Ustekinumab in paediatric patients with moderately to severely active Crohn's disease: UniStar study long-term extension results.

OBJECTIVES: To assess the efficacy, safety, immunogenicity, and pharmacokinetics through 240 weeks of ustekinumab treatment in paediatric patients from the long-term extension (LTE) of the phase 1, double-blind UniStar trial. METHODS: Paediatric patients with moderately to severely active Crohn's disease (CD) were randomised 1:1 and stratified by body weight (<40 or ≥40 kg) to low- or high-dose intravenous ustekinumab followed by a subcutaneous maintenance dose at Week 8. At Week 16, patients were eligible to enter the LTE at the discretion of the investigator and continued maintenance dosing every 8 weeks up to Week 240. RESULTS: Of the 34 patients who entered the LTE, 25 patients with evaluable data completed Week 48, and 41.2% (14/34) achieved clinical remission at Week 48. Among the 24 patients with Week-0 C-reactive protein (CRP) levels ≥3 mg/L, 29.2% (7/24) achieved normalisation of CRP at Week 48, while imputing missing data as failures. Through Week 240, the most common adverse events were infections (n = 28) and gastrointestinal disorders (n = 26). The most common serious adverse event was worsening of CD (n = 6). Only one patient had detectable antibodies to ustekinumab. Median serum ustekinumab concentrations remained consistent through Week 48, were detectable through Week 224, and trended lower in patients <40 kg. CONCLUSIONS: Efficacy and pharmacokinetics through 1 year and safety and immunogenicity through 4 years of ustekinumab treatment in paediatric patients with CD were generally comparable to those previously reported in adults.

Medical Nutrition Terminology and Regulations in the United States and Europe-A Scoping Review: Report of the ISPOR Nutrition Economics Special Interest Group.

BACKGROUND: The term medical nutrition (MN) refers to nutritional products used under medical supervision to manage disease- or condition-related dietary needs. Standardized MN definitions, aligned with regulatory definitions, are needed to facilitate outcomes research and economic evaluation of interventions with MN. OBJECTIVES: Ascertain how MN terms are defined, relevant regulations are applied, and to what extent MN is valued. METHODS: ISPOR's Nutrition Economics Special Interest Group conducted a scoping review of scientific literature on European and US MN terminology and regulations, published between January 2000 and August 2015, and pertinent professional and regulatory Web sites. Data were extracted, reviewed, and reconciled using two-person teams in a two-step process. The literature search was updated before manuscript completion. RESULTS: Of the initial 1687 literature abstracts and 222 Web sites identified, 459 records were included in the analysis, of which 308 used MN terms and 100 provided definitions. More than 13 primary disease groups as per International Classification of Disease, Revision 10 categories were included. The most frequently mentioned and defined terms were enteral nutrition and malnutrition. Less than 5% of the records referenced any MN regulation. The health economic impact of MN was rarely and insufficiently (n = 19 [4.1%]) assessed, although an increase in economic analyses was observed. CONCLUSIONS: MN terminology is not consistently defined, relevant European and US regulations are rarely cited, and economic evaluations are infrequently conducted. We recommend adopting consensus MN terms and definitions, for example, the European Society for Clinical Nutrition and Metabolism consensus guideline 2017, as a foundation for developing reliable and standardized medical nutrition economic methodologies.

Health-related quality of life, temperament, and eating behavior among formula-fed infants in the Philippines: a pilot study.

BACKGROUND: The rising prevalence of childhood obesity in Asia has led to interest in potential risk factors such as infant health-related quality of life (HRQoL), temperament and eating behaviors. This pilot study evaluated the utility of administering parent-reported outcome measures (PROMs) to explore these factors in Filipino infants and examined the relationships between these factors and infant sex, formula intake and weight, over time. METHODS: Forty healthy, 4-week-old, formula-fed infants (n = 20 males) were enrolled in this 6-week, prospective, uncontrolled study during which infants were exclusively fed a standard term infant formula enriched with alpha-lactalbumin. On Day-1 and 42, anthropometrics were measured and mothers completed a 97-item measure of HRQoL [Infant Toddler Quality of Life Questionnaire (ITQOL)] covering 6 infant-focused and 3 parent-focused concepts and a 24-item measure of infant temperament [Infant Characteristics Questionnaire (ICQ)]. At Day-42, mothers also completed an 18-item measure of infant appetite [Baby Eating Behaviour Questionnaire (BEBQ)]. A 3-day formula intake diary was completed before Day-42. Nonparametric statistics were used to evaluate correlations among outcomes and compare outcomes by visit and sex. RESULTS: Thirty-nine infants completed the study; similar results were observed in males and females. Completion of PROMs was 100% with no missing responses, but Cronbach's α was low for many concept scales scores. ITQOL scores [range 0 (worst)-100 (best)] were generally high (median ≥ 80) except for Day-1 and Day-42 Temperament and Mood and Day-1 General Health Perceptions scores. ITQOL but not ICQ temperament scores improved significantly between Day-1 and Day-42 (P < 0.01). Mean ± standard deviation BEBQ scores (range 1-5) were high for Enjoyment of Food (4.59 ± 0.60) and Food Responsiveness (3.53 ± 0.81), and low for Satiety Responsiveness (2.50 ± 0.73) and Slowness in Eating (1.71 ± 0.60). Better HRQoL scores were significantly (P < 0.05) associated with high General Appetite scores (3 ITQOL concepts, r = 0.32 to 0.54), greater Enjoyment of Food (4 ITQOL concepts, r = 0.35 to 0.42) and low levels of Slowness in Eating (7 ITQOL concepts, r = - 0.32 to - 0.47). CONCLUSION: Findings demonstrated the utility of the ITQOL, ICQ and BEBQ for measuring HRQoL, temperament and eating behavior, and the need for further adaptations for use in Filipino infants. TRIAL REGISTRATION: ClinicalTrials.gov identifier NCT02431377; Registered May 1, 2015.

Effect of maternal supplement beverage with and without probiotics during pregnancy and lactation on maternal and infant health: a randomized controlled trial in the Philippines.

BACKGROUND: Adequate nutrition is essential during pregnancy and lactation to provide sufficient energy and nutrients to meet the nutritional requirements of the mother, fetus and infant. The primary objective of this study was to assess the effect of a maternal nutritional supplement enriched with probiotics during pregnancy and early lactation on the incidence of infant diarrhea. METHODS: Healthy, pregnant (24-28 weeks gestation) women were randomized 1:1:1 to receive either no supplement or two servings per day of an oral supplement (140 kcal/serving) providing 7.9 g protein, multivitamin/minerals, and enriched or not with the probiotics Lactobacillus rhamnosus and Bifidobacterium lactis, from the third trimester of pregnancy until at least 2 months post-delivery. Incidence of infant diarrhea until 12 months post-delivery was analyzed by Poisson regression. The effect on maternal health, fetal growth, and infant growth and morbidity were also evaluated and analyzed by ANOVA. RESULTS: A total of 208 mother/infant pairs were included in the analysis. No significant difference in the incidence of infant diarrhea was observed between the three study groups. The mean maternal weight gains at delivery were similar among groups, despite an increase in caloric intake in the supplemented groups. No statistically significant differences between groups were observed in incidence of pregnancy-related or fetal adverse outcomes. Mean weight-, length-, BMI- and head circumference-for-age z-scores were below the WHO median value for all groups. Post-hoc analysis to compare the effect of the combined supplement groups versus the no supplement group on infant growth parameters showed, at 12 months, that the combined supplemented group had gained statistically significant more weight (8.97 vs. 8.61 kg, p = 0.001) and height (74.2 vs. 73.4 cm, p = 0.031), and had a higher weight-for-age z-score (- 0.62 vs. -0.88, p = 0.045) than the no supplement group. CONCLUSIONS: Maternal nutritional supplement with or without probiotics given during late pregnancy and early lactation was well tolerated and safe. Even though no difference in incidence of infant diarrhea was observed between the three groups, the analysis of the combined supplemented groups showed beneficial effects of maternal supplementation on infant weight and length gains at 12 months. TRIAL REGISTRATION: ClinicalTrial.gov: NCT01073033 . Registered 17.02.2010.

Feasibility and Psychometric Properties of the Infant Toddler Quality of Life (ITQOL) Questionnaire in a Community-Based Sample of Healthy Infants in China.

Objective Evaluate the feasibility and psychometric properties of the Infant Toddler Quality of Life (ITQOL) questionnaire as a measure of health-related quality of life (HRQOL) in a sample of Chinese infants. Methods The linguistically validated Simplified Chinese version of the ITQOL was used in a multicenter, observational study of healthy, term infants (N = 427), age 6 weeks at enrollment, in China. At Days 1 and 48, parents/guardians completed the ITQOL, the Short Form Health Survey (SF-12v2) and the Infant Gastrointestinal Symptom Questionnaire (IGSQ). ITQOL feasibility, reliability, ceiling/floor effects, concurrent validity and discriminatory validity were evaluated. Results Feasibility of administering the ITQOL was supported by strong response rates (> 97%) with < 1% missing items for all scales except physical abilities. Reliability was acceptable (Cronbach's alpha > 0.70) for all scales except Day 1 General Health (0.67). Floor effects were minimal (< 2%), except Day 1 physical abilities (7%). Ceiling effects increased from Days 1 to 48 across all scales. Concurrent validity was demonstrated by correlations between ITQOL infant-focused scales and IGSQ score (r = -0.20 to - 0.34, p < 0.001) and between parent-focused scales and SF-12v2 mental health composite (MCS) scores (r = 0.29-0.46, p < 0.001). ITQOL scales discriminated between infant subgroups based on illness-related outcomes (sick visits, adverse events) and between parent subgroups based on SF-12v2 MCS scores. Conclusion The Simplified Chinese version of the ITQOL performed well in a community-based sample of Chinese infants, with evidence supporting the instrument's feasibility, reliability, and validity. These data support the ITQOL as a valuable tool to assess HRQOL in Chinese infants.

Healthcare interventions for the prevention and control of gestational diabetes mellitus in China: a scoping review.

BACKGROUND: Gestational Diabetes Mellitus (GDM) is a type of diabetes which occurs during pregnancy. Women with GDM are at greater risk of complications during pregnancy and delivery, while babies born from mothers with GDM are at greater risk of post-natal complications. Using the most updated diagnosis criteria, the GDM prevalence is estimated at 9.3-25.5% worldwide and 9.3-18.9% in China. Our objective was to identify healthcare interventions aimed at GDM prevention and control in China. METHODS: A best-evidence synthesis was performed based on a systematic search of literature published between 1997 and October 2015 in PubMed, Web of Science, China National Knowledge Infrastructure (CNKI), and Wan-fang databases using keywords "Gestational Diabetes Mellitus", "GDM", "Intervention" "Medical Intervention" "Early Medical Intervention", "Dietary Intervention", "Exercise Intervention", "Lifestyle Intervention", "Therapy", "Treatment" and "China". Inclusion criteria were studies conducted in China, reporting GDM healthcare interventions, and published in either Chinese or English. Two reviewers independently assessed eligibility and quality of the studies and extracted the data. Treatment efficacy was examined with weighted pooled odds ratio (OR) meta-analyses. RESULTS: The search resulted in 5961 articles (published in 276 different Chinese language journals and 6 English language journals), of which 802 were included in this synthesis. While 39.4% (n = 316) failed to report the GDM diagnostic criteria used, the remaining studies classified GDM with various international (n = 5) or Chinese (n = 7) diagnostic standards. Treatment interventions were categorized into 6 types: dietary (18.6%), exercise (1.6%), medication (20.7%), health education (9.0%), psychological (2.6%) and combination (47.4%). No interventions aimed at GDM prevention were identified. Meta-analyses demonstrated a statistically significant overall benefit of GDM treatment strategies in reducing the odds of maternal and infant adverse outcomes (ORs range 0.20-0.34, 95% CI 0.17-0.49, P < 0.05 for all). Dietary, western medication, and combined interventions were the most effective inteventions. CONCLUSIONS: An increasing number of healthcare interventions were found in China aimed at controlling GDM while no interventions were intended for GDM prevention. Well-designed clinical trials are needed to determine the comparative and cost effectiveness of GDM prevention and treatment strategies.

Infant feeding and health-related quality of life in healthy Chinese infants: results from a prospective, observational cohort study.

BACKGROUND: Infant feeding regimens, including breastfeeding, formula-feeding, or a combination of the two, may influence infant health-related quality of life (HRQOL). However, few studies have examined this association. METHODS: This prospective cohort study assessed HRQOL in relation to three parent-selected feeding regimens: exclusively breastfed (n = 136), exclusively study formula-fed (n = 140), and mixed-fed with study formula and breast milk (n = 151). Healthy Chinese infants were enrolled at their first normally scheduled well infant clinic visit at age 42 days (study day 1). Parents independently chose their infants' feeding regimens prior to recruitment into the study, with infants in the formula and mixed-fed groups already consuming an infant formula enriched with α-lactalbumin and increased sn-2 palmitate and oligofructose. The Infant and Toddler Quality of Life Questionnaire, which includes six infant-focused and three parent-focused concepts, was used to assess HRQOL at day 1 and at a follow-up visit 48 days later. Scores for each concept ranged from 0 to 100. Parent quality of life (assessed using the Mental Component Summary score of the SF-12v2 Health Survey) was included in the ANCOVA model to adjust for its potential effect on parent's perception of infant HRQOL. RESULTS: HRQOL concept scores were high in all three study groups at both visits (mean scores 71-95). Day 1 HRQOL scores were not significantly different between groups. At day 48, 5 of 9 HRQOL scores were not significantly different between groups. However, scores for Temperament and Moods, General Health Perceptions and Parent Impact-Time were slightly but statistically significantly lower in the formula-fed group (mean scores 75-86; all p ≤ 0.01) compared to the breastfed (78-90) and mixed-fed (77-91) groups. Day 48 Parent Impact-Emotional scores were also significantly lower by a small margin (4 points; p = 0.003) in the formula-fed group compared with the breastfed group. CONCLUSIONS: HRQOL was high in this population of healthy infants, with only a few small differences in HRQOL concept scores observed between breastfed, formula-fed and mixed-fed infants. These results indicate favorable physical, mental, and social well-being in these infants and parents. Assessment of infant HRQOL is therefore feasible and provides valuable insight into parental perceptions of their child's health and well-being. TRIAL REGISTRATION: ClinicalTrials.gov, NCT01370967 .

A two-year randomized trial of obesity treatment in primary care practice.

BACKGROUND: Calls for primary care providers (PCPs) to offer obese patients behavioral weight-loss counseling have not been accompanied by adequate guidance on how such care could be delivered. This randomized trial compared weight loss during a 2-year period in response to three lifestyle interventions, all delivered by PCPs in collaboration with auxiliary health professionals (lifestyle coaches) in their practices. METHODS: We randomly assigned 390 obese adults in six primary care practices to one of three types of intervention: usual care, consisting of quarterly PCP visits that included education about weight management; brief lifestyle counseling, consisting of quarterly PCP visits combined with brief monthly sessions with lifestyle coaches who instructed participants about behavioral weight control; or enhanced brief lifestyle counseling, which provided the same care as described for the previous intervention but included meal replacements or weight-loss medication (orlistat or sibutramine), chosen by the participants in consultation with the PCPs, to potentially increase weight loss. RESULTS: Of the 390 participants, 86% completed the 2-year trial, at which time, the mean (±SE) weight loss with usual care, brief lifestyle counseling, and enhanced brief lifestyle counseling was 1.7±0.7, 2.9±0.7, and 4.6±0.7 kg, respectively. Initial weight decreased at least 5% in 21.5%, 26.0%, and 34.9% of the participants in the three groups, respectively. Enhanced lifestyle counseling was superior to usual care on both these measures of success (P=0.003 and P=0.02, respectively), with no other significant differences among the groups. The benefits of enhanced lifestyle counseling remained even after participants given sibutramine were excluded from the analyses. There were no significant differences between the intervention groups in the occurrence of serious adverse events. CONCLUSIONS: Enhanced weight-loss counseling helps about one third of obese patients achieve long-term, clinically meaningful weight loss. (Funded by the National Heart, Lung, and Blood Institute; POWER-UP ClinicalTrials.gov number, NCT00826774.).

Outcomes in Adult Inflammatory Bowel Disease Clinical Trials: Assessment of Similarity Among Participants with Adolescent-Onset and Adult-Onset Disease.

BACKGROUND AND AIMS: Most pediatric IBD studies are performed after medications are approved in adults and the majority of participants in these studies are adolescents. We hypothesized that adolescent-onset IBD is not fundamentally different than adult-onset IBD. If this is correct, the value of delaying access to novel drugs in adolescents becomes questioned. METHODS: Data from 11 randomized, double-blind, placebo-controlled adult phase 2 and 3 trials of 4 biologics were analyzed. Participants were categorized as having adolescent- or adult-onset disease (diagnosed 12 to <18, or ≥18 years). Multivariable modelling explored the association between age at diagnosis and response to treatment after adjustment for disease duration, extent, and severity at baseline. Data from dose arms were pooled to evaluate similarity of therapeutic response between adolescent- and adult-onset IBD within the same trial (not between doses or across trials). Ratios of odds ratios between the two groups were evaluated. RESULTS: Data from 6,283 study participants (2,575 with Crohn's disease [CD], 3,708 with ulcerative colitis [UC]) were evaluated. Of 2,575 study participants with CD, 325 were 12-<18 years old at diagnosis; 836 participants (32.4%) received placebo. Of 3,708 participants with UC, 221 were 12-<18 years old at diagnosis; 1,212 (33%) were receiving placebo. The majority of the ratios of ORs were within two-fold, suggesting that responses in adolescent and adult-onset participants are generally similar. CONCLUSION: Data presented lend support for extrapolating efficacy of biologics from adults to adolescents with IBD, which would facilitate earlier labeling and patient access.

Using multiple imputation of real-world data to estimate clinical remission in pediatric inflammatory bowel disease.

Aim: To evaluate the performance of the multiple imputation (MI) method for estimating clinical effectiveness in pediatric Crohn's disease in the ImproveCareNow registry; to address the analytical challenge of missing data. Materials & methods: Simulation studies were performed by creating missing datasets based on fully observed data from patients with moderate-to-severe Crohn's disease treated with non-ustekinumab biologics. MI was used to impute sPCDAI remission statuses in each simulated dataset. Results: The true remission rate (75.1% [95% CI: 72.6%, 77.5%]) was underestimated without imputation (72.6% [71.8%, 73.3%]). With MI, the estimate was 74.8% (74.4%, 75.2%). Conclusion: MI reduced nonresponse bias and improved the validity, reliability, and efficiency of real-world registry data to estimate remission rate in pediatric patients with Crohn's disease.

Validating the Simplified Endoscopic Mucosal Assessment for Crohn's Disease: A Novel Method for Assessing Disease Activity.

BACKGROUND: To demonstrate treatment efficacy in Crohn's disease (CD), regulatory authorities require that trials include an endoscopic remission/response end point; however, standardized endoscopic assessment of disease activity, such as the Simple Endoscopic Score for Crohn's Disease (SES-CD), is not typically recorded by clinicians in practice or outside of clinical trials. The novel Simplified Endoscopic Mucosal Assessment for Crohn's Disease (SEMA-CD) was developed to be easy to use in routine clinical practice and as a trial end point. We conducted a study to assess and validate the reliability and feasibility of SEMA-CD as a measure of endoscopic disease activity. METHODS: Pre- and post-treatment ileocolonoscopy videos of pediatric (n = 36) and adult (n = 74) CD patients from 2 ustekinumab clinical trials were each scored with SEMA-CD by 2 to 3 professional central readers, blinded to clinical history and other video scorings; the correlation between SEMA-CD and SES-CD previously completed during the trials was assessed. Sensitivity to change, inter- and intrarater reliability, and comparative ease of scoring were also assessed. RESULTS: The SEMA-CD strongly correlated with SES-CD (Spearman ρ = 0.89; 95% confidence interval, 0.86-0.92). Pre- to post-treatment changes in SEMA-CD vs in SES-CD were strongly correlated, and the correlation remained strong between the scores when compared by study population (pediatric, adult), disease severity, and video quality. Intra- and inter-rater reliability were good, and SEMA-CD was rated easier than SES-CD to score 63.0% of the time, although slightly more difficult than SES-CD to score <1.0% of the time. CONCLUSIONS: The SEMA-CD is reliable, reproducible, sensitive to change, and easy to use in both pediatric and adult patients with CD.

Sugar-sweetened beverage purchases and intake at event arenas with and without a portion size cap.

This is the first real-world study to examine the association between a voluntary 16-ounce (oz) portion-size cap on sugar-sweetened beverages (SSB) at a sporting arena on volume of SSBs and food calories purchased and consumed during basketball games. Cross-sectional survey data from adults exiting a Brooklyn, NY, USA arena (Barclays, n = 464) with a 16-oz portion-size restriction and a Manhattan, NY, USA arena with no portion-size restriction (Madison Square Garden, control, n = 295) after the portion cap policy was put in place from March through June 2014 were analyzed. Linear regression models adjusting for sex, age, BMI, ethnicity, race, marital status, education, and income were used to compare the two arenas during the post-implementation period. The survey response rate was 45.9% and equivalent between venues. Among all arena goers, participants at Barclays purchased significantly fewer SSB oz (-2.24 oz, 95% CI [-3.95, -0.53], p = .010) and consumed significantly fewer SSB oz (-2.34 oz, 95% CI[-4.01, -0.68], p = .006) compared with MSG after adjusting for covariates. Among those buying at least one SSB, Barclays' participants purchased on average 11.03 fewer SSB oz. (95% CI = [4.86, 17.21], p < .001) and consumed 12.10 fewer SSB oz (95% CI = [5.78, 18.42], p < .001). There were no statistically significant differences between arenas in food calories and event satisfaction. In addition, no one reported not ordering a drink due to small size. An SSB portion-size cap was associated with purchasing and consuming fewer SSB oz. without evidence of decreasing satisfaction with the event experience.

Iyengar Yoga versus Enhanced Usual Care on Blood Pressure in Patients with Prehypertension to Stage I Hypertension: a Randomized Controlled Trial.

The prevalence of prehypertension and Stage 1 hypertension continues to increase despite being amenable to non-pharmacologic interventions. Iyengar yoga (IY) has been purported to reduce blood pressure (BP) though evidence from randomized trials is lacking. We conducted a randomized controlled trial to assess the effects of 12 weeks of IY versus enhanced usual care (EUC) (based on individual dietary adjustment) on 24-h ambulatory BP in yoga-naïve adults with untreated prehypertension or Stage 1 hypertension. In total, 26 and 31 subjects in the IY and EUC arms, respectively, completed the study. There were no differences in BP between the groups at 6 and 12 weeks. In the EUC group, 24-h systolic BP (SBP), diastolic BP (DBP) and mean arterial pressure (MAP) significantly decreased by 5, 3 and 3 mmHg, respectively, from baseline at 6 weeks (P < .05), but were no longer significant at 12 weeks. In the IY group, 24 h SBP was reduced by 6 mmHg at 12 weeks compared to baseline (P = .05). 24 h DBP (P < .01) and MAP (P < .05) decreased significantly each by 5 mmHg. No differences were observed in catecholamine or cortisol metabolism to explain the decrease in BP in the IY group at 12 weeks. Twelve weeks of IY produces clinically meaningful improvements in 24 h SBP and DBP. Larger studies are needed to establish the long term efficacy, acceptability, utility and potential mechanisms of IY to control BP.

Protein levels and protease activity in milk from mothers of pre-term infants: A prospective longitudinal study of human milk macronutrient composition.

BACKGROUND AND AIMS: The composition and enzymology of human milk changes throughout the lactation period, and differ for mothers who give birth prematurely compared to those who deliver at full-term. Understanding the composition of milk from mothers of very low birth weight premature infants is of great significance, and the objective of this study was to evaluate the composition, protein profile and plasmin activity of milk from mothers who delivered infants at different gestational ages. METHODS: Samples of human milk were donated by women (n = 74) in the Cork, Ireland, area who gave birth to full-term (>37 weeks gestation, FT), pre-term (32-37 weeks, PT) and very pre-term (≤32 weeks, VPT) infants. FT milk was collected at 1, 3, 6 and 10 weeks post-partum (PP), while PT and VPT milk was collected weekly until the FT due date of the infant and subsequently followed the FT protocol. RESULTS: Gestational age did not significantly affect lactose or fat content or total energy content of milk. However, protein content, and levels of some individual proteins, were significantly affected by both gestational age at birth and duration of lactation, with significantly higher protein levels in PT or VPT milk samples at 0-7 days and 1-2 months, respectively. Plasmin activity was significantly higher in VPT milk, indicating differences in proteolytic processing in milk. CONCLUSION: Compositional differences between the milk of mothers of term and pre-term infants were greatest in terms of the protein profile, which showed both qualitative and quantitative differences, as well as difference in proteolytic activity.

Safety of Ustekinumab in Inflammatory Bowel Disease: Pooled Safety Analysis of Results from Phase 2/3 Studies.

BACKGROUND: Ustekinumab is currently approved globally in Crohn's disease (CD) and psoriatic diseases. Recent phase 3 data demonstrate safety/efficacy in ulcerative colitis (UC). Crohn's disease and UC phase 3 programs had similar study designs, facilitating integrated safety analyses. METHODS: Data from 6 ustekinumab phase 2/3 CD and UC studies were pooled, and safety was evaluated through 1 year. Patients received 1 placebo or ustekinumab (generally 130 mg or ~6 mg/kg) intravenous induction, then subcutaneous (90 mg) maintenance every 8/12 weeks. Analyses incorporated all patients who received ≥1 ustekinumab dose. Safety outcomes are presented as percentages of patients (induction) and as number of patients with events per 100 patient-years of follow-up (through 1 year). For key safety events, 95% confidence intervals (CIs) are provided, as appropriate. Hazard ratios with 95% CIs from time-to-event analyses for serious adverse events and serious infections were also performed. RESULTS: Through 1 year, 2574 patients received ustekinumab (1733 patient-years of follow-up). The number of patients with adverse events per 100 patient-years (placebo 165.99 [95% CI, 155.81-176.67] vs ustekinumab 118.32 [95% CI, 113.25-123.55]), serious AEs (27.50 [95% CI, 23.45-32.04] vs 21.23 [95% CI, 19.12-23.51]), infections (80.31 [95% CI, 73.28-87.84] vs 64.32 [95% CI, 60.60-68.21]), serious infections (5.53 [95% CI, 3.81-7.77] vs 5.02 [95% CI, 4.02-6.19]), and malignancies excluding nonmelanoma skin cancer (0.17 [95% CI, 0.00-0.93] vs 0.40 [95% CI, 0.16-0.83]) were similar between placebo and ustekinumab. CONCLUSIONS: The safety profile of ustekinumab across the pooled inflammatory bowel disease population through 1 year was favorable and generally comparable to placebo. These data are consistent with the established safety profile of ustekinumab across indications. CLINICALTRIALS.GOV NUMBERS: NCT00265122; NCT00771667; NCT01369329; NCT01369342; NCT01369355; NCT02407236.

Independent but coordinated trials: insights from the practice-based Opportunities for Weight Reduction Trials Collaborative Research Group.

BACKGROUND: The National Heart, Lung, and Blood Institute (NHLBI) funded three institutions to conduct effectiveness trials of weight loss interventions in primary care settings. Unlike traditional multi-center clinical trials, each study was established as an independent trial with a distinct protocol. Still, efforts were made to coordinate and standardize several aspects of the trials. The three trials formed a collaborative group, the 'Practice-based Opportunities for Weight Reduction (POWER) Trials Collaborative Research Group.' PURPOSE: We describe the common and distinct features of the three trials, the key characteristics of the collaborative group, and the lessons learned from this novel organizational approach. METHODS: The Collaborative Research Group consists of three individual studies: 'Be Fit, Be Well' (Washington University in St. Louis/Harvard University), 'POWER Hopkins' (Johns Hopkins), and 'POWER-UP' (University of Pennsylvania). There are a total of 15 participating clinics with ~1100 participants. The common primary outcome is change in weight at 24 months of follow-up, but each protocol has trial-specific elements including different interventions and different secondary outcomes. A Resource Coordinating Unit at Johns Hopkins provides administrative support. RESULTS: The Collaborative Research Group established common components to facilitate potential cross-site comparisons. The main advantage of this approach is to develop and evaluate several interventions, when there is insufficient evidence to test one or two approaches, as would be done in a traditional multi-center trial. LIMITATIONS: The challenges of the organizational design include the complex decision-making process, the extent of potential data pooling, time intensive efforts to standardize reports, and the additional responsibilities of the DSMB to monitor three distinct protocols.

Clinical Response to Two Formulas in Infants with Parent-Reported Signs of Formula Intolerance: A Multi-Country, Double-Blind, Randomized Trial.

BACKGROUND: Signs of feeding intolerance are common in formula-fed infants. We evaluated the clinical response to a partially hydrolyzed 100% whey protein formula with high sn-2 palmitate and reduced lactose (FA) and to an alpha-lactalbumin-enriched whey-predominant intact protein formula with full lactose (FB) in healthy full-term infants with parent-reported signs of feeding intolerance. METHODS: In a double-blind, parallel-group trial in 6 Asian study centers, exclusively formula-fed infants aged 30 to 90 days, whose parents reported fussiness-crying for ≥2 hours/day plus gassiness and/or stooling difficulty, and intended to switch formula, were randomly assigned to FA (n = 130) or FB (n = 129) for 14 days. Primary endpoint was daily duration of fussiness-crying. Secondary endpoints included gassiness, spitting-up, vomiting, sleep pattern, Infant Gastrointestinal Symptom Questionnaire (IGSQ) Index, infant temperament and maternal anxiety. RESULTS: Mean ± SE minutes/day of fussiness-crying in the 256 analyzed infants (FA, n = 127 and FB, n = 129) substantially decreased from baseline to study end in FA (291 ± 14 to 140 ± 8; -52%, P < .001), and FB (313 ± 14 to 153 ± 11, -51%, P < .001) with no difference between groups. Similarly, gassiness, spitting-up, vomiting and sleep pattern significantly improved by study end for both formulas. Mean ± SE IGSQ index scores significantly decreased from baseline to study end (FA: 44.5 ± 0.9 to 28.6 ± 0.7; FB: 44.5 ± 0.8 to 29.0 ± 0.7; P < .001) with no differences between groups. Infant temperament and maternal anxiety also improved significantly in both groups by study end. CONCLUSION: Switching from standard, full-lactose, intact whey/casein infant formulas to either study formula resulted in an improvement of gastrointestinal symptoms and associated behaviors in infants with signs of feeding intolerance. TRIAL REGISTRATION: https://clinicaltrials.gov, NCT02021058.

Correction: Early childhood obesity prevention efforts through a life course health development perspective: A scoping review.

[This corrects the article DOI: 10.1371/journal.pone.0209787.].

Early childhood obesity prevention efforts through a life course health development perspective: A scoping review.

INTRODUCTION: The obesity rate in preschool children in the United States (US) is 13.9%, while even higher rates are associated with racial and ethnic minorities and children from low-income families. These prevalence patterns underscore the need to identify effective childhood obesity prevention programs. METHOD: A scoping review was conducted following Arksey and O'Malley's framework to provide an overview of the types, effectiveness and cost-effectiveness of obesity prevention interventions and policies in children up to 6 years old. Inclusion criteria were studies at least 6-months duration; included a weight-based outcome, conducted in the US, English publications from January 2001 to February 2018. Exclusions: studies in overweight/obese children and obesity treatments, no comparator group. Evidence was characterized across the early life course and multiple-levels of influence. RESULTS: From the 2,180 records identified, 34 met the inclusion criteria. Less than half of the interventions initiated during pregnancy, infancy or preschool reported a significant improvement in a weight-based outcome. All interventions included strategies to influence individual- or interpersonal-level health behaviors, yet few removed obstacles in the healthcare system, physical/built environment, or sociocultural environment. The majority (78%) of the interventions occurred during preschool years, with 63% conducted in early childcare education settings serving low-income families. The health impact of the state-wide and national policies on children under age 6 years remains unclear. There was considerable uncertainty around estimates of the health and economic impacts of obesity prevention interventions and policies. CONCLUSION: There is a need to intensify early childhood obesity preventive efforts during critical periods of health development in the US. Future studies should estimate the feasibility, program effectiveness, and cost of implementing multilevel obesity prevention interventions and policies. Addressing these research gaps will provide stakeholders with the scientific evidence necessary to facilitate funding and policy decisions to decrease the prevalence of early childhood obesity.