Drug-Drug Interactions Between Rifapentine and Dolutegravir in HIV/LTBI Co-Infected Individuals

NCT04272242 | Terminated Phase 2 Results DMC FDA Drug

• 2 other identifiers: ACTG A537238485
• Study Type: interventional
• Target: 37
• Locations: 7 countries
• Sites: 10

Brief Summary

This study evaluated the potential drug-drug interactions between dolutegravir (DTG) and steady state rifapentine (RPT) when RPT was given with isoniazid (INH) daily for 4 weeks (1HP) as part of treatment for latent TB infection (LTBI) in HIV-1 and LTBI co-infected individuals.

Conditions

HIV Infection; LTBI

Keywords

LTBI; HIV and LTBI Co-Infection; Rifapentine; Dolutegravir Interaction

Outcome Measures

Primary Outcomes (8)

• DTG PK Parameter Maximum Plasma Concentration (Cmax) Determined Based on DTG Levels From Individual Participants in Arm 1 by Visit Day

  This evaluates the effect of RPT on the DTG PK parameter Cmax obtained from participants enrolled in Arm 1 at day 0 (DTG QD) and day 28 (DTG BID with 1HP). Cmax defines the model-predicted maximum concentration observed over the 12- or 24- hours of the DTG dosing interval.

  Intensive DTG PK samples at pre-dose, 1h, 2h, 4h, 8h, 12h, 13h, 14h, 23h and 24h post-dose at days 0 and 28

• DTG PK Parameter Area Under the Concentration Time Curve (AUC0-24) Calculated Based on Intensive PK Samples Obtained From Individual Participants Enrolled in Arm 1 by Visit Day

  This evaluates the effect of RPT on the DTG PK parameter AUC 0-24h obtained from participants enrolled in Arm 1 at day 0 (DTG QD) and day 28 (DTG BID with 1HP). AUC 0-24h defines area under the concentration-time curve over the period of 24 hours post-dose estimated based on the fitted model. For Arm 1, Day 28 (BID dosing), participant-specific AUC0-24h was estimated by summing participant-specific estimated AUC values for the 0-12 hour dosing interval (AUC0-12).

  Intensive DTG PK samples at pre-dose, 1h, 2h, 4h, 8h, 12h, 13h, 14h, 23h and 24h post-dose at days 0 and 28

• DTG PK Parameter Minimum Plasma Concentration (Cmin) Determined Based on DTG Levels From Individual Participants in Arm 1 by Visit Day

  This evaluates the effect of RPT on the DTG PK parameter Cmin obtained from participants enrolled in Arm 1 at day 0 (DTG QD) and day 28 (DTG BID with 1HP). Cmin defines the model-predicted minimum concentration observed over the 12- or 24- hour DTG dosing interval.

  Intensive DTG PK samples at pre-dose, 1h, 2h, 4h, 8h, 12h, 13h, 14h, 23h and 24h post-dose at days 0 and 28

• DTG PK Parameter Ctrough Determined Based on DTG Levels From Individual Participants in Arm 1 at Day 28

  This evaluates the effect of RPT on the DTG PK parameter Ctrough obtained from participants enrolled in Arm 1 at day 28 (DTG BID with 1HP). Ctrough defines the observed non-model based minimum concentration observed over the 12- hour DTG dosing interval.

  Intensive DTG PK samples at pre-dose, 1h, 2h, 4h, 8h, 12h, 13h, 14h, 23h and 24h post-dose at day 28

• DTG PK Parameter Maximum Plasma Concentration (Cmax) Determined Based on DTG Levels From Individual Participants in Arm 2 by Visit Day

  This evaluates the effect of RPT on the DTG PK parameter Cmax obtained from participants enrolled in Arm 2 at day 0 (DTG QD) and day 28 (DTG QD with 1HP). Cmax defines the model-predicted maximum concentration observed over the 24- hours of the DTG dosing interval.

  Intensive DTG PK samples at pre-dose, 1h, 2h, 4h, 8h, 12h, 23h and 24h post-dose at days 0 and 28

• DTG PK Parameter Area Under the Concentration Time Curve (AUC0-24) Calculated Based on Intensive PK Samples Obtained From Individual Participants Enrolled in Arm 2 by Visit Day

  This evaluates the effect of RPT on the DTG PK parameter AUC 0-24h obtained from participants enrolled in Arm 2 at day 0 (DTG QD) and day 28 (DTG QD with 1HP). AUC 0-24h defines area under the concentration-time curve over the period of 24 hours post-dose estimated based on the fitted model.

  Intensive DTG PK samples at pre-dose, 1h, 2h, 4h, 8h, 12h, 23h and 24h post-dose at days 0 and 28

• DTG PK Parameter Minimum Plasma Concentration (Cmin) Determined Based on DTG Levels From Individual Participants in Arm 2 by Visit Day

  This evaluates the effect of RPT on the DTG PK parameter Cmin obtained from participants enrolled in Arm 2 at day 0 (DTG QD) and day 28 (DTG QD with 1HP). Cmin defines the model-predicted minimum concentration observed over the 24- hour DTG dosing interval.

  Intensive DTG PK samples at pre-dose, 1h, 2h, 4h, 8h, 12h, 23h and 24h post-dose at days 0 and 28

• DTG PK Parameter Ctrough Determined Based on DTG Levels From Individual Participants in Arm 2 at Day 28

  This evaluates the effect of RPT on the DTG PK parameter Ctrough obtained from participants enrolled in Arm 2 at day 28 (DTG QD with 1HP). Ctrough defines the observed non-model based minimum concentration observed over the 24- hour DTG dosing interval.

  Intensive DTG PK samples at pre-dose, 1h, 2h, 4h, 8h, 12h, 23h and 24h post-dose at days 0 and 28

Secondary Outcomes (8)

• Percentage of Participants in Arm 1 With an Occurrence of Grade 2 or Higher Adverse Event

  From initiation of study treatment to day 28

• Percentage of Participants in Arm 1 Who Completed the Study

  From initiation of study to day 28

• Percentage of Participants in Arm 1 Who Completed Study Drug Treatment

  From initiation of study treatment to day 28

• Percentage of Participants in Arm 1 With HIV-1 RNA Levels >50 Copies/mL

  Measured at Days 28 and 42

• Percentage of Participants in Arm 2 With an Occurrence of Grade 2 or Higher Adverse Event

  From initiation of study treatment to day 28

Study Arms (2)

Arm 1: DTG + INH + RPT

EXPERIMENTAL

Participants received 50 mg of DTG orally twice daily (\~12 hours apart). Participants received 300 mg of INH and 600 mg of RPT orally each morning for 4 weeks. Participants also received 25 or 50 mg of pyridoxine (vitamin B6) with each dose of INH. Participants remained on DTG-based ARV treatment with 2 NRTIs (excluding TAF) during the study. Participants took non-study supply of DTG for morning doses, and study-supplied DTG for evening doses.

Drug: Dolutegravir (DTG); Drug: Isoniazid (INH); Drug: Rifapentine (RPT); Drug: Antiretroviral Therapy (ART); Dietary Supplement: Pyridoxine (Vitamin B6)

Arm 2: DTG + INH + RPT

EXPERIMENTAL

Participants were to receive 50 mg of DTG orally each morning and 300 mg of INH and 600 mg of RPT orally each morning for 4 weeks. Participants were also to have received 25 or 50 mg of pyridoxine (vitamin B6) with each dose of INH. Participants were to remain on once-daily DTG-based ARV treatment with 2 NRTIs (excluding TAF) during the study with DTG supplied from non-study ARV supply. It was decided to not move forward with Arm 2 of the study based on the Arm 1 PK assessment and no participants were enrolled in Arm 2.

Drug: Dolutegravir (DTG); Drug: Isoniazid (INH); Drug: Rifapentine (RPT); Drug: Antiretroviral Therapy (ART); Dietary Supplement: Pyridoxine (Vitamin B6)

Interventions

Dolutegravir (DTG) DRUG

Administered orally

Arm 1: DTG + INH + RPT; Arm 2: DTG + INH + RPT

Isoniazid (INH) DRUG

Administered orally

Arm 1: DTG + INH + RPT; Arm 2: DTG + INH + RPT

Rifapentine (RPT) DRUG

Administered orally

Arm 1: DTG + INH + RPT; Arm 2: DTG + INH + RPT

Antiretroviral Therapy (ART) DRUG

Participants remained on DTG-based ARV treatment with 2 NRTIs (excluding TAF) during the study. NRTIs were not provided by the study. Arm 1 participants took non-study supply of DTG for morning doses, and study-supplied DTG for evening doses. For Arm 2 participants, DTG was to have come from non-study ARV supply.

Arm 1: DTG + INH + RPT; Arm 2: DTG + INH + RPT

Pyridoxine (Vitamin B6) DIETARY_SUPPLEMENT

Participants received 25 or 50 mg of pyridoxine (vitamin B6) with each dose of INH, based on the current local, national, or international dosing guidelines. Pyridoxine was not provided by the study.

Arm 1: DTG + INH + RPT; Arm 2: DTG + INH + RPT

Eligibility Criteria

• Age: 18 Years - 65 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Ability and willingness of participant or legal guardian/representative to provide informed consent.
• Weight ≥40 kg and a body mass index (BMI) of greater than 18.5 kg/m\^2.
• Documentation of HIV-1 infection status, as below:
• HIV-1 infection, documented by any licensed rapid HIV test or HIV-1 E/CIA test kit at any time prior to 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 or plasma HIV-1 RNA viral load. Two or more HIV-1 RNA viral loads of \>1,000 copies/mL are also acceptable as documentation of HIV-1 infection.
• Note A: 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 that are 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.
• Note B: 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.
• HIV-1 plasma viral load \<50 copies/mL 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 is Virology Quality Assessment (VQA) certified.
• At US sites: Evidence of LTBI by tuberculin skin test (TST) reactivity ≥5 mm, or a positive interferon gamma release assay (IGRA) at any time prior to study entry.
• At non-US sites: Indication for LTBI treatment according to WHO latent TB guidelines (Note: TST/IGRA results not required).
• On a stable once daily DTG (50 mg) based ART with once daily 2 NRTIs and
• with at least 28 total days of DTG and NRTI dosing prior to study entry
• with no gaps in self-reported DTG and NRTI adherence of more than 3 consecutive days in the 28 days prior to study entry
• with no intention to change ART for the duration of the study
• NOTE A: Participants who switch from another ART regimen to DTG to meet eligibility requirements for this study will be eligible to enroll as long as the ART is switched at least 28 days prior to study entry.
• Chest radiograph or chest computed tomography (CT) scan performed within 30 days prior to study entry without evidence of active TB.

You may not qualify if:

• Breastfeeding, pregnancy, or plans to become pregnant.
• Known allergy/sensitivity or any hypersensitivity to components of the study drugs, or their formulations.
• Presence of any confirmed or probable active TB based on criteria listed in the current AIDS Clinical Trials Group (ACTG) Diagnosis Appendix at screening.
• History of rifamycin-monoresistant, INH-monoresistant, multi-drug resistant (MDR) or extensively-drug resistant (XDR) TB at any time prior to study entry
• Known exposure to rifamycin-monoresistant, INH-monoresistant, MDR- or XDR-TB (e.g., household member of a person with rifamycin-monoresistant, INH monoresistant, MDR- or XDR-TB) at any time prior to study entry by participant self report or medical records.
• History of peripheral neuropathy Grade ≥2 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, which can be found on the DAIDS RSC website at https://rsc.niaid.nih.gov/clinical-research-sites/daids-adverse-event-grading-tables.
• 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 7 days prior to study entry.
• Known cirrhosis, a history of decompensated liver disease (ascites, hepatic encephalopathy, or esophageal varices) or current Child Pugh Class B or C hepatic impairment.
• Note: Refer to the study protocol for Child Pugh scoring and classification table.
• Initiated, discontinued, or changed doses of drugs that are P-glycoprotein (PGP) inducers, that are P-glycoprotein (PGP) inhibitors,or that are known to have drug interactions with DTG, within 30 days prior to study entry.
• Note: Refer to the list of prohibited and precautionary medications in the study protocol.
• Known porphyria at any time prior to study entry.
• Receipt of any other antiretroviral therapy other than DTG and 2 NRTI within 28 days prior to study entry.
• Receipt of TAF within 28 days prior to study entry.

Sponsors & Collaborators

• National Institute of Allergy and Infectious Diseases (NIAID): lead
• ViiV Healthcare: collaborator

Study Sites (10)

University of California HIV/AIDS CRS

San Francisco, California, 94110, United States

Location

Houston AIDS Research Team CRS

Houston, Texas, 77030, United States

Location

Gaborone CRS

Gaborone, South-East District, Botswana

Location

GHESKIO Institute of Infectious Diseases and Reproductive Health (GHESKIO - IMIS) CRS

Port-au-Prince, HT-6110, Haiti

Location

Les Centres GHESKIO Clinical Research Site (GHESKIO-INLR) CRS

Port-au-Prince, HT-6110, Haiti

Location

Malawi CRS

Lilongwe, Central Malawi, Malawi

Location

University of Cape Town Lung Institute (UCTLI) CRS

Cape Town, 7700, South Africa

Location

South African Tuberculosis Vaccine Initiative (SATVI) CRS

Cape Town, 7705, South Africa

Location

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

Pathum Wan, Bangkok, 10330, Thailand

Location

Milton Park CRS

Milton Park, Harare, Zimbabwe

Location

Related Publications (1)

• Podany AT, Cramer Y, Imperial M, Rosenkranz SL, Avihingsanon A, Arduino R, Samaneka W, Gelmanova I, Savic R, Swindells S, Dawson R, Luetkemeyer AF. Twice-Daily Dolutegravir-Based Antiretroviral Therapy With 1 Month of Daily Rifapentine and Isoniazid for Tuberculosis Prevention. Clin Infect Dis. 2024 Oct 15;79(4):983-989. doi: 10.1093/cid/ciae183.

  PMID: 38568956 DERIVED

Related Links

• Location of Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events (DAIDS AE Grading Table), corrected Version 2.1, July 2017

MeSH Terms

Conditions

HIV Infections

Interventions

dolutegravir; Isoniazid; rifapentine; Antiretroviral Therapy, Highly Active; Pyridoxine; Vitamin B 6

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

Intervention Hierarchy (Ancestors)

Hydrazines; Organic Chemicals; Isonicotinic Acids; Acids, Heterocyclic; Heterocyclic Compounds; Pyridines; Heterocyclic Compounds, 1-Ring; Drug Therapy, Combination; Drug Therapy; Therapeutics; Picolines

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

• Anthony Podany, PharmD

  University of Nebraska

  STUDY CHAIR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

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

Study Record Dates

• First Submitted: February 12, 2020
• First Posted: February 17, 2020
• Study Start: February 27, 2021
• Primary Completion: December 15, 2021
• Study Completion: December 27, 2021
• Last Updated: September 19, 2024
• Results First Posted: August 9, 2024

Record last verified: 2024-09

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://submit.mis.s-3.net/ Researchers of approved proposals will need to sign an AIDS Clinical Trials Group Data Use Agreement before receiving the data.

Locations

BO (1); HA (2); MA (1); TH (1); ZA (2); US (2); ZI (1)