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

• Sponsor: KEMRI-Wellcome Trust Collaborative Research Program (Other)
• Overall Status: Completed
• CT.gov ID: NCT01399723
• Collaborator: University of Oxford (Other), London School of Hygiene and Tropical Medicine (Other), University of Nairobi (Other)
• Enrollment: 561
• Locations: 6
• Arms: 2
• Duration (Months): 24
• Patients Per Site: 93.5
• Patients Per Site Per Month: 3.9

Study Details

Study Description

Brief Summary

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.

Condition or Disease	Intervention/Treatment	Phase
Pneumonia	Drug: Amoxicillin; Drug: Benzyl penicillin	Phase 3

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 Design

• Study Type: Interventional
• Actual Enrollment: 561 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Amoxicillin Versus Benzyl Penicillin for Severe Childhood Pneumonia Amongst Inpatients: An Open Label Randomised Controlled Non-inferiority Trial
• Study Start Date: Sep 1, 2011
• Actual Primary Completion Date: Sep 1, 2013
• Actual Study Completion Date: Sep 1, 2013

Arms and Interventions

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

Outcome Measures

Primary Outcome Measures

1. Treatment Failure at 48 Hours (Two Full Days After Enrollment) [48 hours]

   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

Secondary Outcome Measures

1. Treatment Failure at or Before Discharge / Day 5 Post Enrollment (Whichever Occurs First) [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).]

   Treatment failure as defined in the primary outcome measure.

2. Readmission With Diagnosis of Severe or Very Severe Pneumonia Within 14 Days of Enrollment [Day 0 to Day 14]

3. Death at or Before Five Days Following Enrollment [Day 0 to Day 5]

   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.

4. Outcome (Death/Readmission) at 14 Days as Determined by Telephone or Direct Interview [Day 14]

   Definition of death as described in third secondary outcome measure.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 2 Months to 59 Months
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Kerugoya District Hospital	Kerugoya	Central	Kenya
2	Embu Provincial General Hospital	Embu	Eastern	Kenya
3	Kisumu East District Hospital	Kisumu	Nyanza	Kenya
4	New Nyanza Provincial General Hospital	Kisumu	Nyanza	Kenya
5	Bungoma District Hospital	Bungoma	Western	Kenya
6	Mbagathi District Hospital	Nairobi		Kenya

Sponsors and Collaborators

• KEMRI-Wellcome Trust Collaborative Research Program
• University of Oxford
• London School of Hygiene and Tropical Medicine
• 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

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: KEMRI-Wellcome Trust Collaborative Research Program
• ClinicalTrials.gov Identifier: NCT01399723
• Other Study ID Numbers: KEMRI_CT_2010/0014; SSC 1911
• First Posted: Jul 22, 2011
• Last Update Posted: Feb 13, 2015
• Last Verified: Jan 1, 2015

• Keywords provided by KEMRI-Wellcome Trust Collaborative Research Program: Severe pneumonia
• Additional relevant MeSH terms: Pneumonia; Amoxicillin; Penicillins; Penicillin G; Penicillin G Benzathine; Penicillin G Procaine

Study Results

Participant Flow

Arm/Group Title	Amoxicillin 45mg/kg 12 Hourly	Benzyl Penicillin 50,000IU/kg 6 Hourly
Arm/Group Description	Amoxicillin: Oral 45mg/kg 12 hourly	Benzyl penicillin: Intravenous 50,000IU/kg 6 hourly
Period Title: Overall Study
STARTED	263	264
COMPLETED	263	263
NOT COMPLETED	0	1

Baseline Characteristics

Arm/Group Title	Amoxicillin	Penicillin	Total
Arm/Group Description	Amoxicillin 45mg/kg 12 hourly	Benzyl penicillin 50000 IU 6 hourly	Total of all reporting groups
Overall Participants	263	264	527
Age (years) [Median (Inter-Quartile Range) ]
Median (Inter-Quartile Range) [years]	14	13	13
Sex: Female, Male (Count of Participants)
Female	120 45.6%	106 40.2%	226 42.9%
Male	143 54.4%	158 59.8%	301 57.1%
Region of Enrollment (participants) [Number]
Kenya	263 100%	264 100%	527 100%

Outcome Measures

1. Primary Outcome

Title	Treatment Failure at 48 Hours (Two Full Days After Enrollment)
Description	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
Time Frame	48 hours

