Clinical trial NCT05395195: Erythropoietin for Neonatal Encephalopathy in LMIC (EMBRACE Trial)
Official title: Erythropoietin Monotherapy for Brain Regeneration in Neonatal Encephalopathy in Low and Middle-Income Countries
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE3
Conditions: Encephalopathy
Erythropoietin
Newborn Asphyxia
Lead sponsor: Imperial College London
Sponsor class: OTHER
First posted: 2022-05-27
Enrollment: 504
Sex: ALL
Minimum age (years): 1
Maximum age (years): 6
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Erythropoietin (intravenous or subcutaneous)
Primary purpose: TREATMENT

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.

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 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.

Eligibility criteria: 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)

Primary outcomes:
measure: Number of babies who die or survive with moderate or severe disability
timeFrame: 18 to 22 months
Secondary outcomes:
measure: Number of babies who die
timeFrame: Upto 22 months
measure: Number of babies who survive without neurodisability
timeFrame: 18 to 22 months
measure: Number of babies with cerebral palsy
timeFrame: 18 to 22 months
measure: Number of babies with microcephaly
timeFrame: 18 to 22 months
measure: Number of babies with gastric bleeds
timeFrame: During neonatal hospitalisation (Expected average of 2 weeks)
measure: Number of babies with persistent pulmonary hypertension
timeFrame: During neonatal hospitalisation (Expected average of 2 weeks)
measure: Number of babies with coagulopathy
timeFrame: During neonatal hospitalisation (Expected average of 2 weeks)
measure: Number of babies with intracranial haemorrhage
timeFrame: During neonatal hospitalisation (Expected average of 2 weeks)
measure: Number of babies with culture-proven sepsis
timeFrame: During neonatal hospitalisation (Expected average of 2 weeks)
measure: Number of babies with severe thrombocytopenia
timeFrame: During neonatal hospitalisation (Expected average of 2 weeks)
measure: Number of babies with abnormal neurological examination at discharge
timeFrame: During neonatal hospitalisation (Expected average of 2 weeks)
Other outcomes:
measure: Basal ganglia/thalami magnetic resonance (MR) Lactate/NAA peak area ratio
timeFrame: 10 to 14 days after birth
measure: Basal ganglia/thalami magnetic resonance (MR) NAA/Creatine peak area ratio
timeFrame: 10 to 14 days after birth
measure: White matter magnetic resonance (MR) NAA/Creatine peak area ratio
timeFrame: 10 to 14 days after birth
measure: White matter magnetic resonance (MR) Lactate/NAA peak area ratio
timeFrame: 10 to 14 days after birth
Locations:
city: Dhaka
country: Bangladesh
facility: Bangabandhu Sheikh Mujib Medical University
city: Dhaka
country: Bangladesh
facility: Dhaka Medical College
city: Aurangabad
country: India
facility: Aurangabad Medical College
city: Bangalore
country: India
facility: Bangalore Medical College
city: Bangalore
country: India
facility: Indira Gandhi Institute of Child Health
city: Chennai
country: India
facility: Institute of Child Health, Madras Medical College
city: Chennai
country: India
facility: Kasturba Gandhi Medical College
city: Hubli
country: India
facility: Karnataka Institute of Medical Sciences
city: Mumbai
country: India
facility: Lokmanya Tilak Municipal Medical College
city: Kelaniya
country: Sri Lanka
facility: University of Kelaniya
Study officials:
affiliation: Imperial College London
name: Sudhin Thayyil, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.
citation: 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.