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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
Sponsor:
Collaborators:
University College London, UK.
London School of Hygiene & Tropical Medicine, UK.
Swansea Trials Unit, Swansea University Medical School, Swansea, UK.
Centre for Microbiology Research, Kenya Medical Research Institute, Nairobi, Kenya
Mbagathi Hospital, Nairobi, Kenya
Coast General Hospital, Mombasa, Kenya
Mbale Regional Referral Hospital, Mbale, Uganda
KEMRI/Wellcome Trust Research Programme, Kilifi, Kenya.
Information provided by (Responsible Party):
University of Oxford

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.

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

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.


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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 2000 participants
Allocation: Randomized
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)
Masking Description:

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.

Primary Purpose: Treatment
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

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Ceftriaxone
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.
Drug: Ceftriaxone
Ceftriaxone a third-generation cephalosporin. Ceftriaxone is active against a broad spectrum of Gram positive and Gram negative bacteria.
Other Names:
  • Trixone
  • Zefone

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

Experimental: Metronidazole
Arm 1 Metronidazole: Participants receive 10 to 16 mg/kg oral metronidazole twice a day for seven days.
Drug: Metronidazole
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.
Other: Placebo
Suspension manufactured to match metronidazole




Primary Outcome Measures :
  1. 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.


Secondary Outcome Measures :
  1. 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.

  2. Serious adverse events [ Time Frame: 90 days after enrolment. ]
    Serious adverse events are measured using inpatient and outpatient medical records.

  3. Index admission inpatient mortality [ Time Frame: Through index hospital admission, an average of 7 days. ]
    Mortality during the index hospitalisation, measured using inpatient records.

  4. 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.

  5. Causes of death. [ Time Frame: 90 days after enrolment ]
    Causes of death, as determined by an endpoint review committee.

  6. 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.

  7. Causes of re-admission [ Time Frame: 90 days after enrolment. ]
    Causes of re-admission, as determined by the attending study clinician.

  8. 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.

  9. 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.

  10. 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.

  11. 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.

  12. 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.



Information from the National Library of Medicine

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Ages Eligible for Study:   2 Months to 13 Years   (Child)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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

Information from the National Library of Medicine

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


Contacts
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Contact: Caroline Ogwang, MBChB MSc +254 041 75222063 COgwang@kemri-wellcome.org
Contact: Nancy Kagwanja, BSc MSc +254709983859 NKagwanja@kemri-wellcome.org

Locations
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Kenya
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
Mombasa, Kenya
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
Nairobi, Kenya
Contact: Molly Timbwa, RCO    +254709983476    MTimbwa@kemri-wellcome.org   
Contact: Priya Sukhtankar, MRCPCH    +254 730 162000    PSukhtankar@kemri-wellcome.org   
Uganda
Mbale Regional Referral Hospital Not yet recruiting
Mbale, Uganda
Contact: Peter Olupot-Olupot, MBChB MPH PhD    +256 772 457217    polupotolupot@yahoo.com   
Sponsors and Collaborators
University of Oxford
University College London, UK.
London School of Hygiene & Tropical Medicine, UK.
Swansea Trials Unit, Swansea University Medical School, Swansea, UK.
Centre for Microbiology Research, Kenya Medical Research Institute, Nairobi, Kenya
Mbagathi Hospital, Nairobi, Kenya
Coast General Hospital, Mombasa, Kenya
Mbale Regional Referral Hospital, Mbale, Uganda
KEMRI/Wellcome Trust Research Programme, Kilifi, Kenya.
Investigators
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Principal Investigator: James A Berkely, FRCPCH KEMRI/Wellcome Trust Research Programme & University of Oxford

Additional Information:
Publications:

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Responsible Party: University of Oxford
ClinicalTrials.gov Identifier: NCT03174236     History of Changes
Other Study ID Numbers: KEMRI/SERU/CGMR-C/063/3399
1-17 ( Other Identifier: OxTREC )
105431/Z/14/Z ( Other Grant/Funding Number: Joint Global Health Trials, MRC/DfID/Wellcome Trust )
First Posted: June 2, 2017    Key Record Dates
Last Update Posted: June 2, 2017
Last Verified: May 2017
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: Data sharing will be considered by applying to the Data Governance Committee at CGMR,C Kilifi who will manage the process and ensure that appropriate ethical approval is in place and consent has been obtained for uses outside those given in this protocol:DGC@kemri-wellcome.org. Explanation of this eventuality will be included in the participant information and consent form. We intend to share anonymised data with the CHAIN network cohort study (KEMRI/SERU/CGMR-C /054/3318, OxTREC 34-16) which consists of institutions doing studies in malnourished children in Africa and South Asia; to upload anonymised bacterial and resistance sequences on recognised international repositories; and share anonymised bacterial sequence data relating to bacterial resistance with groups working an antimicrobial resistance in Africa and elsewhere.

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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

Additional relevant MeSH terms:
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Malnutrition
Severe Acute Malnutrition
Nutrition Disorders
Anti-Bacterial Agents
Metronidazole
Gentamicins
Ceftriaxone
Penicillins
Penicillin G
Penicillin G Benzathine
Penicillin G Procaine
Antibiotics, Antitubercular
Anti-Infective Agents
Antitubercular Agents
Antiprotozoal Agents
Antiparasitic Agents
Protein Synthesis Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action