A Study to Evaluate the Effect of a Contraceptive Vaginal Ring Delivering Ulipristal Acetate Combined With a Single or Repeated Levonorgestrel on Inhibition of Ovulation, Endometrial Changes and Bleeding Patterns in Normal Cycling Women

A Randomized Study to Evaluate the Effect of a Contraceptive Vaginal Ring Delivering a Daily Dose of 2500 μg of Ulipristal Acetate Combined With a Single or Repeated Levonorgestrel 1.5mg Oral Dose on Inhibition of Ovulation, Endometrial Changes and Bleeding Patterns in Normal Cycling Women

The purpose of this study is to determine the effect of a contraceptive vaginal ring on inhibition of ovulation, endometrial changes and bleeding patterns in normal cycling women.

Study Overview

• Status: Unknown
• Conditions: Ovulation Inhibition
• Intervention / Treatment: Drug: Ulipristal acetate

• Study Type: Interventional
• Enrollment (Actual): 19
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• Dominican Republic
  • Santo Domingo, Dominican Republic
    • Profamilia

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 21 years to 35 years (Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Female

Description

Inclusion Criteria:

• Not at risk for pregnancy based on one of the following: a. subject has undergone sterilization; b. subject is monogamous and her male partner has undergone sterilization
• Have regular menstrual cycles of 25-35 days duration
• Have an intact uterus and both ovaries
• Will be able to comply with the protocol
• Capable of giving informed consent

Exclusion Criteria:

• Women participating in another clinical trial
• Women not living in the catchment area of the clinic
• Known hypersensitivity to progestins or antiprogestins
• Known hypersensitivity to silicone rubber
• Any chronic disease
• All contraindications to oral contraceptive use, including: a. Thrombophlebitis or thromboembolic disorders; b. Past history of deep vein thrombophlebitis or thromboembolic disorders; c. Past or current cerebrovascular or coronary artery disease; d. Migraine with focal aura; e. Known or suspected carcinoma of the breast; f. Carcinoma of the endometrium or other known or suspected estrogen-dependent neoplasia; g. Undiagnosed abnormal genital bleeding; h. Cholestatic jaundice of pregnancy or jaundice with prior pill use; i. Hepatic adenomas or carcinomas; j. Known or suspected pregnancy
• Desire to get pregnant during the study (through the use of reproductive technology for sterilized women or vasectomy reversal for sterilized partners)
• Breastfeeding
• Undiagnosed vaginal discharge or vaginal lesions or abnormalities
• Women with a current abnormal Pap: In accordance with the Bethesda system of classification: 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 it treatment is indicated.
• Known benign or malignant liver tumors; known active liver disease
• Cancer (past history of any carcinoma or sarcoma)
• Medically diagnosed severe depression currently or in the past
• Known or suspected alcoholism or drug abuse
• Abnormal serum fasting clinical chemistry values
• Women with known abnormal thyroid status
• Women with known impaired hypothalamic-pituitary-adrenal reserve
• Average diastolic BP > 85 mm or systolic BP >135 mm Hg after 5-10 minutes rest
• Body mass index (BMI) > 30.0 (or ≤18)
• Smoking in women who will be 35 years during the course of the trial; women < 35 years who smoke greater than 15 cigarettes per day must be evaluated by the PI for inclusion based on risk factors that would increase their risk for CVD and thromboembolism, e.g. lipid levels, glucose level, BP, BMI, family history of CVD at a young age.
• Women with severe cystoceles or rectoceles
• Use within the past 2 months of any implanted hormonal contraceptives including Mirena [progestin containing intrauterine system (IUS)] or Norplant (subdermal implant delivering LNG). NOTE: Removal of implanted hormonal contraceptives must have been for personal reasons unrelated to the purpose of enrollment in this study.
• Current use of a non-hormone containing IUD. NOTE: Removal of an IUD must have been for personal reasons unrelated to the purpose of enrollment in this study.
• Use of injectable contraceptives during the previous 3 months (e.g. Cyclofem) or 6 months (e.g. DMPA).
• Women who do not have at least two progesterone measurements during the control cycle of ≥10nmol/L will be excluded from further participation in the study (See Section 13.4.1)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: 1.5 mg tablet LNG after 12 weeks; CVR delivering 2,500 µg of Ulipristal acetate per day and a single dose of levonorgestrel delivered in a 1.5 mg tablet after 12 weeks of CVR use	Drug: Ulipristal acetate; CVR delivering Ulipristal acetate and one tablet levonorgestrel.
Active Comparator: 1.5 mg tablet LNG every 4 weeks; CVR delivering 2,500 µg of Ulipristal acetate per day and one 1.5 mg tablet levonorgestrel every 4 weeks of CVR use (three times).	Drug: Ulipristal acetate; CVR delivering Ulipristal acetate and one tablet levonorgestrel.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Pharmacodynamic efficacy as measured by the effects of a vaginal ring delivering Ulipristal acetate consistently combined with levonorgestrel administration on the endometrium	Endometrial biopsies (EB) will be taken as follows, a.During the follicular phase (between Day 9 and Day 12) of the baseline/control cycle, b. At the end of the 14th week of treatment (14 days after the 12 week LNG administration and end of CVR use), c. During the follicular phase (between Day 9 and Day 12 of the second menstrual cycle after ring removal). Also, endometrial changes will be measured by histological examination, immunohistochemistry, and assessment of proliferation markers (Ki67, Phospho H3 and bcl2).	3 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Safety as measured by number of participants with occurrence of adverse events (AEs) and concomitant medication use	Safety as measured by the assessment of a vaginal ring delivering Ulipristal acetate consistently combined with levonorgestrel administration	3 months

Collaborators and Investigators

• Sponsor: Population Council
• Investigators: Study Director: Ruth Merkatz, Ph.D., Population Council

Study record dates

Study Major Dates

• Study Start: May 1, 2015
• Primary Completion (Anticipated): November 1, 2017
• Study Completion (Anticipated): December 31, 2017

Study Registration Dates

• First Submitted: April 16, 2015
• First Submitted That Met QC Criteria: May 21, 2015
• First Posted (Estimate): May 22, 2015

Study Record Updates

• Last Update Posted (Actual): August 15, 2017
• Last Update Submitted That Met QC Criteria: August 11, 2017
• Last Verified: August 1, 2017

More Information

Terms related to this study

• Keywords: ovulation inhibition; endometrial changes; bleeding patterns
• Additional Relevant MeSH Terms: Pathologic Processes; Hemorrhage; Physiological Effects of Drugs; Contraceptive Agents, Hormonal; Contraceptive Agents; Reproductive Control Agents; Contraceptive Agents, Female; Ulipristal acetate
• Other Study ID Numbers: 674