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Clinical Trial Results:
A Phase 3, Multicenter, Randomized, Double-blind, Placebo-controlled, Parallel Group Trial to Evaluate the Safety and Efficacy of Delamanid (OPC-67683) Administered Orally as 200 mg Total Daily Dose for Six Months in Patients With Pulmonary Sputum Culture-positive, Multidrug-resistant Tuberculosis

Summary
EudraCT number	2010-022271-59
Trial protocol	LV EE LT
Global end of trial date	04 Jul 2016

Results information
Results version number	v1(current)
This version publication date	24 Oct 2017
First version publication date	24 Oct 2017
Other versions

Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information

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Trial information

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Sponsor protocol code

242-09-213

ISRCTN number

US NCT number

NCT01424670

WHO universal trial number (UTN)

Sponsor organisation name

Otsuka Pharmaceutical Development & Commercialization,Inc.

Sponsor organisation address

2440 Research Boulevard, Rockville, United States, MD 20850

Public contact

Senior Medical Director, Otsuka Pharmaceutical Development & Commercialization, Inc., +1 4155330152, rajesh.gupta@otsuka-us.com

Scientific contact

Senior Medical Director, Otsuka Pharmaceutical Development & Commercialization, Inc., +1 4155330152, rajesh.gupta@otsuka-us.com

Is trial part of an agreed paediatric investigation plan (PIP)

Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?

Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?

Analysis stage

Final

Date of interim/final analysis

30 Jan 2017

Is this the analysis of the primary completion data?

Yes

Primary completion date

04 Jul 2016

Global end of trial reached?

Yes

Global end of trial date

04 Jul 2016

Was the trial ended prematurely?

Main objective of the trial

To evaluate the efficacy of delamanid administered orally as 100 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.

Protection of trial subjects

The study was conducted according to the International Conference on Harmonisation (ICH) Good Clinical Practice (GCP) Consolidated Guideline and the applicable local laws and regulatory requirements of the countries in which the trial was conducted. Informed consent was obtained from all subjects in writing before any trial related procedures were performed. Prior to start, copies of the protocol, any amendments, and the informed consent form (ICF) were reviewed and approved by the governing institutional review broad (IRB) or independent ethics committee (IEC). Essential information was fully explained in layman's language to the subject by the investigator or a qualified designee. Note: All subjects were 18 to 69 years of age, inclusive, at time of informed consent.

Background therapy

Evidence for comparator

Actual start date of recruitment

02 Sep 2011

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Yes

Number of subjects enrolled per country

Country: Number of subjects enrolled

Moldova, Republic of: 43

Country: Number of subjects enrolled

Peru: 157

Country: Number of subjects enrolled

Philippines: 127

Country: Number of subjects enrolled

South Africa: 101

Country: Number of subjects enrolled

Estonia: 13

Country: Number of subjects enrolled

Latvia: 30

Country: Number of subjects enrolled

Lithuania: 40

Worldwide total number of subjects

511

EEA total number of subjects

Number of subjects enrolled per age group

In utero

Preterm newborn - gestational age < 37 wk

Newborns (0-27 days)

Infants and toddlers (28 days-23 months)

Children (2-11 years)

Adolescents (12-17 years)

Adults (18-64 years)

510

From 65 to 84 years

85 years and over

Subject disposition

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Recruitment details

Out of 714 screened subjects, only 511 (with multidrug-resistant tuberculosis [MDR TB]) were randomized to Delamanid + OBR (341) & Placebo (170). The study was conducted at 17 sites in 7 countries (Estonia, Latvia, Lithuania, Moldova, Peru, Philippines and South Africa).

Screening details

Pretreatment Period: Days -21 to -1. In this period, Screening and baseline safety, electrocardiogram (ECG), and baseline microbiologic assessments were performed.

Period 1 title

Overall study (overall period)

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

Subject, Investigator

Are arms mutually exclusive

Yes

Delamanid+OBR

Arm description

On Day 1, patients were randomized to treatment Group 1- Delamanid + OBR and received orally 100 mg Delamanid BID (morning & evening) + OBR for 2 months (Intensive Treatment Period) followed by 200 mg Delamanid QD (morning) + OBR for 4 months.

Arm type

Experimental

Investigational medicinal product name

Delamanid

Investigational medicinal product code

OPC-67683

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Patients received orally 100 mg Delamanid BID (morning & evening) + OBR for 2 months (Intensive Treatment Period) followed by 200 mg Delamanid QD (morning) + OBR for 4 months.

Placebo + OBR

Arm description

On Day 1, patients were randomized to treatment Group 2 - Placebo+OBR and received orally 2 tablets of placebo (morning & evening) exactly matching the 50-mg tablet of Delamanid for 2 months (Intensive Treatment Period) followed by 4 tablets of matching placebo for 4 months.

Arm type

Placebo

Investigational medicinal product name

Placebo

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Patients received orally 2 tablets of placebo (morning & evening) exactly matching the 50-mg tablet of Delamanid for 2 months (Intensive Treatment Period) followed by 4 tablets of matching placebo for 4 months.

Number of subjects in period 1	Delamanid+OBR	Placebo + OBR
Started	341	170
Completed	288	142
Not completed	53	28
Consent withdrawn by subject	26	11
Met protocol withdrawal criteria	3	2
Subject was withdrawn by investigator	7	7
Adverse event	15	7
Lost to follow-up	2	1

Baseline characteristics

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Reporting group title

Delamanid+OBR

Reporting group description

Reporting group title

Placebo + OBR

Reporting group description

Reporting group values	Delamanid+OBR	Placebo + OBR	Total
Number of subjects	341	170	511
Age categorical
Units: Subjects
In utero	0	0	0
Preterm newborn infants (gestational age < 37 wks)	0	0	0
Newborns (0-27 days)	0	0	0
Infants and toddlers (28 days-23 months)	0	0	0
Children (2-11 years)	0	0	0
Adolescents (12-17 years)	0	0	0
Adults (18-64 years)	341	169	510
From 65-84 years	0	1	1
85 years and over	0	0	0
Age continuous
Units: years
arithmetic mean (standard deviation)	34.3 ( 12.1 )	34.4 ( 12.2 )	-
Gender categorical
Units: Subjects
Female	98	45	143
Male	243	125	368

End points

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Reporting group title

Delamanid+OBR

Reporting group description

Reporting group title

Placebo + OBR

Reporting group description

Primary: Time to Sputum culture conversion (SCC) assessment by Mycobacteria Growth Indicator Tube (MGIT) system to evaluate the efficacy of Delamanid in combination with OBR during 6 month intensive treatment period

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End point title

Time to Sputum culture conversion (SCC) assessment by Mycobacteria Growth Indicator Tube (MGIT) system to evaluate the efficacy of Delamanid in combination with OBR during 6 month intensive treatment period

End point description

SCC Period was defined as the observation of a sputum specimen negative for growth of Mycobacterium tuberculosis (MTB) using the MGIT culture system, followed by at least one confirmatory negative sputum culture at least 25 days after the first negative and not followed by a confirmed positive. The first specimen was collected by the patient early in the morning, preferably prior to the morning meal and second sample was collected by the study staff. Assessment of time to SCC was performed to evaluate the efficacy of orally administered Delamanid, 100 mg with OBR combination therapy by comparing with placebo. A confirmed positive was defined as 2 observed results, not taking into account indeterminate, missing, or contaminated results.

End point type

Primary

End point timeframe

At pretreatment (Day −1), intensive treatment: week 1 to week 26, continuation treatment: month 7 to 18 or early termination (ET) and continuation treatment (OBR alone) or post-treatment follow-up (month 21 to 30)

End point values	Delamanid+OBR	Placebo + OBR
Number of subjects analysed	226	101
Units: Days
median (confidence interval 95%)	51 (43 to 57)	57 (56 to 64)

Stat. Comparision of Distributions of Time to SCC

Statistical analysis description

The hypothesis formulated based on the objective of the primary analysis is as follows: H0: There is no difference in the distribution of time to SCC using the MGIT system during the 6-month Intensive Treatment Period. For testing H0, distributions of time to SCC within the 6-month were compared between the two treatment groups using the stratified modified Peto-Peto modification of Gehan’s Wilcoxon rank sum test.

Comparison groups

Delamanid+OBR v Placebo + OBR

Number of subjects included in analysis

327

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0562

Method

Modified Peto-peto test

Confidence interval

Secondary: Proportion of subjects with SCC using MGIT and solid culture at 2 and 6 months

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End point title

Proportion of subjects with SCC using MGIT and solid culture at 2 and 6 months

End point description

To evaluate proportion of subjects achieving SCC (using the MGIT culture system and solid culture media) at 2 and 6 months for the Delamanid treatment group was compared with that of the placebo treatment group.

End point type

Secondary

End point timeframe

During Intensive Treatment: Month 2 and Month 6

End point values	Delamanid+OBR	Placebo + OBR
Number of subjects analysed	226	101
Units: Participants
number (not applicable)
At 2 months	132	54
At 6 months	198	87

Stat. comparison of Proportions of SCC at 2-months

Statistical analysis description

The proportion of patients with SCC at 2 months for the Delamanid treatment group using the MGIT system was compared with that of the placebo treatment group using the Cochran-Mantel-Haenszel (CMH) test stratified by risk strata (Low Risk/High Risk). In addition, 95% confidence intervals (CIs) for the risk ratio were calculated for each strata and overall.

Comparison groups

Delamanid+OBR v Placebo + OBR

Number of subjects included in analysis

327

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.3818 ^[1]

Method

CMH general association test

Parameter type

Ratio of probability

Point estimate

1.096

Confidence interval

level

95%

sides

2-sided

lower limit

0.889

upper limit

1.352

Notes
[1] - Treatment comparison using CMH general association test. The test on all subjects was stratified by risk category.

Stat. comparison of Proportions of SCC at 6-months

Statistical analysis description

The proportion of patients with SCC at 6 months for the Delamanid treatment group using the MGIT system was compared with that of the placebo treatment group using the CMH test stratified by risk strata (Low Risk/High Risk). In addition, 95% CIs for the risk ratio were calculated for each strata and overall.

Comparison groups

Delamanid+OBR v Placebo + OBR

Number of subjects included in analysis

327

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.7131 ^[2]

Method

CMH general association test

Parameter type

Ratio of probability

Point estimate

1.017

Confidence interval

level

95%

sides

2-sided

lower limit

0.927

upper limit

1.115

Notes
[2] - Treatment comparison using CMH general association test. The test on all subjects was stratified by risk category.

Secondary: Sustained SCC using MGIT at Month 18, Month 24, and Month 30

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End point title

Sustained SCC using MGIT at Month 18, Month 24, and Month 30

End point 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 intermittent, missing, or contaminated results. Sustained SCC using MGIT was analyzed at month 18 to 30 using MGIT SCC in MGIT sample.

End point type

Secondary

End point timeframe

Continuation Treatment OBR Alone: Month 18, Continuation treatment (OBR alone) or Post- treatment Follow up: Month 24, Post-treatment Follow-up: Month 30

End point values	Delamanid+OBR	Placebo + OBR
Number of subjects analysed	226	101
Units: Participants
number (not applicable)
At 18 months	180	83
At 24 months	178	82
At 30 months	173	78

Stat. comparison of sustained SCC at month 18

Comparison groups

Delamanid+OBR v Placebo + OBR

Number of subjects included in analysis

327

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.5945

Method

Cochran-Mantel-Haenszel

Parameter type

Relative ratio of probability

Point estimate

0.969

Confidence interval

level

95%

sides

2-sided

lower limit

0.866

upper limit

1.084

Stat. comparison of sustained SCC at month 24

Comparison groups

Delamanid+OBR v Placebo + OBR

Number of subjects included in analysis

327

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.6164

Method

Cochran-Mantel-Haenszel

Parameter type

Relative ratio of probability

Point estimate

0.97

Confidence interval

level

95%

sides

2-sided

lower limit

0.864

upper limit

1.089

Stat. comparison of sustained SCC at month 30

Comparison groups

Delamanid+OBR v Placebo + OBR

Number of subjects included in analysis

327

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.8951

Method

Cochran-Mantel-Haenszel

Parameter type

Relative ratio of probability

Point estimate

0.991

Confidence interval

level

95%

sides

2-sided

lower limit

0.872

upper limit

1.127

Secondary: Treatment outcomes assessed by principal investigators at the end of treatment with OBR

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End point title

Treatment outcomes assessed by principal investigators at the end of treatment with OBR

End point description

Final treatment outcomes was assessed by the investigator (or managing clinician) at the end of treatment with OBR (i.e., 24 months post randomization) according to the WHO outcome definitions for treating patients with MDR TB. Frequency counts and percentage of patients achieving each treatment outcome (Cured, Treatment Completed, Died,Treatment Failed, Defaulted) was provided by treatment group.

End point type

Secondary

End point timeframe

Post-treatment Follow-up: Month 24

End point values	Delamanid+OBR	Placebo + OBR
Number of subjects analysed	226	101
Units: Participants
number (not applicable)
Favorable outcome	182	85
Unfavorable outcome	42	16

Stat. comp. of treatment outcomes assessed by PI

Statistical analysis description

Frequency counts and percentage of patients achieving each treatment outcome (Cured, Treatment Completed, Died, Treatment Failed, Defaulted) was provided by treatment group as per favorable and unfavorable outcome.

