Efficacy, Safety and Pharmacokinetics of DTG with RIF

Phase 2RecruitingNCT03731559

The HIV Netherlands Australia Thailand Research Collaboration200 enrolled

Overview

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.

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.

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Conditions

HIV/TB Coinfection

Interventions

DTG 50 mg OD with foodDRUG

Dolutegravir 50 mg once daily with food plus 2NRTIs in HIV/TB co-infected patients receiving RIF based anti-TB therapy

DTG 50 mg BIDDRUG

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

Eligibility

Sex: ALLMin age: 18 Years

Medical Language ↔ Plain English

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

Locations (10)

Klang Hospital

Bangkok, Bangkok, Thailand

RECRUITING

Bhumibol Adulyadej Hospital

Bangkok, Bangkok, Thailand

RECRUITING

Outcomes

Primary Outcomes

proportion of subjects from the ITT analysis population with plasma HIV-1 RNA <50 c/mL at Week 24

The primary efficacy endpoint is the proportion of subjects from the ITT analysis population with plasma HIV-1 RNA \<50 c/mL at Week 24.

Time frame: Week 24

Secondary Outcomes

AUC of DTG concentration between DTG 50 mg with food OD and DTG 50 mg BID

Time frame: Week 4

Cmax of DTG concentration between DTG 50 mg with food OD and DTG 50 mg BID

Time frame: Week 4

Cmin of DTG concentration between DTG 50 mg with food OD and DTG 50 mg BID

Time frame: Week 4

Oral clearance of DTG concentration between DTG 50 mg with food OD and DTG 50 mg BID

Time frame: Week 4

Proportion of subjects with plasma HIV-1 RNA <50 c/mL at Week 24

Proportion of subjects with plasma HIV-1 RNA \<50 c/mL at Week 24

Time frame: Week 24

Changes in CD4+ counts from baseline to Week 24 and Week 48

Time frame: Weeks 24 and 48

Central Contacts

June Ohata, BS

CONTACT

6626523040 juneohata4@gmail.com

Data from ClinicalTrials.gov

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