Pilot of a Prebiotic and Probiotic Trial in Young Infants With Severe Acute Malnutrition
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 入组人数
- 87
- 试验地点
- 1
- 主要终点
- Number of colonization of Bifidobacterium infantis in the intestine of the study participants as measured by qPCR during and after 28 days of supplementation (with and without prebiotics)
研究概览
简要总结
Malnutrition is an ever-present problem worldwide. It is estimated that over 18 million children under the age of 5 are affected by the most extreme form of undernutrition, severe acute malnutrition (SAM). In spite of having standardized management protocols, in many hospitals, inpatient mortality reaches up to 30%. Infectious morbidity is common among survivors. Diarrhea, severe intestinal inflammation, low concentrations of fecal short-chain fatty acids (SCFAs), and severe systemic inflammation are significantly associated with mortality in SAM. Investigators of this study have earlier shown that the gut microbiota in children with SAM is immature and is causally related to SAM.
Human milk contains between 10 and 20 g/liter of oligosaccharides (human milk oligosaccharides-HMOs) which is the third most abundant solid component after lactose and lipids. HMOs are resistant to gastrointestinal digestion in host infants, and thus the greater part of HMOs reached the colon and may act as prebiotics to shape a healthy gut ecosystem by stimulating the growth of useful microorganisms by acting as receptor analogs to inhibit the binding of various pathogens and toxins to epithelial cells. Probiotics are live organisms beneficial for a healthy life. The human digestive tract possesses a diverse microbial community throughout its extent, which supports their hosts generally for healthy living. Bifidobacterium spp. is dominant microbiota in infants who are exclusively breastfed and these infants are less likely to suffer from diarrhea. According to recent studies among the most common probiotics genera Lactobacillus and Bifidobacterium, the latter is more abundant in the gut. To carry out their functional activities, Bifidobacteria must be able to survive the gastrointestinal tract transit and persist, at least transiently, in the host. The population of Bifidobacteria in the gut community drastically decreases after weaning. Certain Bifidobacteria possess the metabolic capabilities to break down the HMOs. Consequently, it is observed that HMOs support the growth of select Bifidobacteria in the gut of the infant.
Research done at icddr,b and Washington University indicates that gut microbes are related to undernutrition and that children with SAM have gut dysbiosis that mediates some of the pathologies of their condition. The standard of care in these children should be reinforced by an intervention that corrects the gut dysbiosis, improves weight gain during nutritional rehabilitation, and reduces infectious morbidity. Investigators do not have any published data on the microbiome response to probiotic supplementation (with and without prebiotics) in malnourished infants or preserving the microbiome with probiotics in non-malnourished children.
A short-term pilot study should be conducted to evaluate the microbiome response to probiotic supplementation (with and without prebiotics) in malnourished populations to justify a larger study of clinical outcomes. Additionally, non-malnourished infants who are hospitalized for infectious conditions face challenges related to gut dysbiosis caused by antibiotic usage. Here the investigators will evaluate the ability of a probiotic intervention to rescue the microbiome of primarily breastfed non-malnourished infants.
Intervention: Bifidobacterium longum subspecies infantis (EVC001) with and without prebiotic supplementation for 28 days.
Objectives: To evaluate the microbiome response to probiotic supplementation (with and without prebiotics) in infants under 6 months with severe acute malnutrition and to compare the microbiome response with healthy infants with a probiotic.
Methods: Single-blind RCT, stratified randomization will be based on infant age at the time of transfer to the Nutritional Rehabilitation Unit (NRU).
3 treatment arms for infants with SAM
-
Placebo (Lactose)
-
Bifidobacterium infantis alone (Bif)
-
Bifidobacterium infantis + prebiotic Lacto-N-neotetraose [LNnT] (Bif+prebiotic) Age at enrollment
-
2-3.9 months of age
-
4-5.9 months of age 1 open-label treatment arm for 18 non-malnourished primarily breastfed infants: Bifidobacterium infantis alone (Bif)
Population:
- Group 1 (SAM): Infants between 2 and <6 months old with SAM as defined by weight-for-length Z score < -3 either sex, caregiver willing to provide consent for enrolment of the infant, caregiver willing to stay in the NRU for about 15 days, residence within 15 km from icddr,b
- Group 2 (non-malnourished): Non-malnourished infants (WLZ ≥ -1) <6 months old who are hospitalized for treatment with antibiotics for the infection, infants receiving at least 50% of nutritional intake from breast milk at the time of hospitalization, either sex, residence within 15 km from icddr,b
Primary Outcome measures/variables:
Bifidobacterium infantis colonization measured by qPCR during and after supplementation (with and without prebiotics)
详细描述
Specific Objectives:
To evaluate the microbiome response to probiotic supplementation (with and without prebiotics) in under 6 months infants with severe acute malnutrition and to compare the microbiome response with healthy infants supplemented with probiotic.