Comparison groups

Delamanid+OBR v Placebo + OBR

Number of subjects included in analysis

327

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.5269

Method

Cohran-Mantel-Haenzel Test

Parameter type

Relative ratio of probability

Point estimate

0.965

Confidence interval

level

95%

sides

2-sided

lower limit

0.869

upper limit

1.073

Secondary: Proportion of subjects who developed resistance to Delamanid.

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End point title

Proportion of subjects who developed resistance to Delamanid.

End point 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.

End point type

Secondary

End point timeframe

Pre-treatment: Day -1 Intensive Treatment (Delamanid+OBR): Week 1, 16, 18, 20, 22, 24 and 26 Continuation treatment (OBR alone): Month 7, 8, 9, 10, 11, 12, 15 and 18 Post-treatment Follow-up: Month 21 and 24 Post-treatment Follow-up: Month 27 and 30

End point values	Delamanid+OBR	Placebo + OBR
Number of subjects analysed	341	170
Units: Participants
number (not applicable)	4	0

No statistical analyses for this end point

Secondary: Mean area under the concentration-time curve (AUC) of change from baseline

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End point title

Mean area under the concentration-time curve (AUC) of change from baseline

End point description

The AUC of the change from baseline for Time to detection (TTD), (from baseline to Month 6 [Week 26]) summarizes the overall subject response for the treatment period. A larger AUC of change from baseline for TTD strongly suggested a clinical response with the reduction of the burden of MTB organisms in sputum. The analysis of average change from baseline in original time to detection of MGIT positive signal up to 6 months was performed using using AUC in MGIT sample was presented. The baseline was defined as the average of Day −1 and Day 1 values if cultures on both days were positive; if only one culture was positive, the value for TTD for the positive culture was used as the baseline.

End point type

Secondary

End point timeframe

Pre-treatment: Day 1 Intensive Treatment (Delamanid+OBR): Week 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26

End point values	Delamanid+OBR	Placebo + OBR
Number of subjects analysed	221	98
Units: Mean
arithmetic mean (standard deviation)	21.9 ( 9.44 )	23.3 ( 8.93 )

Stat. Comp. of mean AUC of change from baseline

Comparison groups

Delamanid+OBR v Placebo + OBR

Number of subjects included in analysis

319

Analysis specification

Pre-specified

Analysis type

superiority ^[3]

P-value

= 0.6986

Method

ANCOVA

Parameter type

Mean difference (final values)

Point estimate

-0.3

Confidence interval

level

95%

sides

2-sided

lower limit

-1.9

upper limit

1.3

Notes
[3] - Descriptive statistics and the summary of pair wise treatment comparisons from the analysis of covariance model (ANCOVA) were presented for the average AUC of change from baseline to Day 182. Note that the baseline was defined as the average of Day −1 and Day 1 values if cultures on both days were positive; if only one culture was positive, the value for TTD for the positive culture was used as the baseline.

Secondary: Mean change from baseline in TTD using the MGIT system

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End point title

Mean change from baseline in TTD using the MGIT system

End point 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 on only with the corresponding qualitative sputum results of pure positive and pure negative cultures in days and hours of the first positive signal for TTD from the MGIT printout. The original TTD recorded by the MGIT machine was used in statistical analyses: 1) When a MGIT culture result was negative for MTB complex, TTD was set to 42 days (the value for time-to-result with negative culture). 2) If the MGIT sputum culture result was positive for MTB complex and if the value for time to result in days was less than or equal to 45, then TTD was set to time to result in Days + Hours/24. If the original TTD was greater than 45, then TTD was set to missing.

End point type

Secondary

End point timeframe

Intensive Treatment: Week 1 to 26 Continuation Treatment: Month 7 to 18

End point values	Delamanid+OBR	Placebo + OBR
Number of subjects analysed	226	101
Units: Mean
arithmetic mean (standard deviation)
At baseline (n= 222, 98)	16.7 ( 7.9 )	15.4 ( 7.7 )
At week 1 (n= 204, 94)	20.8 ( 10.3 )	19.9 ( 11.1 )
Change at week 1 (n= 204, 94)	4.3 ( 7.9 )	4.8 ( 7.8 )
At week 2 (n= 206, 87)	24.6 ( 11.5 )	23.1 ( 11.4 )
Change at week 2 (n= 206, 87)	7.7 ( 8.9 )	7.5 ( 7.8 )
At week 3 (n= 209, 89)	28.4 ( 11.8 )	25.5 ( 12.4 )
Change at week 3 (n= 209, 89)	11.6 ( 9.8 )	10.4 ( 9.6 )
At week 24 (n= 195, 80)	40.4 ( 6.6 )	41.3 ( 3.9 )
Change at week 24 (n= 195, 80)	23.4 ( 10.2 )	25.5 ( 8.3 )
At week 26 (n= 188, 82)	40.6 ( 5.9 )	40.5 ( 5.5 )
Change at week 26 (n= 188, 82)	23.8 ( 9.5 )	24.6 ( 9.4 )
At last visit (n= 222, 98)	39.4 ( 8.4 )	40.3 ( 6.3 )
Change at last visit (n= 222, 98)	22.7 ( 10.7 )	24.9 ( 9.5 )

Statistical analysis for week 1

Comparison groups

Delamanid+OBR v Placebo + OBR

Number of subjects included in analysis

327

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.6825

Method

ANCOVA

Confidence interval

Statistical analysis for week 2

Comparison groups

Delamanid+OBR v Placebo + OBR

Number of subjects included in analysis

327

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.807

Method

ANCOVA

Confidence interval

Statistical analysis for week 3

Comparison groups

Delamanid+OBR v Placebo + OBR

Number of subjects included in analysis

327

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.269

Method

ANOVA

Confidence interval

Statiscal analysis for week 24

Comparison groups

Delamanid+OBR v Placebo + OBR

Number of subjects included in analysis

327

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.2333

Method

ANCOVA

Confidence interval

Statistical analysis for week 26

Comparison groups

Delamanid+OBR v Placebo + OBR

Number of subjects included in analysis

327

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.9397

Method

ANCOVA

Confidence interval

Secondary: Distribution of time to SCC using solid culture at month 6

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End point title

Distribution of time to SCC using solid culture at month 6

End point description

To evaluate the distribution of time to SCC by 6 months using solid culture media and the proportion of patients with SCC at 6 months using the solid culture was derived as a single representative culture result for a patient that was negative using the solid culture system, followed by at least one confirmatory single representative negative culture result at least 25 days after the first negative and not followed by a confirmed positive (defined as 2 or more observed positive single representative culture results not taking into account intermittent, missing, or contaminated results). The analysis was carried out using MITT (SOLID) sample population.

