Contraception
Conditions
Keywords
Combined Oral Contraceptives
Brief summary
The purpose of this study was to assess the contraceptive efficacy of a nomegestrol acetate + 17ß-estradiol (NOMAC-E2) combined oral contraceptive (COC) in healthy, sexually-active American women at risk for pregnancy. Vaginal bleeding patterns of women taking NOMAC-E2 were assessed and compared to those of women taking a norethisterone acetate + ethinyl estradiol (NETA-EE) COC. The safety of NOMAC-E2 was also assessed. Participants were randomized to receive either NOMAC-E2 or NETA-EE in a 3:1 ratio. As of Amendment 1 (which increased the sample size of the NOMAC-E2 group), the randomization ratio was adapted accordingly for participants randomized after the sample size increase.
Detailed description
This study was terminated early. The decision to terminate the study was based upon difficulties encountered with data collection (related to incomplete e-Diary entries) in concert with business considerations. The decision was not related to any new or unexpected safety or efficacy findings with NOMAC-E2. As a result of this early termination, none of the pre-specified efficacy endpoints were analyzed.
Interventions
DRUGNOMAC-E2
NOMAC-E2 film-coated oral tablets containing 2.5 mg nomegestrol acetate and 1.5 mg 17ß-estradiol.
DRUGNETA-EE
NETA-EE film-coated oral tablets containing 1 mg norethisterone acetate and 10 μg ethinylestradiol.
OTHERPlacebo
tablet
DRUGethinylestradiol (EE)
EE 10 μg tablet
DRUGferrous fumarate
ferrous fumarate 75 mg tablet
Sponsors
Organon and Co
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
NONE
Eligibility
Sex/Gender
FEMALE
Age
18 Years to 50 Years
Healthy volunteers
Yes
Inclusion criteria
* Sexually active woman, at risk for pregnancy and in need of contraception * Not planning to use other contraceptive methods (including barrier methods \[e.g., condoms\]) than the study drug, during the study * Willing to use a COC for 12 months (13 cycles) * Body mass index (BMI) of ≥18 and \<38 kg/m\^2 * Good physical and mental health * Willing to complete an electronic diary on a daily basis for the duration of the study
Exclusion criteria
* Current smoker and age of \>35 years * Presence or history of either venous thromboembolic diseases (deep vein thrombosis \[DVT\], pulmonary embolism) or arterial thromboembolic diseases (myocardial infarction, stroke) * History of migraine with focal neurological symptoms * Diabetes mellitus with vascular involvement * Less than two weeks of full remobilization from prolonged immobilization, major surgery, any surgery to the legs, or major trauma * Severe hypertension * Severe abnormal lipoproteins in the blood * Pancreatic dysfunction * Presence of history of severe liver disease or liver tumors * Known or suspected sex steroid-influenced malignancies (e.g., of the genital organs or the breasts) * Undiagnosed vaginal bleeding * Known or suspected pregnancy * Current or history of abuse of alcohol or drugs (e.g., laxatives) * Abnormal cervical smear at screening * Prior to start of treatment, spontaneous menstruation has not occurred following a delivery or abortion * Breastfeeding or has been breastfeeding within 2 months prior to start of treatment * Use of any investigational drugs and/or participation in any other clinical trial within 2 months prior to start of treatment * Use of any of the following medications prior to or during the study may prohibit inclusion: sex hormones (other than pre- and post-treatment non-injectable contraceptives), injectable hormonal contraception, phenytoin, barbiturates, primidone, bosentan, carbamazepine, topiramate, felbamate, rifampicin, ritonavir, nevirapine, efavirenz, griseofulvin, herbal remedies containing Hypericum perforatum (e.g., St. John's wort)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of In-Treatment Pregnancies Per 100 Woman Years of Exposure (Pearl Index) | Up to 1 year (13 cycles) | Primary Efficacy Outcome measure for this study was contraceptive efficacy, or the prevention of in-treatment pregnancy. The total incidence of in-treatment pregnancies was expressed as the Pearl Index, which is defined as the number of in-treatment pregnancies per 100 woman-years of exposure. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With an Occurrence of Breakthrough Bleeding/Spotting | Up to 1 year (13 cycles) | Participants kept e-diaries to record their vaginal bleeding events. They were asked to record, on a daily basis, whether they experienced vaginal bleeding, which included BLEEDING or SPOTTING, at any time during a cycle other than normal menstruation while in the study. (This is also known as breakthough bleeding.) Vaginal bleeding that required \>=1 pad/tampon per day was classified as BLEEDING. Vaginal bleeding that did not require a pad/tampon per day was classified as SPOTTING. |
| Percentage of Participants With an Absence of Withdrawal Bleeding | Up to 1 year (13 cycles) | Participants kept e-diaries to record vaginal bleeding events. They were asked to record, on a daily basis, whether vaginal bleeding was present. Absence of withdrawal bleeding was defined as no bleeding/spotting during the expected bleeding period. |
| Percentage of Participants Who Experienced At Least One Adverse Event | Up to 54 weeks | An AE is defined as any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a study drug, whether or not it is considered related to the study drug. |
| Number of Participants Who Experience at Least One Venous or Arterial Thrombotic/Thromboembolic Event | Up to 54 weeks | — |
| Change From Baseline in Body Weight | Baseline and Week 52 | Participants' body weights were measured in a consistent manner throughout the trial, using standardized equirpment. Last In-Treatment Measurement refers to a participant's end of trial visit, the timing of which differed among participants. |
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| NOMAC-E2 Participants received a NOMAC-E2 tablet (2.5 mg nomegestrol acetate and 1.5 mg 17ß-estradiol), taken orally once daily for 13 cycles. Each cycle was 28 days. For each cycle, participants received NOMAC-E2 tablets on Days 1 to 24 and placebo tablets on Days 25 to 28. | 2,466 |
| NETA-EE Participants received a NETA-EE tablet (1 mg norethisterone acetate and 10 μg ethinylestradiol), taken orally once daily for 13 cycles. Each cycle was 28 days. For each cycle, participants received NETA-EE tablets on Days 1 to 24; EE 10 μg tablets on Days 25 and 26; and ferrous fumarate 75 mg tablets on Days 27 and 28. | 604 |
| Total | 3,070 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 199 | 63 |
| Overall Study | Enrollment terminated at trial site | 2 | 0 |
| Overall Study | Lost to Follow-up | 309 | 76 |
| Overall Study | Non-compliance with protocol | 39 | 15 |
| Overall Study | Non-compliance with study drug | 48 | 9 |
| Overall Study | Part. discontinued; unrelated to drug | 55 | 10 |
| Overall Study | Participant discontinued; drug related | 13 | 4 |
| Overall Study | Participant moved | 40 | 12 |
| Overall Study | Participant withdrew consent | 28 | 9 |
| Overall Study | Physician Decision | 7 | 2 |
| Overall Study | Pregnancy | 45 | 10 |
| Overall Study | Pregnancy wish | 18 | 6 |
| Overall Study | Protocol Violation | 7 | 0 |
| Overall Study | Screen failure | 2 | 0 |
| Overall Study | Site discontinued study participation | 24 | 9 |
| Overall Study | Study terminated by sponsor | 1,501 | 348 |
| Overall Study | Withdrawal by Subject | 64 | 7 |
Baseline characteristics
| Characteristic | NOMAC-E2 | NETA-EE | Total |
|---|---|---|---|
| Age, Continuous | 29.2 Years STANDARD_DEVIATION 7.6 | 29.5 Years STANDARD_DEVIATION 7.7 | 29.3 Years STANDARD_DEVIATION 7.6 |
| Sex: Female, Male Female | 2466 Participants | 604 Participants | 3070 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 0 / 2,465 | 0 / 604 |
| serious Total, serious adverse events | 20 / 2,465 | 8 / 604 |
Outcome results
Primary
Number of In-Treatment Pregnancies Per 100 Woman Years of Exposure (Pearl Index)
Primary Efficacy Outcome measure for this study was contraceptive efficacy, or the prevention of in-treatment pregnancy. The total incidence of in-treatment pregnancies was expressed as the Pearl Index, which is defined as the number of in-treatment pregnancies per 100 woman-years of exposure.
Time frame: Up to 1 year (13 cycles)
Population: Planned analysis for this primary endpoint was not performed due to early study termination.
Secondary
Change From Baseline in Body Weight
Participants' body weights were measured in a consistent manner throughout the trial, using standardized equirpment. Last In-Treatment Measurement refers to a participant's end of trial visit, the timing of which differed among participants.
Time frame: Baseline and Week 52
Population: Participants from All Subjects as Treated Population (all randomized participants who took at least one dose of trial medication) who had data available for Change from Baseline in Body Weight endpoint.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| NOMAC-E2 | Change From Baseline in Body Weight | After Cycle 6 (n=1809; n=459) | 0.64 kilograms | Standard Error 0.18 |
| NOMAC-E2 | Change From Baseline in Body Weight | After Cycle 13 (n=462; n=145) | 1.57 kilograms | Standard Error 0.29 |
| NOMAC-E2 | Change From Baseline in Body Weight | After Cycle 9 (n=1468; n=391) | 1.21 kilograms | Standard Error 0.23 |
| NOMAC-E2 | Change From Baseline in Body Weight | Last In-Treatment Measurement (n=2231; n=549) | 1.39 kilograms | Standard Error 0.17 |
| NOMAC-E2 | Change From Baseline in Body Weight | After Cycle 3 (n=2135; n=527) | 0.14 kilograms | Standard Error 0.14 |
| NETA-EE | Change From Baseline in Body Weight | Last In-Treatment Measurement (n=2231; n=549) | 0.75 kilograms | Standard Error 0.29 |
| NETA-EE | Change From Baseline in Body Weight | After Cycle 3 (n=2135; n=527) | 0.41 kilograms | Standard Error 0.24 |
| NETA-EE | Change From Baseline in Body Weight | After Cycle 6 (n=1809; n=459) | 0.29 kilograms | Standard Error 0.28 |
| NETA-EE | Change From Baseline in Body Weight | After Cycle 9 (n=1468; n=391) | 0.32 kilograms | Standard Error 0.35 |
| NETA-EE | Change From Baseline in Body Weight | After Cycle 13 (n=462; n=145) | 0.90 kilograms | Standard Error 0.46 |
Secondary
Number of Participants Who Experience at Least One Venous or Arterial Thrombotic/Thromboembolic Event
Time frame: Up to 54 weeks
Population: All Subjects as Treated Population, which consisted of all randomized participants who took at least one dose of trial medication. One treated participant in the NOMAC-E2 treatment group had incomplete data and was not included in the Safety Analyses.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| NOMAC-E2 | Number of Participants Who Experience at Least One Venous or Arterial Thrombotic/Thromboembolic Event | 0 Participants |
| NETA-EE | Number of Participants Who Experience at Least One Venous or Arterial Thrombotic/Thromboembolic Event | 1 Participants |
Secondary
Percentage of Participants Who Experienced At Least One Adverse Event
An AE is defined as any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a study drug, whether or not it is considered related to the study drug.
Time frame: Up to 54 weeks
Population: All Subjects as Treated Population, which consisted of all randomized participants who took at least one dose of trial medication. One treated participant in the NOMAC-E2 treatment group had incomplete data and was not included in the Safety Analyses.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| NOMAC-E2 | Percentage of Participants Who Experienced At Least One Adverse Event | 41.2 Percentage of Participants |
| NETA-EE | Percentage of Participants Who Experienced At Least One Adverse Event | 45.2 Percentage of Participants |
Secondary
Percentage of Participants With an Absence of Withdrawal Bleeding
Participants kept e-diaries to record vaginal bleeding events. They were asked to record, on a daily basis, whether vaginal bleeding was present. Absence of withdrawal bleeding was defined as no bleeding/spotting during the expected bleeding period.
Time frame: Up to 1 year (13 cycles)
Population: Planned analysis for this secondary endpoint was not performed due to early study termination.
Secondary
Percentage of Participants With an Occurrence of Breakthrough Bleeding/Spotting
Participants kept e-diaries to record their vaginal bleeding events. They were asked to record, on a daily basis, whether they experienced vaginal bleeding, which included BLEEDING or SPOTTING, at any time during a cycle other than normal menstruation while in the study. (This is also known as breakthough bleeding.) Vaginal bleeding that required \>=1 pad/tampon per day was classified as BLEEDING. Vaginal bleeding that did not require a pad/tampon per day was classified as SPOTTING.
Time frame: Up to 1 year (13 cycles)
Population: Planned analysis for this secondary endpoint was not performed due to early study termination.