Contraception
Conditions
Brief summary
The purpose of this study is to assess the contraceptive efficacy of the etonogestrel + 17β-estradiol (ENG-E2) vaginal ring in women between 18 and 35 years of age based on the number of in-treatment pregnancies as expressed by the Pearl Index (PI). The study will also assess the safety and tolerability of ENG-E2 vaginal ring. The levonorgestrel-ethinyl estradiol (LNG-EE) 150/30 μg combined oral contraceptive (COC) will be used as the active comparator.
Interventions
Up to 13 cycles of ENG-E2 125 μg/300 μg administered intravaginally, each cycle consisting of 21 days of vaginal ring use followed by 7 vaginal ring-free days.
DRUGLNG-EE 150 μg/30 μg COC
Up to 13 cycles of LNG-EE 150 μg/30 μg administered orally, each cycle consisting of one tablet per day for 21 days, followed a 7-day tablet-free interval.
Sponsors
Organon and Co
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
NONE
Eligibility
Sex/Gender
FEMALE
Age
18 Years to No maximum
Healthy volunteers
Yes
Inclusion criteria
* Premenopausal female at risk for pregnancy and seeking contraception. * Willing to use a hormonal contraceptive vaginal ring for up to 13 treatment cycles, and not intending to use any other form of contraception. * Body mass index (BMI) of ≥18 and \<38 kg/m\^2. * In good physical and mental health, based upon the medical judgment of the investigator. * Willing to adhere to use of vaginal ring and all required trial procedures.
Exclusion criteria
* Cardiovascular risks and disorders, including history of venous thromboembolic \[VTE\] events, arterial thrombotic or thromboembolic \[ATE\] events, transient ischemic attack, angina pectoris, or claudication; at higher risk of VTE events due to recent prolonged immobilization, plans for surgery requiring prolonged immobilization, or a hereditary or acquired predisposition or elevated risk for venous or arterial thrombosis; currently smoking or uses tobacco/nicotine containing products and is ≥35 years of age; uncontrolled or severe hypertension; history of severe dyslipoproteinemia; \<35 years of age with a history of migraine with aura or focal neurological symptoms or ≥35 years of age with a history of migraines with or without aura or focal neurologic symptoms; diabetes mellitus with end-organ involvement or \>20 years duration; multiple cardiovascular risk factors such as ≥35 years of age, obesity, inadequately controlled hypertension, use of tobacco/ nicotine products, or inadequately controlled diabetes. * Gastrointestinal disorders, including history of pancreatitis associated with severe hypertriglyceridemia; clinically significant liver disease, including active viral hepatitis or cirrhosis; history of malabsorptive bariatric surgery. * Other medical disorders, including history of malignancy ≤5 years prior to signing informed consent except for adequately treated basal cell or squamous cell skin cancer or in situ cervical cancer; any disease that may worsen under hormonal treatment such as disturbances in bile flow, systemic lupus erythematosus, pemphigoid gestationis or idiopathic icterus during previous pregnancy, middle-ear deafness, Sydenham chorea, or porphyria; known allergy/sensitivity or contraindication to the investigational products or their excipients; history of drug or alcohol abuse or dependence. * Recent, current, or suspected pregnancy; or has not had at least 2 menstrual cycles or has not completed two 28-day cycles of a hormonal contraceptive following a recent pregnancy; or is breastfeeding. * Gynecologic conditions: has gonorrhea, chlamydia, or trichomonas or symptomatic vaginitis/cervicitis; has abnormal cervical Pap test or positive high-risk human papillomavirus (HPV) test at screening or documented within 3 years of screening; currently using an intrauterine device/intrauterine system (IUD/IUS) or contraceptive implant; within past 6 months has had undiagnosed (unexplained) abnormal vaginal bleeding or any abnormal vaginal bleeding expected to recur during trial; has stage 4 pelvic organ prolapse (1 cm beyond introitus) or lesser degrees of prolapse with history of difficulty retaining tampons, vaginal rings, or other products within vagina. * Has used investigational drug and/or participated in other clinical trial within past 8 weeks.