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

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

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 Overview

• Status: Completed
• 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

• Study Type: Interventional
• Enrollment (Actual): 101
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• Netherlands
  • Groningen, Netherlands, 9713 GZ
    • Dinox BV

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 50 years (ADULT)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: Female

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: PREVENTION
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: NONE

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: 15 mg E4/3 mg DRSP; 15 mg estetrol/3 mg drospirenone combined oral contraceptive	Drug: 15 mg E4/3 mg DRSP; 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.; Other Names: 15 mg estetrol and 3 mg drospirenone
ACTIVE_COMPARATOR: 30 mcg EE/150 mcg LNG; 30 mcg ethinylestradiol/150 mcg levonorgestrel combined oral contraceptive	Drug: 30 mcg EE/150 mcg LNG; 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.; Other Names: 30 mcg ethinylestradiol and 150 mcg levonorgestrel
ACTIVE_COMPARATOR: 20 mcg EE/3 mg DRSP; 20 mcg ethinylestradiol/3 mg drospirenone combined oral contraceptive	Drug: 20 mcg EE/3 mg DRSP; 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.; Other Names: 20 mcg ethinylestradiol and 3 mg drospirenone

What is the study measuring?

Primary Outcome Measures

Outcome Measure	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).

Collaborators and Investigators

• Sponsor: Estetra

Study record dates

Study Major Dates

• Study Start: September 1, 2016
• Primary Completion (ACTUAL): October 9, 2017
• Study Completion (ACTUAL): October 9, 2017

Study Registration Dates

• First Submitted: October 25, 2016
• First Submitted That Met QC Criteria: November 3, 2016
• First Posted (ESTIMATE): November 8, 2016

Study Record Updates

• Last Update Posted (ACTUAL): February 5, 2018
• Last Update Submitted That Met QC Criteria: February 2, 2018
• Last Verified: March 1, 2017

More Information

Terms related to this study

• Keywords: Hemostasis; Metabolism; Prevention of pregnancy; Oral contraceptive; Drospirenone (DRSP); Levonorgestrel (LNG); Estetrol (E4); Ethinylestradiol (EE)
• Additional Relevant MeSH Terms: Physiological Effects of Drugs; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Estrogens; Natriuretic Agents; Diuretics; Hormone Antagonists; Contraceptive Agents, Hormonal; Contraceptive Agents; Reproductive Control Agents; Contraceptives, Oral; Contraceptive Agents, Female; Contraceptives, Oral, Synthetic; Contraceptives, Oral, Hormonal; Mineralocorticoid Receptor Antagonists; Diuretics, Potassium Sparing; Levonorgestrel; Ethinyl Estradiol; Drospirenone
• Other Study ID Numbers: MIT-Es0001-C201; 2016-001316-37 (EUDRACT_NUMBER)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED