Subdermal Implant-bioabsorbable Gestrinone Pellet for Endometriosis Pelvic Pain Treatment

Study Overview
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Brief Summary
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Pelvic pain is considered a symptom of multifactorial origin among which Endometriosis is the main gynecological cause affecting 5-10% of worldwide women in their reproductive years, negatively impacting their quality of life and work efficiency. Treatment of endometriosis-associated pelvic pain is challenging and there are surgical and/or hormonal treatments available with variable endpoints. Gestrinone is a synthetic derivative of 19-nortestosterone with anti-estrogen, anti-progestin, androgenic, and weak estrogen-like action. Previous studies show that the oral treatment with Gestrinone induced an improvement in symptoms associated with endometriosis but with adverse events such as androgenization and uterine bleeding. Parenteral administration of Gestrinone could be effective to treat pain symptoms secondary to endometriosis and minimize these adverse events. This study evaluates the safety and tolerability of subdermal implant-bioabsorbable gestrinone pellet use in women with pelvic pain secondary to endometriosis after 6 months of Gestrinone pellet insertion versus placebo pellet.

Detailed Description
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This is a phase II study, multicenter, prospective, randomized, double-blind and placebo-controlled study to evaluate the safety and tolerability of of subdermal implant-bioabsorbable gestrinone pellet use in women with pelvic pain secondary to endometriosis. The exploratory aim is to compare the use of a gestrinone pellet with a placebo pellet in the results of participant satisfaction, change in pelvic pain intensity, use of rescue pain medication, quality of life, sexual function, and work activity. One hundred patients will be randomized in a 1: 1 ratio. Initially, all the patients will undergo insertion of an intrauterine system of levonorgestrel release (Kyleena) as a contraceptive method. On the same day, after randomization, the subdermal implantation of the gestrinone (85 mg) or placebo pellet will be performed. Visits will occur after 3 and 6 months of the pellet insertion. Primary endpoint is a combination of serious adverse events (SAEs) accumulated within 6 months of pellet insertion and collected through spontaneous reporting and/or clinical findings.

Official Title
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A Phase II, Randomized, Placebo-controlled, Double-blind, Multicenter Study to Investigate the Safety and Exploratory Efficacy of a Subdermal Implant-bioabsorbable Gestrinone Pellet for Pelvic Pain Secondary to Endometriosis Treatment

Conditions
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Deep Endometriosis, Pelvic Pain

Intervention / Treatment
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* Drug: Gestrinone
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Acceptance to participate and sign the Informed Consent Form Age between 18-50 years-old Participant has ever had penetrative sex Body weight between 50 and 90 kg Pelvic pain secondary to endometriosis Diagnosis of deep infiltrative endometriosis confirmed by histopathological examination Has undergone endometriosis surgery for at least 3 months and continues to complain of pelvic pain Not planning to become pregnant within 12 months of the screening visit or being surgically sterilized Has a mammography report (female aged > 40 years) or a breast ultrasound (female aged < 40 years) from the last 12 months Exclusion Criteria: Serious chronic disorder, including metastatic malignancy, end-stage kidney disease with or without dialysis, clinically unstable heart disease, or any other disorder that, in the investigator's opinion, excludes the study participant Immunosuppression or h confirmed diagnosis of immunodeficiency based on their history and/or physical or laboratory examination Medical or psychiatric conditions, including recent laboratory abnormalities (within the last 12 months) that may increase risks to the study participant or, at the investigator's discretion, make the participant unsuitable for the study Personal history of thromboembolic events Actual use of anticoagulant medication Contraindication for the use of hormonal contraceptives The participant is pregnant or suspected of being pregnant Positive urine human chorionic gonadotropin beta pregnancy test at the time of randomization Breastfeeding Current or recurrent pelvic inflammatory disease or other conditions that increase the risk of pelvic infections Postpartum endometritis or had a septic abortion within the last 3 months Abnormal uterine bleeding of unknown etiology Congenital or acquired uterine anomalies, including fibroids (leiomyomas or fibroids) that cause distortion of the uterine cavity Uterine or cervical malignancy Confirmed or suspected estrogen-dependent malignancy, including breast cancer Cervicitis or vaginitis, including bacterial vaginosis or other uncontrolled lower urinary tract infection cervical dysplasia Active liver disease or dysfunction Allergy, hypersensitivity, or intolerance to levonorgestrel, gestrinone, or any other ingredient or component of the Kyleena® formulation or subdermal pellets Previous inserted device or intrauterine contraceptive system (IUD or IUS) that has not been removed Trophoblastic disease recently, while your hCG levels remain elevated Bacterial endocarditis Hyperandrogenism at the time of screening, defined by: hirsutism: Ferriman-Gallwey score ≥ 8; clitoromegaly: defined by the clitoral index ≥ 35 mm2, acne: defined by the IGA scale (Investigator's global assessment) grade 5 - severe inflammatory acne dominates the area and there is a large number of comedones, pustules, papules, and cystic acne; alopecia, oily skin, and deepening of the voice Diagnosis of polycystic ovary syndrome Participation in another study within 30 days prior to initiation of study treatment

