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

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

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).

Study Overview

• Status: Completed
• Conditions: Tuberculosis, Pulmonary; Extensively Drug-Resistant Tuberculosis; Tuberculosis, Multidrug Resistant
• Intervention / Treatment: Drug: Delamanid; Drug: Optimized Background Regimen (OBR); Drug: Placebo

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 Type: Interventional
• Enrollment (Actual): 481
• Phase: Phase 2

Contacts and Locations

Study Locations

• China
  • Beijing, China, 101149
    • Beijing Chest Hospital
  • Shanghai, China, 200433
    • Shanghai Pulmonary Hospital
• Egypt
  • Cairo, Egypt
    • Abbassia Chest Hospital
• Estonia
  • Tallinn, Estonia, 13419
    • North Estonian Medical Centre Foundation
  • Tartu, Estonia, 13419
    • Tartu University Lung Hospital
• Japan
  • Osaka, Japan, 591-8555
    • Kinki Chuo Chest Hospital
  • Tokyo, Japan, 204-8522
    • Fukujuji Hospital
• Korea, Republic of
  • Changwon, Korea, Republic of, 138-736
    • Masan Medical Center
  • Masan, Korea, Republic of, 631-710
    • National Masan Hospital
  • Seoul, Korea, Republic of, 135-710
    • Samsung Medical Center
  • Seoul, Korea, Republic of, 120-752
    • Younsei University Medical Center (YUMC), Severance Hospital
• Latvia
  • Riga, Latvia, LV2118
    • Clinic of Tuberculosis and Lung Diseases
• Peru
  • Carrion, Peru, Callao 2
    • Hospital Nacional Daniel Alcides Carrion
  • Lima, Peru, Lima 41
    • Hospital Nacional Sergio E. Bernales
  • Unanue, Peru, Lima 10
    • Hospital Nacional Hipólito Unanue
• Philippines
  • Manila, Philippines, 1229
    • Tropical Disease Foundation
• United States
  • Texas
    • San Antonio, Texas, United States, 78223
      • University of Texas Health Center at Tyler / Heartland National TB Center / Texas Center for Infectious Disease

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years to 62 years (Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

3

Arms and Interventions

Participant Group / 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

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of Participants Who Achieved Sputum Culture Conversion (SCC) Using the Mycobacteria Growth Indicator Tube (MGIT) System	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.	From the first dose of study drug up to the end of the Post-treatment Follow-up Period (Up to Day 84)
Tmax 1 and 2: Time to Maximal Peak Concentration (Tmax) for Delamanid Following First and Second Daily Dose	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.	Pre-dose, 2, 3, 4, 10 (pre-evening dose), 12, 13, 14 and 24 hours post-dose up to Day 56
Cmax 1 and 2: Maximal Peak Concentration (Cmax) for Delamanid Following First and Second Daily Dose	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.	Pre-dose, 2, 3, 4, 10 (pre-evening dose), 12, 13, 14 and 24 hours post-dose up to Day 56
Area Under the Plasma Concentration Curve From 0 to 24 Hours (AUC0-24h) for Delamanid	Data for AUC0-24h up to Day 56 was collected on Days 1, 14, 28 and 56.	Pre-dose, 2, 3, 4, 10 (pre-evening dose), 12, 13, 14 and 24 hours post-dose up to Day 56
Accumulation Ratio for Cmax (Rac[Cmax]) for Delamanid	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.	Pre-dose, 2, 3, 4, 10 (pre-evening dose), 12, 13, 14 and 24 hours post-dose up to Day 56
Accumulation Ratio for AUC From Time 0 to 24 Hours (Rac[AUC0-24h]) for Delamanid	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.	Pre-dose, 2, 3, 4, 10 (pre-evening dose), 12, 13, 14 and 24 hours post-dose up to Day 56
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	Data for Tmax up to Day 56 was collected on Days 1, 14, 28 and 56.	0 hours (morning pre-dose), 2, 3, 4, 10 (pre-evening dose), 12, 13, 14 and 24 hours post-dose up to Day 56
Maximal Peak Concentration (Cmax) for DM-6704, DM-6705, DM-6706, DM-6717, DM-6718, DM-6720, DM-6721, and DM-6722	Data for Cmax up to Day 56 was collected on Days 1, 14, 28 and 56.	0 hours (morning pre-dose), 2, 3, 4, 10 (pre-evening dose), 12, 13, 14 and 24 hours post-dose up to Day 56
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	Data for AUC0-24h up to Day 56 was collected on Days 1, 14, 28 and 56.	0 hours (morning pre-dose), 2, 3, 4, 10 (pre-evening dose), 12, 13, 14 and 24 hours post-dose up to Day 56
Accumulation Ratio for Cmax (Rac[Cmax]) for DM-6704, DM-6705, DM-6706, DM-6717, DM-6718, DM-6720, DM-6721, and DM-6722	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.	0 hours (morning pre-dose), 2, 3, 4, 10 (pre-evening dose), 12, 13, 14 and 24 hours post-dose up to Day 56
Accumulation Ratio for AUC (Rac[AUC]) for DM-6704, DM-6705, DM-6706, DM-6717, DM-6718, DM-6720, DM-6721, and DM-6722	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.	0 hours (morning pre-dose), 2, 3, 4, 10 (pre-evening dose), 12, 13, 14 and 24 hours post-dose up to Day 56
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

Outcome Measure	Measure Description	Time Frame
Percentage of Participants Who Achieved Sputum Culture Conversion (SCC) Using Solid Culture Media	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.	From the first dose of study drug up to the end of the Post-treatment Follow-up Period (Up to Day 84)
Change From Baseline in Time to Culture Positivity Using the MGIT System	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.	Baseline, Day 84
Area Under the Curve (AUC) of Change From Baseline in Time to Culture Positivity in the MGIT System	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.	Baseline to Day 57
Percentage of Participants With Sputum Culture Negative at Day 57 Using the MGIT System Without Consideration of Subsequent Culture Results		Day 57
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
Percentage of Participants With Sputum Culture Negative at Day 57 Using Solid Culture Media Without Respect to Subsequent Culture Results		Day 57
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
Percentage of Participants Who Achieved SCC From the MGIT System Analyzed by Cochran-Armitage Linear Trend Test for Dose-response Relationship	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).	From the first dose of study drug up to the end of the Post-treatment Follow-up Period (Up to Day 84)
Percentage of Participants Who Achieved Initial SCC Using the MGIT System	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.	Day 57
Percentage of Participants Who Achieved Initial SCC Using the Solid Culture Media	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.	Day 57
Percentage of Participants Who Achieved Final SCC Using MGIT	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.	Day 57
Percentage of Participants Who Achieved Final SCC Using Solid Culture Media	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.	Day 57
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)
Percentage of Participants With Clinically Significant Vital Sign Abnormalities	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.	From first dose of study drug up to post treatment period (Day 84)
Percentage of Participants With Categorical Changes in 12-lead Electrocardiogram Results at 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	Baseline up to Day 56
Percentage of Participants With Clinically Significant Laboratory Test Abnormalities	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.	From first dose of study drug up to post treatment period (Day 84)
Percentage of Participants With Clinically Significant Audiometry Findings		From first dose of study drug up to post treatment period (Day 84)
Percentage of Participants Using Concomitant Medications	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).	From first dose of study drug up to post treatment period (Day 84)
Percentage of Participants With At Least One Treatment-Emergent Adverse Events (TEAEs)	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.	From first dose of study drug up to post treatment period (Day 84)
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
Mean Change From Baseline in QTcF		Baseline, Days 1, 14, 28 and 56
Mean Change From Baseline in QTcB		Baseline, Days 1, 14, 28 and 56
Mean Change From Baseline in Ventricular Rate		Baseline, Days 1, 14, 28 and 56
Mean Change From Baseline in PR Interval		Baseline, Days 1, 14, 28 and 56
Mean Change From Baseline in QRS Interval		Baseline, Days 1, 14, 28 and 56
Mean Change From Baseline in QT Interval		Baseline, Days 1, 14, 28 and 56
Percentage of Participants With Change in ECG Morphological Patterns From Baseline	Any changes in the ECG waves or segments as assessed by the investigator were reported.	Baseline, Days 1, 14, 28 and 56

Collaborators and Investigators

• Sponsor: Otsuka Pharmaceutical Development & Commercialization, Inc.

Publications and helpful links

General Publications

• Gler MT, Skripconoka V, Sanchez-Garavito E, Xiao H, Cabrera-Rivero JL, Vargas-Vasquez DE, Gao M, Awad M, Park SK, Shim TS, Suh GY, Danilovits M, Ogata H, Kurve A, Chang J, Suzuki K, Tupasi T, Koh WJ, Seaworth B, Geiter LJ, Wells CD. Delamanid for multidrug-resistant pulmonary tuberculosis. N Engl J Med. 2012 Jun 7;366(23):2151-60. doi: 10.1056/NEJMoa1112433.

Study record dates

Study Major Dates

• Study Start (Actual): May 8, 2008
• Primary Completion (Actual): June 11, 2010
• Study Completion (Actual): June 11, 2010

Study Registration Dates

• First Submitted: May 20, 2008
• First Submitted That Met QC Criteria: May 23, 2008
• First Posted (Estimate): May 28, 2008

Study Record Updates

• Last Update Posted (Actual): December 1, 2021
• Last Update Submitted That Met QC Criteria: November 1, 2021
• Last Verified: November 1, 2021

More Information

Terms related to this study

• Keywords: Tuberculosis; Pulmonary; Antitubercular Agents; Multidrug resistant; OPC 67683
• Additional Relevant MeSH Terms: Infections; Respiratory Tract Infections; Respiratory Tract Diseases; Lung Diseases; Bacterial Infections; Bacterial Infections and Mycoses; Gram-Positive Bacterial Infections; Actinomycetales Infections; Mycobacterium Infections; Tuberculosis; Tuberculosis, Pulmonary; Tuberculosis, Multidrug-Resistant; Extensively Drug-Resistant Tuberculosis
• Other Study ID Numbers: 242-07-204; 2007-005229-31 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Yes
• IPD Plan Description: Anonymized Individual participant data (IPD) that underlie the results of this study will be shared with researchers to achieve aims pre-specified in a methodologically sound research proposal. Small studies with less than 25 participants are excluded from data sharing.
• IPD Sharing Time Frame: Data will be available after marketing approval in global markets, or beginning 1-3 years following article publication. There is no end date to the availability of the data.
• IPD Sharing Access Criteria: Otsuka will share data on the Vivli data sharing platform which can be found here: https://vivli.org/ourmember/Otsuka/

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No