Design and conduct of a randomized controlled feeding trial in a residential setting with mitigation for COVID-19.

BACKGROUND: Evaluating effects of different macronutrient diets in randomized trials requires well defined infrastructure and rigorous methods to ensure intervention fidelity and adherence. METHODS: This controlled feeding study comprised two phases. During a Run-in phase (14-15 weeks), study participants (18-50 years, BMI, ≥27 kg/m2) consumed a very-low-carbohydrate (VLC) diet, with home delivery of prepared meals, at an energy level to promote 15 ± 3% weight loss. During a Residential phase (13 weeks), participants resided at a conference center. They received a eucaloric VLC diet for three weeks and then were randomized to isocaloric test diets for 10 weeks: VLC (5% energy from carbohydrate, 77% from fat), high-carbohydrate (HC)-Starch (57%, 25%; including 20% energy from refined grains), or HC-Sugar (57%, 25%; including 20% sugar). Outcomes included measures of body composition and energy expenditure, chronic disease risk factors, and variables pertaining to physiological mechanisms. Six cores provided infrastructure for implementing standardized protocols: Recruitment, Diet and Meal Production, Participant Support, Assessments, Regulatory Affairs and Data Management, and Statistics. The first participants were enrolled in May 2018. Participants residing at the conference center at the start of the COVID-19 pandemic completed the study, with each core implementing mitigation plans. RESULTS: Before early shutdown, 77 participants were randomized, and 70 completed the trial (65% of planned completion). Process measures indicated integrity to protocols for weighing menu items, within narrow tolerance limits, and participant adherence, assessed by direct observation and continuous glucose monitoring. CONCLUSION: Available data will inform future research, albeit with less statistical power than originally planned.

Effects of Sugar-Sweetened, Artificially Sweetened, and Unsweetened Beverages on Cardiometabolic Risk Factors, Body Composition, and Sweet Taste Preference: A Randomized Controlled Trial.

Background A 2018 American Heart Association science advisory indicated that, pending further research, artificially sweetened beverages (ASBs) may be an appropriate initial replacement for sugar-sweetened beverages (SSBs) during transition to unsweetened beverages (USBs). Methods and Results We randomly assigned 203 adults (121 males, 82 females; 91.6% retention), who habitually consumed SSBs, to 3 groups and delivered free SSBs, ASBs, or USBs to their homes for 12 months. Outcomes included serum triglyceride to high-density lipoprotein cholesterol ratio (primary), body weight, and sweet taste preference (experimental assessment, 0%-18% sucrose solutions). Change in serum triglyceride to high-density lipoprotein cholesterol ratio was not different between groups. Although overall change in weight also was not different between groups, we found effect modification (P=0.006) by central adiposity. Among participants in the highest tertile of baseline trunk fat but not other tertiles, weight gain was greater (P=0.002) for the SSB (4.4±1.0 kg, estimate±SE) compared with ASB (0.5±0.9 kg) or USB (-0.2±0.9 kg) group. Both sweetness threshold (-1.0±0.2% m/v; P=0.005) and favorite concentration (-2.3±0.4% m/v; P<0.0001) decreased in the USB group; neither changed in the SSB group. In the ASB group, sweetness threshold did not change, and favorite concentration decreased (-1.1±0.5% m/v; P=0.02). Pairwise comparison between the ASB and USB groups indicated a difference in sweetness threshold (P=0.015). Conclusions Replacing SSBs with noncaloric beverages for 12 months did not affect serum triglyceride to high-density lipoprotein cholesterol ratio. Among individuals with central adiposity, replacing SSBs with either ASBs or USBs lowered body weight. However, USBs may have the most favorable effect on sweet taste preference. Registration URL: https://www.clinicaltrials.gov; unique identifier: NCT01295671.

Effects of a low carbohydrate diet on energy expenditure during weight loss maintenance: randomized trial.