End point type

Secondary

End point timeframe

Intensive Treatment: Month 6

End point values	Delamanid+OBR	Placebo + OBR
Number of subjects analysed	167	81
Units: Days
median (confidence interval 95%)	36 (29 to 43)	42 (29 to 51)

Statistical analysis at 6 months

Statistical analysis description

The proportion of patients with SCC at 6 months using the solid culture was derived as a single representative culture result for a patient that was negative using the MGIT culture system, followed by at least one confirmatory single representative negative culture result at least 25 days after the first negative and not followed by a confirmed positive (defined as 2 or more observed positive single representative culture results not taking into account intermittent, missing, or contaminated).

Comparison groups

Delamanid+OBR v Placebo + OBR

Number of subjects included in analysis

248

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.3975

Method

Modified peto-peto test

Confidence interval

Secondary: Final outcome at month 30 as a treatment success or failure (including relapse)

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End point title

Final outcome at month 30 as a treatment success or failure (including relapse)

End point description

Treatment success was defined as achieving SCC by 6 months, completing the trial out to 30 months with sustained SCC and alive at the last contact for follow-up. All other patients were treatment failures who failed to achieve SCC by week 26, 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. Analysis of Treatment Success and failure at 30 months Based on MGIT in MGIT Sample.

End point type

Secondary

End point timeframe

Continuation Treatment: Month 30

End point values	Delamanid+OBR	Placebo + OBR
Number of subjects analysed	226	101
Units: Participants
number (not applicable)
Success	173	78
Failure	53	23

Stat. comp. of treatment success at month 30

Statistical analysis description

The proportions of Treatment success at Month 30 between treatment groups was statistically compared with the Cochran-Mantel-Haenszel test stratified by risk strata (Low Risk/High Risk). The analysis of treatment success at month 30 was calculated using relative ratio of probability of success between Delamanid+OBR and Placebo+OBR, produced using Proc Freq procedure with CMH option.

Comparison groups

Delamanid+OBR v Placebo + OBR

Number of subjects included in analysis

327

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.8951

Method

Treatment comparison using CMH

Parameter type

Relative ratio of probability

Point estimate

0.991

Confidence interval

level

95%

sides

2-sided

lower limit

0.872

upper limit

1.127

Secondary: Sustained SCC using solid culture at Month 18, Month 24, and Month 30

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End point title

Sustained SCC using solid culture at Month 18, Month 24, and Month 30

End point 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 intermittent, missing, or contaminated results. Sustained SCC using solid culture was analyzed at month 18 to 30 using MITT (solid) sample.

End point type

Secondary

End point timeframe

Continuation Treatment (OBR Alone): Month 18, Continuation treatment (OBR alone) or Post- treatment Follow up: Month 24, Post-treatment Follow-up: Month 30

End point values	Delamanid+OBR	Placebo + OBR
Number of subjects analysed	167	81
Units: Participants
number (not applicable)
At month 18	130	61
At month 24	130	60
At month 30	125	57

Stat. comparison of sustained SCC at month 18

Comparison groups

Delamanid+OBR v Placebo + OBR

Number of subjects included in analysis

248

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.6727

Method

Cochran-Mantel-Haenszel

Parameter type

Relative ratio of probability

Point estimate

1.032

Confidence interval

level

95%

sides

2-sided

lower limit

0.89

upper limit

1.197

Stat. comparison of sustained SCC at month 24

Comparison groups

Delamanid+OBR v Placebo + OBR

Number of subjects included in analysis

248

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.5314

Method

Cochran-Mantel-Haenszel

Parameter type

Relative ratio of probability

Point estimate

1.049

Confidence interval

level

95%

sides

2-sided

lower limit

0.901

upper limit

1.22

Stat. comparison of sustained SCC at month 30

Comparison groups

Delamanid+OBR v Placebo + OBR

Number of subjects included in analysis

248

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.4729

Method

Cochran-Mantel-Haenszel

Parameter type

Relative ratio of probability

Point estimate

1.061

Confidence interval

level

95%

sides

2-sided

lower limit

0.899

upper limit

1.253

Adverse events

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Timeframe for reporting adverse events

Adverse events were collected throughout the study (30 Months)

Adverse event reporting additional description

Adverse events were collected for randomized patients who received any amount of study drug, regardless of any protocol deviation or violation.

Assessment type

Non-systematic

Dictionary name

MedDRA

Dictionary version

19.0

Reporting group title

Delamanid + Optimized background regimen (OBR)

Reporting group description

On Day 1, patients were randomized to treatment Group 1- Delamanid + OBR and received orally 100 mg. Delamanid BID (morning & evening) + OBR for 2 months (Intensive Treatment Period) followed by 200 mg Delamanid QD (morning) + OBR for 4 months.

Reporting group title

Placebo + OBR

Reporting group description

On Day 1, patients were randomized to treatment Group 2 - Placebo+OBR and received orally 2 tablets. Placebo (morning & evening) exactly matching the 50-mg tablet of Delamanid for 2 months (Intensive Treatment Period) followed by 4 tablets of matching placebo for 4 months.

