Magnesium Sulphate for Severe Hand, Foot and Mouth Disease in Vietnam
Recruitment status was: Recruiting
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.
Hand, Foot and Mouth Disease
Drug: Magnesium Sulphate
Drug: Sterile water
|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.|
- 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:
- Blood pressure criteria necessitating addition of milrinone following Vietnam Ministry of Health guidelines for the treatment of hand, foot and mouth disease
- Need for mechanical ventilation
- Development of shock
- 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
- 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.
|Study Start Date:||April 2014|
|Estimated Study Completion Date:||December 2016|
|Estimated Primary Completion Date:||December 2016 (Final data collection date for primary outcome measure)|
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:
Drug: Magnesium Sulphate
MgSO4 IV infusion
Other Name: magnesi sulfat krabi 15%
Show Detailed Description
Please refer to this study by its ClinicalTrials.gov identifier: NCT01940250
|Children's Hospital 1|
|Ho Chi Minh City, Vietnam|
|Hospital for Tropical Diseases|
|Ho CHi Minh City, Vietnam|
|Principal Investigator:||Bridget Wills, MD||Oxford University Clinical Research Unit|