Targeting the Gut-brain Axis to Facilitate Weight Loss in High Fat Diet Consumers

Overweight and Obesity Clinical Trial

Official title:

Targeting the Gut-brain Axis to Facilitate Weight Loss in High Fat Diet Consumers

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT04614233
• Other study ID #: 2000028769
• Secondary ID: 1R01DK126295-01A
• Status: Active, not recruiting
• Phase: Phase 4
• Start date: April 6, 2021
• Est. completion date: December 31, 2027

Study information

• Verified date: February 2024
• Source: Yale University
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

The primary objective is to test if fat intake moderates the ability of oleoylethanolamide (OEA) to improve weight loss maintenance after the LEARN® weight loss program.

Description:

The proposed work takes a precision medicine approach to obesity treatment and focuses specifically on weight loss maintenance. We propose to optimize a stratification strategy, using neural, metabolic and behavioral measures to identify individuals who will maintain clinically significant weight loss by daily supplementation with the fatty acid amide, oleoylethanolamide (OEA) following a gold-standard behavioral weight loss program. We will also test a model underlying the efficacy of our intervention to provide insight for the further development of therapeutic avenues. Our first aim is to conduct a randomized double-blind placebo-controlled trial to determine if fat intake moderates the ability of OEA to improve weight loss maintenance after the (LEARN®) weight loss program. We predict fat intake will strongly moderate the ability of OEA to produce clinically significant weight loss and weight loss maintenance 4- and 12-months) after LEARN and that this should not be influenced by sex.

Our second aim is to test if the Dietary Fat and Sugar intake questionnaire (DFS) is associated with measures of saturated fat intake and to optimize a clinically useful stratification strategy. Towards this end we will: (1) perform a neuroimaging study to assess brain response to a high fat milkshake (2) assess blood-based biomarkers of fat intake and synthesis; and (3) collect dietary intake records and food frequency questionnaires (FFQs). We predict that (1) the DFS predicts measures of saturated fat intake (2) that baseline dorsal striatal (DS) response to milkshake predicts weight loss in the OEA but not the placebo group and that connectome based predictive modeling (CPM) reveals a "neural fingerprint" that predicts weight loss on OEA; and (3) LASSO regression will identify baseline measures that best predict outcome to inform selection of a practical clinical stratification recommendation.

Our third aim is to test a model of OEA effectiveness. We predict that weight loss outcome is associated with shifts in fat preference and intake and these effects are mediated by increases in DS response to milkshake in the OEA but not placebo group. We will also test whether high fat diet (HFD) is associated with performance on reinforcement and cognitive measures or changes in energy expenditure or substrate utilization. If so, we will test whether these associations and their reversal by OEA contribute to outcome mediation.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 120
• Est. completion date: December 31, 2027
• Est. primary completion date: December 31, 2027
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 55 Years

Eligibility

Inclusion Criteria:

• Ages 18-55

• Right-handed with a score of = +50 on the modified Edinburgh handedness scale

• English-speaking

• BMI > 25.0

• Comfortable with the fMRI procedures during the mock scanning session and rate milkshake as at least mildly liked

Exclusion Criteria:

• Serious or unstable medical illness (e.g., cancer)

• Past or current history of alcoholism or consistent drug use

• Current major psychiatric illness as defined by DSM-IV criteria including eating disorders

• Medications that affect alertness (e.g., barbiturates, benzodiazepines, chloral hydrate, haloperidol, lithium, carbamazepine, phenytoin, etc.)

• History of major head trauma with loss of consciousness

• Ongoing pregnancy

• History of metalworking, injury with shrapnel or metal slivers, or major surgery

• History of pacemaker or neurostimulator implantation

• Known taste or smell dysfunction

• A diagnosis of diabetes

• Any known allergy to foods used in the study, or any known life-threatening food allergy

• Tobacco use

Related Conditions & MeSH terms

• Overweight
• Overweight and Obesity
• Weight Loss

Intervention

Dietary Supplement:
• RiduZone (90% OEA)
Participants will be randomly assigned to take 2 capsules of RiduZone (each capsule contains 90% OEA ) daily for 16 months

Drug:
• Placebo
Participants will be randomly assigned to take 2 capsules of placebo daily for 16 months. Placebo capsules will consist of 180mg of hypromellose.

