Pharmacokinetics and Safety of Double-dose Dolutegravir When Used With Rifapentine for HIV-associated Tuberculosis
Trial Snapshot
- Phase
- Phase 2
- Status
- Completed
- Enrollment
- 30
- Locations
- 4
- Primary Endpoint
- Model-simulated 5th Percentile and Corresponding 95% Confidence Interval of DTG Cmin at 50 mg BID When Co-administered With Daily RPT 1200 mg Plus HZM
Study Overview
Brief Summary
A5406 hypothesized that dolutegravir (DTG) 50 mg taken twice daily provides adequate exposures to maintain viral suppression when dosed with rifapentine (RPT) 1200 mg for HIV-associated tuberculosis (TB).
Detailed Description
This was an open-label, single arm, phase II, multicenter pharmacokinetic (PK) study to investigate the effect of daily RPT 1200 mg on DTG exposure in participants with HIV-associated TB. Adults with HIV with newly diagnosed drug susceptible tuberculosis (DS-TB) who were not on antiretroviral therapy (ART) were recruited around the time of DS-TB diagnosis. At study entry, daily rifapentine (R) and moxifloxacin (M) plus isoniazid (H) and pyrazinamide (P) was initiated for 8 weeks followed by daily rifapentine-moxifloxacin plus isoniazid for 9 weeks for anti-tuberculosis (anti-TB) therapy. This regimen is known as the 2HPZM/2HPM regimen. DTG-based ART at 50 mg twice daily (BID) was started after 6 weeks of TB therapy. DTG 50 mg BID was continued for 2 weeks after completion of TB therapy, after which DTG was reduced to standard dose 50 mg once daily (QD).
Intensive PK sampling was performed at study week 8 (2 weeks after initiating DTG-based ART) and week 21 (2 weeks after reducing DTG to once daily) to obtain full plasma PK profiles for DTG during and after RPT co-administration.
HIV-1 viral load was measured to assess for viral suppression at study entry (pre-ART), at weeks 10 and 14 (while on RPT/DTG therapy), at week 21, week 30 (24 weeks after initiating ART and 13 weeks after completion of TB treatment), and at week 48.
Safety monitoring included hematology and liver/renal function testing at each study visit, plus clinical assessments for rifamycin hypersensitivity syndrome, and drug-induced liver injury.
Study Design
- Study Type
- Interventional
- Allocation
- Na
- Intervention Model
- Single Group
- Primary Purpose
- Treatment
- Masking
- None
Eligibility Criteria
- Ages
- 18 Years to — (Adult, Older Adult)
- Sex
- All
- Accepts Healthy Volunteers
- No
Inclusion Criteria
- •Weight ≥40 kg.
- •Ability and willingness of participant or legal guardian/representative to provide informed consent.
- •Documentation of HIV-1 status.
- •CD4+ cell count ≥50 cells/mm3 obtained within 30 days prior to study entry at any network-approved non-US laboratory that is IQA certified.
- •ART-naïve or not on ART for 12 consecutive weeks prior to TB diagnosis.
- •Willingness and eligibility to start DTG-based ART at 6 weeks, with a window of ±1 week, after starting TB treatment, with no intention to change ART for the duration of the study.
- •Documentation of pulmonary TB.
- •Willingness to start 2HPZM/2HPM therapy for DS-TB.
- •The following laboratory values obtained within 30 days prior to study entry:
- •Absolute neutrophil count (ANC) >750 cells/mm3
- •Hemoglobin ≥7.4 g/dL
- •Platelet count ≥50,000/mm3
- •Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT]) <2.5 X the upper limit of normal (ULN)
- •Alanine aminotransferase (ALT) (serum glutamic pyruvic transaminase [SGPT]) <2.5 x ULN
- •Total bilirubin ≤1.5 x ULN
- •Creatinine <1.3 x ULN
- •For participants who can become pregnant, negative serum or urine pregnancy test at screening within 30 days prior to entry and within 48 hours prior to entry.
- •Participants who can become pregnant must agree not to participate in the conception process and if participating in sexual activity that could lead to pregnancy, must agree to use one reliable nonhormonal method of contraception.
- •Documentation of Karnofsky performance score ≥50 within 30 days prior to entry.
Exclusion Criteria
- •Breastfeeding, pregnant, or plans to become pregnant.
- •Known allergy/sensitivity or any hypersensitivity to components of the study drugs, or their formulations.
- •Active drug or alcohol use or dependence that, in the opinion of the site investigator, would interfere with adherence to study requirements.
- •Requirement for ongoing use of drugs that are known to have significant drug-drug interactions with DTG or RPT.
- •Known history of acute intermittent porphyria.
- •Previous treatment for active TB disease within 6 months preceding initiation of study drugs.
- •More than 5 days of treatment directed against active TB for the current TB episode preceding study entry.
- •At the time of study entry, documentation of an M. tuberculosis isolate from the current or previous treatment episode known to be resistant to RIF or INH.
- •Known history of prolonged QT syndrome.
- •Known cirrhosis, a history of decompensated liver disease (ascites, hepatic encephalopathy, or esophageal varices).
- •Documentation of severe opportunistic infections, in the opinion of the site investigator, within 3 months of study entry.
- •Documentation of severe extra-pulmonary TB (e.g., meningitis, osteomyelitis, disseminated TB) at the time of screening.
- •Acute gout at the time of screening.
Arms & Interventions
Adults with HIV and newly diagnosed DS-TB not currently on ART
Participants received daily rifapentine-moxifloxacin plus isoniazid and pyrazinamide for 8 weeks followed by daily rifapentine-moxifloxacin plus isoniazid for 9 weeks (referred to as 2HPZM/2HPM) for anti-TB therapy at study entry.
DTG-based ART at 50 mg BID was started after 6 weeks of TB therapy and continued for 2 weeks after completion of TB therapy.
Two weeks after completion of TB therapy DTG was reduced to standard dose 50 mg QD.
Intervention: Dolutegravir (DTG) 50 mg orally BID (~12 hours apart) plus TDF/3TC (Drug)
Adults with HIV and newly diagnosed DS-TB not currently on ART
Participants received daily rifapentine-moxifloxacin plus isoniazid and pyrazinamide for 8 weeks followed by daily rifapentine-moxifloxacin plus isoniazid for 9 weeks (referred to as 2HPZM/2HPM) for anti-TB therapy at study entry.
DTG-based ART at 50 mg BID was started after 6 weeks of TB therapy and continued for 2 weeks after completion of TB therapy.
Two weeks after completion of TB therapy DTG was reduced to standard dose 50 mg QD.
Intervention: DTG 50 mg orally QD plus TDF/3TC (Drug)
Adults with HIV and newly diagnosed DS-TB not currently on ART
Participants received daily rifapentine-moxifloxacin plus isoniazid and pyrazinamide for 8 weeks followed by daily rifapentine-moxifloxacin plus isoniazid for 9 weeks (referred to as 2HPZM/2HPM) for anti-TB therapy at study entry.
DTG-based ART at 50 mg BID was started after 6 weeks of TB therapy and continued for 2 weeks after completion of TB therapy.
Two weeks after completion of TB therapy DTG was reduced to standard dose 50 mg QD.
Intervention: 2HPZM (Drug)
Adults with HIV and newly diagnosed DS-TB not currently on ART
Participants received daily rifapentine-moxifloxacin plus isoniazid and pyrazinamide for 8 weeks followed by daily rifapentine-moxifloxacin plus isoniazid for 9 weeks (referred to as 2HPZM/2HPM) for anti-TB therapy at study entry.
DTG-based ART at 50 mg BID was started after 6 weeks of TB therapy and continued for 2 weeks after completion of TB therapy.
Two weeks after completion of TB therapy DTG was reduced to standard dose 50 mg QD.
Intervention: 2HPM (Drug)
Outcomes
Primary Outcomes
Model-simulated 5th Percentile and Corresponding 95% Confidence Interval of DTG Cmin at 50 mg BID When Co-administered With Daily RPT 1200 mg Plus HZM
Time Frame: Measured at week 8 and week 21. Samples were drawn pre-dose and at 1, 2, 4, 6, 8-10, and 24 hours (but prior to next dose) post-dosing.
Model-simulated 5th percentile and corresponding 95% confidence interval of dolutegravir (DTG) minimum concentrations (Cmin) at 50 mg BID (twice daily) when co-administered with daily rifapentine (RPT) 1200 mg plus HZM (isoniazid, pyrazinamide, and ethambutol). Pharmacokinetic parameters were estimated using nonlinear mixed-effects modelling (FOCE-I). The final model was used to simulate 10000 individuals, incorporating parameter uncertainty. Covariates included fat-free mass on disposition parameters, rifapentine on clearance and bioavailability, and baseline unconjugated bilirubin on clearance. Measurements were taken at steady state, which was assumed to be achieved after at least 5 half-lives.
Secondary Outcomes
- DTG Minimum Concentration (Cmin)(Measured at week 8 and week 21; Samples were drawn pre-dose and at 1, 2, 4, 6, 8-10, and 24 hours (but prior to next dose) post-dosing.)
- DTG Maximum Concentration (Cmax)(Measured at week 8 and week 21; Samples were drawn pre-dose and at 1, 2, 4, 6, 8-10, and 24 hours (but prior to next dose) post-dosing.)
- DTG Area Under the Concentration-time Curve (AUC0-24)(Measured at week 8 and week 21; Samples were drawn pre-dose and at 1, 2, 4, 6, 8-10, and 24 hours (but prior to next dose) post-dosing.)
- DTG Clearance(Measured at week 8 and week 21; Samples were drawn pre-dose and at 1, 2, 4, 6, 8-10, and 24 hours (but prior to next dose) post-dosing.)
- DTG Terminal Half Life(Measured at week 8 and week 21; Samples were drawn pre-dose and at 1, 2, 4, 6, 8-10, and 24 hours (but prior to next dose) post-dosing.)
- Percent of Participants Who Experienced Grade 3 or Higher Adverse Events (AE)(Week 6 through week 17)
- Percent of Participants Who Experienced Rifamycin Hypersensitivity(Week 6 through week 17)
- Percent of Participants Who Experienced Drug-induced Liver Injury(Week 6 through week 17)
- Percent of Participants Who Prematurely Discontinued Study Treatment(Week 6 through week 17)
- Percent of Participants With Viral Suppression(Weeks 10, 14, 21, and 30)