Subdermal Implant-bioabsorbable Gestrinone Pellet for Endometriosis Pelvic Pain Treatment

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

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. PK profile of the gestrinone pellet will be monitored.

This is a 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. PK profile of the gestrinone pellet will be monitored. 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 treatment-related serious adverse events (SAEs) accumulated within 6 months of pellet insertion and collected through spontaneous reporting and/or clinical findings.

Inclusion Criteria

1. Willingness to provide informed consent
2. Woman aged between 18 and 50 years
3. Body weight between 50 ± 5 kg and 90 ± 5 kg
4. Pelvic pain secondary to endometriosis surgically treated with refractory symptoms, independent of pain intensity
5. Endometriosis documented by biopsies (histopathological examination)
6. Last endometriosis surgery at least 3 months before randomization
7. Not planning to become pregnant within 12 months after the screening visit or be surgically sterilized
8. Absence of changes in the breast (BI-RADS1 and BIRADS-2 classification) documented by an imaging report (mammogram for women aged > 40 years or bilateral breast ultrasound for women aged < 40 years) performed less than 12 months before randomization
9. Agreement not to use other hormones (estrogens, androgens and progestins) in any pharmaceutical form during the study

Exclusion Criteria

1. Chronic severe disorders, including metastatic malignancies, end-stage renal disease with or without dialysis, clinically unstable heart disease, or any other disorder that, in the opinion of the investigator, excludes the participant from the study
2. Suspected or confirmed diagnosis of immunodeficiency based on medical history and/or physical or laboratory examination
3. Other medical or psychiatric conditions, including recent laboratory abnormalities (within the last 12 months) that may increase risks to the study participant or, at the discretion of the investigator, make the participant inappropriate for the study
4. Personal history of thromboembolic events
5. Use anticoagulant medication
6. Contraindication to the use of hormonal contraceptives
7. Suspected or confirmed pregnancy
8. Breastfeeding
9. Current or recurrent pelvic inflammatory disease or other conditions that increase the risk of pelvic infections
10. Postpartum endometritis or septic miscarriage in the last 3 months
11. Abnormal uterine bleeding of unknown etiology
12. Congenital or acquired uterine anomalies, including fibroids (leiomyomas or fibromas) that cause distortion of the uterine cavity
13. Uterine or cervical malignancy
14. Suspected or confirmed diagnosis of estrogen-dependent neoplasm, including breast cancer
15. Cervicitis or vaginitis, including bacterial vaginosis or another uncontrolled lower urinary tract infection
16. Cervical dysplasia
17. Active liver disease or dysfunction
18. Benign or malignant liver tumors
19. Allergy or intolerance to levonorgestrel, gestrinone or any other ingredient or component of the Kyleena® formulation or hormonal pellets
20. Previously inserted intrauterine device or levonorgestrel-releasing intrauterine system that has not been removed
21. History of recent trophoblastic disease and continued high HCG levels
22. Bacterial endocarditis
23. Hyperandrogenism at the time of randomization, 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 with sequelae of scalp thinning
24. Diagnosis of polycystic ovary syndrome
25. Participation in another pharmacotherapeutic or investigational medical device study within 30 days prior to the start of study treatment
26. Tobacco Use
27. Use of testosterone-derived hormones and analogues in the last month