Locations

Country	Name	City	State
United States	Modern Diet and Physiology Research Lab	New Haven	Connecticut

Sponsors (2)

Lead Sponsor	Collaborator
Yale University	National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Percent change in body weight	Weight in kg will be used to measure the percent change in body weight.	Baseline, 4 month, 8 month, and 16 months
Primary	Change in absolute body weight	Weight in kg will be used to measure absolute body weight	Baseline, 4 month, 8 month, and 16 months
Primary	Change in waist circumference	Waist circumference to the nearest 0.1 cm	Baseline, 4 month, 8 month, 16 month
Primary	Change in hip circumference	Hip circumference to the nearest 0.1 cm	Baseline, 4 month, 8 month, and 16 months
Primary	Change in thigh circumference	Thigh circumference to the nearest 0.1 cm	Baseline, 4 month, 8 month, and 16 months
Primary	Change in body fat percent	Percentage of body fat measured with bioimpedance analysis	Baseline, 4 month, 8 month, and 16 months
Primary	Change in visceral adipose tissue	Visceral adipose tissue in liters measured with bioimpedance analysis	Baseline, 4 month, 8 month, 16 month
Primary	Change in saturated fat intake as measured by the DFS	Dietary fat intake will be measured monthly by diet fat and sugar intake questionnaire (DFS) and for 16 months starting from baseline. Higher scores indicate a higher frequency of saturated fat intake.	Baseline, 4 month, 8 month, and 16 months
Primary	Change in saturated fat intake as measured by the ASA24	Saturated fat intake will be measured monthly by the automated self-administered 24-Hour recall (ASA24) for 16 months starting from baseline.Saturated fat intake will be reported in grams.	Baseline, 4 month, 8 month, and 16 months
Primary	Change in total saturated fat intake as measured by 3-day food diaries	Saturated fat intake will be measured monthly by 3-day food diaries for 16 months starting from baseline. The 3-day food diaries will be processed with the Nutrition Data System for Research (NDSR). Saturated fat intake will be reported in grams.	Baseline, 4 month, 8 month, and 16 months
Primary	Change in total fat intake as measured by 3-day food diaries	Fat intake will be measured monthly by 3-day food diaries for 16 months starting from baseline. The 3-day food diaries will be processed with the Nutrition Data System for Research (NDSR). Total fat intake will be reported in grams.	Baseline, 4 month, 8 month, and 16 months
Primary	Change in total saturated fat intake as measured by C-reactive protein	Saturated fat intake will be measured by plasma C-reactive protein in mg/L	Baseline, 8 month
Primary	Change in brain response to milkshake	The Blood-oxygen-level-dependent response (BOLD) in the dorsal striatum to the taste of milkshake and tasteless stimuli will be measured using a 3T fMRI scanner at baseline for all participants and at month 8 for participants in the intervention group.	baseline, 8 month
Primary	Change in fat perception with Visual Analogue Scale	Fat perception will be measured with the Visual Analogue Scale. Participants will be asked to sample Jello's and puddings of differing fat concentrations and rate their perceptual attributes at baseline, month 4, month 8, and month 16 The Visual Analogue Scale (VAS) will be used to assess perceptual attributes such as oiliness, fattiness, and creaminess, while accounting for hunger, fullness, thirst, and wanting. The VAS is a horizontal line anchored by 'not at all' at one end and 'extremely' at the other. The scale value of 'not at all' will be 0% and the scale value of 'extremely' will be 100%. Higher values indicate that a subject perceives these attributes as more intense.	Baseline, 4 month, 8 month, and 16 months
Primary	Change in fat perception with General Labeled Magnitude Scale	Fat perception will be measured with the General Labeled Magnitude Scale (GLMS). Participants will be asked to sample Jello's and puddings of differing fat concentrations and rate their perceptual attributes at baseline, month 4, month 8, and month 16 The GLMS will assess intensity perception. The GLMS is a vertical line with quasi-logarithmic spaced labels that start at the bottom 'barely detectable' to 'strongest imaginable' at the top.	Baseline, 4 month, 8 month, and 16 months
Primary	Change in fat preference with Labeled Hedonic Scale	Fat preference will be measured. Participants will be asked to sample Jello's and puddings of differing fat concentrations and rate their hedonic attributes at baseline, month 4, month 8, and month 16 The Labeled Hedonic Scale (LHS) will assess liking. The LHS is a vertical line with quasi-logarithmic spaced labels that start at the bottom with 'most imaginable dislike' and go to 'most imaginable like' at the top, with the label 'neutral' in the middle. The scale value of 'most imaginable dislike' will be -100; the scale value of 'neutral' will be 0; the scale value of 'most imaginable like' will be 100. Higher values indicate greater liking of the sample.	Baseline, 4 month, 8 month, and 16 months
