Pharmacokinetic Aspects of 25-mg Estradiol Pellet in Climacteric Women (CLARA)

Pharmacokinetic Aspects of 25-mg Estradiol Pellet in Climacteric Women Comprehensive Longitudinal Assessment of Release With Estradiol Pellet Analysis (CLARA Study)

A multicenter, prospective, open-label clinical study will be conducted, to monitor serum concentration and pharmacokinetic profile after subcutaneous implantation of a 25mg absorbable pellet containing estradiol in climacteric women.

Study Overview

• Status: Recruiting
• Conditions: Menopause; Hypoestrogenism; Climacteric Syndrome
• Intervention / Treatment: Drug: s.c 25 mg estradiol pellet

Detailed Description

Assessing serum total estradiol concentration and determination of pharmacokinetic parameters will be performed in participants eligible for the study before and after the insertion of estradiol pellet (25 mg) at different collection times [in the first 24 hours, weekly in the first month and monthly until 6 months are complete]. Additionally, the concentration of other hormones influenced by the action of estradiol will be determined (total testosterone, estrone, FSH, LH, SHBG, and prolactin). Medical visits will be carried out for clinical evaluation and follow-up of the participants in the baseline and after 1 month, 3 months, and 6 months. Assessment of the primary outcome will be performed 6 months after estradiol pellet insertion.

• Study Type: Interventional
• Enrollment (Estimated): 25
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Leandro Agati; Phone Number: +551144688183; Email: agati@svriglobal.com
• Study Contact Backup: Name: Eduardo Ramacciotti, MD, PhD; Email: eduardoramacciotti@gmail.com

Study Locations

• Brazil
  • São Paulo
    • Santos, São Paulo, Brazil, 11075-900
      • Recruiting
      • Irmandade Da Santa Casa De Misericórdia De Santos - Science Valley Research Center
      • Contact: Science Valley Research Center; Phone Number: +55 (13) 3202-0600; Email: provedoria@scsantos.com.br

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult
• Accepts Healthy Volunteers: Yes

Description

Inclusion Criteria:

• Signed Informed Consent Form
• Woman aged ≥ 41 and ≤ 59 years
• Weight ≥ 50 kg and ≤ 90 kg- BMI ≥ 18.5 and ≤ 34.9 kg/m²
• Hysterectomy (with or without oophorectomy)
• Hypoestrogenism defined by serum total estradiol concentration ≤ 50 pg/mL and serum FSH concentration ≥ 25 mIU/mL
• Women with climacteric 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

Exclusion Criteria:

• 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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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 Outcome Measures

Outcome Measure	Measure Description	Time Frame
Total testosterone concentration	Multiple blood 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 total testosterone concentrations will be determined by Liquid chromatography - mass spectrometry	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	Multiple blood 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 , 28days , 56 days, 84 days, 112 days , 140 days and 168 days and estrone concentrations will be determined by enzyme immunoassay.	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	Multiple blood 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 Follicle-stimulating hormone concentrations will be determined by electrochemiluminescence	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	Multiple blood 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 Follicle-stimulating hormone concentrations will be determined by electrochemiluminescence	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	Multiple blood 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 dyas, 56 days, 84 days, 112 days, 140 days and 168 days and Follicle-stimulating hormone concentrations will be determined by electrochemiluminescence	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
Prolactin concentration	Multiple blood 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 Follicle-stimulating hormone concentrations will be determined by electrochemiluminescence	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 Outcome Measures

Outcome Measure	Measure Description	Time Frame
Adverse events	Number of participants experiencing serious adverse events (SAEs) and adverse events leading to discontinuation in the study. Adverse events reported by study participants (any including non-serious ones)	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

Collaborators and Investigators

• Sponsor: Science Valley Research Institute
• Collaborators: Biós Farmacêutica
• Investigators: Study Chair: André Luiz Malavasi de Oliveira Longo, MD, PhD, Science Valley Research Institute

Publications and helpful links

General Publications

• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.

Study record dates

Study Major Dates

• Study Start (Actual): December 13, 2023
• Primary Completion (Estimated): October 30, 2024
• Study Completion (Estimated): October 30, 2024

Study Registration Dates

• First Submitted: October 31, 2023
• First Submitted That Met QC Criteria: November 13, 2023
• First Posted (Actual): November 18, 2023

Study Record Updates

• Last Update Posted (Actual): March 20, 2024
• Last Update Submitted That Met QC Criteria: March 19, 2024
• Last Verified: March 1, 2024

More Information

Terms related to this study

• Keywords: Menopause; Climateric; Estradiol Pellet; Pharmacokinectic
• Additional Relevant MeSH Terms: Physiological Effects of Drugs; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Estrogens; Estradiol
• Other Study ID Numbers: CLARA Study

Drug and device information, study documents

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