Clinical trial NCT04150224
Conditions: Healthy Subjects
Keywords: PBTZ169 Macozinone Antimycobacterial Tuberculosis Drug Resistant Tubercolosis MDR-TB XDR-TB
Sponsor: Nearmedic Plus LLC
Start date: 2018-07-03; Completion date: 2019-02-01
Enrollment: 60 participants; Allocation: RANDOMIZED; Intervention model: SEQUENTIAL

Brief summary:
Open-label prospective non-comparative ascending dose randomized cohort study of single and multiple oral administration of PBTZ169 (capsules 80 mg) in healthy volunteers

Detailed description:
Open-label prospective non-comparativerandomized cohort study of safety, tolerability, pharmacokinetics and the effect of food of PBTZ169 in adult healthy volunteers after single and multiple oral administration. Study was conducted in one study center in the Russian Federation. The study included two stages:

Stage 1 - single or double oral administration with dose escalation (fasted/after meal) in 5 cohorts 10 healthy volunteers each plus 5 back-up volunteers;

Stage 2 - multiple oral administration once a day after meal for 14 days in 1 cohort of 10 healthy volunteers.

Arms: arm 1: Two doses of PBTZ169: 640 mg OD fasted and 640 mg OD after meal. Wash-out period ≥6 days. arm 2: Two doses of PBTZ169: 640 mg OD after meal and 640 OD mg fasted. Wash-out period ≥6 days. arm 3: Single dose of PBTZ169: 960 mg fasted arm 4: Two doses of PBTZ169: 640 mg twice a day (fasted) with a 12-hour interval; total daily dose - 1280 mg arm 5: Single dose of PBTZ169: 1280 mg fasted arm 6: Multiple administration of PBTZ169: 1280 mg once a day after meal for 14 days
Interventions: intervention 1: PBTZ169 640 mg OD intervention 2: PBTZ169 640 mg BiD intervention 3: PBTZ169 960 mg SD intervention 4: PBTZ169 1280 mg SD intervention 5: PBTZ169 1280 mg MD
Intervention descriptions: intervention 1: Two administrations once a day with a wash-out period: food effect intervention 2: Twice a day fasted; 1 day of administration intervention 3: Once a day fasted intervention 4: Once a day fasted intervention 5: Once a day after meal, 14 doses

Protocol documents:
Prot_SAP_000.pdf: 
NEARMEDIC PLUS LTD. 
CONFIDENTIAL
Protocol № PBTZ169-Z00-C01-3 
version 2.0 от 11.10.2018
 
CLINICAL STUDY PROTOCOL 
№ PBTZ169-Z00-C01-3 
 
 
Open-label prospective study to evaluate the safety, tolerability, 
pharmacokinetics and the effect of food of medicinal product PBTZ169 in 80 
mg capsules when used in increasing doses in healthy volunteers 
 
 
Sponsor Name: 
NEARMEDIC PLUS LTD. 
Sponsor Address: 
12 
Aviakonstruktora 
Mikoyana 
St., 
Moscow 
125252, Russia 
Tel.: +7(495)741-4989; Fax: +7(499)193-4350 
Document name 
Clinical study protocol 
Study design: 
 
Prospective 
Version 
2.0 
 
 
Date 
11.10.2018 
This document as well as all the information contained in it is a property of NEARMEDIC 
PLUS LTD and is strictly confidential and cannot be copied as whole or partially. This 
information should be available for consideration by researchers, potential researchers and 
special Ethics Committee. Any information contained in this protocol cannot be used or 
transferred to the third parties without previous whirren approval of NEARMEDIC PLUS 
LTD except for the information necessary to obtain informed consent from potential study 
subjects. 
Moscow, 2018 


2 / 20 
1 STUDY SUMMARY 
Study name 
Open prospective study to evaluate the safety, tolerability, 
pharmacokinetics and the effect of food of medicinal product 
PBTZ169 in 80 mg capsules when used in increasing doses in 
healthy volunteers 
Identification 
number/study code 
PBTZ169-Z00-C01-3 
Study phase 
Phase I 
Planned study dates 
Expected duration of the study – 7 months. 
Recruitment period is approximately 10 days. Maximum duration 
of participation of one volunteer in the study at the first stage (dose 
escalation when used once or twice, effect of food when used once) 
– 24 days, at the second stage (repeated use) – 30 days. 
Study goals 
At the first stage – study the safety, tolerability and evaluate the 
pharmacokinetics of PBTZ169, 80 mg capsules, in healthy 
volunteers when administered once or twice on an empty stomach 
successively in increasing doses (640, 960, 1280 mg once a day and 
640 mg twice daily), evaluate the effect of food with single 
administration of the product at a dose of 640 mg.  
At the second stage – study the safety, tolerability and evaluate the 
pharmacokinetics of PBTZ169, 80 mg capsules, in healthy 
volunteers with repeated use for 14 days, at a dose and following a 
regimen (on an empty stomach or after meal, once a day or twice 
day) determined by results of analysis of tolerability, safety and 
pharmacokinetics after the completion of the first stage of the study.
Study objective 
Main objectives 
 Evaluate the safety and tolerability of PBTZ169, 80 mg 
capsules, in healthy volunteers once or twice on an empty 
stomach in increasing doses (640, 960, 1280 mg once daily 
and 640 mg twice daily) and repeated administration for 14 
days at maximum dose and following a regimen determined 
by results of analysis of tolerability, safety and 
pharmacokinetics after the completion of the first stage of 
the study. 
 Evaluate the effect of food on the pharmacokinetics of 
PBTZ169, 80 mg oral capsules at a dose of 640 mg. 
Compare the test (T) method of administration (8 80 mg 
capsules after meal) with the reference (R) method of 
administration (8 80 mg capsules on an empty stomach). 
Secondary objectives 
 Evaluate the safety of PBTZ169 based on all possible 
adverse events. 


3 / 20 
 Evaluate the effect of PBTZ169 on vital signs (blood 
pressure, HR, body temperature, RR) and results of physical 
examination. 
 Evaluate the effect of PBTZ169 on laboratory and 
instrumental 
examinations 
(complete 
blood 
count, 
biochemical blood test, urine analysis, ECG). 
 To evaluate the pharmacokinetic parameters of PBTZ169, 
80 mg capsules, in healthy volunteers when used once or 
twice on an empty stomach in increasing doses (640, 960, 
1280 mg once a day and 640 mg twice daily): maximum 
concentration Cmax, time to reach maximum concentration 
Tmax, area under the pharmacokinetic curve AUC0-t and 
AUC0-, half-life T1/2, total clearance Clt/F, volume of 
distribution Vd/F, elimination constant kel. 
 Evaluate the pharmacokinetic parameters of PBTZ169, 80 
mg capsules, with repeated use for 14 days at the maximum 
dose and following a regimen determined by results of 
analysis of tolerability, safety and pharmacokinetics after 
the completion of the first stage of the study in healthy 
volunteers, namely: maximum concentration of Cmax, 
residual concentration with repeated use of Ctrough, time to 
reach the maximum concentration Tmax, area under the 
pharmacokinetic curve AUC0-t, AUC0- and AUC0-τ, half-
life T1/2, total clearance Clt/F, volume of distribution Vd/F, 
elimination constant kel. 
Planned 
number 
of 
research sites and their 
location 
It is planned to involve up to 2 research sites in the Russian 
Federation. 
Design 
and 
methodology 
This is an open-label prospective non-comparative study to evaluate 
the safety, tolerability, pharmacokinetics and the effect of food of 
medicinal product PBTZ169 in 80 mg capsules when used in 
increasing doses. 
The study will be divided into 2 stages. 
First stage – dose escalation when used once or twice, effect of 
food with single administration 
Volunteers who meet the selection criteria for the study will be 
included in 5 cohorts: 
 Cohort 1A (C1A) – includes 10 healthy volunteers of the 
main group, each of whom will receive PBTZ169 only 
twice: during period 1 of the First stage of the study on an 
empty stomach at a dose of 640 mg (8 80 mg capsules once 
a day) and during period 2 of the First stage of the study 
after meal at a dose of 640 mg (8 80 mg capsules, once a 
day) and 1 healthy backup volunteer. 


4 / 20 
 Cohort 1A (C1A) – includes 10 healthy volunteers of the 
main group, each of whom will receive PBTZ169 only 
twice: during period 1 of the First stage of the study after 
meal at a dose of 640 mg (8 80 mg capsules once a day) 
and during period 2 of the First stage of the study on an 
empty stomach at a dose of 640 mg (8 80 mg capsules, 
once a day) and 1 healthy backup volunteer. 
 Cohort 2 (C2) – includes 10 healthy volunteers of the main 
group, each of whom will receive a single dose of 
PBTZ169 on an empty stomach at a dose of 960 mg (12 80 
mg capsules, once a day) and 1 healthy backup volunteer. 
 Cohort 3 (C3) – includes 10 healthy volunteers of the main 
group, each of whom will receive PBTZ169 twice on an 
empty stomach at a dose of 640 mg (8 80 mg capsules, 
twice daily with a 12-hour interval; total daily dose – 1280 
mg) and 1 healthy backup volunteer. 
 Cohort 4 (C4) – includes 10 healthy volunteers of the main 
group, each of whom will receive a single dose of 
PBTZ169 on an empty stomach at a dose of 1280 mg (16 
80 mg capsules, once a day) and 1 healthy backup 
volunteer. 
Randomization will be done after hospitalization on the day before 
the first administration of the investigational product (Day 0 of the 
study) within each cohort by the envelope randomization method. 
Volunteers of each cohort (C1A, C1B, C2, C3 and C4) will be 
randomized at a ratio of 10:1: 
 main therapy group – 10 volunteers who will receive a 
single dose or two doses of the investigational product; 
 group of backup volunteers – 1 volunteer who receive 
one dose or two doses of the investigational product only 
if one of the volunteers of the main group of this cohort 
leaves the study before dosing and within 4 hours from 
the moment of dosing due to a reason unrelated to 
AE/SAE. 
Volunteers of the main group and backup volunteers will be 
hospitalized in the evening on the day before the administration of 
the product, but at least 12 hours before planned administration of 
the product. Volunteers of the main group will be hospitalized for 
about 2.5 days, including the visit on the day of hospitalization, day 
of administration of the investigational product and 48 hours after 
the administration of the investigational product. Backup volunteers 
of cohorts of the First stage of the study will be discharged from 


5 / 20 
the hospital at least 4 hours after the administration of the last 
capsule by the last volunteer of the main group if there will be no 
need to replace a dropped out volunteer. 
Administration of the product will start simultaneously in cohorts 
C1A and C1B. The use of the product in volunteers of the C2 cohort 
will begin after the administration of the product by volunteers of 
the C1A and C1B cohorts. In volunteers of the C3 and C4 cohorts, 
the product will be used at least 7 days after volunteers from the 
previous C2 cohort take the investigational product and after 
obtaining results of safety evaluation of the investigational product 
(adverse events, changes in vital signs, laboratory test results, ECG 
and physical examinations) in volunteers of the previous C2 cohort. 
In volunteers of the C3 and C4 cohorts, the investigational product 
will be used in case of dose-limiting toxicity (DLT) in less than 50% 
of volunteers from the C2 cohort.  
All volunteers of the C1A and C1B cohorts will take the product on 
the same day in two periods (1 therapy day in each) between which 
there will be a carry-over period (≥6 days). 
 
 
Order 
Number of 
volunteers 
Study period 
1 
2 
1 
10 
 PBTZ169, 640 
mg (8 80 mg 
capsules), on an 
empty stomach 
PBTZ169, 640 
mg (8 80 mg 
capsules), after a 
standard meal
2 
10 
PBTZ169, 640 
mg (8 80 mg 
capsules), after a 
standard meal
PBTZ169, 640 
mg (8 80 mg 
capsules), on an 
empty stomach 
On an empty stomach the product is administered (by volunteers of 
cohorts C2 and C4, cohort C1A during period 1, cohort C1B during 
period 2) after 10 hours of night fasting, washing down 300 mL of 
bottled water. Each volunteer will administer 4 capsules within 2 
minutes broken down into few portions, depending on the total 
number of capsules, washing down each portion with a few sips of 
water On the day of administration it is allowed to drink as much 
water as one wants except for 1 hour prior to administration of the 
product, during which water consumption is not allowed, and 4 
hours after the administration of the product (during the first hour 
water consumption is not allowed, during the next 3 hours water 
consumption will be regulated: the volunteer will need to drink 100 
mL of bottled water every hour). Within 4 hours after 
administration, volunteers will not be allowed to eat. 4 hours after 
administration, volunteers will receive a standard meal. 


6 / 20 
After food intake (by volunteers of the C1A cohort – during period 
2, of the C1B cohort – during period 1) the medicinal product is 
administered 30 minutes (± 2 minutes) after the beginning of a 
standard breakfast, washing down with 300 mL of bottled water 
(within 2 minutes, 4 capsules broken down into few portions 
depending on the total number of capsules, washing down each 
portion with a few sips of water). Breakfast is provided after 10 
hours of night fasting. On the day of administration it is allowed to 
drink as much water as one wants except for 30 minutes prior to 
administration of the product, during which water consumption is 
not allowed (except for that present in the breakfast), and 4 hours 
after the administration of the product (during the first hour water 
consumption is not allowed, during the next 3 hours water 
consumption will be regulated: the volunteer will need to drink 100 
mL of bottled water every hour). Within 4 hours after 
administration, volunteers will not be allowed to eat. 4 hours after 
administration, volunteers will receive a standard meal. 
Volunteers of the C3 cohort (two administrations) will take the 
product twice a day, washing down with 300 mL of bottled water 
each time (within 2 minutes, 4 capsules broken down into few 
portions depending on the total number of capsules, washing down 
each portion with a few sips of water). For the first time, volunteers 
of the C3 cohort will take the medicinal product in the morning on 
an empty stomach after 10 hours of night fasting, second time – 12 
hours after the first administration after 3 hours of fasting. On the 
day of administration it is allowed to drink as much water as one 
wants except for 1 hour prior to each administration of the product, 
during which water consumption is not allowed, and 4 hours after 
each administration of the product (during the first hour water 
consumption is not allowed, during the next 3 hours water 
consumption will be regulated: the volunteer will need to drink 100 
mL of bottled water every hour). Within 4 hours after each 
administration, volunteers will not be allowed to eat. 4 hours after 
the first administration, volunteers will receive a standard meal. 
Standard dinner will be offered to volunteers of the C3 cohort no 
later than 3 hours before the second administration of the medicinal 
product. 
Each volunteer in the C1A, C1B, C2 and C4 cohorts will have their 
venous blood collected to determine the concentration of PBTZ169 
and its metabolites before the administration of the product (point 
0, blood sample in the range from -5 min to -1 min), and then at the 
following time points after the administration of the medicinal 
product: at 0:30, 1:00, 1:30, 2:00, 3:00, 4:00, 6:00, 9:00, 12:00, 
24:00, 48:00 and 72:00 (h:min).  


7 / 20 
For volunteers of the C3 cohort (two administrations), venous blood 
will be collected to determine the concentration of PBTZ169 and its 
metabolites before the first administration of the medicinal product 
(point 0, blood sample in the range from -5 min to -1 min), and then 
within 72 hours at the following times points after each 
administration of the medicinal product: at 0:30, 1:00, 1:30, 2:00, 
3:00, 4:00, 6:00, 9:00, 12:00 (the point before the second 
administration of the medicinal product in the range from -5 min to 
-1 min), 12:30, 13:00, 13:30, 14:00, 15:00, 16:00, 18:00, 21:00, 
24:00, 48:00 , 72:00 (h:min) after the first administration of the 
medicinal product. 
During blood sampling for pharmacokinetics before the time 
point of 48:00 after the administration of the medicinal product, 
volunteers will be staying in the hospital and will be discharged 
after all procedures planned by the protocol have been completed, 
then follow-up will continue on an outpatient basis. After discharge 
from the hospital, volunteers will visit the research site in 1 day (on 
Day 4 volunteers of all cohorts and on Day 10 only volunteers of 
cohorts C1A and C1B). Venous blood samples will be collected 
from each volunteer at the time point of 72:00 after the 
administration of the medicinal product and follow-up procedures 
will be carried out. 5±1 days after the last administration of the 
medicinal product (on Day 12±1 of the study for volunteers of 
cohorts C1A and C1B or on Day 6±1 of the study for cohorts C2-
C4), volunteers will visit the research site for to undergo procedures 
of follow-up visit (FUV; safety evaluation). 
Point 0 before the administration of the medicinal product, 
including the point before the second administration of the 
medicinal product, can be within the range from -5 min to -1 min. 
For time points of 24:00, 48:00, 72:00 after the administration of 
the medicinal product, deviations of 10 minutes from the specified 
time are allowed in either direction (±10 min). For all other time 
points for blood sampling after the administration of the 
investigational medicinal product, deviations of not more than 2 
min in either direction (± 2 min) are allowed.  
At each time point of blood sampling for the purpose of 
determination of the concentration of PBTZ169, additional venous 
blood samples will also be collected for storage for determination 
of additional parameters should it become necessary. A detailed 
description of the work with clinical blood samples for the purpose 
of study of pharmacokinetics will be provided in the instructions 
prepared by the central laboratory. 
After the completion of the first part of the study, main samples 
(blood plasma samples of volunteers) will be sent to the central 
laboratory to determine the concentration of the investigational 


8 / 20 
product PBTZ169 and its two metabolites (MET-11526124 3-OXO 
MET-11526115 3-OH). Additional samples (blood plasma samples 
of volunteers) will be stored in the research site in a freezer at a 
temperature not exceeding -65 °C until the end of the 
pharmacokinetic part of the study or until further directions from 
the Sponsor. 
After the study is completed by the last volunteer from the First 
stage (C1A, C1B, C2, C3 and C4), safety and pharmacokinetics, as 
well as the effect of food will be analyzed based on the data of all 
cohorts who administered the product once or twice.  
Based on the results of the evaluation of safety, pharmacokinetics 
and analysis of the effect of food after the end of the First stage, the 
Sponsor: 
 will determine the dose for the study of PBTZ169 with 
repeated use in Phase 2 of the study. 
 will decide on the mode of administration of PBTZ169: on 
an empty stomach or after meal, once a day or twice a day. 
 can decide to adjust time points for sampling (if necessary, 
appropriate amendments will be made to the protocol); 
 can decide to make changes to study procedures at Stage 2 
(where necessary, appropriate amendments will be made to 
the protocol). 
Second stage – repeated administration 
At the second stage, it is planned to recruit 1 cohort consisting of 10 
healthy volunteers, to study the medicinal product with repeated 
use.  
Volunteers who meet selection criteria for the study will be enrolled 
in the next cohort for multiple product administration: 
• 
Cohort 5 (C5) – includes 10 healthy volunteers, each of 
whom will receive the medicinal product PBTZ169 at a dose of X1 
mg daily on an empty stomach or after meal, once or twice a day1 
at the same time ±15 minutes for 14 days. It is possible to enroll 
additional 4 backup volunteer. Backup volunteers will be enrolled 
as per the decision of the Sponsor only if two or more volunteers 
from the main group of cohort 5 drop out before Day 7 of the study, 
for any reason other than AE/SAE, in the same number as there are 
dropped out volunteers, for which an additional screening will be 
carried out. 
Volunteers will be hospitalized in the evening on the day before the 
administration of the product, but at least 12 hours before planned 
 
1 The dose of PBTZ169 and the mode of administration of the product (on an empty stomach or after meal, 
once or twice a day) will be determined by analyzing the data obtained in the first stage. 


9 / 20 
administration of the product. Mode of administration of the 
medicinal product and corresponding restrictions on consumption 
of food and water will be determined based on the results of the 
evaluation of safety, pharmacokinetics and analysis of the effect of 
food with administration of the investigational product once or 
twice after the First stage of the clinical study. For volunteers from 
the C5 cohort, blood for determination of the concentration of 
PBTZ169 and its metabolites will be collected before and after the 
administration of the first, 7th and last (14th) dose of the medicinal 
product at the following time points: 5 minutes before the 
administration of the medicinal product (only until the first dose), 0 
min and within 24 h after the administration of the first, 7th and last 
(14th) dose of the medicinal product in: 0:15, 0:30, 1:00, 1:30, 2:00, 
3:00, 4:00, 6:00, 8:00, 10:00, 12:00, 24:00 (h:min after the 
administration of a dose of the medicinal product). During days 3-
6 and 9-13 of administration of the medicinal product, in order to 
determine the concentration of PBTZ169, venous blood will be 
collected daily at 0 min (before the administration of the medicinal 
product). After the administration of the last (14th) dose of the 
medicinal product, blood samples will also be collected at 48 h and 
72 h points. During the entire time of administration of the 
medicinal product and before blood collection at 48 h time point 
after the last administration of the medicinal product, volunteers 
will be followed-up in a hospital. Then, after all procedures planned 
under the protocol, volunteers will be discharged, after which they 
will be followed up on an outpatient basis. Blood sampling at the 
time point of 72 hours after the last administration of the medicinal 
product will be done on an outpatient basis. After discharge from 
the hospital, volunteers from the C5 cohort will have to visit the 
research site after 2 days to have their blood sampled at the time 
point of 72 hours, and also 7±1 days after the last administration of 
the medicinal product (Day 21±1 of the study) to undergo procedure 
of follow-up visit (FUV, safety evaluation).  
For the following time points, deviations from the specified time of 
10 minutes in either direction are allowed (± 10 min): 24 h after the 
administration of the first, 7th and last (14th) dose of the 
investigational product. For time points of 48 and 72 hours after the 
administration of the last (14th) dose, deviation from the specified 
time of 20 minutes in either direction (± 20 min) is allowed. For all 
other time points for blood sampling after the administration of the 
investigational medicinal product, deviations of not more than 2 
min in either direction (± 2 min) are allowed. In case of early drop-
out of a volunteer, in the absence of risk for the volunteer, attempts 
will be made to collect blood samples from them according to 
schedule for the last (14th) dose of the medicinal product. 


10 / 20 
At each time point of blood sampling for the purpose of 
determination of the concentration of PBTZ169, additional venous 
blood samples will also be collected for storage for determination 
of additional parameters should it become necessary. A detailed 
description of the work with clinical blood samples for the purpose 
of study of pharmacokinetics will be provided in the instructions 
prepared by the central laboratory. 
After the completion of the first part of the study, main samples 
(blood plasma samples of volunteers) will be sent to the central 
laboratory to determine the concentration of the investigational 
product PBTZ169 and its two metabolites (MET-11526124 3-OXO 
MET-11526115 3-OH). Additional samples (blood plasma samples 
of volunteers) will be stored in the research site in a freezer at a 
temperature not exceeding -65 °C until the end of the 
pharmacokinetic part of the study or until further directions from 
the Sponsor. 
Follow-up period 
Follow-up of volunteers from cohorts of the First stage (C1A, C1B, 
C2, C3 and C4) will be 5±1 days after the last dose of the medicinal 
product. After discharge from the hospital, volunteers will need to 
visit the research site 5±1 days after the administration of the 
medicinal product (on Day 12±1 of the study for volunteers of 
cohorts C1A and C1B or on Day 6±1 of the study for cohort C2-
C4) to undergo procedures of follow-up visit (FUV; safety 
evaluation), after which the volunteers will end their participation 
in the study. 
Total duration of the follow-up period for each volunteer of the C5 
cohort (cohort of Second stage) is 7±1 days after the last dose of the 
medicinal product. After discharge from the hospital, volunteers 
from the C5 cohort will need to visit the research site 7±1 days after 
the last administration of the medicinal product (Day 21±1 of the 
study) to undergo procedures of follow-up visit (FUV; safety 
evaluation), after which volunteers will end their participation in the 
study. 
Maximum duration of participation in the study will be 30 days (for 
healthy volunteers from cohorts C1A and C1B – 24 days, cohorts 
C2, C3 and C4 – 18 days, cohort C5 – 30 days). 
Justification 
of 
dose 
choice 
Dose selection for single administration 
To date, two clinical studies of PBTZ169 have been completed: 
Phase I clinical study (protocol No. PBTZ169-Z00-C01-1), where 
PBTZ169 was first used in humans, and Phase IIa clinical study 
(protocol No. PBTZ169-A15-C2A-1), where the medicinal product 
PBTZ169 was used in patients with newly diagnosed respiratory 


11 / 20 
tuberculosis with bacterial excretion and preserved sensitivity to 
isoniazid and rifampicin. 
Based on the results of analysis of pharmacokinetics of PBTZ169 
in these studies, it was decided to further study the product in higher 
doses in healthy volunteers. The highest dose in the two previous 
clinical studies of PBTZ169 was 640 mg. The 640 mg dose was well 
tolerated both by volunteers of the Phase I study and by patients of 
the Phase IIa study, at a dose of 640 mg the medicinal product had 
an acceptable safety profile. During the Phase I study, the only case 
of dose-limiting toxicity (DLT) recorded during the study was 
related to an increase in blood glucose after a single dose of 80 mg. 
During the Phase I study, no serious adverse event was recorded. 6 
AEs had a relationship with the investigational product, the 
following AEs were recorded during the study: headache (4 cases 
in 4 volunteers, possible relationship), leukocytosis (1 case in 1 
volunteer, possible relationship) and increased blood glucose (only 
1 case in 1 volunteer, probable relationship).  
In the Phase IIa study, there was one serious adverse event of 
moderate severity, without a connection with the medicinal product 
– a spontaneous tuberculous-related paraproctitis in one patient 
(from the group receiving the medicinal product at a dose of 640 
mg), which led to withdrawal of the medicinal product and 
subsequent drop-out of the patient. Possible relationship with 
therapy with the investigational product was suspected in 4 cases of 
AEs, all of which were in a patient who dropped out of the study 
due to SAE. In both studies, as the dose increased, no increase in 
the frequency of AEs was observed. 
To study the effect of food, in this study it was decided to use 
the maximum dose that had been studied in the previous two clinical 
studies (640 mg), which had an acceptable safety profile. 
Calculation of doses for single use is done based on 
recommendations provided in Guidelines for Determination of a 
Safe Dose of Medicinal Product for Phase I Clinical Studies in 
Adult Volunteers (Guidelines for Pre-Clinical Studies of Medicinal 
Products, Part One, 2012). 
Determination of no-observed-adverse-effect level (NOAEL) and 
calculation of human equivalent dose (HED) 
Preclinical study of subchronic toxicity of finished dosage form was 
done on rats with intragastric administration of the medicinal 
product at doses of active pharmaceutical ingredient (API) of 9-180 
mg/kg/day daily for 30 days. According to study results, NOAEL 
in rats was 180 mg/kg.  
Preclinical study of acute toxicity of finished dosage form was done 
on rats with intragastric administration of the medicinal product at 
doses of 9-360 mg/kg (API).  


12 / 20 
During experiments evaluating the toxicity of the medicinal product 
in rats, the investigational product had no effect on the appearance, 
general status, physiological parameters, had no adverse effect on 
hematological and biochemical indicators of blood and basic 
physiological 
functions 
of 
the 
body, 
did 
not 
cause 
pathomorphological changes. There were no deaths, sex differences 
and differences from control groups. 
For rats, a conversion factor of 6 was used for calculating HED. 
HED, calculated based on NOAEL in rats, was 30 mg/kg [180 
(mg/kg)/6]. 
Maximum dose for this study will be 1280 mg once. The maximum 
dose can be justified by the absence of a negative effect of the 
medicinal product when used at doses of API up to 180 mg/kg 
(HED=30 mg/kg; 2100 mg for a person weighing 70 kg) in rats in 
the study of subchronic toxicity of the medicinal product, up to 360 
mg/kg of API (HED=60 mg/kg; 4200 mg for a person weighing 70 
kg) in rats in the study of acute toxicity of medicinal product. Thus, 
the selected maximum dose of 1280 mg (once or 640 mg twice 
daily) is in the range of doses studied on animals (rats): 2100 to 
4200 mg. 
Thus, for further study of safety, tolerability and evaluation of 
pharmacokinetics, 960 mg and 1280 mg doses (once or 640 mg 
twice daily) were selected. Dose step was selected based on Phase 
I study, where the dose step was 40 to 320 mg (40 mg, 80 mg, 160 
mg, 320 mg and 640 mg). 
Selection of doses and duration of administration for repeated 
dosing 
Doses of PBTZ169 for repeated administration will be selected 
based on analysis of data of safety and pharmacokinetics after the 
end of the study by volunteers from the cohorts of the First stage 
(C1A, C1B, C2, C3 and C4).  
For multiple dosing, it is planned to select a single dose. Primary 
criterion for dose selection will be good tolerability and safety of 
the medicinal product administered once or twice at a 
corresponding dose, including detection of dose-limiting toxicity 
(DLT) in less than 50% of volunteers from a corresponding cohort 
administering the product once. It is anticipated that the chosen dose 
will be the maximum dose within the range studied with single or 
double administration provided the medicinal product is well 
tolerated. A decision will also be made on the mode of 
administration of PBTZ169: on an empty stomach or after meal, 
once a day or twice a day.  
Repeated use of PBTZ169 will take place in the hospital under 
careful monitoring of volunteers. Given that in the subchronic 
toxicity study and in the chronic toxicity study the duration of 


13 / 20 
administration of the product in rabbits and rats was 30 and 180 
days respectively, according to Guidelines for Evaluation of 
Medicinal Products of 2013 (Volume I), duration of administration 
of 14 days in this clinical study is justified. 
Planned 
number 
of 
subjects in the study 
Total number of volunteers: it is planned to enroll up to 69 healthy 
volunteers (10 per each cohort, 60 volunteers in 6 cohorts + 9 
possible backup volunteers). Screening – up to 100 volunteers. 
Selection criteria 
Healthy volunteers, male and female, aged 18-45 years (inclusive) 
that meet all acceptance criteria. 
Inclusion criteria 
Volunteers who meet each of the following criteria will be included 
in the study: 
1. Written informed consent from the volunteer. 
2. Men and women aged 18-45 years, inclusive. 
3. Body mass index of 18.5-30 kg/m2. 
4. Verified 
“healthy” 
diagnosis 
based 
on 
physical 
examination, vital signs, standard laboratory tests (complete 
blood count and biochemical blood test, urine analysis) and 
instrumental tests (ECG, fluorography examination or X-ray 
examination). 
5. Negative results of tests for human immunodeficiency virus 
(HIV), syphilis, hepatitis B (Hbs Ag) and hepatitis C 
(antibodies to HCV). 
6. Ability to comply with all the requirements of the protocol 
in the opinion of the investigator. 
7. Consent of the participant and his/her partner to use reliable 
contraceptive methods during the study and within 90 days 
after the end of their participation. A reliable method of 
contraception is a combination of a male condom with at 
least one of the following methods: 
 hormonal contraceptives used by the male’s partner 
(only if she does not participate in this clinical study); 
 use of aerosols, creams, suppositories and other agents 
containing spermicides; 
 use of intrauterine device by female partner. 
Exclusion criteria 
Volunteers who meet at least one of the following criteria will not 
be included in the clinical study: 
1. History of allergies, including at least one episode of allergy 
to medications. 
2. Chronic diseases of the cardiovascular, bronchopulmonary, 
neuroendocrine systems, ENT, as well as diseases of the 
gastrointestinal tract, liver, kidneys, blood, skin. 
3. Hypolactasia (lactose intolerance, lactase deficiency) or 
glucose-galatose malabsorption in medical history. 
4. Chronic eye diseases except for myopia, hypermetropia and 
astigmatism of mild and moderate severity. 


14 / 20 
5. Surgeries on the gastrointestinal tract (except for 
appendectomy done more than 1 year before screening). 
6. Regular administration or use (including externally) of 
hormonal agent for more than 1 week less than 45 days 
before screening 
7. Regular administration of medicinal products less than 4 
weeks before screening. 
8. Use of medicinal products that have a pronounced effect on 
liver function or hemodynamics (barbiturates, omeprazole, 
cimetidine, etc.) less than 30 days before screening. 
9. Positive test for narcotics and psychotropic products. 
10. Blood pressure after resting in supine position for at least 5 
minutes above 130 mm Hg (systolic blood pressure) and 90 
mm Hg (diastolic blood pressure) or below 110 mm Hg 
(systolic blood pressure) and 60 mm Hg (diastolic blood 
pressure). 
11. Heart rate (according to ECG) after resting in supine 
position for at least 5 minutes above 90 bpm or below 60 
bpm.  
12. Blood donation (450 mL of blood or plasma and more) less 
than 3 months before the screening. 
13. Acute infectious diseases less than 4 weeks before 
screening. 
14. Administration of more than 10 units of alcohol per week (1 
unit of alcohol is equivalent to 500 mL of beer, 200 mL of 
wine or 50 mL of a spirit) or history of alcoholism, drug 
abuse, substance abuse. 
15. Mental diseases. 
16. Smoking for three months before screening. 
17. Participation in any clinical study less than 3 months before 
screening. 
18. Planned conception or sperm donation during the study after 
the administration of the investigational product or within 3 
months after the last administration of the product. 
19. Positive pregnancy test for women. 
20. Breastfeeding period. 
Withdrawal criteria 
Withdrawal criteria are: 
1. Refusal of volunteer to participate in the study at any stage. 
2. Developed adverse event, including serious: individual 
intolerance of the investigational medicinal product, 
hypersensitivity to components of the medicinal product 
discovered 
after 
administration, 
making 
further 
participation of the volunteer in the study impossible. 