Serious adverse events	Delamanid + Optimized background regimen (OBR)	Placebo + OBR
Total subjects affected by serious adverse events
subjects affected / exposed	89 / 341 (26.10%)	47 / 170 (27.65%)
number of deaths (all causes)	15	6
number of deaths resulting from adverse events	15	6
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Brain neoplasm
subjects affected / exposed	1 / 341 (0.29%)	0 / 170 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Lung adenocarcinoma metastatic
subjects affected / exposed	0 / 341 (0.00%)	1 / 170 (0.59%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 1
Malignant neoplasm of unknown primary site
subjects affected / exposed	1 / 341 (0.29%)	0 / 170 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0
Meningioma
subjects affected / exposed	1 / 341 (0.29%)	0 / 170 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Squamous cell carcinoma of lung
subjects affected / exposed	1 / 341 (0.29%)	1 / 170 (0.59%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 1	0 / 0
Squamous cell carcinoma of the oral cavity
subjects affected / exposed	0 / 341 (0.00%)	1 / 170 (0.59%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Vascular disorders
Deep vein thrombosis
subjects affected / exposed	3 / 341 (0.88%)	0 / 170 (0.00%)
occurrences causally related to treatment / all	0 / 3	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Hypertension
subjects affected / exposed	1 / 341 (0.29%)	0 / 170 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Hypotension
subjects affected / exposed	1 / 341 (0.29%)	1 / 170 (0.59%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 1
General disorders and administration site conditions
Asthenia
subjects affected / exposed	2 / 341 (0.59%)	0 / 170 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Hypothermia
subjects affected / exposed	1 / 341 (0.29%)	0 / 170 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0
Multiple organ dysfunction syndrome
subjects affected / exposed	1 / 341 (0.29%)	0 / 170 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Immune system disorders
Hypersensitivity
subjects affected / exposed	0 / 341 (0.00%)	1 / 170 (0.59%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Respiratory, thoracic and mediastinal disorders
Acute respiratory failure
subjects affected / exposed	2 / 341 (0.59%)	0 / 170 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 2	0 / 0
Asphyxia
subjects affected / exposed	1 / 341 (0.29%)	0 / 170 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0
Asthma
subjects affected / exposed	1 / 341 (0.29%)	0 / 170 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Bronchiectasis
subjects affected / exposed	0 / 341 (0.00%)	1 / 170 (0.59%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Bullous lung disease
subjects affected / exposed	1 / 341 (0.29%)	0 / 170 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Chronic obstructive pulmonary disease
subjects affected / exposed	1 / 341 (0.29%)	1 / 170 (0.59%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Haemoptysis
subjects affected / exposed	3 / 341 (0.88%)	2 / 170 (1.18%)
occurrences causally related to treatment / all	0 / 3	0 / 2
deaths causally related to treatment / all	0 / 1	0 / 1
Pneumothorax
subjects affected / exposed	0 / 341 (0.00%)	2 / 170 (1.18%)
occurrences causally related to treatment / all	0 / 0	0 / 5
deaths causally related to treatment / all	0 / 0	0 / 0
Pneumothorax spontaneous
subjects affected / exposed	1 / 341 (0.29%)	0 / 170 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Pulmonary embolism
subjects affected / exposed	1 / 341 (0.29%)	0 / 170 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0
Pulmonary fibrosis
subjects affected / exposed	2 / 341 (0.59%)	2 / 170 (1.18%)
occurrences causally related to treatment / all	0 / 2	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Pulmonary haematoma
subjects affected / exposed	0 / 341 (0.00%)	1 / 170 (0.59%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Pulmonary haemorrhage
subjects affected / exposed	1 / 341 (0.29%)	0 / 170 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Pulmonary oedema
subjects affected / exposed	0 / 341 (0.00%)	1 / 170 (0.59%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 1
Respiratory failure
subjects affected / exposed	1 / 341 (0.29%)	1 / 170 (0.59%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 1	0 / 0
Restrictive pulmonary disease
subjects affected / exposed	0 / 341 (0.00%)	1 / 170 (0.59%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Psychiatric disorders
Acute psychosis
subjects affected / exposed	2 / 341 (0.59%)	0 / 170 (0.00%)
occurrences causally related to treatment / all	0 / 3	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Alcohol abuse
subjects affected / exposed	2 / 341 (0.59%)	0 / 170 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Anxiety
subjects affected / exposed	1 / 341 (0.29%)	0 / 170 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Anxiety disorder
subjects affected / exposed	1 / 341 (0.29%)	0 / 170 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Completed suicide
subjects affected / exposed	1 / 341 (0.29%)	0 / 170 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0
Confusional state
subjects affected / exposed	1 / 341 (0.29%)	1 / 170 (0.59%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Delirium tremens
subjects affected / exposed	1 / 341 (0.29%)	1 / 170 (0.59%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Depression
subjects affected / exposed	1 / 341 (0.29%)	1 / 170 (0.59%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Major depression
subjects affected / exposed	1 / 341 (0.29%)	0 / 170 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Panic attack
subjects affected / exposed	0 / 341 (0.00%)	1 / 170 (0.59%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Psychotic disorder
subjects affected / exposed	3 / 341 (0.88%)	1 / 170 (0.59%)
occurrences causally related to treatment / all	0 / 4	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Reactive psychosis
subjects affected / exposed	1 / 341 (0.29%)	0 / 170 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Substance-induced psychotic disorder
subjects affected / exposed	2 / 341 (0.59%)	0 / 170 (0.00%)
occurrences causally related to treatment / all	1 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Suicidal ideation
subjects affected / exposed	1 / 341 (0.29%)	0 / 170 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Suicide attempt
subjects affected / exposed	1 / 341 (0.29%)	0 / 170 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Investigations
Alanine aminotransferase increased
subjects affected / exposed	1 / 341 (0.29%)	0 / 170 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Aspartate aminotransferase increased
subjects affected / exposed	1 / 341 (0.29%)	0 / 170 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Electrocardiogram QT prolonged
subjects affected / exposed	6 / 341 (1.76%)	1 / 170 (0.59%)
occurrences causally related to treatment / all	4 / 6	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Gamma-glutamyltransferase increased
subjects affected / exposed	1 / 341 (0.29%)	0 / 170 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Transaminases increased
subjects affected / exposed	1 / 341 (0.29%)	3 / 170 (1.76%)
occurrences causally related to treatment / all	0 / 1	0 / 4
deaths causally related to treatment / all	0 / 0	0 / 0
Injury, poisoning and procedural complications
Abdominal injury
subjects affected / exposed	1 / 341 (0.29%)	1 / 170 (0.59%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Alcohol poisoning
subjects affected / exposed	2 / 341 (0.59%)	0 / 170 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0
Ankle fracture
subjects affected / exposed	0 / 341 (0.00%)	2 / 170 (1.18%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Chest injury
subjects affected / exposed	0 / 341 (0.00%)	1 / 170 (0.59%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Femoral neck fracture
subjects affected / exposed	1 / 341 (0.29%)	1 / 170 (0.59%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Foot fracture
subjects affected / exposed	1 / 341 (0.29%)	0 / 170 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Jaw fracture
subjects affected / exposed	1 / 341 (0.29%)	0 / 170 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Kidney contusion
subjects affected / exposed	1 / 341 (0.29%)	0 / 170 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Lower limb fracture
subjects affected / exposed	0 / 341 (0.00%)	1 / 170 (0.59%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Spinal compression fracture
subjects affected / exposed	1 / 341 (0.29%)	0 / 170 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Subdural haematoma
subjects affected / exposed	1 / 341 (0.29%)	0 / 170 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Cardiac disorders
Acute myocardial infarction
subjects affected / exposed	0 / 341 (0.00%)	1 / 170 (0.59%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 1
Atrial fibrillation
subjects affected / exposed	0 / 341 (0.00%)	1 / 170 (0.59%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 1
Cardiac arrest
subjects affected / exposed	0 / 341 (0.00%)	1 / 170 (0.59%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 1
Cardiac failure acute
subjects affected / exposed	1 / 341 (0.29%)	0 / 170 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0
Cardiac failure congestive
subjects affected / exposed	1 / 341 (0.29%)	0 / 170 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Cardiopulmonary failure
subjects affected / exposed	0 / 341 (0.00%)	1 / 170 (0.59%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 1
Cardiovascular insufficiency
subjects affected / exposed	1 / 341 (0.29%)	0 / 170 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0
Cor pulmonale
subjects affected / exposed	1 / 341 (0.29%)	0 / 170 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Metabolic cardiomyopathy
subjects affected / exposed	1 / 341 (0.29%)	0 / 170 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Myocardial infarction
