A Trial to Evaluate Safety, Tolerability, and Efficacy of Orally Administered OPC-67683

A Phase 2, Multi-center, Uncontrolled, Open-label Trial to Evaluate Safety, Tolerability, and Efficacy of Orally Administered OPC-67683 as 100 mg BID With Optional Titration to 200 mg BID for up to Six Months Exposure in Patients With Pulmonary Multi-drug Resistant Tuberculosis

Status

Completed

Phases

Phase 2

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT02573350

Enrollment

213

Registered

2015-10-09

Start date

2009-03-26

Completion date

2011-10-27

Last updated

2021-11-01

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Tuberculosis, Multidrug-Resistant

Brief summary

A phase 2, multicenter, uncontrolled, open-label trial in participants with Multi-drug Resistant Tuberculosis (MDR-TB). Only participants who completed Trial 242-07-204 (NCT00685360) were eligible. The trial was performed globally at 14 sites qualified to treat MDR-TB. All 434 participants who completed Trial 242-07-204 were eligible for this trial if there was still potential clinical benefit to them and all inclusion criteria and no exclusion criteria were met.

Interventions

DRUGDelamanid

Delamanid was administered orally twice daily as 50-mg tablets under fed conditions in the morning and evening.

DRUGOBR

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. Study investigators could change OBR for a participant based on his/her tolerability and drug susceptibility testing (DST) results.

Study design

Allocation

RANDOMIZED

Intervention model

PARALLEL

Primary purpose

TREATMENT

Masking

NONE

Eligibility

Sex/Gender

ALL

Age

18 Years to 64 Years

Healthy volunteers

Inclusion criteria

* Provide written, informed consent prior to all trial-related procedures * Male or female participants aged between 18 and 64 years, inclusive, at the time of enrollment into the 242-07-204 trial. Participants who were 64 years at the time of 204 enrollment and who are now 65 years, are eligible for this trial. * Participants who have completed trial 242-07-204 * Participants judged by the investigator to have the potential for clinical benefit from OPC-67683 exposure * Able to produce sputum for mycobacterial culture or able to obtain sputum produced through induction * Female participants of childbearing potential must have a negative urine pregnancy test and agree to use a highly effective method of birth control throughout the participation in the trial and for 22 weeks after last dose. * 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.

Exclusion criteria

* Greater than 30 days has elapsed from the participant's date of completion in the 242-07-204 trial or greater than 30 days has elapsed since the patient's trial investigator's site was initiated in this trial, whichever is later. * A history of allergy to any nitro-imidazoles or nitro-imidazole derivates at any time. * Use of the medications in Section 5.4.7 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 moles per liter (mol/L) or hepatic impairment characterized by Alanine aminotransferase (ALT) and/or aspartate transferase (AST) levels 3 times the upper limit of the laboratory reference range from the screening lab results. * Current clinically relevant changes in the electrocardiogram (ECG) (between Trial 242-07-204 Day 56 assessment and baseline) such as any atrioventricular (AV) block, prolongation of the QRS complex over 120 milliseconds (msec) (in both male and female participants), or the corrected QT interval using Fridericia's method (QTcF) interval over 450 msec in male participants and 470 msec in female participants. * Current clinically relevant cardiovascular disorders such as heart failure, coronary artery disease, uncontrolled or poorly controlled hypertension, arrhythmia, tachyarrhythmia or status after myocardial infarction. * Any participants with known or reported significant psychiatric history. * For participants with human immunodeficiency virus (HIV) infection, CD4 cell count less than 350/cubic millimeter (mm\^3) or on treatment with antiretroviral medication for HIV infection. * Karnofsky score under 50 percent (%) while hospitalized and less than 60% while not hospitalized. * Any current 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 participants in the opinion of the investigator. * Administered an investigational medicinal product (IMP) within 1 month prior to Visit 1 other than OPC-67683 given as IMP in trial 242-07-204. * 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/methamphetamine, tetrahydrocannabinol, barbiturates, and opiates as determined by a urine drug screen, unless evidence is provided that the positive drug screen is the result of authorized medications or 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.

Design outcomes

Primary

Measure	Time frame	Description
Number of Participants With Clinically Significant Abnormality in Vital Signs	From first dose of study drug up to Week 26	Vital signs included weight (kg), body temperature (degree Celsius), heart rate \[beats/minute (bpm)\], systolic and diastolic blood pressure \[millimetre of mercury (mm Hg)\]. The criteria for clinically significant abnormal value for: weight was decrease or increase of \>=5% in body weight, heart rate was \<=60 bpm and decrease of \>=15 bpm; \>=120 bpm and Increase of \>=15 bpm, systolic blood pressure (SBP) \<=90 mm Hg and decrease of \>=20 mm Hg; diastolic blood pressure (DBP) \<=50 mm Hg and decrease of \>=15 mm Hg, all vital signs relative to Baseline. Baseline is Study 204 completion visit (Day 84) for participants who complete the baseline visit within 7 days of completing Study 204. Only categories with data for potentially clinically significant abnormal vital sign parameter values are reported.
Number of Participants With Clinically Significant Abnormalities in Electrocardiogram (ECG) Values	From first dose of study drug up to Week 26	The criteria for clinically significant abnormal ECG values were ventricular rate outlier (\<50 bpm and decrease of \>=25%, \>100 bpm and increase of \>=25%), PR outlier (increase of \>=25% when PR \>200 milliseconds (ms)), QRS outlier (increase of \>=25% when QRS \>100 ms), QT (new onset (in treatment period but not at Baseline) \[\>500 ms\]), QT interval corrected by Bazett's formula (QTcB) (new onset \[\>450, \>480, \>500 ms\], increase of \>=30 ms and \<= 60 ms or increase of \>60 ms), QT interval corrected by Fridericia's formula (QTcF) (new onset \[\>450, \>480, \>500 ms\], increase of \>=30 ms and \<= 60 ms or increase of \>60 ms), new abnormal U waves, new ST segment changes, new T wave changes, new abnormal rhythm, new conduction abnormality were reported as categories. Only categories with data are reported.
Number of Participants With Clinical Significant Abnormality in Laboratory Test	From first dose of study drug up to Week 26	Laboratory assessments included parameters for serum chemistry (alkaline phosphatase, alanine aminotransferase, alanine transaminase, total bilirubin, cholesterol, gamma-glutamyl transferase, glucose, lactic dehydrogenase, potassium, sodium, triglycerides, uric acid), hematology (white blood cell count eosinophils, absolute, hematocrit, hemoglobin, lymphocytes, absolute, mean corpuscular volume, neutrophil, bands, neutrophils, neutrophils, absolute, platelet count, red blood cell (RBC) count, reticulocyte count) and urinalysis (blood, epithelial cast, granular cast, hyaline cast, RBCs per high power field (RBC/HPF)). The participants were categorized based on the clinically significant laboratory values as per predefined criteria. The categories with at least one participant with clinically significant value outside the normal range for laboratory assessments are reported.
Number of Participants With Abnormality in Audiometry at Baseline	Baseline	Audiometry assessments were done at Baseline.
Number of Participants With Abnormality in Visual Acuity	From first dose of study drug up to Week 26	—
Number of Participants With Abnormality in Neurological and Psychiatric Assessment Reported as Treatment-emergent Adverse Event (TEAE)	From first dose through 28 days after last dose of study drug (up to approximately 30 weeks)	Participants with abnormal neurological and psychiatric assessments were reported. An adverse event (AE) is any untoward medical occurrence in a participant/clinical investigation participant administered a pharmaceutical product and which does not necessarily have a causal relationship with treatment. A TEAE is any new AE or worsening of an existing condition after initiation of study drug.
Number of Participants With Clinical Significant Abnormality in Thyroid Function Test Reported as TEAE	From first dose through 28 days after last dose of study drug (up to approximately 30 weeks)	Participants with abnormal thyroid free T4 nanograms per deciliter (ng/dL) and thyroid-stimulating hormone (\>=3 OR \<=0.3 micro-international units per litre (uIU/mL). An AE is any untoward medical occurrence in a participant/clinical investigation participant administered a pharmaceutical product and which does not necessarily have a causal relationship with treatment. A TEAE is any new AE or worsening of an existing condition after initiation of study drug.
Number of Participants With Any Concomitant Medication Usage	From first dose of study drug up to Week 26	Concomitant medications are defined as medications that started on or after the first day of study treatment or were started prior to study treatment but were ongoing on the first day of study treatment.
Percentage of Participants With At Least One TEAEs and Serious Adverse Events (SAEs)	From first dose through 28 days after last dose of study drug (up to approximately 30 weeks)	An adverse event (AE) is any untoward medical occurrence in a participant/clinical investigation participant administered a pharmaceutical product and which does not necessarily have a causal relationship with treatment. A TEAE is any new AE or worsening of an existing condition after initiation of study drug. An SAE is an AE that resulted in death, inpatient hospitalization/prolongation of existing hospitalization, persistent or significant disability or incapacity, life-threatening, a congenital anomaly/birth defect, or an important medical event.
Number of Participants With Clinical Significant Abnormality in Coagulation (PT and aPTT) Reported as TEAE	From first dose through 28 days after last dose of study drug (up to approximately 30 weeks)	Participants with clinically significant abnormal coagulation (prothrombin time (PT) \>17.5 seconds and activated partial thromboplastin time (aPTT) \>45 seconds) were reported.
Number of Participants With Clinical Significant Abnormality in Cortisol	From first dose of study drug up to Week 26	Participants with clinically significant cortisol \>=26 micrograms/decilitre (ug/dL) were reported.

