Conditions: Tuberculosis
Keywords: Tuberculosis
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 40
Healthy volunteers: yes

Brief summary:
Open-label prospective non-comparative safety, tolerability and pharmacokinetics ascending dose randomized cohort study of PBTZ169 (capsules 40 mg) in fasted healthy volunteers after single and multiple oral administration

Detailed description:
Open-label prospective non-comparative safety, tolerability and pharmacokinetics ascending dose randomized cohort study of PBTZ169 (capsules 40 mg) in adult man healthy volunteers after single and multiple oral fasting administration. Study was conducted in one study center in Russian Federation. The study included two stages:

* Stage 1 - single oral fasting administration with dose escalation in 5 cohorts 6 healthy man volunteers each in main groups (plus 1 back-up volunteer in every group);
* Stage 2 - multiple oral fasting administration with dose escalation in 2 cohorts 6 healthy man volunteers each in main groups (plus 1 back-up volunteer in every group).

Screening procedures for each cohort performed within 7 days before the drug prescription and after the end of administration period in previous cohort. Screening in cohorts 2 and 6 was started only after safety tolerability and PK data analysis of previous cohorts.

All volunteers met the study inclusion/exclusion criteria was included successively into the following cohorts on Stage 1 (actual data):

* Cohort 1 (C1) - 6 volunteers of the main group each of whom received once single dose of the drug - 1 capsule containing 40 mg of PBTZ169;
* Cohort 2 (C2) - 6 volunteers of the main group each of whom received once 80 mg of PBTZ169 (2 capsules 40 mg);
* Cohort 3 (C3) - 6 volunteers of the main group each of whom received once 160 mg of PBTZ169 (4 capsules 40 mg);
* Cohort 4 (C4) - 6 volunteers of the main group each of whom received once 320 mg of PBTZ169 (8 capsules 40 mg);
* Cohort 5 (C5) - 6 volunteers of the main group each of whom received once 640 mg of PBTZ169 (16 capsules 40 mg).

On Stage 2 (actual data):

* Cohort 6 (C6) - 5 volunteers of the main group each of whom received 320 mg of PBTZ169 (8 capsules 40 mg) once daily for 14 days;
* Cohort 7 (C7) - 5 volunteers of the main group each of whom received 640 mg of PBTZ169 (16 capsules 40 mg) once daily for 14 days.

Safety was assessed throughout the study. For every volunteer series of urine and venous blood samples was collected for the safety, tolerability and PK assessment of PBTZ169.

Arms:
arm 1: 6 male healthy volunteers each of whom received once single oral dose of PBTZ169 - 40 mg (1 capsule) arm 2: 6 male healthy volunteers each of whom received once single oral dose of PBTZ169 - 80 mg (2 capsules) arm 3: 6 male healthy volunteers each of whom received once single oral dose of PBTZ169 - 160 mg (4 capsules) arm 4: 6 male healthy volunteers each of whom received once single oral dose of PBTZ169 - 320 mg (8 capsules) arm 5: 6 male healthy volunteers each of whom received once single oral dose of PBTZ169 - 640 mg (16 capsules) arm 6: 5 male healthy volunteers each of whom received once daily for 14 days 320 mg of PBTZ169 (8 capsules 40 mg) arm 7: 5 male healthy volunteers each of whom received once daily for 14 days 640 mg of PBTZ169 (16 capsules 40 mg)

Interventions: intervention 1: PBTZ169 - 40 mg intervention 2: PBTZ169 - 80 mg intervention 3: PBTZ169 - 160 mg intervention 4: PBTZ169 - 320 mg intervention 5: PBTZ169 - 640 mg intervention 6: PBTZ169 - 320 mg (multiple administration) intervention 7: PBTZ169 - 640 mg (multiple administration)
Intervention descriptions: intervention 1: 40 mg of PBTZ169 (1 capsule) orally once in fasting state intervention 2: 80 mg of PBTZ169 (2 capsules 40 mg) orally once in fasting state intervention 3: 160 mg of PBTZ169 (4 capsules 40 mg) orally once in fasting state intervention 4: 320 mg of PBTZ169 (8 capsules 40 mg) orally once in fasting state intervention 5: 640 mg of PBTZ169 (16 capsules 40 mg) orally once in fasting state intervention 6: 320 mg of PBTZ169 (8 capsules 40 mg) orally once per day in fasting state for 14 days intervention 7: 640 mg of PBTZ169 (16 capsules 40 mg) orally once per day in fasting state for 14 days

Protocol document:
Prot_SAP_000.pdf: 
NEARMEDIC PLUS LTD. 
CONFIDENTIAL 
Page 1 of 116
Protocol No. PBTZ169-Z00-C01-1 
Version 2.0 dated 17.03.2016
 
 
 
 
CLINICAL STUDY PROTOCOL 
 
No. PBTZ169-Z00-C01-1 
 
 
 
Open-label, prospective, single-arm study of PBTZ169 safety, 
tolerance and pharmacokinetics study in healthy volunteers 
after single and multiple oral administrations with dose 
escalation 
 
 
 
 
Study Sponsor 
NEARMEDIC PLUS LTD. 
 
Address 
12 Aviakonstruktora Mikoyana Str., Moscow 125252, 
 
Russia 
 
Phone: +7 (495) 741 49 89 
 
Fax: +7 (499) 193 43 50 
 
Document type 
Clinical study protocol 
 
Study type 
Prospective 
 
Version 
2.0 
 
Date 
17.03.2016 
 
 
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, 2015 


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Protocol No. PBTZ169-Z00-C01-1 
Version 2.0 dated 17.03.2016
 
1 STUDY SUMMARY 
 
Study title 
Open-label,  prospective,  single-arm  study  of  PBTZ169  safety, 
tolerance  and  pharmacokinetics  study  in  healthy  volunteers  after 
single and multiple oral administrations with dose escalation 
Study ID/code 
PBTZ169-Z00-C01-1 
Study phase 
phase I, first in human 
Planned study period 
01.12.2015 – 01.09.2016 
Study objectives 
To   investigate   safety   and   tolerance   and   evaluate   the 
pharmacokinetics of PBTZ169, capsules 40 mg, in healthy volunteers 
after single administration under fasting condition at rising doses (40 
mg, 80 mg, 160 mg, 320 mg, 640 mg) and multiple administration 
under fasting conditions at doses that will be defined according to the results 
of the analysis of the drug’s tolerance, safety and pharmacokinetics after 
single administration. 
Study tasks 
 To evaluate safety and tolerance of PBTZ169,  capsules 40 mg, 
in healthy volunteers after single administration under fasting 
condition at rising doses (40 mg, 80 mg, 160 mg, 320 mg,  640  
mg)  and  multiple  administration under fasting conditions at 
doses that will be defined according to the results of the analysis 
of the drug’s tolerance, safety and pharmacokinetics after single 
administration, on the basis of recording all possible adverse 
events.  
 To evaluate effects of PBTZ169, capsules 40 mg, on vital 
functions (blood pressure, HR,  body temperature,  RR)  in 
healthy volunteers after single administration under fasting 
condition at rising doses (40 mg, 80 mg, 160 mg, 320 mg, 640 
mg) and multiple administration under fasting conditions at 
doses that will be defined according to the results of the analysis 
of the drug’s tolerance, safety and pharmacokinetics after single 
administration.  
 
 To evaluate effects of PBTZ169, capsules 40 mg, on 
investigations (complete blood count, blood biochemistry, 
coagulogram, urinalysis, ECG) in healthy volunteers after single 
administration under fasting condition at rising doses (40 mg, 80 
mg, 160 mg, 320 mg, 640 mg) and multiple administration 
under fasting conditions at doses that will be defined according 
to the results of the analysis of the drug’s tolerance, safety and 
pharmacokinetics after single administration.  
 To evaluate pharmacokinetic parameters of PBTZ169, capsules 
40 mg in healthy volunteers after single administration under 
fasting condition at rising doses (40 mg, 80 mg, 160 mg, 320 
mg, 640 mg): maximum concentration Сmax, time to maximum 
concentration Tmax, areas under the curve AUC0-t and AUC0-
∞, ratio of AUC0-t to AUC0-∞, half-life T1/2, mean retention 
time MRT, total clearance Clt, distribution volume Vd, 
elimination constant kel.  


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Protocol No. PBTZ169-Z00-C01-1 
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• 
To evaluate pharmacokinetic parameters of PBTZ169, capsules 40 
mg, after multiple administration under fasting conditions at doses 
that will be defined according to the results of the analysis of the 
drug’s tolerance, safety and pharmacokinetics after single 
administration 
in 
healthy 
volunteers, 
i.e.: 
maximum 
concentrations Сmax and Сmax,ss, trough concentration after 
multiple administration Ctrough, time to maximum concentration 
Tmax and Tmax,ss, areas under the curve AUC0-t, AUC0- and 
AUCss, half-life T1/2, mean retention time MRT, total clearance 
Clt, distribution volume Vd and Vss, elimination constant kel. 
 
 To evaluate the elimination kinetics of PBTZ169, capsules 40 mg, 
in urine (renal clearance Clren) in healthy volunteers after single 
administration under fasting condition at rising doses (40 mg, 80 
mg, 160 mg, 320 mg, 640 mg) and multiple administration under 
fasting conditions at doses that will be defined according to the 
results of the analysis of the drug’s tolerance, safety and 
pharmacokinetics after single administration. 
 
Planned number of the 
study centers and their 
location 
At the territory of the RF, the 
participation of 3 study centers is 
planned 
 
 
Design and methodology 
It is open-label safety, tolerance and pharmacokinetics study 
with intra-cohortal randomization of PBTZ169, capsules 40 mg in 
healthy volunteers after single and multiple oral administrations. The 
study includes two stages: 
- Stage 1 - single dosing with dose escalation 
- Stage 2 - multiple dosing with dose escalation. 
 
Stage 1 (single dosing with dose escalation) 
 
Totally, 5 cohorts (C1-C5) are planned to be enrolled during 
the first stage of the study with 7 subjects in each (6 volunteers and 1 
back-up) to investigate the drug after single administration. 
Screening procedures to include volunteers into each cohort will be 
performed within 7 days before the drug prescription. 
 
Healthy volunteers complying with the study inclusion 
criteria, will be admitted to hospital in the evening before the test 
drug administration and randomized into the main group and back-up 
group. 
 
Healthy volunteers complying with the study inclusion 
criteria will be included successively into the following cohorts: 
 
 Cohort 1 (C1) includes 6 healthy volunteers of the main 
group each of whom received a single dose of the drug - 1 
capsule containing 40 mg of PBTZ169 and 1 healthy back-up 
volunteer.

