Pharmacologic Strategies for the Etonogestrel Implant in HIV-Infected Women

Pharmacokinetic and Pharmacodynamic Evaluation of Etonogestrel Dose Escalation With Efavirenz-based Antiretroviral Therapy in HIV-infected Ugandan

This study will evaluate the frequency of ovulation and cervical mucus quality of HIV-infected Ugandan women on efavirenz-based antiretroviral therapy using either a single etonogestrel implant or two etonogestrel implants for at least one year.

Study Overview

• Status: Completed
• Conditions: HIV/AIDS; Contraception
• Intervention / Treatment: Drug: etonogestrel implant

Detailed Description

This study is being done to compare the rate of ovulation when women receive two subdermal implant contraception devices containing the hormone etonogestrel (instead of only one device) while taking the HIV drug efavirenz. The etonogestrel implant is a device that is inserted under the skin on the upper arm and releases a small amount of drug into the body every day over a long period of time to prevent pregnancy for 3 years. A total of 72 non-pregnant women in Uganda, who agree to use the copper intrauterine device throughout the study, will participate in this study. Half will be assigned by chance to use one implant and half will be assigned to use two implants at the entry visit. After the entry visit to place the implant, visits will be scheduled 1 week, 4 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 21 weeks, 22, weeks, 23 weeks, 24 weeks, 36 weeks, 45 weeks, 46 weeks, 47 weeks, and 48 weeks after the implant(s) were placed. The rate of ovulation (determined by weekly endogenous progesterone concentrations in the blood during months 3, 6, and 12) will be compared between women that receive two 68 mg etonogestrel implants compared to one 68 mg etonogestrel implant in combination with efavirenz-based antiretroviral therapy. Cervical mucus quality (from cervical mucus samples collected weekly at months 3, 6, and 12), the blood concentration of etonogestrel (from blood samples collected at day 3 and weeks 1, 4, 12, 24, 36, 48) and efavirenz (from blood samples collected at enrollment and weeks 4, 12, 24, 36, 48, and the number of adverse events deemed related to etonogestrel implant use through 48 weeks will also be compared between the one- and two-implant study arms.

• Study Type: Interventional
• Enrollment (Actual): 72
• Phase: Phase 2

Contacts and Locations

Study Locations

• Uganda
  • Kampala, Uganda
    • Infectious Disease Institute

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 40 years (Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Evidence of a personally signed and dated informed consent document indicating that the participant has been informed of all pertinent aspects of the study.
2. Participants who are willing and able to comply with scheduled visits, treatment plan, laboratory tests, and other study procedures.
3. Women aged 18 years to 40 years.
4. Diagnosed with HIV infection.
5. Medically eligible for the etonogestrel subdermal implant as a contraceptive method.
6. Receiving efavirenz-based anti-retroviral therapy for a minimum of 3 months prior to screening.
7. Must agree to have concurrent highly effective non-hormonal contraception with a copper intrauterine device, if not previously medically sterilized.
8. Participants must report regular menses (bleeding for 4-8 days at 21- to 35-day intervals) for the preceding 2 months.
9. Participants must have a negative urine pregnancy test at entry and report no unprotected sex since the last menstrual period or in the last two weeks.

Exclusion Criteria:

1. HIV RNA > 50 copies/mL at screening visit.
2. Serum hemoglobin < 10.0 g/dL.
3. Elevations in serum levels of alanine transaminase above 5 times the upper limit of normal.
4. Elevations in serum creatinine above 2.5 times the upper limit of normal.
5. Use of drugs known to be contraindicated with etonogestrel or efavirenz within 30 days of study entry. Due to the dynamic nature of drug interactions related to antiretroviral therapy, the study team will review all concomitant medications at screening for drug interactions with efavirenz and the etonogestrel implant.
6. Currently pregnant or postpartum less than 30 days at study entry.
7. Breastfeeding women within 6 months of delivery.
8. Use of hormonal contraception in the preceding 3 months prior to entry
9. Participants determined to be ineligible for intrauterine device placement.
10. Patients with a history of hypersensitivity to etonogestrel implant, undiagnosed vaginal bleeding, diagnosed or suspected sex hormone dependent neoplasia, benign or malignant liver tumor, or thromboembolic disease.
11. Presence of any active clinically significant disease or life-threatening disease that, in the investigator's opinion, would compromise the subject's safety or outcome of the study.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Standard Dose Etonogestrel Implant; Single 68 mg etonogestrel implant	Drug: etonogestrel implant; The etonogestrel implant is an contraceptive implant that is placed into the upper arm.; Other Names: Nexplanon; Implanon
Experimental: Increased Dose Etonogestrel Implant; Two 68 mg (136 mg total) etonogestrel implants	Drug: etonogestrel implant; The etonogestrel implant is an contraceptive implant that is placed into the upper arm.; Other Names: Nexplanon; Implanon

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Proportion of Participants That Ovulate During Month 3	Proportion of participants that experience at least one ovulation during month 3 of etonogestrel implant use. Serum progesterone concentrations are measured weekly during month 3 (weeks 9-12). Ovulation is defined as endogenous progesterone concentrations of >3 ng/mL.	3 months
Proportion of Participants That Ovulate During Month 6	Proportion of participants that experience at least one ovulation during month 6 of etonogestrel implant use. Serum progesterone concentrations are measured weekly during month 6 (weeks 21-24). Ovulation is defined as endogenous progesterone concentrations of >3 ng/mL.	6 months
Proportion of Participants That Ovulate During Month 12	Proportion of participants that experience at least one ovulation during month 12 of etonogestrel implant use. Serum progesterone concentrations are measured weekly during month 12 (weeks 45-48). Ovulation is defined as endogenous progesterone concentrations of >3 ng/mL.	12 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Proportion of Cervical Mucus Scores Greater Than 10	The proportion of World Health Organization cervical mucus scores that are greater than 10 from weekly samples collected during months 3, 6 and 12 of etonogestrel implant use. A cervical mucus score greater than 10 indicates the mucus is favorable for sperm penetration or lack of contraceptive effect. The cervical mucus score ranges from 0 indicating least favorable for sperm penetration to 15 for most favorable for sperm penetration.	12 months
Median Efavirenz Concentration at Enrollment	Median efavirenz concentrations measured in plasma samples collected at enrollment, prior to insertion of the etonogestrel implant(s). Plasma efavirenz concentrations were quantified using a high-performance liquid chromatography assay with ultraviolet detection.	Day 0
Median Efavirenz Concentration at Week 4	Median efavirenz concentrations measured in plasma samples collected 4 weeks after insertion of the etonogestrel implant(s). Plasma efavirenz concentrations were quantified using a high-performance liquid chromatography assay with ultraviolet detection.	4 weeks
Median Efavirenz Concentration at Week 12	Median efavirenz concentrations measured in plasma samples collected 12 weeks after insertion of the etonogestrel implant(s). Plasma efavirenz concentrations were quantified using a high-performance liquid chromatography assay with ultraviolet detection.	12 weeks
Median Efavirenz Concentration at Week 24	Median efavirenz concentrations measured in plasma samples collected 24 weeks after insertion of the etonogestrel implant(s). Plasma efavirenz concentrations were quantified using a high-performance liquid chromatography assay with ultraviolet detection.	24 weeks
Median Efavirenz Concentration at Week 36	Median efavirenz concentrations measured in plasma samples collected 36 weeks after insertion of the etonogestrel implant(s). Plasma efavirenz concentrations were quantified using a high-performance liquid chromatography assay with ultraviolet detection.	36 weeks
Median Efavirenz Concentration at Week 48	Median efavirenz concentrations measured in plasma samples collected 48 weeks after insertion of the etonogestrel implant(s). Plasma efavirenz concentrations were quantified using a high-performance liquid chromatography assay with ultraviolet detection.	48 weeks
Median Etonogestrel Concentration at Week 1	Median etonogestrel concentrations measured in plasma samples collected 1 week after insertion of the etonogestrel implant(s). Plasma etonogestrel concentrations were quantified using liquid chromatography tandem mass spectrometry.	1 week
Median Etonogestrel Concentration at Week 4	Median etonogestrel concentrations measured in plasma samples collected 4 weeks after insertion of the etonogestrel implant(s). Plasma etonogestrel concentrations were quantified using liquid chromatography tandem mass spectrometry.	4 weeks
Median Etonogestrel Concentration at Week 12	Median etonogestrel concentrations measured in plasma samples collected 12 weeks after insertion of the etonogestrel implant(s). Plasma etonogestrel concentrations were quantified using liquid chromatography tandem mass spectrometry.	12 weeks
Median Etonogestrel Concentration at Week 24	Median etonogestrel concentrations measured in plasma samples collected 24 weeks after insertion of the etonogestrel implant(s). Plasma etonogestrel concentrations were quantified using liquid chromatography tandem mass spectrometry.	24 weeks
Median Etonogestrel Concentration at Week 36	Median etonogestrel concentrations measured in plasma samples collected 36 weeks after insertion of the etonogestrel implant(s). Plasma etonogestrel concentrations were quantified using liquid chromatography tandem mass spectrometry.	36 weeks
Median Etonogestrel Concentration at Week 48	Median etonogestrel concentrations measured in plasma samples collected 48 weeks after insertion of the etonogestrel implant(s). Plasma etonogestrel concentrations were quantified using liquid chromatography tandem mass spectrometry.	48 weeks

Collaborators and Investigators

• Sponsor: Catherine Anne Chappell
• Collaborators: University of Nebraska; Infectious Disease Institute, Kampala, Uganda
• Investigators: Principal Investigator: Catherine A Chappell, MD MSc, University of Pittsburgh

Study record dates

Study Major Dates

• Study Start (Actual): February 19, 2019
• Primary Completion (Actual): December 22, 2020
• Study Completion (Actual): October 25, 2022

Study Registration Dates

• First Submitted: September 12, 2017
• First Submitted That Met QC Criteria: September 13, 2017
• First Posted (Actual): September 14, 2017

Study Record Updates

• Last Update Posted (Actual): September 5, 2024
• Last Update Submitted That Met QC Criteria: August 30, 2024
• Last Verified: August 1, 2024

More Information

Terms related to this study

• Keywords: HIV; efavirenz; antiretroviral therapy; etonogestrel
• Additional Relevant MeSH Terms: RNA Virus Infections; Virus Diseases; Infections; Blood-Borne Infections; Communicable Diseases; Sexually Transmitted Diseases, Viral; Sexually Transmitted Diseases; Lentivirus Infections; Retroviridae Infections; Immunologic Deficiency Syndromes; Immune System Diseases; Slow Virus Diseases; Urogenital Diseases; Genital Diseases; HIV Infections; Acquired Immunodeficiency Syndrome; Physiological Effects of Drugs; Contraceptive Agents, Hormonal; Contraceptive Agents; Reproductive Control Agents; Contraceptive Agents, Female; Etonogestrel
• Other Study ID Numbers: PRO17080453

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No