Clincosm LogoSign in Get a demo

A Trial to Evaluate OPC 67683 in Participants With Pulmonary Sputum Culture-positive, Multidrug-resistant Tuberculosis (TB)

Sponsor
Otsuka Pharmaceutical Development & Commercialization, Inc. (Industry)
Overall Status
Completed
CT.gov ID
NCT00685360
Collaborator
(none)
481
Enrollment
17
Locations
3
Arms
25.1
Actual Duration (Months)
28.3
Patients Per Site
1.1
Patients Per Site Per Month

Study Details

Study Description

Brief Summary

This is a clinical trial to evaluate the safety and efficacy of OPC-67683 in the treatment of multidrug resistant tuberculosis (MDR TB) for 56 days. In addition to an optimized background regimen (OBR), participants will be randomized to receive:

  • 100 mg OPC-67683 twice daily (BID)

  • 200 mg OPC-67683 BID

  • Placebo BID

After 56 days participants will complete their optimized background regimen (OBR).

Condition or Disease Intervention/Treatment Phase
Phase 2

Detailed Description

This is a multi center, randomized, double-blinded, stratified, placebo-controlled clinical trial in three parallel groups. Participants will be randomized to one of the following three treatment groups:

  • OBR plus 100 mg OPC-67683 BID

  • OBR plus 200 mg OPC-67683 BID

  • OBR plus placebo BID

The three treatment groups will comprise approximately 140 participants each (male or female). The trial will consist of the following periods:

  • Pre-treatment Period (Visits 1 to 3 [Day -9 to Day -1])

  • Treatment Period (Visits 4 to 59 [Days 1 to 56])

  • Post-treatment Period (Visits 60 to 64 [Days 57 to 84])

Enrolled participants (those accepted into the screening period of the trial who signed an informed consent form) will be stratified at randomization by extent of pulmonary TB; an equal number of participants with and without cavities visible in the lung fields on baseline chest radiograph will be allocated to each treatment group. A total of approximately 430 male or female participants aged 18 to 64 years, inclusive, with pulmonary, sputum culture-positive MDR TB (TB caused by Mycobacterium tuberculosis strains resistant to at least isoniazid and rifampicin) or with sputum smears positive for acid fast bacilli (AFB) and a positive rapid test for rifampicin resistance on direct sputum within 60 days prior to the expected date of enrollment. Participants with positive AFB smears and a positive rapid rifampicin resistance test will be enrolled as presumptively culture positive and withdrawn as ineligible if they are confirmed to not have sputum culture positive MDR TB.

Study Design

Study Type:
Interventional
Actual Enrollment :
481 participants
Allocation:
Randomized
Intervention Model:
Parallel Assignment
Masking:
Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose:
Treatment
Official Title:
A Multi Center, Randomized, Double-blind, Placebo-controlled Phase 2 Trial to Evaluate the Safety, Efficacy and Pharmacokinetics of Multiple Doses of OPC 67683 in Patients With Pulmonary Sputum Culture-Positive, Multidrug-resistant Tuberculosis
Actual Study Start Date :
May 8, 2008
Actual Primary Completion Date :
Jun 11, 2010
Actual Study Completion Date :
Jun 11, 2010

Arms and Interventions

Arm Intervention/Treatment
Experimental: Delamanid 100 mg BID + OBR

Participants received delamanid 100 milligrams (mg) (two 50 mg tablets), orally, BID with two matching placebo tablets plus optimized background regimen (OBR) for 56 consecutive days (from Day 1 to Day 56). Participants were administered OBR as directed by the given investigator based on World Health Organization (WHO) guidelines and clinical judgment, in conjunction with national TB program guidelines in each country.

Drug: Delamanid
Delamanid was administered orally twice daily as 50-mg tablets under fed conditions in the morning and evening.
Other Names:
  • OPC-67683

    • Drug: Optimized Background Regimen (OBR)
    Selection and administration of the treatment medications (i.e., OBRs) was based on World Health Organization (WHO's) Guidelines for the programmatic management of drug-resistant TB, in conjunction with national TB program guidelines in each country. Study Investigator could change OBR for a participant based on participant's tolerability and drug susceptibility testing (DST) results.

    Drug: Placebo
    Placebo tablets matching 50-mg tablets of delamanid
    Experimental: Delamanid 200 mg BID + OBR

    Participants received delamanid 200 mg (four 50 mg tablets), orally, BID plus OBR for 56 consecutive days (from Day 1 to Day 56). Participants were administered OBR as directed by the given investigator based on WHO guidelines and clinical judgment, in conjunction with national TB program guidelines in each country.

    Drug: Delamanid
    Delamanid was administered orally twice daily as 50-mg tablets under fed conditions in the morning and evening.
    Other Names:
  • OPC-67683

    • Drug: Optimized Background Regimen (OBR)
    Selection and administration of the treatment medications (i.e., OBRs) was based on World Health Organization (WHO's) Guidelines for the programmatic management of drug-resistant TB, in conjunction with national TB program guidelines in each country. Study Investigator could change OBR for a participant based on participant's tolerability and drug susceptibility testing (DST) results.
    Placebo Comparator: Placebo + OBR

    Participants received four placebo tablets matching 50-mg tablets of delamanid, orally, BID plus OBR for 56 consecutive days (from Day 1 to Day 56). Participants were administered OBR as directed by the given investigator based on WHO guidelines and clinical judgment, in conjunction with national TB program guidelines in each country.

    Drug: Optimized Background Regimen (OBR)
    Selection and administration of the treatment medications (i.e., OBRs) was based on World Health Organization (WHO's) Guidelines for the programmatic management of drug-resistant TB, in conjunction with national TB program guidelines in each country. Study Investigator could change OBR for a participant based on participant's tolerability and drug susceptibility testing (DST) results.

    Drug: Placebo
    Placebo tablets matching 50-mg tablets of delamanid

    Outcome Measures

    Primary Outcome Measures

    1. Percentage of Participants Who Achieved Sputum Culture Conversion (SCC) Using the Mycobacteria Growth Indicator Tube (MGIT) System [From the first dose of study drug up to the end of the Post-treatment Follow-up Period (Up to Day 84)]

      Sputum culture conversion was defined to occur at the time of the collection of a sputum specimen with mycobacterial culture negative for growth of Mycobacterium tuberculosis (MTB) followed by at least one additional sputum specimen with mycobacterial culture negative for growth at least 27 days after the first negative specimen and not followed by any sputum specimens positive for growth in the MGIT system at any point during the remainder of the 84-day trial after the first negative culture.

    2. Tmax 1 and 2: Time to Maximal Peak Concentration (Tmax) for Delamanid Following First and Second Daily Dose [Pre-dose, 2, 3, 4, 10 (pre-evening dose), 12, 13, 14 and 24 hours post-dose up to Day 56]

      Time to maximum (peak) plasma concentration following the first daily dose (Cmax1) was reported as tmax1 and time to maximum (peak) plasma concentration following the second daily dose (Cmax2) was reported as tmax2. Data for Tmax up to Day 56 was collected on Days 1, 14, 28 and 56.

    3. Cmax 1 and 2: Maximal Peak Concentration (Cmax) for Delamanid Following First and Second Daily Dose [Pre-dose, 2, 3, 4, 10 (pre-evening dose), 12, 13, 14 and 24 hours post-dose up to Day 56]

      Maximum (peak) plasma concentration following the first daily dose was reported as Cmax1 and maximum (peak) plasma concentration following the second daily dose was reported as Cmax2. Data for Cmax up to Day 56 was collected on Days 1, 14, 28 and 56.

    4. Area Under the Plasma Concentration Curve From 0 to 24 Hours (AUC0-24h) for Delamanid [Pre-dose, 2, 3, 4, 10 (pre-evening dose), 12, 13, 14 and 24 hours post-dose up to Day 56]

      Data for AUC0-24h up to Day 56 was collected on Days 1, 14, 28 and 56.

    5. Accumulation Ratio for Cmax (Rac[Cmax]) for Delamanid [Pre-dose, 2, 3, 4, 10 (pre-evening dose), 12, 13, 14 and 24 hours post-dose up to Day 56]

      Data for Rac (Cmax) up to Day 56 was collected on Days 14, 28 and 56. Rac (Cmax) on Days 14, 28 or 56 compared to Cmax on Day 1 was computed.

    6. Accumulation Ratio for AUC From Time 0 to 24 Hours (Rac[AUC0-24h]) for Delamanid [Pre-dose, 2, 3, 4, 10 (pre-evening dose), 12, 13, 14 and 24 hours post-dose up to Day 56]

      Data for Rac (AUC) up to Day 56 was collected on Days 14, 28 and 56. Rac (AUC) on Days 14, 28 or 56 compared to AUC0-24h on Day 1 was computed.

    7. Time to Maximal Peak Concentration (Tmax) for Delamanid Metabolite (DM)-6704, DM-6705, DM-6706, DM-6717, DM-6718, DM-6720, DM-6721, and DM-6722 [0 hours (morning pre-dose), 2, 3, 4, 10 (pre-evening dose), 12, 13, 14 and 24 hours post-dose up to Day 56]

      Data for Tmax up to Day 56 was collected on Days 1, 14, 28 and 56.

    8. Maximal Peak Concentration (Cmax) for DM-6704, DM-6705, DM-6706, DM-6717, DM-6718, DM-6720, DM-6721, and DM-6722 [0 hours (morning pre-dose), 2, 3, 4, 10 (pre-evening dose), 12, 13, 14 and 24 hours post-dose up to Day 56]

      Data for Cmax up to Day 56 was collected on Days 1, 14, 28 and 56.

    9. Area Under the Plasma Concentration Curve From 0 to 24 Hours (AUC0-24h) for DM-6704, DM-6705, DM-6706, DM-6717, DM-6718, DM-6720, DM-6721, and DM-6722 [0 hours (morning pre-dose), 2, 3, 4, 10 (pre-evening dose), 12, 13, 14 and 24 hours post-dose up to Day 56]

      Data for AUC0-24h up to Day 56 was collected on Days 1, 14, 28 and 56.

    10. Accumulation Ratio for Cmax (Rac[Cmax]) for DM-6704, DM-6705, DM-6706, DM-6717, DM-6718, DM-6720, DM-6721, and DM-6722 [0 hours (morning pre-dose), 2, 3, 4, 10 (pre-evening dose), 12, 13, 14 and 24 hours post-dose up to Day 56]

      Data for Rac (Cmax) up to Day 56 was to be collected on Days 1, 14, 28 and 56. Rac (Cmax) on Days 14, 28 or 56 compared to Cmax on Day 1 was to be computed. Due to limited measurable data on Day 1 for delamanid metabolites, pharmacokinetic (PK) analysis was not conducted on Day 1 data for delamanid metabolites, and data for Rac (Cmax) was not available.

    11. Accumulation Ratio for AUC (Rac[AUC]) for DM-6704, DM-6705, DM-6706, DM-6717, DM-6718, DM-6720, DM-6721, and DM-6722 [0 hours (morning pre-dose), 2, 3, 4, 10 (pre-evening dose), 12, 13, 14 and 24 hours post-dose up to Day 56]

      Data for Rac (AUC) up to Day 56 was to be collected on Days 1, 14, 28 and 56. Rac (AUC) on Days 14, 28 or 56 compared to AUC0-24h on Day 1 was to be computed. Due to limited measurable data on Day 1 for delamanid metabolites, PK analysis was not conducted on Day 1 data for delamanid metabolites, and data for Rac (AUC) was not available.

    12. Elimination Half-life (t1/2) for DM-6704, DM-6705, DM-6706, DM-6717, DM-6718, DM-6720, DM-6721, and DM-6722 [0 hours (morning pre-dose), 2, 3, 4, 10 (pre-evening dose), 12, 13, 14 and 24 hours post-dose on Day 56]

    Secondary Outcome Measures

    1. Percentage of Participants Who Achieved Sputum Culture Conversion (SCC) Using Solid Culture Media [From the first dose of study drug up to the end of the Post-treatment Follow-up Period (Up to Day 84)]

      A participant achieving SCC using solid culture media was defined as one with sputum culture negative for growth of MTB on Day 57, and (a) not followed by a positive culture at any point thereafter, and (b) confirmed by at least one additional negative sputum culture at Day 84.

    2. Change From Baseline in Time to Culture Positivity Using the MGIT System [Baseline, Day 84]

      Mean change from baseline in time to culture positivity using the MGIT system was the value for "time to results" when a sputum culture result was positive (in days) using the MGIT system during the routine 42-day incubation period. A longer time to culture positivity represented a lower burden of MTB organisms present in the sputum. Baseline was defined as the average of Day -1 and Day 1 values, if the cultures on both days were positive; if only one culture was positive, the value for the positive culture was used as baseline.

    3. Area Under the Curve (AUC) of Change From Baseline in Time to Culture Positivity in the MGIT System [Baseline to Day 57]

      AUC of change from baseline for time to culture positivity (i.e., TTD) (Days 0 to 57), summarizes overall participant response for treatment period. Larger AUC of change from baseline for time to culture positivity would strongly suggest a clinical response with reduction of burden of MTB organisms in sputum. For this analysis, ti=visit day of each visit; t0=Day 0, t1=Day 8, t2=Day 15, etc. and xi=change from baseline in time to culture positivity at each visit; AUC at each visit was determined as AUCi=(ti - ti-1)(xi+ xi-1)/2. Average AUC of change from baseline was the sum of all AUCi divided by a given participant's duration in the trial up to 57 days. Baseline (Day 0)=the average of Day -1 and Day 1 values, if cultures on both days were positive; if only one culture was positive, value for time to culture positivity for positive culture was used as baseline.

    4. Percentage of Participants With Sputum Culture Negative at Day 57 Using the MGIT System Without Consideration of Subsequent Culture Results [Day 57]

    5. Percentage of Participants With Sputum Culture Negative at Day 57 and Day 84 Using the MGIT System Without Respect to Interim Culture Results [Day 57 and Day 84]

    6. Percentage of Participants With Sputum Culture Negative at Day 57 Using Solid Culture Media Without Respect to Subsequent Culture Results [Day 57]

    7. Percentage of Participants With Sputum Culture Negative at Day 57 and Day 84 Using Solid Culture Media Without Respect to Interim Culture Results [Day 57 and Day 84]

    8. Percentage of Participants Who Achieved SCC From the MGIT System Analyzed by Cochran-Armitage Linear Trend Test for Dose-response Relationship [From the first dose of study drug up to the end of the Post-treatment Follow-up Period (Up to Day 84)]

      A participant achieving SCC using solid media is defined as one with sputum culture negative for growth of MTB on Day 57, and (a) not followed by a positive culture at any point thereafter, and (b) confirmed by at least one additional negative sputum culture at Day 84. A dose response in the percentage of participants achieving SCC using the MGIT system was tested by the Cochran-Armitage linear trend test with equally spaced dose scores (0, 1, and 2 for placebo, 100 mg BID, and 200 mg BID, respectively).

    9. Percentage of Participants Who Achieved Initial SCC Using the MGIT System [Day 57]

      Initial SCC occurred at the time of the collection of the first sputum specimen with mycobacterial culture negative for growth of MTB using the MGIT system followed by at least one additional MGIT negative sputum specimen at least 27 days after the first negative specimen and no sputum specimens MGIT positive for growth at any point between the negative MGIT sputum specimens. Survival analysis methodology was performed to compare the Kaplan-Meier curves for time to SCC across 3 treatment groups. Comparisons between 100 mg BID and placebo and 200 mg BID and placebo were also performed with stratified log-rank tests. The benefit ratios (ratio of likelihoods that participants treated with delamanid BID + OBR would achieve SCC more rapidly than participants treated with placebo + OBR) for participants achieving SCC were computed.

    10. Percentage of Participants Who Achieved Initial SCC Using the Solid Culture Media [Day 57]

      Initial SCC occurred at the time of the collection of the first sputum specimen with mycobacterial culture negative for growth of MTB using solid culture media that was followed by at least one additional negative sputum specimen at least 27 days after the first negative specimen and no sputum specimens positive for growth on solid culture media at any point between the negative sputum specimens using solid culture media. Survival analysis methodology was performed to compare the Kaplan-Meier curves for time to SCC across 3 treatment groups. Comparisons between 100 mg BID and placebo and 200 mg BID and placebo were also performed with stratified log-rank tests. The benefit ratios (ratio of likelihoods that participants treated with delamanid BID + OBR would achieve SCC more rapidly than participants treated with placebo + OBR) for participants achieving SCC were computed.

    11. Percentage of Participants Who Achieved Final SCC Using MGIT [Day 57]

      Final SCC was defined as SCC at Day 57 or the latest time point of the first negative sputum culture establishing SCC for a given participant after the last positive sputum culture observed during the 56-day treatment period, whichever comes first. Survival analysis methodology was performed to compare the Kaplan-Meier curves for time to SCC across 3 treatment groups. Comparisons between 100 mg BID and placebo and 200 mg BID and placebo were also performed with stratified log-rank tests. The benefit ratios (ratio of likelihoods that participants treated with delamanid BID + OBR would achieve SCC more rapidly than participants treated with placebo + OBR) for participants achieving SCC were computed.

    12. Percentage of Participants Who Achieved Final SCC Using Solid Culture Media [Day 57]

      Final SCC is defined as SCC at Day 57 or the latest time point of the first negative sputum culture establishing SCC for a given participant after the last positive sputum culture observed during the 56-day treatment period, whichever comes first. Survival analysis methodology was performed to compare the Kaplan-Meier curves for time to SCC across 3 treatment groups. Comparisons between 100 mg BID and placebo and 200 mg BID and placebo were also performed with stratified log-rank tests. The benefit ratios (ratio of likelihoods that participants treated with delamanid BID + OBR would achieve SCC more rapidly than participants treated with placebo + OBR) for participants achieving SCC were computed.

    13. Percentage of Participants With Clinically Significant Physical Examination Findings, Including Vision and Neuropsychiatric Assessments [From first dose of study drug up to post treatment period (Day 84)]

    14. Percentage of Participants With Clinically Significant Vital Sign Abnormalities [From first dose of study drug up to post treatment period (Day 84)]

      Criteria for potentially clinically significant vital sign abnormalities: Heart rate [beats per minute (BPM)]: >=120, increase >=15, <=60, decrease >=15; systolic blood pressure [millimeter of mercury (mmHg)]: >=160, increase >=20, <=90, decrease >=20; diastolic blood pressure (mmHg): >=105, increase >=15, <=50, decrease >=15; weight (kg) gain: increase >=5%; or weight loss: decrease >=5%; temperature [degrees Celsius (C)]: >=38.5, increase of >=1.1. Only categories with at least 1 participant with event are reported.

    15. Percentage of Participants With Categorical Changes in 12-lead Electrocardiogram Results at Day 56 [Baseline up to Day 56]

      Criteria for categorical changes in 6 12-lead Electrocardiogram results: Vent Rate Outliers Notable Decreases- >= 25% decrease from Baseline and ventricular rate < 50 beats per minute (beats/min), notable increases- >= 25% decrease from Baseline and ventricular rate > 100 beats/min; PR outliers notable changes- >= 25% change from Baseline when PR > 200 milliseconds (msec); QRS outliers notable changes- >= 25% change from Baseline when QRS > 100 msec; QT new onset (> 500 msec); QT correction with Bazett formula (QTcB) and QT interval with Fridericia's correction (QTcF) new onset > 500 msec, > 480 msec, > 450 msec, where new onset (> 450, 480, 500 msec) means a participant who attains a value > 450, 480, 500 msec during Treatment Period but not at each Baseline Visit; change >= 30, <= 60 msec; change > 60 msec; and new abnormal U waves, ST segment changes, T wave changes, abnormal rhythm, RBBB, LBBB, myocardial infarction(MI). Only categories with at least 1 participant with event are r

    16. Percentage of Participants With Clinically Significant Laboratory Test Abnormalities [From first dose of study drug up to post treatment period (Day 84)]

      The laboratory values were one of the parameters to measure the safety and tolerability of individual participants. Participants with potentially clinically significant laboratory values in clinical chemistry, hematology, coagulation, adrenal function tests, urinalysis and thyroid function tests that were identified based on pre-defined criteria were reported. Any value outside the normal range was flagged for the attention of the investigator who assessed whether or not a flagged value is of clinical significance. The categories with at least one participant with abnormal lab value as assessed by the investigator are reported.

    17. Percentage of Participants With Clinically Significant Audiometry Findings [From first dose of study drug up to post treatment period (Day 84)]

    18. Percentage of Participants Using Concomitant Medications [From first dose of study drug up to post treatment period (Day 84)]

      The concomitant anti-TB medication were classified as per WHO 2008 guidelines and included: Category 1- first-line oral anti-tuberculosis drugs; Category 2- injectable anti-tuberculosis drugs; Category 3- fluoroquinolones; Category 4- oral bacteriostatic second-line anti-tuberculosis drugs; Category 5- anti-tuberculosis drugs with unclear efficacy or unclear role in MDR-TB treatment (not recommended by WHO for routine use in MDR-TB participants).

    19. Percentage of Participants With At Least One Treatment-Emergent Adverse Events (TEAEs) [From first dose of study drug up to post treatment period (Day 84)]

      An adverse event (AE) was defined as any untoward medical occurrence in a clinical trial participant and which does not necessarily have a causal relationship with the treatment. An AE can therefore be any unfavorable and unintended sign (including e.g., an abnormal laboratory assessment result), symptom or disease temporally associated with participation in the clinical trial, whether or not it is considered causally related to the medicinal product or procedures of the clinical trial. A clinically significant worsening in the health of the participant compared with the participant's health status documented at baseline constituted a TEAE.

    20. Time-matched Change From Baseline (Day -1) in QTcF at Day 56 [Baseline, and 2, 3, 4, 10, 12, and 24 hours post dose on Day 56]

    21. Mean Change From Baseline in QTcF [Baseline, Days 1, 14, 28 and 56]

    22. Mean Change From Baseline in QTcB [Baseline, Days 1, 14, 28 and 56]

    23. Mean Change From Baseline in Ventricular Rate [Baseline, Days 1, 14, 28 and 56]

    24. Mean Change From Baseline in PR Interval [Baseline, Days 1, 14, 28 and 56]

    25. Mean Change From Baseline in QRS Interval [Baseline, Days 1, 14, 28 and 56]

    26. Mean Change From Baseline in QT Interval [Baseline, Days 1, 14, 28 and 56]

    27. Percentage of Participants With Change in ECG Morphological Patterns From Baseline [Baseline, Days 1, 14, 28 and 56]

      Any changes in the ECG waves or segments as assessed by the investigator were reported.

    Eligibility Criteria

    Criteria

    Ages Eligible for Study:
    18 Years to 64 Years
    Sexes Eligible for Study:
    All
    Accepts Healthy Volunteers:
    No
    Inclusion Criteria:

    • Provide written, informed consent prior to all trial-related procedures

    • Male and female participants aged between 18 and 64 years, inclusive.

    • Either mycobacterial culture of sputum positive for growth of Mycobacterium tuberculosis or sputum smear positive for acid fast bacilli within 60 days prior to the expected date of enrollment.

    • Participant with TB caused by isolates of Mycobacterium tuberculosis complex confirmed to be resistant to treatment with isoniazid and rifampicin, or with positive rapid test for rifampicin resistance on direct sputum positive for acid fast bacilli within 60 days prior to the expected date of enrollment.

    • Findings on chest radiograph consistent with TB.

    • Able to produce sputum for mycobacterial culture.

    • Female participants of childbearing potential must have a negative urine pregnancy test and agree to use a highly effective method of birth control (for example, two of the following precautions: tubal ligation, vaginal diaphragm, intrauterine device, oral contraceptives, contraceptive implant, combined hormonal patch, combined injectable contraceptive or depot-medroxyprogesterone acetate) throughout the participation in the trial and for 22 weeks after last dose (to cover duration of ovulation).

    • Male participants must agree to use an adequate method of contraception (double barrier) throughout the participation in the trial and for 30 weeks after last dose (to cover duration of spermatogenesis).

    Exclusion Criteria:

    • A history of allergy to any nitro-imidazoles or nitro-imidazole derivates at any time.

    • Use of the medications including: use of amiodarone at any time during the previous 12 months, use of other anti-arrhythmics for the previous 30 days, and use of certain other medications, including certain anti-depressants, anti-histamines, and macrolides, for the previous 14 days.

    • Any current serious concomitant conditions or renal impairment characterized by serum creatinine levels ≥265 micromol/L or hepatic impairment characterized by alanine transaminase (ALT) and/or aspartate transferase (AST) levels 3 times the upper limit of the laboratory reference range.

    • Current clinically relevant changes in the electrocardiogram (ECG) such as any atrioventricular (AV) block, prolongation of the QRS complex over 120 milliseconds (in both male and female participants), or of either the QT interval corrected by Fridericia's formula (QTcF) or QT interval corrected by Bazett's formula (QTcB) interval over 430 milliseconds in male participants and 450 milliseconds in female participants.

    • Current clinically relevant cardiovascular disorder such as heart failure, coronary heart disease, hypertension, arrhythmia, tachyarrhythmia or status after myocardial infarction.

    • For participants with human immunodeficiency virus (HIV) infection, cluster of differentiation 4 helper/inducer T cell[s] (CD4) cell count < 350/mm3 or on treatment with anti-retroviral medication for HIV infection.

    • Karnofsky score < 60%.

    • Any diseases or conditions in which the use of nitro-imidazoles or nitro-imidazole derivates is contra-indicated.

    • Evidence of clinically significant metabolic, gastrointestinal, neurological, psychiatric or endocrine diseases, malignancy, or other abnormalities (other than the indication being studied).

    • Known or suspected alcohol abuse, that is, abuse sufficient enough to compromise the safety or cooperation of the participant in the opinion of the investigator.

    • Administered an investigational medicinal product (IMP) within 1 month prior to Visit 1 (Screening [Days -9 to -3]).

    • Pregnant, breast-feeding, or planning to conceive or father a child within the timeframe described in the informed consent form.

    • Recent use of methadone, benzodiazepines, cocaine, amphetamine/metamphetamine, tetrahydrocannabinol, barbiturates, tricyclic antidepressants, and opiates as determined by a urine drug screen unless evidence is provided that the positive drug screen is the result of authorized medications products prescribed by a physician for a non-abuse-related indication.

    • Any disorder that in the judgment of the investigator makes the participant not a good candidate for the trial or may prevent the participant from reliably participating in the entire course of the trial.

    Contacts and Locations

    Locations

    Site City State Country Postal Code
    1 University of Texas Health Center at Tyler / Heartland National TB Center / Texas Center for Infectious Disease San Antonio Texas United States 78223
    2 Beijing Chest Hospital Beijing China 101149
    3 Shanghai Pulmonary Hospital Shanghai China 200433
    4 Abbassia Chest Hospital Cairo Egypt
    5 North Estonian Medical Centre Foundation Tallinn Estonia 13419
    6 Tartu University Lung Hospital Tartu Estonia 13419
    7 Kinki Chuo Chest Hospital Osaka Japan 591-8555
    8 Fukujuji Hospital Tokyo Japan 204-8522
    9 Masan Medical Center Changwon Korea, Republic of 138-736
    10 National Masan Hospital Masan Korea, Republic of 631-710
    11 Younsei University Medical Center (YUMC), Severance Hospital Seoul Korea, Republic of 120-752
    12 Samsung Medical Center Seoul Korea, Republic of 135-710
    13 Clinic of Tuberculosis and Lung Diseases Riga Latvia LV2118
    14 Hospital Nacional Daniel Alcides Carrión Carrion Peru Callao 2
    15 Hospital Nacional Sergio E. Bernales Lima Peru Lima 41
    16 Hospital Nacional Hipolito Unanue Unanue Peru Lima 10
    17 Tropical Disease Foundation Manila Philippines 1229

    Sponsors and Collaborators

    • Otsuka Pharmaceutical Development & Commercialization, Inc.

    Investigators

    • Study Director: Study Director, Otsuka Pharmaceutical Development & Commercialization, Inc.

    Study Documents (Full-Text)

    None provided.

    More Information

    Publications

    None provided.
    Responsible Party:
    Otsuka Pharmaceutical Development & Commercialization, Inc.
    ClinicalTrials.gov Identifier:
    NCT00685360
    Other Study ID Numbers:
    • 242-07-204
    • 2007-005229-31
    First Posted:
    May 28, 2008
    Last Update Posted:
    Dec 1, 2021
    Last Verified:
    Nov 1, 2021
    Individual Participant Data (IPD) Sharing Statement:
    Yes
    Plan to Share IPD:
    Yes
    Studies a U.S. FDA-regulated Drug Product:
    Yes
    Studies a U.S. FDA-regulated Device Product:
    No
    Keywords provided by Otsuka Pharmaceutical Development & Commercialization, Inc.
    Tuberculosis
    Pulmonary
    Multidrug resistant
    Antitubercular Agents
    OPC 67683
    Additional relevant MeSH terms:
    Tuberculosis
    Tuberculosis, Pulmonary
    Tuberculosis, Multidrug-Resistant
    Extensively Drug-Resistant Tuberculosis

    Study Results

    Participant Flow

    Recruitment Details Participants took part in the study at 17 investigative sites in the Philippines, Latvia, Estonia, South Korea, Peru, China, Japan, Egypt, and the United States from 08 May 2008 to 11 June 2010.
    Pre-assignment Detail Participants with pulmonary sputum culture-positive, multidrug-resistant tuberculosis were randomized in 1:1:1 ratio to 1 of the 3 groups to receive either optimized background regimen (OBR) + 100 milligrams (mg) BID delamanid or OBR + 200 mg BID delamanid or OBR + placebo.
    Arm/Group Title Delamanid 100 mg BID + OBR Delamanid 200 mg BID + OBR Placebo + OBR
    Arm/Group Description Participants received delamanid 100 mg (two 50 mg tablets), orally, twice daily (BID) with two matching placebo tablets plus OBR for 56 consecutive days (from Day 1 to Day 56). Participants were administered OBR as directed by the given investigator based on World Health Organization (WHO) guidelines and clinical judgment, in conjunction with national TB program guidelines in each country. Participants received delamanid 200 mg (four 50 mg tablets), orally, BID plus OBR for 56 consecutive days (from Day 1 to Day 56). Participants were administered OBR as directed by the given investigator based on WHO guidelines and clinical judgment, in conjunction with national TB program guidelines in each country. Participants received four placebo tablets matching 50-mg tablets of delamanid, orally, BID plus OBR for 56 consecutive days (from Day 1 to Day 56). Participants were administered OBR as directed by the given investigator based on WHO guidelines and clinical judgment, in conjunction with national TB program guidelines in each country.
    Period Title: Overall Study
    STARTED 161 160 160
    Modified Intent-to-Treat (MITT) 141 136 125
    MITT (Solid Culture) 119 115 113
    COMPLETED 143 146 145
    NOT COMPLETED 18 14 15

    Baseline Characteristics

    Arm/Group Title Delamanid 100 mg BID + OBR Delamanid 200 mg BID + OBR Placebo + OBR Total
    Arm/Group Description Participants received delamanid 100 mg (two 50 mg tablets), orally, BID with two matching placebo tablets plus OBR for 56 consecutive days (from Day 1 to Day 56). Participants were administered OBR as directed by the given investigator based on WHO guidelines and clinical judgment, in conjunction with national TB program guidelines in each country. Participants received delamanid 200 mg (four 50 mg tablets), orally, BID plus OBR for 56 consecutive days (from Day 1 to Day 56). Participants were administered OBR as directed by the given investigator based on WHO guidelines and clinical judgment, in conjunction with national TB program guidelines in each country. Participants received four placebo tablets matching 50-mg tablets of delamanid, orally, BID plus OBR for 56 consecutive days (from Day 1 to Day 56). Participants were administered OBR as directed by the given investigator based on WHO guidelines and clinical judgment, in conjunction with national TB program guidelines in each country. Total of all reporting groups
    Overall Participants 161 160 160 481
    Age (years) [Mean (Standard Deviation) ]
    Mean (Standard Deviation) [years]
    37.4
    (12.1)
    35.4
    (12.0)
    36.1
    (11.4)
    36.3
    (11.8)
    Sex: Female, Male (Count of Participants)
    Female
    56
    34.8%
    52
    32.5%
    49
    30.6%
    157
    32.6%
    Male
    105
    65.2%
    108
    67.5%
    111
    69.4%
    324
    67.4%
    Ethnicity (NIH/OMB) (Count of Participants)
    Hispanic or Latino
    42
    26.1%
    44
    27.5%
    47
    29.4%
    133
    27.7%
    Not Hispanic or Latino
    118
    73.3%
    116
    72.5%
    113
    70.6%
    347
    72.1%
    Unknown or Not Reported
    1
    0.6%
    0
    0%
    0
    0%
    1
    0.2%
    Race/Ethnicity, Customized (Count of Participants)
    White
    38
    23.6%
    31
    19.4%
    26
    16.3%
    95
    19.8%
    Black or African American
    0
    0%
    1
    0.6%
    0
    0%
    1
    0.2%
    Asian
    82
    50.9%
    87
    54.4%
    88
    55%
    257
    53.4%
    Other
    41
    25.5%
    41
    25.6%
    46
    28.8%
    128
    26.6%

    Outcome Measures

    1. Primary Outcome
    Title Percentage of Participants Who Achieved Sputum Culture Conversion (SCC) Using the Mycobacteria Growth Indicator Tube (MGIT) System
    Description Sputum culture conversion was defined to occur at the time of the collection of a sputum specimen with mycobacterial culture negative for growth of Mycobacterium tuberculosis (MTB) followed by at least one additional sputum specimen with mycobacterial culture negative for growth at least 27 days after the first negative specimen and not followed by any sputum specimens positive for growth in the MGIT system at any point during the remainder of the 84-day trial after the first negative culture.
    Time Frame From the first dose of study drug up to the end of the Post-treatment Follow-up Period (Up to Day 84)

    Outcome Measure Data

    Analysis Population Description
    Modified Intent-to-Treat (MITT) Population included all participants who had sputum cultures positive for multidrug resistant tuberculosis (MDR TB) at baseline (Day -1 and/or Day 1) using the MGIT system.
    Arm/Group Title Delamanid 100 mg BID + OBR Delamanid 200 mg BID + OBR Placebo + OBR
    Arm/Group Description Participants received delamanid 100 mg (two 50 mg tablets), orally, BID with two matching placebo tablets plus OBR for 56 consecutive days (from Day 1 to Day 56). Participants were administered OBR as directed by the given investigator based on WHO guidelines and clinical judgment, in conjunction with national TB program guidelines in each country. Participants received delamanid 200 mg (four 50 mg tablets), orally, BID plus OBR for 56 consecutive days (from Day 1 to Day 56). Participants were administered OBR as directed by the given investigator based on WHO guidelines and clinical judgment, in conjunction with national TB program guidelines in each country. Participants received four placebo tablets matching 50-mg tablets of delamanid, orally, BID plus OBR for 56 consecutive days (from Day 1 to Day 56). Participants were administered OBR as directed by the given investigator based on WHO guidelines and clinical judgment, in conjunction with national TB program guidelines in each country.
    Measure Participants 141 136 125
    Number [percentage of participants]
    45.4
    28.2%
    41.9
    26.2%
    29.6
    18.5%
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Delamanid 100 mg BID + OBR, Placebo + OBR
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value =0.0083
    Comments
    Method Cochran-Mantel-Haenszel
    Comments P-value was derived using Cochran-Mantel-Haenszel (CMH) test stratified by randomization strata (cavitation).
    Method of Estimation Estimation Parameter Risk Ratio Mean
    Estimated Value 1.534
    Confidence Interval (2-Sided) 95%
    1.107 to 2.124
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Delamanid 200 mg BID + OBR, Placebo + OBR
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value =0.0393
    Comments P-value was derived using CMH test stratified by randomization strata (cavitation).
    Method Cochran-Mantel-Haenszel
    Comments
    Method of Estimation Estimation Parameter Risk Ratio Mean
    Estimated Value 1.416
    Confidence Interval (2-Sided) 95%
    1.012 to 1.980
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    2. Primary Outcome
    Title Tmax 1 and 2: Time to Maximal Peak Concentration (Tmax) for Delamanid Following First and Second Daily Dose
    Description Time to maximum (peak) plasma concentration following the first daily dose (Cmax1) was reported as tmax1 and time to maximum (peak) plasma concentration following the second daily dose (Cmax2) was reported as tmax2. Data for Tmax up to Day 56 was collected on Days 1, 14, 28 and 56.
    Time Frame Pre-dose, 2, 3, 4, 10 (pre-evening dose), 12, 13, 14 and 24 hours post-dose up to Day 56