 Cohort 2 (C2) includes 6 healthy volunteers of the main 
group each of whom received a single 80 mg dose of 
PBTZ169 (2 capsules 40 mg) and 1 healthy back-up 
volunteer.
 


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Cohort  3 (C3)  includes  6  healthy  volunteers  of  the  main
group  each  of  whom  received  a  single  160  mg  dose  of 
PBTZ169  (4  capsules  40  mg)  and  1  healthy  back-up 
volunteer. 
Cohort  4 (C4)  includes  6  healthy  volunteers  of  the  main
group  each  of  whom  received  a  single  320  mg  dose  of 
PBTZ169  (8  capsules  40  mg)  and  1  healthy  back-up 
volunteer. 
Cohort  5 (C5)  includes  6  healthy  volunteers  of  the  main
group  each  of  whom  received  a  single  640  mg  dose  of 
PBTZ169  (16  capsules  40  mg)  and  1  healthy  back-up 
volunteer. 
 
In Cohort 1, initially 3 volunteers from the main group will 
receive the drug simultaneously and the rest 3 volunteers will receive 
the drug 24 h after it will be have been taken by previous volunteers. 
In the successive Cohorts, all 6 volunteers of the main group will 
receive the drug simultaneously. 
 
Before the volunteers will be included into Cohort 2, the drug 
pharmacokinetic results will have been received for Cohort 1. Time 
points for blood and urine sampling can be adjusted for all successive 
cohorts based on the data concerning pharmacokinetics and safety of 
administration of PBTZ169 capsules 40 mg. 
 
Screening of volunteers into each successive cohort can be 
started not earlier than 24 h after all the volunteers from the previous 
cohort have received the drug. The subjects will be randomized 
within the cohort after volunteers from previous cohort have received 
the drug. The volunteers of each successive cohort will administer 
single dose of the drug minimum 7 days after the volunteers from the 
previous cohort have received the drug if dose-limited toxicity (DLT) 
is found in less than 50% volunteers from the group. For Cohort 1, 
DLT reported in 2 volunteers from the first three patients will be 
considered as achievement of this criterion and will result in the 
study termination, thus, the successive three subjects will not be 
included into the study. In this study, DLT will include any class 3 
and more toxicity according to Toxicity Grading Scale for Healthy 
Adult and Adolescent Volunteers Enrolled in Preventive Vaccine 
Clinical Trials which is "possibly", "probably" and "definitely" 
related with the administration of PBTZ169. 
 
The volunteers from each group will be admitted to hospital 
in the evening before dosing. 
 
Back-ups from cohorts C1-C5 will be admitted to hospital 
simultaneously with the main volunteers of the cohorts for not more 
than 24 h and will be discharged and complete the study participation 


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if their participation is not necessary. If back-up is necessary in any 
cohort, the period of hospitalization and all the study procedures for 
respective back-up will be equivalent to those for substituted 
volunteer. In Cohort 1, back-up will be hospitalized with the second 
three volunteers. 
 
Each healthy volunteer from the main groups of cohorts C1-
C5 will receive only one dose of the test drug in the morning under 
fasting conditions (10 h of night fasting) with 300 mL of bottled 
water. On the day of administration, water intake is ad libitum, 
except for 1 h within the drug administration during which water 
intake is prohibited and for 4 h after the drug administration (water 
intake is prohibited during the first hour, water intake will be limited 
by 100 mL of bottled water ever hour for the successive 3 h). Food 
intake will be prohibited for 4 h after the drug administration. 
 
Volunteers from cohorts C1 and C2 will have their venous 
blood samples taken to determine PBTZ169 concentration before the 
drug administration: -5 min, 0 min, afterwards at the following time 
points after the drug administration: in 0:10, 0:20, 0:30, 0:45, 1:00, 
1:30, 2:00, 2:30, 3:00, 3:30, 4:00, 5:00, 6:00, 8:00, 10:00, 12:00 and 
24:00 (h:min). 
 
Volunteers from Cohort 3 will have their venous blood 
samples taken to determine PBTZ169 concentration before the drug 
administration: -5 min, 0 min, afterwards at the following time points 
after the drug administration: in 0:10, 0:20, 0:30, 0:45, 1:00, 1:30, 
2:00, 2:30, 3:00, 3:30, 4:00, 5:00, 6:00, 8:00, 10:00, 12:00, 48:00 
(h:min). 
 
Volunteers from Cohort 4 will have their venous blood 
samples taken to determine PBTZ169 concentration before the drug 
administration: -5 min, 0 min, afterwards at the following time points 
after the drug administration: in 0:10, 0:20, 0:30, 0:45, 1:00, 1:30, 
2:00, 3:00, 4:00, 5:00, 6:00, 8:00, 10:00, 12:00, 24:00 and 48:00 
(h:min). 
 
Volunteers from Cohort 5 will have their venous blood 
samples taken to determine PBTZ169 concentration before the drug 
administration: -5 min, 0 min, afterwards at the following time points 
after the drug administration: in 0:10, 0:20, 0:30, 0:45, 1:00, 1:30, 
2:00, 3:00, 4:00, 5:00, 6:00, 8:00, 10:00, 12:00, 24:00, 48:00 and 
72:00 (h:min). 
 
At every time point of blood sampling for PBTZ169 
concentration determination, additional venous blood will be also 
sampled for further storage of samples for possible determination of 
additional parameters. Additional blood can be sampled to control 
the current parameters to assure safety of volunteers. 
 
Urine will be sampled from every volunteer in each of cohorts 
during the first 24 hours after dosing within the the following time 


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periods: 0–2, 2–6, 6–12 and 12–24 h to evaluate pharmacokinetics. 
12-24 h urine samples will be analyzed only at non-zero 
concentration of PBTZ169 in 6-12 h sample. 
 
During 
the 
whole 
period 
of 
blood 
sampling 
for 
pharmacokinetics after the drug administration, the volunteers will be 
at hospital and will be discharged after all procedures planned in the 
protocol have been finished, afterwards the monitoring will be 
continued under out-patient conditions. 
 
Thus, total in-patient period for every cohort will be as 
follows: 
 
 C1 and C2 - 3 days (including the admission day, day of 
the test drug administration and 24 h after the drug 
administration)

 C3 and C4 - 4 days (including the admission day, day of 
the test drug administration and 48 h after the drug 
administration)

 C5 - 5 days (including the admission day, day of the test 
drug administration and 72 h after the test drug
 
administration). 
 
After the discharge from hospital, volunteers from C1-C5 
should visit the study center in 5±1 days after the drug administration 
for follow-up procedures (safety evaluation). 
 
14±1 days after the drug administration, the last visit (Visit 3) 
will take place in the form of phone contact after which the 
volunteers will finish the study participation. Thus, total follow-up 
period will be 14 days after the drug administration for each 
volunteer. 
After the last volunteer from those enrolled in the cohorts of 
Stage 1 completes the study, safety and pharmacokinetics will be 
analyzed using the data of all cohorts of a single dose study. Upon 
the termination of an analysis of the data obtained during the Stage 
I, an independent Committee for data evaluation and study 
subjects‘ safety will be called. The results of the session of the 
Committee dedicated to the discussion of the data obtained in the 
first 5 cohorts (the results of the statistical analysis) will serve for 
preparing 
a 
resolution 
about 
the 
safety, 
tolerance 
and 
pharmacokinetics of the drug taken once in the first 5 cohorts. 
Takin into account the resolution of the independent Committee 
about the data evaluation and the safety of study subjects, the 
Sponsor will: 
 Determine the doses of PBTZ-169 for multiple 
administration during the Stage 2 of the study; 
 Take the decision on the necessity to adjust blood 
and urine sampling timepoints ; 
 Take the decision about the necessity of a study 
procedure correction. 
 


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According to the results of the analysis of all the data 
obtained after the completion of the study by all volunteers from 
cohorts 1 to 5, a clinical study report will be prepared. 
 
Stage 2 (multiple dosing with dose escalation) 
Up to 3 cohorts are planned to be enrolled during the second 
stage of the study with 6 subjects in each to investigate the drug after 
multiple administration. 
Volunteers complying with the study inclusion criteria will be 
included successively into the following cohorts for multiple drug 
administration: 
 Cohort 6 (C6) includes 6 healthy volunteers each of whom 
will receive X* mg of PBTZ169 daily under fasting 
conditions once a day in the morning at the same time ±15 
min for 14 days.  
 Cohort 7 (C7) includes 6 healthy volunteers each of whom 
will receive Y* mg of PBTZ169 daily under fasting 
conditions once a day in the morning at the same time ±15 
min for 14 days. 

The dose of PBTZ-169 will be defined taking into account 
the results of the data analysis and the conclusions of the 
independent Committee for data evaluation and study 
subjects‘ safety.  
The same inclusion criteria will be used to select volunteers 
into cohorts C6-C7 as those used to select volunteers into Cohorts 1-
5. 
If two or more volunteers drop out from multiple 
administration cohorts before the study Day 7 inclusive due to 
different reasons, except for AE/SAE, according to Sponsor's 
decision, volunteers can be additionally enrolled by the number of 
drop outs for whom an additional screening will be performed. Up to 
4 back up volunteers are supposed to be additionally required for 
each of multiple dosing cohorts. If back-up is necessary in multiple 
dosing cohort, the period of hospitalization and all the study 
procedures for a back up will be equivalent to those for substituted 
volunteer. 
Screening procedures to include volunteers into each cohort 
will be performed within 10 days before the drug prescription. 
Screening of volunteers into Cohort 7 can be started not 
earlier than 24 h after all the volunteers from the previous cohort 
have received the last dose of the drug. 
 
The drug administration in Cohort 7 can be started not earlier 
than 7 days after all the volunteers from the previous cohort 
administer the last drug dose if DLT is reported in less than 50% 
volunteers from the previous cohort before the latest volunteer is 
discharged from the hospital. DLT will include any class 3 and more 
toxicity according to Toxicity Grading Scale for Healthy Adult and 
Adolescent Volunteers Enrolled in Preventive Vaccine Clinical Trials 
which is "possibly", "probably" and "definitely" related with the 


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Protocol No. PBTZ169-Z00-C01-1 
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administration of PBTZ169. 
Volunteers included in cohorts C6-C7 are hospitalized in the 
evening on Day 0 before the first drug dose administration. In the 
evening of Day 1, every healthy volunteer will take the first dose of 
the test drug under fasting condition (10 h of night fasting) with 300 
mL of bottled water. Afterwards the volunteers will continue daily 
administration of the test drug at constant dose (depending on  the  
cohort)  under  in-patient conditions.  The  drug  will  be  
administered  daily  under  fasting condition (10 h of night fasting) 
o.d. in the morning at the same time ±15  and  always  with  300 mL  
of  bottled  water.  Food  intake  is prohibited for the volunteers 
during 4 hours after the first, 7th and last (14th) dose of the test 
drug; water intake will be also regulated during this time: not more 
than 100 mL of bottled water per hour. On the  days  of  the  rest  
drug administrations,  the volunteers are prohibited to take food for 
2 h after the drug administration; water intake will be also regulated 
during this time: not more than 100 mL of bottled water per hour. 
The drug administration period will be 14 days. 
 
