Bioequivalence of Two Fixed-dose Combination Tablets Containing Estradiol and Nomegestrol Acetate

NCT03749733 | Withdrawn Phase 1

• 3 other identifiers: ESTNMG-04-GRUHP8010-0117-CI-09 012 084
• Study Type: interventional
• Target: N/A
• Locations: 1 country
• Sites: 1

Brief Summary

This study will investigate the bioavailability in fasting post-menopausal women of 2 film-coated tablet formulations containing 1.5 milligrams (mg) of estradiol and 2.5 mg of nomegestrol acetate. The study will be performed at a single site. Participants will take a single oral dose of the test product and reference product in 2 periods and 2 sequences (either test after reference or reference after test). There will be a washout of at least 21 days between each study period.

Conditions

Bioequivalence

Keywords

Bioequivalence; Estradiol; Nomegestrol acetate

Outcome Measures

Primary Outcomes (6)

• Total estrone (corrected): area under the plasma concentration-time curve from 0 to time t (AUC0-t)

  Three blood samples will be taken before the medication is administered and 19 samples up to 72 hours after the administration in each period. The samples taken at pre-dose will be taken to establish the baseline concentration of total estrone. The baseline-corrected AUC0-t will be calculated.

  Blood samples drawn at baseline (up to 1 hour before tablet intake) and up to 72 hours after tablet intake

• Total estradiol (corrected): area under the plasma concentration-time curve from 0 to time t (AUC0-t)

  Three blood samples will be taken before the medication is administered and 19 samples up to 72 hours after the administration in each period. The samples taken at pre-dose will be taken to establish the baseline concentration of total estradiol. The baseline-corrected AUC0-t will be calculated.

  Blood samples drawn at baseline (up to 1 hour before tablet intake) and up to 72 hours after tablet intake

• Total nomegestrol: area under the plasma concentration-time curve from 0 to 72 hours (AUC0-72)

  Three blood samples will be taken before the medication is administered and 19 samples up to 72 hours after the administration in each period. The samples taken at pre-dose will be taken to establish the baseline concentration of total nomegestrol. The AUC0-72 will be calculated.

  From tablet intake and up to 72 hours after tablet intake

• Total estrone (corrected): Maximum plasma concentration (Cmax)

  Three blood samples will be taken before the medication is administered and 19 samples up to 72 hours after the administration in each period. The baseline-corrected Cmax of estrone will be calculated.

  Blood samples drawn at baseline (up to 1 hour before tablet intake) and up to 72 hours after tablet intake

• Total estradiol (corrected): Maximum plasma concentration (Cmax)

  Three blood samples will be taken before the medication is administered and 19 samples up to 72 hours after the administration in each period. The baseline-corrected Cmax of estradiol will be calculated.

  Blood samples drawn at baseline (up to 1 hour before tablet intake) and up to 72 hours after tablet intake

• Total nomegestrol: Maximum plasma concentration (Cmax)

  Three blood samples will be taken before the medication is administered and 19 samples up to 72 hours after the administration in each period. The achieved Cmax of nomegestrol will be calculated.

  From tablet intake up to 72 hours after tablet intake

Secondary Outcomes (7)

• Total estrone: Time to achieve maximum plasma concentration (tmax)

  From tablet intake up to 72 hours after tablet intake

• Total estradiol: Time to achieve maximum plasma concentration (tmax)

  From tablet intake up to 72 hours after tablet intake

• Total nomegestrol: Time to achieve maximum plasma concentration (tmax)

  From tablet intake up to 72 hours after tablet intake

• Total estrone (uncorrected): area under the plasma concentration-time curve from 0 to time t (AUC0-t)

  Blood samples drawn at baseline (up to 1 hour before tablet intake) and up to 72 hours after tablet intake

• Total estradiol (uncorrected): area under the plasma concentration-time curve from 0 to time t (AUC0-t)

  Blood samples drawn at baseline (up to 1 hour before tablet intake) and up to 72 hours after tablet intake

Study Arms (2)

Test Product

EXPERIMENTAL

Participants will receive a single film-coated tablet of the test formulation containing estradiol 1.5 mg/nomegestrol acetate 2.5 mg. The tablet will be taken with water and in a fasting condition.

Drug: Estradiol 1.5 mg/nomegestrol acetate 2.5 mg (Test Product)

Reference Product

ACTIVE COMPARATOR

Participants will receive a single film-coated tablet of the marketed reference formulation containing estradiol 1.5 mg/nomegestrol acetate 2.5 mg. The tablet will be taken with water and in a fasting condition.

Drug: Estradiol 1.5 mg/nomegestrol acetate 2.5 mg (Reference Product)

Interventions

Estradiol 1.5 mg/nomegestrol acetate 2.5 mg (Reference Product) DRUG

Marketed Drug

Also known as: Stezza (Trade Mark)

Reference Product

Estradiol 1.5 mg/nomegestrol acetate 2.5 mg (Test Product) DRUG

Investigational Medicinal Product

Test Product

Eligibility Criteria

• Age: 40 Years - 65 Years
• Sex: female
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• A. Participation will be voluntary and according to the guidelines proposed by the Health General Law (Mexico), and informed consent will be obtained according to the previously mentioned law. In addition, the study will be conducted according to the ethical principles that have their origin in the Declaration of Helsinki, the current Brazilian laws, and Good Clinical Practice.
• B. Only post-menopausal women aged between 40 years and 65 years who meet any of the following criteria:
• months of spontaneous amenorrhea.
• months of spontaneous amenorrhea with follicle-stimulating hormone levels above 40 international units per liter and below 20 nanograms per liter estradiol.
• Bilateral oophorectomy with or without hysterectomy.
• C. The body mass index must be between 18.5 and 29.99 kilograms per square meter according to the Quetelet index.
• D. Participants must be healthy determined by the results of a complete clinical history recorded by the clinical investigational site physicians and the results of the laboratory examinations done by a certified clinical laboratory.
• E. Participants with pre-existing illnesses must be controlled with stable doses of medication for a period of at least 3 months.
• F. Non-smoker and/or not having used nicotine or nicotine-containing products (e.g., nicotine plasters) within 3 months prior to the beginning of the study.
• G. The allowed limits of variation within normal in the screening visit will be: systolic blood pressure (sitting) below 120 mmHg, diastolic blood pressure below 80 mmHg, heart rate between 50 and 100 beats per minute and respiratory rate between 14 and 20 breaths per minute according to the current standard operating procedure. Vital signs will be measured after 10 minutes of resting in a sitting position.
• Complete blood count: leukocytes, erythrocytes, hemoglobin, hematocrit, mean corpuscular volume, mean corpuscular hemoglobin, mean corpuscular hemoglobin concentration, erythrocyte distribution width, platelets, neutrophils, lymphocytes, monocytes, eosinophils, basophils.
• Blood chemistry 27 elements: glucose, urea, blood urea nitrogen (BUN), creatinine, BUN/creatinine ratio, uric acid, cholesterol, high-density lipoprotein (HDL) cholesterol, triglycerides, low-density lipoprotein (LDL), cholesterol, non-HDL cholesterol, atherogenic index, total protein, albumin, globulins, albumin/globulin ratio, total bilirubin, direct bilirubin, indirect bilirubin, aspartate aminotransferase, alanine aminotransferase, total alkaline phosphatase, gamma-glutamyl transferase, lactate dehydrogenase, iron, calcium, sodium, potassium, and chloride.
• Urinalysis: Physical examination (color, appearance, density); chemical examination (pH, leukocytes, nitrite, protein, glucose, ketones, bilirubin, urobilinogen, hemoglobin); microscopic examination (leukocytes, erythrocytes, dysmorphic erythrocytes, casts, crystals, squamous epithelial cells, tubular renal cells, mucus, bacteria and yeasts).
• Hepatitis B screening (Antibody to hepatitis B core antigen \[Anti-HBc\], antibody to hepatitis B surface antigen \[HBs-Ab\], antibody to hepatitis B surface antigen \[Anti-HBs\]) and hepatitis C antibodies.
• HIV test: Antibodies to the human immunodeficiency virus (Anti-HIV 1 and 2).

