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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

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    Trial identification
    Sponsor protocol code
    242-09-213
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT01424670
    WHO universal trial number (UTN)
    -
    Sponsors
    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
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    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?
    No
    General information about the trial
    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
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    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
    Country: Number of subjects enrolled
    Moldova, Republic of: 43
    Country: Number of subjects enrolled
    Peru: 157
    Country: Number of subjects enrolled
    Philippines: 127
    Worldwide total number of subjects
    511
    EEA total number of subjects
    83
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    510
    From 65 to 84 years
    1
    85 years and over
    0

    Subject disposition

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    Recruitment
    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).

    Pre-assignment
    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
    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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    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.

    Arm title
    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
         Adverse event
    15
    7
         Met protocol withdrawal criteria
    3
    2
         Subject was withdrawn by investigator
    7
    7
         Consent withdrawn by subject
    26
    11
         Lost to follow-up
    2
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Delamanid+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 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.

    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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    End points reporting groups
    Reporting group title
    Delamanid+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 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.

    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)
    Statistical analysis title
    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
    Statistical analysis title
    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.
    Statistical analysis title
    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
    Statistical analysis title
    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
    Statistical analysis title
    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
    Statistical analysis title
    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
    Statistical analysis title
    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
    Statistical analysis title
    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 title
    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 title
    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 title
    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
    Statistical analysis title
    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 title
    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 title
    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
    Statistical analysis title
    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
    Statistical analysis title
    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
    Statistical analysis title
    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
    Statistical analysis title
    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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    Adverse events information
    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 used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    19.0
    Reporting groups
    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
    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
    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
    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
    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
    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
    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
    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
    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
    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
    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
    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
    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
    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
    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
    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
    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
    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
    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
    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
    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
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    17 / 341 (4.99%)
    9 / 170 (5.29%)
         occurrences all number
    21
    11
    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
    Eye disorders
    Vision blurred
         subjects affected / exposed
    13 / 341 (3.81%)
    10 / 170 (5.88%)
         occurrences all number
    14
    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
    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
    Renal and urinary disorders
    Proteinuria
         subjects affected / exposed
    18 / 341 (5.28%)
    7 / 170 (4.12%)
         occurrences all number
    24
    10
    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
    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
    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
    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

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    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).

    Interruptions (globally)

    Were there any global interruptions to the trial? No

    Limitations and caveats

    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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