Severe Hypoxic Ischemic EncephalopathyPhase 3MagCoolNCT01646619
Efficacy Study of Hypothermia Plus Magnesium Sulphate(MgSO4) in the Management of Term and Near Term Babies With Hypoxic Ischemic Encephalopathy
A Phase 3 study testing Magnesium Sulphate in people with Severe Hypoxic Ischemic Encephalopathy and Moderate Hypoxic Ischemic Encephalopathy, run by Sajjad Rahman at 7 sites in 6 countries.
Trial 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. Read more about this study
- Who is it for?
- Ages Up to 6 hours
- Conditions the study is for
- Severe Hypoxic Ischemic Encephalopathy, Moderate Hypoxic Ischemic Encephalopathy
- What is being tested?
- Magnesium Sulphate
- Type of treatment
- Injection or infusion
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 300 participants
- Where
- 7 sitesin 6 countries
- Study dates
- May 2012to Jun 2014
- Phase
- Phase 3
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages Up to 6 hours
- All sexes
- No healthy volunteers
- Child
Who may be able to join
- The babies will be assessed sequentially by criteria A, B and C listed below:
- Evidence of Perinatal Asphyxia at birth: Infants ≥35 completed weeks gestation admitted to the NICU with at least one of the following:
- Apgar score of <5 at 10 minutes after birth
- Continued need for resuscitation, including endotracheal or mask ventilation, at 10 minutes after birth
- 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)
- Base Deficit (-16 mmol/L or more) in umbilical cord or any blood sample (arterial, venous or capillary) within 60 minutes of birth
Show all 18Show fewer
- Infants that meet criteria A will be assessed for whether they meet the neurological abnormality entry criteria (B) by trained personnel:
- Clinical Evidence of Moderate to severe encephalopathy, consisting of altered state of consciousness (lethargy, stupor or coma) AND at least one of the following:
- hypotonia
- abnormal reflexes including oculomotor or pupillary abnormalities
- absent or weak suck
- 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.
- (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:
- normal background with some seizure activity
- continuous seizure activity
- moderately abnormal activity: Only Lower border below 5 mV. upper border remains above 10mV
- Severely Abnormal activity (suppressed activity): Both Lower border below 5 mV and upper border below 10mV
Who cannot join
- 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.
Trial locations and contacts
7 sites in 6 countries.
7 sites in 6 countries
Turkey (Türkiye)2 sites, 2 recruiting
- Recruiting
Zekai Tahir Burak Maternity Teaching Hospital
Ankara
Fuat E Canpolat, MD, +905326315185, femrecan@gmail.com
Prof. Ugur Dilmen, +903123065267, ugurdilmen@gmail.com
- Recruiting
Diyarbakir Children's Hospital
Diyarbakır
Melek Akar, MD, 904122245751507, Melek_akar@yahoo.com.tr
Heybet Tuzun, Pharm, drheybet@hotmail.com
Egypt1 site, 1 recruiting
- Recruiting
Mansoura University Children's Hospital
Al Mansurah
Islam A Noor, MD, +20103893026, islamnoor79@yahoo.com
Prof. Mohammed T Khashaba, +20502317925, khashabamohamed@hotmail.com
Malaysia1 site, 1 recruiting
- Recruiting
University Malaya Medical Center (UMMC)
Kuala Lumpur
Lucy CS Lum, Prof, 60379492065, lumcs@ummc.edu.my
Hasimah B Zainol, Nursing, 03-79492428/ 016-6217549, hasimah@ummc.edu.my
Qatar1 site, 1 recruiting
- Recruiting
NICU,Women's Hospital, Hamad Medical Corporation
Doha, Baladiyat ad Dawhah, 00000
Sarrah A Eltinay, MBBS, +974-44398940, magcoolcoordinator@gmail.com
Sajjad Ur Rahman, MBBS,DCH,MCPS,FCPS,FRCPCH,FNP, +974-44396123, magcoolstudy@hotmail.com
Saudi Arabia1 site, 1 recruiting
- Recruiting
Arrayan Hospital-Dr Sulaiman Al Habib Medical Group
Riyadh, Riyadh Region
Jassim Anabrees, MD,MRCPCH, +96614904000 ext. 9690, jasim1800@yahoo.com
Jassim Anabress, MD
United Arab Emirates1 site, 1 recruiting
- Recruiting
Tawam Hospital
AlAin
Aiman Rahmani, MD, 97137072181, arahmani@tawamhospital.ae
Fares Chedid, MD, 971504474661, fchedid@tawamhospital.ae
About this study
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
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.
