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Multicentre randomised clinical study to compare the efficacy of chloramphenicol with that of ampicillin plus gentamicin in children aged 2 to 59 months with very severe pneumonia: multicentre study conducted in Bangladesh, India, Mexico, Pakistan, Yemen, Vietnam, and Zambia
ISRCTN ISRCTN39543942
DOI 10.1186/ISRCTN39543942
ClinicalTrials.gov identifier
EudraCT number
Public title Multicentre randomised clinical study to compare the efficacy of chloramphenicol with that of ampicillin plus gentamicin in children aged 2 to 59 months with very severe pneumonia: multicentre study conducted in Bangladesh, India, Mexico, Pakistan, Yemen, Vietnam, and Zambia
Scientific title
Acronym N/A
Serial number at source WHO/CAH ID 98022
Study hypothesis Primary objective:
To evaluate whether injectable ampicillin plus gentamicin reduces treatment failure in children, aged 2 - 59 months, with very severe pneumonia by 30% or more compared to chloramphenicol after completing 5 days of therapy. The specific null hypothesis to be tested is that treatment failure will be equal in children aged 2 - 59 months with very severe pneumonia whether treated with injectable chloramphenicol or injectable ampicillin plus gentamicin.

Secondary objectives:
1. To determine the proportion of treatment failures by 48 hours after randomisation
2. To determine the proportion of children with treatment failure at 11 days after randomisation
3. To determine the proportion of children with treatment failure at 21 - 30 days after randomisation
4. To report the proportion of children who died up to Day 30 after randomisation
5. To determine bacterial pathogens in the etiology of very severe pneumonia
6. To determine the antimicrobial susceptibility of bacterial pathogens causing very severe pneumonia
7. To determine predictors of treatment failure in children with very severe pneumonia

Please note that the following changes have been made to this record: the site at Zambia only enrolled patients form April 2001 to November 2001 and then the enrolment was stopped there. The DSMB ended accrual at the Zambia site after 23 enrolments (2.4% of total) in November 2001 because of a high mortality rate - likely due to Human Immunodeficiency Virus (HIV)/Acquired Immune Deficiency Syndrome (AIDS). A new site at in Ecuador was added in March 2003 that started enrolling patients in April 2003.
Lay summary Not provided at time of registration
Ethics approval Ethics approval was received from the following Institutional Review Boards (IRBs):
1. Dhaka Shishu Hospital, Institute of Child Health, Dhaka, Bangladesh
2. Dr. Francisco de Icaza Bustamente Children's Hospital, Guayaquil, Ecuador
3. Post Graduate Institute of Medical Research and Education, Chandigarh, India
4. National Institute of Pediatrics, Mexico City, Mexico
5. Rawalpindi General Hospital, Rawalpindi, Pakistan
6. Nishter Medical College Hospital, Multan, Pakistan
7. Al-Sabeen Hospital, Sana'a University, Sana'a, Yemen
8. Children Hospital No 1, Ho Chi Minh City, Vietnam
9. University Teaching Hospital, Lusaka, Zambia
10. Boston University
11. World Health Organization (WHO) Ethical Review Committee
Study design Randomised controlled trial
Countries of recruitment Bangladesh, Ecuador, India, Mexico, Pakistan, Viet Nam, Yemen, Zambia
Disease/condition/study domain Severe pneumonia
Participants - inclusion criteria 1. Age 5 - 59 months
2. History of cough or difficult breathing
3. Central cyanosis or inability to drink
4. Caretaker is willing to sign informed consent form
Participants - exclusion criteria 1. Current illness greater than 10 days old
2. Past history of more than two wheezing episodes or diagnosed asthma
3. Known cardiac patient
4. Known Human Immunodeficiency Virus (HIV) infected
5. Known family member to be HIV infected
6. More than 24 hours hospitalisation within the last 7 days
7. History of severe adverse reaction to study drugs
8. Prior enrolment in the study
9. Injection of antibiotic more than 24 hours prior to enrolment
10. Stridor
11. Known renal failure or not passed urine in last 24 hours
12. Cerebral malaria
13. Bacterial meningitis
14. Clinical jaundice
15. Oral thrush
16. Hepatosplenomegaly
17. Follow-up to home not possible
Anticipated start date 01/10/2000
Anticipated end date 01/06/2002
Status of trial Completed
Patient information material
Target number of participants 1,182 patients (591 in each group)
Interventions For the primary end-point, a total of two looks at the data would require 1,182 patients (591 in each group) to be studied. This sample size assumes a study power of 80% to look for differences between the groups, and maintains an overall two-sided alpha level of 0.05 and includes adjustment for 2% loss to follow-up.

Patients will be radomised to:
Group 1: 5 days of injectable chloramphenicol in hospital followed by 5 days of oral chloramphenicol at home
Group 2: 5 days of injectable ampicillin and gentamicin in hospital followed by 5 days of oral ampicillin and gentamicin at home
Primary outcome measure(s) The primary outcome variable is "treatment failure at day 6" defined as follows:
1. If at any time after randomisation the following occur:
1.1. Death
1.2. Development of bacterial meningitis, empyema, septic shock or renal failure
1.3. Serious adverse events leading to change of therapy or any modification of antibiotic therapy before day 6 (modification of the dosage of the antibiotic will not be considered as a "treatment failure")
1.4. Left Against Medical Advice (LAMA), or withdrawal of consent (reason of including this in treatment failure is because parents may LAMA or withdraw the consent thinking their child is not improving on the study treatment), or loss to follow-up

OR

2. Development of any of the two signs at 48 hours after randomisation:
2.1. Worsening of tachypnoea (defined as 20 breaths above baseline), or
2.2. Development/persistence of abnormal sleepiness or difficulty in awakening, or
2.3. Development/persistence of inability to drink

OR

3. Development of two or more of the following at Day 6 after randomisation:
3.1. Worsening of tachypnoea (defined as 20 breaths above baseline, or
3.2. Development/persistence of abnormal sleepiness or difficulty in awakening, or
3.3. Development/persistence of inability to drink
Secondary outcome measure(s) 1. Treatment failures, as defined above, 48 hours after randomisation
2. Treatment failures, as defined above, 11 days after randomisation
3. Treatment failures, as defined above, 21 - 30 days after randomisation (if a patient develops signs given for treatment failure within two weeks after stopping treatment it will be considered a relapse)
4. Deaths by 21 30 days after randomisation
5. Bacterial pathogens isolated in blood cultures from children with very severe pneumonia
6. Antimicrobial susceptibility in blood culture isolates from children with very severe pneumonia
Sources of funding The Department of Child and Adolescent Health (CAH)/World Health Organization (WHO) (Switzerland)
Trial website
Publications 2008 results in http://www.ncbi.nlm.nih.gov/pubmed/18182412
Contact name Dr  Shamim  Qazi
  Address 20, Avenue Appia
  City/town Geneva -27
  Zip/Postcode CH 1211
  Country Switzerland
  Email qazis@who.int
Sponsor The Department of Child and Adolescent Health (CAH)/World Health Organization (WHO) (Switzerland)
  Address 20, Avenue Appia
  City/town Geneva -27
  Zip/Postcode CH 1211
  Country Switzerland
  Sponsor website: http://www.who.int
Date applied 27/07/2004
Last edited 25/08/2011
Date ISRCTN assigned 28/07/2004
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