Limited Amount of Formula May Facilitate Breastfeeding: Randomized, Controlled Trial to Compare Standard Clinical Practice versus Limited Supplemental Feeding.

OBJECTIVES: Breastfeeding is known to reduce infant morbidity and improve well-being. Nevertheless, breastfeeding rates remain low despite public health efforts. Our study aims to investigate the effect of controlled limited formula usage during birth hospitalisation on breastfeeding, using the primary hypothesis that early limited formula feeds in infants with early weight loss will not adversely affect the rate of exclusive or any breastfeeding as measured at discharge, 3 and 6 months of age. MATERIAL AND METHODS: We randomly assigned 104 healthy term infants, 24 to 48 hours old, with ≥ 5% loss of birth weight to controlled limited formula (CLF) intervention (10 ml formula by syringe after each breastfeeding, discontinued at onset of lactation) or control group (standard approach, SA). Groups were compared for demographic data and breastfeeding rates at discharge, 3 months and 6 months of age (p-values adjusted for multiple testing). RESULTS: Fifty newborns were analysed in CLF and 50 in SA group. There were no differences in demographic data or clinical characteristics between groups. We found no evidence of difference between treatment groups in the rates of exclusive as well as any breastfeeding at discharge (p-value 0.2 and >0.99 respectively), 3 months (p-value 0.12 and 0.10) and 6 months of infants' age (p-value 0.45 and 0.34 respectively). The percentage weight loss during hospitalisation was significantly higher in the SA group (7.3% in CLF group, 8.4% in SA group, p = 0.002). CONCLUSION: The study shows that controlled limited formula use does not have an adverse effect on rates of breastfeeding in the short and long term. Larger studies are needed to confirm a possible potential in controlled limited formula use to support establishing breastfeeding and to help to improve the rates of breastfeeding overall. TRIAL REGISTRATION: ISRCTN registry ISRCTN61915183.

Sexually dimorphic response to feeding mode in the growth of infants.

BACKGROUND: The relation between infant feeding and growth has been extensively evaluated, but studies examining sex differences in the influence of infant milk feeding on growth are limited. OBJECTIVE: We examined the interaction of infant feeding and sex in relation to infant growth and compared growth trajectories in breastfed and formula-fed boys and girls. DESIGN: In 932 infants in a Singapore mother-offspring cohort, feeding practices in the first 6 mo were classified into the breastfeeding group (BF), mixed feeding group (MF), and formula feeding group (FF). Infant weight and length were measured and converted to WHO standards for weight-for-age z scores (WAZs) and length-for-age z scores (LAZs). Differences in WAZ and LAZ from birth to 6 mo, 6 to 12 mo, and 12 to 24 mo of age were calculated. Three-way interactions were examined between feeding mode, sex, and age intervals for WAZ and LAZ changes, with adjustment for confounders. RESULTS: The interaction between feeding mode, sex, and age intervals was significant for LAZ changes (P = 0.003) but not WAZ changes (P = 0.103) after adjustment for potential confounders. Compared with BF girls, BF boys showed similar LAZ gain (+0.28 compared with +0.39, P = 0.544) from 0 to 6 mo of age but greater LAZ gain from 6 to 12 mo of age (+0.39 compared with -0.10, P = 0.008). From 0 to 6 mo of age, FF boys and girls showed greater LAZ gains than their BF counterparts; from 6 to 12 mo of age, FF girls showed higher LAZ gain (+0.25 compared with -0.10, P = 0.031) than BF girls, which was not seen in boys. CONCLUSIONS: During infancy, there is a sexually dimorphic growth response to the mode of infant milk feeding, raising questions about whether formula feeding ought to remain sex neutral. However, further investigations on sex-specific feeding and infant growth are warranted before a conclusive message can be drawn based on our current findings. This trial was registered at www.clinicaltrials.gov as NCT01174875.

Differences in infant feeding practices by mode of conception in a United States cohort.

