Clinical trial NCT03334734
Conditions: Tuberculosis
Keywords: Tuberculosis PBTZ169 antimycobacterial
Sponsor: Nearmedic Plus LLC
Start date: 2016-12-16; Completion date: 2018-02-22
Enrollment: 16 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Multicenter, open, randomized study with active control (isoniazid) to evaluate the early antibacterial activity, safety and pharmacokinetics of the drug PBTZ169 (capsules 80 mg) when used in patients with first-diagnosed tuberculosis of the respiratory system with bacterial excretion and saved bacterial susceptibility to isoniazid and rifampicin

Detailed description:
This phase 2a study is aimed to evaluate the early bactericidal activity of a new anti-tuberculosis drug PBTZ169 (capsules 80 mg), and its results will allow preliminary evaluate antimycobacterial properties of PBTZ169 and confirm a potentially more effective dose for subsequent studies. This study is an open, randomized comparative efficacy (on the parameter of early bactericidal activity), safety and pharmacokinetics study of PBTZ169 in patients with first-diagnosed lung tuberculosis and preserved sensitivity to base antimycobacterial drugs: rifampicin and isoniazid.

Within the framework of the study, it is planned to use the studied drugs (PBTZ169 and isoniazid) as monotherapy within 14 days. Isoniazid is used as a "positive control", that is, in order to determine whether the method of assessing efficacy on the parameter of early bactericidal activity is working.

Arms: arm 1: 2 capsules 80 mg of PBTZ169 once a day for 14 days arm 2: 4 capsules 80 mg of PBTZ169 once a day for 14 days arm 3: 8 capsules 80 mg of PBTZ169 once a day for 14 days arm 4: 2 tablets 300 mg of Isoniazid once a day for 14 days
Interventions: intervention 1: PBTZ169 intervention 2: Isoniazid
Intervention descriptions: intervention 1: Once a day for 14 days intervention 2: Once a day for 14 days

Protocol documents:
Prot_SAP_000.pdf: 
NEARMEDIC PLUS LTD. 
 
Clinical study report 
PBTZ169-A15-C2A-1 
 
CONFIDENTIAL  
Final version 5.0 dated 20.07.2017 
Page 1 of 16 
 
CLINICAL STUDY PROTOCOL 
1 TITLE PAGE  
Study Title: 
Multicenter Open-Label Randomized Active-Comparator Study 
to 
Evaluate 
Early 
Bactericidal 
Activity, Safety, 
and 
Pharmacokinetics of PBTZ169 in Patients with Newly Diagnosed 
Microbiologically 
Proven 
Respiratory 
Tuberculosis 
with 
Preserved Susceptibility to Isoniazid and Rifampicin 
Studied indication: 
Newly Diagnosed Respiratory Tuberculosis 
Study design: 
Open-label randomized parallel-group active-comparator study to 
evaluate efficacy (based on the early bactericidal activity), safety, 
and pharmacokinetics of the study medication. 
Study drug: 
PBTZ169 80 mg oral capsules 
Comparator: 
Isoniazid 300 mg tablets 
Sponsor Name: 
NEARMEDIC PLUS LTD. 
Sponsor Address: 
12 Aviakonstruktora Mikoyana St., Moscow 125252, Russia 
Tel.: +7(495)741-4989; Fax: +7(499)193-4350 
Sponsor Name: 
NEARMEDIC PLUS LTD. 
Protocol Number/Code: 
PBTZ169-A15-C2A-1 
Study Phase: 
IIa 
Medical Expert appointed 
by the Sponsor: 
Nikolay V. Yemelyanov, 
Head of the Medical Studies and Information Section of the 
Project Development Department at NEARMEDIC PLUS LTD. 
POA to sign for the 
Sponsor: 
Roman N. Bolgarin, 
Director of Development of NEARMEDIC PLUS LTD 
Statement on Conducting 
the Clinical Study in 
Accordance with the Good 
Clinical Practice: 
The given study is carried out in accordance with the Good 
Clinical Practice (GCP) provided by the International 
Harmonization Council (ICH), including retention of the essential 
documents 
Report Version and Date: 
5.0 dated 20.07.2017 
 
STATEMENT OF CONFIDENTIALITY 
The information in this document is confidential and shall not be disclosed. Reproduction, distribution, or 
transfer of this information in any- form or by any means without prior written permission from NEARMEDIC 
PLUS LTD. is prohibited. 
 
 


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Clinical study report 
PBTZ169-A15-C2A-1 
 
CONFIDENTIAL  
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SIGNATURE PAGES  
Sponsor's Signature Page 
 
Reviewed and approved by: 
Head of Project Development Department 
 
 
 
Roman N. Bolgarin, 
Director of Development of NEARMEDIC PLUS LTD 
 
 
Date 
 
Head of the Medical Studies and Information Section 
 
 
 
Nikolay V. Yemelyanov, 
Head of the Medical Studies and Information  
Section of the Project Development Department 
NEARMEDIC PLUS LTD. 
 
 
Date 
 
Head of the Medicinal Products Sector 
 
 
 
Nataliya A. Shevkun, 
Head of the Medicinal Product Sector  
of the Project Development Department  
NEARMEDIC PLUS LTD. 
 
 
Date 
 
Head of Pharmacovigilance 
 
 
 
Yelena I. Zotova, 
Head of Pharmacovigilance of the Project  
Development Department  
NEARMEDIC PLUS LTD. 
 
 
Date 
 
 
 


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Clinical study report 
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CONFIDENTIAL  
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Page 3 of 16 
 
Signature Page of the Contract Research Organization (CRO) 
Reviewed and approved by: 
Project Manager (CSI) 
 
 
 
Irina V. Ivushkina,  
Project Manager, OCT Rus LLC  
48 Myasnitskaya St., Moscow 
Tel.: +7(495)660-6550, ext. 4017 
 
Date 
 
Biostatistician 
 
 
 
Irina B. Bondareva,  
lead biostatistician, Data MATRIX LLC 
5 Kovenskiy Pereulok, Saint Petersburg 
 
Date 
 
Medical writer 
 
 
 
Boris D. Yeliseyev,  
medical writer, OCT Rus LLC,  
48 Myasnitskaya St., Moscow 
Tel.: +7(495)660-6550, ext. 4032 
 
Date 
 


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Clinical study report 
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2 SUMMARY (SYNOPSIS) 
Name of active substance: 
PBTZ169 Hydrochloride 
 
 
Study Title: Multicenter Open-Label Randomized Active-Comparator Study to 
Evaluate Early Bactericidal Activity, Safety, and Pharmacokinetics of PBTZ169 in 
Patients with Newly Diagnosed Microbiologically Proven Respiratory Tuberculosis 
with Preserved Susceptibility to Isoniazid and Rifampicin 
 
Protocol Number/Code: PBTZ169-A15-C2A-1 
 
Primary investigators and study centers: 
Study Center 1: 
Federal State Budgetary Institution Central Tuberculosis Research Institute of the 
Russian Academy of Medical Sciences Address: 2 Yauzskaya Alleya, Moscow 
107564, Russia Principal investigator: Tatevik R. Bagdasaryan. 
Study Center 2: 
Federal State Budget Educational Institution of Higher Professional Education 
Sechenov First Moscow State Medical University of the Ministry of Health of the 
Russian Federation Address: 8/2 Trubetskaya St., Moscow 119991, Russia Principal 
investigator: Pavel V. Senchikhin. 
Study Center 3: 
Moscow State Budgetary Health-Care Institution Moscow Municipal Research 
and Practical Center for Tuberculosis Control of the Moscow City Health-Care 
Department Address: 10 Stromynka St., Moscow 107014, Russia Principal 
investigator: Taisiya N. Ivanushkina. 
Study Center 4: 
State Budgetary Health-Care Institution of the Orel Region Orel Tuberculosis 
Dispensary. Address: 15 Tsvetayeva St., Oryol 302027, Russia Principal 
investigator: Boris Ya. Kazyonnyy 
Study Center 5: 
State Health-Care Institution of the Voronezh Region Pokhvisneva Voronezh 
Regional Clinical Tuberculosis Dispensary Address: 1 Teplichnaya St., Voronezh 
394070, Russia. Detached building А and A1, entrance A and A1. Principal 
investigator: Galina A. Batishcheva 
Study Center 6: 
State Budgetary Health-Care Institution of the Vladimir Region Center for 
Phthisiatric and Pulmonologic Specialty Care Address: 63 Sudogodskoye Shosse, 
Vladimir 600023, Russia Principal investigator: Grigoriy V. Volchenkov  
Study Center 7: 


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Clinical study report 
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Name of active substance: 
PBTZ169 Hydrochloride 
 
 
State Budgetary Health-Care Institution of the Arkhangelsk Region Arkhangelsk 
Clinical Tuberculous Dispensary Address: 28 Novgorodskiy Prospekt, Arkhangelsk 
163002, Russia Principal investigator: Andrey O. Maryandyshev 
Study Center 9: 
Regional State Budgetary Health-Care Institution Tomsk Phthisiatric and 
Pulmonologic Medical Center Address: 17 Rozy Luksemburg St., Tomsk 634009, 
Russia Principal investigator: Yelena V. Vorobyova 
Study Center 10: 
State Health-Care Institution of the Samara Region Tolyatti Municipal Tuberculous 
Dispensary Address: 34 Telegrafnaya St., Tolyatti, Samara Region 445013, Russia 
Principal investigator: Yelena A. Borodulina 
Study Center 11: 
Federal State Budgetary Institution Novosibirsk Tuberculosis Research Institute of 
the Ministry of Health Care of the Russian Federation Address: 81A Okhotskaya St., 
Novosibirsk 630040, Russia Principal investigator: Yekaterina V. Kulchavenya 
Study Center 12: 
State Autonomous Health-Care Institution Republican Clinical Tuberculosis 
Dispensary Address: 27A Sibirskiy Trakt St., Kazan 420029, Russia Principal 
investigator: Marat F. Yaushev 
Study Center 13: 
Federal State Budgetary Institution Saint Petersburg Research Institute of 
Phthisiopulmonology of the Ministry of Health Care of the Russian Federation 
Address: 2/4 Ligovskiy Prospekt, Saint Petersburg 197758, Russia Principal 
investigator: Pyotr K. Yablonskiy 
 
Publications (references): none 
Phase of drug development: IIa 
Goals: to study the efficacy of PBTZ169 in the daily doses of 160, 320, and 640 mg 
based on its early bactericidal activity, safety, and pharmacokinetics of PBTZ169 
p.o. as monotherapy for 14 days in patients with newly diagnosed microbiologically 
proven respiratory tuberculosis with preserved susceptibility to Isoniazid and 
Rifampicin. 
 
Design: this study is a randomized open-label study of efficacy (in terms of early 
bactericidal activity), safety, and pharmacokinetics of PBTZ169 in parallel groups 
with active control in patients with newly diagnosed respiratory tuberculosis. The 
study comprises the following stages: 


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Clinical study report 
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CONFIDENTIAL  
Final version 5.0 dated 20.07.2017 
Page 6 of 16 
 
Name of active substance: 
PBTZ169 Hydrochloride 
 
 
• 
Screening, up to 10 days 
• 
Monotherapy, 14 days 
• 
Follow-up, 7 days 
Screening procedures are carried out within 10 days before randomization. 
Screening procedures can be carried out on an outpatient or inpatient basis. If the 
screening procedures are performed outpatiently, subjects are admitted to hospital 
on the day before the first dose of the study drugs. If the screening procedures are 
performed inpatiently, subjects stay hospitalized for the purpose of participation in 
the clinical study. 
Eligible subjects are randomized. During randomization, each subject is assigned a 
randomization number generated by the IWRS. Each patient is assigned to one of 
the following four groups based on the randomization number: 
• 
Group 1: subjects receive PBTZ169 capsules at a daily dose of 160 mg 
for 14 days as a monotherapy, after which the drug is discontinued, and 
standard antituberculosis therapy is prescribed (hereinafter, standard 
antituberculosis therapy is defined as the tuberculosis therapy provided 
for under Order of the Ministry of Health of the Russian Federation 
No. 951 dated December 29, 2014). Up to 15 subjects are planned to be 
randomized to this group. 
• 
Group 2: subjects receive PBTZ169 capsules at a daily dose of 320 mg 
for 14 days as a monotherapy, after which the drug is discontinued, and 
standard antituberculosis therapy is prescribed. Up to 15 subjects are 
planned to be randomized to this group. 
• 
Group 3: subjects receive PBTZ169 capsules at a daily dose of 640 mg 
for 14 days as a monotherapy, after which the drug is discontinued, and 
standard antituberculosis therapy is prescribed. Up to 15 subjects are 
planned to be randomized to this group. 
• 
Group 4: subjects receive isoniazid tablets at a standard daily dose of 
600 mg for 4 days as a monotherapy, after which standard 
antituberculosis therapy follows. Up to 7 subjects are planned to be 
randomized to this group. 
All study procedures are conducted in the subjects and documented under the 
randomization number. 
 


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Clinical study report 
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CONFIDENTIAL  
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Name of active substance: 
PBTZ169 Hydrochloride 
 
 
Nocturnal sputum is collected from all subjects in the morning at V1. After that, 
every patient received the study drug (PBTZ169 or isoniazid) as a monotherapy for 
14 consecutive days. After 14 days of monotherapy (Day 15 of the study, V8), 
PBTZ169 is discontinued in Groups 1 to 3 (Day 14 being the day of the last 
PBTZ169 dose). Standard therapy is initiated 3 days after the monotherapy end date 
(Day 18 of the study, V10). Standard therapy drugs are resumed in Group 4 
(standard dose of isoniazid) without a break—that is, the day following the 
monotherapy end date (Day 15 of the study). Patient monitoring during clinical 
study is continued on a hospital basis and ended 7 days following the monotherapy 
end date. 
Venous blood samples are taken from all subjects in Groups 1, 2, and 3 (PBTZ169 
monotherapy) to measure PBTZ169 levels. Blood samples are drawn before the first 
doze of PBTZ169 (0 min time point) and later at the following time points after the 
first dose: in 0:20, 0:40, 1:00, 1:30, 2:00, 2:30, 3:00, 4:00, 6:00, 8:00, 10:00, 12:00, 
and 24:00 (hr:min). Blood samples are also taken before the last doze of PBTZ169 
(0 min time point) and later at the following time points after the last dose: after 
0:20, 0:40, 1:00, 1:30, 2:00, 2:30, 3:00, 4:00, 6:00, 8:00, 10:00, 12:00, 24:00, 48:00, 
and 72:00 (hr:min). 
All venous blood samples are kept in case any additional parameters have to be 
measured. 
Subjects are hospitalized throughout the monotherapy and follow-up periods. 
 
Number of subjects: It’s planned to randomize 52 eligible subjects for the study, 
namely 15 subjects in each PBTZ169 group and 7 subjects in the isoniazid group. 
The data of subjects who will receive at least one dose of the study drug and whose 
study drug concentrations are known will be processed in the final statistical analysis 
of efficacy and pharmacokinetics. 
The data of subjects of ITT population will be processed in the final statistical 
analysis of safety. 
 
Diagnosis and key inclusion criteria:  
Subjects complying with all of the following criteria will be included into the clinical 
study: 
1. 
Written informed consent received from the subject. 
2. 
Men and women aged 18 to 45 years old, inclusive. 
3. 
Newly diagnosed active pulmonary tuberculosis confirmed by 
characteristic radiological findings (infiltration, dissemination, and 
destruction) in chest X-ray or computed tomography not involving other 


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Name of active substance: 
PBTZ169 Hydrochloride 
 
 
organs or involving one or more of the following: the larynx, the trachea, 
the bronchi, and lymph nodes. 
4. 
The patient's sputum volume must be enough for any tests provided for 
under the Protocol but not less than 4 to 5 mL at screening. 
5. 
Acid-fast mycobacteria found in sputum smear microscopy (1+ and more 
using the luminescent dye microscopy according to Order of the Russian 
Ministry of Health No. 109 dated March 21, 2003, latest revision) and 
tuberculosis mycobacterial DNA found in molecular genetic tests. 
6. 
A body weight of at least 51 kg. 
7. 
Body mass index of 18.5–25 kg/m2.  
8. 
The ability (according to the investigator's opinion) to comply with all 
requirements of the Protocol. 
9. 
Agreement to use reliable contraception methods during the study and 
3 months after the last dose of the drug, including temporary abstinence 
from sex or double contraception combining male condoms with at least 
one of the following: 
• 
Using hormonal contraception 
• 
Using aerosols, creams, suppositories, and other agents containing 
spermicides 
• 
Using an intrauterine device 
Subjects who meet any of the following criteria will not be included in the clinical 
study: 
1. 
Extrapulmonary localization of tuberculosis. 
2. 
Resistance to rifampicin and/or isoniazid found in molecular -genetic tests 
on sputum samples. 
3. 
Administration of any antituberculosis drugs from the moment of 
tuberculosis diagnosis to enrolment in the study. 
4. 
Absolute indications for surgical treatment of tuberculosis at screening. 
5. 
Testing positive for syphilis or HIV infection serological markers at 
screening, active hepatitis, or decompensated liver cirrhosis. 
6. 
History of allergic reactions. 
7. 
Laboratory renal and/or hepatic parameters measured as follows (with due 
regard to the laboratory's reference range): 
• 
AST > 2.0 x upper limit of normal values (ULN) 


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Clinical study report 
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Name of active substance: 
PBTZ169 Hydrochloride 
 
 
• 
ALT > 2.0 x ULN 
• 
Total bilirubin > 1.5 х ULN 
• 
Creatinine > 1.5 х ULN 
8. 
Individual intolerance to any ingredients of the study drug. 
9. 
History of malignant tumors, except for basal cell carcinoma. 
10. 
Decompensated severe chronic somatic diseases, including cardiovascular, 
bronchopulmonary, neuroendocrine, ENT, -gastrointestinal, hepatic, renal, 
blood, skin diseases, and other somatic or mental diseases that the 
investigator believes to prevent the subject's enrolment. 
11. 
Gastrointestinal- surgery (except for appendectomy performed more than 
1 year before the screening). 
12. 
Any mental disorders that can affect the patient's compliance with the 
Protocol. 
13. 
Diabetes mellitus. 
14. 
Acute viral and bacterial infections at enrolment or within 2 weeks prior to 
enrolment. 
 
15. 
Alcoholism (unless the investigator believes the subject to be able to 
abstain from alcohol consumption during the study) or substance abuse. 
16. 
A positive test for narcotic and psychotropic products. 
17. 
Regular administration (including topical) of any hormonal drugs for over 
1 week within 30 days before the screening (except for oral hormonal 
contraceptives and hormonal intrauterine devices). 
18. 
Use of cytotoxic drugs within 30 days before the screening. 
19. 
Repeated administration of any drugs where the instruction for medical use 
mentions nervous system, hemodynamics, and liver function adverse 
events as "very frequent" (≥10%) or "frequent" (≥1% and <10%) within 
21 days before the screening. 
20. 
Pregnancy or lactation. 
21. 
Planned conception or sperm donation during the study after the study drug 
administration or within 3 months after the date of the last drug 
administration. 
22. 
Participation in other clinical trials of drugs within less than 3 months 
before the screening. 


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Name of active substance: 
PBTZ169 Hydrochloride 
 
 
Study drug, dose, administration, and batch number: 
Study drug code: PBTZ169 
Brand name: none 
International nonproprietary name: none 
Dosage form: 80 mg capsules. 
Pharmacotherapeutic group: antituberculosis drug 
ATC code: J04A 
Dose and administration route: patients receive PBTZ169 orally once a day in the 
morning in the fasting state in the following doses: 
• 
Group 1: 160 mg daily 
• 
Group 2: 320 mg daily 
• 
Group 3: 640 mg daily 


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Clinical study report 
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Name of active substance: 
PBTZ169 Hydrochloride 
 
 
Duration of treatment with the study drug:  
Monotherapy for 14 consecutive days. 
Comparator, dose and administration, batch number: 
Brand name: Isoniazid 
International nonproprietary name: isoniazid 
Dosage form: 300 mg tablets. 
Pharmacotherapeutic group: antituberculosis drug 
ATC code: J04AC01 
Dose and administration route: Isoniazid is prescribed to subjects randomized into 
Group 4 in the daily dose of 600 mg of orally in the morning after meals. 
 
Comparator treatment duration: 
Monotherapy for 14 consecutive days. Isoniazid is then continued as part of the 
combined antituberculosis therapy. 
 
Assessment parameters: 
Efficacy: 
Primary efficacy endpoint: 
• 
Early bactericidal activity 14 days from the monotherapy start date 
(EBA0-14). 
Variables for the secondary efficacy endpoint: 
• 
Early bactericidal activity 2 days from the monotherapy start date 
(EBA0-2). 
• 
Early bactericidal activity 7 days from the monotherapy start date 
(EBA0-7). 
Safety: 
Variables for the safety endpoint 
• 
Adverse events 
• 
Changes in vital signs 
• 
Results of laboratory tests (complete blood count, biochemical blood 
analysis, urinalysis) 
• 
ECG findings 
• 
Physical examination results 
 


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Clinical study report 
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Name of active substance: 
PBTZ169 Hydrochloride 
 
 
Pharmacokinetics: 
Variables for pharmacokinetics evaluation: 
• 
Maximum concentration (Cmax) within the dosing interval of 24 hours 
after single and multiple dosing 
• 
Minimum concentration (Cmin) within the dosing interval after single 
and multiple dosing 
• 
Trough concentration (Ctrough) (measured 24 hours after the first dose 
administration, prior to the last dose, and 24 hours after the last dose) 
• 
Time to maximum concentration (Tmax) within the dosing interval after 
single and multiple dosing 
• 
Area under the concentration–time curve within the dosing interval 
(AUC0-24) after single and multiple dosing 
• 
Area under the concentration–time curve within the interval from 0 to 
the last measurement value above LLoQ (AUC0-t) after single and 
multiple dosing 
• 
Area under the concentration–time curve within the interval from 0 to 
infinity (AUC0-∞) after single and multiple dosing 
• 
Mean concentration (Css,av) within the dosing interval after multiple 
dosing 
• 
Fluctuations (%) within the dosing interval after multiple dosing 
([Cmax-Cmin]×100%/Css,av) 
• 
Apparent total clearance following oral administration (Clt/F) as 
measured after single and multiple dosing 
• 
Distribution volume (Vd) measured after single and multiple dosing 
• 
Half-life (T1/2) measured after single and multiple dosing 
• 
Elimination constant kel measured after single and multiple dosing. 
 
Pharmacodynamics: 
• 
Cmax,ss and AUC0-24,ss measured after multiple dosing after 14 days of 
therapy are used for early bacterial activity EBA0-14 and EBA2-14 as 
parameters for PK comparison. 
Cmax, Cmin, and AUC0-24 measured after the first dose administration are 
used for early bacterial activity EBA0-2 as parameters for PK 
comparison. 


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Clinical study report 
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Name of active substance: 
PBTZ169 Hydrochloride 
 
 
Statistical methods: 
Descriptive statistics will be provided for all demographics and other baseline 
characteristics, efficacy and safety parameters, and changes in them (if applicable) 
in the course of the study by means of assessment time points and treatment groups. 
Descriptive statistics for quantitative variables include mean value, standard 
deviation (SD), minimum and maximum values, and the number of valid 
observations. Qualitative data is presented as rates and percentages. 95% confidence 
intervals around point estimations are provided as well (where applicable). 
 
Efficacy analysis 
According to the EMA Guidance, early bactericidal activity (EBA) assessment 
should be based on determining the count of live mycobacteria in the patient's 
sputum during monotherapy with the drug. The primary method of determining 
mycobacterial count used is inoculating agar with sputum to count CFU/mL. The 
method is chosen as it is used as the primary method in nearly all studies assessing 
early bactericidal activity, which means it can be considered conventional [16-–19]. 
The method of quantitative PCR for counting mycobacterial cells in sputum is used 
as a secondary method for secondary analysis [23]. 
All assessments of log10 CFU/mL sputum, mycobacterial cell count estimates 
obtained with PCR, and their changes from baseline are tabulated by measurement 
points and treatment groups. 
In the primary analysis of treatment efficacy, changes from baseline in log10 
CFU/mL sputum (for agar inoculation) 14 days after the therapy start date are 
estimated. Changes in log10 CFU/mL sputum 2 and 7 days after the therapy start date 
are also estimated in the secondary analysis of treatment efficacy. Early bactericidal 
activity (EBA) is assessed as a change in log10 of CFU/mL of sputum specified for 
the treatment day [24] with a two-sided 95% confidence interval.  
Though sample size is estimated empirically disregarding formal comparisons 
between the two dose levels, the Kruskal–-Wallis test is used to compare the values 
for different dose levels of the study drug at a two-sided 5% significance level. 
The history of mean changes in log10 CFU/mL from baseline by assessment points 
is presented graphically by treatment groups. 
The Jonckheere- –-Terpstra test is used to identify the trend for the primary efficacy 
endpoint depending on the increase in dose level (increasing EBA0–-14 for increasing 
doses).  
A similar efficacy analysis (based on changes in log10 cells/mL) is carried out by 
determining mycobacterial cell count with quantitative PCR. 
Graphical methods and calculation of correlation coefficients between individual 
measurements obtained using the two quantification methods are used to analyze the 


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Name of active substance: 
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consistency of the results between the two methods of determining mycobacterial 
count. 
Only available measurements are used in efficacy analysis. No missing values are 
restored. The analysis is based on average values for each measurement point. An 
additional analysis at the maximum of two measurements is carried out (with the 
highest number of CFU or MBT DNA copies using agar inoculation and quantitative 
PCR, respectively). 
 
Safety analysis 
The MedDRA dictionary is used to code adverse events. The number (percentage) 
of patients with AEs and the number of AEs are tabulated by system organ class and 
preferred term as well as by study treatment, severity, and treatment group. Each 
patient is included within each system organ class and preferred term only once 
regarding the study treatment and maximum severity. 
Laboratory test values and their changes from baseline (at screening) following the 
administration of the study drug and "shift tables" based on reference values are 
tabulated by treatment groups and measurement points. 
The findings of ECG, vital sign assessment, and body temperature measurements 
are tabulated by study group for each measurement point, including changes from 
the most recent measurement made prior to dosing. 
Physical examination findings are presented descriptively by treatment group and 
measurement point. 
 
Pharmacokinetic analysis 
All concentration measurements after single and multiple dosing are tabulated by 
time point and treatment group and listed. Reasons are explained for any missing 
measurements and measurements not included in the pharmacokinetic analysis. 
Descriptive statistics for concentration measurements and PK parameters include the 
mean, standard deviation, the median, the minimum, the maximum, coefficient of 
variation (%), and the number of valid cases (N). Geometric means and geometric 
coefficient of variation are also presented for concentrations and PK parameters such 
as C and AUC. 
The actual values of sampling time are used to calculate individual values of PK 
parameters using the noncompartmental approach. The dependence of drug 
concentration on time is presented graphically for each individual patient based on 
actual sampling time. The descriptive statistics and average PK curves are presented 
based on the estimated sampling time points. Average and individual PK curves are 
presented on the arithmetic and logarithmic scale. 


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Name of active substance: 
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Pharmacokinetic and pharmacodynamic analysis 
An additional analysis is carried out to compare pharmacokinetic and 
pharmacodynamic parameters. Cmax,ss and AUC0–24,ss measured after multiple dosing 
after 14 days of therapy are used for early bacterial activity EBA0–14 and EBA2–14 as 
parameters for PK comparison. Cmax, Cmin, and AUC0–24, measured after the first dose 
administration are used for early bacterial activity EBA0–2. 
PK/PD indicators are compared using graphical representation (plotting pairs of 
individual values against on X and Y for each comparison of parameters X and Y) 
and by calculating coefficients of correlation within treatment group as well as in 
general. 
 
An interim analysis is to be carried out when at least 15 patients across all groups 
have completed the study. The interim analysis is not carried out since the study is 
terminated early. 


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CONFIDENTIAL  
Final version 5.0 dated 20.07.2017 
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