Subdermal Implant-bioabsorbable Gestrinone Pellet for Endometriosis Pelvic Pain Treatment (GLADE)

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.

Study Overview

• Status: Completed
• Conditions: Endometriosis; Pelvic Pain
• Intervention / Treatment: Drug: Gestrinone; Drug: Placebo

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.

• Study Type: Interventional
• Enrollment (Actual): 100
• Phase: Phase 2

Contacts and Locations

Study Locations

• Brazil
  • São Paulo
    • São Paulo, São Paulo, Brazil
      • Science Valley Research Institute

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 50 years (Adult)
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Gestrinone; 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; The intradermal gestrinone/placebo pellet will be inserted on the same day as the levonorgestrel intrauterine hormonal device (Kyleena®)
Placebo Comparator: Placebo; 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; Subdermal implant-bioabsorbable placebo pellet (cholesterol)

What is the study measuring?

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 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.	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

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
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
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
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
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
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
Area under the curve (AUC(0 ∞))	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
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
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
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
Pelvic pain intensity	Median of pelvic pain and dysmenorrhea intensity assessed by the NPRS 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

Collaborators and Investigators

• Sponsor: Science Valley Research Institute
• Collaborators: Biós Farmacêutica
• Investigators: Study Chair: Eduardo Ramacciotti, MD, PhD, Science Valley Research Institute; Principal Investigator: André Luiz M Oliveira, MD, MHS, Science Valley Research Institute

Publications and helpful links

General Publications

• 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.
• 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.
• 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.
• 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.
• 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.
• Malavasi A, Ribeiro CM, Agati LB, Silva Filho A, Berger C, Schor E, Comin A, Bezerra Neto EJ, Oliveira TH, Caldas PR, Lopes F, Westphalen N, Vieira F, Socca EAR, Komar D, Ramacciotti E. Rationale and design of the GLADE study: a randomized, multicenter, double-blind, placebo-controlled trial evaluating the safety and efficacy of gestrinone subdermal bioabsorbable pellet in endometriosis-related pelvic pain. Ann Med. 2025 Dec;57(1):2527352. doi: 10.1080/07853890.2025.2527352. Epub 2025 Jul 11.

Study record dates

Study Major Dates

• Study Start (Actual): February 13, 2023
• Primary Completion (Actual): May 21, 2025
• Study Completion (Actual): October 31, 2025

Study Registration Dates

• First Submitted: October 3, 2022
• First Submitted That Met QC Criteria: October 3, 2022
• First Posted (Actual): October 7, 2022

Study Record Updates

• Last Update Posted (Actual): June 3, 2026
• Last Update Submitted That Met QC Criteria: May 31, 2026
• Last Verified: January 1, 2026

More Information

Terms related to this study

• Keywords: Pelvic pain; Endometriosis; Hormone Pellet Therapy; Implantable Hormone Pellets
• Additional Relevant MeSH Terms: Urogenital Diseases; Genital Diseases; Pain; Neurologic Manifestations; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Genital Diseases, Female; Pathological Conditions, Signs and Symptoms; Signs and Symptoms; Endometriosis; Pelvic Pain; Polycyclic Compounds; Steroids; Fused-Ring Compounds; Norpregnanes; Norsteroids; Norpregnatrienes; Norgestrienone; Gestrinone
• Other Study ID Numbers: GLADE

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No