Pharmacokinetic Aspects of 25-mg Estradiol Pellet in Climacteric Women

NCT06136208 | Completed DMC

• 1 other identifier: CLARA Study
• Study Type: interventional
• Target: 20
• Locations: 1 country
• Sites: 1

Brief Summary

A single center, prospective, open-label clinical study will be conducted, to monitor serum concentration and pharmacokinetic profile after subcutaneous implantation of a 25mg-estradiol bioabsorbable implant in postmenopausal women.

Conditions

Climacteric Syndrome; Menopause; Hypoestrogenism

Keywords

Climateric; Estradiol Pellet; Menopause; Pharmacokinectic

Outcome Measures

Primary Outcomes (5)

• Serum total estradiol concentration

  Multiple blood sample will be collected before pellet implantation and 2 hours, 4 hours, 6 hours, 8 hours, 10 hours, 12 hours, 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)

  0, 2 hours, 4 hours, 6 hours, 8 hours, 10 hours, 12 hours, 24 hours; 7 days, 14 days , 21 days , 28 days , 56 days, 84 days, 112 days, 140 days and 168 days

• Area under the curve (AUC(0 ∞))

  Multiple blood sample will be collected before pellet implantation and 2 hours, 4 hours, 6 hours, 8 hours, 10 hours, 12 hours, 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)

  0, 2 hours, 4 hours, 6 hours, 8 hours, 10 hours, 12 hours, 24 hours; 7 days, 14 days, 21 days, 28 days, 56 days, 84 days, 112 days, 140 days and 168 days

• Maximum concentration (Cmax)

  Multiple blood sample will be collected before pellet implantation and 2 hours, 4 hours, 6 hours, 8 hours, 10 hours, 12 hours, 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)

  0, 2 hours, 4 hours, 6 hours, 8 hours, 10 hours, 12 hours, 24 hours; 7 days, 14 days, 21 days, 28 days, 56 days, 84 days, 112 days, 140 days and 168 days

• Time to reach maximum concentration (tmax)

  Multiple blood sample will be collected before pellet implantation and 2 hours, 4 hours, 6 hours, 8 hours, 10 hours, 12 hours, 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)

  0, 2 hours, 4 hours, 6 hours, 8 hours, 10 hours, 12 hours, 24 hours; 7 days, 14 days, 21 days, 28 days, 56 days, 84 days, 112 days, 140 days and 168 days

• Half Life (t1/2)

  Multiple blood sample will be collected before pellet implantation and 2 hours, 4 hours, 6 hours, 8 hours, 10 hours, 12 hours, 24 hours; 7 days, 14 days, 21 dyas, 28 days, 56 days, 84 days, 112 days, 140 days and 168 days and will be determined by liquid chromatography (LC-MS/MS).

  0, 2 hours, 4 hours, 6 hours, 8 hours, 10 hours, 12 hours, 24 hours; 7 days, 14 days, 21 days, 28 days, 56 days, 84 days, 112 days, 140 days and 168 days

Secondary Outcomes (6)

• Total testosterone concentration

  Pre-insertion of the estradiol pellet; 2 hours, 4 hours, 6 hours, 8 hours, 10 hours, 12 hours, 24 hours; 7 days, 14 days, 21 days, 28 days, 56 days, 84 days, 112 days,140 days and 168 days

• Estrone concentration

  Pre-insertion of the estradiol pellet; 2h, 4h, 6h, 8h, 10h, 12, 24h; 7, 14, 21, 28, 56, 84, 112, 140 and 168 days

• Follicle - stimulating hormone FSH concentration

  Pre-insertion of the estradiol pellet; 2 hours, 4 hours, 6 hours, 8 hours, 10 hours, 12 hours, 24 hours; 7days, 14 days, 21 days, 28 days, 56 days, 84 days, 112 days, 140 days and 168 days

• Luteinizing hormone - hormone LH concentration

  Pre-insertion of the estradiol pellet; 2 hours, 4 hours, 6 hours, 8 hours, 10 hours, 12 hours, 24 hours; 7 days, 14 days, 21 days, 28 days, 56 days, 84 days, 112 days, 140 days and 168 days

