First Line Antimicrobials in Children With Complicated Severe Acute Malnutrition (FLACSAM)
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|ClinicalTrials.gov Identifier: NCT03174236|
Recruitment Status : Not yet recruiting
First Posted : June 2, 2017
Last Update Posted : June 2, 2017
|Condition or disease||Intervention/treatment||Phase|
|Malnutrition Severe Antibiotic Resistance Antibiotic Toxicity||Drug: Ceftriaxone Drug: Benzyl penicillin plus gentamicin Drug: Metronidazole Other: Placebo||Phase 3|
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.
|Study Type :||Interventional (Clinical Trial)|
|Estimated Enrollment :||2000 participants|
|Intervention Model:||Factorial Assignment|
|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.|
|Masking:||Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)|
Metronidazole and its placebo will be masked. They will both be contained in similar bottles labelled with sequential study numbers according to a prepared blocked randomisation list before the trial begins. They will also be of similar appearance.
Ceftriaxone and penicillin + gentamicin will not be masked.
|Official Title:||First Line Antimicrobials in Children With Complicated Severe Acute Malnutrition|
|Estimated Study Start Date :||June 5, 2017|
|Estimated Primary Completion Date :||April 30, 2020|
|Estimated Study Completion Date :||December 31, 2021|
Arm 1 IV Ceftriaxone: Participants in this group receive 80mg/kg IV ceftriaxone once a day. IV ceftriaxone is given for a minimum of 48 hours and a usual maximum of seven days. If a child receiving IV ceftriaxone is feeding well and no longer has any signs of infection or complications after two days and before seven days, they are prescribed standard care for uncomplicated SAM with oral amoxicillin (40mg/kg every 12 hours) to complete a total of seven days of antibiotics, as per WHO guidance. If a participant has a specific and documented indication to continue ceftriaxone beyond seven days (e.g. proven bacterial meningitis), ceftriaxone is continued beyond those seven days.
Ceftriaxone a third-generation cephalosporin. Ceftriaxone is active against a broad spectrum of Gram positive and Gram negative bacteria.
Active Comparator: Benzyl penicillin plus gentamicin
Arm 2 IV Benzyl penicillin plus gentamicin (usual care): Participants in this group receive 50 000 U/kg IV benzyl penicillin every six hours. In the usual care arm, as per WHO guidelines, IV benzyl penicillin plus gentamicin is given for a minimum of two days and a maximum of seven days. If a child receiving IV penicillin and gentamicin is feeding well and no longer has any signs of infection or complications after two days and before seven days, they are prescribed standard care for uncomplicated severe acute malnutrition (SAM) with oral amoxicillin (40mg/kg every 12 hours) to complete a total of seven days of antibiotics, as per WHO guidance.
Drug: Benzyl penicillin plus gentamicin
The currently recommended first-line antibiotics for the treatment of severe acute malnutrition are gentamicin plus ampicillin or penicillin.
Other Name: Cristapen
Arm 1 Metronidazole: Participants receive 10 to 16 mg/kg oral metronidazole twice a day for seven days.
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."
Other Name: Flagyl
Placebo Comparator: Placebo
Arm 2 Placebo: Participants receive an oral placebo dose to match that for Metronidazole twice a day for seven days.
Suspension manufactured to match metronidazole
- Mortality [ Time Frame: 90 days after enrolment. ]Mortality is measured using source documents from medical records, verbal autopsy, or death or burial certificates in the community.
- Grade 4 toxicity [ Time Frame: Up to 7 days following enrolment ]Grade 4 toxicity events are measured according to the Division of AIDS Tables for Grading the Severity of Adverse Events using medical records.
- Serious adverse events [ Time Frame: 90 days after enrolment. ]Serious adverse events are measured using inpatient and outpatient medical records.
- Index admission inpatient mortality [ Time Frame: Through index hospital admission, an average of 7 days. ]Mortality during the index hospitalisation, measured using inpatient records.
- Mortality after discharge from index admission. [ Time Frame: 90 days after enrolment ]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.
- Causes of death. [ Time Frame: 90 days after enrolment ]Causes of death, as determined by an endpoint review committee.
- Re-admission to hospital. [ Time Frame: From discharge from hospital to 90 days after enrolment ]Re-admission to hospital defined as at least one overnight stay in a hospital or health facility are measured using inpatient records.
- Causes of re-admission [ Time Frame: 90 days after enrolment. ]Causes of re-admission, as determined by the attending study clinician.
- Duration of hospitalisation. [ Time Frame: 90 days after enrolment. ]Total duration of hospitalisation is measured in days using inpatient records at the start and end of each admission to hospital.
- Duration of administration of antibiotics. [ Time Frame: 90 days after enrolment. ]Total duration of administration of antibiotics in hospital is measured using inpatient records at the start and end of each admission to hospital.
- Change in nutritional status [ Time Frame: 90 days after enrolment. ]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.
- Aetiology of invasive infections [ Time Frame: 90 days after enrolment. ]Aetiology of invasive infections is measured using microbial culture and sensitivity testing of blood, cerebrospinal fluid, urine or other sterile site samples taken for clinical investigation.
- Faecal carriage of bacteria expressing Extended Spectrum Lactamase (ESBL) [ Time Frame: Through study completion an average of 90 days. ]Faecal carriage of bacteria expressing Extended Spectrum Lactamase (ESBL) is measured using microbial culture and sensitivity testing of rectal swabs.
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03174236
|Contact: Caroline Ogwang, MBChB MSc||+254 041 75222063||COgwang@kemri-wellcome.org|
|Contact: Nancy Kagwanja, BSc MSc||+254709983859||NKagwanja@kemri-wellcome.org|
|Kilifi County Hospital||Not yet recruiting|
|Kilifi, Coast, Kenya, 80108|
|Contact: Shalton M Mwaringa, RCO +254 041 75222063 SMwaringa@kemri-wellcome.org|
|Contact: Caroline A Ogwang, MBChB MSc +254 041 75222063 COgwang@kemri-wellcome.org|
|Principal Investigator: James A Berkley, FRCPCH|
|Coast General Hospital - Study site||Not yet recruiting|
|Contact: Laura M Mwalekwa, RCO +254709983412 LMwalekwa@kemri-wellcome.org|
|Contact: Caroline A Ogwang, MBChB MSc +254 041 75222063 COgwang@kemri-wellcome.org|
|Mbagathi Hospital||Not yet recruiting|
|Contact: Molly Timbwa, RCO +254709983476 MTimbwa@kemri-wellcome.org|
|Contact: Priya Sukhtankar, MRCPCH +254 730 162000 PSukhtankar@kemri-wellcome.org|
|Mbale Regional Referral Hospital||Not yet recruiting|
|Contact: Peter Olupot-Olupot, MBChB MPH PhD +256 772 457217 email@example.com|
|Principal Investigator:||James A Berkely, FRCPCH||KEMRI/Wellcome Trust Research Programme & University of Oxford|