Safety, Efficacy, Tolerability and Pharmacokinetics of LF111 (Drospirenone 4.0 mg) During 13 Cycles

A Pivotal, Multicenter, Non-Comparative Trial on the Contraceptive Efficacy, Safety, Tolerability and Pharmacokinetics of LF111 (Drospirenone 4.0 mg) During 13 Cycles

To demonstrate the contraceptive efficacy of LF111 . To demonstrate the safety and tolerability of LF111 and assessment of pharmacokinetics of LF111.

Study Overview

• Status: Completed
• Conditions: Contraception
• Intervention / Treatment: Drug: LF111 (drospirenone)

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.

• Study Type: Interventional
• Enrollment (Actual): 1552
• Phase: Phase 3

Contacts and Locations

Study Locations

• United States
  • Alabama
    • Birmingham, Alabama, United States, 35235
      • Alabama Clinical Therapeutics
  • California
    • Anaheim, California, United States, 92801
      • Anaheim Clinical Trials, LLC
    • Costa Mesa, California, United States, 92626
      • WCCT Global
    • San Diego, California, United States, 92123
      • Women's Health Care Research Corp.
  • Colorado
    • Denver, Colorado, United States, 80220
      • Horizons Clinical Research Center, LLC
    • Denver, Colorado, United States, 80209
      • Downtown Women's Health Care
  • Connecticut
    • Stamford, Connecticut, United States, 06095
      • Stamford Therapeutics Consortium
  • Florida
    • Lake Worth, Florida, United States, 33461
      • Altus Research
    • Miami, Florida, United States, 33143
      • Miami Research Associates
    • North Miami, Florida, United States, 33161
      • Segal Institute for Clinical Research
    • Saint Petersburg, Florida, United States, 33709
      • Meridien Research - St. Petersburg
    • Tampa, Florida, United States, 33606
      • Meridien Research - Tampa
    • West Palm Beach, Florida, United States, 33409
      • Comprehensive Clinical Trials, Llc
  • Georgia
    • Savannah, Georgia, United States, 31406
      • Fellows Research Alliance, Inc.
  • Idaho
    • Idaho Falls, Idaho, United States, 83404
      • Rosemark WomenCare Specialists
  • Kentucky
    • Louisville, Kentucky, United States, 40291
      • Bluegrass Clinical Research, Inc
  • Maryland
    • Baltimore, Maryland, United States, 21224
      • Johns Hopkins School of Medicine
  • Michigan
    • Kalamazoo, Michigan, United States, 49009
      • Beyer Research
  • New Jersey
    • Lawrenceville, New Jersey, United States, 08648
      • Lawrence OBGYN Clinical Research, LLC
    • Plainsboro, New Jersey, United States, 08536
      • The Center for Women's Health & Wellness, LLC
  • New Mexico
    • Albuquerque, New Mexico, United States, 87109
      • Southwest Clinical Research
  • New York
    • New York, New York, United States, 10016
      • NYU School of Medicine
  • North Carolina
    • New Bern, North Carolina, United States, 28562
      • Eastern Carolina Women's Center
    • Raleigh, North Carolina, United States, 27612
      • Wake Research Associates
    • Winston-Salem, North Carolina, United States, 27103
      • Hawthorne Medical Research, Inc.
  • Ohio
    • Cincinnati, Ohio, United States, 45267
      • University of Cincinnati
    • Columbus, Ohio, United States, 43213
      • Columbus Obstetricians-Gynecology, Inc./Radiant Research, Inc.
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104
      • University of Pennsylvania School of Medicine
    • Philadelphia, Pennsylvania, United States, 19114
      • Clinical Research of Philadelphia
  • South Carolina
    • Bluffton, South Carolina, United States, 29910
      • Fellows Research Alliance, Inc.
  • Texas
    • Corpus Christi, Texas, United States, 78414
      • Advanced Research Associates
    • Dallas, Texas, United States, 75230
      • Practice Research Organization
    • Houston, Texas, United States, 77054
      • TMC Life Research, Inc.
  • Utah
    • Draper, Utah, United States, 84020
      • Physicians' Research Options
    • Pleasant Grove, Utah, United States, 84062
      • Physicians' Research Options
  • Virginia
    • Norfolk, Virginia, United States, 23507
      • Eastern Virginia Medical School
  • Washington
    • Seattle, Washington, United States, 98105
      • Seattle Women's Health, Research, Gynecology

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 11 years and older (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Female

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: LF111 (drospirenone); single treatment arm receives LF111	Drug: LF111 (drospirenone); One LF111 tablet once per day for 24 days followed by 4 placebo tablets for 4 days equals one cycle.; Other Names: CF111

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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	up to 13 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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)	up to 13 months
Number of Pregnancies (Method Failures)	PI for method failures in women aged ≤ 35 years (at the time of trial enrollment) (confirmed pregnancies)	up to 13 months
Pregnancy Ratio	Pregnancy ratio in women aged ≤ 35 years (at the time of trial enrollment)	up to 13 months
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)	up to 13 months
Number of Participants With Adverse Events as a Measure of Safety	Adverse events and changes in vital signs, clinical laboratory parameters	up to to 13 months
Tolerability; Vaginal Bleeding Pattern	Vaginal bleeding pattern	up to 13 months

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
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	up to 13 months
Overall Pregnancies	Overall PI based on confirmed and on confirmed and suspected, non-confirmed pregnancies in total and by BMI and weight subgroups	up to 13 months

Collaborators and Investigators

• Sponsor: Laboratories Leon Farma, S.A.
• Collaborators: Chemo France
• Investigators: Study Director: Enrico Colli, MD, Exeltis

Publications and helpful links

General Publications

• Palacios S, Colli E, Regidor PA. Efficacy and cardiovascular safety of the new estrogen-free contraceptive pill containing 4 mg drospirenone alone in a 24/4 regime. BMC Womens Health. 2020 Oct 2;20(1):218. doi: 10.1186/s12905-020-01080-9.

Study record dates

Study Major Dates

• Study Start (Actual): October 9, 2014
• Primary Completion (Actual): October 4, 2017
• Study Completion (Actual): October 4, 2017

Study Registration Dates

• First Submitted: October 6, 2014
• First Submitted That Met QC Criteria: October 16, 2014
• First Posted (Estimate): October 21, 2014

Study Record Updates

• Last Update Posted (Actual): August 6, 2019
• Last Update Submitted That Met QC Criteria: July 24, 2019
• Last Verified: October 1, 2017

More Information

Terms related to this study

• Keywords: contraception; drospirenone; oral contraceptive; birth control; hormonal oral contraceptive agents; hormonal oral contraceptive; LF111
• Additional Relevant MeSH Terms: Physiological Effects of Drugs; Hormones, Hormone Substitutes, and Hormone Antagonists; Natriuretic Agents; Diuretics; Hormone Antagonists; Mineralocorticoid Receptor Antagonists; Diuretics, Potassium Sparing; Drospirenone
• Other Study ID Numbers: CF111/303