Clinical Trials

MainTitle

Pharmacokinetic Study to Evaluate Double-Dose Levonorgestrel Emergency Contraception in Combination With Efavirenz-Based Antiretroviral Therapy or Rifampicin-Containing Anti-Tuberculosis Therapy

This study is currently recruiting participants. (see Contacts and Locations)

Verified June 2019 by AIDS Clinical Trials Group

Sponsor
AIDS Clinical Trials Group

Collaborator
National Institute of Allergy and Infectious Diseases (NIAID)

Information provided by (Responsible Party)
AIDS Clinical Trials Group
ClinicalTrials.gov Identifier
NCT03819114

First received: January 25, 2019
Last updated: June 27, 2019
Last Verified: June 2019
History of Changes
Purpose

Purpose

The purpose of this pharmacokinetic (PK) study is to evaluate if a double dose (3 mg) of levonorgestrel (LNG) emergency contraception (EC) 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 EC versus standard-dose (1.5 mg) will also be compared.

Condition Intervention Phase
HIV Infections
Tuberculosis

Drug : Levonorgestrel Emergency Contraception (LNG EC)
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
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

Further study details as provided by AIDS Clinical Trials Group:

Primary Outcome Measures

  • LNG PK Parameter 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 will be 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 (Certera®). This version of the trapezoidal rule uses 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 50 pg/mL; values < LLOQ were imputed as 0 (if pre-dose) or as 25 (if post-dose).
Secondary Outcome Measures:
  • Percentage of participants experiencing either an SAE or AE potentially or definitely associated with single dose LNG administration. [ Time Frame: From Day 0 through study Day 28 ]
    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. Relationship of adverse events to study treatment was determined by the study core team and DAIDS clinical representative.
  • 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 ]
    Cmax for each participant will be calculated as the maximum observed LNG concentration from LNG PK samples at pre-dose through 48 hours post-dose. Standard noncompartmental techniques will be used to determine Cmax using the software package Phoenix WinNonLin (Certera®).
  • 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 ]
    Cmin for each participant will be calculated as the minimum observed LNG concentration from LNG PK samples at pre-dose through 48 hours post-dose. Standard noncompartmental techniques will be used to determine Cmin using the software package Phoenix WinNonLin (Certera®). Assay lower limit of quantification for LNG was 50 pg/mL; values < LLOQ were imputed as 0 (if pre-dose) or as 25 (if 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 ]
    Apparent oral clearance (CL/F) for each participant will be 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 will be used to determine CL/F using the software package Phoenix WinNonLin (Certera®).
  • 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 ]
    Vd for each participant will be calculated from observed LNG concentration from LNG PK samples at pre-dose through 48 hours post-dose. Standard noncompartmental techniques will be used to determine Vd using the software package Phoenix WinNonLin (Certera®).
  • 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 ]
    T1/2 for each participant will be 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 will be used to determine T1/2 using the software package Phoenix WinNonLin (Certera®).
  • LNG PK Parameter 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 ]
    AUC for each participant will be 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 Pheonix WinNonLin (Certera®). This version of the trapezoidal rule uses 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 50 pg/mL; values < LLOQ were imputed as 0 (if pre-dose) or as 25 (if post-dose).
  • LNG PK Parameter 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 ]
    AUC for each participant will be 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 Pheonix WinNonLin (Certera®). This version of the trapezoidal rule uses 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 50 pg/mL; values < LLOQ were imputed as 0 (if pre-dose) or as 25 (if post-dose).
  • LNG PK Parameter 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 ]
    AUC for each participant will be 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 Pheonix WinNonLin (Certera®). This version of the trapezoidal rule uses 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 50 pg/mL; values < LLOQ were imputed as 0 (if pre-dose) or as 25 (if post-dose).

Estimated Enrollment: 116
Study Start Date: May 6, 2019
Estimated Study Completion Date: October 1, 2020
Estimated Primary Completion Date: October 1, 2020 (Final data collection date for primary outcome measure)

Arms Assigned Interventions
Experimental: A: LNG EC 1.5 mg among women on EFV-based ART (randomized)
Participants will receive one 1.5 mg tablet of LNG EC on Day 0 and will be followed post-treatment for 4 weeks.
Drug: Levonorgestrel Emergency Contraception (LNG EC)

LNG EC tablet(s) will be administered by mouth in a directly observed manner.

Experimental: B: LNG EC 3.0 mg among women on EFV-based ART (randomized)
Participants will receive two 1.5 mg tablets (3 mg) of LNG EC on Day 0 and will be followed post-treatment for 4 weeks.
Drug: Levonorgestrel Emergency Contraception (LNG EC)

LNG EC tablet(s) will be administered by mouth in a directly observed manner.

Experimental: C: LNG EC 1.5 mg among women on DTG-based ART (assigned)
Participants will receive one 1.5 mg tablet of LNG EC on Day 0 and will be followed post-treatment for 4 weeks.
Drug: Levonorgestrel Emergency Contraception (LNG EC)

LNG EC tablet(s) will be administered by mouth in a directly observed manner.

Experimental: D: LNG EC 3.0 mg among women on RIF-INH TB Therapy (assigned)
Participants will receive two 1.5 mg tablets (3 mg) of LNG EC on Day 0 and will be followed post-treatment for 4 weeks.
Drug: Levonorgestrel Emergency Contraception (LNG EC)

LNG EC tablet(s) will be administered by mouth in a directly observed manner.

Detailed Description:

This pharmacokinetic (PK) study will evaluate if a double dose (3.0 mg) of levonorgestrel (LNG) emergency contraception (EC) 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 EC versus standard-dose (1.5 mg) will also be compared.
Participants will be volunteers who do not currently require EC for contraception. This study will enroll women who are 16 years of age or older. Group assignment will be determined by infection status (HIV or TB; participants cannot be coinfected), and, for those who are living with HIV, by ART regimen at enrollment. Women living with HIV who are taking EFV-based ART will be randomized to receive a standard dose LNG EC (Group A) or a double dose of LNG EC (Group B). Women taking dolutegravir (DTG)-based ART will be assigned to a standard dose of LNG EC (Group C). Women who are HIV-negative and in the continuation phase of active TB treatment taking RIF and isoniazid (INH) will be assigned to a double dose of LNG EC (Group D).
At study entry, participants in Groups A and C will receive a standard single dose of LNG EC. Participants in Groups B and D will receive a double dose of LNG EC. Intensive PK monitoring will be conducted pre-dose, and after the LNG EC dose. Women are expected to be at the clinical site while the initial 8 hour PK samples are collected and may return for the 24 and 48 hour samples.
All participants will complete self-report questionnaires to assess adherence to TB therapy and ART, menstrual history and patterns after LNG EC administration, and to collect adverse effects commonly reported with LNG EC (i.e., irregular bleeding patterns). Adherence to ART and RIF will be assessed by collecting hair samples and single plasma concentrations at entry. All participants will be followed for 4 weeks.

Eligibility

Eligibility

Ages Eligible for Study: 16 Years and older  
Sexes Eligible for Study: Female  
Accepts Healthy Volunteers: No  

Criteria

Inclusion Criteria:

  • Postmenarcheal female.
    • Note: Participant report and clinician's opinion are acceptable.
  • The following laboratory values obtained within 30 days prior to study entry by any US laboratory that has a Clinical Laboratory Improvement Amendments (CLIA) certification or its equivalent, or at any network-approved non-US laboratory that operates in accordance with Good Clinical Laboratory Practices (GCLP) and participates 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 occurs more than 48 hours prior to entry) by any US clinic or US laboratory that has a CLIA certification or its equivalent, or is using a point of care (POC)/CLIA-waived test, or at any network-approved non-US laboratory or non-US clinic that operates in accordance with GCLP and participates in appropriate EQA programs. The serum or urine pregnancy test must have a sensitivity of at least 25 mIU/mL.
  • Has 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 must agree 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 are participating in sexual activity that could lead to pregnancy, must agree to use at least one reliable method of contraception while in the study. Acceptable forms of contraceptives include:
      • 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
  • Women and girls 16 years of age and older.
  • Ability and willingness of participant or legal guardian/representative to provide 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 will be allowed in each arm B-D and a maximum of 3 participants in Arm A.
  • For women living 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" refers to a US Food and Drug Administration (FDA)-approved kit, which is required for all investigational new drug (IND) studies, or for sites located in countries other than the United States, a kit that has been certified or licensed by an oversight body within that country and validated internally. Non-US sites are encouraged to use US FDA-approved methods for IND studies.
    • World Health Organization (WHO) and Centers for Disease Control and Prevention (CDC) guidelines mandate that confirmation of the initial test result must use a test that is different from the one used for the initial assessment. A reactive initial rapid test should be confirmed by either another type of rapid assay or an E/CIA that is 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 women living with HIV: Receiving 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 women who are 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" refers to a US FDA-approved kit, which is required for all IND studies, or for sites located in countries other than the United States, a kit that has been certified or licensed by an oversight body within that country and validated internally. Non-US sites are encouraged to use US FDA-approved methods for IND studies.
    • WHO and CDC guidelines mandate that confirmation of the initial test result must use a test that is different from the one used for the initial assessment. A reactive initial rapid test should be confirmed by either another type of rapid assay or an E/CIA that is 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 women who are HIV-negative and being treated for TB: Receiving 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 is allowed.
  • Ability and willingness of participant to be 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 is defined as amenorrhea for at least 12 consecutive months prior to study entry (in the absence of medications known to induce amenorrhea), and have 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 is 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 are acceptable.
  • Currently pregnant, within 6 weeks of delivery, or currently breastfeeding an infant under 6 months of age.
    • Note: For recent pregnancy resolution during the first or second trimester, the participant is only eligible when the pregnancy test result is 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.
  • Use of 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 interfere with adherence to study requirements.
  • Acute or serious illness requiring 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 interfere with completion of study procedures and or adherence to study drug.
  • For women living with HIV: Currently receiving medications for TB infection.
  • For women living with HIV: Has missed one or more of the prescribed doses of HIV medications within 3 days prior to study entry.
    • Note: The entry visit may be rescheduled within the screening period once the participant has taken all prescribed doses within 3 days prior to study entry.
  • For women who are HIV-negative and being treated for TB: Has missed one or more of the prescribed doses of TB medication within 3 days prior to study entry.
    • Note: The entry visit may be rescheduled within the screening period once the
    participant has taken all prescribed doses within 3 days prior to study entry.

contacts and locations

Contacts and Locations

Choosing to participate in a study is an important personal decision.Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below.For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT03819114

Locations

United States, Colorado
University of Colorado Hospital CRS (6101) Recruiting
Aurora, Colorado, United States, 80045
Contact: Suzanne G Fiorillo, MSPH    303-724-5931    suzanne.fiorillo@ucdenver.edu
Principal Investigator: Thomas B Campbell, MD
United States, North Carolina
Unc Aids Crs (3201) Recruiting
Chapel Hill, North Carolina, United States, 27514
Contact: Becky Straub, RN, BSN, MPH    919-843-9975    bstraub@med.unc.edu
Principal Investigator: David A. Wohl, MD
United States, Pennsylvania
Hosp. of the Univ. of Pennsylvania CRS (6201) Recruiting
Philadelphia, Pennsylvania, United States, 19104
Contact: Eileen Donaghy, BSN, CRNP    215-349-8092    eileen.donaghy2@uphs.upenn.edu
Principal Investigator: Pablo Tebas, MD
Pitt CRS (1001) Recruiting
Pittsburgh, Pennsylvania, United States, 15213
Contact: Renee Weinman, MPPM    412-383-1748    drw39@pitt.edu
Principal Investigator: Sharon A. Riddler, MD, MPH
United States, Rhode Island
The Miriam Hosp. ACTG CRS (2951) Recruiting
Providence, Rhode Island, United States, 02906
Contact: Pamela Poethke, RN    401-793-4971    ppoethke@lifespan.org
Principal Investigator: Karen T. Tashima, MD

Sponsors and Collaborators

AIDS Clinical Trials Group
National Institute of Allergy and Infectious Diseases (NIAID)

Investigators

Study Chair: Kimberly Scarsi, PharmD, MS Northwestern University CRS, University of Nebraska Medical Center
More Information

More Information


Responsible Party: AIDS Clinical Trials Group  
ClinicalTrials.gov Identifier: NCT03819114   History of Changes  
Other Study ID Numbers: ACTG A5375  
  38493  
Study First Received: January 25, 2019  
Last Updated: June 27, 2019  
Individual Participant Data    
Plan to Share IPD: Yes  

Studies a U.S. FDA-regulated Drug Product: Yes  
Studies a U.S. FDA-regulated Device Product: No  

Keywords provided by AIDS Clinical Trials Group:

Levonorgestrel
Pharmacokinetics
Efavirenz
Dolutegravir
Rifampin

Additional relevant MeSH terms:
Tuberculosis
Emergencies
Efavirenz
Rifampin
Antitubercular Agents
Levonorgestrel

ClinicalTrials.gov processed this data on December 13, 2019
This information is provided by ClinicalTrials.gov.