Clinical trial NCT03394664: FB4 (Framingham, Boston, Bloomington, Birmingham, and Baylor)
Official title: Macronutrients and Body Fat Accumulation: A Mechanistic Feeding Study
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: NA
Conditions: Obesity
Keywords: Body composition
Feeding study
Ketogenic diet
Weight loss
Energy Expenditure
Lead sponsor: Boston Children's Hospital
Sponsor class: OTHER
Collaborators: name: Indiana University
name: University of Alabama at Birmingham
name: Framingham State University
name: Baylor University
First posted: 2018-01-09
Enrollment: 166
Sex: ALL
Minimum age (years): 18
Maximum age (years): 50
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: This study will evaluate the effects of dietary carbohydrate and sugar consumption, independent of energy content, on body fatness and metabolism in a rigorous feeding study.

Detailed description: Many people with obesity can lose weight for a few months, but most have difficulty maintaining weight loss over the long term. Extensive research has shown that weight loss elicits biological adaptations - including a decline in energy expenditure and an increase in hunger - that promote weight regain. However, this observation leaves unanswered why average body weight has recently increased among populations that are mostly genetically stable. According to the Carbohydrate-Insulin Model, increased consumption of processed carbohydrates during the low-fat diet era of the last 40 years has raised the average body weight being defended by biological mechanisms on a population basis. Specifically, the investigators hypothesize that diets high in total carbohydrate (with or without added sugar) acting through increased insulin secretion, alter substrate partitioning toward storage in body fat, leading to increased hunger, slowing metabolism, and accumulation of body fat.

To test this hypothesis, the investigators plan a randomized-controlled feeding study involving 125 adults with obesity. During the run-in phase, participants will be given a hypocaloric very-low-carbohydrate (VLC) diet, with adjustment of energy intake to produce 15 ± 3% weight loss over 3 to 4 months on an outpatient basis. After weight stabilization, participants will be admitted to a residential center for 13 weeks. During the first 3 weeks, energy intake and expenditure will be closely monitored during weight-loss maintenance. Then, energy intake will be individually "locked" at levels equal to energy expenditure and participants will be administered one of three randomly-assigned test diets for 10 weeks. The test diets include VLC, High Carbohydrate-Low Sugar (HC-LS), and High Carbohydrate-High Sugar (HC-HS).

Eligibility criteria: Inclusion Criteria:

* Aged 18 to 50 years
* BMI ≥ 27 kg/m2
* Weight ≤ 350 lb
* Medical clearance from a primary care provider
* Willingness to follow a VLC weight-loss diet
* Willingness to reside in a research unit for 3 months and eat/drink only provided study foods and beverages
* No major food allergies or aversions
* Willingness to obtain seasonal flu shot or provide documentation of flu shot for current flu season (winter/spring cohort only)
* Willingness to discuss work options (e.g., remote work) with employer, and make appropriate arrangements prior to the Residential phase.

Exclusion Criteria:

* Change in body weight ≥ 10% during prior 6 months
* Specialized diets (e.g., for medical or religious reasons)
* Chronic use of any medication or dietary supplement that could affect study outcomes (e.g., insulin, metformin, thyroxine)
* Current smoking (1 cigarette in the last week)
* Greater than moderate alcohol consumption (\> 14 drinks/wk) or history of binge drinking (≥5 drinks in 1 day within past 6 months)
* Physician diagnosis of a major medical illness or eating disorder
* History of kidney stones
* Laboratory tests: ALT\>2x upper limit; abnormal HgA1c; abnormal TSH; abnormal creatinine; abnormal uric acid (using the male upper limit for both sexes)
* Failed criminal offender background check or sex offender background check
* Use of recreational drugs
* Current diagnosis or history of kidney stones, gout, or gall stones; or removal of gall bladder
* Exercise restrictions or at high risk for complications during exercise

Female-specific exclusion criteria:

* Menopausal
* Any change in birth control medication during the 3 months prior to enrollment
* Pregnancy or lactation during the 12 months prior to enrollment, or intent to become pregnant during study participation

