Phentermine-Topiramate for Obesity

Overseen By Claudia Fox, MD

Age: < 65

Sex: Any

Trial Phase: Phase 2

Sponsor: University of Minnesota

Must not be taking: Stimulants, MAO inhibitors

Disqualifiers: Diabetes, Bariatric surgery, Glaucoma, others

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: 1

Duration: 52 weeks

100 Participants Needed

Trial Summary

What is the purpose of this trial?

Long-term weight loss maintenance is seldom achieved by individuals with obesity owing to numerous biological adaptations occurring in the post-weight loss setting, including neuroendocrine-mediated changes in appetite/satiety and reduction of energy expenditure. Following weight loss, peripheral and central mechanisms respond in a way similar to starvation by conveying a sense that energy reserves have dwindled, activating a strong counter-response to increase caloric intake. Moreover, metabolic rate drops, further compounding the propensity for weight rebound. Adolescents with severe obesity are not immune to the vexing issue of weight regain; therefore, effective and scalable treatments are urgently needed. Pharmacotherapy has the potential to prevent weight regain by targeting counter-regulatory mechanisms in the post-weight loss setting. Unfortunately, only one obesity medication is FDA-approved for long-term use in adolescents and is seldom prescribed owing to modest efficacy and notable side effects. Among the most promising candidates in the pediatric pipeline is the combination of phentermine and topiramate, which is the most effective adult weight loss medication currently available. The mechanisms of action are thought to reduce appetite, enhance satiety, and potentially increase energy expenditure, making this medication particularly well-suited for the purpose of weight loss maintenance since it targets many of the biological adaptations known to induce relapse and subsequent weight regain. The investigators have generated preliminary data demonstrating that both phentermine and topiramate reduce BMI in adolescents with severe obesity and have acceptable safety profiles. In this clinical trial, the investigators will utilize combination phentermine/topiramate to target counter-regulatory pathways responsible for weight regain after meal replacement therapy (structured meals of known caloric content) in adolescents with severe obesity with a goal of enhancing weight loss maintenance and improving obesity-related complications. Importantly, the investigators will maximize the clinical utility and overall impact of the study by comprehensively characterizing the safety of phentermine/topiramate utilizing sensitive measures of cardiac autonomic function, arterial stiffness, cognition, and bone health as well as examine the extent to which this medication counteracts mechanisms of weight regain.

Will I have to stop taking my current medications?

The trial requires that you stop taking certain medications, such as anti-obesity drugs and stimulant medications, before joining. If you are currently using any of these, you will need to stop them to participate.

What data supports the effectiveness of the drug Phentermine-Topiramate for obesity?

Phentermine-Topiramate, known as Qsymia, has been shown to help people lose more weight than using either of its components alone. It works by reducing appetite and making people feel full, and it has been approved for use in both adults and adolescents for managing obesity. ^{1 2 3 4 5}

Is Phentermine-Topiramate safe for humans?

Phentermine-Topiramate (Qsymia) has been approved for obesity treatment, but it can have side effects like a slight increase in heart rate, mood and thinking changes, and metabolic acidosis (a condition where the body produces too much acid). It also carries a risk of birth defects, so women who can become pregnant need to take precautions. ^{1 3 4 5 6}

How is the drug Phentermine-Topiramate unique for treating obesity?

Phentermine-Topiramate is unique because it combines two medications: phentermine, which suppresses appetite, and topiramate, which is typically used for seizures and migraines but also helps increase feelings of fullness. This combination results in more significant weight loss than using either drug alone, and it is taken once daily as an extended-release capsule. ^{1 3 4 5 7}

Research Team

Aaron Kelly, PhD

Principal Investigator

University of Minnesota

Eligibility Criteria

Adolescents aged 12-17 with severe obesity (BMI ≥120% of the 95th percentile or BMI ≥35 kg/m2) can join this trial. They must not be using stimulants, have diabetes, major psychiatric disorders, uncontrolled hypertension, or a history of certain medical conditions like kidney stones. Sexually active females must use two forms of contraception.

