Multidrug-resistant TuberculosisPhase 3Tri-Do-ReNCT04260477
Novel Triple-dose Tuberculosis Retreatment Regimen
A Phase 3 study testing 6EH³R³Z and 6EHRZ in people with Multidrug-resistant Tuberculosis and Pulmonary Tuberculosis, run by Institute of Tropical Medicine, Belgium at 1 site in Niger.
Trial 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). Read more about this study
- Who is it for?
- Any age
- Conditions the study is for
- Multidrug-resistant Tuberculosis, Pulmonary Tuberculosis, Tuberculosis
- What is being tested?
- 6EH³R³Z and 6EHRZ
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 370 participants
- Where
- 1 siteNiger
- Study dates
- 1 Mar 2021to Sep 2025
- Phase
- Phase 3
- Are there results?
- Not yet: the study is under way
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages Any age
- All sexes
- No healthy volunteers
- Child, Adult, Older adult
Who may be able to join
- 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
Who cannot join
- 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 locations and contacts
1 site in 1 country. Contact the study team or a site near you to ask about taking part.
Niger1 site, 1 recruiting
- Recruiting
Damien Foundation
Niamey
Bassirou Souleymane, +227 94985157, bachirsoul@gmail.com
Sani Kadri
About this study
Official title: Novel Triple-dose Tuberculosis Retreatment Regimen: How to Overcome Resistance Without Creating More in Niger
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).
Read the 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.
- Conditions
- Multidrug-resistant Tuberculosis, Pulmonary Tuberculosis, Tuberculosis, Resistance to Tuberculostatic Drugs
- Being tested
- 6EH³R³Z, 6EHRZ
- Keywords
- rifampicin-susceptible-TB, Tuberculosis, first-line, TB relapse, TB treatment failure, high dose retreatment
- Medical subject headings
- Tuberculosis, Multidrug-Resistant, Tuberculosis, Pulmonary, Tuberculosis
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
6EH³R³ZDrug
Also called Ethambutol; isoniazid; rifampicin; pyrazinamide, triple dose isoniazid, triple dose rifampicin
A triple dose is defined as the triple of the routine dose used for a specific WHO weight band. Hence, the mg/kg within a weigh-band varies, as is the case in routine practice.
Dosing takings into consideration the fixed dose combination (FDC) tablets (one tablet: 150 mg R + 75 mg H + 400 mg Z + 275mg E). Dosage relies on tables with dosage by weight-bands used by WHO for the Cat. 1 regimen. The dosage used for the intensive phase of the Cat. 1 regimen applies for the whole treatment duration. A double dose of H and R is added to the recommended normal dose for adults (WHO,2003)
6EHRZDrug
Also called Ethambutol; isoniazid; rifampicin; pyrazinamide
Recommended normal dose adults (WHO, 2003)
- H: 5 (4-6) mg/kg/day
- R: 10 (8-12) mg/kg/day
- Z: 25 (20-30)mg/kg/day
- E: 15 (15-18)mg/kg/day
| Study group | Role | What they receive |
|---|---|---|
| 6EH³R3Z | Experimental | (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). Receives: Drug: 6EH³R³Z |
| 6EHRZ | Active comparator | Standard of care: 6-month 6RHZE regimen with dose combination tablets (one tablet: 150 mg R + 75 mg H + 400 mg Z + 275mg E) Receives: Drug: 6EHRZ |
What is being measured
The primary outcome is the main question the study is designed to answer.
STAGE 1:number of patients with any grade 3-5 Adverse Event (AE) during treatment, assessed as probably or definitely related to TB treatment
Measured: 18 months
STAGE 2: Describe bacterial effectiveness
for stage 2 participants of the trial
Measured: 18 months
STAGE 2: Describe acquired resistance
for stage 2 participants of the trial
Measured: 18 months
Secondary outcomes (17)
STAGE 1: number of previously treated patients with H-monoresistance and H-polyresistance, rifampicin (RMP) resistance missed by Xpert Mycobacterium tuberculosis (MTB)/rifampicin (RIF)
frequency of initial resistance patterns and mutations conferring resistance
Measured: 18 months
STAGE 1: Programmatical effectiveness:number of participants with treatment success divided by number of participants with failure, death, or Lost to follow-up (LTFU)
6 months treatment success: A patient with smear-positive Pulmonary Tuberculosis (PTB) at the beginning of treatment who completed treatment and sputum smear microscopy (SSM) negative in the last month of treatment and on at least one previous occasion or culture-negative at 6 months. A patient with smear-positive PTB at the beginning of treatment who completed treatment without clinical evidence of failure but with no record of sputum smear or culture results in the last month of treatment (either because tests were not done or because results are unavailable) 18 months treatment success: Those who were cured or completed treatment and were evaluated at 12 months post-treatment to be a) SSM negative , or b) SSM positive but culture (CU) negative, or c) without sputum and no clinical signs of TB.
