Erythropoietin for Neonatal Encephalopathy in LMIC (EMBRACE Trial)
Study Details
Study Description
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. 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.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
| Phase 3 |
Detailed Description
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 Erythropoeitin versus sham injection (placebo) in babies with neonatal encephalopathy in low and middle-income countries. The investigators plan to randomise 504 babies in this trial. The dosing regimen will be IV 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. The trial will have an 18 month recruitment period, a 18 month follow-up period, and 5 months for data analysis and write up.
Study Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Experimental: Erythropoietin Intravenous injections of erythropoietin |
Drug: Erythropoietin
Intravenous injections of erythropoietin
|
| Placebo Comparator: Placebo Normal saline |
Drug: Erythropoietin
Intravenous injections of erythropoietin
|
Outcome Measures
Primary Outcome Measures
- Number of babies who die or survive with moderate or severe disability [18 to 22 months]
Death or moderate or severe disability in survivors
Secondary Outcome Measures
- Number of babies who die [Upto 22 months]
Mortality from all causes
- Number of babies who survive without neurodisability [18 to 22 months]
Survival with Bayley composite scale scores >84 in all domains, no cerebral palsy, no seizure disorder, hearing or visual defect
- Number of babies with cerebral palsy [18 to 22 months]
Cerebral palsy with a Gross Motor Function Classification Score >1
- Number of babies with microcephaly [18 to 22 months]
Head circumference more than 2 standard deviations below the mean
- Number of babies with gastric bleeds [During neonatal hospitalisation (Expected average of 2 weeks)]
Fresh blood > 5 ml from nasogastric tube
- Number of babies with persistent pulmonary hypertension [During neonatal hospitalisation (Expected average of 2 weeks)]
Severe hypoxemia disproportionate to the severity of lung disease with a significant pre-and post ductal saturation difference on pulse oximetry
- Number of babies with coagulopathy [During neonatal hospitalisation (Expected average of 2 weeks)]
Prolonged blood coagulation requiring blood products
- Number of babies with intracranial haemorrhage [During neonatal hospitalisation (Expected average of 2 weeks)]
Major parenchymal or intraventricular bleed on cranial ultrasound or magnetic resonance imaging.
- Number of babies with culture-proven sepsis [During neonatal hospitalisation (Expected average of 2 weeks)]
Isolation of a pathogenic organism from blood or cerebrospinal fluid along with clinical evidence of sepsis or elevation of C-reactive protein
- Number of babies with severe thrombocytopenia [During neonatal hospitalisation (Expected average of 2 weeks)]
Platelet count of less than 25 000 per μL or less than 50 000 per μL with active bleeding
- Number of babies with abnormal neurological examination at discharge [During neonatal hospitalisation (Expected average of 2 weeks)]
Structured neurological examination as per the NICHD NRN trial (Shankaran et al NEJM 2005) discharge exam criteria
Eligibility Criteria
Criteria
Inclusion Criteria (all of below should be met)
-
Inborn babies born at a gestational age > 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 3 hours after birth.
Exclusion Criteria:
-
Imminent death at the time of recruitment
-
Babies born at home or those admitted after 6 hours of birth.
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Major life-threatening congenital malformations
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Head circumference <30 cm at birth
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Polycythaemia with a venous haematocrit >65% of Hb > 22g/dL at the time of recruitment
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Babies undergoing therapeutic hypothermia
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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)
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | Bangabandhu Sheikh Mujib Medical University | Dhaka | Bangladesh | 1000 | |
| 2 | Dhaka Medical College | Dhaka | Bangladesh | ||
| 3 | Aurangabad Medical College | Aurangabad | India | ||
| 4 | Bangalore Medical College | Bangalore | India | ||
| 5 | Indira Gandhi Institute of Child Health | Bangalore | India | ||
| 6 | Institute of Child Health, Madras Medical College | Chennai | India | ||
| 7 | Kasturba Gandhi Medical College | Chennai | India | ||
| 8 | Karnataka Institute of Medical Sciences | Hubli | India | ||
| 9 | Lokmanya Tilak Municipal Medical College | Mumbai | India | ||
| 10 | University of Kelaniya | Kelaniya | Sri Lanka |
Sponsors and Collaborators
- Thayyil, Sudhin
Investigators
None specified.Study Documents (Full-Text)
None provided.More Information
Publications
- 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. Review.
- 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. Erratum in: Lancet Glob Health. 2021 Oct;9(10):e1371.
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