Working...
ClinicalTrials.gov
ClinicalTrials.gov Menu

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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
ClinicalTrials.gov Identifier: NCT03819114
Recruitment Status : Recruiting
First Posted : January 28, 2019
Last Update Posted : June 28, 2019
Sponsor:
Collaborator:
National Institute of Allergy and Infectious Diseases (NIAID)
Information provided by (Responsible Party):
AIDS Clinical Trials Group

Brief Summary:
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 or disease Intervention/treatment Phase
HIV Infections Tuberculosis Drug: Levonorgestrel Emergency Contraception (LNG EC) Phase 2

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.


Layout table for study information
Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 116 participants
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
Actual Study Start Date : May 6, 2019
Estimated Primary Completion Date : October 1, 2020
Estimated Study Completion Date : October 1, 2020

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
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.




Primary Outcome Measures :
  1. 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 :
  1. 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.

  2. 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®).

  3. 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).

  4. 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®).

  5. 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®).

  6. 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®).

  7. 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).

  8. 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).

  9. 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).



Information from the National Library of Medicine

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, Learn About Clinical Studies.


Layout table for eligibility information
Ages Eligible for Study:   16 Years and older   (Child, Adult, Older Adult)
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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03819114


Locations
Layout table for location information
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
Layout table for investigator information
Study Chair: Kimberly Scarsi, PharmD, MS Northwestern University CRS, University of Nebraska Medical Center

Layout table for additonal information
Responsible Party: AIDS Clinical Trials Group
ClinicalTrials.gov Identifier: NCT03819114     History of Changes
Other Study ID Numbers: ACTG A5375
38493 ( Registry Identifier: DAIDS-ES Registry Number )
First Posted: January 28, 2019    Key Record Dates
Last Update Posted: June 28, 2019
Last Verified: June 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: Individual participant data that underlie results in the publication, after deidentification.
Supporting Materials: Study Protocol
Statistical Analysis Plan (SAP)
Time Frame: Beginning 3 months following publication and available throughout period of funding of the AIDS Clinical Trials Group by NIH
Access Criteria:
  • With whom? Researchers who provide a methodologically sound proposal for use of the data that is approved by the AIDS Clinical Trials Group.
  • For what types of analyses? To achieve aims in the proposal approved by the AIDS Clinical Trials Group.
  • By what mechanism will data be made available? Researchers may submit a request for access to data using the AIDS Clinical Trials Group "Data Request" form at: https://actgnetwork.org/about-actg/templates-and-forms. Researchers of approved proposals will need to sign an AIDS Clinical Trials Group Data Use Agreement before receiving the data.

Layout table for additional information
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:
Layout table for MeSH terms
Levonorgestrel
HIV Infections
Emergencies
Tuberculosis
Lentivirus Infections
Retroviridae Infections
RNA Virus Infections
Virus Diseases
Sexually Transmitted Diseases, Viral
Sexually Transmitted Diseases
Immunologic Deficiency Syndromes
Immune System Diseases
Disease Attributes
Pathologic Processes
Mycobacterium Infections
Actinomycetales Infections
Gram-Positive Bacterial Infections
Bacterial Infections
Anti-Retroviral Agents
Efavirenz
Rifampin
Antitubercular Agents
Antiviral Agents
Anti-Infective Agents
Reverse Transcriptase Inhibitors
Nucleic Acid Synthesis Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Cytochrome P-450 CYP2C9 Inhibitors
Cytochrome P-450 Enzyme Inhibitors