Naltrexone/Bupropion for Obesity

Overseen By Sarah Borden, MPH

Age: 18+

Sex: Any

Trial Phase: Phase 4

Sponsor: Columbia University

Must be taking: Naltrexone/bupropion

Must not be taking: Dopamine agonists, Opioid analgesics

Disqualifiers: Diabetes, Cardiovascular disease, Seizures, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Prior Safety Data This treatment has passed at least one previous human trial

Approved in 3 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: Unknown

120 Participants Needed

Trial Summary

Will I have to stop taking my current medications?

Yes, you may need to stop taking certain medications. The trial excludes participants using dopamine agonists, opioid analgesics, antipsychotics, antidepressants, neuroleptics, naltrexone, diabetes medications, and MAO inhibitors within 14 days prior to screening. It also excludes those using weight loss medication within the prior six months.

What evidence supports the effectiveness of the drug naltrexone/bupropion for obesity?

Research shows that naltrexone/bupropion can lead to significant weight loss and improved quality of life in patients with genetic obesity, as seen in a case where a patient lost 48.9 kg over 17 months. Additionally, a study found that individuals with a specific genetic variant experienced greater weight loss with this drug, suggesting it may be more effective for certain people. ^{1 2 3 4 5}

Is Naltrexone/Bupropion safe for humans?

Research shows that Naltrexone/Bupropion does not increase the risk of major heart-related events in humans, suggesting it is generally safe for use. ^{1 2 3 6 7}

How does the drug naltrexone/bupropion work for obesity?

Naltrexone/bupropion is unique because it combines two drugs that work on the brain to help control appetite and cravings, which can lead to significant weight loss. This combination is particularly effective for people with certain genetic traits, like the Taq1A variant, and has shown success where other treatments have failed. ^{1 2 3 8 9}

What is the purpose of this trial?

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 question\[s\] 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 naltrexone/bupropion for 28 weeks. This phase includes in-person and phone visits, blood tests, vital signs, questionnaires, body weight, and nutritional visits.

Research Team

Judith Korner, MD,PhD

Principal Investigator

Columbia University

Eligibility Criteria

This trial is for men and women aged 18-65 with obesity, defined as a BMI of 30-50, or overweight individuals (BMI 27-29.99) with certain weight-related health issues like controlled high blood pressure, cholesterol problems, sleep apnea, or joint arthritis.

Inclusion Criteria

My BMI is between 30-50, or 27-29.99 with a weight-related health issue.

Exclusion Criteria

My current weight is more than 5% less than my highest weight ever.

I am not taking drugs that interfere with CYP2B6.

An affirmative answer to any question in the Columbia-Suicide Severity Rating Scale

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Nutritional Counseling

Participants receive individual nutritional counseling on a calorie restricted diet, including in-person visits, blood tests, an EKG, vital signs, questionnaires, body weight, and nutritional visits

12 weeks

In-person visits

Treatment with Naltrexone/Bupropion

Participants continue dietary counseling and receive treatment with naltrexone/bupropion, including in-person and phone visits, blood tests, vital signs, questionnaires, body weight, and nutritional visits

28 weeks

In-person and phone visits

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Treatment Details

Interventions

• Genetics and Response to Naltrexone/Bupropion

Trial Overview The study tests if genetic differences affect how well people lose weight on a calorie-restricted diet and the FDA-approved medication Naltrexone-Bupropion (NB). It's divided into three phases over one year: initial diet counseling and assessments; continued dieting plus NB treatment; then a wash-out period to see if genetics relate to maintaining weight loss.

Participant Groups

Group I: All participants Experimental Treatment 1 Intervention

Calorie restricted diet and treatment with Naltrexone/Bupropion

Who Is Running the Clinical Trial?

Columbia University

Lead Sponsor

Trials

1,529

Recruited

2,832,000+

National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

Collaborator

Trials

2,513

Recruited

4,366,000+

Findings from Research

A 33-year-old patient with severe obesity due to a genetic variant experienced significant weight loss of -48.9 kg (-26.7%) after 17 months of treatment with naltrexone-bupropion, following unsuccessful attempts with other treatments.

Naltrexone-bupropion not only led to substantial weight loss but also improved the patient's hyperphagia and overall quality of life, highlighting its potential as an effective treatment for genetic obesity.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Successful naltrexone-bupropion treatment after several treatment failures in a patient with severe monogenic obesity. Welling, MS., Mohseni, M., van der Valk, ES., et al.[2023]

In a study of 1,496 overweight and obese participants, the combination therapy of naltrexone and bupropion (NB32) resulted in significantly greater weight loss compared to placebo, with participants losing an average of 6.5% of their body weight at 28 weeks versus 1.9% for placebo.

NB32 not only led to substantial weight loss but also improved cardiometabolic risk factors and quality of life related to weight, with nausea being the most common mild side effect, and no increase in depression or suicidality observed.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A randomized, phase 3 trial of naltrexone SR/bupropion SR on weight and obesity-related risk factors (COR-II). Apovian, CM., Aronne, L., Rubino, D., et al.[2021]

In a pilot study of 33 subjects, individuals with the A1+ genotype (carrying the A allele) experienced a mean weight loss of 5.9% with naltrexone/bupropion treatment, which was significantly above the clinically significant target of 4%.