OBJECTIVE: To identify associations between fertility treatment use (assisted reproductive technologies, ovulation induction, and artificial insemination) and subsequent infant feeding practices. DESIGN: The Upstate KIDS population-based cohort enrolled mothers who delivered live births in New York (2008-2010), sampling on fertility treatment and plurality. SETTING: Not applicable. PATIENT(S): Data regarding singletons and one randomly selected infant between twins were used. INTERVENTION(S): Not applicable. MAIN OUTCOME MEASURE(S): Mothers reported breast feeding and formula feeding practices at 4, 8, and 12 months postpartum. Modified Poisson regression was used to compare risks for feeding practices by mode of conception. Marginal structural models were used to estimate the controlled direct effects of fertility treatment on feeding, independent of preterm birth. RESULT(S): Among 4,591 mothers, 1,361 (30%) conceived with the use of fertility treatments. Mothers who used fertility treatments were less likely to breast feed to 12 months after birth and were more likely to provide formula, solids, and juice by 4 months than mothers who did not conceive with treatments. Fertility treatment remained associated with breast feeding cessation and formula feeding in mediation analyses, suggesting that preterm birth does not fully explain these associations. CONCLUSION(S): Women who conceived with the use of fertility treatments were less likely to breast feed later in infancy and were more likely to provide formula, solids, and juice earlier in infancy. Our analyses accounted for confounding and preterm birth, but other contributing factors may include difficulties feeding twins or workplace breast feeding accommodations.

Enteral Feedings in Children: Sorting Out Tubes, Buttons, and Formulas.

Enteral nutrition (EN) is the provision of food or nutrients beyond the esophagus via a tube either to the stomach or small intestines. Choosing the route, method, and formula for administration of EN to infants and children is complicated by the increasing options available. Indications and contraindications change as surgical procedures and medical treatments advance. Human milk remains the normative standard for infant formulas; if a safe supply is available, it is recommended as optimal nutrition for infants, including via enteral tube access. For infants without an available supply of human milk and children older than 12 months, a wide variety of formulas are available, including the renewed interest in formulas using cooked table foods. This article presents the different methods of EN access placement, maintenance, formula recommendations, and advancement of EN. It is important for healthcare professionals to be aware of the options and recommendations for EN.

Manifestations of Cow's-Milk Protein Intolerance in Preterm Infants.

OBJECTIVES: Cow's-milk protein intolerance (CMPI) is poorly recognized in preterm infants. This study examined the clinical events that preceded the diagnosis of CMPI in preterm infants. METHODS: This was a retrospective study of infants in a level-III neonatal intensive care unit of those who received parenteral nutrition (PN) support during a 12-month period. Parameters assessed included birth weight (g), diagnosis, duration and frequency on PN, type of enteral feeds at initiation, and achievement of enteral autonomy. CMPI was diagnosed based on persistent feeding intolerance that resolved after change of feeds from intact protein to a protein hydrolysate or crystalline amino acid formula. RESULTS: Three hundred forty-eight infants with birth weight (median/range) 1618 g (425-5110) received PN. Fifty-one (14%) infants required multiple courses of PN, and 19 of 348 (5%) were diagnosed with CMPI. The requirement for multiple courses on PN versus single course was associated with a high likelihood of CMPI: 14 of 51 versus 5 of 297, P < 0.001. Nine of the 14 infants identified with CMPI were initially diagnosed with necrotizing enterocolitis (NEC) after a median duration of 22 days (19-57) on intact protein feeds. After recovery from NEC, they had persistent feeding intolerance including recurrence of "NEC-like illness" (N = 3) that resolved after change of feeds to a protein hydrolysate or crystalline amino acid formula. CONCLUSIONS: The requirement for multiple courses of PN because of persistent feeding intolerance after recovery from NEC and recurrence of "NEC-like illness" may be a manifestation of CMPI in preterm infants.

Enteral but not parenteral antibiotics enhance gut function and prevent necrotizing enterocolitis in formula-fed newborn preterm pigs.

