First Line Antimicrobials in Children With Complicated Severe Acute Malnutrition

Study Overview
=================
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.

Official Title
-----------------
First Line Antimicrobials in Children With Complicated Severe Acute Malnutrition

Conditions
-----------------
Malnutrition Severe, Antibiotic Resistance, Antibiotic Toxicity

Intervention / Treatment
-----------------
* Drug: Ceftriaxone
* Drug: Benzyl penicillin
* Drug: Metronidazole
* Other: Placebo
* Drug: Gentamicin


Participation Criteria
=================
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

Ages Eligible for Study
-----------------
Minimum Age: 2 Months
Maximum Age: 13 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Factorial Assignment
Interventional 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.
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Ceftriaxone<br>Arm 1 IV Ceftriaxone: Participants in this group receive 80mg/kg IV ceftriaxone once a day for a minimum of 48 hours and a usual maximum of seven days. | Drug: Ceftriaxone<br>* Ceftriaxone a third-generation cephalosporin. Ceftriaxone is active against a broad spectrum of Gram positive and Gram negative bacteria.<br>|
| Active Comparator: Benzyl penicillin plus gentamicin<br>Arm 2 IV Benzyl penicillin plus gentamicin (usual care): Participants in this group receive 50 000 U/kg IV benzyl penicillin every six hours for a minimum of two days and a maximum of seven days. | Drug: Benzyl penicillin<br>* The currently recommended first-line antibiotics for the treatment of severe acute malnutrition are gentamicin plus ampicillin or penicillin.<br>Drug: Gentamicin<br>* The currently recommended first-line antibiotics for the treatment of severe acute malnutrition are gentamicin plus ampicillin or penicillin.<br>|
| Experimental: Metronidazole<br>Arm 1 Metronidazole: Participants receive 10 to 16 mg/kg oral metronidazole twice a day for seven days. | Drug: Metronidazole<br>* The WHO guidelines recommend that Metronidazole may be given in addition to broad-spectrum antibiotics, however, the efficacy of this treatment has not been established in clinical trials.<br>|
| Placebo Comparator: Placebo<br>Arm 2 Placebo: Participants receive an oral placebo dose to match that for Metronidazole twice a day for seven days. | Other: Placebo<br>* Suspension manufactured to match metronidazole<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mortality | Mortality is measured using source documents from medical records, verbal autopsy, or death or burial certificates in the community. | 90 days after enrolment. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mortality during the first 7 days | Mortality during the first 7 days | 7 days | 
| Mortality during the first 30 days | Mortality during the first 30 days | 7 days | 
| Index admission inpatient mortality | Mortality during the index hospitalisation, measured using inpatient records. | Through index hospital admission, an average of 7 days. | 
| Mortality after discharge from index admission. | Mortality occurring after discharge from the index hospital admission is measured using inpatient medical records, verbal autopsy, or death or burial certificates in the community. | 90 days after enrolment | 
| Grade 4 toxicity | Grade 4 toxicity events are measured according to the Division of AIDS Tables for Grading the Severity of Adverse Events using medical records. | Up to 7 days following enrolment | 
| Serious adverse events | Serious adverse events are measured using inpatient and outpatient medical records. | 90 days after enrolment. | 
| Tolerability - relevant side effects during the first 7 day | Vomiting, diarrhoea, NG tube in place and convulsions during the first 7 days | 7 days | 
| Causes of death. | Causes of death, as determined by an endpoint review committee. | 90 days after enrolment | 
| Re-admission to hospital. | Re-admission to hospital defined as at least one overnight stay in a hospital or health facility are measured using inpatient records. | From discharge from hospital to 90 days after enrolment | 
| Duration of hospitalisation. | Total duration of hospitalisation is measured in days using inpatient records at the start and end of each admission to hospital. | 90 days after enrolment. | 
| Duration of administration of antibiotics. | Duration of administration of intravenous antibiotics measured using inpatient records. | 90 days after enrolment. | 
| Change in nutritional status | Change in nutritional status is measured using mid-upper arm circumference, weight-for-length, weight-for-age and length-for-age compared to at enrollment. | 90 days after enrolment. | 
| Faecal carriage of bacteria expressing Extended Spectrum Lactamase (ESBL) | Faecal carriage of bacteria expressing Extended Spectrum Lactamase (ESBL) is measured using microbial culture and sensitivity testing of rectal swabs. | Through study completion an average of 90 days. |