Clinical trial NCT03731559: Efficacy, Safety and Pharmacokinetics of DTG with RIF
Official title: 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
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE2
Conditions: HIV/TB Coinfection
Keywords: Efficacy
safety
pharmacokinetics
Dolutegravir
HIV/TB co-infected patients
rifampin-based antituberculosis therapy
Lead sponsor: The HIV Netherlands Australia Thailand Research Collaboration
Sponsor class: OTHER
Collaborators: name: Chest Division, Chulalongkorn University
name: Infectious Disease, Chulalongkorn University
name: Bamrasnaradura Infectious Diseases Institute
name: Bhumibol Adulyadej Hospital
name: Infectious Disease Taksin Hospital
name: Klang Hospital
name: Infectious Disease Chiangrai Prachanukroh Hospital
name: Infectious Disease Chonburi Hospital
name: Infectious Disease Buddhachinaraj Phitsanulok Hospital
name: Radboud University Medical Center
name: Ministry of Health, Thailand
First posted: 2018-11-06
Enrollment: 200
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

Eligibility criteria: 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

Primary outcomes:
measure: proportion of subjects from the ITT analysis population with plasma HIV-1 RNA <50 c/mL at Week 24
timeFrame: Week 24
Secondary outcomes:
measure: AUC of DTG concentration between DTG 50 mg with food OD and DTG 50 mg BID
timeFrame: Week 4
measure: Cmax of DTG concentration between DTG 50 mg with food OD and DTG 50 mg BID
timeFrame: Week 4
measure: Cmin of DTG concentration between DTG 50 mg with food OD and DTG 50 mg BID
timeFrame: Week 4
measure: Oral clearance of DTG concentration between DTG 50 mg with food OD and DTG 50 mg BID
timeFrame: Week 4
measure: Proportion of subjects with plasma HIV-1 RNA <50 c/mL at Week 24
timeFrame: Week 24
measure: Changes in CD4+ counts from baseline to Week 24 and Week 48
timeFrame: Weeks 24 and 48
measure: Incidence of disease progression
timeFrame: Week 48
measure: Proportion of subjects that have completed TB treatment
timeFrame: Week 48
measure: Proportion of subjects that are cured from TB
timeFrame: Week 48
measure: Proportion of subjects that have relapsed
timeFrame: Week 48
measure: Proportion of subjects that have defaulted
timeFrame: Week 48
measure: TB outcome in terms of cure
timeFrame: Week 48
measure: TB outcome in terms of relapse
timeFrame: Week 48
measure: TB outcome in terms of treatment failure due to TB resistance
timeFrame: Week 48
measure: TB outcome in terms of incidence
timeFrame: Week 48
measure: TB outcome in terms of severity
timeFrame: Week 48
measure: discontinuation from the study
timeFrame: Week 48
measure: discontinuation from the study drugs
timeFrame: Week 48
measure: Proportion of subjects with TB-associated IRIS
timeFrame: Week 48
measure: AUC of DTG at Weeks 4 (with RIF) and 48 (without RIF)
timeFrame: Weeks 4 and 48
measure: Cmax of DTG at Weeks 4 (with RIF) and 48 (without RIF)
timeFrame: Weeks 4 and 48
measure: Ctrough of DTG at Weeks 4 (with RIF) and 48 (without RIF)
timeFrame: Weeks 4 and 48
measure: proportion of subjects with plasma HIV-1 RNA <50 c/mL at Week 48
timeFrame: Week 48
Other outcomes:
Locations:
city: Chiang Rai
country: Thailand
facility: Infectious Disease Chiangrai Prachanukroh Hospital
state: Chiangrai
city: Bangkok
country: Thailand
facility: Klang Hospital
city: Bangkok
country: Thailand
facility: Bhumibol Adulyadej Hospital
city: Bangkok
country: Thailand
facility: Chest Division, Faculty of Medicine, Chulalongkorn University
city: Bangkok
country: Thailand
facility: HIV-NAT, Thai Red Cross - AIDS Research Centre
city: Bangkok
country: Thailand
facility: Infectious Disease, Chulalongkorn University
city: Bangkok
country: Thailand
facility: Infectious Disease Taksin Hospital
city: Chon Buri
country: Thailand
facility: Infectious Disease Chonburi Hospital
city: Nonthaburi
country: Thailand
facility: Bamrasnaradura Infectious Diseases Institute
city: Phitsanulok
country: Thailand
facility: Infectious Disease Buddhachinaraj Phitsanulok Hospital
Study officials:
affiliation: HIV-NAT, Thai Red Cross - AIDS Research Centre
name: Anchalee Avihingsanon, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References: