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Safety Tolerability DDI Short Course Treatment of LTBI Infection With High-dose Rifapentine and Isoniazid or Standard Isoniazid Preventive Therapy in HIV+ Patients (DOLPHIN & DOLPHIN TOO) (IMPAACT4TB)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03435146
Recruitment Status : Active, not recruiting
First Posted : February 15, 2018
Last Update Posted : February 12, 2020
Sponsor:
Collaborators:
Johns Hopkins University
University of California
Information provided by (Responsible Party):
Prof Gavin John Churchyard, The Aurum Institute NPC

Brief Summary:
Single-arm, single-center, Phase I/II clinical trial, in four groups. Individuals with HIV infection taking Efavirenz (EFV) and two nucleoside reverse transcriptase inhibitors (NRTI) who have undetectable (Groups 1 and 2) or detectable (Group 3 and 4) HIV viral load and an indication for TPT, will be switched to DTG with tenofovir/emtricitabine (Groups 1 and 2) or lamivudine/tenofovir (Groups 3 and 4). Group 1 and 2 will receive weekly HP for 12 total doses starting 8 weeks after initiating DTG. 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. Individuals with HIV infection who are ART treatment naïve at any HIV viral load level and have an indication for TPT will start DTG and be enrolled to receive standard IPT (Group 3) or HP (Group 4) initiated at the same time as DTG. Group 3 and 4 will be enrolled after follow up of Group 1 and 2 has been completed.

Condition or disease Intervention/treatment Phase
Respiratory Tract Infections HIV Infections Combination Product: 3HP plus DTG +2NRTIs Phase 1 Phase 2

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 135 participants
Intervention Model: Sequential Assignment
Intervention Model Description: Group 1A:12 ppts will take DTG 50mg/TDF/FTC once daily + once weekly HP for 12 weeks. Semi-intensive PK for DTG,RPT,INH will be collected per protocol.An interim PK, safety,and HIV VL assessment will be performed to ensure that DTG 50mg once daily is safe and meets PK targets.Group 1B:18 ppts will receive either DTG 50mg or dose adjusted DTG + once weekly HP. Semi-intensive PK for DTG,RPT,INH will be collected per protocol.Group 2: 30 ppts will receive DTG at the same dose and frequency as Group 1B. Sparse PK for DTG, safety labs and HIV VL will be measured per protocol.Group 3: 25 ppts who are HIV tx naive will start DTG 50mg/TDF/3TC daily as a FDC tablet + standard of care isoniazid preventive therapy. ART and IPT will start together. Sparse PK for DTG will be collected per protocol.Group 4: 50 ppts who are HIV treatment naive will start DTG 50mg/TDF/3TC daily as a FDC tablet + weekly HP for 12 weeks. ART and 3HP will start together. Sparse PK for DTG will be collected per protocol.
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 or Standard Isoniazid Preventative Therapy Among HIV-infected Patients Taking Dolutegravir-based Antiretroviral Treatment
Actual Study Start Date : January 18, 2018
Estimated Primary Completion Date : February 21, 2021
Estimated Study Completion Date : June 30, 2021

Resource links provided by the National Library of Medicine

MedlinePlus related topics: HIV/AIDS

Arm Intervention/treatment
Experimental: Groups 1,2,3 and 4

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 next 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

Group 3: The next 25 (Group 3) will receive dolutegravir at the same dose as Group 2 and will only have sparse PK sampling. All will undergo safety and HIV VL assessments.

IPT plus DTG +2NRTIs

Group 4: The next 50 (Group 4) will receive dolutegravir at the same dose as Group 2 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 (Groups 1 and 2) or with TDF/3TC (Groups 3 and 4).
  • LTBI treatment: 3HP will be given once-weekly for a total of 12 doses, with doses as follows:

Rifapentine: 900 mg; Isoniazid: 900 mg (Groups 1,2 and 4) Isoniazid at standard of care dosing (Group 3)





Primary Outcome Measures :
  1. PK sampling of Dolutegravir - Ctau [ Time Frame: PK sampling at Week 9 (Group 1), Week 11 (Groups 1 and 2) and Week 16 (Groups 1 and 2); Day 1 (Groups 3 and 4), Week 3 (Groups 3 and 4) and Week 8 (Groups 3 and 4) to be reported at end of trial ]
    Trough concentration in the presence or absence of once weekly HP

  2. 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); Day 1 (Groups 3 and 4), Week 3 (Groups 3 and 4) and Week 8 (Groups 3 and 4) to be reported at end of trial ]
    Daily area under curve (AUC) in the presence or absence of once weekly HP

  3. 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); Day 1 (Groups 3 and 4), Week 3 (Groups 3 and 4) and Week 8 (Groups 3 and 4) to be reported at end of trial ]
    Minimum concentration (Cmin) in the presence or absence of once weekly HP

  4. 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 :
  1. HIV-1 RNA viral load [ Time Frame: HIV viral load to be measured in Groups 1 and 2 at screening, weeks 11 and 24; and in Groups 3 and 4 at screening and weeks 3, 8, 12 and 24, to be reported at end of trial ]
    HIV-1 RNA viral load (copies/ml)

  2. PK sampling of RPT - AUC parameter [ Time Frame: PK sampling at Weeks 9 and 11 (Group 1); and Week 11 (Group 2), Day 1 (Groups 3 and 4), Week 3 (Groups 3 and 4) and Week 8 (Groups 3 and 4) to be reported at end of trial ]
    Area under curve (AUC).

  3. PK sampling of RPT - Cmax parameter [ Time Frame: PK sampling at Weeks 9 and 11 (Group 1); and Week 11 (Group 2), Day 1 (Groups 3 and 4), Week 3 (Groups 3 and 4) and Week 8 (Groups 3 and 4) to be reported at end of trial ]
    Maximum concentration (Cmax).

  4. PK sampling of RPT - Cmin parameter [ Time Frame: PK sampling at Weeks 9 and 11 (Group 1); and Week 11 (Group 2), Day 1 (Groups 3 and 4), Week 3 (Groups 3 and 4) and Week 8 (Groups 3 and 4) to be reported at end of trial ]
    Minimum concentration (Cmax).

  5. 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

  6. 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

  7. 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

  8. 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.



Information from the National Library of Medicine

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, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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, or ART treatment naïve, depending upon the enrolling treatment Group
  5. Undetectable or detectable HIV-1 viral load, depending upon the enrolling treatment Group

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 < 80
  17. On prohibited medications e.g. dofetilide (see Appendix 1)
  18. Known porphyria

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03435146


Locations
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South Africa
The Aurum Institute: Tembisa Clinical Research Centre
Tembisa, Gauteng, South Africa, 1736
Sponsors and Collaborators
The Aurum Institute NPC
Johns Hopkins University
University of California
Investigators
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Principal Investigator: Gavin J Churchyard, MBBCh PhD Global CEO: The Aurum Institute, NPC
  Study Documents (Full-Text)

Documents provided by Prof Gavin John Churchyard, The Aurum Institute NPC:
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
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Responsible Party: Prof Gavin John Churchyard, Global CEO: The Aurum Institute, The Aurum Institute NPC
ClinicalTrials.gov Identifier: NCT03435146    
Other Study ID Numbers: 3HP DTG AUR1-6-212 IMPAACT4TB
First Posted: February 15, 2018    Key Record Dates
Last Update Posted: February 12, 2020
Last Verified: February 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description:

To be shared amongst the collaborators on shared database when study starts and is complete.

Results will be disseminated via conferences and publication by scientific peer reviewed journal(s)

Supporting Materials: Study Protocol
Informed Consent Form (ICF)
Clinical Study Report (CSR)
Time Frame:

Pre-study start: Study protocol and Informed Consent Form to collaborators on SharePoint).

Post-study completion: Clinical Study Report, Results with Statistical Analysis will be shared with scientific peer reviewed journal(s) and collaborators.

Access Criteria:

Password protected and user defined credentials (Pre-study via SharePoint)

Open access (Post-study completion)


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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:
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Infection
Communicable Diseases
Respiratory Tract Infections
Respiratory Tract Diseases