Preterm infants are susceptible to infection and necrotizing enterocolitis (NEC) and are often treated with antibiotics. Simultaneous administration of enteral and parenteral antibiotics during the first days after preterm birth prevents formula-induced NEC lesions in pigs, but it is unknown which administration route is most effective. We hypothesized that only enteral antibiotics suppress gut bacterial colonization and NEC progression in formula-fed preterm pigs. Caesarean-delivered preterm pigs (90-92% of gestation) were fed increasing amounts of infant formula from birth to day 5 and given saline (CON) or antibiotics (ampicillin, gentamicin, and metronidazole) via the enteral (ENT) or parenteral (PAR) route (n = 16-17). NEC lesions, intestinal morphology, function, microbiology, and inflammatory mediators were evaluated. NEC lesions were completely prevented in ENT pigs, whereas there were high incidences of mild NEC lesions (59-63%) in CON and PAR pigs (P < 0.001). ENT pigs had elevated intestinal weight, villus height/crypt depth ratio, and goblet cell density and reduced gut permeability, mucosal adherence of bacteria, IL-8 levels, colonic lactic acid levels, and density of Gram-positive bacteria, relative to CON pigs (P < 0.05). Values in PAR pigs were intermediate with few affected parameters (reduced lactic acid levels and density and adherence of Gram-positive bacteria, relative to CON pigs, P < 0.05). There was no evidence of increased antimicrobial resistance following the treatments. We conclude that enteral, but not parenteral, administration of antibiotics reduces gut bacterial colonization, inflammation, and NEC lesions in newborn, formula-fed preterm pigs. Delayed colonization may support intestinal structure, function, and immunity in the immediate postnatal period of formula-fed preterm neonates.

Safety of a thickened extensive casein hydrolysate formula.

OBJECTIVES: Cow's milk allergy (CMA) is treated in formula-fed infants with an extensive protein hydrolysate. This study aimed to evaluate the nutritional safety of a non-thickened and thickened extensively casein hydrolyzed protein formula (NT- and T-eCHF) in infants with CMA. METHODS: Infants younger than 6 mo old with a positive cow milk challenge test, positive IgE, or skin prick test for cow milk were selected. Weight and length were followed during the 6 mo intervention with the NT-eCHF and T-eCHF. RESULTS: A challenge was performed in 50/71 infants with suspected CMA and was positive in 34/50. All children with confirmed CMA tolerated the eCHF. The T-eCHF leads to a significant improvement of the stool consistency in the whole population and in the subpopulation of infants with proven CMA. Height and weight evolution was satisfactory throughout the 6 mo study. CONCLUSIONS: The eCHF fulfills the criteria of a hypoallergenic formula and the NT- and T-eCHF reduced CMA symptoms. Growth was within normal range.

Growth and tolerance of formula with lactoferrin in infants through one year of age: double-blind, randomized, controlled trial.

BACKGROUND: Human milk provides necessary macronutrients (protein, carbohydrate, fat) required for infant nutrition. Lactoferrin (Lf), a multifunctional iron-binding protein predominant in human milk, shares similar protein sequence, structure, and bioactivity with bovine Lf (bLf). This large-scale pediatric nutrition study was designed to evaluate growth and tolerance in healthy infants who received study formulas with bLf at concentrations within the range of mature human milk. METHODS: In this multi-center, double-blind, parallel-designed, gender-stratified prospective study 480 infants were randomized to receive a marketed routine cow's milk-based infant formula (Control; n = 155) or one of two investigational formulas with bLf at 0.6 g/L (LF-0.6; n = 165) or 1.0 g/L (LF-1.0; n = 160) from 14-365 days of age. Investigational formulas also had a prebiotic blend of polydextrose (PDX) and galactooligosaccharides (GOS) and adjusted arachidonic acid (ARA). The primary outcome was weight growth rate from 14-120 days of age. Anthropometric measurements were taken at 14, 30, 60, 90, 120, 180, 275, and 365 days of age. Parental recall of formula intake, tolerance, and stool characteristics was collected at each time point. Medically-confirmed adverse events were collected throughout the study period. RESULTS: There were no group differences in growth rate (g/day) from 14-120 days of age; 353 infants completed the study through 365 days of age ( CONTROL: 110; LF-0.6: 127; LF-1.0: 116). Few differences in growth, formula intake, and infant fussiness or gassiness were observed through 365 day of age. Group discontinuation rates and the overall group incidence of medically-confirmed adverse events were not significantly different. From 30 through 180 days of age, group differences in stool consistency (P < 0.005) were detected with softer stools for infants in the LF-0.6 and LF-1.0 groups versus CONTROL. CONCLUSION: Compared to the Control, infants who received investigational formulas with bLf and the prebiotic blend of PDX and GOS experienced a softer stooling pattern similar to that reported in breastfed infants. This study demonstrated routine infant formulas with bLf, a blend of PDX and GOS, and adjusted ARA were safe, well-tolerated, and associated with normal growth when fed to healthy term infants through 365 days of age. TRIAL REGISTRATION: ClinicalTrials.gov NCT01122654 . Registered 10 May 2010.

