A Study to Assess the Skin Irritation and Sensitization of Estradiol/Levonorgestrel TDS in Healthy Postmenopausal Subjects

This is a multi-center, evaluator-blinded, randomized phase 1 study evaluating skin irritation and skin sensitization of Estradiol/Levonorgestrel transdermal system in comparison to Climara Pro® transdermal patch in healthy postmenopausal women. The study will consist of a 5 week Screening Phase and a Treatment Phase. The Treatment Phase will consist of the following periods: an Induction Period, a Rest Period followed by a Challenge Period and if needed, a Re-Challenge Period.

Trained study staff will examine the patch application sites at scheduled time points and will score any skin reactions using standardized assessment scales specified within FDA Product Specific Guidance.

Furthermore, the overall safety of the test product will be compared with that of the comparator product by monitoring and recording any adverse events, side effects, or discomfort experienced during the study.

Inclusion criteria

• Naturally or surgically postmenopausal female, with or without an intact uterus, aged 40-75 years, inclusive. Postmenopausal is defined by FDA Draft Guidance as:

• At least 12 months natural spontaneous amenorrhea; or
• ≥ 6 months and < 12 months natural spontaneous amenorrhea with serum FSH levels > 40 mIU/mL at screening; or
• At least 6 weeks postsurgical bilateral oophorectomy with or without hysterectomy.

Any participant who meets criteria a) or c) above and has an FSH level that is considered postmenopausal by national lab standards, is eligible for study enrollment.

• For participants with an intact uterus, has a vaginal ultrasonography and/or MRI (performed at screening or within 3 months before initial patch application) demonstrating inactive endometrial lining with endometrial thickness < 4 mm.
• A body weight ≤ 90 kg.
• Good health as determined by lack of clinically significant abnormalities in the participant's medical history or health assessments performed at screening (as applicable), as determined by the Investigator (or designee), including a negative mammogram and/or breast MRI (performed at screening or within 9 months before initial patch application), and a normal clinical breast examination.
• Total cholesterol level ≤ 275 mg/dL.
• Triglycerides level ≤ 350 mg/dL.
• For participants at the US clinical site, the participant will be required to read, understand, sign and date the informed consent form, which meets all criteria of current FDA regulations, and must be able to understand the information and instruction given to them during the study.
• For participants at the India clinical site, the participant is able to understand and comply with the study procedures, in the opinion of the Investigator, and able to give voluntary written consent for participation in the study.
• Able and willing to comply with protocol restrictions, required study procedures, and visit requirements.

