Magnesium Sulphate for Severe Hand, Foot and Mouth Disease in Vietnam

NCT01940250 | Completed Phase 2 DMC

• 1 other identifier: 02EI
• Study Type: interventional
• Target: 26
• Locations: 1 country
• Sites: 2

Brief Summary

Hand foot and mouth disease (HFMD) is a common infectious disease caused by a number of different viruses - a small proportion of children infected with a particular type of enterovirus (EV71) develop neurological and systemic complications that may prove fatal. Very large epidemics of EV71 related HFMD have occurred across Asia in recent years; in 2011, in excess of 100,000 Vietnamese children were diagnosed with HFMD and 164 died. In children with severe HFMD the particular part of the brain that regulates the heart, blood circulation, and breathing responses can be affected. Management of this complication is very difficult and we currently use an expensive drug (milrinone) that is hard to obtain and has significant side effects, without having good evidence that it is effective. Magnesium sulphate (Mg) is a cheap, readily available drug that has been used in other diseases with similar complications, and we have preliminary data from a small case series that suggests it might be a good treatment for HFMD patients with signs indicating this type of brain involvement. We think that early intervention with Mg, when signs of brain involvement are still relatively mild, will control this problem better than waiting until it is well established and giving milrinone as at present, and this in turn may prevent progression to severe disease. The aims of the project are to evaluate the effects of Mg on hypertension, signs of brain dysfunction, outcome (death or neurological sequelae), changes in a variety of blood and urine components, and measures of cardiovascular function, in severe HFMD. The study design is a randomized double-blind placebo-controlled clinical trial. Children on the pediatric intensive care unit with a clinical diagnosis of hand, foot and mouth disease will be eligible for enrolment if the blood pressure exceeds the internationally recognized threshold for Stage 1 hypertension, they exhibit at least one other sign of brain stem dysfunction, and there is written informed consent by a parent or guardian. According to the randomization, patients will receive an initial loading dose followed by a maintenance infusion, of either Mg or identical placebo for 72 hours; all staff involved in patient care will remain unaware of the treatment allocation, but staff from another department will monitor Mg blood levels to ensure safety and adequate dosing. A total of 190 patients (95 in each arm) will be recruited.

Conditions

Hand, Foot and Mouth Disease

Keywords

Hand, foot and mouth disease; Autonomic nervous system dysregulation; Magnesium sulphate

Outcome Measures

Primary Outcomes (1)

• Number of patients who experience at least one of the clinical events listed below (composite endpoint)

  Number of patients who meet one or more of the following criteria: 1. Blood pressure criteria necessitating addition of milrinone following Vietnam Ministry of Health guidelines for the treatment of hand, foot and mouth disease 2. Need for mechanical ventilation 3. Development of shock 4. Death

  72 hours after start of study drug infusion

Secondary Outcomes (9)

• Death

  72 hours after start of study drug infusion

• Blood pressure criteria necessitating addition of milrinone following Vietnam Ministry of Health guidelines for the treatment of hand, foot and mouth disease

  72 hours after start of study drug infusion

• Need for mechanical ventilation

  72 hours after start of study drug infusion

• Development of shock

  72 hours after start of study drug infusion

• Requirement for inotropic agents (eg dobutamine)

  During hospital admission - expected average length of admission 5 days

Study Arms (2)

Sterile water

PLACEBO COMPARATOR

Sterile water will be packaged identically to the active comparator. Each patient randomized to the placebo arm of the trial will receive a loading dose of 0.5ml/kg intravenous over 20 minutes , followed by a maintenance dose of 0.3 ml/kg/hr to 0.5 ml/kg/hr randomly adjusted by an independent doctor to mimic adjustments made in the active comparator arm for 72 hrs.

Drug: Sterile water

Magnesium sulphate

ACTIVE COMPARATOR

Each patient randomized to the treatment arm of the trial will receive a loading dose of 50mg/kg intravenous over 20 minutes (0.5ml/kg), followed by a maintenance dose of 30-50 mg/kg/hr (0.3 ml/kg/hr to 0.5 ml/kg/hr) for 72 hrs. The maintenance dose will be determined by increasing the loading infusion dose 0.1 ml/kg/hr (10mg/kg/hr) every 15 minutes to a maximum dose of 0.5 ml/kg/hr (50 mg/kg/hr), with the following caveats: * If the systolic BP decreases to \< 90th percentile for age, gender and length the dose will be reduced by 1 stage every 15 mins * If the systolic BP increases to the levels detailed in the study protocol for treatment failure, action will be taken as indicated * If the systolic BP decrease rapidly more than 25% over 15 minutes * If the plasma Mg level \> 2.5 mmol/l or \< 1.8 mmol/l a 25% increase or decrease in the infusion rate will be implemented as appropriate.

Drug: Magnesium Sulphate

Interventions

Magnesium Sulphate DRUG

MgSO4 IV infusion

Also known as: magnesi sulfat krabi 15%

Magnesium sulphate

Sterile water DRUG

H2O IV infusion

Sterile water

Eligibility Criteria

• Age: 6 Months - 15 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17)

You may qualify if:

• Age 6 months to 15 years
• Clinical suspicion of HFMD requiring PICU/HDU admission
• Considered severe enough to warrant invasive blood pressure monitoring by PICU/HDU staff
• Development of hypertension defined as follows:
• For children aged 1 year and over, at least 3 consecutive systolic blood pressure recordings above the 95th centile for age, gender and length (USA guidelines for defining Stage 1 hypertension in children, (Appendix 2)) measured invasively over a period of 20 minutes provided the child is not distressed or crying \[30, 31\].
• For children aged 6 months to 1 year, systolic BP \> 100 mm Hg measured invasively on at least 3 occasions over a period for 20 minutes provided the child is not distressed or crying
• Plus one or more of the following criteria:
• Tachypnoea for age
• Irregular or labored breathing, but with SpO2 above 92% in air and normal ABG (pH, pCO2, pO2, HCO3 all within the normal range for the local laboratory)
• Resting heart rate \> 150 bpm
• Mottled skin
• Profuse sweating
• Refractory fever
• Hyperglycemia
• Informed consent

You may not qualify if:

• Past history of hypertension, chronic renal, cardiac or pulmonary disease, or any neurological disorder
• Hypertensive emergency
• Already commenced milrinone or any other inotropic agents
• Respiratory distress with SpO2\<92% in air or PaCO2\>45 mm Hg
• AV block or any arrhythmia
• Acute renal failure

Sponsors & Collaborators

• Oxford University Clinical Research Unit, Vietnam: lead
• Hospital for Tropical Diseases, Ho Chi Minh City, Vietnam: collaborator
• Children's Hospital Number 1, Ho Chi Minh City, Vietnam: collaborator

Study Sites (2)

Children's Hospital 1

Ho Chi Minh City, Vietnam

Location

Hospital for Tropical Diseases

Ho Chi Minh City, Vietnam

Location

Related Publications (2)

• Phan QT, Phung LK, Truong KH, Huynh TT, Pham GT, Nguyen BN, Tran QT, Huynh VNT, Nguyen TTM, Le TPK, Le NNT, Sabanathan S, van Doorn HR, Van Le T, Nguyen TD, Merson L, Nguyen DTP, Geskus R, Nguyen HT, Nguyen CVV, Wills B. Assessing the efficacy and safety of magnesium sulfate for management of autonomic nervous system dysregulation in Vietnamese children with severe hand foot and mouth disease. BMC Infect Dis. 2019 Aug 22;19(1):737. doi: 10.1186/s12879-019-4356-x.

  PMID: 31438878 DERIVED

• Qui PT, Khanh TH, Trieu HT, Giang PT, Bich NN, Thoa le PK, Nhan le NT, Sabanathan S, Van Doorn R, Toan ND, Merson L, Dung NT, Khanh LP, Wolbers M, Hung NT, Chau NV, Wills B. Intravenous magnesium sulfate for the management of severe hand, foot, and mouth disease with autonomic nervous system dysregulation in Vietnamese children: study protocol for a randomized controlled trial. Trials. 2016 Feb 19;17:98. doi: 10.1186/s13063-016-1215-6.

  PMID: 26896318 DERIVED

Related Links

• Oxford University Clinical Research Unit, Viet Nam

MeSH Terms

Conditions

Hand, Foot and Mouth Disease

Interventions

Magnesium Sulfate

Condition Hierarchy (Ancestors)

Coxsackievirus Infections; Enterovirus Infections; Picornaviridae Infections; RNA Virus Infections; Virus Diseases; Infections

Intervention Hierarchy (Ancestors)

Magnesium Compounds; Inorganic Chemicals; Sulfates; Sulfuric Acids; Sulfur Acids; Sulfur Compounds

Study Officials

• Bridget Wills, MD

  Oxford University Clinical Research Unit

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: August 22, 2013
• First Posted: September 12, 2013
• Study Start: April 21, 2014
• Primary Completion: June 30, 2016
• Study Completion: December 28, 2016
• Last Updated: March 7, 2017

Record last verified: 2014-11

Locations

VN (2)