HIV InfectionsPhase 2NCT03819114
Pharmacokinetic Study to Evaluate Double-Dose Levonorgestrel Emergency Contraception in Combination With Efavirenz-Based Antiretroviral Therapy or Rifampicin-Containing Anti-Tuberculosis Therapy
A Phase 2 study testing Levonorgestrel (LNG) in people with HIV Infections and Tuberculosis, run by Advancing Clinical Therapeutics Globally for HIV/AIDS and Other Infections at 18 sites in 7 countries.
Trial summary
The purpose of this pharmacokinetic (PK) study was to evaluate if a double dose (3 mg) of levonorgestrel (LNG) overcomes known drug-drug interactions (DDIs) with efavirenz (EFV)-based antiretroviral therapy (ART) or rifampicin (RIF)-containing tuberculosis (TB) therapy. Read more about this study
- Who is it for?
- Ages 16 years and older, women only
- Conditions the study is for
- HIV Infections, Tuberculosis
- What is being tested?
- Levonorgestrel (LNG)
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 122 participants
- Where
- 18 sitesin 7 countries
- Study dates
- 6 May 2019to 30 Nov 2020
- Phase
- Phase 2
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
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 16 years and older
- Women only
- No healthy volunteers
- Child, Adult, Older adult
Who may be able to join
- Postmenarcheal female.
- Note: Participant report and clinician's opinion were acceptable.
- The following laboratory values obtained within 30 days prior to study entry by any US laboratory that had a Clinical Laboratory Improvement Amendments (CLIA) certification or its equivalent, or at any ACTG network-approved non-US laboratory that operated in accordance with Good Clinical Laboratory Practices (GCLP) and participated in appropriate external quality assurance (EQA) programs.
- Absolute neutrophil count (ANC) greater than or equal to 500 cells/mm^3
- Platelet count greater than or equal to 50,000 platelets/mm^3
- Hemoglobin greater than or equal to 8.0 g/dL
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- Aspartate transaminase (AST) less than 5 x upper limit of normal (ULN)
- Alanine aminotransferase (ALT) less than 5 x ULN
- Creatinine less than or equal to 1.5 x ULN
- Total bilirubin less than or equal to 2.0 x ULN
- Negative serum or urine pregnancy test within 30 days prior to study entry and within 48 hours prior to entry (if screening occurred more than 48 hours prior to entry) by any US clinic or US laboratory that had a CLIA certification or its equivalent, or used a point of care (POC)/CLIA-waived test, or at any network-approved non-US laboratory or non-US clinic that operated in accordance with GCLP and participated in appropriate EQA programs. The serum or urine pregnancy test must have had a sensitivity of at least 25 mIU/mL.
- Had not had sex that could lead to pregnancy without contraception within 14 days prior to study entry as defined in the criteria below, according to participant self-report.
- Contraception requirements
- All participants agreed not to participate in a conception process (e.g., active attempt to become pregnant or in vitro fertilization) for the duration of the study. Women of reproductive potential, who were participating in sexual activity that could lead to pregnancy, agreed to use at least one reliable method of contraception while in the study. Acceptable forms of contraceptives included:
- Male condom with or without a spermicidal agent
- Diaphragm or cervical cap with spermicide
- Non-hormonal intrauterine device (IUD)
- Bilateral tubal ligation
- Male partner vasectomy
- Ability and willingness of participant or legal guardian/representative to have provided informed consent.
- Body mass index (BMI) (kg/m^2) available at entry. See the study protocol for BMI calculation instructions.
- Note: A maximum of 5 participants with BMI greater than or equal to 30 kg/m^2 were allowed in each arm B-D and a maximum of 3 participants in Arm A.
- For participants with HIV: HIV-1 infection, documented by any licensed rapid HIV test or HIV enzyme or chemiluminescence immunoassay (E/CIA) test kit at any time prior to study entry and confirmed by a licensed Western blot or a second antibody test by a method other than the initial rapid HIV and/or E/CIA, or by HIV-1 antigen, plasma HIV-1 RNA viral load.
- Note: The term "licensed" referred to a US Food and Drug Administration (FDA)-approved kit, which was required for all investigational new drug (IND) studies, or for sites located in countries other than the United States, a kit that had been certified or licensed by an oversight body within that country and validated internally. Non-US sites were encouraged to use US FDA-approved methods for IND studies.
- World Health Organization (WHO) and Centers for Disease Control and Prevention (CDC) guidelines mandated that confirmation of the initial test result must have used a test that was different from the one used for the initial assessment. A reactive initial rapid test was confirmed by either another type of rapid assay or an E/CIA that was based on a different antigen preparation and/or different test principle (e.g., indirect versus competitive), or a Western blot or a plasma HIV-1 RNA viral load.
- For participants with HIV: Received a stable qualifying concomitant ART regimen containing either once-daily DTG 50 mg or EFV 600 mg with no changes in the components of their ART for at least 30 days prior to study entry.
- For participants who were being treated for TB: HIV-negative at screening, documented within the prior 6 months by any licensed rapid HIV test or HIV enzyme or chemiluminescence immunoassay (E/CIA) test kit and confirmed by a licensed Western blot or a second antibody test by a method other than the initial rapid HIV and/or E/CIA, or by HIV-1 antigen, or plasma HIV-1 RNA viral load.
- Note: The term "licensed" referred to a US FDA-approved kit, which was required for all IND studies, or for sites located in countries other than the United States, a kit that had been certified or licensed by an oversight body within that country and validated internally. Non-US sites were encouraged to use US FDA-approved methods for IND studies.
- WHO and CDC guidelines mandated that confirmation of the initial test result must have used a test that was different from the one used for the initial assessment. A reactive initial rapid test was confirmed by either another type of rapid assay or an E/CIA that was based on a different antigen preparation and/or different test principle (e.g., indirect versus competitive), or a Western blot or a plasma HIV-1 RNA viral load.
- For participants who were living without HIV and being treated for TB: Received RIF and INH on a once daily dosing (7 days per week) schedule at study entry, after completion of the intensive phase of TB treatment.
- Note: Inclusion of ethambutol as part of continuation phase of TB therapy was allowed.
- Ability and willingness of participant to have been contacted remotely for study visits.
Who cannot join
- Known allergy/sensitivity or any hypersensitivity to LNG or components of the formulation.
- Bilateral oophorectomy, hysterectomy, or postmenopausal
- Note: Postmenopausal was defined as amenorrhea for at least 12 consecutive months prior to study entry (in the absence of medications known to induce amenorrhea), and had a documented follicle stimulated hormone-release factor (FSH) measurement greater than 40 mIU/mL or a result in the testing laboratory's menopausal range. If an FSH level was not available, 24 consecutive months of amenorrhea prior to study entry (in the absence of medications known to induce amenorrhea).
- Note: Clinical assessment and clinician's opinion were acceptable.
- Was currently pregnant, was within 6 weeks of delivery, or was currently breastfeeding an infant under 6 months of age.
- Note: For recent pregnancy resolution during the first or second trimester, the participant was only eligible when the pregnancy test result was negative.
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- Receipt of LNG within 30 days prior to study entry.
- Receipt of depo-medroxyprogesterone for 90 days prior to study entry, or norethisterone enanthate (NET-EN) within 60 days prior to study entry, or other hormonal contraceptives within 30 days prior to study entry.
- Used any drugs other than RIF and EFV known to: 1) induce CYP3A4 system within 30 days prior to study entry, and 2) inhibit the CYP3A4 system within 7 days prior to study entry. See the study protocol for prohibited and precautionary medications.
- Active drug or alcohol use or dependence that, in the opinion of the site investigator, would have interfered with adherence to study requirements.
- Acute or serious illness that required systemic treatment and/or hospitalization within 14 days prior to study entry.
- Other medical, psychiatric, or psychological condition that, in the opinion of the site investigator, would have interfered with completion of study procedures and or adherence to study drug.
- For participants with HIV: Was currently receiving medications for TB infection.
