Safety and Efficacy of High Dose Rifampicin in Tuberculosis (TB)-HIV Co-infected Patients on Efavirenz- or Dolutegravir-based Antiretroviral Therapy

NCT03982277 | Completed Phase 2 DMC

• 1 other identifier: ST/224/219
• Study Type: interventional
• Target: 130
• Locations: 1 country
• Sites: 1

Brief Summary

Higher doses of rifampicin has been associated with a faster drop in bacterial load over time, and shorter treatment regimens with high dose rifampicin are being proposed. Sub-therapeutic rifampicin concentrations are common in TB patients and have been demonstrated in several studies carried out among patients with tuberculosis receiving the standard dose (10mg/kg) of rifampicin. Insufficient exposure to isoniazid and rifampicin, which are the cornerstones of TB treatment, has been associated with drug resistance, treatment failure and delayed bacterial clearance from sputum. Evidence has indicated that the current dose of rifampicin (10mg/kg) is inadequate for many patients. Several studies have suggested that dose escalation (to 20-35mg/kg) is safe, and that higher doses (35mg/kg) may accelerate clearance of TB bacteria from the sputum of infected individuals and achievement of target concentrations.15,16 However, these studies have almost entirely been conducted among HIV negative TB patients, or TB-HIV co-infected patients without severe immunosuppression who are not yet receiving antiretroviral therapy (ART). TB-HIV co-infected patients on multiple additional drugs, including ART, are at increased risk of drug-drug interactions and drug related toxicities, including hepatotoxicity. Increasing the dose of rifampicin is a promising approach; however, there is paucity of data on the safety of higher doses of rifampicin in HIV infected patients on ART, and almost no information on the enzyme induction effect of high dose rifampicin on Efavirenz (EFV) and Dolutegravir (DTG). In this study, the investigators will not only evaluate for the enzyme induction effect of 35mg/kg of rifampicin on the most widely used first-line antiretrovirals, but will also look at the safety of these combinations in a population in which there is still scarce safety data. The aim of this study is to determine the safety of higher doses of rifampicin and its effect on the pharmacokinetics of efavirenz and dolutegravir in TB-HIV co-infected patients.

Conditions

Tuberculosis

Keywords

High dose rifampicin; TB/HIV co-infected persons; safety; pharmacokinetics; efficacy

Outcome Measures

Primary Outcomes (2)

• Measures of model predicted exposure/pharmacokinetic (PK) parameters

  Area under the concentration-time curve over 24 hours (AUC(0-24h)) of DTG, EFV and rifampicin, by rifampicin dose (10 vs. 35 mg/kg rifampicin)

  6 (+/-2) weeks from ART initiation

• Pharmacokinetics of high dose rifampicin on DTG and EFV

  Maximum concentrations (Cmax), trough concentrations) of DTG, EFV and rifampicin, by rifampicin dose (10 vs. 35 mg/kg rifampicin)

  6 (+/-2) weeks from ART initiation

Secondary Outcomes (2)

• Safety of high dose rifampicin

  up to 24 weeks

• Efficacy of high dose rifampicin

  8 weeks after TB treatment initiation

Study Arms (4)

High dose Rifampin + DTG

EXPERIMENTAL

High dose Rifampicin (35mg/kg ) and standard doses of Isoniazid + Ethambutol + Pyrazinamide Dolutegravir based ART regimen

Drug: Rifampin 300 Mg Oral Capsule

Standard dose Rifampin + DTG

NO INTERVENTION

Standard dose rifampicin (10mg/kg) and standard doses of Isoniazid + Ethambutol + Pyrazinamide Dolutegravir based ART regimen

High dose Rifampin + EFV

EXPERIMENTAL

High dose rifampicin (35mg/kg) and standard doses of Isoniazid + Ethambutol + Pyrazinamide Efavirenz based ART regimen

Drug: Rifampin 300 Mg Oral Capsule

Standard dose Rifampin + EFV

NO INTERVENTION

Standard dose rifampicin (10mg/kg) and standard doses of Isoniazid + Ethambutol + Pyrazinamide Efavirenz based ART regimen

Interventions

Rifampin 300 Mg Oral Capsule DRUG

High dose rifampicin at 35mg/kg

High dose Rifampin + DTG; High dose Rifampin + EFV

Eligibility Criteria

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

You may qualify if:

• Evidence of a personally signed and dated informed consent document.
• Willing and able to comply with scheduled visits, treatment plan, laboratory tests, and other study procedures.
• Age of ≥18 years
• Confirmed HIV-1 infection
• Already started on EFV-based or DTG-based ART or planned to start on ART
• Diagnosed with tuberculosis and due to initiate rifampicin-containing therapy

You may not qualify if:

• Rifampicin resistant TB identified by baseline Xpert Mycobacterium Tuberculous (MTB)/ Rifampicin (RIF)
• Pregnant women or women planning to get pregnant during TB treatment
• Women of reproductive age on DTG who decline the use of effective contraception methods (in particular: intrauterine device or condoms)
• Decompensated liver disease and/or aminotransferases \>5x upper limit of normal (ULN)
• Glomerular filtration rate \< 50 ml/min

Sponsors & Collaborators

• Makerere University: lead

Study Sites (1)

Infectious Diseases Institute

Kampala, 256, Uganda

Location

Related Publications (18)

• Milstein M, Lecca L, Peloquin C, Mitchison D, Seung K, Pagano M, Coleman D, Osso E, Coit J, Vargas Vasquez DE, Sanchez Garavito E, Calderon R, Contreras C, Davies G, Mitnick CD. Evaluation of high-dose rifampin in patients with new, smear-positive tuberculosis (HIRIF): study protocol for a randomized controlled trial. BMC Infect Dis. 2016 Aug 27;16(1):453. doi: 10.1186/s12879-016-1790-x.

  PMID: 27567500 BACKGROUND

• Diacon AH, Patientia RF, Venter A, van Helden PD, Smith PJ, McIlleron H, Maritz JS, Donald PR. Early bactericidal activity of high-dose rifampin in patients with pulmonary tuberculosis evidenced by positive sputum smears. Antimicrob Agents Chemother. 2007 Aug;51(8):2994-6. doi: 10.1128/AAC.01474-06. Epub 2007 May 21.

  PMID: 17517849 BACKGROUND

• Mitchison DA. Role of individual drugs in the chemotherapy of tuberculosis. Int J Tuberc Lung Dis. 2000 Sep;4(9):796-806.

  PMID: 10985648 BACKGROUND

• Boeree MJ, Heinrich N, Aarnoutse R, Diacon AH, Dawson R, Rehal S, Kibiki GS, Churchyard G, Sanne I, Ntinginya NE, Minja LT, Hunt RD, Charalambous S, Hanekom M, Semvua HH, Mpagama SG, Manyama C, Mtafya B, Reither K, Wallis RS, Venter A, Narunsky K, Mekota A, Henne S, Colbers A, van Balen GP, Gillespie SH, Phillips PPJ, Hoelscher M; PanACEA consortium. High-dose rifampicin, moxifloxacin, and SQ109 for treating tuberculosis: a multi-arm, multi-stage randomised controlled trial. Lancet Infect Dis. 2017 Jan;17(1):39-49. doi: 10.1016/S1473-3099(16)30274-2. Epub 2016 Oct 26.

  PMID: 28100438 BACKGROUND

• Sekaggya-Wiltshire C, von Braun A, Lamorde M, Ledergerber B, Buzibye A, Henning L, Musaazi J, Gutteck U, Denti P, de Kock M, Jetter A, Byakika-Kibwika P, Eberhard N, Matovu J, Joloba M, Muller D, Manabe YC, Kamya MR, Corti N, Kambugu A, Castelnuovo B, Fehr JS. Delayed Sputum Culture Conversion in Tuberculosis-Human Immunodeficiency Virus-Coinfected Patients With Low Isoniazid and Rifampicin Concentrations. Clin Infect Dis. 2018 Aug 16;67(5):708-716. doi: 10.1093/cid/ciy179.

