Contact information
Type
Scientific
Primary contact
Dr Shamim Qazi
ORCID ID
Contact details
20
Avenue Appia
Geneva -27
CH 1211
Switzerland
qazis@who.int
Additional identifiers
EudraCT number
ClinicalTrials.gov number
Protocol/serial number
WHO/CAH ID 98011
Study information
Scientific title
Acronym
Study hypothesis
Primary 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
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
Study design
Randomised controlled trial
Primary study design
Interventional
Secondary study design
Randomised controlled trial
Trial setting
Not specified
Trial type
Treatment
Patient information sheet
Condition
Bacterial meningitis
Intervention
All 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 type
Drug
Phase
Not Specified
Drug names
Ceftriaxone
Primary outcome measure
Rate 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 measures
1. 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 trial start date
01/09/2002
Overall trial end date
14/06/2006
Reason abandoned (if study stopped)
Eligibility
Participant inclusion criteria
1. 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
Participant type
Patient
Age group
Child
Gender
Both
Target number of participants
1500 (787 recruited as of end of trial)
Participant exclusion criteria
1. 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
Recruitment start date
01/09/2002
Recruitment end date
14/06/2006
Locations
Countries of recruitment
Bangladesh, Egypt, Malawi, Pakistan, South Africa, Viet Nam
Trial participating centre
20, Avenue Appia
Geneva -27
CH 1211
Switzerland
Sponsor information
Organisation
The Department of Child and Adolescent Health (CAH)/World Health Organization (WHO) (Switzerland)
Sponsor details
20
Avenue Appia
Geneva -27
CH 1211
Switzerland
Sponsor type
Research organisation
Website
Funders
Funder type
Research organisation
Funder name
The Department of Child and Adolescent Health (CAH)/World Health Organization (WHO) (Switzerland)
Alternative name(s)
Funding Body Type
Funding Body Subtype
Location
Results and Publications
Publication and dissemination plan
Not provided at time of registration
Intention to publish date
Participant level data
Not provided at time of registration
Basic results (scientific)
Publication list
1. 2011 results in http://www.ncbi.nlm.nih.gov/pubmed/21620467
Publication citations
-
Results
Molyneux E, Nizami SQ, Saha S, Huu KT, Azam M, Bhutta ZA, Zaki R, Weber MW, Qazi SA, , 5 versus 10 days of treatment with ceftriaxone for bacterial meningitis in children: a double-blind randomised equivalence study., Lancet, 2011, 377, 9780, 1837-1845, doi: 10.1016/S0140-6736(11)60580-1.