OBJECTIVE: To determine the effects of diets varying in carbohydrate to fat ratio on total energy expenditure. DESIGN: Randomized trial. SETTING: Multicenter collaboration at US two sites, August 2014 to May 2017. PARTICIPANTS: 164 adults aged 18-65 years with a body mass index of 25 or more. INTERVENTIONS: After 12% (within 2%) weight loss on a run-in diet, participants were randomly assigned to one of three test diets according to carbohydrate content (high, 60%, n=54; moderate, 40%, n=53; or low, 20%, n=57) for 20 weeks. Test diets were controlled for protein and were energy adjusted to maintain weight loss within 2 kg. To test for effect modification predicted by the carbohydrate-insulin model, the sample was divided into thirds of pre-weight loss insulin secretion (insulin concentration 30 minutes after oral glucose). MAIN OUTCOME MEASURES: The primary outcome was total energy expenditure, measured with doubly labeled water, by intention-to-treat analysis. Per protocol analysis included participants who maintained target weight loss, potentially providing a more precise effect estimate. Secondary outcomes were resting energy expenditure, measures of physical activity, and levels of the metabolic hormones leptin and ghrelin. RESULTS: Total energy expenditure differed by diet in the intention-to-treat analysis (n=162, P=0.002), with a linear trend of 52 kcal/d (95% confidence interval 23 to 82) for every 10% decrease in the contribution of carbohydrate to total energy intake (1 kcal=4.18 kJ=0.00418 MJ). Change in total energy expenditure was 91 kcal/d (95% confidence interval -29 to 210) greater in participants assigned to the moderate carbohydrate diet and 209 kcal/d (91 to 326) greater in those assigned to the low carbohydrate diet compared with the high carbohydrate diet. In the per protocol analysis (n=120, P<0.001), the respective differences were 131 kcal/d (-6 to 267) and 278 kcal/d (144 to 411). Among participants in the highest third of pre-weight loss insulin secretion, the difference between the low and high carbohydrate diet was 308 kcal/d in the intention-to-treat analysis and 478 kcal/d in the per protocol analysis (P<0.004). Ghrelin was significantly lower in participants assigned to the low carbohydrate diet compared with those assigned to the high carbohydrate diet (both analyses). Leptin was also significantly lower in participants assigned to the low carbohydrate diet (per protocol). CONCLUSIONS: Consistent with the carbohydrate-insulin model, lowering dietary carbohydrate increased energy expenditure during weight loss maintenance. This metabolic effect may improve the success of obesity treatment, especially among those with high insulin secretion. TRIAL REGISTRATION: ClinicalTrials.gov NCT02068885.

A randomized study of dietary composition during weight-loss maintenance: Rationale, study design, intervention, and assessment.

BACKGROUND: While many people with overweight or obesity can lose weight temporarily, most have difficulty maintaining weight loss over the long term. Studies of dietary composition typically focus on weight loss, rather than weight-loss maintenance, and rely on nutrition education and dietary counseling, rather than controlled feeding protocols. Variation in initial weight loss and insufficient differentiation among treatments confound interpretation of results and compromise conclusions regarding the weight-independent effects of dietary composition. The aim of the present study was to evaluate three test diets differing in carbohydrate-to-fat ratio during weight-loss maintenance. DESIGN AND DIETARY INTERVENTIONS: Following weight loss corresponding to 12±2% of baseline body weight on a standard run-in diet, 164 participants aged 18 to 65years were randomly assigned to one of three test diets for weight-loss maintenance through 20weeks (test phase). We fed them high-carbohydrate (60% of energy from carbohydrate, 20% fat), moderate-carbohydrate (40% carbohydrate, 40% fat), and low-carbohydrate (20% carbohydrate, 60% fat) diets, controlled for protein content (20% of energy). During a 2-week ad libitum feeding phase following the test phase, we assessed the effect of the test diets on body weight. OUTCOMES: The primary outcome was total energy expenditure, assessed by doubly-labeled water methodology. Secondary outcomes included resting energy expenditure and physical activity, chronic disease risk factors, and variables to inform an understanding of physiological mechanisms by which dietary carbohydrate-to-fat ratio might influence metabolism. Weight change during the ad libitum feeding phase was conceptualized as a proxy measure of hunger.

Effect on Physical Activity of a Randomized Afterschool Intervention for Inner City Children in 3rd to 5th Grade.

BACKGROUND: Less than 45% of U.S. children meet the 60 min·d(-1) physical activity (PA) guideline. Structured after-school PA programing is one approach to help increase activity levels. This study aimed to evaluate the feasibility and short-term impact of a supervised after-school PA and nutrition education program on activity levels. METHODS: Forty-two 3rd-5th graders from an inner-city school in Boston, MA were randomly assigned to a 10-wk after-school program of either: 1) weekly nutrition education, or 2) weekly nutrition education plus supervised PA 3 d·wk(-1) at a community-based center. At baseline and follow-up, PA was measured using accelerometry and fitness (VO2max) was estimated using the PACER 15-m shuttle run. Additional measures obtained were non-fasting finger stick total cholesterol (TC) and glucose levels, waist circumference (WC), body mass index (BMI), percent body fat (%BF), and blood pressure (BP). Values are presented as mean±SE, unless noted otherwise. RESULTS: Thirty-six participants completed the study (mean±SD; age 9.7±0.9 years). Participants attended >80% of the sessions. After adjusting for accelerometer wear time and other design factors, light and moderate-to-vigorous PA (MVPA) increased in the nutrition+PA group (+21.5±14.5 and +8.6±8.0 min·d(-1), respectively) and decreased in the nutrition only group (-35.2±16.3 and -16.0±9.0 min·d(-1), respectively); mean difference between groups of 56.8±21.7 min·d(-1) (light PA, p = 0.01) and 24.5±12.0 min·d(-1) (MVPA, p = 0.04). Time spent in sedentary behaviors declined in the nutrition+PA group (-14.8±20.7 min·d(-1)) and increased in the nutrition only group (+55.4±23.2 min·d(-1)); mean difference between groups of -70.2±30.9 min·d(-1) (p = 0.02). Neither group showed changes in TC, BP, WC, %BF, BMI percentile, or fitness (p>0.05). CONCLUSIONS: The supervised afterschool community-based nutrition and PA program was well accepted and had high attendance. The changes in light PA and MVPA has potential to promote weight maintenance in inner-city elementary school children, however longer term studies with larger samples are needed. TRIAL REGISTRATION: ClinicalTrials.gov NCT01104038.

Factors Associated with Clinical Research Recruitment in a Pediatric Academic Medical Center--A Web-Based Survey.

BACKGROUND: One of the most difficult aspects of conducting clinical research is the ability to successfully recruit participants. Pediatric clinical research presents unique recruitment challenges that relate to the need for parental consent on behalf of a minor, child assent, and school attendance. Yet, this has been less well studied. We conducted a survey of investigators performing human subjects research in a single large academic pediatric hospital to better understand characteristics of studies with successful recruitment. METHODS: We conducted a web-based survey from September 2011 to December 2011 of all principal investigators with an Institutional Review Board approved human subjects protocol at Boston Children's Hospital, a pediatric Academic Medical Center. The survey captured various characteristics of the protocols including study design, staffing, resources, and investigator experience and training as well as respondents' perceived barriers and facilitators to recruitment. We used chi square tests and Mantel-Haenszel test for linear trend to examine the relationship between selected predictor variables and the binary outcome of successful vs. unsuccessful recruitment and multivariable logistic regression analyses to examine the simultaneous influence of potential predictors on each outcome. RESULTS: Among the 349 eligible investigators, 52% responded to the survey, and 181 with valid data were included in the analyses. Two-thirds of the 87 protocols closed to enrollment reached 80% or more of their target enrollment, whereas, only one-third of the 94 protocols actively recruiting were meeting 80% of their target. Recruitment method appeared to be the only significant and independent factor associated with achieving 80% or more of target enrollment in closed to enrollment protocols. Closed to enrollment protocols that used recruitment in person were 4.55 times (95% CI 1.30 to 15.93; p = 0.02) more likely to achieve 80% or more of their target enrollment when compared to those that used other recruitment methods. Other potentially modifiable factors such as number of study visits, study duration and investigator experience were suggestive of being meaningfully related to recruitment. CONCLUSION: Recruiting in person may promote reaching an acceptable target enrollment in pediatric as well as adult clinical research. Future research is needed on larger and more diverse samples to gain a better understanding of how the characteristics and qualifications of the individuals who conduct recruitment influence participant enrollment as well as how best to approach patient and families for their participation.

Using high-dose omega-3 fatty acid supplements to lower triglyceride levels in 10- to 19-year-olds.

BACKGROUND: Omega-3 fatty acids supplements lower triglyceride (TG) levels in adults; little pediatric information is available. We evaluated their effect in hypertriglyceridemic adolescents. METHODS: Twenty-five patients aged 10 to 19 years with TG levels 150 to 1000 mg/dL were randomized to 6 months double-blind trial of Lovaza (~3360 mg docosahexaenoic acid + eicosapentaenoic acid per day) versus placebo. RESULTS: Baseline mean TG levels were 227 mg/dL (standard deviation = 49). TG levels declined at 3 months in the Lovaza group by 54 ± 27 mg/dL (mean ± standard error; P = .02) and by 34 ± 26 mg/dL (P = .16) in the placebo group. The difference in TG lowering between groups was not significant (P = .52). There were no between-group differences in endothelial function, blood pressure, body mass index, C-reactive protein, or side effects. CONCLUSIONS: High-dose omega-3 fatty acid supplements are well tolerated in adolescents. However, declines in TG levels did not differ significantly from Placebo in this small study.

Randomized controlled trial of an immunization recall intervention for adolescents.

OBJECTIVE: Determine if adolescent immunization rates can be improved by contacting the parents or by contacting both the parents and adolescents. METHODS: Thirteen- to 17-year-olds overdue for at least 1 of 3 immunizations were randomized to (1) a control arm (Control), (2) telephone calls to the parent/guardian (Parent Only), or (3) telephone calls to the parent/guardian and the adolescent (Parent/Adol). Immunization records were assessed 4 weeks and 1 year after the intervention. Two-sided χ(2) tests and logistic regression models were used to compare receipt of immunizations by study arm. RESULTS: The intention-to-treat analysis showed improved immunization rates at 4 weeks (adjusted odds ratio 2.27, 95% confidence interval 1.00-5.18), but not at 1 year, in the Parent/Adol group compared with controls. There was a trend toward increased immunization in the Parent Only group (odds ratio 2.02, 95% confidence interval 0.89-4.56). However, phone contact was not achieved for many parents and adolescents in the intervention groups. A post hoc analysis of the impact of actual phone contact showed significant improvement in immunization rates both 4 weeks and 1 year after the intervention among those who were reached successfully. CONCLUSIONS: Improvement in immunization rates was seen in the short term but not the long term after contacting both the parent and adolescent. Although telephone interventions may be effective when rapid immunization is necessary, the difficulty in reaching parents and adolescents by phone highlights the importance of up-to-date contact information and a need to assess the effectiveness of alternative means of communication.