A Study to Compare Different Antibiotics and Different Modes of Fluid Treatment for Children With Severe Pneumonia (SEARCH)

Supportive Care and Antibiotics for Severe Pneumonia Among Hospitalized Children (SEARCH): A Pragmatic Randomised Controlled Trial

Pneumonia is one of the top causes of death in children aged below 5. More than 10% of children with severe pneumonia die. We are not sure that the currently recommended antibiotics used in children with pneumonia are the most effective. No studies have been carried out to find out whether children with pneumonia should be given intravenous (IV) fluids or nasogastric (NG) feeds.

The SEARCH trial aims to find out which antibiotics and modes of feeding are the most effective in treating children with severe pneumonia and therefore helping reduce mortality.

Study Overview

• Status: Completed
• Conditions: Pneumonia
• Intervention / Treatment: Drug: Benzyl penicillin; Drug: Gentamicin Sulfate; Other: Intravenous fluid; Drug: Ampicillin; Drug: Ceftriaxone; Drug: Amoxicillin Clavulanate; Other: Nasogastric feeds

Detailed Description

Pneumonia is one of the leading causes of death among young children with more than 10% of children aged under-five with severe pneumonia dying. The World Health Organisation (WHO) guidelines recommend the use of benzyl penicillin plus gentamicin as the standard of care of treatment for severe pneumonia. However, there have been increasing concerns about the effectiveness of the current recommendations.

Some authorities advise against the use of enteral nutrition in severely ill patients due to concerns of compromised respiratory status and risk of aspiration with nasogastric feeding. Evidence to support these concerns is lacking.

This trial aims to find out which antibiotics are the most effective in the treatment of children with severe pneumonia by comparing the current standard of care (benzyl penicillin or ampicillin plus gentamicin) to injectable ceftriaxone and injectable amoxicillin-clavulanic acid. The study will also determine whether providing feeds through a nasogastric tube is superior to intravenous fluid therapy in children with severe pneumonia.

The SEARCH trial will be a multi-site pragmatic randomised controlled trial that will assess the efficacy of both interventions in children admitted with severe pneumonia in a 3x2 factorial design. The sites will be in East Africa.

Data from the trial will be used to inform policy and contribute to guidelines and improve clinical practice in settings where the burden of pneumonia is highest.

• Study Type: Interventional
• Enrollment (Actual): 4392
• Phase: Phase 3

Contacts and Locations

Study Locations

• Kenya
  • Machakos, Kenya
    • Machakos Level 5 Hospital

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

• Age 2 to 59 months.
• History of cough or difficulty breathing and signs of severe pneumonia based on WHO 2013 criteria
• Admitted to any one of the study hospitals.
• Informed consent provided by the parents/guardian.

Exclusion Criteria:

• Children presenting in cardiorespiratory arrest requiring emergency basic life support (bag-valve-mask ventilation and/or chest compressions).
• Children for whom concurrent condition precludes the use of the first-line antibiotics for severe pneumonia such as readmission or meningitis
• Known allergy or contraindication to penicillin, gentamicin, ceftriaxone or amoxicillin-clavulanic acid.
• Referral from another inpatient facility following treatment with injectable antibiotics for more than 24 hours or because the first-line regimen is considered to have failed
• Previously enrolled in the study.
• For supportive care intervention (Intravenous fluids versus nasogastric feeds): children with absent gag reflex.
• For supportive care intervention (Intravenous fluids versus nasogastric feeds): children unable to maintain oxygen saturations greater 90% on pulse oximetry while receiving supplemental oxygen.
• For supportive care intervention (Intravenous fluids versus nasogastric feeds): children with severe acute malnutrition
• For supportive care intervention (Intravenous fluids versus nasogastric feeds): shock or severe dehydration
• For supportive care intervention (Intravenous fluids versus nasogastric feeds): Child able to feed
• For supportive care intervention (Intravenous fluids versus nasogastric feeds): Vomiting everything

Study Plan

How is the study designed?

Design Details

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

Number of Arms

6

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Benzyl penicillin/ampicillin + gentamicin & IV fluids; Participants are assigned to receive benzyl penicillin at 50,000 IU/kg every 6 hours or ampicillin 50mg/kg every 8 hours plus gentamicin 7.5 mg/kg once daily given intravenously (IV) or via intramuscular (IM) injection for a minimum of 48 hours and for up to 7 days. Maintenance fluids will be given as a continuous infusion for at least 24 hours.	Drug: Benzyl penicillin; Benzyl penicillin is a penicillin antibiotic.; Other Names: Medipen; Cristapen; Drug: Gentamicin Sulfate; Gentamicin is an aminoglycoside antibiotic.; Other Names: Gentamicin; Gentamed; Other: Intravenous fluid; Maintenance fluids administered for at least 24 hours.; Other Names: Hartmann's Solution with 5% dextrose; Ringer's Lactate with 5% dextrose; Normal Saline with 5% dextrose; Drug: Ampicillin; Ampicillin is a penicillin-type antibiotic.
Experimental: Ceftriaxone and IV fluids; Participants are assigned to receive ceftriaxone at 50 mg/kg every 12 hours given IV or IM for a minimum of 48 hours and for up to 7 days. Intravenous fluids will be given as a continuous infusion for at least 24 hours.	Other: Intravenous fluid; Maintenance fluids administered for at least 24 hours.; Other Names: Hartmann's Solution with 5% dextrose; Ringer's Lactate with 5% dextrose; Normal Saline with 5% dextrose; Drug: Ceftriaxone; Ceftriaxone is a third generation cephalosporin antibiotic active against a wide range of gram negative and positive bacteria.; Other Names: Desefin
Experimental: Amoxicillin-clavulanate and IV fluids; Participants are assigned to receive amoxicillin clavulanic acid at 30 mg/kg every 8 hours given IV or IM for a minimum of 48 hours and for up to 7 days. Intravenous fluids will be given as a continuous infusion for at least 24 hours.	Other: Intravenous fluid; Maintenance fluids administered for at least 24 hours.; Other Names: Hartmann's Solution with 5% dextrose; Ringer's Lactate with 5% dextrose; Normal Saline with 5% dextrose; Drug: Amoxicillin Clavulanate; Amoxicillin Clavulanate is a combination of amoxicillin, a β-lactam antibiotic, and potassium clavulanate, a β-lactamase inhibitor.; Other Names: Amoxicillin-clavulanic acid; Amoxi-clav; Amoklavin; Co-amoxiclav
Experimental: Benzyl penicillin/ampicillin + gentamicin & NG feeds; Participants are assigned to receive Benzyl penicillin at 50,000 IU/kg every 6 hours or ampicillin 50mg/kg every 8 hours plus gentamicin 7.5 mg/kg once daily given intravenously (IV) or via intramuscular (IM) injection for a minimum of 48 hours and for up to 7 days. Nasogastric feeds will be given 3 hourly for at least 24 hours.	Drug: Benzyl penicillin; Benzyl penicillin is a penicillin antibiotic.; Other Names: Medipen; Cristapen; Drug: Gentamicin Sulfate; Gentamicin is an aminoglycoside antibiotic.; Other Names: Gentamicin; Gentamed; Drug: Ampicillin; Ampicillin is a penicillin-type antibiotic.; Other: Nasogastric feeds; Feeds given via nasogastric tube. Feeds may include cow's milk, breast milk, porridge, formula among others.
Experimental: Ceftriaxone and NG feeds; Participants are assigned to receive ceftriaxone at 50 mg/kg every 12 hours given IV or IM for up to 7 days. Nasogastric feeds will be given 3 hourly for at least 24 hours.	Drug: Ceftriaxone; Ceftriaxone is a third generation cephalosporin antibiotic active against a wide range of gram negative and positive bacteria.; Other Names: Desefin; Other: Nasogastric feeds; Feeds given via nasogastric tube. Feeds may include cow's milk, breast milk, porridge, formula among others.
Experimental: Amoxicillin-clavulanic acid and NG feeds; Participants are assigned to receive amoxicillin clavulanic acid at 30 mg/kg every 8 hours given IV or IM for up to 7 days. Nasogastric feeds will be given 3 hourly for at least 24 hours.	Drug: Amoxicillin Clavulanate; Amoxicillin Clavulanate is a combination of amoxicillin, a β-lactam antibiotic, and potassium clavulanate, a β-lactamase inhibitor.; Other Names: Amoxicillin-clavulanic acid; Amoxi-clav; Amoklavin; Co-amoxiclav; Other: Nasogastric feeds; Feeds given via nasogastric tube. Feeds may include cow's milk, breast milk, porridge, formula among others.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Mortality	Mortality of participants receiving any of the injectable antibiotic treatments who die within the first five days of admission measured from source documents, medical records, verbal autopsy or death certificates.	Up to Day 5

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of serious adverse events	Serious adverse events that my be likely or definitely related to any of the interventions given to the participants. Serious adverse events include death, a life threatening event, persistent or significant disability or incapacity, hospitalisation or prolonged hospitalisation.	Up to Day 30
Length of hospitalisation	Total days a participant is admitted or receives inpatient care measured in days using hospital records at the start and end of each admission.	Through duration of hospitalisation, an average of 5 days
Duration taken to tolerate full fluids by mouth	Number of days it takes for participants to fully tolerate fluids orally.	An average of 3 days
Mortality 30 days after enrollment	Number of participants who die within 30 days of enrollment into the study measured using source documents, medical records, verbal autopsy or death certificates.	Day 30 post enrollment

Collaborators and Investigators

• Sponsor: University of Oxford
• Collaborators: London School of Hygiene and Tropical Medicine; Medical Research Council; Wellcome Trust; Department for International Development, United Kingdom; University of Nairobi; National Institute for Health Research, United Kingdom; Kenya Ministry of Health
• Investigators: Principal Investigator: Ambrose Agweyu, PhD, KEMRI-Wellcome Trust Research Programme, University of Oxford

Study record dates

Study Major Dates

• Study Start (Actual): August 19, 2019
• Primary Completion (Actual): April 5, 2024
• Study Completion (Actual): April 5, 2024

Study Registration Dates

• First Submitted: July 29, 2019
• First Submitted That Met QC Criteria: July 31, 2019
• First Posted (Actual): August 1, 2019

Study Record Updates

• Last Update Posted (Actual): July 8, 2024
• Last Update Submitted That Met QC Criteria: July 4, 2024
• Last Verified: July 1, 2024

More Information

Terms related to this study

• Keywords: nutrition; children; supportive care; antibiotics; intravenous fluids; severe pneumonia; World Health Organisation
• Additional Relevant MeSH Terms: Infections; Respiratory Tract Infections; Respiratory Tract Diseases; Lung Diseases; Pneumonia; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Enzyme Inhibitors; Anti-Bacterial Agents; Protein Synthesis Inhibitors; beta-Lactamase Inhibitors; Third Generation Cephalosporins; Beta Lactam Antibiotics; Ceftriaxone; Ampicillin; Gentamicins; Amoxicillin; Clavulanic Acid; Clavulanic Acids; Amoxicillin-Potassium Clavulanate Combination; Penicillins; Penicillin G Benzathine; Penicillin G; Penicillin G Procaine
• Other Study ID Numbers: KEMRI/CGMR-C/141/3772

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO
• IPD Plan Description: Data requests will be considered by applying to the Data Governance Committee at the Kenya Medical Research Institute (KEMRI) Centre for Geographic Medicine Research-Kilifi, Kenya who will manage the process and ensure that appropriate ethical approval is in place and consent has been obtained for dissemination and use outside of the scope of the trial.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No