• Sex hormone binding globulin SHBG concentration

  Pre-insertion of the estradiol pellet; 2 hours, 4 hours, 6 hours, 8 hours, 10 hours, 12 hours, 24 hours; 7 days, 14 days, 21 days, 28 days, 56 days, 84 days, 112 days, 140 days and 168 days

Other Outcomes (2)

• Adverse events

  pre-insertion of the estradiol pellet; 2 hours, 4 hours, 6 hours, 8 hours, 10 hours, 12 hours, 24 hours; 28 days, 84 days, and 168 days

• Change from baseline in the Menopause Rating Scale (MRS) score (global, psychological, somatic, and urogenital domains evaluated in clinical visits

  28 days, 84 days, and 168 days post-insertion of the estradiol pellet

Interventions

s.c 25 mg estradiol pellet DRUG

Subcutaneous insertion of 25 mg estradiol pellet.

Eligibility Criteria

• Age: 41 Years - 59 Years
• Sex: female
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• Signed Informed Consent Form
• Woman aged ≥ 41 and ≤ 59 years
• Weight ≥ 50 kg and ≤ 98 kg
• BMI ≥ 18.5 and ≤ 34.9 kg/m²
• Hysterectomy (with or without oophorectomy)
• Serum total estradiol concentration ≤ 50 pg/mL and serum FSH concentration ≥ 25 mIU/mL, both determined by immunoassays
• Presence of menopause-associated symptoms
• Absence of signs and symptoms and propedeutics suggestive of breast cancer evidenced by mammography report (woman aged \> 40 years) for less than 12 months = BI-RADS1 or BI-RADS2
• Agreement not to use other hormones (estrogens, androgens and/or progestogens) in any pharmaceutical form during the study

You may not qualify if:

• Contraindications to the use of menopausal hormone therapy: Bleeding vaginal of unknown cause; personal history of hormone-dependent neoplasm including breast cancer, precursor lesions of breast cancer; liver disease; porphyria; personal history of coronary artery disease, cerebrovascular and venous thromboembolism; systemic lupus erythematosus with high thromboembolic risk and meningioma
• Comorbidities associated with increased cardiovascular risk: smoking, uncontrolled diabetes, dyslipidemia, and uncontrolled hypertension
• Serious chronic disorders, including metastatic malignancies, kidney disease in the end-stage with or without dialysis, clinically unstable heart disease, or any another disorder that, in the opinion of the investigator, excludes the participant from the study
• Immunocompromise or suspected or confirmed diagnosis of immunodeficiency based on history and/or physical or laboratory examination
• Active liver disease or dysfunction
• Benign or malignant tumors of the liver
• Clinical diagnosis of polycystic ovary syndrome
• Use of other hormones (estrogens, androgens and/or progestogens) in any pharmaceutical form in the last month
• Current use of drugs that alter cytochrome P450 and metabolization of Estrogens
• Current use of tamoxifen, aromatase inhibitors, or agonists/antagonists GnRH for cancer or any other condition
• Current use of phytoestrogens
• Participation in another clinical study within 30 days prior to the start of the Study treatment

Sponsors & Collaborators

• Science Valley Research Institute: lead
• Biòs Farmacêutica: collaborator

Study Sites (1)

Irmandade Da Santa Casa De Misericórdia De Santos - Science Valley Research Center

Santos, São Paulo, 11075-900, Brazil

Location

Related Publications (13)

• Casals G, Costa RF, Rull EU, Escobar-Morreale HF, Argente J, Sesmilo G, Biagetti B. Recommendations for the measurement of sexual steroids in clinical practice. A position statement of SEQCML/SEEN/SEEP. Adv Lab Med. 2023 Mar 9;4(1):52-69. doi: 10.1515/almed-2023-0020. eCollection 2023 Apr.

  PMID: 37359897 BACKGROUND

• del Carmen Cravioto M, Larrea F, Delgado NE, Escobar AR, Diaz-Sanchez V, Dominguez J, de Leon RP. Pharmacokinetics and pharmacodynamics of 25-mg estradiol implants in postmenopausal Mexican women. Menopause. 2001 Sep-Oct;8(5):353-60. doi: 10.1097/00042192-200109000-00010.

  PMID: 11528362 BACKGROUND

• Hamoda H, Panay N, Pedder H, Arya R, Savvas M. The British Menopause Society & Women's Health Concern 2020 recommendations on hormone replacement therapy in menopausal women. Post Reprod Health. 2020 Dec;26(4):181-209. doi: 10.1177/2053369120957514. Epub 2020 Oct 12. No abstract available.

  PMID: 33045914 BACKGROUND

• Kuhl H. Pharmacology of estrogens and progestogens: influence of different routes of administration. Climacteric. 2005 Aug;8 Suppl 1:3-63. doi: 10.1080/13697130500148875.

  PMID: 16112947 BACKGROUND

• Lobo RA, March CM, Goebelsmann U, Krauss RM, Mishell DR Jr. Subdermal estradiol pellets following hysterectomy and oophorectomy. Effect upon serum estrone, estradiol, luteinizing hormone, follicle-stimulating hormone, corticosteroid binding globulin-binding capacity, testosterone-estradiol binding globulin-binding capacity, lipids, and hot flushes. Am J Obstet Gynecol. 1980 Nov 15;138(6):714-9.

  PMID: 6776814 BACKGROUND

• Lobo RA. Hormone-replacement therapy: current thinking. Nat Rev Endocrinol. 2017 Apr;13(4):220-231. doi: 10.1038/nrendo.2016.164. Epub 2016 Oct 7.

  PMID: 27716751 BACKGROUND

• Manson JE, Bassuk SS, Kaunitz AM, Pinkerton JV. The Women's Health Initiative trials of menopausal hormone therapy: lessons learned. Menopause. 2020 Aug;27(8):918-928. doi: 10.1097/GME.0000000000001553.

  PMID: 32345788 BACKGROUND

• Notelovitz M, Johnston M, Smith S, Kitchens C. Metabolic and hormonal effects of 25-mg and 50-mg 17 beta-estradiol implants in surgically menopausal women. Obstet Gynecol. 1987 Nov;70(5):749-54.

  PMID: 3658285 BACKGROUND

• Owen EJ, Siddle NC, McGarrigle HT, Pugh MA. 25 mg oestradiol implants--the dosage of first choice for subcutaneous oestrogen replacement therapy? Br J Obstet Gynaecol. 1992 Aug;99(8):671-5. doi: 10.1111/j.1471-0528.1992.tb13853.x.

  PMID: 1327094 BACKGROUND

• Stanczyk FZ, Shoupe D, Nunez V, Macias-Gonzales P, Vijod MA, Lobo RA. A randomized comparison of nonoral estradiol delivery in postmenopausal women. Am J Obstet Gynecol. 1988 Dec;159(6):1540-6. doi: 10.1016/0002-9378(88)90591-1.

  PMID: 3144919 BACKGROUND

• Stuenkel CA, Davis SR, Gompel A, Lumsden MA, Murad MH, Pinkerton JV, Santen RJ. Treatment of Symptoms of the Menopause: An Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab. 2015 Nov;100(11):3975-4011. doi: 10.1210/jc.2015-2236. Epub 2015 Oct 7.

  PMID: 26444994 BACKGROUND

• Suhonen SP, Allonen HO, Lahteenmaki P. Sustained-release subdermal estradiol implants: a new alternative in estrogen replacement therapy. Am J Obstet Gynecol. 1993 Nov;169(5):1248-54. doi: 10.1016/0002-9378(93)90291-p.

  PMID: 8238193 BACKGROUND

• Thom MH, Collins WP, Studd JW. Hormonal profiles in postmenopausal women after therapy with subcutaneous implants. Br J Obstet Gynaecol. 1981 Apr;88(4):426-33. doi: 10.1111/j.1471-0528.1981.tb01008.x.

  PMID: 6784745 BACKGROUND

Study Officials

• André Luiz Malavasi de Oliveira Longo, MD, PhD

  Science Valley Research Institute

  STUDY CHAIR

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: October 31, 2023
• First Posted: November 18, 2023
• Study Start: December 13, 2023
• Primary Completion: October 9, 2024
• Study Completion: July 30, 2025
• Last Updated: September 8, 2025

Record last verified: 2025-09

Locations

BR (1)