The purpose of this trial is to determine whether delamanid is effective in the treatment of multidrug-resistant tuberculosis (MDR TB) in combination with other MDR TB medications during 6 months of treatment.
The primary objective of this trial is to evaluate the efficacy of delamanid administered orally as 100 milligrams (mg) twice daily (BID) for 2 months followed by 200 mg once daily (QD) for 4 months in combination with an optimized background treatment regimen (OBR) versus placebo with OBR during the 6-month Intensive Period of MDR TB treatment. Following the 6-month Intensive Period, OBR was administered alone during the Continuation Period for 12 to 18 months (from Month 7 up to Month 24). The trial also included a post-treatment follow-up period of 6 to 12 months (Month 19 to Month 24 to the end of Month 30). OBR given throughout the study was administered as per World Health Organization (WHO) guidelines and national treatment norms. This trial is a multicenter, randomized, double-blind, stratified, placebo-controlled trial that was conducted globally in 2 parallel groups at 17 sites in 7 countries qualified to treat MDR TB.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
TRIPLE
Enrollment
511
The assigned doses of delamanid were administered with an OBR. The selection and administration of the OBR were based on WHO's guidelines for the programmatic management of drug-resistant TB, in conjunction with national TB program guidelines in each country.
Matching placebo was administered with an OBR. The selection and administration of the OBR were based on WHO's guidelines for the programmatic management of drug-resistant TB, in conjunction with national TB program guidelines in each country.
Unnamed facility
Tartu, Estonia
Unnamed facility
Riga, Latvia
Unnamed facility
Šiauliai, Lithuania
Time To Sputum Culture Conversion (SCC) During 6-Month Intensive Period Using The Mycobacteria Growth Indicator Tube (MGIT) System
SCC at 6 months was determined by the observation of a sputum specimen negative for growth of mycobacterium tuberculosis (MTB) using the MGIT culture system, followed by at least 1 confirmatory negative sputum culture at least 25 days after the first negative and not followed by a confirmed positive (defined as at least 2 observed positive results, not taking into account indeterminate, missing, or contaminated results). 2 specimens were collected at each visit and an algorithm in the statistical analysis plan (SAP) was used to define a single representative result. Time to SCC was then defined as the interval between the date of first dose of IMP and the date of first of 2 consecutive negative single representative time points that were at least 25 days apart. The median time in days to SCC up to Month 6 is presented.
Time frame: Month 6
Proportion of Participants With SCC At 2 And 6 Months Using MGIT
SCC was evaluated at 2 and 6 months (6-month Intensive Period) using MGIT. SCC at 2 months was defined to occur at the date of collection of the first sputum specimen with mycobacterial culture negative for growth of MTB using MGIT culture, followed by at least 1 confirmatory negative MGIT culture result at least 25 days after the first negative specimen and not followed by any sputum specimens positive for growth in the MGIT culture at any point up to 3 months (Week 12). SCC at 6 months was determined by the observation of a sputum specimen negative for growth of MTB using the MGIT culture system, followed by at least 1 confirmatory negative sputum culture at least 25 days after the first negative and not followed by a confirmed positive (defined as at least 2 observed positive results, not taking into account indeterminate, missing, or contaminated results). 2 specimens were collected at each visit and an algorithm in the SAP was used to define a single representative result.
Time frame: Month 2 and Month 6
Proportion of Participants With Sustained SCC At Month 18, Month 24, And Month 30 Using MGIT
Sustained SCC was defined as SCC achieved by Month 6 and not followed by a confirmed positive thereafter, where confirmed positive was defined as 2 or more observed positive single representative culture results, not taking into account indeterminate, missing, or contaminated results. Sustained SCC was analyzed at Month 18 to 30 using MGIT.
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Unnamed facility
Vilnius, Lithuania
Unnamed facility
Chisinau, Moldova
Unnamed facility
Vorniceni, Moldova
Unnamed facility
Alfonso Ugarte, Peru
Unnamed facility
Comas, Peru
Unnamed facility
El Agustino, Peru
Unnamed facility
Lima Cercado, Peru
...and 7 more locations
Time frame: Month 18, Month 24, and Month 30
Treatment Outcomes Assessed By Principal Investigators (PI)At The End Of Treatment With OBR
Final treatment outcomes were assessed by the Principal Investigator (PI) at the end of treatment with OBR (24 months post randomization) according to the 2008 World Health Organization (WHO) outcome definitions for treating participants with multidrug-resistant tuberculosis (MDR TB). Frequency counts and percentage of participants achieving favorable and unfavorable outcomes were provided by treatment group. Participants who had non-missing Principal Investigator assessed treatment outcomes at the end of treatment with OBR were included in the analysis.
Time frame: Month 24
Number of Participants Who Developed Resistance To Delamanid
Acquired resistance was defined as a post-baseline resistant result at any time point after a Baseline susceptible result. The overall resistance to delamanid during the trial was assessed.
Time frame: Up to Month 30
Mean (Time Averaged) Area Under The Curve (AUC) Of Change From Baseline In Time To Detection (TTD) To Month 6 Using MGIT
The value for TTD was defined (in days) as the time interval from inoculation until a MGIT machine detects a positive signal for a sputum culture. The AUC of the change from Baseline for TTD in days (from Baseline to Month 6) summarizes the overall participant response for the treatment period. The change from Baseline in original time to detection of MGIT positive signal, in days, up to 6 months was performed using AUC in MGIT. The Baseline was defined as the average of Day -1 and Day 1 values if cultures on both days were positive; if only 1 culture was positive, the value for TTD for the positive culture was used as the Baseline. The TTD is Time to Detection measured by day, so the unit of AUC of change from baseline in TTD is day\*day. Since "Mean AUC" is reported, which is actually "Time Averaged AUC," the AUC was divided by the duration of the observation, and thus the unit of the Mean AUC is day.
Time frame: Baseline, up to Month 6
Mean Change From Baseline In TTD Using The MGIT System
The value for TTD was defined (in days) as the time interval from inoculation until a MGIT machine detects a positive signal for a sputum culture during the routine 42-day incubation period. TTD analysis was based only on the corresponding qualitative sputum results of pure positive and pure negative cultures in days and hours of the initial positive signal for a culture from the MGIT printout. Mean change is reported for Baseline, Week 1, Week 2, Week 3, Week 24, Week 26, and Last visit (Month 18 or last visit for participants treated beyond Month 18).
Time frame: Baseline, Week 1, Week 2, Week 3, Week 24, Week 26, and Last visit (Month 18 or last visit for participants treated beyond Month 18)
Proportion of Participants With Final Outcome At Month 30 As A Treatment Success Or Failure (Including Relapse) Using MGIT
Treatment success was defined as achieving SCC by 6 months using MGIT, completing the trial out to 30 months with sustained SCC and alive at the last contact for follow-up. All other participants were treatment failures who failed to achieve SCC by Month 6, achieved SCC but have a confirmed positive, early terminate from the trial prior to the Month 30 visit but are alive at the last contact for follow-up, lost to follow-up and vital status unknown and death.
Time frame: Month 30