Clinical trial NCT04260477: Novel Triple-dose Tuberculosis Retreatment Regimen
Official title: Novel Triple-dose Tuberculosis Retreatment Regimen: How to Overcome Resistance Without Creating More in Niger
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE3
Conditions: Multidrug-resistant Tuberculosis
Pulmonary Tuberculosis
Tuberculosis
Resistance to Tuberculostatic Drugs
Keywords: rifampicin-susceptible-TB
Tuberculosis
first-line
TB relapse
TB treatment failure
high dose retreatment
Lead sponsor: Institute of Tropical Medicine, Belgium
Sponsor class: OTHER
Collaborators: name: Damien Foundation
First posted: 2020-02-07
Enrollment: 370
Sex: ALL
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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).

Detailed 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.

Eligibility criteria: 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

Primary outcomes:
measure: STAGE 1:number of patients with any grade 3-5 Adverse Event (AE) during treatment, assessed as probably or definitely related to TB treatment
timeFrame: 18 months
measure: STAGE 2: Describe bacterial effectiveness
timeFrame: 18 months
measure: STAGE 2: Describe acquired resistance
timeFrame: 18 months
Secondary outcomes:
measure: STAGE 1: number of previously treated patients with H-monoresistance and H-polyresistance, rifampicin (RMP) resistance missed by Xpert Mycobacterium tuberculosis (MTB)/rifampicin (RIF)
timeFrame: 18 months
measure: STAGE 1: Programmatical effectiveness:number of participants with treatment success divided by number of participants with failure, death, or Lost to follow-up (LTFU)
timeFrame: 6 months, 18 months
measure: STAGE 1: Clinical effectiveness: number of participants with treatment success, divided by number of participants with failure or death
timeFrame: 6 months, 18 months
measure: STAGE 1:Bacteriological effectiveness : number of participants with treatment success, divided by number of participants with failure
timeFrame: 6 months, 18 months
measure: STAGE 2:Bacteriological effectiveness : number of participants with treatment success, divided by number of participants with failure
timeFrame: 6 months, 18 months
measure: STAGE 2: number of participants with acquired resistance, to Isoniazid (INH) and/or RMP
timeFrame: 6 months, 18 months
measure: number of participants with stable (without reversion) SSM conversion
timeFrame: 2 months
measure: STAGE 1: number of participants with drug-induced hepatotoxicity
timeFrame: 18 months
measure: STAGE 1:number of participants with any TB treatment change due to drug-induced hepatoxicity
timeFrame: 18 months
measure: STAGE 1:number of participants with any TB treatment change due to AE
timeFrame: 18 months
measure: STAGE 1:number of participants with any grade 3-5 AE
timeFrame: 18 months
measure: STAGE 1:number of participants with any Serious Adverse Event (SAE)
timeFrame: 18 months
measure: STAGE 2: number of participants with drug-induced hepatotoxicity
timeFrame: 18 months
measure: STAGE 2:number of participants with any TB treatment change due to drug-induced hepatoxicity
timeFrame: 18 months
measure: STAGE 2:number of participants with any TB treatment change due to AE
timeFrame: 18 months
measure: STAGE 2:number of participants with any grade 3-5 AE
timeFrame: 18 months
measure: STAGE 2:number of participants with any Serious Adverse Event (SAE)
timeFrame: 18 months
Other outcomes:
Locations:
city: Niamey
country: Niger
facility: Damien Foundation
Study officials:
affiliation: Ministry of Health, Niger
name: Sani Kadri
role: PRINCIPAL_INVESTIGATOR
References: