"E4/DRSP Endocrine Function, Metabolic Control and Hemostasis Study"

Estetra101 enrolled

Overview

The proposed study will provide an assessment of the effect of this combination on endocrine function, metabolic control and hemostasis during 6 treatment cycles. This will be compared to the effects of two reference COCs.

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

PREVENTION

Masking

NONE

Enrollment

101

Conditions

Contraception Liver Metabolism Hemostasis Parameter

Interventions

15 mg E4/3 mg DRSPDRUG

15 mg E4 combined with 3 mg DRSP administered in a 24/4-day regimen (i.e. 24 days of pink active tablets followed by 4 days of white placebo tablets). One tablet per day orally for 6 treatment cycles.

30 mcg EE/150 mcg LNGDRUG

30 mcg EE combined with 150 mcg LNG administered in a 21/7-day regimen (i.e. 21 days of yellow active tablets followed by 7 days of white placebo tablets). One tablet per day orally for 6 treatment cycles.

20 mcg EE/3 mg DRSPDRUG

20 mcg EE combined with 3 mg DRSP administered in a 24/4-day regimen (i.e. 24 days of pink active tablets followed by 4 days of white placebo tablets). One tablet per day orally for 6 treatment cycles.

Eligibility

Sex: FEMALEMin age: 18 YearsMax age: 50 YearsHealthy volunteers:

Medical Language ↔ Plain English

Inclusion Criteria: * Healthy adult woman * Negative pregnancy test at subject screening and randomization * Aged 18-50 years (inclusive) at the time of signing the ICF * Good physical and mental health on the basis of medical, surgical and gynecological history, physical examination, gynecological examination, clinical laboratory, ECG, echocardiography and vital signs * BMI from 18.0 to 30.0 kg/m², inclusive, at time of screening visit * Able to fulfil the requirements of the protocol and have indicated a willingness to participate in the study by providing written informed consent Exclusion Criteria: * Known hypersensitivity to any of the investigational product ingredients * Smoking if \> 35 years old * Dyslipoproteinemia or use of antilipidemic agent * Known diabetes mellitus * Current use of antidiabetic drugs, including insulin * Arterial hypertension * Any condition associated with an increased risk of venous thromboembolism and/or arterial thromboembolism. * Any condition associated with abnormal uterine/vaginal bleeding. * Presence of an undiagnosed breast mass * Current symptomatic gallbladder disease * History of pregnancy- or COC-related cholestasis * Presence or history of severe hepatic disease * Presence or history of pancreatitis if associated with hypertriglyceridemia * Porphyria * Presence or history of benign liver tumors (focal nodular hyperplasia and hepatocellular adenoma) * Presence of renal impairment (glomerular filtration rate \[GFR\] \<60 mL/min/1.73m²) * Hyperkalemia or presence of conditions that predispose to hyperkalemia * Presence or history of hormone-related malignancy * History of non-hormone-related malignancy within 5 years before screening; subjects with a non-melanoma skin cancer are allowed in the study * Use of drugs potentially triggering interactions with COCs * History of alcohol or drug abuse within 12 months prior to screening * Presence or history of thyroid disorders * Participation in another investigational drug clinical study within 1 month (30 days) or have received an investigational drug within the last 3 months (90 days) prior to randomization. Subjects who participated in an oral contraceptive clinical study using Food and Drug Administration (FDA)/European Union (EU) approved active ingredients, may be randomized 2 months (60 days) after completing the preceding study * Sponsor, contract research organization (CRO) or Principal Investigator's (PI's) site personnel directly affiliated with this study * Is judged by the PI to be unsuitable for any reason

Locations (1)

Dinox BV

Groningen, Netherlands

Outcomes

Primary Outcomes

Plasma concentration of prothrombin fragment 1+2

Time frame: Between Days 18 and 21 for the pretreatment Cycle, and between Days 18 and 21 for the Cycles 3 and 6 (1 cycle = 28 days).

Plasma concentration of APC resistance (ETP-based, APTT-based)

Time frame: Between Days 18 and 21 for the pretreatment Cycle, and between Days 18 and 21 for the Cycles 3 and 6 (1 cycle = 28 days).

Plasma concentration of D-dimer

Time frame: Between Days 18 and 21 for the pretreatment Cycle, and between Days 18 and 21 for the Cycles 3 and 6 (1 cycle = 28 days).

Plasma concentration of factor VII

Time frame: Between Days 18 and 21 for the pretreatment Cycle, and between Days 18 and 21 for the Cycles 3 and 6 (1 cycle = 28 days).

Plasma concentration of factor VIII

Time frame: Between Days 18 and 21 for the pretreatment Cycle, and between Days 18 and 21 for the Cycles 3 and 6 (1 cycle = 28 days).

Plasma concentration of von Willebrand factor

Time frame: Between Days 18 and 21 for the pretreatment Cycle, and between Days 18 and 21 for the Cycles 3 and 6 (1 cycle = 28 days).

