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

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.

Study Overview

• Status: Completed
• Conditions: Ovulation
• Intervention / Treatment: Drug: NES/E2 gel

• Study Type: Interventional
• Enrollment (Anticipated): 18
• Phase: Phase 2

Contacts and Locations

Study Locations

• Chile
  • Santiago, Chile
    • Instituto Chileno de Medicina Reproductiva
• Dominican Republic
  • Santo Domingo, Dominican Republic
    • Profamilia
• United States
  • California
    • Los Angeles, California, United States, 90033
      • Women's and Children's Hospital; LA County/USC Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 40 years (Adult)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: Female

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Single

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: 1; 0.5 ml of NES/E2 equaling 0.45 g and contains 1.5 mg NES/0.5 mg E2	Drug: NES/E2 gel; 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.
Active Comparator: 2; 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; 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.
Active Comparator: 3; 1.5 ml of NES/E2 gel equaling 4.5 mg NES/1.5 mg E2	Drug: NES/E2 gel; 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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	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	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

Collaborators and Investigators

• Sponsor: Population Council

Publications and helpful links

General Publications

• Brache V, Merkatz R, Kumar N, Jesam C, Sussman H, Hoskin E, Roberts K, Alami M, Taylor D, Jorge A, Croxatto H, Lorange E, Mishell DR, Sitruk-Ware R. A dose-finding, cross-over study to evaluate the effect of a Nestorone(R)/Estradiol transdermal gel delivery on ovulation suppression in normal ovulating women. Contraception. 2015 Oct;92(4):289-97. doi: 10.1016/j.contraception.2015.05.011. Epub 2015 May 29.

Study record dates

Study Major Dates

• Study Start: November 1, 2008
• Primary Completion (Actual): January 1, 2014
• Study Completion (Actual): January 1, 2014

Study Registration Dates

• First Submitted: November 21, 2008
• First Submitted That Met QC Criteria: November 21, 2008
• First Posted (Estimate): November 24, 2008

Study Record Updates

• Last Update Posted (Estimate): April 17, 2015
• Last Update Submitted That Met QC Criteria: April 16, 2015
• Last Verified: April 1, 2015

More Information

Terms related to this study

• Keywords: contraception; ovulation; bleeding patterns; NES/E2; transdermal gel delivery
• Other Study ID Numbers: Population Council #427