Drug + IUD & Weight Intervention for Hyperplasia

Overseen By Andrea R Hagemann, M.D., MSCI

Age: 18 - 65

Sex: Female

Trial Phase: Phase 2

Sponsor: Washington University School of Medicine

Must be taking: Progestin

Must not be taking: GLP-1R agonists, DPP-4 inhibitors

Disqualifiers: Diabetes, Obesity surgery, Cancer, 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 4 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 12

Duration: 104 weeks

96 Participants Needed

Trial Summary

What is the purpose of this trial?

This trial tests if using semaglutide and an LNG-IUD together can help premenopausal women with thickened uterine linings keep their uterus, lose weight, and improve their quality of life. The levonorgestrel intrauterine device (LNG-IUD) has been used effectively for various conditions including thickened uterine linings, heavy menstrual bleeding, and as part of hormone replacement therapy.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications. However, you cannot have used certain diabetes medications like GLP-1 receptor agonists in the last 3 months, and you cannot be on other weight management drugs. If you are on progestin or metformin, you can continue taking them.

What data supports the effectiveness of the drug for treating hyperplasia?

Research shows that weight loss during progestin treatment can improve outcomes for women with obesity-related endometrial hyperplasia. Additionally, the levonorgestrel-releasing intrauterine system (LNG-IUS) has been effective in treating endometrial hyperplasia without atypia. ^{1 2 3 4 5}

Is the treatment generally safe for humans?

The research articles provided do not contain specific safety data for the treatment involving Progestin, Medroxyprogesterone acetate, Megestrol acetate, Levonorgestrel, Semaglutide, Ozempic, Wegovy, Rybelsus, or Telemedicine Behavioral Weight Intervention. Therefore, no relevant safety information is available from these sources. ^{6 7 8 9 10}

How is the drug Semaglutide unique for treating hyperplasia?

Semaglutide is unique because it is a once-weekly injection that mimics incretin hormones to help with weight loss and improve insulin sensitivity, which can be beneficial for conditions like hyperplasia where weight management is crucial. It has shown significant weight loss results in patients unresponsive to lifestyle changes, with minimal side effects. ^{11 12 13 14 15}

Research Team

Andrea R Hagemann, M.D., MSCI

Principal Investigator

Washington University School of Medicine

Eligibility Criteria

This trial is for premenopausal women aged 18-45 with obesity (BMI ≥ 30 kg/m2) and complex atypical endometrial hyperplasia who want to preserve their uterus. They must not have used GLP-1R agonists recently, have a history of certain diseases like MEN 2 or MTC, uncontrolled illnesses, renal dysfunction, or be pregnant/breastfeeding.

Inclusion Criteria

I have been diagnosed with a specific type of abnormal uterine cell growth.

BMI ≥ 30 kg/m2

I have AEH and am on progestin therapy without having used GLP-1R agonists in the last 3 months.

Exclusion Criteria

History of suicidal attempts or active suicidal ideation

I have severe chronic heart failure.

I do not have any serious ongoing illnesses like heart problems or infections.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive semaglutide or placebo injections weekly and progestin via LNG-IUD for up to 104 weeks

104 weeks

Weekly self-administration

Behavioral Weight Program

Participants optionally attend a behavioral weight program with 12 weekly sessions, recurring every three months

12 weeks per session, recurring

12 weekly visits per session

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Treatment Details

Interventions

• Progestin
• Semaglutide
• Telemedicine Behavioral Weight Intervention

Trial Overview The study tests if semaglutide combined with a levonorgestrel intrauterine device (LNG-IUD) is more effective than LNG-IUD alone in preserving the uterus and aiding weight loss in women with endometrial hyperplasia. It also examines the impact on quality of life.

Participant Groups

Group I: Arm 1: Semaglutide + progestin Experimental Treatment 3 Interventions

* The progestin will be delivered via the levonorgestrel-releasing IUD and it is standard of care. * Will receive injectable pens containing semaglutide and will be self-administered on a weekly basis for up to 104 weeks. Dosing will be escalated during weeks 1 through 16 (start at 0.24 mg up to 2.4 mg). * Will be enrolled in a behavioral weight program that is optional to attend. The program will be delivered in a closed-group format. The group program will consist of 12 consecutive 60 minute weekly visits, and will recur every three months such that participants can join the soonest available Week 1 session after study enrollment. Each group session will focus on providing education and cognitive/behavioral strategies to achieve a healthier, reduced-calorie diet and a more physically active lifestyle. Cognitive/behavioral strategies will consist of goal setting, problem solving, cognitive restructuring, stimulus control, and stress management.

Group II: Arm 2: Placebo + Progestin Active Control 3 Interventions

* The progestin will be delivered via the levonorgestrel-releasing IUD and it is standard of care. * Will receive injectable pens containing the placebo and will be self-administered on a weekly basis for up to 104 weeks. * Will be enrolled in a behavioral weight program that is optional to attend. The program will be delivered in a closed-group format. The group program will consist of 12 consecutive 60 minute weekly visits, and will recur every three months such that participants can join the soonest available Week 1 session after study enrollment. Each group session will focus on providing education and cognitive/behavioral strategies to achieve a healthier, reduced-calorie diet and a more physically active lifestyle. Cognitive/behavioral strategies will consist of goal setting, problem solving, cognitive restructuring, stimulus control, and stress management.

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

Approved in European Union as Ozempic for:

• Type 2 diabetes
• Cardiovascular disease
• Obesity

Approved in United States as Ozempic for:

• Type 2 diabetes
• Cardiovascular disease
• Obesity

Approved in Canada as Ozempic for:

• Type 2 diabetes
• Cardiovascular disease
• Obesity

Approved in Japan as Ozempic for:

• Type 2 diabetes
• Cardiovascular disease
• Obesity

Approved in United States as Wegovy for:

• Obesity

Approved in United States as Rybelsus for:

• Type 2 diabetes

Who Is Running the Clinical Trial?

Washington University School of Medicine

Lead Sponsor

Trials

2,027

Recruited

2,353,000+

Novo Nordisk A/S

Industry Sponsor

Trials

1,578

Recruited

3,813,000+

Lars Fruergaard Jørgensen

Novo Nordisk A/S

Chief Executive Officer since 2017

MSc in Finance and Business Administration, Aarhus School of Business, Aarhus University, Denmark

Martin Holst Lange

Novo Nordisk A/S

Chief Medical Officer since 2021

MD from University of Copenhagen

Findings from Research

The combination of relugolix, estradiol, and norethisterone acetate (Ryeqo®; Myfembree®) effectively reduces heavy menstrual bleeding and improves other symptoms associated with uterine fibroids, as demonstrated in two phase 3 LIBERTY trials.

This treatment is generally well tolerated, with minimal risk of clinically significant bone loss over up to 2 years, making it a safe and convenient once-daily option for premenopausal women suffering from symptomatic uterine fibroids.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Relugolix/Estradiol/Norethisterone (Norethindrone) Acetate: A Review in Symptomatic Uterine Fibroids. Syed, YY.[2022]

In a study of 219 women with complex endometrial hyperplasia, those treated with the levonorgestrel-releasing intrauterine system (LNG-IUS) had a significantly lower relapse rate (13.7%) compared to those treated with oral progestogens (30.3%), indicating LNG-IUS may be a more effective long-term treatment option.

The study also found that hysterectomy rates were lower in the LNG-IUS group (19.6%) compared to the oral progestogen group (31.8%), suggesting that LNG-IUS not only reduces relapse but may also decrease the need for surgical intervention.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Relapse of endometrial hyperplasia after conservative treatment: a cohort study with long-term follow-up. Gallos, ID., Krishan, P., Shehmar, M., et al.[2013]

In a study of 71 women with obesity and atypical hyperplasia or low-grade endometrial cancer, those who lost more than 10% of their body weight during progestin treatment had a significantly higher response rate to the treatment, suggesting that weight loss may enhance oncological outcomes.

Women who underwent bariatric surgery lost an average of 33.4 kg, while those on a low-calorie diet lost 4.6 kg, indicating that more significant weight loss is associated with better treatment responses in this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Weight Loss During Intrauterine Progestin Treatment for Obesity-associated Atypical Hyperplasia and Early-Stage Cancer of The Endometrium. Barr, CE., Ryan, NAJ., Derbyshire, AE., et al.[2023]

The FDA launched the REMS Public Dashboard in December 2021, providing an interactive tool for healthcare providers, patients, and researchers to access and visualize Risk Evaluation and Mitigation Strategy (REMS) information for drugs approved since 2008.

The dashboard allows users to explore various REMS characteristics and trends over time, enhancing public access to important drug safety information and supporting informed decision-making in healthcare.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The Risk Evaluation and Mitigation Strategy (REMS) Public Dashboard: Improving Transparency of Regulatory Activities. Toyserkani, GA., Lee, JH., Zhou, EH.[2023]

Montelukast sodium, administered intravenously in doses ranging from 3 to 18 mg, showed linear pharmacokinetics in healthy males, with consistent safety and tolerability across all doses.

Both males and females demonstrated similar pharmacokinetic profiles for montelukast sodium, with oral bioavailability averaging around 66% for males and 58% for females, indicating effective absorption regardless of gender.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pharmacokinetics, bioavailability, and safety of montelukast sodium (MK-0476) in healthy males and females. Cheng, H., Leff, JA., Amin, R., et al.[2022]

Nitrofurantoin is less effective and poses a higher risk of adverse events in patients with creatinine clearance below 60 ml/min, indicating the need for careful monitoring of kidney function before prescribing.

Azithromycin has been associated with QT prolongation and an increased risk of death, highlighting the importance of assessing cardiac health before use.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Pharmacovigilance update]. Diezi, L., Renard, D., Rothuizen, LE., et al.[2018]

Ivabradine has been linked to an increased risk of cardiovascular death and myocardial infarction when used at high dosages in patients with symptomatic angina, highlighting the need for careful dosage management.

