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Safety and Pharmacokinetics (PK) in Multidrug-Resistant (MDR) Refractive Tuberculosis

Primary Purpose

Tuberculosis

Status
Terminated
Phase
Phase 2
Locations
International
Study Type
Interventional
Intervention
Delamanid
Optimized Background Regimen (OBR)
Sponsored by
Otsuka Pharmaceutical Development & Commercialization, Inc.
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Tuberculosis focused on measuring MDR-TB, Dose Escalation, Phase II, Open Label, Non Controlled, Pulmonary Multidrug-Resistant Tuberculosis (MDR TB)

Eligibility Criteria

18 Years - 64 Years (Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  1. Provide written, informed consent prior to all trial-related procedures
  2. Male or female participants aged between 18 and 64 years, inclusive.
  3. Able to produce sputum for mycobacterium culture or able to obtain sputum produced through Induction.
  4. At least three sputum mycobacterium cultures positive for MTB with in-vitro resistance to isoniazid and rifampicin during the previous 270 days (9 months) despite treatment with first and second line anti-TB drugs, including one positive culture within the previous 60 days from the time of sputum collection, prior to date of screening initiation [defined as the date the informed consent form (ICF) is signed and screening begins].
  5. Sputum mycobacterial culture positive for MTB with in-vitro susceptibility to at least one anti-TB medication within the previous 60 days prior to the date of screening initiation.
  6. Participant judged by the investigator to have potential for clinical benefit from OPC-67683 exposure.
  7. 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).
  8. Male participant 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:

  1. A history of allergy to any nitro-imidazoles or nitro-imidazole derivatives at any time.
  2. Use of the medications in Section 4.1 including: use of amiodarone at any time during the previous 12 months, use of other antiarrhythmics for the previous 30 days, as well as use of certain antidepressants, anti-histamines, any macrolides, for the previous 14 days.
  3. Any current serious concomitant conditions or renal impairment characterized by serum creatinine levels ~265 micromoles (μmol)/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.
  4. Current clinically relevant changes in the Screening electrocardiogram (ECG) such as any atrioventricular (AV) block, prolongation of the QRS complex over 120 msec (in both male and female participants), or of the QT interval with Fridericia's correction (QTcF) interval over 450 msec in male participants and over 470 msec in female participants.
  5. Current clinically relevant cardiovascular disorder such as heart failure, coronary heart disease, uncontrolled or poorly controlled hypertension, arrhythmia, tachyarrhythmia or status after myocardial infarction.
  6. For participants with human immunodeficiency virus (HIV) infection, helper/inducer T-lymphocyte (CD4 cell) count < 350/mm^3 or on treatment with anti-retroviral medication for HIV infection.
  7. Karnofsky score < 50%.
  8. Any current diseases or conditions in which the use of nitro-imidazoles or nitro-imidazole derivates is contra-indicated.

Sites / Locations

  • Infectology Center of Latvia - Clinic of Tuberculosis and Lung Diseases
  • Hospital for Tuberculosis and Lung Diseases
  • National Tuberculosis and Infectious Diseases University Hospital

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Experimental

Arm Label

Delamanid 250 mg BID+ OBR

Delamanid 300 mg BID+ OBR

Arm Description

Participants received delamanid five 50 milligrams (mg) (250 mg) tablets, twice a day (BID), along with at least 2 additional anti-TB medications per optimized background regimen (OBR) for up to 28 weeks.

Participants received delamanid six 50 mg (300 mg) tablets, BID, along with at least 2 additional anti-TB medications per OBR for up to 28 weeks.

Outcomes

Primary Outcome Measures

Percentage of Participants With Potentially Clinically Significant Abnormalities in Vital Signs
Vital signs included body weight [kilogram (kg)], body temperature [degree Celsius (°C)], heart rate [beats per minute (BPM)], respiratory rate (breaths/minute), systolic and diastolic blood pressure [millimeter of mercury (mmHg)]. The criteria for clinically significant abnormal value were: body weight (kg): increase >=5% or decrease >=5%; body temperature (°C): >=38.5°C and increase of >=1.1°C; heart rate (BPM): >=120 bpm and increase of >=15 bpm, or <=60 bpm and decrease of >=15 bpm; systolic blood pressure (mmHg): >=160 mmHg and increase of >=20 mmHg, or <=90 mmHg and decrease of >=20 mmHg; diastolic blood pressure (mmHg): >=105 mmHg and increase of >=15 mmHg, or <=50 mmHg and decrease of >=15 mmHg; respiration rate (breaths per minute) >30 breaths per minute. Only categories with data for potentially clinically significant abnormal vital sign parameter values are reported.
Percentage of Participants With Potentially Clinically Significant Abnormalities in Electrocardiogram (ECG) Results
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. Baseline was defined as the average of the ECGs taken at Day -1. Only categories with data for potentially clinically significant abnormal ECG values are reported.
Percentage of Participants With Potentially Clinically Significant Laboratory Values
Clinical laboratory tests included hematology, coagulation, chemistry, and urinalysis. The participants were categorized based on the clinically significant laboratory values as per protocol predefined criteria. The categories with at least one participant with clinically significant value outside the normal range for laboratory assessments are reported.
Percentage of Participants With Abnormal Audiometry Assessment Values
Percentage of Participants With Abnormal Visual Acuity Assessment Values
Percentage of Participants Taking Concomitant Anti-Tuberculosis (TB) Medication During the Trial
Percentage of Participants Taking Concomitant (Excluding Anti-TB) Medication During the Trial
Percentage of Participants With Adverse Events (AEs)
An AE was defined as any new medical problem, or exacerbation of an existing problem, experienced by a participant while enrolled in the trial, whether or not it was considered drug-related by the investigator.
Percentage of Participants With Immediately Reportable Events (IREs)
An AE was considered serious if it was fatal; life-threatening; persistently or significantly disabling or incapacitating; required in-participant hospitalization or prolonged hospitalization; a congenital anomaly/birth defect; or other medically significant event that, based upon appropriate medical judgment, may have jeopardized the participant and may have required medical or surgical intervention to prevent one of the outcomes listed above. The following were considered as IREs- serious adverse events (SAEs), pregnancies in trial participants or their partners, and all events involving overdose, misuse and abuse.
Cmax: Maximal Peak Plasma Concentration for Delamanid
Tmax: Time to Reach Maximal Peak Plasma Concentration for Delamanid
AUC0-24h: Area Under the Plasma Concentration-Time Curve From 0 To 24 Hours for Delamanid
AUC0-24h was calculated as 2×AUC0-12h.
Rac (Cmax): Ratio of Accumulation for Cmax of Delamanid
Ratio of accumulation for Cmax was assessed on Days 14, 28, 56, 112 and 196 with respect to Day 1.
Rac (AUC): Ratio of Accumulation for AUC of Delamanid
Ratio of accumulation for AUC was assessed on Days 14, 28, 56, 112 and 196 with respect to Day 1.