Primary	Change in sensitivity to the long-chain oleic acid C18:1 - measured by a 3-alternative forced choice test	Subjects will be presented with a set of three samples, one test sample with a specific concentration of fat and two control samples. Subjects will be instructed to choose "the odd one out". If the subject chooses incorrectly, the fat concentration of the fatty test sample will be increased in the next set of three samples. If the subject chooses correctly, the next set of three samples will have the fatty test sample would contain the same fat concentration as in the previously correctly identified set with two control samples. This will continue until the subject correctly chooses the fatty test sample three times consecutively.	Baseline, 4 month, 8 month, 16 month
Primary	Change in sugar perception with General Labeled Magnitude Scale	Sugar perception will be measured with the General Labeled Magnitude Scale. Participants will be asked to sample Jello's and puddings of differing sugar concentrations and rate their perceptual and attributes at baseline, month 4, month 8 , and month 16 The GLMS will assess intensity perception. The GLMS is a vertical line with quasi-logarithmic spaced labels that start at the bottom 'barely detectable' to 'strongest imaginable' at the top.	Baseline, 4 month, 8 month, and 16 months
Primary	Change in sugar preference with Labeled Hedonic Scale	Sugar perception will be measured with the Labeled Hedonic Scale. Participants will be asked to sample Jello's and puddings of differing sugar concentrations and rate their hedonic attributes at baseline, month 4, month 8, and month 16 The LHS will assess liking. The LHS is a vertical line with quasi-logarithmic spaced labels that start at the bottom with 'most imaginable dislike' and go to 'most imaginable like' at the top, with the label 'neutral' in the middle.	Baseline, 4 month, 8 month, and 16 months
Primary	Change in fat concentration preference measured by the Monell forced choice test	Fat concentration preference will be measured by the Monell forced-choice test. Participants will be asked to sample Jello's and puddings of differing fat concentrations at baseline, month 4, month 8 , and month 16.; Subjects will be presented with pairs of puddings of varying fat concentrations in a two-series test. Subjects will taste two puddings of different fat concentrations and indicate their preferred pudding. The following pairs of puddings will be presented based on the subject's previous choice. This will continue until selection of the same fat concentration twice relative to both a lower and a higher concentration, or until the lowest or highest concentration is chosen twice consecutively.	Baseline, 4 month, 8 month, and 16 months
Primary	Change in sweet concentration preference measured by the Monell forced choice test	Sweet concentration preference will be measured by the Monell forced-choice test. Participants will be asked to sample Jello's and puddings of differing sugar concentrations at baseline, month 4, month 8 , and month 16.; Subjects will be presented with pairs of puddings/Jello's of varying sugar concentrations in a two-series test. Subjects will taste two puddings/Jello's of different sugar concentrations and indicate their preference. The following pairs of puddings/Jello's will be presented based on the subject's previous choice. This will continue until selection of the same sugar concentration twice relative to both a lower and a higher concentration, or until the lowest or highest concentration is chosen twice consecutively.	Baseline, 4 month, 8 month, and 16 months
Primary	Change in food reinforcement with RED-13	The relative reinforcing value of foods will be measured using the Reward-Related Eating (RED-13) Questionnaire. This questionnaire results in a score from 0 as the lowest measure of reward-based eating drive and 36 as the highest.	Baseline and 8 month
Primary	Change in food reinforcement with Becker DeGroot Markov Auction Task	The relative reinforcing value of foods will be measured using a computerized auction task at baseline and month 8. The relative reinforcing value of foods will be measured with a modified version of the Becker DeGroot Markov Auction task. The outcome measure is willingness to pay, such that higher willingness to pay indicates higher relative reinforcing value of foods.	Baseline and 8 month
Primary	Change in cognition with Kirby Delay Discounting	A neuropsychological test battery will be performed to assess obesity or dopamine-related differences in cognition at baseline, month 4, month 8, and month 16. The neuropsychological test battery will include Kirby Delay Discounting, which measures temporal discounting (tendency for people to prefer small, immediate, monetary rewards over larger, delayed rewards). The steepness of the discounting curve represents the tendency for temporal discounting, such that a more steeply declining curve indicates a tendency to devalue rewards as they become more temporally remote.	Baseline, 4 month, 8 month, and 16 months
Primary	Change in cognition with the Relational Task	A neuropsychological test battery will be performed to assess obesity or dopamine-related differences in cognition at baseline, month 4, month 8, and month 16. The neuropsychological test battery will include the Relational Task which measures visual relational processing. The number of correct responses in the relational condition is the outcome measurement, such that more correct responses indicates higher visual relational processing.	Baseline, 4 month, 8 month, and 16 months
Primary	Change in cognition with Penn Progressive Matrices Test	A neuropsychological test battery will be performed to assess obesity or dopamine-related differences in cognition at baseline, month 4, month 8, and month 16. The neuropsychological test battery will include the Penn Progressive Matrices Test, which measures fluid intelligence. The number of correct responses is the outcome measurement, such that more correct responses indicates higher fluid intelligence.	Baseline, 4 month, 8 month, and 16 months
Primary	Change in cognition with Oral Reading Recognition Test	A neuropsychological test battery will be performed to assess obesity or dopamine-related differences in cognition at baseline, month 4, month 8, and month 16. The neuropsychological test battery will include the Oral Reading Recognition Test, which measures language decoding and reading. The score based on accuracy is the outcome measure, such that a higher score indicates higher language decoding and reading ability.	Baseline, 4 month, 8 month, and 16 months
Primary	Change in cognition with Variable Short Penn Line Orientation Test	A neuropsychological test battery will be performed to assess obesity or dopamine-related differences in cognition at baseline, month 4, month 8, and month 16. The neuropsychological test battery will include the Variable Short Penn Line Orientation Test, which measures visuospatial processing. The number of correct responses is the outcome measure, such that a higher number of correct responses indicates higher visuospatial processing ability.	Baseline, 4 month, 8 month, and 16 months
Primary	Change in cognition with Matrix Reasoning Task (Core NMOB)	A neuropsychological test battery will be performed to assess obesity or dopamine-related differences in cognition at baseline, month 4, month 8, and month 16. The neuropsychological test battery will include the Core Neuropsychological Measures for Obesity and Diabetes (Core NMOB). Core NMOB includes the Matrix Reasoning task, which reflects general cognitive ability or nonverbal reasoning ability. Accuracy across 35 trials is the outcome measure, such that higher accuracy indicates higher general cognitive ability or nonverbal reasoning ability.	Baseline, 4 month, 8 month, and 16 months
Primary	Change in cognition with Digit Symbol Substitution (Core NMOB)	A neuropsychological test battery will be performed to assess obesity or dopamine-related differences in cognition at baseline, month 4, month 8, and month 16. The neuropsychological test battery will include the Core Neuropsychological Measures for Obesity and Diabetes (Core NMOB). Core NMOB includes the Digit Symbol Substitution task, which reflects processing speed. The number of correctly matched symbols, within the administration time (90 seconds) is the outcome measure, such that higher number of correctly matched symbols indicates higher processing speed.	Baseline, 4 month, 8 month, and 16 months
Primary	Change in cognition with Go/No-Go Task (Core NMOB)	A neuropsychological test battery will be performed to assess obesity or dopamine-related differences in cognition at baseline, month 4, month 8, and month 16. The neuropsychological test battery will include the Core Neuropsychological Measures for Obesity and Diabetes (Core NMOB). Core NMOB includes the Go/No-Go task, which reflects response inhibition. The sensitivity index (d') and commission error rate is the outcome measure, such that higher d' and lower commission error rates indicate higher response inhibition.	Baseline, 4 month, 8 month, and 16 months
Primary	Change in cognition with Penn Word Memory Test	A neuropsychological test battery will be performed to assess obesity or dopamine-related differences in cognition at baseline, month 4, month 8, and month 16. The neuropsychological test battery will include the Penn Word Memory Test, which measures verbal episodic memory. The number of correct responses is the outcome measure, such that a higher number of correct responses indicates higher verbal episodic memory.	Baseline, 4 month, 8 month, and 16 months
Primary	Change in cognition with Dimensional Change Card Sorting (Core NMOB)	A neuropsychological test battery will be performed to assess obesity or dopamine-related differences in cognition at baseline, month 4, month 8, and month 16. The neuropsychological test battery will include the Core Neuropsychological Measures for Obesity and Diabetes (Core NMOB). Core NMOB includes the Dimensional Change Card Sorting task, which reflects cognitive flexibility and task-switching ability. The accuracy score is the outcome measure, such that higher accuracy indicates higher cognitive flexibility and task-switching ability.	Baseline, 4 month, 8 month, and 16 months
Primary	Change in cognition with Picture Sequence Memory (Core NMOB)	A neuropsychological test battery will be performed to assess obesity or dopamine-related differences in cognition at baseline, month 4, month 8, and month 16. The neuropsychological test battery will include the Core Neuropsychological Measures for Obesity and Diabetes (Core NMOB). Core NMOB includes the Picture Sequence Memory task, which reflects learning and memory. The accuracy score is the outcome measure, such that higher accuracy indicates higher learning and memory abilities.	Baseline, 4 month, 8 month, and 16 months
Primary	Change in cognition with Stockings of Cambridge (SOC) test (CANTAB)	A neuropsychological test battery will be performed to assess obesity or dopamine-related differences in cognition at baseline, month 4, month 8, and month 16. The neuropsychological test battery will include the Cambridge Neuropsychological Test Automated Battery (CANTAB). The CANTAB includes the Stockings of Cambridge test, which reflects spatial planning. Outcome measures assess the problem difficulty level reached, mean moves used and thinking time are the outcome measures. Scores will be compared to normative data from age and sex-matched peers.	Baseline, 4 month, 8 month, and 16 months
Primary	Change in cognition with Intra-Extra Dimensional Set Shift test (CANTAB)	A neuropsychological test battery will be performed to assess obesity or dopamine-related differences in cognition at baseline, month 4, month 8, and month 16. The neuropsychological test battery will include the Cambridge Neuropsychological Test Automated Battery (CANTAB). The CANTAB includes the Intra-Extra Dimensional Set Shift test, which reflects rule acquisition and reversal. Outcome measures assess the number of errors made, the number of trials completed, the number of stages completed and latency. Scores will be compared to normative data from age and sex-matched peers.	Baseline, 4 month, 8 month, and 16 months
Primary	Change in cognition with delayed non-matching to sample test (CANTAB)	A neuropsychological test battery will be performed to assess obesity or dopamine-related differences in cognition at baseline, month 4, month 8, and month 16. The neuropsychological test battery will include the Cambridge Neuropsychological Test Automated Battery (CANTAB). The CANTAB includes the delayed non-matching to sample test, which reflects visuospatial memory. Outcome measures include latency (the participant's speed of response), the number of correct patterns selected and a statistical measure giving the probability of an error after a correct or incorrect response. Scores will be compared to normative data from age and sex-matched peers.	Baseline, 4 month, 8 month, and 16 months
Primary	Change in cognition with Paired Associates Learning task (CANTAB)	A neuropsychological test battery will be performed to assess obesity or dopamine-related differences in cognition at baseline, month 4, month 8, and month 16. The neuropsychological test battery will include the Cambridge Neuropsychological Test Automated Battery (CANTAB). The CANTAB includes the Paired Associates Learning task, which assesses episodic memory and new learning. Outcome measures include the errors made by the participant, the number of trials required to locate the pattern(s) correctly, memory scores and stages completed. Scores will be compared to normative data from age and sex-matched peers.	Baseline, 4 month, 8 month, and 16 months
Primary	Change in cognition with Probabilistic-Feedback Reward Task	A neuropsychological test battery will be performed to assess obesity or dopamine-related differences in cognition at baseline, month 4, month 8, and month 16. The neuropsychological test battery will include the Probabilistic-Feedback Reward Task, which assesses the ability to learn from positive and negative outcome. Outcome measures include the number of times a symbol associated with positive feedback is chosen and the number of times a symbol associated with negative feedback is avoided. Scores will be compared to normative data from age and sex-matched peers.	Baseline, 4 month, 8 month, and 16 months
Primary	Change in resting energy expenditure	Indirect Calorimetry (IC) will be performed to measure fasting resting energy expenditure at baseline and month 8.	Baseline and 8 month
Primary	Change in respiratory exchange ratio	Indirect Calorimetry (IC) will be performed to measure fasting respiratory exchange ratio at baseline and month 8	Baseline and 8 month
Secondary	Change in Healthy Eating Index (HEI)	The overall Healthy Eating Index 2015 (HEI-2015) score will be calculated for each participant from 3-day food diaries processed through NDSR. This score is made up of 13 components that reflect recommendations in the 2015-2020 Dietary Guidelines for Americans. The maximum score for the HEI is 100, where points are awarded based on adequate intakes of total fruit, whole fruits, total vegetables, greens and beans, whole grains, dairy, protein foods, seafood and plant proteins, and unsaturated fatty acids. Points are also awarded for moderate intakes of refined grains, sodium, added sugars and saturated fats.	Baseline, 4 month, 8 month, 16 month
Secondary	Change in 3-day food diary total solid fat intake	Solid fat intake will be measured monthly by 3-day food diaries for 16 months starting from baseline. The 3-day food diaries will be processed with the Nutrition Data System for Research (NDSR) and solid fat intake will be reported in grams.	Baseline, 4 month, 8 month, 16 month
Secondary	Change in saturated fat intake measured by plasma cholesterol	Plasma cholesterol LDL/HDL will be measured at baseline and month 8	Baseline, 8 month
Secondary	Change in saturated fat intake measured by plasma triglycerides	Plasma triglycerides will be measured at baseline and month 8	Baseline, 8 month