Ignite Creation Date:
2024-10-26 @ 3:36 PM
Last Modification Date:
2024-10-26 @ 3:36 PM
Study NCT ID:
NCT06526039
Status:
NOT_YET_RECRUITING
Last Update Posted:
None
First Post:
2024-07-10
Brief Title:
A Short Regimen for Rifampicin-resistant Isoniazid-susceptible TB
Sponsor:
None
Organization:
None
Study Overview
Official Title:
A Short Regimen for Patients With Rifampicin-resistant Isoniazid-susceptible Tuberculosis
Status:
NOT_YET_RECRUITING
Status Verified Date:
2024-07
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
No
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
None
Brief Summary:
To assess outcome of treatment and safety among patients with rifampicin-resistant isoniazid-susceptible pulmonary tuberculosis treated with a novel regimen consisting of isoniazid bedaquiline and moxifloxacin throughout for 6 months supplemented by pyrazinamide for the initial 2 months
Detailed Description:
Rifampicin-resistant tuberculosis RR-TB could be classified into rifampicin-resistant isoniazid-susceptible TB RrHs-TB and rifampicin-resistant isoniazid-resistant TB MDR-TB that is MDR-TB RrHs-TB and MDR-TB are different because isoniazid has potent early bactericidal activity EBA and remains susceptible in RrHs-TB
The standard first line anti-TB regimen recommended by WHO consisting of isoniazid and rifampicin throughout for 6 months supplemented by pyrazinamide and ethambutol for the initial 2 months 2HRZE4HR The duration of treatment of the first line standard 6-month regimen is mainly determined by the sterilization power of the core drug namely rifampicin paired with pyrazinamide Moxifloxacin had potent EBA that is comparable to that of isoniazid Bedaquiline has delayed onset of action but after a few days of treatment its EBA is comparable to that of isoniazid and rifampicin Both moxifloxacin and bedaquiline have potent sterilizing activity
To avoid the use of a toxic MDR-TB regimen we hypothesize that the combination of bedaquiline and moxifloxacin is non inferior to rifampicin in terms of EBA and sterilizing activity and could be used to substitute for rifampicin in the standard first line anti-TB regimen 2HRZE4HR as a novel approach for the treatment of RrHs-TB as well as TB patients for whom rifamycin is intolerable Ri-TB and TB patients for whom rifamycin-sparing anti-TB regimens are preferred due to drug-drug interaction Rs-TB
Trial intervention
The novel regimen will be given in two phases
1 An intensive phase consisting of isoniazid bedaquiline moxifloxacin and pyrazinamide for 2 months 9 weeks Exclusion of isoniazid resistance by conventional phenotypic method or by a rapid molecular test before treatment initiation is required Amikacin will be added before obtaining results of conventional DST if exclusion of isoniazid resistance is done by a molecular test at treatment initiation If isoniazid resistance is again excluded by a repeat molecular test either the same or a different molecular test amikacin could be dropped after two weeks of treatment
2 A continuation phase consisting of isoniazid bedaquiline and levofloxacin for 4 months 17 weeks Treatment may be extended for 3 months 13 weeks in patients with severe disease or with delayed culture conversion defined by culture positive at 4 months of treatment If pyrazinamide is discontinued earlier due to adverse reaction the continuation phase will be extended for 3 months 13 weeks for a total treatment duration of 9 months 39 weeks
Selection of patients
The target population is
1 Patients diagnosed with rifampicin-resistant isoniazid-susceptible TB RrHs-TB
The following two type of patients will also be enrolled because rifamycin will not be used in the treatment of TB
2 Patients diagnosed with susceptible TB who are not able to tolerate rifampicin due to adverse reactions in whom rifabutin is intolerable or clinically not indicated Ri-TB
3 Patients with TB for whom rifampicin-sparing anti-TB regimens is preferred such as organ transplant recipients due to drug-drug interaction Rs-TB
Type of design
This is a prospective open-label single-group study that participants will be treated with a novel regimen
Trial objectives
The primary objectives of the trial are
1 To assess the proportion of patients with a favourable efficacy outcome on the study regimen
2 To assess the proportion of patients who experience grade 3 or greater adverse events during treatment and follow-up in the study regimen
Outcome measures
The primary efficacy outcome measure is the proportion of patients with a favourable outcome at 12 months 53 weeks post treatment initiation
A patients outcome will be classified as favourable if they have a negative culture result 12 months 53 weeks after treatment initiation not having been previously classified as unfavourable
A patients outcome will be classified as unfavourable if
1 they are discontinued from their allocated study treatment and subsequently restarted on a different regimen
2 treatment is extended beyond the scheduled end of treatment for any reason other than making up of missed treatment
3 they are restarted on any MDR-TB treatment after the scheduled end of treatment
4 they change their allocated study treatment for any reason other than the replacement of a single drug
5 they die at any point up to 12 months post treatment initiation
6 they have a positive culture result at 12 months post treatment initiation
The primary safety outcome measure is the proportion of patients experiencing a grade 3 or greater adverse event as defined by the CTCAE criteria except hyperuricemia which will be defined by the DAIDS criteria during treatment and follow-up to 12 months 53 weeks post treatment initiation
Secondary outcome measures include
Time to sputum smear and culture conversion
Time to unfavourable efficacy outcome
The proportion of patients with a favourable outcomes at 24 months post treatment initiation
All causes mortality during treatment and follow-up
The proportion of patients with a change of 2 or more drugs for adverse drug reactions
Number of adverse reactions occurring on treatment
The proportion of patients with treatment interruption for 2 or months
Sample Size
We adopt the approach of the Nix-TB study and the ZeNix trial and hypothesize that the proportion of patients with favourable efficacy outcomes at 12 months 53 weeks after treatment initiation would be greater than 50 The trial does not have a control group A sample of 45 participants would provide more than 90 power to demonstrate that the lower boundary of the 95 confidence interval is greater than 50 using a two-sided 5 significance level We plan to expand the enrollment to at least 80 patients to assess the primary efficacy of the study regimen
Analysis population definitions
Intention-to-treat ITT
All enrolled patients will be included in the ITT analysis population
Safety population
All patients who have taken at least one dose of trial treatment will be included in the safety analysis population
Modified intention-to-treat mITT
The mITT population is defined as all enrolled patients that have a positive culture for M tuberculosis on LJ or MGIT media at screening with the exception of rifampicin-resistant isoniazid susceptible TB patients with isolates taken before treatment initiation that are subsequently found to be susceptible to rifampicin and patients with isolates taken before treatment initiation that are subsequently found to be resistant to fluoroquinolones on phenotypic DST Whole genome sequencing will be done for strains with discordant results between phenotypic and genotypic methods Results from the national reference mycobacteriology laboratory of Taiwan CDC will take priority over any results from local laboratories where available
Per protocol PP
The PP population will be the same as the mITT population with the exclusion of patients not completing a protocol-adherent course of treatment other than for treatment failure or death Treatment failure is defined as failure to attain and maintain culture negativity until the end of allocated treatment
Definition of a protocol-adherent course of treatment
Patients will be excluded from the per-protocol analysis if they do not complete a protocol adherent course of treatment other than for treatment failure or death
A patient will have completed a protocol-adherent course of treatment when they have taken 80 of doses within 120 of the minimum duration in both the intensive phase and in the whole treatment period For this purpose a dose is defined as all the study medications at the correct dose for that particular day
For the study Regimen with or without an extension a patient will have completed a protocol-adherent course of treatment if they have taken
50 doses 80 of 9 weeks within 76 days 120 of 9 weeks in the intensive phase and
157 doses 80 of 28 weeks within 235 days 120 of 28 weeks over the whole treatment period ie the combined intensive and continuation phases regardless of treatment extensions
Statistical significance
P value 005 will be considered statistically significant in this trial
The standard first line anti-TB regimen recommended by WHO consisting of isoniazid and rifampicin throughout for 6 months supplemented by pyrazinamide and ethambutol for the initial 2 months 2HRZE4HR The duration of treatment of the first line standard 6-month regimen is mainly determined by the sterilization power of the core drug namely rifampicin paired with pyrazinamide Moxifloxacin had potent EBA that is comparable to that of isoniazid Bedaquiline has delayed onset of action but after a few days of treatment its EBA is comparable to that of isoniazid and rifampicin Both moxifloxacin and bedaquiline have potent sterilizing activity
To avoid the use of a toxic MDR-TB regimen we hypothesize that the combination of bedaquiline and moxifloxacin is non inferior to rifampicin in terms of EBA and sterilizing activity and could be used to substitute for rifampicin in the standard first line anti-TB regimen 2HRZE4HR as a novel approach for the treatment of RrHs-TB as well as TB patients for whom rifamycin is intolerable Ri-TB and TB patients for whom rifamycin-sparing anti-TB regimens are preferred due to drug-drug interaction Rs-TB
Trial intervention
The novel regimen will be given in two phases
1 An intensive phase consisting of isoniazid bedaquiline moxifloxacin and pyrazinamide for 2 months 9 weeks Exclusion of isoniazid resistance by conventional phenotypic method or by a rapid molecular test before treatment initiation is required Amikacin will be added before obtaining results of conventional DST if exclusion of isoniazid resistance is done by a molecular test at treatment initiation If isoniazid resistance is again excluded by a repeat molecular test either the same or a different molecular test amikacin could be dropped after two weeks of treatment
2 A continuation phase consisting of isoniazid bedaquiline and levofloxacin for 4 months 17 weeks Treatment may be extended for 3 months 13 weeks in patients with severe disease or with delayed culture conversion defined by culture positive at 4 months of treatment If pyrazinamide is discontinued earlier due to adverse reaction the continuation phase will be extended for 3 months 13 weeks for a total treatment duration of 9 months 39 weeks
Selection of patients
The target population is