- For participants with HIV: Had missed one or more of the prescribed doses of HIV medications within 3 days prior to study entry.
- Note: The entry visit could have been rescheduled within the screening period once the participant had taken all prescribed doses within 3 days prior to study entry.
- For participants who were not living with HIV and were being treated for TB: Had missed one or more of the prescribed doses of TB medication within 3 days prior to study entry.
- Note: The entry visit could have been rescheduled within the screening period once the participant had taken all prescribed doses within 3 days prior to study entry.
Trial locations and contacts
18 sites in 7 countries.
18 sites in 7 countries
United States7 sites
Unc Aids Crs (3201)
Chapel Hill, North Carolina, 27514
2701 Northwestern University CRS
Chicago, Illinois, 60611
Rush Univ. Med. Ctr. ACTG CRS (2702)
Chicago, Illinois, 60612
Trinity Health and Wellness Center CRS (31443)
Dallas, Texas, 75208
Weill Cornell Upton CRS (7803)
New York, New York, 10065
Hosp. of the Univ. of Pennsylvania CRS (6201)
Philadelphia, Pennsylvania, 19104
Pitt CRS (1001)
Pittsburgh, Pennsylvania, 15213
South Africa4 sites
Family Clinical Research Unit (FAM-CUR) CRS (8950)
Cape Town, West Cape, 7505
Durban Adult HIV CRS (11201)
Durban, 4013 SF
University of the Witwatersrand Helen Joseph (WITS HJH) CRS (11101)
Johannesburg, Gauteng, 2193
Soweto ACTG CRS (12301)
Johannesburg
Thailand2 sites
31802 Thai Red Cross AIDS Research Centre (TRC-ARC) CRS
Bangkok, Patumwan, 10330
31784 Chiang Mai University HIV Treatment CRS
Chiang Mai, 50200
Brazil1 site
12101 Instituto de Pesquisa Clinica Evandro Chagas (IPEC) CRS
Rio de Janeiro, 21040
Kenya1 site
Kenya Medical Research Institute/Walter Reed Project Clinical Research Center (KEMRI/WRP) CRS (12501)
Kericho, 20200
About this study
Official title: An Open-Label, Phase II Pharmacokinetic Study to Evaluate Double-Dose Levonorgestrel Emergency Contraception in Combination With Efavirenz-Based Antiretroviral Therapy or Rifampicin-Containing Anti-Tuberculosis Therapy
The purpose of this pharmacokinetic (PK) study was to evaluate if a double dose (3 mg) of levonorgestrel (LNG) overcomes known drug-drug interactions (DDIs) with efavirenz (EFV)-based antiretroviral therapy (ART) or rifampicin (RIF)-containing tuberculosis (TB) therapy. The safety of double-dose (3.0 mg) LNG versus standard-dose (1.5 mg) was also compared.
Read the detailed description
This pharmacokinetic (PK) study evaluated if a double dose (3.0 mg) of levonorgestrel (LNG) overcomes known drug-drug interactions (DDIs) with efavirenz (EFV)-based antiretroviral therapy (ART) or rifampicin (RIF)-containing tuberculosis (TB) therapy. The safety of double-dose (3.0 mg) LNG versus standard-dose (1.5 mg) was also compared.
Participants were volunteers who did not require emergency contraception (EC) for contraception at the time of trial participation. This trial enrolled persons assigned female sex at birth who were 16 years of age or older. Group assignment was determined by disease status (HIV or TB; participants could not have been living with both HIV and TB), and, for those with HIV, by ART regimen at enrollment. Participants with HIV who were taking EFV-based ART were randomized to receive a standard dose LNG (Group A) or a double dose of LNG (Group B). Participants taking dolutegravir (DTG)-based ART were assigned to a standard dose of LNG (Group C). Participants in the continuation phase of active TB treatment taking RIF and isoniazid (INH) with or without ethambutol were assigned to a double dose of LNG (Group D).
