Clinical trial NCT05570786: Subdermal Implant-bioabsorbable Gestrinone Pellet for Endometriosis Pelvic Pain Treatment
Official title: 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
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE2
Conditions: Deep Endometriosis
Pelvic Pain
Keywords: Hormone Pellet Therapy
Implantable Hormone Pellets
Endometriosis
Pelvic pain
Lead sponsor: Science Valley Research Institute
Sponsor class: OTHER
Collaborators: name: Biós Farmacêutica
First posted: 2022-10-07
Enrollment: 100
Sex: FEMALE
Minimum age (years): 18
Maximum age (years): 50
Standard ages: ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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 serious adverse events (SAEs) accumulated within 6 months of pellet insertion and collected through spontaneous reporting and/or clinical findings.

Eligibility criteria: 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 45 and 95 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 = BI-RADS1 and BI-RADS2

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
* Using 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

Primary outcomes:
measure: 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
timeFrame: From randomization to the end of study on Day 180
Secondary outcomes:
measure: Androgenization
timeFrame: pre-insertion assessment of the pellet (baseline), 3 and 6 months after insertion of the gestrinone or placebo pellet
measure: Plasma concentration of steroid hormones
timeFrame: pre-insertion of the pellet (baseline) and 3 months after pellet insertion of the gestrinone or placebo pellet
measure: Lipid profile
timeFrame: pre-insertion of the pellet (baseline) and 3 months after pellet insertion of the gestrinone or placebo pellet
measure: Uterine Bleeding Pattern
timeFrame: daily for 3 months after pellet insertion of the gestrinone or placebo pellet
measure: Hematological disorders
timeFrame: pre-insertion of the pellet (baseline) and 3 months after pellet insertion of the gestrinone or placebo pellet
measure: Hepatic adverse events
timeFrame: pre-insertion of the pellet (baseline) and 3 months after pellet insertion of the gestrinone or placebo pellet
measure: Renal adverse events
timeFrame: pre-insertion of the pellet (baseline) and 3 months after pellet insertion of the gestrinone or placebo pellet
Other outcomes:
measure: Overall participant satisfaction
timeFrame: 3 months after pellet insertion of the gestrinone or placebo pellet
measure: Pelvic pain intensity
timeFrame: pre-insertion assessment of the pellet (baseline), 3 and 6 months after insertion of the gestrinone or placebo pellet
measure: Use of pain relief medication
timeFrame: pre-insertion assessment of the pellet (baseline), 3 and 6 months after insertion of the gestrinone or placebo pellet
measure: Patient-reported Quality of Life
timeFrame: pre-insertion assessment of the pellet (baseline), 3 and 6 months after insertion of the gestrinone or placebo pellet
measure: Endometriosis Health Profile
timeFrame: pre-insertion of the pellet (baseline) and 3 months after pellet insertion of the gestrinone or placebo pellet
measure: Serum total gestrinone concentration
timeFrame: pre-insertion of the pellet (baseline) and 24 hours; 7 days, 14 days , 21 days , 28 days , 56 days, 84 days, 112 days, 140 days and 168 days post-insertion
measure: Area under the curve (AUC(0 ∞))
timeFrame: pre-insertion of the pellet (baseline) and 24 hours; 7 days, 14 days , 21 days , 28 days , 56 days, 84 days, 112 days, 140 days and 168 days post-insertion
measure: Maximum concentration (Cmax)
timeFrame: pre-insertion of the pellet (baseline) and 24 hours; 7 days, 14 days , 21 days , 28 days , 56 days, 84 days, 112 days, 140 days and 168 days post-insertion
measure: Time to reach maximum concentration (tmax)
timeFrame: pre-insertion of the pellet (baseline) and 24 hours; 7 days, 14 days , 21 days , 28 days , 56 days, 84 days, 112 days, 140 days and 168 days post-insertion
measure: Half Life (t1/2)
timeFrame: pre-insertion of the pellet (baseline) and 24 hours; 7 days, 14 days , 21 days , 28 days , 56 days, 84 days, 112 days, 140 days and 168 days post-insertion
Locations:
city: São Paulo
country: Brazil
facility: Science Valley Research Institute
state: Sao Paulo
Study officials:
affiliation: Science Valley Research Institute
name: Eduardo Ramacciotti, MD, PhD
role: STUDY_CHAIR
affiliation: Science Valley Research Institute
name: André Luiz Malavasi Oliveira, MD, MHS
role: PRINCIPAL_INVESTIGATOR
References:
citation: Becker CM, Bokor A, Heikinheimo O, Horne A, Jansen F, Kiesel L, King K, Kvaskoff M, Nap A, Petersen K, Saridogan E, Tomassetti C, van Hanegem N, Vulliemoz N, Vermeulen N; ESHRE Endometriosis Guideline Group. ESHRE guideline: endometriosis. Hum Reprod Open. 2022 Feb 26;2022(2):hoac009. doi: 10.1093/hropen/hoac009. eCollection 2022.
citation: Coutinho EM. Treatment of endometriosis with gestrinone (R-2323), a synthetic antiestrogen, antiprogesterone. Am J Obstet Gynecol. 1982 Dec 15;144(8):895-8. doi: 10.1016/0002-9378(82)90180-6.
citation: Venturini PL, Bertolini S, Brunenghi MC, Daga A, Fasce V, Marcenaro A, Cimato M, De Cecco L. Endocrine, metabolic, and clinical effects of gestrinone in women with endometriosis. Fertil Steril. 1989 Oct;52(4):589-95. doi: 10.1016/s0015-0282(16)60969-x.
citation: Gestrinone versus a gonadotropin-releasing hormone agonist for the treatment of pelvic pain associated with endometriosis: a multicenter, randomized, double-blind study. Gestrinone Italian Study Group. Fertil Steril. 1996 Dec;66(6):911-9. doi: 10.1016/s0015-0282(16)58682-8.
citation: Devogelaer JP, Nagant de Deuxchaisnes C, Donnez J. Endometriosis. Lancet. 1993 Jan 30;341(8840):312-3. doi: 10.1016/0140-6736(93)92673-h. No abstract available.