INSIGHT: INSTI's For The Management of HIV-associated TB

Sponsor

Centre for the AIDS Programme of Research in South Africa (Other)

Overall Status

Recruiting

CT.gov ID

NCT04734652

Collaborator

Johns Hopkins University (Other), National Institute of Allergy and Infectious Diseases (NIAID) (NIH), University of Cape Town (Other), Medical Research Council, South Africa (Other)

120

Enrollment

Location

Arms

31.5

Anticipated Duration (Months)

3.8

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

This study is being conducted to assess the antiretroviral activity of a fixed-drug, single tablet, combination of Bictegravir 50mg/ Emtricitabine 200mg/ Tenofovir alafenamide 25mg (Biktarvy®) dosed twice daily in HIV-1 infected, ART-naïve patients with TB co-infection receiving a rifampicin-based tuberculosis (TB) treatment regimen. This study will assess the activity of Bictegravir and dolutegravir-containing ART regimens in patients with drug-susceptible TB through 48 weeks

Condition or Disease	Intervention/Treatment	Phase
HIV/AIDS Tuberculosis, Pulmonary	Combination Product: Biktarvy® Combination Product: TLD- fixed-drug combination single tablet	Phase 2

Detailed Description

Primary objective: To characterize viral suppression rates (proportion of patients with suppressed viral load) at week 24 in the BIC arm

Secondary objectives:

To characterize viral suppression rates at weeks 12, 24 and 48 in the standard of care treatment (SOC) arm (currently, TDF 300mg/3TC 300mg/DTG 50mg) and at weeks 12 and 48 in the BIC/FTC/TAF arm.

To compare the pharmacokinetics (PK) of BIC when given twice daily and co-administered with Rifampicin during tuberculosis treatment vs when given alone after discontinuation of Rifampicin

To assess the incidence of TB associated IRIS in each arm, through week 24.

To characterize the tolerability of treatment in each arm by assessing frequency of clinician-initiated treatment interruptions or switches through week 48.

To assess frequency of ART drug resistance mutations in participants with detectable viral load at study visit weeks 24 and 48.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

120 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Intervention Model Description:

80 participants for the Intervention Arm ART regimen which is a fixed-drug combination of a single tablet co-formulated regimen containing Bictegravir 50mg Emtricitabine 200mg and tenofovir alafenamide 25mg (BIC/FTC/TAF; Biktarvy®) that will be taken twice a day during rifampicin-containing TB treatment and 2 weeks after stopping TB treatment, thereafter the BIC/FTC/TAF single tablet co-formulation will be taken once daily. 40 participants in the Control ARM: Dolutegravir 50mg /Lamivudine 300mg/ Tenofovir 300mg (TLD- fixed-drug combination single tablet) plus Dolutegravir 50mg evening dose during TB treatment and for two weeks after completion of TB treatment, then TLD once daily thereafter- as per Standard of Care (SOC)80 participants for the Intervention Arm ART regimen which is a fixed-drug combination of a single tablet co-formulated regimen containing Bictegravir 50mg Emtricitabine 200mg and tenofovir alafenamide 25mg (BIC/FTC/TAF; Biktarvy®) that will be taken twice a day during rifampicin-containing TB treatment and 2 weeks after stopping TB treatment, thereafter the BIC/FTC/TAF single tablet co-formulation will be taken once daily. 40 participants in the Control ARM: Dolutegravir 50mg /Lamivudine 300mg/ Tenofovir 300mg (TLD- fixed-drug combination single tablet) plus Dolutegravir 50mg evening dose during TB treatment and for two weeks after completion of TB treatment, then TLD once daily thereafter- as per Standard of Care (SOC)

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

A Phase 2b Study to Evaluate the Efficacy, Safety and PK of a Combination of Bictegravir, Emtricitabine, and Tenofovir Alafenamide Fumarate for Treatment of HIV-1 Infection in Patients With Drug-susceptible Tuberculosis on a Rifampicin-based Regimen

Actual Study Start Date :

Feb 18, 2022

Anticipated Primary Completion Date :

Jul 7, 2023

Anticipated Study Completion Date :

