Clinical trial NCT02619994
Conditions: Tuberculosis, Multidrug-Resistant
Keywords: Multidrug-resistant tuberculosis Linezolid Delamanid Multicenter randomized trial Non-inferiority Shorter regimen
Sponsor: Seoul National University Hospital
Start date: 2016-01-01; Completion date: 2021-06-01
Enrollment: 214 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to compare the efficacy of a 'new treatment regimen including delamanid, linezolid, levofloxacin, and pyrazinamide for nine or twelve months (investigational arm)' and 'the standard treatment regimen including injectables for 20 to 24 months (control arm)' for treating fluoroquinolone-sensitive multidrug-resistant tuberculosis.

Detailed description:
This study is a phase II/III, multicenter, randomized, open-label clinical trial of non-inferiority design comparing a new regimen to the World Health Organization-endorsed conventional regimen for fluoroquinolone-sensitive MDR-TB. The control arm uses a conventional treatment regimen with second-line drugs including injectables for 20-24 months. The investigational arm uses a new shorter regimen including delamanid, linezolid, levofloxacin, and pyrazinamide for 9 or 12 months depending on time to sputum culture conversion. The primary outcome is the treatment success rate at 24 months after treatment initiation. Secondary outcomes include time to sputum culture conversion on liquid and solid media, proportions of sputum culture conversion on liquid media after 2 and 6 months of treatment, treatment success rate according to pyrazinamide resistance, and occurrence of adverse events grade 3 and above as evaluated by the Common Terminology Criteria for Adverse Events. The population number is calculated as 102 per group (204 in total).

Arms: arm 1: Regimen is the locally-used WHO-approved MDR-TB regimen in Korea based on 2014 Korean guideline of TB management.

* Intensive phase regimen consists of four effective second-line anti-TB drugs (including injectables) and pyrazinamide.
* Treatment duration: for at least 20 months arm 2: Regimen consists of only oral medication using delamanid, linezolid, levofloxacin, and pyrazinamide, for nine or twelve months depending on the time of sputum culture conversion to negative.

* Delamanid (100 mg bid for the entire treatment period)
* Linezolid (600mg/day for 2 months and 300mg/day afterwards until the end of treatment)
* Levofloxacin (750 \~1000 mg/day)
* Pyrazinamide (1000\~ 2000 mg/day)
Interventions: intervention 1: Linezolid intervention 2: Delamanid intervention 3: Levofloxacin intervention 4: Pyrazinamide intervention 5: Locally-used WHO-approved MDR-TB regimen in Korea
Intervention descriptions: intervention 1: None intervention 2: None intervention 3: None intervention 4: None intervention 5: None

Protocol documents:
Prot_SAP_000.pdf: 
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Delamanid, linezolid, levofloxacin, and pyrazinamide for treatment of 
patients with fluoroquinolone-sensitive multidrug-resistant 
tuberculosis:  
A Phase II/III, Multicenter, Randomized, Open-label, Clinical Trial 
(Treatment Shortening of MDR TB using Existing and New Drugs, 
MDR-END) 
 
 
1. Protocol Number: MDR-END 
2. Version Number: 14.0, Version Date: 2020.03.20 
 
 


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Table of Contents 
Summary of Research Plans ...................................................................................................................................... 4 
1. 
Background of the Study ................................................................................................................................... 6 
1.1. 
Prevalence of and Threat Posed by MDR-TB........................................................................................... 6 
1.2. 
Difficulties with Treatment of MDR-TB .................................................................................................. 6 
1.3. 
Introduction of New Anti-TB Drugs ......................................................................................................... 7 
2. 
Rationale ............................................................................................................................................................ 8 
2.1. 
Shortening of Treatment Duration ............................................................................................................ 8 
2.2. 
Improvement of Treatment Efficacy ......................................................................................................... 8 
2.3. 
Contribution to International Community through Research on MDR-TB .............................................. 8 
3. 
Previous Research Results ............................................................................................................................... 10 
3.1. 
Comparison of Levofloxacin versus Moxifloxacin for Multidrug-Resistant Tuberculosis ..................... 10 
3.2. 
Substitution of ethambutol with linezolid during the intensive phase of treatment of pulmonary 
tuberculosis .............................................................................................................................................................. 10 
4. 
Purpose of the Study ........................................................................................................................................ 11 
5. 
Design of the Study ......................................................................................................................................... 11 
5.1. 
Study Design ........................................................................................................................................... 11 
5.1.1. 
Study Drug .............................................................................................................................................. 11 
5.1.2. 
Multicenter, randomized, open-label, two arms, phase II/III clinical trial .............................................. 12 
5.2. 
Primary Outcome .................................................................................................................................... 14 
5.3. 
Secondary Outcomes .............................................................................................................................. 15 
5.4. 
Inclusion Criteria .................................................................................................................................... 15 
5.5. 
Exclusion Criteria ................................................................................................................................... 15 
5.6. 
Precautions for Use and Expected Adverse Events (AE) ........................................................................ 16 
5.6.1. 
Prohibited medications while on the study drugs ................................................................................... 16 
5.6.2. 
Warning and precautions against using simultaneously .......................................................................... 16 
5.6.3. 
Expected Adverse Events (AE) ............................................................................................................... 17 
6. 
Definition ......................................................................................................................................................... 20 
6.1. 
Culture Conversion to Negative ............................................................................................................. 20 
6.2. 
Date of Culture Conversion .................................................................................................................... 20 
6.3. 
Reversion ................................................................................................................................................ 20 
6.4. 
Treatment Outcome Definitions.............................................................................................................. 20 
7. 
Study Timeline ................................................................................................................................................. 22 
7.1. 
Control arm ............................................................................................................................................. 22 
7.2. 
Investigational arm ................................................................................................................................. 23 
8. 
Screening and Procedures ................................................................................................................................ 24 
8.1. 
Subject Screening and Enrollment .......................................................................................................... 24 
8.2. 
Randomization ........................................................................................................................................ 24 
8.3. 
Baseline Visit and Beginning of Treatment ............................................................................................ 25 
8.4. 
Study Visits ............................................................................................................................................. 25 
8.4.1. 
Study tests of visits while on anti-TB medication .................................................................................. 25 
8.4.2. 
Follow-up visits after EOT (Investigational arm only) ........................................................................... 26 
8.5. 
Details of Study Procedures .................................................................................................................... 26 
8.6. 
Study Drug Adherence ............................................................................................................................ 28 
8.7. 
Withdrawal.............................................................................................................................................. 28 
9. 
Checking for Developing Resistance Against Study Drug .............................................................................. 29 
9.1. 
Subjects ................................................................................................................................................... 29 
9.2. 
Method .................................................................................................................................................... 29 
10. 
Sample size justification and Statistical Analysis Method ...................................................................... 30 
10.1. 
Sample size justification ......................................................................................................................... 30 
10.2. 
Statistical Analysis Method .................................................................................................................... 31 
11. 
Safety Assessment .................................................................................................................................. 34 
11.1. 
Definition ................................................................................................................................................ 34 
11.2. 
Adverse Event Collection and Reporting................................................................................................ 35 
11.3. 
Suspected Unexpected Serious Adverse Reaction (SUSAR) Report ...................................................... 36 
12. 
Monitoring .............................................................................................................................................. 37 
12.1. 
Installation of Data and Safety Monitoring Board (DSMB) ................................................................... 37 


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12.2. 
Monitoring Plans .................................................................................................................................... 37 
13. 
Ethical Considerations of the Study ........................................................................................................ 38 
13.1. 
Compliance of Study Ethical Regulations .............................................................................................. 38 
13.2. 
Obtaining written informed consent from Subjects ................................................................................ 39 
13.3. 
Protection of Personal Records ............................................................................................................... 40 
13.4. 
Compensation and Indemnities Provided to Subjects ............................................................................. 40 
14. 
Administrative Requirements ................................................................................................................. 41 
14.1. 
Change of Study Protocols ..................................................................................................................... 41 
14.2. 
Subject identification log and screening/enrollment log ......................................................................... 41 
14.3. 
Completing Case Report Forms (CRF) ................................................................................................... 41 
14.4. 
Quality Assurance of Data ...................................................................................................................... 41 
14.5. 
Storage of Records .................................................................................................................................. 42 
14.6. 
Completion and Stopping the Study ....................................................................................................... 42 
15. 
References .............................................................................................................................................. 43 
 
 
 


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Summary of Research Plans 
1. Background 
Tuberculosis, and especially drug-resistant tuberculosis, is a huge threat to public health not only in 
Korea, but throughout the world. Treatment of multidrug-resistant tuberculosis (MDR-TB), which 
exhibits resistance to the two most powerful drugs, must use second-line anti-TB drugs. However, 
usage of the conventional second-line anti-TB drugs not only has low success rates, but is also 
accompanied by a range of issues such as side effects due to prolonged use of drugs for about two years 
for treatment, low compliance, and high costs. Therefore, by developing new treatment regimens for 
MDR-TB treatment including recently introduced new drugs to improve the treatment efficacy and 
shortening the therapy period, it will be possible to increase treatment compliance, and consequently 
raise the treatment success rate. 
2. Purpose 
This clinical trial is to compare the efficacy of a ‘new treatment regimen including delamanid, linezolid, 
levofloxacin, and pyrazinamide for nine or twelve months (investigational arm)’ and ‘the standard 
treatment regimen including injectables for 20 to 24 months (control arm)’ for treating fluoroquinolone 
sensitive multidrug-resistant tuberculosis. 
3. Design of the Study 
Multicenter, randomized, open-label, two arms, phase II/III clinical trial 
① Group 1 (Control arm) 
Minimum 20 months treatment according to the 2014 Korean guidelines for the treatment of  
tuberculosis and 2014 World Health Organization (WHO) guidelines   
② Group 2 (Investigational arm) 
Treament regimen made up of only oral medication using delamanid, linezolid, levofloxacin, and 
pyrazinamide, and treatment duration of nine months or twelve months depending on the time to  
sputum culture conversion to negative. 
 
4. Outcomes 
The primary outcome is the treatment success rate at 24 months after the initiation of treatment. The 
secondary outcomes are the time to sputum culture conversion to negative on liquid and solid media 
after the initiation of treatment, the proportion of participants with sputum culture conversion at 2 and 
6 months of treatment on liquid and solid media, and the occurrence of adverse events grade of 3 and 
higher,  proportion of participants with a treatment success at the end of treatment, proportion of 
relapse after treatment success, proportion of deaths and time-to-death, comparison of treatment 
success rates between treatment groups according to pyrazinamide resistance.   
5. Expected Effects 
 
 


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If it is proven that the new treatment regimen is not inferior to the existing treatment regimens through 
this trial, it will be an epochal opportunity for treating MDR-TB in nine months or twelve months, 
which is a year shorter than the current 20 to 24 months. 
Moreover, by reducing the ‘time to Mycobacterium tuberculosis (MTB) culture conversion to negative’ 
of the current treatment, it will be possible to reduce the transmission of tuberculosis from patients to 
others.  


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1. Background of the Study 
1.1. Prevalence of and Threat Posed by MDR-TB 
Multidrug-resistant tuberculosis (MDR-TB) is tuberculosis that is resistant to at least isoniazid and 
rifampicin, the two most important anti-TB drugs, and it accounts for 3.5% of newly diagnosed TB 
patients in the world and 20.5% of patients who have been treated in the past. In 2013, approximately 
480,000 people were diagnosed with MDR-TB, and approximately 9% of the cases are extensively 
drug-resistant tuberculosis (XDR-TB) against the conventional TB drugs.(1) 
In 2013, there were 951 patients reported with MDR-TB (2), but considering the drug resistance rate 
in Korea, it is estimated that there are actually about 2,000 new MDR-TB cases occurring in Korea 
annually. 
1.2. Difficulties with Treatment of MDR-TB 
In order to treat MDR-TB, second-line anti-TB drugs including injectables must be used for 18-24 
months, but the success rate of treatment has recently been reported as 83.7% in Korea (3). It is only 
32.2% to 62.0% in other parts of the world (4,5). The WHO estimates the average treatment success 
rate of MDR-TB to be approximately 48% (Figure 1). 
 
 
Furthermore, there is a report about frequent side effects of using these second-line drugs that 
commonly have side effects for usage over long periods of time. And 30% of the 818 MDR-TB patients, 
or 245 patients, had to stop use of drugs because of adverse drug reactions such as nausea/vomiting, 
diarrhea, joint pains, dizziness, hearing difficulty, headache, and sleep disorders. (6) 
A considerable amount of money is used for treating MDR-TB patients. In the case of Korea, it costs 
7-22 times more to treat MDR-TB patients than drug-susceptible TB patients. The expenses needed to 
treat MDR-TB are similar to that for treating malignant diseases, and thus depletes huge amounts of 
money.(7, Figure 2)  


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1.3. Introduction of New Anti-TB Drugs 
A few new anti-TB drugs have been clinically introduced recently. These include drugs like 
moxifloxacin and linezolid which were developed originally to treat ordinary bacterial infections and 
were found to have strong anti-TB effects, and a few others developed to targeting Mycobacterium 
tuberculosis (MTB) such as bedaquiline, delamanid and PA-824. Research has been conducted on 
moxifloxacin to evaluate whether it can reduce the treatment period of drug-susceptible TB patients,(8, 
9) and it is also reported that linezolid (10,11), bedaquiline,(12) delamanid (13) can improve the 
treatment outcomes of MDR-TB patients. 
In the case of linezolid, it was administered to extensively drug-resistant TB (XDR-TB) patients who 
did not report improvement with any drugs. Treatment using linezolid showed powerful anti-TB effects 
obtaining sputum culture conversion to negative in 87% of these patients after six months of treatment 
(10). The focus of studies is now on how to use linezolid for MDR-TB patients, instead of administering 
to only XDR-TB patients. 
As strong anti-TB medications, such as delamanid and linezolid, were introduced, Dr. Caminero of the 
International Union Against Tuberculosis and Lung Disease (IUATLD) suggested a new classification 
(14). Based on the new classification by Dr. Caminero, the regimen with shorter treatment duration 
consisted of delamanid, linezolid, levofloxacin, and pyrazinamide. 


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2. Rationale 
2.1. Shortening of Treatment Duration  
The main reason for treatment failure in MDR-TB is that patients stop taking their treatment voluntarily 
for various reasons prematurely. From 1988 to 1996, 342 (39.0%) of 1,175 MDR-TB patients that 
received treatment at the TB Clinic of Korean National Tuberculosis Association stopped treatment 
arbitrarily prior to treatment completion (15), and 453 (32.2%) of 1,407 patients who received treatment 
at eight university hospitals and two national TB hospitals between 2000 and 2002 arbitrarily stopped 
treatment. (16)  
Thus, shortening the treatment duration that currently lasts 24 months is necessary to solve the MDR-
TB issue.   
There was a recent report that 427 MDR-TB patients in Bangladesh participated in a study and received 
seven anti-TB drugs including kanamycin and gatifloxacin for 9months. The study reported a cure rate 
of  82.5%, but 39.8% of participating patients complained of side effects which revealed the 
difficulties of taking medicine (17). 
2.2. Improvement of Treatment Efficacy 
Even after treatment failure, MDR-TB patients live for several years and continuously spread MDR-
TB bacilli to people they come in contact with. Considering this, it is necessary to raise the treatment 
success rate that is currently at 48~ 83.7% to solve the issues pertaining to MDR-TB. 
It is expected that MDR-TB patient treatment success rate could be improved by using linezolid that 
was introduced to treat vancomycin resistant bacterial infection or using the newly developed anti-TB 
drugs like delamanid and bedaquiline. The biggest interest for now is on how to use it together with 
current anti-TB drugs. 
In other words, the most urgent task is to investigate how to combine existing second-line anti-TB drugs 
such as fluoroquinolone, with the new drugs such as linezolid, delamanid and bedauquiline for 
treatment use.  
2.3. Contribution to International Community through Research on MDR-TB 
It is widely known that Korea has excessively high TB incidence for its economic level.  
 
 


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The annual TB incidence rate of Korea in 2013 was 97 per 100,000, which is much higher than the rates 
for Japan (18 per 100,000) and the United States (3.3 per 100,000) (1).  
Although the incidence of tuberculosis is shameful, it is also true that a world-class medical environment 
and excellent researchers provide an appropriate research environment that can lead to innovation in 
tuberculosis treatment. 
It will be a considerable contribution to the international community to solve the burden on public health 
caused by TB, especially by MDR-TB, as investigators can get meaningful research conclusions through 
this clinical trial in Korea.  


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3. Previous Research Results 
3.1. Comparison of Levofloxacin versus Moxifloxacin for Multidrug-Resistant Tuberculosis 
As a coordinating principal investigator, Yim Jae-Joon is an experienced researcher who oversaw the 
present clinical trials for comparing the efficacy of levofloxacin versus moxifloxacin for the treatment 
of MDR-TB patients. The study was conducted in a prospective, multicenter, randomized trial format 
from February 2010 to July 2012 with cooperation of 19 domestic institutes in total supported by the 
Korean Academy of Tuberculosis and Respiratory Diseases. (Clinicaltrial.gov Enrollment Number; 
NCT01055145)  
The purpose of this study was to compare the efficacy between levofloxacin and moxifloxacin, two 
most commonly used fluoroquinolones which should be included in MDR-TB treatment regimen. A 
total of 182 MDR-TB patients participated in this study, 88.3% of the levofloxacin group and 90.5% of 
the moxifloxacin group converted culture to negative at three months of treatment, which showed no 
difference between the two groups. This result was published in the American Journal of Respiratory 
and Critical Care Medicine. (18) 
3.2. Substitution of ethambutol with linezolid during the intensive phase of treatment of 
pulmonary tuberculosis 
The principal investigator is conducting a research, supported by the Korean Health Industry 
Development Institute, to investigate whether substituting linezolid for ethambutol can accelerate 
sputum MTB culture conversion to negative for the treatment of drug-susceptible TB patients. This 
prospective, multicenter, randomized clinical trial is being joined by Seoul National University, 
Bundang Seoul National University Hospital, Boramae Hospital, and the National Medical Center. 
(Clinicaltrial.gov Enrollment Number; NCT1994460) 
 


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4. Purpose of the Study 
This is a multicenter, randomized, open-label, two arms, phase II/III clinical trial to compare the effects 
of ‘new treatment regimen including delamanid, linezolid, levofloxacin, and pyrazinamide for nine or 
twelve months for fluoroquinolone-sensitive MDR-TB (investigational arm)’ and ‘standard treatment 
regimen including injectables for 20 to 24 months (control arm)’. The purpose of this study is to verify 
that the success rate of the simpler and shorter treatment is not inferior to conventional treatment. 
 
5. Design of the Study 
5.1. Study Design 
5.1.1. Study Drug 
Investigational drugs (delamanid: Otsuka Pharmaceutical, linezolid: Pfizer Pharmaceutical), 
provided for free from pharmaceutical companies for this study, will be delivered to the sites after 
labeling at Otsuka and Seoul National University Hospital according to investigational product 
labeling regulations. The study drugs will be managed by the designated pharmacists at each site, 
and stock, storage, dispensation, and return will be recorded in research documents. 
① Linezolid 
• Brand Name: Zyvox Tab (Pfizer Korea) 
• Form: White capsule shaped, film coated tablet 
• Composition: linezolid 600mg 
• Dosage and administration: Take one tablet (600mg) every day 
• Storage method: Stored in a sealed container at room temperature (15 - 30°C) 
• Expiration date: 36 months from the manufactured date  
② Delamanid 
• Brand Name: Deltyba Tab (Otsuka Korea), 50mg 
• Form: Yellow, round film-coated table (engraving: DLM, 50) 
• Composition: Delamanid 50mg 
• Dosage and administration: Take 100mg twice a day together with meal 


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• Storage method: Stored in a sealed container at room temperature (1 - 30°C) 
• Expiration date: 60 months from the manufactured date  
 
5.1.2. Multicenter, randomized, open-label, two arms, phase II/III clinical trial 
- Once eligibility is confirmed and the subject consents for participation, he/she will be randomly 
assigned to the following two groups at 1:1.  
① Group 1 (Control arm) 
Treatment will be according to the 2014 Korean guidelines for the treatment of tuberculosis (19) and 
2014 WHO guidelines (20). Treatment principles are summarized as follows.  
• Combination of treatment regimen 
- 
Intensive phase regimen comprising four effective second-line anti-TB drugs (including 
an injectable) and pyrazinamide. 
- 
It is recommended that at least five active drugs be used, selected appropriately based on 
drug susceptibility testing (DST) results.  
- 
Example of regimen: pyrazinamide, a fluoroquinolone, cycloserine, prothionamide, and 
an injectable 
- 
Efforts should always be made to use a fluoroquinolone, preferentially use levofloxacin or 
moxifloxacin.  
- 
Cycloserine should be used preferentially, but when it is not possible para-aminosalicyclic 
acid (PAS) could be used. 
- 
The medication like linezolid, delamanid, or bedaquiline can be added from the beginning 
of the treatment if the patient has a resistance to injectables. In addition, linezolid, 
delamanid, or bedaquiline can be used to fortify the regimen when the adverse drug 
reactions occur to other anti-TB drugs.  
- 
The usage and dosage follow 2014 Korean guidelines for the treatment of tuberculosis 
published by the Committee for the Revision of Korean Guidelines for Tuberculosis and 
the Korea Centers for Disease Control and Prevention (19) but not limited to it. 
 
Type of Drug 
Dose 
Usual dose 
Maximal dose 
Usage 
Ethambutol 
15-20mg/kg 
1600mg 
Once, before or after 


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meal 
Kanamycin 
Amikacin 
Streptomycin 
Capreomycin 
15mg/kg, < 50 years 
10mg/kg, ≥ 50 years 
1000mg, < 50years 
750mg, ≥50 years 
Once 
Cycloserine 
500mg, < 50 kg 
750mg, 50-70 kg 
750-1000mg, >70 kg 
1000mg 
Once or divide in two, 
before or after meal 
(best to take on an 
empty stomach) 
Prothionamide 
500mg, < 50 kg 
750mg, 50-70 kg 
750-1000mg, >70 kg 
1000mg 
Once or divide in two, 
after meal 
PAS 
150mg/kg 
12g 
Divide in two or three 
after meal 
• Treatment duration 
- 
Intensive phase is recommended to be a minimum of 8 months.  
- 
Total treatment duration is recommended to be 20 to 24 months. 
 
② Group 2 (Investigational Group) 
Regimen consists of only oral medication using delamanid, linezolid, levofloxacin, and pyrazinamide, 
for nine or twelve months.  
• Treatment duration 
o A total of 9 months (40 weeks) when sputum culture conversion to negative occurs 
within three months of treatment 
o 
A total of 12 months (52 weeks) when sputum culture conversion to negative occurs 
between 3 and 6 months of treatment 
• Combination of treatment regimen 
- 
Delamanid, 200mg/day (100mg bid) 
o Use for the entire treatment period unless it must be stopped for reasons such as adverse 
events. 
- 
Linezolid 
o 600mg/day during the first two months 
o 300mg/day afterwards until the end of treatment 


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o If linezolid re-administration is required after temporary discontinuation due to adverse 
events, the dose reduction to 300mg is allowed even within two months of treatment. 
- 
Levofloxacin  
o ≤ 50kg, 750mg/day 
o >50kg, 1000mg/day 
o Can be reduced or substituted with moxifloxacin due to reasons such as adverse events, 
and at this time, QT prolongation should be observed closely. Also, this substitution 
will not be considered as a drug change since both are fluoroquinolones of similar 
potency. 
o Once a day 
- 
Pyrazinamide 
o <50kg, 1000mg/day 
o 50-70kg, 1500mg/day 
o >70kg, 2000mg/day 
o Can be reduced due to adverse event. Even if pyrazinamide resistance is discovered on 
the phenotypic drugs susceptibility testing after commencing treatment, it can be 
continued (20). 
o Once or divide in two or three 
 
Since the definition of treatment outcomes follows the 2014 WHO Guidelines (20), as described in 
the ‘Research Protocol 6. Definition’, the change of a drug is allowed according to medical judgments, 
such as adverse drug reactions. However, the change of two or more drugs is considered ‘treatment 
failed’ and the participants will be withdrawn from the study. 
5.2. Primary Outcome 
• Treatment success rate at 24 months after the initiation of treatment: 
- ‘Cured’ and ‘treatment completed’ are defined as treatment success, and ‘culture’ defined below 
refers to results of liquid culture.  
- Treatment failure, death, loss to follow-up, transfer out and relapse were excluded from treatment 
success. 
- Definitions of treatment outcomes refer to 2014 WHO Guidelines (20). However, ‘stopping’ of 
drugs during treatment will not be considered as ‘drug change’ (Please see ‘6 Definitions’ in this 
protocol below.).   
 


