Amoxicillin Versus Benzyl Penicillin for Treatment of Children Hospitalised With Severe Pneumonia

Amoxicillin Versus Benzyl Penicillin for Severe Childhood Pneumonia Amongst Inpatients: An Open Label Randomised Controlled Non-inferiority Trial

This study seeks to determine whether clinical outcome following initial treatment of severe pneumonia with oral amoxicillin is as effective as the current standard benzyl penicillin. The study will also provide an estimate of the proportion of Kenyan children with severe pneumonia who fail treatment with a single antibiotic.

Study Overview

• Status: Completed
• Conditions: Pneumonia
• Intervention / Treatment: Drug: Amoxicillin; Drug: Benzyl penicillin

Detailed Description

Case management for the treatment of childhood acute respiratory infections has been widely promoted in many developing countries for over 20 years. Despite this, pneumonia continues to claim over 1.5 million lives of children under five annually. The use of affordable, easily-administered, safe, effective treatments can potentially reduce the burden of childhood pneumonia. The WHO recommends the use of a single antibiotic for the treatment of severe pneumonia. Whereas in Asia, evidence from large randomized clinical trials has changed policy recommendations for treatment of severe pneumonia from parenteral penicillin to oral amoxicillin, there is little evidence to inform a similar move in African children where pneumonia is associated with poorer outcomes. In this study the investigators will investigate effectiveness of oral amoxicillin versus the current standard treatment, benzyl penicillin in severe childhood pneumonia using a randomized controlled non-inferiority design preceded by a pilot pre-intervention phase. The investigators will also collect observational data HIV-exposed / infected children with severe pneumonia. 594 children aged 2 - 59 months admitted with clinical signs of severe pneumonia to up to 7 hospitals in Kenya will be randomly assigned to receive either oral amoxicillin or injectable benzyl penicillin. They will then be followed up for the primary outcome of pre-defined treatment failure at 48 hours. The results of this trial will provide valuable data on the effectiveness of oral amoxicillin in the treatment of severe pneumonia in a population of Kenyan children and determine the practicability of conducting large pragmatic trials on pneumonia in Africa similar to those done in Asia.

• Study Type: Interventional
• Enrollment (Actual): 561
• Phase: Phase 3

Contacts and Locations

Study Locations

• Kenya
  • Nairobi, Kenya
    • Mbagathi District Hospital
  • Central
    • Kerugoya, Central, Kenya
      • Kerugoya District Hospital
  • Eastern
    • Embu, Eastern, Kenya
      • Embu Provincial General Hospital
  • Nyanza
    • Kisumu, Nyanza, Kenya
      • Kisumu East District Hospital
    • Kisumu, Nyanza, Kenya
      • New Nyanza Provincial General Hospital
  • Western
    • Bungoma, Western, Kenya
      • Bungoma District Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 2 months to 4 years (Child)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Clinical signs of WHO-defined severe pneumonia
• Age 2 months to 59 months

Exclusion Criteria:

• Clinical signs of WHO-defined very severe pneumonia
• Clinical or laboratory diagnosis of meningitis
• Clinical diagnosis of severe malnutrition (marasmus/kwashiorkor)
• Clinical or laboratory diagnosis of severe anaemia requiring transfusion
• HIV-exposure on rapid HIV antibody test (only observational data will be collected from these patients)
• Elimination of signs of severe pneumonia in a child with wheeze after outpatient bronchodilator therapy
• Chronic condition that may underlie or contribute to a presentation with respiratory distress such as: known chronic renal or cardiac disease, presence of cerebral palsy predisposing child to aspiration/hypostatic pneumonia
• Established bronchiectasis or congenital abnormality of the lower respiratory tract
• Upper airway obstruction producing stridor
• Admission from outpatient clinic specifically for treatment of TB
• Referral from another inpatient facility following treatment with injectable antibiotics for more than 24 hours or because the initial regimen is considered to have failed
• Documented history of >48hours treatment with oral amoxicillin
• Failure to obtain informed consent
• Penicillin allergy

