Contraception
Conditions
Keywords
contraception, hormonal oral contraceptive agents, hormonal oral contraceptive, oral contraceptive, drospirenone, LF111, birth control
Brief summary
To demonstrate the contraceptive efficacy of LF111 . To demonstrate the safety and tolerability of LF111 and assessment of pharmacokinetics of LF111.
Detailed description
This trial is a prospective, multicenter, open-label, non-controlled trial in female subjects, including adolescents between the ages of 15+(inclusive) who present to the clinic seeking contraception, who are postmenarcheal and premenopausal. At screening, informed consent will be obtained and the screening procedures will be performed. After confirmation of the subject's eligibility, the subject will be provided with the investigational product and trained in the use of an electronic diary. Afterwards, the subjects will attend visit the clinical site on Day 20±2 of the 1st, 3rd, 6th and 9th cycles and on Day 29+2 of the 13th cycle. The last clinical site visit will occur 10-14 days after the 13th cycle visit. The trial will include women who have never used hormonal contraceptives before consent (naïve users), women who have not used hormonal contraceptives in the past three months before consent or who have used hormonal contraceptives in the past but have a contraceptive-free time of less than three months before consent (previous users) as well as women directly switching from another hormonal method (switchers). Women who have used hormonal contraceptives in the past but have a contraceptive-free time of less than three months before consent are allowed to be included into the trial if they had at least one complete menstrual cycle before enrollment. A population pharmacokinetic (PK) analysis planned in the whole subject population, will obtain sparse blood samples to determine plasma concentrations. In total, four blood samples will be collected: two samples each will be collected during the 1st cycle and during the 6th cycle of treatment. Adverse events and safety information will be collected throughout the study.
Interventions
DRUGLF111 (drospirenone)
One LF111 tablet once per day for 24 days followed by 4 placebo tablets for 4 days equals one cycle.
Sponsors
Chemo France
Laboratories Leon Farma, S.A.
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
FEMALE
Age
15 Years to No maximum
Healthy volunteers
Yes
Inclusion criteria
1. Sexually active, postmenarcheal and premenopausal female subjects at risk of pregnancy including breastfeeding women with no upper age limit. 2. Female subjects at risk of pregnancy, between the ages of 15 and 17 (inclusive) provided that * Applicable national, state and local laws allow subjects in this age group to consent/assent to receive contraceptive services, and * All applicable laws and regulations regarding the informed consent/assent of the subjects to participate in clinical trials are observed. 3. Regular cycles during the last six months before consent/assent when not using hormonal contraception. 4. At least three complete menstrual cycles after delivery (only applicable for women who were pregnant within the last six months and for non-breastfeeding women). Breastfeeding women can be included six weeks after delivery irrespective of menstrual cycles post-delivery. 5. At screening, maximum systolic blood pressure (median value of three values) ≤ 159 mm Hg and diastolic blood pressure (median value of three values) ≤ 99 mm Hg. 6. Be able and willing to provide written informed consent or assent if the subject is adolescent, prior to undergoing any trial-related procedure. 7. Willing to use trial contraception for thirteen 28-day cycles. 8. Be willing to have intercourse each cycle of trial without the need to use back-up contraceptive. 9. Be willing to state that, to her best knowledge, her male sexual partner(s): * Has not had a vasectomy or been previously diagnosed as infertile. * Has not been previously diagnosed or suspected of human immunodeficiency virus (HIV) unless he has subsequently had a negative HIV test. * Has not been known to have engaged in homosexual intercourse in the past five years unless he has had negative HIV test results since then. * Has not shared injection drug needles in the past unless he has had a negative HIV test at least six weeks since last use. 10. Agree not to participate in any other clinical trials during the course of this trial.