At study entry, participants in Groups A and C received a standard single dose of LNG. Participants in Groups B and D received a double dose of LNG. Intensive PK monitoring was conducted pre-dose, and after the LNG dose. Participants were expected to remain at the clinical site while the initial 8 hour PK samples were collected, and to return to the clinical site for the 24 and 48 hour samples.
All participants completed self-report questionnaires to assess adherence to TB therapy and ART, menstrual history and patterns after LNG administration, and to collect adverse effects commonly reported with LNG (i.e., irregular bleeding patterns). Adherence to ART and RIF was also assessed by collecting hair samples and single plasma concentrations at entry. Participants were followed for 4 weeks.
- Conditions
- HIV Infections, Tuberculosis
- Being tested
- Levonorgestrel (LNG)
- Keywords
- Levonorgestrel, Pharmacokinetics, Efavirenz, Dolutegravir, Rifampin
- Medical subject headings
- HIV Infections, Tuberculosis
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Levonorgestrel (LNG)Drug
LNG tablet(s) were administered by mouth in a directly observed manner.
| Study group | Role | What they receive |
|---|---|---|
| A: LNG 1.5 mg among participants on EFV-based ART (randomized) | Experimental | Participants received 1.5 mg of LNG once orally on Day 0 and were followed post-treatment for 4 weeks. Receives: Drug: Levonorgestrel (LNG) |
| B: LNG 3.0 mg among participants on EFV-based ART (randomized) | Experimental | Participants received 3mg of LNG once orally on Day 0 and were followed post-treatment for 4 weeks. Receives: Drug: Levonorgestrel (LNG) |
| C: LNG 1.5 mg among participants on DTG-based ART (assigned) | Experimental | Participants received 1.5 mg of LNG once orally on Day 0 and were followed post-treatment for 4 weeks. Receives: Drug: Levonorgestrel (LNG) |
| D: LNG 3.0 mg among participants on RIF-INH TB Therapy (assigned) | Experimental | Participants received 3mg of LNG once orally on Day 0 and were followed post-treatment for 4 weeks. Receives: Drug: Levonorgestrel (LNG) |
What is being measured
The primary outcome is the main question the study is designed to answer.
LNG Area Under the Concentration-time Curve (AUC0-8h) Calculated Based on Intensive LNG PK Samples Obtained From Individual Participants
AUC for each participant was calculated from all available LNG concentrations measured over 8 hours using the linear up/log down version of trapezoidal rule (i.e., noncompartmental technique) using the software package Phoenix WinNonLin (Certara®). This version of the trapezoidal rule used linear interpolation between untransformed data up to Cmax, and between log-transformed data from Cmax through Clast. Assay lower limit of quantification (LLOQ) for LNG was 0.025 ng/mL; values < LLOQ were imputed as 0 (if pre-dose) or as 0.0125 (if post-dose).
Measured: Intensive LNG PK samples at pre-dose, and 0.5, 1, 1.5, 2, 3, 4, 6, and 8 hours post-dose
Secondary outcomes (10)
Number and Percentage of Participants Experiencing Either a Serious Adverse Event (SAE) or Adverse Event (AE) Potentially or Definitely Associated With Single Dose LNG Administration.
Adverse events were Graded according to the Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events (DAIDS AE Grading Table), corrected Version 2.1, July 2017 and DAIDS AE Grading Table Addendum 1, Female Genital Grading Table for Use in Microbicide Studies, Version 1.0 - November 2007. Relationship of AE to study treatment was determined by the site, study core team, and DAIDS clinical representative.
AEs evaluated in this outcome fulfilled the below criteria:
- Potentially or definitely related to LNG dose
- Grade 3 or higher AEs
- Grade 2 of higher nausea, diarrhea, menorrhagia or metrorrhagia, and ectopic pregnancies
Measured: From Day 0 through study Day 28
Maximum Concentration (Cmax) of LNG
Cmax for each participant was calculated as the maximum observed LNG concentration from LNG PK samples at pre-dose through 48 hours post-dose. Standard noncompartmental techniques were used to determine Cmax using the software package Phoenix WinNonLin (Certara®).