  PMID: 29514175 BACKGROUND

• Park JS, Lee JY, Lee YJ, Kim SJ, Cho YJ, Yoon HI, Lee CT, Song J, Lee JH. Serum Levels of Antituberculosis Drugs and Their Effect on Tuberculosis Treatment Outcome. Antimicrob Agents Chemother. 2015 Oct 12;60(1):92-8. doi: 10.1128/AAC.00693-15. Print 2016 Jan.

  PMID: 26459901 BACKGROUND

• Burhan E, Ruesen C, Ruslami R, Ginanjar A, Mangunnegoro H, Ascobat P, Donders R, van Crevel R, Aarnoutse R. Isoniazid, rifampin, and pyrazinamide plasma concentrations in relation to treatment response in Indonesian pulmonary tuberculosis patients. Antimicrob Agents Chemother. 2013 Aug;57(8):3614-9. doi: 10.1128/AAC.02468-12. Epub 2013 May 20.

  PMID: 23689725 BACKGROUND

• Peloquin CA, Nitta AT, Burman WJ, Brudney KF, Miranda-Massari JR, McGuinness ME, Berning SE, Gerena GT. Low antituberculosis drug concentrations in patients with AIDS. Ann Pharmacother. 1996 Sep;30(9):919-25. doi: 10.1177/106002809603000901.

  PMID: 8876848 BACKGROUND

• Sekaggya-Wiltshire C, von Braun A, Scherrer AU, Manabe YC, Buzibye A, Muller D, Ledergerber B, Gutteck U, Corti N, Kambugu A, Byakika-Kibwika P, Lamorde M, Castelnuovo B, Fehr J, Kamya MR. Anti-TB drug concentrations and drug-associated toxicities among TB/HIV-coinfected patients. J Antimicrob Chemother. 2017 Apr 1;72(4):1172-1177. doi: 10.1093/jac/dkw534.

  PMID: 28108678 BACKGROUND

• Sloan D. Pharmacokinetic Variability in TB Therapy: Associations with HIV and Effect on Outcome. Paper presented at: Conference on Retroviruses and Opportunistic Infections2014.

  BACKGROUND

• Chang KC, Leung CC, Yew WW, Kam KM, Yip CW, Ma CH, Tam CM, Leung EC, Law WS, Leung WM. Peak plasma rifampicin level in tuberculosis patients with slow culture conversion. Eur J Clin Microbiol Infect Dis. 2008 Jun;27(6):467-72. doi: 10.1007/s10096-007-0454-6. Epub 2008 Jan 24.

  PMID: 18214560 BACKGROUND

• van Ingen J, Aarnoutse RE, Donald PR, Diacon AH, Dawson R, Plemper van Balen G, Gillespie SH, Boeree MJ. Why Do We Use 600 mg of Rifampicin in Tuberculosis Treatment? Clin Infect Dis. 2011 May;52(9):e194-9. doi: 10.1093/cid/cir184.

  PMID: 21467012 BACKGROUND

• Boeree MJ, Diacon AH, Dawson R, Narunsky K, du Bois J, Venter A, Phillips PP, Gillespie SH, McHugh TD, Hoelscher M, Heinrich N, Rehal S, van Soolingen D, van Ingen J, Magis-Escurra C, Burger D, Plemper van Balen G, Aarnoutse RE; PanACEA Consortium. A dose-ranging trial to optimize the dose of rifampin in the treatment of tuberculosis. Am J Respir Crit Care Med. 2015 May 1;191(9):1058-65. doi: 10.1164/rccm.201407-1264OC.

  PMID: 25654354 BACKGROUND

• Peloquin CA, Velasquez GE, Lecca L, Calderon RI, Coit J, Milstein M, Osso E, Jimenez J, Tintaya K, Sanchez Garavito E, Vargas Vasquez D, Mitnick CD, Davies G. Pharmacokinetic Evidence from the HIRIF Trial To Support Increased Doses of Rifampin for Tuberculosis. Antimicrob Agents Chemother. 2017 Jul 25;61(8):e00038-17. doi: 10.1128/AAC.00038-17. Print 2017 Aug.

  PMID: 28559269 BACKGROUND

• Schutz C, Ismail Z, Proxenos CJ, Marais S, Burton R, Kenyon C, Maartens G, Wilkinson RJ, Meintjes G. Burden of antituberculosis and antiretroviral drug-induced liver injury at a secondary hospital in South Africa. S Afr Med J. 2012 Mar 2;102(6):506-11. doi: 10.7196/samj.5650.

  PMID: 22668951 BACKGROUND

• Satyaraddi A, Velpandian T, Sharma SK, Vishnubhatla S, Sharma A, Sirohiwal A, Makharia GK, Sinha S, Biswas A, Singh S. Correlation of plasma anti-tuberculosis drug levels with subsequent development of hepatotoxicity. Int J Tuberc Lung Dis. 2014 Feb;18(2):188-95, i-iii. doi: 10.5588/ijtld.13.0128.

  PMID: 24429311 BACKGROUND

• Sekaggya-Wiltshire C, Nabisere R, Musaazi J, Otaalo B, Aber F, Alinaitwe L, Nampala J, Najjemba L, Buzibye A, Omali D, Gausi K, Kengo A, Lamorde M, Aarnoutse R, Denti P, Dooley KE, Sloan DJ. Decreased Dolutegravir and Efavirenz Concentrations With Preserved Virological Suppression in Patients With Tuberculosis and Human Immunodeficiency Virus Receiving High-Dose Rifampicin. Clin Infect Dis. 2023 Feb 8;76(3):e910-e919. doi: 10.1093/cid/ciac585.

  PMID: 35861296 DERIVED

• Nabisere R, Musaazi J, Denti P, Aber F, Lamorde M, Dooley KE, Aarnoutse R, Sloan DJ, Sekaggya-Wiltshire C. Pharmacokinetics, SAfety/tolerability, and EFficacy of high-dose RIFampicin in tuberculosis-HIV co-infected patients on efavirenz- or dolutegravir-based antiretroviral therapy: study protocol for an open-label, phase II clinical trial (SAEFRIF). Trials. 2020 Feb 13;21(1):181. doi: 10.1186/s13063-020-4132-7.

  PMID: 32054536 DERIVED

Related Links

• Published manuscript for results

MeSH Terms

Conditions

Tuberculosis

Interventions

Rifampin

Condition Hierarchy (Ancestors)

Mycobacterium Infections; Actinomycetales Infections; Gram-Positive Bacterial Infections; Bacterial Infections; Bacterial Infections and Mycoses; Infections

Intervention Hierarchy (Ancestors)

Rifamycins; Heterocyclic Compounds, 4 or More Rings; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds; Lactams, Macrocyclic; Macrocyclic Compounds; Polycyclic Compounds

Study Officials

• Christine Sekaggya-Wiltshire, MBChB, PhD

  Infectious Diseases Institute

  PRINCIPAL INVESTIGATOR

Study Design

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

Study Record Dates

• First Submitted: May 30, 2019
• First Posted: June 11, 2019
• Study Start: April 30, 2019
• Primary Completion: March 16, 2021
• Study Completion: July 23, 2021
• Last Updated: March 23, 2023

Record last verified: 2022-03

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP
• Time Frame: 6 months after publication of study results.
• Access Criteria: Direct request shall be made to Infectious Diseases Institute for pooling of data and met-analysis

Locations

UG (1)