A Pharmacokinetic Evaluation of Levonorgestrel Implant and Antiretroviral Therapy

August 30, 2023 updated by: University of Nebraska

A Pharmacokinetic Evaluation of Levonorgestrel Implant and Non-nucleoside Reverse Transcriptase Inhibitor (NNRTI)-Based Antiretroviral Therapy in HIV-infected Ugandan Women

The use of hormone contraception poses a significant challenge for the estimated 16 million HIV-infected women of childbearing age. This is due to known drug interactions with antiretroviral therapy (medicines used to treat HIV) that may jeopardize contraception effectiveness. By evaluating the impact of antiretroviral therapy on a levonorgestrel subdermal implant, the most widely available hormone implant in low and middle-income countries, this study will translate its findings into an evidence-based approach to co-manage these important medications. The investigators hypothesize that women receiving nevirapine or efavirenz-based antiretroviral therapy will have a significant decrease in the mean levonorgestrel plasma concentration measured six months after the implant's insertion as compared to those women who are not taking antiretroviral therapy. Although the implant's efficacy may be retained initially, the investigators propose that a decrease in levonorgestrel concentrations in women receiving antiretroviral therapy may jeopardize the implant's effectiveness near the end of its intended duration of use (5 years).

Study Overview

Status

Status

Indicates the current recruitment status or the expanded access status.
Completed

Conditions

Conditions

The disease, disorder, syndrome, illness, or injury that is being studied. On ClinicalTrials.gov, conditions may also include other health-related issues, such as lifespan, quality of life, and health risks.

Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.

Detailed Description

Family planning services, including hormone contraceptives, are critical for HIV-infected women, in whom prevention of unintended pregnancy not only decreases maternal and child mortality, but also reduces the risk of mother-to-child HIV transmission. Similarly, antiretroviral therapy (ART) is a lifesaving intervention that improves the health and economic status of HIV-infected women throughout the world. Therefore, it is of significant public health importance to guide the appropriate use these essential medications. To this end, millions of HIV-infected women in low and middle income countries (LMIC) currently use or are gaining access to subdermal progestin-containing implants as a preferred method of long-acting reversible contraception. These implants are often combined with ART despite the lack of critically needed pharmacokinetic (PK) drug-interaction data to inform their safe and effective concomitant use. Highlighting this concern are several case reports of unintended pregnancy that occurred in patients with subdermal progestin-containing implants concurrently receiving non-nucleoside reverse transcriptase inhibitor (NNRTI)-based ART, the most commonly used ART in LMICs. While NNRTIs are known to significantly decrease oral pill progestin concentrations, no data are available to inform healthcare providers of the impact of NNRTIs on progestin concentrations following release from subdermal implants. To fill this critical gap in knowledge, the overall aim of this proposal is to conduct a PK study to evaluate the combination of a levonorgestrel (LNG) implant and NNRTI (nevirapine or efavirenz)-based ART in HIV-infected Ugandan women. The investigators propose that lower LNG concentrations will be observed in patients on NNRTI-based ART and although the implant's efficacy may be retained initially, this negative interaction will jeopardize implant effectiveness near the end of its intended duration of use (5 years). The specific aims of this project are (1) to characterize the PK of LNG released from a subdermal implant over one year in HIV-infected women with and without NNRTI-based ART and (2) to evaluate the potential for a bidirectional drug-interaction resulting from the long-term impact of chronic progestin exposure on antiretroviral concentrations. To achieve these aims, this study will enroll 20 HIV-infected women into each of three study groups: a control group not receiving ART and two treatment arms consisting of patients receiving nevirapine- or efavirenz- based ART. Using sparse PK sampling strategies, LNG, nevirapine or efavirenz concentrations will be measured over one-year and compared between and within groups, as appropriate. The LNG data will also be used to develop a PK model that will predict LNG disposition over the following three years of intended use, allowing for identification of the safe duration of LNG implant use in women on NNRTI-based ART. At the conclusion of this project, the first evidence-based medical knowledge will be available to guide the safe and effective concomitant use of subdermal LNG implants and NNRTIs, thereby improving management of reproductive health in millions of HIV-infected women worldwide.

Study Type

Study Type

Describes the nature of a clinical study. Study types include interventional studies (also called clinical trials), observational studies (including patient registries), and expanded access.
Interventional

Enrollment (Actual)

Enrollment

The number of participants in a clinical study. The "anticipated" enrollment is the target number of participants that the researchers need for the study.
60

Phase

Phase

The stage of a clinical trial studying a drug or biological product, based on definitions developed by the U.S. Food and Drug Administration (FDA). The phase is based on the study's objective, the number of participants, and other characteristics. There are five phases: Early Phase 1 (formerly listed as Phase 0), Phase 1, Phase 2, Phase 3, and Phase 4. Not Applicable is used to describe trials without FDA-defined phases, including trials of devices or behavioral interventions.
  • Phase 2

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • Uganda
      • Kampala, Uganda
        • Infectious Diseases Institute

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Eligibility Criteria

The key requirements that people who want to participate in a clinical study must meet or the characteristics they must have. Eligibility criteria consist of both inclusion criteria (which are required for a person to participate in the study) and exclusion criteria (which prevent a person from participating). Types of eligibility criteria include whether a study accepts healthy volunteers, has age or age group requirements, or is limited by sex.

Ages Eligible for Study

18 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

No

Description

Inclusion Criteria:

  • Evidence of a personally signed and dated informed consent document indicating that the subject (or a legal representative) has been informed of all pertinent aspects of the study.
  • Subjects who are willing and able to comply with scheduled visits, treatment plan, laboratory tests, and other study procedures.
  • Women age 18 years or older
  • Diagnosed with HIV-1 infection
  • Desiring LNG subdermal implant as a contraceptive method
  • Subjects not yet eligible for ART (based on the Ugandan Treatment Guidelines); or subjects receiving nevirapine or efavirenz-based ART for a minimum of 1 month prior to screening

Exclusion Criteria:

  • For patients currently on ART: HIV-1 RNA > 400 copies/mL at screening visit
  • Serum hemoglobin < 9.0 g/dl
  • Elevations in serum levels of alanine transaminase (ALT) above 5 times the upper limit of normal
  • Elevations in serum creatinine above 2.5 times the upper limit of normal
  • Use of drugs known to be contraindicated with levonorgestrel, nevirapine (NVP group only), or efavirenz (EFV group only) 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 based on the US Department of Health and Human Services drug interaction tables or the AIDS Clinical Trials Group Drug Interactions Database.
  • Currently pregnant or postpartum <30 days at study entry
  • No concurrent use of other hormonal contraception is allowed during the study period

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

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

Arms and Interventions

Participant Group / Arm

Participant Group / Arm

A group or subgroup of participants in a clinical trial that receives a specific intervention/treatment, or no intervention, according to the trial's protocol.
Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.
Active Comparator: Control group (no current ART)
Levonorgestrel subdermal implant in subjects not yet receiving ART (control group)
Drug: Levonorgestrel
Levonorgestrel 2-rod subdermal implant (75mg/rod) placed on study day 0 after baseline evaluations and remains in place until the subject requests removal or for the duration of drug activity (currently approved for 5 years).
Other Names:
  • Jadelle
  • SinoImplant
Active Comparator: NVP-based ART group
Levonorgestrel subdermal implant in subjects receiving nevirapine-based ART
Drug: Levonorgestrel
Levonorgestrel 2-rod subdermal implant (75mg/rod) placed on study day 0 after baseline evaluations and remains in place until the subject requests removal or for the duration of drug activity (currently approved for 5 years).
Other Names:
  • Jadelle
  • SinoImplant
Drug: Nevirapine
Nevirapine 200mg twice daily as part of a complete antiretroviral therapy regimen. Subjects will be on this therapy prior to entry in this study.
Other Names:
  • Viramune
  • NVP
Active Comparator: EFV-based ART group
Levonorgestrel subdermal implant in subjects receiving efavirenz-based ART
Drug: Levonorgestrel
Levonorgestrel 2-rod subdermal implant (75mg/rod) placed on study day 0 after baseline evaluations and remains in place until the subject requests removal or for the duration of drug activity (currently approved for 5 years).
Other Names:
  • Jadelle
  • SinoImplant
Drug: Efavirenz
Efavirenz 600mg once daily as part of a complete antiretroviral therapy regimen. Subjects will be on this therapy prior to entry in this study.
Other Names:
  • Sustiva
  • Atripla
  • Stocrin
  • EFV

What is the study measuring?

Primary Outcome Measures

Primary Outcome Measures

In a clinical study's protocol, the planned outcome measure that is the most important for evaluating the effect of an intervention/treatment. Most clinical studies have one primary outcome measure, but some have more than one.
Outcome Measure
Measure Description
Time Frame
Levonorgestrel plasma concentrations
Time Frame: 6 months and 1 year after implant
Levonorgestrel plasma concentrations
6 months and 1 year after implant

Secondary Outcome Measures

Secondary Outcome Measures

In a clinical study's protocol, a planned outcome measure that is not as important as the primary outcome measure for evaluating the effect of an intervention but is still of interest. Most clinical studies have more than one secondary outcome measure.
Outcome Measure
Measure Description
Time Frame
Non-nucleoside reverse transcriptase inhibitor (NNRTI) plasma concentrations
Time Frame: Over 1 year (baseline, Months 1, 3, 6, 9, and 12)
Applies to subjects being treated with either efavirenz- or nevirapine-based antiretroviral therapy
Over 1 year (baseline, Months 1, 3, 6, 9, and 12)

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Sponsor

The organization or person who initiates the study and who has authority and control over the study.
University of Nebraska

Collaborators

Collaborators

An organization other than the sponsor that provides support for a clinical study. This support may include activities related to funding, design, implementation, data analysis, or reporting.
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
Makerere University
University of Liverpool

Investigators

Investigators

A researcher involved in a clinical study. Related terms include site principal investigator, site sub-investigator, study chair, study director, and study principal investigator.
  • Principal Investigator: Kimberly K Scarsi, PharmD, MSc, University of Nebraska

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Helpful Links

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

Study Start

The actual date on which the first participant was enrolled in a clinical study. The "anticipated" study start date is the date that the researchers think will be the study start date.
March 4, 2014

Primary Completion (Actual)

Primary Completion

The date on which the last participant in a clinical study was examined or received an intervention to collect final data for the primary outcome measure. Whether the clinical study ended according to the protocol or was terminated does not affect this date. For clinical studies with more than one primary outcome measure with different completion dates, this term refers to the date on which data collection is completed for all the primary outcome measures. The "anticipated" primary completion date is the date that the researchers think will be the primary completion date for the study.
September 1, 2014

Study Completion (Actual)

Study Completion

The date on which the last participant in a clinical study was examined or received an intervention/treatment to collect final data for the primary outcome measures, secondary outcome measures, and adverse events (that is, the last participant's last visit). The "anticipated" study completion date is the date that the researchers think will be the study completion date.
March 4, 2015

Study Registration Dates

First Submitted

First Submitted

The date on which the study sponsor or investigator first submitted a study record to ClinicalTrials.gov. There is typically a delay of a few days between the first submitted date and the record's availability on ClinicalTrials.gov (the first posted date).
February 7, 2013

First Submitted That Met QC Criteria

First Submitted That Met QC Criteria

The date on which the study sponsor or investigator first submits a study record that is consistent with National Library of Medicine (NLM) quality control (QC) review criteria. The sponsor or investigator may need to revise and submit a study record one or more times before NLM's QC review criteria are met. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
February 8, 2013

First Posted (Estimated)

First Posted

The date on which the study record was first available on ClinicalTrials.gov after National Library of Medicine (NLM) quality control (QC) review has concluded. There is typically a delay of a few days between the date the study sponsor or investigator submitted the study record and the first posted date.
February 12, 2013

Study Record Updates

Last Update Posted (Actual)

Last Update Posted

The most recent date on which changes to a study record were made available on ClinicalTrials.gov. There may be a delay between when the changes were submitted to ClinicalTrials.gov by the study's sponsor or investigator (the last update submitted date) and the last update posted date.
September 1, 2023

Last Update Submitted That Met QC Criteria

Last Update Submitted That Met QC Criteria

The most recent date on which the study sponsor or investigator submitted changes to a study record that are consistent with National Library of Medicine (NLM) quality control (QC) review criteria. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
August 30, 2023

Last Verified

Last Verified

The most recent date on which the study sponsor or investigator confirmed the information about a clinical study on ClinicalTrials.gov as accurate and current. If a study with a recruitment status of recruiting; not yet recruiting; or active, not recruiting has not been confirmed within the past 2 years, the study's recruitment status is shown as unknown.
August 1, 2023

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

Other Study ID Numbers

Identifiers or ID numbers other than the NCT number that are assigned to a clinical study by the study's sponsor, funders, or others. These numbers may include unique identifiers from other trial registries and National Institutes of Health grant numbers.
  • 0022-14-EP
  • 1R21HD074462-01 (U.S. NIH Grant/Contract)

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

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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