subjects affected / exposed	1 / 341 (0.29%)	0 / 170 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Myocardial ischaemia
subjects affected / exposed	1 / 341 (0.29%)	0 / 170 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0
Nervous system disorders
Brain oedema
subjects affected / exposed	0 / 341 (0.00%)	1 / 170 (0.59%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 1
Cerebral infarction
subjects affected / exposed	1 / 341 (0.29%)	0 / 170 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Cerebrovascular accident
subjects affected / exposed	1 / 341 (0.29%)	0 / 170 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Seizure
subjects affected / exposed	1 / 341 (0.29%)	0 / 170 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Tremor
subjects affected / exposed	1 / 341 (0.29%)	0 / 170 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Blood and lymphatic system disorders
Anaemia
subjects affected / exposed	1 / 341 (0.29%)	0 / 170 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Anaemia macrocytic
subjects affected / exposed	1 / 341 (0.29%)	0 / 170 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Anaemia of chronic disease
subjects affected / exposed	1 / 341 (0.29%)	0 / 170 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Neutropenia
subjects affected / exposed	1 / 341 (0.29%)	0 / 170 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Thrombocytopenia
subjects affected / exposed	1 / 341 (0.29%)	0 / 170 (0.00%)
occurrences causally related to treatment / all	1 / 4	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Ear and labyrinth disorders
Deafness
subjects affected / exposed	1 / 341 (0.29%)	1 / 170 (0.59%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Deafness bilateral
subjects affected / exposed	4 / 341 (1.17%)	4 / 170 (2.35%)
occurrences causally related to treatment / all	0 / 4	0 / 4
deaths causally related to treatment / all	0 / 0	0 / 0
Eye disorders
Glaucoma
subjects affected / exposed	1 / 341 (0.29%)	0 / 170 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Gastrointestinal disorders
Abdominal pain
subjects affected / exposed	0 / 341 (0.00%)	1 / 170 (0.59%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Abdominal pain upper
subjects affected / exposed	1 / 341 (0.29%)	0 / 170 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Gastritis
subjects affected / exposed	2 / 341 (0.59%)	0 / 170 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Gastroduodenitis
subjects affected / exposed	1 / 341 (0.29%)	0 / 170 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Gastrooesophageal reflux disease
subjects affected / exposed	2 / 341 (0.59%)	0 / 170 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Ileal perforation
subjects affected / exposed	1 / 341 (0.29%)	0 / 170 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Ileus
subjects affected / exposed	1 / 341 (0.29%)	0 / 170 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Oedematous pancreatitis
subjects affected / exposed	1 / 341 (0.29%)	0 / 170 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Pancreatic pseudocyst
subjects affected / exposed	1 / 341 (0.29%)	0 / 170 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Pancreatitis
subjects affected / exposed	1 / 341 (0.29%)	0 / 170 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Pancreatitis acute
subjects affected / exposed	2 / 341 (0.59%)	0 / 170 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Hepatobiliary disorders
Cholecystitis
subjects affected / exposed	1 / 341 (0.29%)	0 / 170 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Cholelithiasis
subjects affected / exposed	1 / 341 (0.29%)	0 / 170 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Cholestasis
subjects affected / exposed	0 / 341 (0.00%)	1 / 170 (0.59%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Drug-induced liver injury
subjects affected / exposed	0 / 341 (0.00%)	1 / 170 (0.59%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Hepatitis acute
subjects affected / exposed	1 / 341 (0.29%)	0 / 170 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Hepatitis alcoholic
subjects affected / exposed	0 / 341 (0.00%)	1 / 170 (0.59%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Hepatitis toxic
subjects affected / exposed	2 / 341 (0.59%)	0 / 170 (0.00%)
occurrences causally related to treatment / all	0 / 3	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Hepatotoxicity
subjects affected / exposed	3 / 341 (0.88%)	2 / 170 (1.18%)
occurrences causally related to treatment / all	0 / 4	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Hypertransaminasaemia
subjects affected / exposed	1 / 341 (0.29%)	0 / 170 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Jaundice
subjects affected / exposed	1 / 341 (0.29%)	0 / 170 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Skin and subcutaneous tissue disorders
Diabetic foot
subjects affected / exposed	0 / 341 (0.00%)	1 / 170 (0.59%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Drug eruption
subjects affected / exposed	0 / 341 (0.00%)	2 / 170 (1.18%)
occurrences causally related to treatment / all	0 / 0	1 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Drug reaction with eosinophilia and systemic symptoms
subjects affected / exposed	1 / 341 (0.29%)	0 / 170 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Urticaria
subjects affected / exposed	0 / 341 (0.00%)	1 / 170 (0.59%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Renal and urinary disorders
Acute kidney injury
subjects affected / exposed	3 / 341 (0.88%)	5 / 170 (2.94%)
occurrences causally related to treatment / all	0 / 3	0 / 5
deaths causally related to treatment / all	0 / 0	0 / 0
Azotaemia
subjects affected / exposed	0 / 341 (0.00%)	2 / 170 (1.18%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Nephropathy toxic
subjects affected / exposed	1 / 341 (0.29%)	0 / 170 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Renal impairment
subjects affected / exposed	1 / 341 (0.29%)	0 / 170 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0
Endocrine disorders
Goitre
subjects affected / exposed	1 / 341 (0.29%)	0 / 170 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Hypothyroidism
subjects affected / exposed	1 / 341 (0.29%)	0 / 170 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Infections and infestations
Appendicitis
subjects affected / exposed	1 / 341 (0.29%)	2 / 170 (1.18%)
occurrences causally related to treatment / all	0 / 1	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Appendicitis perforated
subjects affected / exposed	1 / 341 (0.29%)	0 / 170 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Cellulitis
subjects affected / exposed	1 / 341 (0.29%)	0 / 170 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Empyema
subjects affected / exposed	1 / 341 (0.29%)	0 / 170 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Gastroenteritis
subjects affected / exposed	2 / 341 (0.59%)	1 / 170 (0.59%)
occurrences causally related to treatment / all	0 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Lung abscess
subjects affected / exposed	1 / 341 (0.29%)	0 / 170 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Osteomyelitis
subjects affected / exposed	1 / 341 (0.29%)	0 / 170 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Peritonitis
subjects affected / exposed	1 / 341 (0.29%)	0 / 170 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Pneumonia
subjects affected / exposed	3 / 341 (0.88%)	2 / 170 (1.18%)
occurrences causally related to treatment / all	0 / 3	0 / 2
deaths causally related to treatment / all	0 / 1	0 / 1
Pneumonia necrotising
subjects affected / exposed	0 / 341 (0.00%)	1 / 170 (0.59%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 1
Pneumonia viral
subjects affected / exposed	1 / 341 (0.29%)	0 / 170 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Pulmonary tuberculoma
subjects affected / exposed	1 / 341 (0.29%)	0 / 170 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Pulmonary tuberculosis
subjects affected / exposed	2 / 341 (0.59%)	1 / 170 (0.59%)
occurrences causally related to treatment / all	0 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Sepsis
subjects affected / exposed	1 / 341 (0.29%)	1 / 170 (0.59%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Tuberculoma of central nervous system
subjects affected / exposed	1 / 341 (0.29%)	0 / 170 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Tuberculosis
subjects affected / exposed	11 / 341 (3.23%)	3 / 170 (1.76%)
occurrences causally related to treatment / all	0 / 11	0 / 3
deaths causally related to treatment / all	0 / 3	0 / 0
Tuberculous pleurisy
subjects affected / exposed	1 / 341 (0.29%)	0 / 170 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Urinary tract infection
subjects affected / exposed	1 / 341 (0.29%)	0 / 170 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Viral infection
subjects affected / exposed	1 / 341 (0.29%)	0 / 170 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Metabolism and nutrition disorders
Cachexia
subjects affected / exposed	1 / 341 (0.29%)	0 / 170 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Electrolyte imbalance
subjects affected / exposed	2 / 341 (0.59%)	0 / 170 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Hypocalcaemia
subjects affected / exposed	1 / 341 (0.29%)	1 / 170 (0.59%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Hypochloraemia
subjects affected / exposed	1 / 341 (0.29%)	1 / 170 (0.59%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Hypokalaemia
subjects affected / exposed	9 / 341 (2.64%)	3 / 170 (1.76%)
occurrences causally related to treatment / all	0 / 9	0 / 4
deaths causally related to treatment / all	0 / 0	0 / 0
Hypomagnesaemia
subjects affected / exposed	3 / 341 (0.88%)	1 / 170 (0.59%)
occurrences causally related to treatment / all	0 / 3	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Hyponatraemia
subjects affected / exposed	0 / 341 (0.00%)	1 / 170 (0.59%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0

