Optimization of the TB Treatment Regimen Cascade

NCT02153528 | Completed Phase 3 Results DMC

• 1 other identifier: OneRIF
• Study Type: interventional
• Target: 701
• Locations: 1 country
• Sites: 1

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.

Conditions

Tuberculosis, Pulmonary

Keywords

Bangladesh; Rimfapicin

Outcome Measures

Primary Outcomes (2)

• 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 Outcomes (7)

• High-level Rifampicin Resistant TB Adverse Treatment Outcomes

  12 months after end of TB treatment

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

  at two weeks of treatment

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

  at 2 weeks of treatment

• Proportion of Acquired Rifampicin Resistance Among Failures and Relapses

  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

  Auramine/FDA at 2 weeks and adverse treatment outcome 1 year after treatment completion

Study Arms (2)

Standard TB treatment

ACTIVE COMPARATOR

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

Drug: Standard TB treatment

double rimfampicin

EXPERIMENTAL

2HREZ/4HR Cat. 1, modified by using double dose rifampicin throughout

Drug: double rimfampicin

Interventions

double rimfampicin DRUG

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

Also known as: Intervention arm

double rimfampicin

Standard TB treatment DRUG

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

Also known as: Control arm

Standard TB treatment

Eligibility Criteria

• Age: 15 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)

You may qualify if:

• Diagnosed with smear-positive pulmonary TB
• years or older
• Able and willing to provide written informed consent

You may not qualify if:

• 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

Sponsors & Collaborators

• Damien Foundation: lead
• National TB control Programme Bangladesh: collaborator
• Institute of Tropical Medicine, Belgium: collaborator

Study Sites (1)

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

Dhaka, Greater Mymensingh District, Bangladesh

Location

MeSH Terms

Conditions

Tuberculosis, Pulmonary

Condition Hierarchy (Ancestors)

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

Results Point of Contact

• Title: Clinical Trials Unit ITM
• Organization: Institute of Tropical Medicine Antwerp

jbuyze@itg.be

0032 32470778

Study Officials

• Aung Kya Jai Maug, MD

  Damien Foundation Bangladesh

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: May 26, 2014
• First Posted: June 3, 2014
• Study Start: November 1, 2014
• Primary Completion: August 1, 2017
• Study Completion: August 1, 2017
• Last Updated: February 13, 2020
• Results First Posted: February 13, 2020

Record last verified: 2020-02

Locations

BA (1)