Plasma concentration of factor II

Time frame: Between Days 18 and 21 for the pretreatment Cycle, and between Days 18 and 21 for the Cycles 3 and 6 (1 cycle = 28 days).

Plasma concentration of antithrombin

Time frame: Between Days 18 and 21 for the pretreatment Cycle, and between Days 18 and 21 for the Cycles 3 and 6 (1 cycle = 28 days).

Plasma concentration of free and total Protein S

Time frame: Between Days 18 and 21 for the pretreatment Cycle, and between Days 18 and 21 for the Cycles 3 and 6 (1 cycle = 28 days).

Data from ClinicalTrials.gov

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Plasma concentration of protein C

Time frame: Between Days 18 and 21 for the pretreatment Cycle, and between Days 18 and 21 for the Cycles 3 and 6 (1 cycle = 28 days).

Plasma concentration of plasminogen activator inhibitor type-1 (PAI-1)

Time frame: Between Days 18 and 21 for the pretreatment Cycle, and between Days 18 and 21 for the Cycles 3 and 6 (1 cycle = 28 days).

Plasma concentration of tissue type plasminogen activator (t-PA)

Time frame: Between Days 18 and 21 for the pretreatment Cycle, and between Days 18 and 21 for the Cycles 3 and 6 (1 cycle = 28 days).

Plasma concentration of plasminogen

Time frame: Between Days 18 and 21 for the pretreatment Cycle, and between Days 18 and 21 for the Cycles 3 and 6 (1 cycle = 28 days).

Plasma concentration of free tissue factor pathway inhibitor (TPFI)

Time frame: Between Days 18 and 21 for the pretreatment Cycle, and between Days 18 and 21 for the Cycles 3 and 6 (1 cycle = 28 days).

Plasma concentration of E-selectin

Time frame: Between Days 18 and 21 for the pretreatment Cycle, and between Days 18 and 21 for the Cycles 3 and 6 (1 cycle = 28 days).

Plasma concentration of fibrinogen

Time frame: Between Days 18 and 21 for the pretreatment Cycle, and between Days 18 and 21 for the Cycles 3 and 6 (1 cycle = 28 days).

Serum concentration of insulin

Time frame: At screening, between Days 18 and 21 for the pretreatment Cycle, and between Days 18 and 21 for Cycles 3 and 6 (1 cycle = 28 days).

Serum concentration of glucose

Time frame: At screening, between Days 18 and 21 for the pretreatment Cycle, and between Days 18 and 21 for Cycles 3 and 6 (1 cycle = 28 days).

Serum concentration of C-peptide

Time frame: At screening, between Days 18 and 21 for the pretreatment Cycle, and between Days 18 and 21 for Cycles 3 and 6 (1 cycle = 28 days).

Plasma concentration of glycated hemoglobin (HbA1c)

Time frame: At screening, between Days 18 and 21 for the pretreatment Cycle, and between Days 18 and 21 for the Cycles 3 and 6 (1 cycle = 28 days).

Homeostasis Model Assessment - Insulin Resistance (HOMA-IR)

Time frame: At screening, between Days 18 and 21 for the pretreatment Cycle, and between Days 18 and 21 for the Cycles 3 and 6 (1 cycle = 28 days).

Oral glucose tolerance test (OGTT)

Time frame: At 0 (pre-glucose challenge), 30, 60, 90, 120 and 180 minutes after glucose challenge during pretreatment Cycle; at 0 (pre-glucose challenge), 30, 60, 90, 120 and 180 minutes after glucose challenge during Cycles 3 and 6 (1 cycle = 28 days).

Serum concentration of prolactin

Time frame: Between Days 18 and 21 for the pretreatment Cycle, and between Days 18 and 21 for the Cycles 3 and 6 (1 cycle = 28 days).

Serum concentration of follicle-stimulating hormone (FSH)

Time frame: Between Days 18 and 21 for the pretreatment Cycle, and between Days 18 and 21 for the Cycles 3 and 6 (1 cycle = 28 days).

Serum concentration of luteinizing hormone (LH)

Time frame: Between Days 18 and 21 for the pretreatment Cycle, and between Days 18 and 21 for the Cycles 3 and 6 (1 cycle = 28 days).

Serum concentration of estradiol (E2)

Time frame: Between Days 18 and 21 for the pretreatment Cycle, and between Days 18 and 21 for the Cycles 3 and 6 (1 cycle = 28 days).

Serum concentration of progesterone (P)

Time frame: Between Days 18 and 21 for the pretreatment Cycle, and between Days 18 and 21 for the Cycles 3 and 6 (1 cycle = 28 days).

Serum concentration of thyroïd stimulating hormone (TSH)

Time frame: Between Days 18 and 21 for the pretreatment Cycle, and between Days 18 and 21 for the Cycles 3 and 6 (1 cycle = 28 days).

Serum concentration of free thyroxine (fT3)/free triiodothyronine (fT4)

Time frame: Between Days 18 and 21 for the pretreatment Cycle, and between Days 18 and 21 for the Cycles 3 and 6 (1 cycle = 28 days).

