Behavioral Weight Loss + Progestin for Endometrial Hyperplasia

Recruiting at 2 trial locations

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

Age: 18+

Sex: Female

Trial Phase: Phase 2

Sponsor: Washington University School of Medicine

Must be taking: Progestin

Disqualifiers: Chemotherapy, Radiation, Pregnant, 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: Unknown

Duration: 12 months

96 Participants Needed

Trial Summary

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications. However, if you are already on progestin therapy, you can continue with it as part of the study.

What data supports the effectiveness of the treatment for endometrial hyperplasia?

Research shows that using a levonorgestrel-releasing intrauterine system (a device placed in the uterus that releases hormones) can lower the risk of developing endometrial cancer by up to 50% compared to the general population. Additionally, weight loss during progestin treatment has been found to improve outcomes in women with obesity-related endometrial conditions. ^{1 2 3 4 5}

Is the combination of behavioral weight loss and progestin treatment safe for humans?

The levonorgestrel-releasing intrauterine system (like Mirena) has been used safely for many years, showing benefits in reducing the risk of certain cancers, although there may be a slight increase in breast cancer risk. Intrauterine progestin treatments have shown a good safety profile, with favorable effects on endometrial protection and serum lipids, and are generally well-accepted by patients. ^{1 2 3 4 6}

How is the treatment for endometrial hyperplasia using Levonorgestrel-releasing IUD and behavioral weight loss unique?

This treatment is unique because it combines a Levonorgestrel-releasing intrauterine device (IUD), which directly delivers medication to the uterus, with a telemedicine-based behavioral weight loss program. This approach not only targets the endometrial hyperplasia but also addresses obesity, a significant risk factor, potentially improving treatment outcomes and overall health. ^{1 5 7 8 9}

What is the purpose of this trial?

Up to 60% of endometrial cancer cases are attributed to obesity, in part because obesity promotes development of atypical endometrial hyperplasia (AEH), and up to 40% of women with AEH go on to develop endometrial cancer. The increasing prevalence of obesity in premenopausal women has resulted in increasing rates of AEH in this age group. Hysterectomy with removal of the fallopian tubes and ovaries is 100% effective in preventing endometrial cancer, but this approach results in infertility. Fertility-sparing treatments exist, such as treatment with oral or intrauterine progestin, but these treatments do not work uniformly and do not combat the underlying cause of endometrial cancer, which is obesity and metabolic syndrome. Additionally, up to 41% of women on progestin eventually experience relapse of AEH or endometrial cancer. Third, many patients have insulin resistance that may worsen with progestin therapy. Thus, to improve treatment of AEH and grade 1 endometrial cancer, prevent and reverse endometrial cancer, and allow women to preserve their fertility, the investigators must integrate an effective weight loss strategy to be given with progestin treatment. It is the hypothesis that premenopausal women with AEH desire uterine preservation will be more likely to have atypia-free uterine preservation at one year if they receive progestin in combination with a behavioral weight loss intervention versus progestin plus enhanced usual care.

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) and a diagnosis of complex atypical endometrial hyperplasia or grade 1 endometrial cancer, who want to preserve their uterus. They should be able to have an IUD placed, may already be on progestin therapy for less than six months, and must not have been in a weight loss trial recently or currently receiving chemotherapy/radiation.

Inclusion Criteria

I have AEH or grade 1 endometrial cancer and am on progestin therapy.

I have been diagnosed with a specific type of early-stage uterine cancer or pre-cancer.

I have taken or am currently taking progestin.

Exclusion Criteria

I cannot use an IUD due to certain health conditions or allergies.

Prior participation in a weight loss intervention trial within 3 months prior to date of registration

I am not currently receiving chemotherapy or radiation for cancer.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive a levonorgestrel-releasing IUD and either a behavioral weight loss intervention or enhanced usual care

12 months

Telemedicine sessions for behavioral coaching

Crossover

Participants in the enhanced usual care arm may cross over to the behavioral weight loss intervention if they have not achieved resolution of AEH or grade 1 endometrial cancer

12 months

Follow-up

Participants are monitored for safety and effectiveness after treatment

24 months

Treatment Details

Interventions

• Levonorgestrel-releasing IUD
• Progestin
• Telemedicine behavioral weight intervention

Trial Overview The study tests if combining a behavioral weight loss intervention via telemedicine with progestin treatment is more effective in preserving the uterus without atypia compared to just progestin treatment plus enhanced usual care. Participants will also receive either oral progestin or a levonorgestrel-releasing IUD.

Participant Groups

Group I: Arm 1: Levonorgestrel-releasing IUD (LNG-IUD) + Behavioral Weight Loss Intervention Experimental Treatment 3 Interventions

* The levonorgestrel-releasing IUD is used in this study as per standard care. * The behavioral weight loss intervention consists of a telemedicine cognitive behavioral coaching program. At each session, patients will self-report weight, number of days they kept a food journal during the past week, average daily caloric intake for the week, number of days exercised for the week, total number of minutes of moderate physical activity, and average number of steps per day for the week.

Group II: Arm 2: Levonorgestrel-releasing IUD (LNG-IUD) + Enhanced Usual Care Active Control 2 Interventions

* The levonorgestrel-releasing IUD is used in this study as per standard care. * Participants will be provided with 1- to 3-page handouts on topics including healthy eating, exercise, and behavioral eating strategies from materials provided on the American Cancer Society, Society of Gynecologic Oncology, and WebMD Nourish websites. These materials encourage weight loss through calorie counting, recording dietary intake, engaging in exercise programs, and using portion control strategies. * The participants randomized to this arm will cross over to the behavioral weight loss intervention arm at 12 months if they have not achieved resolution of AEH or grade 1 endometrial cancer.

Levonorgestrel-releasing IUD is already approved in European Union, United States, Canada for the following indications:

Approved in European Union as Mirena for:

• Contraception
• Heavy menstrual bleeding
• Endometrial hyperplasia
• Endometrial cancer

Approved in United States as Mirena for:

• Contraception
• Heavy menstrual bleeding
• Endometrial hyperplasia

Approved in Canada as Mirena for:

• Contraception
• Heavy menstrual bleeding
• Endometrial hyperplasia

Who Is Running the Clinical Trial?

Washington University School of Medicine

Lead Sponsor

Trials

2,027

Recruited

2,353,000+

National Cancer Institute (NCI)

Collaborator

Trials

14,080

Recruited

41,180,000+

Findings from Research

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]

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]

The levonorgestrel-releasing intrauterine system, particularly the Mirena® device, can significantly reduce the risk of endometrial carcinoma by up to 50% compared to the general population, making it an effective preventive measure against certain cancers in women.

While Mirena® may slightly increase the risk of breast carcinoma by about 20%, it also lowers the risk of other cancers such as cervical, ovarian, pancreatic, and lung carcinomas, suggesting its potential as a primary prevention strategy, especially for women who are obese or overweight.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Levonorgestrel-releasing intrauterine system Mirena® (Bayer) for the prevention and treatment of endometrial adenocarcinoma and the incidence of other malignancies in women]. Jóźwik, M., Jóźwik, M., Modzelewska, B., et al.[2019]

The frameless intrauterine drug delivery system releasing 14 micrograms per day of levonorgestrel achieved a 100% cure rate for both nonatypical and atypical endometrial hyperplasia in a study of 12 women over 3 to 4 years.

This treatment method offers a non-invasive alternative to hysterectomy for managing endometrial hyperplasia, as confirmed by repeat endometrial biopsies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Treatment of nonatypical and atypical endometrial hyperplasia with a levonorgestrel-releasing intrauterine system. Wildemeersch, D., Dhont, M.[2019]

A multicenter trial in Korea is evaluating the efficacy of the levonorgestrel-releasing intrauterine system (IUS) as a treatment for endometrial hyperplasia, aiming to determine if it is as effective or more effective than oral progesterone.

The study involves regular monitoring through endometrial biopsies and ultrasounds every 3 months, with the primary goal of assessing the response rate to the IUS, potentially offering a non-surgical alternative for patients who wish to avoid hysterectomy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Management of endometrial hyperplasia with a levonorgestrel-releasing intrauterine system: single arm, prospective multicenter study: Korean gynecologic oncology group study (KGOG2006). Lee, TS., Seong, SJ., Kim, JW., et al.[2016]

Intrauterine progestins, particularly levonorgestrel, provide effective endometrial protection against estrogen-induced hyperstimulation in both peri- and postmenopausal women, with a favorable safety profile observed across 19 studies involving 826 participants.

