A Phase 1, Open-Label, Parallel Group Study to Evaluate the Pharmacokinetics and Safety of DARE-HRT1 in Healthy PostMenopausal Women

Study Overview
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Brief Summary
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An open-label study to assess the PK of estradiol, estrone and progesterone from the DARE-HRT1 intravaginal rings at two different dose strengths.

Official Title
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A Phase 1, Open-Label, Parallel Group Study to Evaluate the Pharmacokinetics and Safety of DARE-HRT1 (80μg Estradiol/4mg Progesterone and 160μg Estradiol/8mg Progesterone Intravaginal Rings) in Healthy PostMenopausal Women

Conditions
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Vulvovaginal Atrophy, Vasomotor Symptoms

Intervention / Treatment
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* Device: IVR Dose 1
* Device: IVR Dose 2
* Drug: Oral Reference


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Postmenopausal women with body mass index >/= 18 and </= 38 kg/m2 Normal cervix and vagina An intact uterus An acceptable results from an endometrial biopsy normal mammogram report within 24 months of screening Exclusion Criteria: Prior abnormal cervical screening test (CST) or Pap result within 2 years of screening. Subject can have atypical squamous cells of undetermined significance (ASCUS), if HPV negative. Subjects with any self-reported active sexually transmitted disease and/or evidence of infection based on visual vaginal exam by the investigator Subjects with a UTI during screening as assessed by urine dipstick test with abnormal test findings (any positive result for leukocytes AND any positive result for nitrites) Subjects with > 4 mm endometrium lining at screening (on the transvaginal ultrasound) Have a history of endometrial hyperplasia or cervical or uterine carcinoma Subjects with indwelling catheters or requiring intermittent catheterization Subjects with multiple or unsuccessful (e.g., still having symptoms) pelvic reconstructive surgery, or suffers from pelvic relaxation Subjects who have had a hysterectomy Subjects taking any estrogen and/or progesterone products (see Section 4.1 for washout requirements) Subjects with concomitant use of personal lubricants (water-based lubricants are allowed) or any intravaginal product or medication, either by prescription or over-the-counter (e.g., Femring [estradiol acetate vaginal ring], ESTRING® [estradiol vaginal ring]) with the exception of those who agree not to use these products during the IVR use period Self-reported or observed vaginal irritation; vaginal, vulvar, or cervical lesions, undiagnosed vaginal bleeding; or tenderness Subjects with a finding of clinically significant uterine fibroids at screening Subjects with a known hypersensitivity to progesterone, estradiol, Femring, or the components of the IVR (e.g., ethylene vinyl acetate) Subjects with known hypersensitivity to peanuts (Prometrium capsules contain peanut oil) Subjects with prior pelvic malignancies Subjects with a history of any severe acute or chronic medical or psychiatric condition or laboratory abnormality that could increase the risk associated with trial participation or study treatment administration or could interfere with the interpretation of trial results and, in the judgment of the investigator, would make the subject inappropriate for entry into the trial. This includes but is not limited to the following: Human immunodeficiency virus (HIV) infection (confirmed by medical history/ serology testing) Active chronic hepatitis B or hepatitis C infection including hepatitis B surface antigen and hepatitis C antigen positive subjects with or without abnormal liver enzymes (confirmed by medical history/serology testing) Concurrent neurodegenerative disease Cardiovascular: uncontrolled hypertension, unstable angina, myocardial infarction or symptomatic congestive heart failure within the past 6 months, serious uncontrolled cardiac arrhythmia, use of Class 1 antiarrhythmic medications, or history of venous thromboembolism or stroke Dementia or significantly altered mental status that would prohibit the understanding or rendering of informed consent and compliance with the requirements of the protocol History of gallbladder disease unless gallbladder removed Symptomatic bacterial vaginosis Have fasting triglyceride of > 300 mg/dL and/or total cholesterol of > 300 mg/dL AST or ALT > 1.5 times the upper limit of normal Fasting glucose > 125 mg/dL Evidence of current alcohol or drug abuse in the past 60 days including a positive result from the urine drugs of abuse or alcohol screen, or history of drug or alcohol dependence in the last two years, as assessed by principal investigator. Alcohol abuse is defined as greater than 14 standard units/week for females and drug abuse is defined as known psychiatric or substance abuse disorder that would interfere with participation with the requirements of this study, including current use of any illicit drugs. Participation in any other investigational drug or device trial in which administration of an investigational study drug/device occurred within 30 days or placement of a non-drug eluting medical device within 15 days prior to screening.
Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Other
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: IVR: estradiol 80 ug/day + progesterone 4mg/day<br>28-day IVR 80/4 | Device: IVR Dose 1<br>* Estradiol 80 ug/progesterone 4 mg<br>|
| Experimental: IVR: estradiol 160 ug/day + progesterone 8mg /day<br>28-day IVR 160/8 | Device: IVR Dose 2<br>* Estradiol 160ug/progesterone 8 mg<br>|
| Active Comparator: Oracle Estrace(R)/Prometrium(R)<br>29 days (estradiol 1mg/progesterone 100 mg oral capsule) | Drug: Oral Reference<br>* estradiol 1mg/progesterone 100 mg<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To determine the steady state concentration (Css) for estradiol | To describe the Pharmacokinetic parameters of estradiol in dose combinations (Estradiol 80 ug/progesterone 4/mg day and Estradiol 160 ug/progesterone 8/mg day) | 28 days | 
| To determine the stead state concentration (Css) for estrone | To describe the Pharmacokinetic parameters of estrone in dose combinations (Estradiol 80 ug/progesterone 4/mg day and Estradiol 160 ug/progesterone 8/mg day) | 28 days | 
| To determine the steady state concentration (Css) for progesterone | To describe the Pharmacokinetic parameters of progesterone in dose combinations (Estradiol 80 ug/progesterone 4/mg day and Estradiol 160 ug/progesterone 8/mg day) | 28 days |