Lactoferrin and Lysozyme Supplementation for Long-term Diarrhea Sequelae
试验速览
- 阶段
- 3 期
- 状态
- 招募中
- 入组人数
- 600
- 试验地点
- 8
- 主要终点
- Incidence of moderate-to-severe diarrhea
研究概览
简要总结
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.
详细描述
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Factorial
- 主要目的
- Treatment
- 盲法
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
入排标准
- 年龄范围
- 6 Months 至 24 Months（Child）
- 性别
- All
- 接受健康志愿者
- 是
入选标准
- •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
排除标准
- •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
结局指标
主要结局
Incidence of moderate-to-severe diarrhea
时间窗: 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
时间窗: 6 months
Defined as the number of days since enrollment to the date of the second of two consecutive MUAC measurements ≥ 12.5 cm.
次要结局
- Concentration of fecal alpha antitrypsin (mg/g)(Measured at baseline, week 4, 16, and 24)
- Concentration of fecal myeloperoxidase (ng/mL)(Measured at baseline, week 4, 16, and 24)
- Concentration of fecal calprotectin (mcg/g)(Measured at baseline, week 4, 16, and 24)
- Incidence of dysentery(6 months)
- Lactulose:rhamnose ratio(Measured at week 4, 10, 16, and 24 for a subset of 200 participants (50 per arm))
- 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))
- 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))
- 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))
- 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)
- Incidence of medically-attended diarrhea(6 months)
- Cumulative duration of diarrhea(6 months)
- Incidence of hospitalization(6 months)
- Composite outcome of time to hospitalization and death(6 months)
- Hemoglobin concentration(Measured at week 16)
- Change in length for age z-score (linear growth)(6 months)
- Change in weight for length z-score(6 months)
- Proportion of children adherent to the recommended dosing based on objectively measured container consumption (± 10% consumption of prescribed IP in all weeks)(16 weeks)
- Incremental costs of diarrhea(6 months)
- Incidence of diarrhea (any severity)(6 months)
- Cost-per-episode of diarrhea averted(6 months)
- Change in mid-upper arm circumference (cm)(6 months)
- Incidence of severe diarrhea(6 months)
- Incidence of diarrhea (any severity)(6 months)
- Incidence of severe diarrhea(6 months)
- Incidence of dysentery(6 months)
- Incidence of medically-attended diarrhea(6 months)
- Cumulative duration of diarrhea(6 months)
- Proportion of children who recovered from wasting based on two consecutive MUAC measurements ≥12.5 at any point during the follow-up period.(6 months)
- Incidence of hospitalization(6 months)
- Composite outcome of time to hospitalization and death(6 months)
- Hemoglobin concentration(Measured at week 16)
- Change in length for age z-score (linear growth)(6 months)
- Change in weight for length z-score(6 months)
- Change in mid-upper arm circumference (cm)(6 months)
- Concentration of fecal alpha antitrypsin (mg/g)(Measured at baseline, week 4, 16, and 24)
- Concentration of fecal myeloperoxidase (ng/mL)(Measured at baseline, week 4, 16, and 24)
- Concentration of fecal calprotectin (mcg/g)(Measured at baseline, week 4, 16, and 24)
- Lactulose:rhamnose ratio(Measured at week 4, 10, 16, and 24 for a subset of 200 participants (50 per arm))
- 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))
- 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))
- 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))
- 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)
- Proportion of children adherent to the recommended dosing based on objectively measured container consumption (± 10% consumption of prescribed IP in all weeks)(16 weeks)
- Incremental costs of diarrhea(6 months)
- Cost-per-episode of diarrhea averted(6 months)
研究者
Patricia B Pavlinac
Associate Professor, SPH: Global Health
University of Washington