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).
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AFB smears and a positive rapid rifampicin resistance test will be enrolled as presumptively culture positive and withdrawn as ineligible if they are confirmed to not have sputum culture positive MDR TB.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
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
QUADRUPLE
Enrollment
481
Delamanid was administered orally twice daily as 50-mg tablets under fed conditions in the morning and evening.
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 tablets matching 50-mg tablets of delamanid
University of Texas Health Center at Tyler / Heartland National TB Center / Texas Center for Infectious Disease
San Antonio, Texas, United States
Beijing Chest Hospital
Beijing, China
Shanghai Pulmonary Hospital
Shanghai, China
Abbassia Chest Hospital
Cairo, Egypt
North Estonian Medical Centre Foundation
Tallinn, Estonia
Tartu University Lung Hospital
Tartu, Estonia
Kinki Chuo Chest Hospital
Osaka, Japan
Fukujuji Hospital
Tokyo, Japan
Clinic of Tuberculosis and Lung Diseases
Riga, Latvia
Hospital Nacional Daniel Alcides Carrión
Carrion, Peru
...and 7 more locations
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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
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
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.
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
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.
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
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.
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
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.
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
Elimination Half-life (t1/2) for DM-6704, DM-6705, DM-6706, DM-6717, DM-6718, DM-6720, DM-6721, and DM-6722
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
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.
Time frame: 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.
Time frame: 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.
Time frame: Baseline to Day 57
Percentage of Participants With Sputum Culture Negative at Day 57 Using the MGIT System Without Consideration of Subsequent Culture Results
Time frame: Day 57
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Percentage of Participants With Sputum Culture Negative at Day 57 and Day 84 Using the MGIT System Without Respect to Interim Culture Results
Time frame: 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
Time frame: 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
Time frame: 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).
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: Day 57
Percentage of Participants With Clinically Significant Physical Examination Findings, Including Vision and Neuropsychiatric Assessments
Time frame: 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.
Time frame: 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
Time frame: 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.
Time frame: From first dose of study drug up to post treatment period (Day 84)
Percentage of Participants With Clinically Significant Audiometry Findings
Time frame: 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).
Time frame: 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.
Time frame: 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
Time frame: Baseline, and 2, 3, 4, 10, 12, and 24 hours post dose on Day 56
Mean Change From Baseline in QTcF
Time frame: Baseline, Days 1, 14, 28 and 56
Mean Change From Baseline in QTcB
Time frame: Baseline, Days 1, 14, 28 and 56
Mean Change From Baseline in Ventricular Rate
Time frame: Baseline, Days 1, 14, 28 and 56
Mean Change From Baseline in PR Interval
Time frame: Baseline, Days 1, 14, 28 and 56
Mean Change From Baseline in QRS Interval
Time frame: Baseline, Days 1, 14, 28 and 56
Mean Change From Baseline in QT Interval
Time frame: 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.
Time frame: Baseline, Days 1, 14, 28 and 56