Read the 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:
- The immediate (primary) hypoxic insult followed by a
- 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.
- Being tested
- Magnesium Sulphate, Placebo
- Keywords
- Hypoxic Ischemic Encephalopathy, Therapeutic Hypothermia, Therapeutic Hypothermia plus Adjuvant Therapy, Cooling
- Medical subject headings
- Hypoxia-Ischemia, Brain
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Magnesium SulphateDrug
Also called MgSo4
10% MgSo4 (100mg/ml) given in a dose of 250mg/kg IV q 24 hrly for 3 doses(2.5ml/kg).
Diluent: Dextrose 5%.
PlaceboDrug
Also called Normal Saline, 0.9% Sodium Chloride
Normal Saline 0.9% Sodium Chloride is diluted in 5% Dextrose to be given as 2.5ml/kg IV q24 hrly for 3 doses.
| Study group | Role | What they receive |
|---|---|---|
| Hypothermia + Magnesium Sulphate | Active comparator | Not described Receives: Drug: Magnesium Sulphate |
| Hypothermia+ Placebo | Placebo comparator | Not described Receives: Drug: Placebo |
What is being measured
The primary outcome is the main question the study is designed to answer.
Combined outcome of Mortality and Severe Neurodevelopmental Disability
Severe Neurodevelopmental Disability will be assessed at discharge from hospital and at 18-24 months of age to assess developmental delay and cerebral palsy using the Bayley Scale of Infant Development II.
Measured: 18 - 24 months of age
Secondary outcomes (23)
Persistent Hypotension
The development of persistently low blood pressure despite adequate measures to maintain normal blood pressure will be assessed and recorded throughout the hypothermia therapy.
Measured: Duration of hypothermia therapy( ie during the first 96 hours)
Pulmonary Hemorrhage
The development of Pulmonary hemorrhage at any stage during the patient's hospital stay will be recorded.
Measured: Duration of hospital stay, an expected average of up to 4 weeks
Intracranial Hemorrhage
The development of Intracranial Hemorrhage at any stage during the patient's hospital stay will be recorded by serial head ultrasounds on day 1 , day 3 and as required.
Measured: Duration of hospital stay, an expected average of up to 4 weeks
Pulmonary Hypertension
The development of pulmonary hypertension at any stage during the patient's hospital stay will be recorded.
Measured: Duration of Hypothermia therapy (ie during the first 96 hours)
Prolonged Blood Coagulation time
The development of abnormal coagulation profile during hypothermia therapy will be recorded.
Measured: Duration of hypothermia therapy ( ie during the first 96 hours)
Culture Proven sepsis
The development of sepsis with a positive blood culture during the patient's hospital stay will be recorded.
Measured: Duration of hospital stay, an expected average of up to 4 weeks
Necrotizing enterocolitis
The development of necrotizing enterocolitis during the patient's hospital stay will be recorded.
Measured: Duration of hospital stay, an expected average of up to 4 weeks
Cardiac Arrhythmias
The development ofcardiac arrythmia during hypothermia therapy will be recorded.
Measured: Duration of hypothermia therapy (ie during the first 96 hours)
Thrombocytopenia
The development of low platelet count (<20,000) during hypothermia therapy will be recorded
Measured: Duration of hypothermia therapy (ie during the first 96 hours)
Major venous thrombosis
The development of major venous thrombosis or a major vein thrombus during the patient's hospital stay will be recorded.