Outcome Measure Data

Analysis Population Description

Intention to treat analysis

Arm/Group Title	Amoxicillin	Penicillin
Arm/Group Description	Amoxicillin 45mg/kg 12 hourly	Benzyl penicillin 50000 IU/kg 6 hourly
Measure Participants	263	263
Number [participants]	20 7.6%	21 8%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Amoxicillin, Penicillin
	Comments
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	Noninferiority between amoxicillin and benzyl penicillin was defined a priori as a risk difference of treatment failure and associated upper bound of the 95% confidence interval (CI) of <7%. A sample size of 576 would provide 80% power to detect noninferiority of amoxicillin against benzyl penicillin within a margin of 7% at a 1-sided level of significance of 0.025, assuming a prevalence of treatment failure of 10% at 48 hours derived from a preintervention pilot phase of the study
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Risk Difference (RD)
	Estimated Value	-0.4
	Confidence Interval	(2-Sided) 95%; -5.0 to 4.2
	Parameter Dispersion	Type: Value:
	Estimation Comments	Risk difference comparison is for amoxicillin versus benzyl penicillin

2. Secondary Outcome

Title	Treatment Failure at or Before Discharge / Day 5 Post Enrollment (Whichever Occurs First)
Description	Treatment failure as defined in the primary outcome measure.
Time Frame	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).

Outcome Measure Data

Analysis Population Description

Intention to treat analysis

Arm/Group Title	Amoxicillin	Penicillin
Arm/Group Description	Amoxicillin 45mg/kg 12 hourly	Benzyl Penicillin 50,000IU/kg 6 hourly
Measure Participants	263	263
Number [participants]	30 11.4%	29 11%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Amoxicillin, Penicillin
	Comments
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	The initial sample size estimate of 576 children (288 per group) would provide 80% power to detect noninferiority of amoxicillin against benzyl penicillin within a margin of 7% at a 1-sided level of significance of 0.025, assuming a prevalence of treatment failure of 10% at 48 hours derived from a preintervention pilot phase of the study
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Risk Difference (RD)
	Estimated Value	0.4
	Confidence Interval	(2-Sided) 95%; -5.0 to 5.8
	Parameter Dispersion	Type: Value:
	Estimation Comments	Risk difference comparison is for amoxicillin versus benzyl penicillin

3. Secondary Outcome

Title	Readmission With Diagnosis of Severe or Very Severe Pneumonia Within 14 Days of Enrollment
Time Frame	Day 0 to Day 14

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

4. Secondary Outcome

Title	Death at or Before Five Days Following Enrollment
Description	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.
Time Frame	Day 0 to Day 5

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

5. Secondary Outcome

Title	Outcome (Death/Readmission) at 14 Days as Determined by Telephone or Direct Interview
Description	Definition of death as described in third secondary outcome measure.
Time Frame	Day 14

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Amoxicillin	Penicillin
Arm/Group Description	Amoxicillin 45mg/kg 12 hourly	Benzyl Penicillin 50,000IU/kg 6 hourly
Measure Participants	244	250
Number [participants]	33 12.5%	42 15.9%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Amoxicillin, Penicillin
	Comments
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	The initial sample size estimate of 576 children (288 per group) would provide 80% power to detect noninferiority of amoxicillin against benzyl penicillin within a margin of 7% at a 1-sided level of significance of 0.025, assuming a prevalence of treatment failure of 10% at 48 hours derived from a preintervention pilot phase of the study
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Risk Difference (RD)
	Estimated Value	-3.3
	Confidence Interval	(2-Sided) 95%; -10.0 to 3.0
	Parameter Dispersion	Type: Value:
	Estimation Comments	Risk difference comparison is for amoxicillin versus benzyl penicillin

Adverse Events

Arm/Group Title	Amoxicillin		Benzyl Penicillin
Arm/Group Description	Amoxicillin 45mg/kg 12 hourly		Benzyl Penicillin 50,000IU/kg 6 hourly
All Cause Mortality
	Amoxicillin		Benzyl Penicillin
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Amoxicillin		Benzyl Penicillin
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/263 (0.4%)		3/263 (1.1%)
Cardiac disorders
Congestive heart failure	1/263 (0.4%)	1	0/263 (0%)	0
Gastrointestinal disorders
Hypovolemic shock	0/263 (0%)	0	1/263 (0.4%)	1
Renal and urinary disorders
Renal failure	0/263 (0%)	0	1/263 (0.4%)	1
Respiratory, thoracic and mediastinal disorders
Respiratory failure	0/263 (0%)	0	1/263 (0.4%)	1
Other (Not Including Serious) Adverse Events
	Amoxicillin		Benzyl Penicillin
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/263 (0%)		0/263 (0%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.