Clinical trial NCT02957630: "E4/DRSP Endocrine Function, Metabolic Control and Hemostasis Study"
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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
PHASE2
Conditions: Contraception
Liver Metabolism
Hemostasis Parameter
Keywords: Estetrol (E4)
Drospirenone (DRSP)
Ethinylestradiol (EE)
Levonorgestrel (LNG)
Oral contraceptive
Prevention of pregnancy
Hemostasis
Metabolism
Lead sponsor: Estetra
Sponsor class: INDUSTRY
First posted: 2016-11-08
Enrollment: 101
Sex: FEMALE
Minimum age (years): 18
Maximum age (years): 50
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: PREVENTION

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.


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

Primary outcomes:
measure: Plasma concentration of prothrombin fragment 1+2
timeFrame: 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).
measure: Plasma concentration of APC resistance (ETP-based, APTT-based)
timeFrame: 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).
measure: Plasma concentration of D-dimer
timeFrame: 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).
measure: Plasma concentration of factor VII
timeFrame: 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).
measure: Plasma concentration of factor VIII
timeFrame: 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).
measure: Plasma concentration of von Willebrand factor
timeFrame: 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).
measure: Plasma concentration of factor II
timeFrame: 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).
measure: Plasma concentration of antithrombin
timeFrame: 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).
measure: Plasma concentration of free and total Protein S
timeFrame: 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).
measure: Plasma concentration of protein C
timeFrame: 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).
measure: Plasma concentration of plasminogen activator inhibitor type-1 (PAI-1)
timeFrame: 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).
measure: Plasma concentration of tissue type plasminogen activator (t-PA)
timeFrame: 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).
measure: Plasma concentration of plasminogen
timeFrame: 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).
measure: Plasma concentration of free tissue factor pathway inhibitor (TPFI)
timeFrame: 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).
measure: Plasma concentration of E-selectin
timeFrame: 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).
measure: Plasma concentration of fibrinogen
timeFrame: 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).
measure: Serum concentration of insulin
timeFrame: 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).
measure: Serum concentration of glucose
timeFrame: 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).
measure: Serum concentration of C-peptide
timeFrame: 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).
measure: Plasma concentration of glycated hemoglobin (HbA1c)
timeFrame: 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).
measure: Homeostasis Model Assessment - Insulin Resistance (HOMA-IR)
timeFrame: 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).
measure: Oral glucose tolerance test (OGTT)
timeFrame: 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).
measure: Serum concentration of prolactin
timeFrame: 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).
measure: Serum concentration of follicle-stimulating hormone (FSH)
timeFrame: 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).
measure: Serum concentration of luteinizing hormone (LH)
timeFrame: 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).
measure: Serum concentration of estradiol (E2)
timeFrame: 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).
measure: Serum concentration of progesterone (P)
timeFrame: 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).
measure: Serum concentration of thyroïd stimulating hormone (TSH)
timeFrame: 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).
measure: Serum concentration of free thyroxine (fT3)/free triiodothyronine (fT4)
timeFrame: 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).
measure: Serum concentration of dihydroepiandrostenedione (DHEAS)
timeFrame: 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).
measure: Serum concentration of androstenedione
timeFrame: 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).
measure: Serum concentration of total testosterone (T)
timeFrame: 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).
measure: Serum concentration of dihydrotestosterone (DHT)
timeFrame: 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).
measure: Serum concentration of total cortisol
timeFrame: 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).
measure: Serum concentration of aldosterone
timeFrame: 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).
measure: Serum concentration of high density lipoprotein (HDL)-cholesterol
timeFrame: 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).
measure: Serum concentration of low density lipoprotein (LDL)-cholesterol
timeFrame: 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).
measure: Serum concentration of total cholesterol
timeFrame: 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).
measure: Serum concentration of triglycerides
timeFrame: 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).
measure: Serum concentration of lipoprotein (a)
timeFrame: 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).
measure: Serum concentration of apoliporotein A1
timeFrame: 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).
measure: Serum concentration of apoliporotein B
timeFrame: 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).
measure: Serum concentration of C-reactive protein
timeFrame: 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).
measure: Serum concentration of corticosteroid binding globulin (CBG)
timeFrame: 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).
measure: Serum concentration of sex hormone binding globulin (SHBG)
timeFrame: 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).
measure: Serum concentration of thyroxin binding globulin (TBG)
timeFrame: 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).
measure: Serum concentration of angiotensinogen
timeFrame: 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:
measure: Number of subjects with adverse events as a measure of safety and tolerability
timeFrame: From up to 28 days before randomization to maximum Day 4 of the Cycle 7 (1 cycle = 28 days).
measure: Serum concentration of lactate dehydrogenase (LDH) 1 and 2
timeFrame: Between Days 18 and 21 for the pretreatment Cycle and between Days 18 and 21 for the Cycle 6 (1 cycle = 28 days)
measure: Serum concentration of tropinin T and I
timeFrame: Between Days 18 and 21 for the pretreatment Cycle and between Days 18 and 21 for the Cycle 6 (1 cycle = 28 days)
measure: Electrocardiogram (ECG) parameters
timeFrame: At screening and between Days 18 and 21 for Cycle 6 (1 cycle = 28 days).
measure: Echocardiographic parameters
timeFrame: At screening and between Days 18 and 21 for Cycle 6 (1 cycle = 28 days).
measure: Change from baseline to end of treatment in the different items of the menstrual distress questionnaires (MDQ) form C
timeFrame: At pretreatment Cycle and between Days 18 and 21 for Cycle 6 (1 cycle = 28 days).
Other outcomes:
Locations:
city: Groningen
country: Netherlands
facility: Dinox BV
Study officials:
affiliation: Dinox BV
name: Christine Klipping
role: PRINCIPAL_INVESTIGATOR
References: