Ignite Creation Date:
2024-05-06 @ 7:09 PM
Last Modification Date:
2024-10-26 @ 3:01 PM
Study NCT ID:
NCT05919797
Status:
RECRUITING
Last Update Posted:
2024-04-02
First Post:
2023-06-16
Brief Title:
Weight Loss Study Genetics and Response to NaltrexoneBupropion
Sponsor:
Columbia University
Organization:
Columbia University
Study Overview
Official Title:
Association of Genetic Variations and Weight Loss Response to NaltrexoneBupropion
Status:
RECRUITING
Status Verified Date:
2024-03
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
None
Brief Summary:
The goal of this clinical trial is to understand if genetic variations are associated with the amount of weight loss with diet and while taking an FDA-approved medication for weight loss The main questions it aims to answer are
In Aim One the investigators propose to rigorously test the hypothesis that presence of the Taq1A A1 polymorphism is associated with greater weight loss with NB compared with the A1- genotype
In Aim Two the investigators will explore other genetic polymorphisms that might influence the efficacy of NB such as the fat mass and obesity-associated FTO gene which modulates DRD2 signaling as carriers of risk alleles in both the FTO and ANKK1 gene demonstrate altered responses to reward-learning tasks associated with negative outcomes
Participants will be in the study for 40 weeks which consists of two phases
1 From baseline to week 12 participants will receive individual nutritional counseling on a calorie restricted diet This phase includes in-person visits blood tests an EKG vital signs questionnaires body weight and nutritional visits
2 From week 12 to week 40 participants will continue to receive dietary counseling and will receive treatment with naltrexonebupropion for 28 weeks This phase includes in-person and phone visits blood tests vital signs questionnaires body weight and nutritional visits
In Aim One the investigators propose to rigorously test the hypothesis that presence of the Taq1A A1 polymorphism is associated with greater weight loss with NB compared with the A1- genotype
In Aim Two the investigators will explore other genetic polymorphisms that might influence the efficacy of NB such as the fat mass and obesity-associated FTO gene which modulates DRD2 signaling as carriers of risk alleles in both the FTO and ANKK1 gene demonstrate altered responses to reward-learning tasks associated with negative outcomes
Participants will be in the study for 40 weeks which consists of two phases
1 From baseline to week 12 participants will receive individual nutritional counseling on a calorie restricted diet This phase includes in-person visits blood tests an EKG vital signs questionnaires body weight and nutritional visits
2 From week 12 to week 40 participants will continue to receive dietary counseling and will receive treatment with naltrexonebupropion for 28 weeks This phase includes in-person and phone visits blood tests vital signs questionnaires body weight and nutritional visits
Detailed Description:
Weight loss can improve or prevent many obesity-related co-morbidities yet time and again the cornerstone of obesity therapy - diet physical activity and behavioral modification - fails to produce sufficient long-term weight loss in most individuals In such cases clinical guidelines recommend the addition of anti-obesity medication AOM when conservative methods are less than optimal Yet even with the use of AOM there is a wide range of inter-individual weight loss suggesting that there are responders and non-responders The variability in response to AOMs underscores the heterogeneity of obesity and the need for more personalized treatment that accounts for individual differences in etiologic factors Given the strong heritability of obesity it is possible that genetic factors play a role in an individuals response to a given pharmacotherapy
This proposal focuses on the FDA-approved AOM Contrave which is a combination of two medications naltrexone 32 mg and bupropion 360 mg NB Naltrexone is a ยต-opioid receptor MOPR antagonist and bupropion inhibits the reuptake of dopamine and norepinephrine Clinical trials of NB demonstrate a mean weight loss of 61 after 56 weeks of treatment however only 48 of patients achieved a clinically significant reduction in body weight of at least 5 Knowledge of the likely mechanisms of action of NB makes it possible to address what might underlie the variability in response The bupropion component of NB activates the proopiomelanocortin POMC neuron a key regulator in decreasing food intake and stimulating energy expenditure through stimulation of dopamine D2 receptors DRD2 Naltrexone also activates POMC neurons by binding MOPR
