Contraception
Conditions
Brief summary
An open-label, randomized, parallel group trial in healthy female subjects to compare the pharmacokinetics of ethinyl estradiol (EE) of NuvaRing®, a contraceptive patch (EVRA(TM)) and an oral contraceptive (Microgynon® 30).
Interventions
DRUGLevonorgestrel (LNG)/Ethinylestradiol (EE) oral contraceptive tablets
LNG/EE oral contraceptive tablets (Microgynon® 30), 21 in total, containing 0.150 mg LNG and 0.030 mg EE per tablet administered once daily orally for 21 consecutive days.
DRUGnorelgestrominum and ethinylestradiol patch oral contraceptive patch
A contraceptive patch (EVRA ™), one patch for 7 days for three consecutive weeks, 3 patches in total, applied on the lower abdomen. Dose: per patch 6 mg norelgestromin and 0.750 mg EE releasing 0.150 mg norelgestromin and 0.020 mg EE per day.
DRUGNuvaring ™ (etonorgestrel/ethinylestradiol)
NuvaRing ™ , one ring for a period of 21 days, inserted vaginally. Dose: per ring 11.7 mg etonogestrel and 2.7 mg EE releasing a daily average amount of 0.120 mg etonogestrel and 0.015 mg EE.
Sponsors
Organon and Co
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
BASIC_SCIENCE
Masking
NONE
Eligibility
Sex/Gender
FEMALE
Age
18 Years to 40 Years
Healthy volunteers
No
Inclusion criteria
* Subject is at least 18 but not older than 40 years of age on Day 1 of treatment. * Subject has uterus and ovaria in situ * Subject who does not use hormonal contraception and is willing to use adequate nonhormonal contraceptive measures during the timeframe between screening and start treatment. * Subject is able and willing to refrain from caffeine and/or xanthine containing food and/or beverages (e.g. coffee, tea, cola or chocolate) from 24 hours before the first administration of the trial medication until the last PK blood sample. * Subject is willing not to consume grapefruit containing products 14 days prior to the start of the first administration of the trial medication until the last PK blood sample. * Subject is willing to refrain from smoking from 7 days prior to first administration of the trial medication until the last pharmacokinetic blood sample. * Subject is willing to refrain from alcohol containing products from 24 hours prior to first administration of the trial medication until the last pharmacokinetic blood sample.
Exclusion criteria
* Contraindications for use of NuvaRing, contraceptive patch and oral contraceptive: * Presence or history of venous thrombosis, with or without the involvement of pulmonary embolism. * Presence or history of arterial thrombosis (e.g. cerebrovascular accident, myocardial infarction) or prodromi of a thrombosis (e.g. angina pectoris or transient ischaemic attack). * Known predisposition for venous or arterial thrombosis, with or without hereditary involvement such as Activated Protein C (APC) resistance, antithrombin-III deficiency, protein C deficiency, protein S deficiency, hyperhomocysteinaemia, antiphospholipid antibodies (anticardiolipin antibodies, lupus anticoagulant) and Factor V Leiden mutation. * Diabetes mellitus with vascular involvement * The presence of a severe or multiple risk factor(s) for venous or arterial thrombosis (to be judged by the (sub-) investigator * Presence or history of severe hepatic disease as long as liver function values had not returned to normal or were judged to be clinically significant by the investigator. * Presence or history of liver tumours (benign or malignant). * Known or suspected malignant conditions of the genital organs or the breasts, if sex-steroid-influenced. * Undiagnosed vaginal bleeding. * Hypersensitivity to the active substances or to any of the excipients of NuvaRing, contraceptive patch and oral contraceptive. * Migraine with focal aura * Known or suspected pregnancy * Breastfeeding, or within 2 months after stopping breastfeeding on the day preceding the first administration of trial medication (Day -1). * Clinically significant abnormal laboratory, ECG (electrocardiogram) vital signs, physical and gynecological findings at screening. * A significant (history of) allergic or other serious disease, particularly gastrointestinal tract disease. * Smoking more than 5 cigarettes or 1 pipe or 1 cigar per day for a period of at least 3 months prior to screening. * Using any systemic medication (including over the counter (OTC) medication) during the 14 days prior to the day preceding the first administration of trial medication (Day -1), except for oral contraceptive used for synchronization and occasional Ibuprofen. * Used any drug or substance that is known to induce drug-metabolizing enzymes within two months prior to the start of synchronization. * Received a contraceptive by injection, an implant or hormonal intra-uterine device within 6 months of the day preceding the first administration of trial medication (Day -1), or a hormonal implant or hormonal intra-uterine device removed within 6 months of the day preceding the first administration of trial medication (Day -1). * Participated in a drug trial and was administered an investigational drug during the 90 days prior to start of synchronization. * Donated blood during the 90 days prior to the day preceding the first administration of trial medication (Day -1). * History (within the last 2 years) of excessive alcohol use, use of solvents or of drug abuse. * Positive drug test at screening and/or admission (Day -1), or a positive alcohol test at admission (Day -1). * Clinically significant abnormal cervical smear result (papaninecolaou (PAP) III or higher) at screening. * Acute or chronic hepatitis B/C or human immune deficiency virus (HIV) 1&2 infection.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Maximum Concentration (Cmax) (Pharmacokinentic Parameter (PK)) for All Subjects in the Pharmacokinetically Evaluable (ASPE) Group | 21 days of active treatment and washout period thereafter | Cmax was measured using ethinylstradiol serum concentration at several time points during the 21 days of active treatment and the washout thereafter. |
| Area Under the Curve (AUC) 0-21 Days (PK Parameter) Measured for the ASPE Group | 21 days | AUC 0-21 days was measured using ethinylestradiol serum concentration using a radio-immune assay at several time points during the 21 days of active treatment |
| AUC 0-tlast (PK Parameter) for the ASPE Group. | 21 days of active treatment and washout period thereafter | AUC 0-tlast was measured using ethinylestradiol serum concentrations using a radio-immune assay at several time points during the 21 days of active treatment and the washout period thereafter. |
| AUC 0-infinity (PK Parameter) for the ASPE Group. | 21 days of active treatment and the washout period thereafter | AUC 0-infinity was measured using ethinylestradiol serum concentration using a radio-immune assay at several time points during the 21 days of active treatment and the washout period thereafter. AUC 0-infinity was calculated as AUC 0-tlast extrapolated to infinity using the regression line from which t 1/2 was calculated. |
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Levonorgestrel/Ethinylestradiol Oral Contraceptive Pill Levonorgestrel (LNG)/ethinylestradiol (EE) oral contraceptive tablets (Microgynon® 30), 21 in total, containing 0.150 mg LNG and 0.030 mg EE per tablet administered once daily orally for 21 consecutive days. | 8 |
| Norelgestrominum and Ethinylestradiol Contraceptive Patch A contraceptive patch (EVRA(TM)), one patch for seven (7) days for three consecutive weeks, three (3) patches in total, applied on the lower abdomen. Dose: per patch 6 mg norelgestromin and 0.750 mg EE releasing 0.150 mg norelgestromin and 0.020 mg EE per day. | 8 |
| Etonogestrel and Ethinylestradiol Contraceptive Vaginal Ring NuvaRing®, one ring for a period of 21 days, inserted vaginally. Dose: per ring 11.7 mg etonogestrel (ENG) and 2.7 mg EE releasing a daily average amount of 0.120 mg etonogestrel and 0.015 mg EE. | 8 |
| Total | 24 |
Baseline characteristics
| Characteristic | Levonorgestrel/Ethinylestradiol Oral Contraceptive Pill | Norelgestrominum and Ethinylestradiol Contraceptive Patch | Etonogestrel and Ethinylestradiol Contraceptive Vaginal Ring | Total |
|---|---|---|---|---|
| Age, Continuous | 25.6 years STANDARD_DEVIATION 5.44 | 24.8 years STANDARD_DEVIATION 6.59 | 23.1 years STANDARD_DEVIATION 3.64 | 24.5 years STANDARD_DEVIATION 5.24 |
| Region of Enrollment Netherlands | 8 participants | 8 participants | 8 participants | 24 participants |
| Sex: Female, Male Female | 8 Participants | 8 Participants | 8 Participants | 24 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 5 / 8 | 8 / 8 | 8 / 8 |
| serious Total, serious adverse events | 0 / 8 | 0 / 8 | 0 / 8 |
Outcome results
Primary
Area Under the Curve (AUC) 0-21 Days (PK Parameter) Measured for the ASPE Group
AUC 0-21 days was measured using ethinylestradiol serum concentration using a radio-immune assay at several time points during the 21 days of active treatment
Time frame: 21 days
Population: Subjects who received at least one dose of medication.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Levonorgestrel/Ethinylestradiol Oral Contraceptive Pill | Area Under the Curve (AUC) 0-21 Days (PK Parameter) Measured for the ASPE Group | 21.9 nh.h/mL | Standard Deviation 2.9 |
| Norelgestrominum and Ethinylestradiol Contraceptive Patch | Area Under the Curve (AUC) 0-21 Days (PK Parameter) Measured for the ASPE Group | 35.8 nh.h/mL | Standard Deviation 5.5 |
| Etonogestrel and Ethinylestradiol Contraceptive Vaginal Ring | Area Under the Curve (AUC) 0-21 Days (PK Parameter) Measured for the ASPE Group | 10.6 nh.h/mL | Standard Deviation 2.5 |
Primary
AUC 0-infinity (PK Parameter) for the ASPE Group.