Measured: 6 months, 18 months
STAGE 1: Clinical effectiveness: number of participants with treatment success, divided by number of participants with failure or death
6 months treatment success: A patient with smear-positive PTB at the beginning of treatment who completed treatment and SSM negative in the last month of treatment and on at least one previous occasion or culture-negative at 6 months. A patient with smear-positive PTB at the beginning of treatment who completed treatment without clinical evidence of failure but with no record of sputum smear or culture results in the last month of treatment (either because tests were not done or because results are unavailable) 18 months treatment success: Those who were cured or completed treatment and were evaluated at 12 months post-treatment to be a) SSM negative , or b) SSM positive but CU negative, or c) without sputum and no clinical signs of TB.
Measured: 6 months, 18 months
STAGE 1:Bacteriological effectiveness : number of participants with treatment success, divided by number of participants with failure
6 months treatment success: A patient with smear-positive PTB at the beginning of treatment who completed treatment and SSM negative in the last month of treatment and on at least one previous occasion or culture-negative at 6 months. A patient with smear-positive PTB at the beginning of treatment who completed treatment without clinical evidence of failure but with no record of sputum smear or culture results in the last month of treatment (either because tests were not done or because results are unavailable) 18 months treatment success: Those who were cured or completed treatment and were evaluated at 12 months post-treatment to be a) SSM negative , or b) SSM positive but CU negative, or c) without sputum and no clinical signs of TB.
Measured: 6 months, 18 months
STAGE 2:Bacteriological effectiveness : number of participants with treatment success, divided by number of participants with failure
6 months treatment success: A patient with smear-positive PTB at the beginning of treatment who completed treatment and SSM negative in the last month of treatment and on at least one previous occasion or culture-negative at 6 months. A patient with smear-positive PTB at the beginning of treatment who completed treatment without clinical evidence of failure but with no record of sputum smear or culture results in the last month of treatment (either because tests were not done or because results are unavailable) 18 months treatment success: Those who were cured or completed treatment and were evaluated at 12 months post-treatment to be a) SSM negative , or b) SSM positive but CU negative, or c) without sputum and no clinical signs of TB.
Measured: 6 months, 18 months
STAGE 2: number of participants with acquired resistance, to Isoniazid (INH) and/or RMP
In patients with recurrence, the recurrent strain will be compared with the diagnostic strain to identify possible differences in the resistance pattern. If the strain is the same, and resistance is not present in the diagnostic sample but is identified in the recurrence sample, then this resistance is considered as acquired. Resistance is defined as a) on genotypic Drug susceptibility testing (DST) (Deeplex or other): presence of a mutation in the resistance determining region for the drug with exception of generally recognized polymorphisms and silent mutations not leading to an error in the gene product. Heteroresistance at the proportion detectable by these methods will be considered at par with full-blown resistance, or b) growth at the critical concentration for the drug tested in phenotypic DST.
Measured: 6 months, 18 months
number of participants with stable (without reversion) SSM conversion
conversion to 0 AFB per field, without subsequent treatment failure
Measured: 2 months
STAGE 1: number of participants with drug-induced hepatotoxicity
hepatotoxicity due to anti-TB drug treatment was defined as the following criteria:
- Grade 3-5 elevation of Liver function test (LFT), or grade 2 elevation of liver function tests with jaundice; AND
- absence of serological evidence of infection with hepatitis B or C, AND
- normalization or at least a 50% improvement in abnormal liver chemistry results after withdrawal of anti-TB drugs
Measured: 18 months
STAGE 1:number of participants with any TB treatment change due to drug-induced hepatoxicity
Measured: 18 months
STAGE 1:number of participants with any TB treatment change due to AE
Measured: 18 months
STAGE 1:number of participants with any grade 3-5 AE
Measured: 18 months
STAGE 1:number of participants with any Serious Adverse Event (SAE)
Measured: 18 months
STAGE 2: number of participants with drug-induced hepatotoxicity
hepatotoxicity due to anti-TB drug treatment was defined as the following criteria:
- Grade 3-5 elevation of Liver function test (LFT), or grade 2 elevation of liver function tests with jaundice; AND
- absence of serological evidence of infection with hepatitis B or C, AND
- normalization or at least a 50% improvement in abnormal liver chemistry results after withdrawal of anti-TB drugs
Measured: 18 months
STAGE 2:number of participants with any TB treatment change due to drug-induced hepatoxicity
Measured: 18 months
STAGE 2:number of participants with any TB treatment change due to AE
Measured: 18 months
STAGE 2:number of participants with any grade 3-5 AE
Measured: 18 months
STAGE 2:number of participants with any Serious Adverse Event (SAE)
Measured: 18 months
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted7 Feb 2020
- Study start1 Mar 2021
- Primary completionJun 2025 (estimated)
- Study completionSep 2025 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Multidrug-resistant TuberculosisStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 3
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Enrolment
- 370 participants (estimated)
Sponsor and investigators
- Lead sponsor
- Institute of Tropical Medicine, Belgium
- Sponsor type
- University, hospital or other
- Collaborators
- Damien Foundation
- Responsible party
- Sponsor
- Investigators
- Sani Kadri, Principal investigator, Ministry of Health, Niger
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT04260477
- Sponsor's protocol ID
- ITM202001
- Acronym
- Tri-Do-Re
- Status last verified
- Apr 2025
- First submitted
- 3 Feb 2020
- Last updated
- 13 Apr 2025
- Results posted
- No
- Data monitoring committee
- Yes
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- No
Study at a glance
From the registry record, last updated by the sponsor on 13 Apr 2025. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Novel Triple-dose Tuberculosis Retreatment Regimen: How to Overcome Resistance Without Creating More in Niger
- ClinicalTrials.gov ID
- NCT04260477
- Acronym / sponsor ID
- Tri-Do-Re / ITM202001
- 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
- Phase
- Phase 3
- Study type
- Interventional
- Recruitment status
- Recruiting
- Enrolment
- 370 participants (estimated)
- Lead sponsor
- Institute of Tropical Medicine, BelgiumUniversity, hospital or other
- Collaborators
- Damien Foundation
- Study start
- 1 Mar 2021 (actual)
- Primary completion
- Jun 2025 (estimated)
- Study completion
- Sep 2025 (estimated)
- First posted
- 7 Feb 2020 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| 6EH³R3Z | Experimental | Drug: 6EH³R³Z(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). |
| 6EHRZ | Active comparator | Drug: 6EHRZStandard of care: 6-month 6RHZE regimen with dose combination tablets (one tablet: 150 mg R + 75 mg H + 400 mg Z + 275mg E) |
Who may qualify
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Child, Adult, Older adult
Key inclusion criteria (4 listed)
- 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
Key exclusion criteria (6 listed)
- 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
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| 6EH³R³ZAlso: Ethambutol; isoniazid; rifampicin; pyrazinamide, triple dose isoniazid, triple dose rifampicinA triple dose is defined as the triple of the routine dose used for a specific WHO weight band. Hence, the mg/kg within a weigh-band varies, as is the case in routine practice. Dosing takings into consideration the fixed dose combination (FDC) tablets (one tablet: 150 mg R + 75 mg H + 400 mg Z + 275mg E). Dosage relies on tables with dosage by weight-bands used by WHO for the Cat. 1 regimen. The dosage used for the intensive phase of the Cat. 1 regimen applies for the whole treatment duration. A double dose of H and R is added to the recommended normal dose for adults (WHO,2003) | Drug | 6EH³R3Z |
