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

Official title

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

Overview

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 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.

Interventions

• 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.
• 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.

Primary outcome measures

• Frequency and severity of adverse events (AEs) and serious adverse events (SAEs) by treatment group at Day 14 [Time frame: Day 1 to Day 14]
• Frequency and severity of events of special interest and SAEs by treatment group at 24 months [Time frame: Day 1 to 24 months]
• Frequency of premature discontinuation by treatment group due to AEs at Day 14 [Time frame: Day 1 to Day 14]
• Acute brain injury at Day 4, assessed through magnetic resonance imaging (MRI), using a standardized scoring system [Time frame: Day 4]
• Acute brain injury at Day 12, assessed through magnetic resonance imaging (MRI), using a standardized scoring system [Time frame: Day 12]

Secondary outcome measures (12)

• Composite of mortality and neurodevelopmental impairment (NDI) at 24 months [Time frame: Day 1 to 24 months]
• Mortality at 3, 6, 12, 18, and 24 months [Time frame: Day 1 to 3, 6, 12, 18, and 24 months]
• Number of participants with clinically significant laboratory abnormalities, events of special interest, and SAEs at 3, 6, 12, and 18 months [Time frame: Day 1 to 3, 6, 12, and 18 months]
• Neurocognitive developmental outcome assessed by Bayley-4 at 24 months of age [Time frame: 24 months]
• Neurodevelopmental growth impact: Diagnosis of cerebral palsy at 24 months of age [Time frame: 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 [Time frame: 24 months]
• Number of participants diagnosed with mild, moderate, or severe visual impairment and hearing impairment [Time frame: Day 1 to 24 months]
• Number of days of supplemental nutritional support required [Time frame: Day 1 to 24 months]
• Seizure occurrence [Time frame: Day 1 to Day 14]
• Total seizure burden (total number of minutes seizing as measured by continuous electroencephalogram [EEG]) during hospitalization [Time frame: Day 1 to Day 14]
• Electrical activity abnormality scoring as measured by EEG [Time frame: Day 1 to Day 14]
• Impact on infant and family wellness, assessed by the Mother-to-Infant Bonding Scale (MIBS) [Time frame: 3 and 12 months]

Eligibility criteria

Inclusion criteria

• ≥ 36 weeks gestation.
• 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.
• Moderate or severe encephalopathy based on at least one risk of encephalopathy criterion (a) and one clinical signs of encephalopathy criterion (b):

• 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 \[CPAP\]).
• 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).
• Be eligible to receive therapeutic hypothermia.
• Active whole-body cooling to be started prior to 6 hours of age (passive cooling is permitted prior to active whole body cooling).
• Product of a singleton pregnancy.
• Written informed consent obtained from parent or legal guardian.

Exclusion criteria

• Inability to enroll in the study and initiate the first dose of RLS-0071 within 10 hours of life.
• Known major congenital and/or chromosomal abnormality(ies).
• Severe growth restriction (birth weight ≤ 1800 g).
• Prenatal diagnosis of brain abnormality or hydrocephalus.
• Patient's head circumference is < 30 cm.
• 10-minute APGAR score < 2, if available.
• Infants suspected of overwhelming sepsis or congenital infection based on the Investigator's clinical consideration at the time of enrollment.
• Persistent severe hypotension unresponsive to inotropic support (requiring >2 inotropes, not inclusive of hydrocortisone).
• Persistent severe hypoxia in the setting of 100% fraction of inspired oxygen (FiO₂) and unresponsive to nitric oxide or requiring extracorporeal membrane oxygenation (ECMO).
• Severe disseminated intravascular coagulation with clinical bleeding.
• Neonatal encephalopathy believed to be due to a cause other than perinatal hypoxia (ie, other than HIE).
• Moribund infants for whom withdrawal of care being considered.
• Suspected or confirmed fetal alcohol syndrome or suspected substance withdraw seizures.
• 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).

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Quadruple blind

Primary purpose

Treatment

Study locations

United States · 15 centers

• Study Site 016 — Little Rock
• Study Site 013 — Orange
• Study Site 020 — San Diego
• Study Site 019 — San Diego
• Study Site 001 — Gainesville
• Study Site 018 — Miami
• Study Site 010 — Orlando
• Study Site 014 — Indianapolis
• … and 7 more centers

Identifiers

NCT: NCT05778188 · RLS-0071-202

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