Trial Outcomes & Findings for Optimization of the TB Treatment Regimen Cascade (NCT NCT02153528)

Last Updated: 2020-02-13

Results Overview

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)

Recruitment status

COMPLETED

Study phase

PHASE3

Target enrollment

701 participants

Primary outcome timeframe

12 months after end of treatment

Results posted on

2020-02-13

Participant Flow

Participant milestones

Participant milestones
Measure	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	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
Overall Study STARTED	348	353
Overall Study COMPLETED	348	353
Overall Study NOT COMPLETED	0	0

Reasons for withdrawal

Withdrawal data not reported

Baseline Characteristics

Race and Ethnicity were not collected from any participant.

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Standard TB Treatment n=346 Participants 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	Double Rimfampicin n=352 Participants 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	Total n=698 Participants Total of all reporting groups
Age, Continuous	42 years n=346 Participants	45 years n=352 Participants	44 years n=698 Participants
Sex/Gender, Customized Male	251 Participants n=346 Participants	260 Participants n=352 Participants	511 Participants n=698 Participants
Sex/Gender, Customized Female	95 Participants n=346 Participants	92 Participants n=352 Participants	187 Participants n=698 Participants
Race and Ethnicity Not Collected	—	—	0 Participants Race and Ethnicity were not collected from any participant.
Weight	41 kg n=346 Participants	42 kg n=352 Participants	41.5 kg n=698 Participants
Height	159 cm n=346 Participants	158 cm n=352 Participants	159 cm n=698 Participants
Temperature	99.1 °F n=346 Participants	99.2 °F n=352 Participants	99.2 °F n=698 Participants
Direct smear auramine	98 Acid Fast Bacilli/field n=346 Participants	90.0 Acid Fast Bacilli/field n=352 Participants	93.3 Acid Fast Bacilli/field n=698 Participants
Intervention smear auramine	NA AFB/field n=346 Participants	100.0 AFB/field n=352 Participants	100.0 AFB/field n=698 Participants
Intervention smear FDA	NA number of AFB n=346 Participants	10.0 number of AFB n=352 Participants	10.0 number of AFB n=698 Participants
ALT	20 IU/L n=346 Participants	20 IU/L n=352 Participants	20 IU/L n=698 Participants
New case of TB No	20 Participants n=346 Participants	29 Participants n=352 Participants	49 Participants n=698 Participants
New case of TB Yes	326 Participants n=346 Participants	323 Participants n=352 Participants	649 Participants n=698 Participants
Diabetes No	331 Participants n=346 Participants	335 Participants n=352 Participants	666 Participants n=698 Participants
Diabetes Yes	15 Participants n=346 Participants	17 Participants n=352 Participants	32 Participants n=698 Participants
Liver problems No	346 Participants n=346 Participants	351 Participants n=352 Participants	697 Participants n=698 Participants
Liver problems Yes	0 Participants n=346 Participants	1 Participants n=352 Participants	1 Participants n=698 Participants
Kidney problems No	346 Participants n=346 Participants	351 Participants n=352 Participants	697 Participants n=698 Participants
Kidney problems Yes	0 Participants n=346 Participants	1 Participants n=352 Participants	1 Participants n=698 Participants
Lung/Heart problems No	344 Participants n=346 Participants	349 Participants n=352 Participants	693 Participants n=698 Participants
Lung/Heart problems Yes	2 Participants n=346 Participants	3 Participants n=352 Participants	5 Participants n=698 Participants
Sign of Hepatitis No	346 Participants n=346 Participants	352 Participants n=352 Participants	698 Participants n=698 Participants
Sign of Hepatitis Yes	0 Participants n=346 Participants	0 Participants n=352 Participants	0 Participants n=698 Participants
Cough No	1 Participants n=346 Participants	1 Participants n=352 Participants	2 Participants n=698 Participants
Cough Yes	345 Participants n=346 Participants	351 Participants n=352 Participants	696 Participants n=698 Participants

PRIMARY outcome

Timeframe: 12 months after end of treatment

Population: 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.

Outcome measures

Outcome measures
Measure	Standard TB Treatment n=343 Participants 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	Double Rimfampicin n=347 Participants 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
Tuberculose Treatment Outcome Default	8 Participants	8 Participants
Tuberculose Treatment Outcome Died	11 Participants	5 Participants
Tuberculose Treatment Outcome Failure	8 Participants	12 Participants
Tuberculose Treatment Outcome Completed	6 Participants	3 Participants
Tuberculose Treatment Outcome Cured	310 Participants	319 Participants

PRIMARY outcome

Timeframe: until month eight

Population: 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.

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)

Outcome measures

Outcome measures
Measure	Standard TB Treatment n=343 Participants 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	Double Rimfampicin n=350 Participants 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
Number of Participants Who Develop Liver Toxicity	7 Participants	3 Participants

SECONDARY outcome

Timeframe: 12 months after end of TB treatment

Population: 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).

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.

Outcome measures

Outcome measures
Measure	Standard TB Treatment n=335 Participants 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	Double Rimfampicin n=331 Participants 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
High-level Rifampicin Resistant TB Adverse Treatment Outcomes Rif-sensitive with adverse treatment outcome	52 Participants	40 Participants
High-level Rifampicin Resistant TB Adverse Treatment Outcomes Rif-sensitive cured/completed without relapse	281 Participants	290 Participants
High-level Rifampicin Resistant TB Adverse Treatment Outcomes Rif-resistant with adverse treatment outcome	0 Participants	0 Participants
High-level Rifampicin Resistant TB Adverse Treatment Outcomes Rif-resistant cured/completed without relapse	2 Participants	1 Participants

SECONDARY outcome

Timeframe: at two weeks of treatment

Population: 7 initial resistant cases (5 in control group and 2 in intervention group).

To assess the effectiveness of FDA vital staining versus fever screening for early switch of non-responding rifampicin resistant TB to MDR-TB treatment

Outcome measures

Outcome measures
Measure	Standard TB Treatment n=5 Participants 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	Double Rimfampicin n=2 Participants 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
Number of Initial Resistant TB Cases Who Switched to MDR-TB Treatment or Were Cured	5 Participants	2 Participants

SECONDARY outcome

Timeframe: at 2 weeks of treatment

Population: ITT analysis. This analysis only includes participants in the intervention arm who are negative on auramine smear resp. FDA smear at 2 weeks.

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).

Outcome measures

Outcome measures
Measure	Standard TB Treatment n=91 Participants 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	Double Rimfampicin n=193 Participants 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
the Negative Predictive Value of Conversion at 2 Weeks for Relapse.	0 Participants	0 Participants

SECONDARY outcome

Timeframe: 12 months after end of TB treatment

Population: ITT analysis. This analysis only includes failure / relapse cases without mutation detected at diagnosis

number of failure / relapse cases without mutation detected at diagnosis as the denominator and comparing intervention and control arms.

Outcome measures

Outcome measures
Measure	Standard TB Treatment n=8 Participants 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	Double Rimfampicin n=12 Participants 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
Proportion of Acquired Rifampicin Resistance Among Failures and Relapses	0 Participants	0 Participants

SECONDARY outcome

Timeframe: 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.

Outcome measures

Outcome measures
Measure	Standard TB Treatment n=344 Participants 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	Double Rimfampicin n=344 Participants 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
Area Under the Curve of Auramine Resp. FDA at 2 Weeks to Predict Adverse Treatment Outcome at 1 Year After Treatment Completion	0.52 no unit is used for AUROC Interval 0.42 to 0.61	0.54 no unit is used for AUROC Interval 0.45 to 0.63

SECONDARY outcome

Timeframe: until end of treatment (month eight)

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

Outcome measures

Outcome measures
Measure	Standard TB Treatment n=320 Participants 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	Double Rimfampicin n=331 Participants 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
Weight Gain	2.93 kg Standard Deviation 2.44	2.79 kg Standard Deviation 2.44

SECONDARY outcome

Timeframe: after 2 weeks of treatment

Population: Total of participants with fever at baseline.

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

Outcome measures

Outcome measures
Measure	Standard TB Treatment n=82 Participants 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	Double Rimfampicin n=72 Participants 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
Fever Resolution	81 Participants	71 Participants

Adverse Events

Standard TB Treatment

Serious events: 24 serious events

Other events: 0 other events

Deaths: 17 deaths

Double Rimfampicin

Serious events: 13 serious events

Other events: 0 other events

Deaths: 12 deaths

Serious adverse events

Other adverse events

Adverse event data not reported

Additional Information

Clinical Trials Unit ITM

Institute of Tropical Medicine Antwerp

Phone: 0032 32470778

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place

Measure	Standard TB Treatment n=348 participants at risk 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	Double Rimfampicin n=353 participants at risk 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
Cardiac disorders Cardiopulmonary failure	0.29% 1/348 • Serious adverse events are recorded until end of treatment (up to 8 months). No (non-serious) adverse events are recorded in this trial.	0.28% 1/353 • Serious adverse events are recorded until end of treatment (up to 8 months). No (non-serious) adverse events are recorded in this trial.
Gastrointestinal disorders Abdominal pain	0.29% 1/348 • Serious adverse events are recorded until end of treatment (up to 8 months). No (non-serious) adverse events are recorded in this trial.	0.00% 0/353 • Serious adverse events are recorded until end of treatment (up to 8 months). No (non-serious) adverse events are recorded in this trial.
Gastrointestinal disorders Vomiting	0.57% 2/348 • Serious adverse events are recorded until end of treatment (up to 8 months). No (non-serious) adverse events are recorded in this trial.	0.00% 0/353 • Serious adverse events are recorded until end of treatment (up to 8 months). No (non-serious) adverse events are recorded in this trial.
General disorders Asthenia	0.00% 0/348 • Serious adverse events are recorded until end of treatment (up to 8 months). No (non-serious) adverse events are recorded in this trial.	0.28% 1/353 • Serious adverse events are recorded until end of treatment (up to 8 months). No (non-serious) adverse events are recorded in this trial.
Hepatobiliary disorders Hepatitis	0.57% 2/348 • Serious adverse events are recorded until end of treatment (up to 8 months). No (non-serious) adverse events are recorded in this trial.	0.28% 1/353 • Serious adverse events are recorded until end of treatment (up to 8 months). No (non-serious) adverse events are recorded in this trial.
Hepatobiliary disorders Jaundice	1.1% 4/348 • Serious adverse events are recorded until end of treatment (up to 8 months). No (non-serious) adverse events are recorded in this trial.	1.4% 5/353 • Serious adverse events are recorded until end of treatment (up to 8 months). No (non-serious) adverse events are recorded in this trial.
Investigations Alanine aminotransferase increased	1.4% 5/348 • Serious adverse events are recorded until end of treatment (up to 8 months). No (non-serious) adverse events are recorded in this trial.	0.57% 2/353 • Serious adverse events are recorded until end of treatment (up to 8 months). No (non-serious) adverse events are recorded in this trial.
Metabolism and nutrition disorders Decreased appetite	0.29% 1/348 • Serious adverse events are recorded until end of treatment (up to 8 months). No (non-serious) adverse events are recorded in this trial.	0.28% 1/353 • Serious adverse events are recorded until end of treatment (up to 8 months). No (non-serious) adverse events are recorded in this trial.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Adenocarcinoma	0.00% 0/348 • Serious adverse events are recorded until end of treatment (up to 8 months). No (non-serious) adverse events are recorded in this trial.	0.28% 1/353 • Serious adverse events are recorded until end of treatment (up to 8 months). No (non-serious) adverse events are recorded in this trial.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Gallbladder cancer metastatic	0.00% 0/348 • Serious adverse events are recorded until end of treatment (up to 8 months). No (non-serious) adverse events are recorded in this trial.	0.28% 1/353 • Serious adverse events are recorded until end of treatment (up to 8 months). No (non-serious) adverse events are recorded in this trial.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Malignant neoplasm	0.29% 1/348 • Serious adverse events are recorded until end of treatment (up to 8 months). No (non-serious) adverse events are recorded in this trial.	0.00% 0/353 • Serious adverse events are recorded until end of treatment (up to 8 months). No (non-serious) adverse events are recorded in this trial.
Nervous system disorders Ataxia	0.29% 1/348 • Serious adverse events are recorded until end of treatment (up to 8 months). No (non-serious) adverse events are recorded in this trial.	0.00% 0/353 • Serious adverse events are recorded until end of treatment (up to 8 months). No (non-serious) adverse events are recorded in this trial.
Nervous system disorders Cerebrovascular accident	0.29% 1/348 • Serious adverse events are recorded until end of treatment (up to 8 months). No (non-serious) adverse events are recorded in this trial.	0.28% 1/353 • Serious adverse events are recorded until end of treatment (up to 8 months). No (non-serious) adverse events are recorded in this trial.
Nervous system disorders Ischaemic stroke	0.00% 0/348 • Serious adverse events are recorded until end of treatment (up to 8 months). No (non-serious) adverse events are recorded in this trial.	0.28% 1/353 • Serious adverse events are recorded until end of treatment (up to 8 months). No (non-serious) adverse events are recorded in this trial.
Renal and urinary disorders Anuria	0.29% 1/348 • Serious adverse events are recorded until end of treatment (up to 8 months). No (non-serious) adverse events are recorded in this trial.	0.00% 0/353 • Serious adverse events are recorded until end of treatment (up to 8 months). No (non-serious) adverse events are recorded in this trial.
Respiratory, thoracic and mediastinal disorders Haemoptysis	0.57% 2/348 • Serious adverse events are recorded until end of treatment (up to 8 months). No (non-serious) adverse events are recorded in this trial.	0.00% 0/353 • Serious adverse events are recorded until end of treatment (up to 8 months). No (non-serious) adverse events are recorded in this trial.
Respiratory, thoracic and mediastinal disorders Pleural effusion	0.29% 1/348 • Serious adverse events are recorded until end of treatment (up to 8 months). No (non-serious) adverse events are recorded in this trial.	0.00% 0/353 • Serious adverse events are recorded until end of treatment (up to 8 months). No (non-serious) adverse events are recorded in this trial.
Respiratory, thoracic and mediastinal disorders Respiratory distress	0.57% 2/348 • Serious adverse events are recorded until end of treatment (up to 8 months). No (non-serious) adverse events are recorded in this trial.	0.00% 0/353 • Serious adverse events are recorded until end of treatment (up to 8 months). No (non-serious) adverse events are recorded in this trial.
Skin and subcutaneous tissue disorders Pruritus	0.00% 0/348 • Serious adverse events are recorded until end of treatment (up to 8 months). No (non-serious) adverse events are recorded in this trial.	0.28% 1/353 • Serious adverse events are recorded until end of treatment (up to 8 months). No (non-serious) adverse events are recorded in this trial.
Social circumstances Victim of homicide	0.29% 1/348 • Serious adverse events are recorded until end of treatment (up to 8 months). No (non-serious) adverse events are recorded in this trial.	0.00% 0/353 • Serious adverse events are recorded until end of treatment (up to 8 months). No (non-serious) adverse events are recorded in this trial.