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 50 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
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Gestrinone<br>Subdermal implant-bioabsorbable gestrinone pellet (85 mg) All patients will undergo insertion of an intrauterine system of levonorgestrel release (Kyleena®) as a contraceptive method | Drug: Gestrinone<br>* The intradermal gestrinone/placebo pellet will be inserted on the same day as the levonorgestrel intrauterine hormonal device (Kyleena®)<br>|
| Placebo Comparator: Placebo<br>Subdermal implant-bioabsorbable placebo pellet (cholesterol) All patients will undergo insertion of an intrauterine system of levonorgestrel release (Kyleena®) as a contraceptive method | Drug: Placebo<br>* Subdermal implant-bioabsorbable placebo pellet (cholesterol)<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Combination of serious adverse events (SAEs) accumulated within 6 months of gestrinone or placebo pellet insertion and collected through spontaneous reporting and/or clinical findings | Proportion of patients who do NOT have SAEs: defined as a combination of death, conditions that threat or present risk to life, conditions needing hospitalization or prolonging the pre-existing hospitalization, conditions causing disability or permanent damage, conditions leading to a congenital anomaly and any other significant medical occurrence that, based on appropriate medical judgment, may harm the participant and/or require medical or surgical intervention to prevent any of the other aforementioned occurrences. | From randomization to the end of study on Day 180 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Androgenization | Number of participants who experience androgenization defined by: Hirsutism (Ferriman-Gallwey Score ≥ 8), Clitoromegaly (Clitoridian index ≥ 35 mm2), Acne (IGA scale grade 5 - severe inflammatory acne dominates the area and there are large numbers of comedones, pustules, papules, and cystic acne), Alopecia, oiliness of the skin, and deepening of the voice | pre-insertion assessment of the pellet (baseline), 3 and 6 months after insertion of the gestrinone or placebo pellet | 
| Plasma concentration of steroid hormones | plasma concentration of total testosterone, free testosterone, and SHBG | pre-insertion of the pellet (baseline) and 3 months after pellet insertion of the gestrinone or placebo pellet | 
| Lipid profile | Serum levels of total cholesterol, HDL-C, VLDL-C, and triglycerides | pre-insertion of the pellet (baseline) and 3 months after pellet insertion of the gestrinone or placebo pellet | 
| Uterine Bleeding Pattern | Changes in uterine bleeding pattern (spotting/bleeding) | daily for 3 months after pellet insertion of the gestrinone or placebo pellet | 
| Hematological disorders | Number of participants with decreased lymphocyte count < 500/mm3 (or < 0.5 × 109/l); decrease in neutrophil count < 500/mm3 (or < 0.5 × 109/l); decrease in platelet count < 30,000/mm3 (or < 30.0 × 109/l); and anemia with decreased Hb < 7.0 g/dl (or < 4.35 mmol/l) | pre-insertion of the pellet (baseline) and 3 months after pellet insertion of the gestrinone or placebo pellet | 
| Hepatic adverse events | Number of participants with increased ALT or AST > 3 times ULN or baseline, alterations in ALP levels suspected hepatocellular or cholestatic hepatotoxicity | pre-insertion of the pellet (baseline) and 3 months after pellet insertion of the gestrinone or placebo pellet | 
| Renal adverse events | Number of participants with increased serum creatinine ≥ 1.5 times ULN or baseline; clinically significant increase in serum urea | pre-insertion of the pellet (baseline) and 3 months after pellet insertion of the gestrinone or placebo pellet | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Hormone Pellet Therapy, Implantable Hormone Pellets, Endometriosis, Pelvic pain