HIV InfectionPhase 2NCT01601626
Rifampin-Based Tuberculosis Treatment Versus Rifabutin-Based Tuberculosis Treatment in Persons With HIV
A Phase 2 study testing Standard-dose Lopinavir/Ritonavir, Double-dose Lopinavir/Ritonavir and Raltegravir in people with HIV Infection and Tuberculosis, run by Advancing Clinical Therapeutics Globally for HIV/AIDS and Other Infections at 9 sites in 5 countries.
Trial 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). Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- HIV Infection, Tuberculosis
- What is being tested?
- Standard-dose Lopinavir/Ritonavir, Double-dose Lopinavir/Ritonavir and Raltegravir
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 71 participants
- Where
- 9 sitesin 5 countries
- Study dates
- 13 Jul 2013to 28 Jun 2017
- Phase
- Phase 2
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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)
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- 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
Who cannot join
- 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
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- 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
Trial locations and contacts
9 sites in 5 countries.
9 sites in 5 countries
Brazil2 sites
Hospital Nossa Senhora da Conceicao CRS (12201)
Porto Alegre, Rio Grande do Sul, 9043010
Instituto de Pesquisa Clinica Evandro Chagas (12101)
Rio de Janeiro, 21045
Haiti2 sites
Les Centres GHESKIO CRS (30022)
Port-au-Prince, HT-6110
GHESKIO Institute of Infectious Diseases and Reproductive Health (GHESKIO - IMIS) CRS (31730)
Port-au-Prince
Peru2 sites
Asociacion Civil Impacta Salud y Educacion - Miraf CRS (11301)
Lima, 18 PE
Investigaciones Medicas en Salud (INMENSA) (11302)
San Isidro, Lima region
South Africa2 sites
Durban Adult HIV CRS (11201)
Durban, 4013 SF
Wits HIV CRS (11101)
Johannesburg, Gauteng
About this study
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
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.
Read the 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.
- Conditions
- HIV Infection, Tuberculosis
- Being tested
- Standard-dose Lopinavir/Ritonavir, Double-dose Lopinavir/Ritonavir, Raltegravir, Isoniazid, Pyridoxine
- Medical subject headings
- HIV Infections, Tuberculosis
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Standard-dose Lopinavir/RitonavirDrug
Also called LPV/RTV, LPV/r, Aluvia, Kaletra
Two LPV 200 mg/RTV 50 mg fixed-dose combination tablets orally twice daily from entry to Week 72.
Double-dose Lopinavir/RitonavirDrug
Also called LPV/RTV, LPV/r, Aluvia, Kaletra
Four LPV 200 mg/RTV 50 mg fixed-dose combination tablets orally twice daily from entry through Week 72.
RaltegravirDrug
Also called RAL, Isentress
One 400 mg tablet orally twice daily from entry to Week 72.
IsoniazidDrug
Also called INH
300 mg orally once daily from entry through Week 24.
PyridoxineDrug
Also called Vitamin B6
25 mg orally once daily from entry to Week 24.
PyrazinamideDrug
Also called PZA
20 to 30 mg/kg orally once daily (not to exceed 2 g per day) from entry through Week 8 study visit (or until completion of intensive TB treatment as determined after dose adjustment in accrual period 1 participants).
EthambutolDrug
Also called EMB
15 to 20 mg/kg orally once daily from entry through Week 8 study visit (or until completion of intensive TB treatment as determined after dose adjustment in accrual period 1 participants).
RifabutinDrug
Also called RBT
300 mg of rifabutin orally once until LPV/RTV is started; then the dose will be reduced to 150 mg daily from the start of LPV/RTV through Week 24.
RifampinDrug
Also called RIF
Weight-based dose; for weight < 45 kg: 450 mg orally once daily; for weight > 45 kg: 600 mg orally once daily, from entry to week 24.
| Study group | Role | What they receive |
|---|---|---|
| A: Standard-dose LPV/r w/RBT | Experimental | 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). Receives: Drug: Standard-dose Lopinavir/Ritonavir; Drug: Isoniazid; Drug: Pyridoxine; Drug: Pyrazinamide; Drug: Ethambutol; Drug: Rifabutin |
| B: Double-dose LPV/r w/RIF | Active comparator | 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). Receives: Drug: Double-dose Lopinavir/Ritonavir; Drug: Isoniazid; Drug: Pyridoxine; Drug: Pyrazinamide; Drug: Ethambutol; Drug: Rifampin |
| C: Standard-Dose LPV/r w/RBT + RAL | Experimental | 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). Receives: Drug: Standard-dose Lopinavir/Ritonavir; Drug: Raltegravir; Drug: Isoniazid; Drug: Pyridoxine; Drug: Pyrazinamide; Drug: Ethambutol; Drug: Rifabutin |
What is being measured
The primary outcome is the main question the study is designed to answer.
Percent of Participants Whose HIV Viral Load Was Less Than 400 Copies/mL at Week 48.
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.
Measured: 48 weeks
Secondary outcomes (19)
Percent of Participants Who Experienced Sputum Conversion at Week 8.
Sputum conversion was defined as culture MTB-negative at week 8 or AFB smear negative at week 8 (and culture contaminated or missing at week 8); there were no Xpert MTB/RIF results at week 8. The percent of participants experienced sputum conversion at week 8 was calculated with an associated standard error. The confidence interval was calculated using Wilson's score method. As stated in the Detailed Study Description of the Protocol Section, formal statistical comparisons were not undertaken because of limited sample size.
Measured: 8 weeks
Percent of Participants Who Experienced TB Treatment Failure
TB treatment failure was defined as having a MTB-positive culture after 16 weeks of TB treatment for a participant who was documented to be taking TB medications. The percent of participants who experienced TB treatment failure was calculated with an associated standard error. The confidence interval was calculated using Wilson's score method. As stated in the Detailed Study Description of the Protocol Section, formal statistical comparisons were not undertaken because of limited sample size.
Measured: After 16 weeks and through week 72
Percent of Participants Who Experienced TB Relapse/Recurrence
TB relapse/recurrence was defined as having had 2 consecutive MTB-negative cultures and subsequently had clinical or radiographic deterioration consistent with active TB at or after week 24 and before week 72. The percent of participants who experienced TB relapse/recurrence was calculated with an associated standard error. The confidence interval was calculated using Wilson's score method. As stated in the Detailed Study Description of the Protocol Section, formal statistical comparisons were not undertaken because of limited sample size.
Measured: At or after 24 weeks and through week 72
Percent of Participants Who Experienced TB Relapse/Recurrence and Who Had TB Drug Resistance
TB relapse/recurrence was defined as having had 2 consecutive MTB-negative cultures and subsequently had clinical or radiographic deterioration consistent with active TB at or after week 24 and before week 72. The drug resistance was determined based on phenotypic methods. The percent of participants who experienced TB relapse/recurrence and who had TB drug resistance was calculated with an associated standard error. The confidence interval was calculated using Wilson's score method. As stated in the Detailed Study Description of the Protocol Section, formal statistical comparisons were not undertaken because of limited sample size.
Measured: 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
The percent of participants whose HIV viral load was less than 50 copies/mL at week 48 was calculated with an associated standard error. Participants who were lost-to-follow-up or dead by week 48 or had missing RNA at week 48 were coded as having HIV viral load greater than 50 copies/mL. The confidence interval was calculated using Wilson's score method. As stated in the Detailed Study Description of the Protocol Section, formal statistical comparisons were not undertaken because of limited sample size.
Measured: 48 weeks
Number of Participants Reporting a Grade 3 or 4 Sign or Symptom
The number of participants reporting a grade 3 (severe) or grade 4 (life-threatening) sign or symptom were summarized. As stated in the Detailed Study Description of the Protocol Section, formal statistical comparisons were not undertaken because of limited sample size.
Measured: After randomization and through week 72
Number of Participants Reporting a Grade 3 or 4 Laboratory Abnormality
The number of participants reporting a grade 3 (severe) or grade 4 (life-threatening) laboratory abnormality were summarized. As stated in the Detailed Study Description of the Protocol Section, formal statistical comparisons were not undertaken because of limited sample size.
Measured: After randomization and through week 72
Percent of Participants Who Interrupted or Discontinued at Least One HIV Drug Due to Toxicity
The percent of participants who interrupted or discontinued at least one HIV drug due to toxicity was calculated with an associated standard error. The confidence interval was calculated using Wilson's score method. As stated in the Detailed Study Description of the Protocol Section, formal statistical comparisons were not undertaken because of limited sample size.
Measured: After randomization and through week 72
Percent of Participants Who Interrupted or Discontinued at Least One TB Drug Due to Toxicity
The percent of participants who interrupted or discontinued at least one TB drug due to toxicity was calculated with an associated standard error. The confidence interval was calculated using Wilson's score method. As stated in the Detailed Study Description of the Protocol Section, formal statistical comparisons were not undertaken because of limited sample size.
Measured: After randomization and through to the discontinuation of the last TB drug
Percent of Participants Who Experienced HIV Virologic Failure
Virologic failure was defined as the occurrence of two consecutive plasma HIV-1 RNA levels ≥1000 copies/mL at or after 16 weeks and within 24 weeks of treatment initiation or ≥400 copies/mL at or after 24 weeks of treatment, regardless of whether randomized ART was being taken at the time of virologic failure. Participants who were missing data due to being lost-to-follow-up or dead were coded as virologic failures. The percent of participants who experienced HIV virologic failure was calculated with an associated standard error. The confidence interval was calculated using Wilson's score method. As stated in the Detailed Study Description of the Protocol Section, formal statistical comparisons were not undertaken because of limited sample size.
Measured: At weeks 16, 24, 48, and 72
Cumulative Probability of HIV Virologic Failure at Week 72
Virologic failure was defined as the occurrence of two consecutive plasma HIV-1 RNA levels ≥1000 copies/mL at or after 16 weeks and within 24 weeks of treatment initiation or ≥400 copies/mL at or after 24 weeks of treatment, regardless of whether randomized ART was being taken at the time of virologic failure. The percent of participants with HIV virologic failure at week 72 was calculated using a Kaplan-Meier estimator with an associated standard error. The confidence interval was calculated using a log-log transformation. As stated in the Detailed Study Description of the Protocol Section, formal statistical comparisons were not undertaken because of limited sample size.
Measured: At weeks 16, 24, 48, and 72
Number of Participants Who Experienced MTB IRIS
The number of participants who experienced MTB immune reconstitution inflammatory syndrome (IRIS) was summarized. As stated in the Detailed Study Description of the Protocol Section, formal statistical comparisons were not undertaken because of limited sample size.
Measured: After randomization and through week 72
CD4 Count Change From Baseline to Week 8
The difference in CD4 count from baseline to week 8 was calculated as the CD4 count at week 8 minus the CD4 count at baseline. As stated in the Detailed Study Description of the Protocol Section, formal statistical comparisons were not undertaken because of limited sample size.
Measured: Baseline and 8 weeks
CD4 Count Change From Baseline to Week 24
The difference in CD4 count from baseline to week 24 was calculated as the CD4 count at week 24 minus the CD4 count at baseline. As stated in the Detailed Study Description of the Protocol Section, formal statistical comparisons were not undertaken because of limited sample size.
Measured: Baseline and 24 weeks
CD4 Count Change From Baseline to Week 48
The difference in CD4 count from baseline to week 48 was calculated as the CD4 count at week 48 minus the CD4 count at baseline. As stated in the Detailed Study Description of the Protocol Section, formal statistical comparisons were not undertaken because of limited sample size.
Measured: Baseline and 48 weeks
CD4 Count Change From Baseline to Week 72
The difference in CD4 count from baseline to week 72 was calculated as the CD4 count at week 72 minus the CD4 count at baseline. As stated in the Detailed Study Description of the Protocol Section, formal statistical comparisons were not undertaken because of limited sample size.
Measured: Baseline and 72 weeks
Percent of Participants Who Experienced a New AIDS-defining Illness
New post-randomization diagnoses were considered AIDS-defining based on the CDC classification system. The percent of participants who experienced a new AIDS-defining illness was calculated with an associated standard error. The confidence interval was calculated using Wilson's score method. As stated in the Detailed Study Description of the Protocol Section, formal statistical comparisons were not undertaken because of limited sample size.
Measured: After randomization and through week 72
Percent of Participants Who Died
The percent of participants who died was calculated with an associated standard error. Confidence intervals were calculated using Wilson's score method. As stated in the Detailed Study Description of the Protocol Section, formal statistical comparisons were not undertaken because of limited sample size.
Measured: After randomization and through week 72
Percent of Participants Who Experienced a New AIDS-defining Illness or Died
New post-randomization diagnoses were considered AIDS-defining based on the CDC classification system. The percent of participants who experienced a new AIDS-defining illness or died was calculated with an associated standard error. Confidence intervals were calculated using Wilson's score method. As stated in the Detailed Study Description of the Protocol Section, formal statistical comparisons were not undertaken because of limited sample size.