Application effect of extensively hydrolyzed milk protein formula and follow-up in preterm children with a gestational age of less than 34 weeks: study protocol for a randomized controlled trial.

BACKGROUND: The average incidence of preterm birth in the world is up to 11.1 %, and deaths of preterm children account for more than 50 % of neonatal deaths. Gastrointestinal function of preterm children with a gestational age less than 34 weeks is immaturely developed. For preterm children who can only be fed with formula due to their mothers' sickness, choosing a suitable formula can not only meet the high nutritional needs of preterm children, but also solve their low gastrointestinal tolerability, and is thus very important. METHODS/DESIGN: The study is a prospective, randomized, single-blind and controlled clinical trial. Preterm children with a gestational age less than 34 weeks meeting the inclusion criteria who cannot be breastfed will be included. To demonstrate the application effect of extensively hydrolyzed milk protein formula on the target population, preterm children will be randomized into two groups, 185 subjects in each group. The observation group will be fed with extensively hydrolyzed milk protein (100 % whey protein) formula, while the control group will be fed with preterm children's formula until the children are discharged from the neonatal intensive care unit (NICU). All the formula involved in this study will be from Dumex. After discharge, both groups will be uniformly fed with formula for 0 to 6-month-old infants. For statistical analysis, a chi-square test and Student's t test will be applied using SAS 9.4. DISCUSSION: This will be the first randomized controlled clinical study with long-term observation of the growth and development of preterm children during the NICU stay and at 3-month follow-up after discharge from the NICU. Results from this study will be used to determine whether the extensively hydrolyzed formula is more suitable for the low gastrointestinal tolerability of preterm children, and also whether feeding preterm children who are fed with such formula during the NICU stay with ordinary infant formula after discharge from the NICU would affect the normal growth and development of preterm children in the early stage of their lives. TRIAL REGISTRATION: This study was registered with the Chinese Clinical Trial Registry ( http://www.chictr.org.cn/ ) with number ChiCTR-IOR-14005696 , on December 22, 2014.

Theoretical Impact of Replacing Whole Cow's Milk by Young-Child Formula on Nutrient Intakes of UK Young Children: Results of a Simulation Study.

BACKGROUND: Research into the role of young-child formulae (YCF) in a child's diet is limited and there is no consensual recommendation on its use. We evaluated the theoretical nutritional impact of replacing the existing practice of consuming cow's milk by YCF. METHODS: From the UK Diet and Nutrition Survey of Infants and Young Children, whole cow's milk consumers, aged 12-18 months (n = 591) were selected for simulation scenarios. In Scenario 1, we tested the replacement of all whole cow's milk (434 ± 187 ml/day) by a matching volume of YCF, and in Scenario 2, all whole cow's milk was replaced by the on-pack recommended daily intake of 300 ml. Nutrient intakes before and after simulation scenarios were compared and evaluated against nutrient recommendations. RESULTS: Intakes of protein and saturated fatty acids were significantly decreased, whereas essential fatty acid intakes were increased. The prevalence of nutrient inadequacy before simulation was 95.2% for vitamin D and 53.8% for iron. After simulation, inadequacy decreased to 4.9% (Scenario 1) and 0% (Scenario 2) for vitamin D and to 2.7% (Scenario 1) and 1.1% (Scenario 2) for iron. CONCLUSIONS: Replacement of habitual cow's milk intake by a matching volume or 300 ml of YCF may lead to nutritional intakes more in line with recommendations in young children.

Effects on childhood body habitus of feeding large volumes of cow or formula milk compared with breastfeeding in the latter part of infancy.

BACKGROUND: There is controversy over whether a lack of breastfeeding is related to obesity development. OBJECTIVE: We examined the effects of feeding different types of milk in late infancy on childhood growth. DESIGN: A cohort of 1112 term, singleton children (born in 1992) from the Avon Longitudinal Study of Parents and Children, United Kingdom, were studied prospectively. Food records collected at 8 mo of age were used to define the following 5 mutually exclusive feeding groups on the basis of the type and amount of milk consumed: breast milk (BM), <600 mL formula milk/d (FMlow), ≥600 mL formula milk/d (FMhigh), <600 mL cow milk/d (CMlow), and ≥600 mL cow milk/d (CMhigh). Weight, height, and BMI were measured at 14 time points from birth to 10 y of age, and SD scores (SDSs) were calculated. Dietary energy and macronutrient intakes were available at 7 time points. RESULTS: CMhigh children were heavier than were BM children from 8 mo to 10 y of age with weight differences (after adjustment for maternal education, smoking, and parity) ≥0.27 SDSs and an average of 0.48 SDSs. The maximum weight difference was at 18 mo of age (0.70 SDS; 95% CI: 0.41, 1.00 SDS; P = <0.0001). CMhigh children were taller at some ages (25-43 mo; P < 0.01) and had greater BMI SDSs from ≥8 mo of age (at 9 y of age; P = 0.001). FMhigh children were heavier and taller than were BM children from 8 to 37 mo of age. There were marked dietary differences between milk groups at 8 mo of age, some of which persisted to 18 mo of age. Adjustments for current energy and protein intakes did not attenuate the growth differences observed. CONCLUSIONS: The feeding of high volumes of cow milk in late infancy is associated with faster weight and height gain than is BM feeding. The feeding of bottle-fed infants with high volumes of cow milk in late infancy may have a persisting effect on body habitus through childhood.

Highest Plasma Phenylalanine Levels in (Very) Premature Infants on Intravenous Feeding; A Need for Concern.

OBJECTIVE: To analyse the association in newborns between blood levels of phenylalanine and feeding method and gestational age. STUDY DESIGN: This observational, cross-sectional study included a sample of 11,829 infants between 2008 and 2013 in a Spanish region. Data were recorded on phenylalanine values, feeding method [breast, formula, mixed (breast plus formula), or partial or fully intravenous feeding], gestational age in weeks (<32, 32-37, ≥37), gender and days since birth at the moment of blood collection. Outcomes were [phenylalanine] and [phenylalanine] ≥95th percentile. Associations were analysed using multivariate models [linear (means difference) and logistic regression (adjusted odds ratios)]. RESULTS: Higher phenylalanine values were associated with lower gestational age (p<0.001) and with intravenous feeding (p<0.001). CONCLUSION: The degree of prematurity and intravenous feeding influenced the plasma concentration of phenylalanine in the newborn. Caution should be taken in [phenylalanine] for newborns with intravenous feeding, monitoring them carefully. Very preterm infants given the recommended amount of amino acids should also be strictly monitored. These findings should be taken into consideration and call for adapting the amounts to the needs of the infant.

Persistent effects of early infant diet and associated microbiota on the juvenile immune system.

Early infant diet has significant impacts on the gut microbiota and developing immune system. We previously showed that breast-fed and formula-fed rhesus macaques develop significantly different gut microbial communities, which in turn are associated with different immune systems in infancy. Breast-fed animals manifested greater T cell activation and proliferation and harbored robust pools of T helper 17 (TH17) cells. These differences were sustained throughout the first year of life. Here we examine groups of juvenile macaques (approximately 3 to 5 y old), which were breast-fed or formula-fed in infancy. We demonstrate that juveniles breast-fed in infancy maintain immunologic differences into the fifth year of life, principally in CD8(+) memory T cell activation. Additionally, long-term correlation networks show that breast-fed animals maintain persistent relationships between immune subsets that are not seen in formula-fed animals. These findings demonstrate that infant feeding practices have continued influence on immunity for up to 3 to 5 y after birth and also reveal mechanisms for microbial modulation of the immune system.

[EFFECT OF FEEDING METHOD ON THE DEVELOPMENT OF ATOPY IN NEWBORNS AT RISK].

The analysis of risk factors for the realization of allergy was carried out; the effect of genetic factors on the atopy development at the ages of 6 and 12 months was analyzed; incidence (prevalence) structure at the ages of 6 and 12 months was analyzed; based on the studies of the effects of feeding, nature of the formulas, and the terms of formula administration the conclusions about the methods of optimization of feeding of newborns at risk were drawn.

Similar Occurrence of Febrile Episodes Reported in Non-Atopic Children at Three to Five Years of Age after Prebiotics Supplemented Infant Formula.