In contrast, the A1- genotype group (without the A allele) had a mean weight loss of only 4.2%, indicating that those with the A1+ genotype may respond more effectively to this antiobesity medication.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Weight-loss response to naltrexone/bupropion is modulated by the Taq1A genetic variant near DRD2 (rs1800497): A pilot study. Mullally, JA., Chung, WK., LeDuc, CA., et al.[2022]

Pharmacotherapy, when combined with lifestyle changes, can significantly enhance weight loss in obese patients, serving as a viable alternative to bariatric surgery for some individuals.

Pharmacogenetics aims to identify which patients will benefit most from obesity medications while reducing the risk of side effects, highlighting the importance of personalized treatment strategies in obesity management.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pharmacogenetics of obesity drug therapy. Guzman, AK., Ding, M., Xie, Y., et al.[2021]

Research suggests that the same brain circuits that drive drug addiction are also involved in food cravings, particularly in overweight and obese individuals, indicating a potential link between obesity and addictive behaviors.

A specific genetic variation in the D2 dopamine receptor may reduce sensitivity to dopamine, which could lead to increased cravings for food and substances, highlighting the need to explore interactions with other obesity-related genes and the role of inflammation in promoting these behaviors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Addictive genes and the relationship to obesity and inflammation. Heber, D., Carpenter, CL.[2021]

A systematic review of 70 studies involving naltrexone/bupropion extended release (ER) found no increased risk of major adverse cardiovascular events (MACE) in patients using this medication compared to nonusers.

The evidence suggests that naltrexone/bupropion ER is safe regarding cardiovascular events, with no significant differences in MACE rates compared to other treatments or placebo, indicating it can be a viable option for patients with obesity or overweight and cardiovascular risk.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Use of Contrave, Naltrexone with Bupropion, Bupropion, or Naltrexone and Major Adverse Cardiovascular Events: A Systematic Literature Review. Dahlberg, S., Chang, ET., Weiss, SR., et al.[2022]

Naltrexone/bupropion ER, marketed as Contrave, is a newly approved medication specifically designed for chronic weight management in obese adults.

This combination therapy targets both appetite suppression and energy expenditure, offering a new option for individuals struggling with obesity.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Naltrexone/Bupropion ER (Contrave): Newly Approved Treatment Option for Chronic Weight Management in Obese Adults. Sherman, MM., Ungureanu, S., Rey, JA.[2020]

In a 56-week study involving 505 overweight or obese individuals with type 2 diabetes, the combination of naltrexone and bupropion (NB) led to significantly greater weight loss (-5.0% vs. -1.8%) and a higher percentage of participants achieving at least 5% weight loss compared to placebo (44.5% vs. 18.9%).

NB therapy also improved glycemic control, with a greater reduction in HbA1c levels (-0.6% vs. -0.1%) and a higher proportion of patients reaching HbA1c <7% (44.1% vs. 26.3%), although it was associated with increased gastrointestinal side effects like nausea and vomiting.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effects of naltrexone sustained-release/bupropion sustained-release combination therapy on body weight and glycemic parameters in overweight and obese patients with type 2 diabetes. Hollander, P., Gupta, AK., Plodkowski, R., et al.[2022]

Bupropion and naltrexone have both been shown to promote weight loss individually, with bupropion demonstrating greater efficacy when used alone.

The combination of sustained-release formulations of naltrexone and bupropion may enhance weight loss effects beyond what is achieved with either drug alone, and ongoing Phase III trials will provide more information on their safety and effectiveness together.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Bupropion and naltrexone: a review of their use individually and in combination for the treatment of obesity. Plodkowski, RA., Nguyen, Q., Sundaram, U., et al.[2019]

References

1. United States pubmed.ncbi.nlm.nih.gov

Successful naltrexone-bupropion treatment after several treatment failures in a patient with severe monogenic obesity. [2023]

2. United States pubmed.ncbi.nlm.nih.gov

A randomized, phase 3 trial of naltrexone SR/bupropion SR on weight and obesity-related risk factors (COR-II). [2021]

3. England pubmed.ncbi.nlm.nih.gov

Weight-loss response to naltrexone/bupropion is modulated by the Taq1A genetic variant near DRD2 (rs1800497): A pilot study. [2022]

4. Netherlands pubmed.ncbi.nlm.nih.gov

Pharmacogenetics of obesity drug therapy. [2021]

5. United States pubmed.ncbi.nlm.nih.gov

Addictive genes and the relationship to obesity and inflammation. [2021]

6. New Zealand pubmed.ncbi.nlm.nih.gov

Use of Contrave, Naltrexone with Bupropion, Bupropion, or Naltrexone and Major Adverse Cardiovascular Events: A Systematic Literature Review. [2022]

7. United States pubmed.ncbi.nlm.nih.gov

Naltrexone/Bupropion ER (Contrave): Newly Approved Treatment Option for Chronic Weight Management in Obese Adults. [2020]

8. United States pubmed.ncbi.nlm.nih.gov

Effects of naltrexone sustained-release/bupropion sustained-release combination therapy on body weight and glycemic parameters in overweight and obese patients with type 2 diabetes. [2022]

9. England pubmed.ncbi.nlm.nih.gov

Bupropion and naltrexone: a review of their use individually and in combination for the treatment of obesity. [2019]