Limited Versus Extended Trophic Feeding (LET-FEED) Trial
试验速览
- 阶段
- 2 期
- 状态
- 招募中
- 入组人数
- 350
- 试验地点
- 7
- 主要终点
- Late Onset Sepsis
研究概览
简要总结
Study Hypothesis/Question In infants born very preterm, advancing enteral feeds after 24 hours from birth (limited trophic feeds) versus after 72 hours (extended trophic feeds) reduces the risk of all-cause late onset sepsis (LOS) without increasing the risk of other adverse outcomes.
Study Design Type This is a multi-center, open-label, parallel-group, individual randomized controlled trial comparing two different trophic feeding regimens in preterm infants born between 25w0d and 31w6d. These infants will be randomly assigned to either the intervention group, receiving limited trophic feeding (20 to 25 mL/kg/day for one day) or the control group, receiving extended trophic feeding (20 to 25 mL/kg/day for three days) prior to advancing enteral feeds until full feeding volume (140 mL/kg/day) is achieved.
Eligibility Criteria Preterm infants with gestational ages between 25 0/7 and 31 6/7 weeks and a birthweight of <1500 grams who are admitted to six participating neonatal units will be eligible for inclusion. Infants with <5th percentile for weight at birth, vasopressor use within first 24 hours of life major congenital/genetic anomalies affecting enteral feeding, growth, or mortality, and those with a terminal illness in which decisions to withhold or limit support have been made will be excluded. Infants of parents or legal guardians who are unable to provide consent within 36 hours of birth will also be excluded.
Study Intervention/Methods Written parental informed consent will be obtained prenatally or within the first 36 hours of birth. Infants will be randomized to receive limited trophic feeds of 24 to 36 hours or extended trophic feeds for 72 hours prior to the advancement of enteral feeds. Infants will be fed parent's own milk (POM) with donor human milk as the alternative if POM is unavailable.
Primary Outcome Late-onset sepsis, defined as positive blood, urine, and/or cerebrospinal fluid (CSF) cultures in the presence of compatible clinical signs of sepsis, occurring after postnatal day 3 and before hospital discharge, and treated with antibiotics for 5 days or more.
Secondary Outcome(s) The trial will assess various secondary outcomes including length of hospital stay, all-cause in-hospital mortality, duration of IV fluids and central line utilization, necrotizing enterocolitis (Bell's stage IIa or higher), severe intraventricular hemorrhage (grade III or IV either unilaterally or bilaterally), bronchopulmonary dysplasia (oxygen requirement or positive pressure ventilation at 36 weeks corrected gestational age), or retinopathy of prematurity requiring intervention. Additionally, growth metrics throughout hospitalization will be evaluated using change in weight, length, and head circumference z-scores from birth to 36 weeks' corrected gestational age between infants in the limited and extended trophic feeding groups.
We will also evaluate the 2 year developmental outcomes of a subset of participants who consent to follow up. This will include the Bayley Scales of Infant and Toddler Development-4th edition Language, Cognitive, and Motor domain scores at 2 years corrected age.
详细描述
Up to 30% of all very preterm (VP; defined as those born before 32 weeks' gestation) newborns born within the United States develop late onset sepsis (LOS), a life-threatening infection that occurs after 72 hours from birth. LOS is the leading cause of morbidity in all very preterm newborns. VP newborns who develop LOS have significantly lower survival rates (adjusted risk ratio [aRR] 0.89, 95% confidence interval [CI] 0.87-0.90), 32% increased risk of being discharged on oxygen (aRR 1.32, 95% CI 1.26-1.38), 288% increased risk of needing a tracheostomy (aRR 2.88, 95% CI 2.47-3.37), and a 209% increased risk of requiring a gastrostomy tube (aRR 2.09, 95% CI 1.93-2.57).27 Thus, clinical practices that can reduce LOS are critically important to ensure VP newborns not only survive, but thrive, living lives free of disability or impairment.
One of the most protective factors in preventing LOS is an exclusive human milk-based diet. Common clinical practice for VP newborns includes starting human milk-based enteral feeds at approximately 20 mL/kg/day (e.g. "trophic feeds") and then progressively advancing the volume of enteral feeds daily until reaching a sufficient quantity to achieve adequate hydration and nutrition (e.g. "full feeds"). While enteral feeds are being advanced, VP newborns receive additional supplementary fluids and nutrition via intravenous (IV) infusions. Yet, any indwelling catheter to provide IV nutrition inherently increases the risk of LOS because the catheter breaches the newborn's protective skin barrier, thereby increasing risk of invasive infection from skin microbes.
One way to reduce the need for IV fluids is to initiate enteral human milk feeds earlier and advance feeds faster, thereby limiting the duration of indwelling IV catheters. An additional benefit of this approach is that early introduction of human milk prevents dysbiosis of the neonatal microbiome that is associated with LOS. By preventing the growth of harmful, pathogenic, sepsis-causing bacteria within the gut of VP newborns, these newborns have overall less risk of developing LOS. Yet, these benefits are with an exclusive human milk-based diet as meta-analyses and systematic reviews have demonstrated that feeding formula significantly increases the risk of necrotizing enterocolitis (NEC), a devastating inflammatory process within the gastrointestinal system that is associated with a 30-50% mortality rate.
A Gerber-funded (AA Salas PI, novice research award), pilot randomized trial that compared early versus delayed progressive feeding in 60 extremely preterm infants born at the University of Alabama Hospital showed that early progressive feeding reduced the need for central venous access (p=0.0001) and parenteral nutrition by 4 days (p=0.0005). Culture-proven sepsis (10% vs. 27%; p= 0.18) tended to be lower in the early progressive feeding group but did not reach statistical significance due to the limited power and sample size of the study.
