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Trial record 2 of 22 for:    delamanid

Safety and Efficacy Trial of Delamanid for 6 Months in Participants With Multidrug-resistant Tuberculosis

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ClinicalTrials.gov Identifier: NCT01424670
Recruitment Status : Completed
First Posted : August 29, 2011
Results First Posted : May 15, 2019
Last Update Posted : May 15, 2019
Sponsor:
Information provided by (Responsible Party):
Otsuka Pharmaceutical Development & Commercialization, Inc.

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: Triple (Participant, Care Provider, Investigator);   Primary Purpose: Treatment
Condition Multidrug-resistant Tuberculosis
Interventions Drug: Delamanid + OBR
Drug: Placebo + OBR
Enrollment 511
Recruitment Details  
Pre-assignment Details 511 participants were randomized to receive investigational medicinal product (IMP) and an optimized background treatment regimen (OBR) for 6 months, followed by OBR treatment alone for 12-18 months. The trial also included a post-treatment follow-up period of 6-12 months. Participants who stopped taking IMP and/or OBR could remain in the study.
Arm/Group Title Delamanid + OBR Placebo + OBR
Hide Arm/Group Description

In the first period of this study, known as the 6-month Intensive Period, participants were randomized to receive 100 milligrams (mg) delamanid orally twice daily (BID) (morning and evening) + OBR for 2 months, followed by 200 mg delamanid once daily (QD) (every morning) + OBR for 4 months.

Following the 6-month Intensive Period, participants entered the second period of the study, known as the Continuation Period, wherein OBR was administered alone for 12 to 18 months.

In the first period of this study, known as the 6-month Intensive Period, participants were randomized to receive placebo orally BID (morning and evening) + OBR for 2 months followed by placebo QD (every morning) + OBR for 4 months.

Following the 6-month Intensive Period, participants entered the second period of the study, known as the Continuation Period, wherein OBR was administered alone for 12 to 18 months.

Period Title: 6-Month Intensive Period (182 Days)
Started 341 170
Received at Least 1 Dose of Study Drug 341 170
Completed [1] 322 156
Not Completed 19 14
Reason Not Completed
Adverse Event             2             2
Lost to Follow-up             0             1
Met Protocol Withdrawal Criteria             2             1
Physician Decision             2             3
Withdrawal by Subject             13             7
[1]
The duration of the 6-month Intensive Period was over 182 days from the date of the first dose.
Period Title: Continuation Period
Started 322 156
Completed 288 142
Not Completed 34 14
Reason Not Completed
Adverse Event             13             5
Lost to Follow-up             2             0
Met Protocol Withdrawal Criteria             1             1
Physician Decision             5             4
Withdrawal by Subject             13             4
Arm/Group Title Delamanid + OBR Placebo + OBR Total
Hide Arm/Group Description

In the first period of this study, known as the 6-month Intensive Period, participants were randomized to receive 100 mg delamanid orally BID (morning and evening) + OBR for 2 months, followed by 200 mg delamanid QD (every morning) + OBR for 4 months.

Following the 6-month Intensive Period, participants entered the second period of the study, known as the Continuation Period, wherein OBR was administered alone for 12 to 18 months.

In the first period of this study, known as the 6-month Intensive Period, participants were randomized to receive placebo orally BID (morning and evening) + OBR for 2 months followed by placebo QD (every morning) + OBR for 4 months.

Following the 6-month Intensive Period, participants entered the second period of the study, known as the Continuation Period, wherein OBR was administered alone for 12 to 18 months.

Total of all reporting groups
Overall Number of Baseline Participants 341 170 511
Hide Baseline Analysis Population Description
The Intent-to-treat Sample comprised all participants who were randomized to receive either delamanid + OBR or placebo + OBR in this study.
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 341 participants 170 participants 511 participants
34.3  (12.1) 34.4  (12.2) 34.3  (12.1)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 341 participants 170 participants 511 participants
Female
98
  28.7%
45
  26.5%
143
  28.0%
Male
243
  71.3%
125
  73.5%
368
  72.0%
1.Primary Outcome
Title Time To Sputum Culture Conversion (SCC) During 6-Month Intensive Period Using The Mycobacteria Growth Indicator Tube (MGIT) System
Hide Description 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
Hide Outcome Measure Data
Hide Analysis Population Description
The modified intent-to-treat (MITT) sample comprised all randomized participants who had a positive sputum culture for MTB in MGIT and were resistant to both isoniazid and rifampicin from the sputum samples collected on either Day -1 or Day 1, or both.
Arm/Group Title Delamanid + OBR Placebo + OBR
Hide Arm/Group Description:
In the 6-month Intensive Period, participants were randomized to receive 100 mg delamanid orally BID (morning and evening) + OBR for 2 months, followed by 200 mg delamanid QD (every morning) + OBR for 4 months.
In the 6-month Intensive Period, participants were randomized to receive placebo orally BID (morning and evening) + OBR for 2 months followed by placebo QD (every morning) + OBR for 4 months.
Overall Number of Participants Analyzed 226 101
Median (95% Confidence Interval)
Unit of Measure: Days
51
(43 to 57)
57
(56 to 64)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Delamanid + OBR, Placebo + OBR
Comments Comparison of distributions of time to SCC using the MGIT culture system during the 6-month (26-week) Intensive Period.
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0562
Comments For testing the null hypothesis, the distribution of the time to SCC within the 6-month Intensive Period were compared between the 2 treatment groups using the stratified modified Peto-Peto modification of Gehan’s Wilcoxon rank sum test.
Method Modified Peto-Peto test
Comments [Not Specified]
2.Secondary Outcome
Title Proportion of Participants With SCC At 2 And 6 Months Using MGIT
Hide Description

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
Hide Outcome Measure Data
Hide Analysis Population Description
The MITT sample comprised all randomized participants who had a positive sputum culture for MTB in MGIT and were resistant to both isoniazid and rifampicin from the sputum samples collected on either Day -1 or Day 1, or both.
Arm/Group Title Delamanid + OBR Placebo + OBR
Hide Arm/Group Description:
In the 6-month Intensive Period, participants were randomized to receive 100 mg delamanid orally BID (morning and evening) + OBR for 2 months, followed by 200 mg delamanid QD (every morning) + OBR for 4 months.
In the 6-month Intensive Period, participants were randomized to receive placebo orally BID (morning and evening) + OBR for 2 months followed by placebo QD (every morning) + OBR for 4 months.
Overall Number of Participants Analyzed 226 101
Measure Type: Count of Participants
Unit of Measure: Participants
At Month 2
132
  58.4%
54
  53.5%
At Month 6
198
  87.6%
87
  86.1%
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Delamanid + OBR, Placebo + OBR
Comments Statistical comparison of proportion of participants with SCC at 2 months.
Type of Statistical Test Superiority
Comments For testing the homogeneity of proportions, 2 samples were compared using the stratified Cochran-Mantel-Haenszel test.
Statistical Test of Hypothesis P-Value 0.3818
Comments [Not Specified]
Method Cochran-Mantel-Haenszel
Comments [Not Specified]
Method of Estimation Estimation Parameter Ratio of Probability
Estimated Value 1.096
Confidence Interval (2-Sided) 95%
0.889 to 1.352
Estimation Comments The stratified Cochran-Mantel-Haenszel test statistics were used for estimation.
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Delamanid + OBR, Placebo + OBR
Comments Statistical comparison of proportion of participants with SCC at 6 months.
Type of Statistical Test Superiority
Comments For testing the homogeneity of proportions, 2 samples were compared using the stratified Cochran-Mantel-Haenszel test.
Statistical Test of Hypothesis P-Value 0.7131
Comments [Not Specified]
Method Cochran-Mantel-Haenszel
Comments [Not Specified]
Method of Estimation Estimation Parameter Ratio of Probability
Estimated Value 1.017
Confidence Interval (2-Sided) 95%
0.927 to 1.115
Estimation Comments The stratified Cochran-Mantel-Haenszel test statistics were used for estimation.
3.Secondary Outcome
Title Proportion of Participants With Sustained SCC At Month 18, Month 24, And Month 30 Using MGIT
Hide Description 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.
Time Frame Month 18, Month 24, and Month 30
Hide Outcome Measure Data
Hide Analysis Population Description
The MITT sample comprised all randomized participants who had a positive sputum culture for MTB in MGIT and were resistant to both isoniazid and rifampicin from the sputum samples collected on either Day -1 or Day 1, or both.
Arm/Group Title Delamanid + OBR Placebo + OBR
Hide Arm/Group Description:

In the first period of this study, known as the 6-month Intensive Period, participants were randomized to receive 100 mg delamanid orally BID (morning and evening) + OBR for 2 months, followed by 200 mg delamanid QD (every morning) + OBR for 4 months.

Following the 6-month Intensive Period, participants entered the second period of the study, known as the Continuation Period, wherein OBR was administered alone for 12 to 18 months.

In the first period of this study, known as the 6-month Intensive Period, participants were randomized to receive placebo orally BID (morning and evening) + OBR for 2 months followed by placebo QD (every morning) + OBR for 4 months.

Following the 6-month Intensive Period, participants entered the second period of the study, known as the Continuation Period, wherein OBR was administered alone for 12 to 18 months.

Overall Number of Participants Analyzed 226 101
Measure Type: Count of Participants
Unit of Measure: Participants
At 18 months
180
  79.6%
83
  82.2%
At 24 months
178
  78.8%
82
  81.2%
At 30 months
173
  76.5%
78
  77.2%
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Delamanid + OBR, Placebo + OBR
Comments Statistical comparison of proportion with sustained SCC at Month 18.
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.5945
Comments [Not Specified]
Method Cochran-Mantel-Haenszel
Comments [Not Specified]
Method of Estimation Estimation Parameter Relative Ratio of Probability
Estimated Value 0.969
Confidence Interval (2-Sided) 95%
0.866 to 1.084
Estimation Comments [Not Specified]
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Delamanid + OBR, Placebo + OBR
Comments Statistical comparison of proportion with sustained SCC at Month 24.
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.6164
Comments [Not Specified]
Method Cochran-Mantel-Haenszel
Comments [Not Specified]
Method of Estimation Estimation Parameter Relative Ratio of Probability
Estimated Value 0.97
Confidence Interval (2-Sided) 95%
0.864 to 1.089
Estimation Comments [Not Specified]
Show Statistical Analysis 3 Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Delamanid + OBR, Placebo + OBR
Comments Statistical comparison of proportion with sustained SCC at Month 30.
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.8951
Comments [Not Specified]
Method Cochran-Mantel-Haenszel
Comments [Not Specified]
Method of Estimation Estimation Parameter Relative Ratio of Probability
Estimated Value 0.991
Confidence Interval (2-Sided) 95%
0.872 to 1.127
Estimation Comments [Not Specified]
4.Secondary Outcome
Title Treatment Outcomes Assessed By Principal Investigators (PI)At The End Of Treatment With OBR
Hide Description 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
Hide Outcome Measure Data
Hide Analysis Population Description
The MITT sample comprised all randomized participants who had a positive sputum culture for MTB in MGIT and were resistant to both isoniazid and rifampicin from the sputum samples collected on either Day -1 or Day 1, or both.
Arm/Group Title Delamanid + OBR Placebo + OBR
Hide Arm/Group Description:

In the first period of this study, known as the 6-month Intensive Period, participants were randomized to receive 100 mg delamanid orally BID (morning and evening) + OBR for 2 months, followed by 200 mg delamanid QD (every morning) + OBR for 4 months.

Following the 6-month Intensive Period, participants entered the second period of the study, known as the Continuation Period, wherein OBR was administered alone for 12 to 18 months.

In the first period of this study, known as the 6-month Intensive Period, participants were randomized to receive placebo orally BID (morning and evening) + OBR for 2 months followed by placebo QD (every morning) + OBR for 4 months.

Following the 6-month Intensive Period, participants entered the second period of the study, known as the Continuation Period, wherein OBR was administered alone for 12 to 18 months.

Overall Number of Participants Analyzed 226 101
Measure Type: Count of Participants
Unit of Measure: Participants
Favorable outcome
182
  80.5%
85
  84.2%
Unfavorable outcome
42
  18.6%
16
  15.8%
Missing PI Assessments
2
   0.9%
0
   0.0%
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Delamanid + OBR, Placebo + OBR
Comments Statistical comparison of proportions with favorable treatment outcomes assessed by the Principal Investigator.
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.5269
Comments [Not Specified]
Method Cochran-Mantel-Haenszel
Comments [Not Specified]
Method of Estimation Estimation Parameter Relative Ratio of Probability
Estimated Value 0.965
Confidence Interval (2-Sided) 95%
0.869 to 1.073
Estimation Comments [Not Specified]
5.Secondary Outcome
Title Number of Participants Who Developed Resistance To Delamanid
Hide Description 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
Hide Outcome Measure Data
Hide Analysis Population Description
The intent-to-treat (ITT) sample comprised all randomized participants.
Arm/Group Title Delamanid + OBR Placebo + OBR
Hide Arm/Group Description:

In the first period of this study, known as the 6-month Intensive Period, participants were randomized to receive 100 mg delamanid orally BID (morning and evening) + OBR for 2 months, followed by 200 mg delamanid QD (every morning) + OBR for 4 months.

Following the 6-month Intensive Period, participants entered the second period of the study, known as the Continuation Period, wherein OBR was administered alone for 12 to 18 months.

In the first period of this study, known as the 6-month Intensive Period, participants were randomized to receive placebo orally BID (morning and evening) + OBR for 2 months followed by placebo QD (every morning) + OBR for 4 months.

Following the 6-month Intensive Period, participants entered the second period of the study, known as the Continuation Period, wherein OBR was administered alone for 12 to 18 months.

Overall Number of Participants Analyzed 341 170
Measure Type: Number
Unit of Measure: participants
3 0
6.Secondary Outcome
Title Mean (Time Averaged) Area Under The Curve (AUC) Of Change From Baseline In Time To Detection (TTD) To Month 6 Using MGIT
Hide Description

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
Hide Outcome Measure Data
Hide Analysis Population Description
The MITT sample comprised all randomized participants who had a positive sputum culture for MTB in MGIT and were resistant to both isoniazid and rifampicin from the sputum samples collected on either Day -1 or Day 1, or both, who had both a baseline and at least one post baseline TTD value.
Arm/Group Title Delamanid + OBR Placebo + OBR
Hide Arm/Group Description:
In the 6-month Intensive Period, participants were randomized to receive 100 mg delamanid orally BID (morning and evening) + OBR for 2 months, followed by 200 mg delamanid QD (every morning) + OBR for 4 months.
In the 6-month Intensive Period, participants were randomized to receive placebo orally BID (morning and evening) + OBR for 2 months followed by placebo QD (every morning) + OBR for 4 months.
Overall Number of Participants Analyzed 221 98
Mean (Standard Deviation)
Unit of Measure: days
21.9  (9.44) 23.3  (8.93)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Delamanid + OBR, Placebo + OBR
Comments Statistical comparison of mean AUC of change from Baseline.
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.6986
Comments [Not Specified]
Method ANCOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value -0.3
Confidence Interval (2-Sided) 95%
-1.9 to 1.3
Estimation Comments [Not Specified]
7.Secondary Outcome
Title Mean Change From Baseline In TTD Using The MGIT System
Hide Description 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)
Hide Outcome Measure Data
Hide Analysis Population Description
The MITT sample comprised all randomized participants who had a positive sputum culture for MTB in MGIT and were resistant to both isoniazid and rifampicin from the sputum samples collected on either Day -1 or Day 1, or both.
Arm/Group Title Delamanid + OBR Placebo + OBR
Hide Arm/Group Description:

In the first period of this study, known as the 6-month Intensive Period, participants were randomized to receive 100 mg delamanid orally BID (morning and evening) + OBR for 2 months, followed by 200 mg delamanid QD (every morning) + OBR for 4 months.

Following the 6-month Intensive Period, participants entered the second period of the study, known as the Continuation Period, wherein OBR was administered alone for 12 to 18 months.

In the first period of this study, known as the 6-month Intensive Period, participants were randomized to receive placebo orally BID (morning and evening) + OBR for 2 months followed by placebo QD (every morning) + OBR for 4 months.

Following the 6-month Intensive Period, participants entered the second period of the study, known as the Continuation Period, wherein OBR was administered alone for 12 to 18 months.

Overall Number of Participants Analyzed 226 101
Mean (Standard Deviation)
Unit of Measure: days
At Baseline Number Analyzed 222 participants 98 participants
16.7  (7.9) 15.4  (7.7)
At Week 1 Number Analyzed 204 participants 94 participants
20.8  (10.3) 19.9  (11.1)
Change from Baseline at Week 1 Number Analyzed 204 participants 94 participants
4.3  (7.9) 4.8  (7.8)
At Week 2 Number Analyzed 206 participants 87 participants
24.6  (11.5) 23.1  (11.4)
Change from Baseline at Week 2 Number Analyzed 206 participants 87 participants
7.7  (8.9) 7.5  (7.8)
At Week 3 Number Analyzed 209 participants 89 participants
28.4  (11.8) 25.5  (12.4)
Change from Baseline at Week 3 Number Analyzed 209 participants 89 participants
11.6  (9.8) 10.4  (9.6)
At Week 24 Number Analyzed 195 participants 80 participants
40.4  (6.6) 41.3  (3.9)
Change from Baseline at Week 24 Number Analyzed 195 participants 80 participants
23.4  (10.2) 25.5  (8.3)
At Week 26 Number Analyzed 188 participants 82 participants
40.6  (5.9) 40.5  (5.5)
Change from Baseline at Week 26 Number Analyzed 188 participants 82 participants
23.8  (9.5) 24.6  (9.4)
At Last Visit Number Analyzed 222 participants 98 participants
39.4  (8.4) 40.3  (6.3)
Change from Baseline at Last Visit Number Analyzed 222 participants 98 participants
22.7  (10.7) 24.9  (9.5)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Delamanid + OBR, Placebo + OBR
Comments Statistical analysis for Week 1.
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.6825
Comments [Not Specified]
Method ANCOVA
Comments [Not Specified]
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Delamanid + OBR, Placebo + OBR
Comments Statistical analysis for Week 2.
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.807
Comments [Not Specified]
Method ANCOVA
Comments [Not Specified]
Show Statistical Analysis 3 Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Delamanid + OBR, Placebo + OBR
Comments Statistical analysis for Week 3.
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.269
Comments [Not Specified]
Method ANCOVA
Comments [Not Specified]
Show Statistical Analysis 4 Hide Statistical Analysis 4
Statistical Analysis Overview Comparison Group Selection Delamanid + OBR, Placebo + OBR
Comments Statistical analysis for Week 24.
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.2333
Comments [Not Specified]
Method ANCOVA
Comments [Not Specified]
Show Statistical Analysis 5 Hide Statistical Analysis 5
Statistical Analysis Overview Comparison Group Selection Delamanid + OBR, Placebo + OBR
Comments Statistical analysis for Month 6.
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.9397
Comments [Not Specified]
Method ANCOVA
Comments [Not Specified]
8.Secondary Outcome
Title Proportion of Participants With Final Outcome At Month 30 As A Treatment Success Or Failure (Including Relapse) Using MGIT
Hide Description 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
Hide Outcome Measure Data
Hide Analysis Population Description
The MITT sample comprised all randomized participants who had a positive sputum culture for MTB in MGIT and were resistant to both isoniazid and rifampicin from the sputum samples collected on either Day -1 or Day 1, or both.
Arm/Group Title Delamanid + OBR Placebo + OBR
Hide Arm/Group Description:

In the first period of this study, known as the 6-month Intensive Period, participants were randomized to receive 100 mg delamanid orally BID (morning and evening) + OBR for 2 months, followed by 200 mg delamanid QD (every morning) + OBR for 4 months.

Following the 6-month Intensive Period, participants entered the second period of the study, known as the Continuation Period, wherein OBR was administered alone for 12 to 18 months.

In the first period of this study, known as the 6-month Intensive Period, participants were randomized to receive placebo orally BID (morning and evening) + OBR for 2 months followed by placebo QD (every morning) + OBR for 4 months.

Following the 6-month Intensive Period, participants entered the second period of the study, known as the Continuation Period, wherein OBR was administered alone for 12 to 18 months.

Overall Number of Participants Analyzed 226 101
Measure Type: Count of Participants
Unit of Measure: Participants
Success
173
  76.5%
78
  77.2%
Failure
53
  23.5%
23
  22.8%
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Delamanid + OBR, Placebo + OBR
Comments Statistical comparison of proportion with treatment success at Month 30.
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.8951
Comments [Not Specified]
Method Cochran-Mantel-Haenszel
Comments [Not Specified]
Method of Estimation Estimation Parameter Relative Ratio of Probability
Estimated Value 0.991
Confidence Interval (2-Sided) 95%
0.872 to 1.127
Estimation Comments [Not Specified]
Time Frame Adverse events were collected throughout the study (30 months)
Adverse Event Reporting Description Adverse events were collected for randomized participants who received any amount of study drug, regardless of any protocol deviation or violation.
 
Arm/Group Title Delamanid + OBR Placebo + OBR
Hide Arm/Group Description

In the first period of this study, known as the 6-month Intensive Period, participants were randomized to receive 100 mg delamanid orally BID (morning and evening) + OBR for 2 months, followed by 200 mg delamanid QD (every morning) + OBR for 4 months.

Following the 6-month Intensive Period, participants entered the second period of the study, known as the Continuation Period, wherein OBR was administered alone for 12 to 18 months.

In the first period of this study, known as the 6-month Intensive Period, participants were randomized to receive placebo orally BID (morning and evening) + OBR for 2 months followed by placebo QD (every morning) + OBR for 4 months.

Following the 6-month Intensive Period, participants entered the second period of the study, known as the Continuation Period, wherein OBR was administered alone for 12 to 18 months.

All-Cause Mortality
Delamanid + OBR Placebo + OBR
Affected / at Risk (%) Affected / at Risk (%)
Total   18/341 (5.28%)   8/170 (4.71%) 
Show Serious Adverse Events Hide Serious Adverse Events
Delamanid + OBR Placebo + OBR
Affected / at Risk (%) Affected / at Risk (%)
Total   89/341 (26.10%)   47/170 (27.65%) 
Blood and lymphatic system disorders     
Anaemia  1  1/341 (0.29%)  0/170 (0.00%) 
Anaemia macrocytic  1  1/341 (0.29%)  0/170 (0.00%) 
Anaemia of chronic disease  1  1/341 (0.29%)  0/170 (0.00%) 
Neutropenia  1  1/341 (0.29%)  0/170 (0.00%) 
Thrombocytopenia  1  1/341 (0.29%)  0/170 (0.00%) 
Cardiac disorders     
Acute myocardial infarction  1  0/341 (0.00%)  1/170 (0.59%) 
Atrial fibrillation  1  0/341 (0.00%)  1/170 (0.59%) 
Cardiac arrest  1  0/341 (0.00%)  1/170 (0.59%) 
Cardiac failure acute  1  1/341 (0.29%)  0/170 (0.00%) 
Cardiac failure congestive  1  1/341 (0.29%)  0/170 (0.00%) 
Cardiopulmonary failure  1  0/341 (0.00%)  1/170 (0.59%) 
Cardiovascular insufficiency  1  1/341 (0.29%)  0/170 (0.00%) 
Cor pulmonale  1  1/341 (0.29%)  0/170 (0.00%) 
Metabolic cardiomyopathy  1  1/341 (0.29%)  0/170 (0.00%) 
Myocardial infarction  1  1/341 (0.29%)  0/170 (0.00%) 
Myocardial ischaemia  1  1/341 (0.29%)  0/170 (0.00%) 
Ear and labyrinth disorders     
Deafness  1  1/341 (0.29%)  1/170 (0.59%) 
Deafness bilateral  1  4/341 (1.17%)  4/170 (2.35%) 
Endocrine disorders     
Goitre  1  1/341 (0.29%)  0/170 (0.00%) 
Hypothyroidism  1  1/341 (0.29%)  0/170 (0.00%) 
Eye disorders     
Glaucoma  1  1/341 (0.29%)  0/170 (0.00%) 
Gastrointestinal disorders     
Abdominal pain  1  0/341 (0.00%)  1/170 (0.59%) 
Abdominal pain upper  1  1/341 (0.29%)  0/170 (0.00%) 
Gastritis  1  2/341 (0.59%)  0/170 (0.00%) 
Gastroduodenitis  1  1/341 (0.29%)  0/170 (0.00%) 
Gastrooesophageal reflux disease  1  2/341 (0.59%)  0/170 (0.00%) 
Ileal perforation  1  1/341 (0.29%)  0/170 (0.00%) 
Ileus  1  1/341 (0.29%)  0/170 (0.00%) 
Oedematous pancreatitis  1  1/341 (0.29%)  0/170 (0.00%) 
Pancreatic pseudocyst  1  1/341 (0.29%)  0/170 (0.00%) 
Pancreatitis  1  1/341 (0.29%)  0/170 (0.00%) 
Pancreatitis acute  1  2/341 (0.59%)  0/170 (0.00%) 
General disorders     
Asthenia  1  2/341 (0.59%)  0/170 (0.00%) 
Hypothermia  1  1/341 (0.29%)  0/170 (0.00%) 
Multiple organ dysfunction syndrome  1  1/341 (0.29%)  0/170 (0.00%) 
Hepatobiliary disorders     
Cholecystitis  1  1/341 (0.29%)  0/170 (0.00%) 
Cholelithiasis  1  1/341 (0.29%)  0/170 (0.00%) 
Cholestasis  1  0/341 (0.00%)  1/170 (0.59%) 
Drug-induced liver injury  1  0/341 (0.00%)  1/170 (0.59%) 
Hepatitis acute  1  1/341 (0.29%)  0/170 (0.00%) 
Hepatitis alcoholic  1  0/341 (0.00%)  1/170 (0.59%) 
Hepatitis toxic  1  2/341 (0.59%)  0/170 (0.00%) 
Hepatotoxicity  1  3/341 (0.88%)  2/170 (1.18%) 
Hypertransaminasaemia  1  1/341 (0.29%)  0/170 (0.00%) 
Jaundice  1  1/341 (0.29%)  0/170 (0.00%) 
Immune system disorders     
Hypersensitivity  1  0/341 (0.00%)  1/170 (0.59%) 
Infections and infestations     
Appendicitis  1  1/341 (0.29%)  2/170 (1.18%) 
Appendicitis perforated  1  1/341 (0.29%)  0/170 (0.00%) 
Cellulitis  1  1/341 (0.29%)  0/170 (0.00%) 
Empyema  1  1/341 (0.29%)  0/170 (0.00%) 
Gastroenteritis  1  2/341 (0.59%)  1/170 (0.59%) 
Lung abscess  1  1/341 (0.29%)  0/170 (0.00%) 
Osteomyelitis  1  1/341 (0.29%)  0/170 (0.00%) 
Peritonitis  1  1/341 (0.29%)  0/170 (0.00%) 
Pneumonia  1  3/341 (0.88%)  2/170 (1.18%) 
Pneumonia necrotising  1  0/341 (0.00%)  1/170 (0.59%) 
Pneumonia viral  1  1/341 (0.29%)  0/170 (0.00%) 
Pulmonary tuberculoma  1  1/341 (0.29%)  0/170 (0.00%) 
Pulmonary tuberculosis  1  2/341 (0.59%)  1/170 (0.59%) 
Sepsis  1  1/341 (0.29%)  1/170 (0.59%) 
Tuberculoma of central nervous system  1  1/341 (0.29%)  0/170 (0.00%) 
Tuberculosis  1  11/341 (3.23%)  3/170 (1.76%) 
Tuberculous pleurisy  1  1/341 (0.29%)  0/170 (0.00%) 
Urinary tract infection  1  1/341 (0.29%)  0/170 (0.00%) 
Viral infection  1  1/341 (0.29%)  0/170 (0.00%) 
Injury, poisoning and procedural complications     
Abdominal injury  1  1/341 (0.29%)  1/170 (0.59%) 
Alcohol poisoning  1  2/341 (0.59%)  0/170 (0.00%) 
Ankle fracture  1  0/341 (0.00%)  2/170 (1.18%) 
Chest injury  1  0/341 (0.00%)  1/170 (0.59%) 
Femoral neck fracture  1  1/341 (0.29%)  1/170 (0.59%) 
