Clinical Trials

MainTitle

Safety Tolerability DDI Short Course Treatment of LTBI Infection With High-dose Rifapentine Isoniazid in HIV+ Patients (IMPAACT4TB)

This study is currently recruiting participants. (see Contacts and Locations)

Verified February 2018 by Prof Gavin John Churchyard

Sponsor
Prof Gavin John Churchyard

Collaborator
Johns Hopkins University
University of California

Information provided by (Responsible Party)
Prof Gavin John Churchyard, The Aurum Institute NPC

ClinicalTrials.gov Identifier
NCT03435146

First received: August 21, 2017
Last updated: February 14, 2018
Last Verified: February 2018
History of Changes
Purpose

Purpose

Single-arm, two-center, Phase I/II clinical trial assessing the pharmacokinetics (PK), safety, and tolerability of once-weekly rifapentine and isoniazid (3HP) for the treatment of latent tuberculosis infection among individuals with HIV infection taking dolutegravir-based (DTG) antiretroviral treatment. The study population will be individuals with HIV taking DTG and 2 nucleoside reverse transcriptase inhibitors for ≥ 4 weeks, who have a suppressed HIV-1 viral load (VL), and are candidates to receive TB preventive therapy. Sample size is 60 participants divided into two main groups Group 1 (1A (n=12) and B (n=18)) and Group 2(n=30). The first 12 participants (Group 1A) will undergo semi-intensive PK sampling and will be key to determining whether an increased dosing of DTG is required in groups 1B and Group 2 due to accelerated DTG clearance due to 3HP induced drug-drug-interactions. Group 1B will receive dolutegravir at the new dose (if applicable) and will also undergo semi-intensive PK sampling. The subsequent 30 (Group 2) will receive DTG at the new dose and will only have sparse PK sampling.

Condition Intervention Phase
Respiratory Tract Infections
HIV Infections

Combination Product : 3HP plus DTG +2NRTIs
Phase 1
Phase 2

Study Type: Interventional
Study Design: Intervention Model: Sequential Assignment
Intervention Model Description: Group 1: The first 12 participants (Group 1a) will take dolutegravir 50mg once daily (with tenofovir/emtricitabine) plus once weekly rifapentine/ isoniazid for the study period. Semi-intensive PK measurements of dolutegravir,rifapentine,isoniazid will be collected at protocol-defined intervals. An interim pharmacokinetic, safety,and HIV viral load assessment will be performed to ensure that dolutegravir 50mg once daily is safe and meets PK targets. The next 18 participants (Group 1B) will receive either dolutegravir 50mg or a higher or more frequent dose of dolutegravir, if adjustment is required, plus once weekly rifapentine/isoniazid. Semi-intensive PK measurements of dolutegravir,rifapentine,isoniazid will be collected at protocol-defined intervals. Group 2: The next 30 participants will receive dolutegravir at the same dose and frequency as Group 1B. Sparse PK samples of dolutegravir, safety labs and HIV viral load will be measured at protocol-defined intervals.
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Safety, Tolerability and Drug-drug Interactions of Short Course Treatment of Latent Tuberculosis Infection With High-dose Rifapentine and Isoniazid Among HIV-infected Patients Taking Dolutegravir-based Antiretroviral Treatment

Further study details as provided by Prof Gavin John Churchyard, The Aurum Institute NPC:

Primary Outcome Measures

  • PK sampling of Dolutegravir - Ka parameter [ Time Frame: PK sampling at Week 9 (Group 1), Week 11 (Groups 1 and 2) and Week 16 (Groups 1 and 2); to be reported at end of trial ]
    Absorption rate constant (Ka) in the presence or absence of once weekly HP
  • PK sampling of Dolutegravir - Vd parameter [ Time Frame: PK sampling at Week 9 (Group 1), Week 11 (Groups 1 and 2) and Week 16 (Groups 1 and 2); to be reported at end of trial ]
    Volume of distribution (Vd) in the presence or absence of once weekly HP
  • PK sampling of Dolutegravir - Cl/F parameter [ Time Frame: PK sampling at Week 9 (Group 1), Week 11 (Groups 1 and 2) and Week 16 (Groups 1 and 2); to be reported at end of trial ]
    Oral clearance (Cl/F) in the presence or absence of once weekly HP
  • PK sampling of Dolutegravir - AUC parameter [ Time Frame: PK sampling at Week 9 (Group 1), Week 11 (Groups 1 and 2) and Week 16 (Groups 1 and 2); to be reported at end of trial ]
    Daily area under curve (AUC) in the presence or absence of once weekly HP
  • PK sampling of Dolutegravir - Cmin parameter [ Time Frame: PK sampling at Week 9 (Group 1), Week 11 (Groups 1 and 2) and Week 16 (Groups 1 and 2); to be reported at end of trial ]
    Minimum concentration (Cmin) in the presence or absence of once weekly HP
  • Adverse Events (Primary) [ Time Frame: Adverse events to be collected from Week 1 through Week 24, to be reported throughout the trial ]
    Grade 3 or higher adverse events (AE)
Secondary Outcome Measures:
  • HIV-1 RNA viral load [ Time Frame: HIV viral load to be measured in Groups 1 and 2 at screening, weeks 11 and 24, to be reported at end of trial ]
    HIV-1 RNA viral load (copies/ml)
  • PK sampling of RPT - AUC parameter [ Time Frame: PK sampling at Weeks 9 and 11 (Group 1); and Week 11 (Group 2), to be reported at end of trial ]
    Area under curve (AUC).
  • PK sampling of RPT - Cmax parameter [ Time Frame: PK sampling at Weeks 9 and 11 (Group 1); and Week 11 (Group 2), to be reported at end of trial ]
    Maximum concentration (Cmax).
  • PK sampling of RPT - Cmin parameter [ Time Frame: PK sampling at Weeks 9 and 11 (Group 1); and Week 11 (Group 2), to be reported at end of trial ]
    Minimum concentration (Cmax).
  • PK sampling of INH - AUC parameter [ Time Frame: PK sampling at Week 11(Group 1 only), to be reported at end of trial ]
    Area under curve (AUC). NAT 2 acetylator status to be taken into account
  • PK sampling of INH - Cmax parameter [ Time Frame: PK sampling at Week 11(Group 1 only), to be reported at end of trial ]
    Maximum concentration (Cmax). NAT 2 acetylator status to be taken into account
  • PK sampling of INH - Cmin parameter [ Time Frame: PK sampling at Week 11(Group 1 only), to be reported at end of trial ]
    Minimum concentration (Cmin). NAT 2 acetylator status to be taken into account
  • DTG Dose selection [ Time Frame: Post Group 1A. Dose will be selected once Group 1a participants' PK data have been analyzed. The dolutegravir dose may be adjusted according to PK results. If warranted, the revised dose will be administered to Groups 1B and 2. ]
    Dose options for DTG with once-weekly HP derived by simulation using nonlinear mixed effects models.

Estimated Enrollment: 60
Study Start Date: January 18, 2018
Estimated Study Completion Date: November 3, 2018
Estimated Primary Completion Date: October 31, 2018 (Final data collection date for primary outcome measure)

Arms Assigned Interventions
Experimental: Group 1 and 2
Group 1: The first 12 participants (Group 1A) will undergo semi-intensive PK sampling and will be key to determining whether an increased dosing of dolutegravir is required in groups 1B. Group 1B will receive dolutegravir at the new dose (if applicable) and will also undergo semi-intensive PK sampling. All will undergo safety and HIV VL assessments. 3HP plus DTG +2NRTIs Group 2: The subsequent 30 (Group 2) will receive dolutegravir at the new dose and will only have sparse PK sampling. All will undergo safety and HIV VL assessments. 3HP plus DTG +2NRTIs
Combination Product: 3HP plus DTG +2NRTIs
  • HIV treatment: DTG will be dosed as described above and will be given with daily TDF/FTC.
LTBI treatment: 3HP will be given once-weekly for a total of 12 doses, with doses as follows:
  • Rifapentine: 900 mg; Isoniazid: 900 mg

Detailed Description:

Single-arm, single-center, Phase I/II clinical trial, in two Groups. Individuals with HIV infection taking EFV and two nucleoside reverse transcriptase inhibitors (NRTI) who have undetectable HIV viral load and an indication for treatment of LTBI, will be switched to DTG with tenofovir/emtricitabine for at least two months and will receive weekly HP for 12 total doses. Individuals who are on an existing DTG-based plus two NRTI ART regimen for at least eight weeks (and have not received efavirenz or nevirapine for at least two months) who have an undetectable HIV viral load may also participate.
Group 1 (n=30): The first 12 participants (Group 1A) will take dolutegravir 50 mg once daily (with tenofovir/emtricitabine) from Days 1-57. Semi-intensive PK sampling for dolutegravir will be performed on Day 57. Participants will continue once-daily dolutegravir and will receive once-weekly HP for 12 total doses beginning on Day 58. Semi-intensive PK sampling for dolutegravir will be performed on Day 72 (with the 3rd dose of HP) and Day 108 (following the 8th dose of HP). Trough concentrations (CT) will be measured on Days 59, 74, and 78. VL will be measured at baseline and weeks 11 and 24. Safety labs (CBC, U&E and creatinine and liver function tests) will be obtained at baseline, and weeks 9, 11, 13, 16, 20 and 24. PK assessments will be performed at weeks 9 and 11 for rifapentine and at week 11 for isoniazid.
After the 12 Group 1A participants have completed the second semi-intensive PK visit, an interim PK, safety, and VL assessment will be performed to ensure that the 50 mg once daily dose is safe and meets PK targets. The subsequent 18 participants in Group 1 (Group 1B) will receive either dolutegravir 50 mg or a higher dose of dolutegravir, if dose adjustment is required (e.g. dolutegravir 50 mg twice daily just on HP dosing days, dolutegravir 50 mg twice daily seven days a week, etc.) Group 2 (n=30): These participants will receive dolutegravir and HP at the same doses and dose schedule as the participants in Group 1B. They will undergo safety assessments at baseline and weeks 9, 11, 13, 16, 20 and 24; HIV VL assessments at baseline and weeks 11 and 24. Sparse (trough) PK samples for dolutegravir will be collected on two occasions.

Eligibility

Eligibility

Ages Eligible for Study: 18 Years and older  
Sexes Eligible for Study: All  
Accepts Healthy Volunteers: Yes  

Criteria

Inclusion Criteria:

    1. Age > 18 years
    2. Weight > 50 kg
    3. Documented HIV infection*
    4. At least 8 weeks of HIV treatment with efavirenz or dolutegravir plus two NRTI
    5. HIV-1 viral load < 400 copies/mL


Exclusion Criteria:
    1. Confirmed or suspected TB disease
    2. Likely to move from the study area during the study period
    3. Known exposure to TB cases with known or suspected resistance to isoniazid or rifampicin in the source case
    4. TB treatment within the past year
    5. TB preventive therapy within the last year
    6. Sensitivity or intolerance to isoniazid or rifamycins
    7. On nevirapine, etravirine, rilpivirine, PI-based, or raltegravir-containing ART regimens
    8. Suspected acute hepatitis or known chronic liver disease; severe hepatic impairment (Class C or greater) as determined by Child Pugh classification
    9. ALT≥ 3 times the upper limit of normal (ULN)
    10. Total bilirubin ≥ 2.5 times the ULN
    11. Absolute neutrophil count (ANC) ≤ 750 cells/mm3
    12. Creatinine clearance < 50 ml/min
    13. Pregnancy or breastfeeding
    14. Women of childbearing potential who are unable or unwilling to use contraception
    15. Self-reported alcohol use exceeding 28 units per week for men, or 21 units for women
    16. Karnofsky status < 90
    17. On prohibited medications e.g. dofetilide (see Appendix 1)
    18. Known porphyria

contacts and locations

Contacts and Locations

Choosing to participate in a study is an important personal decision.Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below.For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT03435146

Contacts

Contact:   Gavin J Churchyard, MBBCh PhD +27 10 590 1300 gchurchyard@auruminstitute.org
Contact:   Trevor R Beattie, BScHons +27 10 590 1319 tbeattie@auruminstitute.org

Locations

South Africa
The Aurum Institute: Tembisa Clinical Research Centre Recruiting
Tembisa, Gauteng, South Africa, 1736
Contact: Modulakgotla Sebe, BCh, MB    27-87-1351645    msebe@auruminstitute.org

Sponsors and Collaborators

Prof Gavin John Churchyard
Johns Hopkins University
University of California

Investigators

Principal Investigator: Gavin J Churchyard, MBBCh PhD Global CEO: The Aurum Institute, NPC
More Information

More Information


Responsible Party: Prof Gavin John Churchyard, Global CEO: The Aurum Institute, The Aurum Institute NPC  
ClinicalTrials.gov Identifier: NCT03435146   History of Changes  
Other Study ID Numbers: 3HP DTG AUR1-6-212 IMPAACT4TB  
Study First Received: August 21, 2017  
Last Updated: February 14, 2018  
Individual Participant Data    
Plan to Share IPD: Yes  

Studies a U.S. FDA-regulated Drug Product: No  
Studies a U.S. FDA-regulated Device Product: No  
Product Manufactured in and Exported from the U.S.: No  

Keywords provided by Prof Gavin John Churchyard, The Aurum Institute NPC:

3HP
LTBI
IMPAACT4TB
DDI
Pharmacokinetics
Dolutegravir

Additional relevant MeSH terms:
Infection
Communicable Diseases
HIV Infections
Respiratory Tract Infections
Isoniazid
Rifapentine
Dolutegravir

ClinicalTrials.gov processed this data on October 15, 2018
This information is provided by ClinicalTrials.gov.