Efficacy, Safety and Pharmacokinetics of DTG with RIF

Phase 2

Recruiting

Conditions: HIV/TB Coinfection

Interventions: Drug: DTG 50 mg OD with food
Drug: DTG 50 mg BID

Registration Number: NCT03731559

Lead Sponsor: The HIV Netherlands Australia Thailand Research Collaboration

Brief Summary: 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: 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.

Recruitment & Eligibility

Status: RECRUITING

Sex: All

Target Recruitment: 200

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

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

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

Primary Outcome Measures

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

Secondary Outcome Measures

Trial Locations

Locations (10): Infectious Disease Chiangrai Prachanukroh Hospital
🇹🇭
Chiang Rai, Chiangrai, Thailand
Klang Hospital
🇹🇭
Bangkok, Thailand
Bhumibol Adulyadej Hospital
🇹🇭
Bangkok, Thailand
Chest Division, Faculty of Medicine, Chulalongkorn University
🇹🇭
Bangkok, Thailand
HIV-NAT, Thai Red Cross - AIDS Research Centre
🇹🇭
Bangkok, Thailand
Infectious Disease, Chulalongkorn University
🇹🇭
Bangkok, Thailand
Infectious Disease Taksin Hospital
🇹🇭
Bangkok, Thailand
Infectious Disease Chonburi Hospital
🇹🇭
Chon Buri, Thailand
Bamrasnaradura Infectious Diseases Institute
🇹🇭
Nonthaburi, Thailand
Infectious Disease Buddhachinaraj Phitsanulok Hospital
🇹🇭
Phitsanulok, Thailand

Efficacy, Safety and Pharmacokinetics of DTG with RIF

Recruitment & Eligibility

Study & Design

Trial Locations

Instant Trial Alerts

Instant Trial Alerts

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