Before and after the administration of the first, 7th and last 
(14th) dose of the test drug, venous blood will be taken from the 
volunteers to determine PBTZ169 concentration at the following 
time points: before the first drug dose administration: 0 min (before 
the drug administration) and for 24 h after the administration of the 
first, 7th and last (14th) dose of the test drug in: 0:15, 0:30, 0:45, 
1:00, 1:30, 2:00, 3:00, 4:00, 6:00, 8:00, 10:00, 12:00, 24:00 (h:min 
after the drug dosing). 24 h point after the administration of 1 and 7 
drug doses should be taken before the successive doses. During drug 
administration days 3-6 and 9-13, venous blood will be daily taken at 
0 min time point (before the drug administration) to determine 
PBTZ169 concentration. Blood will be sampled at 48 h and 72 h time 
points after the administration of the last (14) drug dose. 
 
The deviations from the specified time by 10 min to one or 
another side (± 10 min) are acceptable for the following time points: 
24 hours for administration of the first, 7th and last (14th) doses of 
the test drug. For 48 h and 72 h time points after the last (14th) dose 
administration, deviation from the specified time by 20 min to one or 
another side (± 20 min) is acceptable. For the rest time points, blood 
sampling after the test drug administration can deviate by not more 
than 2 min to one or another side (± 20 min). 
 
In case of preterm withdrawal from the study, if there is no 
risk for a volunteers, attempts to sample their blood according to 
schedule for the last (14) dose will be taken. 
 
At every time point of blood sampling for PBTZ169 


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concentration determination, additional venous blood will be also 
sampled for further storage of samples for possible determination of 
additional parameters. 
Urine will be sampled from every volunteer in each of cohorts 
during the first 24 hours after the first and last dosing within the the 
following  time  periods:  0–2,  2–6,  6–12  and  12–24 h  to  evaluate 
pharmacokinetics. 12-24 h urine samples will be analyzed only at 
non-zero concentration of PBTZ169 in 6-12 h sample. 
During  the  whole  period  of  PBTZ169  administration,  the 
volunteers  will  be  monitored  in  the  hospital;  afterwards  the 
monitoring  will  be  continued  under  outpatient  conditions.  Total 
follow-up  period  will  be  14  days  after  the  last  drug  dose 
administration for each volunteer. 
After the discharge from the hospital, volunteers from cohorts 
C6-C7 should visit the study center in 1 and 2 days for blood 
sampling at 48 h and 72 h time points and in 7±1 days and 14±1 days 
for the last drug dosing (the study Day 19±1 and Day 28±1) for 
follow up procedures (safety evaluation). 
21±1 days after the last drug dosing (the study Day 35±1) in 
volunteers from cohorts C6-C7, final visit will be performed in 
the form of phone contact after which the volunteers will finish the 
study participation. 
For patients, who will receive multiple dosing, hospitalization 
period will be 16 days (including admission day, 14 days of the test 
drug administration and 24 h of patient monitoring under inpatient 
conditions after last drug dosing). 
The  results  obtained  in  this  study  will  be  used  to  plan 
subsequent safety and efficacy clinical studies of PBTZ169. 
Justification 
of 
dose 
Dose selection for single dosing 
selection 
Maximum  recommended  initial  dose  (MRID)  will  be 
calculated  on  the  basis  of  recommendations  of  Methodological 
Recommendations for determination of safe dose of drug for phase I 
clinical studies in adult volunteers (Guidelines for nonclinical studies 
of drugs, part one, 2012). 
Determination of no observed adverse effect level (NOAED) 
Nonclinical investigation of subchronic toxicity of finished 
dosage form was performed in rats after intragastric administration of 
the  drug at  API doses  of  9-180 mg/kg/daily for  30  days  and  on 
rabbits at API doses of 8–32 mg/kg/daily for 30 days. The results of 
studies demonstrated that NOAED in rats was 180 mg/kg  and that in 
rabbits was 32 mg/kg. While investigating subchronic toxicity of the 
drug in  rabbits,  death  of  one  male,  which  received API dose  of 
8 mg/kg, was reported on the drug administration day 9. However, 
this case was treated as accidental death not associated with the drug 


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administered. 
 
Nonclinical investigation of acute toxicity of finished dosage 
form was performed in rats after intragastric administration of the 
drug at API doses of 9-360 mg/kg and on rabbits at API doses of 8– 
32 mg/kg. No fatal cases, gender distinctions and differences from 
the control groups were reported. 
 
Calculation  of  human  equivalent  dose  (HED)  based  on 
 
NOAED 
 
Calculation factor 6 was used for calculation of HED in rats 
and calculation factor 3.2 was used for that in rabbits. 
 
