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)

NCT03435146 | Completed Phase 1 DMC

• 1 other identifier: 3HP DTG AUR1-6-212 IMPAACT4TB
• Study Type: interventional
• Target: 135
• Locations: 1 country
• Sites: 1

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.

Conditions

Respiratory Tract Infections; HIV Infections

Keywords

3HP; LTBI; IMPAACT4TB; DDI; Pharmacokinetics; Dolutegravir

Outcome Measures

Primary Outcomes (4)

• PK sampling of Dolutegravir - Ctau

  Trough concentration in the presence or absence of once weekly HP

  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

• PK sampling of Dolutegravir - AUC parameter

  Daily area under curve (AUC) in the presence or absence of once weekly HP

  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

• PK sampling of Dolutegravir - Cmin parameter

  Minimum concentration (Cmin) in the presence or absence of once weekly HP

  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

• Adverse Events (Primary)

  Grade 3 or higher adverse events (AE)

  Adverse events to be collected from Week 1 through Week 24, to be reported throughout the trial

Secondary Outcomes (8)

• HIV-1 RNA viral load

  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

• PK sampling of RPT - AUC parameter

  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

• PK sampling of RPT - Cmax parameter

  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

• PK sampling of RPT - Cmin parameter

  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

• PK sampling of INH - AUC parameter

  PK sampling at Week 11(Group 1 only), to be reported at end of trial

Study Arms (1)

Groups 1,2,3 and 4

EXPERIMENTAL

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

Interventions

3HP plus DTG +2NRTIs COMBINATION_PRODUCT

* 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)

Groups 1,2,3 and 4

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Age \> 18 years
• Weight \> 50 kg
• Documented HIV infection\*
• At least 8 weeks of HIV treatment with efavirenz or dolutegravir plus two NRTI, or ART treatment naïve, depending upon the enrolling treatment Group
• Undetectable or detectable HIV-1 viral load, depending upon the enrolling treatment Group

You may not qualify if:

• Confirmed or suspected TB disease
• Likely to move from the study area during the study period
• Known exposure to TB cases with known or suspected resistance to isoniazid or rifampicin in the source case
• TB treatment within the past year
• TB preventive therapy within the last year
• Sensitivity or intolerance to isoniazid or rifamycins
• On nevirapine, etravirine, rilpivirine, PI-based, or raltegravir-containing ART regimens
• Suspected acute hepatitis or known chronic liver disease; severe hepatic impairment (Class C or greater) as determined by Child Pugh classification
• ALT≥ 3 times the upper limit of normal (ULN)
• Total bilirubin ≥ 2.5 times the ULN
• Absolute neutrophil count (ANC) ≤ 750 cells/mm3
• Creatinine clearance \< 50 ml/min
• Pregnancy or breastfeeding
• Women of childbearing potential who are unable or unwilling to use contraception
• Self-reported alcohol use exceeding 28 units per week for men, or 21 units for women

Sponsors & Collaborators

• The Aurum Institute NPC: lead
• Johns Hopkins University: collaborator
• University of California: collaborator

Study Sites (1)

The Aurum Institute: Tembisa Clinical Research Centre

Tembisa, Gauteng, 1736, South Africa

Location

Related Publications (3)

• Weld ED, Beattie T, Moodley J, Mapendere M, Salles I, Solans BP, Nonyane BAS, Wiesner L, Nielson T, Edward VA, Chihota V, Savic RM, Dooley KE, Chaisson RE, Churchyard GJ; DOLPHIN-TOO Study Team; Unitaid IMPAACT4TB Research Group. Simultaneous initiation of dolutegravir-based antiretroviral therapy and once-weekly rifapentine and isoniazid for tuberculosis prevention in antiretroviral-naive people with HIV: an open-label, non-randomised, phase 1/2 trial. Lancet HIV. 2025 Jun;12(6):e428-e439. doi: 10.1016/S2352-3018(25)00002-5. Epub 2025 May 8.

  PMID: 40349709 DERIVED

• Jarrett RT, van der Heijden Y, Shotwell MS, Chihota V, Marzinke MA, Chaisson RE, Dooley KE, Churchyard GJ. High Isoniazid Exposures When Administered with Rifapentine Once Weekly for Latent Tuberculosis in Individuals with Human Immunodeficiency Virus. Antimicrob Agents Chemother. 2023 Feb 16;67(2):e0129722. doi: 10.1128/aac.01297-22. Epub 2023 Jan 9.

  PMID: 36622148 DERIVED

• Dooley KE, Savic R, Gupte A, Marzinke MA, Zhang N, Edward VA, Wolf L, Sebe M, Likoti M, Fyvie MJ, Shibambo I, Beattie T, Chaisson RE, Churchyard GJ; DOLPHIN Study Team. Once-weekly rifapentine and isoniazid for tuberculosis prevention in patients with HIV taking dolutegravir-based antiretroviral therapy: a phase 1/2 trial. Lancet HIV. 2020 Jun;7(6):e401-e409. doi: 10.1016/S2352-3018(20)30032-1. Epub 2020 Mar 30.

  PMID: 32240629 DERIVED

MeSH Terms

Conditions

Respiratory Tract Infections; HIV Infections

Condition Hierarchy (Ancestors)

Infections; Respiratory Tract Diseases; Blood-Borne Infections; Communicable Diseases; Sexually Transmitted Diseases, Viral; Sexually Transmitted Diseases; Lentivirus Infections; Retroviridae Infections; RNA Virus Infections; Virus Diseases; Genital Diseases; Urogenital Diseases; Immunologic Deficiency Syndromes; Immune System Diseases

Study Officials

• Gavin J Churchyard, MBBCh PhD

  Global CEO: The Aurum Institute, NPC

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: 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.

Study Record Dates

• First Submitted: August 21, 2017
• First Posted: February 15, 2018
• Study Start: January 18, 2018
• Primary Completion: December 7, 2022
• Study Completion: December 7, 2022
• Last Updated: February 2, 2023

Record last verified: 2023-01

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, ICF, 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)

Locations

ZA (1)