Anti-obesity Medication for Obesity

(STAY-LEAN Trial)

Overseen By Andrea Debs, MS

Age: 18+

Sex: Any

Trial Phase: Phase 4

Sponsor: The Cleveland Clinic

Must be taking: Tirzepatide, Semaglutide

Must not be taking: Glucocorticoids, Beta-blockers

Disqualifiers: Diabetes, Cardiovascular disease, Pregnancy, 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

Compensation: Varies

Number of Visits: 4

150 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores the effectiveness of two different medication plans, alongside lifestyle changes, to aid weight loss in people with obesity. Participants will initially take either tirzepatide or semaglutide, then switch to another medication such as phentermine-topiramate, naltrexone-bupropion, or orlistat. Individuals eligible for this trial must have a body mass index (BMI) between 30 and 45, be covered by the Cleveland Clinic Employee Health Plan, and not have diabetes or certain other health conditions. As a Phase 4 trial, this study involves FDA-approved treatments and aims to understand their benefits for more patients.

Do I need to stop my current medications to join the trial?

The trial does not specify if you need to stop all current medications, but you cannot be on anti-obesity medications or medications for weight loss within the past 6 months. Also, certain medications like glucocorticoids above a specific dose and medications affecting physical performance are not allowed.

What is the safety track record for these treatments?

Research shows that the treatments in this trial are usually well-tolerated, but some side effects require attention.

For naltrexone-bupropion, studies indicate it is generally safe for weight loss. However, it can cause side effects such as nausea, headaches, and dizziness. Some reports suggest it might also affect mood, so discussing any mental health history with a doctor is important.

Phentermine-topiramate has been found to aid weight loss, but it also carries potential risks. Some individuals may experience a faster heartbeat, dry mouth, or trouble sleeping. It can also lead to mood changes, so monitoring during treatment is crucial.

Both treatments have FDA approval for weight management, indicating they have been tested for safety in other contexts. Consulting a healthcare provider is important to weigh these potential side effects against the benefits of weight loss. ^{1 2 3 4 5}

Why are researchers enthusiastic about this study treatment?

Researchers are excited about these treatments because they combine a comprehensive weight loss program with enhanced lifestyle changes and innovative medication combinations. The first treatment uses a sequential therapy approach, integrating phentermine-topiramate or naltrexone-bupropion, which targets multiple pathways in the brain to reduce appetite and enhance weight loss. The second treatment arm uses orlistat, which works by blocking fat absorption in the intestines. These combinations provide a multifaceted strategy that may offer more effective and sustainable weight loss compared to single-medication approaches.

What evidence suggests that this trial's treatments could be effective for obesity?

Studies have shown that the combination of naltrexone and bupropion, which participants in Group 1 AOM of this trial may receive, can lead to significant weight loss. Research indicates that people taking this combination lost an average of 9.5% of their body weight over 56 weeks, significantly more than those taking a placebo. Similarly, the combination of phentermine and topiramate, also part of Group 1 AOM in this trial, has proven effective, with some individuals losing up to 13% of their body weight. One study found that those taking the highest dose of this combination lost about 9.8% of their body weight. Both treatments have resulted in more weight loss compared to just diet and exercise, highlighting their potential effectiveness for obesity. ^{2 6 7 8 9}

Who Is on the Research Team?

Bartolome Burguera, M.D

Principal Investigator

The Cleveland Clinic

Are You a Good Fit for This Trial?

The STAY-LEAN Trial is for individuals with obesity who are seeking weight loss. Participants will join a comprehensive weight management program and must be willing to take anti-obesity medications (AOMs). Specific eligibility details aren't provided, but typically participants should meet certain health criteria and commit to the full duration of the trial.

Inclusion Criteria

An Employee, or the significant other of an employee, that is covered by the Cleveland Clinic Employee Health Plan

Ethnicity: all ethnic groups

I am between 25 and 64 years old.

Exclusion Criteria

Patients with history of diabetes

Glomerular Filtration Rate <30 mL/min/1.73 m2 (calculated by the Chronic Kidney Disease Epidemiology Collaboration Equation, CKD-EPI)

Any condition, unwillingness, or inability, not covered by any of the other exclusion criteria, which, in the study clinician's opinion, might jeopardize the subject's safety or compliance with the protocol

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment Phase 1

Participants receive tirzepatide 15 mg or semaglutide 2.4 mg for 9 months as part of the enhanced lifestyle changes program.

9 months

Monthly shared medical appointments

Treatment Phase 2

Participants continue enhanced lifestyle changes and are randomly assigned to a different oral AOM therapy for another 12 months.

12 months

Monthly shared medical appointments for the first 4 months, then every other month

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Comprehensive weight loss
• Naltrexone-Bupropion Combination
• Phentermine-Topiramate

Trial Overview This trial tests enhanced lifestyle changes combined with AOM therapies over 21 months. Initially, all receive tirzepatide or semaglutide for 9 months. Then they're randomly assigned to either phentermine-topiramate/naltrexone-bupropion or orlistat for another 12 months, alongside continued lifestyle changes.