Inclusion Criteria

I am between 12 and 17 years old, in puberty stage 2 or higher, and agree to use two forms of birth control if sexually active.

I am severely obese according to BMI standards.

Exclusion Criteria

I have a history of glaucoma.

ALT or AST >/= 3 times the upper limit of normal

You currently smoke or use tobacco products.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Meal Replacement Therapy

Participants undergo a short-term meal replacement induction period to achieve at least 5% BMI reduction

6 weeks

Weekly visits for monitoring

Treatment

Participants receive phentermine/topiramate or placebo to maintain weight loss

52 weeks

Visits at Baseline, 1 day of Randomization, Week 26, and Week 52

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Treatment Details

Interventions

• Phentermine-Topiramate

Trial Overview The trial is testing if phentermine-topiramate can help maintain weight loss after meal replacement therapy in adolescents with severe obesity. It compares this drug combination to a placebo and measures its effects on appetite control and energy expenditure.

Participant Groups

Group I: Meal Replacement Therapy Experimental Treatment 1 Intervention

Participants who are enrolled in the study will be administered a short-term (six weeks) meal replacement induction period. Because the trial is deigned to evaluate weight loss maintenance, participants must achieve at least 5% BMI reduction at week six of the meal replacement period in order to be randomized. Subjects will be asked to strictly follow the eating regimen, which will include a total of approximately 1,000 kcals per day of commercially-available liquid shakes (breakfast and lunch), pre-packaged frozen entrée meals for dinner, two servings of fruit, and three servings of vegetables. Shakes/meals will be provided free of charge - fruits/vegetables will be purchased by the participants. Guidance will be provided regarding the use of the meal replacement shakes at school, and participants will be encouraged to engage in family meal sessions despite eating different foods.

Group II: Phentermine/Topiramate Active Control 2 Interventions

Participants who achieve at least 5% BMI reduction at week six of the meal replacement period will be randomized (1:1) to receive either phentermine/topiramate or placebo. Participants randomized to phentermine/topiramate will start treatment at 3.75 mg/23 mg orally once daily in the morning for 14 days, then increased to 7.5 mg/46 mg orally once daily in the morning for 14 days, then be increased to 11.25 mg/69 mg orally once daily in the morning for 14 days, then increased to 15 mg/92 mg orally once daily in the morning for the remainder of the trial. Following the final study visit, participants will be down-titrated gradually by taking medication every other day for seven days before stopping treatment altogether.

Group III: Placebo Placebo Group 2 Interventions

Participants who achieve at least 5% BMI reduction at week six of the meal replacement period will be randomized (1:1) to receive either phentermine/topiramate or placebo. Participants randomized to the placebo will receive inert tablets that look like the active comparator. In order to mimic the active comparator arm, subjects randomized to the placebo arm will up titrate their placebo at the beginning of the study treatment and will down titrate as in the active comparator arm. Participants will be instructed to take the medication under the supervision of a parent/guardian and pill counts of returned product will serve as a proxy of treatment compliance.

Who Is Running the Clinical Trial?

University of Minnesota

Lead Sponsor

Trials

1,459

Recruited

1,623,000+

Findings from Research

Phentermine/topiramate controlled-release (PHEN/TPM CR) led to significant weight loss of 8.1-10.9% in patients, compared to only 1.4-1.8% in placebo groups, and also reduced waist circumference and improved metabolic markers like blood pressure and lipid profiles.

The treatment was generally well-tolerated, with severe adverse events being similar to those in placebo groups, although common side effects included paresthesia, dry mouth, and insomnia. Long-term safety and efficacy still need further investigation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A review of the metabolic effects of controlled-release Phentermine/Topiramate. Kiortsis, DN.[2019]

In a 108-week study involving 676 overweight and obese participants with cardiometabolic disease, controlled-release phentermine/topiramate (PHEN/TPM CR) led to significant and sustained weight loss compared to placebo, with mean percentage changes in body weight of -9.3% and -10.5% for the lower and higher doses, respectively.

PHEN/TPM CR not only facilitated weight loss but also improved cardiovascular and metabolic health, showing a reduction in diabetes incidence, and was well tolerated over the study duration, with fewer adverse events reported in the second half of the trial.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Two-year sustained weight loss and metabolic benefits with controlled-release phentermine/topiramate in obese and overweight adults (SEQUEL): a randomized, placebo-controlled, phase 3 extension study. Garvey, WT., Ryan, DH., Look, M., et al.[2023]

Qsymia™, a combination of phentermine and topiramate, has been shown to produce greater weight loss than either drug alone, making it an effective treatment for obesity since its approval in 2012.

While Qsymia™ is effective, it carries potential risks such as teratogenicity, increased heart rate, psychiatric and cognitive side effects, and metabolic acidosis, which are consistent with the known side effects of its individual components.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clinical utility of phentermine/topiramate (Qsymia™) combination for the treatment of obesity. Shin, JH., Gadde, KM.[2021]

Phentermine/topiramate (Qsymia®) is a combination medication approved in July 2022 for chronic weight management in pediatric patients aged 12 and older with obesity, specifically those with a BMI in the 95th percentile or greater.

This medication works by decreasing appetite and increasing feelings of fullness, and it is also being studied for other conditions like sleep apnea and type 2 diabetes in obese patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phentermine/Topiramate: Pediatric First Approval. Dhillon, S.[2022]

Qsymia™, a once-daily oral capsule combining phentermine and extended-release topiramate, has been approved in the US for treating obesity, leveraging phentermine's appetite-suppressing effects and topiramate's ability to increase feelings of fullness.

The formulation is also being explored for potential benefits in treating sleep apnea and type 2 diabetes, indicating its broader therapeutic applications beyond weight loss.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phentermine and topiramate extended release (Qsymia™): first global approval. Cameron, F., Whiteside, G., McKeage, K.[2021]

The approval of phentermine/topiramate in 2012 led to a significant increase in the initiation rate of topiramate among patients with obesity, rising more than 2.5 times in early 2013, indicating a shift in prescribing patterns.

Despite the increased use of topiramate, it is important for healthcare providers to educate patients about the risks associated with its use, especially regarding prenatal exposure, as it lacks the same Risk Evaluation and Mitigation Strategy (REMS) that phentermine/topiramate has.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Topiramate Utilization After Phentermine/Topiramate Approval for Obesity Management: Risk Minimization in the Era of Drug Repurposing. Sarayani, A., Hampp, C., Brown, JD., et al.[2022]

Phentermine/topiramate extended-release capsules (Qsymia) have been shown to be effective for weight loss, as indicated by clinical studies that demonstrate significant reductions in body weight among participants.

The combination of phentermine, an appetite suppressant, and topiramate, which may help reduce cravings, works synergistically to enhance weight loss outcomes compared to placebo.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phentermine/Topiramate extended-release capsules (qsymia) for weight loss. Lonneman, DJ., Rey, JA., McKee, BD.[2021]

References

1. Switzerland pubmed.ncbi.nlm.nih.gov

A review of the metabolic effects of controlled-release Phentermine/Topiramate. [2019]

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

Two-year sustained weight loss and metabolic benefits with controlled-release phentermine/topiramate in obese and overweight adults (SEQUEL): a randomized, placebo-controlled, phase 3 extension study. [2023]

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

Clinical utility of phentermine/topiramate (Qsymia™) combination for the treatment of obesity. [2021]

4. Switzerland pubmed.ncbi.nlm.nih.gov

Phentermine/Topiramate: Pediatric First Approval. [2022]

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

Phentermine and topiramate extended release (Qsymia™): first global approval. [2021]

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

Topiramate Utilization After Phentermine/Topiramate Approval for Obesity Management: Risk Minimization in the Era of Drug Repurposing. [2022]

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

Phentermine/Topiramate extended-release capsules (qsymia) for weight loss. [2021]