Efficacy, Safety and Pharmacokinetics of DTG with RIF

The HIV Netherlands Australia Thailand Research Collaboration

Status and phase: Enrolling; Phase 2

Conditions: HIV/TB Coinfection

Treatments: Drug: DTG 50 mg OD with food; Drug: DTG 50 mg BID

Study type: Interventional

Funder types: Other

Identifiers

NCT03731559

HIV-NAT 254

Details and patient eligibility

About

The overall aim of the project is to evaluate optimal DTG dose for the combined treatment of TB and HIV infections with RIF based anti-TB therapy. This Stage II trial will determine precisely the PK parameters of DTG in combination with RIF regimen in Thai HIV/TB co-infected patients. After the optimal dose of DTG has been found, it will be further tested in a larger Stage III trial to assess its safety, tolerability and efficacy when used with RIF based regimen.

Full description

This is a Stage II, randomized, open-label study describing the efficacy and safety of DTG 50 mg OD with food and DTG 50 mg BID plus 2NRTIs in HIV/TB co-infected patients receiving RIF based anti-TB therapy. The study will be conducted in approximately 200 HIV-1 infected individuals who are ART-naïve and newly diagnosed with probable or confirmed pulmonary, pleural, or lymph node (LN) Mycobacterium TB (MTB) taking RIF-containing first-line TB treatment. Subjects should have confirmed RIF-sensitive MTB infection as determined by GeneXpert (or equivalent approved molecular test) or mycobacterial culture.

The study is comprised two different stages:

1. Stage1, investigators will test the safety and tolerability, as well as Pharmacokinetics (PK), of two different doses of dolutegravir co-administered with standard anti-TB treatment. Overall, 40 HIV/TB patients will be enrolled. They will be randomized to 2 groups (DTG 50 mg with food and DTG 50 mg BID). Intensive PK of DTG will be performed at week 4. Interim analysis will be performed if all 40 cases completed 12 weeks and 24 weeks. Premature study termination will be set for

   1. proportion of HIV RNA < 50 copies/ml at week 24 between 2 group is different > 20%
   2. DTG 50 mg with food has geometric mean DTG Ctrough < 0.3 mg/L If there is no premature study termination met, the study will move to stage 2. Stage 2 will only be recruited if two different doses of dolutegravir are well tolerated and safe.

2. Stage 2: 160 HIV/TB patients will be enrolled. They will be randomized to 2 groups (DTG 50 mg with food and DTG 50 mg BID). DTG concentration will be performed at week 4 and 48. Interim analysis will be performed if all 200 cases completed 24 weeks.

Enrollment: 200 estimated patients

Sex: All

Ages: 18+ years old

Volunteers: No Healthy Volunteers

Inclusion criteria

1. documented HIV positive
2. Aged >18 years
3. ARV naïve (previous exposure to ARV for < 2 weeks)
4. Any CD4 cell count
5. ALT <5 times ULN
6. estimated GFR>60 ml/min/1.73m2
7. Hemoglobin >7 mg/L
8. TB is diagnosed and there is a plan to receive stable doses of RIF containing anti-TB therapy for at least another 4 week period after initiation of ART
9. No other active OI (CDC class C event) except oral candidiasis or disseminated MAC
10. Body weight >40kg
11. Able to provide written informed consent

Exclusion criteria

1. Have documented history of HIV treatment failure or HIV mutation to NRTI, NNRTI, and/or INIs
2. Have previously treated for tuberculosis
3. Currently using immunosuppressive agents.
4. Currently using any prohibited medications that can affect the pharmacokinetics of the study drug such as phenobarbital, and carbamazepine
5. Currently using alcohol or illicit substances that may affect the conduct of the trial as per the opinion of the site Principal Investigator
6. Unlikely to be able to remain in the follow-up period as defined by the protocol
7. Patients with proven or suspected acute hepatitis. Patients with chronic viral hepatitis are eligible provided ALT, AST < 5 x ULN.
8. Have Karnofsky performance score <30%
9. Have TB meningitis, bone/joints (due to prolonged use of anti-TB drug)
10. Pregnant or breastfeeding

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: None (Open label)

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200 participants in 2 patient groups

DTG 50 mg OD with food

Active Comparator group

Description:

DTG 50 mg OD with food plus 2NRTIs in HIV/TB co-infected patients receiving RIF based anti-TB therapy.

Treatment:

Drug: DTG 50 mg OD with food

DTG 50 mg BID

Active Comparator group

Description:

DTG 50 mg BID plus 2NRTIs in HIV/TB co-infected patients receiving RIF based anti-TB therapy.

Treatment:

Drug: DTG 50 mg BID