Clinical trial NCT05051163: Strategies to Reduce Mortality Among HIV-infected and HIV-exposed Children Admitted With Severe Acute Malnutrition
Official title: 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
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE2
PHASE3
Conditions: HIV-1-infection
Malnutrition, Child
Lead sponsor: Makerere University
Sponsor class: OTHER
First posted: 2021-09-21
Enrollment: 300
Sex: ALL
Minimum age (years): 1
Maximum age (years): 59
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Open label parallel group randomized controlled trial
Primary purpose: TREATMENT

Brief summary: 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.

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.

Eligibility criteria: 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.

Primary outcomes:
measure: In hospital mortality
timeFrame: 4 weeks
Secondary outcomes:
measure: Length of hospitalization
timeFrame: 90 days
measure: Weight-for-height z-score
timeFrame: 90 days
measure: Weight-for-age z-score
timeFrame: 90 days
measure: Height-for-age z-score
timeFrame: 90 days
measure: Pattern and antimicrobial sensitivity of pathogens
timeFrame: 7 days
measure: HIV infection
timeFrame: Baseline
measure: Area under the curve (AUC 0- 12h)
timeFrame: 12hours
measure: Maximum concentration (Cmax)
timeFrame: 12hours
measure: Concentration at 12hours post dose (C12h)
timeFrame: 12hours
Other outcomes:
Locations:
city: Kampala
country: Uganda
facility: Makerere University College of Health Sciences
state: Central
Study officials:
References:
citation: 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.