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

Study Overview
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Brief Summary
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This study will evaluate the potential drug-drug interactions between dolutegravir (DTG) and steady state rifapentine (RPT) when RPT is 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
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The purpose of this study is to evaluate the potential drug-drug interactions between dolutegravir (DTG) and steady state rifapentine (RPT) when RPT is 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 will receive study-provided INH and RPT once daily for 4 weeks (1HP). During the 1HP treatment, DTG will be administered twice daily in Arm 1, and once daily in Arm 2. At study entry, all participants must also be on DTG-based antiretroviral (ARV) treatment with 2 nucleoside reverse transcriptase inhibitors (NRTIs) (excluding tenofovir alafenamide [TAF]) during the study. In Arm 1 participants, DTG 50 mg will be administered twice daily; the morning dose from non-study ARV supply and the evening dose from study supply. In Arm 2 participants, DTG 50 mg will be administered once daily, in the morning, from non-study ARV supply. Participants must 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) will not be provided by the study. The study will begin enrollment with Arm 1. Opening of Arm 2 will depend on assessment of DTG pharmacokinetics (PK) data from participants in Arm 1. The majority of participants will be on study for 6 weeks (a 4-week on-study treatment period and a 2-week follow-up period). Some participants may be on study for up to 11 weeks if the on-study treatment duration has been extended or if participants need to have additional follow-up visits to measure viral load.

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

Conditions
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HIV Infection, LTBI

Intervention / Treatment
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* Drug: Dolutegravir (DTG)
* Drug: Isoniazid (INH)
* Drug: Rifapentine (RPT)
* Drug: Antiretroviral Therapy (ART)
* Dietary Supplement: Pyridoxine (Vitamin B6)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Males and females at least 18 but no more than 65 years of age at study entry. 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. 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 NOTE A: Condoms (male or female) with or without a spermicidal agent are not acceptable, as they are not sufficiently reliable. 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-monoresistent, 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.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm 1: DTG + INH + RPT<br>Participants will receive 50 mg of DTG orally twice daily ( 12 hours apart). Participants will receive 300 mg of INH and 600 mg of RPT orally each morning for 4 weeks. Participants will also receive 25 or 50 mg of pyridoxine (vitamin B6) with each dose of INH. Participants will remain on DTG-based ARV treatment with 2 NRTIs (excluding TAF) during the study. Participants will take non-study supply of DTG for morning doses, and will take study-supplied DTG for evening doses. | Drug: Dolutegravir (DTG)<br>* Administered orally<br>Drug: Isoniazid (INH)<br>* Administered orally<br>Drug: Rifapentine (RPT)<br>* Administered orally<br>Drug: Antiretroviral Therapy (ART)<br>* Participants will remain on DTG-based ARV treatment with 2 NRTIs (excluding TAF) during the study. NRTIs will not be provided by the study. Arm 1 participants will take non-study supply of DTG for morning doses, and will take study-supplied DTG for evening doses. For Arm 2 participants, DTG will be from non-study ARV supply.<br>Dietary Supplement: Pyridoxine (Vitamin B6)<br>* All participants must receive 25 or 50 mg of pyridoxine (vitamin B6) with each dose of INH, based on the current local, national, or international dosing guidelines. Pyridoxine is not provided by the study.<br>|
| Experimental: Arm 2: DTG + INH + RPT<br>Participants will receive 50 mg of DTG orally each morning. Participants will receive 300 mg of INH and 600 mg of RPT orally each morning for 4 weeks. Participants will also receive 25 or 50 mg of pyridoxine (vitamin B6) with each dose of INH. Participants will remain on once-daily DTG-based ARV treatment with 2 NRTIs (excluding TAF) during the study. DTG will be from non-study ARV supply. NOTE: Arm 2 will only open based on assessment of DTG pharmacokinetics (PK) data from participants in Arm 1. | Drug: Dolutegravir (DTG)<br>* Administered orally<br>Drug: Isoniazid (INH)<br>* Administered orally<br>Drug: Rifapentine (RPT)<br>* Administered orally<br>Drug: Antiretroviral Therapy (ART)<br>* Participants will remain on DTG-based ARV treatment with 2 NRTIs (excluding TAF) during the study. NRTIs will not be provided by the study. Arm 1 participants will take non-study supply of DTG for morning doses, and will take study-supplied DTG for evening doses. For Arm 2 participants, DTG will be from non-study ARV supply.<br>Dietary Supplement: Pyridoxine (Vitamin B6)<br>* All participants must receive 25 or 50 mg of pyridoxine (vitamin B6) with each dose of INH, based on the current local, national, or international dosing guidelines. Pyridoxine is not provided by the study.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| DTG PK Parameter Maximum Plasma Concentration (Cmax) by visit week and arm |  | Measured at Days 0 and 28 | 
| DTG PK Parameter Area Under the Curve (AUC0-12 for BID & AUC0-24 for QD dosing) by visit week and arm |  | Measured at Days 0 and 28 | 
| DTG PK Parameter Minimum Plasma Concentration (Cmin) by visit week and arm |  | Measured at Days 0 and 28 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of participants with all adverse events meeting the reporting criteria in the study protocol during administration of DTG with 1HP, by arm | 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 | Measured through Week 4 | 
| Proportion of participants who discontinue study or study drugs during DTG and 1HP dosing, by arm |  | Measured through Week 4 | 
| Proportion of participants with HIV-1 RNA levels >50 copies/mL |  | Measured at Days 28 and 42 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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HIV and LTBI Co-Infection, Rifapentine, Dolutegravir Interaction, LTBI