    Outcome Measure Data

    Analysis Population Description
    All randomized participants who received at least one dose of study medication. Number analyzed is the number of participants with data available for analysis at the given time point.
    Arm/Group Title Delamanid 100 mg BID + OBR Delamanid 200 mg BID + OBR
    Arm/Group Description Participants received delamanid 100 mg (two 50 mg tablets), orally, BID with two matching placebo tablets plus OBR for 56 consecutive days (from Day 1 to Day 56). Participants were administered OBR as directed by the given investigator based on WHO guidelines and clinical judgment, in conjunction with national TB program guidelines in each country. Participants received delamanid 200 mg (four 50 mg tablets), orally, BID plus OBR for 56 consecutive days (from Day 1 to Day 56). Participants were administered OBR as directed by the given investigator based on WHO guidelines and clinical judgment, in conjunction with national TB program guidelines in each country.
    Measure Participants 161 160
    Day 1: tmax1
    4.00
    4.00
    Day 1: tmax2
    14.0
    14.0
    Day 14: tmax1
    3.02
    3.00
    Day 14: tmax2
    14.0
    14.0
    Day 28: tmax1
    3.02
    3.00
    Day 28: tmax2
    14.0
    14.0
    Day 56: tmax1
    3.02
    3.02
    Day 56: tmax2
    14.0
    14.0
    3. Primary Outcome
    Title Cmax 1 and 2: Maximal Peak Concentration (Cmax) for Delamanid Following First and Second Daily Dose
    Description Maximum (peak) plasma concentration following the first daily dose was reported as Cmax1 and maximum (peak) plasma concentration following the second daily dose was reported as Cmax2. Data for Cmax up to Day 56 was collected on Days 1, 14, 28 and 56.
    Time Frame Pre-dose, 2, 3, 4, 10 (pre-evening dose), 12, 13, 14 and 24 hours post-dose up to Day 56

    Outcome Measure Data

    Analysis Population Description
    All randomized participants who received at least one dose of study medication. Number analyzed is the number of participants with data available for analysis at the given time point.
    Arm/Group Title Delamanid 100 mg BID + OBR Delamanid 200 mg BID + OBR
    Arm/Group Description Participants received delamanid 100 mg (two 50 mg tablets), orally, BID with two matching placebo tablets plus OBR for 56 consecutive days (from Day 1 to Day 56). Participants were administered OBR as directed by the given investigator based on WHO guidelines and clinical judgment, in conjunction with national TB program guidelines in each country. Participants received delamanid 200 mg (four 50 mg tablets), orally, BID plus OBR for 56 consecutive days (from Day 1 to Day 56). Participants were administered OBR as directed by the given investigator based on WHO guidelines and clinical judgment, in conjunction with national TB program guidelines in each country.
    Measure Participants 161 160
    Day 1: Cmax1
    135
    (54.9)
    187
    (74.3)
    Day 1: Cmax2
    151
    (60.4)
    228
    (91.5)
    Day 14: Cmax1
    369
    (137)
    547
    (200)
    Day 14: Cmax2
    361
    (127)
    513
    (178)
    Day 28: Cmax1
    404
    (144)
    599
    (222)
    Day 28: Cmax2
    381
    (128)
    560
    (196)
    Day 56: Cmax1
    414
    (165)
    611
    (217)
    Day 56: Cmax2
    400
    (162)
    588
    (213)
    4. Primary Outcome
    Title Area Under the Plasma Concentration Curve From 0 to 24 Hours (AUC0-24h) for Delamanid
    Description Data for AUC0-24h up to Day 56 was collected on Days 1, 14, 28 and 56.
    Time Frame Pre-dose, 2, 3, 4, 10 (pre-evening dose), 12, 13, 14 and 24 hours post-dose up to Day 56

    Outcome Measure Data

    Analysis Population Description
    All randomized participants who received at least one dose of study medication. Number analyzed is the number of participants with data available for analysis at the given time point.
    Arm/Group Title Delamanid 100 mg BID + OBR Delamanid 200 mg BID + OBR
    Arm/Group Description Participants received delamanid 100 mg (two 50 mg tablets), orally, BID with two matching placebo tablets plus OBR for 56 consecutive days (from Day 1 to Day 56). Participants were administered OBR as directed by the given investigator based on WHO guidelines and clinical judgment, in conjunction with national TB program guidelines in each country. Participants received delamanid 200 mg (four 50 mg tablets), orally, BID plus OBR for 56 consecutive days (from Day 1 to Day 56). Participants were administered OBR as directed by the given investigator based on WHO guidelines and clinical judgment, in conjunction with national TB program guidelines in each country.
    Measure Participants 161 160
    Day 1: AUC0-24h
    2441
    (880)
    3598
    (1312)
    Day 14: AUC0-24h
    7234
    (2346)
    10490
    (3377)
    Day 28: AUC0-24h
    7700
    (2322)
    11251
    (3626)
    Day 56: AUC0-24h
    7925
    (2973)
    11837
    (3975)
    5. Primary Outcome
    Title Accumulation Ratio for Cmax (Rac[Cmax]) for Delamanid
    Description Data for Rac (Cmax) up to Day 56 was collected on Days 14, 28 and 56. Rac (Cmax) on Days 14, 28 or 56 compared to Cmax on Day 1 was computed.
    Time Frame Pre-dose, 2, 3, 4, 10 (pre-evening dose), 12, 13, 14 and 24 hours post-dose up to Day 56

    Outcome Measure Data

    Analysis Population Description
    All randomized participants who received at least one dose of study medication. Number analyzed is the number of participants with data available for analysis at the given time point.
    Arm/Group Title Delamanid 100 mg BID + OBR Delamanid 200 mg BID + OBR
    Arm/Group Description Participants received delamanid 100 mg (two 50 mg tablets), orally, BID with two matching placebo tablets plus OBR for 56 consecutive days (from Day 1 to Day 56). Participants were administered OBR as directed by the given investigator based on WHO guidelines and clinical judgment, in conjunction with national TB program guidelines in each country. Participants received delamanid 200 mg (four 50 mg tablets), orally, BID plus OBR for 56 consecutive days (from Day 1 to Day 56). Participants were administered OBR as directed by the given investigator based on WHO guidelines and clinical judgment, in conjunction with national TB program guidelines in each country.
    Measure Participants 161 160
    Day 14: Rac Cmax1
    3.05
    (1.28)
    4.74
    (19.5)
    Day 14: Rac Cmax2
    2.65
    (1.11)
    2.43
    (0.870)
    Day 28: Rac Cmax1
    3.35
    (1.63)
    4.94
    (18.0)
    Day 28: Rac Cmax2
    2.85
    (1.65)
    2.65
    (1.01)
    Day 56: Rac Cmax1
    3.37
    (1.46)
    5.09
    (18.0)
    Day 56: Rac Cmax2
    2.92
    (1.43)
    2.81
    (1.19)
    6. Primary Outcome
    Title Accumulation Ratio for AUC From Time 0 to 24 Hours (Rac[AUC0-24h]) for Delamanid
    Description Data for Rac (AUC) up to Day 56 was collected on Days 14, 28 and 56. Rac (AUC) on Days 14, 28 or 56 compared to AUC0-24h on Day 1 was computed.
    Time Frame Pre-dose, 2, 3, 4, 10 (pre-evening dose), 12, 13, 14 and 24 hours post-dose up to Day 56

    Outcome Measure Data

    Analysis Population Description
    All randomized participants who received at least one dose of study medication. Number analyzed is the number of participants with data available for analysis at the given time point.
    Arm/Group Title Delamanid 100 mg BID + OBR Delamanid 200 mg BID + OBR
    Arm/Group Description Participants received delamanid 100 mg (two 50 mg tablets), orally, BID with two matching placebo tablets plus OBR for 56 consecutive days (from Day 1 to Day 56). Participants were administered OBR as directed by the given investigator based on WHO guidelines and clinical judgment, in conjunction with national TB program guidelines in each country. Participants received delamanid 200 mg (four 50 mg tablets), orally, BID plus OBR for 56 consecutive days (from Day 1 to Day 56). Participants were administered OBR as directed by the given investigator based on WHO guidelines and clinical judgment, in conjunction with national TB program guidelines in each country.
    Measure Participants 161 160
    Day 14: Rac AUC0-24h
    3.14
    (0.965)
    3.13
    (1.06)
    Day 28: Rac AUC0-24h
    3.35
    (1.24)
    3.33
    (1.12)
    Day 56: Rac AUC0-24h
    3.41
    (1.19)
    3.52
    (1.38)
    7. Primary Outcome
    Title Time to Maximal Peak Concentration (Tmax) for Delamanid Metabolite (DM)-6704, DM-6705, DM-6706, DM-6717, DM-6718, DM-6720, DM-6721, and DM-6722
    Description Data for Tmax up to Day 56 was collected on Days 1, 14, 28 and 56.
    Time Frame 0 hours (morning pre-dose), 2, 3, 4, 10 (pre-evening dose), 12, 13, 14 and 24 hours post-dose up to Day 56

    Outcome Measure Data

    Analysis Population Description
    All randomized participants who received at least one dose of study medication. Number analyzed is the number of participants with data available for analysis at the given time point for the specified category.
    Arm/Group Title Delamanid 100 mg BID + OBR Delamanid 200 mg BID + OBR
    Arm/Group Description Participants received delamanid 100 mg (two 50 mg tablets), orally, BID with two matching placebo tablets plus OBR for 56 consecutive days (from Day 1 to Day 56). Participants were administered OBR as directed by the given investigator based on WHO guidelines and clinical judgment, in conjunction with national TB program guidelines in each country. Participants received delamanid 200 mg (four 50 mg tablets), orally, BID plus OBR for 56 consecutive days (from Day 1 to Day 56). Participants were administered OBR as directed by the given investigator based on WHO guidelines and clinical judgment, in conjunction with national TB program guidelines in each country.
    Measure Participants 161 160
    All Metabolites: Tmax at Day 1
    NA
    NA
    DM-6704: Tmax at Day 14
    13.0
    13.0
    DM-6704: Tmax at Day 28
    3.97
    3.99
    DM-6704: Tmax at Day 56
    3.97
    4.00
    DM-6705: Tmax at Day 14
    12.0
    9.97
    DM-6705: Tmax at Day 28
    9.97
    9.97
    DM-6705: Tmax at Day 56
    9.97
    12.0
    DM-6706: Tmax at Day 14
    14.0
    12.0
    DM-6706: Tmax at Day 28
    3.01
    4.00
    DM-6706: Tmax at Day 56
    3.03
    4.00
    DM-6717: Tmax at Day 14
    24.0
    24.0
    DM-6717: Tmax at Day 28
    9.99
    13.0
    DM-6717: Tmax at Day 56
    9.97
    9.99
    DM-6718: Tmax at Day 14
    24.0
    24.0
    DM-6718: Tmax at Day 28
    10.0
    12.9
    DM-6718: Tmax at Day 56
    9.96
    9.97
    DM-6720: Tmax at Day 14
    11.0
    10.0
    DM-6720: Tmax at Day 28
    9.97
    9.97
    DM-6720: Tmax at Day 56
    9.97
    9.97
    DM-6721: Tmax at Day 14
    13.0
    10.0
    DM-6721: Tmax at Day 28
    4.02
    4.00
    DM-6721: Tmax at Day 56
    4.02
    9.97
    DM-6722: Tmax at Day 14
    13.0
    9.98
    DM-6722: Tmax at Day 28
    3.00
    4.00
    DM-6722: Tmax at Day 56
    4.00
    4.00
    8. Primary Outcome
    Title Maximal Peak Concentration (Cmax) for DM-6704, DM-6705, DM-6706, DM-6717, DM-6718, DM-6720, DM-6721, and DM-6722
    Description Data for Cmax up to Day 56 was collected on Days 1, 14, 28 and 56.
    Time Frame 0 hours (morning pre-dose), 2, 3, 4, 10 (pre-evening dose), 12, 13, 14 and 24 hours post-dose up to Day 56

    Outcome Measure Data

    Analysis Population Description
    All randomized participants who received at least one dose of study medication. Number analyzed is the number of participants with data available for analysis at the given time point for the specified category.
    Arm/Group Title Delamanid 100 mg BID + OBR Delamanid 200 mg BID + OBR
    Arm/Group Description Participants received delamanid 100 mg (two 50 mg tablets), orally, BID with two matching placebo tablets plus OBR for 56 consecutive days (from Day 1 to Day 56). Participants were administered OBR as directed by the given investigator based on WHO guidelines and clinical judgment, in conjunction with national TB program guidelines in each country. Participants received delamanid 200 mg (four 50 mg tablets), orally, BID plus OBR for 56 consecutive days (from Day 1 to Day 56). Participants were administered OBR as directed by the given investigator based on WHO guidelines and clinical judgment, in conjunction with national TB program guidelines in each country.
    Measure Participants 161 160
    All Metabolites: Cmax at Day 1
    NA
    (NA)
    NA
    (NA)
    DM-6704: Cmax at Day 14
    40.9
    (29.9)
    57.1
    (40.7)
    DM-6704: Cmax at Day 28
    48.9
    (31.4)
    78.3
    (53.0)
    DM-6704: Cmax at Day 56
    60.6
    (37.7)
    90.3
    (58.5)
    DM-6705: Cmax at Day 14
    78.3
    (35.1)
    124
    (57.8)
    DM-6705: Cmax at Day 28
    121
    (57.4)
    187
    (78.5)
    DM-6705: Cmax at Day 56
    151
    (67.3)
    233
    (94.5)
    DM-6706: Cmax at Day 14
    32.5
    (15.9)
    46.5
    (24.2)
    DM-6706: Cmax at Day 28
    47.1
    (22.1)
    69.9
    (32.0)
    DM-6706: Cmax at Day 56
    59.2
    (30.5)
    84.3
    (41.5)
    DM-6717: Cmax at Day 14
    5.44
    (4.04)
    7.61
    (4.51)
    DM-6717: Cmax at Day 28
    16.9
    (11.7)
    25.5
    (17.0)
    DM-6717: Cmax at Day 56
    34.7
    (20.5)
    53.4
    (30.3)
    DM-6718: Cmax at Day 14
    26.6
    (20.2)
    32.6
    (17.1)
    DM-6718: Cmax at Day 28
    66.5
    (34.9)
    84.9
    (34.5)
    DM-6718: Cmax at Day 56
    107
    (46.6)
    138
    (47.9)
    DM-6720: Cmax at Day 14
    19.5
    (11.7)
    26.5
    (11.6)
    DM-6720: Cmax at Day 28
    39.4
    (17.1)
    53.6
    (18.7)
    DM-6720: Cmax at Day 56
    57.4
    (22.6)
    79.3
    (26.3)
    DM-6721: Cmax at Day 14
    3.19
    (2.26)
    4.38
    (3.35)
    DM-6721: Cmax at Day 28
    4.95
    (4.37)
    7.74
    (6.37)
    DM-6721: Cmax at Day 56
    6.38
    (5.65)
    9.92
    (7.04)
    DM-6722: Cmax at Day 14
    23.1
    (22.1)
    33.4
    (27.3)
    DM-6722: Cmax at Day 28
    31.2
    (31.8)
    48.5
    (41.3)
    DM-6722: Cmax at Day 56
    33.3
    (23.0)
    56.1
    (39.7)
    9. Primary Outcome
    Title Area Under the Plasma Concentration Curve From 0 to 24 Hours (AUC0-24h) for DM-6704, DM-6705, DM-6706, DM-6717, DM-6718, DM-6720, DM-6721, and DM-6722
    Description Data for AUC0-24h up to Day 56 was collected on Days 1, 14, 28 and 56.
    Time Frame 0 hours (morning pre-dose), 2, 3, 4, 10 (pre-evening dose), 12, 13, 14 and 24 hours post-dose up to Day 56