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of In-Treatment Pregnancies Per 100 Woman-Years of Exposure in Participants 18-35 Years of Age (Pearl Index) | Up to 1 year (13 28-day cycles) | The 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 (one woman-year defined as a period of 365.25 days). NOTE: Due to early termination of this study, the ENG-E2 reporting group received only up to 10 cycles of treatment, and the LNG-EE reporting group received only up to 9 cycles of treatment. |
| Number of Participants Who Experienced an Adverse Event (AE) | Up to 1 year | An AE is any untoward medical occurrence in a participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a medicinal product or protocol-specified procedure, whether or not considered related to the medicinal product or protocol specified procedure. Any worsening (i.e., any clinically significant adverse change in frequency and/or intensity) of a preexisting condition that is temporally associated with the use of the Sponsor's product, is also an AE. NOTE: Due to early termination of this study, the ENG-E2 reporting group received only up to 10 cycles of treatment, and the LNG-EE reporting group received only up to 9 cycles of treatment. |
| Number of Participants Who Discontinued Treatment Due to an AE | Up to 1 year | An AE is any untoward medical occurrence in a participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a medicinal product or protocol-specified procedure, whether or not considered related to the medicinal product or protocol specified procedure. Any worsening (i.e., any clinically significant adverse change in frequency and/or intensity) of a preexisting condition that is temporally associated with the use of the Sponsor's product, is also an AE. NOTE: Due to early termination of this study, the ENG-E2 reporting group received only up to 10 cycles of treatment, and the LNG-EE reporting group received only up to 9 cycles of treatment. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Breakthrough Bleeding/Spotting (BTB-S), by Cycle | Up to 1 year | BTB-S was considered any bleeding/spotting that occurred during expected non-bleeding interval that was neither early nor continued withdrawal bleeding. BTB-S was classified as follows: Bleeding = any bloody vaginal discharge that required one or more sanitary pads or tampons per day; Spotting = any bloody vaginal discharge that required no sanitary pads or tampons per day. NOTE: Due to early termination of this study, the ENG-E2 reporting group received only up to 10 cycles of treatment, and the LNG-EE reporting group received only up to 9 cycles of treatment. |
| Number of Participants With Absence of Withdrawal Bleeding (AWB), by Cycle | Up to 1 year | Participants were asked to keep a daily diary to record vaginal bleeding events. AWB was defined as no bleeding/spotting during the expected bleeding period. NOTE: Due to early termination of this study, the ENG-E2 reporting group received only up to 10 cycles of treatment, and the LNG-EE reporting group received only up to 9 cycles of treatment. |
Countries
Austria, Costa Rica, Denmark, Finland, Germany, Hungary, Italy, Mexico, Netherlands, Norway, Peru, Poland, South Africa, Sweden
Participant flow
Recruitment details
Note: One participant less than 18 years of age was inadvertently randomized and received study medication. She was discontinued from the study due to the major protocol violation.
Participants by arm
| Arm | Count |
|---|---|
| ENG-E2 125 μg/300 μg Participants were to receive up to 13 cycles of ENG-E2 125 μg/300 μg. Each cycle was to consist of 21 days of vaginal ring use followed by 7 vaginal ring-free days. | 1,512 |
| LNG-EE 150 μg/30 μg Participants were to receive up to 13 cycles of LNG-EE 150 μg/30 μg. Each cycle was to consist of one tablet per day for 21 days, followed a 7-day tablet-free interval. | 504 |
| Total | 2,016 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 64 | 24 |
| Overall Study | Lost to Follow-up | 23 | 13 |
| Overall Study | Non-compliance with study drug | 4 | 2 |
| Overall Study | Non-compliance with study protocol | 2 | 0 |
| Overall Study | Participant moved | 4 | 3 |
| Overall Study | Physician Decision | 2 | 1 |
| Overall Study | Pregnancy | 2 | 2 |
| Overall Study | Pregnancy wish | 3 | 0 |
| Overall Study | Protocol Violation | 6 | 3 |
| Overall Study | Study terminated by sponsor | 1,372 | 432 |
| Overall Study | Withdrawal by Subject | 30 | 24 |
Baseline characteristics
| Characteristic | ENG-E2 125 μg/300 μg | LNG-EE 150 μg/30 μg | Total |
|---|---|---|---|
| Age, Continuous | 27.5 Years STANDARD_DEVIATION 6.3 | 27.5 Years STANDARD_DEVIATION 6.3 | 27.5 Years STANDARD_DEVIATION 6.3 |
| Sex: Female, Male Female | 1512 Participants | 504 Participants | 2016 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 | 116 / 1,504 | 40 / 492 |
| serious Total, serious adverse events | 8 / 1,504 | 3 / 492 |
Outcome results
Primary
Number of In-Treatment Pregnancies Per 100 Woman-Years of Exposure in Participants 18-35 Years of Age (Pearl Index)
The 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 (one woman-year defined as a period of 365.25 days). NOTE: Due to early termination of this study, the ENG-E2 reporting group received only up to 10 cycles of treatment, and the LNG-EE reporting group received only up to 9 cycles of treatment.
Time frame: Up to 1 year (13 28-day cycles)
Population: restricted Full Analysis Set (rFAS) population, defined as the population of women with at least one at risk treatment cycle without documented use of hormonal or nonhormonal backup contraception during the cycle, or participants with a treatment cycle (at risk or not) in which a pregnancy has occurred.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| ENG-E2 125 μg/300 μg | Number of In-Treatment Pregnancies Per 100 Woman-Years of Exposure in Participants 18-35 Years of Age (Pearl Index) | 1.54 Pregnancies per 100 woman years |
| LNG-EE 150 μg/30 μg | Number of In-Treatment Pregnancies Per 100 Woman-Years of Exposure in Participants 18-35 Years of Age (Pearl Index) | 2.93 Pregnancies per 100 woman years |
Primary
Number of Participants Who Discontinued Treatment Due to an AE
An AE is any untoward medical occurrence in a participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a medicinal product or protocol-specified procedure, whether or not considered related to the medicinal product or protocol specified procedure. Any worsening (i.e., any clinically significant adverse change in frequency and/or intensity) of a preexisting condition that is temporally associated with the use of the Sponsor's product, is also an AE. NOTE: Due to early termination of this study, the ENG-E2 reporting group received only up to 10 cycles of treatment, and the LNG-EE reporting group received only up to 9 cycles of treatment.
Time frame: Up to 1 year
Population: This primary endpoint was based on all randomized participants in whom at least one vaginal ring was inserted or one comparator tablet was ingested.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| ENG-E2 125 μg/300 μg | Number of Participants Who Discontinued Treatment Due to an AE | 61 Participants |
| LNG-EE 150 μg/30 μg | Number of Participants Who Discontinued Treatment Due to an AE | 23 Participants |
Primary
Number of Participants Who Experienced an Adverse Event (AE)
An AE is any untoward medical occurrence in a participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a medicinal product or protocol-specified procedure, whether or not considered related to the medicinal product or protocol specified procedure. Any worsening (i.e., any clinically significant adverse change in frequency and/or intensity) of a preexisting condition that is temporally associated with the use of the Sponsor's product, is also an AE. NOTE: Due to early termination of this study, the ENG-E2 reporting group received only up to 10 cycles of treatment, and the LNG-EE reporting group received only up to 9 cycles of treatment.
Time frame: Up to 1 year
Population: This primary endpoint was based on all randomized participants in whom at least one vaginal ring was inserted or one comparator tablet was ingested.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| ENG-E2 125 μg/300 μg | Number of Participants Who Experienced an Adverse Event (AE) | 530 Participants |
| LNG-EE 150 μg/30 μg | Number of Participants Who Experienced an Adverse Event (AE) | 140 Participants |
Secondary
Number of Participants With Absence of Withdrawal Bleeding (AWB), by Cycle
Participants were asked to keep a daily diary to record vaginal bleeding events. AWB was defined as no bleeding/spotting during the expected bleeding period. NOTE: Due to early termination of this study, the ENG-E2 reporting group received only up to 10 cycles of treatment, and the LNG-EE reporting group received only up to 9 cycles of treatment.
Time frame: Up to 1 year
Population: FAS Evaluable population, defined as a subset of FAS population that met the following criteria: a) No more than 2 consecutive days with missing bleeding data on Daily Diary unless there was at least one day with BTB-S during the ring-use interval; and b) treatment cycle length (including hormone-free interval) is between 22 and 35 days, inclusive.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| ENG-E2 125 μg/300 μg | Number of Participants With Absence of Withdrawal Bleeding (AWB), by Cycle | Cycle 1 | 76 Participants |
| ENG-E2 125 μg/300 μg | Number of Participants With Absence of Withdrawal Bleeding (AWB), by Cycle | Cycle 6 | 3 Participants |
| ENG-E2 125 μg/300 μg | Number of Participants With Absence of Withdrawal Bleeding (AWB), by Cycle | Cycle 4 | 17 Participants |
| ENG-E2 125 μg/300 μg | Number of Participants With Absence of Withdrawal Bleeding (AWB), by Cycle | Cycle 7 | 0 Participants |
| ENG-E2 125 μg/300 μg | Number of Participants With Absence of Withdrawal Bleeding (AWB), by Cycle | Cycle 2 | 34 Participants |
| ENG-E2 125 μg/300 μg | Number of Participants With Absence of Withdrawal Bleeding (AWB), by Cycle | Cycle 8 | 0 Participants |
| ENG-E2 125 μg/300 μg | Number of Participants With Absence of Withdrawal Bleeding (AWB), by Cycle | Cycle 5 | 3 Participants |
| ENG-E2 125 μg/300 μg | Number of Participants With Absence of Withdrawal Bleeding (AWB), by Cycle | Cycle 9 | 0 Participants |
| ENG-E2 125 μg/300 μg | Number of Participants With Absence of Withdrawal Bleeding (AWB), by Cycle | Cycle 3 | 26 Participants |
| LNG-EE 150 μg/30 μg | Number of Participants With Absence of Withdrawal Bleeding (AWB), by Cycle | Cycle 9 | 0 Participants |
| LNG-EE 150 μg/30 μg | Number of Participants With Absence of Withdrawal Bleeding (AWB), by Cycle | Cycle 3 | 10 Participants |
| LNG-EE 150 μg/30 μg | Number of Participants With Absence of Withdrawal Bleeding (AWB), by Cycle | Cycle 1 | 15 Participants |
| LNG-EE 150 μg/30 μg | Number of Participants With Absence of Withdrawal Bleeding (AWB), by Cycle | Cycle 2 | 10 Participants |
| LNG-EE 150 μg/30 μg | Number of Participants With Absence of Withdrawal Bleeding (AWB), by Cycle | Cycle 4 | 6 Participants |
| LNG-EE 150 μg/30 μg | Number of Participants With Absence of Withdrawal Bleeding (AWB), by Cycle | Cycle 5 | 0 Participants |
| LNG-EE 150 μg/30 μg | Number of Participants With Absence of Withdrawal Bleeding (AWB), by Cycle | Cycle 6 | 1 Participants |
| LNG-EE 150 μg/30 μg | Number of Participants With Absence of Withdrawal Bleeding (AWB), by Cycle | Cycle 7 | 2 Participants |
| LNG-EE 150 μg/30 μg | Number of Participants With Absence of Withdrawal Bleeding (AWB), by Cycle | Cycle 8 | 1 Participants |
Secondary
Number of Participants With Breakthrough Bleeding/Spotting (BTB-S), by Cycle
BTB-S was considered any bleeding/spotting that occurred during expected non-bleeding interval that was neither early nor continued withdrawal bleeding. BTB-S was classified as follows: Bleeding = any bloody vaginal discharge that required one or more sanitary pads or tampons per day; Spotting = any bloody vaginal discharge that required no sanitary pads or tampons per day. NOTE: Due to early termination of this study, the ENG-E2 reporting group received only up to 10 cycles of treatment, and the LNG-EE reporting group received only up to 9 cycles of treatment.
Time frame: Up to 1 year
Population: FAS Evaluable population, defined as a subset of FAS population that met the following criteria: a) No more than 2 consecutive days with missing bleeding data on Daily Diary unless there was at least one day with BTB-S during the ring-use interval; and b) treatment cycle length (including hormone-free interval) is between 22 and 35 days, inclusive.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| ENG-E2 125 μg/300 μg | Number of Participants With Breakthrough Bleeding/Spotting (BTB-S), by Cycle | Cycle 2 | 166 Participants |
| ENG-E2 125 μg/300 μg | Number of Participants With Breakthrough Bleeding/Spotting (BTB-S), by Cycle | Cycle 6 | 29 Participants |
| ENG-E2 125 μg/300 μg | Number of Participants With Breakthrough Bleeding/Spotting (BTB-S), by Cycle | Cycle 4 | 79 Participants |
| ENG-E2 125 μg/300 μg | Number of Participants With Breakthrough Bleeding/Spotting (BTB-S), by Cycle | Cycle 7 | 13 Participants |
| ENG-E2 125 μg/300 μg | Number of Participants With Breakthrough Bleeding/Spotting (BTB-S), by Cycle | Cycle 3 | 112 Participants |
| ENG-E2 125 μg/300 μg | Number of Participants With Breakthrough Bleeding/Spotting (BTB-S), by Cycle | Cycle 8 | 8 Participants |
| ENG-E2 125 μg/300 μg | Number of Participants With Breakthrough Bleeding/Spotting (BTB-S), by Cycle | Cycle 9 | 1 Participants |
| ENG-E2 125 μg/300 μg | Number of Participants With Breakthrough Bleeding/Spotting (BTB-S), by Cycle | Cycle 5 | 42 Participants |
| LNG-EE 150 μg/30 μg | Number of Participants With Breakthrough Bleeding/Spotting (BTB-S), by Cycle | Cycle 9 | 0 Participants |
| LNG-EE 150 μg/30 μg | Number of Participants With Breakthrough Bleeding/Spotting (BTB-S), by Cycle | Cycle 2 | 54 Participants |
| LNG-EE 150 μg/30 μg | Number of Participants With Breakthrough Bleeding/Spotting (BTB-S), by Cycle | Cycle 3 | 36 Participants |
| LNG-EE 150 μg/30 μg | Number of Participants With Breakthrough Bleeding/Spotting (BTB-S), by Cycle | Cycle 4 | 20 Participants |
| LNG-EE 150 μg/30 μg | Number of Participants With Breakthrough Bleeding/Spotting (BTB-S), by Cycle | Cycle 5 | 13 Participants |
| LNG-EE 150 μg/30 μg | Number of Participants With Breakthrough Bleeding/Spotting (BTB-S), by Cycle | Cycle 6 | 8 Participants |
| LNG-EE 150 μg/30 μg | Number of Participants With Breakthrough Bleeding/Spotting (BTB-S), by Cycle | Cycle 7 | 7 Participants |
| LNG-EE 150 μg/30 μg | Number of Participants With Breakthrough Bleeding/Spotting (BTB-S), by Cycle | Cycle 8 | 2 Participants |