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

• 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: Otsuka Pharmaceutical Development & Commercialization, Inc.
• 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

Participant Flow

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
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

Baseline Characteristics

Arm/Group Title		Delamanid + OBR	Placebo + OBR	Total
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
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%

Outcome Measures

1. Primary Outcome

Title	Time To Sputum Culture Conversion (SCC) During 6-Month Intensive Period Using The Mycobacteria Growth Indicator Tube (MGIT) System
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

Outcome Measure Data

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
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)

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
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

Outcome Measure Data

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
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%

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.

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
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

Outcome Measure Data

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
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%

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]

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]

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
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

Outcome Measure Data

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
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%

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
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

Outcome Measure Data

Analysis Population Description

The intent-to-treat (ITT) sample comprised all randomized participants.

Arm/Group Title	Delamanid + OBR	Placebo + OBR
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
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

Outcome Measure Data

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
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)

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
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)

Outcome Measure Data

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
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)

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]

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]

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]

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]

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
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

Outcome Measure Data

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
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%

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]

Adverse Events

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
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%)
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
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

Limitations and Caveats

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.

More Information

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

• Name/Title: Global Clinical Development
• Organization: Otsuka Pharmaceutical Development & Commercialization, Inc.
• Phone: +1-609-524-6788
• EMail: clinicaltransparency@otsuka-us.com

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

von Groote-Bidlingmaier F, Patientia R, Sanchez E, Balanag V Jr, Ticona E, Segura P, Cadena E, Yu C, Cirule A, Lizarbe V, Davidaviciene E, Domente L, Variava E, Caoili J, Danilovits M, Bielskiene V, Staples S, Hittel N, Petersen C, Wells C, Hafkin J, Geiter LJ, Gupta R. Efficacy and safety of delamanid in combination with an optimised background regimen for treatment of multidrug-resistant tuberculosis: a multicentre, randomised, double-blind, placebo-controlled, parallel group phase 3 trial. Lancet Respir Med. 2019 Mar;7(3):249-259. doi: 10.1016/S2213-2600(18)30426-0. Epub 2019 Jan 7.

• Responsible Party: Otsuka Pharmaceutical Development & Commercialization, Inc.
• ClinicalTrials.gov Identifier: NCT01424670
• 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