Oct 4, 2024

Arms and Interventions

Arm	Intervention/Treatment
Experimental: BIC arm The Intervention Arm ART regimen is a fixed-drug combination of a single tablet co-formulated regimen containing Bictegravir 50mg Emtricitabine 200mg and tenofovir alafenamide 25mg (BIC/FTC/TAF; Biktarvy®) that will be taken twice a day during rifampicin-containing TB treatment and 2 weeks after stopping TB treatment, thereafter the BIC/FTC/TAF single tablet co-formulation will be taken once daily.	Combination Product: Biktarvy® Biktarvy® is a fixed dose combination, single tablet containing bictegravir (BIC), emtricitabine (FTC), and tenofovir alafenamide (TAF) for oral administration. BIC is an integrase strand transfer inhibitor (INSTI). FTC, a synthetic nucleoside analog of cytidine, is an HIV nucleoside analog reverse transcriptase inhibitor (HIV NRTI). TAF, an HIV NRTI, is converted in vivo to tenofovir, an acyclic nucleoside phosphonate (nucleotide) analog of adenosine 5'-monophosphate. Each tablet contains 50 mg of BIC (equivalent to 52.5 mg of bictegravir sodium), 200 mg of FTC, and 25 mg of TAF (equivalent to 28 mg of tenofovir alafenamide fumarate) and the following inactive ingredients: croscarmellose sodium, magnesium stearate, and microcrystalline cellulose.
Active Comparator: DTG Arm Dolutegravir 50mg /Lamivudine 300mg/ Tenofovir 300mg (TLD- fixed-drug combination single tablet) plus Dolutegravir 50mg evening dose during TB treatment and for two weeks after completion of TB treatment, then TLD once daily thereafter- as per Standard of Care (SOC)	Combination Product: TLD- fixed-drug combination single tablet Standard of care Dolutegravir-based regimen Other Names: Dolutegravir 50mg /Lamivudine 300mg/ Tenofovir 300mg

Arm

Intervention/Treatment

Experimental: BIC arm

The Intervention Arm ART regimen is a fixed-drug combination of a single tablet co-formulated regimen containing Bictegravir 50mg Emtricitabine 200mg and tenofovir alafenamide 25mg (BIC/FTC/TAF; Biktarvy®) that will be taken twice a day during rifampicin-containing TB treatment and 2 weeks after stopping TB treatment, thereafter the BIC/FTC/TAF single tablet co-formulation will be taken once daily.

Combination Product: Biktarvy®

Biktarvy® is a fixed dose combination, single tablet containing bictegravir (BIC), emtricitabine (FTC), and tenofovir alafenamide (TAF) for oral administration. BIC is an integrase strand transfer inhibitor (INSTI). FTC, a synthetic nucleoside analog of cytidine, is an HIV nucleoside analog reverse transcriptase inhibitor (HIV NRTI). TAF, an HIV NRTI, is converted in vivo to tenofovir, an acyclic nucleoside phosphonate (nucleotide) analog of adenosine 5'-monophosphate. Each tablet contains 50 mg of BIC (equivalent to 52.5 mg of bictegravir sodium), 200 mg of FTC, and 25 mg of TAF (equivalent to 28 mg of tenofovir alafenamide fumarate) and the following inactive ingredients: croscarmellose sodium, magnesium stearate, and microcrystalline cellulose.

Active Comparator: DTG Arm

Dolutegravir 50mg /Lamivudine 300mg/ Tenofovir 300mg (TLD- fixed-drug combination single tablet) plus Dolutegravir 50mg evening dose during TB treatment and for two weeks after completion of TB treatment, then TLD once daily thereafter- as per Standard of Care (SOC)

Combination Product: TLD- fixed-drug combination single tablet

Standard of care Dolutegravir-based regimen

Other Names:

Dolutegravir 50mg /Lamivudine 300mg/ Tenofovir 300mg

Outcome Measures

Primary Outcome Measures

Viral suppression rate [Week 24]
Viral suppression rate (HIV-1 RNA <50 copies/mL) at week 24 in the BIC arm (using the FDA snapshot algorithm)

