A Phase 3 interventional study of Erythropoietin and Supportive neonatal intensive care in Encephalopathy, Erythropoietin and Newborn Asphyxia, sponsored by Imperial College London. Recruiting at 10 sites in 3 countries. Open to participants aged 1 Hour to 6 Hours. Per ClinicalTrials.gov, last updated 2024-03-19.
Sponsored by Imperial College London · Phase 3, Interventional, and Treatment
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.
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.
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Exclusion Criteria:
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
Mock administration of injections (pretend) behind a screen by a dedicated personal
Other: Supportive neonatal intensive care
Erythropoietin injections (500u/kg) x 9 doses
Neonatal intensive care monitoring and support including ventilatory and inotropic support as clinically indicated
Number of babies who die or survive with moderate or severe disability
Death or moderate or severe disability in survivors
Time frame: 18 to 22 months
Number of babies who die
Mortality from all causes
Time frame: 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
Time frame: 18 to 22 months
Number of babies with cerebral palsy
Cerebral palsy with a Gross Motor Function Classification Score \>1
Time frame: 18 to 22 months
Number of babies with microcephaly
Head circumference more than 2 standard deviations below the mean
Time frame: 18 to 22 months
Number of babies with gastric bleeds
Fresh blood \> 5 ml from nasogastric tube
Time frame: 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
Time frame: During neonatal hospitalisation (Expected average of 2 weeks)
Number of babies with coagulopathy
Prolonged blood coagulation requiring blood products
Time frame: 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.
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: During neonatal hospitalisation (Expected average of 2 weeks)
Basal ganglia/thalami magnetic resonance (MR) Lactate/NAA peak area ratio
Lactate/NAA peak area metabolic rations in the deep brain nuclei on proton MR spectroscopy
Time frame: 10 to 14 days after birth
Basal ganglia/thalami magnetic resonance (MR) NAA/Creatine peak area ratio
NAA/Creatine peak area metabolic rations in the deep brain nuclei on proton MR spectroscopy
Time frame: 10 to 14 days after birth
White matter magnetic resonance (MR) NAA/Creatine peak area ratio
NAA/Creatine peak area metabolic rations in the White matter on proton MR spectroscopy
Time frame: 10 to 14 days after birth
White matter magnetic resonance (MR) Lactate/NAA peak area ratio
Lactate/NAA peak area metabolic rations in the White matter on proton MR spectroscopy
Time frame: 10 to 14 days after birth
Plan to share: Yes — Protocol, SAP, consent forms
Supporting information: Study protocol, Statistical analysis plan, Informed consent form
Time frame: Protocol, SAP and consent forms will be shared midway through the trial recruitment following appropriate requests
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Studies of the drug tested here: Erythropoietin