HIVPhase 2NCT01789879
A Pharmacokinetic Evaluation of Levonorgestrel Implant and Antiretroviral Therapy
A Phase 2 study testing Levonorgestrel, Nevirapine and Efavirenz in people with HIV and Contraception, run by University of Nebraska at 1 site in Uganda.
Trial 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. Read more about this study
- Who is it for?
- Ages 18 years and older, women only
- Conditions the study is for
- HIV, Contraception
- What is being tested?
- Levonorgestrel, Nevirapine and Efavirenz
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 60 participants
- Where
- 1 siteUganda
- Study dates
- 4 Mar 2014to 4 Mar 2015
- Phase
- Phase 2
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- Women only
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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
Who cannot join
- 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
Trial locations and contacts
1 site in 1 country.
About this study
Official title: 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).
Read the 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.
- Conditions
- HIV, Contraception
- Being tested
- Levonorgestrel, Nevirapine, Efavirenz
- Keywords
- Levonorgestrel, Efavirenz, Nevirapine, Pharmacokinetics
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
LevonorgestrelDrug
Also called Jadelle, SinoImplant
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).
NevirapineDrug
Also called Viramune, NVP
Nevirapine 200mg twice daily as part of a complete antiretroviral therapy regimen. Subjects will be on this therapy prior to entry in this study.
EfavirenzDrug
Also called Sustiva, Atripla, Stocrin, EFV
Efavirenz 600mg once daily as part of a complete antiretroviral therapy regimen. Subjects will be on this therapy prior to entry in this study.
| Study group | Role | What they receive |
|---|---|---|
| Control group (no current ART) | Active comparator | Levonorgestrel subdermal implant in subjects not yet receiving ART (control group) Receives: Drug: Levonorgestrel |
| NVP-based ART group | Active comparator | Levonorgestrel subdermal implant in subjects receiving nevirapine-based ART Receives: Drug: Levonorgestrel; Drug: Nevirapine |
| EFV-based ART group | Active comparator | Levonorgestrel subdermal implant in subjects receiving efavirenz-based ART Receives: Drug: Levonorgestrel; Drug: Efavirenz |
What is being measured
The primary outcome is the main question the study is designed to answer.
Levonorgestrel plasma concentrations
Levonorgestrel plasma concentrations
Measured: 6 months and 1 year after implant
Secondary outcomes (1)
Non-nucleoside reverse transcriptase inhibitor (NNRTI) plasma concentrations
Applies to subjects being treated with either efavirenz- or nevirapine-based antiretroviral therapy
Measured: Over 1 year (baseline, Months 1, 3, 6, 9, and 12)
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted12 Feb 2013 (estimated)
- Study start4 Mar 2014
- Primary completion1 Sep 2014
- Study completion4 Mar 2015
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (3)Papers the sponsor has linked to this study.
- Other trials for HIVStudies of the same condition, open and under way.
- More trials run by University of NebraskaThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 2
- Primary purpose
- Treatment
- Allocation
- Non-randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Enrolment
- 60 participants (actual)
Sponsor and investigators
- Lead sponsor
- University of Nebraska
- Sponsor type
- University, hospital or other
- Collaborators
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), Makerere University, University of Liverpool
- Responsible party
- Sponsor
- Investigators
- Kimberly K Scarsi, PharmD, MSc, Principal investigator, University of Nebraska
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT01789879
- Sponsor's protocol ID
- 0022-14-EP
- Other IDs
- 1R21HD074462-01
- Status last verified
- Aug 2023
- First submitted
- 7 Feb 2013
- Last updated
- 1 Sep 2023
- Results posted
- No
- Data monitoring committee
- No
- Individual data sharing
- No
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.
PubMed 25393993Scarsi KK, Darin KM, Nakalema S, Back DJ, Byakika-Kibwika P, Else LJ, Dilly Penchala S, 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):675-682. doi: 10.1093/cid/civ1001. Epub 2015 Dec 8.
PubMed 26646680
Study at a glance
From the registry record, last updated by the sponsor on 1 Sep 2023. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- A Pharmacokinetic Evaluation of Levonorgestrel Implant and Non-nucleoside Reverse Transcriptase Inhibitor (NNRTI)-Based Antiretroviral Therapy in HIV-infected Ugandan Women
- ClinicalTrials.gov ID
- NCT01789879
- Acronym / sponsor ID
- 0022-14-EP
- Conditions
- HIV, Contraception
- Keywords
- Levonorgestrel, Efavirenz, Nevirapine, Pharmacokinetics
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 60 participants (actual)
- Lead sponsor
- University of NebraskaUniversity, hospital or other
- Collaborators
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), Makerere University, University of Liverpool
- Study start
- 4 Mar 2014 (actual)
- Primary completion
- 1 Sep 2014 (actual)
- Study completion
- 4 Mar 2015 (actual)
- First posted
- 12 Feb 2013 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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 design
- Primary purpose
- Treatment
- Allocation
- Non-randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Number of arms
- 3
| Arm | Type | Receives |
|---|---|---|
| Control group (no current ART) | Active comparator | Drug: LevonorgestrelLevonorgestrel subdermal implant in subjects not yet receiving ART (control group) |
| NVP-based ART group | Active comparator | Drug: Levonorgestrel, Drug: NevirapineLevonorgestrel subdermal implant in subjects receiving nevirapine-based ART |
| EFV-based ART group | Active comparator | Drug: Levonorgestrel, Drug: EfavirenzLevonorgestrel subdermal implant in subjects receiving efavirenz-based ART |
Who may qualify
- Ages
- 18 years and older
- Sex
- Female only
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (6 listed)
- 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
Key exclusion criteria (7 listed)
- 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.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| LevonorgestrelAlso: Jadelle, SinoImplantLevonorgestrel 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). | Drug | Control group (no current ART), EFV-based ART group, NVP-based ART group |
| NevirapineAlso: Viramune, NVPNevirapine 200mg twice daily as part of a complete antiretroviral therapy regimen. Subjects will be on this therapy prior to entry in this study. | Drug | NVP-based ART group |
| EfavirenzAlso: Sustiva, Atripla, Stocrin, EFVEfavirenz 600mg once daily as part of a complete antiretroviral therapy regimen. Subjects will be on this therapy prior to entry in this study. | Drug | EFV-based ART group |
Primary outcome
Levonorgestrel plasma concentrations
Time frame: 6 months and 1 year after implant
Levonorgestrel plasma concentrations
1 secondary outcome
Non-nucleoside reverse transcriptase inhibitor (NNRTI) plasma concentrations
Time frame: Over 1 year (baseline, Months 1, 3, 6, 9, and 12)
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 1 Sep 2023.
- Results publicationScarsi 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.
- Results publication: PubMed 25393993Scarsi 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.
- Results publication: PubMed 26646680Scarsi KK, Darin KM, Nakalema S, Back DJ, Byakika-Kibwika P, Else LJ, Dilly Penchala S, 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):675-682. doi: 10.1093/cid/civ1001. Epub 2015 Dec 8.
- Individual participant dataSharing planned: No
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Kimberly K Scarsi, PharmD, MSc principal investigator
University of Nebraska
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2 study testing Levonorgestrel, Nevirapine and Efavirenz in people with HIV and Contraception, run by University of Nebraska at 1 site in Uganda.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 6 inclusion and 7 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 1 Sep 2023. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in Uganda. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Levonorgestrel plasma concentrations (time frame: 6 months and 1 year after implant). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT01789879, which also lists 3 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 1 Sep 2023.