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
试验速览
- 阶段
- 2 期
- 状态
- 终止
- 发起方
- 入组人数
- 71
- 试验地点
- 9
- 主要终点
- Percent of Participants Whose HIV Viral Load Was Less Than 400 Copies/mL at Week 48.
研究概览
简要总结
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.
详细描述
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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
排除标准
- •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
研究组 & 干预措施
A: Standard-dose LPV/r w/RBT
ART: lopinavir 400 mg/ritonavir 100 mg twice daily + two nucleoside reverse transcriptase inhibitors.
Anti-TB therapy: isoniazid 300 mg, rifabutin 300 mg, weight-based dosing for ethambutol and pyrazinamide, and pyridoxine 25 mg daily.
After completion of TB treatment through week 72: lopinavir 400 mg/ritonavir 100 mg twice daily + two nucleoside reverse transcriptase inhibitors (NRTIs).
干预措施: Standard-dose Lopinavir/Ritonavir (Drug)
A: Standard-dose LPV/r w/RBT
ART: lopinavir 400 mg/ritonavir 100 mg twice daily + two nucleoside reverse transcriptase inhibitors.
Anti-TB therapy: isoniazid 300 mg, rifabutin 300 mg, weight-based dosing for ethambutol and pyrazinamide, and pyridoxine 25 mg daily.
After completion of TB treatment through week 72: lopinavir 400 mg/ritonavir 100 mg twice daily + two nucleoside reverse transcriptase inhibitors (NRTIs).
干预措施: Isoniazid (Drug)
A: Standard-dose LPV/r w/RBT
ART: lopinavir 400 mg/ritonavir 100 mg twice daily + two nucleoside reverse transcriptase inhibitors.
Anti-TB therapy: isoniazid 300 mg, rifabutin 300 mg, weight-based dosing for ethambutol and pyrazinamide, and pyridoxine 25 mg daily.
After completion of TB treatment through week 72: lopinavir 400 mg/ritonavir 100 mg twice daily + two nucleoside reverse transcriptase inhibitors (NRTIs).
干预措施: Pyridoxine (Drug)
A: Standard-dose LPV/r w/RBT
ART: lopinavir 400 mg/ritonavir 100 mg twice daily + two nucleoside reverse transcriptase inhibitors.
Anti-TB therapy: isoniazid 300 mg, rifabutin 300 mg, weight-based dosing for ethambutol and pyrazinamide, and pyridoxine 25 mg daily.
After completion of TB treatment through week 72: lopinavir 400 mg/ritonavir 100 mg twice daily + two nucleoside reverse transcriptase inhibitors (NRTIs).
干预措施: Pyrazinamide (Drug)
A: Standard-dose LPV/r w/RBT
ART: lopinavir 400 mg/ritonavir 100 mg twice daily + two nucleoside reverse transcriptase inhibitors.
Anti-TB therapy: isoniazid 300 mg, rifabutin 300 mg, weight-based dosing for ethambutol and pyrazinamide, and pyridoxine 25 mg daily.
After completion of TB treatment through week 72: lopinavir 400 mg/ritonavir 100 mg twice daily + two nucleoside reverse transcriptase inhibitors (NRTIs).
干预措施: Ethambutol (Drug)
A: Standard-dose LPV/r w/RBT
ART: lopinavir 400 mg/ritonavir 100 mg twice daily + two nucleoside reverse transcriptase inhibitors.
Anti-TB therapy: isoniazid 300 mg, rifabutin 300 mg, weight-based dosing for ethambutol and pyrazinamide, and pyridoxine 25 mg daily.
After completion of TB treatment through week 72: lopinavir 400 mg/ritonavir 100 mg twice daily + two nucleoside reverse transcriptase inhibitors (NRTIs).
干预措施: Rifabutin (Drug)
B: Double-dose LPV/r w/RIF
ART: lopinavir 800 mg/ritonavir 200 mg twice daily + two nucleoside reverse transcriptase inhibitors.
Anti-TB therapy: isoniazid 300 mg, weight-based dosing for rifampin, ethambutol, and pyrazinamide, and pyridoxine 25 mg daily.
After completion of TB treatment through week 72: lopinavir 400 mg/ritonavir 100 mg twice daily + two nucleoside reverse transcriptase inhibitors (NRTIs).
干预措施: Double-dose Lopinavir/Ritonavir (Drug)
B: Double-dose LPV/r w/RIF
ART: lopinavir 800 mg/ritonavir 200 mg twice daily + two nucleoside reverse transcriptase inhibitors.
Anti-TB therapy: isoniazid 300 mg, weight-based dosing for rifampin, ethambutol, and pyrazinamide, and pyridoxine 25 mg daily.
After completion of TB treatment through week 72: lopinavir 400 mg/ritonavir 100 mg twice daily + two nucleoside reverse transcriptase inhibitors (NRTIs).
干预措施: Isoniazid (Drug)
B: Double-dose LPV/r w/RIF
ART: lopinavir 800 mg/ritonavir 200 mg twice daily + two nucleoside reverse transcriptase inhibitors.
Anti-TB therapy: isoniazid 300 mg, weight-based dosing for rifampin, ethambutol, and pyrazinamide, and pyridoxine 25 mg daily.
After completion of TB treatment through week 72: lopinavir 400 mg/ritonavir 100 mg twice daily + two nucleoside reverse transcriptase inhibitors (NRTIs).
干预措施: Pyridoxine (Drug)
B: Double-dose LPV/r w/RIF
ART: lopinavir 800 mg/ritonavir 200 mg twice daily + two nucleoside reverse transcriptase inhibitors.
Anti-TB therapy: isoniazid 300 mg, weight-based dosing for rifampin, ethambutol, and pyrazinamide, and pyridoxine 25 mg daily.
After completion of TB treatment through week 72: lopinavir 400 mg/ritonavir 100 mg twice daily + two nucleoside reverse transcriptase inhibitors (NRTIs).
干预措施: Pyrazinamide (Drug)
B: Double-dose LPV/r w/RIF
ART: lopinavir 800 mg/ritonavir 200 mg twice daily + two nucleoside reverse transcriptase inhibitors.
Anti-TB therapy: isoniazid 300 mg, weight-based dosing for rifampin, ethambutol, and pyrazinamide, and pyridoxine 25 mg daily.
After completion of TB treatment through week 72: lopinavir 400 mg/ritonavir 100 mg twice daily + two nucleoside reverse transcriptase inhibitors (NRTIs).
干预措施: Ethambutol (Drug)
B: Double-dose LPV/r w/RIF
ART: lopinavir 800 mg/ritonavir 200 mg twice daily + two nucleoside reverse transcriptase inhibitors.
Anti-TB therapy: isoniazid 300 mg, weight-based dosing for rifampin, ethambutol, and pyrazinamide, and pyridoxine 25 mg daily.
After completion of TB treatment through week 72: lopinavir 400 mg/ritonavir 100 mg twice daily + two nucleoside reverse transcriptase inhibitors (NRTIs).
干预措施: Rifampin (Drug)
C: Standard-Dose LPV/r w/RBT + RAL
ART: lopinavir 400 mg/ritonavir 100 mg twice daily + raltegravir 400 mg twice daily + two nucleoside reverse transcriptase inhibitors.
Anti-TB therapy: isoniazid 300 mg, rifabutin 300 mg, weight-based dosing for ethambutol and pyrazinamide, and pyridoxine 25 mg daily.
After completion of TB treatment through week 72: lopinavir 400 mg/ritonavir 100 mg twice daily + two nucleoside reverse transcriptase inhibitors (NRTIs).
干预措施: Standard-dose Lopinavir/Ritonavir (Drug)
C: Standard-Dose LPV/r w/RBT + RAL
ART: lopinavir 400 mg/ritonavir 100 mg twice daily + raltegravir 400 mg twice daily + two nucleoside reverse transcriptase inhibitors.
Anti-TB therapy: isoniazid 300 mg, rifabutin 300 mg, weight-based dosing for ethambutol and pyrazinamide, and pyridoxine 25 mg daily.
After completion of TB treatment through week 72: lopinavir 400 mg/ritonavir 100 mg twice daily + two nucleoside reverse transcriptase inhibitors (NRTIs).
干预措施: Raltegravir (Drug)
C: Standard-Dose LPV/r w/RBT + RAL
ART: lopinavir 400 mg/ritonavir 100 mg twice daily + raltegravir 400 mg twice daily + two nucleoside reverse transcriptase inhibitors.
Anti-TB therapy: isoniazid 300 mg, rifabutin 300 mg, weight-based dosing for ethambutol and pyrazinamide, and pyridoxine 25 mg daily.
After completion of TB treatment through week 72: lopinavir 400 mg/ritonavir 100 mg twice daily + two nucleoside reverse transcriptase inhibitors (NRTIs).
干预措施: Isoniazid (Drug)
C: Standard-Dose LPV/r w/RBT + RAL
ART: lopinavir 400 mg/ritonavir 100 mg twice daily + raltegravir 400 mg twice daily + two nucleoside reverse transcriptase inhibitors.
Anti-TB therapy: isoniazid 300 mg, rifabutin 300 mg, weight-based dosing for ethambutol and pyrazinamide, and pyridoxine 25 mg daily.
After completion of TB treatment through week 72: lopinavir 400 mg/ritonavir 100 mg twice daily + two nucleoside reverse transcriptase inhibitors (NRTIs).
干预措施: Pyridoxine (Drug)
C: Standard-Dose LPV/r w/RBT + RAL
ART: lopinavir 400 mg/ritonavir 100 mg twice daily + raltegravir 400 mg twice daily + two nucleoside reverse transcriptase inhibitors.
Anti-TB therapy: isoniazid 300 mg, rifabutin 300 mg, weight-based dosing for ethambutol and pyrazinamide, and pyridoxine 25 mg daily.
After completion of TB treatment through week 72: lopinavir 400 mg/ritonavir 100 mg twice daily + two nucleoside reverse transcriptase inhibitors (NRTIs).
干预措施: Pyrazinamide (Drug)
C: Standard-Dose LPV/r w/RBT + RAL
ART: lopinavir 400 mg/ritonavir 100 mg twice daily + raltegravir 400 mg twice daily + two nucleoside reverse transcriptase inhibitors.
Anti-TB therapy: isoniazid 300 mg, rifabutin 300 mg, weight-based dosing for ethambutol and pyrazinamide, and pyridoxine 25 mg daily.
After completion of TB treatment through week 72: lopinavir 400 mg/ritonavir 100 mg twice daily + two nucleoside reverse transcriptase inhibitors (NRTIs).
干预措施: Ethambutol (Drug)
C: Standard-Dose LPV/r w/RBT + RAL
ART: lopinavir 400 mg/ritonavir 100 mg twice daily + raltegravir 400 mg twice daily + two nucleoside reverse transcriptase inhibitors.
Anti-TB therapy: isoniazid 300 mg, rifabutin 300 mg, weight-based dosing for ethambutol and pyrazinamide, and pyridoxine 25 mg daily.
After completion of TB treatment through week 72: lopinavir 400 mg/ritonavir 100 mg twice daily + two nucleoside reverse transcriptase inhibitors (NRTIs).
干预措施: Rifabutin (Drug)
结局指标
主要结局
Percent of Participants Whose HIV Viral Load Was Less Than 400 Copies/mL at Week 48.
时间窗: 48 weeks
The percent of participants whose HIV viral load was less than 400 copies/mL at week 48 was calculated with an associated standard error. The confidence interval was calculated using Wilson's score method. Participants who were lost-to-follow-up or dead by week 48 or had missing results at week 48 were coded as having HIV viral load greater than 400 copies/mL. As stated in the Detailed Study Description of the Protocol Section, formal statistical comparisons were not undertaken because of limited sample size.
次要结局
- Number of Participants Reporting a Grade 3 or 4 Laboratory Abnormality(After randomization and through week 72)
- Percent of Participants Who Experienced Sputum Conversion at Week 8.(8 weeks)
- Percent of Participants Who Experienced TB Treatment Failure(After 16 weeks and through week 72)
- Percent of Participants Who Experienced TB Relapse/Recurrence(At or after 24 weeks and through week 72)
- Percent of Participants Who Experienced TB Relapse/Recurrence and Who Had TB Drug Resistance(At or after 24 weeks and through week 72)
- Percent of Participants Whose HIV Viral Load Was Less Than 50 Copies/mL at Week 48(48 weeks)
- Number of Participants Reporting a Grade 3 or 4 Sign or Symptom(After randomization and through week 72)
- Percent of Participants Who Interrupted or Discontinued at Least One HIV Drug Due to Toxicity(After randomization and through week 72)
- Percent of Participants Who Interrupted or Discontinued at Least One TB Drug Due to Toxicity(After randomization and through to the discontinuation of the last TB drug)
- Percent of Participants Who Experienced HIV Virologic Failure(At weeks 16, 24, 48, and 72)
- Cumulative Probability of HIV Virologic Failure at Week 72(At weeks 16, 24, 48, and 72)
- Number of Participants Who Experienced MTB IRIS(After randomization and through week 72)
- CD4 Count Change From Baseline to Week 8(Baseline and 8 weeks)
- CD4 Count Change From Baseline to Week 24(Baseline and 24 weeks)
- CD4 Count Change From Baseline to Week 48(Baseline and 48 weeks)
- CD4 Count Change From Baseline to Week 72(Baseline and 72 weeks)
- Percent of Participants Who Experienced a New AIDS-defining Illness(After randomization and through week 72)
- Percent of Participants Who Died(After randomization and through week 72)
- Percent of Participants Who Experienced a New AIDS-defining Illness or Died(After randomization and through week 72)