You may not qualify if:

• A. Participants with a history of the following diseases: cardiovascular (myocardial infarction, not-controlled hypertension, thromboembolic arterial or venous diseases), renal (kidney failure), hepatic (hepatitis, jaundice), muscular, metabolic, gastrointestinal, neurologic (cerebrovascular disease), psychiatric (depression) endocrinological (not-controlled diabetes mellitus), hematopoietic, respiratory or other organic abnormalities that are not appropriately controlled and that require a pharmacological treatment that could result in a drug interaction with the study medication. Women who have had muscular trauma within 21 days previous to the study will also be excluded.
• B. History of major surgeries (cranial surgery, thorax, abdomen or extensive surgeries in extremity requiring the use of general or regional anesthesia and/or respiratory support) within 3 months previous to the study.
• C. Participants with a history of dyspepsia, gastritis, esophagitis, duodenal or gastric ulcer.
• D. History of lactose intolerance.
• E. Participants who have been exposed to medications known to be hepatic enzyme inducers or inhibitors within 72 hours previous to the start of the study.
• F. Participants who have taken any type of vitamin supplements (with or without prescription) or herbal remedies within 30 days (or 7 half-lives) previous to the start of the study.
• G. Participants undergoing hormone replacement therapy or taking thyroid hormones.
• H. Participants with uterine bleeding.
• I. Participants with endometrial thickness equal to or greater than 7 mm as determined in the transvaginal ultrasound.
• J. Participants who have been hospitalized for any reason within 6 months prior to study start.
• K. Participants who have taken investigational medicinal products from other investigations within 180 days (i.e., 6 months) prior to study start.
• L. Participants with a history of allergy or hypersensitivity to the study medication (estradiol/nomegestrol), any other medication, food, or substance.
• M. Participants who have consumed alcohol, carbonated beverages, or beverages that contain methylxanthines (coffee, tea, cocoa, chocolate, mate, cola, etc.), grapefruit juice, or charbroiled foods within 12 hours prior to the start of the hospitalization period.
• N. Participants with any of the following results for hepatitis B: acute infection, chronic infection, or unclear result based on the interpretation of results of the hepatitis B virus serology (CDC Interpretation of Hepatitis B Serologic Test Results).
• O. Participants who have donated or lost more than 450 milliliters of blood within 90 days prior to study start.

Sponsors & Collaborators

• Grünenthal GmbH: lead
• Grünenthal, S.A.: collaborator

Study Sites (1)

Investigacíon Farmacológica y Biofarmacéutica (IFaB), S.A.P.I. de C.V.

Mexico City, C.P. 14610, Mexico

Location

MeSH Terms

Interventions

Estradiol; nomegestrol acetate

Intervention Hierarchy (Ancestors)

Estrenes; Estranes; Steroids; Fused-Ring Compounds; Polycyclic Compounds; Estradiol Congeners; Gonadal Steroid Hormones; Gonadal Hormones; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists

Study Officials

• Grünenthal Study Director

  Grünenthal GmbH

  STUDY DIRECTOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: BASIC SCIENCE
• Intervention Model: CROSSOVER
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: November 9, 2018
• First Posted: November 21, 2018
• Study Start: October 1, 2019
• Primary Completion: December 1, 2019
• Study Completion: December 1, 2019
• Last Updated: July 15, 2019

Record last verified: 2019-07

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, CSR

Locations

ME (1)