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

NCT02957630 | Completed Phase 1

• 2 other identifiers: MIT-Es0001-C2012016-001316-37
• Study Type: interventional
• Target: 101
• Locations: 1 country
• Sites: 1

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.

Conditions

Contraception; Liver Metabolism; Hemostasis Parameter

Keywords

Estetrol (E4); Drospirenone (DRSP); Ethinylestradiol (EE); Levonorgestrel (LNG); Oral contraceptive; Prevention of pregnancy; Hemostasis; Metabolism

Outcome Measures

Primary Outcomes (47)

• 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 Outcomes (6)

• 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

  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).

Study Arms (3)

15 mg E4/3 mg DRSP

EXPERIMENTAL

15 mg estetrol/3 mg drospirenone combined oral contraceptive

Drug: 15 mg E4/3 mg DRSP

30 mcg EE/150 mcg LNG

ACTIVE COMPARATOR

30 mcg ethinylestradiol/150 mcg levonorgestrel combined oral contraceptive

Drug: 30 mcg EE/150 mcg LNG

20 mcg EE/3 mg DRSP

ACTIVE COMPARATOR

20 mcg ethinylestradiol/3 mg drospirenone combined oral contraceptive

Drug: 20 mcg EE/3 mg DRSP

Interventions

15 mg E4/3 mg DRSP DRUG

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.

Also known as: 15 mg estetrol and 3 mg drospirenone

15 mg E4/3 mg DRSP

30 mcg EE/150 mcg LNG DRUG

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.

Also known as: 30 mcg ethinylestradiol and 150 mcg levonorgestrel

30 mcg EE/150 mcg LNG

20 mcg EE/3 mg DRSP DRUG

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.

Also known as: 20 mcg ethinylestradiol and 3 mg drospirenone

20 mcg EE/3 mg DRSP

Eligibility Criteria

• Age: 18 Years - 50 Years
• Sex: female
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• 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

You may not qualify if:

• 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)

Sponsors & Collaborators

• Estetra: lead

Study Sites (1)

Dinox BV

Groningen, 9713 GZ, Netherlands

Location

MeSH Terms

Interventions

Estetrol; drospirenone; Ethinyl Estradiol; Levonorgestrel

Intervention Hierarchy (Ancestors)

Estriol; Estrenes; Estranes; Steroids; Fused-Ring Compounds; Polycyclic Compounds; Estradiol Congeners; Gonadal Steroid Hormones; Gonadal Hormones; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Norpregnatrienes; Norpregnanes; Norsteroids; Estrogenic Steroids, Alkylated; Norgestrel; Norpregnenes

Study Officials

• Christine Klipping

  Dinox BV

  PRINCIPAL INVESTIGATOR

Study Design

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

Study Record Dates

• First Submitted: October 25, 2016
• First Posted: November 8, 2016
• Study Start: September 1, 2016
• Primary Completion: October 9, 2017
• Study Completion: October 9, 2017
• Last Updated: February 5, 2018

Record last verified: 2017-03

Locations

NL (1)