Dopamine Action on Metabolism in Relation to Genotype

Study Overview
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Brief Summary
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Obesity is a widespread disease with increasing prevalence and associated with serious secondary complications. So far, the origin of the disease, regardless of an existing positive energy balance, is not fully understood. In addition to environmental factors, the genetic background plays an important role in the pathogenesis of obesity. Of common genetic polymorphisms, variants in the fat mass and obesity associated gene (FTO) locus have the highest effect size on body weight. Animal and first clinical studies indicate that FTO variants interact with dopamine signaling in the brain, thus influencing the risk of overweight. In fact, preliminary results indicate that enhancing dopamine signaling with the dopamine agonist bromocriptine, depending on the FTO genotype, either induces weight loss or has a neutral effect on body weight. The planned clinical trial serves to develop a genotype-specific and thus individualized therapy approach for obesity. The influence of dopamine agonist therapy on weight loss as a function of the FTO (rs8050136) genotype is to be tested. Here, the greatest weight loss is expected to occur in subjects carrying the homozygous risk-allele (AA). So far, there are only a few established conservative therapy forms of obesity, so that bariatric interventions with an increasing rate are necessary to achieve weight loss and thus a reduction in overall morbidity and mortality. Among the approved drug therapies for obesity, bromocriptine is commonly used. In addition, some interventions require injections. An early, conservative individualized, genotype-specific treatment with little side-effects would enable simple treatment of obesity. Study design: 150 obese (BMI > 30) subjects (50 / study center) will be enrolled in the study. The subjects will be stratified according to their FTO genotype (rs8050136). Subjects will be randomized into placebo or bromocriptine treatment group. Treatment will last for 18 weeks and a follow-up will be performed 30 weeks after baseline.

Official Title
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Dopamine Action on Metabolism Depending on Genetic Heterogeneity - a Randomized, Placebo-controlled Double Blind Study

