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Completed

NCT Number: NCT02153528

Optimization of the TB Treatment Regimen Cascade

- 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.

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Key information

Conditions

Tuberculosis, Pulmonary Actinomycetales Infections Bacterial Infections Bacterial Infections and Mycoses Gram-Positive Bacterial Infections Infections Lung Diseases Mycobacterium Infections Respiratory Tract Diseases Respiratory Tract Infections Tuberculosis

Age range

15 year and older

Sex eligibility

All sexes

Study type

Interventional

Phase

Phase 3

Primary location

Damien Foundation Bangladesh TB project in Greater Mymensingh district (8 selected clinics)

Dhaka, Greater Mymensingh District, Bangladesh

Who can participate

Healthy volunteers accepted: No

Only the study team can determine whether someone qualifies for participation.

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

Treatment and study plan

double rimfampicin

Drug

Compared to standard regimen dosing of rifampicin is doubled, while standard dose isoniazid, pyrazinamide and ethambutol are maintained

Other names: Intervention arm

Standard TB treatment

Drug

Standard regimen for TB treatment according to guidelines of the International Union against Tuberculosis and Lung Disease

Other names: Control arm

Primary outcomes

  1. Tuberculose Treatment Outcome

    Time frame: 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)

  2. Number of Participants Who Develop Liver Toxicity

    Time frame: 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 outcomes

  1. High-level Rifampicin Resistant TB Adverse Treatment Outcomes

    Time frame: 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.

  2. Number of Initial Resistant TB Cases Who Switched to MDR-TB Treatment or Were Cured

    Time frame: 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

  3. the Negative Predictive Value of Conversion at 2 Weeks for Relapse.

    Time frame: 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).

  4. Proportion of Acquired Rifampicin Resistance Among Failures and Relapses

    Time frame: 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.

  5. Area Under the Curve of Auramine Resp. FDA at 2 Weeks to Predict Adverse Treatment Outcome at 1 Year After Treatment Completion

    Time frame: 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.

  6. Weight Gain

    Time frame: until end of treatment (month eight)

    Weight gain from baseline until end-of-treatment comparison between both treatment arms.

  7. Fever Resolution

    Time frame: after 2 weeks of treatment

    Comparison of fever resolution after 2 weeks of treatment between both treatment arms.

Sponsors and collaborators

Lead sponsor

Damien Foundation

Other

Collaborators

  • Institute of Tropical Medicine, Belgium
  • National TB control Programme Bangladesh

Registry information

Acronym: OneRIF

Important dates

Study start
2014
Primary completion
2017
Study completion
2017
First posted
Jun 3, 2014
Registry last updated
Feb 13, 2020

OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.

View the official ClinicalTrials.gov record (opens in a new tab)

This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.

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