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5.3. Secondary Outcomes 
• 
Time to sputum Mycobacterium tuberculosis (MTB) culture conversion to negative (liquid and 
solid culture media) 
• 
Sputum MTB culture conversion proportion at two months of treatment (liquid and solid 
culture media) 
• 
Sputum MTB culture conversion proportion at six months of treatment (liquid and solid culture 
media) 
• 
AE of grade 3 and higher  
• 
Proportion of participants with a treatment success at the end of treatment. 
• 
Proportion of relapse after treatment success (investigational arm) 
• 
Proportion of death and time-to-death 
• 
Comparison of treatment success rates between treatment groups according to pyrazinamide 
resistance. 
 
5.4. Inclusion Criteria 
1) Men and women age ≥19 and ≤85 
2) Confirmed pulmonary MDR-TB by phenotypic or genotypic drug susceptibility tests or RR-TB 
by genotypic tests such as Xpert® MTB/RIF assay regardless of being positive for sputum acid-
fast bacilli smear 
3) Use of current anti-TB regimen with second-line drugs for ≤ 14 days at the time of enrollment  
 
5.5. Exclusion Criteria 
1) Known any fluoroquinolone-resistant MDR-TB patients 
2) Known XDR-TB patients  
3) Patients who are pregnant or who are unwilling to use proper contraceptives at childbearing age 
4) Medical history of galactose intolerance, Lapp lactase deficiency, glucose-galactose 


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malabsorption 
5) The need for ongoing use of prohibited drugs while on study drugs   
6) History of optic neuropathy or peripheral neuropathy 
7) People with any of the following test results 
i. 
Absolute neutrophil count < 2000 /㎕  
ii. 
White blood cell count (WBC) < 3.0 X 103/µL 
iii. 
Hemoglobin < 7.0 g/dL 
iv. 
Serum creatinine > 2.0 mg/dL  
v. 
Aspartate aminotransferase (AST or SGOT) >100 IU/L 
vi. 
Alanine aminotransferase (ALT or SGPT) >100 IU/L 
vii. 
Total bilirubin > 2.0 mg/dL 
viii. 
Albumin < 2.8 g/dL 
ix. 
QTcF > 500 ms  
8) History of hypersensitivity reaction to the study drugs  
 
5.6. Precautions for Use and Expected Adverse Events (AE) 
5.6.1. Prohibited medications while on the study drugs 
- 
MAOIs (phenelzine, isocarboxazid, selegiline, and moclobemide) 
- 
Strong CYP3A inducer (i.e.; carbamazepine) 
 
5.6.2. Warning and precautions against using simultaneously  
① Delamanid 
• 
Drugs listed below that may expand QT intervals 
i. 
Antiarrhythmic drugs (amiodarone, disopyramide, dofetilide, ibutilide, procainamide, 
quinidine, hydroquinidine, sotalol) 
ii. 
Neuroleptics (phenothiazine, sertindole, sultopride, chlorpromazine, haloperidol, 
mesoridazine, pimozide, thioridazine), antidepressants 
iii. 
Antimicrobials: Macrolides (erythromycin, clarithromycin), moxifloxacin, 
sparfloxacin, Bedaquiline, Triazole antifungal agents, Pentamidine, Saquinavir 


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iv. 
Non-sedating antihistamine agents (terfenadine, astemizole, mizolastine) 
v. 
Cisapride, droperidol, domperidone, bepridil, probucol, levomethadyl, methadone, 
vinca alkaloids, arsenic trioxide 
• 
Strong inhibitors of CYP3A: Increases delamanid metabolites in blood (approximately 30%) 
• 
When having medical history related to the following heart abnormality 
i. 
QTc prolongation (> 450ms for males, and >470ms for females)  
ii. 
History of symptomatic arrhythmia, or taking anti-arrhythmic agents 
iii. 
Alleged severe hypertension, left ventricular hypertrophy, or congenital heart disease 
with decreased ejection fraction of left ventricle 
• 
Breastfeeding patient: It is recommended that women should not breastfeed during treatment 
② Linezolid 
• 
When there is possibility of causing serotonin syndrome 
i. 
Patients with carcinoid syndrome  
ii. 
Selective Serotonin reuptake inhibitors (SSRI), tricyclic antidepressants, serotonin 5-
HT1 receptor agonists (triptans), meperidine, bupropion, or buspirone 
• 
When requiring blood pressure monitoring 
i. 
Uncontrolled hypertension, pheochromocytoma, thyrotoxicosis  
ii. 
Administer together with sympathomimetic agents (e.g., pseudoephedrine), vasopressive 
agents (e.g., epinephrine, norepinephrine), dopaminergic agents (e.g., dopamine, 
dobutamine)  
• 
Blood glucose monitoring of diabetic patients: Precaution for possibility of hypoglycemia  
 
5.6.3. Expected Adverse Events (AE) 
- 
The subjects will be monitored for AEs of delamanid and linezolid treatments by the 
primary medical team at each site. The expected major AEs are as follows. 
① Delamanid  
 
System 
Organ 
Class 
Frequency 
uncommon 
Frequency 
common 
Frequency 
very common 
Infections 
and 
infestations 
Herpes zoster 
Oropharyngeal candidiasis 
Tinea versicolor* 
 
 
Blood 
and 
lymphatic 
system 
Leukopenia 
Thrombocytopaenia 
Anemia* 
Eosinophilia* 
Reticulocytosis 


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disorders 
Metabolism and 
nutrition 
disorders 
Dehydration 
Hypocalcemia 
Hypercholesterolemia 
Hypertriglyceridemia 
Hypokalemia 
Decreased 
appetite 
Hyperuricemia* 
Psychiatric 
disorders 
Aggression 
Delusional disorder, persecutory 
type 
Panic disorder 
Adjustment 
disorder 
with 
depressed mood 
Neurosis 
Dysphoria 
Mental disorder 
Sleep disorder 
Libido increased* 
Psychotic disorder 
Agitation 
Anxiety 
and 
anxiety 
disorder 
Depression and depressed 
mood 
Restlessness 
Insomnia 
Nervous system 
disorders 
Lethargy 
Balance disorder 
Radicular pain 
Poor quality sleep 
Neuropathy peripheral 
Somnolence* 
Hypoesthesia 
 
Dizziness* 
Headache 
Paresthesia 
Tremor 
Eye disorders 
Conjunctivitis allergic* 
Dry eye* 
Photophobia 
 
Ear 
and 
labyrinth 
disorders 
 
Ear pain 
Tinnitus 
Cardiac 
disorders 
Atrioventricular block first degree 
Ventricular extrasystoles* 
Supraventricular extrasystoles 
 
Palpitations 
Vascular 
disorders 
 
Hypertension 
Hypotension 
Hematoma* 
Hot flush* 
 
Respiratory, 
thoracic 
and 
mediastinal 
disorders 
 
Dyspnea 
Cough 
Oropharyngeal pain 
Throat irritation 
Dry throat* 
Rhinorrhea* 
Hemoptysis 
Gastrointestinal 
disorders 
Dysphagia 
Paraesthesia oral 
Abdominal tenderness* 
Gastritis* 
Constipation* 
Abdominal pain 
Abdominal pain (lower) 
Dyspepsia 
Abdominal discomfort 
Vomiting 
Diarrhoea* 
Nausea 
Abdominal pain 
(upper) 
Hepatobiliary 
disorders 
Hepatic function abnormal 
 
 
Skin 
and 
subcutaneous 
tissue disorders 
Alopecia* 
Eosinophilic pustular folliculitis* 
Pruritus generalized* 
Rash erythematous 
Dermatitis 
Urticaria 
Rash pruritic* 
Pruritus* 
Rash maculo-papular* 
Rash* 
Acne 
Hyperhidrosis 
 
Musculoskeletal 
and connective 
tissue disorders 
 
Osteochondrosis 
Muscular weakness 
Musculoskeletal pain* 
Flank pain 
Pain in extremity 
Arthralgia* 
Myalgia* 
Renal 
and 
urinary 
disorders 
Urinary retention 
Dysuria* 
Nocturia 
Hematuria* 
 
 
General 
Feeling hot 
Pyrexia* 
Asthenia 


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disorders 
and 
administration 
site conditions 
Chest pain 
Malaise 
Chest discomfort* 
Oedema peripheral* 
Investigations 
Electrocardiogram ST - segment 
depression 
Transaminases increased* 
Activated partial thromboplastin 
time prolonged* 
Gamma-glutamyltransferase 
increased* 
Blood cortisol decreased 
Blood pressure increased 
Blood cortisol increased 
Electrocardiogra
m QT prolonged 
* The frequency for these events was lower for the combined Deltyba plus OBR group in comparison to 
the placebo plus OBR group. 
 
② Linezolid 
The most common adverse events include diarrhea (2.8%-11.0%), headache (0.5%-11.3%), vomiting 
(3.4%-9.6%), and 
• 
Systemic: headaches, moniliasis, fungal infection, fever 
• 
Mental & Nervous system: dizziness, insomnia 
• 
Special organs: taste alteration 
• 
Digestive system: diarrhea, nausea, vomiting, abdominal pains, abdominal clamping, 
abdominal distension, constipation, dyspepsia, tongue discoloration and teeth discoloration 
• 
Cardiovascular system: hypertension 
• 
Blood/Lymphatic system: thrombocytopenia, low hemoglobin level, leukopenia, neutropenia 
• 
Urogenital system: vaginal moniliasis 
• 
Skin: rash, pruritus 
• 
Investigation: abnormal blood tests and abnormal liver function tests 
 


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6. Definition 
 
6.1. Culture Conversion to Negative  
i. 
Culture is considered to have converted to negative when two consecutive cultures, taken at 
least 4 weeks apart, are found to be negative. 
ii. 
When a subject cannot produce sputum after the first culture negative sputum, that is also 
defined as culture conversion.  
iii. 
Encourage to expectorate sputum as much as possible (including induced sputum), but if the 
subject cannot produce sputum, it will not be deemed as protocol violation. 
6.2. Date of Culture Conversion  
For both the above i and ii, the date of culture conversion is defined as the date of the initial negative 
culture. 
6.3. Reversion 
When Mycobacterium tuberculosis (MTB) is cultured at least two or more times after negative 
conversion.  
6.4. Treatment Outcome Definitions  
 
Definitions of treatment outcomes refer to 2014 WHO Guidelines (20). For investigational group, 6 
months will be considered as intensive phase.  
 
<Definitions of treatment outcomes for drug-resistant patients> 
 
TREATMENT 
OUTCOME 
DEFINITION 
Cured 
Treatment completed as recommended by the national policy without 
evidence of failure AND three or more consecutive cultures taken at least 30 
days apart are negative after the intensive phase.
a 
Treatment completed 
Treatment completed as recommended by the national policy without 
evidence of failure BUT no record that three or more consecutive cultures 
taken at least 30 days apart are negative after the intensive phase.
a 
Treatment failed 
Treatment terminated or need for permanent regimen change of at least two 
anti-TB drugs because of: 
•Lack of conversion
b by the end of the intensive phase
a; or 
•Bacteriological reversion
b in the continuation phase after conversion
b to 
negative; or 
•Evidence of additional acquired resistance to fluoroquinolones or second-line 
injectable drugs; or 
•Adverse drug reactions. 


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Died 
A patient who dies for any reason during the course of treatment. 
Lost to follow-up 
A patient whose treatment was interrupted for two consecutive months or 
more. 
Not evaluated  
A patient for whom no treatment outcome is assigned. (This includes cases 
“transferred out” to another treatment unit and whose treatment outcome is 
unknown). 
Treatment success 
The sum of Cured and Treatment completed. 
a For Treatment failed, lack of conversion by the end of the intensive phase† implies that the patient does 
not convert within the maximum duration of the intensive phase† applied by the programme. If no 
maximum duration is defined, an 8-month cut-off is proposed. For regimens without a clear distinction 
between intensive and continuation phases, a cut-off eight months after the start of treatment is 
suggested to determine when the criteria for Cured, Treatment completed and Treatment failed start to 
apply. (†For investigational group, 6 months will be considered as intensive phase.)  
 
 
b The terms “conversion” and “reversion” of culture as used here are defined as follows : 
Conversion (to negative): culture is considered to have converted to negative when two consecutive 
cultures, taken at least 30 days* apart, are found to be negative. In such a case, the specimen collection 
date of the first negative culture is used as the date of conversion. (*According to intervals of research 
visits, it will be 4 weeks)  
 
Reversion (to positive): culture is considered to have reverted to positive when, after an initial 
conversion, two consecutive cultures, taken at least 30 days* apart, are found to be positive. For the 
purpose of defining Treatment failure, reversion is considered only when it occurs in the continuation 
phase. (*According to intervals of research visits, it will be 4 weeks)  
 
 
 
 
 


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7. Study Timeline 
7.1. Control arm 
 
 
Screening 
Baseline 
Visit1 
Treatment 
End of 
Treatment 7 
End of 
Study 
Weeks (w) 
-2w ~ 0d 
0 
1w 
2w 
4w 
8w 
12w ~ 
(Every 4w) 
52w ~ 
(Every 2month) 
80w ~ 
24month 
Visit window 
n-a 
n-a 
±4d 
±4d 
±1w 
±2w 
±2w 
±2w 
±2w 
±2w 
Consent 
O 
 
 
 
 
 
 
 
 
 
Randomization 
 
O 
 
 
 
 
 
 
 
 
Medical history 
O 
 
 
 
 
 
 
 
 
 
Physical Exam 
O 
 
O 
O 
O 
O 
O 
O 
O 
O 
Neurologic exam 
O 
 
 
 
 
 
 
 
 
 
Sputum AFB smear 
O5 
O5 
O 
O 
O 
O 
O 
O 
O 
O 
TB culture (solid) 
O5 
O5 
O 
O 
O 
O 
O 
O 
O 
O 
TB culture (liquid) 
O5 
O5 
O 
O 
O 
O 
O 
O 
O 
O 
Genotypic DST 
If available 
Phenotypic DST2 
With first/reverted cultured M.TB 
Chest X-ray (CXR) 
O5 
O5 
O8 
O8 
O 
O 
O 
O 
O 
O 
Chemistry, Electrolyte 
O5 
O5 
O 
O 
O 
O 
O 
O 
O 
 
Complete blood count 
O5 
O5 
O 
O 
O 
O 
O 
O 
O 
 
ECG 
O5 
 
 
 
 
 
 
 
 
 
Urine HCG3 
O 
O 
 
 
 
 
 
 
 
 
HIV, HBV4 
 
O5 
 
 
 
 
 
 
 
 
Optic test 
O 
 
 
 
 
 
 
 
 
 
Compliance of drug 
intake 
 
 
O 
O 
O 
O 
O 
O 
O 
 
Adverse drug reaction 
 
 
O 
O 
O 
O 
O 
O 
O 
 
Other medication6 
O 
O 
O 
O 
O 
O 
O 
O 
O 
 
 
1Administration of anti-TB regimen can begin at baseline visit since drug-resistant TB must be treated immediately. 
2Drug susceptibility test for isoniazid, rifampicin, ethambutol, pyrazinamide, streptomycin, kanamycin, amikacin, 
capreomycin, ofloxacin, levofloxacin, moxifloxacin, prothionamide, cycloserine, and para-aminosalicylic acid (omit for 
patients with results already provided). 
3Only for childbearing age (the blood HCG test result can be extracted)  
4Study drugs can be administered before the obtaining of results since eligibility is not determined by these results. 
5Could be skipped if previous tests except ECG were done within four weeks. In case of ECG, within 1week.   
6Check prohibited drugs for exclusion criteria at screening visit, and check immunosuppressants including steroids after 
enrollment. 
7End of treatment(EOT) visit will be determined by the standard TB treatment guidelines. If  EOT visit and the end of study(EOS) 
visit are the same, a test corresponding to the EOT visit will be conducted. 
8Could be skipped if previous CXR test was performed within 2 weeks 
 
 
 
 
 


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7.2. Investigational arm 
 
 
 
Screening 
Baseline 
Visit1 
Treatment 
End of 
Treatment 7 
Treatment 
completion 
to 
End of Study 
Weeks (w) 
-2w ~ 0d 
0 
1w 
2w 
4w 
8w 
12w ~ 
(Every 4w) 
40w ~ 52w 
~ 24month 
(Every 2month) 
Visit window 
n-a 
n-a 
±4d 
±4d 
±1w 
±2w 
±2w 
±2w 
±2w 
Consent 
O 
 
 
 
 
 
 
 
 
Randomization 
 
O 
 
 
 
 
 
 
 
Medical history 
O 
 
 
 
 
 
 
 
 
Physical Exam 
O 
 
O 
O 
O 
O 
O 
O7 
 
Neurologic exam 
O 
 
O 
O 
O 
O 
O 
O7 
 
Sputum AFB smear 
O5 
O5 
O 
O 
O 
O 
O 
O 
O 
TB culture (solid) 
O5 
O5 
O 
O 
O 
O 
O 
O 
O 
TB culture (liquid) 
O5 
O5 
O 
O 
O 
O 
O 
O 
O 
Genotypic DST 
If available 
Phenotypic DST2 
With first/reverted cultured M.TB 
LZD, Delamanid resistance 
examination 
If needed (please see the protocol section 9.0) 
Chest X-ray (CXR) 
O5 
O5 
O8 
O8 
O 
O 
O 
O 
O 
Chemistry, Electrolyte 
O5 
O5 
O 
O 
O 
O 
O 
O7 
 
Complete blood count 
O5 
O5 
O 
O 
O 
O 
O 
O7 
 
ECG 
O5 
O5 
O 
O 
O 
O 
O 
O7 
 
Urine HCG3 
O 
O 
O 
O 
O 
O 
O 
O7 
 
HIV, HBV4 
 
O5 
 
 
 
 
 
 
 
Optic test 
O 
O 
O 
O 
O 
O 
O 
O7 
 
Compliance of drug intake 
 
 
O 
O 
O 
O 
O 
O7 
 
Adverse drug reaction 
 
 
O 
O 
O 
O 
O 
O7 
 
Other medication6 
O 
O 
O 
O 
O 
O 
O 
O7 
 
 
1Administration of anti-TB regimen can begin at baseline visit since drug-resistant TB must be treated immediately. 
2Drug susceptibility test for isoniazid, rifampicin, ethambutol, pyrazinamide, streptomycin, kanamycin, amikacin, capreomycin, 
ofloxacin, levofloxacin, moxifloxacin, prothionamide, cycloserine, and para-aminosalicylic acid (omit for patients with results 
provided already). 
3Only for childbearing age (the blood HCG test result can be extracted).  
4Study drugs can be administered before the obtaining of results since eligibility is not determined by these results. 
5Could be skipped if previous tests except ECG were been done within four weeks. In case of ECG, within 1week.  
6Check prohibited drugs for exclusion criteria at screening visit, and check immunosupperessants including steroids after 
enrollment. 
7 End of treatment visit will be determined by the time of culture conversion. Omit test after end of treatment (EOT) visit. 
8Could be skipped if previous CXR test was performed within 2 weeks 


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8. Screening and Procedures 
 
8.1. Subject Screening and Enrollment 
- When resistance to rifampicin is confirmed, screening can be done after subject signs the consent form.  
- Recording of medical history, physical examinations and neurological examinations will be performed. 
Sputum AFB smear microscopy, MTB culture on both liquid and solid media will be performed.  
- Genotypic DST (MTBDRsl and etc.) could be performed, if available. 
- Phenotypic DST will be performed for the first positive culture and reversion specimen if available.  
- Chest X-ray (CXR), Electrocardiogram (ECG), complete blood count, electrolytes, chemistry (glucose, 
albumin, total bilirubin, AST, ALT, Creatinine) will be performed. The results of the test performed 
according to the standard TB treatment guidelines (calcium, phosphorus, uric acid, cholesterol, protein, 
alkaline phosphatase, BUN, etc.) can be further reviewed. 
* Tests could be skipped in case of having available results or tests were performed recently within four 
weeks (In case of ECG, within a week). It is possible to extract chest CT results instead of chest X-
ray(CXR) test. 
- For subject of childbearing potential, urine HCG will be performed (the blood HCG test result can be 
extracted).  
 
8.2. Randomization 
- Once a subject has signed informed consent form and found eligible, subject will be randomly assigned 
to investigational or control arm at a rate of 1:1 on week 0.  
- The study will use block randomization method, using block sizes of 4 or 6 chosen randomly, stratified 
by ①presence/absence of cavitation on baseline chest radiographs, ②presence/absence of baseline 
diabetes mellitus. Randomization table will be prepared by using SAS 9.3.  
- Randomization table and web-based randomization is operated by the person in charge of this clinical 
trial at the Medical Research Collaborating Center (MRCC) in Seoul National University Hospital 
Biomedical Research Institute. The access and management of randomization information will be carried 
out independently from the clinical investigator or clinical trial sponsor. 
- Diabetes mellitus will be diagnosed for one of the following three. ① fasting blood glucose ≥ 
126mg/dL ② random blood glucose ≥ 200mg/dL ③ currently taking hypoglycemics. 


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8.3. Baseline Visit and Beginning of Treatment 
- AFB smear microscopy, and MTB culture on liquid and solid media of sputum or bronchoscopic 
specimen will be performed.  
- CXR, ECG, complete blood count, electrolytes, chemistry (albumin, total bilirubin, alkaline phosphatase, 
AST, ALT, Creatinine), anti-HIV antibody and HBsAg will be performed.  
- Ishihara Test for Color-blindness will be performed to check baseline abnormalities of color blindness.  
* Tests could be skipped in case of having available results or tests were performed recently within four 
weeks (In case of ECG, within a week).  
* Study drugs can be administered before the obtaining of anti-HIV Ab, HBsAg, and alkaline phosphatase 
results since eligibility is not determined by these results.  
* Administration of anti-TB regimen can begin at baseline visit since drug-resistant TB must be treated 
immediately.  
 