| 6EHRZAlso: Ethambutol; isoniazid; rifampicin; pyrazinamideRecommended normal dose adults (WHO, 2003) * H: 5 (4-6) mg/kg/day * R: 10 (8-12) mg/kg/day * Z: 25 (20-30)mg/kg/day * E: 15 (15-18)mg/kg/day | Drug | 6EHRZ |
Primary outcome
STAGE 1:number of patients with any grade 3-5 Adverse Event (AE) during treatment, assessed as probably or definitely related to TB treatment
Time frame: 18 months
STAGE 2: Describe bacterial effectiveness
Time frame: 18 months
for stage 2 participants of the trial
STAGE 2: Describe acquired resistance
Time frame: 18 months
for stage 2 participants of the trial
17 secondary outcomes
STAGE 1: number of previously treated patients with H-monoresistance and H-polyresistance, rifampicin (RMP) resistance missed by Xpert Mycobacterium tuberculosis (MTB)/rifampicin (RIF)
Time frame: 18 months
STAGE 1: Programmatical effectiveness:number of participants with treatment success divided by number of participants with failure, death, or Lost to follow-up (LTFU)
Time frame: 6 months, 18 months
STAGE 1: Clinical effectiveness: number of participants with treatment success, divided by number of participants with failure or death
Time frame: 6 months, 18 months
STAGE 1:Bacteriological effectiveness : number of participants with treatment success, divided by number of participants with failure
Time frame: 6 months, 18 months
STAGE 2:Bacteriological effectiveness : number of participants with treatment success, divided by number of participants with failure
Time frame: 6 months, 18 months
STAGE 2: number of participants with acquired resistance, to Isoniazid (INH) and/or RMP
Time frame: 6 months, 18 months
number of participants with stable (without reversion) SSM conversion
Time frame: 2 months
STAGE 1: number of participants with drug-induced hepatotoxicity
Time frame: 18 months
STAGE 1:number of participants with any TB treatment change due to drug-induced hepatoxicity
Time frame: 18 months
STAGE 1:number of participants with any TB treatment change due to AE
Time frame: 18 months
STAGE 1:number of participants with any grade 3-5 AE
Time frame: 18 months
STAGE 1:number of participants with any Serious Adverse Event (SAE)
Time frame: 18 months
STAGE 2: number of participants with drug-induced hepatotoxicity
Time frame: 18 months
STAGE 2:number of participants with any TB treatment change due to drug-induced hepatoxicity
Time frame: 18 months
STAGE 2:number of participants with any TB treatment change due to AE
Time frame: 18 months
STAGE 2:number of participants with any grade 3-5 AE
Time frame: 18 months
STAGE 2:number of participants with any Serious Adverse Event (SAE)
Time frame: 18 months
Results and safety
This study is still under way. Results are not available in the source record yet.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 13 Apr 2025.
- Individual participant dataSharing planned: No
Related trials for Multidrug-resistant Tuberculosis
RecruitingObservational study
Training Protocol on the Natural History of Tuberculosis
Mycobacterium Infections, Tuberculosis, Multidrug-Resistant
RecruitingPhase 3
A Study of Quabodepistat-containing Regimens for the Treatment of Drug-resistant Pulmonary Tuberculosis
Rifampicin-Resistant Pulmonary Tuberculosis, Multidrug-Resistant Pulmonary Tuberculosis
Recruiting
Bring BPaL2Me Trial Comparing Nurse-Led RR-TB Treatment to Physician-Led RR-TB Treatment
Drug Resistant Tuberculosis
RecruitingObservational study
Bioneer Q-RFIA Clinical Evaluation
Tuberculosis, Multidrug-Resistant
RecruitingPhase 3
Feasibility of the Application of a New Six-month Treatment for Multidrug-resistant Tuberculosis (MDR-TB) Patients in France (FAST-MDR)
MDR-TB, Tuberculosis Multi Drug Resistant Active
Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part.
Sani Kadri principal investigator
Ministry of Health, Niger
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 3 study testing 6EH³R³Z and 6EHRZ in people with Multidrug-resistant Tuberculosis and Pulmonary Tuberculosis, run by Institute of Tropical Medicine, Belgium at 1 site in Niger.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 4 inclusion and 6 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: looking for participants now, as of the sponsor's last update on 13 Apr 2025. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in Niger. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
This study is still under way. Results are not available in the source record yet.
How can a doctor refer a patient or contact the research team?
Contact Natacha Herssens, MSc (003232470778, nherssens@itg.be), or a site near the patient. AzTrials does not enrol participants or take referrals.
What does the primary outcome 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 (time frame: 18 months). The study lists 3 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 13 Apr 2025.