Anti-inflammatory Drugs for Obesity

(MAPLE Trial)

Overseen By Davina A Clonch

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: University of Kansas Medical Center

Must not be taking: Clonidine, Beta-blockers, Hypertension meds

Disqualifiers: Heart disease, Neurological disorders, Transplant, others

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

Compensation: Varies

Number of Visits: Unknown

Duration: 4 weeks

60 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to determine if clonidine can reduce inflammation in individuals with obesity and high blood pressure over four weeks. Participants will receive clonidine, another blood pressure medication (hydrochlorothiazide), or a placebo to compare effects on inflammation markers. Ideal candidates are those who are obese, have high blood pressure, and experience related symptoms like insulin resistance, but are not currently on similar medications or smokers. As a Phase 1 trial, the research focuses on understanding how the treatment works in people, offering participants the opportunity to be among the first to receive this treatment.

Will I have to stop taking my current medications?

The trial requires that you are not currently taking hypertension medication or clonidine. If you are on these medications, you would need to stop taking them to participate.

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

Studies have shown that clonidine is generally well-tolerated in people. The FDA has approved it for treating high blood pressure and ADHD (attention deficit hyperactivity disorder). However, it can cause side effects like dry mouth, sleepiness, and dizziness. Serious side effects are rare but may include a slow heartbeat or low blood pressure.

Research on hydrochlorothiazide (HCTZ) indicates it is also commonly used and generally safe for treating high blood pressure. Some people might experience side effects like increased urination, dizziness, or an upset stomach. Notably, some studies have found a slight increase in cholesterol levels with HCTZ use.

Both medications have been used safely for various conditions, but individual reactions can vary. It is important to consult a healthcare provider about any concerns before joining a trial. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about these treatments because they offer unique approaches to managing hypertension in individuals with obesity, which is often treated with lifestyle changes, ACE inhibitors, or ARBs. Clonidine stands out by targeting vascular function and blood flow, utilizing a different mechanism by acting on alpha-2 adrenergic receptors to potentially improve cardiovascular health. Meanwhile, Hydrochlorothiazide (HCTZ) is a diuretic that helps reduce blood pressure by eliminating excess fluid, which could be beneficial in managing hypertension more effectively. Both treatments provide alternative options that may enhance current therapeutic strategies for patients struggling with hypertension linked to obesity.

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

Research has shown that clonidine, one of the treatments studied in this trial for its potential to reduce inflammation in obesity, has promising effects. Although it did not stop weight gain, clonidine prevented insulin resistance and high blood pressure in animal studies. This suggests it might help manage blood pressure and metabolism issues in people.

Hydrochlorothiazide is another treatment option in this trial. Past studies have linked it to slight weight loss and effective blood pressure control. However, it might also cause insulin resistance and changes in metabolism. These findings support further exploration of both clonidine and hydrochlorothiazide for managing conditions related to obesity. ^{1 5 6 7 8}

Who Is on the Research Team?

Seth W. W Holwerda, PhD

Principal Investigator

University of Kansas Medical Center

Are You a Good Fit for This Trial?

This trial is for adults aged 18-79 with obesity (BMI >30), high blood pressure (>130/80 mmHg), and insulin resistance, but not diabetes. Participants should have a waist circumference over 102 cm for men or 88 cm for women, and be willing to visit the research lab. Those on hypertension meds, using clonidine or beta-blockers, with a history of heart disease or neurological disorders, smokers, or in other studies cannot join.

Inclusion Criteria

Your blood pressure is higher than 130/80.

Your body has trouble using insulin (HOMA-IR > 2.5).

Willing to visit research lab (Fairway CTSU)

Exclusion Criteria

Your blood test shows that you have high levels of triglycerides after fasting.

I am currently on medication for high blood pressure.

Actively participating in other studies, except for a registry study

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive 4 weeks of SNA blockade with oral clonidine, hydrochlorothiazide, or placebo

4 weeks

Weekly visits for monitoring and drug administration

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Clonidine
• Hydrochlorothiazide 12.5Mg Tab
• Placebo

Trial Overview The study tests if inhibiting sympathetic nerve activity (SNA) with oral clonidine reduces inflammation markers compared to a diuretic (hydrochlorothiazide) or placebo. It's a prospective study where participants are randomly assigned to one of these three groups without knowing which one they're getting.

How Is the Trial Designed?

Group I: Hydrochlorothiazide (HCTZ) Experimental Treatment 1 Intervention

KU Investigational Pharmacy will provide the drug prescription bottle with 35-day supply of Hydrochlorothiazide to the research coordinator to give to the research participant. Planned use in this study 1. Condition/disease indication(s): Hypertension 2. Subject population: Hypertension 3. Dose(s): 25 mg/day 4. Administration: Oral 5. Dosing regimen: 12.5 mg twice per day

Group II: Clonidine Experimental Treatment 1 Intervention

KU Investigational Pharmacy will provide the drug prescription bottle with 35-day supply of clonidine to the research coordinator to give to the research participant. Planned use in this study 1. Condition/disease indication(s): Vascular function and blood flow 2. Subject population: Hypertension 3. Dose(s): 0.1 mg (oral) 4. Administration: Oral 5. Dosing regimen: 0.1 mg twice daily by mouth

Group III: Placebo Placebo Group 1 Intervention

KU Investigational Pharmacy will provide the drug prescription bottle with 35-day supply of placebo to the research coordinator to give to the research participant. The placebo is an inert substance with no intended medical value and is used as a negative control for comparison with the study drug. Participants will receive a Placebo Pill; has no active ingredients but is made to look like the study drug.