Secondary Outcome Measures

Cmax: Maximal Peak Plasma Concentration for Delamanid Metabolites
The primary metabolites of delamanid are DM-6704, DM-6705 and DM-6706.
Tmax: Time to Reach Maximal Peak Plasma Concentration for Delamanid Metabolites
The primary metabolites of delamanid are DM-6704, DM-6705 and DM-6706.
AUC0-24h: Area Under the Plasma Concentration-Time Curve From 0 To 24 Hours for Delamanid Metabolites
The primary metabolites of delamanid are DM-6704, DM-6705 and DM-6706.
Rac (Cmax): Ratios of Accumulation for Cmax for Delamanid Metabolites
The primary metabolites of delamanid are DM-6704, DM-6705 and DM-6706. Ratio of accumulation for Cmax was planned to be assessed on Days 14, 28, 56, 112 and 196 with respect to Day 1.
Rac (AUC): Ratios of Accumulation for AUC for Delamanid Metabolites
The primary metabolites of delamanid are DM-6704, DM-6705 and DM-6706. Ratio of accumulation for AUC was planned to be assessed on Days 14, 28, 56, 112 and 196 with respect to Day 1. Limited metabolite exposure on Day 1 did not allow for estimation of Rac for metabolites.
Percentage of Participants With Sputum Culture Conversion by Mycobacteria Growth Indicator Tube (MGIT) at Day 168
Sputum culture conversion was evaluated using the MGIT culture system. A participant was classified as demonstrating a sputum culture conversion if he/she achieved two consecutive sputum cultures negative for growth of Mycobacterium tuberculosis at least 28 days apart after his/her last sputum culture positive for growth and not followed by any sputum specimens positive for growth.
Percentage of Participants With Sputum Culture Conversion on Solid Mycobacterial Culture Media at Day 168
Sputum culture status was determined using solid mycobacterial culture media and measuring colony counts per milliliter of sputum. The unit for colony counts: log10 colony-forming unit (CFU)/mL. A participant was classified as demonstrating a sputum culture conversion if he/she achieved two consecutive sputum cultures negative for growth of Mycobacterium tuberculosis at least 28 days apart after his/her last sputum culture positive for growth and not followed by any sputum specimens positive for growth.
Mean Change From Baseline in Time to Culture Positivity Using MGIT
The value for time to positivity was defined (in days) as the time interval from inoculation until a positive signal was detected for MTB on sputum culture in the MGIT system during the routine 42 day incubation period. Time to positivity analysis was based on the corresponding qualitative sputum results of positive and negative sputum cultures in days of the initial positive signal for a culture from the MGIT system. Mean is reported for Baseline and mean change from baseline is reported for Days 7, 14, 21, 28, 35, 42, 49, 56, 70, 84, 98, 112, 126, 140, 154, 168, 182, 196, 224, 252, and 280. Baseline is Day -2 and -1. Mean time to culture positivity at Baseline was defined as the average of Day -2 and Day -1 values, if the cultures on both days were positive; and if only one culture was positive, the value for the positive culture was used as baseline.

Full Information

First Posted
May 25, 2010
Last Updated
October 14, 2021
Sponsor
Otsuka Pharmaceutical Development & Commercialization, Inc.
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1. Study Identification

Unique Protocol Identification Number
NCT01131351
Brief Title
Safety and Pharmacokinetics (PK) in Multidrug-Resistant (MDR) Refractive Tuberculosis
Official Title
A Phase 2, Multi-center, Non-controlled, Open-label Dose Escalation Trial to Assess the Safety, Tolerability, Pharmacokinetics, and Efficacy of Orally Administered OPC-67683 Two Times Daily to Patients With Pulmonary Multidrug-Resistant Tuberculosis Refractory to Conventional Treatment
Study Type
Interventional

2. Study Status

Record Verification Date
October 2021
Overall Recruitment Status
Terminated
Why Stopped
The study was terminated early due to lack of efficacy after 10 participants enrolled.
Study Start Date
February 19, 2010 (Actual)
Primary Completion Date
May 12, 2011 (Actual)
Study Completion Date
May 12, 2011 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Otsuka Pharmaceutical Development & Commercialization, Inc.

4. Oversight

Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes

5. Study Description

Brief Summary
The purpose of this study is: To evaluate the safety and tolerability of orally administered OPC-67683 when administered two times daily to MDR tuberculosis (TB) participants refractory to treatment with an optimized background regimen of anti-TB medications (OBR). To evaluate the pharmacokinetics (PK) of OPC-67683 and metabolites.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Tuberculosis
Keywords
MDR-TB, Dose Escalation, Phase II, Open Label, Non Controlled, Pulmonary Multidrug-Resistant Tuberculosis (MDR TB)

