Efficacy, Safety and Pharmacokinetics of DTG With RIF

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

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.

Study Overview

• Status: Recruiting
• Conditions: HIV/TB Coinfection
• Intervention / Treatment: Drug: DTG 50 mg OD with food; Drug: DTG 50 mg BID

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.

• Study Type: Interventional
• Enrollment (Anticipated): 200
• Phase: Phase 2

Contacts and Locations

Study Locations

• Thailand
  • Bangkok, Thailand, 10220
    • Recruiting
    • Bhumibol Adulyadej Hospital
  • Bangkok, Thailand, 10100
    • Recruiting
    • Klang Hospital
  • Bangkok, Thailand, 10330
    • Recruiting
    • Chest Division, Faculty of Medicine, Chulalongkorn University
  • Bangkok, Thailand, 10330
    • Recruiting
    • HIV-NAT, Thai Red Cross - AIDS Research Centre
  • Bangkok, Thailand, 10330
    • Recruiting
    • Infectious Disease, Chulalongkorn University
  • Bangkok, Thailand, 10600
    • Recruiting
    • Infectious Disease Taksin Hospital
  • Chon Buri, Thailand, 20000
    • Recruiting
    • Infectious Disease Chonburi Hospital
  • Nonthaburi, Thailand, 11000
    • Recruiting
    • Bamrasnaradura Infectious Diseases Institute
  • Phitsanulok, Thailand, 65000
    • Recruiting
    • Infectious Disease Buddhachinaraj Phitsanulok Hospital
  • Chiangrai
    • Chiang Rai, Chiangrai, Thailand, 57000
      • Recruiting
      • Infectious Disease Chiangrai Prachanukroh Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

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

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: The HIV Netherlands Australia Thailand Research Collaboration
• Collaborators: Radboud University Medical Center; Bhumibol Adulyadej Hospital; Klang Hospital; Bamrasnaradura Infectious Diseases Institute; Chest Division, Chulalongkorn University; Infectious Disease, Chulalongkorn University; Infectious Disease Taksin Hospital; Infectious Disease Chiangrai Prachanukroh Hospital; Infectious Disease Chonburi Hospital; Infectious Disease Buddhachinaraj Phitsanulok Hospital; Department of Disease Control, Ministry of Public Health (MOPH), Thailand

Study record dates

Study Major Dates

• Study Start (Actual): June 25, 2019
• Primary Completion (Anticipated): June 30, 2024
• Study Completion (Anticipated): June 30, 2024

Study Registration Dates

• First Submitted: October 31, 2018
• First Submitted That Met QC Criteria: November 2, 2018
• First Posted (Actual): November 6, 2018

Study Record Updates

• Last Update Posted (Actual): March 1, 2023
• Last Update Submitted That Met QC Criteria: February 27, 2023
• Last Verified: February 1, 2023

More Information

Terms related to this study

• Keywords: safety; Efficacy; pharmacokinetics; Dolutegravir; HIV/TB co-infected patients; rifampin-based antituberculosis therapy
• Additional Relevant MeSH Terms: Infections; Coinfection
• Other Study ID Numbers: HIV-NAT 254

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No