The use of intrauterine progestins has shown promising results in terms of bleeding profiles and positive effects on serum lipids, although further comparative studies with other hormone replacement therapies are needed to confirm these findings.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Intrauterine application of progestins in hormone replacement therapy: a review. Riphagen, FE.[2019]

In a study of 60 women undergoing fertility-preserving therapy for complex atypical hyperplasia and endometrial cancer, those treated with oral progestin (megestrol acetate) experienced significantly greater weight gain compared to those using the levonorgestrel-containing intrauterine device (LNG-IUD), with a median weight change of +2.95 kg versus +0.05 kg, respectively.

Younger patients with a lower body mass index (BMI < 35) gained more weight during therapy, but even among those with a higher BMI (≥ 35), megestrol acetate was still linked to more weight gain than the LNG-IUD, indicating that LNG-IUD may be a better option for minimizing weight changes during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effect of oral versus intrauterine progestins on weight in women undergoing fertility preserving therapy for complex atypical hyperplasia or endometrial cancer. Cholakian, D., Hacker, K., Fader, AN., et al.[2016]

Obesity, polycystic ovarian syndrome (PCOS), and type-2 diabetes mellitus (T2DM) are significant risk factors for developing malignant endometrial pathology, particularly in reproductive-aged women, highlighting the need for targeted interventions.

Glucagon-like peptide 1 receptor agonists, typically used for diabetes management, may offer a promising adjunct treatment for obese patients with malignant endometrial pathology by potentially improving weight, inflammation, and insulin resistance, which could enhance fertility outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The potential role of GLP-1 receptor agonist targeting in fertility-sparing treatment in obese patients with endometrial malignant pathology: a call for research. Violette, CJ., Agarwal, R., Mandelbaum, RS., et al.[2023]

The Levonorgestrel-releasing intrauterine system (LNG-IUS) is recommended for managing endometrial hyperplasia without atypia, as it can reduce the risk of developing endometrial cancer, particularly in obese patients.

Despite the use of LNG-IUS, there is still a risk of developing endometrial cancer, as demonstrated by a case study of a 56-year-old woman with morbid obesity who developed endometrioid adenocarcinoma, emphasizing the importance of monitoring for early signs of cancer in high-risk individuals.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Development of endometrioid adenocarcinoma despite Levonorgestrel-releasing intrauterine system: a case report with discussion and review of the RCOG/BSGE Guideline on the Management of Endometrial Hyperplasia. van der Meer, AC., Hanna, LS.[2017]

References

1. 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]

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

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

3. Poland pubmed.ncbi.nlm.nih.gov

[Levonorgestrel-releasing intrauterine system Mirena® (Bayer) for the prevention and treatment of endometrial adenocarcinoma and the incidence of other malignancies in women]. [2019]

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

Treatment of nonatypical and atypical endometrial hyperplasia with a levonorgestrel-releasing intrauterine system. [2019]

5. England pubmed.ncbi.nlm.nih.gov

Management of endometrial hyperplasia with a levonorgestrel-releasing intrauterine system: single arm, prospective multicenter study: Korean gynecologic oncology group study (KGOG2006). [2016]

6. England pubmed.ncbi.nlm.nih.gov

Intrauterine application of progestins in hormone replacement therapy: a review. [2019]

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

Effect of oral versus intrauterine progestins on weight in women undergoing fertility preserving therapy for complex atypical hyperplasia or endometrial cancer. [2016]

8. England pubmed.ncbi.nlm.nih.gov

The potential role of GLP-1 receptor agonist targeting in fertility-sparing treatment in obese patients with endometrial malignant pathology: a call for research. [2023]

9. England pubmed.ncbi.nlm.nih.gov

Development of endometrioid adenocarcinoma despite Levonorgestrel-releasing intrauterine system: a case report with discussion and review of the RCOG/BSGE Guideline on the Management of Endometrial Hyperplasia. [2017]