Erythropoietin for Neonatal Encephalopathy in LMIC (EMBRACE Trial)

NCT05395195 | Recruiting Phase 3 DMC

• 1 other identifier: 5623613
• Study Type: interventional
• Target: 504
• Locations: 3 countries
• Sites: 10

Brief Summary

One million babies die, and at least 2 million survive with lifelong disabilities following neonatal encephalopathy (NE) in low and middle-income countries (LMICs), every year. Cooling therapy in the context of modern tertiary intensive care improves outcome after NE in high-income countries. However, the uptake and applicability of cooling therapy in LMICs is poor, due to the lack of intensive care and transport facilities to initiate and administer the treatment within the six-hours window after birth as well as the absence of safety and efficacy data on hypothermia for moderate or severe NE. Erythropoietin (Epo) is a promising neuroprotectant with both acute effects (anti-inflammatory, anti-excitotoxic, antioxidant, and antiapoptotic) and regenerative effects (neurogenesis, angiogenesis, and oligodendrogenesis),which are essential for the repair of injury and normal neurodevelopment when used as a mono therapy in pre-clinical models (i.e without adjunct hypothermia). The preclinical data on combined use of Eythropoeitin and hypothermia is less convincing as the mechanisms overlap. Thus, the HEAL (High dose erythropoietin for asphyxia and encephalopathy) trial, a large phase III clinical trial involving 500 babies with with encephalopathy reported that that Erythropoietin along with hypothermia is not beneficial. In contrast, the pooled data from 5 small randomized clinical trials (RCTs) (n=348 babies), suggests that Epo (without cooling therapy) reduce the risk of death or disability at 3 months or more after NE (Risk Ratio 0.62 (95% CI 0.40 to 0.98). Hence, a definitive trial (phase III) for rigorous evaluation of the safety and efficacy of Epo monotherapy in LMIC is now warranted.

Conditions

Encephalopathy; Erythropoietin; Newborn Asphyxia

Outcome Measures

Primary Outcomes (1)

• Number of babies who die or survive with moderate or severe disability

  Death or moderate or severe disability in survivors

  18 to 22 months

Secondary Outcomes (11)

• Number of babies who die

  Upto 22 months

• Number of babies who survive without neurodisability

  18 to 22 months

• Number of babies with cerebral palsy

  18 to 22 months

• Number of babies with microcephaly

  18 to 22 months

• Number of babies with gastric bleeds

  During neonatal hospitalisation (Expected average of 2 weeks)

Other Outcomes (4)

• Basal ganglia/thalami magnetic resonance (MR) Lactate/NAA peak area ratio

  10 to 14 days after birth

• Basal ganglia/thalami magnetic resonance (MR) NAA/Creatine peak area ratio

  10 to 14 days after birth

• White matter magnetic resonance (MR) NAA/Creatine peak area ratio

  10 to 14 days after birth

Study Arms (2)

Erythropoietin

EXPERIMENTAL

Intravenous or subcutaneous injections of erythropoietin (500 U/kg/dose). Total of 9 doses will be administered. First dose will be given within 6 hours of birth. Second dose between 12 to 24 hours from the first dose. Subsequent 7 doses every 24 hours from the second dose.

Drug: Erythropoietin; Other: Supportive neonatal intensive care

Control

SHAM COMPARATOR

Mock administration of injections (pretend) behind a screen by a dedicated personal

Other: Supportive neonatal intensive care

Interventions

Erythropoietin DRUG

Erythropoietin injections (500u/kg) x 9 doses

Erythropoietin

Supportive neonatal intensive care OTHER

Neonatal intensive care monitoring and support including ventilatory and inotropic support as clinically indicated

Control; Erythropoietin

Eligibility Criteria

• Age: 1 Hour - 6 Hours
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17)

You may qualify if:

• Inborn babies born at a gestational age greater than or equal to 36 weeks, with a birth weight \>=1.8 kg
• At least one of the following: need for continued resuscitation at 5 minutes of age; 5-minute Apgar score \< 6; metabolic acidosis (pH \< 7.0; base deficit \> 16 mmol/L) in cord or blood gas within the first hour of birth.
• Moderate or severe neonatal encephalopathy on modified Sarnat staging performed between 1 to 6 hours after birth.

You may not qualify if:

• Imminent death at the time of recruitment
• Babies born at home or those admitted after 6 hours of birth.
• Major life-threatening congenital malformations
• Head circumference \<30 cm at birth
• Babies undergoing induced hypothermia
• Migrant family or parents unable/unlikely to come back for follow-up at 18 months
• Sentinel event and encephalopathy occurred only after birth
• Unable to consent in primary language of parent(s)

Sponsors & Collaborators

• Imperial College London: lead

Study Sites (10)

Bangabandhu Sheikh Mujib Medical University

Dhaka, 1000, Bangladesh

RECRUITING

Dhaka Medical College

Dhaka, Bangladesh

NOT YET RECRUITING

Aurangabad Medical College

Aurangabad, India

RECRUITING

Bangalore Medical College

Bangalore, India

RECRUITING

Indira Gandhi Institute of Child Health

Bangalore, India

RECRUITING

Institute of Child Health, Madras Medical College

Chennai, India

RECRUITING

Kasturba Gandhi Medical College

Chennai, India

RECRUITING

Karnataka Institute of Medical Sciences

Hubli, India

RECRUITING

Lokmanya Tilak Municipal Medical College

Mumbai, India

RECRUITING

University of Kelaniya

Kelaniya, Sri Lanka

NOT YET RECRUITING

Related Publications (3)

• Ivain P, Montaldo P, Khan A, Elagovan R, Burgod C, Morales MM, Pant S, Thayyil S. Erythropoietin monotherapy for neuroprotection after neonatal encephalopathy in low-to-middle income countries: a systematic review and meta-analysis. J Perinatol. 2021 Sep;41(9):2134-2140. doi: 10.1038/s41372-021-01132-4. Epub 2021 Jun 26.