Serum concentration of dihydroepiandrostenedione (DHEAS)

Time frame: Between Days 18 and 21 for the pretreatment Cycle, and between Days 18 and 21 for the Cycles 3 and 6 (1 cycle = 28 days).

Serum concentration of androstenedione

Time frame: Between Days 18 and 21 for the pretreatment Cycle, and between Days 18 and 21 for the Cycles 3 and 6 (1 cycle = 28 days).

Serum concentration of total testosterone (T)

Time frame: Between Days 18 and 21 for the pretreatment Cycle, and between Days 18 and 21 for the Cycles 3 and 6 (1 cycle = 28 days).

Serum concentration of dihydrotestosterone (DHT)

Time frame: Between Days 18 and 21 for the pretreatment Cycle, and between Days 18 and 21 for the Cycles 3 and 6 (1 cycle = 28 days).

Serum concentration of total cortisol

Time frame: Between Days 18 and 21 for the pretreatment Cycle, and between Days 18 and 21 for the Cycles 3 and 6 (1 cycle = 28 days).

Serum concentration of aldosterone

Time frame: Between Days 18 and 21 for the pretreatment Cycle, and between Days 18 and 21 for the Cycles 3 and 6 (1 cycle = 28 days).

Serum concentration of high density lipoprotein (HDL)-cholesterol

Time frame: At screening, between Days 18 and 21 for the pretreatment Cycle, and between Days 18 and 21 for the Cycles 3 and 6 (1 cycle = 28 days).

Serum concentration of low density lipoprotein (LDL)-cholesterol

Time frame: At screening, between Days 18 and 21 for the pretreatment Cycle, and between Days 18 and 21 for the Cycles 3 and 6 (1 cycle = 28 days).

Serum concentration of total cholesterol

Time frame: At screening, between Days 18 and 21 for the pretreatment Cycle, and between Days 18 and 21 for the Cycles 3 and 6 (1 cycle = 28 days).

Serum concentration of triglycerides

Time frame: At screening, between Days 18 and 21 for the pretreatment Cycle, and between Days 18 and 21 for the Cycles 3 and 6 (1 cycle = 28 days).

Serum concentration of lipoprotein (a)

Time frame: Between Days 18 and 21 for the pretreatment Cycle, and between Days 18 and 21 for the Cycles 3 and 6 (1 cycle = 28 days).

Serum concentration of apoliporotein A1

Time frame: Between Days 18 and 21 for the pretreatment Cycle, and between Days 18 and 21 for the Cycles 3 and 6 (1 cycle = 28 days).

Serum concentration of apoliporotein B

Time frame: Between Days 18 and 21 for the pretreatment Cycle, and between Days 18 and 21 for the Cycles 3 and 6 (1 cycle = 28 days).

Serum concentration of C-reactive protein

Time frame: Between Days 18 and 21 for the pretreatment Cycle, and between Days 18 and 21 for the Cycles 3 and 6 (1 cycle = 28 days).

Serum concentration of corticosteroid binding globulin (CBG)

Time frame: Between Days 18 and 21 for the pretreatment Cycle, and between Days 18 and 21 for the Cycles 3 and 6 (1 cycle = 28 days).

Serum concentration of sex hormone binding globulin (SHBG)

Time frame: Between Days 18 and 21 for the pretreatment Cycle, and between Days 18 and 21 for the Cycles 3 and 6 (1 cycle = 28 days).

Serum concentration of thyroxin binding globulin (TBG)

Time frame: Between Days 18 and 21 for the pretreatment Cycle, and between Days 18 and 21 for the Cycles 3 and 6 (1 cycle = 28 days).

Serum concentration of angiotensinogen

Time frame: Between Days 18 and 21 for the pretreatment Cycle, and between Days 18 and 21 for the Cycles 3 and 6 (1 cycle = 28 days).

Secondary Outcomes

Number of subjects with adverse events as a measure of safety and tolerability

Time frame: From up to 28 days before randomization to maximum Day 4 of the Cycle 7 (1 cycle = 28 days).

Serum concentration of lactate dehydrogenase (LDH) 1 and 2

Time frame: Between Days 18 and 21 for the pretreatment Cycle and between Days 18 and 21 for the Cycle 6 (1 cycle = 28 days)

Serum concentration of tropinin T and I

Time frame: Between Days 18 and 21 for the pretreatment Cycle and between Days 18 and 21 for the Cycle 6 (1 cycle = 28 days)

Electrocardiogram (ECG) parameters

The following ECG parameters will be recorded: heart rate, PR-interval, QRS-duration, QT-interval, QTc interval (Fridericias's)

Time frame: At screening and between Days 18 and 21 for Cycle 6 (1 cycle = 28 days).

Echocardiographic parameters

Time frame: At screening and between Days 18 and 21 for Cycle 6 (1 cycle = 28 days).

Change from baseline to end of treatment in the different items of the menstrual distress questionnaires (MDQ) form C

Time frame: At pretreatment Cycle and between Days 18 and 21 for Cycle 6 (1 cycle = 28 days).