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Examination of Bromocriptine on Homeostatic and Hedonic Mechanisms of Food Intake in Individuals at High Risk for T2DM

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ClinicalTrials.gov Identifier: NCT05405244
Recruitment Status : Completed
First Posted : June 6, 2022
Results First Posted : August 10, 2022
Last Update Posted : September 7, 2022
Sponsor:
Collaborator:
American Diabetes Association
Information provided by (Responsible Party):
University of North Carolina, Chapel Hill

Tracking Information
First Submitted Date  ICMJE May 31, 2022
First Posted Date  ICMJE June 6, 2022
Results First Submitted Date  ICMJE June 14, 2022
Results First Posted Date  ICMJE August 10, 2022
Last Update Posted Date September 7, 2022
Actual Study Start Date  ICMJE September 19, 2017
Actual Primary Completion Date September 19, 2019   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: August 12, 2022)
  • Ad Libitum Food and Beverage Intake (g) [ Time Frame: Within 15 minutes of completion of the ad libitum period ]
    Ad libitum food intake of highly-palatable snacks is assessed during each intervention arm. Participants are left alone for 25 minutes to eat as much as they want from a selection of snacks (M&Ms, Skittles, Doritos, cheddar popcorn) and a chocolate milkshake. Both snacks and milkshake are pre- and post-weighed to determine ad libitum food intake.
  • Hedonic Ratings of Food as Measured by a Visual Analog Scale [ Time Frame: Up to 5 minutes prior to ad libitum period start ]
    Testing the effects of the drug on hedonic ratings (pleasantness, desire to consume) of milkshake and snacks on a scale from -100 to 100. Pleasantness was assessed by asking 'How pleasant is this taste?', with responses ranging from -100 (most unpleasant imaginable) to 100 (most pleasant imaginable). Desire to consume was assessed by asking 'How much would you want to eat/drink this?', with responses ranging from -100 (least desirable imaginable) to 100 (most desirable imaginable).
  • Change in Voxel-wise Blood Oxygen Level-Dependent (BOLD) Brain Activation in Response to Milkshake Anticipation and Receipt vs. Water [ Time Frame: Baseline and 2 Weeks ]
    The fMRI paradigm assesses evoked BOLD response to cue-elicited anticipation and receipt of a milkshake and water. A region-of-interest (ROI) approach is used to assess changes in BOLD signal in the striatum. The striatal response is assessed for the two contrasts of interest: milkshake>h2o anticipation and milkshake>h2o receipt. Positive values reflect a higher striatal BOLD activation for the milkshake; negative reflects a higher striatal BOLD activation for the water. Parameter estimates of the relative BOLD response to each of these contrasts are extracted and compared between the two arms. The paradigm has 64 trials and each trial starts with the presentation of a cue for 1s signaling the impending delivery of either 3 mL of highly palatable milkshake or a control water solution over a period of 6s. Taste delivery is followed by a wait period and rinse (tasteless solution). The next trial begins after a 1-9s jitter. Order of milkshake and water trials is pseudo-randomized.
Original Primary Outcome Measures  ICMJE
 (submitted: May 31, 2022)
  • Ad libitum Food Intake (g) [ Time Frame: Within 15 minutes of completion of the ad libitum period ]
    Ad libitum food intake of highly-palatable snacks is assessed during each intervention arm. Participants are left alone for 25 minutes to eat as much as they want from a selection of snacks (M&Ms, Skittles, Doritos, cheddar popcorn) and drink as much as they want from a high-fat/high-sugar chocolate milkshake. Both snacks and milkshake is pre- and post-weighed to determine ad libitum food intake.
  • Hedonic Ratings of Food as Measured by a Visual Analog Scale [ Time Frame: Up to 5 minutes prior to ad libitum period start ]
    Participants use an iPad to complete visual analog scale (VAS) ratings of the food items offered during the ad libitum intake in each intervention arm. They were asked to rate perceived pleasantness and desire to consume each of the foods using adapted labeled scales. Pleasantness was assessed by asking 'How pleasant is this taste?', with responses ranging from -100 (most unpleasant imaginable) to 100 (most pleasant imaginable). Desire to consume was assessed by asking 'How much would you want to eat/drink this?', with responses ranging from -100 (least desirable imaginable) to 100 (most desirable imaginable).
  • Change in Voxel-wise Blood Oxygen Level-Dependent (BOLD) Brain Activation in Response to Milkshake Anticipation and Receipt vs. Baseline [ Time Frame: Baseline and 2 Weeks ]
    The fMRI paradigm assesses evoked BOLD response to cue-elicited anticipation and receipt of a chocolate milkshake and a water solution. A region-of-interest (ROI) approach will be used to assess changes in BOLD response in the striatum. The paradigm is controlled by in-house Python scripts. Each trial in the paradigm starts with the presentation of a cue (duration: 1s) signaling the impending delivery of either 3 mL of highly palatable milkshake or a control water solution over a period of 6s. Taste delivery is followed by a 1s wait period and 2s rinse (tasteless solution). The next trial begins after a 1-9s jitter. Order of milkshake and water trials is pseudo randomized. In total, there are 32 trials per run for a total of 2 8-minute runs.
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: August 12, 2022)
  • Ad Libitum Food and Milkshake Intake (g) by TaqIA Allele Status (A1 vs. A2/A2) [ Time Frame: Within 15 minutes of completion of the ad libitum period ]
    Testing the drug by gene (TaqIA) interaction on ad libitum food intake (g).The presence of the high-risk A1 allele of the TaqIA polymorphism (rs1800497) in the DRD2 gene was determined from saliva samples and is compared to the A2/A2 variant.
  • Hedonic Ratings of Milkshake Pleasantness and Desire as Measured by a Visual Analog Scale by TaqIA Allele Status (A1 vs. A2/A2) [ Time Frame: Up to 5 minutes prior to ad libitum period start ]
    Testing the drug by gene (TaqIA) interaction on hedonic ratings (pleasantness, desire to consume) of milkshake on a scale from -100 to 100. Testing the drug by gene (TaqIA) interaction on ad libitum milkshake (g). The presence of the high-risk A1 allele of the TaqIA polymorphism (rs1800497) in the DRD2 gene was determined from saliva samples and is compared to the A2/A2 variant. Pleasantness was assessed by asking 'How pleasant is this taste?', with responses ranging from -100 (most unpleasant imaginable) to 100 (most pleasant imaginable). Desire to consume was assessed by asking 'How much would you want to eat/drink this?', with responses ranging from -100 (least desirable imaginable) to 100 (most desirable imaginable).
  • Change in Voxel-wise Blood Oxygen Level-Dependent (BOLD) Brain Activation in Response to Milkshake Anticipation and Receipt vs. Water by TaqIA Allele Status (A1 vs. A2/A2) [ Time Frame: Baseline and 2 Weeks ]
    The fMRI paradigm assesses evoked BOLD response to cue-elicited anticipation and receipt of a milkshake and water. A region-of-interest (ROI) approach is used to assess changes in BOLD signal in the striatum. The striatal response is assessed for the two contrasts of interest: milkshake>h2o anticipation and milkshake>h2o receipt. Positive values reflect a higher striatal BOLD activation for the milkshake; negative reflects a higher striatal BOLD activation for the water. Parameter estimates of the relative BOLD response to these contrasts are extracted and used to test the drug by gene (TaqIA) interaction. The paradigm has 64 trials and each trial starts with the presentation of a cue signaling the impending delivery of either 3 mL of highly palatable milkshake or a control water solution over a 6s period. Taste delivery is followed by a wait period and rinse (tasteless solution). The next trial begins after a 1-9s jitter. Order of milkshake and water trials is pseudo-randomized.
Original Secondary Outcome Measures  ICMJE
 (submitted: May 31, 2022)
  • Ad libitum Food intake (g) by TaqIA allele status (A1 vs. A2/A2) [ Time Frame: Within 15 minutes of completion of the ad libitum period ]
    Testing the drug by gene (TaqIA) interaction on ad libitum food intake (g). Ad libitum food intake is described in outcome #1. Presence of the high risk A1 allele of the TaqIA polymorphism (rs1800497) in the DRD2 gene will be determined from saliva samples. Saliva collected at a pre-screening visit (~65 days prior to 1st intervention visit) is used to extract DNA using standard salting-out and solvent precipitation methods, to yield an average of 45 µg of DNA. The TaqIA assays are done using a fluorogenic 5_nuclease (Taqman, ABI) method on an ABI Prism 7000 Sequence Detection System via the allelic discrimination mode. Reactions containing 20ng of DNA are performed in 10 µl reactions with TaqMan Universal Polymerase Chain Reaction Master Mix using standard cycling conditions. Independent investigators score allele sizes; inconsistencies are reviewed and rerun when necessary. For every assay, each 96-well plate includes non-template and DNA standards of known genotype.
  • Hedonic Ratings of Food as Measured by a Visual Analog Scale by TaqIA allele status (A1 vs. A2/A2) [ Time Frame: Up to 5 minutes prior to ad libitum period start ]
    Testing the drug by gene (TaqIA) interaction on hedonic ratings of food. Participants use an iPad to complete visual analog scale (VAS) ratings of the food items offered during the ad libitum intake in each intervention arm. They were asked to rate perceived pleasantness and desire to consume each of the foods using adapted labeled scales. Pleasantness was assessed by asking 'How pleasant is this taste?', with responses ranging from -100 (most unpleasant imaginable) to 100 (most pleasant imaginable). Desire to consume was assessed by asking 'How much would you want to eat/drink this?', with responses ranging from -100 (least desirable imaginable) to 100 (most desirable imaginable).
  • Change in Voxel-wise Blood Oxygen Level-Dependent (BOLD) Brain Activation in Response to Milkshake Anticipation and Receipt vs. Baseline by TaqIA allele status (A1 vs. A2/A2) [ Time Frame: Baseline and 2 Weeks ]
    Testing the drug by gene (TaqIA) interaction on BOLD brain response to milkshake receipt and anticipation (relative to baseline). The fMRI paradigm assesses evoked BOLD response to cue-elicited anticipation and receipt of a chocolate milkshake and a water solution. A region-of-interest (ROI) approach will be used to assess changes in BOLD response in the striatum. The paradigm is controlled by in-house Python scripts. Each trial in the paradigm starts with the presentation of a cue (duration: 1s) signaling the impending delivery of either 3 mL of highly palatable milkshake or a control water solution over a period of 6s. Taste delivery is followed by a 1s wait period and 2s rinse (tasteless solution). The next trial begins after a 1-9s jitter. Order of milkshake and water trials is pseudo randomized. In total, there are 32 trials per run for a total of 2 8-minute runs.
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Examination of Bromocriptine on Homeostatic and Hedonic Mechanisms of Food Intake in Individuals at High Risk for T2DM
Official Title  ICMJE A Multimodel Examination of Bromocriptine on Homeostatic and Hedonic Mechanisms of Food Intake in Individuals at High Risk for Type 2 Diabetes
Brief Summary The current project applies an integrative three-prong approach to investigate the potential of the dopamine D2 receptor (DRD2) agonist bromocriptine to: 1) increase homeostatic satiation signaling, 2) alter neural circuitry to reduce hedonically motivated food intake, and 3) examines a genetic predisposition that may markedly impact the effectiveness of this medication in those at high risk for T2DM.
Detailed Description