8.4. Study Visits 
- Subjects will visit for study at 1 week, 2 weeks and 4 weeks after enrollment, and then every four weeks 
until 12 months(52 weeks), afterwards every 2 months until the end of treatment (EOT). The time of EOT 
is 40 or 52 weeks for the Investigational arm and will be determined individually for control arm 
according to the standard of care treatment.  
- Subjects in the investigational arm will visit every 2 months after EOT even if it is before 12 
months(52weeks). 
8.4.1. Study tests of visits while on anti-TB medication 
① Control arm 
• 
Physical examination  
• 
Sputum AFB smear microscopy and MTB culture on liquid and solid media 
• 
CXR 
• 
Complete blood count, chemistry (total bilirubin, alkaline phosphatase, AST, ALT, creatinine) 


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• 
Check taking systemic steroid and immunosuppressive agents. 
② Investigational arm 
• 
Physical examination, neurological examination 
• 
Sputum AFB smear microscopy and MTB culture on liquid and solid media 
• 
CXR, ECG  
• 
Complete blood count, electrolyte, chemistry (total bilirubin, albumin alkaline phosphatase, 
AST, ALT, creatinine) 
• 
Ishihara Test for Color-blindness to detect occurrence of color vision abnormalites. 
• 
Check all other concomitant medications including systemic steroid and immunosuppressive 
agents. 
• 
For subject of childbearing potential, urine HCG will be performed (the blood HCG test result 
can be extracted). 
8.4.2. Follow-up visits after EOT (Investigational arm only) 
• 
Sputum AFB smear microscopy and MTB culture on liquid and solid media 
• 
CXR 
8.5. Details of Study Procedures 
 
Standard-of-care testing for the treatment and differentiation of multi-drug resistant TB will be performed 
after obtaining informed consent form of the study. The following test results may be used for research 
purposes. 
1) Medical history 
Medical history, especially for TB treatment history, diabetes mellitus and abnormal color vision 
2) Physical examination 
Routine physical examination 
3) Neurological examination 
Neurological examination, especially for abnormal sensation on legs and feet.  
Any neurologic AE is developed, information including location, severity, and the relationship to the 


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study drug will be documented. Additional neurologic tests could be done, if necessary.  
4) Sputum acid-fast bacilli (AFB) smear and culture  
Approximately 4mL or more of sputum will be collected and mixed with the same amount of 4% 
sodium hydroxide and then centrifuged for 20 minutes at 3,000xg to get pellet for AFB smear 
microscopy and MTB culture. AFB smear will be performed with Auramine-Rhodamine fluorescent 
staining at first and then with Ziehl-Neelsen staining for positive samples. For MTB culture, tubes with 
samples in the solid media (Ogawa culture medium) and liquid media (BACTEC  MGITTM  or other) 
are continuously incubated at 5~10% CO2 incubator for 6 weeks.  
5) Drug Susceptibility Test (DST) 
Phenotypic DST will be performed at outside laboratories other than the treatment sites. Resistance to 
each drug tested is defined as ≥1% bacterial growth in Löwenstein- Jensen medium using the absolute 
concentration method observed with the following critical concentrations of anti-tuberculosis drugs: 
isoniazid 0.2 μg/ml; streptomycin 10.0 μg/ml; ethambutol 2.0 μg/ml; rifampicin 40.0 μg/ml; para-
aminosalicylic acid 1.0 μg/ml; prothionamide 40.0 μg/ml; cycloserine 30.0 μg/ml; kanamycin 40.0 
μg/ml; capreomycin 40.0 μg/ml; ofloxacin 2.0 μg/ml; levofloxacin 2.0 μg/ml; and moxifloxacin 2.0 
μg/ml;. Pyrazinamide susceptibility is determined using the pyrazinamidase test. 
Genotypic DST (MTBDRsl and etc.) could be performed, if available. 
6) CXR 
Plain chest PA is performed per routine diagnostic method at each site. If possible, below conditions 
will be followed: 120kV, tube current (in milliamperes) with automatic exposure control, and a 12:1 
antiscatter grid with a 180-cm focus-detector distance. 
7) HIV, HBV Test 
Peripheral blood 5mL is collected in plain tube and ELISA performed to detect anti-HIV antibody, HBs 
Ag.  
8) Complete Blood Count  
Peripheral blood 3mL is collected in EDTA tube to test red blood cell count (RBC), mean corpuscular 
volume (MCV), white blood cell count (WBC) with differential count, hemoglobin, hematocrit, and 
platelet count.  
9) Chemistry 
Peripheral blood 3mL is collected in SST tube to test total bilirubin, albumin, alkaline phosphatase, 
AST, ALT, Creatinine, and electrolytes examination.  
10) Urine HCG Test 


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Urine 10-50mLis collected to test pregnancy by human chorionic gonadotropin (β-hCG) determination 
kit.  
11) Color vision test 
Identify number of plates accurately read using the Ishihara Test for Color Blindness (24 plates).  
12) Electrocardiography  
Measure QT interval.  
 
8.6. Study Drug Adherence 
- DOT (Directly Observed Therapy) is not performed per Korean guidelines for the treatment of 
tuberculosis. 
- The study nurse checks the study drug adherence by comparing the drug packaging with residual pill 
count at each visit. In the event that a scheduled visit is changed, the administration status of the study 
drugs and other drugs during that period will be checked as well. 
Drug adherence = (actually taken dosage/prescribed dosage) * 100 
8.7.  Withdrawal 
1) When the investigator judges that participating in this clinical trial would not be in the best interests 
of the subject 
2) When the subject withdraws consent  
3) Treatment failure 
4) When the subject becomes pregnant while on anti-TB medication. 
5) When investigators get additional test results of resistance like below, 
a) fluoroquinolone resistance (phenotypic or molecular method) 
b) rifampicin monoresistance is confirmed 
c) rifampicin susceptible 
* Subjects who withdrawn from the study will receive the same treatment with other TB patients by 
standard of care treatment.  
 
 


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9. Checking for Developing Resistance Against Study Drug  
9.1. Subjects 
When culture conversion fails 6 months into treatment among subjects assigned to the investigational 
group, identify whether resistance to linezolid and delamanid manifested in MTB isolate cultured in 
sputum or bronchoscopic specimens at the time of participating in the study and at 6 months after 
treatment.  
9.2. Method 
1) Linezolid resistance examination: Same as method in ① or ②. 
① MGIT960: Judge resistance using 1.0 µg/ml critical concentration.  
② Broth microdilution method: Inoculate bacteria in Middlebrook 7H9 containing a suitable 
concentration of linezolid in culture media and determine minimal concentration for suppressing 
bacterial growth, and judge as having resistance when the minimal suppression concentration 
considerably increases than the strain when first participating in the research. 
③ May check mutation of genes related to already known linezolid resistance. 
2) Delamanid resistance test  
① Agar proportion method using Middlebrook 7H11 culture media, and judged as having resistance 
when, for over 1% of control group, growth of strain is not included in drug at Delamanid 0.2 
µg/ml.  
② May check mutation of genes related to already known delamanid resistance. 
 
 


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10. Sample size justification and Statistical Analysis Method 
10.1. Sample size justification  
The hypothesis of this study is that the treatment success rate at 24 months after the initiation of treatment 
for MDR TB using the new regimen including new anti-TB drugs will not be inferior to conventional 
treatment regimens. (Non-inferiority test) 
Presumptions when calculating sample size are as follows. 
1) Level of significance, α = 0.025 (one-sided test) 
2) Type 2 error (β) set at 0.20 to maintain 80% for power of the test 
3) Subject no. ratio (control arm : investigational arm) = 1 : 1 
4) Primary outcome: treatment success rate at 24 months after the initiation of treatment 
5) The hypothesis of the study is as follows. 
① Null hypothesis: Four drug regimen treatment success rates at 24 month are inferior to 
conventional treatment outcomes. (
) 
② Alternative hypothesis: Four drug regimen treatment success rates at 24 month are not inferior 
to conventional treatment outcomes. (
) 
Based on the study result of Kwak et al, ‘Changes in treatment outcomes of multidrug-resistant 
tuberculosis, Int J Tuberc Lung Dis 19(5):525-530’(3), presuming 24 month treatment success rate of 
control arm as 80% and 24 month treatment success rate of investigational arm as 90%, the non-inferiority 
margin (
) is -0.10 which is regarded as non-inferior when the difference is less than 10% between the 
two arms. The number of study subjects is 48 per arm.  
In addition, reflecting 1) proportion of fluoroquinolone-susceptible MDR-TB among participants with 
positive Xpert MTB/RIF assay of 50%, and 2) anticipating 5% lost to follow-up, the final number of 
participants is calculated as N/(0.50*0.95) resulting in 102 persons per arm, 204 in total. 
If a participant withdrew for any reasons within two weeks after enrollment, the participant will be 
replaced. Considering the number of replaced participants, the enrollment accrual ceiling is 220 persons 
maximum. 
δ
P
P
:
H
C
T
0
≤
−
δ
P
P
:
H
C
T
1
>
−
δ


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10.2. Statistical Analysis Method 
1) Analysis Group Definition 
Data obtained from subjects through clinical trials will be analyzed by mITT (Modified Intention-
To-Treatment) analysis and PP (Per-Protocol) analysis. Efficacy evaluation will be based on a mITT 
(Modified Intention-To-Treatment) and additional analysis on PP (Per-Protocol) group. Safety 
analysis will be performed on the safety group. 
- 
The mITT (Modified Intention-To-Treatment) group includes participants who are 
randomized after satisfying eligibility criteria and receive study drugs at least one time.  
- 
The PP (Per-Protocol) group includes participants that satisfy the following among mITT 
group.  
1) When completing over 80% of the planned treatment (in other words, for control arm, 
64 weeks or longer treatment; For investigational arm, 32 weeks or longer treatment in the 
9-month treatment group and 42 weeks or longer treatment in the 12-month treatment group)  
2) Participants who completed the study per protocol during the clinical trial period. 
- 
The Safety analysis group includes participants who receive study drugs at least one time. 
2) Handling of Missing Data   
 When categorized as ‘loss to follow-up’, ‘withdrawal’, or ‘withdrawal of consent’, it is deemed as 
following. 
① ‘Treatment failure’ in the case of dropping out due to ‘loss to follow-up’, ‘investigator’s 
decision’, ‘withdrawal of consent’, ‘treatment failure’, or ‘death’ during the treatment 
② ‘Not accessible’ in the case of dropping out due to pregnancy during the treatment 
③ ‘Treatment failure’ in the case of dropping out due to ‘relapse’ after the treatment 
completion 
④ ‘Not accessible’ when there is no evidence of treatment failure, such as bacteria reversion 
in the case of withdrawal due to ‘loss to follow-up’, ‘investigator’s decision’, ‘withdrawal 
of consent’, ‘pregnancy’, or ‘death’ after the treatment completion 
3) Basic Characteristics Analysis of Subjects Prior to Administration of Study Drugs 
In order to check if there is any significant difference in demographic or clinical characteristics 
among the two arms prior to administration of study drugs, the serial data is summarized as mean, 
standard deviation, median and minimum and maximum, and the two arms are compared by 
independent t-test or Wilcoxon rank sum test. For categorical variables, the frequency and proportion 
per group is found and the two arms are compared by Chi-square test and Fisher’s exact test. This 
analysis is carried out on the ITT analysis group. 


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4) Efficacy Evaluation 
All statistical analysis of the two arms is carried out at significance level of 5% for both sides unless 
stated otherwise. For additional analysis, stratified analysis will be performed for primary and 
secondary outcome evaluation by stratification into sputum smear positive patient groups and sputum 
smear negative patient groups based on the sputum smear microscopy results.  
①  Primary Efficacy Evaluation 
The primary outcome of this clinical trial is treatment success rate at 24 months after the initiation 
of treatment. 
Describe the treatment success rate of the control arm and the investigational arm with a two-sided 
95% confidence interval. Then, in order to test for non-inferiority of the investigational arm, when 
the lower limit of one-sided 97.5% confidence interval of the difference (PT - PC) between control 
and investigational arm is larger than the non-inferiority margin of -10%, it is concluded that the 
treatment success rate of the investigational arm is non-inferior to the treatment success rate of the 
control arm. The subjects whose treatment result is assessed ‘Not accessible’ are excluded from 
the primary outcome evaluation. 
②  Secondary Efficacy Evaluation 
  The secondary outcomes are analyzed as following and describe at exploratory levels.  
• Time to sputum culture conversion after the initiation of treatment (liquid and solid 
culture media) 
- In order to test whether the time to sputum culture conversion after the initiation of treatment 
of the control arm and investigational arm (liquid and solid culture media) are different 
statistically, the median time is estimated in each group using the Kaplan-Meier method, and the 
difference of the distribution of time to culture conversion of the two arms is compared using 
the Log-rank test.  
• Sputum culture conversion proportion at two months of treatment (liquid and solid culture 
media) 
- In order to test whether there is a statistical difference in sputum culture conversion proportion 
at two months of treatment between the control arm and the investigational arm (liquid and solid 
culture media), each arm is summarized by conversion frequency and proportion, and the sputum 
culture conversion proportions at two months between the two arms are compared using the Chi-
square test and Fisher’s exact test.  
• Sputum culture conversion proportion at six months of treatment (liquid and solid culture 
media) 
- In order to test whether there is a statistical difference in sputum culture conversion proportion 
at six months of treatment between the control arm and the investigational arm (liquid and solid 
culture media), each arm is summarized by conversion frequency and proportion, and the sputum 
culture conversion proportions at six months between the two arms are compared using the Chi-
square test and Fisher’s exact test. 


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• Proportion of treatment success at the end of treatment 
-Summarize the frequency and proportion of treatment success at the end of treatment in the 
investigational arm. 
• Proportion of relapse after treatment success 
-Summarize the frequency and proportion of relapse after treatment success in the 
investigational arm. 
• Proportion of deaths and time-to-death 
-Summarize the frequency and proportion of death in the investigational arm, and estimate 
median survival time using the Kaplan-Meier method. 
• Primary outcome evaluation between treatment groups according to pyrazinamide 
resistance 
-Presentation of treatment success rate in the control arm and the investigational arm in small 
groups according to the presence or absence of pyrazinamide resistance, and verification of non-
inferiority of treatment success rate difference between the treatment groups 
5) Safety Evaluation 
Safety evaluation is performed using adverse events that occur during the clinical trial period. 
Summarize all adverse events and serious adverse events, adverse event frequency and percentage, 
and 95% confidence interval on it. Also, summarize and evaluate the occurrence rate of adverse 
events in relationship to the study drug and severity. The incidence of adverse events (CTCAE Grade 
3 and above toxicity) between the two arms are compared using the Chi-square test or Fisher’s exact 
test. 


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11. Safety Assessment 
11.1. Definition 
1) Adverse Events (AEs) 
Adverse events are undesirable  medical occurrence in subjects administered a pharmaceutical product 
in clinical trials, and which does not necessarily have a causal relationship with the drugs. An adverse 
event(AE) can therefore be any unfavourable and unintended sign (including an abnormal laboratory 
finding), symptoms or diseases temporarily associated with the use of medicinal (investigational) 
product, whether or not related to the medicinal(investigational) product. 
Adverse events may include not only those newly occurring after the participation in the research, but 
also worsened severity or frequencies compared to the initial evaluation, as well as abnormal diagnostic 
test results including abnormal laboratory findings.  
2) Serious Adverse Events (SAEs) 
In this study, SAE is defined as any untoward medical occurrence that: 
① Results in death during the study 
② Is life-threatening 
③ Results in a persistent or significant disability/incapacity 
④ Results in congenital anomaly/birth defect 
⑤ Results in inpatient hospitalization or prolongation of existing hospitalization 
In addition to the situations stated above, medical and scientific judgments will be made to determine 
whether the prompt reports are suitable. For example, an AE that may place the subject in danger, or 
that needs treatment to prevent worsening from the situations stated above, or that is regarded as having 
significant clinical influence by the investigator’s decision, will be regarded as a SAE although it is not 
life-threatening or does not result in death or hospitalization.  
3) Unlisted (Unexpected) Adverse Event 
Unexpected Adverse Events refer to AEs in which the nature or severity is different compared to the 
information of approved package insert.  
4) Relationship to the Study Drug 
The definition of relationship is as follows.  
① Not related: Adverse Event having no relationship with use of study drug 
② Unlikely (Doubtful): Adverse events whose relationship to study drug makes a temporary causal 
relationship or improbable and in which other concomitant medications or underlying disease 
provides plausible explanations 


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③ Possible: Adverse events may be due to the use of the study drug. Other explanations, such as 
other concomitant medications or underlying diseases, are not conclusive. As the temporal 
relationship is reasonable, the causal relationship cannot be excluded.  
④ Probable: Adverse events may be due to the use of the study drug. The temporal relationship is 
reasonable (e.g., confirmed by drug discontinuation) and does not appear to be due to 
concomitant medications or underlying diseases. 
⑤ Definite: Adverse event is described as a possible adverse reaction and cannot be explained as a 
concomitant drug or a underlying disease. The temporal relationship is very plausible (e.g., 
confirmed by stopping and re-administering the study drug). 
 
The Adverse Event will be judged to be related to the use of the study drug when the contribution of 
the drug to adverse event is Possible, Probable or Definite according to the above definition. 
5) Grading for Severity 
The severity of AE will be determined using CTCAE Version 4.0. 
 
11.2. Adverse Event Collection and Reporting 
1) All Adverse Events(AEs) 
All AEs found in subjects who received the study drugs from baseline visit or after the randomization 
will be collected. Any AEs that falls within the definition of a serious adverse event(SAE) will be 
reported as SAE regardless of specific evaluation items in the protocol. 
All AEs regardless of the severity, seriousness, or relationship to the study drug, will be documented 
on source document (SD) and case report form (CRF) using English medical terms. When possible, if 
the signs and symptoms are due to common diseases (e.g., cough, runny nose, sneezing, 
laryngopharyngitis, stuffy head, will be reported as “upper respiratory infection”), it will be recorded 
using its diagnostic name in principle. The investigator will record his/her opinion of the relationship 
of AE to the study drugs on both SD and CRF, and record all evaluations necessary for management of 
AE on SD and report according to the regulations. 
2) Serious Adverse Events (SAEs) 
The investigator will report all SAEs that occur during the study in a timely manner according to the 
regulations of their respective IRB. 
All SAEs that are not recovered by the end of the study or not resolved due to withdrawal from the 
study will be followed-up until the following instances. 
① Recovery of AE 
② Stabilization of AE 


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③ When there are baseline evaluations, until restoration to the baseline status 
④ When judged to be due to drugs other than the study drug or factors other than the study 
intervention 
⑤ When there is a high possibility of not being able to receive additional information (when the 
subject or health manager denies giving additional information or when follow-up is not possible 
despite attempts) 
Deaths of subjects during clinical trials will be judged as a SAE regardless of relationship to the study 
drug or whether or not being expected.  
Requiring hospitalization (or prolongation of hospitalization) during the study will also be reported as 
a SAE, except for hospitalization in the following cases: 
① Hospitalization scheduled for the study 
② Hospitalization for social reasons without having AE 
③ Elective operations or procedures scheduled prior to participation in the study (must be recorded 
in the case report form (CRF)) 
3) Pregnancy  
Pregnancy of subjects while on medication of the study drugs must be reported within 24 hours of 
awareness by the investigator. The investigator must complete a pregnancy notification form and 
submit it to the relevant person. Subjects who become pregnant while on medication of the study drugs 
must be withdrawn from the study immediately. Additional follow-up evaluation information is 
requested for side effects on newborns after giving birth as well as during pregnancy. 
11.3.  Suspected Unexpected Serious Adverse Reaction (SUSAR) Report 
In the event a Suspected Unexpected Serious Adverse Reaction (SUSAR) occurs during the clinical 
trial, the principal investigator (PI) will report to the Institutional Review Board (IRB) to determine 
whether to continue or stop the study, and the main PI will report to the Minister of Food and Drug 
Safety (MFDS) within a period described below. 
1) Unexpected Adverse Drug Reaction causing death or life threatening conditions will be reported 
immediately. The coordinating principal investigator will report it to MFDS within 7 days of 
awareness by phone calls, Fax, or report forms. Full documentation will be reported within 15 days 
of awareness.  
2) Other unexpected and serious adverse drug reactions will be reported within 15 days of 
awareness.by the coordinating principal investigator. 
3) The coordinating principal investigator will report follow-up report with additional safety 
information until the AE is resolved (or until lost to follow-up). At this time, the investigator will 
actively cooperate in providing data and information on the report. 
 


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12. Monitoring 
12.1. Installation of Data and Safety Monitoring Board (DSMB) 
- A DSMB composed of two respiratory specialists (including one who has MDR-TB experience, if 
available) and one statistician from other institutes having no conflict of interests will be formed.    
- The DSMB may review data on side effects in the middle of the study, and may provide 
recommendations such as change, continuation or stopping of protocols to the investigators based on 
the results.  
12.2. Monitoring Plans 
- The coordinating principal investigator will be responsible for monitoring. Doctors and nurses, not 
participating in this study and having abundant clinical trial experience, designated by the main 
principal investigator will check GCP compliance, protection of study subjects, and accuracy of data 
by source document verification (SDV) of the study per each 50 subjects (i.e., when 50, 100). 
- AE, unexpected problems and noncompliance of protocols discovered through DSMB will be reported 
by the coordinating principal investigator to Institutional Review Board(IRB) according to the 
regulations and the SOPs of the Human Research Protection Program (HRPP) of Seoul National 
University Hospital and each site. 
- The respective investigator should take corrective action to resolve issues identified during the 
monitoring process, and cooperate with the monitoring personnel to implement countermeasures to 
prevent the recurrence of the issue. In the event that compliance is not achieved, the respective 
investigator’s participation in the study will be discontinued.  
 


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13. Ethical Considerations of the Study 
13.1. Compliance of Study Ethical Regulations 
1) Duties of the Investigator 
Investigators will be responsible for guaranteeing that the clinical study is conducted according to the 
protocols, the most recent International Conference on Harmonization of Technical Requirements for 
Enrollment of Pharmaceuticals for Human Use (ICH), the tenets of Good Clinical Practice (GCP) and 
relevant regulations. 
GCP is a set of internationally-recognized ethical and scientific quality requirements that must be 
followed when designing, conducting, recording and reporting clinical trials that involve people. GCP 
compliance from the Helsinki Declaration provides public assurance that the rights, safety and well-
being of human subjects involved in research are protected, and that it is officially guaranteed that the 
clinical trial data are reliable. 
2) Institutional Review Board(IRB) 
Prior to beginning trials, investigators will submit all of the most recent documents listed below to the 
IRB. 
① Final protocol and if applicable, amended protocol 
② Subject informed consent form (and all other documents provided to subjects) 
③ Investigator’s brochure (or equivalent information) and revised versions 
④ Tools for recruiting subjects 
⑤ Information on compensation for damages related to the study and, if applicable, information on 
financial compensation for participants of the study 
⑥ Resume or equivalent information of the investigator 
⑦ Study funding, sponsor name, related institutes and information on other potential conflict of 
interest elements and those related to compensation of subjects 
⑧ All other documents required by the IRB to fulfill its responsibilities 
This trial will begin after receiving full approval by the IRB for the final protocol, amended protocol 
(if applicable), subject informed consent form, applicable recruitment tools and subject compensation 
programs.  
When necessary, investigators will submit the following documents during clinical trials to the IRB for 
review and approval. 
① Amended version of the protocol 
② Revised version of subject informed consent form and written tools provided to the subjects 
③ If applicable, all new or revised subject recruitment tools 
④ Compensation for damages related to the clinical trial and, if applicable, revisions on financial 


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compensation for participants of the studies 
⑤ Revisions or the latest version of clinical trial data book 
⑥ Summary of the clinical trial situations (at least once a year or when otherwise specified by the 
IRB) 
⑦ Report of serious and unlisted adverse events related to the test drugs 
⑧ New information that can have an adverse effect on the safety of subjects or clinical execution 
⑨ Change and modification of the protocol to remove immediate threat elements to subjects 
⑩ Report of death of subjects under the administration of the investigator 
⑪ Notification in the case that a new clinical investigator from the trial institute becomes the 
principal investigator  
- All other requirements of the IRB 
In the case of changes to protocol that may increase threats to subjects, the changes and the 
corresponding revised version of the subject informed consent form will be submitted to the IRB for 
review and approval to apply the changes.  
Once the trials are complete, the investigators will notify the IRB of the time that the trial has ended.  
13.2. Obtaining written informed consent from Subjects 
- Each subject will fill out the consent form according to relevant regulations after sufficiently listening 
to explanations on this clinical trial, and the consent forms must be signed prior to beginning any 
activities related to the trial. The consent form will be used after being approved by the IRB. 
Investigators are to draft the subject informed consent form in accordance with the Helsinki Declaration, 
current ICH and GCP guidelines, and relevant regulations. 
- Prior to commencing trials, the principal investigator and co-investigators will explain to potential 
subjects the purpose and method of the clinical trial, reasonably expected benefits of the trial and 
potential risks and all associated discomforts. Subjects will be notified that participation is voluntary 
and that they may retract their consent at any time, and that even if the subject does not participate in 
the clinical trials, it will not affect treatment of their current diseases. Subjects will also be notified that 
there may be other treatment regimens available even if they deny participation, and that denying 
participation will not affect their treatment in the future. Lastly, subjects will also be notified that the 
investigator will hold the subject’s personal information for long-term follow-ups, and that there will 
be no infringement on the subject’s privacy within the allowable range of the corresponding laws and 
regulations, and that the institute and relevant investigators reserve the right to peruse the information. 
The subject’s signature on the informed consent form is deemed to allow such provision of information 
by the subject or their legal representative.  
- Subjects and/or their legal representative will be given sufficient time and opportunity to look over 
and ask questions about the informed consent form, and after listening to the explanation and prior to 
participating in clinical trials, the subject and their legal representative will be instructed to properly 
record their signature and date on the consent form. After receiving the consent form, the principal 
investigator and co-investigator will issue a copy of the consent form to the subjects.  


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13.3. Protection of Personal Records 
- Collection and operation of personal information of the subjects who participate in this study will be 
limited to only information necessary for the efficacy, safety and tolerability evaluation of the study 
drugs. Such data will be collected and operated taking precautions for compliance to laws on privacy 
protection and to guarantee confidentiality. 
- The investigator will guarantee the following contents for personal information. 
① Be operated fairly and legally 
② Collected for a clear and fair purpose, and will not be operated in methods inappropriate for such 
purpose 
③ Will be collected appropriately and relatively, and will not exceed the mentioned purpose 
④ Possess accurate, and if necessary, the latest information  
- The investigators must receive clear consent for use of personal information from participating 
subjects prior to collection of data. Such consent will mention that it may be passed on to other institutes 
or countries. 
- Subjects have the right to request their personal information from the investigator and reserve the 
right to request revision of inaccurate or incomplete information. For such a request, reasonable 
procedures must be completed considering the essence of the request, trial situation, and relevant laws 
and regulations. 
- Appropriate technical and structural methods must be established to protect personal information from 
unauthorized viewing, disclosure, accidental or illegal destruction, or coincidental loss or change. 
Personnel requiring access to personal information will agree to confidentiality on the identities of the 
subjects. 
- Information collected for the study will be stored as a password-protected file in a lab with a locking 
device. Access to the research files will be limited to authorized investigators. 
13.4. Compensation and Indemnities Provided to Subjects 
No monetary compensation will be given for participating in this clinical trial. However, transportation 
costs used for visiting the trial institute by subjects will be compensated for at 100,000 KRW each at 
the time of completing the intensive phase and when completing treatment. In the case of AE caused 
by the investigational productor to correct and handle adverse events that may have occurred, the 
principal investigator will appropriately treat damages caused directly by the clinical trial drug and 
provide compensation to trial subjects according to the ‘Rules on Victim Compensation’. 


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14. Administrative Requirements 
14.1. Change of Study Protocols 
- Investigators are not allowed to change the protocols without official amendment procedure. All 
amended versions of study protocols must be issued by the investigator and be signed and dated. If the 
IRB or the relevant authorities may find basis for disapproval of the amendment, the amended protocol 
must not be applied unless there is need to immediately remove risks against subjects (in this case, the 
amended version must be submitted to the IRB and competent authorities immediately). When changes 
are on the managerial or administrative procedures of the trial, it can be notified only to the IRB. 
14.2. Subject identification log and screening/enrollment log 
- During or after trials, investigators will record subject identification log to easily identify each subject.   
- The subject identification log will be dealt with confidentially, and investigators will store them in the 
trial institute files. No copies will be maintained for the sake of the confidentiality of subjects. All 
reports and exchange of information regarding the trials will mark subjects by only their initials or 
assigned numbers. 
- Investigators will record a subject screening/enrollment log. This is a document for all subjects to 
determine eligibility of this trial. 
14.3. Completing Case Report Forms (CRF) 
- All data related to the study will be entered in the case report forms (CRF). Excluding results for tests 
conducted outside of the investigator’s office, CRF will be completed upon the subject’s visit, and the 
latest observations will be reflected for subjects who participated in the trials. 
- All subjective evaluations recorded in CRF will, whenever possible, be continuously performed by 
the person who made the initial evaluation. Investigators will confirm that all information recorded in 
the CRF is consistent with the corresponding source document (SD). 
- All inputs, edits and changes of CRF will be carried out by the investigator or delegated personnel. 
- Data entry will be made directly in the e-CRF (www.phactax.org) constructed at the request of the 
Medical Research Collaborating Center(MRCC) and management of data will be performed by the 
MRCC.   
14.4. Quality Assurance of Data 
The process to guarantee the accuracy and reliability of data will include selection of qualified 
investigators and study institutes, as well as review of protocol procedures by all investigators, and 
delegated persons. 


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14.5. Storage of Records 
- The investigators/institutes will store essential documents in accordance to ICH/GCP E6 part 8, KGCP 
part 9 and relevant laws and regulations. The investigator/institute will take necessary measures to 
prevent loss or discarding due to accidents. 
- Study documents, including essential documents, must be stored for at least three years from the date 
of study completion. These documents may be stored for a longer period at the request of the 
administrative authority.  
- In the event that the investigator responsible for archiving retires, is repositioned, or cannot fulfill the 
responsibility for storing the study documents due to any other reason, the duty of archiving will be 
handed over to another person qualified to fulfill the said duties. 
- The coordinating principal investigator determines the retention period of research documents of each 
institution and disposal after the expiration, and the detailed procedure follows the internal disposal 
regulation of each institution. 
14.6. Completion and Stopping the Study 
- Completion of Study 
The study is defined as being completed when the final visit of the last subject participating in this 
study has been completed.   
- Stopping of the Study 
The investigator may close the trial site at any time when there is a feasible reason, and it must be 
notified sufficiently prior to termination. Reasons for closing the trial site or termination of the study 
are defined as follows. 
① When the investigator does not comply with protocols or GCP guidelines 
② Safety issues 
③ Sufficient data to prove the lack of efficacy 
④ Inappropriate recruitment by investigator 


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15. References 
1. WHO. Global tuberculosis report 2014. 
2. Collection of Tuberculosis Patient Report Status 2013. 
3. Kwak et al, Changes in treatment outcomes of multidrug-resistant tuberculosis, Int J Tuberc Lung Dis 
19(5):525-530 
4. van der Werf M, Ko ̈dmo ̈n C, HolloV, SandgrenA, Zucs P. Drug resistance among tuberculosis cases 
in the European Union and European Economic Area, 2007 to 2012. Euro Surveill 2014; 19: 20733. . 
5. Falzon D, Gandhi N, Migliori G B, et al. Resistance to fluoroquinolones and second-line injectable 
drugs: impact on MDR-TB outcomes. Eur Respir J 2013; 42: 156–168.  
6. Nathanson E, Gupta R, Huamani P, Leimane V, Pasechnikov AD, Tupasi TE, Vink K, Jaramillo E, Es
pinal MA. Adverse events in the treatment of multidrug-resistant tuberculosis: results from the DOTS-
Plus initiative. Int J Tuberc Lung Dis 8(11):1382-1384 
7. Kang , Choi Y J, Cho Y J, et al. Cost of treatment for multidrug-resistant tuberculosis in South Korea. 
Respirology 2006; 11: 793–798.  
8. Dorman SE, Johnson JL, Goldberg S, Muzanye G, Padayatchi N, Bozeman L, Heilig CM, Bernardo 
J, Choudhri S, Grosset JH, Guy E, Guyadeen P, Leus MC, Maltas G, Menzies D, Nuermberger EL, 
Villarino M, Vernon A, Chaisson RE, Tuberculosis Trials C. Substitution of moxifloxacin for isoniazid 
during intensive phase treatment of pulmonary tuberculosis. Am J Respir Crit Care Med 2009;180:273-
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9. Conde MB, Efron A, Loredo C, De Souza GR, Graca NP, Cezar MC, Ram M, Chaudhary MA, Bishai 
WR, Kritski AL, Chaisson RE. Moxifloxacin versus ethambutol in the initial treatment of tuberculosis: A 
double-blind, randomised, controlled phase ii trial. Lancet 2009;373:1183-1189 
10. Lee M, Lee J, Carroll MW, Choi H, Min S, Song T, Via LE, Goldfeder LC, Kang E, Jin B, Park H, 
Kwak H, Kim H, Jeon HS, Jeong I, Joh JS, Chen RY, Olivier KN, Shaw PA, Follmann D, Song SD, Lee 
JK, Lee D, Kim CT, Dartois V, Park SK, Cho SN, Barry CE, 3rd. Linezolid for treatment of chronic 
extensively drug-resistant tuberculosis. N Engl J Med 2012;367:1508-1518 
11. Sotgiu G, Centis R, D’Ambrosio L, et al. Efficacy, safety and tolerability of linezolid containing 
regimens in treating MDR- TB and XDR-TB: systematic review and meta-analysis. Eur Respir J 2012; 
40: 1430–1442. 
12. Diacon AH, Pym A, Grobusch M, Patientia R, Rustomjee R, Page-Shipp L, Pistorius C, Krause R, 
Bogoshi M, Churchyard G, Venter A, Allen J, Palomino JC, De Marez T, van Heeswijk RP, Lounis N, 
Meyvisch P, Verbeeck J, Parys W, de Beule K, Andries K, Mc Neeley DF. The diarylquinoline tmc207 
for multidrug-resistant tuberculosis. N Engl J Med 2009;360:2397-2405. 
13. 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;366:2151-2160. 
14. Jose A. Caminero, Anna Scardigli. Classification of antituberculosis drugs: a new proposal based on 
the most recent evidence. Eur Respir J 2015; 46: 887-893 
15. Kim HJ, Hong YP, Kim SJ, Lew WJ, Lee EG. Ambulatory treatment of multidrtug-resistant pulmonary 
tuberculosis patients at a chest clinic. Int J Tuberc Lung Dis 5(12):1129-1136 
16. Kim DH, Kim HJ, Park SK, Kong SJ, Kim YS, Kim TH, Kim EK, Lee KM, Lee SS, Park JS, Koh WJ, 
Lee CH, Kim JY, Shim TS. Treatment outcomes and long-term survival in patients with extensively drug-


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resistant tuberculosis. Am J Respir Crit Care Med 2008;178:1075-1082 
17. Deun AV, Maug AKJ, Salim MAH, Das PK, Sarker MR, Daru P, Rieder HL. Short, highly effective 
and inexpensive standardized treatment of multidrug-resistant tuberculosis. Am J Respir Crit Care Med 
2010;182:684-692 
 
18. Koh WJ , Lee SH, Kang YA, Lee CH, Choi JC, Lee JH, Jang SH, Yoo KH, Jung KH, Kim KU, Choi 
SB, Ryu YJ, Kim KC, Um S, Kwon YS, Kim YH, Choi WI, Jeon K, Hwang YI,  Kim SJ, Lee YS, Heo 
EY, Lee J, Ki YW, Shim TS, Yim JJ. Comparison of Levofloxacin versus Moxifloxacin for Multidrug-
Resistant Tuberculosis. Am J Respir Crit Care Med 2013;188:858–864 
19. Korean guidelines for the treatment of tuberculosis (revision). Committee for the Revision of Korean 
Guidelines for Tuberculosis. 2014 
20. World Health Organization. Companion handbook to the guidelines for the programmatic 
management of drug-resistant tuberculosis. 2014 
 
 


 
 
 
 
 
 
Delamanid, linezolid, levofloxacin, and pyrazinamide 
for treatment of patients with fluoroquinolone-
sensitive multidrug-resistant tuberculosis: 
A Phase 2/3, Multicenter, Randomized, Open-label, 
Clinical Trial 
(Treatment Shortening of MDR TB using Existing 
and New Drugs, MDR-END) 
 
Version 
v 2.2 
 
 
Collaborating 
Institutions 
Seoul National University Hospital, National Medical Center, 
Dankook University Hospital, Pusan National University 
Hospital, Korea University Ansan Hospital, Samsung Medical 
Center, Asan Medical Center, SMG-SNU Boramae Medical 
Center, 
Pusan 
National 
University Yangsan 
Hospital, 
Severance Hospital, Ulsan University Hospital, The Catholic 
University of Korea Incheon St. Mary’s Hospital, International 
Tuberculosis Research Center, and The Korean Institute of 
Tuberculosis 
 
 
Principal 
Investigator 
Professor Yim Jae-Jun, Department of Pulmonary and Critical 
Care Medicine, Seoul National University Hospital 
 
 
Data 
management 
and analysis 
Medical Research Collaborating Center, Biomedical Research 
Institute, Seoul National University Hospital 
Statistical Analysis Plan 


 
 
2 
 
Contents 
1. 
Objective ......................................................................................................................................................... 6 
2. 
Objective and Design of Clinical Trial ................................................................................................. 6 
2.1 
Objective................................................................................................................................................. 6 
2.2 
Design ..................................................................................................................................................... 6 
2.3 
Sample Size Justification ................................................................................................................. 6 
2.3.1 
Sample Size .......................................................................................................................................... 6 
3. 
Statistical Analysis Plan ............................................................................................................................ 7 
3.1 
General Principle of Result Analysis ........................................................................................... 7 
3.2 
Handling of Missing Data ................................................................................................................. 8 
3.3 
Clinical Trial Participation Status of Subjects and Protocol Violation ............................ 8 
3.4 
Demographic Characteristics and Characteristics Prior to Administration of Study 
Drug 
8 
3.5 
Adherence Assessment ................................................................................................................... 9 
3.6 
Efficacy Evaluation .......................................................................................................................... 10 
3.6.1 
Primary Efficacy Evaluation ......................................................................................................... 10 
3.6.2 
Secondary Efficacy Evaluation ................................................................................................... 10 
3.7 
Safety Analysis ................................................................................................................................. 12 
4. 
Subjects ....................................................................................................................................................... 13 
4.1 
Subject Participation Status in Clinical Trial.......................................................................... 13 
4.2 
Enrollment Status for Each Site/Randomization Stratification ....................................... 17 
4.3 
Subjects’ Demographic Characteristics and Characteristics Before Treatment..... 18 
4.3.1 
Demographic Characteristics and Vital Signs ........................................................................................ 18 
4.3.2 
Past History........................................................................................................................................................... 19 
4.3.3 
Medication History ............................................................................................................................................. 20 


 
 
3 
 
4.3.4 
Physical/Neurological Examination............................................................................................................. 21 
4.3.5 
Drug Susceptibility Test ................................................................................................................................... 21 
4.3.6 
Sputum AFB Smear and CXR ...................................................................................................................... 23 
4.3.7 
HIV/HBV test ........................................................................................................................................................ 26 
4.3.8 
Chemistry/Electrolyte/Complete Blood Count ........................................................................................ 27 
4.3.9 
Urine HCG ............................................................................................................................................................. 29 
4.3.10 ECG ......................................................................................................................................................................... 30 
4.3.11 Optic test (Ishihara Color Plate) ................................................................................................................... 31 
4.4 
Adherence Assessment ................................................................................................................ 32 
5. 
Efficacy Evaluation Results .................................................................................................................. 33 
5.1 
Primary Efficacy Evaluation Results ........................................................................................ 34 
5.1.1 
Treatment Success Rate at 24 Months after the initiation of treatment..................... 34 
5.2 
Secondary Efficacy Evaluation Results .................................................................................. 36 
5.2.1 
Time to sputum culture conversion after the initiation of treatment (Liquid and 
Solid Culture Media) ....................................................................................................................................... 36 
5.2.2 
Sputum culture conversion proportion at two months of treatment (Liquid and Solid 
Culture Media) ................................................................................................................................................... 39 
5.2.3 
Sputum culture conversion proportion at six months of treatment (Liquid and Solid 
Culture Media) ................................................................................................................................................... 41 
5.2.4 
Proportion of Treatment Success at the End of Treatment ............................................ 42 
5.2.5 
Proportion of Relapse after Treatment Success ................................................................. 43 
5.2.6 
Proportion of Death and Time-to-Death ................................................................................. 45 
5.2.7 
Treatment Success Rate at 24 Months after the initiation of treatment According to 
Pyrazinamide Resistance ............................................................................................................................. 48 
6. 
Safety Assessment Results ................................................................................................................. 50 
6.1 
Adverse Events................................................................................................................................. 50 
6.2 
Physical/Neurological Examination Result ............................................................................ 62 


 
 
4 
 
6.3 
Chemistry/Electrolyte/Complete Blood Count ...................................................................... 63 
6.4 
Concomitant Medication................................................................................................................ 65 
7. 
Conclusion .................................................................................................................................................. 67 
7.1 
Efficacy ................................................................................................................................................. 67 
7.2 
Safety .................................................................................................................................................... 67 
 
Figures 
Figure 1. Subject Enrollment Distribution ..................................................................................................... 14 
Figure 2. Time to Sputum Culture Conversion after Initiation of treatment (Liquid and Solid 
Culture media) ................................................................................................................................................ 39 
Figure 3. Time to Death ....................................................................................................................................... 47 
 
Tables 
Table 1. Clinical Trial Results............................................................................................................................. 15 
※ 
Safety analysis (per the administration of study drugs) ................................................................ 16 
Table 2. Enrollment Status for Each Site/Randomization Stratification Factor .......................... 17 
Table 3. Demographic Characteristics and Vital Signs........................................................................... 18 
Table 4. Past History ............................................................................................................................................. 19 
Table 5. Medication History .............................................................................................................................. 20 
Table 6. Physical/Neurological Examination .............................................................................................. 21 
Table 7. Drug Susceptibility Test ..................................................................................................................... 21 
Table 8. Sputum AFB Smear and CXR .......................................................................................................... 24 
Table 9. HIV/HBV test .......................................................................................................................................... 26 
Table 10. Chemistry/Electrolyte/Complete Blood Count ..................................................................... 27 
Table 11. Urine HCG ............................................................................................................................................. 29 
Table 12. ECG Examination ................................................................................................................................ 30 


 
 
5 
 
Table 13. Optic Test (Ishihara Color Plate) ................................................................................................. 31 
Table 14.Adherence Assessment ..................................................................................................................... 32 
Table 15. Treatment Success Rate at 24 Months after the initiation of treatment ................. 34 
Table 16. Time to sputum culture conversion after the initiation of treatment (Liquid and 
Solid Culture Media) ................................................................................................................................... 36 
Table 17.  Sputum culture conversion proportions at two months of treatment ................. 40 
Table 18.  Sputum culture conversion proportion at six months of treatment ...................... 41 
Table 19. Proportion of Treatment Success at the End of Treatment ........................................... 42 
Table 20. Proportion of Relapse after Treatment Success .................................................................. 43 
Table 21. Proportion of death and Time-to-Death ................................................................................ 45 
Table 22. Treatment Success Rate at 24 Months after the initiation of treatment According 
to Pyrazinamide Resistance ..................................................................................................................... 48 
Table 23. Summary of Adverse Event Reported during Study Period .......................................... 50 
Table 24. Adverse Events for Each Body System..................................................................................... 57 
Table 25. Adverse Events for Each Severity of Body System ............................................................. 58 
Table 26. Adverse Events for Each Relation of Body System ............................................................ 59 
Table 27. Serious Adverse Event Evaluation Results .............................................................................. 61 
Table 28. Physical/Neurological Examination Result ............................................................................. 62 
Table 29. Chemistry/Electrolyte/Complete Blood Count ..................................................................... 63 
Table 30. Concomitant Medication (Unit: Persons) ................................................................................ 66 
 
 
 
 
 


 
 
6 
 
1. Objective 
 
The purpose of this statistical analysis plan is to describe the statistical analysis method to be performed 
in this clinical trial to state the analyzed items clearly and prevent unplanned analysis in the future. 
 
2. Objective and Design of Clinical Trial 
 
2.1 Objective 
 
The purpose of this clinical trial is to compare the efficacy of a new treatment regimen including 
Delamanid, Linezolid, Levofloxacin, and Pyrazinamide for 9 or 12 months (investigational arm) and the 
standard treatment regimen including injectables for 20 to 24 months (control arm) for treating 
fluoroquinolone-sensitive multidrug-resistant tuberculosis (TB) patients through a phase 2/3, 
multicenter, randomized, open-label, clinical trial. 
 
2.2 Design 
Multicenter, randomized, open-label, two arms, phase II clinical trial. 
 
2.3 Sample Size Justification 
 
2.3.1 Sample Size 
 
The hypothesis of this study is that the treatment success rate at 24 months of treatment for multidrug-
resistant TB using the new regimen including new anti-TB drugs will not be inferior to conventional 
treatment regimen (Non-inferiority test). Presumptions when calculating sample size are as follows. 
 
1) The level of significance, α=0.025 (one-sided test) 
2) The type II error (β) set at 0.20 to maintain 80% for the power of the test 
3) The ratio of the number of subjects (control arm investigational arm) = 1 : 1 
4) Primary outcome: treatment success rate at 24 months after the initiation of treatment 
5) The hypothesis of the study is as follows. 
① Null hypothesis: Treatment success rates of the four-drug regimen at 24 month are inferior to 
those of the conventional treatment. (H0: PT – PC ≤ δ). 
② Alternative hypothesis: Treatment success rates of the four-drug regimen at 24 month are not 
inferior to those of the conventional treatment. (H1: PT – PC 〉 δ). 
Based on the study result of Kwak et al, ‘Changes in treatment outcomes of multidrug-resistant 
tuberculosis, Int J Tuberc Lung Dis 19(5):525-530’(3), presuming 24 month treatment success rate 
of control arm as 80% and 24 month treatment success rate of investigational arm as 90%, the 


 
 
7 
 
noninferiority margin (δ) is -0.10 which is regarded as non-inferior when the difference is less than 
10% between the two arms. The number of study subjects is 48 per arm. 
Additionally, reflecting 1) proportion of fluoroquinolone-susceptible MDR-TB among participants with 
positive Xpert MTB/RIF assay of 50%, and 2) anticipating 5% lost to follow-up, the final number of 
participants is calculated as N/(0.50*0.95), resulting in 102 persons per arm, 204 in total. 
If a participant withdrew for any reasons within two weeks after enrollment, the participant will be 
replaced. Considering the number of replaced participants, the enrollment accrual ceiling is 220 
persons maximum. 
 
3. Statistical Analysis Plan 
 
3.1 General Principle of Result Analysis 
 
Data obtained from subjects through clinical trial will be analyzed by mITT (modified Intention-To-
Treatment) analysis and PP (Per-Protocol) analysis. Efficacy evaluation will be based on a mITT 
(modified Intention-To-Treatment) and additional analysis on PP (Per-Protocol) group. Safety analysis 
will be performed on mITT, PP and the safety group (study drug administration group). 
 
 
Subject Group  
Definition 
mITT 
- The mITT group includes participants who are randomized after satisfying 
eligibility criteria and receive study drugs at least one time. The subjects are 
not confirmed to be additionally resistant to fluoroquinolone, mono-resistant 
to rifampicin, or susceptible to rifampicin. 
PP 
The PP (Per-Protocol) group includes participants that satisfy the following 
among the mITT group. 
When completing over 80% of the planned treatment 
: For control arm, 64 weeks or longer treatment; For investigational arm, 32 
weeks or longer treatment in the 9-month treatment group and 42 weeks or 
longer treatment in the 12-month treatment group 
  
Participants who completed the study per protocol during the clinical trial 
period 
: More than 80% of the planned period before treatment is completed, the 
following cases are considered protocol violation and excluded from the 
analysis group 
① withdrawal or death. 
② The sputum test before culture conversion was not conducted 
③ Administration of study drug in the control arm 
Safety 
The Safety analysis group includes participants who have taken study drugs 
at least one time.  
: Evaluation based on the administration of study drug (delamanid or 
linezolid) 
 
 
 


 
 
8 
 
3.2 Handling of Missing Data 
 
When categorized as ‘loss to follow-up’, ‘withdrawal’, or ‘withdrawal of consent’ will be considered as 
below. 
①‘Treatment failure’ in the case of dropping out due to ‘loss to follow-up’, ‘investigator’s decision’, 
‘withdrawal of consent', ‘treatment failure’, or ‘death’ during the treatment 
② ‘Not accessible’ in the case of dropping out due to ‘pregnancy’ during the treatment 
③ ‘Treatment failure’ in the case of dropping out due to ‘relapse’ after the treatment completion. 
However, reinfection by other strain is ‘not assessable’. 
④ ‘Not accessible’ when there is no evidence of treatment failure, such as bacteria reversion in the 
case of withdrawal due to ‘loss to follow-up’, ‘investigator’s decision’, ‘withdrawal of consent’, 
‘pregnancy’, or ‘death’ after the treatment completion 
 
 
3.3 Clinical Trial Participation Status of Subjects and Protocol Violation  
 
The table of clinical trial participation status of subjects (mITT, PP, and safety analysis groups), reasons 
for early withdrawal, and the distribution of the clinical trial protocol violations will be presented. 
 
3.4 Demographic Characteristics and Characteristics Prior to Administration of Study Drug 
 
As a way to check significant differences in demographic and clinical characteristics between the two 
arms prior to administration of study drugs, the serial data is summarized into mean, standard deviation, 
median, minimum, and maximum values, and the two arm are compared by an independent t-test or 
the Wilcoxon rank sum test. For categorical variables, the frequency and proportion per group is found 
and the two arms are compared by Chi-square test or Fisher's exact test. This analysis is performed for 
the ITT analysis group. 
 
The following items will be evaluated for the subjects’ characteristics prior to administration of the study 
drug and presented for each randomized arm. 
Type 
Endpoints 
Enrollment of each site and randomization 
stratification factor 
- To summarize the frequency and proportion of 
randomization per each site, stratification factor 
(presence/absence of cavitation on baseline 
chest 
radiographs, 
presence/absence 
of 
baseline diabetes mellitus) 
Demographic characteristics and vitality signs 
- Age, gender, height, weight, blood pressure, 
and pulse 
 
Past history 
- Past history of tuberculosis and the number of 
treatments 
- Diabetes mellitus, optic neuropathy, or 
peripheral neuropathy 


 
 
9 
 
- Galactose intolerance, Lapp lactase deficiency, 
and glucose-galactose malabsorption 
- Other diseases 
Medication history 
- Other medication except for TB medication or 
use of prohibited medication while on study drug 
Physical/neurological examination 
- Physical examination result and neurological 
examination result 
Drug susceptibility test 
- Screening visit: Xpert MTB/RIF assay (MTB and 
RIF resistance), MTBDRsl (fluoroquinolone 
resistance 
and 
XDR-TB), 
resistance, 
and 
resistant drug 
- Baseline visit: Resistance and resistant drug 
Sputum AFB smear and CXR (Chest CT) 
- Sputum AFB panel (AFB smear, solid culture, 
liquid culture) 
- CXR (range of lesions and presence or absence 
of cavity), Chest CT (range of lesions and 
presence or absence of cavity) 
HIV/HBV test 
- HIV test and HBV test result 
Chemistry/Electrolyte/Complete blood count 
Chemistry 
- T-bilirubin, alkaline phosphatase, BUN, AST, 
ALT, creatinine, calcium, phosphorus, uric acid, 
glucose, cholesterol, protein, and albumin 
Electrolyte 
- Sodium, potassium, and chloride 
Complete blood count 
- WBC, ANC, hemoglobin, and PLT 
Urine HCG/ECG/Optic Test (Ishihara Color 
Plate) 
Urine HCG 
- Performance and result 
ECG 
- Performance and result, Rhythm, QTcF 
Optic test (Ishihara Color Plate) 
- Performance and the number of correct 
answers of 24 Ishihara color plates 
 
 
3.5 Adherence Assessment 
 


 
 
10 
 
- The study coordinator checks the study drug adherence by comparing the drug package with residual 
pill count at each visit. 
In the event that a scheduled visit is changed, the study coordinator checks administration status of the 
study drug and other medication during that period as well.  
- Drug Adherence by each drug = (actual dosing day/ prescribed dosing day) * 100 
- Final Adherence = Average value of medication adherence by each drug 
 
In this case, the prescribed dosing day is defined as the sum of the prescribed dosing days for the entire 
period and the actual dosing day is defined as the total of the actual dosing days for the entire period, 
and the Final Adherence is defined as the average value of the Drug Adherence by each drug.  
The Adherence to study drug and throughout the total treatment period of both arms is summarized 
with the final adherence and by each drug taken, with the mean, standard deviation, median and 
minimum and maximum value, and the final adherence will be compared between the two arms by 
conducting an independent t-test or Wilcoxon rank sum test. 
 
 
3.6 Efficacy Evaluation 
 
All statistical analysis of the two arms is carried out at a significance level of 5% for both sides unless 
stated otherwise. For additional analysis, a stratified analysis is performed for primary and secondary 
outcomes evaluation by stratification into sputum smear positive patient groups and sputum smear 
negative patient groups based on the sputum smear microscopy results. 
 
3.6.1  Primary Efficacy Evaluation 
 
The primary outcome of this clinical trial is the treatment success rate at 24 months after the initiation 
of treatment (based on the results of liquid culture). It describes the treatment success rate of the 
control arm and the investigational arm with a two-sided 95% confidence interval. Then, in order to tests 
for non-inferiority of the investigational arm, when the lower limit of one-sided 97.5% confidence interval 
of the difference (PT - PC) between control and investigational arm is larger than the non-inferiority 
margin of -10%, it is concluded that the treatment success rate of the investigational arm is non-inferior 
to the treatment success rate of the control arm. The subjects whose treatment result is assessed as 
‘Not accessible’ are excluded from the primary outcome evaluation.  
 
3.6.2  Secondary Efficacy Evaluation 
 
① Time to sputum culture conversion1 after the initiation of treatment (liquid and solid culture media)  
② Sputum culture conversion proportion at two months of treatment (liquid and solid culture media) 
③ Sputum culture conversion proportion at six months of treatment (liquid and solid culture media)  
 
1 The definition of ‘culture conversion to negative’ is per the protocol section '6. Definition’. 
Contamination after the first negative culture also corresponds to the 'culture conversion' because 
Mycobacterium tuberculosis was not cultured based on the section 6.1 ① in the protocol. 


 
 
11 
 
④ Proportion of treatment success at the end of treatment  
⑤ Proportion of relapse after treatment success 
⑥ Proportion of death and time-to-death  
⑦ Primary outcome evaluation between treatment groups according to pyrazinamide resistance 
 
The secondary outcomes are analyzed as following and describe at exploratory levels.  
 
1) Time To Sputum Culture Conversion After the initiation of treatment (Liquid and Solid Culture 
Media) 
- In order to test whether the time to sputum culture conversion after initiation of treatment of the control 
arm and investigational arm (liquid and solid culture media) are different statistically, the median time 
is estimated in each group using the Kaplan-Meier method, and the difference of the distribution of 
time to culture conversion of the two arms is compared using the log-rank test. 
 
2) Sputum Culture Conversion Proportion at Two Months of Treatment (Liquid and Solid Culture 
Media) 
- In order to test whether there is a statistical difference in sputum culture conversion proportions at 
two months of the treatment between the control arm and the investigational arm (liquid and solid 
culture media), each arm is summarized by conversion frequency and proportion, and the proportion 
of sputum culture conversion at two months between the two arms are compared using the Chi-square 
test and Fisher’s exact test. 
  
3) Sputum Culture Conversion Proportion at Six Months of Treatment (Liquid and Solid Culture 
Media) 
- In order to test whether there is a statistical difference in sputum culture conversion proportions at 
six months of the treatment between the control arm and the investigational arm (liquid and solid 
culture media), each arm is summarized by conversion frequency and proportion, and the sputum 
culture conversion proportion at six months between the two arms are compared using the Chi-square 
test and Fisher’s exact test. 
 
4) Proportion of Treatment Success at the End of Treatment 
- Summarize the frequency and proportion of treatment success at the end of Treatment in the 
investigational arm. 
 
5) Proportion of Relapse after Treatment Success 
- Summarize the frequency and proportion of relapse after the treatment success in the investigational 
arm. 
Relapse is defined as mycobacterium tuberculosis (MTB) is cultured again at least two or more 
consecutive times, taken at least 4 weeks apart, after treatment success (excluding re-infection 
confirmed by other strains). 
6) Proportion of deaths and Time-to-Death 


 
 
12 
 
- Summarize the frequency and proportion of death in the investigational arm and estimates the 
median survival time using the Kaplan-Meier method. 
 
7) Primary Outcome Evaluation Between Treatment Groups According to the Pyrazinamide 
Resistance 
- Presentation of treatment success rate in the control arm and the investigational arm in small groups 
according to the presence or absence of Pyrazinamide resistance, and verification of non-inferiority of 
treatment success rate difference between the treatment groups. 
 
 
3.7 Safety Analysis 
 
The safety analysis evaluates subjects enrolled in this clinical trial and administered the study drug at 
least one time. 
 
1) 
Adverse Events 
- The analysis obtains the 95% confidence interval of the proportion of the subjects who have 
experienced one or more adverse event within each arm and performs the Chi-Square Test or Fisher's 
Exact Test to compare the treatment groups. 
- It compares the occurrence rate of adverse drug reactions of the two arms using the Chi-square test 
or Fisher’s exact test.  
- It summarizes the number of adverse events of each arm. 
- It summaries the number of expressions of five items (seriousness, severity, relation, action taken, 
and outcome) for each arm.  
- The classification of adverse events by body system is organized according to the SOC (System 
Organ Class) and PT (Preferred Term) of MedDRA system. 
- It describes the details such as demographic information, event date, end date, severity, relation, 
action taken, and outcome for the subjects who reveal serious adverse events. 
 
2) 
Physical/Neurological Examination Result 
- For the results of the physical/neurological examination, the analysis presents the proportion of 
subjects who were normal in screening visit (Visit1) and changed to abnormal at the final visit. 
 
3) 
Chemistry/Electrolyte/Complete Blood Count Result 
- The analysis presents the proportion of subjects who showed the chemistry/electrolyte/complete blood 
count result of “Normal” or “Abnormal NCS” at the baseline visit (Visit2) and changed to “Abnormal CS” 
at the final visit. 
 
4) 
Concomitant Medication 
- The analysis classifies the concomitant medication using the ATC (Anatomical Therapeutic Chemical) 


 
 
13 
 
Code presents it for each arm. 
 
 
4. Subjects 
 
4.1 Subject Participation Status in Clinical Trial 
 
The subject distribution can be summarized as follows as the result of the clinical trial (Figure 1 and 
Table 1). 
 
 


 
 
14 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Figure 1. Subject Enrollment Distribution
Excluded (XX persons): XX persons in the investigational arm and 
XX persons in the control arm 
 
Reasons for exclusion 
▪ No administration of the study drug (XX persons): XX persons in 
the investigational arm and XX persons in the 
Safety Group 
(Based on  
medication) 
Total 
(XX persons) 
 
Administration of 
Delamanid and 
linezolid  
(XX persons) 
No administration 
of Delamanid and 
linezolid 
 (XX persons) 
Enrolled Subjects 
(XX persons) 
mITT Group 
PP Group 
Total 
(XX persons) 
Investigational 
Arm 
(XX persons) 
Control Arm 
(XX persons) 
Total 
(XX persons) 
Investigational 
Arm 
(XX persons) 
Control Arm 
(XX persons) 
Excluded (XX persons): XX persons in the investigational arm 
and XX persons in the control arm 
 
Reasons for exclusion 
• Treatment of less than 80% throughout the planned period 
(XX persons): XX persons in the investigational arm and XX 
persons in the control arm 
• Withdrawal or death (XX persons): XX persons in the 
investigational arm and XX persons in the control arm 
• No sputum test before culture conversion to negative (XX 
persons): XX persons in the investigational arm and XX 
persons in the control arm 
• Administration of study drug in control arm: XX persons in 
the control arm 
 
Excluded (XX persons): XX persons in the investigational arm and 
XX persons in the control arm 
Reasons for exclusion 
• Not randomized (XX persons): XX persons in the investigational 
arm and XX persons in the control arm 
• Violation of the selection criteria (XX persons): XX persons in the 
investigational arm and XX persons in the control arm 
• Confirmed resistance to fluoroquinolone during the study (XX 
persons): XX persons in the investigational arm and XX persons in 
the control arm 
• Confirmed mono-resistance to rifampicin during the study (XX 
persons): XX persons in the investigational arm and XX persons in 
the control arm 
• Confirmed susceptibility to rifampicin during the study (XX persons): 
XX persons in the investigational arm and XX persons in the control 
arm 


 
 
15 
 
Table 1. Clinical Trial Results 
 
Investigational Arm 
Control Arm 
Enrollment, n 
xx 
xx 
Non administration of study drug 
xx 
xx 
No randomization due to screening failure 
xx 
xx 
  Violation of inclusion/exclusion criteria 
xx 
xx 
    Violation of the inclusion criterion 1 
xx 
xx 
    Violation of the inclusion criterion 2 
xx 
xx 
    Violation of the inclusion criterion 3 
xx 
xx 
    Violation of the exclusion criterion 1 
xx 
xx 
    Violation of the exclusion criterion 2 
xx 
xx 
    Violation of the exclusion criterion 3 
xx 
xx 
    Violation of the exclusion criterion 4 
xx 
xx 
    Violation of the exclusion criterion 5 
xx 
xx 
    Violation of the exclusion criterion 6 
xx 
xx 
    Violation of the exclusion criterion 7 
xx 
xx 
    Violation of the exclusion criterion 8 
xx 
xx 
Fluoroquinolone resistance confirmed during the study 
xx 
xx 
 Rifampicin mono-resistance confirmed during the study 
xx 
xx 
 Rifampicin susceptibility confirmed during the study 
xx 
xx 
mITT analysis group, n 
xx 
xx 
 Treatment of less than 80% throughout the planned period 
xx 
xx 
  Withdrawal or death before treatment completion (less than 80% of 
the planned period) 
xx 
xx 
    Investigator’s judgment that participating in the study is not 
beneficial to the subject 
xx 
xx 


 
 
16 
 
    Withdrawal of consent 
xx 
xx 
Treatment failure 
xx 
xx 
Pregnancy 
xx 
xx 
    Death 
xx 
xx 
 Non-execution of sputum testing before culture conversion to 
negative 
xx 
xx 
Administration of study drug in the control arm 
xx 
xx 
PP analysis group, n 
xx 
xx 
 
※ Safety analysis (per the administration of study drugs) 
 
Investigational 
Arm 
Control Arm 
Total 
Number of enrollments, n 
xx 
xx 
xx 
Non-administration of study drug 
xx 
xx 
xx 
Safety analysis (per the administration of 
study drugs), n 
xx 
xx 
xx 
  Administration of Delamanid or linezolid 
xx 
xx 
xx 
  No administration of Delamanid or 
linezolid 
xx 
xx 
xx 
 
 
 
 
 
 


 
 
17 
 
4.2 Enrollment Status for Each Site/Randomization Stratification 
The analysis presents enrollment status by each site and randomization stratification factor (presence or absence of cavity in CXR or chest CT/diabetes 
mellitus) (Table 2). 
 
Table 2. Enrollment Status for Each Site/Randomization Stratification Factor 
  
Investigational arm (N=xx) 
Control arm (N=xx) 
Site, n (%) 
 
 
  Seoul National University Hospital 
xx (xx.xx) 
xx (xx.xx) 
  National Medical Center 
xx (xx.xx) 
xx (xx.xx) 
  Dankook University Hospital 
xx (xx.xx) 
xx (xx.xx) 
  Pusan National University Hospital 
xx (xx.xx) 
xx (xx.xx) 
  Korea University Ansan Hospital 
xx (xx.xx) 
xx (xx.xx) 
  Samsung Medical Center 
xx (xx.xx) 
xx (xx.xx) 
  Asan Medical Center 
xx (xx.xx) 
xx (xx.xx) 
SMG-SNU Boramae Medical Center 
xx (xx.xx) 
xx (xx.xx) 
  Pusan National University Yangsan Hospital 
xx (xx.xx) 
xx (xx.xx) 
  Severance Hospital 
xx (xx.xx) 
xx (xx.xx) 
  Ulsan National University Hospital 
xx (xx.xx) 
xx (xx.xx) 
The Catholic University of Korea Incheon St. 
Mary’s Hospital 
xx (xx.xx) 
xx (xx.xx) 
Presence of cavity in CXR or chest CT, n (%) 
 
 
  Yes 
xx (xx.xx) 
xx (xx.xx) 
  No 
xx (xx.xx) 
xx (xx.xx) 
Diabetes mellitus, n (%) 
 
 
  Yes 
xx (xx.xx) 
xx (xx.xx) 


 
 
18 
 
  No 
xx (xx.xx) 
xx (xx.xx) 
 
 
4.3 Subjects’ Demographic Characteristics and Characteristics Before Treatment 
The analysis investigates the subjects’ demographic characteristics and the characteristics before treatment. 
 
4.3.1  Demographic Characteristics and Vital Signs 
 
Table 3 below presents the comparison of the demographic characteristics and vital signs of the two arms. 
 
Table 3. Demographic Characteristics and Vital Signs 
  
 
  
  
Investigational arm (N=xx) 
  
Control arm (N=xx) 
p-value 
Age (Years) 
n mean±sd 
xx 
xx.xx±xx.xx 
xx 
xx.xx±xx.xx 
0.xxxx † or * 
 
 
median [min, 
max] 
 
xx.xx[xx.xx,xx.xx] 
 
xx.xx[xx.xx,xx.xx] 
 
Gender 
 
Male, n (%) 
 
xx (xx.xx) 
 
xx (xx.xx) 
0.xxxx †† or 
** 
 
 
Female, n (%) 
 
xx (xx.xx) 
 
xx (xx.xx) 
 
Height (cm) 
n mean±sd 
xx 
xx.xx±xx.xx 
xx 
xx.xx±xx.xx 
0.xxxx † or * 
 
 
median [min, 
max] 
 
xx.xx[xx.xx,xx.xx] 
 
xx.xx[xx.xx,xx.xx] 
 
Weight (kg) 
n mean±sd 
xx 
xx.xx±xx.xx 
xx 
xx.xx±xx.xx 
0.xxxx † or * 
  
 
median [min, 
max] 
  
xx.xx[xx.xx,xx.xx] 
  
xx.xx[xx.xx,xx.xx] 
  
SBP (mmHg) 
n mean±sd 
xx 
xx.xx±xx.xx 
xx 
xx.xx±xx.xx 
0.xxxx † or * 
 
 
median [min, 
max] 
  
xx.xx[xx.xx,xx.xx] 
  
xx.xx[xx.xx,xx.xx] 
  
DBP (mmHg) 
n mean±sd 
xx 
xx.xx±xx.xx 
xx 
xx.xx±xx.xx 
0.xxxx † or * 


 
 
19 
 
 
 
median [min, 
max] 
  
xx.xx[xx.xx,xx.xx] 
  
xx.xx[xx.xx,xx.xx] 
  
Pulse 
n mean±sd 
xx 
xx.xx±xx.xx 
xx 
xx.xx±xx.xx 
0.xxxx † or * 
 
 
median [min, 
max] 
  
xx.xx[xx.xx,xx.xx] 
  
xx.xx[xx.xx,xx.xx] 
  
† p-value by the t-test             * p-value by the Wilcoxon rank sum test 
†† p-value by the Chi-square test   ** p-value by the Fisher’s exact test 
 
 
 
4.3.2  Past History 
 
Table 4 below presents the past history distribution of the two arms before treatment. 
 
Table 4. Past History 
  
   
 
Investigational arm (N=xx) 
 
Control arm (N=xx) 
 
p-value 
Past history of TB  
 
 
 
 
 
 
 
 
Yes or No 
 
No, n (%) 
 
xx (xx.xx) 
 
xx (xx.xx) 
 
0.xxxx †† or ** 
 
 
Yes, n (%) 
 
xx (xx.xx) 
 
xx (xx.xx) 
 
 
Number of times 
 
1 time, n (%) 
 
xx (xx.xx) 
 
xx (xx.xx) 
 
0.xxxx †† or ** 
 
 
2 times, n (%) 
 
xx (xx.xx) 
 
xx (xx.xx) 
 
 
 
 
3 times, n (%) 
 
xx (xx.xx) 
 
xx (xx.xx) 
 
 
 
 
4 times, n (%) 
 
xx (xx.xx) 
 
xx (xx.xx) 
 
 
 
 
5 times, n (%) 
 
xx (xx.xx) 
 
xx (xx.xx) 
 
 
 
 
6 times, n (%) 
 
xx (xx.xx) 
 
xx (xx.xx) 
 
 
 
 
Unknown 
 
xx (xx.xx) 
 
xx (xx.xx) 
 
 
Diabetes mellitus 
 
 
 
 
 
 
 
 
 
 
No, n (%) 
 
xx (xx.xx) 
 
xx (xx.xx) 
 
0.xxxx †† or ** 
 
 
Yes, n (%) 
 
xx (xx.xx) 
 
xx (xx.xx) 
 
 
Optic neuropathy 
 
 
 
 
 
 
 
 


 
 
20 
 
 
 
No, n (%) 
 
xx (xx.xx) 
 
xx (xx.xx) 
 
0.xxxx †† or ** 
 
 
Yes, n (%) 
 
xx (xx.xx) 
 
xx (xx.xx) 
 
 
Peripheral neuropathy 
 
 
 
 
 
 
 
 
 
 
No, n (%) 
 
xx (xx.xx) 
 
xx (xx.xx) 
 
0.xxxx †† or ** 
 
 
Yes, n (%) 
 
xx (xx.xx) 
 
xx (xx.xx) 
 
 
Galactose intolerance,  
Lapp lactase deficiency,  
glucose-galactose malabsorption 
 
 
 
 
 
 
 
 
 
 
No, n (%) 
 
xx (xx.xx) 
 
xx (xx.xx) 
 
0.xxxx †† or ** 
 
 
Yes, n (%) 
 
xx (xx.xx) 
 
xx (xx.xx) 
 
 
Other diseases 
 
 
 
 
 
 
 
 
   
 
No, n (%) 
 
xx (xx.xx) 
 
xx (xx.xx) 
 
0.xxxx †† or ** 
  
 Yes, n (%) 
 
xx (xx.xx) 
 
xx (xx.xx) 
 
  
†† p-value by the Chi-square test   ** p-value by the Fisher’s exact test 
 
 
4.3.3  Medication History 
 
Table 5 below presents medication history other than the TB medication before treatment of study drug of the two arms. 
 
Table 5. Medication History 
  
  
Investigational arm (N=xx) 
Control arm (N=xx) 
p-value 
Medication other than TB medication 
 
 
 
 
 
No, n (%) 
xx (xx.xx) 
xx (xx.xx) 
0.xxxx †† or ** 
 
Yes, n (%) 
xx (xx.xx) 
xx (xx.xx) 
 
Prohibited medications/cautious medication 
 
 
 
 
    Antidepressant, n (%) 
 
xx (xx.xx) 
xx (xx.xx) 
0.xxxx †† or ** 
    Meperidine, n (%) 
 
xx (xx.xx) 
xx (xx.xx) 
0.xxxx †† or ** 
    Dopaminergic drug, n (%) 
 
xx (xx.xx) 
xx (xx.xx) 
0.xxxx †† or ** 


 
 
21 
 
†† p-value by the Chi-square test   ** p-value by the Fisher’s exact test 
 
 
4.3.4  Physical/Neurological Examination 
 
Table 6 below presents the distribution of physical/neurological examination results of the two arms before treatment of study drug. 
 
Table 6. Physical/Neurological Examination  
  
  
Investigational arm (N=xx) 
Control arm (N=xx) 
p-value 
Physical Examination 
Normal, n (%) 
xx (xx.xx) 
xx (xx.xx) 
0.xxxx †† or ** 
 
Abnormal, n (%) 
xx (xx.xx) 
xx (xx.xx) 
 
Neurological examination 
Normal, n (%) 
xx (xx.xx) 
xx (xx.xx) 
0.xxxx †† or ** 
 
Abnormal, n (%) 
xx (xx.xx) 
xx (xx.xx) 
 
†† p-value by the Chi-square test   ** p-value by the Fisher’s exact test 
 
 
4.3.5  Drug Susceptibility Test 
 
Table 7 below presents drug susceptibility test before treatment of study drug to the two arms. 
 
Table 7. Drug Susceptibility Test 
    Buspirone, n (%) 
 
xx (xx.xx) 
xx (xx.xx) 
0.xxxx †† or ** 
    Strong CYP3A inducer like carbamazepine, n (%) 
 
xx (xx.xx) 
xx (xx.xx) 
0.xxxx †† or ** 
    Others, specify, n (%) 
 
xx (xx.xx) 
xx (xx.xx) 
0.xxxx †† or ** 
  
Investigational arm (N=xx) 
Control arm (N=xx) 
p-value 
Screening 
  
 
 
 


 
 
22 
 
Xpert MTB/RIF assay 
 
 
 
 
  Execution 
No, n (%) 
xx (xx.xx) 
xx (xx.xx) 
0.xxxx †† or ** 
 
Yes, n (%) 
xx (xx.xx) 
xx (xx.xx) 
 
  MTB 
No, n (%) 
xx (xx.xx) 
xx (xx.xx) 
0.xxxx †† or ** 
 
Yes, n (%) 
xx (xx.xx) 
xx (xx.xx) 
 
RIF resistance 
No, n (%) 
xx (xx.xx) 
xx (xx.xx) 
0.xxxx †† or ** 
 
Yes, n (%) 
xx (xx.xx) 
xx (xx.xx) 
 
MTBDRsl 
 
 
 
 
Execution 
No, n (%) 
xx (xx.xx) 
xx (xx.xx) 
0.xxxx †† or ** 
 
Yes, n (%) 
xx (xx.xx) 
xx (xx.xx) 
 
Fluoroquinolone resistance 
No, n (%) 
xx (xx.xx) 
xx (xx.xx) 
0.xxxx †† or ** 
 
Yes, n (%) 
xx (xx.xx) 
xx (xx.xx) 
 
XDR TB 
No, n (%) 
xx (xx.xx) 
xx (xx.xx) 
0.xxxx †† or ** 
 
Yes, n (%) 
xx (xx.xx) 
xx (xx.xx) 
 
Drug Susceptibility Test 
 
 
 
 
Execution 
No, n (%) 
xx (xx.xx) 
xx (xx.xx) 
0.xxxx †† or ** 
 
Yes, n (%) 
xx (xx.xx) 
xx (xx.xx) 
 
  Resistance 
No, n (%) 
xx (xx.xx) 
xx (xx.xx) 
0.xxxx †† or ** 
 
Yes, n (%) 
xx (xx.xx) 
xx (xx.xx) 
 
Resistant drug 
 
 
 
 
    Isoniazid, n (%) 
 
xx (xx.xx) 
xx (xx.xx) 
 
    Rifampicin, n (%) 
 
xx (xx.xx) 
xx (xx.xx) 
 
    Ethambutol, n (%) 
 
xx (xx.xx) 
xx (xx.xx) 
 
    Pyrazinamide, n (%) 
 
xx (xx.xx) 
xx (xx.xx) 
 
    Streptomycin, n (%) 
 
xx (xx.xx) 
xx (xx.xx) 
 
    Kanamycin, n (%) 
 
xx (xx.xx) 
xx (xx.xx) 
 
    Amikacin, n (%) 
 
xx (xx.xx) 
xx (xx.xx) 
 
    Capreomycin, n (%) 
 
xx (xx.xx) 
xx (xx.xx) 
 
    Ofloxacin, n (%) 
 
xx (xx.xx) 
xx (xx.xx) 
 
    Levofloxacin, n (%) 
 
xx (xx.xx) 
xx (xx.xx) 
 
    Moxifloxacin, n (%) 
 
xx (xx.xx) 
xx (xx.xx) 
 


 
 
23 
 
†† p-value by the Chi-square test   ** p-value by the Fisher’s exact test 
 
 
4.3.6  Sputum AFB Smear and CXR 
 
Table 8 below presents the distribution of sputum AFB smear and CXR results of the two arms before treatment of study drug. 
    Prothionamide, n (%) 
 
xx (xx.xx) 
xx (xx.xx) 
 
    Cycloserine, n (%) 
 
xx (xx.xx) 
xx (xx.xx) 
 
Para-aminosalicyllc acid, n (%) 
 
xx (xx.xx) 
xx (xx.xx) 
 
Baseline visit 
 
 
 
 
Drug susceptibility test 
 
 
 
 
Execution 
No, n (%) 
xx (xx.xx) 
xx (xx.xx) 
0.xxxx †† or ** 
 
Yes, n (%) 
xx (xx.xx) 
xx (xx.xx) 
 
  Resistance 
No, n (%) 
xx (xx.xx) 
xx (xx.xx) 
0.xxxx †† or ** 
 
Yes, n (%) 
xx (xx.xx) 
xx (xx.xx) 
 
Resistant drug 
 
 
 
 
    Isoniazid, n (%) 
 
xx (xx.xx) 
xx (xx.xx) 
 
    Rifampicin, n (%) 
 
xx (xx.xx) 
xx (xx.xx) 
 
    Ethambutol, n (%) 
 
xx (xx.xx) 
xx (xx.xx) 
 
    Pyrazinamide, n (%) 
 
xx (xx.xx) 
xx (xx.xx) 
 
    Streptomycin, n (%) 
 
xx (xx.xx) 
xx (xx.xx) 
 
    Kanamycin, n (%) 
 
xx (xx.xx) 
xx (xx.xx) 
 
    Amikacin, n (%) 
 
xx (xx.xx) 
xx (xx.xx) 
 
    Capreomycin, n (%) 
 
xx (xx.xx) 
xx (xx.xx) 
 
    Ofloxacin, n (%) 
 
xx (xx.xx) 
xx (xx.xx) 
 
    Levofloxacin, n (%) 
 
xx (xx.xx) 
xx (xx.xx) 
 
    Moxifloxacin, n (%) 
 
xx (xx.xx) 
xx (xx.xx) 
 
    Prothionamide, n (%) 
 
xx (xx.xx) 
xx (xx.xx) 
 
    Cycloserine, n (%) 
 
xx (xx.xx) 
xx (xx.xx) 
 
Para-aminosalicyllc acid, n (%) 
 
xx (xx.xx) 
xx (xx.xx) 
 


 
 
24 
 
Table 8. Sputum AFB Smear and CXR 
  
  
Investigational arm (N=xx) Control arm (N=xx) 
p-value 
Screening 
  
 
 
 
Sputum AFB panel 
 
 
 
 
Execution 
No, n (%) 
xx (xx.xx) 
xx (xx.xx) 
0.xxxx †† or ** 
 
Yes, n (%) 
xx (xx.xx) 
xx (xx.xx) 
 
  AFB smear 
-, n (%) 
xx (xx.xx) 
xx (xx.xx) 
0.xxxx †† or ** 
 
scanty, n (%) 
xx (xx.xx) 
xx (xx.xx) 
 
 
1+, n (%) 
xx (xx.xx) 
xx (xx.xx) 
 
 
2+, n (%) 
xx (xx.xx) 
xx (xx.xx) 
 
 
3+, n (%) 
xx (xx.xx) 
xx (xx.xx) 
 
 
4+, n (%) 
xx (xx.xx) 
xx (xx.xx) 
 
  Solid culture 
Negative, n (%) 
xx (xx.xx) 
xx (xx.xx) 
0.xxxx †† or ** 
 
Positive, n (%) 
xx (xx.xx) 
xx (xx.xx) 
 
 
  NTM suspected 
 
 
 
 
Yes, n (%) 
xx (xx.xx) 
xx (xx.xx) 
 
 
No, n (%) 
xx (xx.xx) 
xx (xx.xx) 
 
 
Not done, n (%) 
xx (xx.xx) 
xx (xx.xx) 
 
 
Contaminated, n (%) 
xx (xx.xx) 
xx (xx.xx) 
 
 
Not done, n (%) 
xx (xx.xx) 
xx (xx.xx) 
 
  Liquid culture 
Negative, n (%) 
xx (xx.xx) 
xx (xx.xx) 
0.xxxx †† or ** 
 
Positive, n (%) 
xx (xx.xx) 
xx (xx.xx) 
 
 
  PCR results 
 
 
 
 
MTB, n (%) 
xx (xx.xx) 
xx (xx.xx) 
 
 
NTM, n (%) 
xx (xx.xx) 
xx (xx.xx) 
 
 
Not done, n (%) 
xx (xx.xx) 
xx (xx.xx) 
 
 
Contaminated, n (%) 
xx (xx.xx) 
xx (xx.xx) 
 
 
Not done, n (%) 
xx (xx.xx) 
xx (xx.xx) 
 
CXR/Chest CT 
 
 
 
 
Execution 
No, n (%) 
xx (xx.xx) 
xx (xx.xx) 
0.xxxx †† or ** 
 
Yes, n (%) 
xx (xx.xx) 
xx (xx.xx) 
 


 
 
25 
 
Examination type CXR, n (%) 
xx (xx.xx) 
xx (xx.xx) 
0.xxxx †† or ** 
 
Chest CT, n (%) 
xx (xx.xx) 
xx (xx.xx) 
 
Lesion range 
One lung, n (%) 
xx (xx.xx) 
xx (xx.xx) 
0.xxxx †† or ** 
 
Both lungs, n (%) 
xx (xx.xx) 
xx (xx.xx) 
 
  Cavity presence 
Yes, n (%) 
xx (xx.xx) 
xx (xx.xx) 
0.xxxx †† or ** 
 
No, n (%) 
xx (xx.xx) 
xx (xx.xx) 
 
Baseline visit 
  
 
 
 
Sputum AFB panel 
 
 
 
 
Execution 
No, n (%) 
xx (xx.xx) 
xx (xx.xx) 
0.xxxx †† or ** 
 
Yes, n (%) 
xx (xx.xx) 
xx (xx.xx) 
 
  AFB smear 
-, n (%) 
xx (xx.xx) 
xx (xx.xx) 
0.xxxx †† or ** 
 
Scanty, n (%) 
xx (xx.xx) 
xx (xx.xx) 
 
 
1+, n (%) 
xx (xx.xx) 
xx (xx.xx) 
 
 
2+, n (%) 
xx (xx.xx) 
xx (xx.xx) 
 
 
3+, n (%) 
xx (xx.xx) 
xx (xx.xx) 
 
 
4+, n (%) 
xx (xx.xx) 
xx (xx.xx) 
 
  Solid culture 
Negative, n (%) 
xx (xx.xx) 
xx (xx.xx) 
0.xxxx †† or ** 
 
Positive, n (%) 
xx (xx.xx) 
xx (xx.xx) 
 
 
  NTM suspected 
 
 
 
 
Yes, n (%) 
xx (xx.xx) 
xx (xx.xx) 
 
 
No, n (%) 
xx (xx.xx) 
xx (xx.xx) 
 
 
Not done, n (%) 
xx (xx.xx) 
xx (xx.xx) 
 
 
Contaminated, n (%) 
xx (xx.xx) 
xx (xx.xx) 
 
 
Not done, n (%) 
xx (xx.xx) 
xx (xx.xx) 
 
  Liquid culture 
Negative, n (%) 
xx (xx.xx) 
xx (xx.xx) 
0.xxxx †† or ** 
 
Positive, n (%) 
xx (xx.xx) 
xx (xx.xx) 
 
 
  PCR results 
 
 
 
 
MTB, n (%) 
xx (xx.xx) 
xx (xx.xx) 
 
 
NTM, n (%) 
xx (xx.xx) 
xx (xx.xx) 
 
 
Not done, n (%) 
xx (xx.xx) 
xx (xx.xx) 
 
 
Contaminated, n (%) 
xx (xx.xx) 
xx (xx.xx) 
 


 
 
26 
 
 
Not done, n (%) 
xx (xx.xx) 
xx (xx.xx) 
 
CXR/Chest CT 
 
 
 
 
Execution 
No, n (%) 
xx (xx.xx) 
xx (xx.xx) 
0.xxxx †† or ** 
 
Yes, n (%) 
xx (xx.xx) 
xx (xx.xx) 
 
Examination type CXR, n (%) 
xx (xx.xx) 
xx (xx.xx) 
0.xxxx †† or ** 
 
Chest CT, n (%) 
xx (xx.xx) 
xx (xx.xx) 
 
Lesion range 
One lung, n (%) 
xx (xx.xx) 
xx (xx.xx) 
0.xxxx †† or ** 
 
Both lungs, n (%) 
xx (xx.xx) 
xx (xx.xx) 
 
  Cavity presence 
Yes, n (%) 
xx (xx.xx) 
xx (xx.xx) 
0.xxxx †† or ** 
 
No, n (%) 
xx (xx.xx) 
xx (xx.xx) 
 
†† p-value by the Chi-square test   ** p-value by the Fisher’s exact test 
 
 
4.3.7  HIV/HBV test 
 
Table 9 below presents the distribution of the HIV/HBV test results of the two arms before treatment of study drug. 
 
Table 9. HIV/HBV test 
  
  
Investigational arm (N=xx) Control arm (N=xx) 
p-value 
HIV 
 
 
 
 
  Result 
Negative, n (%) 
xx (xx.xx) 
xx (xx.xx) 
0.xxxx †† or ** 
 
Positive, n (%) 
xx (xx.xx) 
xx (xx.xx) 
 
HBV 
 
 
 
 
   results Negative, n (%) 
xx (xx.xx) 
xx (xx.xx) 
0.xxxx †† or ** 
 
Positive, n (%) 
xx (xx.xx) 
xx (xx.xx) 
 
†† p-value by the Chi-square test   ** p-value by the Fisher’s exact test 
 
 


 
 
27 
 
4.3.8  Chemistry/Electrolyte/Complete Blood Count 
 
Table 10 below presents the distribution of the chemistry/electrolyte/complete blood count results of the two arms before treatment of study drug. 
 
Table 10. Chemistry/Electrolyte/Complete Blood Count 
  
    
  
Investigational arm (N=xx) 
 
Control arm (N=xx) 
p-value 
Screening 
    
 
  
 
  
  
Chemistry 
 
 
 
 
 
 
 
  T-bilirubin 
n mean±sd 
xx 
xx.xx±xx.xx 
xx 
xx.xx±xx.xx 
0.xxxx † or * 
 
 
median [min, max] 
 
xx.xx[xx.xx,xx.xx] 
 
xx.xx[xx.xx,xx.xx] 
 
  Alkaline phosphatase n mean±sd 
xx 
xx.xx±xx.xx 
xx 
xx.xx±xx.xx 
0.xxxx † or * 
 
 
median [min, max] 
 
xx.xx[xx.xx,xx.xx] 
 
xx.xx[xx.xx,xx.xx] 
 
  AST  
n mean±sd 
xx 
xx.xx±xx.xx 
xx 
xx.xx±xx.xx 
0.xxxx † or * 
  
 
median [min, max] 
 
xx.xx[xx.xx,xx.xx] 
 
xx.xx[xx.xx,xx.xx] 
 
  ALT 
n mean±sd 
xx 
xx.xx±xx.xx 
xx 
xx.xx±xx.xx 
0.xxxx † or * 
 
 
median [min, max] 
 
xx.xx[xx.xx,xx.xx] 
 
xx.xx[xx.xx,xx.xx] 
 
  Creatinine 
n mean±sd 
xx 
xx.xx±xx.xx 
xx 
xx.xx±xx.xx 
0.xxxx † or * 
 
 
median [min, max] 
 
xx.xx[xx.xx,xx.xx] 
 
xx.xx[xx.xx,xx.xx] 
 
Electrolyte 
 
 
 
 
 
 
 
  Sodium 
n mean±sd 
xx 
xx.xx±xx.xx 
xx 
xx.xx±xx.xx 
0.xxxx † or * 
 
 
median [min, max] 
 
xx.xx[xx.xx,xx.xx] 
 
xx.xx[xx.xx,xx.xx] 
 
  Potassium 
n mean±sd 
xx 
xx.xx±xx.xx 
xx 
xx.xx±xx.xx 
0.xxxx † or * 
 
 
median [min, max] 
 
xx.xx[xx.xx,xx.xx] 
 
xx.xx[xx.xx,xx.xx] 
 
  Chloride 
n mean±sd 
xx 
xx.xx±xx.xx 
xx 
xx.xx±xx.xx 
0.xxxx † or * 


 
 
28 
 
 
 
median [min, max] 
 
xx.xx[xx.xx,xx.xx] 
 
xx.xx[xx.xx,xx.xx] 
 
Complete blood count 
 
 
 
 
 
 
 
  WBC 
n mean±sd 
xx 
xx.xx±xx.xx 
xx 
xx.xx±xx.xx 
0.xxxx † or * 
 
 
median [min, max] 
 
xx.xx[xx.xx,xx.xx] 
 
xx.xx[xx.xx,xx.xx] 
 
  ANC 
n mean±sd 
xx 
xx.xx±xx.xx 
xx 
xx.xx±xx.xx 
0.xxxx † or * 
 
 
median [min, max] 
 
xx.xx[xx.xx,xx.xx] 
 
xx.xx[xx.xx,xx.xx] 
 
  Hemoglobin 
n mean±sd 
xx 
xx.xx±xx.xx 
xx 
xx.xx±xx.xx 
0.xxxx † or * 
 
 
median [min, max] 
 
xx.xx[xx.xx,xx.xx] 
 
xx.xx[xx.xx,xx.xx] 
 
  PLT 
n mean±sd 
xx 
xx.xx±xx.xx 
xx 
xx.xx±xx.xx 
0.xxxx † or * 
 
 
median [min, max] 
 
xx.xx[xx.xx,xx.xx] 
 
xx.xx[xx.xx,xx.xx] 
 
Baseline visit 
    
 
  
 
  
  
Chemistry 
 
 
 
 
 
 
 
  T-bilirubin 
n mean±sd 
xx 
xx.xx±xx.xx 
xx 
xx.xx±xx.xx 
0.xxxx † or * 
 
 
median [min, max] 
 
xx.xx[xx.xx,xx.xx] 
 
xx.xx[xx.xx,xx.xx] 
 
  Alkaline phosphatase n mean±sd 
xx 
xx.xx±xx.xx 
xx 
xx.xx±xx.xx 
0.xxxx † or * 
 
 
median [min, max] 
 
xx.xx[xx.xx,xx.xx] 
 
xx.xx[xx.xx,xx.xx] 
 
  AST  
n mean±sd 
xx 
xx.xx±xx.xx 
xx 
xx.xx±xx.xx 
0.xxxx † or * 
  
 
median [min, max] 
 
xx.xx[xx.xx,xx.xx] 
 
xx.xx[xx.xx,xx.xx] 
 
  ALT 
n mean±sd 
xx 
xx.xx±xx.xx 
xx 
xx.xx±xx.xx 
0.xxxx † or * 
 
 
median [min, max] 
 
xx.xx[xx.xx,xx.xx] 
 
xx.xx[xx.xx,xx.xx] 
 
  Creatinine 
n mean±sd 
xx 
xx.xx±xx.xx 
xx 
xx.xx±xx.xx 
0.xxxx † or * 
 
 
median [min, max] 
 
xx.xx[xx.xx,xx.xx] 
 
xx.xx[xx.xx,xx.xx] 
 
Electrolyte 
 
 
 
 
 
 
 
Sodium 
n mean±sd 
xx 
xx.xx±xx.xx 
xx 
xx.xx±xx.xx 
0.xxxx † or * 
 
 
median [min, max] 
 
xx.xx[xx.xx,xx.xx] 
 
xx.xx[xx.xx,xx.xx] 
 


 
 
29 
 
† p-value by t-test           * p-value by Wilcoxon rank sum test 
 
 
 
4.3.9  Urine HCG 
 
Table 11 below presents the distribution of the urine HCG examination results of the two arms before treatment of study drug. 
 
Table 11. Urine HCG 
  
   
 Investigational arm (N=xx)  Control arm (N=xx)  
p-value 
Screening 
   
 
  
 
  
 
  
Urine HCG 
  
 
 
 
 
 
 
  Execution 
 Yes, n (%) 
 
xx (xx.xx) 
 
xx (xx.xx) 
 0.xxxx †† or ** 
  Potassium 
n mean±sd 
xx 
xx.xx±xx.xx 
xx 
xx.xx±xx.xx 
0.xxxx † or * 
 
 
median [min, max] 
 
xx.xx[xx.xx,xx.xx] 
 
xx.xx[xx.xx,xx.xx] 
 
  Chloride 
n mean±sd 
xx 
xx.xx±xx.xx 
xx 
xx.xx±xx.xx 
0.xxxx † or * 
 
 
median [min, max] 
 
xx.xx[xx.xx,xx.xx] 
 
xx.xx[xx.xx,xx.xx] 
 
Complete blood count 
 
 
 
 
 
 
 
WBC 
n mean±sd 
xx 
xx.xx±xx.xx 
xx 
xx.xx±xx.xx 
0.xxxx † or * 
 
 
median [min, max] 
 
xx.xx[xx.xx,xx.xx] 
 
xx.xx[xx.xx,xx.xx] 
 
  ANC 
n mean±sd 
xx 
xx.xx±xx.xx 
xx 
xx.xx±xx.xx 
0.xxxx † or * 
 
 
median [min, max] 
 
xx.xx[xx.xx,xx.xx] 
 
xx.xx[xx.xx,xx.xx] 
 
  Hemoglobin 
n mean±sd 
xx 
xx.xx±xx.xx 
xx 
xx.xx±xx.xx 
0.xxxx † or * 
 
 
median [min, max] 
 
xx.xx[xx.xx,xx.xx] 
 
xx.xx[xx.xx,xx.xx] 
 
  PLT 
n mean±sd 
xx 
xx.xx±xx.xx 
xx 
xx.xx±xx.xx 
0.xxxx † or * 
 
 
median [min, max] 
 
xx.xx[xx.xx,xx.xx] 
 
xx.xx[xx.xx,xx.xx] 
 


 
 
30 
 
 
 No, n (%) 
 
xx (xx.xx) 
 
xx (xx.xx) 
 
 
 
 Not applicable, n (%)  
xx (xx.xx) 
 
xx (xx.xx) 
 
 
  Result 
 Negative, n (%) 
 
xx (xx.xx) 
 
xx (xx.xx) 
 0.xxxx †† or ** 
  
 Positive, n (%) 
 
xx (xx.xx) 
 
xx (xx.xx) 
 
  
Baseline visit    
 
  
 
  
 
  
Urine HCG 
  
 
 
 
 
 
 
  Execution 
 Yes, n (%) 
 
xx (xx.xx) 
 
xx (xx.xx) 
 0.xxxx †† or ** 
 
 No, n (%) 
 
xx (xx.xx) 
 
xx (xx.xx) 
 
 
 
 Not applicable, n (%)  
xx (xx.xx) 
 
xx (xx.xx) 
 
 
  Result 
 Negative, n (%) 
 
xx (xx.xx) 
 
xx (xx.xx) 
 0.xxxx †† or ** 
  
 Positive, n (%) 
 
xx (xx.xx) 
 
xx (xx.xx) 
 
  
†† p-value by the Chi-square test   ** p-value by the Fisher’s exact test 
 
 
4.3.10 ECG 
 
Table 12 below presents the distribution of the ECG examination results of the two arms before treatment of study drug. 
 
Table 12. ECG Examination 
  
    
 
Investigational arm(N=xx) 
 
Control arm(N=xx)  
p-value 
Screening 
    
 
  
 
  
 
  
ECG 
 
 
 
 
 
 
 
 
  Execution 
 
Yes, n (%) 
 
xx (xx.xx) 
 
xx (xx.xx) 
 
0.xxxx †† or ** 
 
 
No, n (%) 
 
xx (xx.xx) 
 
xx (xx.xx) 
 
 
Rhythm 
 
Sinus rhythm, n (%) 
 
xx (xx.xx) 
 
xx (xx.xx) 
 
0.xxxx †† or ** 


 
 
31 
 
 
 
Other, n (%) 
 
xx (xx.xx) 
 
xx (xx.xx) 
 
 
QTcF 
n mean±sd 
xx 
xx.xx±xx.xx 
xx 
xx.xx±xx.xx 
 
0.xxxx † or * 
 
 
median [min, max] 
 
xx.xx[xx.xx,xx.xx] 
 
xx.xx[xx.xx,xx.xx] 
 
 
Baseline visit     
 
  
 
  
 
  
ECG 
 
 
 
 
 
 
 
 
  Execution 
 
Yes, n (%) 
 
xx (xx.xx) 
 
xx (xx.xx) 
 
 
 
 
No, n (%) 
 
xx (xx.xx) 
 
xx (xx.xx) 
 
 
 
 
Not applicable, n (%)  
xx (xx.xx) 
 
xx (xx.xx) 
 
 
Rhythm 
 
Sinus rhythm, n (%) 
 
xx (xx.xx) 
 
- 
 
 
 
 
Others, n (%) 
 
xx (xx.xx) 
 
- 
 
 
QTcF 
n mean±sd 
xx 
xx.xx±xx.xx 
 
- 
 
 
 
 
median [min, max] 
 
xx.xx[xx.xx,xx.xx] 
 
- 
 
 
† p-value by t-test                * p-value by Wilcoxon rank sum test 
†† p-value by the Chi-square test   ** p-value by the Fisher’s exact test 
 
 
4.3.11 Optic test (Ishihara Color Plate) 
 
Table 13 below presents the distribution of the optic test results of the two arms before treatment of study drug. 
 
Table 13. Optic Test (Ishihara Color Plate) 
  
 
  
 
Investigational arm (N=xx) 
 
Control arm (N=xx) 
p-value 
Screening 
  
 
  
 
  
  
Execution 
 
 
 
 
 
 
 
  
Yes, n (%) 
 
xx (xx.xx) 
 
xx (xx.xx) 
0.xxxx †† or ** 


 
 
32 
 
  
No, n (%) 
 
xx (xx.xx) 
 
xx (xx.xx) 
 
- Performance and the number of correct 
answers of 24 Ishihara color plates 
n mean±sd 
x
x 
xx.xx±xx.xx 
x
x 
xx.xx±xx.xx 
0.xxxx † or * 
 
 
median [min, 
max] 
 
xx.xx[xx.xx,xx.xx] 
 
xx.xx[xx.xx,xx.xx] 
  
Baseline visit 
  
 
  
 
  
  
Execution 
 
 
 
 
 
 
 
 
 
Yes, n (%) 
 
xx (xx.xx) 
 
xx (xx.xx) 
- 
 
 
No, n (%) 
 
xx (xx.xx) 
 
xx (xx.xx) 
 
- Performance and the number of correct 
answers of 24 Ishihara color plates 
n mean±sd 
x
x 
xx.xx±xx.xx 
x
x 
xx.xx±xx.xx 
0.xxxx † or * 
 
 
median [min, 
max] 
 
xx.xx[xx.xx,xx.xx] 
 
xx.xx[xx.xx,xx.xx] 
  
† p-value by t-test                * p-value by Wilcoxon rank sum test 
†† p-value by the Chi-square test   ** p-value by the Fisher’s exact test 
 
 
4.4 Adherence Assessment 
 
Table 14 below presents the distribution of adherence to study drug of both arms at each visit and throughout the entire treatment period. 
In this case, for the final adherence of each subject, the total adherence to each drug is calculated separately, and the average value is defined as the final 
adherence. An independent t-test or Wilcoxon rank sum test is performed only for final adherence and comparisons are made between groups. 
 
Table 14.Adherence Assessment 
  
  
  
  
Investigational arm (N=xx) 
  
Control arm (N=xx) 
p-value 
Final 
Adherence 
n 
mean±sd 
xx 
xx.xx±xx.xx 
xx 
xx.xx±xx.xx 
0.xxxx † or * 
Delamanid 
 
median [min, max] 
 
xx.xx[xx.xx,xx.xx] 
 
xx.xx[xx.xx,xx.xx] 
 
Linezolid 
n 
mean±sd 
xx 
xx.xx±xx.xx 
xx 
xx.xx±xx.xx 
0.xxxx † or * 


 
 
33 
 
 
 
median [min, max] 
 
xx.xx[xx.xx,xx.xx] 
 
xx.xx[xx.xx,xx.xx] 
 
Levofloxacin 
n 
mean±sd 
xx 
xx.xx±xx.xx 
xx 
xx.xx±xx.xx 
0.xxxx † or * 
 
 
median [min, max] 
 
xx.xx[xx.xx,xx.xx] 
 
xx.xx[xx.xx,xx.xx] 
 
Pyrazinamide 
n 
mean±sd 
xx 
xx.xx±xx.xx 
xx 
xx.xx±xx.xx 
0.xxxx † or * 
 
 
median [min, max] 
 
xx.xx[xx.xx,xx.xx] 
 
xx.xx[xx.xx,xx.xx] 
 
Other drug 1 
n 
mean±sd 
xx 
xx.xx±xx.xx 
xx 
xx.xx±xx.xx 
0.xxxx † or * 
 
 
median [min, max] 
 
xx.xx[xx.xx,xx.xx] 
 
xx.xx[xx.xx,xx.xx] 
 
Other drug 2 
n 
mean±sd 
xx 
xx.xx±xx.xx 
xx 
xx.xx±xx.xx 
0.xxxx † or * 
 
 
median [min, max] 
 
xx.xx[xx.xx,xx.xx] 
 
xx.xx[xx.xx,xx.xx] 
 
   
n 
mean±sd 
xx 
xx.xx±xx.xx 
xx 
xx.xx±xx.xx 
0.xxxx † or * 
 
 
median [min, max] 
 
xx.xx[xx.xx,xx.xx] 
 
xx.xx[xx.xx,xx.xx] 
 
† p-value by t-test           * p-value by Wilcoxon rank sum test 
 
 
5. Efficacy Evaluation Results 
 
The efficacy evaluation uses the mITT group as the main analysis group and the PP group as the auxiliary analysis group. The mITT analysis includes 
randomized subjects after satisfying eligibility criteria and receive study drugs at least one time. The subjects are not confirmed to be additionally resistant 
to fluoroquinolone, mono-resistant to rifampicin, or susceptible to rifampicin.  
The PP analysis includes subjects included in the mITT group and have completed 80% or more administration through the planned treatment period has 
completed the clinical trial according to the study protocol during the clinical trial period. 
The mITT analysis of the primary efficacy evaluation excludes the subjects judged to be “Not assessable”. The subgroups according to the presence or 
absence of pyrazinamide resistance are additionally analyzed of the primary outcome. 
Stratification analysis is performed for primary and secondary outcome evaluation by dividing subjects into sputum smear positive and sputum smear negative 
patient groups based on the sputum smear results. 


 
 
34 
 
 
5.1  Primary Efficacy Evaluation Results 
 
5.1.1  Treatment Success Rate at 24 Months after the initiation of treatment 
 
- The analysis presents the frequency and proportion of treatment success rate after 24 months of each arm to check if the treatment success rate of the 
investigational arm 24 months after the initiation of treatment is inferior to the control arm. It presents the 95% confidence interval of the treatment success 
rate difference (investigational arm’s treatment success rate - control arm’s treatment success rate) 24 months after the initiation of treatment. The one-sided 
test is performed at the significant level of 2.5% using the lower limit of the 95% confidence interval about the difference of the treatment success rate 
between the two arms. If the lower limit of the confidence interval is larger than 0.1, it proves that the treatment success rate of the investigational arm is 
inferior to the control arm. If it is equal to or less than 0.1, it cannot prove that the investigational arm is not inferior to the control arm (Table 15). 
 
Table 15. Treatment Success Rate at 24 Months after the initiation of treatment 
   
Investigational Arm 
Control Arm 
All 
mITT analysis group 
xx 
xx 
xx 
 Not assessable2) 
xx 
xx 
xx 
 Treatment success rate at 24 months after the initiation of treatment, n 
(%) 
xx (xx.xx) 
xx (xx.xx) 
xx (xx.xx) 
 
Difference [95% CI] 
xx.xx[xx.xx, ∞]1) 
 
 Treatment failure, n (%) 
xx (xx.xx) 
xx (xx.xx) 
xx (xx.xx) 
PP analysis group 
xx 
xx 
xx 
 Not assessable2) 
xx 
xx 
xx 
 Treatment success rate at 24 months after the initiation of treatment, n 
(%) 
xx (xx.xx) 
xx (xx.xx) 
xx (xx.xx) 
 
Difference [95% CI] 
xx.xx[xx.xx, ∞]1) 
 
 Treatment failure, n (%) 
xx (xx.xx) 
xx (xx.xx) 
xx (xx.xx) 


 
 
35 
 
Sub-group analysis 
xx 
xx 
xx 
1-1. Sputum smear positive3) 
xx 
xx 
xx 
mITT analysis group 
xx 
xx 
xx 
 Not assessable2) 
xx 
xx 
xx 
 Treatment success rate at 24 months after the initiation of treatment, n 
(%) 
xx (xx.xx) 
xx (xx.xx) 
xx (xx.xx) 
 
Difference [95% CI] 
xx.xx[xx.xx, ∞]1) 
 
 Treatment failure, n (%) 
xx (xx.xx) 
xx (xx.xx) 
xx (xx.xx) 
PP analysis group 
xx 
xx 
xx 
 Not assessable2) 
xx 
xx 
xx 
 Treatment success rate at 24 months after the initiation of treatment, n 
(%) 
xx (xx.xx) 
xx (xx.xx) 
xx (xx.xx) 
 
Difference [95% CI] 
xx.xx[xx.xx, ∞]1) 
 
 Treatment failure, n (%) 
xx (xx.xx) 
xx (xx.xx) 
xx (xx.xx) 
1-2. Sputum smear negative4) 
xx 
xx 
xx 
mITT analysis group 
xx 
xx 
xx 
 Not assessable2) 
xx 
xx 
xx 
 Treatment success rate at 24 months after the initiation of treatment, n 
(%) 
xx (xx.xx) 
xx (xx.xx) 
xx (xx.xx) 
 
Difference [95% CI] 
xx.xx[xx.xx, ∞]1) 
 
 Treatment failure, n (%) 
xx (xx.xx) 
xx (xx.xx) 
xx (xx.xx) 
PP analysis group 
xx 
xx 
xx 
 Not assessable2) 
xx 
xx 
xx 
 Treatment success rate at 24 months after the initiation of treatment, n 
(%) 
xx (xx.xx) 
xx (xx.xx) 
xx (xx.xx) 
 
Difference [95% CI] 
xx.xx[xx.xx, ∞]1) 
 
 Treatment failure, n (%) 
xx (xx.xx) 
xx (xx.xx) 
xx (xx.xx) 
1) If the lower limit of the confidence interval is larger than -10%, it proves that the efficacy of the study drug is inferior to the control drug. 
2) The subjects judged to be “Not assessable are excluded from the primary assessment. 


 
 
36 
 
3) Sputum smear positive at screening visit (visit1) 
4) Sputum smear negative at screening visit (visit1) 
 
 
5.2 Secondary Efficacy Evaluation Results 
 
The secondary outcomes of this clinical trial include the time to sputum Mycobacterium TB (MTB) culture conversion to negative (liquid and solid culture 
media), the proportion of sputum MTB culture conversion to negative at two months of treatment (liquid and solid culture media), the proportion of sputum 
MTB culture conversion to negative at six months of treatment (liquid and solid culture media), the proportion of treatment success at the end of treatment, 
the proportion of relapse after treatment success (investigational arm), and the proportion of death and time-to-death. Additionally, the primary outcome 
between treatment groups according to resistance to pyrazinamide is performed. 
 
5.2.1  Time to sputum culture conversion after the initiation of treatment (Liquid and Solid Culture Media) 
 
To test whether the time to sputum culture conversion after the initiation of treatment of the control arm and investigational arm (liquid and solid culture media) 
are different statistically, the median time is estimated in each group using the Kaplan-Meier method, and the difference of the distribution of time to culture 
conversion of the two arms is compared using the Log-rank test (Table 16). 
 
Table 16. Time to sputum culture conversion after the initiation of treatment (Liquid and Solid Culture Media) 
  
  
Investigational Arm 
Control Arm 
p-value 1) 
mITT analysis group, n 
 
xx 
xx 
 
  Solid media 
median time [95% CI] 
xx[xx.xx-xx.xx] 
xx[xx.xx-xx.xx] 
0.xxxx 
  Liquid media 
median time [95% CI] 
xx[xx.xx-xx.xx] 
xx[xx.xx-xx.xx] 
 
PP analysis group, n 
 
 
 
 
  Solid media 
median time (95% CI) 
xx[xx.xx-xx.xx] 
xx[xx.xx-xx.xx] 
0.xxxx 


 
 
37 
 
  Liquid media 
median time (95% CI) 
xx[xx.xx-xx.xx] 
xx[xx.xx-xx.xx] 
 
Sub-group analysis 
 
xx 
xx 
 
1-1. Sputum smear 
positive2) 
 
xx 
xx 
 
mITT analysis group, n 
 
xx 
xx 
 
  Solid media 
median time [95% CI] 
xx[xx.xx-xx.xx] 
xx[xx.xx-xx.xx] 
0.xxxx 
  Liquid media 
median time [95% CI] 
xx[xx.xx-xx.xx] 
xx[xx.xx-xx.xx] 
 
PP analysis group, n 
 
 
 
 
  Solid media 
median time (95% CI) 
xx[xx.xx-xx.xx] 
xx[xx.xx-xx.xx] 
0.xxxx 
  Liquid media 
median time (95% CI) 
xx[xx.xx-xx.xx] 
xx[xx.xx-xx.xx] 
 
1-2. Sputum smear 
negative3) 
 
xx 
xx 
 
mITT analysis group, n 
 
xx 
xx 
 
  Solid media 
median time [95% CI] 
xx[xx.xx-xx.xx] 
xx[xx.xx-xx.xx] 
0.xxxx 
  Liquid media 
median time [95% CI] 
xx[xx.xx-xx.xx] 
xx[xx.xx-xx.xx] 
 
PP analysis group, n 
 
 
 
 
  Solid media 
median time (95% CI) 
xx[xx.xx-xx.xx] 
xx[xx.xx-xx.xx] 
0.xxxx 
  Liquid media 
median time (95% CI) 
xx[xx.xx-xx.xx] 
xx[xx.xx-xx.xx] 
 
1) P-value for the comparison test of the time to negative between Investigational arm and Control arm. The test assumes that the negative distribution difference between Investigational and 
Control arm is the same at all time points. 
2) Sputum smear positive at screening visit (visit1) 
3) Sputum smear negative at screening visit (visit1) 
 


 
 
38 
 
 
mITT analysis group 
PP analysis group 
Solid 
media 
 
 
Sample  
Sample  
Control Arm 
Investigational Arm 
Control Arm 
Investigational Arm 


 
 
39 
 
Figure 2. Time to Sputum Culture Conversion after Initiation of treatment (Liquid and Solid Culture media) 
 
 
 
5.2.2   Sputum culture conversion proportion at two months of treatment (Liquid and Solid Culture Media) 
 
- To compare the proportion of sputum MTB culture conversion to negative between the investigational arm and control arm at two months of treatment, the 
frequency and proportion of each arm are summarized, and the Chi-square test or Fisher’s exact test is performed (Table 17).  
 
Liquid 
media 
 
 
Control Arm 
Investigational Arm 
Sample  
Sample  
Control Arm 
Investigational Arm 


 
 
40 
 
Table 17.  Sputum culture conversion proportions at two months of treatment 
  
  
Investigational Arm 
Control Arm 
p-value 1) 
mITT analysis group, xx persons (Investigational arm: xx persons, 
Control arm: xx persons) 
 
 
 
 
  Solid media 
n (%) 
xx (xx.xx) 
xx (xx.xx) 
0.xxxx †† or ** 
  Liquid media 
n (%) 
xx (xx.xx) 
xx (xx.xx) 
0.xxxx †† or ** 
PP analysis group, xx persons (Investigational arm: xx persons, 
Control arm: xx persons) 
 
 
 
 
  Solid media 
n (%) 
xx (xx.xx) 
xx (xx.xx) 
0.xxxx †† or ** 
  Liquid media 
n (%) 
xx (xx.xx) 
xx (xx.xx) 
0.xxxx †† or ** 
Sub-group analysis 
 
 
 
 
1-1. Sputum smear positive2) 
 
 
 
 
mITT analysis group, xx persons (Investigational arm: xx persons, 
Control arm: xx persons) 
 
 
 
 
  Solid media 
n (%) 
xx (xx.xx) 
xx (xx.xx) 
0.xxxx †† or ** 
  Liquid media 
n (%) 
xx (xx.xx) 
xx (xx.xx) 
0.xxxx †† or ** 
PP analysis group, xx persons (Investigational arm: xx persons, 
Control arm: xx persons) 
 
 
 
 
  Solid media 
n (%) 
xx (xx.xx) 
xx (xx.xx) 
0.xxxx †† or ** 
  Liquid media 
n (%) 
xx (xx.xx) 
xx (xx.xx) 
0.xxxx †† or ** 
1-2. Sputum smear negative3) 
 
 
 
 
mITT analysis group, xx persons (Investigational arm: xx persons, 
Control arm: xx persons) 
 
 
 
 
  Solid media 
n (%) 
xx (xx.xx) 
xx (xx.xx) 
0.xxxx †† or ** 
  Liquid media 
n (%) 
xx (xx.xx) 
xx (xx.xx) 
0.xxxx †† or ** 
PP analysis group, xx persons (Investigational arm: xx persons, 
Control arm: xx persons) 
 
 
 
 
  Solid media 
n (%) 
xx (xx.xx) 
xx (xx.xx) 
0.xxxx †† or ** 
  Liquid media 
n (%) 
xx (xx.xx) 
xx (xx.xx) 
0.xxxx †† or ** 


 
 
41 
 
†† p-value by the Chi-square test   ** p-value by the Fisher’s exact test 
1) p-value of the comparison test of the negative conversion rate between the Investigational arm and Control arm 
2) Sputum smear positive at screening visit (visit1) 
3) Sputum smear negative at screening visit (visit1) 
 
 
5.2.3   Sputum culture conversion proportion at six months of treatment (Liquid and Solid Culture Media) 
 
To compare the proportion of sputum MTB culture conversion to negative between the investigational arm and control arm at six months of treatment, the 
frequency and proportion of each arm are summarized, and the chi-square test or Fisher’s exact test is performed (Table 18). 
 
Table 18.  Sputum culture conversion proportion at six months of treatment 
  
  
Investigational arm 
Control arm 
p-value 1) 
mITT analysis group 
 
xx 
xx 
 
  Solid media 
n (%) 
xx (xx.xx) 
xx (xx.xx) 
0.xxxx †† or ** 
  Liquid media 
n (%) 
xx (xx.xx) 
xx (xx.xx) 
0.xxxx †† or ** 
PP analysis group 
 
xx 
xx 
 
  Solid media 
n (%) 
xx (xx.xx) 
xx (xx.xx) 
0.xxxx †† or ** 
  Liquid media 
n (%) 
xx (xx.xx) 
xx (xx.xx) 
0.xxxx †† or ** 
Sub-group analysis 
 
xx 
xx 
 
1-1. Sputum smear positive2) 
 
xx 
xx 
 
mITT analysis group 
 
xx 
xx 
 
  Solid media 
n (%) 
xx (xx.xx) 
xx (xx.xx) 
0.xxxx †† or ** 
  Liquid media 
n (%) 
xx (xx.xx) 
xx (xx.xx) 
0.xxxx †† or ** 
PP analysis group 
 
xx 
xx 
 
  Solid media 
n (%) 
xx (xx.xx) 
xx (xx.xx) 
0.xxxx †† or ** 
  Liquid media 
n (%) 
xx (xx.xx) 
xx (xx.xx) 
0.xxxx †† or ** 


 
 
42 
 
1-2. Sputum smear negative3) 
 
xx 
xx 
 
mITT analysis group 
 
xx 
xx 
 
  Solid media 
n (%) 
xx (xx.xx) 
xx (xx.xx) 
0.xxxx †† or ** 
  Liquid media 
n (%) 
xx (xx.xx) 
xx (xx.xx) 
0.xxxx †† or ** 
PP analysis group 
 
xx 
xx 
 
  Solid media 
n (%) 
xx (xx.xx) 
xx (xx.xx) 
0.xxxx †† or ** 
  Liquid media 
n (%) 
xx (xx.xx) 
xx (xx.xx) 
0.xxxx †† or ** 
†† p-value by the Chi-square test   ** p-value by the Fisher’s exact test 
1) p-value of the comparison test of the negative rate between the Investigational and Control arms 
2) Sputum smear positive at screening visit (visit1) 
3) Sputum smear negative at screening visit (visit1) 
 
 
5.2.4  Proportion of Treatment Success at the End of Treatment 
 
- The analysis presents the frequency and proportion of treatment success and failure in the investigational arm (Table 19). 
 
Table 19. Proportion of Treatment Success at the End of Treatment 
   
Investigational arm 
mITT analysis group 
xx 
 Proportion of treatment success at the end of treatment, n (%) 
xx (xx.xx) 
 Treatment failure, n (%) 
xx (xx.xx) 
PP analysis group 
xx 
 Proportion of treatment success at the end of treatment, n (%) 
xx (xx.xx) 
 Treatment failure, n (%) 
xx (xx.xx) 
Sub-group analysis 
xx 


 
 
43 
 
1-1. Sputum smear positive1) 
xx 
mITT analysis group 
xx 
 Proportion of treatment success at the end of treatment, n (%) 
xx (xx.xx) 
 Treatment failure, n (%) 
xx (xx.xx) 
PP analysis group 
xx 
 Proportion of treatment success at the end of treatment, n (%) 
xx (xx.xx) 
 Treatment failure, n (%) 
xx (xx.xx) 
1-2. Sputum smear negative2) 
xx 
mITT analysis group 
xx 
 Proportion of treatment success at the end of treatment, n (%) 
xx (xx.xx) 
 Treatment failure, n (%) 
xx (xx.xx) 
PP analysis group 
xx 
 Proportion of treatment success at the end of treatment, n (%) 
xx (xx.xx) 
 Treatment failure, n (%) 
xx (xx.xx) 
1) Sputum smear positive at screening visit (visit1) 
2) Sputum smear negative at screening visit (visit1) 
 
 
5.2.5  Proportion of Relapse after Treatment Success 
 
The analysis presents the frequency and proportion of relapse after treatment success in the investigational arm. 
 
Table 20. Proportion of Relapse after Treatment Success 
   
Investigational Arm 
mITT analysis group 
xx 


 
 
44 
 
 Treatment success 
xx 
 Proportion of relapse after treatment 
success, n (%) 
xx (xx.xx) 
PP analysis group 
xx 
 Treatment success 
xx 
 Proportion of relapse after treatment 
success, n (%) 
xx (xx.xx) 
Sub-group analysis 
xx 
1-1. Sputum smear positive1) 
xx 
mITT analysis group 
xx 
 Treatment success 
xx 
 Proportion of relapse after treatment 
success, n (%) 
xx (xx.xx) 
PP analysis group 
xx 
 Treatment success 
xx 
 Proportion of relapse after treatment 
success, n (%) 
xx (xx.xx) 
1-2. Sputum smear negative2) 
xx 
mITT analysis group 
xx 
 Treatment success 
xx 
 Proportion of relapse after treatment 
success, n (%) 
xx (xx.xx) 
PP analysis group 
xx 
 Treatment success 
xx 
 Proportion of relapse after treatment 
success, n (%) 
xx (xx.xx) 
1) Sputum smear positive at screening visit (visit1) 
2) Sputum smear negative at screening visit (visit1) 
 
 


 
 
45 
 
5.2.6 Proportion of Death and Time-to-Death 
 
The analysis presents the frequency and proportion of death in the investigational arm and estimates the median survival time using Kaplan-Meier method 
(Table 21). 
Table 21. Proportion of death and Time-to-Death 
   
Investigational Arm 
mITT analysis group 
xx 
 Death, n (%) 
xx (xx.xx) 
 median survival time [95% CI] 
xx[xx.xx-xx.xx] 
PP analysis group 
xx 
 Death, n (%) 
xx (xx.xx) 
 median survival time [95% CI] 
xx[xx.xx-xx.xx] 
Sub-group analysis 
 
1-1. Sputum smear positive1) 
 
mITT analysis group 
xx 
 Death, n (%) 
xx (xx.xx) 
 median survival time [95% CI] 
xx[xx.xx-xx.xx] 
PP analysis group 
xx 
 Death, n (%) 
xx (xx.xx) 
 median survival time [95% CI] 
xx[xx.xx-xx.xx] 
1-2. Sputum smear negative2) 
 
mITT analysis group 
xx 
 Death, n (%) 
xx (xx.xx) 
 median survival time [95% CI] 
xx[xx.xx-xx.xx] 
PP analysis group 
xx 


 
 
46 
 
 Death, n (%) 
xx (xx.xx) 
 median survival time [95% CI] 
xx[xx.xx-xx.xx] 
1) Sputum smear positive at screening visit (visit1) 
2) Sputum smear negative at screening visit (visit1) 
 
 
 
mITT analysis group 
PP analysis group 
Total  
Investigational  
Arm 
  
 
Sample  
Sample  


 
 
47 
 
Sputum  
smear positive 
 
 
Sputum  
smear negative 
 
 
Figure 3. Time to Death 
 
 
Sample 
Sample 
Sample 
Sample 


 
 
48 
 
5.2.7  Treatment Success Rate at 24 Months after the initiation of treatment According to Pyrazinamide Resistance 
 
In order to test whether the treatment success rate after 24 months of the investigational arm is non-inferior to the control arm in the subgroup according to 
the presence or absence of pyrazinamide resistance, 95% confidence interval of the treatment success rate after 24 months in each arm is presented in 
terms of frequency. It presents the 95% confidence interval of the treatment success rate difference (investigational arm’s treatment success rate - control 
arm’s treatment success rate) 24 months after initiation of treatment. The one-sided test is performed at the significant level of 2.5% using the lower limit of 
the 95% confidence interval of the treatment success rate difference between the two arms. If the lower limit of the confidence interval is larger than 0.1, it 
proves that the success rate of the investigational arm is inferior to the control arm. If it is equal to or less than 0.1, it cannot prove that the investigational 
arm is not inferior to the control arm (Table 22). 
 
Table 22. Treatment Success Rate at 24 Months after the initiation of treatment According to Pyrazinamide Resistance 
   
Investigational Arm 
Control Arm 
All 
Pyrazinamide resistant 
 
 
 
mITT analysis group 
xx 
xx 
xx 
 Not assessable2) 
xx 
xx 
xx 
 Treatment success rate at 24 months 
after the initiation of treatment, n (%) 
xx (xx.xx) 
xx (xx.xx) 
xx (xx.xx) 
 
Difference [95% CI] 
xx.xx[xx.xx,∞]1) 
 
 Treatment failure, n (%) 
xx (xx.xx) 
xx (xx.xx) 
xx (xx.xx) 
PP analysis group 
 
 
 
 Not assessable2) 
xx 
xx 
xx 
 Treatment success rate at 24 months 
after the initiation of treatment, n (%) 
xx (xx.xx) 
xx (xx.xx) 
xx (xx.xx) 
 
Difference [95% CI] 
xx.xx[xx.xx,∞]1) 
 
 Treatment failure, n (%) 
xx (xx.xx) 
xx (xx.xx) 
xx (xx.xx) 
No pyrazinamide resistant 
xx 
xx 
xx 
mITT analysis group 
 
 
 


 
 
49 
 
 Not assessable2) 
xx 
xx 
xx 
 Treatment success rate at 24 months 
after the initiation of treatment, n (%) 
xx (xx.xx) 
xx (xx.xx) 
xx (xx.xx) 
 
Difference [95% CI] 
xx.xx[xx.xx ∞]1) 
 
 Treatment failure, n (%) 
xx (xx.xx) 
xx (xx.xx) 
xx (xx.xx) 
PP analysis group 
 
 
 
 Not assessable2) 
xx 
xx 
xx 
 Treatment success rate at 24 months 
after the initiation of treatment, n (%) 
xx (xx.xx) 
xx (xx.xx) 
xx (xx.xx) 
 
Difference [95% CI] 
xx.xx[xx.xx ∞]1) 
 
 Treatment failure, n (%) 
xx (xx.xx) 
xx (xx.xx) 
xx (xx.xx) 
1) If the lower limit of the confidence interval is larger than -10%, it proves that the efficacy of the study drug is inferior to the control drug. 
2) The subjects judged to be “Not assessable are excluded from the assessment. 
 
 
 
 


 
 
50 
 
6. Safety Assessment Results 
 
The safety analysis will be conducted for the mITT analysis group and the PP analysis group. Additionally, the safety analysis regarding the safety analysis 
group, that divides groups according to whether study drug delamanid or linezolid is administered, will be carried out for the subjects enrolled in this clinical 
trial and administered the study drug at least one time. The results of the safety evaluation will be summarized, focusing on adverse reactions and physical 
examinations, neurological examinations, chemistry, electrolyte, and complete blood count evaluated during this clinical trial period. The severity of adverse 
event will be evaluated based on CTCAE Version 4.0. 
 
6.1 Adverse Events 
 
The analysis presents the summary of the total number of adverse events, the number of subjects experiencing adverse events, and the serious adverse 
events, adverse event with grade 3-5 in this clinical trial (Table 23). 
 
Table 23. Summary of Adverse Event Reported during Study Period 
 
Investigational Arm 
Control Arm 
Total 
 mITT 
 N=xx 
 N=xx 
N=xx 
Number of subjects showing adverse events, n 
(%) 
xx (xx.xx) 
xx (xx.xx) 
xx (xx.xx) 
95% confidence interval of adverse event rate 
xx.xx±xx.xx 
xx.xx±xx.xx 
xx.xx±xx.xx 
p-value1) 
0.xxxx †† or ** 
 
Number of adverse events, n 
xx 
xx 
xx 
Adverse drug reaction2) 
 
 
 
Number of subjects showing adverse drug 
reaction, n (%) 
xx (xx.xx) 
xx (xx.xx) 
xx (xx.xx) 
p-value3) 
0.xxxx †† or ** 
 
Number of adverse drug reaction, n 
xx 
xx 
xx 
Serious adverse events 
  
  
  


 
 
51 
 
Number of subjects showing serious adverse 
events, n (%) 
xx (xx.xx) 
xx (xx.xx) 
xx (xx.xx) 
p-value4) 
0.xxxx †† or ** 
 
 
Number of adverse events, n 
xx 
xx 
xx 
Adverse event of grade 3-5 
  
  
  
Number of subjects showing over grade 3 of 
adverse event, n (%) 
xx (xx.xx) 
xx (xx.xx) 
xx (xx.xx) 
p-value5) 
0.xxxx †† or ** 
 
Number of grade 3 of adverse event, n  
xx 
xx 
xx 
Death 
  
  
  
Death, n (%) 
xx (xx.xx) 
xx (xx.xx) 
xx (xx.xx) 
p-value6) 
0.xxxx †† or ** 
 
Seriousness 
  
  
  
  Not serious, n 
xx 
xx 
xx 
  Serious, n 
xx 
xx 
xx 
Severity 
  
  
  
  Mild, n 
xx 
xx 
xx 
  Moderate, n 
xx 
xx 
xx 
  Severe, n 
xx 
xx 
xx 
  life threatening or disabling, n 
xx 
xx 
xx 
  Death, n 
xx 
xx 
xx 
Relation 
  
  
  
  not related, n 
xx 
xx 
xx 
  doubtful, n 
xx 
xx 
xx 
  possible, n 
xx 
xx 
xx 
  probable, n 
xx 
xx 
xx 


 
 
52 
 
  definite, n 
xx 
xx 
xx 
Action taken 
  
  
  
  No action taken, n 
xx 
xx 
xx 
  Dosage Adjustment of study drug, n 
xx 
xx 
xx 
  Suspension of study drug, n 
xx 
xx 
xx 
  Permanent termination of study drug, n 
xx 
xx 
xx 
Unknown, n 
xx 
xx 
xx 
Not applicable, n 
xx 
xx 
xx 
Dosage adjustment of TB medication other 
than the study drug, n 
xx 
xx 
xx 
Suspension of TB medication other than the 
study drug, n 
xx 
xx 
xx 
Permanent termination of TB medication 
other than the study drug, n 
xx 
xx 
xx 
Outcome 
  
  
  
  Resolved, n 
xx 
xx 
xx 
  Resolved with residual effect, n 
xx 
xx 
xx 
Ongoing, n 
xx 
xx 
xx 
Death, n 
xx 
xx 
xx 
Unknown, n 
xx 
xx 
xx 
PP 
N=xx 
N=xx 
N=xx 
Number of subjects showing adverse event, n 
(%) 
xx (xx.xx) 
xx (xx.xx) 
xx (xx.xx) 
95% confidence interval of adverse event rate 
[xx.xx, xx.xx] 
[xx.xx, xx.xx] 
[xx.xx, xx.xx] 
p-value1) 
0.xxxx †† or ** 
 
xx 
Number of adverse events, n 
xx 
xx 
xx 
Adverse drug reaction2) 
 
 
 


 
 
53 
 
Number of subjects showing adverse drug 
reaction, n (%) 
xx (xx.xx) 
xx (xx.xx) 
xx (xx.xx) 
p-value3) 
0.xxxx †† or ** 
 
xx 
Number of adverse drug reaction, n 
xx 
xx 
xx 
Serious adverse event 
  
  
  
Number of subjects showing serious adverse 
events, n (%) 
xx (xx.xx) 
xx (xx.xx) 
xx (xx.xx) 
p-value4) 
0.xxxx †† or ** 
 
xx 
Number of adverse events, n 
xx 
xx 
xx 
Adverse event of Grade 3-5  
  
  
  
Number of subjects showing over grade 3 of 
adverse event, n (%) 
xx (xx.xx) 
xx (xx.xx) 
xx (xx.xx) 
p-value5) 
0.xxxx †† or ** 
 
  
Number of grade 3 of adverse event, n  
xx 
xx 
xx 
Death 
  
  
  
Death, n (%) 
xx (xx.xx) 
xx (xx.xx) 
xx (xx.xx) 
p-value6) 
0.xxxx †† or ** 
 
xx 
Seriousness 
  
  
  
Not serious, n 
xx 
xx 
xx 
Serious, n 
xx 
xx 
xx 
Severity 
  
  
  
  Mild, n 
xx 
xx 
xx 
  Moderate, n 
xx 
xx 
xx 
  Severe, n 
xx 
xx 
xx 
  life threatening or disabling, n 
xx 
xx 
xx 
  Death, n 
xx 
xx 
xx 
Relation 
  
  
  


 
 
54 
 
  not related, n 
xx 
xx 
xx 
  doubtful, n 
xx 
xx 
xx 
  possible, n 
xx 
xx 
xx 
  probable, n 
xx 
xx 
xx 
  definite, n 
xx 
xx 
xx 
Action taken 
  
  
  
  No action taken, n 
xx 
xx 
xx 
  Dosage Adjustment of study drug, n 
xx 
xx 
xx 
  Suspension of study drug, n 
xx 
xx 
xx 
  Permanent termination of study drug, n 
xx 
xx 
xx 
Unknown, n 
xx 
xx 
xx 
Not applicable, n 
xx 
xx 
xx 
Dosage adjustment of TB medication other than 
the study drug, n 
xx 
xx 
xx 
Suspension of TB medication other than the 
study drug, n 
xx 
xx 
xx 
Permanent termination of TB medication other 
than the study drug, n 
xx 
xx 
xx 
Outcome 
  
  
  
  Resolved, n 
xx 
xx 
xx 
  Resolved with residual effect, n 
xx 
xx 
xx 
Ongoing, n 
xx 
xx 
xx 
Death, n 
xx 
xx 
xx 
Unknown, n 
xx 
xx 
xx 
Safety 
N=xx 
N=xx 
N=xx 
Number of subjects showing adverse events, n 
(%) 
xx (xx.xx) 
xx (xx.xx) 
xx (xx.xx) 
95% confidence interval of adverse event rate 
[xx.xx, xx.xx] 
[xx.xx, xx.xx] 
[xx.xx, xx.xx] 


 
 
55 
 
p-value1) 
0.xxxx †† or ** 
 
Number of adverse events, n 
xx 
xx 
xx 
Adverse drug reaction2) 
 
 
 
Number of subjects showing adverse drug 
reaction, n (%) 
xx (xx.xx) 
xx (xx.xx) 
xx (xx.xx) 
p-value3) 
0.xxxx †† or ** 
 
Number of adverse drug reaction, n 
xx 
xx 
xx 
Serious adverse events 
  
  
  
Number of subjects showing serious adverse 
events, n (%) 
xx (xx.xx) 
xx (xx.xx) 
xx (xx.xx) 
p-value4) 
0.xxxx †† or ** 
 
Number of adverse events, n 
xx 
xx 
xx 
Adverse event of grade 3-5 
  
  
  
Number of subjects showing over grade 3 of 
adverse event, n (%) 
xx (xx.xx) 
xx (xx.xx) 
xx (xx.xx) 
p-value5) 
0.xxxx †† or ** 
 
Number of grade 3 of adverse event, n  
xx 
xx 
xx 
Death 
  
  
  
Death, n (%) 
xx (xx.xx) 
xx (xx.xx) 
xx (xx.xx) 
p-value6) 
0.xxxx †† or ** 
 
Seriousness 
  
  
  
  Not serious, n 
xx 
xx 
xx 
  Serious, n 
xx 
xx 
xx 
Severity 
  
  
  
  Mild, n 
xx 
xx 
xx 
  Moderate, n 
xx 
xx 
xx 
  Severe, n 
xx 
xx 
xx 


 
 
56 
 
  life threatening or disabling, n 
xx 
xx 
xx 
  Death, n 
xx 
xx 
xx 
Relation 
  
  
  
  not related, n 
xx 
xx 
xx 
  doubtful, n 
xx 
xx 
xx 
  possible, n 
xx 
xx 
xx 
  probable, n 
xx 
xx 
xx 
  definite, n 
xx 
xx 
xx 
Action taken 
  
  
  
  No action taken, n 
xx 
xx 
xx 
  Dosage Adjustment of study drug, n 
xx 
xx 
xx 
  Suspension of study drug, n 
xx 
xx 
xx 
  Permanent termination of study drug, n 
xx 
xx 
xx 
Unknown, n 
xx 
xx 
xx 
Not applicable, n 
xx 
xx 
xx 
Dosage adjustment of TB medication other than 
the study drug, n 
xx 
xx 
xx 
Suspension of TB medication other than the 
study drug, n 
xx 
xx 
xx 
Permanent termination of TB medication other 
than the study drug, n 
xx 
xx 
xx 
Outcome 
  
  
  
  Resolved, n 
xx 
xx 
xx 
  Resolved with residual effect, n 
xx 
xx 
xx 
Ongoing, n 
xx 
xx 
xx 
Death, n 
xx 
xx 
xx 
Unknown, n 
xx 
xx 
xx 


 
 
57 
 
 
†† p-value by the Chi-square test   ** p-value by the Fisher’s exact test 
1) p-value for comparison test of adverse reaction incidence rate between groups 
2) In the case of an adverse reaction related to the drug used, the contribution of the drug is Possible, Probable, or Definite 
3) p-value for comparison test of the incidence of adverse drug reactions between groups 
4) p-value for comparison test of incidence of serious adverse events between groups 
5) p-value for the comparison test for the incidence of grade 3 adverse events between groups 
6) p-value for intergroup mortality comparison test 
 
The analysis presents the adverse events occurring for each body system during the clinical trial period. The body system is classified according to SOC 
(System Organ Class) and PT (Preferred Term) of the MedDRA system. The adverse events are summarized for each severity of the body system, relation, 
and body system (Tables 24, 25, and 26). 
 
Table 24. Adverse Events for Each Body System 
 
 
Investigational Arm (N=xx) 
Control Arm (N=xx) 
Total (N=xx) 
mITT


 
 
SystemOrganClass Preferred
Term



SOC1
 
x
x
x

xxx
x
x
x
 
xxx
x
x
x
SOC2
 
x
x
x

xxx
x
x
x
 
xxx
x
x
x
PP


 
 
SystemOrganClass Preferred
Term





 
 
58 
 
SOC1
 
x
x
x

xxx
x
x
x
 
xxx
x
x
x
SOC2
 
x
x
x

xxx
x
x
x
 
xxx
x
x
x
Safety


 
 
SystemOrganClass Preferred
Term



SOC1
 
x
x
x

xxx
x
x
x
 
xxx
x
x
x
SOC2
 
x
x
x

xxx
x
x
x
 
xxx
x
x
x
 
 
Table 25. Adverse Events for Each Severity of Body System 
  
  
Investigational Arm (N=xx) 
Control Arm (N=xx) 
  
  
Severity 
Severity 
  
  
1 
2 
3 
4 
5 
>=3 
1 
2 
3 
4 
5 
>=3 
mITT 
 
  
  
  
  
  
  
  
  
  
  
System Organ Class 
Preferred Term 
  
  
  
  
  
  
  
  
  
  
SOC1 
  
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 


 
 
59 
 
 
xxx 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
  
xxx 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
SOC2 
  
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
xxx 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
  
xxx 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
PP 
 
  
  
  
  
  
  
  
  
  
  
System Organ Class 
Preferred Term 
  
  
  
  
  
  
  
  
  
  
SOC1 
  
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
xxx 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
  
xxx 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
SOC2 
  
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
xxx 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
  
xxx 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Safety 
 
  
  
  
  
  
  
  
  
  
  
System Organ Class 
Preferred Term 
  
  
  
  
  
  
  
  
  
  
SOC1 
  
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
xxx 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
  
xxx 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
SOC2 
  
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
xxx 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
  
xxx 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
Table 26. Adverse Events for Each Relation of Body System 
 


 
 
60 
 
  
  
Investigational Arm (N=xx) 
Control Arm (N=xx) 
  
  
Relation 
Relation 
  
  
1 
2 
3 
4 
5 
>=3 
1 
2 
3 
4 
5 
>=3 
mITT 
 
  
  
  
  
  
  
  
  
  
  
System Organ Class 
Preferred Term 
  
  
  
  
  
  
  
  
  
  
SOC1 
  
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
xxx 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
  
xxx 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
SOC2 
  
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
xxx 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
  
xxx 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
PP 
 
  
  
  
  
  
  
  
  
  
  
System Organ Class 
Preferred Term 
  
  
  
  
  
  
  
  
  
  
SOC1 
  
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
xxx 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
  
xxx 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
SOC2 
  
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
xxx 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
  
xxx 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Safety 
 
  
  
  
  
  
  
  
  
  
  
System Organ Class 
Preferred Term 
  
  
  
  
  
  
  
  
  
  
SOC1 
  
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
xxx 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
  
xxx 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 


 
 
61 
 
SOC2 
  
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
xxx 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
  
xxx 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
 
The analysis summarizes in detail the serious adverse events reported during this clinical trial period (Table 27). 
 
Table 27. Serious Adverse Event Evaluation Results 
Subject No Gender Age Adverse event name Adverse event 
Onset date 
Adverse event 
End date 
Severity Relation Action taken Outcome Remarks 
mITT 
Investigational Arm 
 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
Control Group 
 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
PP 
Investigational Arm  
 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
Control Group 
 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
xx 


 
 
62 
 
 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
Safety 
Investigational arm 
 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
Control arm  
 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
 
 
 
6.2 Physical/Neurological Examination Result 
 
For the results of the physical/neurological examination, the analysis presents the proportion of subjects who were normal at Screening visit (Visit1) and 
changed to abnormal at End of Study (Table 28). 
 
Table 28. Physical/Neurological Examination Result 
  
Investigational arm (N=xx) 
Control arm (N=xx) 
  
n (%) Normal → Abnormal, n (%) n (%) Normal → Abnormal, n (%) 
mITT 
 
 
 
 
Physical examination 
xx 
xx (xx.xx) 
xx 
xx (xx.xx) 
Neurological examination xx 
xx (xx.xx) 
xx 
xx (xx.xx) 
PP 
 
 
 
 
Physical examination 
xx 
xx (xx.xx) 
xx 
xx (xx.xx) 


 
 
63 
 
Neurological examination xx 
xx (xx.xx) 
xx 
xx (xx.xx) 
Safety 
 
 
 
 
Physical examination 
xx 
xx (xx.xx) 
xx 
xx (xx.xx) 
Neurological examination xx 
xx (xx.xx) 
xx 
xx (xx.xx) 
 
 
6.3 Chemistry/Electrolyte/Complete Blood Count 
 
The analysis presents the proportion of subjects who showed the chemistry/electrolyte/complete blood count result of “Normal” or “Abnormal NCS” at 
Baseline visit (Visit2) and changed to “Abnormal CS” at End of Study (Table 29). 
 
Table 29. Chemistry/Electrolyte/Complete Blood Count 
 
  
Investigational arm (N=xx) 
Control arm (N=xx) 
  
n 
Normal or Abnormal NCS 
à Abnormal CS, n (%) 
n 
Normal or Abnormal NCS 
àAbnormal CS, n (%) 
mITT 
 
 
 
 
Chemistry 
 
 
 
 
  T-bilirubin 
xx 
xx (xx.xx) 
xx 
xx (xx.xx) 
  Alkaline phosphatase xx 
xx (xx.xx) 
xx 
xx (xx.xx) 
  AST 
xx 
xx (xx.xx) 
xx 
xx (xx.xx) 
  ALT 
xx 
xx (xx.xx) 
xx 
xx (xx.xx) 
  Creatinine 
xx 
xx (xx.xx) 
xx 
xx (xx.xx) 
  Albumin 
xx 
xx (xx.xx) 
xx 
xx (xx.xx) 


 
 
64 
 
Electrolyte 
 
 
 
 
  Sodium 
xx 
xx (xx.xx) 
xx 
xx (xx.xx) 
  Potassium 
xx 
xx (xx.xx) 
xx 
xx (xx.xx) 
  Chloride 
xx 
xx (xx.xx) 
xx 
xx (xx.xx) 
Complete blood count 
 
 
 
  WBC 
xx 
xx (xx.xx) 
xx 
xx (xx.xx) 
  ANC 
xx 
xx (xx.xx) 
xx 
xx (xx.xx) 
  Hemoglobin 
xx 
xx (xx.xx) 
xx 
xx (xx.xx) 
  PLT 
xx 
xx (xx.xx) 
xx 
xx (xx.xx) 
PP 
 
 
 
 
Chemistry 
 
 
 
 
  T-bilirubin 
xx 
xx (xx.xx) 
xx 
xx (xx.xx) 
  Alkaline phosphatase xx 
xx (xx.xx) 
xx 
xx (xx.xx) 
  AST 
xx 
xx (xx.xx) 
xx 
xx (xx.xx) 
  ALT 
xx 
xx (xx.xx) 
xx 
xx (xx.xx) 
  Creatinine 
xx 
xx (xx.xx) 
xx 
xx (xx.xx) 
  Albumin 
xx 
xx (xx.xx) 
xx 
xx (xx.xx) 
Electrolyte 
 
 
 
 
  Sodium 
xx 
xx (xx.xx) 
xx 
xx (xx.xx) 
  Potassium 
xx 
xx (xx.xx) 
xx 
xx (xx.xx) 
  Chloride 
xx 
xx (xx.xx) 
xx 
xx (xx.xx) 
Complete blood count 
 
 
 
  WBC 
xx 
xx (xx.xx) 
xx 
xx (xx.xx) 
  ANC 
xx 
xx (xx.xx) 
xx 
xx (xx.xx) 
  Hemoglobin 
xx 
xx (xx.xx) 
xx 
xx (xx.xx) 


 
 
65 
 
  PLT 
xx 
xx (xx.xx) 
xx 
xx (xx.xx) 
Safety 
 
 
 
 
Chemistry 
 
 
 
 
  T-bilirubin 
xx 
xx (xx.xx) 
xx 
xx (xx.xx) 
  Alkaline phosphatase xx 
xx (xx.xx) 
xx 
xx (xx.xx) 
  AST 
xx 
xx (xx.xx) 
xx 
xx (xx.xx) 
  ALT 
xx 
xx (xx.xx) 
xx 
xx (xx.xx) 
  Creatinine 
xx 
xx (xx.xx) 
xx 
xx (xx.xx) 
  Albumin 
xx 
xx (xx.xx) 
xx 
xx (xx.xx) 
Electrolyte 
 
 
 
 
  Sodium 
xx 
xx (xx.xx) 
xx 
xx (xx.xx) 
  Potassium 
xx 
xx (xx.xx) 
xx 
xx (xx.xx) 
  Chloride 
xx 
xx (xx.xx) 
xx 
xx (xx.xx) 
Complete blood count 
 
 
 
 
  WBC 
xx 
xx (xx.xx) 
xx 
xx (xx.xx) 
  ANC 
xx 
xx (xx.xx) 
xx 
xx (xx.xx) 
  Hemoglobin 
xx 
xx (xx.xx) 
xx 
xx (xx.xx) 
  PLT 
xx 
xx (xx.xx) 
xx 
xx (xx.xx) 
 
 
6.4 Concomitant Medication 
 
Concomitant medication during the study period will be classified using the ATC (Anatomical Therapeutic Chemical) Code and presented and presented for 
each arm (Table 30). 
 


 
 
66 
 
Table 30. Concomitant Medication (Unit: Persons) 
ATCcode
Investigational arm(N=xx)
Control arm(N=xx)
Total (N=xx)
mITT



XXX,n(%)
xx(xx.xx)
xx(xx.xx)
xx(xx.xx)
XXX,n(%)
xx(xx.xx)
xx(xx.xx)
xx(xx.xx)
XXX,n(%)
xx(xx.xx)
xx(xx.xx)
xx(xx.xx)
PP



XXX,n(%)
xx(xx.xx)
xx(xx.xx)
xx(xx.xx)
XXX,n(%)
xx(xx.xx)
xx(xx.xx)
xx(xx.xx)
XXX,n(%)
xx(xx.xx)
xx(xx.xx)
xx(xx.xx)
Safety



XXX,n(%)
xx(xx.xx)
xx(xx.xx)
xx(xx.xx)
XXX,n(%)
xx(xx.xx)
xx(xx.xx)
xx(xx.xx)
XXX,n(%)
xx(xx.xx)
xx(xx.xx)
xx(xx.xx)
 
 


 
 
67 
 
7. Conclusion 
 
7.1 Efficacy 
 
The analysis describes the statistical analysis results. 
 
7.2 Safety 
 
The analysis describes the statistical analysis results.