Oral Glycerol and High-Dose Rectal Paracetamol to Improve the Prognosis of Childhood Bacterial Meningitis (GLYIP)
Primary Purpose
Bacterial Meningitis
Status
Completed
Phase
Phase 3
Locations
Malawi
Study Type
Interventional
Intervention
Glycerol and paracetamol
Paracetamol
Paracetamol
Paracetamol
Placebo
Paracetamol and glycerol
Glycerol
Sponsored by
About this trial
This is an interventional treatment trial for Bacterial Meningitis focused on measuring Bacterial meningitis, glycerol, high dose paracetamol, children
Eligibility Criteria
Inclusion Criteria:
- All children aged ≥ 2 months, admitted to Queen Elizabeth Hospital, Blantyre, Malawi, with possible or confirmed acute bacterial meningitis
Exclusion Criteria:
- Age less than two months
- Trauma
- Relevant underlying illness such as intracranial shunt, previous neurological disease (cerebral palsy, Down's syndrome)
- Previous permanent hearing loss (not conductive hearing loss) if known
- Immunosuppression except HIV infection.
Sites / Locations
- College of Medicine, Queen Elizabeth Central Hospital
Arms of the Study
Arm 1
Arm 2
Arm 3
Arm 4
Arm Type
Active Comparator
Active Comparator
Active Comparator
Placebo Comparator
Arm Label
A
B
C
D
Arm Description
Two active ingredients
One active ingredient
One (other) active ingredient
Outcomes
Primary Outcome Measures
Primary end points are death, severe neurological sequelae, hearing loss.
Secondary Outcome Measures
Secondary end points are audiological or neurological sequelae (according to the Denver-II developmental screening test).
Full Information
NCT ID
NCT00619203
First Posted
February 7, 2008
Last Updated
July 9, 2012
Sponsor
Kamuzu University of Health Sciences
1. Study Identification
Unique Protocol Identification Number
NCT00619203
Brief Title
Oral Glycerol and High-Dose Rectal Paracetamol to Improve the Prognosis of Childhood Bacterial Meningitis
Acronym
GLYIP
Official Title
Oral Glycerol and High-Dose Rectal Paracetamol to Improve the Prognosis of Childhood Bacterial Meningitis - A Prospective, Randomized, and Double-Blind Clinical Study Using a Two-by-Two Factorial Design
Study Type
Interventional
2. Study Status
Record Verification Date
July 2012
Overall Recruitment Status
Completed
Study Start Date
March 2008 (undefined)
Primary Completion Date
March 2012 (Actual)
Study Completion Date
March 2012 (Actual)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
Kamuzu University of Health Sciences
4. Oversight
Data Monitoring Committee
No
5. Study Description
Brief Summary
Bacterial meningitis remains a significant cause of morbidity and mortality in children, especially in countries with limited resources. Efforts to improve the grim outcome have included altering the first line antibiotic therapy, controlling seizures and managing fluids more carefully. Adjuvant therapy of steroids has been used with limited success in children in the West and with no proven value in Malawi and other resource constrained settings. Glycerol has been used to reduce brain oedema in neurosurgery and it has recently been shown to reduce morbidity in childhood meningitis in South America. Paracetamol in a high dosage has been shown to reduce inflammation and cytokine levels in septicaemia with improved outcomes in adults.
In Malawi the investigators have tried adjuvant steroids with no improvement in outcome of childhood meningitis. They have recently concluded a study of ceftriaxone which has shown no improvement in mortality though there is less hearing loss than with chloramphenicol and benzyl penicillin.
Following the encouraging results of the Childhood South American Study it is important to assess the use of adjuvant glycerol in children in the investigators' setting. Paracetamol is routinely used in meningitis because of the accompanying fever and headache. This is an opportunity to study its place as adjuvant therapy more carefully than has previously been done.
The investigators propose a prospective, randomized, double blind 2 by 2 factorial designed study to assess the advantage of ceftriaxone (antibiotic) given with paracetamol and glycerol in combination, singly or with neither adjuvant therapy in childhood bacterial meningitis.
Detailed Description
Bacterial meningitis (BM) is a major cause of morbidity and death in the developing world. Hib and pneumococcal conjugate vaccines have the potential to prevent meningitis but neither vaccine is available in many countries with limited resources. New (and expensive) antimicrobials have done little to improve the prognosis. A background of HIV infection in many parts of the world adds to the grim prognosis of childhood BM. Adjuvant dexamethasone has gained much attention, because of its effects in damping the host's inflammatory response in childhood BM. However, little or no clinical benefit has been observed in several studies. Most importantly, the first sufficiently powered study in Malawi found no benefit at all. Another sufficiently powered (N=654) study on childhood BM, recently completed in Latin America, showed little benefit of dexamethasone even in Hib meningitis but did show benefit from adjuvant oral glycerol.
It is not known how glycerol works, and there is probably more than one mechanism. One-third of children with bacterial meningitis suffer from significantly reduced cerebral blood flow caused by intracranial oedema. Glycerol slightly increases serum osmolality, and this small change may improve rheology and enhance cerebral circulation, perhaps by increasing perfusion pressure. Thus, extravascularization of water and hidden hypovolemia is improved. Osmotic diuresis is of less importance, because urinary output does not increase with these doses (6 ml/kg/day) of glycerol. A gradient between the body compartments would require an intact or nearly intact blood brain barrier (BBB), and that is not the case in BM. Glycerol is also a scavenger of free oxygen radicals. This activity may alleviate the inflammation characteristic of BM.
Paracetamol is used widely as an antipyretic, analgesic, and anti inflammatory agent. It is effective, safe, inexpensive, and available as a syrup, tablet, suppository and injection; it suits all ages. The effect is dose-dependent. There are very few contraindications, eg allergy. The mechanisms are not well understood, but NSAIDs dampen inflammatory reactions other than those mediated by inhibition of arachidonic acid metabolism. There are differences between paracetamol and other NSAIDs: paracetamol inhibits the centrally located COX 3 and NMDA receptors, other NSAIDs inhibit COX 2 receptors in periphery. These mechanisms may partly explain the different results in patient outcome. In a retrospective analysis of 809 adult patients with bacteremia in Finland, those who received paracetamol had a better survival rate than those treated with other NSAIDs or salicylate.
A prospective clinical trial on childhood BM in which the value of glycerol is reviewed, and the potential of paracetamol is examined is warranted. Both adjuvants aim to improve the poor prognosis of this disease.
Objectives
A Prospective, Randomized, and Double-Blind Clinical Study Using a Two-by-Two Factorial Design to answer two questions:
Can the prognosis of childhood BM be improved by giving adjuvant oral glycerol?
Can the outcome be further improved by large doses of rectal paracetamol?
The primary end points are:
death,
severe neurological sequelae on discharge
post meningitis, severe, sensorineural hearing loss on hospital discharge.
Various patient characteristics are taken into account as covariates, eg severity of illness, age, aetiological agent, haemoglobin level, HIV status and presence of malaria co-infection.
The secondary end points are
1. audiological or neurological sequelae (according to the Denver-II developmental screening test).
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Bacterial Meningitis
Keywords
Bacterial meningitis, glycerol, high dose paracetamol, children
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 3
Interventional Study Model
Factorial Assignment
Masking
ParticipantCare ProviderInvestigatorOutcomes Assessor
Allocation
Randomized
Enrollment
466 (Actual)
8. Arms, Groups, and Interventions
Arm Title
A
Arm Type
Active Comparator
Arm Description
Two active ingredients
Arm Title
B
Arm Type
Active Comparator
Arm Description
One active ingredient
Arm Title
C
Arm Type
Active Comparator
Arm Description
One (other) active ingredient
Arm Title
D
Arm Type
Placebo Comparator
Intervention Type
Drug
Intervention Name(s)
Glycerol and paracetamol
Intervention Description
glycerol by mouth (po) 1.5ml/kg max 25 ml/dose x 6 hourly x 8 doses
paracetamol PR 35 mg/kg first dose, then 20 mg/kg 6 hourly x 7
Intervention Type
Drug
Intervention Name(s)
Paracetamol
Intervention Description
paracetamol 35 mg/kg first dose, then 20 mg/kg 6 hourly x 7 doses
Intervention Type
Drug
Intervention Name(s)
Paracetamol
Intervention Description
paracetamol po 35 mg/kg first dose, then 20 mg/kg 6 hourly x 7 doses plus placebo suppository
Intervention Type
Drug
Intervention Name(s)
Paracetamol
Intervention Description
po 35 mg/kg first dose, then 20 mg/kg 6 hourly x 7 doses plus placebo suppository
Intervention Type
Drug
Intervention Name(s)
Placebo
Intervention Description
2 placebos, one po, one suppository
Intervention Type
Drug
Intervention Name(s)
Paracetamol and glycerol
Intervention Description
35 mg/kg po first dose, then 20 mg/kg 6 hourly x 7 paracetamol
1.5 ml/kg max 25 ml/dose 6 hourly x 8 doses
Intervention Type
Drug
Intervention Name(s)
Glycerol
Intervention Description
glycerol 1.5 ml/kg /dose 6 hourly x 8 max dose = 25ml
Primary Outcome Measure Information:
Title
Primary end points are death, severe neurological sequelae, hearing loss.
Time Frame
2008-2011
Secondary Outcome Measure Information:
Title
Secondary end points are audiological or neurological sequelae (according to the Denver-II developmental screening test).
Time Frame
2008-2011
10. Eligibility
Sex
All
Minimum Age & Unit of Time
2 Months
Maximum Age & Unit of Time
15 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria:
All children aged ≥ 2 months, admitted to Queen Elizabeth Hospital, Blantyre, Malawi, with possible or confirmed acute bacterial meningitis
Exclusion Criteria:
Age less than two months
Trauma
Relevant underlying illness such as intracranial shunt, previous neurological disease (cerebral palsy, Down's syndrome)
Previous permanent hearing loss (not conductive hearing loss) if known
Immunosuppression except HIV infection.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Elizabeth M Molyneux, FRCPCH
Organizational Affiliation
College of Medicine, Blantyre, Malawi
Official's Role
Principal Investigator
Facility Information:
Facility Name
College of Medicine, Queen Elizabeth Central Hospital
City
Blantyre
ZIP/Postal Code
3
Country
Malawi
12. IPD Sharing Statement
Learn more about this trial
Oral Glycerol and High-Dose Rectal Paracetamol to Improve the Prognosis of Childhood Bacterial Meningitis
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