Clinical trial NCT01601626: Rifampin-Based Tuberculosis Treatment Versus Rifabutin-Based Tuberculosis Treatment in Persons With HIV
Official title: A Randomized, Phase 2b Study of a Double-Dose Lopinavir/Ritonavir-Based Antiretroviral Regimen With Rifampin-Based Tuberculosis Treatment Versus a Standard-Dose Lopinavir/Ritonavir-Based Antiretroviral Regimen With Rifabutin-Based Tuberculosis Treatment With or Without Raltegravir in HIV-1-Infected Persons Requiring Treatment for Active TB and HIV
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE2
Conditions: HIV Infection
Tuberculosis
Lead sponsor: Advancing Clinical Therapeutics Globally for HIV/AIDS and Other Infections
Sponsor class: NETWORK
Collaborators: name: National Institute of Allergy and Infectious Diseases (NIAID)
First posted: 2012-05-18
Enrollment: 71
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: There is a rapidly-growing need to identify evidence-based, safe, and effective co-treatment regimens for HIV-related tuberculosis (TB) among patients who require protease inhibitor (PI)-based antiretroviral therapy (ART). This study compared three alternative co-treatment options among participants in high TB endemic resource-constrained settings, in which one co-treatment option explores if an additional anti-HIV drug needs to be used when patients are being treated with a PI together with rifabutin-based anti-TB treatment.

Detailed description: Rifampin (RIF), the cornerstone of TB treatment, has very problematic drug-drug interactions with PIs. The use of relatively high doses of ritonavir appear necessary to overcome this interaction, but it is unclear whether the co-treatment regimen of RIF-based TB treatment and double-dose PI-based ART will be safe and tolerable for patients with HIV-related TB and effective in treating both HIV and TB. The study proposed to determine if, for HIV-1-infected participants with active TB who require PI-based ART, a standard-dose lopinavir/ritonavir (LPV/r) regimen, with or without raltegravir (RAL), coupled with rifabutin (RBT)-based TB treatment is superior to a double-dose LPV/r regimen coupled with RIF-based TB treatment.

At study entry, participants were randomized (1:1:1) to receive standard-dose LPV/r-based HIV treatment plus RBT-based TB treatment (Arm A), double-dose LPV/r-based HIV treatment plus RIF-based TB treatment (Arm B), or standard-dose LPV/r-based HIV treatment plus RAL plus RBT-based TB treatment (Arm C).

Accrual was planned to take place in two accrual periods. Accrual period 1 would enroll 60 participants who would undergo an initial dose-finding period before continuing regular study follow-up. Once the review of the dose-finding pharmacokinetic (PK) and safety data from accrual period 1 participants was completed, accrual period 2 was planned to open to accrual.

Study duration was 72 weeks. Visits occurred at weeks 2, 4, 8, 12, 16, 20, 24, 32, 40, 48, and 72. The key evaluations included physical examination, clinical assessments, TB evaluations including chest x-ray, acid-fast bacilli (AFB) smear, mycobacterial culture, and drug susceptibility testing, CD4 cell count, HIV viral load, hematology, chemistry, and pregnancy testing in women of reproductive potential. Sputum, serum, and urine were stored for use in future analyses. An intensive PK visit occurred at day 12. PK blood draws in participants in Arms A and C were at RBT pre-dose and at 2, 4, 5, 6, and 24 hours RBT post-dose. PK blood draws in participants in Arm B were at LPV/r pre-dose and at 2, 4, 5, and 6 hours LPV/r post-dose.

The target sample size was 471 participants, but the study was terminated after 71 participants due to feasibility concerns. The 71 participants were followed for the planned 72 weeks. Because of the limited sample size, formal statistical comparisons were not undertaken as originally planned.

Eligibility criteria: Inclusion Criteria:

* HIV-1 infection
* CD4+/CD8+ T-cell count obtained within 30 days prior to study entry
* Confirmed or probable pulmonary or extrapulmonary TB (more information on the criterion can be found in the protocol)
* Chest x-ray within 30 days prior to study entry
* A PI-based antiretroviral regimen is required, as determined by the participant's primary clinician/clinical facility
* Certain laboratory values obtained within 14 days prior to study entry (more information on the criterion can be found in the protocol)
* For females of reproductive potential, negative serum or urine pregnancy test within 7 days prior to study entry and 72 hours of starting study medications
* Willing to use acceptable methods of contraception while on study drugs and for 6 weeks after stopping these drugs
* Karnofsky performance score \> 40 within 14 days prior to study entry, and likelihood of survival, in the opinion of the site investigator, for at least 6 months
* Ability to swallow oral medications
* Ability and willingness of participant or legal guardian/representative to provide informed consent

Exclusion Criteria:

* History of completed TB treatment and resolution of TB symptoms less than 1 year prior to the current TB episode at study entry, or incomplete treatment for a prior episode of TB (i.e., defaulted past TB treatment) at any time prior to the current TB episode
* Documented multidrug-resistant tuberculosis (MDR TB) or extensively drug-resistant tuberculosis (XDR TB)
* Participants infected with a rifamycin resistant strain of TB (more information on the criterion can be found in the protocol)
* Receipt of more than 28 cumulative days of anti-TB treatment for the current TB episode prior to study entry
* Active drug or alcohol use or dependence that, in the opinion of the site investigator, would interfere with adherence to study requirements
* Active illness requiring systemic treatment and/or hospitalization within 30 days prior to study entry, or that in the opinion of the site investigator, might otherwise interfere with adherence to study requirements
* Pregnant or breastfeeding
* Anticipated receipt of prohibited medications (more information on the criterion can be found in the protocol)
* Known intolerance/allergy/sensitivity or any hypersensitivity to components of study drugs or their formulations
* History of close contact with known MDR or XDR TB patients at any time prior to study entry

Primary outcomes:
measure: Percent of Participants Whose HIV Viral Load Was Less Than 400 Copies/mL at Week 48.
timeFrame: 48 weeks
Secondary outcomes:
measure: Percent of Participants Who Experienced Sputum Conversion at Week 8.
timeFrame: 8 weeks
measure: Percent of Participants Who Experienced TB Treatment Failure
timeFrame: After 16 weeks and through week 72
measure: Percent of Participants Who Experienced TB Relapse/Recurrence
timeFrame: At or after 24 weeks and through week 72
measure: Percent of Participants Who Experienced TB Relapse/Recurrence and Who Had TB Drug Resistance
timeFrame: At or after 24 weeks and through week 72
measure: Percent of Participants Whose HIV Viral Load Was Less Than 50 Copies/mL at Week 48
timeFrame: 48 weeks
measure: Number of Participants Reporting a Grade 3 or 4 Sign or Symptom
timeFrame: After randomization and through week 72
measure: Number of Participants Reporting a Grade 3 or 4 Laboratory Abnormality
timeFrame: After randomization and through week 72
measure: Percent of Participants Who Interrupted or Discontinued at Least One HIV Drug Due to Toxicity
timeFrame: After randomization and through week 72
measure: Percent of Participants Who Interrupted or Discontinued at Least One TB Drug Due to Toxicity
timeFrame: After randomization and through to the discontinuation of the last TB drug
measure: Percent of Participants Who Experienced HIV Virologic Failure
timeFrame: At weeks 16, 24, 48, and 72
measure: Cumulative Probability of HIV Virologic Failure at Week 72
timeFrame: At weeks 16, 24, 48, and 72
measure: Number of Participants Who Experienced MTB IRIS
timeFrame: After randomization and through week 72
measure: CD4 Count Change From Baseline to Week 8
timeFrame: Baseline and 8 weeks
measure: CD4 Count Change From Baseline to Week 24
timeFrame: Baseline and 24 weeks
measure: CD4 Count Change From Baseline to Week 48
timeFrame: Baseline and 48 weeks
measure: CD4 Count Change From Baseline to Week 72
timeFrame: Baseline and 72 weeks
measure: Percent of Participants Who Experienced a New AIDS-defining Illness
timeFrame: After randomization and through week 72
measure: Percent of Participants Who Died
timeFrame: After randomization and through week 72
measure: Percent of Participants Who Experienced a New AIDS-defining Illness or Died
timeFrame: After randomization and through week 72
Other outcomes:
measure: LPV Cmax and Cmin in Participants Enrolled in Arms A, B, and C
timeFrame: At 2 weeks: pre-dose and at 2, 4, 5, and 6 hours post-dose
measure: LPV AUC in Participants Enrolled in Arms A, B, and C
timeFrame: At 2 weeks: pre-dose and at 2, 4, 5, and 6 hours post-dose
measure: RBT Cmax and Cmin in Participants Enrolled in Arms A and C
timeFrame: At 2 weeks: pre-dose and at 2, 4, 5, 6, and 24 hours post-dose
measure: RBT AUC in Participants Enrolled in Arms A and C
timeFrame: At 2 weeks: pre-dose and at 2, 4, 5, 6, and 24 hours post-dose
measure: RAL Cmax and Cmin in Participants Enrolled in Arm C
timeFrame: At 2 weeks: pre-dose and at 2, 4, 5, 6, and 24 hours post-dose
measure: RAL AUC in Participants Enrolled in Arm C
timeFrame: At 2 weeks: pre-dose and at 2, 4, 5, 6, and 24 hours post-dose
Locations:
city: Porto Alegre
country: Brazil
facility: Hospital Nossa Senhora da Conceicao CRS (12201)
state: RS
city: Rio de Janeiro
country: Brazil
facility: Instituto de Pesquisa Clinica Evandro Chagas (12101)
city: Port Au Prince
country: Haiti
facility: GHESKIO Institute of Infectious Diseases and Reproductive Health (GHESKIO - IMIS) CRS (31730)
city: Port-au-Prince
country: Haiti
facility: Les Centres GHESKIO CRS (30022)
city: Eldoret
country: Kenya
facility: Moi University Clinical Research Center CRS (12601)
city: San Isidro
country: Peru
facility: Investigaciones Medicas en Salud (INMENSA) (11302)
state: Lima
city: Lima
country: Peru
facility: Asociacion Civil Impacta Salud y Educacion - Miraf CRS (11301)
city: Johannesburg
country: South Africa
facility: Wits HIV CRS (11101)
state: Gauteng
city: Durban
country: South Africa
facility: Durban Adult HIV CRS (11201)
Study officials:
affiliation: University of California, San Diego
name: Constance A Benson, MD
role: STUDY_CHAIR
affiliation: Nelson R. Mandela School of Medicine
name: Umesh Lalloo, MD, FRCP
role: STUDY_CHAIR
References: