A Phase 2, Dose-finding, Cross-over Study to Evaluate the Effect of a NES/E2 Transdermal Gel Delivery on Ovulation Suppression in Normal Ovulating Women

Study Overview
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Brief Summary
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This is a Phase 2, dose-finding, cross-over study for the purposes of evaluating the effect of a NES/E2 transdermal gel delivery on ovulation suppression in normal ovulating women.

Official Title
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A Phase 2, Dose-finding, Cross-over Study to Evaluate the Effect of a NES/E2 Transdermal Gel Delivery on Ovulation Suppression in Normal Ovulating Women

Conditions
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Ovulation

Intervention / Treatment
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* Drug: NES/E2 gel


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Woman is between 18 and 40 years of age Has intact uterus and ovaries Has regular menstrual cycles of 25-35 days duration Able to comply with the protocol, including frequent blood sampling, and lives within the catchment area of the clinic Understands the study procedures and agrees to participate in the study by giving written informed consent Able to use non-hormonal, double-barrier contraceptives (e.g. condoms and diaphragm) with every act of intercourse, or has been sterilized with tubal ligation, or only male partner has been sterilized with vasectomy Progesterone >10 nmol/L in at least one sample in the lead-in cycle Exclusion Criteria: All contraindications to OC use including Thrombophlebitis or thromboembolic disorders Past history of deep vein thrombophlebitis or thromboembolic disorders Past or current cerebrovascular or coronary artery disease Known or suspected carcinoma of the breast Carcinoma of the endometrium or other known or suspected estrogen-dependent neoplasia Undiagnosed abnormal genital bleeding Cholestatic jaundice of pregnancy or jaundice with prior pill use Hepatic adenomas or carcinomas Woman has a history of headaches with focal neurological symptoms Known or suspected pregnancy Aged >35 and smoker BMI >29 Positive urine pregnancy test at the screening or baseline visit Desired pregnancy within the duration of the study Known hypersensitivity to progestins Known hypersensitivity to estrogen Undiagnosed vaginal discharge or vaginal lesions or abnormalities In accordance with the Bethesda system of classification Women with a current abnormal Pap smear suggestive of high-grade pre cancerous lesion(s), including HGSIL, are excluded Women with LGSIL or ASCUS/high-risk HPV positive may participate if further evaluated with colposcopy and biopsy and no evidence of a lesion with a severity >CIN I is present and/or endocervical curettage is negative Women with a biopsy finding of CIN I should have follow up for this finding per standard of care; women are excluded if treatment is indicated In accordance with other Pap class systems Women with high grade dysplasia are excluded Women with low grade dysplasia or CIN I interpretation on Pap smear may participate based on investigator discretion in accordance with local standard of care Breastfeeding Cancer (past history of any carcinoma or sarcoma) History of a significant psychiatric disorder, including severe depression. Chronic or acute liver or renal disease Hypertension-- controlled by medication or defined by diastolic BP 85 mm Hg or systolic BP 135mm Hg after 15 minutes rest Dermatitis, psoriasis or other severe skin disorder Known or suspected alcoholism or drug abuse Clinically significant abnormalities of laboratory safety tests Chronic disease or history of illness that, in the opinion of the investigator, might confound the results of the study or pose additional risk to the subject Woman is participating or has participated in another clinical study (involving an investigational drug) within one month prior to enrollment. Use of injectable contraceptives during the previous 3 months (e.g. cyclofem) or 9 months (e.g. DMPA) Use of oral contraceptives within the past 1 month Use of concomitant drugs that may interact with the study drugs

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 40 Years

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: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: 1<br>0.5 ml of NES/E2 equaling 0.45 g and contains 1.5 mg NES/0.5 mg E2 | Drug: NES/E2 gel<br>* Lowest effective dose of 3 formulations of the NES/E2 gel to ensure ovulation suppression (P<10nmol/L) in 90-95% of the cycles. The high dose will deliver 4.5mg of NES; the medium dose will deliver 3mg of NES, and a low dose of 1.5mg of NES. Based on a 10% absorption rate, 450 µg/d, 300 µg/d and 150 µg/d will be absorbed respectively. The doses of Estradiol will also be tailored to the 3 formulations.<br>|
| Active Comparator: 2<br>1.0 ml of NES/E2 gel equaling 0.9 g and contains 3.0 mg NES/1.0 mg E2 | Drug: NES/E2 gel<br>* Lowest effective dose of 3 formulations of the NES/E2 gel to ensure ovulation suppression (P<10nmol/L) in 90-95% of the cycles. The high dose will deliver 4.5mg of NES; the medium dose will deliver 3mg of NES, and a low dose of 1.5mg of NES. Based on a 10% absorption rate, 450 µg/d, 300 µg/d and 150 µg/d will be absorbed respectively. The doses of Estradiol will also be tailored to the 3 formulations.<br>|
| Active Comparator: 3<br>1.5 ml of NES/E2 gel equaling 4.5 mg NES/1.5 mg E2 | Drug: NES/E2 gel<br>* Lowest effective dose of 3 formulations of the NES/E2 gel to ensure ovulation suppression (P<10nmol/L) in 90-95% of the cycles. The high dose will deliver 4.5mg of NES; the medium dose will deliver 3mg of NES, and a low dose of 1.5mg of NES. Based on a 10% absorption rate, 450 µg/d, 300 µg/d and 150 µg/d will be absorbed respectively. The doses of Estradiol will also be tailored to the 3 formulations.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Determine with ultrasound scan (USS) measures and serum progesterone (P) assessment the lowest effective dose of 3 formulations of the NES/E2 gel to ensure ovulation suppression (P<10nmol/L) in 90-95% of the cycles |  | Subjects will remain in the study for approximately 8 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Determine with USS and E2 serum levels the dose that can suppress follicle growth and replace estradiol at the physiological early follicular phase level |  | Subjects will remain in the study for approximately 8 months | 
| Evaluate the correlation of NES and E2 serum levels with the percentage of ovulation suppression |  | Subjects will remain in the study for approximately 8 months | 
| Evaluate the safety and tolerability of the formulations |  | Subjects will remain in the study for approximately 8 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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NES/E2, transdermal gel delivery, contraception, ovulation, bleeding patterns