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

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ClinicalTrials.gov Identifier: NCT03982277
Recruitment Status : Recruiting
First Posted : June 11, 2019
Last Update Posted : July 12, 2019
Sponsor:
Information provided by (Responsible Party):
Makerere University

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.

Condition or disease Intervention/treatment Phase
Tuberculosis Drug: Rifampin 300 Mg Oral Capsule Phase 2

Detailed Description:

The investigators will enroll 120 TB-HIV co-infected patients initiating TB treatment. Participants will be randomized to either high dose (35mg/kg) or standard dose (10mg/kg) rifampicin in addition to either dolutegravir (DTG) or efavirenz (EFV), for those who are antiretroviral therapy (ART) naïve. Patients who are already on ART will remain on their current ART regimen. The randomization groups (30 participants in each arm) include:Arm One A: R35mg/kg Isoniazid/Ethambutol/Pyrazinamide (HEZ) + DTG, Arm One B: R10mg/kg HEZ + DTG (Control 1), Arm Two A: R35mg/kg HEZ + EFV, Arm Two B: R10mg/kg HEZ + EFV (Control 2).

High dose rifampicin will be administered for the first 8 weeks (intensive phase) of TB treatment. All other anti-TB drugs will be administered at the standard dose using fixed-dose combinations (FDC). All participants will receive standard dose rifampicin during the continuation phase (weeks 9 -24). Pharmacokinetic (PK) blood sampling will be performed after 6 weeks (±2 weeks) of TB treatment. PK sampling will occur pre-dose and at 1, 2, 4 and 8 hours after observed dose for rifampicin and DTG concentrations and approximately 12-14 hours post-dose for EFV (to measure mid-dose interval (MDI) concentration). The EFV MDI and rifampicin pre-dose samples will be collected concurrently in the EFV arms. Safety laboratory tests including liver and renal function tests will be measured every two weeks or when patients present with symptoms suggestive of toxicity. In participants with culture positive TB at baseline, sputum cultures will be performed after 8 weeks of anti-TB treatment.

The investigators will use population pharmacokinetic modelling to determine the rifampicin and DTG exposure in each arm. Using these models the investigators will evaluate for drug-drug interactions between ART and the standard and high dose of rifampicin. Investigators will compare the mid-dose concentrations of EFV and trough concentrations of DTG in each intervention and control arm using Wilcoxon rank-sum test. The investigators will also compare the proportion of participants with grade 3 or 4 adverse events in each arm using the chi-squared test. Investigators will compare the proportion of participants who are sputum culture negative after 8 weeks of treatment among those in the high dose and standard dose arms using the chi-squared test.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 120 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Randomized, Four-arm Open Label Phase Two-b Clinical Trial to Evaluate the Pharmacokinetics, Safety/Tolerability and Efficacy of High Dose Rifampicin in TB-HIV Co-infected Patients on Efavirenz- or Dolutegravir-based Antiretroviral Therapy
Actual Study Start Date : April 30, 2019
Estimated Primary Completion Date : October 30, 2020
Estimated Study Completion Date : January 31, 2021

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: High dose Rifampin + DTG
High dose Rifampicin (35mg/kg ) and standard doses of Isoniazid + Ethambutol + Pyrazinamide Dolutegravir based ART regimen
Drug: Rifampin 300 Mg Oral Capsule
High dose rifampicin at 35mg/kg

No Intervention: Standard dose Rifampin + DTG
Standard dose rifampicin (10mg/kg) and standard doses of Isoniazid + Ethambutol + Pyrazinamide Dolutegravir based ART regimen
Experimental: High dose Rifampin + EFV
High dose rifampicin (35mg/kg) and standard doses of Isoniazid + Ethambutol + Pyrazinamide Efavirenz based ART regimen
Drug: Rifampin 300 Mg Oral Capsule
High dose rifampicin at 35mg/kg

No Intervention: Standard dose Rifampin + EFV
Standard dose rifampicin (10mg/kg) and standard doses of Isoniazid + Ethambutol + Pyrazinamide Efavirenz based ART regimen



Primary Outcome Measures :
  1. Measures of model predicted exposure/pharmacokinetic (PK) parameters [ Time Frame: 6 (+/-2) weeks from ART initiation ]
    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)

  2. Pharmacokinetics of high dose rifampicin on DTG and EFV [ Time Frame: 6 (+/-2) weeks from ART initiation ]
    Maximum concentrations (Cmax), trough concentrations) of DTG, EFV and rifampicin, by rifampicin dose (10 vs. 35 mg/kg rifampicin)


Secondary Outcome Measures :
  1. Safety of high dose rifampicin [ Time Frame: up to 24 weeks ]
    Grade 3 or 4 laboratory or clinical adverse events, according to the National Institutes of Health Division of AIDS toxicity tables (DAIDS).

  2. Efficacy of high dose rifampicin [ Time Frame: 8 weeks after TB treatment initiation ]
    Negative sputum cultures



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • 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

Exclusion Criteria:

  • 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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03982277


Contacts
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Contact: Christine Sekaggya-Wiltshire, MBChB, PhD 256312307000 csekaggya@idi.co.ug

Locations
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Uganda
Infectious Diseases Institute Recruiting
Kampala, Uganda, 256
Contact: Christine Sekaggya-Wiltshire, MBChB, PhD       csekaggya@idi.co.ug   
Principal Investigator: Christine Sekaggya-Wiltshire, MBChB, PhD         
Sponsors and Collaborators
Makerere University
Investigators
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Principal Investigator: Christine Sekaggya-Wiltshire, MBChB, PhD Infectious Diseases Institute

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

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
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Responsible Party: Makerere University
ClinicalTrials.gov Identifier: NCT03982277    
Other Study ID Numbers: ST/224/219
First Posted: June 11, 2019    Key Record Dates
Last Update Posted: July 12, 2019
Last Verified: July 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: Individual patient data (IPD) will made available to other researchers for further analysis or met-analysis following direct request to the sponsor (Infectious Diseases Institute).
Supporting Materials: Study Protocol
Statistical Analysis Plan (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

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Makerere University:
High dose rifampicin
TB/HIV co-infected persons
safety
pharmacokinetics
efficacy
Additional relevant MeSH terms:
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Tuberculosis
Mycobacterium Infections
Actinomycetales Infections
Gram-Positive Bacterial Infections
Bacterial Infections
Efavirenz
Dolutegravir
Rifampin
Anti-Retroviral Agents
Antiviral Agents
Anti-Infective Agents
Reverse Transcriptase Inhibitors
Nucleic Acid Synthesis Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Cytochrome P-450 CYP2C9 Inhibitors
Cytochrome P-450 Enzyme Inhibitors
Cytochrome P-450 CYP2C19 Inhibitors
Cytochrome P-450 CYP2B6 Inducers
Cytochrome P-450 Enzyme Inducers
Cytochrome P-450 CYP3A Inducers
Antibiotics, Antitubercular
Antitubercular Agents
Anti-Bacterial Agents
Leprostatic Agents
Cytochrome P-450 CYP2C8 Inducers
Cytochrome P-450 CYP2C19 Inducers
Cytochrome P-450 CYP2C9 Inducers
HIV Integrase Inhibitors
Integrase Inhibitors