Pharmacokinetic Study to Evaluate Double-Dose Levonorgestrel Emergency Contraception in Combination With Efavirenz-Based Antiretroviral Therapy or Rifampicin-Containing Anti-Tuberculosis Therapy
Condition: HIV Infections; Tuberculosis
MeSH terms: Tuberculosis; Emergencies
Intervention: Levonorgestrel (LNG)
Intervention description: LNG tablet(s) were administered by mouth in a directly observed manner.
Intervention MeSH terms: Levonorgestrel
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Enrollment: 122.0
Sex: Female
Minimum age: 16 Years
Healthy volunteers: No
Keywords: Levonorgestrel; Pharmacokinetics; Efavirenz; Dolutegravir; Rifampin

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. The
      safety of double-dose (3.0 mg) LNG versus standard-dose (1.5 mg) was also compared.
    

Eligibility criteria:

        Inclusion Criteria:

          -  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

               -  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.

        Exclusion Criteria

          -  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.

          -  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.