Effects on Bone Mineral Density (BMD) 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: Active, not recruiting

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 NOMAC-E2 combined oral contraceptive on bone mineral density (BMD).

Official title: An Open-Label, Randomized, Single Center Trial in Healthy Young Women, to Evaluate the Effects of a Monophasic Combined Oral Contraceptive (COC) Containing 2.5 mg NOMAC and 1.5 mg E2 on Bone Mineral Density (BMD) Compared to a Monophasic COC Containing 0.150 mg Levonorgestrel and 0.030 mg Ethinyl Estradiol

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

Primary outcome: Bone Mineral Density (BMD) of the lumbar spine (L2-L4) and femoral neck. BMD will be measured by DEXA scans. In addition to the BMD value (g/cm2), the "z-score" will also be determined.

Secondary 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 diary records.

Detailed description: Studies on BMD, especially on combined oral contraceptives, have received increasing attention in the medical literature. Most studies report on ethinyl estradiol containing preparations. For the present nomegestrol acetate / estradiol compound, it was decided to perform a BMD trial, since it is a novel combination for oral contraception of a progestin and E2 instead of a progestin and EE.

Exposure to estrogens has been associated with improvements in BMD in some of the recently published literature. However, the association between hormonal contraception and improvements in BMD is controversial. Other reports of the lack of effect of hormonal contraceptives on BMD continue to appear. The literature also contains a few reports of associations between hormonal contraceptives and the loss of BMD.

The present study is an open-label, randomized comparative trial, whereas randomization was often not employed in many of the studies found in the medical literature. In trials with non-randomized control groups there is a high risk of bias in the study results. This may be due to enrollment bias and different baseline populations. To avoid these biases, it was decided to choose a randomized design and an active comparator.

The primary parameters are the change from baseline in z-scores of the BMD measurements of the lumbar spine (L2-L4) and the proximal femur (femoral neck) measured after two years. These two anatomical sites were selected since they are of the most predictive value for future risk of fracture. The z-score measures the distance of the measured BMD value from the appropriate normal age matched population mean value in units of standard deviation of this population. The estimates for the variability of these parameters are based on three recent studies in healthy young women with a treatment duration between two and three years. Based on these studies, results regarding standard deviation (SD) in z-scores in the range of 0. 30 to 0. 50 are anticipated in the present study.

Subjects will be asked to return to the clinic every three cycles to have their blood pressure and weight checked. They will be asked whether they had any complaints, which will be recorded on the AE Form, if appropriate. Vaginal Bleeding Cards will be checked and the women will receive new medication for the following three or four cycles.

Minimum age: 20 Years. Maximum age: 35 Years. Gender(s): Female.

Criteria:

Inclusion criteria:

- Sexually active women, at risk for pregnancy and not planning to use condoms during

treatment;

- At least 20 but not older than 35 years of age at the time of screening;

- BMI ≥17 and ≤35;

- Good physical and mental health;

- Willing to give informed consent in writing;

- Willing to take part in the trial for two years.

Exclusion criteria:

- Family history of osteoporotic fracture below the age of 70;

- Postgastrectomy;

- History of eating disorder, viz. anorexia nervosa, bulimia;

- Endocrine disorder (including controlled diabetes, [para]thyroid disease, Cushing's

disease);

- Rheumatoid arthritis;

- Significant scoliosis;

- Fasting parathyroid hormone (PTH) outside the reference range at screening;

- Fasting calcitonin outside the reference range at screening;

- Prolactin above the reference range (hyperprolactinemia) at screening;

- Fasting cholesterol and/or triglycerides above the reference range for age at

screening (treatment with lipid lowering drugs not allowed);

- Engaging in vigorous exercise such as marathon, competitive swimming, triathlon;

- Smoking more than ten cigarettes/day;

- Use of more than two units of alcohol a day;

- Use of one or more of the following drugs:

- gonadotropin releasing hormone (GnRH) analogues (also past use for more than six

months at any time, or for any period of time less than six months ago is a contraindication);

- systemic or inhaled administration of corticosteroids (also past use for more

than one year, less than five years ago or any period of time in the past year is a contraindication);

- thiazide diuretics;

- thyroid hormone;

- bisphosphonates;

- calcium supplementation in combination with vitamin D supplementation/

calcitonin;

- ever treatment after childhood with fluorides;

- Contraindications for contraceptive steroids

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

squamous intraepithelial lesion [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;

- Within 12 months after a pregnancy prior to the start of trial medication;

- Breastfeeding or within 12 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 post-treatment 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, Trondheim, Norway

Starting date: September 2006
Ending date: August 2009
Last updated: May 30, 2008