2026
• Last Verified: April 1, 2026

More Information

Terms related to this study

• Keywords: Anoxic brain injury; Birth Asphyxia
• Additional Relevant MeSH Terms: Cerebrovascular Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Vascular Diseases; Cardiovascular Diseases; Infant, Newborn, Diseases; Brain Ischemia; Signs and Symptoms, Respiratory; Hypoxia, Brain; Hypoxia; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Pathological Conditions, Signs and Symptoms; Signs and Symptoms; Hypoxia-Ischemia, Brain; Asphyxia Neonatorum; RLS-0071
• Other Study ID Numbers: RLS-0071-202

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
• product manufactured in and exported from the U.S.: No