Measured: Duration of hospital stay, an expected average of up to 4 weeks
Renal Failure
The development of renal failure during the patient's hospital stay will be recorded
Measured: Duration of hospital stay, an expected average of up to 4 weeks
Abnormal liver funcion tests (elevated liver enzymes)
The devlopment of raised liver enzymes during the patient's hospital stay will be recorded.
Measured: Duration of hospital stay, an expected average of up to 4 weeks
Pneumonia
The development of pneumonia during the patient's hospital stay will be assessed and recorded.
Measured: Duration of hospital stay, an expected average of up to 4 weeks
Pulmonary air leak syndrome
The development of pulmonary air leak syndrome during the patient's hospital stay will be recorded.
Measured: Duration of hospital stay, an expected average of up to 4 weeks
Prolonged vs shortened hospital stay
The entire duration of hopital stay will be assessed
Measured: First day of NICU admission till the day of discharge, an expected average of up to 4 weeks
Neurodevelopment score
A developmental paediatrician blinded to the study groups will assess the patient's neurodevlopment on the day of his or her discharge.
Measured: On the day of discharge from hospital, an expected average of 4 weeks after admission
Abnormal aEEG
The aEEG is used to measure the severity of Hypoxic Ischemic Encephalopathy (moderate or severe).
Measured: Before randomization and during hypothermia therapy (0 hours till 96 hours)
Presence of multiple handicaps
Multiple handicaps (( defined as the presence of any two of the following in an infant at the age of 18-24 months: neuromotor disability (level 3-5 on GMF Classification), mental delay (Bayley MDI score <70),epilepsy, cortical visual impairment, sensorineural hearing loss)).
Measured: 18-24 months of age
Bayley Psychomotor Development Score less than 70
Measured: 18-24 months of age
Sensorineural hearing loss equal to, or more than, 40 dB
Measured: 18-24 months of age
Epilepsy
Epilepsy is defined as recurrent seizures beyond the neonatal period, requiring anticonvulsant therapy at the time of assessment
Measured: 18-24 months of age
Microcephaly
Defined as Head circumference more than 2 standard deviations below the mean
Measured: 18-24 months of age
Result of EEG or MRI
To moniter any abnormal EEG patterns and any evidence of Ischemic/Hemorrhagic lesions on MRI
Measured: within the first 14 days of life
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted20 Jul 2012 (estimated)
- Study startMay 2012
- Primary completionDec 2013 (estimated)
- Study completionJun 2014 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (15)Papers the sponsor has linked to this study.
- Other trials for Severe Hypoxic Ischemic EncephalopathyStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 3
- Primary purpose
- Prevention
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Quadruple blind
- Who is masked
- Participant, Care provider, Investigator, Outcomes assessor
- Enrolment
- 300 participants (estimated)
Sponsor and investigators
- Lead sponsor
- Sajjad Rahman
- Sponsor type
- Industry (pharma, biotech, devices)
- Responsible party
- Sponsor-investigator, Sajjad Rahman, Hamad Medical Corporation
- Investigators
- Sajjad Ur Rahman, MBBS.DCH.MCPS.FCPS.FRCPCH.FNP, Principal investigator, Hamad Medical Corporation
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT01646619
- Sponsor's protocol ID
- GC 1028A
- Other IDs
- HMC-GC1028A
- Acronym
- MagCool
- Status last verified
- Apr 2013
- First submitted
- 5 Jul 2012
- Last updated
- 4 Apr 2013
- Results posted
- No
- Data monitoring committee
- Yes
Publications
Paul VK. Neonatal morbidity and mortality: report of the national neonatal and perinatal database. Indian Pediatr. 1999 Feb;36(2):167-9. No abstract available.
