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

NCT01601626 | Terminated Phase 2 Results DMC

• 2 other identifiers: ACTG A52901U01AI068636
• Study Type: interventional
• Target: 71
• Locations: 5 countries
• Sites: 9

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.

Conditions

HIV Infection; Tuberculosis

Outcome Measures

Primary Outcomes (1)

• 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 Outcomes (19)

• 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

Other Outcomes (6)

• LPV Cmax and Cmin in Participants Enrolled in Arms A, B, and C

  At 2 weeks: pre-dose and at 2, 4, 5, and 6 hours post-dose

• LPV AUC in Participants Enrolled in Arms A, B, and C

  At 2 weeks: pre-dose and at 2, 4, 5, and 6 hours post-dose

• RBT Cmax and Cmin in Participants Enrolled in Arms A and C

  At 2 weeks: pre-dose and at 2, 4, 5, 6, and 24 hours post-dose

Study Arms (3)

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).

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).

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).

Drug: Standard-dose Lopinavir/Ritonavir; Drug: Raltegravir; Drug: Isoniazid; Drug: Pyridoxine; Drug: Pyrazinamide; Drug: Ethambutol; Drug: Rifabutin

Interventions

Standard-dose Lopinavir/Ritonavir DRUG

Two LPV 200 mg/RTV 50 mg fixed-dose combination tablets orally twice daily from entry to Week 72.

Also known as: LPV/RTV, LPV/r, Aluvia, Kaletra

A: Standard-dose LPV/r w/RBT; C: Standard-Dose LPV/r w/RBT + RAL

Double-dose Lopinavir/Ritonavir DRUG

Four LPV 200 mg/RTV 50 mg fixed-dose combination tablets orally twice daily from entry through Week 72.

Also known as: LPV/RTV, LPV/r, Aluvia, Kaletra

B: Double-dose LPV/r w/RIF

Raltegravir DRUG

One 400 mg tablet orally twice daily from entry to Week 72.

Also known as: RAL, Isentress

C: Standard-Dose LPV/r w/RBT + RAL

Isoniazid DRUG

300 mg orally once daily from entry through Week 24.

Also known as: INH

A: Standard-dose LPV/r w/RBT; B: Double-dose LPV/r w/RIF; C: Standard-Dose LPV/r w/RBT + RAL

Pyridoxine DRUG

25 mg orally once daily from entry to Week 24.

Also known as: Vitamin B6

A: Standard-dose LPV/r w/RBT; B: Double-dose LPV/r w/RIF; C: Standard-Dose LPV/r w/RBT + RAL

Pyrazinamide DRUG

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).

Also known as: PZA

A: Standard-dose LPV/r w/RBT; B: Double-dose LPV/r w/RIF; C: Standard-Dose LPV/r w/RBT + RAL

Ethambutol DRUG

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).

Also known as: EMB

A: Standard-dose LPV/r w/RBT; B: Double-dose LPV/r w/RIF; C: Standard-Dose LPV/r w/RBT + RAL

Rifabutin DRUG

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.

Also known as: RBT

A: Standard-dose LPV/r w/RBT; C: Standard-Dose LPV/r w/RBT + RAL

Rifampin DRUG

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.

Also known as: RIF

B: Double-dose LPV/r w/RIF

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• Advancing Clinical Therapeutics Globally for HIV/AIDS and Other Infections: lead
• National Institute of Allergy and Infectious Diseases (NIAID): collaborator

Study Sites (9)

Hospital Nossa Senhora da Conceicao CRS (12201)

Porto Alegre, Rio Grande do Sul, 9043010, Brazil

Location

Instituto de Pesquisa Clinica Evandro Chagas (12101)

Rio de Janeiro, 21045, Brazil

Location

Les Centres GHESKIO CRS (30022)

Port-au-Prince, HT-6110, Haiti

Location

GHESKIO Institute of Infectious Diseases and Reproductive Health (GHESKIO - IMIS) CRS (31730)

Port-au-Prince, Haiti

Location

Moi University Clinical Research Center CRS (12601)

Eldoret, 30100, Kenya

Location

Investigaciones Medicas en Salud (INMENSA) (11302)

San Isidro, Lima region, Peru

Location

Asociacion Civil Impacta Salud y Educacion - Miraf CRS (11301)

Lima, 18 PE, Peru

Location

Wits HIV CRS (11101)

Johannesburg, Gauteng, South Africa

Location

Durban Adult HIV CRS (11201)

Durban, 4013 SF, South Africa

Location

Related 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

MeSH Terms

Conditions

HIV Infections; Tuberculosis

Interventions

Lopinavir; Ritonavir; lopinavir-ritonavir drug combination; Raltegravir Potassium; Isoniazid; Pyridoxine; Vitamin B 6; Pyrazinamide; Ethambutol; Rifabutin; Rifampin

Condition Hierarchy (Ancestors)

Blood-Borne Infections; Communicable Diseases; Infections; Sexually Transmitted Diseases, Viral; Sexually Transmitted Diseases; Lentivirus Infections; Retroviridae Infections; RNA Virus Infections; Virus Diseases; Genital Diseases; Urogenital Diseases; Immunologic Deficiency Syndromes; Immune System Diseases; Mycobacterium Infections; Actinomycetales Infections; Gram-Positive Bacterial Infections; Bacterial Infections; Bacterial Infections and Mycoses

Intervention Hierarchy (Ancestors)

Pyrimidinones; Pyrimidines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Thiazoles; Sulfur Compounds; Organic Chemicals; Azoles; Pyrrolidinones; Pyrrolidines; Hydrazines; Isonicotinic Acids; Acids, Heterocyclic; Pyridines; Picolines; Pyrazines; Ethylenediamines; Diamines; Polyamines; Amines; Rifamycins; Heterocyclic Compounds, 4 or More Rings; Heterocyclic Compounds, Fused-Ring; Lactams, Macrocyclic; Macrocyclic Compounds; Polycyclic Compounds

Limitations and Caveats

The study was terminated after 71 of 471 participants enrolled. Therefore, the study was under-powered and formal statistical comparisons between study arms were not undertaken as originally planned. Instead, summaries within study arm were provided.

Results Point of Contact

• Title: ACTG Clinicaltrials.gov Coordinator
• Organization: ACTG Network Coordinating Center, Social and Scientific Systems, Inc.

ACTGCT.Gov@s-3.com

(301) 628-3313

Study Officials

• Constance A Benson, MD

  University of California, San Diego

  STUDY CHAIR

• Umesh Lalloo, MD, FRCP

  Nelson R. Mandela School of Medicine

  STUDY CHAIR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: NETWORK
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: May 16, 2012
• First Posted: May 18, 2012
• Study Start: July 13, 2013
• Primary Completion: January 19, 2017
• Study Completion: June 28, 2017
• Last Updated: February 13, 2018
• Results First Posted: February 13, 2018

Record last verified: 2018-02

Locations

BR (2); PE (2); ZA (2); HA (2); KE (1)