Clonidine is already approved in United States, European Union for the following indications:

Approved in United States as Catapres for:

• Hypertension
• ADHD
• Severe cancer pain
• Withdrawal symptoms from various substances
• Diagnosis of pheochromocytoma
• Prevention of migraines

Approved in European Union as Catapres for:

• Hypertension
• ADHD
• Severe cancer pain
• Withdrawal symptoms from various substances
• Diagnosis of pheochromocytoma
• Prevention of migraines

Who Is Running the Clinical Trial?

University of Kansas Medical Center

Lead Sponsor

Trials

527

Recruited

181,000+

Published Research Related to This Trial

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]

A comprehensive analysis of 15 clinical studies involving 6638 patients showed that liraglutide, a GLP-1 receptor agonist, had a lower incidence of major adverse cardiovascular events (MACE) compared to other diabetes treatments, with an incidence ratio of 0.73.

The study confirmed that liraglutide's cardiovascular safety profile is within the limits set by the FDA for diabetes therapies, indicating it is a safe option for patients at risk of cardiovascular issues.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cardiovascular safety of liraglutide assessed in a patient-level pooled analysis of phase 2: 3 liraglutide clinical development studies. Marso, SP., Lindsey, JB., Stolker, JM., et al.[2022]

Sibutramine and orlistat are two FDA-approved medications for long-term obesity treatment, with distinct mechanisms of action: sibutramine acts as a reuptake inhibitor of monoamines, while orlistat inhibits pancreatic lipase to reduce fat absorption.

Dexfenfluramine has been withdrawn from the market due to its association with serious heart valve issues, highlighting the importance of safety monitoring in obesity pharmacotherapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Recent progress in obesity pharmacotherapy. Ryan, DH.[2019]

Obesity is a significant public health issue linked to various health risks, and while current pharmacological agents like lipase inhibitors and GLP-1 receptor agonists help reduce weight, they are not effective for genetic-related obesity disorders.

Emerging therapies targeting leptin and melanocortin-4 receptors (MC4Rs) show promise in treating genetic causes of obesity, with leptin analogs and MC4R agonists aiming to restore normal appetite and energy balance regulation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Advances in Anti-obesity Pharmacotherapy: Current Treatments, Emerging Therapies, and Challenges. Brandfon, S., Eylon, A., Khanna, D., et al.[2023]

A new classification system for anti-obesity medications categorizes them into four groups: appetite suppressants, absorption inhibitors, medical nutrition therapy, and energy expenditure enhancers, aiding physicians in selecting the right treatment for individual patients.

This classification aims to enhance personalized treatment strategies for obesity management, addressing the challenges posed by the variety of new weight management drugs being developed.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Person-centered choice of anti-obesity pharmacotherapy. Kalra, S., Arora, S., Kapoor, N.[2022]

Currently, there are three FDA-approved medications for obesity: phentermine and sibutramine, which suppress appetite, and orlistat, which blocks fat absorption, highlighting the evolving landscape of pharmacological treatments for obesity.

Over 150 new weight loss agents are in development, suggesting that future obesity treatments may involve combinations of therapies targeting different physiological mechanisms to enhance efficacy and overcome the body's natural resistance to weight loss.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pharmacological therapies for obesity. Kaplan, LM.[2007]

Obesity is linked to serious health issues like type 2 diabetes and cardiovascular disease, and pharmacotherapy is recommended when lifestyle changes alone do not lead to weight loss in patients with a BMI of 25 kg/m2 or higher.

The paper reviews available long-term anti-obesity medications, which include centrally acting anorexiants and peripherally acting drugs like orlistat, highlighting the need for individualized treatment approaches.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Current Long-Term Pharmacotherapies for the Management of Obesity. Kim, BY., Kang, SM., Kang, JH., et al.[2020]

A compounded oral clonidine hydrochloride powder (0.2 mg/g) maintained its stability and quality for 120 days under controlled storage conditions, ensuring consistent dosing for pediatric patients.

No degradation products were detected, and the clonidine content remained within the acceptable range (90.0% to 110.0% of initial content), indicating that the compounded formulation is safe and effective for use.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Stability of clonidine hydrochloride in an oral powder form compounded for pediatric patients in Japan. Saito, J., Hanawa, T., Matsumoto, T., et al.[2021]

Clonidine (Catapres-TTS) was effective in significantly reducing blood pressure in 11 out of 25 patients with mild to moderate hypertension during the first four weeks of treatment, but did not show significant effects in patients with more severe hypertension.

