Endometriosis, Pelvic Pain
Conditions
Keywords
Hormone Pellet Therapy, Implantable Hormone Pellets, Endometriosis, Pelvic pain
Brief summary
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.
Detailed description
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.
Interventions
DRUGGestrinone
The intradermal gestrinone/placebo pellet will be inserted on the same day as the levonorgestrel intrauterine hormonal device (Kyleena®)
DRUGPlacebo
Subdermal implant-bioabsorbable placebo pellet (cholesterol)
Sponsors
Science Valley Research Institute
Biós Farmacêutica
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
FEMALE
Age
18 Years to 50 Years
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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 | From randomization to the end of study on Day 180 | Proportion of patients who dhave 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. The treatment-related SAEs were considered for the primary safety outcome. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Androgenization | pre-insertion assessment of the pellet (baseline), 3 and 6 months after insertion of the gestrinone or placebo pellet | 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 |
| Plasma concentration of steroid hormones | pre-insertion of the pellet (baseline) and 3 months after pellet insertion of the gestrinone or placebo pellet | plasma concentration of total testosterone, free testosterone, and SHBG |
| Lipid profile | pre-insertion of the pellet (baseline) and 3 months after pellet insertion of the gestrinone or placebo pellet | Serum levels of total cholesterol, HDL-C, VLDL-C, and triglycerides |
| Uterine Bleeding Pattern | daily for 3 months after pellet insertion of the gestrinone or placebo pellet | Changes in uterine bleeding pattern (spotting/bleeding) |
| Hematological disorders | pre-insertion of the pellet (baseline) and 3 months after pellet insertion of the gestrinone or placebo pellet | 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) |
| Hepatic adverse events | pre-insertion of the pellet (baseline) and 3 months after pellet insertion of the gestrinone or placebo pellet | Number of participants with increased ALT or AST \> 3 times ULN or baseline, alterations in ALP levels suspected hepatocellular or cholestatic hepatotoxicity |
| Renal adverse events | pre-insertion of the pellet (baseline) and 3 months after pellet insertion of the gestrinone or placebo pellet | Number of participants with increased serum creatinine ≥ 1.5 times ULN or baseline; clinically significant increase in serum urea |
Countries
Brazil
Contacts
STUDY_CHAIREduardo Ramacciotti, MD, PhD
Science Valley Research Institute
PRINCIPAL_INVESTIGATORAndré Luiz M Oliveira, MD, MHS
Science Valley Research Institute
Outcome results
None listed