This is a follow up study of a multicenter randomised placebo-controlled trial in seven centres in five West European countries. The RCT assessed the effect of infant formula supplemented with a mixture of prebiotics (with neutral short-chain and long-chain oligosaccharides and pectin-derived acidic oligosaccharides) during infancy in term-born children (n=1130). In the follow-up study 672 children (60% of the study population) participated: 232 (56%) from the prebiotics group (PG), 243 (58%) from the control group (CG), and 197 (66%) from the non-randomised breast-fed group (BG). The primary outcome was the occurrence of febrile episodes at three to five years of age prospectively documented by the parents: in the PG 1.17 (interquartile range 0.50-2.08) episodes per year versus 1.20 (0.52-2.57) in the CG; and 1.48 (0.65-2.60) in the BG. This specific prebiotics mixture given during infancy in healthy non-atopic subjects does not decrease febrile episodes and therefore seems not to prevent infection between their third and fifth birthday.

Provision of 10-40 g/d Lipid-Based Nutrient Supplements from 6 to 18 Months of Age Does Not Prevent Linear Growth Faltering in Malawi.

BACKGROUND: Complementing infant diets with lipid-based nutrient supplements (LNSs) has been suggested to improve growth and reduce morbidity, but the daily quantity and the milk content of LNSs affect their cost. OBJECTIVE: We tested the hypotheses that the change in mean length-for-age z score (LAZ) for infants provided with 10-40 g LNSs/d from ages 6 to 18 mo would be greater than that for infants receiving no dietary intervention at the same age and that provision of LNSs that did not contain milk would be as good as milk-containing LNSs in promoting linear growth. METHODS: We enrolled in a randomized single-blind trial 6-mo-old infants who were allocated to 1 of 6 groups to receive 10, 20, or 40 g LNSs/d containing milk powder; 20 or 40 g milk-free LNSs/d; or no supplement until 18 mo of age. The primary outcome was change in LAZ. RESULTS: Of the 1932 enrolled infants, 78 (4.0%) died and 319 (16.5%) dropped out during the trial. The overall reported supplement consumption was 71.6% of days, with no difference between the groups (P = 0.26). The overall mean ± SD length and LAZ changes were 13.0 ± 2.1 cm and -0.45 ± 0.77 z score units, respectively, which did not differ between the groups (P = 0.66 for length and P = 0.74 for LAZ). The difference in mean LAZ change in the no-milk LNS group compared with the milk LNS group was -0.02 (95% CI: -0.10, 0.06; P = 0.72). CONCLUSION: Our results do not support the hypothesis that LNS supplementation during infancy and childhood promotes length gain or prevents stunting between 6 and 18 mo of age in Malawi. This trial was registered at clinicaltrials.gov as NCT00945698.

Randomized Clinical Trial of Preoperative Feeding to Evaluate Intestinal Barrier Function in Neonates Requiring Cardiac Surgery.

OBJECTIVES: To evaluate intestinal barrier function in neonates undergoing cardiac surgery using lactulose/mannitol (L/M) ratio measurements, and to determine correlations with early breast milk feeding. STUDY DESIGN: This was a single-center, prospective, randomized pilot study of 27 term-born neonates (≥ 37 weeks gestation) requiring cardiac surgery who were randomized to 1 of 2 preoperative feeding groups: nil per os (NPO) or trophic (10 mL/kg/day) breast milk feeds. At 3 time points (preoperative [preop], postoperative [postop] day 7, and postop day 14), subjects were administered an oral L/M solution, after which urine L/M ratios were measured using gas chromatography, with higher ratios indicative of increased intestinal permeability. Trends over time in the mean urine L/M ratios for each group were estimated using a general linear mixed model. RESULTS: There were no adverse events related to preoperative trophic feeding. In the NPO group (n = 13), the mean urine L/M ratio was 0.06 at preop, 0.12 at postop day 7, and 0.17 at postop day 14. In the trophic breast milk feeds group (n = 14), the mean urine L/M ratio was 0.09 at preop, 0.19 at postop day 7, and 0.15 at postop day 14. In both groups, L/M ratios were significantly higher at postop day 7 and postop day 14 compared with preop (P < .05). CONCLUSION: Neonates have increased intestinal permeability after cardiac surgery extending to at least postop day 14. This pilot study was not powered to detect differences in benefit or adverse events comparing the NPO and trophic breast milk feeds groups. Further studies to identify mechanisms of intestinal injury and therapeutic interventions are warranted. TRIAL REGISTRATION: Registered with ClinicalTrials.gov: NCT01475357.