Novel Triple-dose Tuberculosis Retreatment Regimen (Tri-Do-Re)

Institute of Tropical Medicine, Belgium

Status and phase: Enrolling; Phase 3

Conditions: Tuberculosis; Pulmonary Tuberculosis; Resistance to Tuberculostatic Drugs; Multidrug-resistant Tuberculosis

Treatments: Drug: 6EHRZ; Drug: 6EH³R³Z

Study type: Interventional

Funder types: Other

Identifiers

NCT04260477

ITM202001

Details and patient eligibility

About

To determine if a high-dose first-line regimen is non-inferior (non-inferiority margin 10%) in terms of safety to the same regimen at regular dosing, in previously treated patients with rifampicin-susceptible recurrent Tuberculosis (TB).

Full description

Stage 1: This is a pragmatic open-label multi-stage randomized clinical trial. Potential participants will be screened and enrolled in Damien Foundation (DF) clinics participating in the trial.

First we will perform a two-arm study with 6EHRZ as control arm and 6EH³R³Z as intervention arm. If at interim analysis the intervention arm is not considered to be non-inferior to the control arm, the intervention stops and enrolment will continue in a an adapted intervention arm and the control arm (6EHRZ). Otherwise, enrolment continues to 6EHRZ and 6EH³R³Z.

Observational study (stage 2): The DSMB members agreed due to safety concerns to continuing the study as a cohort with only the control arm. The control regimen will remain the same (6EHRZ).

As per routine practice, during treatment patients are in daily contact with the direct observed therapy (DOT) supervisor and minimally monthly clinic visits are scheduled for monitoring of safety and treatment response.

Additionally, liver function tests will be performed at fixed intervals during treatment. Six month and one year after treatment completion or cure the patient will be checked for relapse with systematic sputum acid-fast bacilli (AFB)-microscopy and TB culture.

Enrollment: 370 estimated patients

Sex: All

Volunteers: No Healthy Volunteers

Inclusion criteria

• All newly registered patients with smear-positive recurrent pulmonary TB
• Adults as well as children (no age limit)
• Able and willing to provide written informed consent
• Added for stage 2: lives within 5 km of a health facility with a medical doctor

Exclusion criteria

• All patients with TB initially resistant to rifampicin on Xpert MTB/RIF testing
• Patients transferred to a health facility not supported by the Damien Foundation
• Patients previously enrolled in the trial, and with another episode of rifampicin-susceptible TB during the study period
• Those with grade III elevation of liver function tests at baseline, or with clinically active liver disease at screening
• Pregnant or breastfeeding woman
• HIV co-infected patients requiring treatment with a protease inhibitor

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: None (Open label)

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370 participants in 2 patient groups

6EH³R3Z

Experimental group

Description:

(Rifampicin (R)/ Isoniazid (H) / Pyrazinamide (Z)/Ethambutol (E)) 6-month high-dose treatment; New high-dose isoniazid / high-dose rifampicin retreatment regimen (6EH³R3Z) - that includes triple-dose rifampicin (R3; 30 mg/kg), and triple-dose isoniazid (H3; 15 mg/kg), complemented with pyrazinamide (Z) and ethambutol (E).

Treatment:

Drug: 6EH³R³Z

6EHRZ

Active Comparator group

Description:

Standard of care: 6-month 6RHZE regimen with dose combination tablets (one tablet: 150 mg R + 75 mg H + 400 mg Z + 275mg E)

Treatment:

Drug: 6EHRZ