Efficacy, Safety and Pharmacokinetics of DTG With RIF

Study Overview
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Brief Summary
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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.

Detailed Description
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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: 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 proportion of HIV RNA < 50 copies/ml at week 24 between 2 group is different > 20% 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. 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.

Official Title
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Efficacy, Safety and Pharmacokinetics of Dolutegravir 50 mg Once Daily With Food Versus Dolutegravir 50 mg Twice Daily in HIV/TB Co-infected Patients Receiving Rifampin-based Antituberculosis Therapy

Conditions
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HIV/TB Coinfection

Intervention / Treatment
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* Drug: DTG 50 mg OD with food
* Drug: DTG 50 mg BID


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: documented HIV positive Aged >18 years ARV naïve (previous exposure to ARV for < 2 weeks) Any CD4 cell count ALT <5 times ULN estimated GFR>60 ml/min/1.73m2 Hemoglobin >7 mg/L 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 No other active OI (CDC class C event) except oral candidiasis or disseminated MAC Body weight >40kg Able to provide written informed consent Exclusion Criteria: Have documented history of HIV treatment failure or HIV mutation to NRTI, NNRTI, and/or INIs Have previously treated for tuberculosis Currently using immunosuppressive agents. Currently using any prohibited medications that can affect the pharmacokinetics of the study drug such as phenobarbital, and carbamazepine Currently using alcohol or illicit substances that may affect the conduct of the trial as per the opinion of the site Principal Investigator Unlikely to be able to remain in the follow-up period as defined by the protocol Patients with proven or suspected acute hepatitis. Patients with chronic viral hepatitis are eligible provided ALT, AST < 5 x ULN. Have Karnofsky performance score <30% Have TB meningitis, bone/joints (due to prolonged use of anti-TB drug) Pregnant or breastfeeding

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: DTG 50 mg OD with food<br>DTG 50 mg OD with food plus 2NRTIs in HIV/TB co-infected patients receiving RIF based anti-TB therapy. | Drug: DTG 50 mg OD with food<br>* Dolutegravir 50 mg once daily with food plus 2NRTIs in HIV/TB co-infected patients receiving RIF based anti-TB therapy<br>|
| Active Comparator: DTG 50 mg BID<br>DTG 50 mg BID plus 2NRTIs in HIV/TB co-infected patients receiving RIF based anti-TB therapy. | Drug: DTG 50 mg BID<br>* Dolutegravir 50 mg BID plus 2NRTIs in HIV/TB co-infected patients receiving RIF based anti-TB therapy.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | Week 24 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| AUC of DTG concentration between DTG 50 mg with food OD and DTG 50 mg BID | AUC of DTG concentration between DTG 50 mg with food OD and DTG 50 mg BID | Week 4 | 
| Cmax of DTG concentration between DTG 50 mg with food OD and DTG 50 mg BID | Cmax of DTG concentration between DTG 50 mg with food OD and DTG 50 mg BID | Week 4 | 
| Cmin of DTG concentration between DTG 50 mg with food OD and DTG 50 mg BID | Cmin of DTG concentration between DTG 50 mg with food OD and DTG 50 mg BID | Week 4 | 
| Oral clearance of DTG concentration between DTG 50 mg with food OD and DTG 50 mg BID | Oral clearance of DTG concentration between DTG 50 mg with food OD and DTG 50 mg BID | 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 | Week 24 | 
| Changes in CD4+ counts from baseline to Week 24 and Week 48 | Changes in CD4+ counts from baseline to Week 24 and Week 48 | Weeks 24 and 48 | 
| Incidence of disease progression | Incidence of disease progression (HIV-associated conditions, new AIDS diagnoses, and death) | Week 48 | 
| Proportion of subjects that have completed TB treatment | Proportion of subjects that have completed TB treatment | Week 48 | 
| Proportion of subjects that are cured from TB | Proportion of subjects that are cured from TB | Week 48 | 
| Proportion of subjects that have relapsed | Proportion of subjects that have relapsed | Week 48 | 
| Proportion of subjects that have defaulted | Proportion of subjects that have defaulted | Week 48 | 
| TB outcome in terms of cure | Number of participants that have been cured of TB | Week 48 | 
| TB outcome in terms of relapse | Number of participants with relapse | Week 48 | 
| TB outcome in terms of treatment failure due to TB resistance | Number of participants with treatment failure due to TB resistance | Week 48 | 
| TB outcome in terms of incidence | Incidence of all AEs, SAEs, and laboratory abnormalities | Week 48 | 
| TB outcome in terms of severity | Severity of all AEs, SAEs, and laboratory abnormalities | Week 48 | 
| discontinuation from the study | Proportion of subjects who permanently discontinued randomization arm due to AEs or death | Week 48 | 
| discontinuation from the study drugs | Proportion of subjects who temporarily discontinued the study drugs and/or TB therapy due to AEs | Week 48 | 
| Proportion of subjects with TB-associated IRIS | Proportion of subjects with TB-associated IRIS | Week 48 | 
| AUC of DTG at Weeks 4 (with RIF) and 48 (without RIF) | AUC of DTG at Weeks 4 (with RIF) and 48 (without RIF) will be analyzed using population PK modeling approach to estimate AUC | Weeks 4 and 48 | 
| Cmax of DTG at Weeks 4 (with RIF) and 48 (without RIF) | Cmax of DTG at Weeks 4 (with RIF) and 48 (without RIF) will be analyzed using population PK modeling approach to estimate Cmax | Weeks 4 and 48 | 
| Ctrough of DTG at Weeks 4 (with RIF) and 48 (without RIF) | Ctrough of DTG at Weeks 4 (with RIF) and 48 (without RIF) will be analyzed using population PK modeling approach to estimate Ctrough | Weeks 4 and 48 | 
| proportion of subjects with plasma HIV-1 RNA <50 c/mL at Week 48 | proportion of subjects with plasma HIV-1 RNA <50 c/mL at Week 48 (viral suppression) | Week 48 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Efficacy, safety, pharmacokinetics, Dolutegravir, HIV/TB co-infected patients, rifampin-based antituberculosis therapy