Primary outcomes:
measure: Body fat mass
timeFrame: Change from post-weight loss (PWL, 0 weeks) to end of residential study (END, 10 weeks)
Secondary outcomes:
measure: Lean body mass
timeFrame: Change from post-weight loss (PWL, 0 weeks) to end of residential study (END, 10 weeks)
measure: Body weight
timeFrame: Change from post-weight loss (PWL, 0 weeks) to end of residential study (END, 10 weeks)
measure: Total energy expenditure (TEE)
timeFrame: Change from post-weight loss (PWL, 0 weeks) to end of residential study (END, 10 weeks)
measure: Resting energy expenditure (REE)
timeFrame: Change from post-weight loss (PWL, 0 weeks) to end of residential study (END, 10 weeks)
measure: Physical activity level, (moderate to vigorous)
timeFrame: Measurements made daily during 2 weeks at PWL, 2 weeks at END, and alternating non-assessment weeks of the residential phase and integrated into a unified outcome
measure: Insulin sensitivity
timeFrame: Change from post-weight loss (PWL, 0 weeks) to end of residential study (END, 10 weeks)
measure: Insulin secretion
timeFrame: Change from post-weight loss (PWL, 0 weeks) to end of residential study (END, 10 weeks)
measure: Glycemic control
timeFrame: Change from post-weight loss (PWL, 0 weeks) to end of residential study (END, 10 weeks)
measure: Total cholesterol
timeFrame: Change from post-weight loss (PWL, 0 weeks) to end of residential study (END, 10 weeks)
measure: HDL-cholesterol
timeFrame: Change from post-weight loss (PWL, 0 weeks) to end of residential study (END, 10 weeks)
measure: LDL-cholesterol
timeFrame: Change from post-weight loss (PWL, 0 weeks) to end of residential study (END, 10 weeks)
measure: Non-HDL cholesterol
timeFrame: Change from post-weight loss (PWL, 0 weeks) to end of residential study (END, 10 weeks)
measure: Triglycerides
timeFrame: Change from post-weight loss (PWL, 0 weeks) to end of residential study (END, 10 weeks)
measure: Plasminogen Activator Inhibitor-1 [PAI-1]
timeFrame: Change from post-weight loss (PWL, 0 weeks) to end of residential study (END, 10 weeks)
measure: High-sensitivity C-reactive protein [hsCRP]
timeFrame: Change from post-weight loss (PWL, 0 weeks) to end of residential study (END, 10 weeks)
measure: Uric acid
timeFrame: Change from post-weight loss (PWL, 0 weeks) to end of residential study (END, 10 weeks)
measure: Systolic blood pressure
timeFrame: Change from post-weight loss (PWL, 0 weeks) to end of residential study (END, 10 weeks)
measure: Diastolic blood pressure
timeFrame: Change from post-weight loss (PWL, 0 weeks) to end of residential study (END, 10 weeks)
measure: Thyroxine (T4)
timeFrame: Change from post-weight loss (PWL, 0 weeks) to end of residential study (END, 10 weeks)
measure: Free T4
timeFrame: Change from post-weight loss (PWL, 0 weeks) to end of residential study (END, 10 weeks)
measure: Thyroid stimulating hormone [TSH]
timeFrame: Change from post-weight loss (PWL, 0 weeks) to end of residential study (END, 10 weeks)
measure: Insulin-like growth factor-1 [IGF-1]
timeFrame: Change from post-weight loss (PWL, 0 weeks) to end of residential study (END, 10 weeks)
measure: Urine cortisol
timeFrame: Change from post-weight loss (PWL, 0 weeks) to end of residential study (END, 10 weeks)
measure: Urine catecholamines
timeFrame: Change from post-weight loss (PWL, 0 weeks) to end of residential study (END, 10 weeks)
measure: Leptin
timeFrame: Change from post-weight loss (PWL, 0 weeks) to end of residential study (END, 10 weeks)
measure: Total Adiponectin
