Clinical trial NCT01646619: Efficacy Study of Hypothermia Plus Magnesium Sulphate(MgSO4) in the Management of Term and Near Term Babies With Hypoxic Ischemic Encephalopathy
Official title: A Multicenter Randomized Controlled Trial of Therapeutic Hypothermia Plus Magnesium Sulphate (MgSO4) Versus Therapeutic Hypothermia Plus Placebo in the Management of Term and Near Term Babies With Hypoxic Ischemic Encephalopathy
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE3
Conditions: Severe Hypoxic Ischemic Encephalopathy
Moderate Hypoxic Ischemic Encephalopathy
Keywords: Hypoxic Ischemic Encephalopathy
Therapeutic Hypothermia
Therapeutic Hypothermia plus Adjuvant Therapy
Cooling
Lead sponsor: Hamad Medical Corporation
Sponsor class: INDUSTRY
First posted: 2012-07-20
Enrollment: 300
Sex: ALL
Maximum age (years): 6
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: PREVENTION

Brief summary: The purpose of this study is to assess whether the addition of a drug such as Magnesium sulphate while providing therapeutic hypothermia (or cooling) to babies who are asphyxiated at birth provides additional benefit to the babies' survival and outcome compared to cooling alone.

Detailed description: Perinatal Asphyxia continues to be a major cause of neonatal mortality and morbidity even in the most technologically advanced and prosperous countries of the world. The incidence remains unchanged; 1-2% of live births in developed world countries and much higher in developing world countries. Perinatal Asphyxia is a multisystem disorder. Neonatal brain is the most important organ affected by Asphyxic insult because the resulting neuronal damage is permanent. Hypoxic Ischemic Encephalopathy (HIE), the pathognomonic clinical syndrome of asphyxic neuronal insult, occurs in 50-60% of babies with Perinatal Asphyxia. Moderate and severe HIE causes significant neonatal mortality and morbidity. Among patients with moderate HIE, 10-20% die and 30-40% develop neurological deficit, whereas 50% of patients with severe HIE die and almost all survivors develop neurological deficits. Hence the toll on the society continues to be very high in spite of dramatic improvements in neonatal intact survival, particularly in developed world countries.

Until recent years, the management of HIE was limited to supportive intensive care only because there was no specific treatment available to rescue neurons during HIE. However, over the last decade, therapeutic Hypothermia, has emerged as a promising new therapy in reducing neonatal mortality and morbidity due to HIE. This is due to improved understanding of the physiology of neuronal damage during asphyxia insult. Hypoxic Ischemic Encephalopathy (HIE) is a dynamic process which evolves over a period of seventy two hours starting from the time of insult. Two distinct episodes of neuronal damage occur during this time:

1. The immediate (primary) hypoxic insult followed by a
2. latent period of recovery which lasts for almost six hours.

This is followed by a much longer and profound period of secondary neuronal damage due to the release of chemical mediators. Therapeutic modalities which can potentially reduce the release of these chemical mediators will provide neuronal rescue. Moderate controlled hypothermia (33.5-34.5 0C) offered during the first 72 hours after the asphyxic insult is one such therapeutic modality which has been the subject of animal studies as well as extensive multicenter trails in human infants over the last two decades.

The studies on animal models have not only confirmed the safety of moderate therapeutic hypothermia; they have also shown a dramatic neuronal rescue in experimental HIE model of lambs subjected to prolonged therapeutic hypothermia immediately after birth. This was followed by pilot RCT's in human infants; the outcomes of which were very encouraging. However a universal change of practice requires large well designed multicenter trails and Meta analyses.

After having established therapeutic hypothermia as a safe and effective modality for neuroprotection in HIE, the neonatologists are facing a new question. Can the investigators enhance the neuroprotective effect of therapeutic hypothermia by adding other potential neuroprotective agents? These potential therapeutic agents include Xenon, Erythropoetin, Magnisium sulphate, Allopurinol, opoids, Topiramate, Inhaled Nitric Oxide (iNO), N-Acetylcystine, Minocycline and Melatonin.13,17 Due to their different mechanisms of action, it is likely that these neuroprotective therapies may add incrementally to the proven beneficial effects of hypothermia. Indeed hypothermia may buy additional time for these neuroprotective agents to act within an expanded 'therapeutic window'.13 These Hypothermia plus therapies are going to be the subject of many new RCT's worldwide over the next few years.

Magnesium Sulphate, a potential neuroprotective agent, acts by reducing neuronal excitotoxicity. MgSO4 has long been used in Obstertrics as a tocolytic agent and has a proven neuroprotective effect in preterm babies born to mothers tocolyzed with MgSO4. A recently conducted RCT in human neonates has compared postnatal magnesium sulfate with placebo in the management of Neonatal HIE. This study, which did not use hypothermia therapy due to lack of facilities, has shown that treatment with MgSO4 improves neurologic outcomes at discharge in term neonates with severe perinatal asphyxia. The animal studies done by Knuckley's group has compared a combination of therapeutic hypothermia and MgSO4 with therapeutic hypothermia alone. In their rat model MgSO4 alone had a minimal beneficial effect. However, MgSO4 plus hypothermia had a significant beneficial effect in reducing the size of the post asphyxia infarct. This animal focal stroke model provides an intriguing suggestion that hypothermia plus MgSO4 provides an additive neuroprotection. No human studies have been done so far to test the difference between therapeutic hypothermia alone and therapeutic hypothermia plus MgSO4. Mag Cool Study (Hypothermia plus MgSO4 Vs Hypothermia plus placebo) will test this hypothesis.

Eligibility criteria: Inclusion Criteria:

The babies will be assessed sequentially by criteria A, B and C listed below:

A. Evidence of Perinatal Asphyxia at birth: Infants ≥35 completed weeks gestation admitted to the NICU with at least one of the following:

1. Apgar score of \<5 at 10 minutes after birth
2. Continued need for resuscitation, including endotracheal or mask ventilation, at 10 minutes after birth
3. Acidosis within 60 minutes of birth (defined as any occurrence of umbilical cord arterial or venous pH \<7.00 or otherwise arterial or capillary pH \<7.00)
4. Base Deficit (-16 mmol/L or more) in umbilical cord or any blood sample (arterial, venous or capillary) within 60 minutes of birth

Infants that meet criteria A will be assessed for whether they meet the neurological abnormality entry criteria (B) by trained personnel:

B. Clinical Evidence of Moderate to severe encephalopathy, consisting of altered state of consciousness (lethargy, stupor or coma) AND at least one of the following:

1. hypotonia
2. abnormal reflexes including oculomotor or pupillary abnormalities
3. absent or weak suck
4. clinical seizures

Infants who meet criteria A \& B will be assessed by aEEG only in units where facility for Cerebral Function Monitoring (CFM) is available.

C. (Optional) At least 30 minutes duration of amplitude integrated EEG recording that shows abnormal background aEEG activity or seizures. There must be one of the following:

1. normal background with some seizure activity
2. continuous seizure activity
3. moderately abnormal activity: Only Lower border below 5 mV. upper border remains above 10mV
4. Severely Abnormal activity (suppressed activity): Both Lower border below 5 mV and upper border below 10mV

Exclusion Criteria:

* Infants expected to be \> 6 hours of age at the time of randomization.Every effort will be made to ensure entry to the study before 3 hours of age.
* Major congenital abnormalities, such as diaphragmatic hernia requiring ventilation, or congenital abnormalities suggestive of chromosomal anomaly or other syndromes that includes brain dysgenesis.

Primary outcomes:
measure: Combined outcome of Mortality and Severe Neurodevelopmental Disability
timeFrame: 18 - 24 months of age
Secondary outcomes:
measure: Persistent Hypotension
timeFrame: Duration of hypothermia therapy( ie during the first 96 hours)
measure: Pulmonary Hemorrhage
timeFrame: Duration of hospital stay, an expected average of up to 4 weeks
measure: Intracranial Hemorrhage
timeFrame: Duration of hospital stay, an expected average of up to 4 weeks
measure: Pulmonary Hypertension
timeFrame: Duration of Hypothermia therapy (ie during the first 96 hours)
measure: Prolonged Blood Coagulation time
timeFrame: Duration of hypothermia therapy ( ie during the first 96 hours)
measure: Culture Proven sepsis
timeFrame: Duration of hospital stay, an expected average of up to 4 weeks
measure: Necrotizing enterocolitis
timeFrame: Duration of hospital stay, an expected average of up to 4 weeks
measure: Cardiac Arrhythmias
timeFrame: Duration of hypothermia therapy (ie during the first 96 hours)
measure: Thrombocytopenia
timeFrame: Duration of hypothermia therapy (ie during the first 96 hours)
measure: Major venous thrombosis
timeFrame: Duration of hospital stay, an expected average of up to 4 weeks
measure: Renal Failure
timeFrame: Duration of hospital stay, an expected average of up to 4 weeks
measure: Abnormal liver funcion tests (elevated liver enzymes)
timeFrame: Duration of hospital stay, an expected average of up to 4 weeks
measure: Pneumonia
timeFrame: Duration of hospital stay, an expected average of up to 4 weeks
measure: Pulmonary air leak syndrome
timeFrame: Duration of hospital stay, an expected average of up to 4 weeks
measure: Prolonged vs shortened hospital stay
timeFrame: First day of NICU admission till the day of discharge, an expected average of up to 4 weeks
measure: Neurodevelopment score
timeFrame: On the day of discharge from hospital, an expected average of 4 weeks after admission
measure: Abnormal aEEG
timeFrame: Before randomization and during hypothermia therapy (0 hours till 96 hours)
measure: Presence of multiple handicaps
timeFrame: 18-24 months of age
measure: Bayley Psychomotor Development Score less than 70
timeFrame: 18-24 months of age
measure: Sensorineural hearing loss equal to, or more than, 40 dB
timeFrame: 18-24 months of age
measure: Epilepsy
timeFrame: 18-24 months of age
measure: Microcephaly
timeFrame: 18-24 months of age
measure: Result of EEG or MRI
timeFrame: within the first 14 days of life
Other outcomes:
Locations:
city: Mansoura
country: Egypt
facility: Mansoura University Children's Hospital
city: Kuala Lumpur
country: Malaysia
facility: University Malaya Medical Center (UMMC)
city: Doha
country: Qatar
facility: NICU,Women's Hospital, Hamad Medical Corporation
city: Riyadh
country: Saudi Arabia
facility: Arrayan Hospital-Dr Sulaiman Al Habib Medical Group
city: Ankara
country: Turkey
facility: Zekai Tahir Burak Maternity Teaching Hospital
city: Diyarbakir
country: Turkey
facility: Diyarbakir Children's Hospital
city: AlAin
country: United Arab Emirates
facility: Tawam Hospital
Study officials:
affiliation: Hamad Medical Corporation
name: Sajjad Ur Rahman, MBBS.DCH.MCPS.FCPS.FRCPCH.FNP
role: PRINCIPAL_INVESTIGATOR
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