Lactoferrin and Lysozyme Supplementation for Long-term Diarrhea Sequelae
- Conditions
- WastingDiarrheaMalnutrition, Child
- Interventions
- Other: PlaceboDietary Supplement: LactoferrinCombination Product: Lactoferrin + LysozymeDietary Supplement: Lysozyme
- Registration Number
- NCT05519254
- Lead Sponsor
- University of Washington
- 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.
Recruitment & Eligibility
- Status
- RECRUITING
- Sex
- All
- Target Recruitment
- 600
- 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
- 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
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- FACTORIAL
- Arm && Interventions
Group Intervention Description Placebo Arm Placebo 16-week course of taste/appearance-matched placebo Lactoferrin Arm Lactoferrin 16-week course of lactoferrin Combination Arm (Lactoferrin + Lysozyme) Lactoferrin + Lysozyme 16-week course of lactoferrin and lysozyme Lysozyme Arm Lysozyme 16-week course of lysozyme
- Primary Outcome Measures
Name Time Method Incidence of moderate-to-severe diarrhea 6 months Defined as total number of new diarrhea episodes (\> 48 hours after a diarrhea-free period) deemed moderate-to-severe, divided by the child-time at risk during the 6-month follow-up period. Moderate-to-severe diarrhea will be defined as ≥ 3 using the CODA (Community DiarrhoeA) diarrhea severity score or dysentery (evidence or reported visible blood in stool).
Time to nutritional recovery 6 months Defined as the number of days since enrollment to the date of the second of two consecutive MUAC measurements ≥ 12.5 cm.
- Secondary Outcome Measures
Name Time Method Cost-per-episode of diarrhea averted 6 months Cost-per-episode of diarrhea averted will be measured in each arm and compared to the placebo arm
Incidence of medically-attended diarrhea 6 months Medically-attended diarrhea will be defined as diarrhea that led to an outpatient or inpatient visit at a health facility or hospital that is typically attended by a nurse, clinical officer, and/or physician. Episodes will be defined as per the primary outcome.
Cumulative duration of diarrhea 6 months Defined as cumulative days of diarrhea ascertained from follow-up visit questionnaires and a diarrhea diary, irrespective of episodes
Incidence of dysentery 6 months Dysentery will be defined as evidence or reported visible blood in stool. Episodes will be defined as per the primary outcome.
Concentration of fecal myeloperoxidase (ng/mL) Measured at baseline, week 4, 16, and 24 Fecal biomarker of enteric function
Incidence of severe diarrhea 6 months Severe diarrhea defined by the CODA diarrhea severity score of 7 or more or dysentery. Episodes will be defined as per the primary outcome.
Hemoglobin concentration Measured at week 16 Will be determined at week 16
Change in weight for length z-score 6 months Growth that includes length and weight measurements at each time point will be used to create age-standardized z-scores, calculated using WHO-established reference standards and the WHO ANTHRO software. Ponderal growth will be defined as change (Δ) in weight for length z-score (WLZ) and Δ MUAC.
Proportion of participants with enteric infections Measured at week 4 for all participants and at week 16 and 24 for a subset of 200 participants (50 per arm) Determined by qPCR at or below the minimum limit of detection (cycle thresholds \[CT\] \<35)
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) Week 4, 10, 16 (surveys) and 6 months (FGDs) Acceptability measure
Incidence of diarrhea (any severity) 6 months Diarrhea (any severity) will be defined as diarrhea (3 or more abnormally loose or watery stool) during follow-up, irrespective of severity, ascertained through follow-up visit questionnaires and a diarrhea diary. Episodes will be defined as per the primary outcome.
Incidence of hospitalization 6 months Defined as any inpatient admission that results in an overnight stay (irrespective of diagnosis) in a health-facility and time to hospitalization or death analyzed as a combined outcome
Change in length for age z-score (linear growth) 6 months Growth that includes length and weight measurements at each time point will be used to create age-standardized z-scores, calculated using WHO-established reference standards and the WHO ANTHRO software. Linear growth will be defined as change (Δ) in LAZ.
Change in mid-upper arm circumference (cm) 6 months Growth that includes length and weight measurements at each time point will be used to create age-standardized z-scores, calculated using WHO-established reference standards and the WHO ANTHRO software. Ponderal growth will be defined as change (Δ) in weight for length z-score (WLZ) and Δ MUAC.
Concentration of fecal calprotectin (mcg/g) Measured at baseline, week 4, 16, and 24 Fecal biomarker of enteric function
Composite outcome of time to hospitalization and death 6 months Hospitalization will be defined as any inpatient admission that results in an overnight stay (irrespective of diagnosis) in a health-facility
Concentration of fecal alpha antitrypsin (mg/g) Measured at baseline, week 4, 16, and 24 Fecal biomarker of enteric function
Proportion of caregivers self-reporting their child consumed some or all of the investigational product ≥95% of the time using daily pictorial logs 16 weeks Adherence measure
Incremental costs of diarrhea 6 months Incremental costs of diarrhea will be measured in each arm and compared to the placebo arm
Lactulose:rhamnose ratio Measured at week 4, 10, 16, and 24 for a subset of 200 participants (50 per arm) Lactulose:rhamnose ratio is a functional assessment of enteric integrity. Ratio will be measured in subset of 50 children per arm (200 children total).
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) Week 16 (surveys) and 6 months (FGDs) Acceptability measure
Proportion of children adherent to the recommended dosing based on objectively measured container consumption (± 10% consumption of prescribed IP in all weeks) 16 weeks Adherence measure
Trial Locations
- Locations (4)
Homa Bay County Referral Hospital
🇰🇪Homa Bay, Kenya
Isebania Sub-County Hospital
🇰🇪Isibania, Kenya
Kisii Teaching and Referral Hospital
🇰🇪Kisii, Kenya
Rongo Sub-County Hospital
🇰🇪Rongo, Kenya