Measured: After randomization and through week 72
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted18 May 2012 (estimated)
- Study start13 Jul 2013
- Primary completion19 Jan 2017
- Study completion28 Jun 2017
Why it stopped: The study was stopped early due to feasibility concerns.
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Other trials for HIV InfectionStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 2
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Enrolment
- 71 participants (actual)
Sponsor and investigators
- Lead sponsor
- Advancing Clinical Therapeutics Globally for HIV/AIDS and Other Infections
- Sponsor type
- Research network
- Responsible party
- Sponsor
- Investigators
- Constance A Benson, MD, Study chair, University of California, San DiegoUmesh Lalloo, MD, FRCP, Study chair, Nelson R. Mandela School of Medicine
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT01601626
- Sponsor's protocol ID
- ACTG A5290
- Other IDs
- 1U01AI068636
- Status last verified
- Feb 2018
- First submitted
- 16 May 2012
- Last updated
- 13 Feb 2018
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- Yes
Study at a glance
From the registry record, last updated by the sponsor on 13 Feb 2018. Recruitment status is as the sponsor reported it: confirm with the study team.
- 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
- ClinicalTrials.gov ID
- NCT01601626
- Acronym / sponsor ID
- ACTG A5290
- Conditions
- HIV Infection, Tuberculosis
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- TerminatedReason stopped: The study was stopped early due to feasibility concerns.
- Enrolment
- 71 participants (actual)
- Lead sponsor
- Advancing Clinical Therapeutics Globally for HIV/AIDS and Other InfectionsResearch network
- Collaborators
- National Institute of Allergy and Infectious Diseases (NIAID)
- Study start
- 13 Jul 2013 (actual)
- Primary completion
- 19 Jan 2017 (actual)
- Study completion
- 28 Jun 2017 (actual)
- First posted
- 18 May 2012 (estimated)
- Results
- Posted 13 Feb 2018
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Number of arms
- 3
| Arm | Type | Receives |
|---|---|---|
| A: Standard-dose LPV/r w/RBT | Experimental | Drug: Standard-dose Lopinavir/Ritonavir, Drug: Isoniazid, Drug: Pyridoxine, Drug: Pyrazinamide, Drug: Ethambutol, Drug: RifabutinART: 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). |
| B: Double-dose LPV/r w/RIF | Active comparator | Drug: Double-dose Lopinavir/Ritonavir, Drug: Isoniazid, Drug: Pyridoxine, Drug: Pyrazinamide, Drug: Ethambutol, Drug: RifampinART: 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). |
| C: Standard-Dose LPV/r w/RBT + RAL | Experimental | Drug: Standard-dose Lopinavir/Ritonavir, Drug: Raltegravir, Drug: Isoniazid, Drug: Pyridoxine, Drug: Pyrazinamide, Drug: Ethambutol, Drug: RifabutinART: 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). |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (11 listed)
- 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
Key exclusion criteria (10 listed)
- 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
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Standard-dose Lopinavir/RitonavirAlso: LPV/RTV, LPV/r, Aluvia, KaletraTwo LPV 200 mg/RTV 50 mg fixed-dose combination tablets orally twice daily from entry to Week 72. | Drug | A: Standard-dose LPV/r w/RBT, C: Standard-Dose LPV/r w/RBT + RAL |
| Double-dose Lopinavir/RitonavirAlso: LPV/RTV, LPV/r, Aluvia, KaletraFour LPV 200 mg/RTV 50 mg fixed-dose combination tablets orally twice daily from entry through Week 72. | Drug | B: Double-dose LPV/r w/RIF |
| RaltegravirAlso: RAL, IsentressOne 400 mg tablet orally twice daily from entry to Week 72. | Drug | C: Standard-Dose LPV/r w/RBT + RAL |
| IsoniazidAlso: INH300 mg orally once daily from entry through Week 24. | Drug | A: Standard-dose LPV/r w/RBT, B: Double-dose LPV/r w/RIF, C: Standard-Dose LPV/r w/RBT + RAL |
| PyridoxineAlso: Vitamin B625 mg orally once daily from entry to Week 24. | Drug | A: Standard-dose LPV/r w/RBT, B: Double-dose LPV/r w/RIF, C: Standard-Dose LPV/r w/RBT + RAL |
| PyrazinamideAlso: PZA20 to 30 mg/kg orally once daily (not to exceed 2 g per day) from entry through Week 8 study visit (or until completion of intensive TB treatment as determined after dose adjustment in accrual period 1 participants). | Drug | A: Standard-dose LPV/r w/RBT, B: Double-dose LPV/r w/RIF, C: Standard-Dose LPV/r w/RBT + RAL |
| EthambutolAlso: EMB15 to 20 mg/kg orally once daily from entry through Week 8 study visit (or until completion of intensive TB treatment as determined after dose adjustment in accrual period 1 participants). | Drug | A: Standard-dose LPV/r w/RBT, B: Double-dose LPV/r w/RIF, C: Standard-Dose LPV/r w/RBT + RAL |
| RifabutinAlso: RBT300 mg of rifabutin orally once until LPV/RTV is started; then the dose will be reduced to 150 mg daily from the start of LPV/RTV through Week 24. | Drug | A: Standard-dose LPV/r w/RBT, C: Standard-Dose LPV/r w/RBT + RAL |
| RifampinAlso: RIFWeight-based dose; for weight < 45 kg: 450 mg orally once daily; for weight > 45 kg: 600 mg orally once daily, from entry to week 24. | Drug | B: Double-dose LPV/r w/RIF |
Primary outcome
Percent of Participants Whose HIV Viral Load Was Less Than 400 Copies/mL at Week 48.
