Erythropoietin Monotherapy for Brain Regeneration in Neonatal Encephalopathy in Low and Middle-Income Countries
试验速览
- 阶段
- 3 期
- 状态
- 招募中
- 入组人数
- 504
- 试验地点
- 10
- 主要终点
- Number of babies who die or survive with moderate or severe disability
研究概览
简要总结
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.
详细描述
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
盲法说明
All injections with be administered behind a screen by dedicated personnel. The control arm will have mock (pretend) injections.
入排标准
- 年龄范围
- 1 Hour 至 6 Hours（Child）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- 未提供
排除标准
- •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)
研究组 & 干预措施
Erythropoietin
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.
干预措施: Erythropoietin (Drug)
Erythropoietin
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.
干预措施: Supportive neonatal intensive care (Other)
Control
Mock administration of injections (pretend) behind a screen by a dedicated personal
干预措施: Supportive neonatal intensive care (Other)
结局指标
主要结局
Number of babies who die or survive with moderate or severe disability
时间窗: 18 to 22 months
Death or moderate or severe disability in survivors
次要结局
- 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))
- Number of babies with persistent pulmonary hypertension(During neonatal hospitalisation (Expected average of 2 weeks))
- Number of babies with coagulopathy(During neonatal hospitalisation (Expected average of 2 weeks))
- Number of babies with intracranial haemorrhage(During neonatal hospitalisation (Expected average of 2 weeks))
- Number of babies with culture-proven sepsis(During neonatal hospitalisation (Expected average of 2 weeks))
- Number of babies with severe thrombocytopenia(During neonatal hospitalisation (Expected average of 2 weeks))
- Number of babies with abnormal neurological examination at discharge(During neonatal hospitalisation (Expected average of 2 weeks))