Estetrol/Drospirenone to Reduce the Average Size of Endometriomas

Study Overview
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Brief Summary
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Endometriosis, a chronic gynecological disorder associated with pain and infertility, is a common condition affecting approximately one in ten women. Up to 50% of patients with endometriosis have ovarian endometriomas (or chocolate cysts). These cysts directly impact fertility and ovarian reserve (ie. ability to have children) and can cause additional symptoms in women such as added pain, discomfort, and surgical emergencies (cyst rupture, or more rarely twisting). While endometriomas tend to require surgical excision as a solution, medical management with a variety of medications has been shown to be effective in reducing their size. Medical management (ie. medications and treatments that don't involve surgery) to reduce cyst size can help relieve symptoms either as a long term solution, before fertility treatments, or temporarily until surgery can be offered. Because the COVID-19 pandemic caused significantly reduced access to surgery and resources, medical management has become important for relief of the overburdened healthcare network. The purpose of this study is to see how effective Estetrol/drospirenone, a combined oral contraceptive (COC), is in the reduction of ovarian endometriomas after a 3- and 6-month period of treatment. This single arm interventional study will recruit women 18 years or older with an ovarian endometrioma of at least 3cm, who are seeking a hormonal treatment for their endometrioma(s). Consenting participants of the study will take Estetrol/drospirenone once daily, orally, for a 6 month duration. An ultrasound assessment of ovarian endometrioma(s) will be performed before starting the drug (0 months), and will be repeated at 3-months and 6-months time. At each of these hospital visits (0, 3 & 6 months), participants will have their weight and blood pressure measured, and they will complete questionnaires regarding their endometriosis symptoms, incidence of amenorrhea, compliance and incidence of any adverse effects.

Detailed Description
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Ovarian endometriomas (or chocolate cysts) are present in up to 50% of patients with endometriosis - a chronic gynecological disorder associated with pain and infertility. These cysts directly impact fertility and ovarian reserve and can cause additional symptoms in women such as added pain, discomfort, and surgical emergencies (cyst rupture, or more rarely torsion). While endometriomas tend to require surgical excision for definitive resolution, medical management with a variety of agents has been shown to be effective in reducing their size; these agents include combined oral contraceptives (COC), aromatase inhibitors, progestins, androgens, cabergoline, and gonadotropin-releasing hormone agonists (GnRH-a). Medical management to reduce their size can help alleviate symptoms indefinitely without damaging ovarian reserve prior to fertility treatments, or to temporize until surgical management can be offered. Medical management has become particularly important in light of the COVID-19 pandemic, with significantly reduced access to surgery, and resource allocation to alleviate an overburdened healthcare network. Estetrol/drospirenone (Nextstellis™) is a prescription-only COC available in Canada containing two hormones: a progestin (drospirenone - well known as both a standalone contraceptive and in other combined formulations), and an estrogen (estetrol - newly introduced with this product). While ethinyl estradiol (EE) is the most common estrogen currently used in COC, estetrol (E4) has proven safety and tolerability, and emerging evidence points towards a lower risk of thrombosis than traditional EE used in other COC. Studies have documented efficacy and safety for the combination estetrol/drospirenone, with a favourable bleeding profile, and very low rates of adverse reactions. While there exists already encouraging data on drospirenone and drospirenone containing products on alleviating symptoms of endometriosis and reducing the size of endometriomas, there are no studies to date evaluating this novel combination of estetrol/drospirenone in managing ovarian endometriomas. The primary objective of this study is to determine the effectiveness of Estetrol/drospirenone, a combined oral contraceptive (COC), in the reduction of ovarian endometriomas after a 3- and 6-month period of treatment. This is a single-center, open label, single arm interventional study that will be performed at the McGill University Health Centre (MUHC) Royal Victoria Hospital (RVH). Women 18 years of age or older with at least one ovarian endometrioma, of at least 3cm, who are seeking a hormonal treatment for their endometrioma(s), will be recruited. The study will aim to recruit 25 women. Consenting participants will be given a 6-month course of oral estetrol/drospirenone (15 mg estetrol monohydrate / 3 mg drospirenone) once daily for the study duration. An ultrasound assessment of ovarian endometrioma(s) will be performed prior to drug initiation (baseline), and will be repeated at 3-months and 6-months time. All ultrasounds will be performed by the same ultrasonographer using a standardized technique and 3-D volumetric assessment. At each of these hospital visits, participants will have their weight and blood pressure measured and they will complete questionnaires regarding their endometriosis symptoms with a research coordinator. Safety, tolerability, and the incidence of adverse effects will also be monitored at the same time intervals.

Official Title
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Estetrol/Drospirenone to Reduce the Average Size of Endometriomas

Conditions
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Ovarian Endometrioma, Endometrioma

Intervention / Treatment
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* Drug: Estetrol/Drospirenone


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: equal to or greater than 18 years old has at least one ovarian endometrioma, of at least 3 cm elects to start estetrol/drospirenone (after usual counselling on medical options with their doctor) Exclusion criteria: inability to provide informed consent Any hormone use, from the following list, within last 3 months: Estrogen (agonist or antagonist), Progestogen (agonist or antagonist), Androgen (agonist or antagonist), GnRH (agonist or antagonist), Cabergoline

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Women with an ovarian endometrioma who will take drospirenone / estetrol<br>Women 18 years of age or older with endometriosis who have at least one ovarian endometrioma, of at least 3 cm in diameter, who will take oral Drospirenone / Estetrol treatment for 6 months | Drug: Estetrol/Drospirenone<br>* 6-month course of oral estetrol/drospirenone (15 mg estetrol monohydrate / 3 mg drospirenone) once daily for the study duration<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in ovarian endometrioma volume at 6-months (from baseline) | Endometrioma volume will be assessed by the same ultrasonographer (Dr. DB Nguyen) at each hospital visit, using a standardized technique, with 3-dimensional volumetric assessment. | pre-study, 6-months of treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of adverse effects (safety, tolerability) | Incidence of adverse effects (yes/no) including: nausea/vomiting, edema, breast tenderness, headache, cramps/bloating, mood swings (specified), as well as any unexpected adverse effects will be evaluated by having the participant complete a questionnaire at each hospital visit after starting estetrol/drospirenone. | 3-months of treatment, 6-months of treatment | 
| Compliance | Drug compliance will be evaluated by having the participant complete a questionnaire at each hospital visit after starting estetrol/drospirenone. If they have been taking the prescribed dosage of 1 oral tablet of estetrol/drospirenone a day (yes/no) If they have been taking the prescribed dosage at the same time every day (yes/no) How often they miss a pill, on a 4-point likert scale (Never/Rarely/Occasionally/Often) | 3-months of treatment, 6-months of treatment | 
| Change in endometrioma volume at 3-months (from baseline) | Endometrioma volume will be assessed by the same ultrasonographer (Dr. DB Nguyen) at each hospital visit, using a standardized technique, with 3-dimensional volumetric assessment. | pre-study, 3-months of treatment | 
| change in endometrioma maximal diameter at 6-months (from baseline) | Endometrioma maximal diameter will be assessed by the same ultrasonographer (Dr. DB Nguyen) at each hospital visit, using a standardized technique, with 3-dimensional volumetric assessment. | pre-study, 6-months of treatment | 
| change in endometrioma maximal diameter at 3-months (from baseline) | Endometrioma maximal diameter will be assessed by the same ultrasonographer (Dr. DB Nguyen) at each hospital visit, using a standardized technique, with 3-dimensional volumetric assessment. | pre-study, 3-months of treatment | 
| Incidence of amenorrhea | Incidence of amenorrhea will be evaluated by having the participant complete a questionnaire at each hospital visit. If they have gotten their period in the last 3 months: measured by (yes/no) The frequency of spotting in the last month: measured by a 4-point likert scale (Never/Rarely/Occasionally/Often) | pre-study, 3-months of treatment, 6-months of treatment | 
| Change in patient reported endometriosis symptoms | Change of endometriosis symptoms will be evaluated by monitoring the changes in participants's responses to the modified Biberoglu & Behrman (B&B) scale questionnaire. This is a validated scale that evaluates endometriosis pain by patient's self-assessment of three pain symptoms (dysmenorrhea, dyspareunia, and chronic pelvic pain) on a 4-point likert scale (none=0/mild=1/moderate=2/severe=3). Minimum value: 0 --> best outcome Maximum value: 9 --> worst outcome | pre-study, 3-months of treatment, 6-months of treatment | 
| Change in weight | Weight will be measured by a research coordinator or nurse at each hospital visit. | pre-study, 3-months of treatment, 6-months of treatment | 
| Change in blood pressure | Blood pressure will be measured by a research coordinator or nurse at each hospital visit. | pre-study, 3-months of treatment, 6-months of treatment | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Estetrol/drospirenone, Nextstellis, Endometriosis, volume reduction, ultrasound, Estetrol-drospirenone