HED calculated based on NOAED in rats for 30 mg/kg [180 
(mg/kg)/6]. 
 
HED calculated based on NOAED in rabbits for 10 mg/kg [32 
(mg/kg)/3.2]. 
 
Selection of the most suitable animal species for HED 
determination 
 
In toxicity evaluation experiments in rats and rabbits, the test 
drug had no effect on the appearance, general condition, 
physiological parameters, did not affect negatively hematological and 
biochemical blood parameters and vital signs; did not cause 
pathomorphological changes. Thus, taking into consideration that use 
of the lowest HED assures the safest initial human dose, the most 
suitable species is rabbits (calculated HED is 10 mg/h). 
 
Use of safety coefficient, determination of MRID 
 
Standard safety coefficient 10 is used in the calculation of 
 
MRID. MRID is 1 mg/kg [10 (mg/kg)/10]. 
 
Determination of pharmacologically active dose (PAD) 
 
Anti-tuberculosis activity of the drug substance was 
determined on experimental model of acute and chronic tuberculosis 
in mice and in experimental chronic tuberculosis in guinea pigs. 
 
In the experiments, PAD in mice was 25 mg/kg. HED 
calculated using PAD in mice was 2.08 mg/kg [25 (mg/kg)/12.0]. 
 
In the experiments, PAD in guinea pigs was 80 mg/kg. HED 
calculated using PAD in guinea pigs was 17.02 mg/kg [80 
(mg/kg)/4.7]. 
 
Thus, HED calculated on the basis of substance activity study 
varies between 2.08 and 17.02 mg/kg. 
 
Taking into consideration that HED calculated using PAD 
value higher than MRID, initial dose (dose for Cohort 1) will be 1 
mg/kg (for subject with 70 kg of body weight complies with 70 mg 
dose). 
 
As volunteers with body weight less than 70 kg can 


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participate in the study, taking into consideration that PBTZ169 is a 
novel drug and that the test drug has been manufactured at dose of 40 
mg, 40 mg dose will be administered as an initial dose. 
 
Maximum dose for this study will be 640 mg as a single dose. 
Maximum dose can be selected on the basis of lack of negative drug 
effects   when administered at API  doses up to 180 mg/kg (HED=30 
mg/kg, calculated for a human of 70 kg in body weight - 2100  mg)  
in rats  in  subchronic  toxicity  study,  up  to  360 mg/kg (HED=60 
mg/kg, calculated for a human of 70 kg in body weight - 4200 mg) 
in rats in acute toxicity study. Thus, selected maximum dose 640 mg 
is within the range of investigated doses in animals (rats) up to 
2100-4200 mg. 
Dose selection  and  period  of  administration  for  multiple 
dosing 
Doses of PBTZ169 for  multiple  administration  will  be defined 
taking into account the results of the data analysis upon study 
completion by the volunteers from Cohorts 1 to 5, and the 
conclusions of the independent Committee for data evaluation and 
study subjects‘ safety. Two different doses are expected to be 
chosen for multiple dosing. Good tolerance and safety of the 
corresponding single dose of the drug will be the defining criteria, 
including also a determination of a dose-limiting toxicity (DLT) in 
less than 50% of the volunteers from the respective cohort with 
single dosing. Presumably, two highest doses among those studied 
in single administration will be selected, on the condition of a good 
tolerance of the drug.  
Multiple administration of PBTZ169 will be performed at 
hospital under thorough monitoring of volunteers.  
Taking into consideration that the drug administration period in 
rabbits and rats was 30 days in the subchronic toxicity study and 180 
days in the chronic toxicity study, according to Guidelines for drug 
evaluation, 2013 (volume I), 14-day period of the test drug 
administration in this clinical study is justified. 
Planned number of study 
At Stage 1, 53 volunteers are planned to be screened (taking into  
consideration supposed withdrawal  of  18  subjects  -  50%  of 
planned number of subjects included at screening stage) which will 
result in inclusion of totally 35 healthy volunteers complying with 
inclusion criteria: 6 male volunteers of the main group into each of 5 
cohorts of single dosing and one back-up in each cohort at the first 
stage. 
At Stage 2, 30 volunteers are planned to be screened (taking into  
consideration  supposed  withdrawal  of  15  subjects  -  50%  of 
planned maximum number of subjects included at screening stage) 
which will result in inclusion of totally up to 20 healthy volunteers 
complying with inclusion criteria: 6 male volunteers of the main 
group into each of 2 cohorts of multiple dosing (C6 and C7) with 
possible additional inclusion of 4 volunteers into each cohort in case 
of withdrawal at the second stage. 
subjects 


