Clinical trial NCT05778188: 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
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE2
Conditions: Hypoxic-Ischemic Encephalopathy
Keywords: Birth Asphyxia
Anoxic brain injury
Lead sponsor: ReAlta Life Sciences, Inc.
Sponsor class: INDUSTRY
Collaborators: name: Premier Research Group plc
First posted: 2023-03-21
Enrollment: 42
Sex: ALL
Maximum age (years): 10
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Two-Stage, Randomized, Double-Blind, Placebo-Controlled, Multiple-Ascending Dose Study
Primary purpose: TREATMENT

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 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.

Eligibility criteria: 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).

Primary outcomes:
measure: Frequency and severity of adverse events (AEs) and serious adverse events (SAEs) by treatment group at Day 14
timeFrame: Day 1 to Day 14
measure: Frequency and severity of events of special interest and SAEs by treatment group at 24 months
timeFrame: Day 1 to 24 months
measure: Frequency of premature discontinuation by treatment group due to AEs at Day 14
timeFrame: Day 1 to Day 14
measure: Acute brain injury at Day 4, assessed through magnetic resonance imaging (MRI), using a standardized scoring system
timeFrame: Day 4
measure: Acute brain injury at Day 12, assessed through magnetic resonance imaging (MRI), using a standardized scoring system
timeFrame: Day 12
Secondary outcomes:
measure: Composite of mortality and neurodevelopmental impairment (NDI) at 24 months
timeFrame: Day 1 to 24 months
measure: Mortality at 3, 6, 12, 18, and 24 months
timeFrame: Day 1 to 3, 6, 12, 18, and 24 months
measure: Number of participants with clinically significant laboratory abnormalities, events of special interest, and SAEs at 3, 6, 12, and 18 months
timeFrame: Day 1 to 3, 6, 12, and 18 months
measure: Neurocognitive developmental outcome assessed by Bayley-4 at 24 months of age
timeFrame: 24 months
measure: Neurodevelopmental growth impact: Diagnosis of cerebral palsy at 24 months of age
timeFrame: 24 months
measure: 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
timeFrame: 24 months
measure: Number of participants diagnosed with mild, moderate, or severe visual impairment and hearing impairment
timeFrame: Day 1 to 24 months
measure: Number of days of supplemental nutritional support required
timeFrame: Day 1 to 24 months
measure: Seizure occurrence
timeFrame: Day 1 to Day 14
measure: Total seizure burden (total number of minutes seizing as measured by continuous electroencephalogram [EEG]) during hospitalization
timeFrame: Day 1 to Day 14
measure: Electrical activity abnormality scoring as measured by EEG
timeFrame: Day 1 to Day 14
measure: Impact on infant and family wellness, assessed by the Mother-to-Infant Bonding Scale (MIBS)
timeFrame: 3 and 12 months
measure: Impact on infant and family wellness, assessed by the Parenting Stress Index, 4th Edition Short Form (PSI-4-SF)
timeFrame: 3, 12, and 24 months
measure: Quality of life assessment over the first 24 months of life
timeFrame: Day 4 to 24 months
Other outcomes:
measure: PK parameters of RLS-0071 at multiple-ascending doses: Cmax
timeFrame: Day 1 to Day 5
measure: PK parameters of RLS-0071 at multiple-ascending doses: Ctrough
timeFrame: Day 1 to Day 5
measure: PK parameters of RLS-0071 at multiple-ascending doses: Area under the curve
timeFrame: Day 1 to Day 5
measure: Number of participants diagnosed with epilepsy during the first 2 years of life
timeFrame: Day 1 to 24 months
measure: Number of participants requiring anti-seizure medications during the first 2 years of life
timeFrame: Day 1 to 24 months
measure: Brain injury MRI score at Day 4 and Day 12 for the white matter injury domain
timeFrame: Day 4 and Day 12
measure: Brain injury MRI score at Day 4 and Day 12 for the grey matter injury domain
timeFrame: Day 4 and Day 12
measure: Number of days of mechanical ventilatory support required
timeFrame: Day 1 to Day 14 (or until discharge from hospital, if later)
measure: Number of participants with pulmonary hypertension
timeFrame: Day 1 to 24 months
measure: Number of days spent in the Neonatal Intensive Care Unit and number of days spent in the hospital
timeFrame: Day 1 to Day 14 (or until discharge from hospital, if later)
measure: Severity of organ reperfusion injury as measured by clinical laboratory assessments: liver enzymes
timeFrame: Day 1 to Day 14
measure: Severity of organ reperfusion injury as measured by clinical laboratory assessments: serum creatinine
timeFrame: Day 1 to Day 14
measure: Severity of organ reperfusion injury as measured by synthetic liver function
timeFrame: Day 1 to Day 14
Locations:
city: Little Rock
country: United States
facility: Study Site 016
state: Arkansas
city: Orange
country: United States
facility: Study Site 013
state: California
city: San Diego
country: United States
facility: Study Site 020
state: California
city: San Diego
country: United States
facility: Study Site 019
state: California
city: Gainesville
country: United States
facility: Study Site 001
state: Florida
city: Miami
country: United States
facility: Study Site 018
state: Florida
city: Orlando
country: United States
facility: Study Site 010
state: Florida
city: Indianapolis
country: United States
facility: Study Site 014
state: Indiana
city: Lexington
country: United States
facility: Study Site 012
state: Kentucky
city: Boston
country: United States
facility: Study Site 002
state: Massachusetts
city: Saint Louis
country: United States
facility: Study Site 006
state: Missouri
city: Durham
country: United States
facility: Study Site 003
state: North Carolina
city: Cleveland
country: United States
facility: Study Site 021
state: Ohio
city: Fort Worth
country: United States
facility: Study Site 022
state: Texas
city: Morgantown
country: United States
facility: Study Site 005
state: West Virginia
Study officials:
References: