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Optimization of the TB Treatment Regimen Cascade (OneRIF)

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ClinicalTrials.gov Identifier: NCT02153528
Recruitment Status : Completed
First Posted : June 3, 2014
Last Update Posted : August 1, 2019
Sponsor:
Collaborators:
National TB control Programme Bangladesh
Institute of Tropical Medicine, Belgium
Information provided by (Responsible Party):
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.


Condition or disease Intervention/treatment Phase
Tuberculosis, Pulmonary Drug: double rimfampicin Drug: Standard TB treatment Phase 3

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 701 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Optimization of the TB Treatment Regimen Cascade
Study Start Date : November 2014
Actual Primary Completion Date : August 1, 2017
Actual Study Completion Date : August 1, 2017

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Tuberculosis

Arm Intervention/treatment
Active Comparator: Standard TB treatment
Standard regimen for TB treatment according to guidelines of the International Union against Tuberculosis and Lung Disease
Drug: Standard TB treatment
Standard regimen for TB treatment according to guidelines of the International Union against Tuberculosis and Lung Disease
Other Name: Control arm

Experimental: double rimfampicin
2HREZ/4HR Cat. 1, modified by using double dose rifampicin throughout
Drug: double rimfampicin
Compared to standard regimen dosing of rifampicin is doubled, while standard dose isoniazid, pyrazinamide and ethambutol are maintained
Other Name: Intervention arm




Primary Outcome Measures :
  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. Serious Adverse Events and 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 Outcome Measures :
  1. low-level rifampicin resistant TB adverse treatment outcomes [ Time Frame: 12 months after end of TB treatment ]
    To assess whether the study regimen also cures low-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. effectiveness of standard auramine [ Time Frame: at two weeks of treatment ]
    To assess the effectiveness of standard auramine versus FDA vital staining screening for early switch of non-responding rifampicin resistant TB to MDR-TB treatment

  3. assess the negative predictive value of conversion 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. estimate the 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.



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Ages Eligible for Study:   15 Years and older   (Child, Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02153528


Locations
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Bangladesh
Damien Foundation Bangladesh TB project in Greater Mymensingh district (8 selected clinics)
Dhaka, Greater Mymensingh District, Bangladesh
Sponsors and Collaborators
Damien Foundation
National TB control Programme Bangladesh
Institute of Tropical Medicine, Belgium
Investigators
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Principal Investigator: Aung Kya Jai Maug, MD Damien Foundation Bangladesh
  Study Documents (Full-Text)

Documents provided by Damien Foundation:
Study Protocol  [PDF] April 15, 2015
Statistical Analysis Plan  [PDF] September 18, 2015


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Responsible Party: Damien Foundation
ClinicalTrials.gov Identifier: NCT02153528     History of Changes
Other Study ID Numbers: OneRIF
First Posted: June 3, 2014    Key Record Dates
Last Update Posted: August 1, 2019
Last Verified: July 2019
Keywords provided by Damien Foundation:
Bangladesh
Rimfapicin
Additional relevant MeSH terms:
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Tuberculosis
Tuberculosis, Pulmonary
Mycobacterium Infections
Actinomycetales Infections
Gram-Positive Bacterial Infections
Bacterial Infections
Lung Diseases
Respiratory Tract Diseases
Respiratory Tract Infections