Study Site: The study will be conducted at Dhaka Hospital of the International Centre for Diarrheal Disease Research, Bangladesh (icddr,b). The institution possesses well equipped clinical care as well as laboratory facilities capable of performing all the clinical tests.
Study population:
Group 1 (SAM) Group 2 (non-malnourished)
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Basic Science
- 盲法
- Triple (Participant, Care Provider, Outcomes Assessor)
入排标准
- 年龄范围
- 2 Months 至 6 Months（Child）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Group 1 (SAM):
- •Infants between 2 and <6 months old with SAM as defined by weight-for-length < -3 Z and/ or bilateral pedal edema
- •either sex
- •caregiver willing to provide consent for enrolment of the infant
- •caregiver willing to stay in the Nutritional Rehabilitation Unit for about 15 days
- •residence within 15 km from icddr,b
- •Group 2 (non-malnourished):
- •Non-malnourished infants (WLZ ≥ -1) <6 months old who are hospitalized for treatment with antibiotics for infection (infants who come with a history of antibiotic intake for 3 days or more will be eligible; the last dose of such an antibiotic will have to be taken within last 24hours, the antibiotic intake should be documented by the verification of a prescription, the bottle of antibiotic or asking the caregiver about the name of antibiotic or its price and how it is reconstituted)
- •infant receiving at least 50% of nutritional intake from breast milk at the time of hospitalization
- •either sex
- •residence within 15 km from icddr,b
排除标准
- •Septic shock or very severe pneumonia requiring assisted ventilation
- •acute kidney injury on admission
- •congenital defects interfering with feeding such as cleft palate
- •chromosomal anomalies
- •tuberculosis
- •presence of bilateral pedal edema ongoing maternal antibiotic usage for breastfeeding infants
- •Group 1 (SAM) additional exclusion criteria:
- •Infants receiving ≥75% of nutrition from breast milk
- •Group 2 (non-malnourished) additional exclusion criteria:
- •Infants receiving <50% of nutrition from breast milk
结局指标
主要结局
Number of colonization of Bifidobacterium infantis in the intestine of the study participants as measured by qPCR during and after 28 days of supplementation (with and without prebiotics)
时间窗: 28 days
Number of colonization of Bifidobacterium infantis in the intestine of the study participants as measured by qPCR during and after 28 days of supplementation (with and without prebiotics)
次要结局
- Baseline stool pH(At screening)
- Bifidobacterium colonization (relative abundance) estimated by metagenomic analysis during/after supplementation of 28 days(28 days)
- Colonization of naturally occurring Bifidobacterium infantis strains identified by qPCR(28 days)
- Composition of breast milk microbiota(28 days)
- Recovery from Severe Acute Malnourished state by the infants as measured by absence (Secondary clinical outcome for Severe Acute Malnourished infants)(2 weeks (approximated))
- Length-for-age Z score measured by length (Secondary clinical outcome for Severe Acute Malnourished infants)(8 weeks)
- Etiology of diarrhea in young infants by TAC assay(28 days)
- Baseline composition of gut microbiota of the study participants as estimated by metagenomic analysis(28 days)
- Breast milk Human Milk oligosaccharide contents(28 days)
- Morbidity during Nutrition Rehabilitation Unit stay and post-discharge including number of (Secondary clinical outcome for Severe Acute Malnourished infants)(8 weeks)
- Duration of hospital stay (Secondary clinical outcome for Not Severe Acute Malnourished infants)(Through study completion, an average of 2 weeks)
- Change of anthropometry in long term follow up(20 months)
- Fecal Myeloperoxidase levels. (Secondary clinical outcome for Not Severe Acute Malnourished infants)(28 days)
- Change from baseline in stool pH during supplementation for 28 days(28 days)
- Rate of body weight gain (g/kg per day) by the study participants (Secondary clinical outcome for Severe Acute Malnourished infants)(8 weeks)
- Fecal Myeloperoxidase levels (Secondary clinical outcome for Severe Acute Malnourished infants)(28 days)
- Re-hospitalization rates (Secondary clinical outcome for Not Severe Acute Malnourished infants)(6 weeks)
- Recovery from moderate acute malnutrition (MAM) measured by achievement of Weight-for-Length Z-score ≥ -1 (Secondary clinical outcome for Severe Acute Malnourished infants)(8 weeks)