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	https://doi.org/10.1186/ISRCTN39543942
Protocol serial number	WHO/CAH ID 98022
Sponsor	The Department of Child and Adolescent Health (CAH)/World Health Organization (WHO) (Switzerland)
Funder	The Department of Child and Adolescent Health (CAH)/World Health Organization (WHO) (Switzerland)

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: Respiratory

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

Primary study design	Interventional
Study design	Randomised controlled trial
Secondary study design	Randomised controlled trial
Scientific title
Study objectives	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.
Ethics approval(s)	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
Health condition(s) or problem(s) studied	Severe pneumonia
Intervention	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
Intervention type	Drug
Phase	Not Specified
Drug / device / biological / vaccine name(s)	Chloramphenicol, ampicillin, gentamicin
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
Key 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
Completion date	01/06/2002

Eligibility

Participant type(s)	Patient
Age group	Child
Lower age limit	5 Months
Upper age limit	59 Months
Sex	All
Target sample size at registration	1182
Key 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
Key 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
Date of first enrolment	01/10/2000
Date of final enrolment	01/06/2002

Locations

Countries of recruitment

Bangladesh
Ecuador
India
Mexico
Pakistan
Switzerland
Viet Nam
Yemen
Zambia

Study participating centre

20, Avenue Appia

Geneva -27
CH 1211
Switzerland

Results and Publications

Individual participant data (IPD) Intention to share	No
IPD sharing plan summary	Not provided at time of registration
IPD sharing plan

Study outputs

Output type	Details	Date created	Date added	Peer reviewed?	Patient-facing?
Results article	results	12/01/2008		Yes	No