Sympathetic Blockade for Obesity

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: Vanderbilt University Medical Center

Must be taking: Antihypertensives

Must not be taking: Glucocorticoids, Investigational drugs

Disqualifiers: Pregnancy, Smoking, Cardiovascular disease, others

Compensation: Varies

Number of Visits: 3

Duration: 6 weeks

12 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests whether two weeks of moxonidine treatment can enhance the body's natural glucose production in individuals with both obesity and high blood pressure. Participants will also receive a placebo and amlodipine (a medication that widens blood vessels) at different times. The goal is to determine if moxonidine outperforms the other options. Individuals diagnosed with obesity (BMI of 30 or higher) and high blood pressure may be suitable for this study. As a Phase 1, Phase 2 trial, this research aims to understand how the treatment works and measure its effectiveness in an initial group, offering participants a chance to contribute to groundbreaking medical advancements.

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

The trial protocol does not specify if you need to stop taking your current medications. However, since the study involves hypertensive patients, you may need to continue your antihypertensive medication. It's best to discuss this with the trial coordinators.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research shows that amlodipine is usually well-tolerated, but some people might experience side effects like swelling, shock, or difficulty breathing. The FDA has approved it for treating high blood pressure, indicating its safety for many people. However, some studies have found that these side effects can occur, especially in those with severe obesity.

Studies have also shown that moxonidine is safe and effective for controlling high blood pressure in people who are overweight or obese. After eight weeks of use, some participants even lost weight, suggesting that moxonidine is generally well-tolerated.

Both treatments are undergoing further testing, but past studies show they have a history of safety in similar groups. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about these treatments for obesity because they offer unique ways to tackle the condition. Amlodipine, typically used for high blood pressure, might help in managing obesity by reducing the sympathetic nervous system's activity, which plays a role in fat storage. Moxonidine, on the other hand, is intriguing because it targets specific receptors that may help regulate appetite and metabolism, providing a new angle compared to standard weight-loss drugs. Unlike current options that often focus on appetite suppression or calorie absorption, these treatments could address the underlying physiological processes contributing to obesity.

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

This trial will compare the effects of Amlodipine and Moxonidine on obesity-related conditions. Research has shown that Amlodipine, a calcium channel blocker, effectively lowers blood pressure in obese individuals. One study found that this treatment works well for people of different body sizes and helps manage high blood pressure in obese patients. Meanwhile, Moxonidine, another medication under study in this trial, has been shown to aid in weight loss and control blood pressure in overweight and obese individuals. In a study, participants taking Moxonidine lost an average of 1.4 kg (about 3 pounds) after 8 weeks, with noticeable improvements in overall health. Both treatments show promise in addressing issues related to obesity, such as high blood pressure. ^{6 7 8 9 10}

Are You a Good Fit for This Trial?

This trial is for men and women aged 18-65 with obesity (BMI ≥ 30 kg/m2) and high blood pressure (>130/85 mmHg or on medication). Participants must be able to consent. Exclusions include immunological/hematological disorders, allergies to study meds, impaired kidney function, Type I diabetes, serious cerebrovascular disease, heavy smoking, substance abuse, certain cardiovascular diseases.

Inclusion Criteria

Able and willing to provide informed consent

Obesity will be defined as having a body mass index (BMI) ≥ 30 kg/m2

I have high blood pressure or am on medication for it.

Exclusion Criteria

Pregnancy or breast feeding

I have not had a heart attack or serious heart issues in the last 6 months.

I have been on long-term steroid treatment for more than a week in the past month.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive 2 weeks of treatment with either placebo, amlodipine, or moxonidine in a randomized, crossover design

6 weeks

3 visits (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Amlodipine
• Moxonidine
• Placebo

Trial Overview The study tests if sympathetic blockade by moxonidine improves glucose production in obese hypertensive subjects compared to amlodipine and placebo. It's a randomized crossover trial where patients receive each treatment for two weeks with random order and are blinded to the treatments.

How Is the Trial Designed?

Group I: Moxonidine Experimental Treatment 1 Intervention

Subjects will received 2 weeks of capsules containing moxonidine.