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Total number of screened volunteers during the both study 
stages will be up to 83 subjects. 
Total number of volunteers included at the both study stages 
will be up to 55 subjects. 
As  the  main  tasks  of  this  study  are  safety  and  tolerance 
evaluation and the study is not comparative in design, acceptable 
from this point of view sample size for such clinical studies has been 
chosen which allows, first of all, to study safety and tolerance profile 
of the test drug. 
Selection criteria 
At each of two stages, healthy male volunteers aged 18 to 45 
years old are planned to be included into the study according to 
inclusion  criteria  with  no  non-inclusion  criteria.  Similar  selection 
criteria are used for all cohorts. 
Inclusion criteria 
Volunteers complying with each of the following criteria will 
be included into the clinical study: 
1.  Written informed consent received from a volunteer. 
2.  Men aged 18 to 45 years old, inclusive. 
3.  Body mass index of 18.5–25 kg/m2. 
4.  Verified diagnosis: "healthy" according to data of standard 
clinical,  laboratory  and  instrumental  examination  methods 
performed at screening: 
Absence  of  deviations  of  physical examination 
parameters and vital signs (systolic blood pressure - 100-
129 mm Hg, inclusive; diastolic blood pressure - 70-89  
mm  Hg,  inclusive;  heart  rate  -  60-80 bpm, inclusive); 
Absence  of  deviations  of  laboratory parameters 
(complete  blood  count,  blood  biochemistry,  HIV, HBV, 
HCV, syphilis and urinalysis); 
  Normal parameters of 12-lead ECG; 
Normal   results   of   photofluorographic   or   X-ray 
examination (the results received maximum 6 months 
before screening can be used); 
Normal blood glucose levels during the oral glucose 
tolerance test (less than 5.6 mmol/l at fasting state and less 
than 7.8 mmol/l 2 hours after glucose charge). This test is 
only used for volunteer inclusion screening in cohorts with 
multiple dosing. 
5.  Ability,  according  to  investigator,  to  comply  with  all 
requirements of the protocol. 
6.  Agreement to use double contraception method during the 
study  participation  and  for  3  months  after  the  test  drug  
administration - combination of male condom with not less 
than one of the following methods: 
  female partner using hormonal contraception; 
  using  aerosols,  creams,  suppositories  and  other  agents 
containing spermicides; 
  female partner using intrauterine device. 
Non-inclusion criteria 
Volunteers who will comply with at least one of the following 
criteria will not be included in the clinical study: 


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1. Aggravated allergic history, including presence of at least one 
episode of drug allergy. 
 
2. Chronic diseases of cardiovascular, bronchopulmonary, 
neuroendocrine systems, ENT and gastrointestinal, hepatic, 
renal, blood and cutaneous diseases. 
 
3. Chronic diseases of eyes except for myopia, hypermetropia 
and mild to moderate astigmatism. 
 
4. Gastrointestinal 
surgeries 
(except 
for 
appendectomy 
performed not more than 1 year before screening). 
 
5. Acute infections within less than 4 weeks before screening. 
 
6. Regular drug administration within less than 4 weeks before 
screening. 
 
7. Regular administration or application (including topical) of 
hormonal drugs for more than 1 week within less than 45 
days before the screening. 
 
8. Administration of drugs exerting evident effects on 
hemodynamics, 
hepatic 
function, 
etc. 
(barbiturates, 
omeprazole, cimetidine, etc.) within less than 45 days before 
the screening. 
 
9. Positive test for narcotic and psychotropic agents. 
 
10. Donation (450 mL of blood or plasma) within less than 3 
months before the screening. 
 
11. Intake of more than 10 U of alcohol per week (1 unit of 
alcohol is equivalent to 500 mL of beer, 200 mL of vine or 50 
mL of strong alcoholic drink) or historical data on 
alcoholism, narcomania, drug abuse. 
 
12. Mental illnesses. 
 
13. Smoking within half a year before the screening. 
 
14. Previous participation in this clinical study and withdrawal 
from it due to any reason. 
 
15. Participation in other clinical studies of drugs within less than 
6 months before the screening. 
 
16. Planned conception or sperm donation during the study after 
the test drug administration or during 3 months after the date 
of the last drug administration. 
 
Withdrawal criteria 
Withdrawal criteria should be considered as follows: 
1. Volunteer's refusal to participate in the study at any stage of 
its performance. 
2. Occurrence of adverse event, including serious adverse event: 
individual intolerance of the test drug, hypersensitivity to the 
drug ingredients found directly in the drugs administration 
due to which further participation in the study is not possible. 
3. Intolerance of the study procedures by a volunteer. 
4. Any  event  or  volunteer's  condition  which,  according  to 
investigator, makes further participation of the volunteer in 
 


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the study impossible. 
 
5. Misbehavior of a volunteer (including if the volunteer was 
admitted to hospital later than appointed), loss of contact with 
a volunteer (including due to change of residence). 
 
6. Intake of alcohol or products containing grapefruit, pomelo, 
cranberry and their juices is prohibited 72 h before the drug 
administration and further till the end of participation in the 
study. 
 
7. Vomiting during the first 4 hours after the drug 
administration. 
 
8. Inclusion of volunteer into the study in case of incompliance 
with the inclusion/non-inclusion criteria. 
 
9. Study termination by the Sponsor. 
 
10. Study termination by the Investigator. 
 
11. Study termination by the Regulatory Authorities. 
If patient is withdrawn from the study due to any reason, all 
biosamples collected will be analyzed and investigators will make 
attempts to obtain maximum complete information on volunteer 
(including collection of biosamples and clinical information unless 
informed consent is withdrawn) to assure his safety. 
If a volunteer is withdrawn from the study cohorts C1-C7 
before dosing and during 4 months since dosing (for volunteers of 
C1-C5) or before the end of visit on the drug administration day 7 
(for volunteers of C6-C7) due to the following reasons, a withdrawn 
patient can be substituted with a back-up according to the 
Investigator: 
 
1. 
Refusal of a volunteer to participate in the study. 
 
2. 
Intolerance of study procedures by a volunteer. 
 
3. 
Any event or volunteer's condition which, according to 
investigator, makes further participation of the 
volunteer in the study impossible. 
 