    Outcome Measure Data

    Analysis Population Description
    All randomized participants who received at least one dose of study medication. Number analyzed is the number of participants with data available for analysis at the given time point for the specified category.
    Arm/Group Title Delamanid 100 mg BID + OBR Delamanid 200 mg BID + OBR
    Arm/Group Description Participants received delamanid 100 mg (two 50 mg tablets), orally, BID with two matching placebo tablets plus OBR for 56 consecutive days (from Day 1 to Day 56). Participants were administered OBR as directed by the given investigator based on WHO guidelines and clinical judgment, in conjunction with national TB program guidelines in each country. Participants received delamanid 200 mg (four 50 mg tablets), orally, BID plus OBR for 56 consecutive days (from Day 1 to Day 56). Participants were administered OBR as directed by the given investigator based on WHO guidelines and clinical judgment, in conjunction with national TB program guidelines in each country.
    Measure Participants 161 160
    All Metabolites: AUC0-24h at Day 1
    NA
    (NA)
    NA
    (NA)
    DM-6704: AUC0-24h at Day 14
    848
    (647)
    1192
    (859)
    DM-6704: AUC0-24h at Day 28
    1022
    (679)
    1610
    (1097)
    DM-6704: AUC0-24h at Day 56
    1251
    (766)
    1902
    (1252)
    DM-6705: AUC0-24h at Day 14
    1597
    (632)
    2485
    (920)
    DM-6705: AUC0-24h at Day 28
    2480
    (1051)
    3857
    (1486)
    DM-6705: AUC0-24h at Day 56
    3125
    (1397)
    4907
    (1987)
    DM-6706: AUC0-24h at Day 14
    685
    (339)
    992
    (525)
    DM-6706: AUC0-24h at Day 28
    1004
    (474)
    1475
    (676)
    DM-6706: AUC0-24h at Day 56
    1256
    (643)
    1796
    (870)
    DM-6717: AUC0-24h at Day 14
    108
    (81.9)
    153
    (93.2)
    DM-6717: AUC0-24h at Day 28
    349
    (240)
    524
    (342)
    DM-6717: AUC0-24h at Day 56
    720
    (436)
    1112
    (623)
    DM-6718: AUC0-24h at Day 14
    528
    (360)
    687
    (363)
    DM-6718: AUC0-24h at Day 28
    1424
    (757)
    1800
    (726)
    DM-6718: AUC0-24h at Day 56
    2285
    (992)
    2954
    (994)
    DM-6720: AUC0-24h at Day 14
    396
    (193)
    551
    (222)
    DM-6720: AUC0-24h at Day 28
    822
    (353)
    1120
    (368)
    DM-6720: AUC0-24h at Day 56
    1206
    (474)
    1668
    (549)
    DM-6721: AUC0-24h at Day 14
    65.4
    (49.7)
    90.5
    (68.7)
    DM-6721: AUC0-24h at Day 28
    103
    (92.9)
    161
    (134)
    DM-6721: AUC0-24h at Day 56
    132
    (118)
    210
    (154)
    DM-6722: AUC0-24h at Day 14
    482
    (475)
    707
    (589)
    DM-6722: AUC0-24h at Day 28
    655
    (695)
    1013
    (883)
    DM-6722: AUC0-24h at Day 56
    699
    (489)
    1191
    (862)
    10. Primary Outcome
    Title Accumulation Ratio for Cmax (Rac[Cmax]) for DM-6704, DM-6705, DM-6706, DM-6717, DM-6718, DM-6720, DM-6721, and DM-6722
    Description Data for Rac (Cmax) up to Day 56 was to be collected on Days 1, 14, 28 and 56. Rac (Cmax) on Days 14, 28 or 56 compared to Cmax on Day 1 was to be computed. Due to limited measurable data on Day 1 for delamanid metabolites, pharmacokinetic (PK) analysis was not conducted on Day 1 data for delamanid metabolites, and data for Rac (Cmax) was not available.
    Time Frame 0 hours (morning pre-dose), 2, 3, 4, 10 (pre-evening dose), 12, 13, 14 and 24 hours post-dose up to Day 56

    Outcome Measure Data

    Analysis Population Description
    Due to limited measurable data as the metabolite concentration was below the level of detection on Day 1 for delamanid metabolites, PK analysis was not conducted on Day 1 data for delamanid metabolites, and data for Rac (Cmax) was not available.
    Arm/Group Title Delamanid 100 mg BID + OBR Delamanid 200 mg BID + OBR
    Arm/Group Description Participants received delamanid 100 mg (two 50 mg tablets), orally, BID with two matching placebo tablets plus OBR for 56 consecutive days (from Day 1 to Day 56). Participants were administered OBR as directed by the given investigator based on WHO guidelines and clinical judgment, in conjunction with national TB program guidelines in each country. Participants received delamanid 200 mg (four 50 mg tablets), orally, BID plus OBR for 56 consecutive days (from Day 1 to Day 56). Participants were administered OBR as directed by the given investigator based on WHO guidelines and clinical judgment, in conjunction with national TB program guidelines in each country.
    Measure Participants 0 0
    11. Primary Outcome
    Title Accumulation Ratio for AUC (Rac[AUC]) for DM-6704, DM-6705, DM-6706, DM-6717, DM-6718, DM-6720, DM-6721, and DM-6722
    Description Data for Rac (AUC) up to Day 56 was to be collected on Days 1, 14, 28 and 56. Rac (AUC) on Days 14, 28 or 56 compared to AUC0-24h on Day 1 was to be computed. Due to limited measurable data on Day 1 for delamanid metabolites, PK analysis was not conducted on Day 1 data for delamanid metabolites, and data for Rac (AUC) was not available.
    Time Frame 0 hours (morning pre-dose), 2, 3, 4, 10 (pre-evening dose), 12, 13, 14 and 24 hours post-dose up to Day 56

    Outcome Measure Data

    Analysis Population Description
    Due to limited measurable data as the metabolite concentration was below the level of detection on Day 1 for delamanid metabolites, PK analysis was not conducted on Day 1 data for delamanid metabolites, and data for Rac (AUC) was not available.
    Arm/Group Title Delamanid 100 mg BID + OBR Delamanid 200 mg BID + OBR
    Arm/Group Description Participants received delamanid 100 mg (two 50 mg tablets), orally, BID with two matching placebo tablets plus OBR for 56 consecutive days (from Day 1 to Day 56). Participants were administered OBR as directed by the given investigator based on WHO guidelines and clinical judgment, in conjunction with national TB program guidelines in each country. Participants received delamanid 200 mg (four 50 mg tablets), orally, BID plus OBR for 56 consecutive days (from Day 1 to Day 56). Participants were administered OBR as directed by the given investigator based on WHO guidelines and clinical judgment, in conjunction with national TB program guidelines in each country.
    Measure Participants 0 0
    12. Primary Outcome
    Title Elimination Half-life (t1/2) for DM-6704, DM-6705, DM-6706, DM-6717, DM-6718, DM-6720, DM-6721, and DM-6722
    Description
    Time Frame 0 hours (morning pre-dose), 2, 3, 4, 10 (pre-evening dose), 12, 13, 14 and 24 hours post-dose on Day 56

    Outcome Measure Data

    Analysis Population Description
    All randomized participants who received at least one dose of study medication. Number analyzed is the number of participants with data available for analysis for the specified category.
    Arm/Group Title Delamanid 100 mg BID + OBR Delamanid 200 mg BID + OBR
    Arm/Group Description Participants received delamanid 100 mg (two 50 mg tablets), orally, BID with two matching placebo tablets plus OBR for 56 consecutive days (from Day 1 to Day 56). Participants were administered OBR as directed by the given investigator based on WHO guidelines and clinical judgment, in conjunction with national TB program guidelines in each country. Participants received delamanid 200 mg (four 50 mg tablets), orally, BID plus OBR for 56 consecutive days (from Day 1 to Day 56). Participants were administered OBR as directed by the given investigator based on WHO guidelines and clinical judgment, in conjunction with national TB program guidelines in each country.
    Measure Participants 161 160
    t1/2 for DM-6704
    195
    (115)
    191
    (67.2)
    t1/2 for DM-6705
    231
    (84.7)
    233
    (87.9)
    t1/2 for DM-6706
    180
    (43.1)
    184
    (40.3)
    t1/2 for DM-6717
    265
    (98.2)
    265
    (115)
    t1/2 for DM-6718
    302
    (132)
    305
    (131)
    t1/2 for DM-6720
    394
    (158)
    424
    (192)
    t1/2 for DM-6721
    168
    (49.7)
    153
    (53.1)
    t1/2 for DM-6722
    134
    (85.1)
    148
    (60.3)
    13. Secondary Outcome
    Title Percentage of Participants Who Achieved Sputum Culture Conversion (SCC) Using Solid Culture Media
    Description A participant achieving SCC using solid culture media was defined as one with sputum culture negative for growth of MTB on Day 57, and (a) not followed by a positive culture at any point thereafter, and (b) confirmed by at least one additional negative sputum culture at Day 84.
    Time Frame From the first dose of study drug up to the end of the Post-treatment Follow-up Period (Up to Day 84)

    Outcome Measure Data

    Analysis Population Description
    MITT (Solid Culture) Population included all participants who had sputum cultures positive for MDR TB at baseline (Day -1 and/or Day 1) using solid culture medium.
    Arm/Group Title Delamanid 100 mg BID + OBR Delamanid 200 mg BID + OBR Placebo + OBR
    Arm/Group Description Participants received delamanid 100 mg (two 50 mg tablets), orally, BID with two matching placebo tablets plus OBR for 56 consecutive days (from Day 1 to Day 56). Participants were administered OBR as directed by the given investigator based on WHO guidelines and clinical judgment, in conjunction with national TB program guidelines in each country. Participants received delamanid 200 mg (four 50 mg tablets), orally, BID plus OBR for 56 consecutive days (from Day 1 to Day 56). Participants were administered OBR as directed by the given investigator based on WHO guidelines and clinical judgment, in conjunction with national TB program guidelines in each country. Participants received four placebo tablets matching 50-mg tablets of delamanid, orally, BID plus OBR for 56 consecutive days (from Day 1 to Day 56). Participants were administered OBR as directed by the given investigator based on WHO guidelines and clinical judgment, in conjunction with national TB program guidelines in each country.
    Measure Participants 119 115 113
    Number [percentage of participants]
    53.8
    33.4%
    65.2
    40.8%
    33.6
    21%
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Delamanid 100 mg BID + OBR, Placebo + OBR
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value =0.0021
    Comments
    Method Cochran-Mantel-Haenszel
    Comments P-value was derived using CMH test stratified by randomization strata (cavitation).
    Method of Estimation Estimation Parameter Risk Ratio Mean
    Estimated Value 1.599
    Confidence Interval (2-Sided) 95%
    1.175 to 2.177
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Delamanid 200 mg BID + OBR, Placebo + OBR
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value <.0001
    Comments
    Method Cochran-Mantel-Haenszel
    Comments
    Method of Estimation Estimation Parameter Risk Ratio Mean
    Estimated Value 1.939
    Confidence Interval (2-Sided) 95%
    1.449 to 2.595
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    14. Secondary Outcome
    Title Change From Baseline in Time to Culture Positivity Using the MGIT System
    Description Mean change from baseline in time to culture positivity using the MGIT system was the value for "time to results" when a sputum culture result was positive (in days) using the MGIT system during the routine 42-day incubation period. A longer time to culture positivity represented a lower burden of MTB organisms present in the sputum. Baseline was defined as the average of Day -1 and Day 1 values, if the cultures on both days were positive; if only one culture was positive, the value for the positive culture was used as baseline.
    Time Frame Baseline, Day 84

    Outcome Measure Data

    Analysis Population Description
    Last Observation Carried Forward(LOCF)Population:all randomized participants with positive sputum culture for MDR TB at baseline(pre-dose)by MGIT system and when sputum collection was not possible,a specimen was contaminated with other bacteria,or a result was missing due to a participant withdrawing from trial, the preceding non-missing result for that variable at a postbaseline visit was carried forward. Overall number analyzed=participants with data available for analysis.
    Arm/Group Title Delamanid 100 mg BID + OBR Delamanid 200 mg BID + OBR Placebo + OBR
    Arm/Group Description Participants received delamanid 100 mg (two 50 mg tablets), orally, BID with two matching placebo tablets plus OBR for 56 consecutive days (from Day 1 to Day 56). Participants were administered OBR as directed by the given investigator based on WHO guidelines and clinical judgment, in conjunction with national TB program guidelines in each country. Participants received delamanid 200 mg (four 50 mg tablets), orally, BID plus OBR for 56 consecutive days (from Day 1 to Day 56). Participants were administered OBR as directed by the given investigator based on WHO guidelines and clinical judgment, in conjunction with national TB program guidelines in each country. Participants received four placebo tablets matching 50-mg tablets of delamanid, orally, BID plus OBR for 56 consecutive days (from Day 1 to Day 56). Participants were administered OBR as directed by the given investigator based on WHO guidelines and clinical judgment, in conjunction with national TB program guidelines in each country.
    Measure Participants 140 135 123
    Least Squares Mean (Standard Error) [days]
    25.9
    (1.0)
    26.0
    (1.0)
    24.2
    (1.1)
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Delamanid 100 mg BID + OBR, Placebo + OBR
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value =0.2419
    Comments
    Method ANCOVA
    Comments Pairwise comparison was derived from analysis of covariance(ANCOVA)model with factors of treatment, baseline cavitation status and covariate baseline.
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Delamanid 200 mg BID + OBR, Placebo + OBR
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value =0.2239
    Comments
    Method ANCOVA
    Comments Pairwise comparison is derived from ANCOVA model with factors of treatment, baseline cavitation status and covariate baseline.
    Statistical Analysis 3
    Statistical Analysis Overview Comparison Group Selection Delamanid 100 mg BID + OBR, Delamanid 200 mg BID + OBR
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value =0.9544
    Comments
    Method ANCOVA
    Comments Pairwise comparison is derived from ANCOVA model with factors of treatment, baseline cavitation status and covariate baseline.
    15. Secondary Outcome
    Title Area Under the Curve (AUC) of Change From Baseline in Time to Culture Positivity in the MGIT System
    Description AUC of change from baseline for time to culture positivity (i.e., TTD) (Days 0 to 57), summarizes overall participant response for treatment period. Larger AUC of change from baseline for time to culture positivity would strongly suggest a clinical response with reduction of burden of MTB organisms in sputum. For this analysis, ti=visit day of each visit; t0=Day 0, t1=Day 8, t2=Day 15, etc. and xi=change from baseline in time to culture positivity at each visit; AUC at each visit was determined as AUCi=(ti - ti-1)(xi+ xi-1)/2. Average AUC of change from baseline was the sum of all AUCi divided by a given participant's duration in the trial up to 57 days. Baseline (Day 0)=the average of Day -1 and Day 1 values, if cultures on both days were positive; if only one culture was positive, value for time to culture positivity for positive culture was used as baseline.
    Time Frame Baseline to Day 57

    Outcome Measure Data

    Analysis Population Description
    MITT Population included all participants who had sputum cultures positive for MDR TB at baseline (Day -1 and/or Day 1) using the MGIT system. Overall number analyzed are the participants with data available for analysis.
    Arm/Group Title Delamanid 100 mg BID + OBR Delamanid 200 mg BID + OBR Placebo + OBR
    Arm/Group Description Participants received delamanid 100 mg (two 50 mg tablets), orally, BID with two matching placebo tablets plus OBR for 56 consecutive days (from Day 1 to Day 56). Participants were administered OBR as directed by the given investigator based on WHO guidelines and clinical judgment, in conjunction with national TB program guidelines in each country. Participants received delamanid 200 mg (four 50 mg tablets), orally, BID plus OBR for 56 consecutive days (from Day 1 to Day 56). Participants were administered OBR as directed by the given investigator based on WHO guidelines and clinical judgment, in conjunction with national TB program guidelines in each country. Participants received four placebo tablets matching 50-mg tablets of delamanid, orally, BID plus OBR for 56 consecutive days (from Day 1 to Day 56). Participants were administered OBR as directed by the given investigator based on WHO guidelines and clinical judgment, in conjunction with national TB program guidelines in each country.
    Measure Participants 137 134 121
    Least Squares Mean (Standard Error) [days]
    13.4
    (0.7)
    13.1
    (0.7)
    11.1
    (0.7)
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Delamanid 100 mg BID + OBR, Placebo + OBR
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value =0.0246
    Comments
    Method ANCOVA
    Comments Pairwise comparison was derived from ANCOVA model with factors of treatment, baseline cavitation status and covariate baseline.
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Delamanid 200 mg BID + OBR, Placebo + OBR
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value =0.0529
    Comments
    Method ANCOVA
    Comments Pairwise comparison was derived from ANCOVA model with factors of treatment, baseline cavitation status and covariate baseline.
    Statistical Analysis 3
    Statistical Analysis Overview Comparison Group Selection Delamanid 100 mg BID + OBR, Delamanid 200 mg BID + OBR
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value =0.7508
    Comments
    Method ANCOVA
    Comments Pairwise comparison was derived from ANCOVA model with factors of treatment, baseline cavitation status and covariate baseline.
    16. Secondary Outcome
    Title Percentage of Participants With Sputum Culture Negative at Day 57 Using the MGIT System Without Consideration of Subsequent Culture Results
    Description
    Time Frame Day 57

    Outcome Measure Data

    Analysis Population Description
    MITT Population included all participants who had sputum cultures positive for MDR TB at baseline (Day -1 and/or Day 1) using the MGIT system.
    Arm/Group Title Delamanid 100 mg BID + OBR Delamanid 200 mg BID + OBR Placebo + OBR
    Arm/Group Description Participants received delamanid 100 mg (two 50 mg tablets), orally, BID with two matching placebo tablets plus OBR for 56 consecutive days (from Day 1 to Day 56). Participants were administered OBR as directed by the given investigator based on WHO guidelines and clinical judgment, in conjunction with national TB program guidelines in each country. Participants received delamanid 200 mg (four 50 mg tablets), orally, BID plus OBR for 56 consecutive days (from Day 1 to Day 56). Participants were administered OBR as directed by the given investigator based on WHO guidelines and clinical judgment, in conjunction with national TB program guidelines in each country. Participants received four placebo tablets matching 50-mg tablets of delamanid, orally, BID plus OBR for 56 consecutive days (from Day 1 to Day 56). Participants were administered OBR as directed by the given investigator based on WHO guidelines and clinical judgment, in conjunction with national TB program guidelines in each country.
    Measure Participants 141 136 125
    Number [percentage of participants]
    56.0
    34.8%
    52.9
    33.1%
    44.0
    27.5%
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Delamanid 100 mg BID + OBR, Placebo + OBR
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value =0.0518
    Comments
    Method Cochran-Mantel-Haenszel
    Comments P-value was derived using CMH test stratified by randomization strata (cavitation).
    Method of Estimation Estimation Parameter Risk Ratio Mean
    Estimated Value 1.272
    Confidence Interval (2-Sided) 95%
    0.995 to 1.627
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Delamanid 200 mg BID + OBR, Placebo + OBR
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value =0.1506
    Comments
    Method Cochran-Mantel-Haenszel
    Comments P-value was derived using CMH test stratified by randomization strata (cavitation).
    Method of Estimation Estimation Parameter Risk Ratio Mean
    Estimated Value 1.203
    Confidence Interval (2-Sided) 95%
    0.934 to 1.550
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    17. Secondary Outcome
    Title Percentage of Participants With Sputum Culture Negative at Day 57 and Day 84 Using the MGIT System Without Respect to Interim Culture Results
    Description
    Time Frame Day 57 and Day 84

    Outcome Measure Data

    Analysis Population Description
    MITT Population included all participants who had sputum cultures positive for MDR TB at baseline (Day -1 and/or Day 1) using the MGIT system.
    Arm/Group Title Delamanid 100 mg BID + OBR Delamanid 200 mg BID + OBR Placebo + OBR
    Arm/Group Description Participants received delamanid 100 mg (two 50 mg tablets), orally, BID with two matching placebo tablets plus OBR for 56 consecutive days (from Day 1 to Day 56). Participants were administered OBR as directed by the given investigator based on WHO guidelines and clinical judgment, in conjunction with national TB program guidelines in each country. Participants received delamanid 200 mg (four 50 mg tablets), orally, BID plus OBR for 56 consecutive days (from Day 1 to Day 56). Participants were administered OBR as directed by the given investigator based on WHO guidelines and clinical judgment, in conjunction with national TB program guidelines in each country. Participants received four placebo tablets matching 50-mg tablets of delamanid, orally, BID plus OBR for 56 consecutive days (from Day 1 to Day 56). Participants were administered OBR as directed by the given investigator based on WHO guidelines and clinical judgment, in conjunction with national TB program guidelines in each country.
    Measure Participants 141 136 125
    Number [percentage of participants]
    50.4
    31.3%
    44.9
    28.1%
    40.8
    25.5%
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Delamanid 100 mg BID + OBR, Placebo + OBR
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value =0.1201
    Comments
    Method Cochran-Mantel-Haenszel
    Comments P-value was derived using CMH test stratified by randomization strata (cavitation).
    Method of Estimation Estimation Parameter Risk Ratio Mean
    Estimated Value 1.234
    Confidence Interval (2-Sided) 95%
    0.945 to 1.612
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Delamanid 200 mg BID + OBR, Placebo + OBR
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value =0.5112
    Comments
    Method Cochran-Mantel-Haenszel
    Comments P-value was derived using CMH test stratified by randomization strata (cavitation).
    Method of Estimation Estimation Parameter Risk Ratio Mean
    Estimated Value 1.099
    Confidence Interval (2-Sided) 95%
    0.829 to 1.456
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    18. Secondary Outcome
    Title Percentage of Participants With Sputum Culture Negative at Day 57 Using Solid Culture Media Without Respect to Subsequent Culture Results
    Description
    Time Frame Day 57

    Outcome Measure Data

    Analysis Population Description
    MITT (Solid Culture) Population included all participants who had sputum cultures positive for MDR TB at baseline (Day -1 and/or Day 1) using solid culture medium.
    Arm/Group Title Delamanid 100 mg BID + OBR Delamanid 200 mg BID + OBR Placebo + OBR
    Arm/Group Description Participants received delamanid 100 mg (two 50 mg tablets), orally, BID with two matching placebo tablets plus OBR for 56 consecutive days (from Day 1 to Day 56). Participants were administered OBR as directed by the given investigator based on WHO guidelines and clinical judgment, in conjunction with national TB program guidelines in each country. Participants received delamanid 200 mg (four 50 mg tablets), orally, BID plus OBR for 56 consecutive days (from Day 1 to Day 56). Participants were administered OBR as directed by the given investigator based on WHO guidelines and clinical judgment, in conjunction with national TB program guidelines in each country. Participants received four placebo tablets matching 50-mg tablets of delamanid, orally, BID plus OBR for 56 consecutive days (from Day 1 to Day 56). Participants were administered OBR as directed by the given investigator based on WHO guidelines and clinical judgment, in conjunction with national TB program guidelines in each country.
    Measure Participants 119 115 113
    Number [percentage of participants]
    65.5
    40.7%
    71.3
    44.6%
    49.6
    31%
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Delamanid 100 mg BID + OBR, Placebo + OBR
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value =0.0141
    Comments
    Method Cochran-Mantel-Haenszel
    Comments P-value was derived using CMH test stratified by randomization strata (cavitation).
    Method of Estimation Estimation Parameter Risk Ratio Mean
    Estimated Value 1.323
    Confidence Interval (2-Sided) 95%
    1.053 to 1.661
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Delamanid 200 mg BID + OBR, Placebo + OBR
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value =0.0008
    Comments
    Method Cochran-Mantel-Haenszel
    Comments P-value was derived using CMH test stratified by randomization strata (cavitation).
    Method of Estimation Estimation Parameter Risk Ratio Mean
    Estimated Value 1.438
    Confidence Interval (2-Sided) 95%
    1.155 to 1.791
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    19. Secondary Outcome
    Title Percentage of Participants With Sputum Culture Negative at Day 57 and Day 84 Using Solid Culture Media Without Respect to Interim Culture Results
    Description
    Time Frame Day 57 and Day 84

    Outcome Measure Data

    Analysis Population Description
    MITT (Solid Culture) Population included all participants who had sputum cultures positive for MDR TB at baseline (Day -1 and/or Day 1) using solid culture medium.
    Arm/Group Title Delamanid 100 mg BID + OBR Delamanid 200 mg BID + OBR Placebo + OBR
    Arm/Group Description Participants received delamanid 100 mg (two 50 mg tablets), orally, BID with two matching placebo tablets plus OBR for 56 consecutive days (from Day 1 to Day 56). Participants were administered OBR as directed by the given investigator based on WHO guidelines and clinical judgment, in conjunction with national TB program guidelines in each country. Participants received delamanid 200 mg (four 50 mg tablets), orally, BID plus OBR for 56 consecutive days (from Day 1 to Day 56). Participants were administered OBR as directed by the given investigator based on WHO guidelines and clinical judgment, in conjunction with national TB program guidelines in each country. Participants received four placebo tablets matching 50-mg tablets of delamanid, orally, BID plus OBR for 56 consecutive days (from Day 1 to Day 56). Participants were administered OBR as directed by the given investigator based on WHO guidelines and clinical judgment, in conjunction with national TB program guidelines in each country.
    Measure Participants 119 115 113
    Number [percentage of participants]
    60.5
    37.6%
    67.8
    42.4%
    45.1
    28.2%
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Delamanid 100 mg BID + OBR, Placebo + OBR
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value =0.0196
    Comments
    Method Cochran-Mantel-Haenszel
    Comments P-value was derived using CMH test stratified by randomization strata (cavitation).
    Method of Estimation Estimation Parameter Risk Ratio Mean
    Estimated Value 1.341
    Confidence Interval (2-Sided) 95%
    1.044 to 1.722
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Delamanid 200 mg BID + OBR, Placebo + OBR
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value =0.0006
    Comments
    Method Cochran-Mantel-Haenszel
    Comments P-value was derived using CMH test stratified by randomization strata (cavitation).
    Method of Estimation Estimation Parameter Risk Ratio Mean
    Estimated Value 1.503
    Confidence Interval (2-Sided) 95%
    1.183 to 1.909
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    20. Secondary Outcome
    Title Percentage of Participants Who Achieved SCC From the MGIT System Analyzed by Cochran-Armitage Linear Trend Test for Dose-response Relationship
    Description A participant achieving SCC using solid media is defined as one with sputum culture negative for growth of MTB on Day 57, and (a) not followed by a positive culture at any point thereafter, and (b) confirmed by at least one additional negative sputum culture at Day 84. A dose response in the percentage of participants achieving SCC using the MGIT system was tested by the Cochran-Armitage linear trend test with equally spaced dose scores (0, 1, and 2 for placebo, 100 mg BID, and 200 mg BID, respectively).
    Time Frame From the first dose of study drug up to the end of the Post-treatment Follow-up Period (Up to Day 84)

    Outcome Measure Data

    Analysis Population Description
    MITT Population included all participants who had sputum cultures positive for multidrug resistant tuberculosis (MDR TB) at baseline (Day -1 and/or Day 1) using the MGIT system.
    Arm/Group Title Delamanid 100 mg BID + OBR Delamanid 200 mg BID + OBR Placebo + OBR
    Arm/Group Description Participants received delamanid 100 mg (two 50 mg tablets), orally, BID with two matching placebo tablets plus OBR for 56 consecutive days (from Day 1 to Day 56). Participants were administered OBR as directed by the given investigator based on WHO guidelines and clinical judgment, in conjunction with national TB program guidelines in each country. Participants received delamanid 200 mg (four 50 mg tablets), orally, BID plus OBR for 56 consecutive days (from Day 1 to Day 56). Participants were administered OBR as directed by the given investigator based on WHO guidelines and clinical judgment, in conjunction with national TB program guidelines in each country. Participants received four placebo tablets matching 50-mg tablets of delamanid, orally, BID plus OBR for 56 consecutive days (from Day 1 to Day 56). Participants were administered OBR as directed by the given investigator based on WHO guidelines and clinical judgment, in conjunction with national TB program guidelines in each country.
    Measure Participants 141 136 125
    Number [percentage of participants]
    45.4
    28.2%
    41.9
    26.2%
    29.6
    18.5%
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Delamanid 100 mg BID + OBR, Delamanid 200 mg BID + OBR, Placebo + OBR
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value =0.0468
    Comments
    Method Cochran-Armitage Linear Trend Test
    Comments Cochran-Armitage test was performed for dose response with the treatment group ordered as placebo, delamanid 100 mg BID, and delamanid 200 mg BID.
    21. Secondary Outcome
    Title Percentage of Participants Who Achieved Initial SCC Using the MGIT System
    Description Initial SCC occurred at the time of the collection of the first sputum specimen with mycobacterial culture negative for growth of MTB using the MGIT system followed by at least one additional MGIT negative sputum specimen at least 27 days after the first negative specimen and no sputum specimens MGIT positive for growth at any point between the negative MGIT sputum specimens. Survival analysis methodology was performed to compare the Kaplan-Meier curves for time to SCC across 3 treatment groups. Comparisons between 100 mg BID and placebo and 200 mg BID and placebo were also performed with stratified log-rank tests. The benefit ratios (ratio of likelihoods that participants treated with delamanid BID + OBR would achieve SCC more rapidly than participants treated with placebo + OBR) for participants achieving SCC were computed.
    Time Frame Day 57

    Outcome Measure Data

    Analysis Population Description
    MITT Population included all participants who had sputum cultures positive for MDR TB at baseline (Day -1 and/or Day 1) using the MGIT system.
    Arm/Group Title Delamanid 100 mg BID + OBR Delamanid 200 mg BID + OBR Placebo + OBR
    Arm/Group Description Participants received delamanid 100 mg (two 50 mg tablets), orally, BID with two matching placebo tablets plus OBR for 56 consecutive days (from Day 1 to Day 56). Participants were administered OBR as directed by the given investigator based on WHO guidelines and clinical judgment, in conjunction with national TB program guidelines in each country. Participants received delamanid 200 mg (four 50 mg tablets), orally, BID plus OBR for 56 consecutive days (from Day 1 to Day 56). Participants were administered OBR as directed by the given investigator based on WHO guidelines and clinical judgment, in conjunction with national TB program guidelines in each country. Participants received four placebo tablets matching 50-mg tablets of delamanid, orally, BID plus OBR for 56 consecutive days (from Day 1 to Day 56). Participants were administered OBR as directed by the given investigator based on WHO guidelines and clinical judgment, in conjunction with national TB program guidelines in each country.
    Measure Participants 141 136 125
    Number [percentage of participants]
    50.4
    31.3%
    50.0
    31.3%
    31.2
    19.5%
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Delamanid 100 mg BID + OBR, Placebo + OBR
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value =0.0011
    Comments
    Method Stratified Log-Rank Test
    Comments p-value was derived from log-rank test with SAS Proc lifetest for comparisons with placebo.
    Method of Estimation Estimation Parameter Hazard Ratio (HR)
    Estimated Value 1.856
    Confidence Interval (2-Sided) 95%
    1.255 to 2.745
    Parameter Dispersion Type:
    Value:
    Estimation Comments Hazard ratio computed with SAS PROC PHREG for comparisons with placebo.
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Delamanid 200 mg BID + OBR, Placebo + OBR
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value =0.0013
    Comments
    Method Stratified Log-Rank Test
    Comments p-value was derived from log-rank test with SAS Proc lifetest for comparisons with placebo.
    Method of Estimation Estimation Parameter Hazard Ratio (HR)
    Estimated Value 1.849
    Confidence Interval (2-Sided) 95%
    1.246 to 2.743
    Parameter Dispersion Type:
    Value:
    Estimation Comments Hazard ratio computed with SAS PROC PHREG for comparisons with placebo.
    22. Secondary Outcome
    Title Percentage of Participants Who Achieved Initial SCC Using the Solid Culture Media
    Description Initial SCC occurred at the time of the collection of the first sputum specimen with mycobacterial culture negative for growth of MTB using solid culture media that was followed by at least one additional negative sputum specimen at least 27 days after the first negative specimen and no sputum specimens positive for growth on solid culture media at any point between the negative sputum specimens using solid culture media. Survival analysis methodology was performed to compare the Kaplan-Meier curves for time to SCC across 3 treatment groups. Comparisons between 100 mg BID and placebo and 200 mg BID and placebo were also performed with stratified log-rank tests. The benefit ratios (ratio of likelihoods that participants treated with delamanid BID + OBR would achieve SCC more rapidly than participants treated with placebo + OBR) for participants achieving SCC were computed.
    Time Frame Day 57

    Outcome Measure Data

    Analysis Population Description
    MITT (Solid Culture) Population included all participants who had sputum cultures positive for MDR TB at baseline (Day -1 and/or Day 1) using solid culture medium.
    Arm/Group Title Delamanid 100 mg BID + OBR Delamanid 200 mg BID + OBR Placebo + OBR
    Arm/Group Description Participants received delamanid 100 mg (two 50 mg tablets), orally, BID with two matching placebo tablets plus OBR for 56 consecutive days (from Day 1 to Day 56). Participants were administered OBR as directed by the given investigator based on WHO guidelines and clinical judgment, in conjunction with national TB program guidelines in each country. Participants received delamanid 200 mg (four 50 mg tablets), orally, BID plus OBR for 56 consecutive days (from Day 1 to Day 56). Participants were administered OBR as directed by the given investigator based on WHO guidelines and clinical judgment, in conjunction with national TB program guidelines in each country. Participants received four placebo tablets matching 50-mg tablets of delamanid, orally, BID plus OBR for 56 consecutive days (from Day 1 to Day 56). Participants were administered OBR as directed by the given investigator based on WHO guidelines and clinical judgment, in conjunction with national TB program guidelines in each country.
    Measure Participants 119 115 113
    Number [percentage of participants]
    60.5
    37.6%
    68.7
    42.9%
    37.2
    23.3%
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Delamanid 100 mg BID + OBR, Placebo + OBR
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value =0.0004
    Comments
    Method Stratified Log-Rank Test
    Comments P-value was derived from Log-rank test with SAS PROC LIFETEST for comparisons with placebo.
    Method of Estimation Estimation Parameter Hazard Ratio (HR)
    Estimated Value 1.926
    Confidence Interval (2-Sided) 95%
    1.315 to 2.820
    Parameter Dispersion Type:
    Value:
    Estimation Comments Hazard ratio computed with SAS PROC PHREG for comparisons with placebo.
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Delamanid 200 mg BID + OBR, Placebo + OBR
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value <.0001
    Comments
    Method Stratified Log-Rank Test
    Comments
    Method of Estimation Estimation Parameter Hazard Ratio (HR)
    Estimated Value 2.190
    Confidence Interval (2-Sided) 95%
    1.504 to 3.189
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    23. Secondary Outcome
    Title Percentage of Participants Who Achieved Final SCC Using MGIT
    Description Final SCC was defined as SCC at Day 57 or the latest time point of the first negative sputum culture establishing SCC for a given participant after the last positive sputum culture observed during the 56-day treatment period, whichever comes first. Survival analysis methodology was performed to compare the Kaplan-Meier curves for time to SCC across 3 treatment groups. Comparisons between 100 mg BID and placebo and 200 mg BID and placebo were also performed with stratified log-rank tests. The benefit ratios (ratio of likelihoods that participants treated with delamanid BID + OBR would achieve SCC more rapidly than participants treated with placebo + OBR) for participants achieving SCC were computed.
    Time Frame Day 57

    Outcome Measure Data

    Analysis Population Description
    MITT Population included all participants who had sputum cultures positive for MDR TB at baseline (Day -1 and/or Day 1) using the MGIT system.
    Arm/Group Title Delamanid 100 mg BID + OBR Delamanid 200 mg BID + OBR Placebo + OBR
    Arm/Group Description Participants received delamanid 100 mg (two 50 mg tablets), orally, BID with two matching placebo tablets plus OBR for 56 consecutive days (from Day 1 to Day 56). Participants were administered OBR as directed by the given investigator based on WHO guidelines and clinical judgment, in conjunction with national TB program guidelines in each country. Participants received delamanid 200 mg (four 50 mg tablets), orally, BID plus OBR for 56 consecutive days (from Day 1 to Day 56). Participants were administered OBR as directed by the given investigator based on WHO guidelines and clinical judgment, in conjunction with national TB program guidelines in each country. Participants received four placebo tablets matching 50-mg tablets of delamanid, orally, BID plus OBR for 56 consecutive days (from Day 1 to Day 56). Participants were administered OBR as directed by the given investigator based on WHO guidelines and clinical judgment, in conjunction with national TB program guidelines in each country.
    Measure Participants 141 136 125
    Number [percentage of participants]
    45.4
    28.2%
    41.9
    26.2%
    29.6
    18.5%
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Delamanid 100 mg BID + OBR, Placebo + OBR
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value =0.0056
    Comments
    Method Stratified Log-Rank Test
    Comments P-value was derived from Log-rank test with SAS PROC LIFETEST for comparisons with placebo.
    Method of Estimation Estimation Parameter Hazard Ratio (HR)
    Estimated Value 1.727
    Confidence Interval (2-Sided) 95%
    1.152 to 2.591
    Parameter Dispersion Type:
    Value:
    Estimation Comments Hazard ratio computed with SAS PROC PHREG for comparisons with placebo.
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Delamanid 200 mg BID + OBR, Placebo + OBR
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value =0.0232
    Comments
    Method Stratified Log-Rank Test
    Comments P-value was derived from Log-rank test with SAS PROC LIFETEST for comparisons with placebo.
    Method of Estimation Estimation Parameter Hazard Ratio (HR)
    Estimated Value 1.585
    Confidence Interval (2-Sided) 95%
    1.048 to 2.399
    Parameter Dispersion Type:
    Value:
    Estimation Comments Hazard ratio computed with SAS PROC PHREG for comparisons with placebo.
    24. Secondary Outcome
    Title Percentage of Participants Who Achieved Final SCC Using Solid Culture Media
    Description Final SCC is defined as SCC at Day 57 or the latest time point of the first negative sputum culture establishing SCC for a given participant after the last positive sputum culture observed during the 56-day treatment period, whichever comes first. Survival analysis methodology was performed to compare the Kaplan-Meier curves for time to SCC across 3 treatment groups. Comparisons between 100 mg BID and placebo and 200 mg BID and placebo were also performed with stratified log-rank tests. The benefit ratios (ratio of likelihoods that participants treated with delamanid BID + OBR would achieve SCC more rapidly than participants treated with placebo + OBR) for participants achieving SCC were computed.
    Time Frame Day 57

    Outcome Measure Data

    Analysis Population Description
    MITT (Solid Culture) Population included all participants who had sputum cultures positive for MDR TB at baseline (Day -1 and/or Day 1) using solid culture medium.
    Arm/Group Title Delamanid 100 mg BID + OBR Delamanid 200 mg BID + OBR Placebo + OBR
    Arm/Group Description Participants received delamanid 100 mg (two 50 mg tablets), orally, BID with two matching placebo tablets plus OBR for 56 consecutive days (from Day 1 to Day 56). Participants were administered OBR as directed by the given investigator based on WHO guidelines and clinical judgment, in conjunction with national TB program guidelines in each country. Participants received delamanid 200 mg (four 50 mg tablets), orally, BID plus OBR for 56 consecutive days (from Day 1 to Day 56). Participants were administered OBR as directed by the given investigator based on WHO guidelines and clinical judgment, in conjunction with national TB program guidelines in each country. Participants received four placebo tablets matching 50-mg tablets of delamanid, orally, BID plus OBR for 56 consecutive days (from Day 1 to Day 56). Participants were administered OBR as directed by the given investigator based on WHO guidelines and clinical judgment, in conjunction with national TB program guidelines in each country.
    Measure Participants 119 115 113
    Number [percentage of participants]
    53.8
    33.4%
    65.2
    40.8%
    33.6
    21%
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Delamanid 100 mg BID + OBR, Placebo + OBR
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value =0.0016
    Comments
    Method Stratified Log-Rank Test
    Comments P-value was derived from log-rank test with SAS PROC LIFETEST for comparisons with placebo.
    Method of Estimation Estimation Parameter Hazard Ratio (HR)
    Estimated Value 1.846
    Confidence Interval (2-Sided) 95%
    1.235 to 2.759
    Parameter Dispersion Type:
    Value:
    Estimation Comments Hazard ratio computed with SAS PROC PHREG for comparisons with placebo.
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Delamanid 200 mg BID + OBR, Placebo + OBR
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value <.0001
    Comments
    Method Stratified Log-Rank Test
    Comments P-value was derived from Log-rank test with SAS PROC LIFETEST for comparisons with placebo.
    Method of Estimation Estimation Parameter Hazard Ratio (HR)
    Estimated Value 2.301
    Confidence Interval (2-Sided) 95%
    1.555 to 3.405
    Parameter Dispersion Type:
    Value:
    Estimation Comments Hazard ratio computed with SAS PROC PHREG for comparisons with placebo.
    25. Secondary Outcome
    Title Percentage of Participants With Clinically Significant Physical Examination Findings, Including Vision and Neuropsychiatric Assessments
    Description
    Time Frame From first dose of study drug up to post treatment period (Day 84)

    Outcome Measure Data

    Analysis Population Description
    ITT population included all randomized participants who received any amount of IMP, regardless of any protocol deviation or violation.
    Arm/Group Title Delamanid 100 mg BID + OBR Delamanid 200 mg BID + OBR Placebo + OBR
    Arm/Group Description Participants received delamanid 100 mg (two 50 mg tablets), orally, BID with two matching placebo tablets plus OBR for 56 consecutive days (from Day 1 to Day 56). Participants were administered OBR as directed by the given investigator based on WHO guidelines and clinical judgment, in conjunction with national TB program guidelines in each country. Participants received delamanid 200 mg (four 50 mg tablets), orally, BID plus OBR for 56 consecutive days (from Day 1 to Day 56). Participants were administered OBR as directed by the given investigator based on WHO guidelines and clinical judgment, in conjunction with national TB program guidelines in each country. Participants received four placebo tablets matching 50-mg tablets of delamanid, orally, BID plus OBR for 56 consecutive days (from Day 1 to Day 56). Participants were administered OBR as directed by the given investigator based on WHO guidelines and clinical judgment, in conjunction with national TB program guidelines in each country.
    Measure Participants 161 160 160
    Number [percentage of participants]
    0
    0%
    0
    0%
    0
    0%
    26. Secondary Outcome
    Title Percentage of Participants With Clinically Significant Vital Sign Abnormalities
    Description Criteria for potentially clinically significant vital sign abnormalities: Heart rate [beats per minute (BPM)]: >=120, increase >=15, <=60, decrease >=15; systolic blood pressure [millimeter of mercury (mmHg)]: >=160, increase >=20, <=90, decrease >=20; diastolic blood pressure (mmHg): >=105, increase >=15, <=50, decrease >=15; weight (kg) gain: increase >=5%; or weight loss: decrease >=5%; temperature [degrees Celsius (C)]: >=38.5, increase of >=1.1. Only categories with at least 1 participant with event are reported.
    Time Frame From first dose of study drug up to post treatment period (Day 84)

    Outcome Measure Data

    Analysis Population Description
    ITT population included all randomized participants who received any amount of IMP, regardless of any protocol deviation or violation. Number analyzed is the number of participants who had at least one post-baseline numerical result for the given test.
    Arm/Group Title Delamanid 100 mg BID + OBR Delamanid 200 mg BID + OBR Placebo + OBR
    Arm/Group Description Participants received delamanid 100 mg (two 50 mg tablets), orally, BID with two matching placebo tablets plus OBR for 56 consecutive days (from Day 1 to Day 56). Participants were administered OBR as directed by the given investigator based on WHO guidelines and clinical judgment, in conjunction with national TB program guidelines in each country. Participants received delamanid 200 mg (four 50 mg tablets), orally, BID plus OBR for 56 consecutive days (from Day 1 to Day 56). Participants were administered OBR as directed by the given investigator based on WHO guidelines and clinical judgment, in conjunction with national TB program guidelines in each country. Participants received four placebo tablets matching 50-mg tablets of delamanid, orally, BID plus OBR for 56 consecutive days (from Day 1 to Day 56). Participants were administered OBR as directed by the given investigator based on WHO guidelines and clinical judgment, in conjunction with national TB program guidelines in each country.
    Measure Participants 161 160 160
    Weight: Decrease of >=5% in Body Weight
    16.4
    10.2%
    13.9
    8.7%
    6.4
    4%
    Weight: Increase of >=5% in Body Weight
    35.2
    21.9%
    32.3
    20.2%
    44.6
    27.9%
    Temperature: >=38.5C + Increase of >=1.1C
    0.0
    0%
    0.6
    0.4%
    0.0
    0%
    Heart Rate: <=60 BPM + Decrease of >=15
    4.4
    2.7%
    5.1
    3.2%
    2.5
    1.6%
    Heart Rate: >=120 BPM + Increase of >=15
    0.6
    0.4%
    0.6
    0.4%
    0.0
    0%
    Systolic Blood Pressure: <=90 mmHg + Decrease of >=20 mmHg
    4.4
    2.7%
    9.5
    5.9%
    8.9
    5.6%
    Systolic Blood Pressure: >=160 mmHg + Increase of >=20 mmHg
    0.6
    0.4%
    0.0
    0%
    0.0
    0%
    Diastolic Blood Pressure <=50 mmHg + Decrease of >=15 mmHg
    1.9
    1.2%
    0.0
    0%
    0.6
    0.4%
    27. Secondary Outcome
    Title Percentage of Participants With Categorical Changes in 12-lead Electrocardiogram Results at Day 56
    Description Criteria for categorical changes in 6 12-lead Electrocardiogram results: Vent Rate Outliers Notable Decreases- >= 25% decrease from Baseline and ventricular rate < 50 beats per minute (beats/min), notable increases- >= 25% decrease from Baseline and ventricular rate > 100 beats/min; PR outliers notable changes- >= 25% change from Baseline when PR > 200 milliseconds (msec); QRS outliers notable changes- >= 25% change from Baseline when QRS > 100 msec; QT new onset (> 500 msec); QT correction with Bazett formula (QTcB) and QT interval with Fridericia's correction (QTcF) new onset > 500 msec, > 480 msec, > 450 msec, where new onset (> 450, 480, 500 msec) means a participant who attains a value > 450, 480, 500 msec during Treatment Period but not at each Baseline Visit; change >= 30, <= 60 msec; change > 60 msec; and new abnormal U waves, ST segment changes, T wave changes, abnormal rhythm, RBBB, LBBB, myocardial infarction(MI). Only categories with at least 1 participant with event are r
    Time Frame Baseline up to Day 56

    Outcome Measure Data

    Analysis Population Description
    The ECG population included all participants who had at least one baseline and one on-treatment ECG (full data set).
    Arm/Group Title Delamanid 100 mg BID + OBR Delamanid 200 mg BID + OBR Placebo + OBR
    Arm/Group Description Participants received delamanid 100 mg (two 50 mg tablets), orally, BID with two matching placebo tablets plus OBR for 56 consecutive days (from Day 1 to Day 56). Participants were administered OBR as directed by the given investigator based on WHO guidelines and clinical judgment, in conjunction with national TB program guidelines in each country. Participants received delamanid 200 mg (four 50 mg tablets), orally, BID plus OBR for 56 consecutive days (from Day 1 to Day 56). Participants were administered OBR as directed by the given investigator based on WHO guidelines and clinical judgment, in conjunction with national TB program guidelines in each country. Participants received four placebo tablets matching 50-mg tablets of delamanid, orally, BID plus OBR for 56 consecutive days (from Day 1 to Day 56). Participants were administered OBR as directed by the given investigator based on WHO guidelines and clinical judgment, in conjunction with national TB program guidelines in each country.
    Measure Participants 161 160 160
    Vent Rate Outliers Notable Decreases
    0.0
    0%
    1.2
    0.8%
    0.6
    0.4%
    Vent Rate Outliers Notable Increases
    1.2
    0.7%
    2.5
    1.6%
    3.7
    2.3%
    QT New Onset (> 500 msec)
    0.0
    0%
    1.8
    1.1%
    0.0
    0%
    QTcB New Onset (> 500 msec)
    1.2
    0.7%
    1.2
    0.8%
    1.2
    0.8%
    QTcB New Onset (> 480 msec)
    7.4
    4.6%
    8.1
    5.1%
    3.1
    1.9%
    QTcB New Onset (> 450 msec)
    39.1
    24.3%
    37.5
    23.4%
    19.3
    12.1%
    QTcB Change >= 30, <= 60 msec
    36.6
    22.7%
    44.3
    27.7%
    17.5
    10.9%
    QTcB Change >60 msec
    1.2
    0.7%
    3.1
    1.9%
    0.6
    0.4%
    QTcF New Onset (> 480 msec)
    0.0
    0%
    3.1
    1.9%
    0.6
    0.4%
    QTcF New Onset (> 450 msec)
    15.5
    9.6%
    13.7
    8.6%
    6.2
    3.9%
    QTcF Change >= 30, <= 60 msec
    36.0
    22.4%
    44.3
    27.7%
    15.6
    9.8%
    QTcF Change > 60 msec
    3.1
    1.9%
    3.7
    2.3%
    0.0
    0%
    New Abnormal Rhythm
    9.3
    5.8%
    10.6
    6.6%
    17.5
    10.9%
    New Right Bundle Branch Block (RBBB), Left Bundle Branch Block (LBBB), Myocardial Infarction (MI)
    2.4
    1.5%
    3.7
    2.3%
    7.5
    4.7%
    28. Secondary Outcome
    Title Percentage of Participants With Clinically Significant Laboratory Test Abnormalities
    Description The laboratory values were one of the parameters to measure the safety and tolerability of individual participants. Participants with potentially clinically significant laboratory values in clinical chemistry, hematology, coagulation, adrenal function tests, urinalysis and thyroid function tests that were identified based on pre-defined criteria were reported. Any value outside the normal range was flagged for the attention of the investigator who assessed whether or not a flagged value is of clinical significance. The categories with at least one participant with abnormal lab value as assessed by the investigator are reported.
    Time Frame From first dose of study drug up to post treatment period (Day 84)

    Outcome Measure Data

    Analysis Population Description
    ITT population included all randomized participants who received any amount of IMP, regardless of any protocol deviation or violation. Number analyzed is the number of participants with at least one non-missing result for a given lab test.
    Arm/Group Title Delamanid 100 mg BID + OBR Delamanid 200 mg BID + OBR Placebo + OBR
    Arm/Group Description Participants received delamanid 100 mg (two 50 mg tablets), orally, BID with two matching placebo tablets plus OBR for 56 consecutive days (from Day 1 to Day 56). Participants were administered OBR as directed by the given investigator based on WHO guidelines and clinical judgment, in conjunction with national TB program guidelines in each country. Participants received delamanid 200 mg (four 50 mg tablets), orally, BID plus OBR for 56 consecutive days (from Day 1 to Day 56). Participants were administered OBR as directed by the given investigator based on WHO guidelines and clinical judgment, in conjunction with national TB program guidelines in each country. Participants received four placebo tablets matching 50-mg tablets of delamanid, orally, BID plus OBR for 56 consecutive days (from Day 1 to Day 56). Participants were administered OBR as directed by the given investigator based on WHO guidelines and clinical judgment, in conjunction with national TB program guidelines in each country.
    Measure Participants 161 160 160
    Albumin (grams per deciliter [g/dL]) <2.6
    8.1
    5%
    3.1
    1.9%
    8.8
    5.5%
    Alanine Transaminase (ALT) (units per liter [U/L]) >150.0
    0.6
    0.4%
    0.6
    0.4%
    1.3
    0.8%
    Aspartate aminotransferase (AST) (U/L) >150.0
    1.2
    0.7%
    1.9
    1.2%
    2.5
    1.6%
    Bilirubin, Total (mg/dL) >2
    0.6
    0.4%
    Calcium (mg/dL) <7, >11.5
    0.6
    0.4%
    1.9
    1.2%
    3.8
    2.4%
    Chloride (milliequivalents per liter [mEq/L]) <85
    0.6
    0.4%
    2.5
    1.6%
    0.6
    0.4%
    Cholesterol (mg/dL) >300.0
    0.6
    0.4%
    0.6
    0.4%
    Creatinine (mg/dL) >2.0
    1.2
    0.7%
    0.6
    0.4%
    1.9
    1.2%
    Gamma-glutamyl Transferase (U/L); Male >225.0, Female >175.0
    3.1
    1.9%
    1.3
    0.8%
    Glucose (mg/dL) <50, >300
    1.9
    1.2%
    1.9
    1.2%
    4.4
    2.8%
    Lactic Dehydrogenase (U/L) >400
    1.2
    0.7%
    3.8
    2.4%
    1.9
    1.2%
    Potassium (mEq/L) <3, >5.5
    16.1
    10%
    18.1
    11.3%
    18.1
    11.3%
    Protein, Total Serum (g/dL) >9.5
    0.6
    0.4%
    Sodium (mEq/L) <132, >148
    17.4
    10.8%
    16.3
    10.2%
    17.5
    10.9%
    Triglycerides (mg/dL) >300
    4.3
    2.7%
    3.8
    2.4%
    4.4
    2.8%
    Urea Nitrogen (mg/dL) >34
    1.9
    1.2%
    1.3
    0.8%
    1.9
    1.2%
    Uric Acid (mg/dL) >12
    24.2
    15%
    27.9
    17.4%
    22.9
    14.3%
    Activated Partial Thromboplastin Time (seconds [sec]) >45.0
    14.9
    9.3%
    12.5
    7.8%
    16.3
    10.2%
    Eosinophils, Absolute (thousands per microliter [thous/µL]) >=0.8
    14.9
    9.3%
    18.1
    11.3%
    24.4
    15.3%
    Hematocrit (%); Male <32, >58, Female <27, >58
    15.5
    9.6%
    11.3
    7.1%
    11.3
    7.1%
    Hemoglobin (g/dL) <10, >16
    28.6
    17.8%
    23.1
    14.4%
    22.5
    14.1%
    Lymphocytes, Absolute (thous/µL) >=5.0
    0.6
    0.4%
    1.3
    0.8%
    Mean Corpuscular Hemoglobin (picograms [pg]) >40.0
    0.6
    0.4%
    Mean Corpuscular Hemoglobin Concentrate (g/dL) >40.0
    0.6
    0.4%
    Mean Corpuscular Volume (femtoliter [fL]) <=78, >=105
    30.4
    18.9%
    26.3
    16.4%
    26.9
    16.8%
    Neutrophil, Bands (%) >=8.0
    2.6
    1.6%
    2.6
    1.6%
    1.3
    0.8%
    Neutrophils, Absolute (thous/µL) <=2.0
    13.7
    8.5%
    10.0
    6.3%
    13.8
    8.6%
    Platelet Count (thous/µL) <100, >600
    16.1
    10%
    15.6
    9.8%
    13.8
    8.6%
    Prothrombin Time (sec) >17.5
    4.7
    2.9%
    3.7
    2.3%
    1.4
    0.9%
    Red Blood Cell (RBC) Count (million per microliter [mill/µL]) <4, >=6.5
    31.7
    19.7%
    23.1
    14.4%
    26.3
    16.4%
    Reticulocyte Count (%) <=.1, >=3
    21.1
    13.1%
    21.3
    13.3%
    23.8
    14.9%
    White Blood Count (thous/µL) <3, >=15
    11.2
    7%
    12.5
    7.8%
    13.8
    8.6%
    Blood (Urinalysis): Positive
    55.8
    34.7%
    58.6
    36.6%
    55.4
    34.6%
    Epithelial Casts
    100.0
    62.1%
    100.0
    62.5%
    100.0
    62.5%
    Granular Cast
    100.0
    62.1%
    100.0
    62.5%
    100.0
    62.5%
    Hyaline Cast
    100.0
    62.1%
    100.0
    62.5%
    100.0
    62.5%
    RBC Casts
    100.0
    62.1%
    100.0
    62.5%
    White Blood Count Casts
    100.0
    62.1%
    100.0
    62.5%
    Cortisol, Serum (micrograms per deciliter [µg/dL]) >=26
    36.0
    22.4%
    48.8
    30.5%
    29.4
    18.4%
    Free Thyroxine (T4) [nanograms per deciliter (ng/dL)] <=.30, >=2.5
    1.9
    1.2%
    0.6
    0.4%
    1.3
    0.8%
    Thyroid Stimulating Hormone (micro-international units per milliliter [µIU/mL]) <=.30 >=3
    23.6
    14.7%
    20.0
    12.5%
    26.3
    16.4%
    29. Secondary Outcome
    Title Percentage of Participants With Clinically Significant Audiometry Findings
    Description
    Time Frame From first dose of study drug up to post treatment period (Day 84)

    Outcome Measure Data

    Analysis Population Description
    ITT population included all randomized participants who received any amount of IMP, regardless of any protocol deviation or violation.
    Arm/Group Title Delamanid 100 mg BID + OBR Delamanid 200 mg BID + OBR Placebo + OBR
    Arm/Group Description Participants received delamanid 100 mg (two 50 mg tablets), orally, BID with two matching placebo tablets plus OBR for 56 consecutive days (from Day 1 to Day 56). Participants were administered OBR as directed by the given investigator based on WHO guidelines and clinical judgment, in conjunction with national TB program guidelines in each country. Participants received delamanid 200 mg (four 50 mg tablets), orally, BID plus OBR for 56 consecutive days (from Day 1 to Day 56). Participants were administered OBR as directed by the given investigator based on WHO guidelines and clinical judgment, in conjunction with national TB program guidelines in each country. Participants received four placebo tablets matching 50-mg tablets of delamanid, orally, BID plus OBR for 56 consecutive days (from Day 1 to Day 56). Participants were administered OBR as directed by the given investigator based on WHO guidelines and clinical judgment, in conjunction with national TB program guidelines in each country.
    Measure Participants 161 160 160
    Number [percentage of participants]
    0
    0%
    0
    0%
    0
    0%
    30. Secondary Outcome
    Title Percentage of Participants Using Concomitant Medications
    Description The concomitant anti-TB medication were classified as per WHO 2008 guidelines and included: Category 1- first-line oral anti-tuberculosis drugs; Category 2- injectable anti-tuberculosis drugs; Category 3- fluoroquinolones; Category 4- oral bacteriostatic second-line anti-tuberculosis drugs; Category 5- anti-tuberculosis drugs with unclear efficacy or unclear role in MDR-TB treatment (not recommended by WHO for routine use in MDR-TB participants).
    Time Frame From first dose of study drug up to post treatment period (Day 84)

    Outcome Measure Data

    Analysis Population Description
    ITT population included all randomized participants who received any amount of IMP, regardless of any protocol deviation or violation.
    Arm/Group Title Delamanid 100 mg BID + OBR Delamanid 200 mg BID + OBR Placebo + OBR
    Arm/Group Description Participants received delamanid 100 mg (two 50 mg tablets), orally, BID with two matching placebo tablets plus OBR for 56 consecutive days (from Day 1 to Day 56). Participants were administered OBR as directed by the given investigator based on WHO guidelines and clinical judgment, in conjunction with national TB program guidelines in each country. Participants received delamanid 200 mg (four 50 mg tablets), orally, BID plus OBR for 56 consecutive days (from Day 1 to Day 56). Participants were administered OBR as directed by the given investigator based on WHO guidelines and clinical judgment, in conjunction with national TB program guidelines in each country. Participants received four placebo tablets matching 50-mg tablets of delamanid, orally, BID plus OBR for 56 consecutive days (from Day 1 to Day 56). Participants were administered OBR as directed by the given investigator based on WHO guidelines and clinical judgment, in conjunction with national TB program guidelines in each country.
    Measure Participants 161 160 160
    Concomitant Medications (Excluding Anti-TB Medications)
    98.8
    61.4%
    98.8
    61.8%
    98.8
    61.8%
    Concomitant Anti-TB Medications: Category 1
    90.7
    56.3%
    90.6
    56.6%
    88.8
    55.5%
    Concomitant Anti-TB Medications: Category 2
    88.2
    54.8%
    80.0
    50%
    88.8
    55.5%
    Concomitant Anti-TB Medications: Category 3
    97.5
    60.6%
    98.8
    61.8%
    98.1
    61.3%
    Concomitant Anti-TB Medications: Category 4
    99.4
    61.7%
    98.8
    61.8%
    99.4
    62.1%
    Concomitant Anti-TB Medications: Category 5
    26.1
    16.2%
    27.5
    17.2%
    27.5
    17.2%
    31. Secondary Outcome
    Title Percentage of Participants With At Least One Treatment-Emergent Adverse Events (TEAEs)
    Description An adverse event (AE) was defined as any untoward medical occurrence in a clinical trial participant and which does not necessarily have a causal relationship with the treatment. An AE can therefore be any unfavorable and unintended sign (including e.g., an abnormal laboratory assessment result), symptom or disease temporally associated with participation in the clinical trial, whether or not it is considered causally related to the medicinal product or procedures of the clinical trial. A clinically significant worsening in the health of the participant compared with the participant's health status documented at baseline constituted a TEAE.
    Time Frame From first dose of study drug up to post treatment period (Day 84)

    Outcome Measure Data

    Analysis Population Description
    ITT population included all randomized participants who received any amount of IMP, regardless of any protocol deviation or violation.
    Arm/Group Title Delamanid 100 mg BID + OBR Delamanid 200 mg BID + OBR Placebo + OBR
    Arm/Group Description Participants received delamanid 100 mg (two 50 mg tablets), orally, BID with two matching placebo tablets plus OBR for 56 consecutive days (from Day 1 to Day 56). Participants were administered OBR as directed by the given investigator based on WHO guidelines and clinical judgment, in conjunction with national TB program guidelines in each country. Participants received delamanid 200 mg (four 50 mg tablets), orally, BID plus OBR for 56 consecutive days (from Day 1 to Day 56). Participants were administered OBR as directed by the given investigator based on WHO guidelines and clinical judgment, in conjunction with national TB program guidelines in each country. Participants received four placebo tablets matching 50-mg tablets of delamanid, orally, BID plus OBR for 56 consecutive days (from Day 1 to Day 56). Participants were administered OBR as directed by the given investigator based on WHO guidelines and clinical judgment, in conjunction with national TB program guidelines in each country.
    Measure Participants 161 160 160
    Number [percentage of participants]
    90.1
    56%
    93.1
    58.2%
    93.1
    58.2%
    32. Secondary Outcome
    Title Time-matched Change From Baseline (Day -1) in QTcF at Day 56
    Description
    Time Frame Baseline, and 2, 3, 4, 10, 12, and 24 hours post dose on Day 56

    Outcome Measure Data

    Analysis Population Description
    The ECG population included all participants who had at least one baseline and one on-treatment ECG (full data set).
    Arm/Group Title Delamanid 100 mg BID + OBR Delamanid 200 mg BID + OBR Placebo + OBR
    Arm/Group Description Participants received delamanid 100 mg (two 50 mg tablets), orally, BID with two matching placebo tablets plus OBR for 56 consecutive days (from Day 1 to Day 56). Participants were administered OBR as directed by the given investigator based on WHO guidelines and clinical judgment, in conjunction with national TB program guidelines in each country. Participants received delamanid 200 mg (four 50 mg tablets), orally, BID plus OBR for 56 consecutive days (from Day 1 to Day 56). Participants were administered OBR as directed by the given investigator based on WHO guidelines and clinical judgment, in conjunction with national TB program guidelines in each country. Participants received four placebo tablets matching 50-mg tablets of delamanid, orally, BID plus OBR for 56 consecutive days (from Day 1 to Day 56). Participants were administered OBR as directed by the given investigator based on WHO guidelines and clinical judgment, in conjunction with national TB program guidelines in each country.
    Measure Participants 161 160 160
    Day 56: 2 Hours Post Dose
    11.8
    (16.3)
    14.6
    (18.8)
    -0.5
    (14.3)
    Day 56: 3 Hours Post Dose
    12.8
    (16.6)
    14.7
    (16.0)
    -0.4
    (14.5)
    Day 56: 4 Hours Post Dose
    16.8
    (16.3)
    19.4
    (17.3)
    5.0
    (15.8)
    Day 56: 10 Hours Post Dose
    16.5
    (17.4)
    20.8
    (17.3)
    5.2
    (15.5)
    Day 56: 12 Hours Post Dose
    15.6
    (17.4)
    16.7
    (17.0)
    2.6
    (15.6)
    Day 56: 24 Hours Post Dose
    15.5
    (18.9)
    18.3
    (18.5)
    3.4
    (15.0)
    33. Secondary Outcome
    Title Mean Change From Baseline in QTcF
    Description
    Time Frame Baseline, Days 1, 14, 28 and 56

    Outcome Measure Data

    Analysis Population Description
    The ECG population included all participants who had at least one baseline and one on-treatment ECG (full data set).
    Arm/Group Title Delamanid 100 mg BID + OBR Delamanid 200 mg BID + OBR Placebo + OBR
    Arm/Group Description Participants received delamanid 100 mg (two 50 mg tablets), orally, BID with two matching placebo tablets plus OBR for 56 consecutive days (from Day 1 to Day 56). Participants were administered OBR as directed by the given investigator based on WHO guidelines and clinical judgment, in conjunction with national TB program guidelines in each country. Participants received delamanid 200 mg (four 50 mg tablets), orally, BID plus OBR for 56 consecutive days (from Day 1 to Day 56). Participants were administered OBR as directed by the given investigator based on WHO guidelines and clinical judgment, in conjunction with national TB program guidelines in each country. Participants received four placebo tablets matching 50-mg tablets of delamanid, orally, BID plus OBR for 56 consecutive days (from Day 1 to Day 56). Participants were administered OBR as directed by the given investigator based on WHO guidelines and clinical judgment, in conjunction with national TB program guidelines in each country.
    Measure Participants 161 160 160
    Day 1
    0.1
    (7.1)
    0.0
    (7.1)
    -1.8
    (8.3)
    Day 14
    7.7
    (11.1)
    9.3
    (11.2)
    0.8
    (11.0)
    Day 28
    9.9
    (12.3)
    14.1
    (13.2)
    2.4
    (11.2)
    Day 56
    14.9
    (14.3)
    17.5
    (13.9)
    2.7
    (12.2)
    34. Secondary Outcome
    Title Mean Change From Baseline in QTcB
    Description
    Time Frame Baseline, Days 1, 14, 28 and 56

    Outcome Measure Data

    Analysis Population Description
    The ECG population included all participants who had at least one baseline and one on-treatment ECG (full data set).
    Arm/Group Title Delamanid 100 mg BID + OBR Delamanid 200 mg BID + OBR Placebo + OBR
    Arm/Group Description Participants received delamanid 100 mg (two 50 mg tablets), orally, BID with two matching placebo tablets plus OBR for 56 consecutive days (from Day 1 to Day 56). Participants were administered OBR as directed by the given investigator based on WHO guidelines and clinical judgment, in conjunction with national TB program guidelines in each country. Participants received delamanid 200 mg (four 50 mg tablets), orally, BID plus OBR for 56 consecutive days (from Day 1 to Day 56). Participants were administered OBR as directed by the given investigator based on WHO guidelines and clinical judgment, in conjunction with national TB program guidelines in each country. Participants received four placebo tablets matching 50-mg tablets of delamanid, orally, BID plus OBR for 56 consecutive days (from Day 1 to Day 56). Participants were administered OBR as directed by the given investigator based on WHO guidelines and clinical judgment, in conjunction with national TB program guidelines in each country.
    Measure Participants 161 160 160
    Day 1
    0.8
    (7.4)
    1.5
    (7.2)
    -0.4
    (8.5)
    Day 14
    6.5
    (11.5)
    8.1
    (10.7)
    0.5
    (12.0)
    Day 28
    7.9
    (12.1)
    12.5
    (14.0)
    2.1
    (13.0)
    Day 56
    11.7
    (14.5)
    14.6
    (12.6)
    2.3
    (13.6)
    35. Secondary Outcome
    Title Mean Change From Baseline in Ventricular Rate
    Description
    Time Frame Baseline, Days 1, 14, 28 and 56

    Outcome Measure Data

    Analysis Population Description
    The ECG population included all participants who had at least one baseline and one on-treatment ECG (full data set).
    Arm/Group Title Delamanid 100 mg BID + OBR Delamanid 200 mg BID + OBR Placebo + OBR
    Arm/Group Description Participants received delamanid 100 mg (two 50 mg tablets), orally, BID with two matching placebo tablets plus OBR for 56 consecutive days (from Day 1 to Day 56). Participants were administered OBR as directed by the given investigator based on WHO guidelines and clinical judgment, in conjunction with national TB program guidelines in each country. Participants received delamanid 200 mg (four 50 mg tablets), orally, BID plus OBR for 56 consecutive days (from Day 1 to Day 56). Participants were administered OBR as directed by the given investigator based on WHO guidelines and clinical judgment, in conjunction with national TB program guidelines in each country. Participants received four placebo tablets matching 50-mg tablets of delamanid, orally, BID plus OBR for 56 consecutive days (from Day 1 to Day 56). Participants were administered OBR as directed by the given investigator based on WHO guidelines and clinical judgment, in conjunction with national TB program guidelines in each country.
    Measure Participants 161 160 160
    Day 1
    0.9
    (5.5)
    2.0
    (4.9)
    1.9
    (5.3)
    Day 14
    -1.9
    (8.1)
    -2.1
    (9.0)
    -0.6
    (8.6)
    Day 28
    -3.2
    (8.6)
    -3.2
    (9.3)
    -0.8
    (10.2)
    Day 56
    -4.8
    (10.3)
    -4.7
    (12.6)
    -1.2
    (10.6)
    36. Secondary Outcome
    Title Mean Change From Baseline in PR Interval
    Description
    Time Frame Baseline, Days 1, 14, 28 and 56

    Outcome Measure Data

    Analysis Population Description
    The ECG population included all participants who had at least one baseline and one on-treatment ECG (full data set).
    Arm/Group Title Delamanid 100 mg BID + OBR Delamanid 200 mg BID + OBR Placebo + OBR
    Arm/Group Description Participants received delamanid 100 mg (two 50 mg tablets), orally, BID with two matching placebo tablets plus OBR for 56 consecutive days (from Day 1 to Day 56). Participants were administered OBR as directed by the given investigator based on WHO guidelines and clinical judgment, in conjunction with national TB program guidelines in each country. Participants received delamanid 200 mg (four 50 mg tablets), orally, BID plus OBR for 56 consecutive days (from Day 1 to Day 56). Participants were administered OBR as directed by the given investigator based on WHO guidelines and clinical judgment, in conjunction with national TB program guidelines in each country. Participants received four placebo tablets matching 50-mg tablets of delamanid, orally, BID plus OBR for 56 consecutive days (from Day 1 to Day 56). Participants were administered OBR as directed by the given investigator based on WHO guidelines and clinical judgment, in conjunction with national TB program guidelines in each country.
    Measure Participants 161 160 160
    Day 1
    -1.3
    (5.6)
    -1.0
    (4.8)
    -1.6
    (5.4)
    Day 14
    -0.7
    (7.7)
    -0.8
    (7.2)
    -1.4
    (8.1)
    Day 28
    -1.4
    (8.1)
    -0.8
    (8.4)
    -0.6
    (7.4)
    Day 56
    -1.6
    (8.3)
    0.3
    (8.1)
    -0.5
    (7.2)
    37. Secondary Outcome
    Title Mean Change From Baseline in QRS Interval
    Description
    Time Frame Baseline, Days 1, 14, 28 and 56

    Outcome Measure Data

    Analysis Population Description
    The ECG population included all participants who had at least one baseline and one on-treatment ECG (full data set).
    Arm/Group Title Delamanid 100 mg BID + OBR Delamanid 200 mg BID + OBR Placebo + OBR
    Arm/Group Description Participants received delamanid 100 mg (two 50 mg tablets), orally, BID with two matching placebo tablets plus OBR for 56 consecutive days (from Day 1 to Day 56). Participants were administered OBR as directed by the given investigator based on WHO guidelines and clinical judgment, in conjunction with national TB program guidelines in each country. Participants received delamanid 200 mg (four 50 mg tablets), orally, BID plus OBR for 56 consecutive days (from Day 1 to Day 56). Participants were administered OBR as directed by the given investigator based on WHO guidelines and clinical judgment, in conjunction with national TB program guidelines in each country. Participants received four placebo tablets matching 50-mg tablets of delamanid, orally, BID plus OBR for 56 consecutive days (from Day 1 to Day 56). Participants were administered OBR as directed by the given investigator based on WHO guidelines and clinical judgment, in conjunction with national TB program guidelines in each country.
    Measure Participants 161 160 160
    Day 1
    -0.3
    (2.8)
    -0.5
    (2.8)
    -0.2
    (3.3)
    Day 14
    0.1
    (3.3)
    0.1
    (3.5)
    -0.1
    (3.9)
    Day 28
    0.4
    (3.6)
    -0.1
    (4.2)
    -0.3
    (3.8)
    Day 56
    0.7
    (4.1)
    -0.2
    (4.0)
    0.2
    (3.8)
    38. Secondary Outcome
    Title Mean Change From Baseline in QT Interval
    Description
    Time Frame Baseline, Days 1, 14, 28 and 56

    Outcome Measure Data

    Analysis Population Description
    The ECG population included all participants who had at least one baseline and one on-treatment ECG (full data set).
    Arm/Group Title Delamanid 100 mg BID + OBR Delamanid 200 mg BID + OBR Placebo + OBR
    Arm/Group Description Participants received delamanid 100 mg (two 50 mg tablets), orally, BID with two matching placebo tablets plus OBR for 56 consecutive days (from Day 1 to Day 56). Participants were administered OBR as directed by the given investigator based on WHO guidelines and clinical judgment, in conjunction with national TB program guidelines in each country. Participants received delamanid 200 mg (four 50 mg tablets), orally, BID plus OBR for 56 consecutive days (from Day 1 to Day 56). Participants were administered OBR as directed by the given investigator based on WHO guidelines and clinical judgment, in conjunction with national TB program guidelines in each country. Participants received four placebo tablets matching 50-mg tablets of delamanid, orally, BID plus OBR for 56 consecutive days (from Day 1 to Day 56). Participants were administered OBR as directed by the given investigator based on WHO guidelines and clinical judgment, in conjunction with national TB program guidelines in each country.
    Measure Participants 161 160 160
    Day 1
    -1.0
    (11.5)
    -2.7
    (10.9)
    -4.3
    (11.6)
    Day 14
    9.5
    (18.2)
    11.1
    (20.1)
    1.1
    (18.5)
    Day 28
    13.4
    (20.3)
    16.3
    (21.1)
    2.5
    (20.2)
    Day 56
    20.1
    (23.5)
    22.0
    (28.4)
    3.1
    (21.7)
    39. Secondary Outcome
    Title Percentage of Participants With Change in ECG Morphological Patterns From Baseline
    Description Any changes in the ECG waves or segments as assessed by the investigator were reported.
    Time Frame Baseline, Days 1, 14, 28 and 56

    Outcome Measure Data

    Analysis Population Description
    The ECG population included all participants who had at least one baseline and one on-treatment ECG (full data set).
    Arm/Group Title Delamanid 100 mg BID + OBR Delamanid 200 mg BID + OBR Placebo + OBR
    Arm/Group Description Participants received delamanid 100 mg (two 50 mg tablets), orally, BID with two matching placebo tablets plus OBR for 56 consecutive days (from Day 1 to Day 56). Participants were administered OBR as directed by the given investigator based on WHO guidelines and clinical judgment, in conjunction with national TB program guidelines in each country. Participants received delamanid 200 mg (four 50 mg tablets), orally, BID plus OBR for 56 consecutive days (from Day 1 to Day 56). Participants were administered OBR as directed by the given investigator based on WHO guidelines and clinical judgment, in conjunction with national TB program guidelines in each country. Participants received four placebo tablets matching 50-mg tablets of delamanid, orally, BID plus OBR for 56 consecutive days (from Day 1 to Day 56). Participants were administered OBR as directed by the given investigator based on WHO guidelines and clinical judgment, in conjunction with national TB program guidelines in each country.
    Measure Participants 161 160 160
    Day 1: New Abnormal U Waves
    0.0
    0%
    0.0
    0%
    0.0
    0%
    Day 1: New ST Segment Changes
    1.8
    1.1%
    0.6
    0.4%
    1.2
    0.8%
    Day 1: New T Wave Changes
    9.9
    6.1%
    6.2
    3.9%
    6.2
    3.9%
    Day 14: New Abnormal U Waves
    0.0
    0%
    0.0
    0%
    0.0
    0%
    Day 14: New ST Segment Changes
    3.1
    1.9%
    0.6
    0.4%
    1.2
    0.8%
    Day 14: New T Wave Changes
    12.4
    7.7%
    5.6
    3.5%
    4.3
    2.7%
    Day 28: New Abnormal U Waves
    1.2
    0.7%
    0.0
    0%
    0.0
    0%
    Day 28: New ST Segment Changes
    1.8
    1.1%
    0.0
    0%
    0.0
    0%
    Day 28: New T Wave Changes
    11.8
    7.3%
    5.0
    3.1%
    10.0
    6.3%
    Day 56: New Abnormal U Waves
    1.2
    0.7%
    0.6
    0.4%
    0.0
    0%
    Day 56: New ST Segment Changes
    2.4
    1.5%
    0.6
    0.4%
    1.8
    1.1%
    Day 56: New T Wave Changes
    11.1
    6.9%
    10.6
    6.6%
    5.0
    3.1%

    Adverse Events

    Time Frame From first dose of study drug up to post treatment period (up to Day 84)
    Adverse Event Reporting Description ITT population included all randomized participants who received any amount of IMP, regardless of any protocol deviation or violation.
    Arm/Group Title Delamanid 100 mg BID + OBR Delamanid 200 mg BID + OBR Placebo + OBR
    Arm/Group Description Participants received delamanid 100 mg (two 50 mg tablets), orally, BID with two matching placebo tablets plus OBR for 56 consecutive days (from Day 1 to Day 56). Participants were administered OBR as directed by the given investigator based on WHO guidelines and clinical judgment, in conjunction with national TB program guidelines in each country. Participants received delamanid 200 mg (four 50 mg tablets), orally, BID plus OBR for 56 consecutive days (from Day 1 to Day 56). Participants were administered OBR as directed by the given investigator based on WHO guidelines and clinical judgment, in conjunction with national TB program guidelines in each country. Participants received four placebo tablets matching 50-mg tablets of delamanid, orally, BID plus OBR for 56 consecutive days (from Day 1 to Day 56). Participants were administered OBR as directed by the given investigator based on WHO guidelines and clinical judgment, in conjunction with national TB program guidelines in each country.
    All Cause Mortality
    Delamanid 100 mg BID + OBR Delamanid 200 mg BID + OBR Placebo + OBR
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 0/161 (0%) 1/160 (0.6%) 0/160 (0%)
    Serious Adverse Events
    Delamanid 100 mg BID + OBR Delamanid 200 mg BID + OBR Placebo + OBR
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 16/161 (9.9%) 20/160 (12.5%) 14/160 (8.8%)
    Blood and lymphatic system disorders
    Anaemia 3/161 (1.9%) 2/160 (1.3%) 1/160 (0.6%)
    Leukopenia 0/161 (0%) 1/160 (0.6%) 0/160 (0%)
    Thrombocytopenia 1/161 (0.6%) 1/160 (0.6%) 0/160 (0%)
    Cardiac disorders
    Sinus tachycardia 0/161 (0%) 1/160 (0.6%) 0/160 (0%)
    Ear and labyrinth disorders
    Deafness 0/161 (0%) 1/160 (0.6%) 0/160 (0%)
    General disorders
    Chest discomfort 0/161 (0%) 1/160 (0.6%) 0/160 (0%)
    Hepatobiliary disorders
    Hepatitis 1/161 (0.6%) 1/160 (0.6%) 1/160 (0.6%)
    Liver disorder 0/161 (0%) 1/160 (0.6%) 0/160 (0%)
    Infections and infestations
    Lower respiratory tract infection 0/161 (0%) 1/160 (0.6%) 0/160 (0%)
    Oropharyngeal candidiasis 0/161 (0%) 1/160 (0.6%) 0/160 (0%)
    Pneumonia 0/161 (0%) 0/160 (0%) 1/160 (0.6%)
    Injury, poisoning and procedural complications
    Fall 1/161 (0.6%) 0/160 (0%) 0/160 (0%)
    Investigations
    Electrocardiogram QT prolonged 7/161 (4.3%) 9/160 (5.6%) 3/160 (1.9%)
    Electrocardiogram T wave abnormal 0/161 (0%) 1/160 (0.6%) 0/160 (0%)
    Metabolism and nutrition disorders
    Hypoglycaemia 0/161 (0%) 0/160 (0%) 1/160 (0.6%)
    Hypokalaemia 0/161 (0%) 2/160 (1.3%) 0/160 (0%)
    Nervous system disorders
    Syncope 0/161 (0%) 1/160 (0.6%) 1/160 (0.6%)
    Psychiatric disorders
    Agitation 1/161 (0.6%) 1/160 (0.6%) 0/160 (0%)
    Anxiety 0/161 (0%) 1/160 (0.6%) 0/160 (0%)
    Delusional disorder, persecutory type 0/161 (0%) 1/160 (0.6%) 0/160 (0%)
    Hallucination 0/161 (0%) 0/160 (0%) 1/160 (0.6%)
    Hallucination, auditory 1/161 (0.6%) 0/160 (0%) 0/160 (0%)
    Ideas of reference 1/161 (0.6%) 0/160 (0%) 0/160 (0%)
    Mental disorder 0/161 (0%) 1/160 (0.6%) 0/160 (0%)
    Psychotic disorder 2/161 (1.2%) 2/160 (1.3%) 3/160 (1.9%)
    Schizophrenia, paranoid type 0/161 (0%) 0/160 (0%) 1/160 (0.6%)
    Suicidal ideation 0/161 (0%) 1/160 (0.6%) 0/160 (0%)
    Renal and urinary disorders
    Renal failure 0/161 (0%) 1/160 (0.6%) 0/160 (0%)
    Respiratory, thoracic and mediastinal disorders
    Haemoptysis 3/161 (1.9%) 1/160 (0.6%) 2/160 (1.3%)
    Hydropneumothorax 0/161 (0%) 0/160 (0%) 1/160 (0.6%)
    Pneumothorax 1/161 (0.6%) 0/160 (0%) 1/160 (0.6%)
    Respiratory failure 0/161 (0%) 1/160 (0.6%) 0/160 (0%)
    Skin and subcutaneous tissue disorders
    Dermatitis allergic 0/161 (0%) 0/160 (0%) 1/160 (0.6%)
    Vascular disorders
    Haematoma 1/161 (0.6%) 0/160 (0%) 0/160 (0%)
    Hypotension 1/161 (0.6%) 0/160 (0%) 0/160 (0%)
    Other (Not Including Serious) Adverse Events
    Delamanid 100 mg BID + OBR Delamanid 200 mg BID + OBR Placebo + OBR
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 145/161 (90.1%) 148/160 (92.5%) 147/160 (91.9%)
    Blood and lymphatic system disorders
    Anaemia 15/161 (9.3%) 8/160 (5%) 14/160 (8.8%)
    Eosinophilia 7/161 (4.3%) 11/160 (6.9%) 15/160 (9.4%)
    Reticulocytosis 19/161 (11.8%) 20/160 (12.5%) 17/160 (10.6%)
    Cardiac disorders
    Palpitations 13/161 (8.1%) 20/160 (12.5%) 10/160 (6.3%)
    Ear and labyrinth disorders
    Tinnitus 16/161 (9.9%) 22/160 (13.8%) 12/160 (7.5%)
    Eye disorders
    Vision blurred 12/161 (7.5%) 15/160 (9.4%) 9/160 (5.6%)
    Gastrointestinal disorders
    Abdominal discomfort 7/161 (4.3%) 8/160 (5%) 5/160 (3.1%)
    Abdominal distension 5/161 (3.1%) 9/160 (5.6%) 5/160 (3.1%)
    Abdominal pain 16/161 (9.9%) 12/160 (7.5%) 11/160 (6.9%)
    Abdominal pain lower 4/161 (2.5%) 11/160 (6.9%) 7/160 (4.4%)
    Abdominal pain upper 41/161 (25.5%) 36/160 (22.5%) 38/160 (23.8%)
    Constipation 6/161 (3.7%) 8/160 (5%) 8/160 (5%)
    Diarrhoea 20/161 (12.4%) 12/160 (7.5%) 22/160 (13.8%)
    Dyspepsia 6/161 (3.7%) 14/160 (8.8%) 6/160 (3.8%)
    Gastritis 8/161 (5%) 14/160 (8.8%) 16/160 (10%)
    Nausea 58/161 (36%) 65/160 (40.6%) 53/160 (33.1%)
    Toothache 6/161 (3.7%) 7/160 (4.4%) 11/160 (6.9%)
    Vomiting 48/161 (29.8%) 58/160 (36.3%) 44/160 (27.5%)
    General disorders
    Asthenia 20/161 (12.4%) 27/160 (16.9%) 20/160 (12.5%)
    Chest pain 16/161 (9.9%) 13/160 (8.1%) 7/160 (4.4%)
    Injection site pain 13/161 (8.1%) 12/160 (7.5%) 23/160 (14.4%)
    Malaise 12/161 (7.5%) 16/160 (10%) 12/160 (7.5%)
    Pyrexia 9/161 (5.6%) 18/160 (11.3%) 18/160 (11.3%)
    Investigations
    Electrocardiogram QT prolonged 11/161 (6.8%) 13/160 (8.1%) 3/160 (1.9%)
    Metabolism and nutrition disorders
    Anorexia 23/161 (14.3%) 34/160 (21.3%) 24/160 (15%)
    Hyperuricaemia 31/161 (19.3%) 38/160 (23.8%) 35/160 (21.9%)
    Hypokalaemia 20/161 (12.4%) 29/160 (18.1%) 24/160 (15%)
    Musculoskeletal and connective tissue disorders
    Arthralgia 32/161 (19.9%) 43/160 (26.9%) 46/160 (28.8%)
    Back pain 12/161 (7.5%) 16/160 (10%) 19/160 (11.9%)
    Musculoskeletal pain 10/161 (6.2%) 8/160 (5%) 11/160 (6.9%)
    Myalgia 15/161 (9.3%) 21/160 (13.1%) 26/160 (16.3%)
    Neck pain 1/161 (0.6%) 11/160 (6.9%) 9/160 (5.6%)
    Pain in extremity 6/161 (3.7%) 8/160 (5%) 8/160 (5%)
    Nervous system disorders
    Dizziness 48/161 (29.8%) 49/160 (30.6%) 49/160 (30.6%)
    Dysgeusia 5/161 (3.1%) 10/160 (6.3%) 10/160 (6.3%)
    Headache 36/161 (22.4%) 41/160 (25.6%) 30/160 (18.8%)
    Hypoaesthesia 12/161 (7.5%) 7/160 (4.4%) 8/160 (5%)
    Paraesthesia 17/161 (10.6%) 20/160 (12.5%) 12/160 (7.5%)
    Somnolence 11/161 (6.8%) 9/160 (5.6%) 15/160 (9.4%)
    Tremor 19/161 (11.8%) 16/160 (10%) 13/160 (8.1%)
    Psychiatric disorders
    Anxiety 9/161 (5.6%) 11/160 (6.9%) 5/160 (3.1%)
    Depression 4/161 (2.5%) 13/160 (8.1%) 5/160 (3.1%)
    Insomnia 42/161 (26.1%) 51/160 (31.9%) 42/160 (26.3%)
    Respiratory, thoracic and mediastinal disorders
    Cough 8/161 (5%) 8/160 (5%) 7/160 (4.4%)
    Dyspnoea 3/161 (1.9%) 8/160 (5%) 5/160 (3.1%)
    Haemoptysis 16/161 (9.9%) 14/160 (8.8%) 16/160 (10%)
    Oropharyngeal pain 5/161 (3.1%) 9/160 (5.6%) 6/160 (3.8%)
    Rales 12/161 (7.5%) 11/160 (6.9%) 16/160 (10%)
    Throat irritation 5/161 (3.1%) 8/160 (5%) 0/160 (0%)
    Skin and subcutaneous tissue disorders
    Hyperhidrosis 9/161 (5.6%) 17/160 (10.6%) 8/160 (5%)
    Pruritus 15/161 (9.3%) 15/160 (9.4%) 20/160 (12.5%)
    Rash 8/161 (5%) 3/160 (1.9%) 10/160 (6.3%)
    Rash papular 10/161 (6.2%) 12/160 (7.5%) 11/160 (6.9%)

    Limitations/Caveats

    [Not Specified]

    More Information

    Certain Agreements

    Principal Investigators are NOT employed by the organization sponsoring the study.

    A disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 90 days from the time submitted to the sponsor for review. The sponsor cannot require changes to the communication and cannot extend the embargo.

    Results Point of Contact

    Name/Title Global Clinical Development
    Organization Otsuka Pharmaceutical Development & Commercialization, Inc.
    Phone 1-609-524-6788
    Email clinicaltransparency@otsuka-us.com
    Responsible Party:
    Otsuka Pharmaceutical Development & Commercialization, Inc.
    ClinicalTrials.gov Identifier:
    NCT00685360
    Other Study ID Numbers:
    • 242-07-204
    • 2007-005229-31
    First Posted:
    May 28, 2008
    Last Update Posted:
    Dec 1, 2021
    Last Verified:
    Nov 1, 2021