Twenty-nine million Americans have diagnosed type 2 diabetes (T2DM), with fewer than half able to meet treatment goals and considerably more are at risk for development of T2DM. Implementation of healthy eating behavior has been identified as a barrier to T2DM treatment and efficacy. The determinants of eating behavior and weight regulation involve a complex interaction among individual-level homeostatic, hedonic, and genetic systems, and the external food environment. The high prevalence of obesity and T2DM suggests hedonic motivation to consume food overrides homeostatic satiation signaling, resulting in excess food intake. Elevated intake increases body mass and promotes T2DM incidence via dysregulation of glucagon-like peptide 1 (GLP-1), amylin, and adiponectin, which in turn can negatively impact T2DM treatment options.

Use of a pharmaceutical, such as bromocriptine, to aid in behavioral change is a novel method for treating and ameliorating T2DM and warrants investigation given that previous work has shown reward response to food images mediates T2DM control. Use of functional magnetic resonance imaging (fMRI) techniques to predict and evaluate hedonically-motivated eating behavior can be used to measure sensitivity to reward, and the role it plays in developing obesity, and is therefore an excellent tool to examine the associations among bromocriptine, satiety hormones, reward sensitivity and eating behavior.

Moreover, since 20-35% of the population carries the DRD2 TaqIA A1 allele, and 65% of the population is overweight or obese and at high risk for T2DM development or currently diagnosed, as much as 23% of the population may greatly benefit from dopamine agonist treatment. Despite the possibility that bromocriptine may have robust impact on T2DM treatment or as prevention therapy in those that are genetically predisposed, few data are available that directly examine the three systems (homeostatic, hedonic, genetic) available to assess whether a genetically-informed, personalized T2DM treatment is viable.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 3
Study Design  ICMJE Allocation: Randomized
Intervention Model: Crossover Assignment
Intervention Model Description:
Participants are randomly assigned to one of two possible intervention arms (active drug vs. placebo) at baseline. Following a 2-week washout period, participants receive the other intervention.
Masking: Triple (Participant, Investigator, Outcomes Assessor)
Primary Purpose: Diagnostic
Condition  ICMJE
  • Overweight and Obesity
  • Eating Behavior
Intervention  ICMJE
  • Drug: Placebo
    2 capsules, orally administered once
    Other Name: placebo (calcium supplement)
  • Drug: Bromocriptine-QR
    1.6mg (2 0.8mg capsules), orally administered once
    Other Name: quick-release (QR) bromocriptine (cycloset)
Study Arms  ICMJE
  • Bromocriptine, then Placebo
    During the first intervention visit, participants receive a single dose of 1.6mg of bromocriptine (2 0.8mg capsules). Following a 2-week washout period, participants return for the second intervention visit, where they receive 2 capsules of placebo (sugar free calcium supplement) matched in shape (circle) and color (white) to bromocriptine. Both bromocriptine and placebo are administered orally.
    Interventions:
    • Drug: Placebo
    • Drug: Bromocriptine-QR
  • Placebo, then Bromocriptine
    During the first intervention visit, participants receive 2 capsules of placebo (sugar free calcium supplement). Following a 2-week washout period, participants return for the second intervention visit, where they receive a single dose of 1.6mg of bromocriptine (2 0.8mg capsules). Both bromocriptine and placebo are administered orally.
    Interventions:
    • Drug: Placebo
    • Drug: Bromocriptine-QR
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: June 14, 2022)
55
Original Actual Enrollment  ICMJE
 (submitted: May 31, 2022)
56
Actual Study Completion Date  ICMJE September 19, 2019
Actual Primary Completion Date September 19, 2019   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • Baseline BMI between 25 and 35

Exclusion Criteria:

  • Individuals with current fMRI contraindications (e.g., metal implants, braces)
  • Probable current Axis I psychopathology (e.g., major depression disorder, panic disorder, generalized anxiety disorder, bipolar disorder)
  • Habitual use of cigarettes or illicit drugs
  • Pregnancy or breastfeeding
  • Diagnosis of serious medical problems (e.g., diabetes, cardiovascular disease, stroke)
  • Current weight loss dieting and/or weight fluctuations great than 10 lbs in the previous 6 weeks
  • Do not consume dairy
  • Allergy to bromocriptine, dairy, and nuts
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years to 35 Years   (Adult)
Accepts Healthy Volunteers  ICMJE Yes
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT05405244
Other Study ID Numbers  ICMJE 16-3177
1-17-JDF-031 ( Other Grant/Funding Number: American Diabetes Association )
Has Data Monitoring Committee Not Provided
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: Yes
IPD Sharing Statement  ICMJE
Plan to Share IPD: Yes
Plan Description: Deidentified individual data that supports the results will be shared beginning 9 to 36 months following publication provided the investigator who proposes to use the data has approval from an Institutional Review Board (IRB), Independent Ethics Committee (IEC), or Research Ethics Board (REB), as applicable, and executes a data use/sharing agreement with UNC.
Supporting Materials: Study Protocol
Supporting Materials: Statistical Analysis Plan (SAP)
Supporting Materials: Analytic Code
Time Frame: beginning 9 and continuing for 36 months following publication
Access Criteria: Investigator has approved IRB, IEC, or REB and an executed data use/sharing agreement with UNC.
Current Responsible Party University of North Carolina, Chapel Hill
Original Responsible Party Same as current
Current Study Sponsor  ICMJE University of North Carolina, Chapel Hill
Original Study Sponsor  ICMJE Same as current
Collaborators  ICMJE American Diabetes Association
Investigators  ICMJE
Principal Investigator: Kyle S Burger, MPH, RD, PhD University of North Carolina, Chapel Hill
PRS Account University of North Carolina, Chapel Hill
Verification Date May 2022

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP