Strategies to Reduce Mortality Among HIV-infected and HIV-exposed Children Admitted With Severe Acute Malnutrition (REDMOTHIV)

A Randomized Trial to Investigate Strategies to Reduce Mortality Among HIV-infected and HIV-exposed Children Admitted With Severe Acute Malnutrition in Mulago Hospital, Kampala, Uganda

This study to investigate whether empiric use of an antibiotic with greater antimicrobial sensitivity (ceftriaxone) than standard-of-care (ampicillin plus gentamicin) will reduce mortality among HIV-infected/HEU children admitted to Mwanamugimu Nutrition Unit, Mulago Hospital, Kampala, Uganda.

Study Overview

• Status: Recruiting
• Conditions: HIV-1-infection; Malnutrition, Child
• Intervention / Treatment: Drug: Ceftriaxone Sodium; Drug: Ampicillin; Drug: Gentamicin

Detailed Description

Background

HIV-infected and HIV-exposed-uninfected children (HEU) are at increased risk of developing malnutrition. Severely malnourished children have high mortality rates, but mortality is higher in those that are HIV-infected. Preliminary audits at the Mwanamugimu Nutrition Unit, Mulago Hospital, in 2014 showed that 43% of the severely malnourished children that died were HIV-infected/HEU, despite only 30% of admissions being HIV-infected/HEU, with deaths due to infections in 90% of cases.

Objectives

This study aims to investigate whether empiric use of an antibiotic with greater antimicrobial sensitivity (ceftriaxone) than standard-of-care (ampicillin plus gentamicin) will reduce mortality among HIV-infected/HEU children admitted to Mwanamugimu Nutrition Unit. Secondary objectives include: comparing length of hospitalization, weight-for-height, weight-for-age and height-for-age z-scores between ceftriaxone versus standard of care (ampicillin and gentamicin) treatment arms; ascertaining the pattern/antimicrobial sensitivity of pathogens among participants; determining the prevalence and factors associated with HIV-infection among severely malnourished children; and evaluating the pharmacokinetics (PK) of lopinavir/ritonavir (LPV/r) among severely malnourished HIV-infected children.

Methods

This will be an open label randomized controlled trial involving 300 children; 76 HIV-infected (current mortality - 33%) and 224 HEU (current mortality - 26%). The participants will be randomized to receive 1week of ceftriaxone (n= 150) or standard-of-care (ampicillin/gentamicin) (n=150), in addition to other routine care; the ratio of HIV-infected to HEU (1:3) in this sample is reflective of the current proportions of the HIV-infected and HEU children admitted at Mwanamugimu Nutrition Unit. The trial's primary outcome will be in hospital mortality. 300 randomised children provides >80% power to detect reductions in mortality from the expected 28% to 14%, allowing for 10% noncompliance/lost-to-follow-up in each group. Secondary outcomes will be: length of hospitalization; weight-for-height, weight-for-age and height-for-age z-scores; and pattern/antimicrobial sensitivity of pathogens. In addition, 280 severely malnourished children of unknown serostatus will be tested for HIV at admission to determine the prevalence and factors associated with HIV-infection. 280 children provide 80% power to determine the prevalence of HIV-infection. Furthermore, all the HIV-infected children on LPV/r will each provide sparse pharmacokinetic (PK) samples to evaluate the PK of LPV/r among malnourished children. In this PK sub-study, geometric means of steady-state LPV PK parameters [Area Under the Curve (AUC) 0-12h, maximum concentration (Cmax) and concentration at 12 hours after dose (C12h)] will be determined. The PK parameters (AUC 0-12h, Cmax, C12) will then be put in pharmacokinetic-pharmacodynamic (PK-PD) models to determine optimal doses for the study population.

• Study Type: Interventional
• Enrollment (Anticipated): 300
• Phase: Phase 2; Phase 3

Contacts and Locations

• Study Contact: Name: Victor Musiime, PhD; Phone Number: +256772401749; Email: musiimev@yahoo.co.uk

Study Locations

• Uganda
  • Central
    • Kampala, Central, Uganda, 7072
      • Recruiting
      • Makerere University College of Health Sciences
      • Contact: Victor Musiime, PhD; Phone Number: 0772401749; Email: musiimev@yahoo.co.uk
      • Principal Investigator: Victor Musiime, PhD
      • Sub-Investigator: Philippa Musoke, PhD
      • Sub-Investigator: Jackson Mukonzo, PhD
      • Sub-Investigator: Willy Ssengooba, PhD
      • Sub-Investigator: Esther Babirekere, PhD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 1 month to 4 years (Child)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. HIV-infected children aged 1 to 59 months admitted at Mwanamugimu Nutrition Unit with severe acute malnutrition
2. HIV exposed but uninfected children aged 1 to 59 months admitted at Mwanamugimu Nutrition Unit with severe acute malnutrition
3. For prevalence of HIV-infection sub-study, children presenting with severe acute malnutrition on admission at Mwanamugimu Nutrition Unit.
4. For PK sub-study, the child should have been on antiretroviral therapy for at least 2weeks and should have been in hospital for at least 2weeks.

Exclusion Criteria:

• For PK sub-study; a child with documented poor adherence to antiretroviral therapy.
• For PK sub-study; a child known to have vomited the drug on the sampling day.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Ceftriaxone; Ceftriaxone will be administered intravenously at a dose of 50 - 75mg/kg once daily	Drug: Ceftriaxone Sodium; 7 days of once daily dosing; Other Names: ZEFONE-1000
Active Comparator: Ampicillin and Gentamicin; Ampicillin will be administered intravenously at a dose of 50mg/kg 6hourly; Gentamicin will be administered intravenously at a dose 5mg/kg once daily	Drug: Ampicillin; 7 days of 6 hourly dosing; Other Names: AMPIMAX-500; Drug: Gentamicin; 7 days of once daily dosing; Other Names: GENTAMICIN INJECTION

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
In hospital mortality	Cumulative incidence	4 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Length of hospitalization	Number of days	90 days
Weight-for-height z-score	Change from baseline	90 days
Weight-for-age z-score	Change from baseline	90 days
Height-for-age z-score	Change from baseline	90 days
Pattern and antimicrobial sensitivity of pathogens	Frequency	7 days
HIV infection	Prevalence	Baseline
Area under the curve (AUC 0- 12h)	Geometric means	12hours
Maximum concentration (Cmax)	Geometric means	12hours
Concentration at 12hours post dose (C12h)	Geometric means	12hours

Collaborators and Investigators

• Sponsor: Makerere University

Publications and helpful links

General Publications

• Musiime V, Kiggwe A, Beinomugisha J, Kakooza L, Thembo-Mwesige J, Nkinzi S, Naguti E, Atuhaire L, Segawa I, Ssengooba W, Mukonzo JK, Babirekere-Iriso E, Musoke P. Strategies to Reduce Mortality Among Children Living With HIV and Children Exposed to HIV but Are Uninfected, Admitted With Severe Acute Malnutrition at Mulago Hospital, Uganda (REDMOTHIV): A Mixed Methods Study. Front Pediatr. 2022 Jun 24;10:880355. doi: 10.3389/fped.2022.880355. eCollection 2022.

Study record dates

Study Major Dates

• Study Start (Actual): June 14, 2021
• Primary Completion (Anticipated): June 14, 2024
• Study Completion (Anticipated): June 14, 2024

Study Registration Dates

• First Submitted: August 6, 2021
• First Submitted That Met QC Criteria: September 20, 2021
• First Posted (Actual): September 21, 2021

Study Record Updates

• Last Update Posted (Actual): September 30, 2021
• Last Update Submitted That Met QC Criteria: September 24, 2021
• Last Verified: September 1, 2021

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Nutrition Disorders; Malnutrition; Child Nutrition Disorders; Severe Acute Malnutrition; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Enzyme Inhibitors; Anti-Bacterial Agents; Protein Synthesis Inhibitors; Ceftriaxone; Ampicillin; Gentamicins
• Other Study ID Numbers: REC.REF.2020-165; HS1277ES (Other Identifier: Uganda National Council For Science and Technology)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Yes
• IPD Plan Description: When results are required as part of a meta-analysis or as secondary data.
• IPD Sharing Time Frame: 1 year after end of data collection
• IPD Sharing Access Criteria: On request to Principal Investigator
• IPD Sharing Supporting Information Type: Study Protocol

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No