Foot fracture  1  1/341 (0.29%)  0/170 (0.00%) 
Jaw fracture  1  1/341 (0.29%)  0/170 (0.00%) 
Kidney contusion  1  1/341 (0.29%)  0/170 (0.00%) 
Lower limb fracture  1  0/341 (0.00%)  1/170 (0.59%) 
Spinal compression fracture  1  1/341 (0.29%)  0/170 (0.00%) 
Subdural haematoma  1  1/341 (0.29%)  0/170 (0.00%) 
Investigations     
Alanine aminotransferase increased  1  1/341 (0.29%)  0/170 (0.00%) 
Aspartate aminotransferase increased  1  1/341 (0.29%)  0/170 (0.00%) 
Electrocardiogram QT prolonged  1  6/341 (1.76%)  1/170 (0.59%) 
Gamma-glutamyltransferase increased  1  1/341 (0.29%)  0/170 (0.00%) 
Transaminases increased  1  1/341 (0.29%)  3/170 (1.76%) 
Metabolism and nutrition disorders     
Cachexia  1  1/341 (0.29%)  0/170 (0.00%) 
Electrolyte imbalance  1  2/341 (0.59%)  0/170 (0.00%) 
Hypocalcaemia  1  1/341 (0.29%)  1/170 (0.59%) 
Hypochloraemia  1  1/341 (0.29%)  1/170 (0.59%) 
Hypokalaemia  1  9/341 (2.64%)  3/170 (1.76%) 
Hypomagnesaemia  1  3/341 (0.88%)  1/170 (0.59%) 
Hyponatraemia  1  0/341 (0.00%)  1/170 (0.59%) 
Neoplasms benign, malignant and unspecified (incl cysts and polyps)     
Brain neoplasm  1  1/341 (0.29%)  0/170 (0.00%) 
Lung adenocarcinoma metastatic  1  0/341 (0.00%)  1/170 (0.59%) 
Malignant neoplasm of unknown primary site  1  1/341 (0.29%)  0/170 (0.00%) 
Meningioma  1  1/341 (0.29%)  0/170 (0.00%) 
Squamous cell carcinoma of lung  1  1/341 (0.29%)  1/170 (0.59%) 
Squamous cell carcinoma of the oral cavity  1  0/341 (0.00%)  1/170 (0.59%) 
Nervous system disorders     
Brain oedema  1  0/341 (0.00%)  1/170 (0.59%) 
Cerebral infarction  1  1/341 (0.29%)  0/170 (0.00%) 
Cerebrovascular accident  1  1/341 (0.29%)  0/170 (0.00%) 
Seizure  1  1/341 (0.29%)  0/170 (0.00%) 
Tremor  1  1/341 (0.29%)  0/170 (0.00%) 
Psychiatric disorders     
Acute psychosis  1  2/341 (0.59%)  0/170 (0.00%) 
Alcohol abuse  1  2/341 (0.59%)  0/170 (0.00%) 
Anxiety  1  1/341 (0.29%)  0/170 (0.00%) 
Anxiety disorder  1  1/341 (0.29%)  0/170 (0.00%) 
Completed suicide  1  1/341 (0.29%)  0/170 (0.00%) 
Confusional state  1  1/341 (0.29%)  1/170 (0.59%) 
Delirium tremens  1  1/341 (0.29%)  1/170 (0.59%) 
Depression  1  1/341 (0.29%)  1/170 (0.59%) 
Major depression  1  1/341 (0.29%)  0/170 (0.00%) 
Panic attack  1  0/341 (0.00%)  1/170 (0.59%) 
Psychotic disorder  1  3/341 (0.88%)  1/170 (0.59%) 
Reactive psychosis  1  1/341 (0.29%)  0/170 (0.00%) 
Substance-induced psychotic disorder  1  2/341 (0.59%)  0/170 (0.00%) 
Suicidal ideation  1  1/341 (0.29%)  0/170 (0.00%) 
Suicide attempt  1  1/341 (0.29%)  0/170 (0.00%) 
Renal and urinary disorders     
Acute kidney injury  1  3/341 (0.88%)  5/170 (2.94%) 
Azotaemia  1  0/341 (0.00%)  2/170 (1.18%) 
Nephropathy toxic  1  1/341 (0.29%)  0/170 (0.00%) 
Renal impairment  1  1/341 (0.29%)  0/170 (0.00%) 
Respiratory, thoracic and mediastinal disorders     
Acute respiratory failure  1  2/341 (0.59%)  0/170 (0.00%) 
Asphyxia  1  1/341 (0.29%)  0/170 (0.00%) 
Asthma  1  1/341 (0.29%)  0/170 (0.00%) 
Bronchiectasis  1  0/341 (0.00%)  1/170 (0.59%) 
Bullous lung disease  1  1/341 (0.29%)  0/170 (0.00%) 
Chronic obstructive pulmonary disease  1  1/341 (0.29%)  1/170 (0.59%) 
Haemoptysis  1  3/341 (0.88%)  2/170 (1.18%) 
Pneumothorax  1  0/341 (0.00%)  2/170 (1.18%) 
Pneumothorax spontaneous  1  1/341 (0.29%)  0/170 (0.00%) 
Pulmonary embolism  1  1/341 (0.29%)  0/170 (0.00%) 
Pulmonary fibrosis  1  2/341 (0.59%)  2/170 (1.18%) 
Pulmonary haematoma  1  0/341 (0.00%)  1/170 (0.59%) 
Pulmonary haemorrhage  1  1/341 (0.29%)  0/170 (0.00%) 
Pulmonary oedema  1  0/341 (0.00%)  1/170 (0.59%) 
Respiratory failure  1  1/341 (0.29%)  1/170 (0.59%) 
Restrictive pulmonary disease  1  0/341 (0.00%)  1/170 (0.59%) 
Skin and subcutaneous tissue disorders     
Diabetic foot  1  0/341 (0.00%)  1/170 (0.59%) 
Drug eruption  1  0/341 (0.00%)  2/170 (1.18%) 
Drug reaction with eosinophilia and systemic symptoms  1  1/341 (0.29%)  0/170 (0.00%) 
Urticaria  1  0/341 (0.00%)  1/170 (0.59%) 
Vascular disorders     
Deep vein thrombosis  1  3/341 (0.88%)  0/170 (0.00%) 
Hypertension  1  1/341 (0.29%)  0/170 (0.00%) 
Hypotension  1  1/341 (0.29%)  1/170 (0.59%) 
1
Term from vocabulary, MedDRA (19.0)
Indicates events were collected by systematic assessment
Show Other (Not Including Serious) Adverse Events Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 5%
Delamanid + OBR Placebo + OBR
Affected / at Risk (%) Affected / at Risk (%)
Total   335/341 (98.24%)   165/170 (97.06%) 
Blood and lymphatic system disorders     
Anaemia  1  17/341 (4.99%)  9/170 (5.29%) 
Cardiac disorders     
Palpitations  1  19/341 (5.57%)  12/170 (7.06%) 
Ear and labyrinth disorders     
Deafness bilateral  1  15/341 (4.40%)  9/170 (5.29%) 
Hypoacusis  1  15/341 (4.40%)  15/170 (8.82%) 
Tinnitus  1  71/341 (20.82%)  36/170 (21.18%) 
Eye disorders     
Vision blurred  1  13/341 (3.81%)  10/170 (5.88%) 
Gastrointestinal disorders     
Abdominal pain  1  33/341 (9.68%)  21/170 (12.35%) 
Abdominal pain upper  1  35/341 (10.26%)  28/170 (16.47%) 
Constipation  1  12/341 (3.52%)  13/170 (7.65%) 
Diarrhoea  1  62/341 (18.18%)  33/170 (19.41%) 
Dyspepsia  1  33/341 (9.68%)  14/170 (8.24%) 
Gastritis  1  76/341 (22.29%)  27/170 (15.88%) 
Gastrooesophageal reflux disease  1  19/341 (5.57%)  11/170 (6.47%) 
Nausea  1  95/341 (27.86%)  56/170 (32.94%) 
Toothache  1  29/341 (8.50%)  17/170 (10.00%) 
Vomiting  1  92/341 (26.98%)  39/170 (22.94%) 
General disorders     
Asthenia  1  27/341 (7.92%)  10/170 (5.88%) 
Chest pain  1  22/341 (6.45%)  8/170 (4.71%) 
Injection site pain  1  24/341 (7.04%)  20/170 (11.76%) 
Hepatobiliary disorders     
Hepatotoxicity  1  20/341 (5.87%)  11/170 (6.47%) 
Infections and infestations     
Bronchitis  1  19/341 (5.57%)  13/170 (7.65%) 
Influenza  1  21/341 (6.16%)  6/170 (3.53%) 
Nasopharyngitis  1  71/341 (20.82%)  43/170 (25.29%) 
Pharyngitis  1  32/341 (9.38%)  23/170 (13.53%) 
Rhinitis  1  13/341 (3.81%)  10/170 (5.88%) 
Upper respiratory tract infection  1  49/341 (14.37%)  21/170 (12.35%) 
Urinary tract infection  1  36/341 (10.56%)  15/170 (8.82%) 
Injury, poisoning and procedural complications     
Contusion  1  22/341 (6.45%)  10/170 (5.88%) 
Metabolism and nutrition disorders     
Decreased appetite  1  26/341 (7.62%)  9/170 (5.29%) 
Hyperuricaemia  1  34/341 (9.97%)  22/170 (12.94%) 
Hypokalaemia  1  53/341 (15.54%)  29/170 (17.06%) 
Hypomagnesaemia  1  20/341 (5.87%)  7/170 (4.12%) 
Musculoskeletal and connective tissue disorders     
Arthralgia  1  116/341 (34.02%)  65/170 (38.24%) 
Back pain  1  44/341 (12.90%)  31/170 (18.24%) 
Musculoskeletal pain  1  21/341 (6.16%)  10/170 (5.88%) 
Myalgia  1  31/341 (9.09%)  14/170 (8.24%) 
Pain in extremity  1  24/341 (7.04%)  16/170 (9.41%) 
Nervous system disorders     
Dizziness  1  51/341 (14.96%)  23/170 (13.53%) 
Headache  1  104/341 (30.50%)  39/170 (22.94%) 
Neuropathy peripheral  1  28/341 (8.21%)  18/170 (10.59%) 
Tremor  1  21/341 (6.16%)  5/170 (2.94%) 
Psychiatric disorders     
Adjustment disorder  1  8/341 (2.35%)  9/170 (5.29%) 
Alcohol abuse  1  14/341 (4.11%)  15/170 (8.82%) 
Anxiety  1  28/341 (8.21%)  21/170 (12.35%) 
Depression  1  26/341 (7.62%)  19/170 (11.18%) 
Insomnia  1  87/341 (25.51%)  46/170 (27.06%) 
Renal and urinary disorders     
Proteinuria  1  18/341 (5.28%)  7/170 (4.12%) 
Skin and subcutaneous tissue disorders     
Pruritus  1  28/341 (8.21%)  14/170 (8.24%) 
Rash  1  27/341 (7.92%)  9/170 (5.29%) 
1
Term from vocabulary, MedDRA (19.0)
Indicates events were collected by systematic assessment
The primary endpoint was established at 6 months. Treatment, intensive data collection, and statistical power calculations focused on the first 6 months. Given the unexpected placebo + OBR response, cautiously interpret 18, 24, and 30 month outcomes.
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
Results Point of Contact
Layout table for Results Point of Contact information
Name/Title: Global Clinical Development
Organization: Otsuka Pharmaceutical Development & Commercialization, Inc.
Phone: +1-609-524-6788
EMail: clinicaltransparency@otsuka-us.com
Layout table for additonal information
Responsible Party: Otsuka Pharmaceutical Development & Commercialization, Inc.
ClinicalTrials.gov Identifier: NCT01424670     History of Changes
Other Study ID Numbers: 242-09-213
First Submitted: August 25, 2011
First Posted: August 29, 2011
Results First Submitted: October 9, 2018
Results First Posted: May 15, 2019
Last Update Posted: May 15, 2019