Efficacy and Safety of the Combined Oral Contraceptive NOMAC-E2 Compared to a COC Containing DRSP/EE

Condition(s) targeted: Contraception

Intervention: Estradiol and Nomegestrol Acetate Tablets (Drug); Drospirenone 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 assess contraceptive efficacy, vaginal bleeding patterns (cycle control), general safety and acceptability of the NOMAC-E2 COC in a large group of women aged 18-50 years.

Official title: A Randomized, Open-Label, Comparative, Multi-Center Trial to Evaluate Contraceptive Efficacy, Cycle Control, Safety and Acceptability of a Monophasic Combined Oral Contraceptive (COC) Containing 2.5 mg Nomegestrol Acetate (NOMAC) and 1.5 mg Estradiol (E2), Compared to a Monophasic COC Containing 3 mg Drospirenone (DRSP) and 30 µg Ethinyl Estradiol (EE)

Study design: Prevention, Randomized, Open Label, Active Control, Parallel Assignment, Safety/Efficacy Study

Primary outcome:

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 [electronic] diaries.

Acceptability will be evaluated on the basis of discontinuation rates and reasons for discontinuation.

Secondary outcome:

User satisfaction will be evaluated using "Patient Reported Outcome Questionnaires" (self-administered).

Acne will be assessed by regular skin examinations.

Detailed description: This is an open-label, randomized, comparative multi-center trial of the NOMAC-E2 COC versus a COC containing 3 mg DRSP and 30 µg EE in healthy female volunteers at risk for pregnancy and in need for contraception. In total 2080 subjects will be randomly allocated in a 3: 1 ratio to either the NOMAC-E2 COC or DRSP-EE COC, resulting in 1560 women using NOMAC-E2 and 520 using DRSP-EE. Subjects will be treated for 13 consecutive cycles.

This trial - in conjunction with trial 292002 (multi-center trial on safety and efficacy in

USA, Latin America and Canada) - is designed to obtain a sufficient number of evaluable

cycles of exposure to the NOMAC- E2 COC in the subset of women of 35 years or younger to fulfil the CHMP criterion on the precision of the two-sided 95% CI for the Pearl Index estimate with a power of at least 80%. In addition, 400 subjects aged 18-35 years should complete 13 cycles of treatment. Assuming that the Pearl Index is in the range of 0 to 2. 0 (for sample size purposes), an exposure of 16675 evaluable cycles to NOMAC-E2 will be required in women of 35 years and younger. With this sample size, also the FDA requirement of at least 10000 cycles (for women aged ≤ 35 years) will be fulfilled. This trial is designed to contribute half of the required exposure.

Assuming 35% discontinuations and up to 30% non-evaluable cycles (contributing an average of 3 cycles of exposure), approximately 1260 subjects will be randomized to the NOMAC- E2 COC in this trial and age subset (18-35 years) and 420 subjects to the DRSP-EE comparator group. To these numbers, a fixed number of subjects above 35 years of age has been added (NOMAC-E2: 300, DRSP-EE: 100) giving the maximum sample size of 1560 in the NOMAC- E2 group and 520 in the DRSP-EE comparator group.

The trial will be conducted in an open-label fashion, as the differences in regimen between the NOMAC-E2 COC (24 active plus 4 placebo tablets per cycle) and comparator drug (21 active plus 7 placebo tablets per cycle) will lead to obvious differences in the timing of withdrawal bleeding, which will reveal the treatment. To exclude enrollment bias, the randomization process will be done by making use of an Interactive Voice Response System (IVRS).

Bleeding pattern, adherence to the treatment will be assessed by means of an electronic diary, to be completed by the subject on a daily basis. In addition, condom use and vaginal intercourse will be recorded by the subject at the end of each cycle on the electronic diary. Satisfaction and quality of life, libido and menstrual symptoms will be assessed by Patient Reported Outcome Questionnaires. Subjects will also complete these questionnaires on the electronic diary. Acne will be assessed by skin examination. In addition, several safety assessments (vital signs, physical and gynecological examinations, cervical smear, routine laboratory parameters and adverse events) will be performed.

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;

- Women in need for contraception and willing to use an OC for 12 months (13 cycles);

- At least 18 but not older than 50 years of age at the time of screening;

- Body mass index ≥17 and ≤35;

- Good physical and mental health;

- Willing to give informed consent in writing.

Exclusion Criteria:

- Contraindications for contraceptive steroids

- In accordance with the SmPC/Package Insert of DRSP-EE, additional contraindications

related to the antimineralocorticoid activity of drospirenone (conditions that predispose to hyperkalemia):

- Renal insufficiency;

- Hepatic dysfunction;

- Adrenal insufficiency.

- An abnormal cervical smear (i. e.: dysplasia, cervical intraepithelial neoplasia [CIN],

SIL, carcinoma in situ, invasive carcinoma) at screening;

- Clinically relevant abnormal laboratory result at screening as judged by the

investigator;

- Use of an injectable hormonal method of contraception; within 6 months of an injection

with a 3-month duration, within 4 months 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, sex steroids (other than pre- and posttreatment contraceptive method) and herbal remedies containing Hypericum perforatum (St John's Wort);

- 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, Charleroi, Belgium

Organon Study Site, Gent, Belgium

Organon Study Site, Leuven, Belgium

Organon Study site, Liege, Belgium

Organon Study Site, Ekeren, Belgium

Organon Study Site, Praha 3, Czech Republic

Organon Study Site, Pisek, Czech Republic

Organon Study Site, Praha 10, Czech Republic

Organon Study Site, Praha 2, Czech Republic

Organon Study Site, Norager, Denmark

Organon Study Site, Lyngby, Denmark

Organon Study Site, Herning, Denmark

Organon Study Site, Viborg, Denmark

Organon Study Site, Fredericia, Denmark

Organon Study site, Helsinki, Finland

Organon Study Site, Turku, Finland

Organon Study Site, Oulu, Finland

Organon Study Site, Epinay-sous-Senart, France

Organon Study Site, Maisons Laffitte, France

Organon Study Site, Lievin, France

Organon Study Site, Strasbourg cedex, France

Organon Study Site, Paris, France

Organon Study Site, Strasbourg, France

Organon Study Site, Berlin, Germany

Organon Study Site, Hannover, Germany

Organon Study Site, Dortmund, Germany

Organon Study Site, Bad Reichenhall, Germany

Organon Study Site, Eger, Hungary

Organon Study site, Salgotarjan, Hungary

Organon Study Site, Komarom, Hungary

Organon Study Site, Modena, Italy

Organon Study Site, Bologna, Italy

Organon Study Site, Cagliari, Italy

Organon Study Site, Rome, Italy

Organon Study Site, Milano, Italy

Organon Study site, Kuala Lumpur, Malaysia

Organon Study Location, Penang, Malaysia

Organon Study Site, Nijmegen, Netherlands

Organon Study Site, Groningen, Netherlands

Organon Study Site, Deurne, Netherlands

Organon Study Site, Beek en Donk, Netherlands

Organon Study Site, Hamar, Norway

Organon Study Site, Fredrikstad, Norway

Organon Study Site, Bekkestua, Norway

Organon Study Site, Oslo, Norway

Organon Study Site, Elverum, Norway

Organon Study Site, Stavanger, Norway

Organon Study Site, Ski, Norway

Organon Study Site, Kolbotn, Norway

Organon Study Site, Larvik, Norway

Organon Study Site, Bialystok, Poland

Organon Study Site, Wroclaw, Poland

Organon Study Site, Warsaw, Poland

Organon study Site, Warsaw, Poland

Organon Study Site, Poznan, Poland

Organon Study Site, Lublin, Poland

Organon Study Site, Guadalajara, Spain

Organon Study Site, Alicante, Spain

Organon Study Site, Requena, Spain

Organon Study Site, Vitoria, Spain

Organon Study Site, Danderyd, Sweden

Organon Study Site, Umea, Sweden

Organon Study Site, Kungsbacka, Sweden

Organon Study Site, Goteborg, Sweden

Organon Study Site, Stockholm, Sweden

Organon Study Site, Uppsala, Sweden

Organon Study Site, Lund, Sweden

Organon Study Site, Boras, Sweden

Organon Study Site, Linkoping, Sweden

Organon Study Site, Jonkoping, Sweden

Organon Study Site, Bern, Switzerland

Organon Study Site, Zurich, Switzerland

Organon Study Site, Bangkok, Thailand

Organon Study Site, Newcastle upon Tyne, United Kingdom

Organon Study Site, Edinburgh, United Kingdom

Organon Study Site, Sheffield, United Kingdom

Organon Study Site, London, United Kingdom

Organon Study Site, Salt, Girona, Spain

Organon Study Site, Randwick, New South Wales, Australia

Organon Study Site, Ashfield, New South Wales, Australia

Organon Study Site, Milton, Queensland, Australia

Organon Study Site, Dulwich, South Australia, Australia

Organon Study Site, Perth, Western Australia, Australia

Starting date: May 2006
Ending date: April 2008
Last updated: May 30, 2008