The investigators postulated that some of the variability in response to NB may be due to the Taq1A genetic variant rs1800497 located in the ankyrin repeat and kinase domain-containing protein 1 ANKK1 gene adjacent to the DRD2 gene Individuals carrying at least one minor allele of the rs1800497 polymorphism termed Taq1A A1 represent about 45 of the population and have 30-40 fewer brain DRD2 Carriers of the minor allele likely have a relative deficiency in dopaminergic activation of POMC neurons and therefore might receive the greatest benefit from a drug that activates POMC neurons With this hypothesis in mind the investigators conducted a retrospective proof-of-concept pilot study reviewing charts of patients treated with NB and found that individuals with the Taq1A A1 genotype had a greater response compared with non-carriers suggesting that this genotype could be used to predict successful weight loss
In Aim One the investigators propose to rigorously test the hypothesis that presence of the Taq1A A1 polymorphism is associated with greater weight loss with NB compared with the A1- genotype In Aim Two the investigators will explore other genetic polymorphisms that might influence the efficacy of NB such as the fat mass and obesity-associated FTO gene which modulates DRD2 signaling as carriers of risk alleles in both the FTO and ANKK1 gene demonstrate altered responses to reward-learning tasks associated with negative outcomes Functional polymorphisms within genes that influence the metabolism of bupropion and naltrexone will also be examined in relation to weight loss outcomes The ultimate goal is to incorporate pharmacogenetics into obesity medicine in order to maximize positive results and limit unnecessary cost and exposure to side effects of medications that provide minimal benefit to the individual patient
This proposal focuses on the FDA-approved AOM Contrave which is a combination of two medications naltrexone 32 mg and bupropion 360 mg NB Naltrexone is a ยต-opioid receptor MOPR antagonist and bupropion inhibits the reuptake of dopamine and norepinephrine Clinical trials of NB demonstrate a mean weight loss of 61 after 56 weeks of treatment however only 48 of patients achieved a clinically significant reduction in body weight of at least 5 Knowledge of the likely mechanisms of action of NB makes it possible to address what might underlie the variability in response The bupropion component of NB activates the proopiomelanocortin POMC neuron a key regulator in decreasing food intake and stimulating energy expenditure through stimulation of dopamine D2 receptors DRD2 Naltrexone also activates POMC neurons by binding MOPR
The investigators postulated that some of the variability in response to NB may be due to the Taq1A genetic variant rs1800497 located in the ankyrin repeat and kinase domain-containing protein 1 ANKK1 gene adjacent to the DRD2 gene Individuals carrying at least one minor allele of the rs1800497 polymorphism termed Taq1A A1 represent about 45 of the population and have 30-40 fewer brain DRD2 Carriers of the minor allele likely have a relative deficiency in dopaminergic activation of POMC neurons and therefore might receive the greatest benefit from a drug that activates POMC neurons With this hypothesis in mind the investigators conducted a retrospective proof-of-concept pilot study reviewing charts of patients treated with NB and found that individuals with the Taq1A A1 genotype had a greater response compared with non-carriers suggesting that this genotype could be used to predict successful weight loss
In Aim One the investigators propose to rigorously test the hypothesis that presence of the Taq1A A1 polymorphism is associated with greater weight loss with NB compared with the A1- genotype In Aim Two the investigators will explore other genetic polymorphisms that might influence the efficacy of NB such as the fat mass and obesity-associated FTO gene which modulates DRD2 signaling as carriers of risk alleles in both the FTO and ANKK1 gene demonstrate altered responses to reward-learning tasks associated with negative outcomes Functional polymorphisms within genes that influence the metabolism of bupropion and naltrexone will also be examined in relation to weight loss outcomes The ultimate goal is to incorporate pharmacogenetics into obesity medicine in order to maximize positive results and limit unnecessary cost and exposure to side effects of medications that provide minimal benefit to the individual patient
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
True
Is a FDA Regulated Device?:
False
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None
Secondary IDs
| Secondary ID | Type | Domain | Link |
|---|---|---|---|
| R01DK132527 | NIH | None | httpsreporternihgovquickSearchR01DK132527 |