Exclusion criteria

• Male participants.
• Participants who are premenopausal or perimenopausal, as determined by the Investigator, or pregnant, lactating or likely to become pregnant during the study.
• History of allergy (e.g., anaphylactic reaction), hypersensitivity, or angioedema (including hereditary angioedema) to Climara Pro® or any of its components, including glues/adhesives, or history of any drug hypersensitivity or intolerance that, in the opinion of the Investigator, would compromise the safety of the participant or integrity of the study.
• Presence of any current dermatological condition at the application site(s) (e.g., atopy, psoriasis, eczema, chronic or atopic dermatitis, vitiligo, urticaria) or conditions known to alter skin appearance or physiologic response (e.g., diabetes, porphyria) or history of allergic, sensitization or skin sensitivity that would compromise the integrity of the study data.
• Excessive hair or other compounding factors (e.g., tattoos, scar tissue, recently shaved skin, uneven or obvious difference in skin condition or coloration, sunburn, open sores, moles, body piercings, etc.) at the application sites that, in the opinion of the Investigator, would compromise the ability of the patch to be applied or the ability of the evaluator to observe possible irritation.
• History of or current evidence of hypertension, as determined by the Investigator, or has a seated systolic blood pressure > 140 mmHg or diastolic blood pressure > 90 mmHg; determined at screening.
• Participants with known allergic or immunological disorders (e.g., primary or acquired immunodeficiencies such as human immunodeficiency virus [HIV] positive or AIDS, allergic diseases such as anaphylaxis, asthma or generalized drug reaction, rheumatoid arthritis or systemic lupus erythematosus). Resolved childhood asthma or minor allergic reactions to environmental allergens or foods need not be reason for exclusion.
• Significant history or current evidence, as determined by the Investigator, of chronic infectious disease, system disorders, organ dysfunction especially renal disorders, hepatic impairment or disease (especially prior cholestatic jaundice of pregnancy, jaundice with prior estrogen use, or hepatic hemangiomas), gallbladder disease, pancreatitis or hypertriglyceridemia, hypercalcemia, thyroid disorders (especially hypoparathyroidism), residual endometriosis post-hysterectomy, epilepsy, migraine, porphyria, or cardiovascular disorders (especially coronary heart disease).
• Has any risk factors, as determined by the Investigator, for arterial vascular disease/arterial thrombosis (e.g., hypertension, diabetes, tobacco use, or hypercholesterolemia) or venous thromboembolism (VTE) including retinal vascular thrombosis (e.g., personal history or immediate family history of VTE, or systemic lupus erythematosus).
• History or current evidence (i.e., active) of deep venous thrombosis (DVT) or pulmonary embolism (PE), as determined by the Investigator.
• History or current evidence (i.e., active) of arterial thromboembolic disease (e.g., stroke, myocardial infarction, etc.), as determined by the Investigator.
• Known or significant family history (as determined by the Investigator) of coagulation disorders (i.e., bleeding or clotting disorders) such as excessive/prolonged bleeding from cuts, bruising easily, blood clots, etc.
• Known, suspected, significant family history (as determined by the Investigator), or history of breast cancer, bone metastases, endometrial cancer, or ovarian cancer.
• Known or suspected (as determined by the Investigator based on participant's provided medical history) estrogen-dependent neoplasia.
• Known or suspected (as determined by the Investigator based on participant's provided medical history) protein C, protein S, or antithrombin deficiency, or other thrombophilic disorders.
• Undiagnosed persistent or recurring abnormal genital bleeding with unknown etiology.
• Has a scheduled surgery of the type associated with an increased risk of thromboembolism or anticipates periods of prolonged immobilization within 6 weeks after completion of the study.
• Contraindication to estrogen therapy or is currently taking thyroid hormone replacement therapy or anticipates use during the study.
• Within 3 weeks of the study start, use of medications or treatments which, in the opinion of the Investigator, could influence or exaggerate responses to the patches or could alter the inflammatory or immune responses.
• Use of pharmacologic agents or products known to significantly induce or inhibit drug-metabolizing enzymes especially inducers of CYP3A4 and inhibitors of CYP3A4 within 30 days before initial patch application or anticipated use during the study.
• Use of any of the following within the noted times before initial patch application or anticipated use during the study:

• Estrogen pellet therapy or progestin injectable drug therapy within 6 months before initial patch application.
• Progestin implants and estrogen alone injectable drug therapy within 3 months before initial patch application.
• Oral estrogen and/or oral or intrauterine progestin therapy within 8 weeks before initial patch application.
• Transdermal estrogen alone or transdermal estrogen/progestin products within 4 weeks before initial patch application.
• Vaginal hormonal products (e.g., rings, creams, gels) within 1 week before initial patch application.
• Use of prescription or over-the-counter (OTC) antihypertensives (e.g., diuretics, ACE inhibitors, angiotensin II receptor blockers, beta-blockers), pressor agents (e.g., midodrine, vasopressin, norepinephrine, epinephrine, phenylephrine, decongestants, NSAIDs like ibuprofen and naproxen), and estrogens (other than the study drug) from the time screening to initial patch application or anticipated use during the study.
• Use of antihistamines or use of topical drugs at application site within 72 hours before the first patch application.
• Use of any cosmetics, moisturizers, powders, and sunscreen or other topical products (e.g., makeup, oil, lotion, creams sprays, powders, etc.) at the patch application sites within 24 hours before the first patch application.
• Receipt of any drug as part of a research study within at least 30 days before initial dosing.
• Any history of narcotic abuse, drug abuse or alcohol addiction.
• Positive test results for HIV, Hepatitis B surface antigen, or Hepatitis C antibody.
• Positive test results for drugs of abuse or alcohol at screening.
• Positive pregnancy test at screening.
• Use of tobacco- or nicotine-containing products within 30 days before initial patch application or anticipated use during the study.