A Trial to Evaluate OPC 67683 in Participants With Pulmonary Sputum Culture-positive, Multidrug-resistant Tuberculosis (TB)
- Conditions
- Tuberculosis, PulmonaryTuberculosis, Multidrug ResistantExtensively Drug-Resistant Tuberculosis
- Interventions
- Registration Number
- NCT00685360
- Brief Summary
This is a clinical trial to evaluate the safety and efficacy of OPC-67683 in the treatment of multidrug resistant tuberculosis (MDR TB) for 56 days. In addition to an optimized background regimen (OBR), participants will be randomized to receive:
* 100 mg OPC-67683 twice daily (BID)
* 200 mg OPC-67683 BID
* Placebo BID
After 56 days participants will complete their optimized background regimen (OBR).
- 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AFB smears and a positive rapid rifampicin resistance test will be enrolled as presumptively culture positive and withdrawn as ineligible if they are confirmed to not have sputum culture positive MDR TB.
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 481
- 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).
- 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 & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Delamanid 100 mg BID + OBR Placebo 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. Delamanid 200 mg BID + OBR Optimized Background Regimen (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. Delamanid 100 mg BID + OBR Optimized Background Regimen (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. Placebo + OBR Optimized Background Regimen (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. Placebo + OBR Placebo 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. Delamanid 100 mg BID + OBR Delamanid 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. Delamanid 200 mg BID + OBR Delamanid 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.
- Primary Outcome Measures
Name Time Method Accumulation Ratio for Cmax (Rac[Cmax]) for Delamanid Pre-dose, 2, 3, 4, 10 (pre-evening dose), 12, 13, 14 and 24 hours post-dose up to Day 56 Data for Rac (Cmax) up to Day 56 was collected on Days 14, 28 and 56. Rac (Cmax) on Days 14, 28 or 56 compared to Cmax on Day 1 was computed.
Percentage of Participants Who Achieved Sputum Culture Conversion (SCC) Using the Mycobacteria Growth Indicator Tube (MGIT) System From the first dose of study drug up to the end of the Post-treatment Follow-up Period (Up to Day 84) Sputum culture conversion was defined to occur at the time of the collection of a sputum specimen with mycobacterial culture negative for growth of Mycobacterium tuberculosis (MTB) followed by at least one additional sputum specimen with mycobacterial culture negative for growth at least 27 days after the first negative specimen and not followed by any sputum specimens positive for growth in the MGIT system at any point during the remainder of the 84-day trial after the first negative culture.
Area Under the Plasma Concentration Curve From 0 to 24 Hours (AUC0-24h) for Delamanid Pre-dose, 2, 3, 4, 10 (pre-evening dose), 12, 13, 14 and 24 hours post-dose up to Day 56 Data for AUC0-24h up to Day 56 was collected on Days 1, 14, 28 and 56.
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 Tmax 1 and 2: Time to Maximal Peak Concentration (Tmax) for Delamanid Following First and Second Daily Dose Pre-dose, 2, 3, 4, 10 (pre-evening dose), 12, 13, 14 and 24 hours post-dose up to Day 56 Time to maximum (peak) plasma concentration following the first daily dose (Cmax1) was reported as tmax1 and time to maximum (peak) plasma concentration following the second daily dose (Cmax2) was reported as tmax2. Data for Tmax up to Day 56 was collected on Days 1, 14, 28 and 56.
Cmax 1 and 2: Maximal Peak Concentration (Cmax) for Delamanid Following First and Second Daily Dose Pre-dose, 2, 3, 4, 10 (pre-evening dose), 12, 13, 14 and 24 hours post-dose up to Day 56 Maximum (peak) plasma concentration following the first daily dose was reported as Cmax1 and maximum (peak) plasma concentration following the second daily dose was reported as Cmax2. Data for Cmax up to Day 56 was collected on Days 1, 14, 28 and 56.
Time to Maximal Peak Concentration (Tmax) for Delamanid Metabolite (DM)-6704, DM-6705, DM-6706, DM-6717, DM-6718, DM-6720, DM-6721, and DM-6722 0 hours (morning pre-dose), 2, 3, 4, 10 (pre-evening dose), 12, 13, 14 and 24 hours post-dose up to Day 56 Data for Tmax up to Day 56 was collected on Days 1, 14, 28 and 56.
Accumulation Ratio for Cmax (Rac[Cmax]) for DM-6704, DM-6705, DM-6706, DM-6717, DM-6718, DM-6720, DM-6721, and DM-6722 0 hours (morning pre-dose), 2, 3, 4, 10 (pre-evening dose), 12, 13, 14 and 24 hours post-dose up to Day 56 Data for Rac (Cmax) up to Day 56 was to be collected on Days 1, 14, 28 and 56. Rac (Cmax) on Days 14, 28 or 56 compared to Cmax on Day 1 was to be computed. Due to limited measurable data on Day 1 for delamanid metabolites, pharmacokinetic (PK) analysis was not conducted on Day 1 data for delamanid metabolites, and data for Rac (Cmax) was not available.
Accumulation Ratio for AUC From Time 0 to 24 Hours (Rac[AUC0-24h]) for Delamanid Pre-dose, 2, 3, 4, 10 (pre-evening dose), 12, 13, 14 and 24 hours post-dose up to Day 56 Data for Rac (AUC) up to Day 56 was collected on Days 14, 28 and 56. Rac (AUC) on Days 14, 28 or 56 compared to AUC0-24h on Day 1 was computed.
Maximal Peak Concentration (Cmax) for DM-6704, DM-6705, DM-6706, DM-6717, DM-6718, DM-6720, DM-6721, and DM-6722 0 hours (morning pre-dose), 2, 3, 4, 10 (pre-evening dose), 12, 13, 14 and 24 hours post-dose up to Day 56 Data for Cmax up to Day 56 was collected on Days 1, 14, 28 and 56.
Accumulation Ratio for AUC (Rac[AUC]) for DM-6704, DM-6705, DM-6706, DM-6717, DM-6718, DM-6720, DM-6721, and DM-6722 0 hours (morning pre-dose), 2, 3, 4, 10 (pre-evening dose), 12, 13, 14 and 24 hours post-dose up to Day 56 Data for Rac (AUC) up to Day 56 was to be collected on Days 1, 14, 28 and 56. Rac (AUC) on Days 14, 28 or 56 compared to AUC0-24h on Day 1 was to be computed. Due to limited measurable data on Day 1 for delamanid metabolites, PK analysis was not conducted on Day 1 data for delamanid metabolites, and data for Rac (AUC) was not available.
Area Under the Plasma Concentration Curve From 0 to 24 Hours (AUC0-24h) for DM-6704, DM-6705, DM-6706, DM-6717, DM-6718, DM-6720, DM-6721, and DM-6722 0 hours (morning pre-dose), 2, 3, 4, 10 (pre-evening dose), 12, 13, 14 and 24 hours post-dose up to Day 56 Data for AUC0-24h up to Day 56 was collected on Days 1, 14, 28 and 56.
- Secondary Outcome Measures
Name Time Method Change From Baseline in Time to Culture Positivity Using the MGIT System Baseline, Day 84 Mean change from baseline in time to culture positivity using the MGIT system was the value for "time to results" when a sputum culture result was positive (in days) using the MGIT system during the routine 42-day incubation period. A longer time to culture positivity represented a lower burden of MTB organisms present in the sputum. Baseline was defined as the average of Day -1 and Day 1 values, if the cultures on both days were positive; if only one culture was positive, the value for the positive culture was used as baseline.
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 Sputum Culture Conversion (SCC) Using Solid Culture Media From the first dose of study drug up to the end of the Post-treatment Follow-up Period (Up to Day 84) A participant achieving SCC using solid culture media was defined as one with sputum culture negative for growth of MTB on Day 57, and (a) not followed by a positive culture at any point thereafter, and (b) confirmed by at least one additional negative sputum culture at Day 84.
Percentage of Participants With Sputum Culture Negative at Day 57 Using the MGIT System Without Consideration of Subsequent Culture Results Day 57 Area Under the Curve (AUC) of Change From Baseline in Time to Culture Positivity in the MGIT System Baseline to Day 57 AUC of change from baseline for time to culture positivity (i.e., TTD) (Days 0 to 57), summarizes overall participant response for treatment period. Larger AUC of change from baseline for time to culture positivity would strongly suggest a clinical response with reduction of burden of MTB organisms in sputum. For this analysis, ti=visit day of each visit; t0=Day 0, t1=Day 8, t2=Day 15, etc. and xi=change from baseline in time to culture positivity at each visit; AUC at each visit was determined as AUCi=(ti - ti-1)(xi+ xi-1)/2. Average AUC of change from baseline was the sum of all AUCi divided by a given participant's duration in the trial up to 57 days. Baseline (Day 0)=the average of Day -1 and Day 1 values, if cultures on both days were positive; if only one culture was positive, value for time to culture positivity for positive culture was used as baseline.
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 Who Achieved SCC From the MGIT System Analyzed by Cochran-Armitage Linear Trend Test for Dose-response Relationship From the first dose of study drug up to the end of the Post-treatment Follow-up Period (Up to Day 84) A participant achieving SCC using solid media is defined as one with sputum culture negative for growth of MTB on Day 57, and (a) not followed by a positive culture at any point thereafter, and (b) confirmed by at least one additional negative sputum culture at Day 84. A dose response in the percentage of participants achieving SCC using the MGIT system was tested by the Cochran-Armitage linear trend test with equally spaced dose scores (0, 1, and 2 for placebo, 100 mg BID, and 200 mg BID, respectively).
Percentage of Participants Who Achieved Initial SCC Using the Solid Culture Media Day 57 Initial SCC occurred at the time of the collection of the first sputum specimen with mycobacterial culture negative for growth of MTB using solid culture media that was followed by at least one additional negative sputum specimen at least 27 days after the first negative specimen and no sputum specimens positive for growth on solid culture media at any point between the negative sputum specimens using solid culture media. Survival analysis methodology was performed to compare the Kaplan-Meier curves for time to SCC across 3 treatment groups. Comparisons between 100 mg BID and placebo and 200 mg BID and placebo were also performed with stratified log-rank tests. The benefit ratios (ratio of likelihoods that participants treated with delamanid BID + OBR would achieve SCC more rapidly than participants treated with placebo + OBR) for participants achieving SCC were computed.
Percentage of Participants Who Achieved Initial SCC Using the MGIT System Day 57 Initial SCC occurred at the time of the collection of the first sputum specimen with mycobacterial culture negative for growth of MTB using the MGIT system followed by at least one additional MGIT negative sputum specimen at least 27 days after the first negative specimen and no sputum specimens MGIT positive for growth at any point between the negative MGIT sputum specimens. Survival analysis methodology was performed to compare the Kaplan-Meier curves for time to SCC across 3 treatment groups. Comparisons between 100 mg BID and placebo and 200 mg BID and placebo were also performed with stratified log-rank tests. The benefit ratios (ratio of likelihoods that participants treated with delamanid BID + OBR would achieve SCC more rapidly than participants treated with placebo + OBR) for participants achieving SCC were computed.
Percentage of Participants Who Achieved Final SCC Using MGIT Day 57 Final SCC was defined as SCC at Day 57 or the latest time point of the first negative sputum culture establishing SCC for a given participant after the last positive sputum culture observed during the 56-day treatment period, whichever comes first. Survival analysis methodology was performed to compare the Kaplan-Meier curves for time to SCC across 3 treatment groups. Comparisons between 100 mg BID and placebo and 200 mg BID and placebo were also performed with stratified log-rank tests. The benefit ratios (ratio of likelihoods that participants treated with delamanid BID + OBR would achieve SCC more rapidly than participants treated with placebo + OBR) for participants achieving SCC were computed.
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 From first dose of study drug up to post treatment period (Day 84) Criteria for potentially clinically significant vital sign abnormalities: Heart rate \[beats per minute (BPM)\]: \>=120, increase \>=15, \<=60, decrease \>=15; systolic blood pressure \[millimeter of mercury (mmHg)\]: \>=160, increase \>=20, \<=90, decrease \>=20; diastolic blood pressure (mmHg): \>=105, increase \>=15, \<=50, decrease \>=15; weight (kg) gain: increase \>=5%; or weight loss: decrease \>=5%; temperature \[degrees Celsius (C)\]: \>=38.5, increase of \>=1.1. Only categories with at least 1 participant with event are reported.
Percentage of Participants Who Achieved Final SCC Using Solid Culture Media Day 57 Final SCC is defined as SCC at Day 57 or the latest time point of the first negative sputum culture establishing SCC for a given participant after the last positive sputum culture observed during the 56-day treatment period, whichever comes first. Survival analysis methodology was performed to compare the Kaplan-Meier curves for time to SCC across 3 treatment groups. Comparisons between 100 mg BID and placebo and 200 mg BID and placebo were also performed with stratified log-rank tests. The benefit ratios (ratio of likelihoods that participants treated with delamanid BID + OBR would achieve SCC more rapidly than participants treated with placebo + OBR) for participants achieving SCC were computed.
Percentage of Participants With Categorical Changes in 12-lead Electrocardiogram Results at Day 56 Baseline up to Day 56 Criteria for categorical changes in 6 12-lead Electrocardiogram results: Vent Rate Outliers Notable Decreases- \>= 25% decrease from Baseline and ventricular rate \< 50 beats per minute (beats/min), notable increases- \>= 25% decrease from Baseline and ventricular rate \> 100 beats/min; PR outliers notable changes- \>= 25% change from Baseline when PR \> 200 milliseconds (msec); QRS outliers notable changes- \>= 25% change from Baseline when QRS \> 100 msec; QT new onset (\> 500 msec); QT correction with Bazett formula (QTcB) and QT interval with Fridericia's correction (QTcF) new onset \> 500 msec, \> 480 msec, \> 450 msec, where new onset (\> 450, 480, 500 msec) means a participant who attains a value \> 450, 480, 500 msec during Treatment Period but not at each Baseline Visit; change \>= 30, \<= 60 msec; change \> 60 msec; and new abnormal U waves, ST segment changes, T wave changes, abnormal rhythm, RBBB, LBBB, myocardial infarction(MI). Only categories with at least 1 participant with event are r
Percentage of Participants With Clinically Significant Laboratory Test Abnormalities From first dose of study drug up to post treatment period (Day 84) The laboratory values were one of the parameters to measure the safety and tolerability of individual participants. Participants with potentially clinically significant laboratory values in clinical chemistry, hematology, coagulation, adrenal function tests, urinalysis and thyroid function tests that were identified based on pre-defined criteria were reported. Any value outside the normal range was flagged for the attention of the investigator who assessed whether or not a flagged value is of clinical significance. The categories with at least one participant with abnormal lab value as assessed by the investigator are reported.
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 From first dose of study drug up to post treatment period (Day 84) The concomitant anti-TB medication were classified as per WHO 2008 guidelines and included: Category 1- first-line oral anti-tuberculosis drugs; Category 2- injectable anti-tuberculosis drugs; Category 3- fluoroquinolones; Category 4- oral bacteriostatic second-line anti-tuberculosis drugs; Category 5- anti-tuberculosis drugs with unclear efficacy or unclear role in MDR-TB treatment (not recommended by WHO for routine use in MDR-TB participants).
Percentage of Participants With At Least One Treatment-Emergent Adverse Events (TEAEs) From first dose of study drug up to post treatment period (Day 84) An adverse event (AE) was defined as any untoward medical occurrence in a clinical trial participant and which does not necessarily have a causal relationship with the treatment. An AE can therefore be any unfavorable and unintended sign (including e.g., an abnormal laboratory assessment result), symptom or disease temporally associated with participation in the clinical trial, whether or not it is considered causally related to the medicinal product or procedures of the clinical trial. A clinically significant worsening in the health of the participant compared with the participant's health status documented at baseline constituted a TEAE.
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 Baseline, Days 1, 14, 28 and 56 Any changes in the ECG waves or segments as assessed by the investigator were reported.
Trial Locations
- Locations (17)
Hospital Nacional Sergio E. Bernales
🇵🇪Lima, Peru
Hospital Nacional Hipolito Unanue
🇵🇪Unanue, Peru
Hospital Nacional Daniel Alcides Carrión
🇵🇪Carrion, Peru
Clinic of Tuberculosis and Lung Diseases
🇱🇻Riga, Latvia
Beijing Chest Hospital
🇨🇳Beijing, China
Shanghai Pulmonary Hospital
🇨🇳Shanghai, China
University of Texas Health Center at Tyler / Heartland National TB Center / Texas Center for Infectious Disease
🇺🇸San Antonio, Texas, United States
North Estonian Medical Centre Foundation
🇪🇪Tallinn, Estonia
Tropical Disease Foundation
🇵🇭Manila, Philippines
Tartu University Lung Hospital
🇪🇪Tartu, Estonia
Kinki Chuo Chest Hospital
🇯🇵Osaka, Japan
Abbassia Chest Hospital
🇪🇬Cairo, Egypt
Fukujuji Hospital
🇯🇵Tokyo, Japan
Masan Medical Center
🇰🇷Changwon, Korea, Republic of
Younsei University Medical Center (YUMC), Severance Hospital
🇰🇷Seoul, Korea, Republic of
National Masan Hospital
🇰🇷Masan, Korea, Republic of
Samsung Medical Center
🇰🇷Seoul, Korea, Republic of