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

Primary Purpose

Deep Endometriosis, Pelvic Pain

Status
Recruiting
Phase
Phase 2
Locations
Brazil
Study Type
Interventional
Intervention
Gestrinone
Placebo
Sponsored by
Science Valley Research Institute
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Deep Endometriosis focused on measuring Hormone Pellet Therapy, Implantable Hormone Pellets, Endometriosis, Pelvic pain

Eligibility Criteria

18 Years - 50 Years (Adult)FemaleDoes not accept healthy volunteers

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 50 and 90 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

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
  • Actual use of 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

Sites / Locations

  • Science Valley Research Institute - Morumbi siteRecruiting

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Placebo Comparator

Arm Label

Gestrinone

Placebo

Arm Description

Subdermal implant-bioabsorbable gestrinone pellet (85 mg) All patients will undergo insertion of an intrauterine system of levonorgestrel release (Kyleena®) as a contraceptive method

Subdermal implant-bioabsorbable placebo pellet (cholesterol) All patients will undergo insertion of an intrauterine system of levonorgestrel release (Kyleena®) as a contraceptive method

Outcomes

Primary Outcome Measures

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.

Secondary Outcome Measures

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
Plasma concentration of steroid hormones
plasma concentration of total testosterone, free testosterone, and SHBG
Lipid profile
Serum levels of total cholesterol, HDL-C, VLDL-C, and triglycerides
Uterine Bleeding Pattern
Changes in uterine bleeding pattern (spotting/bleeding)
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)
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
Renal adverse events
Number of participants with increased serum creatinine ≥ 1.5 times ULN or baseline; clinically significant increase in serum urea

Full Information

First Posted
October 3, 2022
Last Updated
February 13, 2023
Sponsor
Science Valley Research Institute
Collaborators
Biós Farmacêutica
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1. Study Identification

Unique Protocol Identification Number
NCT05570786
Brief Title
Subdermal Implant-bioabsorbable Gestrinone Pellet for Endometriosis Pelvic Pain Treatment
Acronym
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
Study Type
Interventional

2. Study Status

Record Verification Date
February 2023
Overall Recruitment Status
Recruiting
Study Start Date
February 13, 2023 (Actual)
Primary Completion Date
August 2023 (Anticipated)
Study Completion Date
September 2023 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Science Valley Research Institute
Collaborators
Biós Farmacêutica

4. Oversight

Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes

5. Study Description

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.
Detailed Description
This is a phase II study, 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. 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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Deep Endometriosis, Pelvic Pain
Keywords
Hormone Pellet Therapy, Implantable Hormone Pellets, Endometriosis, Pelvic pain

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Parallel Assignment
Masking
ParticipantCare ProviderInvestigatorOutcomes Assessor
Allocation
Randomized
Enrollment
100 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Gestrinone
Arm Type
Experimental
Arm Description
Subdermal implant-bioabsorbable gestrinone pellet (85 mg) All patients will undergo insertion of an intrauterine system of levonorgestrel release (Kyleena®) as a contraceptive method
Arm Title
Placebo
Arm Type
Placebo Comparator
Arm Description
Subdermal implant-bioabsorbable placebo pellet (cholesterol) All patients will undergo insertion of an intrauterine system of levonorgestrel release (Kyleena®) as a contraceptive method
Intervention Type
Drug
Intervention Name(s)
Gestrinone
Intervention Description
The intradermal gestrinone/placebo pellet will be inserted on the same day as the levonorgestrel intrauterine hormonal device (Kyleena®)
Intervention Type
Drug
Intervention Name(s)
Placebo
Intervention Description
Subdermal implant-bioabsorbable placebo pellet (cholesterol)
Primary Outcome Measure Information:
Title
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
Description
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.
Time Frame
From randomization to the end of study on Day 180
Secondary Outcome Measure Information:
Title
Androgenization
Description
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
Time Frame
pre-insertion assessment of the pellet (baseline), 3 and 6 months after insertion of the gestrinone or placebo pellet
Title
Plasma concentration of steroid hormones
Description
plasma concentration of total testosterone, free testosterone, and SHBG
Time Frame
pre-insertion of the pellet (baseline) and 3 months after pellet insertion of the gestrinone or placebo pellet
Title
Lipid profile
Description
Serum levels of total cholesterol, HDL-C, VLDL-C, and triglycerides
Time Frame
pre-insertion of the pellet (baseline) and 3 months after pellet insertion of the gestrinone or placebo pellet
Title
Uterine Bleeding Pattern
Description
Changes in uterine bleeding pattern (spotting/bleeding)
Time Frame
daily for 3 months after pellet insertion of the gestrinone or placebo pellet
Title
Hematological disorders
Description
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)
Time Frame
pre-insertion of the pellet (baseline) and 3 months after pellet insertion of the gestrinone or placebo pellet
Title
Hepatic adverse events
Description
Number of participants with increased ALT or AST > 3 times ULN or baseline, alterations in ALP levels suspected hepatocellular or cholestatic hepatotoxicity
Time Frame
pre-insertion of the pellet (baseline) and 3 months after pellet insertion of the gestrinone or placebo pellet
Title
Renal adverse events
Description
Number of participants with increased serum creatinine ≥ 1.5 times ULN or baseline; clinically significant increase in serum urea
Time Frame
pre-insertion of the pellet (baseline) and 3 months after pellet insertion of the gestrinone or placebo pellet
Other Pre-specified Outcome Measures:
Title
Cardiac adverse events
Description
Number of participants with prolonged QT interval, defined as mean QTc ≥ 501 ms; or change > 60 ms from baseline
Time Frame
pre-insertion of the pellet (baseline) and 3 months after pellet insertion of the gestrinone or placebo pellet
Title
Overall participant satisfaction
Description
Median of the participant satisfaction scale (ranging from 1 to 5, from very satisfied to very dissatisfied)
Time Frame
3 months after pellet insertion of the gestrinone or placebo pellet
Title
Pelvic pain intensity
Description
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
Time Frame
pre-insertion assessment of the pellet (baseline), 3 and 6 months after insertion of the gestrinone or placebo pellet
Title
Use of pain relief medication
Description
Number of participants who used pain relief medication (analgesics and anti-inflammatories)
Time Frame
pre-insertion assessment of the pellet (baseline), 3 and 6 months after insertion of the gestrinone or placebo pellet
Title
Patient-reported Quality of Life
Description
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
Time Frame
pre-insertion assessment of the pellet (baseline), 3 and 6 months after insertion of the gestrinone or placebo pellet
Title
Endometriosis Health Profile
Description
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
Time Frame
pre-insertion of the pellet (baseline) and 3 months after pellet insertion of the gestrinone or placebo pellet

10. Eligibility

Sex
Female
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
50 Years
Accepts Healthy Volunteers
No
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 50 and 90 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 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 Actual use of 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
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Leandro Barile Agati, PhD
Phone
+55 11 4040-8670
Email
agati@svriglobal.com
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Eduardo Ramacciotti, MD, PhD
Organizational Affiliation
Science Valley Research Institute
Official's Role
Study Chair
First Name & Middle Initial & Last Name & Degree
André Luiz Malavasi Oliveira, MD, MHS
Organizational Affiliation
Science Valley Research Institute
Official's Role
Principal Investigator
Facility Information:
Facility Name
Science Valley Research Institute - Morumbi site
City
São Paulo
State/Province
Sao Paulo
Country
Brazil
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Poliana Goulart
Email
poliana.goulart@svriglobal.com
First Name & Middle Initial & Last Name & Degree
Andre Luiz Malavasi, MHS

12. IPD Sharing Statement

Plan to Share IPD
Undecided
Citations:
PubMed Identifier
35350465
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.
Results Reference
background
PubMed Identifier
6216812
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.
Results Reference
background
PubMed Identifier
2806598
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.
Results Reference
background
PubMed Identifier
8941054
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.
Results Reference
background
PubMed Identifier
8093956
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.
Results Reference
background

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Subdermal Implant-bioabsorbable Gestrinone Pellet for Endometriosis Pelvic Pain Treatment

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