Erythropoietin for Neonatal Encephalopathy in LMIC (EMBRACE Trial)

Study Overview
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Brief Summary
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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.

Detailed Description
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The burden of neonatal encephalopathy is far higher in low and middle-income countries. Recently, the Hypothermia for Encephalopathy in Low and Middle-Income Countries Trial (HELIX) study concluded cooling therapy did not reduce the combined outcome of death or disability at 18 months after neonatal encephalopathy in low-income and middle-income countries. In fact, the results found that cooling therapy significantly increased death alone. This warrants exploration of the efficacy of other treatment adjuncts for these settings. One medication with potential for monotherapy is Erythropoietin. Erythropoietin is an erythropoiesis stimulating cytokine used for the treatment of anaemia. It is a Food and Drug Administration (FDA) approved drug that is widely used for treatment of anaemia including premature babies and has extensive safety profile in newborn babies. Erythropoietin is also produced by neurons and glia in the hippocampus, internal capsule, cortex, and midbrain in response to hypoxia. More recently, erythropoietin has been reported as having anti-apoptotic, anti-inflammatory and anti-oxidative effects, making it a prime neuroprotective candidate. It also reduces free iron accumulation which occurs due to hypoxic ischemia by inducing erythropoiesis, which promotes neurogenesis. Extensive preclinical small and large animal models have demonstrated neuroprotective and neuro reparative effects of Erythropoietin when used as monotherapy. A number of small randomised controlled trials have been reported from low and middle-income countries. A systematic review and meta-analysis of Erythropoietin monotherapy in babies with neonatal encephalopathy in LMIC showed pooled data including a total of 348 babies from 5 clinical trials in LMIC suggest 40% relative risk reduction (Risk Ratio 0.62 (95% Confidence Intervals (CI) 0.40 to 0.98) in death or disability at 18 months with Erythropoietin, compared with placebo. None of these clinical trials have reported any serious adverse events of Erythropoietin monotherapy. Erythropoietin dose used in these trials varied from 300U/kg to 2500U/kg, single dose to a maximum of two weeks of duration starting within 24 hours after birth. The largest of these trials, reported from China have used a low dose (500U/kg) on alternate days for two weeks. This trial recruited 153 babies with moderate or severe encephalopathy and reported that Erythropoietin significantly reduced death or disability at 18 months. More recently, another randomised controlled trial of Erythropoietin involving 62 normothermic babies with moderate or severe neonatal encephalopathy has been reported from Government Medical College, Aurangabad in India. The investigators used an Erythropoietin dose of 500 U/kg alternate days for 10 days starting within 24 hours. Neonatal mortality was significantly lower (39%; 12/31) in the Erythropoietin group compared with the placebo group (71%; 22/31) (p=0.01). No adverse events were reported in the Erythropoietin group. The EMBRACE trial is a phase III, multi-country, double-blinded, placebo-controlled randomised controlled trial of Erythropoietin versus sham injection (placebo) in babies with neonatal encephalopathy in low and middle-income countries. All clinical and study team except for the nurse administering the trial drug will be masked to the intervention. The investigators plan to randomise 504 babies in this trial. The dosing regimen will be IV/Sub cutaneous Erythropoietin 500unit/kg within 6 hours of birth and then daily until 8 days. In total, there will be 9 doses. Body temperature of all babies will be monitored 4 hourly for the first three days after birth and normothermia (36.0-37.5°C) will be maintained as a part of the usual care at these hospitals with an algorithm to prevent/treat hyperthermia. Magnetic resonance biomarkers including spectroscopy and diffusion tensor imaging will be acquired between 1 to 2 weeks of age in all recruited babies. The MR scanners and sequences at each site will be harmonised prior to recruitment. The trial will have an 18 month recruitment period, a 18 month follow-up period, and 5 months for data analysis and write up. A pilot study (external pilot) of 50 babies will be done prior to the start of the EMBRACE trial (Jan 2023 to April 2023) but these patients will not be included in the main trial. Minor updates to the trial protocol may be made after the completion of the pilot trial.

Official Title
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Erythropoietin Monotherapy for Brain Regeneration in Neonatal Encephalopathy in Low and Middle-Income Countries

Conditions
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Encephalopathy, Erythropoietin, Newborn Asphyxia

Intervention / Treatment
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* Drug: Erythropoietin
* Other: Supportive neonatal intensive care


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria (all of below should be met) 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. Exclusion Criteria: 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)

Ages Eligible for Study
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Minimum Age: 1 Hour
Maximum Age: 6 Hours

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Erythropoietin (intravenous or subcutaneous)
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Erythropoietin<br>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<br>* Erythropoietin injections (500u/kg) x 9 doses<br>Other: Supportive neonatal intensive care<br>* Neonatal intensive care monitoring and support including ventilatory and inotropic support as clinically indicated<br>|
| Sham Comparator: Control<br>Mock administration of injections (pretend) behind a screen by a dedicated personal | Other: Supportive neonatal intensive care<br>* Neonatal intensive care monitoring and support including ventilatory and inotropic support as clinically indicated<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of babies who die | Mortality from all causes | Upto 22 months | 
| Number of babies who survive without neurodisability | Survival with Bayley composite scale scores >84 in all domains, no cerebral palsy, no seizure disorder, hearing or visual defect | 18 to 22 months | 
| Number of babies with cerebral palsy | Cerebral palsy with a Gross Motor Function Classification Score >1 | 18 to 22 months | 
| Number of babies with microcephaly | Head circumference more than 2 standard deviations below the mean | 18 to 22 months | 
| Number of babies with gastric bleeds | Fresh blood > 5 ml from nasogastric tube | During neonatal hospitalisation (Expected average of 2 weeks) | 
| Number of babies with persistent pulmonary hypertension | Severe hypoxemia disproportionate to the severity of lung disease with a significant pre-and post ductal saturation difference on pulse oximetry | During neonatal hospitalisation (Expected average of 2 weeks) | 
| Number of babies with coagulopathy | Prolonged blood coagulation requiring blood products | During neonatal hospitalisation (Expected average of 2 weeks) | 
| Number of babies with intracranial haemorrhage | Major parenchymal or intraventricular bleed on cranial ultrasound or magnetic resonance imaging. | During neonatal hospitalisation (Expected average of 2 weeks) | 
| Number of babies with culture-proven sepsis | Isolation of a pathogenic organism from blood or cerebrospinal fluid along with clinical evidence of sepsis or elevation of C-reactive protein | During neonatal hospitalisation (Expected average of 2 weeks) | 
| Number of babies with severe thrombocytopenia | Platelet count of less than 25 000 per μL or less than 50 000 per μL with active bleeding | During neonatal hospitalisation (Expected average of 2 weeks) | 
| Number of babies with abnormal neurological examination at discharge | Structured neurological examination as per the NICHD NRN trial (Shankaran et al NEJM 2005) discharge exam criteria | During neonatal hospitalisation (Expected average of 2 weeks) |