timeFrame: Change from post-weight loss (PWL, 0 weeks) to end of residential study (END, 10 weeks)
measure: High-molecular weight adiponectin
timeFrame: Change from post-weight loss (PWL, 0 weeks) to end of residential study (END, 10 weeks)
measure: Sleep
timeFrame: Measurements made daily during 2 weeks at PWL, 2 weeks at END, and alternating non-assessment weeks of the residential phase and integrated into a unified outcome
measure: Blood glucose
timeFrame: Measurements made daily during residential phase (0 to 10 weeks) and integrated into a unified outcome
measure: Ghrelin
timeFrame: Change from post-weight loss (PWL, 0 weeks) to end of residential study (END, 10 weeks)
measure: Body Circumference
timeFrame: Change from post-weight loss (PWL, 0 weeks) to end of residential study (END, 10 weeks)
measure: Post-prandial energy expenditure and respiratory quotient
timeFrame: Single assessment in weeks 6 to 8 of residential study
measure: Activation of insulin signaling pathways
timeFrame: Change from post-weight loss (PWL, 0 weeks) to end of residential study (END, 10 weeks)
Other outcomes:
measure: 1,5-anhydroglucitol (1,5-AG)
timeFrame: Change from post-weight loss (PWL, 0 weeks) to end of residential study (END, 10 weeks)
measure: Lipoprotein particle subfraction distribution
timeFrame: Change from post-weight loss (PWL, 0 weeks) to end of residential study (END, 10 weeks)
measure: Fibrinogen
timeFrame: Change from post-weight loss (PWL, 0 weeks) to end of residential study (END, 10 weeks)
measure: Interleukin-6 (IL-6)
timeFrame: Change from post-weight loss (PWL, 0 weeks) to end of residential study (END, 10 weeks)
measure: Reverse triiodothyronine (rT3)
timeFrame: Change from post-weight loss (PWL, 0 weeks) to end of residential study (END, 10 weeks)
measure: Insulin-like growth factor-binding protein 3 (IGF-BP3)
timeFrame: Change from post-weight loss (PWL, 0 weeks) to end of residential study (END, 10 weeks)
measure: Luteinizing hormone (LH)
timeFrame: Change from post-weight loss (PWL, 0 weeks) to end of residential study (END, 10 weeks)
measure: Follicle stimulating hormone (FSH)
timeFrame: Change from post-weight loss (PWL, 0 weeks) to end of residential study (END, 10 weeks)
measure: Estradiol (E2)
timeFrame: Change from post-weight loss (PWL, 0 weeks) to end of residential study (END, 10 weeks)
measure: Testosterone (TST, total)
timeFrame: Change from post-weight loss (PWL, 0 weeks) to end of residential study (END, 10 weeks)
measure: Testosterone (TST, free)
timeFrame: Change from post-weight loss (PWL, 0 weeks) to end of residential study (END, 10 weeks)
measure: Metabolomics profile
timeFrame: Change from post-weight loss (PWL, 0 weeks) to end of residential study (END, 10 weeks)
measure: Biomarker of cholesterol synthesis
timeFrame: Change from post-weight loss (PWL, 0 weeks) to end of residential study (END, 10 weeks)
measure: Biomarker of cholesterol absorption
timeFrame: Change from post-weight loss (PWL, 0 weeks) to end of residential study (END, 10 weeks)
measure: MicroRNA
timeFrame: Change from post-weight loss (PWL, 0 weeks) to end of residential study (END, 10 weeks)
measure: Gut microbiome
timeFrame: Change from post-weight loss (PWL, 0 weeks) to end of residential study (END, 10 weeks)
measure: Demographics (mediator/modifier)
timeFrame: Pre-weight loss baseline
measure: Body composition (mediator/modifier)
timeFrame: Pre-weight loss baseline
measure: Measure of glucose homeostasis (insulin-30) (mediator/modifier)
timeFrame: Pre-weight loss baseline