AUC 0-infinity was measured using ethinylestradiol serum concentration using a radio-immune assay at several time points during the 21 days of active treatment and the washout period thereafter. AUC 0-infinity was calculated as AUC 0-tlast extrapolated to infinity using the regression line from which t 1/2 was calculated.
Time frame: 21 days of active treatment and the washout period thereafter
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Levonorgestrel/Ethinylestradiol Oral Contraceptive Pill | AUC 0-infinity (PK Parameter) for the ASPE Group. | 22.7 ng.h/mL | Standard Deviation 2.8 |
| Norelgestrominum and Ethinylestradiol Contraceptive Patch | AUC 0-infinity (PK Parameter) for the ASPE Group. | 37.7 ng.h/mL | Standard Deviation 5.6 |
| Etonogestrel and Ethinylestradiol Contraceptive Vaginal Ring | AUC 0-infinity (PK Parameter) for the ASPE Group. | 11.2 ng.h/mL | Standard Deviation 2.7 |
Primary
AUC 0-tlast (PK Parameter) for the ASPE Group.
AUC 0-tlast was measured using ethinylestradiol serum concentrations using a radio-immune assay at several time points during the 21 days of active treatment and the washout period thereafter.
Time frame: 21 days of active treatment and washout period thereafter
Population: Subjects who received at least one dose of medication.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Levonorgestrel/Ethinylestradiol Oral Contraceptive Pill | AUC 0-tlast (PK Parameter) for the ASPE Group. | 22.5 ng.h/mL | Standard Deviation 2.9 |
| Norelgestrominum and Ethinylestradiol Contraceptive Patch | AUC 0-tlast (PK Parameter) for the ASPE Group. | 37.5 ng.h/mL | Standard Deviation 5.7 |
| Etonogestrel and Ethinylestradiol Contraceptive Vaginal Ring | AUC 0-tlast (PK Parameter) for the ASPE Group. | 11.1 ng.h/mL | Standard Deviation 2.7 |
Primary
Maximum Concentration (Cmax) (Pharmacokinentic Parameter (PK)) for All Subjects in the Pharmacokinetically Evaluable (ASPE) Group
Cmax was measured using ethinylstradiol serum concentration at several time points during the 21 days of active treatment and the washout thereafter.
Time frame: 21 days of active treatment and washout period thereafter
Population: Subjects who received at least one dose of medication
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Levonorgestrel/Ethinylestradiol Oral Contraceptive Pill | Maximum Concentration (Cmax) (Pharmacokinentic Parameter (PK)) for All Subjects in the Pharmacokinetically Evaluable (ASPE) Group | 168 pg/ml | Standard Deviation 29.5 |
| Norelgestrominum and Ethinylestradiol Contraceptive Patch | Maximum Concentration (Cmax) (Pharmacokinentic Parameter (PK)) for All Subjects in the Pharmacokinetically Evaluable (ASPE) Group | 105 pg/ml | Standard Deviation 12.4 |
| Etonogestrel and Ethinylestradiol Contraceptive Vaginal Ring | Maximum Concentration (Cmax) (Pharmacokinentic Parameter (PK)) for All Subjects in the Pharmacokinetically Evaluable (ASPE) Group | 37.1 pg/ml | Standard Deviation 5.1 |