Clinical trial NCT04734652: INSTI's For The Management of HIV-associated TB
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 DS-TB on a Rifampicin-based Regimen
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: HIV/AIDS
Tuberculosis, Pulmonary
Keywords: Biktarvy® is a fixed dose combination
TLD- fixed-drug combination single tablet
Dolutegravir 50mg
HIV/AIDS
Tuberculosis, Pulmonary
Lead sponsor: Centre for the AIDS Programme of Research in South Africa
Sponsor class: NETWORK
Collaborators: name: Johns Hopkins University
name: National Institute of Allergy and Infectious Diseases (NIAID)
name: University of Cape Town
name: Medical Research Council, South Africa
First posted: 2021-02-02
Enrollment: 122
Sex: ALL
Minimum age (years): 18
Maximum age (years): 105
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
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)
Primary purpose: TREATMENT

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

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.

Eligibility criteria: Inclusion Criteria:

* Adults ≥ 18 years of age with Karnofsky score ≥ 70
* Confirmed rifampicin-susceptible tuberculosis and/or
* On first-line rifampicin-based tuberculosis treatment (not \> 8 weeks at the time of enrolment)
* Documented HIV-1 infection, ART-naïve OR ART non-naïve (patients to have no exposure to ART medication at least ≥ 3 months at the time of enrollment)
* 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) \< 3 months at the time of enrolment
* Hepatitis B surface antigen positive OR Hepatitis B virus (HBV) infection OR active systemic infections (other than HIV-1 infection) requiring systemic antibiotic or antifungal therapy current or within 30 days prior to baseline that could, in the opinion of the investigator, interfere with study procedures or assessment of study outcomes
* Participants with a CD4+ cell count of \< 50 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)

Primary outcomes:
measure: Viral suppression rate
timeFrame: Week 24
Secondary outcomes:
measure: Viral suppression rates
timeFrame: At weeks 12, 24 and 48
measure: BIC Drug concentrations ("Area under the plasma concentration versus time curve (AUC)"
timeFrame: Week 4, 8 12, 24, 32 and 40
measure: BIC Drug concentrations [Peak Plasma Concentration (Cmax)]
timeFrame: Week 4, 8 12, 24, 32 and 40
measure: BIC Drug concentrations [Trough/Minimum Plasma Concentration Ctrough)
timeFrame: Week 4, 8 12, 24, 32 and 40
measure: The incidence of TB associated IRIS
timeFrame: Through week 24
measure: The tolerability of treatment in each arm
timeFrame: Through week 48
measure: Frequency of ART drug resistance mutations
timeFrame: study visit weeks 24 and 48.
Other outcomes:
Locations:
city: Durban
country: South Africa
facility: CAPRISA Springfield Clinical Research Site
state: KwaZulu-Natal
Study officials:
affiliation: Centre for the AIDS Programme of Research in South Africa (CAPRISA)
name: Anushka Naidoo, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Vanderbilt University Medical Center
name: Kelly Dooley, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Centre for the AIDS Programme of Research in South Africa
name: Kogieleum Naidoo, PhD
role: STUDY_DIRECTOR
References:
citation: Naidoo A, Dooley KE, Naidoo K, Padayatchi N, Yende-Zuma N, Perumal R, Dorse G, Boodhram R, Osuala EC. INSTIs for the management of HIV-associated TB (INSIGHT study): a phase 2b study to evaluate the efficacy, safety and pharmacokinetics of a combination of bictegravir, emtricitabine and tenofovir alafenamide fumarate for the treatment of HIV-1 infection in patients with drug-susceptible tuberculosis on a rifampicin-based treatment regimen: a phase 2b open-label randomised controlled trial. BMJ Open. 2022 Nov 10;12(11):e067765. doi: 10.1136/bmjopen-2022-067765.