1 Patients diagnosed with rifampicin-resistant isoniazid-susceptible TB RrHs-TB
The following two type of patients will also be enrolled because rifamycin will not be used in the treatment of TB
2 Patients diagnosed with susceptible TB who are not able to tolerate rifampicin due to adverse reactions in whom rifabutin is intolerable or clinically not indicated Ri-TB
3 Patients with TB for whom rifampicin-sparing anti-TB regimens is preferred such as organ transplant recipients due to drug-drug interaction Rs-TB
Type of design
This is a prospective open-label single-group study that participants will be treated with a novel regimen
Trial objectives
The primary objectives of the trial are
1 To assess the proportion of patients with a favourable efficacy outcome on the study regimen
2 To assess the proportion of patients who experience grade 3 or greater adverse events during treatment and follow-up in the study regimen
Outcome measures
The primary efficacy outcome measure is the proportion of patients with a favourable outcome at 12 months 53 weeks post treatment initiation
A patients outcome will be classified as favourable if they have a negative culture result 12 months 53 weeks after treatment initiation not having been previously classified as unfavourable
A patients outcome will be classified as unfavourable if
1 they are discontinued from their allocated study treatment and subsequently restarted on a different regimen
2 treatment is extended beyond the scheduled end of treatment for any reason other than making up of missed treatment
3 they are restarted on any MDR-TB treatment after the scheduled end of treatment
4 they change their allocated study treatment for any reason other than the replacement of a single drug
5 they die at any point up to 12 months post treatment initiation
6 they have a positive culture result at 12 months post treatment initiation
The primary safety outcome measure is the proportion of patients experiencing a grade 3 or greater adverse event as defined by the CTCAE criteria except hyperuricemia which will be defined by the DAIDS criteria during treatment and follow-up to 12 months 53 weeks post treatment initiation
Secondary outcome measures include
Time to sputum smear and culture conversion
Time to unfavourable efficacy outcome
The proportion of patients with a favourable outcomes at 24 months post treatment initiation
All causes mortality during treatment and follow-up
The proportion of patients with a change of 2 or more drugs for adverse drug reactions
Number of adverse reactions occurring on treatment
The proportion of patients with treatment interruption for 2 or months
Sample Size
We adopt the approach of the Nix-TB study and the ZeNix trial and hypothesize that the proportion of patients with favourable efficacy outcomes at 12 months 53 weeks after treatment initiation would be greater than 50 The trial does not have a control group A sample of 45 participants would provide more than 90 power to demonstrate that the lower boundary of the 95 confidence interval is greater than 50 using a two-sided 5 significance level We plan to expand the enrollment to at least 80 patients to assess the primary efficacy of the study regimen
Analysis population definitions
Intention-to-treat ITT
All enrolled patients will be included in the ITT analysis population
Safety population
All patients who have taken at least one dose of trial treatment will be included in the safety analysis population
Modified intention-to-treat mITT
The mITT population is defined as all enrolled patients that have a positive culture for M tuberculosis on LJ or MGIT media at screening with the exception of rifampicin-resistant isoniazid susceptible TB patients with isolates taken before treatment initiation that are subsequently found to be susceptible to rifampicin and patients with isolates taken before treatment initiation that are subsequently found to be resistant to fluoroquinolones on phenotypic DST Whole genome sequencing will be done for strains with discordant results between phenotypic and genotypic methods Results from the national reference mycobacteriology laboratory of Taiwan CDC will take priority over any results from local laboratories where available
Per protocol PP
The PP population will be the same as the mITT population with the exclusion of patients not completing a protocol-adherent course of treatment other than for treatment failure or death Treatment failure is defined as failure to attain and maintain culture negativity until the end of allocated treatment
Definition of a protocol-adherent course of treatment
Patients will be excluded from the per-protocol analysis if they do not complete a protocol adherent course of treatment other than for treatment failure or death
A patient will have completed a protocol-adherent course of treatment when they have taken 80 of doses within 120 of the minimum duration in both the intensive phase and in the whole treatment period For this purpose a dose is defined as all the study medications at the correct dose for that particular day
For the study Regimen with or without an extension a patient will have completed a protocol-adherent course of treatment if they have taken
50 doses 80 of 9 weeks within 76 days 120 of 9 weeks in the intensive phase and
157 doses 80 of 28 weeks within 235 days 120 of 28 weeks over the whole treatment period ie the combined intensive and continuation phases regardless of treatment extensions
Statistical significance
P value 005 will be considered statistically significant in this trial
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
None
Is a FDA Regulated Device?:
None
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None