Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
| Name | Class |
|---|---|
| National TB control Programme Bangladesh | OTHER |
| Institute of Tropical Medicine, Belgium | OTHER |
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
- 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.
Not provided
Not provided
Not provided
Not provided
Not provided
| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Standard TB treatment | Active Comparator | Standard regimen for TB treatment according to guidelines of the International Union against Tuberculosis and Lung Disease |
|
| double rimfampicin | Experimental | 2HREZ/4HR Cat. 1, modified by using double dose rifampicin throughout |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| double rimfampicin | Drug | Compared to standard regimen dosing of rifampicin is doubled, while standard dose isoniazid, pyrazinamide and ethambutol are maintained |
|
| Measure | Description | Time Frame |
|---|---|---|
| Tuberculose Treatment Outcome | Following current WHO guidelines, an adverse treatment outcome is defined as any occurrence of the following:
| 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 |
| 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 |
Not provided
Inclusion Criteria:
Exclusion Criteria:
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
| Name | Affiliation | Role |
|---|---|---|
| Aung Kya Jai Maug, MD | Damien Foundation Bangladesh | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Damien Foundation Bangladesh TB project in Greater Mymensingh district (8 selected clinics) | Dhaka | Greater Mymensingh District | Bangladesh |
Not provided
Not provided
Not provided
| ID | Title | Description |
|---|---|---|
| FG000 | Standard TB Treatment | Standard regimen for TB treatment according to guidelines of the International Union against Tuberculosis and Lung Disease Standard TB treatment: Standard regimen for TB treatment according to guidelines of the International Union against Tuberculosis and Lung Disease |
| FG001 | Double Rimfampicin | 2HREZ/4HR Cat. 1, modified by using double dose rifampicin throughout double rimfampicin: Compared to standard regimen dosing of rifampicin is doubled, while standard dose isoniazid, pyrazinamide and ethambutol are maintained |
| Title | Milestones | Reasons Not Completed | ||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
3 subjects (1 from intervention arm and 2 from control arm) were excluded from the baseline population because they were infected with Non-TB-Mycobacteria (NTM).
Not provided
| ID | Title | Description |
|---|---|---|
| BG000 | Standard TB Treatment | Standard regimen for TB treatment according to guidelines of the International Union against Tuberculosis and Lung Disease Standard TB treatment: Standard regimen for TB treatment according to guidelines of the International Union against Tuberculosis and Lung Disease |
| BG001 |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Median |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | Tuberculose Treatment Outcome | Following current WHO guidelines, an adverse treatment outcome is defined as any occurrence of the following:
| Intention-to-treat analysis. Additional 4 subjects were removed from the ITT analysis because they switched to MDR regimen (3 in control arm, 1 in intervention arm). 4 subjects (intervention arm) were removed from the ITT analysis because they were enrolled twice. | Posted | Count of Participants | Participants | 12 months after end of treatment |
Serious adverse events are recorded until end of treatment (up to 8 months). No (non-serious) adverse events are recorded in this trial.
Not provided
Not provided
| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Standard TB Treatment | Standard regimen for TB treatment according to guidelines of the International Union against Tuberculosis and Lung Disease Standard TB treatment: Standard regimen for TB treatment according to guidelines of the International Union against Tuberculosis and Lung Disease |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Cardiopulmonary failure | Cardiac disorders | Non-systematic Assessment |
Not provided
Not provided
| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Clinical Trials Unit ITM | Institute of Tropical Medicine Antwerp | 0032 32470778 | jbuyze@itg.be |
Not provided
| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot | Yes | No | No | Study Protocol | Apr 15, 2015 | Jun 13, 2019 | Prot_000.pdf |
| SAP | No | Yes | No | Statistical Analysis Plan | Sep 18, 2015 | Jun 13, 2019 | SAP_001.pdf |
Not provided
| ID | Term |
|---|---|
| D014397 | Tuberculosis, Pulmonary |
| ID | Term |
|---|---|
| D014376 | Tuberculosis |
| D009164 | Mycobacterium Infections |
| D000193 | Actinomycetales Infections |
| D016908 | Gram-Positive Bacterial Infections |
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
|
| Standard TB treatment | Drug | Standard regimen for TB treatment according to guidelines of the International Union against Tuberculosis and Lung Disease |
|
|
| 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 |
| Double Rimfampicin |
2HREZ/4HR Cat. 1, modified by using double dose rifampicin throughout double rimfampicin: Compared to standard regimen dosing of rifampicin is doubled, while standard dose isoniazid, pyrazinamide and ethambutol are maintained |
| BG002 | Total | Total of all reporting groups |
| years |
|
| Sex/Gender, Customized | Count of Participants | Participants |
|
| Race and Ethnicity Not Collected | Race and Ethnicity were not collected from any participant. | Count of Participants | Participants |
|
| Weight | Median | Inter-Quartile Range | kg |
|
| Height | Median | Inter-Quartile Range | cm |
|
| Temperature | Median | Inter-Quartile Range | °F |
|
| Direct smear auramine | 200x magnification | Median | Inter-Quartile Range | Acid Fast Bacilli/field |
|
| Intervention smear auramine | 200x magnification | Median | Inter-Quartile Range | AFB/field |
|
| Intervention smear FDA | 200x magnification | Median | Inter-Quartile Range | number of AFB |
|
| ALT | Median | Inter-Quartile Range | IU/L |
|
| New case of TB | Count of Participants | Participants |
|
| Diabetes | Count of Participants | Participants |
|
| Liver problems | Count of Participants | Participants |
|
| Kidney problems | Count of Participants | Participants |
|
| Lung/Heart problems | Count of Participants | Participants |
|
| Sign of Hepatitis | Count of Participants | Participants |
|
| Cough | Count of Participants | Participants |
|
| ID | Title | Description |
|---|---|---|
| OG000 | Standard TB Treatment | Standard regimen for TB treatment according to guidelines of the International Union against Tuberculosis and Lung Disease Standard TB treatment: Standard regimen for TB treatment according to guidelines of the International Union against Tuberculosis and Lung Disease |
| OG001 | Double Rimfampicin | 2HREZ/4HR Cat. 1, modified by using double dose rifampicin throughout double rimfampicin: Compared to standard regimen dosing of rifampicin is doubled, while standard dose isoniazid, pyrazinamide and ethambutol are maintained |
|
|
| Primary | 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) | One participant was allocated to double rifampicin arm but received standard TB treatment, and was analysed in the standard TB treatment arm.Two participants were deleted from analysis because they had grade 3 liver toxicity at baseline and 6 participants were deleted because they did not have any follow-up ALT values. | Posted | Count of Participants | Participants | until month eight |
|
|
|
| Secondary | 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. | ITT analysis population. Compared to analysis population of primary objective - TB treatment outcome, 24 subjects were excluded from this analysis due to missing or negative sequencing results (8 in control group, 16 in intervention group). | Posted | Count of Participants | Participants | 12 months after end of TB treatment |
|
|
|
| Secondary | 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 | 7 initial resistant cases (5 in control group and 2 in intervention group). | Posted | Count of Participants | Participants | at two weeks of treatment |
|
|
|
| Secondary | 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). | ITT analysis. This analysis only includes participants in the intervention arm who are negative on auramine smear resp. FDA smear at 2 weeks. | Posted | Count of Participants | Participants | at 2 weeks of treatment |
|
|
|
| Secondary | 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. | ITT analysis. This analysis only includes failure / relapse cases without mutation detected at diagnosis | Posted | Count of Participants | Participants | 12 months after end of TB treatment |
|
|
|
| Secondary | 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. | Posted | Number | 95% Confidence Interval | no unit is used for AUROC | Auramine/FDA at 2 weeks and adverse treatment outcome 1 year after treatment completion |
|
|
|
| Secondary | Weight Gain | Weight gain from baseline until end-of-treatment comparison between both treatment arms. | Posted | Mean | Standard Deviation | kg | until end of treatment (month eight) |
|
|
|
| Secondary | Fever Resolution | Comparison of fever resolution after 2 weeks of treatment between both treatment arms. | Total of participants with fever at baseline. | Posted | Count of Participants | Participants | after 2 weeks of treatment |
|
|
|
| 17 |
| 348 |
| 24 |
| 348 |
| 0 |
| 348 |
| EG001 | Double Rimfampicin | 2HREZ/4HR Cat. 1, modified by using double dose rifampicin throughout double rimfampicin: Compared to standard regimen dosing of rifampicin is doubled, while standard dose isoniazid, pyrazinamide and ethambutol are maintained | 12 | 353 | 13 | 353 | 0 | 353 |
| Abdominal pain | Gastrointestinal disorders | Non-systematic Assessment |
|
| Vomiting | Gastrointestinal disorders | Non-systematic Assessment |
|
| Asthenia | General disorders | Non-systematic Assessment |
|
| Hepatitis | Hepatobiliary disorders | Non-systematic Assessment |
|
| Jaundice | Hepatobiliary disorders | Non-systematic Assessment |
|
| Alanine aminotransferase increased | Investigations | Non-systematic Assessment |
|
| Decreased appetite | Metabolism and nutrition disorders | Non-systematic Assessment |
|
| Adenocarcinoma | Neoplasms benign, malignant and unspecified (incl cysts and polyps) | Non-systematic Assessment |
|
| Gallbladder cancer metastatic | Neoplasms benign, malignant and unspecified (incl cysts and polyps) | Non-systematic Assessment |
|
| Malignant neoplasm | Neoplasms benign, malignant and unspecified (incl cysts and polyps) | Non-systematic Assessment |
|
| Ataxia | Nervous system disorders | Non-systematic Assessment |
|
| Cerebrovascular accident | Nervous system disorders | Non-systematic Assessment |
|
| Ischaemic stroke | Nervous system disorders | Non-systematic Assessment |
|
| Anuria | Renal and urinary disorders | Non-systematic Assessment |
|
| Haemoptysis | Respiratory, thoracic and mediastinal disorders | Non-systematic Assessment |
|
| Pleural effusion | Respiratory, thoracic and mediastinal disorders | Non-systematic Assessment |
|
| Respiratory distress | Respiratory, thoracic and mediastinal disorders | Non-systematic Assessment |
|
| Pruritus | Skin and subcutaneous tissue disorders | Non-systematic Assessment |
|
| Victim of homicide | Social circumstances | Non-systematic Assessment |
|
Not provided
Not provided
| D001424 | Bacterial Infections |
| D001423 | Bacterial Infections and Mycoses |
| D007239 | Infections |
| D012141 | Respiratory Tract Infections |
| D008171 | Lung Diseases |
| D012140 | Respiratory Tract Diseases |
| Rif-resistant with adverse treatment outcome |
|
| Rif-resistant cured/completed without relapse |
|