Subdermal Implant-bioabsorbable Gestrinone Pellet for Endometriosis Pelvic Pain Treatment

Pelvic Pain Clinical Trial

— GLADE  

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT05570786
• Other study ID #: GLADE
• Status: Recruiting
• Phase: Phase 2
• Start date: February 13, 2023
• Est. completion date: November 2024

Study information

• Verified date: March 2024
• Source: Science Valley Research Institute
• Contact: Leandro Barile Agati, PhD
• Phone: +55 11 4040-8670
• Email: agati[@]svriglobal.com
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 100
• Est. completion date: November 2024
• Est. primary completion date: November 2024
• Accepts healthy volunteers: No
• Gender: Female
• Age group: 18 Years to 50 Years

Eligibility

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

Related Conditions & MeSH terms

• Deep Endometriosis
• Endometriosis
• Pelvic Pain

Intervention

Drug:
• Gestrinone
The intradermal gestrinone/placebo pellet will be inserted on the same day as the levonorgestrel intrauterine hormonal device (Kyleena®)
• Placebo
Subdermal implant-bioabsorbable placebo pellet (cholesterol)

Locations

Country	Name	City	State
Brazil	Science Valley Research Institute	São Paulo	Sao Paulo

Sponsors (2)

Lead Sponsor	Collaborator
Science Valley Research Institute	Biós Farmacêutica

Country where clinical trial is conducted

Brazil, 

References & Publications (5)

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. — View 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. — View 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. — View 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. — View 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. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Overall participant satisfaction	Median of the participant satisfaction scale (ranging from 1 to 5, from very satisfied to very dissatisfied)	3 months after pellet insertion of the gestrinone or placebo pellet
Other	Pelvic pain intensity	Median of pelvic pain and dysmenorrhea intensity assessed by the VAS visual analogue scale, from 0 to 10 points where 10 points indicates worst pain	pre-insertion assessment of the pellet (baseline), 3 and 6 months after insertion of the gestrinone or placebo pellet
Other	Use of pain relief medication	Number of participants who used pain relief medication (analgesics and anti-inflammatories)	pre-insertion assessment of the pellet (baseline), 3 and 6 months after insertion of the gestrinone or placebo pellet
Other	Patient-reported Quality of Life	Number of participants with changes in the 36-Item Short Form Health Survey (SF-36). SF-36 is a patient-reported outcome (PRO) measure evaluating a participant's health status. It comprises 36 items covering 8 domains: physical functioning, role physical, role emotional, bodily pain, vitality, social functioning, mental health, and general health. Items are answered on Likert scales of varying lengths. Items from 8 domains contribute to the PCS. The summary scores range from 0 to 100, with higher scores indicating better levels of function and/or better health	pre-insertion assessment of the pellet (baseline), 3 and 6 months after insertion of the gestrinone or placebo pellet
Other	Endometriosis Health Profile	Number of participants with changes in the Endometriosis Health Profile Questionnaire (EHP-30). The Endometriosis Health Profile Questionnaire is a Health Related Quality of Life (HRQoL) patient self-report PRO, used to measure the wide range of effects that endometriosis can have on women's lives: pain, control and powerlessness, social support, emotional well-being, and self-image, range from 0-100, higher values indicate worse health status	pre-insertion of the pellet (baseline) and 3 months after pellet insertion of the gestrinone or placebo pellet
Other	Serum total gestrinone concentration	Multiple blood sample will be collected before pellet implantation and 24 hours; 7 days, 14 days , 21 days, 28 days, 56 days, 84 days, 112 days, 140 days and 168 days and will be determined by liquid chromatography (LC-MS/MS)	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
Other	Area under the curve (AUC(0 8))	Multiple blood sample will be collected before pellet implantation and 24 hours; 7 days, 14 days , 21 days, 28 days, 56 days, 84 days, 112 days, 140 days and 168 days and will be determined by liquid chromatography (LC-MS/MS)	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
Other	Maximum concentration (Cmax)	Multiple blood sample will be collected before pellet implantation and 24 hours; 7 days, 14 days , 21 days, 28 days, 56 days, 84 days, 112 days, 140 days and 168 days and will be determined by liquid chromatography (LC-MS/MS)	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
Other	Time to reach maximum concentration (tmax)	Multiple blood sample will be collected before pellet implantation and 24 hours; 7 days, 14 days , 21 days, 28 days, 56 days, 84 days, 112 days, 140 days and 168 days and will be determined by liquid chromatography (LC-MS/MS)	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
Other	Half Life (t1/2)	Multiple blood sample will be collected before pellet implantation and 24 hours; 7 days, 14 days , 21 days, 28 days, 56 days, 84 days, 112 days, 140 days and 168 days and will be determined by liquid chromatography (LC-MS/MS)	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
Primary	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	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
Secondary	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
Secondary	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
Secondary	Uterine Bleeding Pattern	Changes in uterine bleeding pattern (spotting/bleeding)	daily for 3 months after pellet insertion of the gestrinone or placebo pellet
Secondary	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
Secondary	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
Secondary	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