Clinical trial NCT04272242: Drug-Drug Interactions Between Rifapentine and Dolutegravir in HIV/LTBI Co-Infected Individuals
Official title: Drug-Drug Interactions Between Rifapentine and Dolutegravir in HIV/LTBI Co-Infected Individuals
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE2
Conditions: HIV Infection
LTBI
Keywords: LTBI
HIV and LTBI Co-Infection
Rifapentine
Dolutegravir Interaction
Lead sponsor: National Institute of Allergy and Infectious Diseases (NIAID)
Sponsor class: NIH
Collaborators: name: ViiV Healthcare
First posted: 2020-02-17
Enrollment: 37
Sex: ALL
Minimum age (years): 18
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SEQUENTIAL
Primary purpose: TREATMENT

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.

Detailed description: The purpose of this study was to evaluate 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.

Participants received study-provided INH and RPT once daily for 4 weeks (1HP). During the 1HP treatment, DTG was administered twice daily in Arm 1. Arm 2 planned to administer DTG once daily.

At study entry, all participants were required to be on DTG-based antiretroviral (ARV) treatment with 2 nucleoside reverse transcriptase inhibitors (NRTIs) (tenofovir alafenamide \[TAF\] was prohibited) during the study. In Arm 1, DTG 50 mg was administered twice daily; the morning dose from non-study ARV supply and the evening dose from study supply.

Participants were also required to receive pyridoxine (vitamin B6) with each dose of INH based on the current local, national, or international dosing guidelines. NRTI therapy and pyridoxine (vitamin B6) was not provided by the study.

The majority of Arm 1 participants were on study for 6 weeks (a 4-week on-study treatment period and a 2-week follow-up period). Arm 1 participants could be on study for up to 11 weeks if the on-study treatment duration was extended or if participants needed additional follow-up visits to measure viral load.

The study began enrollment with Arm 1. Opening of Arm 2 was dependent upon assessment of DTG pharmacokinetics (PK) data from participants in Arm 1.

Arm 1 is complete and results are reported. Arm 2 was not conducted based on the Arm 1 PK assessment.

Eligibility criteria: Inclusion Criteria:

* 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.

  * NOTE: An existing chest X-ray or CT scan from within 30 days prior to entry can be used as qualifying chest imaging. If chest imaging will be performed for study evaluation (i.e., Screening), then chest X-ray should be performed. A CT scan will be used only if an existing scan is already available and will not be performed as part of study.
* The following laboratory values obtained within 30 days prior to study entry by any US laboratory that has a CLIA certification or its equivalent, or at any network approved non-US laboratory that operates in accordance with Good Clinical Laboratory Practice (GCLP) and participates in appropriate external quality assurance programs.

  * Absolute neutrophil count (ANC) \>750 cells/mm\^3
  * Hemoglobin ≥7.4 g/dL
  * Platelet count ≥50,000/mm\^3
  * Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase \[SGOT\]) \<2.5 X the upper limit of normal (ULN)
  * Alanine aminotransferase (ALT) (serum glutamic pyruvic transaminase \[SGPT\]) \<2.5 X ULN
  * Total bilirubin ≤1.5 x ULN
  * Creatinine \<1.3× ULN
* For females of reproductive potential, negative serum or urine pregnancy test at Screening within 30 days prior to entry and within 48 hours prior to entry by any US clinic or 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 clinic that operates in accordance with GCLP and participates in appropriate external quality assurance programs.

  * NOTE A: If screening visit occurs within 48 hours prior to entry, only one test will occur prior to entry.
  * NOTE B: Urine test must have a sensitivity of 15-25 mIU/mL.
* Female participants of reproductive potential must agree not to participate in the conception process (i.e., active attempt to become pregnant, in vitro fertilization), and if participating in sexual activity that could lead to pregnancy, must agree to use one reliable nonhormonal method of contraception, as listed below, while on study treatment and through study completion.
* Acceptable forms of contraception include:

  * Intrauterine device (IUD) or intrauterine system
  * Cervical cap with spermicide
  * Diaphragm with spermicide
  * Condoms (male or female)
  * NOTE A: Hormonal methods may be used, however, one of the other acceptable forms of contraception listed above must also be used through the duration of the study because of potential interactions with RPT.
  * NOTE B: Participant-reported history is acceptable documentation of menopause (i.e., at least 1 year amenorrheic), hysterectomy, or bilateral oophorectomy or bilateral tubal ligation; these candidates are considered not of reproductive potential and are eligible without the required use of contraception.

Exclusion Criteria:

* 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.
* Documented resistance that may confer reduced susceptibility to DTG, at any time prior to study entry. This includes the following INSTI mutations: Q148 substitutions, T66A, L74I/M, E138A/K/T, G140S/A/C, Y143R/C/H, E157Q, G163S/E/K/Q, G193E/R, or N155H.
* Clinically suspected INSTI resistance, at any time prior to study entry, as evidenced by prior receipt of INSTI containing ART, during which time two or more HIV-1 RNA levels of \>200 copies/mL were observed after having attained virologic suppression to \<200 copies/mL and without known interruption.
* Consumption of \>3 alcohol beverages on any day within 30 days prior to entry.

Primary outcomes:
measure: DTG PK Parameter Maximum Plasma Concentration (Cmax) Determined Based on DTG Levels From Individual Participants in Arm 1 by Visit Day
timeFrame: Intensive DTG PK samples at pre-dose, 1h, 2h, 4h, 8h, 12h, 13h, 14h, 23h and 24h post-dose at days 0 and 28
measure: 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
timeFrame: Intensive DTG PK samples at pre-dose, 1h, 2h, 4h, 8h, 12h, 13h, 14h, 23h and 24h post-dose at days 0 and 28
measure: DTG PK Parameter Minimum Plasma Concentration (Cmin) Determined Based on DTG Levels From Individual Participants in Arm 1 by Visit Day
timeFrame: Intensive DTG PK samples at pre-dose, 1h, 2h, 4h, 8h, 12h, 13h, 14h, 23h and 24h post-dose at days 0 and 28
measure: DTG PK Parameter Ctrough Determined Based on DTG Levels From Individual Participants in Arm 1 at Day 28
timeFrame: Intensive DTG PK samples at pre-dose, 1h, 2h, 4h, 8h, 12h, 13h, 14h, 23h and 24h post-dose at day 28
measure: DTG PK Parameter Maximum Plasma Concentration (Cmax) Determined Based on DTG Levels From Individual Participants in Arm 2 by Visit Day
timeFrame: Intensive DTG PK samples at pre-dose, 1h, 2h, 4h, 8h, 12h, 23h and 24h post-dose at days 0 and 28
measure: 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
timeFrame: Intensive DTG PK samples at pre-dose, 1h, 2h, 4h, 8h, 12h, 23h and 24h post-dose at days 0 and 28
measure: DTG PK Parameter Minimum Plasma Concentration (Cmin) Determined Based on DTG Levels From Individual Participants in Arm 2 by Visit Day
timeFrame: Intensive DTG PK samples at pre-dose, 1h, 2h, 4h, 8h, 12h, 23h and 24h post-dose at days 0 and 28
measure: DTG PK Parameter Ctrough Determined Based on DTG Levels From Individual Participants in Arm 2 at Day 28
timeFrame: Intensive DTG PK samples at pre-dose, 1h, 2h, 4h, 8h, 12h, 23h and 24h post-dose at days 0 and 28
Secondary outcomes:
measure: Percentage of Participants in Arm 1 With an Occurrence of Grade 2 or Higher Adverse Event
timeFrame: From initiation of study treatment to day 28
measure: Percentage of Participants in Arm 1 Who Completed the Study
timeFrame: From initiation of study to day 28
measure: Percentage of Participants in Arm 1 Who Completed Study Drug Treatment
timeFrame: From initiation of study treatment to day 28
measure: Percentage of Participants in Arm 1 With HIV-1 RNA Levels >50 Copies/mL
timeFrame: Measured at Days 28 and 42
measure: Percentage of Participants in Arm 2 With an Occurrence of Grade 2 or Higher Adverse Event
timeFrame: From initiation of study treatment to day 28
measure: Percentage of Participants in Arm 2 Who Completed the Study
timeFrame: From initiation of study to day 28
measure: Percentage of Participants in Arm 2 Who Completed Study Drug Treatment
timeFrame: From initiation of study treatment to day 28
measure: Percentage of Participants in Arm 2 With HIV-1 RNA Levels >50 Copies/mL
timeFrame: Measured at Days 28 and 42
Other outcomes:
Locations:
city: San Francisco
country: United States
facility: University of California HIV/AIDS CRS
state: California
city: Houston
country: United States
facility: Houston AIDS Research Team CRS
state: Texas
city: Gaborone
country: Botswana
facility: Gaborone CRS
state: South-East District
city: Port-au-Prince
country: Haiti
facility: GHESKIO Institute of Infectious Diseases and Reproductive Health (GHESKIO - IMIS) CRS
city: Port-au-Prince
country: Haiti
facility: Les Centres GHESKIO Clinical Research Site (GHESKIO-INLR) CRS
city: Lilongwe
country: Malawi
facility: Malawi CRS
state: Central Malawi
city: Cape Town
country: South Africa
facility: University of Cape Town Lung Institute (UCTLI) CRS
city: Cape Town
country: South Africa
facility: South African Tuberculosis Vaccine Initiative (SATVI) CRS
city: Pathum Wan
country: Thailand
facility: Thai Red Cross AIDS Research Centre (TRC-ARC) CRS
state: Bangkok
city: Milton Park
country: Zimbabwe
facility: Milton Park CRS
state: Harare
Study officials:
affiliation: University of Nebraska
name: Anthony Podany, PharmD
role: STUDY_CHAIR
References: