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

NCT03819114 | Completed Phase 2 Results DMC FDA Drug

• 3 other identifiers: ACTG A537538493UM1AI068636
• Study Type: interventional
• Target: 122
• Locations: 7 countries
• Sites: 18

Brief 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.

Conditions

HIV Infections; Tuberculosis

Keywords

Levonorgestrel; Pharmacokinetics; Efavirenz; Dolutegravir; Rifampin

Outcome Measures

Primary Outcomes (1)

• 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).

  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.

  From Day 0 through study Day 28

• Maximum Concentration (Cmax) of LNG

  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

  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

  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

  Intensive LNG PK samples at pre-dose, and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 24, and 48 hours post-dose

Study Arms (4)

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.

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.

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.

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.

Drug: Levonorgestrel (LNG)

Interventions

Levonorgestrel (LNG) DRUG

LNG tablet(s) were administered by mouth in a directly observed manner.

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)

Eligibility Criteria

• Age: 16 Years+
• Sex: female
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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.

Sponsors & Collaborators

• Advancing Clinical Therapeutics Globally for HIV/AIDS and Other Infections: lead
• National Institute of Allergy and Infectious Diseases (NIAID): collaborator

Study Sites (18)

2701 Northwestern University CRS

Chicago, Illinois, 60611, United States

Location

Rush Univ. Med. Ctr. ACTG CRS (2702)

Chicago, Illinois, 60612, United States

Location

Weill Cornell Upton CRS (7803)

New York, New York, 10065, United States

Location

Unc Aids Crs (3201)

Chapel Hill, North Carolina, 27514, United States

Location

Hosp. of the Univ. of Pennsylvania CRS (6201)

Philadelphia, Pennsylvania, 19104, United States

Location

Pitt CRS (1001)

Pittsburgh, Pennsylvania, 15213, United States

Location

Trinity Health and Wellness Center CRS (31443)

Dallas, Texas, 75208, United States

Location

Gaborone CRS (12701)

Gaborone, Botswana

Location

12101 Instituto de Pesquisa Clinica Evandro Chagas (IPEC) CRS

Rio de Janeiro, 21040, Brazil

Location

Kenya Medical Research Institute/Walter Reed Project Clinical Research Center (KEMRI/WRP) CRS (12501)

Kericho, 20200, Kenya

Location

Blantyre CRS (30301)

Blantyre, Malawi

Location

Malawi CRS (12001)

Lilongwe, Malawi

Location

University of the Witwatersrand Helen Joseph (WITS HJH) CRS (11101)

Johannesburg, Gauteng, 2193, South Africa

Location

Family Clinical Research Unit (FAM-CUR) CRS (8950)

Cape Town, West Cape, 7505, South Africa

Location

Durban Adult HIV CRS (11201)

Durban, 4013 SF, South Africa

Location

Soweto ACTG CRS (12301)

Johannesburg, South Africa

Location

31802 Thai Red Cross AIDS Research Centre (TRC-ARC) CRS

Bangkok, Patumwan, 10330, Thailand

Location

31784 Chiang Mai University HIV Treatment CRS

Chiang Mai, 50200, Thailand

Location

Related Links

• The Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events (DAIDS AE Grading Table), Version 2.1, July 2017.
• Manual for Expedited Reporting of Adverse Events to DAIDS (DAIDS EAE Manual), Version 2.0, January 2010
• DAIDS AE Grading Table Addendum 1, Female Genital Grading Table for Use in Microbicide Studies, Version 1.0, November 2007

MeSH Terms

Conditions

HIV Infections; Tuberculosis

Interventions

Levonorgestrel

Condition Hierarchy (Ancestors)

Blood-Borne Infections; Communicable Diseases; Infections; Sexually Transmitted Diseases, Viral; Sexually Transmitted Diseases; Lentivirus Infections; Retroviridae Infections; RNA Virus Infections; Virus Diseases; Genital Diseases; Urogenital Diseases; Immunologic Deficiency Syndromes; Immune System Diseases; Mycobacterium Infections; Actinomycetales Infections; Gram-Positive Bacterial Infections; Bacterial Infections; Bacterial Infections and Mycoses

Intervention Hierarchy (Ancestors)

Norgestrel; Norpregnenes; Norpregnanes; Norsteroids; Steroids; Fused-Ring Compounds; Polycyclic Compounds

Results Point of Contact

• Title: ACTG Clinicaltrials.gov Coordinator
• Organization: ACTG Network Coordinating Center, Social and Scientific Systems, a DLH Holdings Company.

ACTGCT.gov@fstrf.org

(301) 628-3348

Study Officials

• Kimberly Scarsi, PharmD, MS

  Northwestern University CRS, University of Nebraska Medical Center

  STUDY CHAIR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: NETWORK
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: January 25, 2019
• First Posted: January 28, 2019
• Study Start: May 6, 2019
• Primary Completion: November 2, 2020
• Study Completion: November 30, 2020
• Last Updated: December 27, 2021
• Results First Posted: November 30, 2021

Record last verified: 2021-12

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, 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.

Locations

ZA (4); TH (2); BR (1); US (7); BO (1); MA (2); KE (1)