Rifampin-Based Tuberculosis Treatment Versus Rifabutin-Based Tuberculosis Treatment in Persons With HIV

Tuberculosis Clinical Trial

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

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT01601626
• Other study ID #: ACTG A5290
• Secondary ID: 1U01AI068636
• Status: Terminated
• Phase: Phase 2
• First received: May 16, 2012
• Last updated: February 7, 2018
• Start date: July 13, 2013
• Est. completion date: June 28, 2017

Study information

• Verified date: February 2018
• Source: AIDS Clinical Trials Group
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical 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). 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.

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.

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 71
• Est. completion date: June 28, 2017
• Est. primary completion date: January 19, 2017
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• HIV Infection
• HIV Infections
• Tuberculosis

Intervention

Drug:
• Standard-dose Lopinavir/Ritonavir
Two LPV 200 mg/RTV 50 mg fixed-dose combination tablets orally twice daily from entry to Week 72.
• Double-dose Lopinavir/Ritonavir
Four LPV 200 mg/RTV 50 mg fixed-dose combination tablets orally twice daily from entry through Week 72.
• Raltegravir
One 400 mg tablet orally twice daily from entry to Week 72.
• Isoniazid
300 mg orally once daily from entry through Week 24.
• Pyridoxine
25 mg orally once daily from entry to Week 24.
• Pyrazinamide
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).
• Ethambutol
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).
• Rifabutin
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.
• Rifampin
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.

Locations

Country	Name	City	State
Brazil	Hospital Nossa Senhora da Conceicao CRS (12201)	Porto Alegre	RS
Brazil	Instituto de Pesquisa Clinica Evandro Chagas (12101)	Rio de Janeiro
Haiti	GHESKIO Institute of Infectious Diseases and Reproductive Health (GHESKIO - IMIS) CRS (31730)	Port Au Prince
Haiti	Les Centres GHESKIO CRS (30022)	Port-au-Prince
Kenya	Moi University Clinical Research Center CRS (12601)	Eldoret
Peru	Asociacion Civil Impacta Salud y Educacion - Miraf CRS (11301)	Lima
Peru	Investigaciones Medicas en Salud (INMENSA) (11302)	San Isidro	Lima
South Africa	Durban Adult HIV CRS (11201)	Durban
South Africa	Wits HIV CRS (11101)	Johannesburg	Gauteng

Sponsors (2)

Lead Sponsor	Collaborator
AIDS Clinical Trials Group	National Institute of Allergy and Infectious Diseases (NIAID)

Countries where clinical trial is conducted

Brazil,  Haiti,  Kenya,  Peru,  South Africa, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	LPV Cmax and Cmin in Participants Enrolled in Arms A, B, and C	Describe LPV plasma pharmacokinetic (PK) characteristics (maximum concentration [Cmax] and minimum concentration [Cmin]) in participants enrolled in Arms A, B, and C, determined by non-compartmental analysis of 12-hour PK sampling. The pre-dose concentration was determined using a sample drawn 12 hours after the previous LPV dose and was used as the 12-hour LPV concentration. As stated in the Detailed Study Description of the Protocol Section, formal statistical comparisons were not undertaken because of limited sample size.	At 2 weeks: pre-dose and at 2, 4, 5, and 6 hours post-dose
Other	LPV AUC in Participants Enrolled in Arms A, B, and C	Describe LPV plasma PK characteristics (area under the curve [AUC] between 0 and 12 hours) in participants enrolled in Arms A, B, and C, determined by non-compartmental analysis of 12-hour PK sampling. The pre-dose concentration was determined using a sample drawn 12 hours after the previous LPV dose and was used as the 12-hour LPV concentration. As stated in the Detailed Study Description of the Protocol Section, formal statistical comparisons were not undertaken because of limited sample size.	At 2 weeks: pre-dose and at 2, 4, 5, and 6 hours post-dose
Other	RBT Cmax and Cmin in Participants Enrolled in Arms A and C	Describe RBT plasma PK characteristics (Cmax and Cmin) in participants enrolled in Arms A and C, determined by non-compartmental analysis of 24-hour PK sampling. The pre-dose concentration was determined using a sample drawn 24 hours after the previous RBT dose. As stated in the Detailed Study Description of the Protocol Section, formal statistical comparisons were not undertaken because of limited sample size.	At 2 weeks: pre-dose and at 2, 4, 5, 6, and 24 hours post-dose
Other	RBT AUC in Participants Enrolled in Arms A and C	Describe RBT plasma PK characteristics (area under the curve [AUC] between 0 and 24 hours) in participants enrolled in Arms A and C, determined by non-compartmental analysis of 24-hour PK sampling. The pre-dose concentration was determined using a sample drawn 24 hours after the previous RBT dose. As stated in the Detailed Study Description of the Protocol Section, formal statistical comparisons were not undertaken because of limited sample size.	At 2 weeks: pre-dose and at 2, 4, 5, 6, and 24 hours post-dose
Other	RAL Cmax and Cmin in Participants Enrolled in Arm C	Describe RAL plasma PK characteristics (Cmax and Cmin) in participants enrolled in Arm C, determined by non-compartmental analysis of 24-hour PK sampling. The pre-dose concentration was determined using a sample drawn 12 hours after the previous RAL dose and was used as the 12-hour RAL concentration.	At 2 weeks: pre-dose and at 2, 4, 5, 6, and 24 hours post-dose
Other	RAL AUC in Participants Enrolled in Arm C	Describe RAL plasma PK characteristics (area under the curve [AUC] between 0 and 24 hours) in participants enrolled in Arm C, determined by non-compartmental analysis of 24-hour PK sampling. The pre-dose concentration was determined using a sample drawn 12 hours after the previous RAL dose and was used as the 12-hour RAL concentration.	At 2 weeks: pre-dose and at 2, 4, 5, 6, and 24 hours post-dose
Primary	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.	48 weeks
Secondary	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.	8 weeks
Secondary	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.	After 16 weeks and through week 72
Secondary	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.	At or after 24 weeks and through week 72
Secondary	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.	At or after 24 weeks and through week 72
Secondary	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.	48 weeks
Secondary	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.	After randomization and through week 72
Secondary	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.	After randomization and through week 72
Secondary	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.	After randomization and through week 72
Secondary	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.	After randomization and through to the discontinuation of the last TB drug
Secondary	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.	At weeks 16, 24, 48, and 72
Secondary	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.	At weeks 16, 24, 48, and 72
Secondary	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.	After randomization and through week 72
Secondary	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.	Baseline and 8 weeks
Secondary	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.	Baseline and 24 weeks
Secondary	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.	Baseline and 48 weeks
Secondary	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.	Baseline and 72 weeks
Secondary	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.	After randomization and through week 72
Secondary	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.	After randomization and through week 72
Secondary	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.	After randomization and through week 72

External Links

•   DAIDS Table for Grading the Severity of Adult and Pediatric Adverse Events (DAIDS AE Grading Table), Version 1.0, December 2004; Clarification, August 2009
•   Manual for Expedited Reporting of Adverse Events to DAIDS (DAIDS EAE Manual), Version 2.0, January 2010