HIV InfectionPhase 2NCT04272242
Drug-Drug Interactions Between Rifapentine and Dolutegravir in HIV/LTBI Co-Infected Individuals
A Phase 2 study testing Dolutegravir (DTG), Isoniazid (INH) and Rifapentine (RPT) in people with HIV Infection and LTBI, run by National Institute of Allergy and Infectious Diseases (NIAID) at 10 sites in 7 countries.
Trial 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. Read more about this study
- Who is it for?
- Ages 18 to 65 years
- Conditions the study is for
- HIV Infection, LTBI
- What is being tested?
- Dolutegravir (DTG), Isoniazid (INH) and Rifapentine (RPT)
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 37 participants
- Where
- 10 sitesin 7 countries
- Study dates
- 27 Feb 2021to 27 Dec 2021
- Phase
- Phase 2
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 65 years
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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.
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- 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.
Who cannot join
- 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.
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- 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.
Trial locations and contacts
10 sites in 7 countries.
10 sites in 7 countries
United States2 sites
Houston AIDS Research Team CRS
Houston, Texas, 77030
University of California HIV/AIDS CRS
San Francisco, California, 94110
Haiti2 sites
GHESKIO Institute of Infectious Diseases and Reproductive Health (GHESKIO - IMIS) CRS
Port-au-Prince, HT-6110
Les Centres GHESKIO Clinical Research Site (GHESKIO-INLR) CRS
Port-au-Prince, HT-6110
South Africa2 sites
University of Cape Town Lung Institute (UCTLI) CRS
Cape Town, 7700
South African Tuberculosis Vaccine Initiative (SATVI) CRS
Cape Town, 7705
Thailand1 site
Thai Red Cross AIDS Research Centre (TRC-ARC) CRS
Pathum Wan, Bangkok, 10330
About this study
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.
Read the 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.
- Conditions
- HIV Infection, LTBI
- Being tested
- Dolutegravir (DTG), Isoniazid (INH), Rifapentine (RPT), Antiretroviral Therapy (ART), Pyridoxine (Vitamin B6)
- Keywords
- LTBI, HIV and LTBI Co-Infection, Rifapentine, Dolutegravir Interaction
- Medical subject headings
- HIV Infections
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Dolutegravir (DTG)Drug
Administered orally
Isoniazid (INH)Drug
Administered orally
Rifapentine (RPT)Drug
Administered orally
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.
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.
| Study group | Role | What they receive |
|---|---|---|
| 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. Receives: 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. Receives: Drug: Dolutegravir (DTG); Drug: Isoniazid (INH); Drug: Rifapentine (RPT); Drug: Antiretroviral Therapy (ART); Dietary Supplement: Pyridoxine (Vitamin B6) |
What is being measured
The primary outcome is the main question the study is designed to answer.
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.
Measured: 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).
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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
Arm 1 participants with an occurrence of an adverse event (laboratory value, sign/symptom, diagnosis) of grade 2 or higher on a scale of 1 to 5 where 5 is the most severe. Severity 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. Participants were counted once at the highest grade.
Measured: From initiation of study treatment to day 28
Percentage of Participants in Arm 1 Who Completed the Study
Percentage of participants in Arm 1 who completed the study
Measured: From initiation of study to day 28
Percentage of Participants in Arm 1 Who Completed Study Drug Treatment
Percentage of participants in Arm 1 who completed study drug treatment (DTG+1HP)
Measured: From initiation of study treatment to day 28
Percentage of Participants in Arm 1 With HIV-1 RNA Levels >50 Copies/mL
This evaluates the short-term impact on virologic suppression of DTG based ART when coadministered with 1HP by measuring the percentage of participants with plasma HIV-1 RNA levels >50 copies/mL at study day 28 (after 4 weeks of DTG+1HP) and study day 42 (14 days after completing study treatment).
Measured: Measured at Days 28 and 42
Percentage of Participants in Arm 2 With an Occurrence of Grade 2 or Higher Adverse Event
Arm 2 participants with an occurrence of an adverse event (laboratory value, sign/symptom, diagnosis) of grade 2 or higher on a scale of 1 to 5 where 5 is the most severe. Severity 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. Participants will be counted once at the highest grade.
Measured: From initiation of study treatment to day 28
Percentage of Participants in Arm 2 Who Completed the Study
Percentage of participants in Arm 2 who completed the study.
Measured: From initiation of study to day 28
Percentage of Participants in Arm 2 Who Completed Study Drug Treatment
Percentage of participants in Arm 2 who completed study drug treatment (DTG+1HP).
Measured: From initiation of study treatment to day 28
Percentage of Participants in Arm 2 With HIV-1 RNA Levels >50 Copies/mL
This evaluates the short-term impact on virologic suppression of DTG based ART when coadministered with 1HP by measuring the percentage of participants with plasma HIV-1 RNA levels >50 copies/mL at study day 28 (after 4 weeks of DTG+1HP) and study day 42 (14 days after completing study treatment).
Measured: Measured at Days 28 and 42
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted17 Feb 2020
- Study start27 Feb 2021
- Primary completion15 Dec 2021
- Study completion27 Dec 2021
Why it stopped: 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.
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Publications (1)Papers the sponsor has linked to this study.
- Other trials for HIV InfectionStudies of the same condition, open and under way.
- More trials run by National Institute of Allergy and Infectious Diseases (NIAID)The sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 2
- Primary purpose
- Treatment
- Allocation
- Non-randomised
- Intervention model
- Sequential
- Masking
- None (open label)
- Enrolment
- 37 participants (actual)
Sponsor and investigators
- Sponsor type
- US National Institutes of Health
- Collaborators
- ViiV Healthcare
- Responsible party
- Sponsor
- Investigators
- Anthony Podany, PharmD, Study chair, University of Nebraska
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT04272242
- Sponsor's protocol ID
- ACTG A5372
- Other IDs
- 38485
- Status last verified
- Sep 2024
- First submitted
- 12 Feb 2020
- Last updated
- 19 Sep 2024
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- Yes
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
- Individual data sharing
- Yes: Individual participant data that underlie results in the publication, after deidentification.
Publications
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.
PubMed 38568956
Study at a glance
From the registry record, last updated by the sponsor on 19 Sep 2024. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Drug-Drug Interactions Between Rifapentine and Dolutegravir in HIV/LTBI Co-Infected Individuals
- ClinicalTrials.gov ID
- NCT04272242
- Acronym / sponsor ID
- ACTG A5372
- Conditions
- HIV Infection, LTBI
- Keywords
- LTBI, HIV and LTBI Co-Infection, Rifapentine, Dolutegravir Interaction
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- TerminatedReason stopped: 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.
- Enrolment
- 37 participants (actual)
- Lead sponsor
- National Institute of Allergy and Infectious Diseases (NIAID)US National Institutes of Health
- Collaborators
- ViiV Healthcare
- Study start
- 27 Feb 2021 (actual)
- Primary completion
- 15 Dec 2021 (actual)
- Study completion
- 27 Dec 2021 (actual)
- First posted
- 17 Feb 2020 (actual)
- Results
- Posted 9 Aug 2024
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Study design
- Primary purpose
- Treatment
- Allocation
- Non-randomised
- Intervention model
- Sequential
- Masking
- None (open label)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Arm 1: DTG + INH + RPT | Experimental | Drug: Dolutegravir (DTG), Drug: Isoniazid (INH), Drug: Rifapentine (RPT), Drug: Antiretroviral Therapy (ART), Dietary Supplement: Pyridoxine (Vitamin B6)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. |
| Arm 2: DTG + INH + RPT | Experimental | Drug: Dolutegravir (DTG), Drug: Isoniazid (INH), Drug: Rifapentine (RPT), Drug: Antiretroviral Therapy (ART), Dietary Supplement: Pyridoxine (Vitamin B6)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. |
Who may qualify
- Ages
- 18 to 65 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (35 listed)
- 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 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.
Key exclusion criteria (18 listed)
- 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.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Dolutegravir (DTG)Administered orally | Drug | Arm 1: DTG + INH + RPT, Arm 2: DTG + INH + RPT |
| Isoniazid (INH)Administered orally | Drug | Arm 1: DTG + INH + RPT, Arm 2: DTG + INH + RPT |
| Rifapentine (RPT)Administered orally | Drug | Arm 1: DTG + INH + RPT, Arm 2: DTG + INH + RPT |
| Antiretroviral Therapy (ART)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. | Drug | Arm 1: DTG + INH + RPT, Arm 2: DTG + INH + RPT |
| Pyridoxine (Vitamin B6)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. | Dietary supplement | Arm 1: DTG + INH + RPT, Arm 2: DTG + INH + RPT |
Primary outcome
DTG PK Parameter Maximum Plasma Concentration (Cmax) Determined Based on DTG Levels From Individual Participants in Arm 1 by Visit Day
Time frame: Intensive DTG PK samples at pre-dose, 1h, 2h, 4h, 8h, 12h, 13h, 14h, 23h and 24h post-dose at days 0 and 28
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.
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
Time frame: Intensive DTG PK samples at pre-dose, 1h, 2h, 4h, 8h, 12h, 13h, 14h, 23h and 24h post-dose at days 0 and 28
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).
DTG PK Parameter Minimum Plasma Concentration (Cmin) Determined Based on DTG Levels From Individual Participants in Arm 1 by Visit Day
Time frame: Intensive DTG PK samples at pre-dose, 1h, 2h, 4h, 8h, 12h, 13h, 14h, 23h and 24h post-dose at days 0 and 28
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.
DTG PK Parameter Ctrough Determined Based on DTG Levels From Individual Participants in Arm 1 at Day 28
Time frame: Intensive DTG PK samples at pre-dose, 1h, 2h, 4h, 8h, 12h, 13h, 14h, 23h and 24h post-dose 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.
DTG PK Parameter Maximum Plasma Concentration (Cmax) Determined Based on DTG Levels From Individual Participants in Arm 2 by Visit Day
Time frame: Intensive DTG PK samples at pre-dose, 1h, 2h, 4h, 8h, 12h, 23h and 24h post-dose at days 0 and 28
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.
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
Time frame: Intensive DTG PK samples at pre-dose, 1h, 2h, 4h, 8h, 12h, 23h and 24h post-dose at days 0 and 28
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.
DTG PK Parameter Minimum Plasma Concentration (Cmin) Determined Based on DTG Levels From Individual Participants in Arm 2 by Visit Day
Time frame: Intensive DTG PK samples at pre-dose, 1h, 2h, 4h, 8h, 12h, 23h and 24h post-dose at days 0 and 28
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.
DTG PK Parameter Ctrough Determined Based on DTG Levels From Individual Participants in Arm 2 at Day 28
Time frame: Intensive DTG PK samples at pre-dose, 1h, 2h, 4h, 8h, 12h, 23h and 24h post-dose at days 0 and 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.
8 secondary outcomes
Percentage of Participants in Arm 1 With an Occurrence of Grade 2 or Higher Adverse Event
Time frame: From initiation of study treatment to day 28
Percentage of Participants in Arm 1 Who Completed the Study
Time frame: From initiation of study to day 28
Percentage of Participants in Arm 1 Who Completed Study Drug Treatment
Time frame: From initiation of study treatment to day 28
Percentage of Participants in Arm 1 With HIV-1 RNA Levels >50 Copies/mL
Time frame: Measured at Days 28 and 42
Percentage of Participants in Arm 2 With an Occurrence of Grade 2 or Higher Adverse Event
Time frame: From initiation of study treatment to day 28
Percentage of Participants in Arm 2 Who Completed the Study
Time frame: From initiation of study to day 28
Percentage of Participants in Arm 2 Who Completed Study Drug Treatment
Time frame: From initiation of study treatment to day 28
Percentage of Participants in Arm 2 With HIV-1 RNA Levels >50 Copies/mL
Time frame: Measured at Days 28 and 42
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 19 Sep 2024.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Derived from this study: PubMed 38568956Podany 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.
- 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 2017Link provided by the sponsor.
- Individual participant dataSharing planned: Yes. Individual participant data that underlie results in the publication, after deidentification.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Anthony Podany, PharmD study chair
University of Nebraska
10 sites in 7 countries: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2 study testing Dolutegravir (DTG), Isoniazid (INH) and Rifapentine (RPT) in people with HIV Infection and LTBI, run by National Institute of Allergy and Infectious Diseases (NIAID) at 10 sites in 7 countries.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 35 inclusion and 18 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: stopped early, as of the sponsor's last update on 19 Sep 2024. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 10 sites in United States, Haiti, South Africa, Botswana, Malawi and 2 more countries. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 9 Aug 2024). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
DTG PK Parameter Maximum Plasma Concentration (Cmax) Determined Based on DTG Levels From Individual Participants in Arm 1 by Visit Day (time frame: Intensive DTG PK samples at pre-dose, 1h, 2h, 4h, 8h, 12h, 13h, 14h, 23h and 24h post-dose at days 0 and 28). The study lists 8 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT04272242, which also lists 1 linked publication.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 19 Sep 2024.