Comparison of 5 versus 10 days of ceftriaxone therapy for bacterial meningitis in children: multicentre study in Bangladesh, Malawi, Pakistan, South Africa, Vietnam and Egypt

ISRCTN ISRCTN38717320
DOI https://doi.org/10.1186/ISRCTN38717320
Secondary identifying numbers WHO/CAH ID 98011
Submission date
27/07/2004
Registration date
28/07/2004
Last edited
25/08/2011
Recruitment status
No longer recruiting
Overall study status
Completed
Condition category
Nervous System Diseases
Prospectively registered
Protocol
Statistical analysis plan
Results
Individual participant data

Plain English summary of protocol

Not provided at time of registration

Contact information

Dr Shamim Qazi
Scientific

20, Avenue Appia
Geneva -27
CH 1211
Switzerland

Email qazis@who.int

Study information

Study designRandomised controlled trial
Primary study designInterventional
Secondary study designRandomised controlled trial
Study setting(s)Not specified
Study typeTreatment
Scientific title
Study objectivesPrimary objective:
To determine if the bacteriologic failure* between 6 - 40 days is equivalent (after randomising the day 5 survivors) between 10 days versus 5 days of ceftriaxone therapy for treatment of acute bacterial meningitis in children aged 2 months up to 12 years.

Secondary objectives:
1. In children who receive 5 versus 10 days of ceftriaxone therapy for acute bacterial meningitis following rates will be compared by day 40 (after admission):
1.1. Mortality rates by day 40
1.2. Hearing loss on day 40
1.3. Blindness on day 40
1.4. Neurologic, motor deficits by day 40
1.5. Treatment failure
1.6. Bacterial pathogens
2. In children who receive 5 versus 10 days of ceftriaxone therapy for acute bacterial meningitis we will compare the rates of the following at 190 + 30 days after admission:
2.1. Mortality rates
2.2. Hearing loss
2.3. Blindness
2.4. Neurologic, motor and developmental deficits

*Bacteriologic failure will be reappearance of bacteria in CSF between 6-40 days

Please note that after discussions with the Data Safety Monitoring Board (DSMB), the following was decided:
1. In the DSMB meeting in 2002, in order to improve enrolment, the age of enrolment was increased to 144 months. Therefore, the upper limit of weight was also increased from 18.5 kg (see changes made to inclusion criteria)
2. In the DSMB meeting in 2006, due to the challenge in enrolling 1500 children (the original target number of participants, the DSMB decided to stop enrolment after reviewing the interim analysis data. They felt that continuing the trial to achieve the sample size to that originally planned is unlikely to alter in an important way the findings, or the recommendations based on those findings.
Ethics approval(s)Ethics approval received from the Institutional Review Board (IRB) of:
1. Dhaka Shishu Hospital, Institute of Child Health, Dhaka, Bangladesh
2. Abbasiyya Fever Hospital, Cairo, Egypt
3. College of Medicine, Blantyre, Malawi
4. Pakistan Institute of Medical Sciences, Islamabad, Pakistan
5. Aga Khan University, Karachi, Pakistan
6. Children Hospital No 1, Ho Chi Minh City, Vietnam
7. University of Natal, Durban
8. World Health Organization (WHO) Ethical Review Committee
Health condition(s) or problem(s) studiedBacterial meningitis
InterventionAll children to receive ceftriaxone once daily for 1 - 5 days.
From 6 - 10 days children will be randomised to receive the same dose of ceftriaxone or placebo.
Intervention typeDrug
Pharmaceutical study type(s)
PhaseNot Specified
Drug / device / biological / vaccine name(s)Ceftriaxone
Primary outcome measureRate of bacteriologic failure defined as:
1. Cerebrospinal Fluid (CSF) or blood culture positive* on day 6 to 40 for original organism, or
2. CSF or blood culture positive on days 6 to 40 in a patient who had culture negative bacterial meningitis

Note: Repeat lumber puncture will be done between 48-72 hours of admission. A repeat blood cultures will only be done if condition of the patient requires it.

*for H. influenzae, S. pneumoniae, N. meningitidis
Secondary outcome measures1. Perceived treatment failure
2. Hearing loss: Day 40 screen Otoacoustic Emissions (OAE), Auditory Brainstem Response (ABR) greater than 40 db
3. Blindness diagnosed at day 40
4. Motor deficit at day 40 including:
4.1. Two or more abnormalities of tone or strength in any of the limbs or neck, or
4.2. Any palsy of VI or VII cranial nerves
5. Developmental score: abnormal developmental screening on day 190 + 30 days as evaluated by Denver Screening method
6. Seizures: any seizure without fever presenting on days 10 to 40 or 41 to 190 + 30 days
7. Hydrocephalus: defined as any patient with ventriculo-peritoneal shunting or clinical signs and head circumference measurements consistent with hydrocephalous and the perceived need of ventricular derivation
8. Death of an enrolled patient by any cause between days 6 - 40
9. Death of an enrolled patient by any cause between 41 - 190 days
10. Bacterial pathogen
Overall study start date01/09/2002
Completion date14/06/2006

Eligibility

Participant type(s)Patient
Age groupChild
Lower age limit2 Months
Upper age limit71 Months
SexBoth
Target number of participants1500 (787 recruited as of end of trial)
Key inclusion criteria1. Aged 2 - 71 months (as of 11/10/07 the upper age limit was increased to 144 months)
2. Weight 3.0 kg - 18.5 kg (as of 11/10/07 the upper weight limit was increased)
3. Children of acute bacterial meningitis with positive Cerebrospinal Fluid (CSF) culture or latex for H. influenzae, St. pneumoniae, N. meningitidis
4. If CSF culture negative, then CSF White Blood Cell count (WBC) greater than 10/ml and blood culture positive by day 3
5. Treatment with injectable ceftriaxone since admission
6. Informed consent from parent/guardian
Key exclusion criteria1. Neurological conditions
2. Known cerebral palsy, immunodeficiency or chronic afebrile seizure disorder
3. Progressive brain degenerative disorder
4. Cranial fracture with or without CSF leak
5. Known cyanotic heart disorder
6. Known deafness prior to admission
7. Evidence of measles, mumps or chicken pox present
8. Child randomised to the study before
9. Illness more than 7 days
10. Allergic to cephalosporins
11. Lives outside follow-up area of study
Date of first enrolment01/09/2002
Date of final enrolment14/06/2006

Locations

Countries of recruitment

  • Bangladesh
  • Egypt
  • Malawi
  • Pakistan
  • South Africa
  • Switzerland
  • Viet Nam

Study participating centre

20, Avenue Appia
Geneva -27
CH 1211
Switzerland

Sponsor information

The Department of Child and Adolescent Health (CAH)/World Health Organization (WHO) (Switzerland)
Research organisation

20, Avenue Appia
Geneva -27
CH 1211
Switzerland

Website http://www.who.int
ROR logo "ROR" https://ror.org/01f80g185

Funders

Funder type

Research organisation

The Department of Child and Adolescent Health (CAH)/World Health Organization (WHO) (Switzerland)

No information available

Results and Publications

Intention to publish date
Individual participant data (IPD) Intention to shareNo
IPD sharing plan summaryNot provided at time of registration
Publication and dissemination planNot provided at time of registration
IPD sharing plan

Study outputs

Output type Details Date created Date added Peer reviewed? Patient-facing?
Results article results 28/05/2011 Yes No