Clinical trial NCT05519254: Lactoferrin and Lysozyme Supplementation for Long-term Diarrhea Sequelae
Official title: Lactoferrin and Lysozyme Supplementation for Long-term Diarrhea Sequelae
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE3
Conditions: Diarrhea
Wasting
Malnutrition, Child
Lead sponsor: University of Washington
Sponsor class: OTHER
Collaborators: name: Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
First posted: 2022-08-29
Enrollment: 600
Sex: ALL
Minimum age (years): 6
Maximum age (years): 24
Standard ages: CHILD
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: FACTORIAL
Primary purpose: TREATMENT

Brief summary: Children in low- and middle-income countries who are hospitalized for diarrhea and also have malnutrition are at high risk for illness and death in the 6 months period following treatment for diarrhoea despite receiving current guideline recommended diarrhea management (such as oral rehydration solution, or "ORS"). This study will test whether nutritional supplements made from milk (lactoferrin or lysozyme) or a combination of the two (lactoferrin and lysozyme) will prevent children from having repeated diarrhea episodes and help improve their nutrition by improving their stomach health or preventing new disease during this 6-month period. The study is taking place at 7 hospitals in Western Kenya. Six hundred participants will be enrolled if they provide informed consent to participate, are aged 6-24 months, were hospitalized with diarrhea and malnutrition and have been managed by the facility nutritionists and ready to return home. Participation in the study will entail providing information on the child's health history, collection of stool samples, blood, and potentially urine. The caregiver will be provided sachets of the investigational product to take home and mix daily with their child's porridge or other complimentary food, and asked to return to the clinic 4 times in the subsequent 6 months, and also consent to having a community health worker visit their home every two weeks for a follow up visit. The risks to the participant and their caregiver are minimal. The information gained in this study will help us create new treatments and develop new strategies to treat sick children to prevent death and illness.

Detailed description: Current diarrhea management strategies in low- and middle-income countries (oral rehydration solution, ReSoMal and zinc) focus primarily on the management of dehydration and micronutrient replacement and appear to have negligible impact in preventing future diarrheal episodes or improving nutritional outcomes. Lactoferrin and lysozyme are milk-derived nutritional supplements that may reduce the risk of diarrheal episodes and accelerate nutritional recovery by treating or preventing underlying enteric infections and/or improving enteric function. Children with moderate or severe wasting are at particularly high-risk of death, diarrhea recurrence, and nutritional deterioration following a diarrheal episode. This factorial, double-blind, placebo-controlled, randomized trial aims to determine the efficacy of lactoferrin and lysozyme supplementation in decreasing diarrhea incidence and improving nutritional recovery in children convalescing from diarrhea and wasting. We will explore whether these interventions improve outcomes by reducing enteric pathogens, improving enteric function and/or increasing hemoglobin concentrations in these children. This study aims to enroll 600 Kenyan children aged 6-24 months from facilities in Western Kenya. Enrolled children will be randomized to 16-weeks of lactoferrin, lysozyme, a combination of the two, or placebo and be followed up for 24 weeks total, with bi-weekly home visits by community health workers and clinic visits at 4, 10, 16, and 24 weeks. Results of this study will inform management strategies for children with moderate/severe wasting at high risk for mortality, morbidity, and nutritional deterioration following diarrhea.

Aim 1: To determine whether a 16-week course of lactoferrin, lysozyme or a combination of both shortens time to WHO-defined recovery from wasting (MUAC ≥12.5cm) and reduces the incidence of moderate-to-severe diarrhea during the subsequent 6-months following presentation to a health facility with diarrhea among children with moderate/severe childhood wasting (MUAC \<12.5 cm at the time of screening).

Hypothesis: Children randomized to lactoferrin, lysozyme, or the combination of both will experience a lower incidence of moderate-to-severe diarrhea and an earlier recovery from wasting (increased MUAC) over the subsequent 6-months than placebo-treated children. Combination therapy will provide synergistic benefit in reducing diarrhea and improving nutritional recovery.

Aim 2: To explore whether a 16-week course of lactoferrin, lysozyme or combination therapy improves secondary clinical, nutritional, enteric pathogen, and enteric function outcomes.

Hypothesis: Children randomized to lactoferrin, lysozyme, or the combination will experience fewer hospitalizations and deaths, improved linear growth, a reduced prevalence of specific enteric bacteria associated with linear growth failure (Campylobacter, LT-ETEC, EAEC, typical EPEC and/or Shigella), improved markers of enteric dysfunction (myeloperoxidase, alpha antitrypsin, neopterin, and the lactulose:rhamnose ratio) and improved hemoglobin, as compared to placebo-treated children.

