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

University of Oxford

Status and phase: Completed; Phase 3

Conditions: Pneumonia

Treatments: Other: Intravenous fluid; Drug: Ampicillin; Drug: Gentamicin Sulfate; Other: Nasogastric feeds; Drug: Amoxicillin Clavulanate; Drug: Ceftriaxone; Drug: Benzyl penicillin

Study type: Interventional

Funder types: Other

Identifiers

NCT04041791

KEMRI/CGMR-C/141/3772

Details and patient eligibility

About

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.

Full 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.

Enrollment: 4,392 patients

Sex: All

Ages: 2 to 59 months old

Volunteers: No Healthy Volunteers

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

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Factorial Assignment

Masking: None (Open label)

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4,392 participants in 6 patient groups

Benzyl penicillin/ampicillin + gentamicin & IV fluids

Active Comparator group

Description:

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.

Treatment:

Drug: Benzyl penicillin

Drug: Ampicillin

Drug: Gentamicin Sulfate

Other: Intravenous fluid

Ceftriaxone and IV fluids

Experimental group

Description:

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.

Treatment:

Drug: Ceftriaxone

Other: Intravenous fluid

Amoxicillin-clavulanate and IV fluids

Experimental group

Description:

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.

Treatment:

Drug: Amoxicillin Clavulanate

Other: Intravenous fluid

Benzyl penicillin/ampicillin + gentamicin & NG feeds

Experimental group

Description:

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.

Treatment:

Drug: Benzyl penicillin

Other: Nasogastric feeds

Drug: Ampicillin

Drug: Gentamicin Sulfate

Ceftriaxone and NG feeds

Experimental group

Description:

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.

Treatment:

Drug: Ceftriaxone

Other: Nasogastric feeds

Amoxicillin-clavulanic acid and NG feeds

Experimental group

Description:

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.

Treatment:

Drug: Amoxicillin Clavulanate

Other: Nasogastric feeds