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

Condition(s) targeted: Contraception

Intervention: Estradiol and Nomegestrol Acetate Tablets (Drug); Levonorgestrel and Ethinyl Estradiol Tablets (Drug)

Phase: Phase 3

Status: Completed

Sponsored by: Organon

Official(s) and/or principal investigator(s):
Carole Verhoeven, PhD, Study Director, Affiliation: NV Organon, a part of Schering-Plough Corporation

The primary purpose of this study is to evaluate the effects of the combined oral contraceptive 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, 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

Study design: Prevention, Randomized, Open Label, Active Control, Parallel Assignment, Pharmacodynamics Study

Primary outcome:

Effects on hemostasis as determined by prothrombin fragment 1+2, D-dimer, APC resistance ratio (ETP-based), factors VIIa / VIIc / VIII / II, antithrombin, protein S (free and total), protein C, APC resistance ratio (APTT-based), SHBG and CRP.

Effects on lipid metabolism as determined by total cholesterol, HDL-, HDL2, HDL3 and LDL cholesterol, apolipoproteins A-1 and B, lipoprotein (a) and total triglycerides.

Effects on carbohydrate metabolism as determined by oral glucose tolerance test (including fasting glucose and insulin) and HbA1C.

Effects on adrenal function as determined by total cortisol and corticosteroid binding globulin (CBG).

Effects on thyroid function as determined by thyroid stimulating hormone (TSH), free T4, thyroxin binding globulin (TBG).

Secondary outcome:

Effects on androgen levels as determined by total and free testosterone, dehydroepiandrosterone sulphate (DHEAS), androstenedione, dihydrotestosterone (DHT).

Contraceptive efficacy as determined by serum HCG pregnancy test (or home pregnancy test).

Drug safety as determined by [S]AE monitoring, cervical cytology, physical & gynecological exams, vital signs, and routine laboratory parameters.

Cycle control as determined by patient diary records.

Detailed description: This is an open-label, randomized, comparative multi-center trial of the NOMAC-E2 COC (24/4) versus a COC containing 150 µg LNG and 30 µg EE (21/7) in healthy female volunteers. Overall, 120 women will be randomly assigned in a 1: 1 ratio to either NOMAC-E2 or LNG-EE, leading to 60 women using NOMAC-E2 and 60 women using LNG-EE. The duration of treatment is up to 6 cycles of 28 days.

Studies evaluating the effect of new hormonal contraceptives on hemostasis, plasma lipids and carbohydrate metabolism, and on endocrine systems like adrenal and thyroid function are required for registration. LNG-EE 150/30 µg is chosen as the active comparator in the present study, as its effects have been well established in many studies.

The treatment duration of 6 months is considered to be sufficiently long to establish the effects on all parameters, and this duration is also in accordance with the WHO recommendations.

The trial will be conducted in an open-label fashion, as the differences in regimen between NOMAC-E2 (24 active plus 4 placebo tablets per cycle) and the comparator drug LNG-EE (21 active plus 7 placebo tablets per cycle) will lead to obvious differences in the timing of withdrawal bleeding, which will reveal the treatment. Moreover, the primary endpoints, which are all laboratory assessments, are not considered to be subject to bias. To exclude enrollment bias, the randomization process will be done by making use of an interactive voice response system (IVRS). As NOMAC-E2 will be intended for women aged 18 to 50 years, approximately 20 to 25% of the subject should be between 36 and 50 years of age at screening.

Subjects that meet the selection criteria and have given their Informed Consent will undergo the screening evaluations . The subjects will be asked to discontinue the present hormonal contraceptive method (if applicable). In addition, subjects will be instructed to use condoms consistently during the pretreatment period (if necessary) to avoid becoming pregnant. Subjects have to contact the clinic after the first spontaneous menstruation in order to schedule the pretreatment cycle visit. For a hormonal contraceptive user, the first bleeding to occur is considered to be a withdrawal bleeding; the first spontaneous menstruation is hence the second bleeding after the screening visit. The period without hormonal contraceptive use between screening and pre-treatment cycle assessments will avoid carry-over effects on the parameters assessed in this trial. The subjects will be randomized on the day of blood sampling for the special safety assessments in the pre-treatment cycle (Cycle 0). The pre-treatment assessments will serve as baseline values. Intake of trial medication should start on the first day of the subsequent menstrual period. Subsequently, assessments will be performed at Cycle 3 and Cycle 6 to evaluate the effects on the special safety parameters for a sufficiently long period. These assessments need to be done in the third week of the menstrual cycle, in order to have at least 2 consecutive weeks of active tablet intake before the assessments. For the oral glucose tolerance test (OGTT) that is performed to assess carbohydrate metabolism, blood samples will be drawn every 30 to 60 minutes up to 3 hours after drinking an oral glucose solution. This test is more extensive than a regular OGTT to be able to detect any change in glucose metabolism. For the pre-treatment, Cycle 3 and 6 visits, the subjects have to come to the clinic in a fasted condition, as this is required for almost all special safety assessments.

To gain information on the androgenic activity, a panel of androgens will be determined at the pre-treatment cycle, Cycle 3 and Cycle 6.

Bleeding pattern and tablet-intake will be assessed by means of a subject diary, to be completed on a daily basis. In addition, condom use and sexual intercourse during each cycle will be recorded at the end of each cycle, to assess whether the subject has been at risk for pregnancy. In addition, several safety assessments (vital signs, physical, gynecological and breast examinations, cervical cytology, routine laboratory parameters and adverse events) will be performed to safeguard the subject's safety. These assessments (except cervical cytology) will also be performed after the subject has ended trial medication intake (after Cycle 6 visit).

Minimum age: 18 Years. Maximum age: 50 Years. Gender(s): Female.

Criteria:

Inclusion Criteria:

- Sexually active women, at risk for pregnancy and not planning to use condoms 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/m2;

- 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.

Organon Study Site, Oulu, Finland

Organon Study Site, Kuopio, Finland

Organon Study Site, Espoo, Finland

Organon Study Site, Tampere, Finland

Organon Study Site, Turku, Finland

Starting date: September 2006
Ending date: January 2008
Last updated: May 30, 2008