Effects on Bone Mineral Density (BMD) of the Combined Oral Contraceptive NOMAC-E2 Compared to a COC Containing LNG/EE (292005)(P05765)(COMPLETED)

Study Overview
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Brief Summary
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The primary purpose of this study is to evaluate the effects of the NOMAC-E2 combined oral contraceptive (COC) on bone mineral density (BMD).

Official Title
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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

Conditions
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Contraception

Intervention / Treatment
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* Drug: NOMAC-E2
* Drug: LNG-EE


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 20 Years
Maximum Age: 35 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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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 COC | Drug: NOMAC-E2<br>* Nomegestrol Acetate and Estradiol 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 26 consecutive 28-day menstrual cycles (2 years).<br>* Other names: SCH 900121;|
| Active Comparator: LNG-EE<br>Levonorgestrel (LNG) and Ethinyl Estradiol (EE), 0.150 mg LNG and 0.030 mg EE monophasic COC | Drug: LNG-EE<br>* Levonorgestrel and Ethinyl Estradiol Tablets, 0.150 mg Levonorgestrel and 0.030 mg Ethinyl Estradiol taken once daily from Day 1 of menstrual period up to and including Day 28 for 26 consecutive 28-day menstrual cycles (2 years).<br>* Other names: SCH 900121;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mean Change From Baseline in Z-scores of the Lumbar Spine (L2-L4) and Femoral Neck | BMD was measured by a Dual Energy X-ray Absorptiometry (DEXA) machine. 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. More negative scores indicate less BMD compared to age matched population, & more positive scores indicate higher BMD compared to age matched population. The adjusted mean change from baseline to the after Cycle 26 visit of the Z-scores is estimated using a baseline-adjusted analysis of covariance (ANCOVA). | Baseline and after cycle 26 (2 years) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of In-treatment Pregnancies (With +2 Day Window) Per 100 Woman Years of Exposure (Pearl Index) | Contraceptive efficacy parameter of this trial was the 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 two days. Each 13 cycles (28 days per cycle) of exposure 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. | 2 years (26 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 cards. 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: LNG-EE group: 21-day period starting on Day 1 of the cycle; NOMAC-E2: 21-day period starting on Day 4 of the cycle. | Every 28-day cycle for 26 cycles (2 years total) | 
| 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 cards. 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: LNG-EE group: 7-day period starting on Day 22 of the cycle; NOMAC-E2 group: 7-day period starting on Day 25 of the cycle and ending on Day 3 of the next cycle. | Every 28-day cycle for 26 cycles (2 years total) | 
| 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 cards. 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: LNG-EE group: 21-day period starting on Day 1 of the cycle; NOMAC-E2: 21-day period starting on Day 4 of the cycle. | Every 28-day cycle for 26 cycles (2 years total) | 
| 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 cards. 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: LNG-EE group: 21-day period starting on Day 1 of the cycle; NOMAC-E2: 21-day period starting on Day 4 of the cycle. | Every 28-day cycle for 26 cycles (2 years total) | 
| 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 cards. 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: LNG-EE group: 7-day period starting on Day 22 of the cycle; NOMAC-E2 group: 7-day period starting on Day 25 of the cycle and ending on Day 3 of the next cycle. | Every 28-day cycle for 26 cycles (2 years total) | 
| 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 cards. 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: LNG-EE group: 21-day period starting on Day 1 of the cycle; NOMAC-E2: 21-day period starting on Day 4 of the cycle. | Every 28-day cycle for 26 cycles (2 years total) including one week after stopping treatment | 
| 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 cards. Participants documented whether vaginal bleeding was present, and if so, indicated whether it was considered to be spotting or bleeding. Breakthrough bleeding/spotting was defined as any bleeding/spotting episode that occurred during the expected non-bleeding period that was neither an early nor a continued withdrawal bleeding. Expected non-bleeding period: LNG-EE: 21-day period starting on Day 1 of the cycle; NOMAC-E2: 21-day period starting on Day 4 of the cycle. | Every 28-day cycle for 26 cycles (2 years total) | 
| 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 cards. Participants documented whether vaginal bleeding was present, and if present, indicated whether it was considered to be spotting or bleeding. Withdrawal bleeding was defined as bleeding/spotting episode that started during or continued into the expected bleeding period. Expected bleeding period: LNG-EE group: 7-day period starting on Day 22 of the cycle; NOMAC-E2 group: 7-day period starting on Day 25 of the cycle and ending on Day 3 of the next cycle. | Every 28-day cycle for 26 cycles (2 years total) |