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

March 21, 2023 updated by: Makerere University

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

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.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

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.

Study Type

Interventional

Enrollment (Actual)

130

Phase

  • Phase 2

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

  • Name: Christine Sekaggya-Wiltshire, MBChB, PhD
  • Phone Number: 256312307000
  • Email: csekaggya@idi.co.ug

Study Locations

  • Uganda
      • Kampala, Uganda, 256
        • Infectious Diseases Institute

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

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

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / 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

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
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)
6 (+/-2) weeks from ART initiation
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)
6 (+/-2) weeks from ART initiation

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
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).
up to 24 weeks
Efficacy of high dose rifampicin
Time Frame: 8 weeks after TB treatment initiation
Negative sputum cultures
8 weeks after TB treatment initiation

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Makerere University

Investigators

  • Principal Investigator: Christine Sekaggya-Wiltshire, MBChB, PhD, Infectious Diseases Institute

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Helpful Links

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

April 30, 2019

Primary Completion (Actual)

March 16, 2021

Study Completion (Actual)

July 23, 2021

Study Registration Dates

First Submitted

May 30, 2019

First Submitted That Met QC Criteria

June 10, 2019

First Posted (Actual)

June 11, 2019

Study Record Updates

Last Update Posted (Actual)

March 23, 2023

Last Update Submitted That Met QC Criteria

March 21, 2023

Last Verified

March 1, 2022

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • ST/224/219

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

YES

IPD 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).

IPD Sharing Time Frame

6 months after publication of study results.

IPD Sharing Access Criteria

Direct request shall be made to Infectious Diseases Institute for pooling of data and met-analysis

IPD Sharing Supporting Information Type

  • STUDY_PROTOCOL
  • SAP

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

Clinical Trials on Tuberculosis

Clinical Trials on Rifampin 300 Mg Oral Capsule

Search Similar Trials

Sponsors and Collaborators

Medical Conditions

Drug Interventions

CROs by country

CROs in Brazil

Conditions

Rare Diseases

Drug Interventions

Dietary Supplements

Sponsor/Collaborators

Locations

3
Subscribe