Phase II Study of Ovulation in Obese Women

We will perform a single site clinical trial in obese women not at risk of pregnancy aged 18 to 40. We will screen to enroll and complete 22 participants. Each participant after signing an Informed Consent and meeting all inclusion and exclusion criteria will be enrolled on menstrual day 9-10 of a subsequent menstrual cycle following a negative urine pregnancy test. Each participant will be asked to collect a first morning voided urine sample beginning on menstrual day 9 and completing 15 days later on menstrual day 24. The participant will undergo a transvaginal ultrasound on menstrual days 9-10, 12, 13 and day 14 to determine ovarian follicle diameters in two planes frontal and sagittal using transvaginal ultrasound. When the largest follicle diameter is 17±1.0 millimeters (mm) the participant will be given the intervention: placebo in the 1st cycle and levonorgestrel plus meloxicam in the 2nd cycle followed by a second dose of each intervention 48 hours later. The ovarian follicle dimension of 17 mm occurs in the middle of the woman's window of fertility which is the four days preceding plus the day of ovulation. We anticipate that ovulation will take place within 3 days after the first placebo dose in 90% of the participants and will be delayed ≥7 days following the first dose of levonorgestrel plus meloxicam in ≥80% of the participants. The primary outcome is the delay in days from the first dose to evidence of ovarian corpus luteum formation which follows ovulation. All urine samples from the same participant will be analyzed in one assay for estrogen and progesterone metabolites to reduce inter-assay variability. The primary outcome will be delay of ovulation based on changes in the ratio of the urinary metabolites in obese women between placebo and active treatment. Secondary outcomes (exploratory) are a) safety parameters vital signs consisting of blood pressure and pulse obtained at each visit, b) adverse events, unscheduled bleeding, and changes in menstrual bleeding captured by the participant using a daily diary card. She will be instructed to write down any symptoms or problem along with medication taken both study drug and any other medication. Any treatment adverse event considered to be serious will be reported to the local institutional review board and the Food and Drug Administrating within 72 hours of our being made aware of the problem. The occurrence, percentage, and relationship to study drug of minor and moderate adverse events will be noted and categorized using Medical Dictionary for Regulatory Activates (MedRA) adverse event classification and listed in all reports and publications.

Each participant will be involved for a study period of approximately 2.5 months or 75 days. Each participant will undergo a complete history and physical evaluation at entry and a brief interim history and physical evaluation at exit with height and weight at entry. Mean and standard deviation of all vital signs before and after treatment, menstrual bleeding changes and treatment emergent adverse events will be compiled and listed in all reports and publications.

Inclusion criteria

• Female in good general health with no chronic medical conditions that result in periodic exacerbations that require significant medical care.
• Age between 18 to 40 years inclusive at time of enrollment.
• BMI ≥30 kg/m² and no recent rapid weight loss or gain.
• Intact uterus with both ovaries intact.
• Papanicolaou test within American Society for Colposcopy and Cervical Pathology (ASCCP), or American College of Obstetricians and Gynecologists (ACOG) guidelines such that additional testing or evaluation will not be required during the study period. If there is no copy of a recent Papanicolaou test and the subject is 21 years or older a Papanicolaou test should be done during the screening visit.
• Regular menstrual cycles with an interval of 24 to 32 days:

• If postpartum or post-second trimester abortion, she must have 2 spontaneous menses prior to enrollment.
• If the subject has had a first trimester pregnancy loss or abortion, she must have one spontaneous menses prior to enrollment.
• Have a negative urine pregnancy test on menstrual cycle day 9 pre-treatment visit.
• Not at risk of pregnancy for the duration of the study defined as heterosexually abstinent, prior female or male permanent contraception, non-hormonal intrauterine device or willing to use a non-hormonal barrier contraceptive method with each act of intercourse until study exit.
• Subject is willing and able in the Investigators opinion of complying with protocol requirements.
• Subject is willing to collect daily first morning urines and store them until brought to the study site.
• Lives within the study catchment area or a reasonable distance from the study site.
• Understands and signs the IRB approved informed consent prior to undergoing any screening assessment.
• Agrees not to participate in any other clinical trials during the course of this study.
• Screening serum progesterone level greater than 3 ng/ml.-

Exclusion criteria

• Known hypersensitivity or contraindications to progestins.
• Abnormal transvaginal ultrasound or safety laboratory results evaluated during the screening period recognized as clinically significant by the investigator or medically qualified designee.
• Known or suspected alcohol or marijuana abuse.
• Undiagnosed abnormal genital bleeding.
• Undiagnosed vaginal discharge, lesions or abnormalities.
• Women with a history of genital herpes can be included if the outbreaks are infrequent. Antiviral prophylaxis is allowed.
• Uncontrolled Thyroid disorder.
• Current use of hormonal contraception or a levonorgestrel releasing intrauterine device.
• Use of a long-acting injectable hormonal contraceptive within the past 6 months unless has had at least one spontaneous menstrual cycle (two menstrual bleeding episodes) since the last injection.
• Breastfeeding women or those who have not had a spontaneous menstrual bleed since discontinuing breastfeeding.
• Women who plan a major surgical procedure during the study.
• Women who plan to become pregnant during their participation in the study.
• Women who smoke >15 cigarettes per day or who use >1 mL/day of nicotine-containing liquid for electronic cigarettes.
• Current or history of ischemic heart disease or stroke while pregnant or during use of hormonal contraception.
• Current or past deep vein thrombosis or thromboembolic disorder.
• Personal or family history of thrombophilia
• History of retinal vascular lesions or partial or complete loss of vision.
• Known or suspected carcinoma of the breast, endometrium, or other suspected progestin sensitive neoplasia.
• History of other carcinomas excluding basal cell cancers unless in remission for > 5 years.
• Current or past medically diagnosed severe depression unless the potential participant is on stable medication or in the opinion of the Principal Investigator could be exacerbated using a hormonal contraceptive.
• History of headaches with focal neurologic symptoms.
• Have a current need for exogenous hormones or therapeutic anticoagulants.
• History of cholestatic jaundice of pregnancy or jaundice with prior steroid hormone use.
• Other benign or malignant liver tumors or active liver disease.
• Systolic BP ≥145 mm Hg and/or diastolic BP ≥96 mm Hg after 5 -10 minutes of rest in a sitting position. If the initial BP values are above these cut-offs, a total of 3 measurements may be taken and the results averaged. If the averaged BP is below the cut-off levels, the participant may be allowed into the study. Hypertension that is treated and controlled may be allowed based on the Investigator's discretion.
• Clinically significant abnormal serum chemistry value based on the Investigator's judgement.
• Participation in another clinical trial involving an investigational drug or device within the past two months before anticipated enrollment or is planning to participate in another clinical study during this study.
• Use of any liver enzyme inducers or plans to use such medication during the study.
• Known HIV infection.
• History of a gastrointestinal ulcer or bleeding.
• Women who are using medication on the Exclusionary medication list (See Appendix).
• Have issues or concerns, in the opinion of the Investigator, that may compromise the study or confound the reliability of compliance and information that is required in this study.
• Have a known hypersensitivity to either levonorgestrel or a non-steroidal anti-inflammatory drug.
• Use of any medication that could interfere with the metabolism of a hormonal contraceptive or the non-steroidal anti-inflammatory drugs or any drug that falls in FDA Pregnancy and Lactation narrative subsections (Formerly Category D or X medications).
• Be a site member with delegated study responsibilities or a family member of, or have a close relationship with, a site staff member who will be delegated study responsibilities.