  PMID: 34175900 BACKGROUND

• Thayyil S, Pant S, Montaldo P, Shukla D, Oliveira V, Ivain P, Bassett P, Swamy R, Mendoza J, Moreno-Morales M, Lally PJ, Benakappa N, Bandiya P, Shivarudhrappa I, Somanna J, Kantharajanna UB, Rajvanshi A, Krishnappa S, Joby PK, Jayaraman K, Chandramohan R, Kamalarathnam CN, Sebastian M, Tamilselvam IA, Rajendran UD, Soundrarajan R, Kumar V, Sudarsanan H, Vadakepat P, Gopalan K, Sundaram M, Seeralar A, Vinayagam P, Sajjid M, Baburaj M, Murugan KD, Sathyanathan BP, Kumaran ES, Mondkar J, Manerkar S, Joshi AR, Dewang K, Bhisikar SM, Kalamdani P, Bichkar V, Patra S, Jiwnani K, Shahidullah M, Moni SC, Jahan I, Mannan MA, Dey SK, Nahar MN, Islam MN, Shabuj KH, Rodrigo R, Sumanasena S, Abayabandara-Herath T, Chathurangika GK, Wanigasinghe J, Sujatha R, Saraswathy S, Rahul A, Radha SJ, Sarojam MK, Krishnan V, Nair MK, Devadas S, Chandriah S, Venkateswaran H, Burgod C, Chandrasekaran M, Atreja G, Muraleedharan P, Herberg JA, Kling Chong WK, Sebire NJ, Pressler R, Ramji S, Shankaran S; HELIX consortium. Hypothermia for moderate or severe neonatal encephalopathy in low-income and middle-income countries (HELIX): a randomised controlled trial in India, Sri Lanka, and Bangladesh. Lancet Glob Health. 2021 Sep;9(9):e1273-e1285. doi: 10.1016/S2214-109X(21)00264-3. Epub 2021 Aug 3.

  PMID: 34358491 BACKGROUND

• Garegrat R, Londhe A, Manerkar S, Fattepur S, Deshmukh L, Joshi A, Chandriah S, Kariyappa M, Devadas S, Ethirajan T, Srivasan K, Kamalarathnam C, Balachandran A, Krishnan E, Sahayaraj D, Bandiya P, Shivanna N, Burgod C, Thayyil A, Alocious A, Lanza M, Muraleedharan P, Pant S, Venkateswaran H, Morales MM, Montaldo P, Krishnan V, Kalathingal T, Joshi AR, Vare A, Patil GC, Satyanathan BP, Hapat P, Deshmukh A, Shivarudhrappa I, Annayappa MK, Baburaj M, Muradi C, Fernandes E, Thale N, Jahan I, Shahidullah M, Choudhury SM, Dey SK, Neogi SB, Banerjee R, Rameh V, Alobeidi F, Grant E, Juul SE, Wilson M, Vita E, Pressler R, Bassett P, Shankaran S, Thayyil S. Early and extended erythropoietin monotherapy after hypoxic ischaemic encephalopathy: a multicentre double-blind pilot randomised controlled trial. Arch Dis Child Fetal Neonatal Ed. 2024 Oct 18;109(6):594-601. doi: 10.1136/archdischild-2024-327107.

  PMID: 38729748 DERIVED

MeSH Terms

Conditions

Brain Diseases; Asphyxia Neonatorum

Interventions

Erythropoietin

Condition Hierarchy (Ancestors)

Central Nervous System Diseases; Nervous System Diseases; Infant, Newborn, Diseases; Congenital, Hereditary, and Neonatal Diseases and Abnormalities

Intervention Hierarchy (Ancestors)

Colony-Stimulating Factors; Glycoproteins; Glycoconjugates; Carbohydrates; Hematopoietic Cell Growth Factors; Cytokines; Intercellular Signaling Peptides and Proteins; Peptides; Amino Acids, Peptides, and Proteins; Proteins; Biological Factors

Study Officials

• Sudhin Thayyil, PhD

  Imperial College London

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Reema Garegrat, DM

CONTACT

02033132473; r.garegrat@imperial.ac.uk

Ismita Chhettri, PhD

CONTACT

02033132473; i.chhetri@imperial.ac.uk

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Masking Details: All injections with be administered behind a screen by dedicated personnel. The control arm will have mock (pretend) injections.
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: Erythropoietin (intravenous or subcutaneous)

Study Record Dates

• First Submitted: May 24, 2022
• First Posted: May 27, 2022
• Study Start: December 31, 2022
• Primary Completion: December 1, 2024
• Study Completion (Estimated): December 1, 2026
• Last Updated: March 19, 2024

Record last verified: 2024-03

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, ICF
• Time Frame: Protocol, SAP and consent forms will be shared midway through the trial recruitment following appropriate requests

Locations

SR (1); BA (2); IN (7)