Orlistat may interfere with the absorption of HIV antiretrovirals, which could impact treatment effectiveness for patients on these medications.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Pharmacovigilance update]. Fogarasi Szabo, N., Diezi, L., Delenclos, L., et al.[2015]

In a study of 27 obese patients with PCOS who did not respond to lifestyle modifications, treatment with semaglutide led to an average weight loss of 7.6 kg after three months, with 80% of participants achieving at least a 5% reduction in body weight.

Semaglutide treatment not only resulted in significant weight loss but also improved insulin sensitivity and normalized menstrual cycles in 80% of responsive patients, all with minimal side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Semaglutide Treatment of Excessive Body Weight in Obese PCOS Patients Unresponsive to Lifestyle Programs. Carmina, E., Longo, RA.[2023]

High-dose once-weekly semaglutide has been shown to significantly reduce weight in patients with obesity or overweight, as demonstrated in four phase 3 clinical trials involving various populations, including those with diabetes.

While gastrointestinal side effects were common, semaglutide was generally well tolerated and also led to improvements in cardiometabolic risk factors, such as waist circumference and blood pressure.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

High-Dose Once-Weekly Semaglutide: A New Option for Obesity Management. Bradley, CL., McMillin, SM., Hwang, AY., et al.[2022]

Semaglutide (Ozempic®) is an effective once-weekly treatment for type 2 diabetes, showing superior glucose-lowering effects and greater weight loss compared to other GLP-1 receptor agonists in Phase III clinical trials.

It is approved for use in Belgium for patients with type 2 diabetes who have not achieved adequate control with other antidiabetic therapies, particularly in those with a body mass index of 30 kg/m² or higher.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Semaglutide, once weekly GLP-1 receptor agonist (Ozempic®)]. Scheen, AJ.[2019]

Semaglutide, marketed as Rybelsus, is the first oral glucagon-like peptide receptor agonist approved by the FDA in 2019 for treating type 2 diabetes, highlighting its innovative delivery method.

This medication, taken once daily, aids in glucose control and weight management, potentially leading to improved health outcomes for individuals with type 2 diabetes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Semaglutide Is a New Once-Daily Oral Medication to Treat Type 2 Diabetes. Blakely, KK., Weaver, K.[2021]

Semaglutide 2.4 mg, administered weekly, can lead to significant weight loss (average 9.6-17.4% of initial body weight) over 68 weeks, improving obesity-related health issues.

While semaglutide is effective, healthcare providers must evaluate patient suitability carefully, considering factors like safety, potential side effects, and individual health conditions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clinical Insight on Semaglutide for Chronic Weight Management in Adults: Patient Selection and Special Considerations. Chao, AM., Tronieri, JS., Amaro, A., et al.[2023]

References

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

Relugolix/Estradiol/Norethisterone (Norethindrone) Acetate: A Review in Symptomatic Uterine Fibroids. [2022]

2. England pubmed.ncbi.nlm.nih.gov

Relapse of endometrial hyperplasia after conservative treatment: a cohort study with long-term follow-up. [2013]

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

Weight Loss During Intrauterine Progestin Treatment for Obesity-associated Atypical Hyperplasia and Early-Stage Cancer of The Endometrium. [2023]

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

Use of levonorgestrel-releasing intrauterine system in the prevention and treatment of endometrial hyperplasia. [2022]

5. Ireland pubmed.ncbi.nlm.nih.gov

Aromatase inhibitor anastrozole for treating endometrial hyperplasia in obese postmenopausal women. [2018]

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

The Risk Evaluation and Mitigation Strategy (REMS) Public Dashboard: Improving Transparency of Regulatory Activities. [2023]

7. Switzerland pubmed.ncbi.nlm.nih.gov

[Pharmacovigilance update]. [2013]

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

Pharmacokinetics, bioavailability, and safety of montelukast sodium (MK-0476) in healthy males and females. [2022]

9. Switzerland pubmed.ncbi.nlm.nih.gov

[Pharmacovigilance update]. [2018]

10. Switzerland pubmed.ncbi.nlm.nih.gov

[Pharmacovigilance update]. [2015]

11. Switzerland pubmed.ncbi.nlm.nih.gov

Semaglutide Treatment of Excessive Body Weight in Obese PCOS Patients Unresponsive to Lifestyle Programs. [2023]

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

High-Dose Once-Weekly Semaglutide: A New Option for Obesity Management. [2022]

13. Belgium pubmed.ncbi.nlm.nih.gov

[Semaglutide, once weekly GLP-1 receptor agonist (Ozempic®)]. [2019]

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

Semaglutide Is a New Once-Daily Oral Medication to Treat Type 2 Diabetes. [2021]

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

Clinical Insight on Semaglutide for Chronic Weight Management in Adults: Patient Selection and Special Considerations. [2023]