Aim 3: To evaluate acceptability, adherence and cost-effectiveness of lactoferrin and/or lysozyme in Kenya.

Hypothesis: Both therapies will be highly acceptable to caregivers and health workers. Adherence to the therapies will be high among participants (≥ 95%). Lactoferrin and lysozyme, alone and in combination, will be more cost-effective interventions for reducing moderate-to-severe diarrhea in the short-term as compared to the standard-of-care.

Eligibility criteria: Inclusion Criteria:

* Age 6-24 months
* Managed as an outpatient or inpatient for diarrhea at one of the recruiting sites
* MUAC \<12.5 cm at the time of screening
* Plan to stay within the study area for the next 6 months or greater

Exclusion Criteria:

* Age younger than 6 months or older than 24 months
* Caregiver does not provide consent to study participation
* History of 2 or more blood transfusions in the past 12 months
* Exclusively breastfeeding at the time of enrollment
* History of congenital defect or syndrome that prevents age-appropriate feeding (e.g. cleft palate)
* History of allergy to dairy products
* Child is not ready to return home (is not yet discharged), or discharged against medical advice
* Unwilling to participate in the dual sugar permeability sub-study if selected
* Enrollment in another study

Primary outcomes:
measure: Incidence of moderate-to-severe diarrhea
timeFrame: 6 months
measure: Time to nutritional recovery
timeFrame: 6 months
Secondary outcomes:
measure: Incidence of diarrhea (any severity)
timeFrame: 6 months
measure: Incidence of severe diarrhea
timeFrame: 6 months
measure: Incidence of dysentery
timeFrame: 6 months
measure: Incidence of medically-attended diarrhea
timeFrame: 6 months
measure: Cumulative duration of diarrhea
timeFrame: 6 months
measure: Incidence of hospitalization
timeFrame: 6 months
measure: Composite outcome of time to hospitalization and death
timeFrame: 6 months
measure: Hemoglobin concentration
timeFrame: Measured at week 16
measure: Change in length for age z-score (linear growth)
timeFrame: 6 months
measure: Change in weight for length z-score
timeFrame: 6 months
measure: Change in mid-upper arm circumference (cm)
timeFrame: 6 months
measure: Concentration of fecal alpha antitrypsin (mg/g)
timeFrame: Measured at baseline, week 4, 16, and 24
measure: Concentration of fecal myeloperoxidase (ng/mL)
timeFrame: Measured at baseline, week 4, 16, and 24
measure: Concentration of fecal calprotectin (mcg/g)
timeFrame: Measured at baseline, week 4, 16, and 24
measure: Lactulose:rhamnose ratio
timeFrame: Measured at week 4, 10, 16, and 24 for a subset of 200 participants (50 per arm)
measure: Proportion of participants with enteric infections
timeFrame: Measured at week 4 for all participants and at week 16 and 24 for a subset of 200 participants (50 per arm)
measure: Proportion of caregivers reporting that administration of lactoferrin and/or lysozyme was desirable or satisfactory via 5-point Likert scale responses in surveys and focus group discussions (FGDs)
timeFrame: Week 4, 10, 16 (surveys) and 6 months (FGDs)
measure: Proportion of caregivers reporting perceived trust, safety, and comfort in administering lactoferrin and/or lysozyme via 5-point Likert scale responses in surveys and focus group discussions (FGDs)
timeFrame: Week 16 (surveys) and 6 months (FGDs)
measure: Proportion of caregivers self-reporting their child consumed some or all of the investigational product ≥95% of the time using daily pictorial logs
timeFrame: 16 weeks
measure: Proportion of children adherent to the recommended dosing based on objectively measured container consumption (± 10% consumption of prescribed IP in all weeks)
timeFrame: 16 weeks
measure: Incremental costs of diarrhea
timeFrame: 6 months
measure: Cost-per-episode of diarrhea averted
timeFrame: 6 months
Other outcomes:
Locations:
city: Homa Bay
country: Kenya
facility: Homa Bay County Referral Hospital
city: Isibania
country: Kenya
facility: Isebania Sub-County Hospital
city: Kisii
country: Kenya
facility: Kisii Teaching and Referral Hospital
city: Rongo
country: Kenya
facility: Rongo Sub-County Hospital
Study officials:
affiliation: University of Washington
name: Patricia B Pavlinac
role: PRINCIPAL_INVESTIGATOR
References:
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