Frequency threshold for reporting non-serious adverse events: 5%

Non-serious adverse events	Delamanid + Optimized background regimen (OBR)	Placebo + OBR
Total subjects affected by non serious adverse events
subjects affected / exposed	335 / 341 (98.24%)	165 / 170 (97.06%)
General disorders and administration site conditions
Asthenia
subjects affected / exposed	27 / 341 (7.92%)	10 / 170 (5.88%)
occurrences all number	33	14
Chest pain
subjects affected / exposed	22 / 341 (6.45%)	8 / 170 (4.71%)
occurrences all number	23	9
Injection site pain
subjects affected / exposed	24 / 341 (7.04%)	20 / 170 (11.76%)
occurrences all number	33	28
Psychiatric disorders
Adjustment disorder
subjects affected / exposed	8 / 341 (2.35%)	9 / 170 (5.29%)
occurrences all number	11	11
Alcohol abuse
subjects affected / exposed	14 / 341 (4.11%)	15 / 170 (8.82%)
occurrences all number	32	23
Anxiety
subjects affected / exposed	28 / 341 (8.21%)	21 / 170 (12.35%)
occurrences all number	39	32
Depression
subjects affected / exposed	26 / 341 (7.62%)	19 / 170 (11.18%)
occurrences all number	37	22
Insomnia
subjects affected / exposed	87 / 341 (25.51%)	46 / 170 (27.06%)
occurrences all number	145	66
Injury, poisoning and procedural complications
Contusion
subjects affected / exposed	22 / 341 (6.45%)	10 / 170 (5.88%)
occurrences all number	26	11
Cardiac disorders
Palpitations
subjects affected / exposed	19 / 341 (5.57%)	12 / 170 (7.06%)
occurrences all number	21	14
Nervous system disorders
Dizziness
subjects affected / exposed	51 / 341 (14.96%)	23 / 170 (13.53%)
occurrences all number	62	34
Headache
subjects affected / exposed	104 / 341 (30.50%)	39 / 170 (22.94%)
occurrences all number	165	68
Neuropathy peripheral
subjects affected / exposed	28 / 341 (8.21%)	18 / 170 (10.59%)
occurrences all number	33	24
Tremor
subjects affected / exposed	21 / 341 (6.16%)	5 / 170 (2.94%)
occurrences all number	27	6
Blood and lymphatic system disorders
Anaemia
subjects affected / exposed	17 / 341 (4.99%)	9 / 170 (5.29%)
occurrences all number	21	11
Ear and labyrinth disorders
Deafness bilateral
subjects affected / exposed	15 / 341 (4.40%)	9 / 170 (5.29%)
occurrences all number	17	11
Hypoacusis
subjects affected / exposed	15 / 341 (4.40%)	15 / 170 (8.82%)
occurrences all number	16	15
Tinnitus
subjects affected / exposed	71 / 341 (20.82%)	36 / 170 (21.18%)
occurrences all number	102	52
Eye disorders
Vision blurred
subjects affected / exposed	13 / 341 (3.81%)	10 / 170 (5.88%)
occurrences all number	14	11
Gastrointestinal disorders
Abdominal pain
subjects affected / exposed	33 / 341 (9.68%)	21 / 170 (12.35%)
occurrences all number	42	24
Abdominal pain upper
subjects affected / exposed	35 / 341 (10.26%)	28 / 170 (16.47%)
occurrences all number	62	35
Constipation
subjects affected / exposed	12 / 341 (3.52%)	13 / 170 (7.65%)
occurrences all number	14	14
Diarrhoea
subjects affected / exposed	62 / 341 (18.18%)	33 / 170 (19.41%)
occurrences all number	92	51
Dyspepsia
subjects affected / exposed	33 / 341 (9.68%)	14 / 170 (8.24%)
occurrences all number	42	17
Gastritis
subjects affected / exposed	76 / 341 (22.29%)	27 / 170 (15.88%)
occurrences all number	133	46
Gastrooesophageal reflux disease
subjects affected / exposed	19 / 341 (5.57%)	11 / 170 (6.47%)
occurrences all number	20	11
Nausea
subjects affected / exposed	95 / 341 (27.86%)	56 / 170 (32.94%)
occurrences all number	133	80
Toothache
subjects affected / exposed	29 / 341 (8.50%)	17 / 170 (10.00%)
occurrences all number	32	25
Vomiting
subjects affected / exposed	92 / 341 (26.98%)	39 / 170 (22.94%)
occurrences all number	150	62
Hepatobiliary disorders
Hepatotoxicity
subjects affected / exposed	20 / 341 (5.87%)	11 / 170 (6.47%)
occurrences all number	33	15
Skin and subcutaneous tissue disorders
Pruritus
subjects affected / exposed	28 / 341 (8.21%)	14 / 170 (8.24%)
occurrences all number	35	21
Rash
subjects affected / exposed	27 / 341 (7.92%)	9 / 170 (5.29%)
occurrences all number	30	11
Renal and urinary disorders
Proteinuria
subjects affected / exposed	18 / 341 (5.28%)	7 / 170 (4.12%)
occurrences all number	24	10
Musculoskeletal and connective tissue disorders
Arthralgia
subjects affected / exposed	116 / 341 (34.02%)	65 / 170 (38.24%)
occurrences all number	192	121
Back pain
subjects affected / exposed	44 / 341 (12.90%)	31 / 170 (18.24%)
occurrences all number	62	43
Musculoskeletal pain
subjects affected / exposed	21 / 341 (6.16%)	10 / 170 (5.88%)
occurrences all number	24	13
Myalgia
subjects affected / exposed	31 / 341 (9.09%)	14 / 170 (8.24%)
occurrences all number	43	18
Pain in extremity
subjects affected / exposed	24 / 341 (7.04%)	16 / 170 (9.41%)
occurrences all number	29	21
Infections and infestations
Bronchitis
subjects affected / exposed	19 / 341 (5.57%)	13 / 170 (7.65%)
occurrences all number	20	15
Influenza
subjects affected / exposed	21 / 341 (6.16%)	6 / 170 (3.53%)
occurrences all number	34	8
Nasopharyngitis
subjects affected / exposed	71 / 341 (20.82%)	43 / 170 (25.29%)
occurrences all number	121	84
Pharyngitis
subjects affected / exposed	32 / 341 (9.38%)	23 / 170 (13.53%)
occurrences all number	45	30
Rhinitis
subjects affected / exposed	13 / 341 (3.81%)	10 / 170 (5.88%)
occurrences all number	18	10
Upper respiratory tract infection
subjects affected / exposed	49 / 341 (14.37%)	21 / 170 (12.35%)
occurrences all number	114	38
Urinary tract infection
subjects affected / exposed	36 / 341 (10.56%)	15 / 170 (8.82%)
occurrences all number	48	16
Metabolism and nutrition disorders
Decreased appetite
subjects affected / exposed	26 / 341 (7.62%)	9 / 170 (5.29%)
occurrences all number	33	11
Hyperuricaemia
subjects affected / exposed	34 / 341 (9.97%)	22 / 170 (12.94%)
occurrences all number	45	25
Hypokalaemia
subjects affected / exposed	53 / 341 (15.54%)	29 / 170 (17.06%)
occurrences all number	111	71
Hypomagnesaemia
subjects affected / exposed	20 / 341 (5.87%)	7 / 170 (4.12%)
occurrences all number	24	13