How Is the Trial Designed?

Group I: Group 2 AOM Experimental Treatment 3 Interventions

Comprehensive weight loss + Enhanced lifestyle changes + Group 2 AOM Sequential therapy (orlistat)

Group II: Group 1 AOM Experimental Treatment 4 Interventions

Comprehensive weight loss Program + Enhanced lifestyle changes + Group 1 AOM sequential therapy (phentermine-topiramate or naltrexone-bupropion)

Who Is Running the Clinical Trial?

The Cleveland Clinic

Lead Sponsor

Trials

1,072

Recruited

1,377,000+

Published Research Related to This Trial

The combination of naltrexone and bupropion has been approved for obesity treatment and is more effective for weight loss than either medication alone, especially when paired with lifestyle changes and calorie reduction.

Clinical trials indicate that this combination can lead to significant weight loss (over 5% of total body weight) over 6 months to 1 year, but careful patient selection is important to minimize serious side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Naltrexone HCI/bupropion HCI for chronic weight management in obese adults: patient selection and perspectives. Tek, C.[2022]

Naltrexone/bupropion, an investigational weight loss medication, resulted in a significant mean weight loss of 4.7% after one year in obese patients, with 26-33% of participants achieving at least 5% weight loss compared to placebo.

In addition to weight loss, naltrexone/bupropion improved various health markers, including waist circumference and triglyceride levels, and reduced hemoglobin A1c by approximately 0.5% in patients with diabetes, although it had some common side effects like nausea and dizziness.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Naltrexone/bupropion: an investigational combination for weight loss and maintenance. Makowski, CT., Gwinn, KM., Hurren, KM.[2022]

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]

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]

A systematic review of 14 studies, including 10 randomized controlled trials, found that naltrexone/bupropion is effective for weight loss in obese patients, with many achieving at least 5% or 10% weight loss as a primary outcome.

The treatment was generally well tolerated, with few reported side effects, suggesting it is a safe option for weight management, especially when combined with mental health support.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety and efficacy of naltrexone for weight loss in adult patients - a systematic review. Kulak-Bejda, A., Bejda, G., Waszkiewicz, N.[2022]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC4771085/

Naltrexone/Bupropion ER (Contrave) - PubMed Central - NIH After 12 weeks of treatment with naltrexone/bupropion, a patient should have achieved at least a 5% weight loss since initiation of therapy. If this result is ...

2. curraxpharma.com curraxpharma.com/press-releases/currax-announces-obesityweek-data-showing-that-contrave-helps-curb-cravings-and-offers-marked-effectiveness-in-certain-populations-with-obesity/

Currax Announces ObesityWeek® Data Showing that ... The study further showed that patients taking CONTRAVE had an average weight loss of 9.5% at 56 weeks compared to 2.7% for placebo (p <0.0001).

3. thelancet.com thelancet.com/journals/eclinm/article/PIIS2589-5370(22)00166-3/fulltext

The relationship between early weight loss and ... Extended-release (ER) naltrexone/bupropion (NB) was associated with greater weight loss than placebo in four randomized, 56-week trials.

4. contrave.com contrave.com/results/

Results | CONTRAVE® (naltrexone HCl/bupropion HCl) In the studies, people taking CONTRAVE lost 2-4x more weight compared to those who used diet and exercise alone. You can learn more about each study below.

5. karger.com karger.com/ofa/article/18/5/481/925952/The-Effectivity-and-Safety-of-Naltrexone-Bupropion

The Effectivity and Safety of Naltrexone/Bupropion in ... Conclusion: NB treatment combined with lifestyle intervention results in significant weight loss after 6 and 12 months. Despite high ...

6. accessdata.fda.gov accessdata.fda.gov/drugsatfda_docs/label/2021/200063s020lbl.pdf

Contrave - accessdata.fda.gov Safety margins were estimated using body surface area exposure (mg/m2) based on a body weight of 100 kg. Daily oral administration of naltrexone has been shown ...

7. medsafe.govt.nz medsafe.govt.nz/profs/PUArticles/June2025/Spotlight-on-Contrave.html

Spotlight on Contrave (naltrexone + bupropion) Contrave contains naltrexone and bupropion and is indicated for weight management in adults. Significant safety issues associated with Contrave ...

8. mayoclinic.org mayoclinic.org/drugs-supplements/naltrexone-and-bupropion-oral-route/description/drg-20122495

Naltrexone and bupropion (oral route) - Side effects & ... Naltrexone and bupropion combination is used together with a reduced-calorie diet and proper exercise to help lose weight.

9. sciencedirect.com sciencedirect.com/science/article/pii/S0165032721003414

Psychiatric Safety and Weight Loss Efficacy of Naltrexone ... NB is generally well tolerated in patients with overweight or obesity who are on antidepressants and is effective in promoting weight loss regardless of ...