measure: Measure of glucose homeostasis (insulin sensitivity) (mediator/modifier)
timeFrame: Pre-weight loss baseline
measure: Measure of glucose homeostasis (glycemic control) (mediator/modifier)
timeFrame: Pre-weight loss baseline
measure: Obesity related genetic risk (mediator/modifier)
timeFrame: Pre-weight loss baseline
measure: Body composition (mediator/modifier)
timeFrame: Change from post-weight loss (PWL, 0 weeks) to end of residential study (END, 10 weeks)
measure: Measure of glucose homeostasis (insulin-30) (mediator/modifier)
timeFrame: Change from post-weight loss (PWL, 0 weeks) to end of residential study (END, 10 weeks)
measure: Measure of glucose homeostasis (insulin sensitivity) (mediator/modifier)
timeFrame: Change from post-weight loss (PWL, 0 weeks) to end of residential study (END, 10 weeks)
measure: Measure of glucose homeostasis (glycemic control) (mediator/modifier)
timeFrame: Change from post-weight loss (PWL, 0 weeks) to end of residential study (END, 10 weeks)
measure: Physical activity level (moderate to vigorous) (mediator/modifier)
timeFrame: Measurements made daily during 2 weeks at PWL, 2 weeks at END, and alternating non-assessment weeks of the residential phase and integrated into a unified outcome
measure: Sex Hormone-Binding Globulin (SHBG)
timeFrame: Change from post-weight loss (PWL, 0 weeks) to end of residential study (END, 10 weeks)
measure: Urinary nitrogen
timeFrame: End of residential (END, 10 weeks)
measure: Glucagon-like peptide-1 (GLP-1)
timeFrame: Change from post-weight loss (PWL, 0 weeks) to end of residential study (END, 10 weeks)
measure: Glucose-dependent insulinotropic polypeptide (GIP)
timeFrame: Change from post-weight loss (PWL, 0 weeks) to end of residential study (END, 10 weeks)
measure: Glucagon
timeFrame: Change from post-weight loss (PWL, 0 weeks) to end of residential study (END, 10 weeks)
measure: Oxytocin
timeFrame: Change from post-weight loss (PWL, 0 weeks) to end of residential study (END, 10 weeks)
measure: Oxyntomodulin
timeFrame: Change from post-weight loss (PWL, 0 weeks) to end of residential study (END, 10 weeks)
Locations:
city: Ashland
country: United States
facility: Warren Conference Center and Inn
state: Massachusetts
Study officials:
affiliation: Boston Children's Hospital
name: David S Ludwig, MD, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Indiana University, Bloomington
name: David B Allison, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Boston Children's Hospital
name: Cara B Ebbeling, PhD
role: STUDY_DIRECTOR
References:
citation: Ludwig DS, Friedman MI. Increasing adiposity: consequence or cause of overeating? JAMA. 2014 Jun 4;311(21):2167-8. doi: 10.1001/jama.2014.4133. No abstract available.
citation: Ebbeling CB, Swain JF, Feldman HA, Wong WW, Hachey DL, Garcia-Lago E, Ludwig DS. Effects of dietary composition on energy expenditure during weight-loss maintenance. JAMA. 2012 Jun 27;307(24):2627-34. doi: 10.1001/jama.2012.6607.
citation: Jansen LT, Yang N, Wong JMW, Mehta T, Allison DB, Ludwig DS, Ebbeling CB. Prolonged Glycemic Adaptation Following Transition From a Low- to High-Carbohydrate Diet: A Randomized Controlled Feeding Trial. Diabetes Care. 2022 Mar 1;45(3):576-584. doi: 10.2337/dc21-1970.
citation: Wong JMW, Yu S, Ma C, Mehta T, Dickinson SL, Allison DB, Heymsfield SB, Ebbeling CB, Ludwig DS. Stimulated Insulin Secretion Predicts Changes in Body Composition Following Weight Loss in Adults with High BMI. J Nutr. 2022 Mar 3;152(3):655-662. doi: 10.1093/jn/nxab315.