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Sequential Assignment
Masking
None (Open Label)
Allocation
Non-Randomized
Enrollment
10 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Delamanid 250 mg BID+ OBR
Arm Type
Experimental
Arm Description
Participants received delamanid five 50 milligrams (mg) (250 mg) tablets, twice a day (BID), along with at least 2 additional anti-TB medications per optimized background regimen (OBR) for up to 28 weeks.
Arm Title
Delamanid 300 mg BID+ OBR
Arm Type
Experimental
Arm Description
Participants received delamanid six 50 mg (300 mg) tablets, BID, along with at least 2 additional anti-TB medications per OBR for up to 28 weeks.
Intervention Type
Drug
Intervention Name(s)
Delamanid
Other Intervention Name(s)
OPC-67683
Intervention Description
OPC-67683 film-coated tablets
Intervention Type
Drug
Intervention Name(s)
Optimized Background Regimen (OBR)
Intervention Description
OBR was selected at the discretion of the study investigator and included at least 2 anti-TB medications based on World Health Organization (WHO's) guidelines for the programmatic management of drug-resistant TB. Study investigator could change OBR for a participant based on his/her tolerability and drug susceptibility testing (DST) results.
Primary Outcome Measure Information:
Title
Percentage of Participants With Potentially Clinically Significant Abnormalities in Vital Signs
Description
Vital signs included body weight [kilogram (kg)], body temperature [degree Celsius (°C)], heart rate [beats per minute (BPM)], respiratory rate (breaths/minute), systolic and diastolic blood pressure [millimeter of mercury (mmHg)]. The criteria for clinically significant abnormal value were: body weight (kg): increase >=5% or decrease >=5%; body temperature (°C): >=38.5°C and increase of >=1.1°C; heart rate (BPM): >=120 bpm and increase of >=15 bpm, or <=60 bpm and decrease of >=15 bpm; systolic blood pressure (mmHg): >=160 mmHg and increase of >=20 mmHg, or <=90 mmHg and decrease of >=20 mmHg; diastolic blood pressure (mmHg): >=105 mmHg and increase of >=15 mmHg, or <=50 mmHg and decrease of >=15 mmHg; respiration rate (breaths per minute) >30 breaths per minute. Only categories with data for potentially clinically significant abnormal vital sign parameter values are reported.
Time Frame
Up to approximately 40 weeks
Title
Percentage of Participants With Potentially Clinically Significant Abnormalities in Electrocardiogram (ECG) Results
Description
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. Baseline was defined as the average of the ECGs taken at Day -1. Only categories with data for potentially clinically significant abnormal ECG values are reported.
Time Frame
Up to approximately 40 weeks
Title
Percentage of Participants With Potentially Clinically Significant Laboratory Values
Description
Clinical laboratory tests included hematology, coagulation, chemistry, and urinalysis. The participants were categorized based on the clinically significant laboratory values as per protocol predefined criteria. The categories with at least one participant with clinically significant value outside the normal range for laboratory assessments are reported.
Time Frame
Up to approximately 40 weeks
Title
Percentage of Participants With Abnormal Audiometry Assessment Values
Time Frame
Up to approximately 40 weeks
Title
Percentage of Participants With Abnormal Visual Acuity Assessment Values
Time Frame
Up to approximately 40 weeks
Title
Percentage of Participants Taking Concomitant Anti-Tuberculosis (TB) Medication During the Trial
Time Frame
Up to approximately 40 weeks
Title
Percentage of Participants Taking Concomitant (Excluding Anti-TB) Medication During the Trial
Time Frame
Up to approximately 40 weeks
Title
Percentage of Participants With Adverse Events (AEs)
Description
An AE was defined as any new medical problem, or exacerbation of an existing problem, experienced by a participant while enrolled in the trial, whether or not it was considered drug-related by the investigator.
Time Frame
Up to approximately 40 weeks
Title
Percentage of Participants With Immediately Reportable Events (IREs)
Description
An AE was considered serious if it was fatal; life-threatening; persistently or significantly disabling or incapacitating; required in-participant hospitalization or prolonged hospitalization; a congenital anomaly/birth defect; or other medically significant event that, based upon appropriate medical judgment, may have jeopardized the participant and may have required medical or surgical intervention to prevent one of the outcomes listed above. The following were considered as IREs- serious adverse events (SAEs), pregnancies in trial participants or their partners, and all events involving overdose, misuse and abuse.
Time Frame
Up to approximately 40 weeks
Title
Cmax: Maximal Peak Plasma Concentration for Delamanid
Time Frame
At 24 hours post dose on Days 1, 14, 28, 56, 112 and 196
Title
Tmax: Time to Reach Maximal Peak Plasma Concentration for Delamanid
Time Frame
At 24 hours post dose on Days 1, 14, 28, 56, 112 and 196
Title
AUC0-24h: Area Under the Plasma Concentration-Time Curve From 0 To 24 Hours for Delamanid
Description
AUC0-24h was calculated as 2×AUC0-12h.
Time Frame
At 24 hours post dose on Days 1, 14, 28, 56, 112 and 196
Title
Rac (Cmax): Ratio of Accumulation for Cmax of Delamanid
Description
Ratio of accumulation for Cmax was assessed on Days 14, 28, 56, 112 and 196 with respect to Day 1.
Time Frame
At 24 hours post dose on Days 1, 14, 28, 56, 112 and 196
Title
Rac (AUC): Ratio of Accumulation for AUC of Delamanid
Description
Ratio of accumulation for AUC was assessed on Days 14, 28, 56, 112 and 196 with respect to Day 1.
Time Frame
At 24 hours post dose on Days 1, 14, 28, 56, 112 and 196
Secondary Outcome Measure Information:
Title
Cmax: Maximal Peak Plasma Concentration for Delamanid Metabolites
Description
The primary metabolites of delamanid are DM-6704, DM-6705 and DM-6706.
Time Frame
At 24 hours post dose on Days 1, 14, 28, 56, 112 and 196
Title
Tmax: Time to Reach Maximal Peak Plasma Concentration for Delamanid Metabolites
Description
The primary metabolites of delamanid are DM-6704, DM-6705 and DM-6706.
Time Frame
At 24 hours post dose on Days 1, 14, 28, 56, 112 and 196
Title
AUC0-24h: Area Under the Plasma Concentration-Time Curve From 0 To 24 Hours for Delamanid Metabolites
Description
The primary metabolites of delamanid are DM-6704, DM-6705 and DM-6706.
Time Frame
At 24 hours post dose on Days 1, 14, 28, 56, 112 and 196
Title
Rac (Cmax): Ratios of Accumulation for Cmax for Delamanid Metabolites
Description
The primary metabolites of delamanid are DM-6704, DM-6705 and DM-6706. Ratio of accumulation for Cmax was planned to be assessed on Days 14, 28, 56, 112 and 196 with respect to Day 1.
Time Frame
At 24 hours post dose on Days 1, 14, 28, 56, 112 and 196
Title
Rac (AUC): Ratios of Accumulation for AUC for Delamanid Metabolites
Description
The primary metabolites of delamanid are DM-6704, DM-6705 and DM-6706. Ratio of accumulation for AUC was planned to be assessed on Days 14, 28, 56, 112 and 196 with respect to Day 1. Limited metabolite exposure on Day 1 did not allow for estimation of Rac for metabolites.
Time Frame
At 24 hours post dose on Days 1, 14, 28, 56, 112 and 196
Title
Percentage of Participants With Sputum Culture Conversion by Mycobacteria Growth Indicator Tube (MGIT) at Day 168
Description
Sputum culture conversion was evaluated using the MGIT culture system. A participant was classified as demonstrating a sputum culture conversion if he/she achieved two consecutive sputum cultures negative for growth of Mycobacterium tuberculosis at least 28 days apart after his/her last sputum culture positive for growth and not followed by any sputum specimens positive for growth.
Time Frame
Day 168 (Week 24)
Title
Percentage of Participants With Sputum Culture Conversion on Solid Mycobacterial Culture Media at Day 168
Description
Sputum culture status was determined using solid mycobacterial culture media and measuring colony counts per milliliter of sputum. The unit for colony counts: log10 colony-forming unit (CFU)/mL. A participant was classified as demonstrating a sputum culture conversion if he/she achieved two consecutive sputum cultures negative for growth of Mycobacterium tuberculosis at least 28 days apart after his/her last sputum culture positive for growth and not followed by any sputum specimens positive for growth.
Time Frame
Day 168 (Week 24)
Title
Mean Change From Baseline in Time to Culture Positivity Using MGIT
Description
The value for time to positivity was defined (in days) as the time interval from inoculation until a positive signal was detected for MTB on sputum culture in the MGIT system during the routine 42 day incubation period. Time to positivity analysis was based on the corresponding qualitative sputum results of positive and negative sputum cultures in days of the initial positive signal for a culture from the MGIT system. Mean is reported for Baseline and mean change from baseline is reported for Days 7, 14, 21, 28, 35, 42, 49, 56, 70, 84, 98, 112, 126, 140, 154, 168, 182, 196, 224, 252, and 280. Baseline is Day -2 and -1. Mean time to culture positivity at Baseline was defined as the average of Day -2 and Day -1 values, if the cultures on both days were positive; and if only one culture was positive, the value for the positive culture was used as baseline.
Time Frame
Baseline and Days 7, 14, 21, 28, 35, 42, 49, 56, 70, 84, 98, 112, 126, 140, 154, 168, 182, 196, 224, 252, and 280

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
64 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Provide written, informed consent prior to all trial-related procedures Male or female participants aged between 18 and 64 years, inclusive. Able to produce sputum for mycobacterium culture or able to obtain sputum produced through Induction. At least three sputum mycobacterium cultures positive for MTB with in-vitro resistance to isoniazid and rifampicin during the previous 270 days (9 months) despite treatment with first and second line anti-TB drugs, including one positive culture within the previous 60 days from the time of sputum collection, prior to date of screening initiation [defined as the date the informed consent form (ICF) is signed and screening begins]. Sputum mycobacterial culture positive for MTB with in-vitro susceptibility to at least one anti-TB medication within the previous 60 days prior to the date of screening initiation. Participant judged by the investigator to have potential for clinical benefit from OPC-67683 exposure. 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 participant 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 derivatives at any time. Use of the medications in Section 4.1 including: use of amiodarone at any time during the previous 12 months, use of other antiarrhythmics for the previous 30 days, as well as use of certain antidepressants, anti-histamines, any macrolides, for the previous 14 days. Any current serious concomitant conditions or renal impairment characterized by serum creatinine levels ~265 micromoles (μmol)/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. Current clinically relevant changes in the Screening electrocardiogram (ECG) such as any atrioventricular (AV) block, prolongation of the QRS complex over 120 msec (in both male and female participants), or of the QT interval with Fridericia's correction (QTcF) interval over 450 msec in male participants and over 470 msec in female participants. Current clinically relevant cardiovascular disorder such as heart failure, coronary heart disease, uncontrolled or poorly controlled hypertension, arrhythmia, tachyarrhythmia or status after myocardial infarction. For participants with human immunodeficiency virus (HIV) infection, helper/inducer T-lymphocyte (CD4 cell) count < 350/mm^3 or on treatment with anti-retroviral medication for HIV infection. Karnofsky score < 50%. Any current diseases or conditions in which the use of nitro-imidazoles or nitro-imidazole derivates is contra-indicated.
Facility Information:
Facility Name
Infectology Center of Latvia - Clinic of Tuberculosis and Lung Diseases
City
Ogre
ZIP/Postal Code
LV 5015
Country
Latvia
Facility Name
Hospital for Tuberculosis and Lung Diseases
City
Siauliai
ZIP/Postal Code
LT-76231
Country
Lithuania
Facility Name
National Tuberculosis and Infectious Diseases University Hospital
City
Vilnius
ZIP/Postal Code
LT-10214
Country
Lithuania

12. IPD Sharing Statement

Plan to Share IPD
Yes
IPD Sharing Plan Description
Anonymized Individual participant data (IPD) that underlie the results of this study will be shared with researchers to achieve aims prespecified 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/
IPD Sharing URL
https://clinical-trials.otsuka.com

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Safety and Pharmacokinetics (PK) in Multidrug-Resistant (MDR) Refractive Tuberculosis

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