E4/DRSP Endocrine Function, Metabolic Control and Hemostasis Study

Study Overview
=================
Brief Summary
-----------------
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.

Official Title
-----------------
A Single Center, Randomized,Open-label,Controlled, Three-arm Study to Evaluate the Effect of a New Combined Oral Contraceptive (COC) Containing 15 mg Estetrol (E4) and 3 mg Drospirenone (DRSP) and of Two Reference COCs Containing Either 30 mcg Ethinylestradiol (EE) and 150 mcg Levonorgestrel (LNG) or 20 mcg EE and 3 mg DRSP on Endocrine Function, Metabolic Control and Hemostasis During 6 Treatment Cycles

Conditions
-----------------
Contraception, Liver Metabolism, Hemostasis Parameter

Intervention / Treatment
-----------------
* Drug: 15 mg E4/3 mg DRSP
* Drug: 30 mcg EE/150 mcg LNG
* Drug: 20 mcg EE/3 mg DRSP


Participation Criteria
=================
Eligibility Criteria
-----------------
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

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 50 Years

Sexes Eligible for Study
-----------------
Female

Accepts Healthy Volunteers
-----------------
Accepts Healthy Volunteers

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 15 mg E4/3 mg DRSP<br>15 mg estetrol/3 mg drospirenone combined oral contraceptive | Drug: 15 mg E4/3 mg DRSP<br>* 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.<br>* Other names: 15 mg estetrol and 3 mg drospirenone;|
| Active Comparator: 30 mcg EE/150 mcg LNG<br>30 mcg ethinylestradiol/150 mcg levonorgestrel combined oral contraceptive | Drug: 30 mcg EE/150 mcg LNG<br>* 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.<br>* Other names: 30 mcg ethinylestradiol and 150 mcg levonorgestrel;|
| Active Comparator: 20 mcg EE/3 mg DRSP<br>20 mcg ethinylestradiol/3 mg drospirenone combined oral contraceptive | Drug: 20 mcg EE/3 mg DRSP<br>* 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.<br>* Other names: 20 mcg ethinylestradiol and 3 mg drospirenone;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Plasma concentration of prothrombin fragment 1+2 |  | 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) |  | 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 |  | 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 |  | 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 |  | 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 |  | 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 |  | 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 |  | 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 |  | 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 protein C |  | 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) |  | 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) |  | 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 |  | 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) |  | 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 |  | 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 |  | 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 |  | 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 |  | 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 |  | 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) |  | 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) |  | 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) |  | 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 |  | 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) |  | 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) |  | 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) |  | 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) |  | 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) |  | 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) |  | 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) |  | 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 |  | 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) |  | 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) |  | 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 |  | 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 |  | 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 |  | 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 |  | 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 |  | 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 |  | 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) |  | 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 |  | 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 |  | 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 |  | 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) |  | 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) |  | 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) |  | 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 |  | 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 Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of subjects with adverse events as a measure of safety and tolerability |  | 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 |  | 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 |  | 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) | At screening and between Days 18 and 21 for Cycle 6 (1 cycle = 28 days). | 
| Echocardiographic parameters |  | 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 |  | At pretreatment Cycle and between Days 18 and 21 for Cycle 6 (1 cycle = 28 days). | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Estetrol (E4), Drospirenone (DRSP), Ethinylestradiol (EE), Levonorgestrel (LNG), Oral contraceptive, Prevention of pregnancy, Hemostasis, Metabolism