Group II: Amlodipine Active Control 1 Intervention

Subjects will received 2 weeks of capsules containing amlodipine.

Group III: Placebo Placebo Group 1 Intervention

Subjects will received 2 weeks of capsules containing placebo.

Amlodipine is already approved in United States, European Union, Canada, Japan, China, Switzerland for the following indications:

Approved in United States as Norvasc for:

• Hypertension
• Angina
• Variant angina

Approved in European Union as Norvasc for:

• Hypertension
• Coronary artery disease
• Variant angina

Approved in Canada as Norvasc for:

• Hypertension
• Angina

Approved in Japan as Norvasc for:

• Hypertension
• Angina pectoris

Approved in China as Norvasc for:

• Hypertension

Approved in Switzerland as Norvasc for:

• Hypertension
• Coronary artery disease

Who Is Running the Clinical Trial?

Vanderbilt University Medical Center

Lead Sponsor

Trials

922

Recruited

939,000+

Published Research Related to This Trial

Orlistat and sibutramine were found to be more effective than placebo in promoting weight loss in obese individuals with hypertension, as shown in eight studies included in the Cochrane review.

Orlistat not only aided in weight loss but also significantly reduced both systolic and diastolic blood pressure, while sibutramine was associated with an increase in blood pressure, highlighting potential safety concerns.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Long-term effects of weight-reducing drugs in hypertensive patients--a survey of a Cochrane review]. Madsbad, S.[2018]

Sibutramine, a serotonin/noradrenaline reuptake inhibitor, has been shown to reduce body weight by an average of 4.45 kg compared to placebo, while also improving triglycerides and HDL cholesterol, but it may cause increased heart rate and has contraindications for patients with uncontrolled hypertension or cardiovascular issues.

Orlistat, a pancreatic lipase inhibitor, results in an average weight loss of 2.89 kg and significantly decreases waist circumference and blood pressure, but primarily causes gastrointestinal side effects and should be avoided in patients with chronic malabsorption.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Pharmacological therapy of obesity]. Pagotto, U., Vanuzzo, D., Vicennati, V., et al.[2018]

Recent advances in medical weight management have led to the approval of several medications for treating obesity, including orlistat, phentermine/topiramate, and the newer tirzepatide, which primarily work by reducing appetite and increasing feelings of fullness.

While current anti-obesity medications improve weight and metabolic health, there is still no evidence supporting a reduction in serious cardiovascular outcomes, although such data is expected soon.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pharmacotherapy of obesity: an update on the available medications and drugs under investigation. Chakhtoura, M., Haber, R., Ghezzawi, M., et al.[2023]

Sibutramine, an anorectic banned since 2010 due to cardiovascular safety concerns, was found to significantly inhibit hERG channel currents and increase heart rate and blood pressure in beagle dogs, indicating serious cardiovascular risks.

The study demonstrated that sibutramine shortens action potential duration in rabbit Purkinje fibers, further highlighting its potential to cause adverse cardiovascular effects, which is crucial for drug safety regulation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cardiovascular Safety Pharmacology of Sibutramine. Yun, J., Chung, E., Choi, KH., et al.[2020]

Two new medications, phentermine/topiramate ER (Qsymia™) and lorcaserin (Belviq®), have been approved by the FDA for long-term weight management in individuals with obesity or overweight with related health issues, marking a significant advancement in obesity treatment.

The review highlights that these new drugs are either reformulations of existing medications or new approaches targeting previously established mechanisms, indicating a trend of revisiting and optimizing older treatments for obesity management.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pharmacologic treatment options for obesity: what is old is new again. Ryan, DH., Bray, GA.[2021]

Orlistat is preferred for treating obesity-related hypertension as it can lead to a small decrease in blood pressure, while sibutramine may actually increase blood pressure, making it less suitable for these patients.

ACE inhibitors and AT(1) receptor antagonists are recommended for obese hypertensive patients because they lower blood pressure without negatively affecting insulin sensitivity, and they also provide kidney protection.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clinical evidence for drug treatments in obesity-associated hypertensive patients--a discussion paper. Doggrell, SA.[2018]

Lorcaserin and the combination of Phentermine-topiramate (phen-top) are two FDA-approved drugs for obesity, with lorcaserin showing moderate efficacy and an acceptable safety profile, while phen-top has shown reasonable efficacy but carries risks like teratogenicity and psychiatric issues.

Cetilistat, currently in phase 3 trials, is a lipase inhibitor that may offer a better safety profile than orlistat, and other promising anti-obesity drugs targeting the gut, such as exenatide and liraglutide, are also under investigation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

New and emerging drug molecules against obesity. George, M., Rajaram, M., Shanmugam, E.[2014]

Several anti-obesity drugs have been withdrawn from the market due to serious cardiovascular risks, such as fenfluramine and sibutramine, highlighting the importance of safety in obesity treatments.

Current treatments like GLP-1 analogues and metformin not only aid in weight loss but also have favorable cardiovascular profiles, suggesting they could be effective options for managing obesity alongside type 2 diabetes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cardiovascular effects of current and future anti-obesity drugs. Comerma-Steffensen, S., Grann, M., Andersen, CU., et al.[2019]

Obesity is now recognized as a chronic disease, leading to the development of safer long-term pharmacotherapies, such as phentermine/topiramate and bupropion/naltrexone, which target multiple neurotransmitter pathways to help reduce appetite.

New potential treatments like tesofensine and semaglutide are in advanced trials, indicating a shift towards drugs that not only act on the central nervous system but also target peripheral tissues, reflecting a deeper understanding of obesity's complex mechanisms.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Centrally Acting Agents for Obesity: Past, Present, and Future. Coulter, AA., Rebello, CJ., Greenway, FL.[2019]

Pharmacotherapy for obesity can be considered for individuals with a BMI of 30 or greater, or 27 or greater with weight-related health issues, highlighting the importance of medication in weight management when lifestyle changes alone are insufficient.

The effectiveness of antiobesity medications, such as phentermine and liraglutide, relies on customizing treatment to individual patient behaviors and health conditions, along with careful monitoring of their safety and effectiveness.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Obesity Pharmacotherapy. Saunders, KH., Umashanker, D., Igel, LI., et al.[2022]

New generation anti-obesity medications, such as orlistat, phentermine/topiramate, and liraglutide 3.0 mg, have varying safety profiles, with some presenting significant risks like fetal toxicity and gallstone disease, while others mainly cause transient tolerability issues.

Despite their effectiveness in weight loss, the prescription rates for these medications are low, partly due to safety concerns and the need for more long-term data to better understand their risk-benefit profiles.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety and tolerability of new-generation anti-obesity medications: a narrative review. Patel, DK., Stanford, FC.[2023]

Citations

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Weight reduction and pharmacologic treatment in obese ... Each of five groups of obese hypertensives were treated with the long-acting calcium channel blocker (CCB) amlodipine, the angiotensin converting enzyme (ACE) ...

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Articles Effects of body size and hypertension treatments ... Thiazide-based treatment gives less cardiovascular protection in normal weight than obese patients, but amlodipine-based therapy is equally effective across BMI ...

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Long-term Effects of Weight-Reducing Interventions in ... We found that dietary interventions to reduce body weight successfully reduced body weight and lowered BP in 1 year of follow-up in these patients. However, ...

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Antihypertensive treatment in patients with class 3 obesity Selected adverse events (AEs) and safety laboratory data are given in Table 2. Treatment with amlodipine/HCT was associated with the highest incidence of ...

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KATERZIA (amlodipine) - accessdata.fda.gov Absolute bioavailability has been estimated to be between 64 and 90%. Compared to fasted state administration, standard high-fat, high-calorie breakfast did ...

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Olmesartan/Amlodipine/Hydrochlorothiazide in Obese ... Of the 2492 randomized participants, 1555 (62.4%) had BMI ≥30 kg/m2. Irrespective of BMI, triple‐combination treatment resulted in greater LS mean reductions in ...

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Adverse events associated with amlodipine Conclusion: This study provides compelling evidence that amlodipine poses risks of peripheral edema, shock, and dyspnea, among others.

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Journal of Hypertension Treatment with the single pill combination of amlodipine and valsartan in patients with overweight/obesity and hypertension led to pronounced blood pressure ...