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

Contraception Clinical Trial

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02957630
• Other study ID #: MIT-Es0001-C201
• Secondary ID: 2016-001316-37
• Status: Completed
• Phase: Phase 1/Phase 2
• First received: October 25, 2016
• Last updated: February 2, 2018
• Start date: September 2016
• Est. completion date: October 9, 2017

Study information

• Verified date: March 2017
• Source: Estetra
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 101
• Est. completion date: October 9, 2017
• Est. primary completion date: October 9, 2017
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: Female
• Age group: 18 Years to 50 Years

Eligibility

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

Related Conditions & MeSH terms

• Contraception
• Hemostasis Parameter
• Liver Metabolism

Intervention

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.
• 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.
• 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.

Locations

Country	Name	City	State
Netherlands	Dinox BV	Groningen

Sponsors (1)

Lead Sponsor	Collaborator
Estetra

Country where clinical trial is conducted

Netherlands, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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).
Primary	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).
Primary	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).
Primary	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).
Primary	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).
Primary	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).
Primary	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).
Primary	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).
Primary	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).
Primary	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).
Primary	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).
Primary	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).
Primary	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).
Primary	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).
Primary	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).
Primary	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).
Primary	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).
Primary	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).
Primary	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).
Primary	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).
Primary	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).
Primary	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).
Primary	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).
Primary	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).
Primary	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).
Primary	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).
Primary	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).
Primary	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).
Primary	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).
Primary	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).
Primary	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).
Primary	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).
Primary	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).
Primary	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).
Primary	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).
Primary	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).
Primary	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).
Primary	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).
Primary	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).
Primary	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).
Primary	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).
Primary	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).
Primary	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).
Primary	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).
Primary	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).
Primary	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).
Primary	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	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).
Secondary	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)
Secondary	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)
Secondary	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).
Secondary	Echocardiographic parameters		At screening and between Days 18 and 21 for Cycle 6 (1 cycle = 28 days).
Secondary	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).