Bacterial MeningitisPhase 3GLYIPNCT00619203
Oral Glycerol and High-Dose Rectal Paracetamol to Improve the Prognosis of Childhood Bacterial Meningitis
A Phase 3 study testing Glycerol and paracetamol, Paracetamol and Paracetamol and glycerol in people with Bacterial Meningitis, run by Kamuzu University of Health Sciences at 1 site in Malawi.
Trial 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. Read more about this study
- Who is it for?
- Ages 2 months to 15 years
- Conditions the study is for
- Bacterial Meningitis
- What is being tested?
- Glycerol and paracetamol, Paracetamol and Paracetamol and glycerol
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 466 participants
- Where
- 1 siteMalawi
- Study dates
- Mar 2008to Mar 2012
- 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 2 months to 15 years
- All sexes
- No healthy volunteers
- Child
Who may be able to join
- All children aged ≥ 2 months, admitted to Queen Elizabeth Hospital, Blantyre, Malawi, with possible or confirmed acute bacterial meningitis
Who cannot join
- 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.
Trial locations and contacts
1 site in 1 country.
About this study
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
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.
Read more
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.
Read the 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
- audiological or neurological sequelae (according to the Denver-II developmental screening test).
- Conditions
- Bacterial Meningitis
- Being tested
- Glycerol and paracetamol, Paracetamol, Placebo, Paracetamol and glycerol, Glycerol
- Keywords
- Bacterial meningitis, glycerol, high dose paracetamol, children
- Medical subject headings
- Meningitis, Bacterial
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Glycerol and paracetamolDrug
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
ParacetamolDrug
paracetamol 35 mg/kg first dose, then 20 mg/kg 6 hourly x 7 doses
ParacetamolDrug
paracetamol po 35 mg/kg first dose, then 20 mg/kg 6 hourly x 7 doses plus placebo suppository
ParacetamolDrug
po 35 mg/kg first dose, then 20 mg/kg 6 hourly x 7 doses plus placebo suppository
PlaceboDrug
2 placebos, one po, one suppository
Paracetamol and glycerolDrug
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
GlycerolDrug
glycerol 1.5 ml/kg /dose 6 hourly x 8 max dose = 25ml
| Study group | Role | What they receive |
|---|---|---|
| A | Active comparator | Two active ingredients Receives: Drug: Glycerol and paracetamol; Drug: Paracetamol and glycerol |
| B | Active comparator | One active ingredient Receives: Drug: Paracetamol; Drug: Glycerol |
| C | Active comparator | One (other) active ingredient Receives: Drug: Paracetamol |
| D | Placebo comparator | Not described Receives: Drug: Placebo |
What is being measured
The primary outcome is the main question the study is designed to answer.
Primary end points are death, severe neurological sequelae, hearing loss.
Measured: 2008-2011
Secondary outcomes (1)
Secondary end points are audiological or neurological sequelae (according to the Denver-II developmental screening test).
Measured: 2008-2011
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted20 Feb 2008 (estimated)
- Study startMar 2008
- Primary completionMar 2012
- Study completionMar 2012
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Bacterial MeningitisStudies 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
- Treatment
- Allocation
- Randomised
- Intervention model
- Factorial
- Masking
- Quadruple blind
- Who is masked
- Participant, Care provider, Investigator, Outcomes assessor
- Enrolment
- 466 participants (actual)
Sponsor and investigators
- Lead sponsor
- Kamuzu University of Health Sciences
- Sponsor type
- University, hospital or other
- Responsible party
- Principal investigator, Elizabeth Molyneux, Kamuzu University of Health Sciences
- Investigators
- Elizabeth M Molyneux, FRCPCH, Principal investigator, College of Medicine, Blantyre, Malawi
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT00619203
- Sponsor's protocol ID
- P.03/07/499
- Acronym
- GLYIP
- Status last verified
- Jul 2012
- First submitted
- 7 Feb 2008
- Last updated
- 10 Jul 2012
- Results posted
- No
- Data monitoring committee
- No
Study at a glance
From the registry record, last updated by the sponsor on 10 Jul 2012. Recruitment status is as the sponsor reported it: confirm with the study team.
- 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
- ClinicalTrials.gov ID
- NCT00619203
- Acronym / sponsor ID
- GLYIP / P.03/07/499
- Conditions
- Bacterial Meningitis
- Keywords
- Bacterial meningitis, glycerol, high dose paracetamol, children
- Phase
- Phase 3
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 466 participants (actual)
- Lead sponsor
- Kamuzu University of Health SciencesUniversity, hospital or other
- Study start
- Mar 2008
- Primary completion
- Mar 2012 (actual)
- Study completion
- Mar 2012 (actual)
- First posted
- 20 Feb 2008 (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.
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
- audiological or neurological sequelae (according to the Denver-II developmental screening test).
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Factorial
- Masking
- Quadruple blind (participant, care provider, investigator, outcomes assessor)
- Number of arms
- 4
| Arm | Type | Receives |
|---|---|---|
| A | Active comparator | Drug: Glycerol and paracetamol, Drug: Paracetamol and glycerolTwo active ingredients |
| B | Active comparator | Drug: Paracetamol, Drug: GlycerolOne active ingredient |
| C | Active comparator | Drug: ParacetamolOne (other) active ingredient |
| D | Placebo comparator | Drug: Placebo |
Who may qualify
- Ages
- 2 months to 15 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Child
Key inclusion criteria (1 listed)
- All children aged ≥ 2 months, admitted to Queen Elizabeth Hospital, Blantyre, Malawi, with possible or confirmed acute bacterial meningitis
Key exclusion criteria (5 listed)
- 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.
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 |
|---|---|---|
| Glycerol and paracetamolglycerol 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 | Drug | A |
| Paracetamolparacetamol 35 mg/kg first dose, then 20 mg/kg 6 hourly x 7 doses | Drug | B |
| Paracetamolparacetamol po 35 mg/kg first dose, then 20 mg/kg 6 hourly x 7 doses plus placebo suppository | Drug | C |
| Paracetamolpo 35 mg/kg first dose, then 20 mg/kg 6 hourly x 7 doses plus placebo suppository | Drug | C |
| Placebo2 placebos, one po, one suppository | Drug | D |
| Paracetamol and glycerol35 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 | Drug | A |
| Glycerolglycerol 1.5 ml/kg /dose 6 hourly x 8 max dose = 25ml | Drug | B |
Primary outcome
Primary end points are death, severe neurological sequelae, hearing loss.
Time frame: 2008-2011
1 secondary outcome
Secondary end points are audiological or neurological sequelae (according to the Denver-II developmental screening test).
Time frame: 2008-2011
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 10 Jul 2012.
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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.
Elizabeth M Molyneux, FRCPCH principal investigator
College of Medicine, Blantyre, Malawi
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 3 study testing Glycerol and paracetamol, Paracetamol and Paracetamol and glycerol in people with Bacterial Meningitis, run by Kamuzu University of Health Sciences at 1 site in Malawi.
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 1 inclusion and 5 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: finished, as of the sponsor's last update on 10 Jul 2012. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in Malawi. 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?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Primary end points are death, severe neurological sequelae, hearing loss. (time frame: 2008-2011). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
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 10 Jul 2012.