While some patients experienced localized contact dermatitis leading to discontinuation of the patch, other side effects like drowsiness and dry mouth were less common compared to oral clonidine, making Catapres-TTS a potentially better option for those who have trouble with the oral form.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Patient acceptance of transdermal clonidine. A retrospective review of 25 patients. Chen, SW., Vidt, DG.[2019]

Catapres-TTS is a transdermal system that effectively delivers clonidine, an antihypertensive drug, with controlled drug input rates that minimize variability in plasma drug concentrations among patients.

The system's design includes a rate-control element that allows for an initial bolus of drug to quickly achieve steady-state levels, optimizing both the lag time and maintaining consistent drug levels during chronic therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

In vitro/in vivo functionality of Catapres-TTS. Enscore, DJ., Osborne, JL., Shaw, JE.[2014]

Clonidine is a safe and effective medication for detoxifying certain opiate addicts, particularly as a transitional treatment before starting naltrexone for aftercare.

The rising cocaine abuse epidemic in the U.S. may necessitate hospitalization or specialized outpatient programs for effective treatment, highlighting the need for structured care in managing addiction.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Opiate and cocaine dependencies. Techniques to help counter the rising tide. Washton, AM., Gold, MS., Pottash, AC.[2019]

A single large dose of clonidine caused automutilation in individually housed mice, indicating a potential side effect of the drug that could be linked to its effects on behavior.

Chronic administration of clonidine did not significantly change the automutilation behavior, and this effect was not observed in mice that were housed in groups, suggesting that social environment may play a role in the drug's behavioral effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Automutilation induced by clonidine in mice. Razzak, A., Fujiwara, M., Ueki, S.[2019]

Obesity is linked to numerous serious health issues, yet the demand for safe and effective antiobesity drugs is rising as obesity rates continue to climb globally.

Previous antiobesity drugs have faced significant safety concerns, leading to withdrawals due to life-threatening side effects, highlighting the need for better predictive models and new therapeutic targets in drug development.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Review paper: Current strategies in the development of anti-obesity drugs and their safety concerns. Elangbam, CS.[2008]

Pharmacologic treatments for obesity, such as phentermine, sibutramine, and orlistat, typically lead to an additional weight loss of about 2-5 kg compared to placebo, but there is a need for more effective and safer options.

Several new antiobesity drugs are in late-stage development, targeting various mechanisms like appetite suppression and nutrient absorption, which may enhance treatment options for obesity in the near future.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Drugs in the pipeline for the obesity market. Klonoff, DC., Greenway, F.[2021]

Several weight loss agents are being developed that target different systems in the body to help control appetite, including medications like APD356 and rimonabant, which have shown promise in clinical trials.

Innovative approaches, such as surgically implanted gastric pacemakers, are also being explored to help manage weight by influencing the body's hunger signals and gastric emptying processes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Potential role of new therapies in modifying cardiovascular risk in overweight patients with metabolic risk factors. Jensen, MD.[2017]

Citations

1. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/3295935/

A placebo-controlled crossover study of oral clonidine in ... Discontinuation of clonidine was associated with a small but significant weight loss compared to a small weight increase during the initiation of clonidine ...

2. ahajournals.org ahajournals.org/doi/10.1161/01.HYP.33.1.548

Clonidine Prevents Insulin Resistance and Hypertension in ... Clonidine prevented the hypertension, tachycardia, and insulin resistance associated with feeding dogs the high fat diet but did not affect weight gain.

3. accessdata.fda.gov accessdata.fda.gov/drugsatfda_docs/label/2020/022331s021lbl.pdf

KAPVAY® (clonidine hydrochloride) extended-release tablets Based on published lactation studies, clonidine hydrochloride is present in human milk at relative infant doses ranging from 4.1 to 8.4% of the maternal weight- ...

4. hhs.texas.gov hhs.texas.gov/sites/default/files/documents/clonidine-er-kapvay-monograph.pdf

Clonidine Hydrochloride ER (Kapvay®) Due to the lack of controlled clinical trial data and differing pharmacokinetic profiles, substitution of KAPVAY for other clonidine products on ...

5. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC6109660/

Medications that cause weight gain and alternatives in ... In general, changes in weight for alpha-blockers appear to be minor or nonexistent, with the average changes in weight following clonidine (0.4–1.4 kg,) and ...

6. accessdata.fda.gov accessdata.fda.gov/drugsatfda_docs/label/2009/017407s034lbl.pdf

Catapres (clonidine hydrochloride) Label - accessdata.fda.gov Following oral administration about 40-60% of the absorbed dose is recovered in the urine as unchanged drug in 24 hours. About 50% of the absorbed dose is ...

7. mayoclinic.org mayoclinic.org/drugs-supplements/clonidine-oral-route/description/drg-20063252

Clonidine (oral route) - Side effects & dosage Safety and efficacy have not been established. Geriatric. No ... weight gain. Get emergency help immediately if any of the following ...

8. ncbi.nlm.nih.gov ncbi.nlm.nih.gov/books/NBK459124/

Clonidine - StatPearls - NCBI Bookshelf Clonidine is an antihypertensive drug that lowers blood pressure and heart rate by relaxing the arteries and increasing the blood supply to the heart.