A Multi-center, Open-label, Randomized, Parallel Group Study to Evaluate Pharmacokinetic Profile, Effects on the Mechanisms of Contraceptive Efficacy and Safety of Two Progestin-only Patches Containing Different Doses of Levonorgestrel (LNG)

WHAT IS THE STUDY PRODUCT? The study product is a contraceptive patch, which has the study drug on the patch. The patch is applied directly to the skin and it contains Levonorgestrel (LNG) in a time-release form. LNG is a hormone that has been tested and been approved by the Food \& Drug Administration (FDA) in other forms, for example: contraceptive pills, intrauterine devices (IUDs, which are put in the uterus (womb)) and implants (drug in silicon tubing placed under the skin). The use of LNG in the form of a contraceptive patch makes this an experimental drug because the way the drug will be absorbed in the body is a new technique. This study drug does not contain estrogen and it does not protect against HIV, AIDS, or any other sexually transmitted diseases (STDs).

LNG is a progestin (a type of drug that is like a hormone. Progestins can cause changes at the opening of the uterus (womb), such as thickening of the cervical mucus (fluid). This thickened cervical mucus makes it difficult for the male's sperm to reach and fertilize the woman's egg. Since LNG is being absorbed through your skin from the patch, it is experimental, and it is unknown if this study product will really prevent pregnancy like other progestins.

WHY IS THIS STUDY BEING DONE?

The purpose of this study is to find out:

* How well the patch prevents pregnancy
* How safe the patch is to use every day
* How much study drug needs to be in the patch to make sure that it prevents pregnancy
* How the study drug in the patch affects cervical mucus (fluids)
* How the study drug in the patch affects your rate of ovulation (how often you release an egg)
* How well the patch sticks to your skin, without falling off, for a week at a time
* Whether the patch causes any skin irritation or rash (redness or itchiness)
* Whether the study drug in the patch affects your everyday life and if it causes any side effects.

WHAT DOES THE STUDY INVOLVE? We expect that there will be approximately twenty (20) women at each of the six (6) participating clinics in the study. In total, there will be about 120 women from all over the United States who will be in this study. This study is comparing the effectiveness of two different doses of the study drug (40ug and 75 ug) in the patches. This study is an open-label randomized trial, meaning that you and your study doctor will be aware of the dosage of study drug that you will be given. Randomization means that you will be selected by chance, like tossing a coin or rolling a dice. You have a 50% chance of being in the group that receives the 40ug dose patch or the group that receives 75ug dose patch.

This is a Phase I/II, multi-center, open-label, randomized, parallel group, pharmacokinetic, pharmacodynamic study of the AG1000-6.5 and AG1000-12.5 transdermal contraceptive delivery systems (TCDS) in healthy women followed as an outpatient for up to three 28-day cycles (12 weeks or approximately 3 months). During this study, subjects will receive active treatment with the LNG TCDS patches for 11 weeks, followed by one week of post-treatment assessment. The TCDS is designed for one week of patch wear. This study will be conducted by the National Institute of Child Health and Human Development (NICHD) in its Contraceptive Clinical Trials Network (CCTN) at 6 sites in the USA and will enroll approximately 120 women.

This study will enroll approximately 120 subjects, who will be randomized across all sites into the two treatment groups (\~60 subjects at each dose level). The randomization schedule will be further stratified to ensure enrollment of approximately 50% of subjects with BMI \>32 kg/m2 and \<40 kg/m2 and approximately 50% of subjects with BMI \<32 kg/m2 for each dose level.

Eligibility Criteria:
Inclusion Criteria:

* 1. Good general health.
* 2. Aged 18-44 years, inclusive, at the enrollment visit.
* 3. Intact uterus with at least one ovary.
* 4. Pap test within the last 12 months or undergo a Pap test at screening prior to enrollment. If a potential subject states that she has had a Pap test within the last 12 months, then she will need to provide documentation of acceptable test results.
* 5. Cervical mucus score of \>7, which is based on the modified Insler scoring system during the screening cycle. The cervical mucus is collected by aspiration and the assessment is based on the modified Insler scoring system (the volume and pH of the mucus are not included in the total scoring) yielding a total possible score of 12 (3, 4).
* 6. Regular menstrual cycles that occur every 28 ± 7 days.

  1. If subject is postpartum or post-abortal (with abortion in second trimester), she will be required to have two normal menstrual cycles prior to screening.
  2. If subject had an abortion in the first trimester, she will be required to have at least one menstrual cycle (two menses) prior to screening.
* 7. Heterosexually abstinent or, if heterosexually active, must have undergone previous tubal sterilization, be in monogamous relationship with a vasectomized partner, or only use male or female condoms (use of condoms that are pre-lubricated with or without spermicide is acceptable) for the entire duration of the study. Use of a spermicide applied separately is not allowed. Cervical caps or diaphragms are not allowed during study participation.
* 8. In the opinion of the investigator, able to comply with the protocol, willing to record requested information in the daily diary, and live within the study site catchment area or within a reasonable distance from the site.
* 9. Understand and sign an IRB approved informed consent form prior to screening activities (including fasting blood draw).
* 10. Willing to refrain from use of skin lotions/creams/gels on area of patch application and not use any vaginal creams, lubricants, gels, or spermicides for 3 days prior to study admission through to the end of the study.
* 11. Agree not to participate in any other clinical trials during the course of this study.

Exclusion Criteria:

Contraindications for enrollment will be the same as those for use of combined hormonal contraceptives as referenced in the World Health Organization (WHO) Medical Eligibility Criteria(MEC category 1 or 2) (1), in addition to contra-indications specific to this clinical trial including:

* 1. Known hypersensitivity or contraindication to progestins.
* 2. Known or suspected pregnancy.
* 3. Prior hysterectomy or bilateral oophorectomy.
* 4. Prior cervical surgery (LEEP, Cone biopsy, Cryosurgery).
* 5. A history (within prior 12 months) or drug or alcohol abuse.
* 6. Undiagnosed abnormal genital bleeding.
* 7. Undiagnosed vaginal discharge or vaginal lesions or abnormalities. Subjects diagnosed at screening with a Chlamydia or gonococcus infection may not be included in the trial unless they are treated and proof of cure is documented after treatment (i.e. repeat test with negative results). In accordance with PI/medical designee assessment and local standards of practice, women with a history of genital herpes can be included if outbreaks are infrequent. Antiviral prophylactic therapy is permitted.
* 8. Uncontrolled thyroid disorder.
* 9. History or presence of dermal hypersensitivity in response to topical application. Specifically any reaction to application of a plastic bandage (Band-Aid), surgical or bandage tape, other skin patches, or adhesives.
* 10. Any Pap test finding that would require additional workup or treatment during the study interval. HPV testing will not be done at screening for these subjects.
* 11. Use of an injectable hormonal contraceptive (Depo-Provera®) within the past 10 months.
* 12. Use of oral contraceptives, contraceptive implants, or other sex steroid hormones within 30 days prior to screening visit.
* 13. Women who are breastfeeding or within 30 days of discontinuing breast feeding.
* 14. Women planning to undergo major surgery within four months of study enrollment.
* 15. Women planning pregnancy within their months of study enrollment.
* 16. Smoking in women who are ages 18-44 years old that smoke 15 cigarettes or more per day must be evaluated by the PI for inclusion based on risk factors that would increase their risk for CVD and thromboembolism.
* 17. Current or past deep vein thrombophlebitis or thromboembolic disorders.
* 18. History of known thrombophilia in a first-degree relative \<45 years of age suggesting familial defect in blood coagulation system, which in the opinion of the principal investigator, suggests use of a hormonal contraceptive could pose a significant risk.
* 19. Cerebrovascular or cardiovascular disease or increased risk for arterial thrombosis.
* 20. History of retinal vascular lesions, unexplained partial or complete loss of vision.
* 21. Known or suspected carcinoma of the breast, endometrium, or any other known or suspected progestin-dependent neoplasia.
* 22. Past history of any other carcinoma (excluding basal cell carcinomas) unless in remission for more than 5 years.
* 23. Current or past medically diagnosed severe depression, which, in the opinion of the investigator, could be exacerbated by use of a hormonal contraceptive, unless she is stable on antidepressant medication.
* 24. Headaches with focal neurological symptoms only in women over 35 years old.
* 25. History of cholestatic jaundice of pregnancy or jaundice with prior steroid use or other benign or malignant liver tumors; active liver disease.
* 26. Systolic BP \> 140 mm Hg and/or Diastolic blood pressure (BP) \> 90 mm Hg after 5-10 minutes rest.
* 27. Clinically significant abnormal serum chemistry values according to the Principal Investigator's judgment.
* 28. Participation in another clinical trial involving an investigational drug or device within last 30 days (prior to screening).
* 29. Use of liver enzyme inducers within last 90 days (prior to screening) or intention to use liver enzyme inducers during the study (see Appendix 2 Exclusionary Medication List).
* 30. Known HIV infection.
* 31. Women at high risk of contracting HIV, e.g. women with multiple sex partners who need to use condoms consistently, injection drug users. Women enrolled in the study, who use condoms to protect against STIs or pregnancy, should be instructed that they can use condoms that are pre-lubricated with spermicide or lubricated, but they cannot use a spermicide applied separately and they should record all condom use in their diaries.
* 32. Women who use any medications on the Exclusionary Medication List (see Appendix 2) OR used any within the past three months prior to the screening visit.
* 33. Women with BMI ≥40 kg/m2 are excluded.