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Were there any global substantial amendments to the protocol? Yes

21 Mar 2011

Amendment 1 (version 3.0): Decreased dose to 100 mg BID for 2 months and 200 mg QD for 4 months; Increased follow-up period to 12 months; Increased the number of subjects to be enrolled.

12 May 2011

Amendment 2 (version4.0): Addition of safety data and addition of a second ICF for subjects with HIV co-infection.

01 Sep 2011

Amendment 3 (version 5.0): The protocol was divided into 2 protocols - trial and HIV sub trial.

01 Sep 2011

Amendment 3 (version 5.1): The protocol was divided into 2 protocols - trial and HIV subtrial. Added optional genetic testing for HIV-positive subjects.

25 Sep 2012

Amendment 4 (version 6.0): Modified inclusion criteria for MDR TB.

25 Sep 2012

Amendment 4 (version 6.1): Modified eligibility criteria (Maximum date for screening sputum specimen was changed from 90 days to 60 days) for MDR TB and HIV-positive subjects in the subtrial; clarified Holter monitoring (HIV subtrial).

01 Mar 2013

Amendment 4 (version 6.2): Modified eligibility criteria (Maximum date for screening sputum specimen was changed from 90 days to 60 days) for MDR TB and HIV-positive subjects in the subtrial; updated background information (HIV subtrial).

03 Sep 2014

Amendment 5 (version7.0): Refined efficacy endpoints.

03 Sep 2014

Amendment 5 (version7.1): Refined efficacy endpoints (HIV subtrial).

Were there any global interruptions to the trial? No

Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.

None reported

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Clinical trials

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Time to Sputum culture conversion (SCC) assessment by Mycobacteria Growth Indicator Tube (MGIT) system to evaluate the efficacy of Delamanid in combination with OBR during 6 month intensive treatment period

Primary: Time to Sputum culture conversion (SCC) assessment by Mycobacteria Growth Indicator Tube (MGIT) system to evaluate the efficacy of Delamanid in combination with OBR during 6 month intensive treatment period

Secondary: Proportion of subjects with SCC using MGIT and solid culture at 2 and 6 months

Secondary: Proportion of subjects with SCC using MGIT and solid culture at 2 and 6 months

Secondary: Sustained SCC using MGIT at Month 18, Month 24, and Month 30

Secondary: Sustained SCC using MGIT at Month 18, Month 24, and Month 30

Secondary: Treatment outcomes assessed by principal investigators at the end of treatment with OBR

Secondary: Treatment outcomes assessed by principal investigators at the end of treatment with OBR

Secondary: Proportion of subjects who developed resistance to Delamanid.

Secondary: Proportion of subjects who developed resistance to Delamanid.

Secondary: Mean area under the concentration-time curve (AUC) of change from baseline

Secondary: Mean area under the concentration-time curve (AUC) of change from baseline

Secondary: Mean change from baseline in TTD using the MGIT system

Secondary: Mean change from baseline in TTD using the MGIT system

Secondary: Distribution of time to SCC using solid culture at month 6

Secondary: Distribution of time to SCC using solid culture at month 6

Secondary: Final outcome at month 30 as a treatment success or failure (including relapse)

Secondary: Final outcome at month 30 as a treatment success or failure (including relapse)

Secondary: Sustained SCC using solid culture at Month 18, Month 24, and Month 30

Secondary: Sustained SCC using solid culture at Month 18, Month 24, and Month 30

Adverse events

Adverse events

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Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

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