Optimization of the TB Treatment Regimen Cascade

Study Overview
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Brief Summary
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- Hypothesis: Double dose rifampicin together with earlier monitoring of sputum conversion using vital staining reduces unfavorable outcome of Cat. 1 first-line TB treatment without excess serious toxicity, and allows early switch to specific treatment of MDR-TB without using Cat. 2 retreatment regimen - General study design: This open label, randomised clinical trial is intended as a pilot study on the efficacy and safety of high-dose rifampicin and feasibility and added value of auramine and/or FDA vital staining sputum smear after 2 weeks of intensive treatment phase. If this proof-of-concept study provides substantial indication of benefit without indication of excess toxicity, the data from the study will be used to design a larger scale, cluster-randomized study. The aim of this cluster randomised study would be to provide definite proof of the benefit of the intervention on adverse treatment outcomes and lack of excess toxicity associated with high dose rifampicin. In addition, the cluster-randomized study would provide a more precise assessment of the suppression and prevention of (acquired) resistance endpoints. An interim analysis is thus planned at the time the last recruited patient finishes treatment, i.e. about 9 months after the end of recruitment. It will focus on assessment of drug toxicity versus suggested benefits of the intervention. This analysis will be primarily performed for the go/no-go decision and design considerations for the cluster-randomized trial. The decision on proceeding to the cluster randomized study will be based on the absence of excess toxicity, a trend toward a reduction of unfavourable outcomes (excluding relapse), and possible favourable effects on initially present low-resistance mutations / mutations acquired during treatment. It will also allow to adapt the design of the larger study particularly regarding the algorithm for resistance screening, and whether or not treatment shortening could be justified with rapid initial conversion.

Official Title
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Optimization of the TB Treatment Regimen Cascade

Conditions
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Tuberculosis, Pulmonary

Intervention / Treatment
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* Drug: double rimfampicin
* Drug: Standard TB treatment


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Diagnosed with smear-positive pulmonary TB 15 years or older Able and willing to provide written informed consent Exclusion Criteria: contacts of MDR-TB patients and other MDR-TB suspects diagnosed with resistance on rapid DST for rifampicin performed prior to start of treatment according to NTP guidelines smear-negative pulmonary and extra-pulmonary TB cases patients in need of hospitalization because of very bad general condition or complications patients with clinically active liver disease, for the study defined as jaundice confirmed by a local Medical Officer (Government) any known HIV-positive patient (although none are expected) any patient with known hepatitis B or C infection pregnant women; in addition, patients in the intervention arm who become pregnant during treatment will be switched to the control arm

Ages Eligible for Study
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Minimum Age: 15 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Standard TB treatment<br>Standard regimen for TB treatment according to guidelines of the International Union against Tuberculosis and Lung Disease | Drug: Standard TB treatment<br>* Standard regimen for TB treatment according to guidelines of the International Union against Tuberculosis and Lung Disease<br>* Other names: Control arm;|
| Experimental: double rimfampicin<br>2HREZ/4HR Cat. 1, modified by using double dose rifampicin throughout | Drug: double rimfampicin<br>* Compared to standard regimen dosing of rifampicin is doubled, while standard dose isoniazid, pyrazinamide and ethambutol are maintained<br>* Other names: Intervention arm;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Tuberculose Treatment Outcome | Following current WHO guidelines, an adverse treatment outcome is defined as any occurrence of the following: Relapse: Cured previously from TB or completed treatment for TB and now having bacteriologically positive sputum for TB (at 12 months follow-up or at an earlier time point) Default: The patient whose treatment was interrupted for ≥ 2 consecutive months. Failure: Sputum positive for TB at 5 months or later during treatment. In line with current WHO recommendations, patients detected with MDR-TB or rifampicin resistance before this or another outcome applies and switched to the MDR-TB regimen will be excluded from the outcome analysis.18 Failure will also be declared if the regimen has to be changed for at least 2 drugs due to adverse events. Death: All-cause mortality between case registration and end of TB treatment (related or not to TB or TB treatment) | 12 months after end of treatment | 
| Number of Participants Who Develop Liver Toxicity | Grade 3-4 Liver Toxicity following NIH common toxicity criteria (CTC), including transaminase increases to >5-20 ULN (grade 3), or > 20 ULN (grade 4) | until month eight | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| High-level Rifampicin Resistant TB Adverse Treatment Outcomes | To assess whether the study regimen also cures high-level rifampicin resistant TB. Adverse treatment outcomes will be described and compared among treatment groups in subgroups defined by initial rifampicin resistance mutations (performed in all patients) detected. | 12 months after end of TB treatment | 
| Number of Initial Resistant TB Cases Who Switched to MDR-TB Treatment or Were Cured | To assess the effectiveness of FDA vital staining versus fever screening for early switch of non-responding rifampicin resistant TB to MDR-TB treatment | at two weeks of treatment | 
| the Negative Predictive Value of Conversion at 2 Weeks for Relapse. | The Negative Predictive value (and 95% CI) of conversion in the intervention arm will be estimated as the % of relapses among those with a minimum 1 log decline in the number of AFB, or who are already negative or only scanty positive on AFB smear (auramine or FDA). | at 2 weeks of treatment | 
| Proportion of Acquired Rifampicin Resistance Among Failures and Relapses | number of failure / relapse cases without mutation detected at diagnosis as the denominator and comparing intervention and control arms. | 12 months after end of TB treatment | 
| Area Under the Curve of Auramine Resp. FDA at 2 Weeks to Predict Adverse Treatment Outcome at 1 Year After Treatment Completion | Area under the ROC curve (AUC) to predict adverse treatment outcome. The X-axis represents the 1-specificity, the Y-axis represents sensitivity. The AUC is estimated with 95% confidence interval. | Auramine/FDA at 2 weeks and adverse treatment outcome 1 year after treatment completion | 
| Weight Gain | Weight gain from baseline until end-of-treatment comparison between both treatment arms. | until end of treatment (month eight) | 
| Fever Resolution | Comparison of fever resolution after 2 weeks of treatment between both treatment arms. | after 2 weeks of treatment | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Bangladesh, Rimfapicin