Measured: Intensive LNG PK samples at pre-dose, and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 24, and 48 hours post-dose
Minimum Concentration (Cmin) of LNG
Cmin for each participant was calculated as the minimum observed LNG concentration from LNG PK samples at pre-dose through 48 hours post-dose. Standard noncompartmental techniques were used to determine Cmin using the software package Phoenix WinNonLin (Certara®). Assay lower limit of quantification for LNG was 0.025 ng/mL; values < LLOQ were imputed as 0 (if pre-dose) or as 0.0125 (if post-dose).
Measured: Intensive LNG PK samples at pre-dose, and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 24, and 48 hours post-dose
Oral Clearance (CL/F) of LNG
Apparent oral clearance (CL/F) for each participant was calculated as CL/F = dose/AUC0-24 or CL/F = dose/AUC0-48 of the observed LNG concentration from LNG PK samples at pre-dose through 48 hours post-dose. Standard noncompartmental techniques were used to determine CL/F using the software package Phoenix WinNonLin (Certara®).
Measured: Intensive LNG PK samples at pre-dose, and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 24, and 48 hours post-dose
Volume of Distribution (Vd) of LNG
Vd for each participant was calculated from observed LNG concentration from LNG PK samples at pre-dose through 48 hours post-dose. Standard noncompartmental techniques were used to determine Vd using the software package Phoenix WinNonLin (Certara®).
Measured: Intensive LNG PK samples at pre-dose, and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 24, and 48 hours post-dose
Half-life (T1/2) of LNG
T1/2 for each participant was calculated using regression analysis when possible from the observed LNG concentration from LNG PK samples at pre-dose through 48 hours post-dose. Standard noncompartmental techniques were used to determine T1/2 using the software package Phoenix WinNonLin (Certara®).
Measured: Intensive LNG PK samples at pre-dose, and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 24, and 48 hours post-dose
Time of Minimum Concentration (Tmin) of LNG
Tmin for each participant was time to the minimum observed LNG concentration after the observed dose.
Measured: Intensive LNG PK samples at pre-dose, and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 24, and 48 hours pose-dose
LNG Area Under the Concentration Time Curve (AUC0-24h) Calculated Based on Intensive LNG PK Samples Obtained From Individual Participants
AUC for each participant was calculated from all available LNG concentrations measured over 24 hours using the linear up/log down version of trapezoidal rule (i.e., noncompartmental technique) using the software package Phoenix WinNonLin (Certara®). This version of the trapezoidal rule used linear interpolation between untransformed data up to Cmax, and between log-transformed data from Cmax through Clast. Assay lower limit of quantification for LNG was 0.025 ng/mL; values < LLOQ were imputed as 0 (if pre-dose) or as 0.0125 (if post-dose).
Measured: Intensive LNG PK samples at pre-dose, and 0.5, 1, 1.5, 2, 3, 4, 6, 8, and 24 hours post-dose
LNG Area Under the Concentration Time Curve (AUC0-48h) Calculated Based on Intensive LNG PK Samples Obtained From Individual Participants
AUC for each participant was calculated from all available LNG concentrations measured over 48 hours using the linear up/log down version of the trapezoidal rule (i.e., noncompartmental technique) using the software package Phoenix WinNonLin (Certara®). This version of the trapezoidal rule used linear interpolation between untransformed data up to Cmax, and between log-transformed data from Cmax through Clast. Assay lower limit of quantification for LNG was 0.025 ng/mL; values < LLOQ were imputed as 0 (if pre-dose) or as 0.0125 (if post-dose).
Measured: Intensive LNG PK samples at pre-dose, and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 24, and 48 hours pose-dose
LNG Total Area Under the Concentration Time Curve AUCinf (Infinity) Calculated Based on Intensive LNG PK Samples Obtained From Individual Participants
AUC for each participant was calculated from all available LNG concentrations measured to infinity hours using the linear up/log down version of trapezoidal rule (i.e., noncompartmental technique) using the software package Phoenix WinNonLin (Certara®). This version of the trapezoidal rule used linear interpolation between untransformed data up to Cmax, and between log-transformed data from Cmax through Clast. Assay lower limit of quantification for LNG was 0.025 ng/mL; values < LLOQ were imputed as 0 (if pre-dose) or as 0.0125 (if post-dose).
Measured: Intensive LNG PK samples at pre-dose, and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 24, and 48 hours pose-dose
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted28 Jan 2019
- Study start6 May 2019
- Primary completion2 Nov 2020
- Study completion30 Nov 2020
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Other trials for HIV InfectionsStudies of the same condition, open and under way.
- 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
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Enrolment
- 122 participants (actual)
Sponsor and investigators
- Lead sponsor
- Advancing Clinical Therapeutics Globally for HIV/AIDS and Other Infections
- Sponsor type
- Research network
- Responsible party
- Sponsor
- Investigators
- Kimberly Scarsi, PharmD, MS, Study chair, Northwestern University CRS, University of Nebraska Medical Center
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT03819114
- Sponsor's protocol ID
- ACTG A5375
- Other IDs
- 38493, UM1AI068636
- Status last verified
- Dec 2021
- First submitted
- 25 Jan 2019
- Last updated
- 27 Dec 2021
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- Yes
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
- Individual data sharing
- Yes: Individual participant data that underlie results in the publication, after deidentification.
Study at a glance
From the registry record, last updated by the sponsor on 27 Dec 2021. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- An Open-Label, Phase II Pharmacokinetic Study to Evaluate Double-Dose Levonorgestrel Emergency Contraception in Combination With Efavirenz-Based Antiretroviral Therapy or Rifampicin-Containing Anti-Tuberculosis Therapy
- ClinicalTrials.gov ID
- NCT03819114
- Acronym / sponsor ID
- ACTG A5375
- Conditions
- HIV Infections, Tuberculosis
- Keywords
- Levonorgestrel, Pharmacokinetics, Efavirenz, Dolutegravir, Rifampin
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 122 participants (actual)
- Lead sponsor
- Advancing Clinical Therapeutics Globally for HIV/AIDS and Other InfectionsResearch network
- Collaborators
- National Institute of Allergy and Infectious Diseases (NIAID)
- Study start
- 6 May 2019 (actual)
- Primary completion
- 2 Nov 2020 (actual)
- Study completion
- 30 Nov 2020 (actual)
- First posted
- 28 Jan 2019 (actual)
- Results
- Posted 30 Nov 2021
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
The purpose of this pharmacokinetic (PK) study was to evaluate if a double dose (3 mg) of levonorgestrel (LNG) overcomes known drug-drug interactions (DDIs) with efavirenz (EFV)-based antiretroviral therapy (ART) or rifampicin (RIF)-containing tuberculosis (TB) therapy. The safety of double-dose (3.0 mg) LNG versus standard-dose (1.5 mg) was also compared.
Detailed description
This pharmacokinetic (PK) study evaluated if a double dose (3.0 mg) of levonorgestrel (LNG) overcomes known drug-drug interactions (DDIs) with efavirenz (EFV)-based antiretroviral therapy (ART) or rifampicin (RIF)-containing tuberculosis (TB) therapy. The safety of double-dose (3.0 mg) LNG versus standard-dose (1.5 mg) was also compared.
Participants were volunteers who did not require emergency contraception (EC) for contraception at the time of trial participation. This trial enrolled persons assigned female sex at birth who were 16 years of age or older. Group assignment was determined by disease status (HIV or TB; participants could not have been living with both HIV and TB), and, for those with HIV, by ART regimen at enrollment. Participants with HIV who were taking EFV-based ART were randomized to receive a standard dose LNG (Group A) or a double dose of LNG (Group B). Participants taking dolutegravir (DTG)-based ART were assigned to a standard dose of LNG (Group C). Participants in the continuation phase of active TB treatment taking RIF and isoniazid (INH) with or without ethambutol were assigned to a double dose of LNG (Group D).
At study entry, participants in Groups A and C received a standard single dose of LNG. Participants in Groups B and D received a double dose of LNG. Intensive PK monitoring was conducted pre-dose, and after the LNG dose. Participants were expected to remain at the clinical site while the initial 8 hour PK samples were collected, and to return to the clinical site for the 24 and 48 hour samples.
All participants completed self-report questionnaires to assess adherence to TB therapy and ART, menstrual history and patterns after LNG administration, and to collect adverse effects commonly reported with LNG (i.e., irregular bleeding patterns). Adherence to ART and RIF was also assessed by collecting hair samples and single plasma concentrations at entry. Participants were followed for 4 weeks.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Number of arms
- 4
| Arm | Type | Receives |
|---|---|---|
| A: LNG 1.5 mg among participants on EFV-based ART (randomized) | Experimental | Drug: Levonorgestrel (LNG)Participants received 1.5 mg of LNG once orally on Day 0 and were followed post-treatment for 4 weeks. |
| B: LNG 3.0 mg among participants on EFV-based ART (randomized) | Experimental | Drug: Levonorgestrel (LNG)Participants received 3mg of LNG once orally on Day 0 and were followed post-treatment for 4 weeks. |
| C: LNG 1.5 mg among participants on DTG-based ART (assigned) | Experimental | Drug: Levonorgestrel (LNG)Participants received 1.5 mg of LNG once orally on Day 0 and were followed post-treatment for 4 weeks. |
| D: LNG 3.0 mg among participants on RIF-INH TB Therapy (assigned) | Experimental | Drug: Levonorgestrel (LNG)Participants received 3mg of LNG once orally on Day 0 and were followed post-treatment for 4 weeks. |
Who may qualify
- Ages
- 16 years and older
- Sex
- Female only
- Healthy volunteers
- Not accepted
- Age groups
- Child, Adult, Older adult
Key inclusion criteria (32 listed)
- Postmenarcheal female.
- The following laboratory values obtained within 30 days prior to study entry by any US laboratory that had a Clinical Laboratory Improvement Amendments (CLIA) certification or its equivalent, or at any ACTG network-approved non-US laboratory that operated in accordance with Good Clinical Laboratory Practices (GCLP) and participated in appropriate external quality assurance (EQA) programs.
- Negative serum or urine pregnancy test within 30 days prior to study entry and within 48 hours prior to entry (if screening occurred more than 48 hours prior to entry) by any US clinic or US laboratory that had a CLIA certification or its equivalent, or used a point of care (POC)/CLIA-waived test, or at any network-approved non-US laboratory or non-US clinic that operated in accordance with GCLP and participated in appropriate EQA programs. The serum or urine pregnancy test must have had a sensitivity of at least 25 mIU/mL.
- Had not had sex that could lead to pregnancy without contraception within 14 days prior to study entry as defined in the criteria below, according to participant self-report.
- Contraception requirements
Key exclusion criteria (17 listed)
- Known allergy/sensitivity or any hypersensitivity to LNG or components of the formulation.
- Bilateral oophorectomy, hysterectomy, or postmenopausal
- Was currently pregnant, was within 6 weeks of delivery, or was currently breastfeeding an infant under 6 months of age.
- Receipt of LNG within 30 days prior to study entry.
- Receipt of depo-medroxyprogesterone for 90 days prior to study entry, or norethisterone enanthate (NET-EN) within 60 days prior to study entry, or other hormonal contraceptives within 30 days prior to study entry.
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 |
|---|---|---|
| Levonorgestrel (LNG)LNG tablet(s) were administered by mouth in a directly observed manner. | Drug | A: LNG 1.5 mg among participants on EFV-based ART (randomized), B: LNG 3.0 mg among participants on EFV-based ART (randomized), C: LNG 1.5 mg among participants on DTG-based ART (assigned), D: LNG 3.0 mg among participants on RIF-INH TB Therapy (assigned) |
Primary outcome
LNG Area Under the Concentration-time Curve (AUC0-8h) Calculated Based on Intensive LNG PK Samples Obtained From Individual Participants
Time frame: Intensive LNG PK samples at pre-dose, and 0.5, 1, 1.5, 2, 3, 4, 6, and 8 hours post-dose
AUC for each participant was calculated from all available LNG concentrations measured over 8 hours using the linear up/log down version of trapezoidal rule (i.e., noncompartmental technique) using the software package Phoenix WinNonLin (Certara®). This version of the trapezoidal rule used linear interpolation between untransformed data up to Cmax, and between log-transformed data from Cmax through Clast. Assay lower limit of quantification (LLOQ) for LNG was 0.025 ng/mL; values < LLOQ were imputed as 0 (if pre-dose) or as 0.0125 (if post-dose).
10 secondary outcomes
Number and Percentage of Participants Experiencing Either a Serious Adverse Event (SAE) or Adverse Event (AE) Potentially or Definitely Associated With Single Dose LNG Administration.
Time frame: From Day 0 through study Day 28
Maximum Concentration (Cmax) of LNG
Time frame: Intensive LNG PK samples at pre-dose, and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 24, and 48 hours post-dose
Minimum Concentration (Cmin) of LNG
Time frame: Intensive LNG PK samples at pre-dose, and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 24, and 48 hours post-dose
Oral Clearance (CL/F) of LNG
Time frame: Intensive LNG PK samples at pre-dose, and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 24, and 48 hours post-dose
Volume of Distribution (Vd) of LNG
Time frame: Intensive LNG PK samples at pre-dose, and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 24, and 48 hours post-dose
Half-life (T1/2) of LNG
Time frame: Intensive LNG PK samples at pre-dose, and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 24, and 48 hours post-dose
Time of Minimum Concentration (Tmin) of LNG
Time frame: Intensive LNG PK samples at pre-dose, and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 24, and 48 hours pose-dose
LNG Area Under the Concentration Time Curve (AUC0-24h) Calculated Based on Intensive LNG PK Samples Obtained From Individual Participants
Time frame: Intensive LNG PK samples at pre-dose, and 0.5, 1, 1.5, 2, 3, 4, 6, 8, and 24 hours post-dose
LNG Area Under the Concentration Time Curve (AUC0-48h) Calculated Based on Intensive LNG PK Samples Obtained From Individual Participants
Time frame: Intensive LNG PK samples at pre-dose, and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 24, and 48 hours pose-dose
LNG Total Area Under the Concentration Time Curve AUCinf (Infinity) Calculated Based on Intensive LNG PK Samples Obtained From Individual Participants
Time frame: Intensive LNG PK samples at pre-dose, and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 24, and 48 hours pose-dose
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 27 Dec 2021.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- The Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events (DAIDS AE Grading Table), Version 2.1, July 2017.Link provided by the sponsor.
- Manual for Expedited Reporting of Adverse Events to DAIDS (DAIDS EAE Manual), Version 2.0, January 2010Link provided by the sponsor.
- DAIDS AE Grading Table Addendum 1, Female Genital Grading Table for Use in Microbicide Studies, Version 1.0, November 2007Link provided by the sponsor.
- Individual participant dataSharing planned: Yes. Individual participant data that underlie results in the publication, after deidentification.
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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 Scarsi, PharmD, MS study chair
Northwestern University CRS, University of Nebraska Medical Center
18 sites in 7 countries: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2 study testing Levonorgestrel (LNG) in people with HIV Infections and Tuberculosis, run by Advancing Clinical Therapeutics Globally for HIV/AIDS and Other Infections at 18 sites in 7 countries.
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 32 inclusion and 17 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 27 Dec 2021. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 18 sites in United States, South Africa, Malawi, Thailand, Botswana and 2 more countries. 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?
Yes. Results are posted in the registry (first posted 30 Nov 2021). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
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?
LNG Area Under the Concentration-time Curve (AUC0-8h) Calculated Based on Intensive LNG PK Samples Obtained From Individual Participants (time frame: Intensive LNG PK samples at pre-dose, and 0.5, 1, 1.5, 2, 3, 4, 6, and 8 hours post-dose). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
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 27 Dec 2021.