Conditions
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Obesity

Intervention / Treatment
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* Drug: Bromocriptine
* Other: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Body mass index (BMI) between >30 kg/m². Understand and voluntarily sign an informed consent document prior to any study related assessments/procedures. Females of childbearing potential (FCBP) must agree to utilize a reliable form of contraception simultaneously or practice complete abstinence from heterosexual contact while participating in the study. Males must agree to use a latex condom during any heterosexual contact while participating in the study and to refrain from donating semen or sperm while participating in this study. Exclusion Criteria: Women during pregnancy and lactation. History of hypersensitivity to the investigational medicinal product or to any drug with similar chemical structure or to any excipient present in the pharmaceutical form of the investigational medicinal products. Participation in other clinical trials or observation period of competing trials up to 30 days prior to this study. Diabetes mellitus Treatment with Methyldopa, levodopa, dopamine agonists, metoclopramid, domperidon, glycerol nitrate, griseofulvin, azol-antimycotic drugs, macrolide-antibiotics, octreotide, orlistat, tamoxifen, liraglutide Any relevant cardiovascular disease, e.g. myocardial infarction, acute coronary syndrome, unstable angina pectoris, Percutaneous transluminal coronary angioplasty (PTCA), heart failure (NYHA III-IV), stroke or transient ischemic attack (TIA) Acute or chronic viral hepatitis or liver cirrhosis Impaired renal function, defined as estimated Glomerular Filtration Rate (eGFR) ≤ 60 ml/min (MDRD formula) as determined during screening. Medical history of cancer and/or treatment for cancer within the last 5 years. Claustrophobia Any other clinically significant major organ system disease at screening such as relevant gastrointestinal, neurologic, psychiatric, endocrine (i.e. pancreatic), hematologic, malignant, infection or other major systemic diseases making implementation of the protocol or interpretation of the study results difficult. Presence of any contraindication for the conduct of an MRI investigation, such as cardiac pacemakers, ferromagnetic haemostatic clips in the central nervous system, metallic splinters in the eye, ferromagnetic or electronically operated active devices like automatic cardioverter defibrillators, cochlear implants, insulin pumps and nerve stimulators, prosthetic heart valves etc. hyperthyroidism therapy refractary hypertension peripheral arterial disease Parkinson´s disease Known current presence or history of one of the following psychiatric diseases: depression, mania, anxiety and panic disorder, obsessive-compulsive disorder, schizophrenia, psychosis, addiction pituitary disease treatment with bromocriptine during 12 month before entering the trial dementia gastric or intestinal ulcer Persons with limited temperature sensation and / or elevated sensitivity to warming of the body Persons with a hearing disorder or a increased sensitivity for loud noises smoking Refusal to get informed of unexpected detected pathological findings Any other clinical condition that would jeopardize subjects' safety while participating in this clinical trial.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: FTO SNP rs8050136 (AA), Placebo<br>Participants with FTO SNP rs8050136 AA receiving matching Placebo | Other: Placebo<br>* In each FTO genotype group participants will be randomly receive bromocriptine or placebo.<br>|
| Active Comparator: FTO SNP rs8050136 (AA), Bromocriptine<br>Participants with FTO SNP rs8050136 AAreceiving Bromocriptine up to 5 mg | Drug: Bromocriptine<br>* In each FTO genotype group participants will be randomly receive bromocriptine or placebo.<br>|
| Placebo Comparator: FTO SNP rs8050136 (CA), Placebo<br>Participants with FTO SNP rs8050136 CA receiving matching Placebo | Other: Placebo<br>* In each FTO genotype group participants will be randomly receive bromocriptine or placebo.<br>|
| Active Comparator: FTO SNP rs8050136 (CA), Bromocriptine<br>Participants with FTO SNP rs8050136 CA receiving Bromocriptine up to 5 mg | Drug: Bromocriptine<br>* In each FTO genotype group participants will be randomly receive bromocriptine or placebo.<br>|
| Placebo Comparator: FTO SNP rs8050136 (CC), Placebo<br>Participants with FTO SNP rs8050136 CC receiving matching Placebo | Other: Placebo<br>* In each FTO genotype group participants will be randomly receive bromocriptine or placebo.<br>|
| Active Comparator: FTO SNP rs8050136 (CC), Bromocriptine<br>Participants with FTO SNP rs8050136 CC receiving Bromocriptine up to 5 mg | Drug: Bromocriptine<br>* In each FTO genotype group participants will be randomly receive bromocriptine or placebo.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Interaction between FTO genotype and treatment on change in body weight. | Interaction between FTO (single nucleotide peptide) SNP rs8050136 genotype and treatment (bromocriptine or placebo) on change in body weight. | 18 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Effect of bromocriptine vs. placebo on body weight |  | 18 weeks | 
| Effect of bromocriptine vs. placebo on dietary intake | Dietary intake will be monitored by food diaries | 18 weeks | 
| Effect of bromocriptine vs. placebo on processing of food cues in the brain | Processing of food cues in the brain will be assessed by functional magnetic resonance imaging before and after treatment with bromocriptine or placebo | 18 weeks | 
| Effect of bromocriptine vs. placebo on body fat distribution | Body fat distribution will be assessed by magnetic resonance imaging and magnetic resonance spectroscopy before and after treatment with bromocriptine or placebo | 18 weeks | 
| Effect of bromocriptine vs. placebo on whole body insulin sensitivity | Whole body insulin sensitivity will be quantified from 5 point 75g oral glucose tolerance test before and after treatment with bromocriptine or placebo | 18 weeks | 
| Effect of bromocriptine vs. placebo on insulin secretion | Insulin secretion will be quantified from 5 point 75g oral glucose tolerance test before and after treatment with bromocriptine or placebo | 18 weeks | 
| Effect of bromocriptine vs. placebo on glucose tolerance | Glucose tolerance will be assessed by 75g oral glucose tolerance test before and after treatment with bromocriptine or placebo | 18 weeks | 
| Effect of bromocriptine vs. placebo on brain insulin sensitivity | Brain insulin sensitivity will be assessed by functional magnetic resonance imaging combined with intranasal insulin administration before and after treatment with bromocriptine or placebo | 18 weeks | 
| Effect of bromocriptine vs. placebo on resting energy expenditure | Resting energy expenditure will be assessed by indirect calorimetry before and after treatment with bromocriptine or placebo | 18 weeks | 
| Effect of bromocriptine vs. placebo on physical activity | Physical activity will be monitored using an accelerometer | 18 weeks | 
| Effect of bromocriptine vs. placebo on serum prolactin concentrations |  | 18 weeks |