Secondary Outcome Measures

Viral suppression rates [At weeks 12, 24 and 48]
Viral suppression rates (HIV-1 RNA <50 copies/mL) in the DTG arm and at 12 and 48 weeks in the BIC arm
BIC Drug concentrations ("Area under the plasma concentration versus time curve (AUC)" [Week 4, 8 12, 24, 32 and 40]
BIC drug levels (AUC) when given twice daily and co-administered with Rifampicin vs. during TB treatment vs when given alone after TB treatment completion
BIC Drug concentrations [Peak Plasma Concentration (Cmax)] [Week 4, 8 12, 24, 32 and 40]
BIC drug levels (Cmax) when given twice daily and co-administered with Rifampicin vs. during TB treatment vs when given alone after TB treatment completion
BIC Drug concentrations [Trough/Minimum Plasma Concentration Ctrough) [Week 4, 8 12, 24, 32 and 40]
BIC drug levels ( Ctrough) when given twice daily and co-administered with Rifampicin vs. during TB treatment vs when given alone after TB treatment completion
The incidence of TB associated IRIS [Through week 24]
To assess the incidence of TB associated IRIS in each arm
The tolerability of treatment in each arm [Through week 48]
To characterize the tolerability of treatment in each arm by assessing frequency of clinician-initiated treatment interruptions or switches through week 48
Frequency of ART drug resistance mutations [study visit weeks 24 and 48.]
To assess frequency of ART drug resistance mutations in participants with detectable viral load

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 105 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Adults ≥ 18 years of age with Karnofsky score ≥ 70Confirmed rifampicin-susceptible tuberculosis
On first-line rifampicin-based tuberculosis treatment (not > 8 weeks at the time of enrolment)
Documented HIV-1 infection, ART-naïve
Estimated glomerular filtration rate (eGFR) ≥ 60 mL/min/1.73m2
Alanine aminotransferase (ALT) ≤3 times the upper limit of normal (ULN)
Total bilirubin ≤2.5 times ULN
Creatinine ≤2 times ULN
Hemoglobin ≥ 7.0 g/dL (6.5 g/dL for females)
Platelet count ≥ 50,000/mm3
Absolute Neutrophil Count (ANC) ≥650/mm3
Able and willing to provide written informed consent
Female patients agree to use both a barrier and a non-barrier form of contraception during the study, starting at least 14 days prior to enrolment

Exclusion Criteria:

Pregnancy or breastfeeding (or planned pregnancy within 12 months of study entry)
Prior use of antiretroviral drugs for pre-exposure prophylaxis (PrEP) or post-exposure prophylaxis (PEP)
Hepatitis B surface antigen positive, Hepatitis B virus (HBV) infection, active infections (other than HIV-1 infection) requiring systemic antibiotic or antifungal therapy current or within 30 days prior to baseline
Participants with a CD4+ cell count of < 100 cells/ μl
Any verified Grade 4 laboratory abnormality, with the exception of, Grade 4 triglycerides. A single repeat test is allowed during the Screening period to verify a result
Patients on metformin (> 500mg, 12hourly)
Patients with an uncontrolled psychiatric co-morbidity. Patients who, in the investigator's judgment, pose a significant suicidality risk. Recent history of suicidal behavior and/or suicidal ideation may be considered as evidence of serious suicide risk
Other condition or circumstance deemed by clinician/investigators to be detrimental to patient safety or study conduct
Unwilling to be part of the main pharmacokinetic (PK) study and have PK blood draws done (NB there is a semi-intensive PK substudy which is optional)

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	CAPRISA Springfield Clinical Research Site	Durban	KwaZulu-Natal	South Africa	4001

Sponsors and Collaborators

Centre for the AIDS Programme of Research in South Africa
Johns Hopkins University
National Institute of Allergy and Infectious Diseases (NIAID)
University of Cape Town
Medical Research Council, South Africa

Investigators

Principal Investigator: Anushka Naidoo, PhD, Centre for the AIDS Programme of Research in South Africa (CAPRISA)
Principal Investigator: Kelly Dooley, MD, Johns Hopkins University
Study Director: Kogieleum Naidoo, PhD, Centre for the AIDS Programme of Research in South Africa