A Pharmacokinetic Evaluation of Levonorgestrel Implant and Antiretroviral Therapy

This study has been completed.

Sponsor:

Collaborators:

Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)

Makerere University

University of Liverpool

Information provided by (Responsible Party):

Kimberly Scarsi, PharmD, MS, BCPS-ID, University of Nebraska

ClinicalTrials.gov Identifier:

NCT01789879

First received: February 7, 2013

Last updated: March 31, 2016

Last verified: March 2016

History of Changes

Tracking Information

First Received Date ^ICMJE

February 7, 2013

Last Updated Date

March 31, 2016

Start Date ^ICMJE

June 2013

Primary Completion Date

April 2014 (final data collection date for primary outcome measure)

Current Primary Outcome Measures ^ICMJE

Levonorgestrel plasma concentrations [ Time Frame: 6 months after implant is placed ] [ Designated as safety issue: No ]

Original Primary Outcome Measures ^ICMJE

Same as current

Change History

Complete list of historical versions of study NCT01789879 on ClinicalTrials.gov Archive Site

Current Secondary Outcome Measures ^ICMJE

NNRTI plasma concentrations [ Time Frame: Over 1 year (baseline, Months 1, 3, 6, 9, and 12) ] [ Designated as safety issue: No ]
Applies to subjects being treated with either efavirenz- or nevirapine-based antiretroviral therapy
Levonorgestrel plasma concentrations [ Time Frame: 1 year after implant is placed ] [ Designated as safety issue: No ]

Original Secondary Outcome Measures ^ICMJE

Same as current

Current Other Outcome Measures ^ICMJE

Not Provided

Original Other Outcome Measures ^ICMJE

Not Provided

Descriptive Information

Brief Title ^ICMJE

A Pharmacokinetic Evaluation of Levonorgestrel Implant and Antiretroviral Therapy

Official Title ^ICMJE

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

Brief Summary

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).

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 ^ICMJE

Interventional

Study Phase

Phase 2

Study Design ^ICMJE

Allocation: Non-Randomized
Endpoint Classification: Pharmacokinetics Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment

Condition ^ICMJE

HIV
Contraception

Intervention ^ICMJE

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
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

Study Arm (s)

Active Comparator: Control group (no current ART)
Levonorgestrel subdermal implant in subjects not yet receiving ART (control group)

Intervention: Drug: Levonorgestrel
Active Comparator: NVP-based ART group
Levonorgestrel subdermal implant in subjects receiving nevirapine-based ART
Interventions:
- Drug: Levonorgestrel
- Drug: Nevirapine
Active Comparator: EFV-based ART group
Levonorgestrel subdermal implant in subjects receiving efavirenz-based ART
Interventions:
- Drug: Levonorgestrel
- Drug: Efavirenz

Publications *

Scarsi KK*, Darin KM, Nakalema S, Back D, Byakika-Kibwika P, Else L, Dilly-Penchala S, Cohn S, Merry C, Lamorde M. Levonorgestrel implant + EFV-based ART: Unintended pregnancies and associated PK Data. Conference on Retroviruses and Opportunistic Infections. Seattle, WA. February 23-26, 2015. Abstract #85LB.
Scarsi K, Lamorde M, Darin K, Penchala SD, Else L, Nakalema S, Byakika-Kibwika P, Khoo S, Cohn S, Merry C, Back D. Efavirenz- but not nevirapine-based antiretroviral therapy decreases exposure to the levonorgestrel released from a sub-dermal contraceptive implant. J Int AIDS Soc. 2014 Nov 2;17(4 Suppl 3):19484. doi: 10.7448/IAS.17.4.19484. eCollection 2014.
Scarsi KK, Darin KM, Nakalema S, Back DJ, Byakika-Kibwika P, Else LJ, Penchala SD, Buzibye A, Cohn SE, Merry C, Lamorde M. Unintended Pregnancies Observed With Combined Use of the Levonorgestrel Contraceptive Implant and Efavirenz-based Antiretroviral Therapy: A Three-Arm Pharmacokinetic Evaluation Over 48 Weeks. Clin Infect Dis. 2016 Mar 15;62(6):675-82. doi: 10.1093/cid/civ1001. Epub 2015 Dec 8.

* Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.

Recruitment Information

Recruitment Status ^ICMJE

Completed

Enrollment ^ICMJE

Completion Date

October 2014

Primary Completion Date

April 2014 (final data collection date for primary outcome measure)

Eligibility Criteria ^ICMJE

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

Gender

Female

Ages

18 Years and older (Adult, Senior)

Accepts Healthy Volunteers

Contacts ^ICMJE

Contact information is only displayed when the study is recruiting subjects

Listed Location Countries ^ICMJE

Uganda

Removed Location Countries

Administrative Information

NCT Number ^ICMJE

NCT01789879

Other Study ID Numbers ^ICMJE

LNG-NNRTI PK study, 1R21HD074462-01

Has Data Monitoring Committee

Plan to Share Data

IPD Description

Not Provided

Responsible Party

Kimberly Scarsi, PharmD, MS, BCPS-ID, University of Nebraska

Study Sponsor ^ICMJE

University of Nebraska

Collaborators ^ICMJE

Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
Makerere University
University of Liverpool

Investigators ^ICMJE

Principal Investigator:

Kimberly K Scarsi, PharmD, MSc

University of Nebraska

Information Provided By

University of Nebraska

Verification Date

March 2016

^ICMJE Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP

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