Thus, the natural next question is whether early progression of enteral feeds in a multi-center trial improves clinical outcomes, namely prevention of invasive infection, without increased risk of adverse outcomes including mortality. The lack of multi-center clinical trials evaluating faster advancement of enteral feeds to full volume feeds has left clinicians with uncertainty about the risks and benefits of this approach and resulted in a lack of uniformity in clinical practice. This has led to significant differences in how VP newborns are fed across the US and globally, with some centers initiating and advancing feeds within the first few hours after birth and others continuing small volume "trophic" feeds without any advancement until day 4 after birth. Thus, clinicians caring for VP newborns are in dire need of evidence to determine the optimal feeding advancement strategy to improve their short- and long-term outcomes.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Single (Outcomes Assessor)
盲法说明
This will be an open label trial as it relates to do different feeding approaches preventing masking/blinding while in the hospital. However, the developmental assessment at 2 years CA will be masked to group.
入排标准
- 年龄范围
- 0 Years 至 2 Years（Child）
- 性别
- All
- 接受健康志愿者
- 是
入选标准
- •<1500 gram birthweight
- •25w0d-31w6d at birth
- •Consent to feed donor milk when parent's own milk is not available or of insufficient quantity
排除标准
- •<5th percentile for weight at birth (Fenton growth curve)
- •Parent or legal guardian unable to provide consent within 36 hours after birth
- •Congenital anomaly affecting decisions on enteral feedings (e.g. gastroschisis, omphalocele, congenital diaphragmatic hernia, congenital heart disease, etc.)
- •Known genetic condition affecting growth, feeding, or mortality
- •Vasopressor use within first 24 hours after birth (not including hydrocortisone)
- •Considered terminally ill
研究组 & 干预措施
Extended Trophic Feeding
Advancing enteral feeds after 3 days of trophic feeds of 20-25 mL/kg birthweight/day. Advancement of enteral feeds will be by approximately 30 mL/kg birthweight/day after 3 days of trophic feeds. Advancement will occur until achieving at least 140 mL/kg birthweight/day of enteral feeds. Enteral feeds will consist of parent's own milk or donor human milk.
干预措施: Extended Trophic Feeds (3 days of trophics) (Other)
Limited Trophic Feeds
Advancing enteral feeds after 1 day of trophic feeds of 20-25 mL/kg birthweight/day. Advancement of enteral feeds will be by approximately 30 mL/kg birthweight/day until achieving at least 140 mL/kg birthweight/day of enteral feeds. Enteral feeds will consist of parent's own milk or donor human milk.
干预措施: Limited Trophic Feeds (1 day of trophic feeds) (Other)
结局指标
主要结局
Late Onset Sepsis
时间窗: Through study completion, the end of NICU hospitalization, an average of 40 weeks' gestation
Defining LOS: For the purposes of this study, a positive finding of LOS will be defined as the following: a body fluid culture (e.g. blood, urine, CSF) that returns positive, obtained in the presence of compatible clinical signs of sepsis (e.g. hypotension, apnea/bradycardia, increasing oxygen requirements, increasing metabolic acidosis, lactic acidosis, hypoglycemia, hyperglycemia, etc.) occurring after 72 hours from birth and before hospital discharge that was treated with antibiotics for a minimum of 5 days.
次要结局
- All-Cause In-Hospital Mortality(Through study completion, the end of NICU hospitalization, an average of 40 weeks' gestation)
- Duration of parenteral nutrition(Through study completion, the end of NICU hospitalization, an average of 40 weeks' gestation)
- Duration of Central Venous Access(Through study completion, the end of NICU hospitalization, an average of 40 weeks' gestation)
- Length of hospitalization(Through study completion, the end of NICU hospitalization, an average of 40 weeks' gestation)
- Time to reach full enteral feeding volumes(Through study completion, the end of NICU hospitalization, an average of 40 weeks' gestation)
- Number of culture-proven late onset sepsis episodes(Through study completion, the end of NICU hospitalization, an average of 40 weeks' gestation)
- Type of late-onset sepsis(Through study completion, the end of NICU hospitalization, an average of 40 weeks' gestation)
- Necrotizing Enterocolitis(Through study completion, the end of NICU hospitalization, an average of 40 weeks' gestation)
- Spontaneous Intestinal Perforation (SIP)(Through study completion, the end of NICU hospitalization, an average of 40 weeks' gestation)
- Severe Intraventricular Hemorrhage (IVH)(Through study completion, the end of NICU hospitalization, an average of 40 weeks' gestation)
- Bronchopulmonary Dysplasia(At 36 weeks corrected gestational age)
- Retinopathy of Prematurity requiring Intervention(Through study completion, the end of NICU hospitalization, an average of 40 weeks' gestation)
- Patent Ductus Arteriosus Requiring Intervention(Through study completion, the end of NICU hospitalization, an average of 40 weeks' gestation)
- Type of pathogen detected in culture-positive late-onset sepsis(Through study completion, the end of NICU hospitalization, an average of 40 weeks' gestation)
- Change in Z-score of weight(From admission to 36 weeks corrected gestational age)
- Change in Z-score of length(From admission to 36 weeks corrected gestational age)
- Change in Z-score of head circumference(From admission to 36 weeks corrected gestational age)
研究者
Gregory C. Valentine, MD MED FAAP
Associate Professor, Department of Pediatrics
University of Washington