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 women on efavirenz (EFV)-based antiretroviral therapy (ART) using either a single etonogestrel (ENG) implant or two ENG implants for at least one year.

Study Overview

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

Detailed Description

Due to drug-drug interactions between efavirenz (EFV) and progestins, HIV-infected women on EFV-based antiretroviral therapy (ART) and using the etonogestrel implant have significantly lower systemic ENG concentrations than HIV-infected women not on ART. This finding has raised concerns regarding the contraceptive efficacy of the ENG implant for women on EFV-based ART and clinical studies have an increased rate of pregnancies for women on EFV-based ART and using a contraceptive implant. This study a randomized, open-label, longitudinal pharmacodynamic study to compare frequency of ovulation between a control group of HIV-infected women on efavirenz-based antiretroviral therapy receiving standard dose etonogestrel (ENG) implant and a treatment group receiving increased dose ENG implant. The overall goal is to assess the pharmacodynamic significance of the known drug-drug interaction between EFV and ENG and to determine if the increased dose will overcome this interaction. Overall, this study will improve long-acting reversible contraceptive treatment options for women living with HIV and prevent unintended pregnancy.

• 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
• Genders Eligible for Study: Female

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 age 18 years to 40 years
4. Diagnosed with HIV infection
5. Medically eligible for the ENG subdermal implant as a contraceptive method based on the WHO Medical Eligibility Criteria for Contraceptive Use20
6. Receiving EFV-based ART for a minimum of 3 months prior to screening
7. Must agree to have concurrent highly effective non-hormonal contraception with a copper IUD, 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 month
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 (ALT) 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 ENG or EFV within 30 days of study entry. Due to the dynamic nature of drug interactions related to ART, the study team will review all concomitant medications at screening based on the US Department of Health and Human Services drug interaction table45 and the ENG implant product labeling15.
6. Currently pregnant or postpartum <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 IUD placement by the WHO Medical Eligibility Criteria for Contraceptive Use46
10. Patients with a history of hypersensitivity to ENG 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
Ovulation	Ovulation evaluated by endogenous progesterone concentrations of >3ng/mL	weekly at months 3, 6, and 12

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Cervical mucus quality	World Health Organization Cervical Mucus Scores	weekly at months 3, 6, and 12
Etonogestrel pharmacokinetics	Etonogestrel serum concentrations	Week 1, 4, 12, 24, 36, and 48
Adverse events	Safety	up to months 12

Collaborators and Investigators

• Sponsor: Catherine Anne Chappell
• Collaborators: University of Nebraska; Infectious Disease Institute, Kampala, Uganda

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): March 13, 2023
• Last Update Submitted That Met QC Criteria: March 10, 2023
• Last Verified: March 1, 2023

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; 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