Time frame: 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.
19 secondary outcomes
Percent of Participants Who Experienced Sputum Conversion at Week 8.
Time frame: 8 weeks
Percent of Participants Who Experienced TB Treatment Failure
Time frame: After 16 weeks and through week 72
Percent of Participants Who Experienced TB Relapse/Recurrence
Time frame: At or after 24 weeks and through week 72
Percent of Participants Who Experienced TB Relapse/Recurrence and Who Had TB Drug Resistance
Time frame: 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
Time frame: 48 weeks
Number of Participants Reporting a Grade 3 or 4 Sign or Symptom
Time frame: After randomization and through week 72
Number of Participants Reporting a Grade 3 or 4 Laboratory Abnormality
Time frame: After randomization and through week 72
Percent of Participants Who Interrupted or Discontinued at Least One HIV Drug Due to Toxicity
Time frame: After randomization and through week 72
Percent of Participants Who Interrupted or Discontinued at Least One TB Drug Due to Toxicity
Time frame: After randomization and through to the discontinuation of the last TB drug
Percent of Participants Who Experienced HIV Virologic Failure
Time frame: At weeks 16, 24, 48, and 72
Cumulative Probability of HIV Virologic Failure at Week 72
Time frame: At weeks 16, 24, 48, and 72
Number of Participants Who Experienced MTB IRIS
Time frame: After randomization and through week 72
CD4 Count Change From Baseline to Week 8
Time frame: Baseline and 8 weeks
CD4 Count Change From Baseline to Week 24
Time frame: Baseline and 24 weeks
CD4 Count Change From Baseline to Week 48
Time frame: Baseline and 48 weeks
CD4 Count Change From Baseline to Week 72
Time frame: Baseline and 72 weeks
Percent of Participants Who Experienced a New AIDS-defining Illness
Time frame: After randomization and through week 72
Percent of Participants Who Died
Time frame: After randomization and through week 72
Percent of Participants Who Experienced a New AIDS-defining Illness or Died
Time frame: After randomization and through week 72
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 13 Feb 2018.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- DAIDS Table for Grading the Severity of Adult and Pediatric Adverse Events (DAIDS AE Grading Table), Version 1.0, December 2004; Clarification, August 2009Link provided by the sponsor.
- Manual for Expedited Reporting of Adverse Events to DAIDS (DAIDS EAE Manual), Version 2.0, January 2010Link provided by the sponsor.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Constance A Benson, MD study chair
University of California, San Diego
Umesh Lalloo, MD, FRCP study chair
Nelson R. Mandela School of Medicine
9 sites in 5 countries: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2 study testing Standard-dose Lopinavir/Ritonavir, Double-dose Lopinavir/Ritonavir and Raltegravir in people with HIV Infection and Tuberculosis, run by Advancing Clinical Therapeutics Globally for HIV/AIDS and Other Infections at 9 sites in 5 countries.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 11 inclusion and 10 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: stopped early, as of the sponsor's last update on 13 Feb 2018. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 9 sites in Brazil, Haiti, Peru, South Africa, Kenya. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 13 Feb 2018). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Percent of Participants Whose HIV Viral Load Was Less Than 400 Copies/mL at Week 48. (time frame: 48 weeks). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 13 Feb 2018.