Clinical trial NCT05514340: Assess Safety and Efficacy of Sovateltide in Hypoxic-ischemic Encephalopathy
Official title: A Multicenter, Randomized, Double-blind, Placebo-controlled, Phase-II Trial to Assess Safety, and Efficacy of Sovateltide in the Treatment of Hypoxic-ischemic Encephalopathy in Neonates
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE2
Conditions: Hypoxic-Ischemic Encephalopathy
Neonatal Asphyxia
Neonatal Encephalopathy
Keywords: Hypoxic-Ischemic Encephalopathy
Cerebral Asphyxia
Neonatal Encephalopathy
Lead sponsor: Pharmazz, Inc.
Sponsor class: INDUSTRY
First posted: 2022-08-24
Enrollment: 40
Sex: ALL
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: In sovateltide group, 3 doses of sovateltide, at 0.3 μg/kg body weight will be administered as an intravenous bolus over 1 minute every 3 hours ± 1 hour on day 1, 3, and day 6 (total dose/day: 0.9 µg/kg body weight).

In control group, 3 doses of equal volume of normal saline will be administered as an IV bolus over 1 minutes every 3 hours ± 1 hour on day 1, 3 and day 6 post randomization.

In both treatment groups, subjects will be provided the best available standard of care.
Primary purpose: TREATMENT

Brief summary: Sovateltide (PMZ-1620; IRL-1620) is targeted to be used as a "Treatment for hypoxic-ischemic encephalopathy in neonates," which is a life-threatening condition. Sovateltide augments neuronal progenitor cell differentiation and better mitochondrial morphology and biogenesis to activate a regenerative response in the central nervous system. The only treatment for HIE is therapeutic hypothermia with limited success, and studies indicate that sovateltide may be beneficial in these patients.

Detailed description: Neonatal encephalopathy due to perinatal asphyxia is known as hypoxic-ischemic encephalopathy (HIE). HIE is a serious neurological complication affecting premature and full-term neonates, resulting from oxygen deprivation and reduced blood flow to the neonatal brain, leading to neuronal and white matter injury. Currently, no well-established therapies are considered effective for neonatal HIE. The standard of care at present includes supportive management to maintain cerebral perfusion, metabolic balance, and seizure detection and treatment. Currently, the only neuroprotective treatment for HIE is therapeutic hypothermia. However, improvement in patient outcomes following therapy has been moderate, with only 1 in 6 infants benefitting from therapeutic hypothermia.

Additionally, therapeutic hypothermia is time-sensitive, having a narrow therapeutic window wherein therapy must be initiated within 6 hours of delivery to be effective. Timely initiation is also restricted to those neonatal units having adequate equipment and trained staff for therapeutic hypothermia. Death or disability is reported to occur in 55% of infants receiving therapeutic hypothermia. To the best of our knowledge, there is no pharmacotherapy available for the treatment of HIE. Hence, there is a significant unmet medical need.

ETB receptors located widely throughout the CNS are a necessary component of the developing nervous system and also promote neurorestorative processes involving neurogenesis and synaptogenesis. There was an increased expression of neural progenitor markers, NeuroD1 and Double Cortin, and neural markers for mature neurons, NeuN was observed in the sovateltide group compared to vehicle. In addition, Sovateltide increased the expression of presynaptic markers (synapsin1 and synaptophysin) and post-synaptic marker (Postsynaptic Density-95) compared to vehicle. Our results suggest that sovateltide treatment helps recruit and differentiate neural progenitor cells and augments synaptogenesis and endogenous neurorestorative processes.

Sovateltide is a synthetic analog of ET-1 synthesized in 1992 and is a highly specific ETB receptor agonist. We and others have conducted studies to determine the effects of sovateltide upon its interaction with neural ETB receptors and have found that it enhances angiogenesis and neurogenesis and promotes repair and regeneration. This is indicated by neuronal cell proliferation, alleviation of oxidative stress, improvement of neurological and motor functions, and increase in anti-apoptotic markers. In our preclinical study, sovateltide was shown to have neuroprotective effects by promoting repair and regeneration in the brain in a neonatal rat model of HIE. The study showed that sovateltide treatment alone or in combination with hypothermia significantly (p\<0.01) increased ETB receptor expression compared to vehicle-treated rat pups. In addition, enhanced VEGF and NGF expression were observed in rat pups treated with Sovateltide alone or in combination with hypothermia compared to vehicle-treated rat pups (p\<0.0001, p\<0.0001). Sovateltide alone and in combination with hypothermia also demonstrated a significantly reduced number of apoptotic cells compared to the control group. Furthermore, oxidative stress markers, including malondialdehyde, reduced glutathione, and superoxide dismutase was, significantly improved (p\<0.0001, p\<0.0001, p\<0.0001) in those rat pups treated with sovateltide.

Sovateltide was safe and well-tolerated in a Phase I trial (CTRI/2016/11/007509) in healthy human volunteers. In addition, we conducted human studies in patients with cerebral ischemic stroke (NCT04046484, CTRI/2017/11/010654; NCT04047563, CTRI/2019/09/021373), Alzheimer's disease (NCT04052737, CTRI/2017/12/016394), and acute spinal cord injury (NCT04054414, CTRI/2018/12/016667) patients. In summary, about 300 patients have been treated with sovateltide, and no drug-related adverse event has been reported to date.

We plan to conduct a phase II clinical study to evaluate the safety and efficacy of sovateltide therapy along with supportive management in neonates with perinatal asphyxia (HIE). The dose of sovateltide proposed for this phase II study is 0.3µg/kg same as used in the phase II study in ischemic stroke.

Eligibility criteria: Inclusion Criteria:

1. Either sex with ≥ 36 weeks of gestational age
2. Receiving supportive management for perinatal asphyxia
3. Perinatal depression, based on at least one of the following:

   * Apgar score of \<5 at 10 minutes
   * Need for resuscitation (chest compressions or mechanical ventilation) at birth
   * pH \<7.00 or base deficit ≥ 16 mmol/liter in the cord or arterial blood within 60 minutes of birth
   * Moderate/severe encephalopathy evident by at least 3 of 6 modified Sarnat criteria, present between 1 to 6 hours of birth.
4. Informed consent by one of the parents or a legal representative

Exclusion Criteria:

1. Gestational age \<36 weeks
2. Admitted to hospital 12-hours after birth
3. A genetic or congenital condition that affects neuronal development
4. TORCH infection
5. Neonatal sepsis
6. Complex congenital heart disease
7. Severe dysmorphic feature
8. Microcephaly (head circumference \< 2 Standard Deviations below mean for gestational age)

Primary outcomes:
measure: Percentage of patients with death or disability (moderate/severe)
timeFrame: 24 months
Secondary outcomes:
measure: Bayley Scales of Infant and Toddler Development Scores
timeFrame: 24 months
measure: Disabling cerebral palsy
timeFrame: 24 months
measure: Seizures
timeFrame: 24 months
measure: Brain injury
timeFrame: 14 days]
measure: Blindness or hearing impairment
timeFrame: 24 months
measure: Adverse events
timeFrame: 24 months
measure: Tolerance
timeFrame: 7 days
Other outcomes:
Locations:
city: Mangalore
country: India
facility: Father Muller Medical College Hospital
state: Karnataka
city: Ludhiana
country: India
facility: Christian Medical College and Hospital
state: Punjab
city: Hyderabad
country: India
facility: Niloufer Hospital
state: Telangana
city: Kanpur
country: India
facility: GSVM Medical College
state: Uttar Pradesh
Study officials:
affiliation: Chairman and CEO
name: Anil Gulati
role: STUDY_CHAIR
References:
citation: Ramos MD, Briyal S, Prazad P, Gulati A. Neuroprotective Effect of Sovateltide (IRL 1620, PMZ 1620) in a Neonatal Rat Model of Hypoxic-Ischemic Encephalopathy. Neuroscience. 2022 Jan 1;480:194-202. doi: 10.1016/j.neuroscience.2021.11.027. Epub 2021 Nov 23.
citation: Ranjan AK, Gulati A. Sovateltide Mediated Endothelin B Receptors Agonism and Curbing Neurological Disorders. Int J Mol Sci. 2022 Mar 15;23(6):3146. doi: 10.3390/ijms23063146.
citation: Gulati A, Agrawal N, Vibha D, Misra UK, Paul B, Jain D, Pandian J, Borgohain R. Safety and Efficacy of Sovateltide (IRL-1620) in a Multicenter Randomized Controlled Clinical Trial in Patients with Acute Cerebral Ischemic Stroke. CNS Drugs. 2021 Jan;35(1):85-104. doi: 10.1007/s40263-020-00783-9. Epub 2021 Jan 11.
citation: Ranjan AK, Briyal S, Gulati A. Sovateltide (IRL-1620) activates neuronal differentiation and prevents mitochondrial dysfunction in adult mammalian brains following stroke. Sci Rep. 2020 Jul 29;10(1):12737. doi: 10.1038/s41598-020-69673-w.