15 / 20 
3. Any event or condition of the volunteer that according to the 
investigator makes further participation of the volunteer in 
the study impossible. 
4. Volunteer’s lack of discipline, loss of contact with the 
volunteer. 
5. Use of products containing cytochrome P450 inhibitors, 
including 
products 
containing 
grapefruit, 
pomelo, 
cranberries or their juices 72 hours before the administration 
of the medicinal product. 
6. Use of products containing xanthine or its derivatives 
(caffeine, theobromine, etc.), including chocolate, tea, 
coffee or cola 48 hours before the administration of the 
product and before the end of the study. 
7. Vomiting within the first 4 hours after the administration of 
the medicinal product. 
8. Inclusion of the volunteer in the study when he/she does not 
meet inclusion/exclusion criteria. 
9. Use of prohibited therapy. 
10. Termination of the study by the Sponsor. 
11. Termination of the study by the Investigator. 
12. Termination of study by regulatory bodies. 
13. Positive pregnancy test (for women). 
 
In case a volunteer drops out for any reason, all already collected 
samples will be analyzed; moreover, investigators will attempt to 
obtain as much information about the volunteer as possible 
(including collection of bio-samples and clinical information, 
unless informed consent is withheld) to ensure his/her safety. 
In case of a volunteer drops out of the study before dosing and 
within 4 hours from the moment of dosing (for volunteers from 
cohorts C1A, C1B, C2, C3 and C4) or until the end of the visit on 
the 7th day of administration of the medicinal product (for 
volunteers from the C5 cohort) for the following reasons, in the 
absence of risk the volunteer may be replaced with a backup 
volunteer: 
1. Refusal of the volunteer to participate in the study. 
2. Volunteer’s intolerance of study procedures. 
3. Any event or condition of the volunteer that according to the 
investigator makes further participation of the volunteer in 
the study impossible. 
4. Volunteer’s lack of discipline (including if the volunteer 
was admitted to the hospital after designated time), loss of 
contact with the volunteer (including due to change of 
residence). 


16 / 20 
5. Use of alcohol or products containing grapefruit, pomelo, 
cranberries or their juices by volunteers 72 hours before the 
administration of the product and later before the end of 
participation. 
6. Use of products containing xanthine or its derivatives 
(caffeine, theobromine, etc.), including chocolate, tea, 
coffee or cola 48 hours before the administration of the 
product and before the end of the study. 
7. Inclusion of the volunteer in the study when he/she does not 
meet inclusion/exclusion criteria. 
In cohorts C1A, C1B, C2, C3 and C4 one volunteer can be replaced. 
In cohort C5, volunteers can only be replaced in the event if two or 
more volunteers drop out. 
Investigational 
medicinal products 
PBTZ169, capsules for oral administration, 80 mg 
Dose 
and 
route 
of 
administration 
Once orally: 
 Cohort C1A – 640 mg (twice in two periods) 
 Cohort C1B – 640 mg (twice in two periods) 
 Cohort C2 – 960 mg 
 Cohort C4 – 1280 mg 
Twice orally: 
 Cohort C3 – 1280 mg (640 mg, twice with an interval of 12 
hours) 
Multiple times orally: 
 Cohort 5 – X2 mg/day (for 14 days) 
Duration of the study 
for each volunteer 
The expected duration of participation in the study for each 
volunteer from cohorts C1A and C1B (studying the effect of food 
with single administration of PBTZ169) will be 22 to 24 days, 
including the screening period (10 days), hospitalization day, 
therapy in the first period of the study (1 day), follow-up between 
two study periods (≥6 days), therapy in the second study period (1 
day) and follow-up (5±1 days after the last dose). Duration of 
hospitalization of volunteers will be about 2.5 days in each of the 
two study periods (for cohorts C1A and C1B), including 
hospitalization day, the day of administration of the investigational 
product and 48 hours after the administration of the investigational 
product. After discharge from the hospital in each of the two 
periods, volunteers from cohorts C1A and C1B will have to visit the 
research site after 1 day to have their blood collected for 
pharmacokinetics (72 hours after the administration of the 
investigational product), and then visit the research site 5±1 days 
 
2 The dose of PBTZ169 will be determined based on the results of data analysis and taking into account 
conclusion of the Independent Data and Safety Monitoring Board. 


17 / 20 
after the last administration of the product (LA Visit, Day 12±1 
study) to undergo procedures of follow-up visit (safety evaluation), 
after which volunteers will end their participation in the study. 
Expected duration of participation in the study for each volunteer 
from cohorts C2, C3 and C4 (PBTZ169 administered once or twice) 
will be 16 to 18 days, including screening periods (10 days), 
hospitalization day, therapy period (1 day) and follow-up period 
(5±1 days after the last dose). Volunteers from cohorts C2, C3 and 
C4 will be hospitalized for about 2.5 days, including a visit on the 
day of hospitalization, the day of administration of the 
investigational product and 48 hours after the administration of the 
investigational product. After discharge from the hospital, 
volunteers from cohorts C2, C3 and C4 will have to visit the 
research site after 1 day to have their blood collected for 
pharmacokinetics (72 hours after the administration of the 
investigational product), and then visit the research site 5±1 days 
after the last administration of the product (LA Visit, Day 6±1 
study) to undergo procedures of follow-up visit (safety evaluation), 
after which volunteers will end their participation in the study. 
Expected duration of participation in the study for each volunteer of 
the C5 cohort according to protocol will be from 26 to 30 days 
(repeated use of PBTZ169), including screening (7 days), 
hospitalization day, therapy period (14 days) and follow-up after the 
last administration (7±1 days after the last dose). Volunteers from 
the C5 cohort will be hospitalized for about 17 days, including the 
day of hospitalization, the day of administration of the 
investigational product (14 days) and 48 hours after the last 
administration of the investigational product. After discharge from 
the hospital, volunteers from the C5 cohort will need to visit the 
research site after 1 day to have their blood collected at the 72 h 
point, as well as in 7±1 days after the last administration of the 
product (LA Visit, Day 21±1 of the study) to undergo follow-up 
procedures (safety evaluation), after which volunteers will end their 
participation in the study. 
 