Secondary

Measure	Time frame	Description
Percentage of Reverters Using Solid Culture Medium	Week 26	The total percentage of reverters was defined as the percentage of participants in the analysis dataset with SCC at baseline and at least one positive post-baseline result. Efficacy was assessed by the solid culture medium (ie, sputum culture conversion).
Percentage of Sustained Converters Using the MGIT Culture System	Week 26	The total percentage of sustained converters was defined as the percentage of participants in the analysis dataset who had SCC at baseline and non-positive sputum culture results for all post-baseline visits. Efficacy was assessed by the MGIT sputum culture system (ie, sputum culture conversion)
Percentage of Participants Who Developed Resistance to Delamanid While on Treatment	Up to Week 26	Resistance was defined as mycobacterium tuberculosis (MTB) growth on the delamanid-containing medium of greater than 1% of that on the drug-free medium. The overall resistance to delamanid during the study was assessed.
Percentage of Treatment Responders Using the Mycobacterial Growth Indicator Tube (MGIT) Culture System	Week 26	Treatment Responder was defined as a participant classified as sustained converter or a new converter. Sustained Converter was defined as a participant with sputum culture conversion (SCC) at baseline and without any positive culture result during the 26-week trial period. New converter was defined as a participant without SCC at baseline who subsequently met the definition of SCC. A participant was classified as having achieved SCC if he/she achieved 2 consecutive sputum cultures negative for growth of mycobacterium tuberculosis (MTB) at least 28 days apart after his/her last sputum culture that was positive for growth. The total percentage of treatment responders was calculated as the number of sustained converters plus the number of new converters divided by the total number of participants in the analysis population. Efficacy was assessed by the MGIT sputum culture system (ie, sputum culture conversion).
Percentage of Treatment Responders Using Solid Culture Medium	Week 26	Treatment Responder was defined as a participant classified as sustained converter or a new converter. Sustained Converter was defined as a participant with SCC at baseline and without any positive culture result during the 26-week trial period. New converter was defined as a participant without SCC at baseline who subsequently met the definition of SCC. A participant was classified as having achieved SCC if he/she achieved 2 consecutive sputum cultures negative for growth of MTB at least 28 days apart after his/her last sputum culture that was positive for growth. The total percentage of treatment responders was calculated as the number of sustained converters plus the number of new converters divided by the total number of participants in the analysis population. Efficacy was assessed by the solid culture medium (ie, sputum culture conversion)
Percentage of Treatment Non-responders Using the MGIT Culture System	Week 26	Non-responders were defined as participants classified as non-converter or reverter. Non-converters were defined as participants without SCC at baseline and who did not achieve SCC during the 26-week trial period whereas reverters were participants with SCC at baseline and at least one positive post-baseline result. The total percentage of treatment non-responders was calculated as the number of reverters plus the number of non-converters divided by the total number of participants in the analysis population. Efficacy was assessed by the MGIT sputum culture system (ie, sputum culture conversion)
Percentage of Treatment Non-responders Using Solid Culture Medium	Week 26	Non-responders were defined as participants classified as non-converter or reverter. Non-converters were defined as participants without SCC at baseline and who did not achieve SCC during the 26-week trial period whereas reverters were participants with SCC at baseline and at least one positive post-baseline result. Treatment Non-responders was calculated as the number of reverters plus the number of non-converters divided by the total number of participants in the analysis population. Efficacy was assessed by the Solid culture medium (ie, sputum culture conversion).
Percentage of Sustained Converters Using Solid Culture Medium	Week 26	The total percentage of sustained converters was defined as percentage of participants in the analysis dataset who had SCC at baseline and non-positive sputum culture results for all post-baseline visits. Determined by Solid culture medium. Efficacy was assessed by the solid culture medium (ie, sputum culture conversion)
Percentage of New Converters Using the MGIT Culture System	Week 26	The total percentage of new converters was defined as the percentage of participants in the analysis dataset without SCC at baseline who achieved SCC during the 26-week trial period. Efficacy was assessed by the MGIT sputum culture system (ie, sputum culture conversion).
Percentage of New Converters Using Solid Culture Medium	Week 26	The total percentage of new converters was defined as the percentage of participants in the analysis dataset without SCC at baseline who achieved SCC during the 26-week trial period. Efficacy was assessed by the solid culture medium (ie, sputum culture conversion).
Percentage of Non-converters Using the MGIT Culture System	Week 26	The total percentage of non-converters was defined as the percentage of participants in the analysis dataset without SCC at baseline and who did not achieve SCC during the 26-week trial period. Efficacy was assessed by the MGIT sputum culture system (ie, sputum culture conversion).
Percentage of Non-converters Using Solid Culture Medium	Week 26	The total percentage of non-converters was defined as the percentage of participants in the analysis dataset without SCC at baseline and who did not achieve SCC during the 26-week trial period. Efficacy was assessed by the solid culture medium (ie, sputum culture conversion).
Percentage of Reverters Using the MGIT Culture System	Week 26	The total percentage of reverters was defined as the percentage of participants in the analysis dataset with SCC at baseline and at least one positive post-baseline result. Efficacy was assessed by the MGIT sputum culture system (ie, sputum culture conversion).

Countries

China, Estonia, Latvia, Peru, Philippines, South Korea

Participant flow

Recruitment details

Participants took part in the study at 14 investigative sites in the Philippines, Latvia, Estonia, South Korea, Peru, China, and Japan from 26 March 2009 to 27 October 2011.

Pre-assignment details

The study consisted of a Pre-treatment, Treatment, and Follow-up Period. The Pre-treatment Period consisted of a screening and baseline visit. This was followed by a 26-week Treatment Period. There was also a Follow-up Period (28 to 32 days) for the collection of Adverse events (AEs).

Participants by arm

Arm	Count
Delamanid 100 mg BID + OBR Participants received Delamanid 100 mg (2x50 mg tablets), orally, BID along with at least 4 additional anti-TB medications per OBR from Week 0 to Week 26. Participants were administered OBR as directed by the given investigator based on WHO guidelines and clinical judgment.	137
Delamanid 200 mg BID + OBR Participants received Delamanid 200 mg (4x50 mg tablets), orally, BID along with at least 4 additional anti-TB medications per OBR up to Week 26. Participants were administered OBR as directed by the given investigator based on WHO guidelines and clinical judgment. A participant might have been titrated to Delamanid 200 mg BID after an initial hospitalization of 2 weeks. Participants were grouped according to the longest duration of Delamanid dose administered during the study.	76
Total	213

Withdrawals & dropouts

Period	Reason	FG000	FG001
Overall Study	Adverse Event	3	4
Overall Study	Lost to Follow-up	2	1
Overall Study	Protocol Deviation	1	1
Overall Study	Subject met Withdrawal Criteria	1	1
Overall Study	Subject was Withdrawn from Participation by the Investigator	3	1
Overall Study	Subject withdrew consent to participate	6	1

Baseline characteristics

Characteristic	Delamanid 200 mg BID + OBR	Total	Delamanid 100 mg BID + OBR
Age, Continuous	37.1 years STANDARD_DEVIATION 10.98	36.9 years STANDARD_DEVIATION 11.86	36.8 years STANDARD_DEVIATION 12.36
Ethnicity (NIH/OMB) Hispanic or Latino	17 Participants	39 Participants	22 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	59 Participants	174 Participants	115 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	0 Participants	0 Participants	0 Participants
Race/Ethnicity, Customized Race Asian	24 Participants	124 Participants	100 Participants
Race/Ethnicity, Customized Race Other	18 Participants	39 Participants	21 Participants
Race/Ethnicity, Customized Race White	34 Participants	50 Participants	16 Participants
Sex: Female, Male Female	21 Participants	62 Participants	41 Participants
Sex: Female, Male Male	55 Participants	151 Participants	96 Participants

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk
deaths Total, all-cause mortality	1 / 137	0 / 76
other Total, other adverse events	126 / 137	73 / 76
serious Total, serious adverse events	19 / 137	6 / 76

Outcome results

Primary

Number of Participants With Abnormality in Audiometry at Baseline

Audiometry assessments were done at Baseline.

Time frame: Baseline

Population: Safety Population included all participants treated with at least one dose of Delamanid in this study.

Arm	Measure	Value (COUNT_OF_PARTICIPANTS)
Delamanid 100 mg BID + OBR	Number of Participants With Abnormality in Audiometry at Baseline	90 Participants
Delamanid 200 mg BID + OBR	Number of Participants With Abnormality in Audiometry at Baseline	34 Participants

Primary

Number of Participants With Abnormality in Neurological and Psychiatric Assessment Reported as Treatment-emergent Adverse Event (TEAE)

Participants with abnormal neurological and psychiatric assessments were reported. An adverse event (AE) is any untoward medical occurrence in a participant/clinical investigation participant administered a pharmaceutical product and which does not necessarily have a causal relationship with treatment. A TEAE is any new AE or worsening of an existing condition after initiation of study drug.

Time frame: From first dose through 28 days after last dose of study drug (up to approximately 30 weeks)

Population: Safety Population included all participants treated with at least one dose of Delamanid in this study.

Arm	Measure	Group	Value (COUNT_OF_PARTICIPANTS)
Delamanid 100 mg BID + OBR	Number of Participants With Abnormality in Neurological and Psychiatric Assessment Reported as Treatment-emergent Adverse Event (TEAE)	Neurological Disorders	63 Participants
Delamanid 100 mg BID + OBR	Number of Participants With Abnormality in Neurological and Psychiatric Assessment Reported as Treatment-emergent Adverse Event (TEAE)	Psychiatric Disorders	44 Participants
Delamanid 200 mg BID + OBR	Number of Participants With Abnormality in Neurological and Psychiatric Assessment Reported as Treatment-emergent Adverse Event (TEAE)	Neurological Disorders	25 Participants
Delamanid 200 mg BID + OBR	Number of Participants With Abnormality in Neurological and Psychiatric Assessment Reported as Treatment-emergent Adverse Event (TEAE)	Psychiatric Disorders	38 Participants

Primary

Number of Participants With Abnormality in Visual Acuity

Time frame: From first dose of study drug up to Week 26

Population: Safety Population included all participants treated with at least one dose of Delamanid in this study.

Arm	Measure	Value (COUNT_OF_PARTICIPANTS)
Delamanid 100 mg BID + OBR	Number of Participants With Abnormality in Visual Acuity	45 Participants
Delamanid 200 mg BID + OBR	Number of Participants With Abnormality in Visual Acuity	35 Participants

Primary

Number of Participants With Any Concomitant Medication Usage

Concomitant medications are defined as medications that started on or after the first day of study treatment or were started prior to study treatment but were ongoing on the first day of study treatment.

Time frame: From first dose of study drug up to Week 26

Population: Safety Population included all participants treated with at least one dose of Delamanid in this study.

Arm	Measure	Value (COUNT_OF_PARTICIPANTS)
Delamanid 100 mg BID + OBR	Number of Participants With Any Concomitant Medication Usage	135 Participants
Delamanid 200 mg BID + OBR	Number of Participants With Any Concomitant Medication Usage	75 Participants

Primary

Number of Participants With Clinically Significant Abnormalities in Electrocardiogram (ECG) Values

The criteria for clinically significant abnormal ECG values were ventricular rate outlier (\<50 bpm and decrease of \>=25%, \>100 bpm and increase of \>=25%), PR outlier (increase of \>=25% when PR \>200 milliseconds (ms)), QRS outlier (increase of \>=25% when QRS \>100 ms), QT (new onset (in treatment period but not at Baseline) \[\>500 ms\]), QT interval corrected by Bazett's formula (QTcB) (new onset \[\>450, \>480, \>500 ms\], increase of \>=30 ms and \<= 60 ms or increase of \>60 ms), QT interval corrected by Fridericia's formula (QTcF) (new onset \[\>450, \>480, \>500 ms\], increase of \>=30 ms and \<= 60 ms or increase of \>60 ms), new abnormal U waves, new ST segment changes, new T wave changes, new abnormal rhythm, new conduction abnormality were reported as categories. Only categories with data are reported.

Time frame: From first dose of study drug up to Week 26

Population: Safety Population included all participants treated with at least one dose of Delamanid in this study.

Arm	Measure	Group	Value (COUNT_OF_PARTICIPANTS)
Delamanid 100 mg BID + OBR	Number of Participants With Clinically Significant Abnormalities in Electrocardiogram (ECG) Values	QTcF Interval, New Onset (>500 msec)	1 Participants
Delamanid 100 mg BID + OBR	Number of Participants With Clinically Significant Abnormalities in Electrocardiogram (ECG) Values	QTcF Interval, Increase from Baseline >=30 msec and <=60 msec	36 Participants
Delamanid 100 mg BID + OBR	Number of Participants With Clinically Significant Abnormalities in Electrocardiogram (ECG) Values	QTcB Interval, New Onset (>500 msec)	2 Participants
Delamanid 100 mg BID + OBR	Number of Participants With Clinically Significant Abnormalities in Electrocardiogram (ECG) Values	QTcF Interval, Increase from Baseline >60 msec	4 Participants
Delamanid 100 mg BID + OBR	Number of Participants With Clinically Significant Abnormalities in Electrocardiogram (ECG) Values	QTcB Interval, New Onset (>450 msec)	62 Participants
Delamanid 100 mg BID + OBR	Number of Participants With Clinically Significant Abnormalities in Electrocardiogram (ECG) Values	Ventricular Rate Notable Changes, <50 bpm and Decrease from Baseline of >=25%	1 Participants
Delamanid 100 mg BID + OBR	Number of Participants With Clinically Significant Abnormalities in Electrocardiogram (ECG) Values	QTcB Interval, Increase from Baseline >=30 msec and <=60 msec	58 Participants
Delamanid 100 mg BID + OBR	Number of Participants With Clinically Significant Abnormalities in Electrocardiogram (ECG) Values	Ventricular Rate Notable Changes, >100 bpm and Increase from Baseline of >=25%	16 Participants
Delamanid 100 mg BID + OBR	Number of Participants With Clinically Significant Abnormalities in Electrocardiogram (ECG) Values	QTcB Interval, Increase from Baseline >60 msec	5 Participants
Delamanid 100 mg BID + OBR	Number of Participants With Clinically Significant Abnormalities in Electrocardiogram (ECG) Values	New Abnormal U Waves	4 Participants
Delamanid 100 mg BID + OBR	Number of Participants With Clinically Significant Abnormalities in Electrocardiogram (ECG) Values	QT Interval, New Onset (>500 msec)	1 Participants
Delamanid 100 mg BID + OBR	Number of Participants With Clinically Significant Abnormalities in Electrocardiogram (ECG) Values	New ST Segment Changes	11 Participants
Delamanid 100 mg BID + OBR	Number of Participants With Clinically Significant Abnormalities in Electrocardiogram (ECG) Values	QTcF Interval, New Onset (>450 msec)	23 Participants
Delamanid 100 mg BID + OBR	Number of Participants With Clinically Significant Abnormalities in Electrocardiogram (ECG) Values	New T Waves Changes	27 Participants
Delamanid 100 mg BID + OBR	Number of Participants With Clinically Significant Abnormalities in Electrocardiogram (ECG) Values	QTcB Interval, New Onset (>480 msec)	11 Participants
Delamanid 100 mg BID + OBR	Number of Participants With Clinically Significant Abnormalities in Electrocardiogram (ECG) Values	New Abnormal Rhythm	44 Participants
Delamanid 100 mg BID + OBR	Number of Participants With Clinically Significant Abnormalities in Electrocardiogram (ECG) Values	QTcF Interval, New Onset (>480 msec)	3 Participants
Delamanid 100 mg BID + OBR	Number of Participants With Clinically Significant Abnormalities in Electrocardiogram (ECG) Values	New Conduction	10 Participants
Delamanid 100 mg BID + OBR	Number of Participants With Clinically Significant Abnormalities in Electrocardiogram (ECG) Values	QRS Outlier	2 Participants
Delamanid 200 mg BID + OBR	Number of Participants With Clinically Significant Abnormalities in Electrocardiogram (ECG) Values	New Conduction	4 Participants
Delamanid 200 mg BID + OBR	Number of Participants With Clinically Significant Abnormalities in Electrocardiogram (ECG) Values	QTcF Interval, New Onset (>500 msec)	1 Participants
Delamanid 200 mg BID + OBR	Number of Participants With Clinically Significant Abnormalities in Electrocardiogram (ECG) Values	QRS Outlier	0 Participants
Delamanid 200 mg BID + OBR	Number of Participants With Clinically Significant Abnormalities in Electrocardiogram (ECG) Values	QT Interval, New Onset (>500 msec)	0 Participants
Delamanid 200 mg BID + OBR	Number of Participants With Clinically Significant Abnormalities in Electrocardiogram (ECG) Values	QTcB Interval, New Onset (>450 msec)	37 Participants
Delamanid 200 mg BID + OBR	Number of Participants With Clinically Significant Abnormalities in Electrocardiogram (ECG) Values	QTcB Interval, New Onset (>480 msec)	7 Participants
Delamanid 200 mg BID + OBR	Number of Participants With Clinically Significant Abnormalities in Electrocardiogram (ECG) Values	QTcB Interval, New Onset (>500 msec)	3 Participants
Delamanid 200 mg BID + OBR	Number of Participants With Clinically Significant Abnormalities in Electrocardiogram (ECG) Values	QTcB Interval, Increase from Baseline >60 msec	7 Participants
Delamanid 200 mg BID + OBR	Number of Participants With Clinically Significant Abnormalities in Electrocardiogram (ECG) Values	QTcF Interval, New Onset (>450 msec)	10 Participants
Delamanid 200 mg BID + OBR	Number of Participants With Clinically Significant Abnormalities in Electrocardiogram (ECG) Values	QTcF Interval, New Onset (>480 msec)	1 Participants
Delamanid 200 mg BID + OBR	Number of Participants With Clinically Significant Abnormalities in Electrocardiogram (ECG) Values	QTcF Interval, Increase from Baseline >=30 msec and <=60 msec	30 Participants
Delamanid 200 mg BID + OBR	Number of Participants With Clinically Significant Abnormalities in Electrocardiogram (ECG) Values	QTcF Interval, Increase from Baseline >60 msec	4 Participants
Delamanid 200 mg BID + OBR	Number of Participants With Clinically Significant Abnormalities in Electrocardiogram (ECG) Values	Ventricular Rate Notable Changes, <50 bpm and Decrease from Baseline of >=25%	2 Participants
Delamanid 200 mg BID + OBR	Number of Participants With Clinically Significant Abnormalities in Electrocardiogram (ECG) Values	Ventricular Rate Notable Changes, >100 bpm and Increase from Baseline of >=25%	8 Participants
Delamanid 200 mg BID + OBR	Number of Participants With Clinically Significant Abnormalities in Electrocardiogram (ECG) Values	New Abnormal U Waves	0 Participants
Delamanid 200 mg BID + OBR	Number of Participants With Clinically Significant Abnormalities in Electrocardiogram (ECG) Values	New ST Segment Changes	2 Participants
Delamanid 200 mg BID + OBR	Number of Participants With Clinically Significant Abnormalities in Electrocardiogram (ECG) Values	New T Waves Changes	14 Participants
Delamanid 200 mg BID + OBR	Number of Participants With Clinically Significant Abnormalities in Electrocardiogram (ECG) Values	New Abnormal Rhythm	22 Participants
Delamanid 200 mg BID + OBR	Number of Participants With Clinically Significant Abnormalities in Electrocardiogram (ECG) Values	QTcB Interval, Increase from Baseline >=30 msec and <=60 msec	39 Participants

Primary

Number of Participants With Clinically Significant Abnormality in Vital Signs

Vital signs included weight (kg), body temperature (degree Celsius), heart rate \[beats/minute (bpm)\], systolic and diastolic blood pressure \[millimetre of mercury (mm Hg)\]. The criteria for clinically significant abnormal value for: weight was decrease or increase of \>=5% in body weight, heart rate was \<=60 bpm and decrease of \>=15 bpm; \>=120 bpm and Increase of \>=15 bpm, systolic blood pressure (SBP) \<=90 mm Hg and decrease of \>=20 mm Hg; diastolic blood pressure (DBP) \<=50 mm Hg and decrease of \>=15 mm Hg, all vital signs relative to Baseline. Baseline is Study 204 completion visit (Day 84) for participants who complete the baseline visit within 7 days of completing Study 204. Only categories with data for potentially clinically significant abnormal vital sign parameter values are reported.

Time frame: From first dose of study drug up to Week 26

Population: Safety Population included all participants treated with at least one dose of Delamanid in this study. Number analyzed is the number of participants with data available for analyses at the given time point.

Arm	Measure	Group	Value (COUNT_OF_PARTICIPANTS)
Delamanid 100 mg BID + OBR	Number of Participants With Clinically Significant Abnormality in Vital Signs	Weight Decrease of >=5%	23 Participants
Delamanid 100 mg BID + OBR	Number of Participants With Clinically Significant Abnormality in Vital Signs	Heart Rate: <=60 bpm and Decrease of >=15 bpm	10 Participants
Delamanid 100 mg BID + OBR	Number of Participants With Clinically Significant Abnormality in Vital Signs	Weight Increase of >=5%	34 Participants
Delamanid 100 mg BID + OBR	Number of Participants With Clinically Significant Abnormality in Vital Signs	Heart Rate: >=120 bpm and Increase of >=15 bpm	1 Participants
Delamanid 100 mg BID + OBR	Number of Participants With Clinically Significant Abnormality in Vital Signs	SBP: <=90 mm Hg and Decrease of >=20 mm Hg	16 Participants
Delamanid 100 mg BID + OBR	Number of Participants With Clinically Significant Abnormality in Vital Signs	SBP: >=160 mm Hg and Increase of >=20 mm Hg	3 Participants
Delamanid 100 mg BID + OBR	Number of Participants With Clinically Significant Abnormality in Vital Signs	DBP: <=50 mm Hg and Decrease of >=15 mm Hg	1 Participants
Delamanid 200 mg BID + OBR	Number of Participants With Clinically Significant Abnormality in Vital Signs	DBP: <=50 mm Hg and Decrease of >=15 mm Hg	2 Participants
Delamanid 200 mg BID + OBR	Number of Participants With Clinically Significant Abnormality in Vital Signs	Heart Rate: >=120 bpm and Increase of >=15 bpm	0 Participants
Delamanid 200 mg BID + OBR	Number of Participants With Clinically Significant Abnormality in Vital Signs	SBP: <=90 mm Hg and Decrease of >=20 mm Hg	2 Participants
Delamanid 200 mg BID + OBR	Number of Participants With Clinically Significant Abnormality in Vital Signs	Weight Decrease of >=5%	11 Participants
Delamanid 200 mg BID + OBR	Number of Participants With Clinically Significant Abnormality in Vital Signs	SBP: >=160 mm Hg and Increase of >=20 mm Hg	0 Participants
Delamanid 200 mg BID + OBR	Number of Participants With Clinically Significant Abnormality in Vital Signs	Weight Increase of >=5%	25 Participants
Delamanid 200 mg BID + OBR	Number of Participants With Clinically Significant Abnormality in Vital Signs	Heart Rate: <=60 bpm and Decrease of >=15 bpm	11 Participants

Primary

Number of Participants With Clinical Significant Abnormality in Coagulation (PT and aPTT) Reported as TEAE

Participants with clinically significant abnormal coagulation (prothrombin time (PT) \>17.5 seconds and activated partial thromboplastin time (aPTT) \>45 seconds) were reported.

Time frame: From first dose through 28 days after last dose of study drug (up to approximately 30 weeks)

Population: Safety Population included all participants treated with at least one dose of Delamanid in this study. Number analyzed is the number of participants with at least one post-baseline result for the given test.

Arm	Measure	Group	Value (COUNT_OF_PARTICIPANTS)
Delamanid 100 mg BID + OBR	Number of Participants With Clinical Significant Abnormality in Coagulation (PT and aPTT) Reported as TEAE	Prothrombin Time	2 Participants
Delamanid 100 mg BID + OBR	Number of Participants With Clinical Significant Abnormality in Coagulation (PT and aPTT) Reported as TEAE	Activated Partial Thromboplastin Time	12 Participants
Delamanid 200 mg BID + OBR	Number of Participants With Clinical Significant Abnormality in Coagulation (PT and aPTT) Reported as TEAE	Activated Partial Thromboplastin Time	8 Participants
Delamanid 200 mg BID + OBR	Number of Participants With Clinical Significant Abnormality in Coagulation (PT and aPTT) Reported as TEAE	Prothrombin Time	1 Participants

Primary

Number of Participants With Clinical Significant Abnormality in Cortisol

Participants with clinically significant cortisol \>=26 micrograms/decilitre (ug/dL) were reported.

Time frame: From first dose of study drug up to Week 26

Population: Safety Population included all participants treated with at least one dose of Delamanid in this study. Overall number of participants analyzed is the number of participants with at least one post-baseline result for the given test.

Arm	Measure	Value (COUNT_OF_PARTICIPANTS)
Delamanid 100 mg BID + OBR	Number of Participants With Clinical Significant Abnormality in Cortisol	44 Participants
Delamanid 200 mg BID + OBR	Number of Participants With Clinical Significant Abnormality in Cortisol	19 Participants

Primary

Number of Participants With Clinical Significant Abnormality in Laboratory Test

Laboratory assessments included parameters for serum chemistry (alkaline phosphatase, alanine aminotransferase, alanine transaminase, total bilirubin, cholesterol, gamma-glutamyl transferase, glucose, lactic dehydrogenase, potassium, sodium, triglycerides, uric acid), hematology (white blood cell count eosinophils, absolute, hematocrit, hemoglobin, lymphocytes, absolute, mean corpuscular volume, neutrophil, bands, neutrophils, neutrophils, absolute, platelet count, red blood cell (RBC) count, reticulocyte count) and urinalysis (blood, epithelial cast, granular cast, hyaline cast, RBCs per high power field (RBC/HPF)). The participants were categorized based on the clinically significant laboratory values as per predefined criteria. The categories with at least one participant with clinically significant value outside the normal range for laboratory assessments are reported.

Time frame: From first dose of study drug up to Week 26

Arm	Measure	Group	Value (COUNT_OF_PARTICIPANTS)
Delamanid 100 mg BID + OBR	Number of Participants With Clinical Significant Abnormality in Laboratory Test	Glucose	5 Participants
Delamanid 100 mg BID + OBR	Number of Participants With Clinical Significant Abnormality in Laboratory Test	Lymphocytes, Absolute	0 Participants
Delamanid 100 mg BID + OBR	Number of Participants With Clinical Significant Abnormality in Laboratory Test	Alkaline Phosphatase	0 Participants
Delamanid 100 mg BID + OBR	Number of Participants With Clinical Significant Abnormality in Laboratory Test	Mean Corpuscular Volume	20 Participants
Delamanid 100 mg BID + OBR	Number of Participants With Clinical Significant Abnormality in Laboratory Test	Lactic Dehydrogenase	22 Participants
Delamanid 100 mg BID + OBR	Number of Participants With Clinical Significant Abnormality in Laboratory Test	Neutrophil, Bands	0 Participants
Delamanid 100 mg BID + OBR	Number of Participants With Clinical Significant Abnormality in Laboratory Test	Total Bilirubin	7 Participants
Delamanid 100 mg BID + OBR	Number of Participants With Clinical Significant Abnormality in Laboratory Test	Neutrophils	6 Participants
Delamanid 100 mg BID + OBR	Number of Participants With Clinical Significant Abnormality in Laboratory Test	Potassium	13 Participants
Delamanid 100 mg BID + OBR	Number of Participants With Clinical Significant Abnormality in Laboratory Test	Neutrophils, Absolute	17 Participants
Delamanid 100 mg BID + OBR	Number of Participants With Clinical Significant Abnormality in Laboratory Test	Alanine Aminotransferase (SGPT)	2 Participants
Delamanid 100 mg BID + OBR	Number of Participants With Clinical Significant Abnormality in Laboratory Test	Platelet Count	5 Participants
Delamanid 100 mg BID + OBR	Number of Participants With Clinical Significant Abnormality in Laboratory Test	Sodium	16 Participants
Delamanid 100 mg BID + OBR	Number of Participants With Clinical Significant Abnormality in Laboratory Test	Red Blood Cell Count	15 Participants
Delamanid 100 mg BID + OBR	Number of Participants With Clinical Significant Abnormality in Laboratory Test	Cholesterol	1 Participants
Delamanid 100 mg BID + OBR	Number of Participants With Clinical Significant Abnormality in Laboratory Test	Reticulocyte Count	9 Participants
Delamanid 100 mg BID + OBR	Number of Participants With Clinical Significant Abnormality in Laboratory Test	Triglycerides	9 Participants
Delamanid 100 mg BID + OBR	Number of Participants With Clinical Significant Abnormality in Laboratory Test	White Blood Count	6 Participants
Delamanid 100 mg BID + OBR	Number of Participants With Clinical Significant Abnormality in Laboratory Test	Aspartate Aminotransferase (SGOT)	2 Participants
Delamanid 100 mg BID + OBR	Number of Participants With Clinical Significant Abnormality in Laboratory Test	Blood Urine Present	41 Participants
Delamanid 100 mg BID + OBR	Number of Participants With Clinical Significant Abnormality in Laboratory Test	Uric Acid	9 Participants
Delamanid 100 mg BID + OBR	Number of Participants With Clinical Significant Abnormality in Laboratory Test	Epithelial Cast in Urine	1 Participants
Delamanid 100 mg BID + OBR	Number of Participants With Clinical Significant Abnormality in Laboratory Test	Hemoglobin	61 Participants
Delamanid 100 mg BID + OBR	Number of Participants With Clinical Significant Abnormality in Laboratory Test	Granular Cast in Urine	9 Participants
Delamanid 100 mg BID + OBR	Number of Participants With Clinical Significant Abnormality in Laboratory Test	GAMMA-Glutamyl Transferase	2 Participants
Delamanid 100 mg BID + OBR	Number of Participants With Clinical Significant Abnormality in Laboratory Test	Hyaline Cast in Urine	6 Participants
Delamanid 100 mg BID + OBR	Number of Participants With Clinical Significant Abnormality in Laboratory Test	Hematocrit	2 Participants
Delamanid 100 mg BID + OBR	Number of Participants With Clinical Significant Abnormality in Laboratory Test	RBC/HPF in Urine	13 Participants
Delamanid 100 mg BID + OBR	Number of Participants With Clinical Significant Abnormality in Laboratory Test	Eosinophils, Absolute	10 Participants
Delamanid 200 mg BID + OBR	Number of Participants With Clinical Significant Abnormality in Laboratory Test	RBC/HPF in Urine	5 Participants
Delamanid 200 mg BID + OBR	Number of Participants With Clinical Significant Abnormality in Laboratory Test	Total Bilirubin	4 Participants
Delamanid 200 mg BID + OBR	Number of Participants With Clinical Significant Abnormality in Laboratory Test	Alkaline Phosphatase	1 Participants
Delamanid 200 mg BID + OBR	Number of Participants With Clinical Significant Abnormality in Laboratory Test	Alanine Aminotransferase (SGPT)	1 Participants
Delamanid 200 mg BID + OBR	Number of Participants With Clinical Significant Abnormality in Laboratory Test	Cholesterol	2 Participants
Delamanid 200 mg BID + OBR	Number of Participants With Clinical Significant Abnormality in Laboratory Test	GAMMA-Glutamyl Transferase	2 Participants
Delamanid 200 mg BID + OBR	Number of Participants With Clinical Significant Abnormality in Laboratory Test	Glucose	3 Participants
Delamanid 200 mg BID + OBR	Number of Participants With Clinical Significant Abnormality in Laboratory Test	Lactic Dehydrogenase	5 Participants
Delamanid 200 mg BID + OBR	Number of Participants With Clinical Significant Abnormality in Laboratory Test	Potassium	10 Participants
Delamanid 200 mg BID + OBR	Number of Participants With Clinical Significant Abnormality in Laboratory Test	Sodium	16 Participants
Delamanid 200 mg BID + OBR	Number of Participants With Clinical Significant Abnormality in Laboratory Test	Triglycerides	3 Participants
Delamanid 200 mg BID + OBR	Number of Participants With Clinical Significant Abnormality in Laboratory Test	Uric Acid	8 Participants
Delamanid 200 mg BID + OBR	Number of Participants With Clinical Significant Abnormality in Laboratory Test	Eosinophils, Absolute	3 Participants
Delamanid 200 mg BID + OBR	Number of Participants With Clinical Significant Abnormality in Laboratory Test	Hematocrit	4 Participants
Delamanid 200 mg BID + OBR	Number of Participants With Clinical Significant Abnormality in Laboratory Test	Hemoglobin	24 Participants
Delamanid 200 mg BID + OBR	Number of Participants With Clinical Significant Abnormality in Laboratory Test	Lymphocytes, Absolute	1 Participants
Delamanid 200 mg BID + OBR	Number of Participants With Clinical Significant Abnormality in Laboratory Test	Mean Corpuscular Volume	13 Participants
Delamanid 200 mg BID + OBR	Number of Participants With Clinical Significant Abnormality in Laboratory Test	Neutrophil, Bands	1 Participants
Delamanid 200 mg BID + OBR	Number of Participants With Clinical Significant Abnormality in Laboratory Test	Neutrophils	2 Participants
Delamanid 200 mg BID + OBR	Number of Participants With Clinical Significant Abnormality in Laboratory Test	Neutrophils, Absolute	10 Participants
Delamanid 200 mg BID + OBR	Number of Participants With Clinical Significant Abnormality in Laboratory Test	Platelet Count	3 Participants
Delamanid 200 mg BID + OBR	Number of Participants With Clinical Significant Abnormality in Laboratory Test	Red Blood Cell Count	14 Participants
Delamanid 200 mg BID + OBR	Number of Participants With Clinical Significant Abnormality in Laboratory Test	Reticulocyte Count	5 Participants
Delamanid 200 mg BID + OBR	Number of Participants With Clinical Significant Abnormality in Laboratory Test	White Blood Count	3 Participants
Delamanid 200 mg BID + OBR	Number of Participants With Clinical Significant Abnormality in Laboratory Test	Blood Urine Present	29 Participants
Delamanid 200 mg BID + OBR	Number of Participants With Clinical Significant Abnormality in Laboratory Test	Epithelial Cast in Urine	1 Participants
Delamanid 200 mg BID + OBR	Number of Participants With Clinical Significant Abnormality in Laboratory Test	Granular Cast in Urine	3 Participants
Delamanid 200 mg BID + OBR	Number of Participants With Clinical Significant Abnormality in Laboratory Test	Hyaline Cast in Urine	6 Participants
Delamanid 200 mg BID + OBR	Number of Participants With Clinical Significant Abnormality in Laboratory Test	Aspartate Aminotransferase (SGOT)	1 Participants

Primary

Number of Participants With Clinical Significant Abnormality in Thyroid Function Test Reported as TEAE

Participants with abnormal thyroid free T4 nanograms per deciliter (ng/dL) and thyroid-stimulating hormone (\>=3 OR \<=0.3 micro-international units per litre (uIU/mL). An AE is any untoward medical occurrence in a participant/clinical investigation participant administered a pharmaceutical product and which does not necessarily have a causal relationship with treatment. A TEAE is any new AE or worsening of an existing condition after initiation of study drug.

Time frame: From first dose through 28 days after last dose of study drug (up to approximately 30 weeks)

Population: Safety Population included all participants treated with at least one dose of Delamanid in this study.

Arm	Measure	Value (COUNT_OF_PARTICIPANTS)
Delamanid 100 mg BID + OBR	Number of Participants With Clinical Significant Abnormality in Thyroid Function Test Reported as TEAE	0 Participants
Delamanid 200 mg BID + OBR	Number of Participants With Clinical Significant Abnormality in Thyroid Function Test Reported as TEAE	1 Participants

Primary

Percentage of Participants With At Least One TEAEs and Serious Adverse Events (SAEs)

An adverse event (AE) is any untoward medical occurrence in a participant/clinical investigation participant administered a pharmaceutical product and which does not necessarily have a causal relationship with treatment. A TEAE is any new AE or worsening of an existing condition after initiation of study drug. An SAE is an AE that resulted in death, inpatient hospitalization/prolongation of existing hospitalization, persistent or significant disability or incapacity, life-threatening, a congenital anomaly/birth defect, or an important medical event.

Time frame: From first dose through 28 days after last dose of study drug (up to approximately 30 weeks)

Population: Safety Population included all participants treated with at least one dose of Delamanid in this study.

Arm	Measure	Group	Value (NUMBER)
Delamanid 100 mg BID + OBR	Percentage of Participants With At Least One TEAEs and Serious Adverse Events (SAEs)	TEAEs	92.0 percentage of participants
Delamanid 100 mg BID + OBR	Percentage of Participants With At Least One TEAEs and Serious Adverse Events (SAEs)	SAEs	13.9 percentage of participants
Delamanid 200 mg BID + OBR	Percentage of Participants With At Least One TEAEs and Serious Adverse Events (SAEs)	TEAEs	97.4 percentage of participants
Delamanid 200 mg BID + OBR	Percentage of Participants With At Least One TEAEs and Serious Adverse Events (SAEs)	SAEs	7.9 percentage of participants

Secondary

Percentage of New Converters Using Solid Culture Medium

The total percentage of new converters was defined as the percentage of participants in the analysis dataset without SCC at baseline who achieved SCC during the 26-week trial period. Efficacy was assessed by the solid culture medium (ie, sputum culture conversion).

Time frame: Week 26