Optimization of the TB Treatment Regimen Cascade

Phase 3

Completed

Conditions: Tuberculosis, Pulmonary

Interventions: Drug: Standard TB treatment
Drug: double rimfampicin

Registration Number: NCT02153528

Lead Sponsor: Damien Foundation

Brief Summary: - 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.

Detailed Description: Not available

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 701

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

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Standard TB treatment	Standard TB treatment	Standard regimen for TB treatment according to guidelines of the International Union against Tuberculosis and Lung Disease
double rimfampicin	double rimfampicin	2HREZ/4HR Cat. 1, modified by using double dose rifampicin throughout

Primary Outcome Measures

Name	Time	Method
Tuberculose Treatment Outcome	12 months after end of treatment	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)
Number of Participants Who Develop Liver Toxicity	until month eight	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)

Secondary Outcome Measures

Name	Time	Method
Weight Gain	until end of treatment (month eight)	Weight gain from baseline until end-of-treatment comparison between both treatment arms.
High-level Rifampicin Resistant TB Adverse Treatment Outcomes	12 months after end of TB treatment	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.
Number of Initial Resistant TB Cases Who Switched to MDR-TB Treatment or Were Cured	at two weeks of treatment	To assess the effectiveness of FDA vital staining versus fever screening for early switch of non-responding rifampicin resistant TB to MDR-TB treatment
the Negative Predictive Value of Conversion at 2 Weeks for Relapse.	at 2 weeks of treatment	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).
Proportion of Acquired Rifampicin Resistance Among Failures and Relapses	12 months after end of TB treatment	number of failure / relapse cases without mutation detected at diagnosis as the denominator and comparing intervention and control arms.
Area Under the Curve of Auramine Resp. FDA at 2 Weeks to Predict Adverse Treatment Outcome at 1 Year After Treatment Completion	Auramine/FDA at 2 weeks and adverse treatment outcome 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.
Fever Resolution	after 2 weeks of treatment	Comparison of fever resolution after 2 weeks of treatment between both treatment arms.

Trial Locations

Locations (1): Damien Foundation Bangladesh TB project in Greater Mymensingh district (8 selected clinics)
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Dhaka, Greater Mymensingh District, Bangladesh