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

Phase 2

Recruiting

• Conditions: Hypoxic-Ischemic Encephalopathy
• Interventions: Drug: RLS-0071; Drug: Placebo

• Registration Number: NCT05778188
• Lead Sponsor: ReAlta Life Sciences, Inc.

Brief Summary

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.

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 and exploratory 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. Upon DSMB data review of data from Cohort 2 subsets and Sponsor approval of further dose escalation, Cohort 3 subsets (3a \[moderate\] and 3b \[severe\]) will be recruited to receive 20 mg/kg RLS-0071 or a matched volume of placebo.

Study Timeline

• Study First Submitted: 2023-03-03
• Study First Submitted QC: 2023-03-17
• Study First Posted: 2023-03-21
• Study Start: 2023-07-27
• Status Verified: 2024-07
• Last Update Submitted: 2024-07-02
• Last Update Posted: 2024-07-03
• Primary Completion: 2026-04
• Study Completion: 2026-04

Recruitment & Eligibility

• Status: RECRUITING
• Sex: All
• Target Recruitment: 42

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) (cord or infant) or venous blood gas (VBG) (infant) with pH ≤ 7.0 OR base deficit ≥ 16 mmol/L.

      OR

      • Blood gas drawn within 1 hour of birth, either ABG (cord or infant) or VBG (infant) with pH 7.01 to 7.15, a base deficit between 10 and 15.9 mmol/L, or a blood gas was not available, additional criteria are required:

        • Infant born after an acute perinatal event (eg, late or variable decelerations, cord prolapse, cord rupture, uterine rupture, maternal trauma, hemorrhage or cardiorespiratory arrest) and the APGAR score ≤ 5 at 10 minutes OR
        • The infant required assisted ventilation ≥ 10 minutes after birth (ie, endotracheal or mask ventilation).

   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 appearance, pulse, grimace, activity, and respiration (APGAR) score < 2
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 & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
RLS-0071	RLS-0071	Doses of RLS-0071 to be administered every 8 hours (q8h), for a total of 10 doses over 72 hours.
Placebo	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.

Primary Outcome Measures

Name	Time	Method
Frequency of premature discontinuation by treatment group due to AEs at Day 14	Day 1 to Day 14	Number of participants who prematurely discontinue from the study due to AEs
Frequency and severity of adverse events (AEs) and serious adverse events (SAEs) by treatment group at Day 14	Day 1 to Day 14	Number of participants with AEs and SAEs graded between Grade 1 (mild in severity) and Grade 5 (death related to AE).
Frequency and severity of adverse events of special interest (AESIs) and SAEs by treatment group at 24 months	Day 1 to 24 months	Number of participants with AESIs and SAEs graded between Grade 1 (mild in severity) and Grade 5 (death related to AE).; Events defined as AESIs 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, and hypocalcemia.

Secondary Outcome Measures

Name	Time	Method
Quality of life assessment over the first 24 months of life	Day 4 to 24 months	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.
Number of participants with pulmonary hypertension	Day 1 to End of Study
Mortality at 3, 6, 12, 18, and 24 months	Day 1 to 3, 6, 12, 18, and 24 months	Number of participants alive at each timepoint
Total seizure burden (total number of minutes seizing as measured by continuous electroencephalogram) during hospitalization	Day 1 to Day 14
Brain injury MRI score at Day 12 for the grey matter injury domain	Day 12	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.
Severity of organ reperfusion injury as measured by synthetic liver function	Day 1 to End of Study
Composite of mortality and neurodevelopmental impairment (NDI) at 24 months	Day 1 to 24 months
Number of participants with AESIs and SAEs at 3, 6, 12, and 18 months	Day 1 to 3, 6, 12, and 18 months
Neurocognitive developmental outcome assessed by Bayley-4 at 24 months of age	24 months	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.
Brain injury score at Day 12, as assessed through magnetic resonance imaging (MRI), using a standardized scoring system for the white matter injury domain	Day 12	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.
Early neonatal mortality at Day 14	Day 1 to Day 14	Number of participants alive at Day 14
Number of days of mechanical ventilatory support required	Day 1 to End of Study	Duration until ability to breathe without assistance
PK parameters of RLS-0071 at multiple-ascending doses: Area under the curve	Day 1 to Day 5	Area under the curve (AUC) of RLS-0071 concentration in serum
Number of participants requiring anti-seizure medications during the first 2 years of life	Day 1 to 24 months
Severity of organ reperfusion injury as measured by clinical laboratory assessments: liver enzymes	Day 1 to End of Study
Severity of organ reperfusion injury as measured by clinical laboratory assessments: serum creatinine	Day 1 to End of Study
Neurodevelopmental growth impact: Diagnosis of cerebral palsy at 24 months of age	24 months	Number of participants diagnosed with cerebral palsy
Number of participants diagnosed with mild, moderate, or severe visual impairment and hearing impairment	Day 1 to 24 months
Number of participants diagnosed with epilepsy during the first 2 years of life	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 End of Study
Impact on infant and family wellness, assessed by the Parenting Stress Index, 4th Edition Short Form (PSI-4-SF)	3, 12, and 24 months	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 assessed as falling in the 90th or higher percentile indicate clinically significant parenting stress.
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	24 months	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.
Number of days of supplemental nutritional support required	Day 1 to 24 months
PK parameters of RLS-0071 at multiple-ascending doses: Cmax	Day 1 to Day 5	Maximum serum concentration observed (Cmax) of RLS-0071
PK parameters of RLS-0071 at multiple-ascending doses: Ctrough	Day 1 to Day 5	Concentration observed prior to subsequent or final dosing (Ctrough) of RLS-0071
Impact on infant and family wellness, assessed by the Mother-to-Infant Bonding Scale (MIBS)	3 and 12 months	The MIBS is a 9-item questionnaire, with total scores ranging from 0 to 27. A high score indicates weaker mother to infant bonding.

Trial Locations

Locations (13)

Study Site 020; 🇺🇸 San Diego, California, United States

Study Site 019; 🇺🇸 San Diego, California, United States

Study Site 018; 🇺🇸 Miami, Florida, United States

Study Site 014; 🇺🇸 Indianapolis, Indiana, United States

Study Site 005; 🇺🇸 Morgantown, West Virginia, United States

Study Site 013; 🇺🇸 Orange, California, United States

Study Site 006; 🇺🇸 Saint Louis, Missouri, United States

Study Site 002; 🇺🇸 Boston, Massachusetts, United States

Study Site 016; 🇺🇸 Little Rock, Arkansas, United States

Study Site 010; 🇺🇸 Orlando, Florida, United States

Study Site 003; 🇺🇸 Durham, North Carolina, United States

Study Site 001; 🇺🇸 Gainesville, Florida, United States

Study Site 012; 🇺🇸 Lexington, Kentucky, United States