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Amoxicillin 45mg/kg 12 hourly	Drug: Amoxicillin; Oral 45mg/kg 12 hourly
Active Comparator: Benzyl Penicillin 50,000IU/kg 6 hourly	Drug: Benzyl penicillin; Intravenous 50,000IU/kg 6 hourly

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Treatment Failure at 48 Hours (Two Full Days After Enrollment)	Development of any signs of very severe pneumonia at any time Hypoxemia defined as SpO2 <85% or <80% for altitude < or ≥1500m respectively measured after minimum of 3 minutes on ambient air Persistent vomiting (occurring within 30 minutes of administration of amoxicillin with failure to retain drug after 3 successive attempts at administration) at any time Clinical diagnosis of new bacterial co-morbid condition requiring revision of antibiotic treatment at any time Lower chest wall indrawing Temperature ≥38◦C Respiratory rate ≥5bpm of admission rate if above age-adjusted normal upper limit	48 hours

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Treatment Failure at or Before Discharge / Day 5 Post Enrollment (Whichever Occurs First)	Treatment failure as defined in the primary outcome measure.	Patients will be followed up from the day of hospitalisation (day 0) until the day of medical discharge (average duration of 3 days) or until day 5 of hospitalisation (whichever occurs first).
Readmission With Diagnosis of Severe or Very Severe Pneumonia Within 14 Days of Enrollment		Day 0 to Day 14
Death at or Before Five Days Following Enrollment	Death defined as: in-hospital death occurring at any time after randomisation (recruitment for HIV-exposed participants) or verbal report of death of the enrolled patient from parent/guardian communicated either directly or via telephone conversation.	Day 0 to Day 5
Outcome (Death/Readmission) at 14 Days as Determined by Telephone or Direct Interview	Definition of death as described in third secondary outcome measure.	Day 14

Collaborators and Investigators

• Sponsor: KEMRI-Wellcome Trust Collaborative Research Program
• Collaborators: London School of Hygiene and Tropical Medicine; University of Oxford; University of Nairobi
• Investigators: Principal Investigator: Ambrose Agweyu, MSc, Kemri- Wellcome Trust Research Programme, Nairobi, Kenya; Principal Investigator: Elizabeth Obimbo, MMed, Department of Paediatrics and Child Health, University of Nairobi, Nairobi, Kenya; Principal Investigator: Roma Chilengi, MD, Centre for Infectious Disease Research, Zambia; Principal Investigator: Tansy Edwards, MSc, London School of Hygiene and Tropical Medicine; Principal Investigator: Mike English, MD, Kemri - Wellcome Trust Research Programme, Nairobi, Kenya

Publications and helpful links

General Publications

• Agweyu A, Gathara D, Oliwa J, Muinga N, Edwards T, Allen E, Maleche-Obimbo E, English M; Severe Pneumonia Study Group. Oral amoxicillin versus benzyl penicillin for severe pneumonia among kenyan children: a pragmatic randomized controlled noninferiority trial. Clin Infect Dis. 2015 Apr 15;60(8):1216-24. doi: 10.1093/cid/ciu1166. Epub 2014 Dec 30.

Study record dates

Study Major Dates

• Study Start: September 1, 2011
• Primary Completion (Actual): September 1, 2013
• Study Completion (Actual): September 1, 2013

Study Registration Dates

• First Submitted: July 12, 2011
• First Submitted That Met QC Criteria: July 21, 2011
• First Posted (Estimate): July 22, 2011

Study Record Updates

• Last Update Posted (Estimate): February 13, 2015
• Last Update Submitted That Met QC Criteria: January 28, 2015
• Last Verified: January 1, 2015

More Information

Terms related to this study

• Keywords: Severe pneumonia
• Additional Relevant MeSH Terms: Infections; Respiratory Tract Infections; Respiratory Tract Diseases; Lung Diseases; Pneumonia; Anti-Infective Agents; Anti-Bacterial Agents; Amoxicillin; Penicillins; Penicillin G Benzathine; Penicillin G; Penicillin G Procaine
• Other Study ID Numbers: KEMRI_CT_2010/0014; SSC 1911