Primary and secondary 
variables 
Evaluated safety and tolerability variables 
 Adverse events 
 Changes in vital signs 
 Results of laboratory tests (complete blood count, 
biochemical blood test, urine analysis) 
 ECG results 
 Results of physical examination 
 


18 / 20 
Evaluated pharmacokinetic parameters (single or double dosing)
 Maximum concentration (Cmax) 
 Time to reach the maximum concentration (Tmax) 
 Area under the concentration-time curve in the time interval 
from 0 to time (t) when the last blood sample is collected 
with a concentration above the limit of quantification 
(AUC0-t) 
 Area under the concentration-time curve in the time interval 
from 0 to infinity (AUC0-∞) 
 Half-life (T1/2) 
 Total clearance (Clt/F) 
 Volume of distribution (Vd/F) 
 Elimination constant kel 
 
Evaluated pharmacokinetic parameters (repeated dosing) 
 Maximum concentration (Cmax) in the dosing interval 
 Trough concentration with repeated administration (Ctrough) 
 Time to reach the maximum concentration (Tmax) in the 
dosing interval 
 Area under the concentration-time curve in the time interval 
from 0 to the time (t) of collection of the last blood sample 
with a concentration above the limit of quantification 
(AUC0-t)  
 Area under the concentration-time curve in the time interval 
from 0 to infinity (AUC0-∞) 
 Area under the concentration-time curve in the dosing 
interval (AUC0-τ) 
 Total clearance (Clt/F) 
 Apparent volume of distribution (Vd/F) 
 Half-life (T1/2) 
 Elimination constant kel 
Evaluated parameters of relative bioavailability and relative 
degree of absorption (to evaluate the effect of food with single 
dosing)  
 Relative bioavailability: 
f=AUC0-∞(T)/AUC0-∞(R); f’=AUC0-t(T)/AUC0-t(R) 
 Relative degree of absorption f"=Cmax(T)/Cmax(R) 
Statistical methods 
For statistical analysis, the following populations are used: 
 Population of all participants included – will include all 
participants who were screened and meet the selection 
criteria. The population will be used for listings and 
presentation of data on the disposition of participants. 


19 / 20 
 Safety population – consists of participants who took the 
investigational product at least once. The population will 
be used to analyze and evaluate demographic and other 
source data, as well as all safety indicators. 
 Pharmacokinetics evaluation population – consists of all 
participants who took the investigational product at least 
once in at least one period and with at least 1 
measurement of the concentration of the investigational 
product above limit of quantification. Measurements of 
the concentration of the medicinal product will be 
provided in the listing in this subject population.  
 Pharmacokinetic parameters evaluation population – 
consists of all participants with at least one PK 
parameter evaluated in at least one period. This 
population will be used for analysis of PK parameters 
 Population for analysis of relative bioavailability and 
relative degree of absorption in the analysis of the effect 
of food – consists of all participants of the PK 
parameters evaluation population from cohorts C1A and 
C1B who had at least one PK parameter evaluated in two 
compared periods. Results of comparison of PK 
parameters will be presented in this subject population. 
Evaluation of safety parameters 
Safety evaluation will include registration of AE/SAE, vital 
signs, ECG data, physical examination and laboratory tests in the 
safety population. 
All safety parameters will be analyzed using indicators of 
descriptive statistics (mean, standard deviation, median, minimum 
and maximum values, number of valid cases – for quantitative 
variables; absolute number, share, distribution – for qualitative 
variables. 
Evaluation of pharmacokinetic parameters 
All concentration measurements after administration of the product 
once or twice and with repeated administration will be tabulated 
according to time points and therapeutic groups, and also presented 
in the form of listings. Reasons will be provided for all missing 
measurements, as well as measurements not included in the 
pharmacokinetic analysis. 
Descriptive statistics for measurements of concentration and 
PK parameters will consist of the mean, standard deviation, median, 
minimum and maximum values, coefficient of variation (%), 
number of valid cases (N). For concentration and PK parameters 
such as C and AUC there will also be geometric mean and 
geometric coefficient of variation. 


20 / 20 
Actual values of sampling time will be used for calculating 
individual values of PK parameters using non-compartmental 
analysis. Data on dependency of concentration of the medicinal 
product from time will be presented graphically for each healthy 
volunteer, based on actual sampling time. Descriptive statistics and 
mean PK curves will be presented based on planned sampling time 
points. Mean and individual PK curves will be presented on an 
ordinary and semilogarithmic scale. 
Evaluation of relative bioavailability and relative degree of 
absorption (to evaluate the effect of food with single dosing) 
When evaluating the effect of food on the pharmacokinetics 
of PBTZ169, tested (T) method of administration will be 8 80 mg 
capsules after meal, reference (R) method – 8 80 mg capsules on an 
empty stomach. The study will evaluate relative bioavailability and 
relative degree of absorption. 
Changes in PK parameters will be presented descriptively 
and graphically. After logarithmic conversion, primary PK 
parameters (Cmax and AUC) will be analyzed using ANOVA. 
Obtained point estimations and 90% confidence intervals for the 
difference between mean values of a PK parameter after its 
logarithmic transformation (lnT – lnR) are potentiated to obtain a 
point estimation and corresponding 90% confidence interval limits 
for the ratio of geometric means (T/R).