4. 
Misbehavior of a volunteer (including if the volunteer 
was admitted to hospital later than appointed), loss of 
contact with a volunteer (including due to change of 
residence). 
 
5. 
Intake of alcohol or products containing grapefruit, 
pomelo, cranberry and their juices is prohibited 72 h 
before the drug administration and further till the end of 
participation in the study. 
 
6. 
Inclusion  of  volunteer  into  the  study  in  case  of 
 
incompliance with the inclusion/non-inclusion criteria. 
Substitution of 1 volunteer is possible in each of cohorts 
 
C1-C5. In each of cohorts C6-C7, a volunteer can be substituted only 
if two or more volunteers are withdrawn while the substitution will 
not be performed if 1 volunteer is withdrawn. 


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Test drug 
PBTZ169 capsules for oral administration, 40 mg 
Dose  and 
administration 
Single oral: 
route 
  Cohort 1 — 40 mg 
  Cohort 2 — 80 mg 
  Cohort 3 — 160 mg 
  Cohort 4 — 320 mg 
  Cohort 5 — 640 mg 
Multiple oral 
  Cohort 6 — X* mg/day 
  Cohort 7 — Y* mg/day 
 
The dose of PBTZ-169 will be defined taking into account the 
results of the data analysis and the conclusions of the independent
Committee for data evaluation and study subjects‘ safety.  
Administration period 
Single administration in the morning at a fasting state for 
volunteers from cohorts C1-C5. 
For   volunteers   from   cohorts   C6-C7: daily   drug 
administration o.d. in the morning at a fasting state at the 
same time±15 min for 14 days. 
Reference drug 
Not applicable. 
Respective therapy 
Not applicable. 
Primary 
and  secondary 
Safety and tolerance variables evaluated 
variables 
    Adverse events 
 
 Changes in vital signs

 Results of laboratory analyses (complete blood count, blood 
biochemistry, urinalysis)

 Results of ECG

 Results of physical examination
 
Pharmacokinetic parameters evaluated (single dosing) 
 Maximum concentration (Cmax)
 Time to maximum concentration (Tmax)
 Area under the concentration-time curve from 0 to last blood 
sampling (t) (AUC0-t)
 Area under the concentration-time curve from zero to infinity 
(AUC0-∞)
 Ratio AUC0-t to AUC0-∞ (AUC0-t/AUC0-∞)
 Total clearance (Cl)
 Renal clearance (Clren)
 Distribution volume (Vd)
 Half-life (T1/2)
 Mean retention time (MRT)
 Absorption rate (Cmax/AUC0-t)
 


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Pharmacokinetic parameters evaluated (multiple dosing) 
 Maximum concentration (Cmax)
 Maximum steady-state concentration (Сmax,ss)
 Trough concentration after multiple administration (Ctrough)
 Time to maximum concentration (Tmax)
 Time to maximum steady-state concentration (Tmax,ss)

 Area under the concentration-time curve from 0 to last blood 
sampling (t) (AUC0-t)

 Area under the concentration-time curve from zero to infinity 
(AUC0-∞)

 Steady-state area under the concentration-time curve (AUCss)
 Total clearance (Clt)

 Renal clearance (Clren)
 Apparent distribution volume (Vd)
 Steady-state distribution volume (Vss)
 Half-life (T1/2)

 Mean retention time (MRT)
 Elimination constant kel
 
Statistical methods 
The  study  results  will  be statistically analyzed in  the 
following populations: 
  Intent-to-treat   population   -   comprises   of   all   the 
participants who underwent screening and comply with all the  
selection  criteria.  The  population  will  be  used  for listings   
and   presentation   of   data   by   participants' disposition. 
  Safety   population   -   consists   of   participants   who 
administered the test drug (for Cohorts C6-C7 - at least once).  It  
will  be  used  for  analysis  and  evaluation  of demographic  
and  other  baseline  data  and  all  safety parameters including 
adverse events, physical examination,  evaluation  of  vital  
signs,  previous  and current  therapy,  ECG  and  all  the  rest  
instrumental examination methods, all laboratory investigations. 
  Population for single dosing pharmacokinetics evaluation 
consists of all participants who administered the test drug and 
have at least 1 measure of the test drug concentration. 
Calculation  of  PK  parameters  and  their  statistical processing 
will be performed on this population. 
  Population   for   multiple   dosing   pharmacokinetics 
evaluation consists of all participants who administered the test 
drug at least 7 times and have measure of the test drug   
concentration   after   the   first   and   seventh administration  of  
the  test  drug.  For  multiple  dosing cohorts, calculation of PK 
parameters and their statistical 


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processing will be performed on this population. 
 
Safety parameters evaluation 
 
Safety evaluation will include determination of AE/SAE, vital 
signs, ECG data, physical examination and laboratory analyses in the 
safety population. 
 
All the safety parameters will be performed using descriptive 
statistics parameters (mean, standard deviation, median, minimum 
and maximum, range, quartiles, number of valid cases - for 
quantitative variables; absolute count, ratio, distribution - for 
qualitative variables). 
 
Pharmacokinetic parameters 
 
Pharmacokinetic parameters will be determined using 
WinNonlin software (Phoenix Inc) by the results of the drug 
concentration measurement. Individual pharmacokinetic curves will 
be plotted with determination of all calculable parameters and 
descriptive statistics parameters.