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

This study is currently recruiting participants. (see Contacts and Locations)
Verified April 2014 by Oxford University Clinical Research Unit, Vietnam
Sponsor:
Collaborators:
Hospital for Tropical Diseases, Ho Chi Minh City, Vietnam
Children's Hospital 1, Ho Chi Minh City, Viet Nam
Information provided by (Responsible Party):
Oxford University Clinical Research Unit, Vietnam
ClinicalTrials.gov Identifier:
NCT01940250
First received: August 22, 2013
Last updated: April 28, 2014
Last verified: April 2014
  Purpose

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.


Condition Intervention Phase
Hand, Foot and Mouth Disease
Drug: Magnesium Sulphate
Drug: Sterile water
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: A Randomized, Placebo-controlled, Double-blind Trial of Intravenous Magnesium Sulfate for the Management of Severe Hand, Foot and Mouth Disease With Autonomic Nervous System Dysregulation in Vietnamese Children.

Resource links provided by NLM:


Further study details as provided by Oxford University Clinical Research Unit, Vietnam:

Primary Outcome Measures:
  • Number of patients who experience at least one of the clinical events listed below (composite endpoint) [ Time Frame: 72 hours after start of study drug infusion ] [ Designated as safety issue: Yes ]

    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


Secondary Outcome Measures:
  • Death [ Time Frame: 72 hours after start of study drug infusion ] [ Designated as safety issue: Yes ]
  • Blood pressure criteria necessitating addition of milrinone following Vietnam Ministry of Health guidelines for the treatment of hand, foot and mouth disease [ Time Frame: 72 hours after start of study drug infusion ] [ Designated as safety issue: Yes ]
  • Need for mechanical ventilation [ Time Frame: 72 hours after start of study drug infusion ] [ Designated as safety issue: Yes ]

    According to Viet Nam Ministry of Health guidelines: Ventilation Criteria:

    If a patient continues to display any of the following criteria despite oxygenation via nasal cannula and cardiac support with inotropic drugs for more than 60 minutes.

    • Labored breathing
    • Tachypnea with resting respiratory rate > 70 / minute without fever
    • Hypoxemia and/or fluctuating SpO2
    • Poor tissue perfusion and persistent resting heart rate > 180 beats/minute without fever

    Or

    • Decorticate or decerebrate rigidity
    • Coma (Glasgow Coma Scale < 10 )

  • Development of shock [ Time Frame: 72 hours after start of study drug infusion ] [ Designated as safety issue: Yes ]
  • Requirement for inotropic agents (eg dobutamine) [ Time Frame: During hospital admission - expected average length of admission 5 days ] [ Designated as safety issue: Yes ]
    If heart rate> 170 beats/minute

  • Presence of neurological sequelae at discharge in survivors [ Time Frame: At hospital discharge - expected average discharge day 5 ] [ Designated as safety issue: Yes ]
    Number of surviving patients who have neurological sequelae at hospital discharge

  • Neurodevelopmental status [ Time Frame: 6 months ] [ Designated as safety issue: Yes ]
    Measured by . Children 36 months and under at enrollment will use the Bayley infant scales of development III. Children 48 months and above at enrollment will use the Movement ABC-2 tool for their assessments. The children aged between 37 and 47 months at enrolment will have both assessments done at both visits.

  • Duration of hospitalization [ Time Frame: At hospital discharge - expected average discharge day 5 ] [ Designated as safety issue: Yes ]
    Number of days from study enrollment to discharge

  • Number of adverse events and serious adverse events [ Time Frame: During hospital admission - expected average length of admission 5 days ] [ Designated as safety issue: Yes ]
    Number of adverse events and severe adverse events that occur in the two treatment arms during hospitalization.


Estimated Enrollment: 190
Study Start Date: April 2014
Estimated Study Completion Date: August 2016
Estimated Primary Completion Date: March 2016 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Placebo Comparator: Sterile water

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
H2O IV infusion
Active Comparator: Magnesium sulphate

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
MgSO4 IV infusion
Other Name: magnesi sulfat krabi 15%

  Show Detailed Description

  Eligibility

Ages Eligible for Study:   6 Months to 15 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • 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

Exclusion Criteria:

  • 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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01940250

Contacts
Contact: Bridget Wills, MD bwills@oucru.org
Contact: Phan Tu Qui, MD phantuqui@gmail.com

Locations
Vietnam
Hospital for Tropical Diseases Recruiting
Ho CHi Minh City, Vietnam
Contact: Phan Tu Qui, MD PhD       phantuqui@gmail.com   
Children's Hospital 1 Not yet recruiting
Ho Chi Minh City, Vietnam
Contact: Truong Huu Khanh, MD       truonghuukhanh@gmail.com   
Sponsors and Collaborators
Oxford University Clinical Research Unit, Vietnam
Hospital for Tropical Diseases, Ho Chi Minh City, Vietnam
Children's Hospital 1, Ho Chi Minh City, Viet Nam
Investigators
Principal Investigator: Bridget Wills, MD Oxford University Clinical Research Unit
  More Information

Additional Information:
No publications provided

Responsible Party: Oxford University Clinical Research Unit, Vietnam
ClinicalTrials.gov Identifier: NCT01940250     History of Changes
Other Study ID Numbers: 02EI
Study First Received: August 22, 2013
Last Updated: April 28, 2014
Health Authority: Vietnam: Ministry of Health
Vietnam: Ho Chi Minh City Health Service

Keywords provided by Oxford University Clinical Research Unit, Vietnam:
Hand, foot and mouth disease
Autonomic nervous system dysregulation
Magnesium sulphate

Additional relevant MeSH terms:
Hand, Foot and Mouth Disease
Foot-and-Mouth Disease
Mouth Diseases
Coxsackievirus Infections
Enterovirus Infections
Picornaviridae Infections
RNA Virus Infections
Stomatognathic Diseases
Virus Diseases
Magnesium Sulfate
Analgesics
Anesthetics
Anti-Arrhythmia Agents
Anticonvulsants
Calcium Channel Blockers
Cardiovascular Agents
Central Nervous System Agents
Central Nervous System Depressants
Membrane Transport Modulators
Molecular Mechanisms of Pharmacological Action
Peripheral Nervous System Agents
Pharmacologic Actions
Physiological Effects of Drugs
Reproductive Control Agents
Sensory System Agents
Therapeutic Uses
Tocolytic Agents

ClinicalTrials.gov processed this record on October 21, 2014