Effects on Hemostasis, Lipids, Carbohydrate Metabolism, Adrenal & Thyroid Function of the Combined Oral Contraceptive NOMAC-E2 Compared to a COC Containing LNG-EE (292004)(COMPLETED)(P05764)

Study Overview
=================
Brief Summary
-----------------
The primary purpose of this study is to evaluate the effects of the combined oral contraceptive (COC) NOMAC-E2 on hemostasis, lipids, carbohydrate metabolism, adrenal function, and thyroid function.

Official Title
-----------------
A Randomized, Open-Label, Comparative, Multi -Center Trial to Evaluate the Effects on Hemostasis, Lipids and Carbohydrate Metabolism, and on Adrenal and Thyroid Function of a Monophasic COC Containing 2.5 mg NOMAC and 1.5 mg E2 Compared to a Monophasic COC Containing 150 ug LNG and 30 ug EE

Conditions
-----------------
Contraception

Intervention / Treatment
-----------------
* Drug: NOMAC-E2
* Drug: Levonorgestrel and Ethinyl Estradiol


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Sexually active women, at risk for pregnancy and not planning to use during trial medication use; Women in need for contraception and willing to use an oral contraceptive (OC) for 6 months (6 cycles); At least 18 but not older than 50 years of age at the time of screening; Body mass index = 17 and = 29 kg/m^2; Good physical and mental health; Willing to give informed consent in writing Exclusion Criteria: Present use or use within 2 months prior to screening of any other hormonal treatment including sex hormones (other than contraceptives), insulin, thyroid and corticosteroid hormones (with the exception for local dermatological use); Contraindications for contraceptive steroids Presence or history (within 1 year before screening) of alcohol or drug abuse as judged by the (sub)investigator. An abnormal cervical smear (i.e.: dysplasia, cervical intraepithelial neoplasia [CIN], SIL, carcinoma in situ, invasive carcinoma) at screening or documentation of an abnormal smear performed within 6 months before screening; Clinically relevant abnormal laboratory result at screening as judged by the (sub) investigator; Use of an injectable hormonal method of contraception prior to screening; within 6 months of an injection with a 3 -month duration, within 4 months to screening of an injection with a 2-month duration, within 2 months of an injection with a 1-month duration; Before spontaneous menstruation has occurred following a delivery or abortion; Breastfeeding or within 2 months after stopping breastfeeding prior to the start of trial medication; Present use or use within 2 months prior to the start of the trial medication of the following drugs: phenytoin, barbiturates, primidone, carbamazepine, oxcarbazepine, topiramate, felbamate, rifampicin, nelfinavir, ritonavir, griseofulvin, ketoconazole, lipid-lowering drugs, anticoagulants and herbal remedies containing Hypericum perforatum (St John's Wort); Use of pharmacological agents which affect the hemostatic system during the pretreatment blood sampling: vitamin K (only prohibited within two weeks prior to sampling), nonsteroidal anti-inflammatory drugs (NSAIDS) and aspirin (both only prohibited during the week prior to sampling); Administration of investigational drugs and/or participation in another clinical trial within 2 months prior to the start of the trial medication or during the trial period.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 50 Years

Sexes Eligible for Study
-----------------
Female

Accepts Healthy Volunteers
-----------------
Accepts Healthy Volunteers

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: NOMAC-E2<br>Nomegestrol Acetate (NOMAC) and Estradiol (E2), 2.5 mg NOMAC and 1.5 mg E2 monophasic combined oral contraceptive | Drug: NOMAC-E2<br>* Nomegestrol Acetate and Estradiol (NOMAC-E2) Tablets, 2.5 mg NOMAC and 1.5 mg E2 taken once daily from Day 1 of menstrual period up to and including Day 28 for 6 consecutive 28-day cycles.<br>* Other names: Org 2317 (E2);|
| Active Comparator: LNG-EE<br>Levonorgestrel and Ethinyl Estradiol Tablets (LNG-EE), 150 mcg LNG and 30 mcg EE | Drug: Levonorgestrel and Ethinyl Estradiol<br>* Levonorgestrel and Ethinyl Estradiol (LNG-EE) Tablets, 150 mcg LNG and 30 mcg EE taken once daily from Day 1 of menstrual period up to and including Day 28 for 6 consecutive 28-day cycles.<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Serum Concentration of Prothrombin Fragments 1 + 2 | Serum samples were obtained under fasting conditions (no food or alcoholic beverages within 12 hours of serum sampling). Each cycle consists of 28 days. | Baseline and Cycle 6 (between Days 15 and 21 of the cycle) | 
| Serum Concentration of D-Dimer | Serum samples were obtained under fasting conditions (no food or alcoholic beverages within 12 hours of serum sampling). Each cycle consists of 28 days. | Baseline and Cycle 6 (between Days 15 and 21 of the cycle) | 
| Activated Protein C (APC) Resistance Ratio (Endogenous Thrombin Potential [ETP]-Based) | Serum samples were obtained under fasting conditions (no food or alcoholic beverages within 12 hours of serum sampling). APC resistance ratio (ETP-based) measures the anticoagulation response of plasma to APC after activation of the extrinsic coagulation pathway. An increase in the ratio indicates a reduced responsiveness to APC. Each cycle consists of 28 days. | Baseline and Cycle 6 (between Days 15 and 21 of the cycle) | 
| Serum Concentration of Clotting Factor VIIa | Serum samples were obtained under fasting conditions (no food or alcoholic beverages within 12 hours of serum sampling). Each cycle consists of 28 days. | Baseline and Cycle 6 (between Days 15 and 21 of the cycle) | 
| Serum Concentration of Clotting Factor VIIc | Serum samples were obtained under fasting conditions (no food or alcoholic beverages within 12 hours of serum sampling). Each cycle consists of 28 days. | Baseline and Cycle 6 (between Days 15 and 21 of the cycle) | 
| Serum Concentration of Clotting Factor VIII | Serum samples were obtained under fasting conditions (no food or alcoholic beverages within 12 hours of serum sampling). Each cycle consists of 28 days. | Baseline and Cycle 6 (between Days 15 and 21 of the cycle) | 
| Serum Concentration of Clotting Factor II | Serum samples were obtained under fasting conditions (no food or alcoholic beverages within 12 hours of serum sampling). Each cycle consists of 28 days. | Baseline and Cycle 6 (between Days 15 and 21 of the cycle) | 
| Serum Concentration of Antithrombin III | Serum samples were obtained under fasting conditions (no food or alcoholic beverages within 12 hours of serum sampling). Each cycle consists of 28 days. | Baseline and Cycle 6 (between Days 15 and 21 of the cycle) | 
| Serum Concentration of Protein S (Free) | Serum samples were obtained under fasting conditions (no food or alcoholic beverages within 12 hours of serum sampling). Each cycle consists of 28 days. | Baseline and Cycle 6 (between Days 15 and 21 of the cycle) | 
| Serum Concentration of Protein S (Total) | Serum samples were obtained under fasting conditions (no food or alcoholic beverages within 12 hours of serum sampling). Each cycle consists of 28 days. | Baseline and Cycle 6 (between Days 15 and 21 of the cycle) | 
| Serum Concentration of Protein C | Serum samples were obtained under fasting conditions (no food or alcoholic beverages within 12 hours of serum sampling). Each cycle consists of 28 days. | Baseline and Cycle 6 (between Days 15 and 21 of the cycle) | 
| APC Resistance Ratio (Activated Partial Thromboplastin Time [APTT]-Based) | Serum samples were obtained under fasting conditions (no food or alcoholic beverages within 12 hours of serum sampling). APC resistance ratio (APTT-based) measures the anticoagulation response of plasma to APC after activation of the intrinsic coagulation pathway. An increase in the ratio indicates a increased responsiveness to APC. Each cycle consists of 28 days. | Baseline and Cycle 6 (between Days 15 and 21 of the cycle) | 
| Serum Concentration of Sex Hormone Binding Globulin (SHBG) | Serum samples were obtained under fasting conditions (no food or alcoholic beverages within 12 hours of serum sampling). Each cycle consists of 28 days. | Baseline and Cycle 6 (between Days 15 and 21 of the cycle) | 
| Serum Concentration of C-Reactive Protein (CRP) | Serum samples were obtained under fasting conditions (no food or alcoholic beverages within 12 hours of serum sampling). Each cycle consists of 28 days. | Baseline and Cycle 6 (between Days 15 and 21 of the cycle) | 
| Serum Concentration of Total Cholesterol | Serum samples were obtained under fasting conditions (no food or alcoholic beverages within 12 hours of serum sampling). Each cycle consists of 28 days. | Baseline and Cycle 6 (between Days 15 and 21 of the cycle) | 
| Serum Concentration of High Density Lipoprotein (HDL)-Cholesterol | Serum samples were obtained under fasting conditions (no food or alcoholic beverages within 12 hours of serum sampling). Each cycle consists of 28 days. | Baseline and Cycle 6 (between Days 15 and 21 of the cycle) | 
| Serum Concentration of HDL2-cholesterol | Serum samples were obtained under fasting conditions (no food or alcoholic beverages within 12 hours of serum sampling). Each cycle consists of 28 days. | Baseline and Cycle 6 (between Days 15 and 21 of the cycle) | 
| Serum Concentration of HDL3-cholesterol | Serum samples were obtained under fasting conditions (no food or alcoholic beverages within 12 hours of serum sampling). Each cycle consists of 28 days. | Baseline and Cycle 6 (between Days 15 and 21 of the cycle) | 
| Serum Concentration of Low Density Lipoprotein (LDL)-Cholesterol | Serum samples were obtained under fasting conditions (no food or alcoholic beverages within 12 hours of serum sampling). Each cycle consists of 28 days. | Baseline and Cycle 6 (between Days 15 and 21 of the cycle) | 
| Serum Concentration of Apolipoprotein A-1 | Serum samples were obtained under fasting conditions (no food or alcoholic beverages within 12 hours of serum sampling). Each cycle consists of 28 days. | Baseline and Cycle 6 (between Days 15 and 21 of the cycle) | 
| Serum Concentration of Apolipoprotein B | Serum samples were obtained under fasting conditions (no food or alcoholic beverages within 12 hours of serum sampling). Each cycle consists of 28 days. | Baseline and Cycle 6 (between Days 15 and 21 of the cycle) | 
| Serum Concentration of Lipoprotein(a) | Serum samples were obtained under fasting conditions (no food or alcoholic beverages within 12 hours of serum sampling). Each cycle consists of 28 days. | Baseline and Cycle 6 (between Days 15 and 21 of the cycle) | 
| Serum Concentration of Total Triglycerides | Serum samples were obtained under fasting conditions (no food or alcoholic beverages within 12 hours of serum sampling). Each cycle consists of 28 days. | Baseline and Cycle 6 (between Days 15 and 21 of the cycle) | 
| Area Under the Curve Over 3 Hours (AUC3) for Glucose (Oral Glucose Tolerance Test [OGTT]) | Blood glucose levels were determined as fasting values just before oral glucose intake and each half hour thereafter for 2 hours and again after 3 hours. Oral glucose tolerance was analysed using the (unadjusted) area under the curve over the 3 hours (AUC3). Each cycle consists of 28 days. | Baseline and Cycle 6 (between Days 15 and 21 of the cycle) | 
| Incremental AUC3 for Glucose (OGTT) | Blood glucose levels were determined as fasting values just before oral glucose intake and each half hour thereafter for 2 hours and again after 3 hours. Oral glucose tolerance was analysed using the (unadjusted) area under the curve over the 3 hours (AUC3). Incremental area under the curve was defined as incremental AUC3 = AUC3 - 3*fasting concentration. Each cycle consists of 28 days. | Baseline and Cycle 6 (between Days 15 and 21 of the cycle) | 
| AUC3 for Insulin (OGTT) | Blood insulin levels were determined as fasting values just before oral glucose intake and each half hour thereafter for 2 hours and again after 3 hours. Oral glucose tolerance was analysed using the (unadjusted) area under the curve over the 3 hours (AUC3). Each cycle consists of 28 days. | Baseline and Cycle 6 (between Days 15 and 21 of the cycle) | 
| Incremental AUC3 for Insulin (OGTT) | Blood insulin levels were determined as fasting values just before oral glucose intake and each half hour thereafter for 2 hours and again after 3 hours. Oral glucose tolerance was analysed using the (unadjusted) area under the curve over the 3 hours (AUC3). Incremental area under the curve was defined as incremental AUC3 = AUC3 - 3*fasting concentration. Each cycle consists of 28 days. | Baseline and Cycle 6 (between Days 15 and 21 of the cycle) | 
| Serum Concentration of Hemoglobin Type A1c (HbA1c) | Serum samples were obtained under fasting conditions (no food or alcoholic beverages within 12 hours of serum sampling). HbA1c was determined before glucose loading. Each cycle consists of 28 days. | Baseline and Cycle 6 (between Days 15 and 21 of the cycle) | 
| Serum Concentration of Total Cortisol | Serum samples were obtained under fasting conditions (no food or alcoholic beverages within 12 hours of serum sampling). Each cycle consists of 28 days. | Baseline and Cycle 6 (between Days 15 and 21 of the cycle) | 
| Serum Concentration of Corticosteroid Binding Globulin (CBG) | Serum samples were obtained under fasting conditions (no food or alcoholic beverages within 12 hours of serum sampling). Each cycle consists of 28 days. | Baseline to Cycle 6 (between Days 15 and 21 of the cycle) | 
| Serum Concentration of Thyroid Stimulating Hormone (TSH) | Serum samples were obtained under fasting conditions (no food or alcoholic beverages within 12 hours of serum sampling). Each cycle consists of 28 days. | Baseline and Cycle 6 (between Days 15 and 21 of the cycle) | 
| Serum Concentration of Free Thyroxine (T4) | Serum samples were obtained under fasting conditions (no food or alcoholic beverages within 12 hours of serum sampling). Each cycle consists of 28 days. | Baseline and Cycle 6 (between Days 15 and 21 of the cycle) | 
| Serum Concentration of Thyroxin Binding Globulin (TBG) | Serum samples were obtained under fasting conditions (no food or alcoholic beverages within 12 hours of serum sampling). Each cycle consists of 28 days. | Baseline and Cycle 6 (between Days 15 and 21 of the cycle) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Serum Concentration of Total Testosterone | Serum samples were obtained under fasting conditions (no food or alcoholic beverages within 12 hours of serum sampling). Each cycle consists of 28 days. | Baseline and Cycle 6 (between Days 15 and 21 of the cycle) | 
| Serum Concentration of Free Testosterone | Serum samples were obtained under fasting conditions (no food or alcoholic beverages within 12 hours of serum sampling). Each cycle consists of 28 days. | Baseline and Cycle 6 (between Days 15 and 21 of the cycle) | 
| Serum Concentration of Dehydroepiandrosterone Sulphate (DHEAS) | Serum samples were obtained under fasting conditions (no food or alcoholic beverages within 12 hours of serum sampling). Each cycle consists of 28 days. | Baseline and Cycle 6 (between Days 15 and 21 of the cycle) | 
| Serum Concentration of Androstenedione | Serum samples were obtained under fasting conditions (no food or alcoholic beverages within 12 hours of serum sampling). Each cycle consists of 28 days. | Baseline and Cycle 6 (between Days 15 and 21 of the cycle) | 
| Serum Concentration of Dihydrotestosterone (DHT) | Serum samples were obtained under fasting conditions (no food or alcoholic beverages within 12 hours of serum sampling). Each cycle consists of 28 days. | Baseline and Cycle 6 (between Days 15 and 21 of the cycle) | 
| Number of In-treatment Pregnancies (With +2 Day Window) Per 100 Woman Years of Exposure (Pearl Index) | In-treatment pregnancies were pregnancies with an estimated date of conception from the day of first intake of trial medication up to and including the day of last (active or placebo) intake of trial medication extended with a maximum of 2 days. Each 13 cycles (28 days per cycle) constitutes a woman year. The Pearl Index was obtained by dividing the number of in-treatment pregnancies that occurred by the time (in 100 women years) that the women were under risk of becoming pregnant. | 6 cycles | 
| Number of Participants With an Occurrence of Breakthrough Bleeding/Spotting | Cycle control was evaluated on the basis of vaginal bleeding pattern as recorded daily by participants using diary booklets. Participants documented whether vaginal bleeding was present, and if present, indicated whether it was considered to be spotting or bleeding. Breakthrough bleeding/spotting was defined as any episode that occurred during the expected non-bleeding period that was neither an early nor a continued withdrawal bleeding. Expected non-bleeding period: NOMAC-E2: 21-day period starting on Day 4 of the cycle; LNG-EE: 21-day period starting on Day 1 of the cycle. | Every 28-day cycle for 6 cycles | 
| Number of Participants With an Occurrence of Absence of Withdrawal Bleeding | Cycle control was evaluated on the basis of vaginal bleeding pattern as recorded daily by participants using diary booklets. Participants documented whether vaginal bleeding was present, and if present, indicated whether it was considered to be spotting or bleeding. Absence of withdrawal bleeding was defined as no bleeding/spotting episode that began during or continued into the expected bleeding period. Expected bleeding period: NOMAC-E2: 7-day period starting on Day 25 of the cycle and ending on Day 3 of the next cycle; LNG-EE: 7-day period starting on Day 22 of the cycle. | Every 28-day cycle for 6 cycles | 
| Number of Participants With an Occurrence of Breakthrough Bleeding | Cycle control was evaluated on the basis of vaginal bleeding pattern as recorded daily by participants using diary booklets. Participants documented whether vaginal bleeding was present, and if present, indicated whether it was considered to be spotting or bleeding. Breakthrough bleeding was defined as any bleeding episode that occurred during the expected non-bleeding period that was neither part of an early nor continued withdrawal bleeding. Expected non-bleeding period: NOMAC-E2: 21-day period starting on Day 4 of the cycle; LNG-EE: 21-day period starting on Day 1 of the cycle. | Every 28-day cycle for 6 cycles | 
| Number of Participants With an Occurrence of Breakthrough Spotting (Spotting Only) | Cycle control was evaluated on the basis of vaginal bleeding pattern as recorded daily by participants using diary booklets. Participants documented whether vaginal bleeding was present, and if present, indicated whether it was considered to be spotting or bleeding. Breakthrough spotting was defined as any spotting episode that occurred during the expected non-bleeding period that was neither part of an early nor continued withdrawal bleeding. Expected non-bleeding period: NOMAC-E2: 21-day period starting on Day 4 of the cycle; LNG-EE: 21-day period starting on Day 1 of the cycle. | Every 28-day cycle for 6 cycles | 
| Number of Participants With an Occurrence of Early Withdrawal Bleeding | Cycle control was evaluated on the basis of vaginal bleeding pattern as recorded daily by participants using diary booklets. Participants documented whether vaginal bleeding was present, and if present, indicated whether it was considered to be spotting or bleeding. Early withdrawal bleeding was defined as any withdrawal bleeding that started before the current expected bleeding period. Expected bleeding period: NOMAC-E2: 7-day period starting on Day 25 of the cycle and ending on Day 3 of the next cycle; LNG-EE: 7-day period starting on Day 22 of the cycle. | Every 28-day cycle for 6 cycles | 
| Number of Participants With an Occurrence of Continued Withdrawal Bleeding | Cycle control was evaluated on the basis of vaginal bleeding pattern as recorded daily by participants using diary booklets. Participants documented whether vaginal bleeding was present, and if present, indicated whether it was considered to be spotting or bleeding. Continued withdrawal bleeding was defined as any withdrawal bleeding that continued into the expected non-bleeding period of the next cycle. Expected non-bleeding period: NOMAC-E2: 21-day period starting on Day 4 of the cycle; LNG-EE: 21-day period starting on Day 1 of the cycle. | Every 28-day cycle for 5 cycles | 
| Average Number of Breakthrough Bleeding/Spotting Days | Cycle control was evaluated on the basis of vaginal bleeding pattern as recorded daily by participants using diary booklets. Participants documented whether vaginal bleeding was present, and if present, indicated whether it was considered to be spotting or bleeding. Breakthrough bleeding/spotting was defined as any episode that occurred during the expected non-bleeding period that was neither an early nor a continued withdrawal bleeding. Expected non-bleeding period: NOMAC-E2: 21-day period starting on Day 4 of the cycle; LNG-EE: 21-day period starting on Day 1 of the cycle. | Every 28-day cycle for 6 cycles | 
| Average Number of Withdrawal Bleeding/Spotting Days | Cycle control was evaluated on the basis of vaginal bleeding pattern as recorded daily by participants using diary booklets. Participants documented whether vaginal bleeding was present, and if present, indicated whether it was considered to be spotting or bleeding. Withdrawal bleeding/spotting was defined as any episode that occurred during the expected bleeding period. Expected bleeding period: NOMAC-E2: 7-day period starting on Day 25 of the cycle and ending on Day 3 of the next cycle; LNG-EE: 7-day period starting on Day 22 of the cycle. | Every 28-day cycle for 6 cycles |