Subdermalt implantat-bioabsorberbar Gestrinon-pellet til behandling af endometriose bækkensmerter (GLADE)
Et fase II, randomiseret, placebo-kontrolleret, dobbeltblindt, multicenter-studie for at undersøge sikkerheden og udforskningseffektiviteten af en subdermal implantat-bioabsorberbar Gestrinon-pellet til bækkensmerter sekundært til endometriosebehandling
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.
Studieoversigt
Status
Betingelser
Intervention / Behandling
Detaljeret beskrivelse
This is a Phase 2, exploratory, multicenter, randomized, double-blind, placebo-controlled study followed by an optional open-label pharmacokinetic extension.
This study aimed to assess the safety and tolerability profile of a subdermal 85-mg gestrinone bioabsorbable implant compared with a matched placebo bioabsorbable implant, in women with endometriosis-associated pelvic pain. The pharmacokinetics of the gestrinone implant will be monitored. Exploratory efficacy analyses will be descriptively reported for participant satisfaction, change in pelvic pain intensity, use of rescue pain medication, and quality of life.
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.
Undersøgelsestype
Tilmelding (Faktiske)
Fase
- Fase 2
Kontakter og lokationer
Studiesteder
-
-
São Paulo
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São Paulo, São Paulo, Brasilien
- Science Valley Research Institute
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-
Deltagelseskriterier
Berettigelseskriterier
Aldre berettiget til at studere
Tager imod sunde frivillige
Køn, der er berettiget til at studere
Beskrivelse
Inclusion Criteria
- Willingness to provide informed consent
- Woman aged between 18 and 50 years
- Body weight between 50 ± 5 kg and 90 ± 5 kg
- Having pelvic pain secondary to endometriosis, independent of pain intensity
- Endometriosis documented by biopsies (histopathological examination)
- Last endometriosis surgery at least 3 months before randomization
- Not planning to become pregnant within 12 months after the screening visit or be surgically sterilized
- 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
- Agreement not to use other hormones (estrogens, androgens and progestins) in any pharmaceutical form during the study
Exclusion Criteria
- 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
- Suspected or confirmed diagnosis of immunodeficiency based on medical history and/or physical or laboratory examination
- 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
- Personal history of thromboembolic events
- Use anticoagulant medication
- Contraindication to the use of hormonal contraceptives
- Suspected or confirmed pregnancy
- Breastfeeding
- Current or recurrent pelvic inflammatory disease or other conditions that increase the risk of pelvic infections
- Postpartum endometritis or septic miscarriage in the last 3 months
- Abnormal uterine bleeding of unknown etiology
- Congenital or acquired uterine anomalies, including fibroids (leiomyomas or fibromas) that cause distortion of the uterine cavity
- Uterine or cervical malignancy
- Suspected or confirmed diagnosis of estrogen-dependent neoplasm, including breast cancer
- Cervicitis or vaginitis, including bacterial vaginosis or another uncontrolled lower urinary tract infection
- Cervical dysplasia
- Active liver disease or dysfunction
- Benign or malignant liver tumors
- Allergy or intolerance to levonorgestrel, gestrinone or any other ingredient or component of the Kyleena® formulation or hormonal pellets
- Previously inserted intrauterine device or levonorgestrel-releasing intrauterine system that has not been removed
- History of recent trophoblastic disease and continued high HCG levels
- Bacterial endocarditis
- 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
- Diagnosis of polycystic ovary syndrome
- Participation in another pharmacotherapeutic or investigational medical device study within 30 days prior to the start of study treatment
- Tobacco Use
- Use of testosterone-derived hormones and analogues in the last month
Studieplan
Hvordan er undersøgelsen tilrettelagt?
Design detaljer
- Primært formål: Behandling
- Tildeling: Randomiseret
- Interventionel model: Parallel tildeling
- Maskning: Firedobbelt
Våben og indgreb
Deltagergruppe / Arm |
Intervention / Behandling |
|---|---|
|
Eksperimentel: 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 |
The intradermal gestrinone/placebo pellet will be inserted on the same day as the levonorgestrel intrauterine hormonal device (Kyleena®) |
|
Placebo komparator: Placebo
Subdermal implant-bioabsorbable placebo pellet (cholesterol) All patients will undergo insertion of an intrauterine system of levonorgestrel release (Kyleena®) as a contraceptive method |
Subdermal implant-bioabsorbable placebo pellet (cholesterol) |
Hvad måler undersøgelsen?
Primære resultatmål
Resultatmål |
Foranstaltningsbeskrivelse |
Tidsramme |
|---|---|---|
|
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
Tidsramme: From randomization to the end of study on 6 months after insertion of the gestrinone or placebo pellet
|
The primary safety outcome will be the proportion of patients who present serious adverse events (SAEs) over 6 months after randomization, 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. In this study, the occurrence of thromboembolic events (such as, for example, acute myocardial infarction, pulmonary embolism, deep vein thrombosis, ischemic stroke, and transient ischemic attack) was predefined as a significant medical event. |
From randomization to the end of study on 6 months after insertion of the gestrinone or placebo pellet
|
Sekundære resultatmål
Resultatmål |
Foranstaltningsbeskrivelse |
Tidsramme |
|---|---|---|
|
Androgenization
Tidsramme: 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 |
pre-insertion assessment of the pellet (baseline), 3 and 6 months after insertion of the gestrinone or placebo pellet
|
|
Plasma concentration of steroid hormones
Tidsramme: pre-insertion of the pellet (baseline) and 3 months after pellet insertion of the gestrinone or placebo pellet
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Number of participants with clinically relevant laboratory values outside the reference range for 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
Tidsramme: pre-insertion of the pellet (baseline) and 3 months after pellet insertion of the gestrinone or placebo pellet
|
Number of participants with clinically relevant laboratory values outside the reference range for 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
|
|
Hematological disorders
Tidsramme: 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) |
pre-insertion of the pellet (baseline) and 3 months after pellet insertion of the gestrinone or placebo pellet
|
|
Hepatic adverse events
Tidsramme: pre-insertion of the pellet (baseline) and 3 months after pellet insertion of the gestrinone or placebo pellet
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Number of participants with increased ALT or AST > 3 times ULN or baseline, alterations in ALT levels suspected hepatocellular or cholestatic hepatotoxicity |
pre-insertion of the pellet (baseline) and 3 months after pellet insertion of the gestrinone or placebo pellet
|
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Renal adverse events
Tidsramme: pre-insertion of the pellet (baseline) and 3 months after pellet insertion of the gestrinone or placebo pellet
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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
|
Andre resultatmål
Resultatmål |
Foranstaltningsbeskrivelse |
Tidsramme |
|---|---|---|
|
Overall participant satisfaction
Tidsramme: 3 months after pellet insertion of the gestrinone or placebo pellet
|
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
|
|
Pelvic pain intensity
Tidsramme: pre-insertion assessment of the pellet (baseline), 3 and 6 months after insertion of the gestrinone or placebo pellet
|
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
|
|
Use of pain relief medication
Tidsramme: pre-insertion assessment of the pellet (baseline), 3 and 6 months after insertion of the gestrinone or placebo pellet
|
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
Tidsramme: pre-insertion assessment of the pellet (baseline), 3 and 6 months after insertion of the gestrinone or placebo pellet
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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
Tidsramme: pre-insertion of the pellet (baseline) and 3 months after pellet insertion of the gestrinone or placebo pellet
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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
|
|
Uterine Bleeding Pattern
Tidsramme: daily for 3 months after pellet insertion of the gestrinone or placebo pellet
|
Changes in uterine bleeding pattern (spotting/bleeding) |
daily for 3 months after pellet insertion of the gestrinone or placebo pellet
|
|
Serum total gestrinone concentration
Tidsramme: 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
|
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 ∞))
Tidsramme: 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
|
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)
Tidsramme: 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
|
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)
Tidsramme: 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
|
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)
Tidsramme: 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
|
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
|
Samarbejdspartnere og efterforskere
Samarbejdspartnere
Efterforskere
- Studiestol: Eduardo Ramacciotti, MD, PhD, Science Valley Research Institute
- Ledende efterforsker: André Luiz M Oliveira, MD, MHS, Science Valley Research Institute
Publikationer og nyttige links
Generelle publikationer
- 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.
Datoer for undersøgelser
Studer store datoer
Studiestart (Faktiske)
Primær færdiggørelse (Faktiske)
Studieafslutning (Faktiske)
Datoer for studieregistrering
Først indsendt
Først indsendt, der opfyldte QC-kriterier
Først opslået (Faktiske)
Opdateringer af undersøgelsesjournaler
Sidste opdatering sendt (Faktiske)
Sidste opdatering indsendt, der opfyldte kvalitetskontrolkriterier
Sidst verificeret
Mere information
Begreber relateret til denne undersøgelse
Yderligere relevante MeSH-vilkår
- Urogenitale sygdomme
- Genitale sygdomme
- Smerte
- Neurologiske manifestationer
- Urogenitale sygdomme hos kvinder
- Kvinders urogenitale sygdomme og graviditetskomplikationer
- Kønssygdomme, kvindelige
- Patologiske tilstande, tegn og symptomer
- Tegn og symptomer
- Endometriose
- Bækkensmerter
- Polycykliske forbindelser
- Steroider
- SMUSED-RING-forbindelser
- Norpregnanes
- Norsteroider
- Norpregnatrienes
- Norgestrienon
- Gestrinon
Andre undersøgelses-id-numre
- GLADE
Plan for individuelle deltagerdata (IPD)
Planlægger du at dele individuelle deltagerdata (IPD)?
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