Exclusion criteria
1. Pregnant. 2. Subject is known to or suspected of not being able to comply with the trial protocol, the use of the trial medication or the use of the trial diary. 3. History of infertility. 4. Abnormal finding on pelvic, breast or ultrasound examination that in the investigator's opinion contraindicates participation in the trial. 5. Unexplained amenorrhea. 6. Known polycystic ovary syndrome. 7. Women ≥21 years of age with a Papanicolaou (pap) smear reading LGSIL or higher at screening (or six months prior to screening date). Human papilloma virus (HPV) testing in subjects with atypical squamous cells of undetermined significance (ASC-US) can be used as an adjunctive test. * Subjects with ASC-US can be included if they are negative for high-risk HPV strains. * Subjects \<21 years of age do not require a pap smear. 8. Known contraindication or hypersensitivity to ingredients or excipients of the IMP (Investigational Medicinal Product), including: 1. Renal insufficiency 2. Hepatic dysfunction 3. Adrenal insufficiency 4. Current or history of venous thrombophlebitis or thromboembolic disorders (venous thromboembolism, which includes deep vein thrombosis and pulmonary embolism) 5. Current or history of cerebral-vascular or coronary-artery disease 6. Valvular heart disease with thrombogenic complications 7. Diabetes with vascular involvement 8. Headaches with focal neurological symptoms 9. Major surgery with prolonged immobilization 10. Known or suspected carcinoma of the breast 11. Known or suspected sex-steroid sensitive malignancies 12. Undiagnosed abnormal genital bleeding 13. Cholestatic jaundice of pregnancy or jaundice with prior hormonal contraceptive use 14. Liver tumor (benign or malignant) or active clinically significant liver disease. 9. Uncontrolled thyroid disorder (i.e., on stable dose of thyroid replacement for less than two months). 10. Uncontrolled concomitant diseases (i.e., not on a stable treatment dose for at least two months). 11. Evidence or history of alcohol, medication or drug abuse (within the last 12 months prior to consent/assent). 12. Known inherited or acquired predisposition to venous thromboembolism or arterial thromboembolism (e.g., factor V Leiden, Prothrombin mutation, Antiphospholipid antibodies) or bruising within the last 12 months prior to consent/assent. 13. Known or suspected HIV and/or hepatitis infection at screening. 14. Received a dose of depot medroxyprogesterone acetate (DMPA or Depo-Provera®) during the 10 months prior to consent/assent, or received any combined injectable contraceptive (e.g., Cyclofem®) during the six months prior to consent/assent, or no spontaneous menses since last injection. 15. Long-term treatment (longer than seven consecutive days within a month prior to V1b) of any medication that might interfere with the efficacy of hormonal contraceptives. Prohibited medication include: 1. Anticonvulsants (e.g. phenytoin, carbamazepine, oxcarbazepine, topiramate, felbamate, primidone) 2. Barbiturates 3. Rifampin 4. Bosentan 5. Griseofulvin 6. St. John's wort (hypericum perforatum) 16. Administration of human chorionic gonadotropin (hCG) or intake of co-medication containing hCG within a month prior to V1b). 17. Progestin-releasing intra-uterine device (IUD) or contraceptive implant received or in place within the last two months prior to consent/assent. 18. Planned regular concomitant use of barrier contraceptive methods, spermicides, IUDs or other contraceptive measures (excepting occasional use for safety reasons, e.g., to reduce risk of infection). 19. Evidence or history of clinically significant psychiatric illness or suicide risk. 20. Participation in another trial of an investigational drug or device parallel to the current trial or less than 90 days before consent/assent, or previous participation in the current trial and dispensed trial medication. 21. Subject is a member of the investigator's or Sponsor's staff or a relative or family member thereof. 22. Any condition that, in the opinion of the investigator, may jeopardize protocol compliance or the scientific integrity of the trial.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Pregnancies (Evaluable Cycles) | up to 13 months | Pearl index (PI) from Evaluable Cycles in non-breastfeeding women aged ≤ 35 years (at the time of trial enrollment). The PI calculation was based on the following formula: PI(evaluable cycles)= (∑ on-drug confirmed pregnancy ∈{exposure cycles})/(#{exposure cycles} ) X 1300 |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Pregnancies (All) | up to 13 months | Pearl Index based on overall cycles (overall PI) in women aged ≤ 35 years (at the time of trial enrollment) (confirmed pregnancies) |
| Number of Pregnancies (Method Failures) | up to 13 months | PI for method failures in women aged ≤ 35 years (at the time of trial enrollment) (confirmed pregnancies) |
| Pregnancy Ratio | up to 13 months | Pregnancy ratio in women aged ≤ 35 years (at the time of trial enrollment) |
| Number of Participants With Adverse Events as a Measure of Safety | up to to 13 months | Adverse events and changes in vital signs, clinical laboratory parameters |
| Tolerability; Vaginal Bleeding Pattern | up to 13 months | Vaginal bleeding pattern |
| Overall PI, PI for Method Failures | up to 13 months | Overall PI, PI for method failures, PI (using evaluable cycles) and pregnancy ratio (life table analysis) in all women and in women up to 13 months (confirmed pregnancies) |
Other
| Measure | Time frame | Description |
|---|---|---|
| Number of Pregnancies (by BMI and Weight) | up to 13 months | PI for evaluable cycles in women aged ≤ 35 years in total and by BMI and weight subgroups based on confirmed and on confirmed and suspected, non-confirmed pregnancies |
| Overall Pregnancies | up to 13 months | Overall PI based on confirmed and on confirmed and suspected, non-confirmed pregnancies in total and by BMI and weight subgroups |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| LF111 (Drospirenone 4mg) Single treatment arm receives LF111 film-coated tablets (24 white tablets containing 4.0 mg drospirenone, 4 green placebo tablets), oral administration once daily. | 1,006 |
| Total | 1,006 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Adverse Event | 113 |
| Overall Study | At the specific request of the sponsor | 20 |
| Overall Study | Development of an exclusion criteria | 16 |
| Overall Study | Lost to Follow-up | 269 |
| Overall Study | Physician Decision | 7 |
| Overall Study | Pregnancy | 15 |
| Overall Study | Protocol Violation | 1 |
| Overall Study | Screening failures | 546 |
| Overall Study | Several reasons not classified | 53 |
| Overall Study | Wish for pregnancy | 5 |
| Overall Study | Withdrawal by Subject | 155 |
Baseline characteristics
| Characteristic | LF111 (Drospirenone 4mg) |
|---|---|
| Age, Customized <=35 years | 928 participants |
| Age, Customized >35 years | 78 participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 229 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 777 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 13 Participants |
| Race (NIH/OMB) Asian | 20 Participants |
| Race (NIH/OMB) Black or African American | 358 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 5 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 39 Participants |
| Race (NIH/OMB) White | 571 Participants |
| Sex: Female, Male Female | 1006 Participants |
| Sex: Female, Male Male | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 0 / 1,006 |
| other Total, other adverse events | 341 / 1,006 |
| serious Total, serious adverse events | 17 / 1,006 |
Outcome results
Primary
Number of Pregnancies (Evaluable Cycles)
Pearl index (PI) from Evaluable Cycles in non-breastfeeding women aged ≤ 35 years (at the time of trial enrollment). The PI calculation was based on the following formula: PI(evaluable cycles)= (∑ on-drug confirmed pregnancy ∈{exposure cycles})/(#{exposure cycles} ) X 1300
Time frame: up to 13 months
Population: The population includes all non-breastfeeding subjects aged ≤ 35 years who were randomized, received at least one dose of study drug with sexual activity without using back-up contraception.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Drospirenone 4 mg | Number of Pregnancies (Evaluable Cycles) | 2.9 Pearl Index |
Secondary
Number of Participants With Adverse Events as a Measure of Safety
Adverse events and changes in vital signs, clinical laboratory parameters
Time frame: up to to 13 months
Population: The population includes all subjects who received at least one dose of the IMP.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Drospirenone 4 mg | Number of Participants With Adverse Events as a Measure of Safety | 667 Subjects |
Secondary
Number of Pregnancies (All)
Pearl Index based on overall cycles (overall PI) in women aged ≤ 35 years (at the time of trial enrollment) (confirmed pregnancies)
Time frame: up to 13 months
Population: The population includes all non-breastfeeding subjects aged ≤ 35 years who were randomized and received at least one dose of study drug.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Drospirenone 4 mg | Number of Pregnancies (All) | 2.7 Pearl Index |
Secondary
Number of Pregnancies (Method Failures)
PI for method failures in women aged ≤ 35 years (at the time of trial enrollment) (confirmed pregnancies)
Time frame: up to 13 months
Population: The population includes all non-breastfeeding subjects aged ≤ 35 years who were randomized, received at least one dose of study drug and used the IMP correctly.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Drospirenone 4 mg | Number of Pregnancies (Method Failures) | 3.4 Pearl Index |
Secondary
Overall PI, PI for Method Failures
Overall PI, PI for method failures, PI (using evaluable cycles) and pregnancy ratio (life table analysis) in all women and in women up to 13 months (confirmed pregnancies)
Time frame: up to 13 months
Population: The population includes all ages subjects who were randomized and received at least one dose of study drug, non-breastfeeding women and used the IMP correctly.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Drospirenone 4 mg | Overall PI, PI for Method Failures | 2.9 Pearl Index |
Secondary
Pregnancy Ratio
Pregnancy ratio in women aged ≤ 35 years (at the time of trial enrollment)
Time frame: up to 13 months
Population: The population includes all subjects aged ≤ 35 years who were randomized, received at least one dose of study drug with evaluable cycles.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Drospirenone 4 mg | Pregnancy Ratio | 2.46 Cumulative Pregnancy Rate (%) |
Secondary
Tolerability; Vaginal Bleeding Pattern
Vaginal bleeding pattern
Time frame: up to 13 months
Population: The population includes all subjects in full analysis set with bleeding.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Drospirenone 4 mg | Tolerability; Vaginal Bleeding Pattern | 505 Subjects with bleeding |
Other Pre-specified
Number of Pregnancies (by BMI and Weight)
PI for evaluable cycles in women aged ≤ 35 years in total and by BMI and weight subgroups based on confirmed and on confirmed and suspected, non-confirmed pregnancies
Time frame: up to 13 months
Population: The population includes evaluable cycles in non-breastfeeding women aged ≤ 35 years , who were randomized and received at least one dose of study drug, including confirmed and suspected, non-confirmed pregnancies.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Drospirenone 4 mg | Number of Pregnancies (by BMI and Weight) | Pearl Index BMI<30 | 4.1 Pearl Index |
| Drospirenone 4 mg | Number of Pregnancies (by BMI and Weight) | Pearl Index BMI>=30 | 2.9 Pearl Index |
| Drospirenone 4 mg | Number of Pregnancies (by BMI and Weight) | Weight < Median | 5.1 Pearl Index |
| Drospirenone 4 mg | Number of Pregnancies (by BMI and Weight) | Weight >= Median | 2.3 Pearl Index |
Other Pre-specified
Overall Pregnancies
Overall PI based on confirmed and on confirmed and suspected, non-confirmed pregnancies in total and by BMI and weight subgroups
Time frame: up to 13 months
Population: The population includes all ages subjects, non-breastfeeding women, who were randomized and received at least one dose of study drug, including confirmed and suspected, non-confirmed pregnancies.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Drospirenone 4 mg | Overall Pregnancies | Pearl Index BMI>=30 | 2.3 Pearl Index |
| Drospirenone 4 mg | Overall Pregnancies | Weight < Median | 4.2 Pearl Index |
| Drospirenone 4 mg | Overall Pregnancies | Weight >= Median | 1.9 Pearl Index |
| Drospirenone 4 mg | Overall Pregnancies | Pearl Index BMI<30 | 3.3 Pearl Index |