PubMed 10713810Bhat MA, Shah ZA, Makhdoomi MS, Mufti MH. Theophylline for renal function in term neonates with perinatal asphyxia: a randomized, placebo-controlled trial. J Pediatr. 2006 Aug;149(2):180-4. doi: 10.1016/j.jpeds.2006.03.053.
PubMed 16887430Paneth N. The causes of cerebral palsy. Recent evidence. Clin Invest Med. 1993 Apr;16(2):95-102.
PubMed 8513618Dixon G, Badawi N, Kurinczuk JJ, Keogh JM, Silburn SR, Zubrick SR, Stanley FJ. Early developmental outcomes after newborn encephalopathy. Pediatrics. 2002 Jan;109(1):26-33. doi: 10.1542/peds.109.1.26.
PubMed 11773538Edwards AD, Azzopardi DV. Hypothermic neural rescue: work continues. J Pediatr. 2010 Sep;157(3):351-2. doi: 10.1016/j.jpeds.2010.06.029. Epub 2010 Jul 24. No abstract available.
PubMed 20659738Gluckman PD, Wyatt JS, Azzopardi D, Ballard R, Edwards AD, Ferriero DM, Polin RA, Robertson CM, Thoresen M, Whitelaw A, Gunn AJ. Selective head cooling with mild systemic hypothermia after neonatal encephalopathy: multicentre randomised trial. Lancet. 2005 Feb 19-25;365(9460):663-70. doi: 10.1016/S0140-6736(05)17946-X.
PubMed 15721471Azzopardi DV, Strohm B, Edwards AD, Dyet L, Halliday HL, Juszczak E, Kapellou O, Levene M, Marlow N, Porter E, Thoresen M, Whitelaw A, Brocklehurst P; TOBY Study Group. Moderate hypothermia to treat perinatal asphyxial encephalopathy. N Engl J Med. 2009 Oct 1;361(14):1349-58. doi: 10.1056/NEJMoa0900854.
PubMed 19797281Simbruner G, Mittal RA, Rohlmann F, Muche R; neo.nEURO.network Trial Participants. Systemic hypothermia after neonatal encephalopathy: outcomes of neo.nEURO.network RCT. Pediatrics. 2010 Oct;126(4):e771-8. doi: 10.1542/peds.2009-2441. Epub 2010 Sep 20.
PubMed 20855387Zhou WH, Cheng GQ, Shao XM, Liu XZ, Shan RB, Zhuang DY, Zhou CL, Du LZ, Cao Y, Yang Q, Wang LS; China Study Group. Selective head cooling with mild systemic hypothermia after neonatal hypoxic-ischemic encephalopathy: a multicenter randomized controlled trial in China. J Pediatr. 2010 Sep;157(3):367-72, 372.e1-3. doi: 10.1016/j.jpeds.2010.03.030. Epub 2010 May 20.
PubMed 20488453Levene MI. Cool treatment for birth asphyxia, but what's next? Arch Dis Child Fetal Neonatal Ed. 2010 May;95(3):F154-7. doi: 10.1136/adc.2009.165738. No abstract available.
PubMed 20444808Jacobs S, Hunt R, Tarnow-Mordi W, Inder T, Davis P. Cooling for newborns with hypoxic ischaemic encephalopathy. Cochrane Database Syst Rev. 2007 Oct 17;(4):CD003311. doi: 10.1002/14651858.CD003311.pub2.
PubMed 17943788Edwards AD, Brocklehurst P, Gunn AJ, Halliday H, Juszczak E, Levene M, Strohm B, Thoresen M, Whitelaw A, Azzopardi D. Neurological outcomes at 18 months of age after moderate hypothermia for perinatal hypoxic ischaemic encephalopathy: synthesis and meta-analysis of trial data. BMJ. 2010 Feb 9;340:c363. doi: 10.1136/bmj.c363.
PubMed 20144981Rutherford M, Ramenghi LA, Edwards AD, Brocklehurst P, Halliday H, Levene M, Strohm B, Thoresen M, Whitelaw A, Azzopardi D. Assessment of brain tissue injury after moderate hypothermia in neonates with hypoxic-ischaemic encephalopathy: a nested substudy of a randomised controlled trial. Lancet Neurol. 2010 Jan;9(1):39-45. doi: 10.1016/S1474-4422(09)70295-9. Epub 2009 Nov 5.
PubMed 19896902Rouse DJ, Hirtz DG, Thom E, Varner MW, Spong CY, Mercer BM, Iams JD, Wapner RJ, Sorokin Y, Alexander JM, Harper M, Thorp JM Jr, Ramin SM, Malone FD, Carpenter M, Miodovnik M, Moawad A, O'Sullivan MJ, Peaceman AM, Hankins GD, Langer O, Caritis SN, Roberts JM; Eunice Kennedy Shriver NICHD Maternal-Fetal Medicine Units Network. A randomized, controlled trial of magnesium sulfate for the prevention of cerebral palsy. N Engl J Med. 2008 Aug 28;359(9):895-905. doi: 10.1056/NEJMoa0801187.
PubMed 18753646Bhat MA, Charoo BA, Bhat JI, Ahmad SM, Ali SW, Mufti MU. Magnesium sulfate in severe perinatal asphyxia: a randomized, placebo-controlled trial. Pediatrics. 2009 May;123(5):e764-9. doi: 10.1542/peds.2007-3642. Epub 2009 Apr 6.
PubMed 19349375
Study at a glance
From the registry record, last updated by the sponsor on 4 Apr 2013. Recruitment status is as the sponsor reported it: confirm with the study team.
- 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
- ClinicalTrials.gov ID
- NCT01646619
- Acronym / sponsor ID
- MagCool / GC 1028A
- Keywords
- Hypoxic Ischemic Encephalopathy, Therapeutic Hypothermia, Therapeutic Hypothermia plus Adjuvant Therapy, Cooling
- Phase
- Phase 3
- Study type
- Interventional
- Recruitment status
- Unknown status
- Enrolment
- 300 participants (estimated)
- Lead sponsor
- Sajjad RahmanIndustry (pharma, biotech, devices)
- Study start
- May 2012
- Primary completion
- Dec 2013 (estimated)
- Study completion
- Jun 2014 (estimated)
- First posted
- 20 Jul 2012 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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:
- The immediate (primary) hypoxic insult followed by a
- 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.
Study design
- Primary purpose
- Prevention
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Quadruple blind (participant, care provider, investigator, outcomes assessor)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Hypothermia + Magnesium Sulphate | Active comparator | Drug: Magnesium Sulphate |
| Hypothermia+ Placebo | Placebo comparator | Drug: Placebo |
Who may qualify
- Ages
- Up to 6 hours
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Child
Key inclusion criteria (18 listed)
- Evidence of Perinatal Asphyxia at birth: Infants ≥35 completed weeks gestation admitted to the NICU with at least one of the following:
- Apgar score of <5 at 10 minutes after birth
- Continued need for resuscitation, including endotracheal or mask ventilation, at 10 minutes after birth
- 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)
- Base Deficit (-16 mmol/L or more) in umbilical cord or any blood sample (arterial, venous or capillary) within 60 minutes of birth
Key exclusion criteria (2 listed)
- 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.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Magnesium SulphateAlso: MgSo410% MgSo4 (100mg/ml) given in a dose of 250mg/kg IV q 24 hrly for 3 doses(2.5ml/kg). Diluent: Dextrose 5%. | Drug | Hypothermia + Magnesium Sulphate |
| PlaceboAlso: Normal Saline, 0.9% Sodium ChlorideNormal Saline 0.9% Sodium Chloride is diluted in 5% Dextrose to be given as 2.5ml/kg IV q24 hrly for 3 doses. | Drug | Hypothermia+ Placebo |
Primary outcome
Combined outcome of Mortality and Severe Neurodevelopmental Disability
Time frame: 18 - 24 months of age
Severe Neurodevelopmental Disability will be assessed at discharge from hospital and at 18-24 months of age to assess developmental delay and cerebral palsy using the Bayley Scale of Infant Development II.
23 secondary outcomes
Persistent Hypotension
Time frame: Duration of hypothermia therapy( ie during the first 96 hours)
Pulmonary Hemorrhage
Time frame: Duration of hospital stay, an expected average of up to 4 weeks
Intracranial Hemorrhage
Time frame: Duration of hospital stay, an expected average of up to 4 weeks
Pulmonary Hypertension
Time frame: Duration of Hypothermia therapy (ie during the first 96 hours)
Prolonged Blood Coagulation time
Time frame: Duration of hypothermia therapy ( ie during the first 96 hours)
Culture Proven sepsis
Time frame: Duration of hospital stay, an expected average of up to 4 weeks
Necrotizing enterocolitis
Time frame: Duration of hospital stay, an expected average of up to 4 weeks
Cardiac Arrhythmias
Time frame: Duration of hypothermia therapy (ie during the first 96 hours)
Thrombocytopenia
Time frame: Duration of hypothermia therapy (ie during the first 96 hours)
Major venous thrombosis
Time frame: Duration of hospital stay, an expected average of up to 4 weeks
Renal Failure
Time frame: Duration of hospital stay, an expected average of up to 4 weeks
Abnormal liver funcion tests (elevated liver enzymes)
Time frame: Duration of hospital stay, an expected average of up to 4 weeks
Pneumonia
Time frame: Duration of hospital stay, an expected average of up to 4 weeks
Pulmonary air leak syndrome
Time frame: Duration of hospital stay, an expected average of up to 4 weeks
Prolonged vs shortened hospital stay
Time frame: First day of NICU admission till the day of discharge, an expected average of up to 4 weeks
Neurodevelopment score
Time frame: On the day of discharge from hospital, an expected average of 4 weeks after admission
Abnormal aEEG
Time frame: Before randomization and during hypothermia therapy (0 hours till 96 hours)
Presence of multiple handicaps
Time frame: 18-24 months of age
Bayley Psychomotor Development Score less than 70
Time frame: 18-24 months of age
Sensorineural hearing loss equal to, or more than, 40 dB
Time frame: 18-24 months of age
Epilepsy
Time frame: 18-24 months of age
Microcephaly
Time frame: 18-24 months of age
Result of EEG or MRI
Time frame: within the first 14 days of life
Results and safety
Results are not available in the source record.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 4 Apr 2013.
- Background: PubMed 10713810Paul VK. Neonatal morbidity and mortality: report of the national neonatal and perinatal database. Indian Pediatr. 1999 Feb;36(2):167-9. No abstract available.
- Background: PubMed 16887430Bhat MA, Shah ZA, Makhdoomi MS, Mufti MH. Theophylline for renal function in term neonates with perinatal asphyxia: a randomized, placebo-controlled trial. J Pediatr. 2006 Aug;149(2):180-4. doi: 10.1016/j.jpeds.2006.03.053.
- Background: PubMed 8513618Paneth N. The causes of cerebral palsy. Recent evidence. Clin Invest Med. 1993 Apr;16(2):95-102.
- Background: PubMed 11773538Dixon G, Badawi N, Kurinczuk JJ, Keogh JM, Silburn SR, Zubrick SR, Stanley FJ. Early developmental outcomes after newborn encephalopathy. Pediatrics. 2002 Jan;109(1):26-33. doi: 10.1542/peds.109.1.26.
- Background: PubMed 20659738Edwards AD, Azzopardi DV. Hypothermic neural rescue: work continues. J Pediatr. 2010 Sep;157(3):351-2. doi: 10.1016/j.jpeds.2010.06.029. Epub 2010 Jul 24. No abstract available.
- Background: PubMed 15721471Gluckman PD, Wyatt JS, Azzopardi D, Ballard R, Edwards AD, Ferriero DM, Polin RA, Robertson CM, Thoresen M, Whitelaw A, Gunn AJ. Selective head cooling with mild systemic hypothermia after neonatal encephalopathy: multicentre randomised trial. Lancet. 2005 Feb 19-25;365(9460):663-70. doi: 10.1016/S0140-6736(05)17946-X.
- Background: PubMed 19797281Azzopardi DV, Strohm B, Edwards AD, Dyet L, Halliday HL, Juszczak E, Kapellou O, Levene M, Marlow N, Porter E, Thoresen M, Whitelaw A, Brocklehurst P; TOBY Study Group. Moderate hypothermia to treat perinatal asphyxial encephalopathy. N Engl J Med. 2009 Oct 1;361(14):1349-58. doi: 10.1056/NEJMoa0900854.
- Background: PubMed 20855387Simbruner G, Mittal RA, Rohlmann F, Muche R; neo.nEURO.network Trial Participants. Systemic hypothermia after neonatal encephalopathy: outcomes of neo.nEURO.network RCT. Pediatrics. 2010 Oct;126(4):e771-8. doi: 10.1542/peds.2009-2441. Epub 2010 Sep 20.
- Background: PubMed 20488453Zhou WH, Cheng GQ, Shao XM, Liu XZ, Shan RB, Zhuang DY, Zhou CL, Du LZ, Cao Y, Yang Q, Wang LS; China Study Group. Selective head cooling with mild systemic hypothermia after neonatal hypoxic-ischemic encephalopathy: a multicenter randomized controlled trial in China. J Pediatr. 2010 Sep;157(3):367-72, 372.e1-3. doi: 10.1016/j.jpeds.2010.03.030. Epub 2010 May 20.
- Background: PubMed 20444808Levene MI. Cool treatment for birth asphyxia, but what's next? Arch Dis Child Fetal Neonatal Ed. 2010 May;95(3):F154-7. doi: 10.1136/adc.2009.165738. No abstract available.
- Background: PubMed 17943788Jacobs S, Hunt R, Tarnow-Mordi W, Inder T, Davis P. Cooling for newborns with hypoxic ischaemic encephalopathy. Cochrane Database Syst Rev. 2007 Oct 17;(4):CD003311. doi: 10.1002/14651858.CD003311.pub2.
- Background: PubMed 20144981Edwards AD, Brocklehurst P, Gunn AJ, Halliday H, Juszczak E, Levene M, Strohm B, Thoresen M, Whitelaw A, Azzopardi D. Neurological outcomes at 18 months of age after moderate hypothermia for perinatal hypoxic ischaemic encephalopathy: synthesis and meta-analysis of trial data. BMJ. 2010 Feb 9;340:c363. doi: 10.1136/bmj.c363.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Sajjad Ur Rahman, MBBS.DCH.MCPS.FCPS.FRCPCH.FNP principal investigator
Hamad Medical Corporation
7 sites in 6 countries: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 3 study testing Magnesium Sulphate in people with Severe Hypoxic Ischemic Encephalopathy and Moderate Hypoxic Ischemic Encephalopathy, run by Sajjad Rahman at 7 sites in 6 countries.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 18 inclusion and 2 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: status not confirmed, as of the sponsor's last update on 4 Apr 2013. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 7 sites in Turkey (Türkiye), Egypt, Malaysia, Qatar, Saudi Arabia and 1 more country. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Results are not available in the source record.
How can a doctor refer a patient or contact the research team?
Contact Sarrah A Y Eltinay, MBBS (+974-44398940, magcoolcoordinator@gmail.com), or a site near the patient. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Combined outcome of Mortality and Severe Neurodevelopmental Disability (time frame: 18 - 24 months of age). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT01646619, which also lists 15 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 4 Apr 2013; AzTrials last refreshed its copy on 8 Nov 2026.