Clinical trial NCT03174236: First Line Antimicrobials in Children With Complicated Severe Acute Malnutrition
Official title: First Line Antimicrobials in Children With Complicated Severe Acute Malnutrition
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE3
Conditions: Malnutrition Severe
Antibiotic Resistance
Antibiotic Toxicity
Lead sponsor: University of Oxford
Sponsor class: OTHER
Collaborators: name: University College, London
name: London School of Hygiene and Tropical Medicine
name: Swansea Trials Unit
name: Kenya Medical Research Institute
name: KEMRI-Wellcome Trust Collaborative Research Program
First posted: 2017-06-02
Enrollment: 2000
Sex: ALL
Minimum age (years): 2
Maximum age (years): 13
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: FACTORIAL
Intervention model description: The trial will investigate two separate antimicrobial interventions in a 2x2 factorial design randomised controlled clinical trial. A factorial design allows more than one intervention to be tested and is useful in assessing a potential package of care. Two randomisations will be made. The two interventions will be analysed separately. Ceftriaxone and metronidazole is an effective and commonly used antibiotic combination, hence major interactions that interfere with efficacy are considered unlikely. However, evidence for interaction between the two interventions will be tested.
Primary purpose: TREATMENT

Brief summary: Children with severe malnutrition who are admitted sick to hospitals have a high mortality(death rate), usually because of infection. All children with severe malnutrition admitted to hospitals are treated with antibiotics(medication used to kill bacteria). However, the current antibiotics used in hospitals may not be the most effective. It is possible that the antibiotics that are currently used after initial antibiotics should be used first. No studies have been carried out to determine if the current antibiotics used for treating malnourished children who are sick and admitted in hospital are the most appropriate. The aim of this study is to find out if a changed antibiotic system for children with malnutrition is safe, reduces the risk of death and improves nutritional recovery.

Detailed description: Children with complicated severe acute malnutrition (SAM) admitted to hospital in sub-Saharan Africa have a case fatality(death rate) between 12% and more than 20%. Because children with SAM may not exhibit the usual signs of infection, WHO guidelines recommend routine antibiotics(medication used to kill bacteria). However, this is based on "low quality evidence". There is evidence that because of bacterial resistance to the currently recommended first-line antibiotics (gentamicin plus ampicillin or penicillin) could be less effective than potential alternatives. Some hospitals in Africa are already increasing use of ceftriaxone as a first-line treatment. However, this is not based on any data that ceftriaxone actually improves outcomes. Of concern is that ceftriaxone use may also lead to increased antimicrobial resistance, including inducing extended spectrum beta-lactamase (ESBL) and other classes of resistance.

A further area where evidence for policy is lacking is the use of metronidazole in severely malnourished children. The WHO guidelines recommend "Metronidazole 7.5 mg/kg every 8 h for 7 days may be given in addition to broad-spectrum antibiotics; however, the efficacy of this treatment has not been established in clinical trials." Metronidazole is effective against anaerobic bacteria, small bowel bacterial overgrowth, Clostridium difficile colitis and also Giardia, which is common amongst children with SAM. Small cohort studies of metronidazole usage suggest there may be benefits for nutritional recovery in malnourished children. However, metronidazole can cause nausea and anorexia, potentially impairing recovery from malnutrition and may also rarely cause liver and neurological toxicity.

This multi-centre clinical trial will assess the efficacy of two interventions, ceftriaxone and metronidazole, on mortality and nutritional recovery in sick, severely malnourished children in a 2x2 factorial design. There will also be an analysis of antimicrobial resistance and an economic analysis. To extend our understanding of metronidazole and ceftriaxone pharmacokinetics, additional pharmacokinetic data for the dosing schedule used in the trial will be collected from 120 participants in a sub-study. The trial will be conducted at Kilifi County Hospital, Coast General Hospital, Mbagathi Hospital in Kenya and Mbale Regional Referral Hospital in Uganda. The trial will assess antimicrobial resistance that is carried by children in their intestines and in invasive bacterial isolates. A further sub-study will examine the relative costs of care for SAM for health facilities and for families, including antimicrobial usage will also be assessed. Clear data on the benefits, risks and costs of these antimicrobials will influence policy on case management and antimicrobial stewardship in this vulnerable population.

Eligibility criteria: Inclusion:

* Age 2 months to 13 years inclusive
* Severe malnutrition defined as:
* kwashiorkor at any age or:
* for children between 2 to 5 months: MUAC \<11cm or weight-for length Z score \<-3
* for children between 6 to 59 months: MUAC \<11.5cm or weight-for length Z score \<-3
* for children between 5 to 13 years: MUAC \<11.5cm or BMI-for-age Z score \<-3
* Admitted to hospital and eligible for intravenous antibiotics according to WHO guidelines
* Planning to remain within the hospital catchment area and willing to come for specified visits during the 90 day follow up period
* Informed consent provided by the parents/guardian

Exclusion:

* Known allergy or contraindication to penicillin, gentamicin, ceftriaxone or metronidazole
* A specific and documented clinical indication for another class of antibiotic
* Previously enrolled in this study

Primary outcomes:
measure: Mortality
timeFrame: 90 days after enrolment.
Secondary outcomes:
measure: Mortality during the first 7 days
timeFrame: 7 days
measure: Mortality during the first 30 days
timeFrame: 7 days
measure: Index admission inpatient mortality
timeFrame: Through index hospital admission, an average of 7 days.
measure: Mortality after discharge from index admission.
timeFrame: 90 days after enrolment
measure: Grade 4 toxicity
timeFrame: Up to 7 days following enrolment
measure: Serious adverse events
timeFrame: 90 days after enrolment.
measure: Tolerability - relevant side effects during the first 7 day
timeFrame: 7 days
measure: Causes of death.
timeFrame: 90 days after enrolment
measure: Re-admission to hospital.
timeFrame: From discharge from hospital to 90 days after enrolment
measure: Duration of hospitalisation.
timeFrame: 90 days after enrolment.
measure: Duration of administration of antibiotics.
timeFrame: 90 days after enrolment.
measure: Change in nutritional status
timeFrame: 90 days after enrolment.
measure: Faecal carriage of bacteria expressing Extended Spectrum Lactamase (ESBL)
timeFrame: Through study completion an average of 90 days.
Other outcomes:
Locations:
city: Kilifi
country: Kenya
facility: Kemri Wellcome Trust Research Programme
state: Coast Province
city: Kilifi
country: Kenya
facility: Kilifi County Hospital
state: Coast
city: Kilifi
country: Kenya
facility: KEMRI WT Clinical Trials Facility
city: Kilifi
country: Kenya
facility: Kilifi County Hospital
city: Mombasa
country: Kenya
facility: Coast General Hospital - Study site
city: Nairobi
country: Kenya
facility: Mbagathi District Hospital
city: Nairobi
country: Kenya
facility: Mbagathi Hospital
city: Mbale
country: Uganda
facility: Mbale Regional Referral Hospital
Study officials:
affiliation: KEMRI/Wellcome Trust Research Programme & University of Oxford
name: James A Berkely, FRCPCH
role: PRINCIPAL_INVESTIGATOR
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