A Phase I Study to Evaluate the PK and PD of a Single Injection of Levonorgestrel Butanoate for Female Contraception
A Phase I Study to Evaluate the PK and PD of a Single Injection of Levonorgestrel Butanoate for Female Contraception
To evaluate the levonorgestrel (LNG) pharmacokinetic (PK) profile following injection of a
 single 20 mg dose of levonorgestrel butanoate (LB).
This is a Phase I single center, open-label, single dose pharmacokinetic and pharmacodynamic
 study of an injectable formulation of levonorgestrel butanoate (LB) jointly developed by the
 National Institute of Child Health and Human Development (NICHD) and CONRAD, and manufactured
 by Coldstream Laboratories, Inc. Healthy normal weight and obese women will be followed as
 outpatients for up to eight months. During this study, subjects will undergo a screening
 cycle to confirm normal ovulatory function, and then receive active treatment with a single
 injection of LB. They will undergo frequent evaluations to obtain serum samples to evaluate
 drug levels and ovulatory function, as well as transvaginal ultrasound and cervical mucus
 evaluation at selected visits. Follow up will continue until normal ovulatory cycles resume.
 Based upon detailed studies in non-human primates, it is expected that most subjects will
 resume menstrual cyclicity within 12- 26 weeks following the injection. Subjects will
 continue to be followed for one normal cycle after return of menses. This study will be
 conducted by the NICHD at one of the Contraceptive Clinical Trials Network (CCTN) sites
 (Oregon Health & Science University, (OHSU)) in the USA and will enroll approximately 16
 women.

 This study will enroll approximately 16 subjects that demonstrate favorable cervical mucus
 and normal ovulatory function during a baseline cycle. Enrollment will be stratified to
 ensure that 50% of the subjects have a BMI >32 kg/m2 and <40 kg/m2 and approximately 50% of
 subjects have a BMI <32 kg/m2.
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. Serum progesterone value ≥ 3 ng/mL at the Screening Visit (V0-P)

 5. 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

 6. 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)

 7. Regular menstrual cycles that occur every 24 - 35 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

 8. 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

 9. 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

 10. Understand and sign an IRB approved informed consent form prior to screening
 activities (including fasting blood draw)

 11. Willing to refrain from use of any vaginal creams, lubricants, gels, or spermicides
 for 3 days prior to study admission through to the end of the study

 12. Agree not to participate in any other clinical trials during the course of this study

 Exclusion Criteria:

 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)

 5. A history (within prior 12 months) of 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. 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

 10. Use of an injectable hormonal contraceptive (Depo-Provera®) within the past 10 months

 11. Use of oral contraceptives, contraceptive implants, or other sex steroid hormones
 within 30 days prior to screening visit

 12. Women who are breastfeeding or within 30 days of discontinuing breast feeding

 13. Women planning to undergo major surgery within four months of study enrollment

 14. Women planning pregnancy within their months of study enrollment

 15. 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 cardiovascular (CVD) and thromboembolism

 16. Current or past deep vein thrombophlebitis or thromboembolic disorders

 17. 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

 18. Cerebrovascular or cardiovascular disease or increased risk for arterial thrombosis

 19. History of retinal vascular lesions, unexplained partial or complete loss of vision

 20. Known or suspected carcinoma of the breast, endometrium, or any other known or
 suspected progestin-dependent neoplasia

 21. Past history of any other carcinoma (excluding basal cell carcinomas) unless in
 remission for more than 5 years

 22. 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

 23. Headaches with focal neurological symptoms only in women over 35 years old

 24. History of cholestatic jaundice of pregnancy or jaundice with prior steroid use or
 other benign or malignant liver tumors; active liver disease

 25. Systolic BP > 140 mm Hg and/or Diastolic blood pressure (BP) > 90 mm Hg after 5-10
 minutes rest

 26. Clinically significant abnormal serum chemistry values according to the Principal
 Investigator's judgment

 27. Participation in another clinical trial involving an investigational drug or device
 within last 30 days (prior to screening)

 28. Use of liver enzyme inducers within last 90 days (prior to screening) or intention to
 use liver enzyme inducers during the study

 29. Known HIV infection

 30. 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

 31. Women who use any medications on the Exclusionary Medication List OR used any within
 the past three months prior to the screening visit

 32. Women with BMI ≥40 kg/m2 are excluded

 33. Have issues or concerns (in the judgment of the investigator) that may compromise the
 safety of the subject or confound the reliability of compliance and information
 acquired in this study