Phase 2a Study of PBTZ169

• Sponsor: Nearmedic Plus LLC (Industry)
• Overall Status: Terminated
• CT.gov ID: NCT03334734
• Collaborator: OCT LLC (Other)
• Enrollment: 16
• Arms: 4
• Actual Duration (Months): 14.2

Study Details

Study Description

Brief Summary

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

Condition or Disease	Intervention/Treatment	Phase
Tuberculosis	Drug: PBTZ169; Drug: Isoniazid	Phase 2

Detailed Description

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

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

Study Design

• Study Type: Interventional
• Actual Enrollment: 16 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Multicenter, Open, Randomized Study With Active Control to Evaluate the Early Bactericidal Activity, Safety and Pharmacokinetics of the Drug PBTZ169 When Used in Patients With First-diagnosed Tuberculosis of the Respiratory System With Bacterial Excretion and Saved Bacterial Susceptibility to Isoniazid and Rifampicin
• Actual Study Start Date: Dec 16, 2016
• Actual Primary Completion Date: Sep 10, 2017
• Actual Study Completion Date: Feb 22, 2018

Arms and Interventions

Arm	Intervention/Treatment
Experimental: PBTZ169, 160 mg 2 capsules 80 mg of PBTZ169 once a day for 14 days	Drug: PBTZ169; Once a day for 14 days
Experimental: PBTZ169, 320 mg 4 capsules 80 mg of PBTZ169 once a day for 14 days	Drug: PBTZ169; Once a day for 14 days
Experimental: PBTZ169, 640 mg 8 capsules 80 mg of PBTZ169 once a day for 14 days	Drug: PBTZ169; Once a day for 14 days
Active Comparator: Isoniazid, 600 mg 2 tablets 300 mg of Isoniazid once a day for 14 days	Drug: Isoniazid; Once a day for 14 days

Outcome Measures

Primary Outcome Measures

1. Early Bactericidal Activity (0-14) [14 days after the onset of monotherapy]

   Early bactericidal activity 14 days from the monotherapy start date (EBA 0-14): agar inoculation, the mean of two measurements at the Visit

2. Early Bactericidal Activity (0-14) [14 days after the onset of monotherapy]

   Early bactericidal activity 14 days from the monotherapy start date (EBA 0-14): PCR, the mean of two measurements at the Visit

Secondary Outcome Measures

1. Early Bactericidal Activity (0-2) [2 days after the onset of monotherapy]

   EBA (0-2): agar inoculation, the mean of two measurements at the Visit

2. Early Bactericidal Activity (0-7) [7 days after the onset of monotherapy]

   EBA (0-7): agar inoculation, the mean of two measurements at the Visit

3. Early Bactericidal Activity (0-2) [2 days after the onset of monotherapy]

   EBA (0-2): PCR, the mean of two measurements at the Visit

4. Early Bactericidal Activity (0-7) [7 days after the onset of monotherapy]

   EBA (0-7): PCR, the mean of two measurements at the Visit

5. Peak Plasma Concentration (Сmax) of PBTZ169 [Up to 72 hours after the last drug administration]

   Peak plasma concentration (Сmax) of PBTZ169 for multiple dosing

6. Minimal Plasma Concentration (Сmin) of PBTZ169 [for single dosing , Day 1 (24 h after 1st dose of PBTZ169)]

   Minimal plasma concentration (Сmin) of PBTZ169: concentration measurement following single dosing

7. Residual Concentration (Ctrough) of PBTZ169 [Up to 72 hours after the last drug administration]

   Residual concentration (Ctrough) of PBTZ169, measured 24 hours after the first dose administration, prior to the last dose, and 24 hours after the last dose

8. Minimal Plasma Concentration (Сmin) of PBTZ169 [Up to 72 hours after the last drug administration]

   Minimal plasma concentration (Сmin) of PBTZ169: multiple dosing

9. Time to Reach Maximum Concentration (Tmax) of PBTZ169 [for single dosing , Day 1 (24 h after 1st dose of PBTZ169)]

   Time to reach maximum concentration (Tmax) of PBTZ169 after single oral administration in different doses

10. Time to Reach Maximum Concentration (Tmax) of PBTZ169 [Up to 72 hours after the last drug administration]

    Time to reach maximum concentration (Tmax) of PBTZ169 after multiple oral administration in different doses

11. AUC(0-24) [Up to 24 hours after the first drug administration]

    Area under the plasma concentration of PBTZ169 versus time curve in frames [0-24 hours]

12. Peak Plasma Concentration (Сmax) of PBTZ169 [for single dosing , Day 1 (24 h after 1st dose of PBTZ169)]

    Peak plasma concentration (Сmax) of PBTZ169: concentration measurement following single dosing

13. AUC(0-24) [Up to 24 hours after the last drug administration]

    Area under the plasma concentration of PBTZ169 versus time curve in frames [0-24 hours] for the last dosing (Day 14)

14. AUC (0-t) [Up to 72 hours after the last drug administration]

    Area under the plasma concentration of PBTZ169 versus time curve in frames [0-last concentration above lower limit of quantification (LLoQ)]

15. AUC(0-∞) of PBTZ169 [Up to 72 hours after the last drug administration]

    Area under the plasma concentration versus time curve in frames [0-∞]

16. Accumulation Ratios for the PK Parameters AUC(0 -24) [24 hours after the first and the last drug administration]

    Accumulation ratios for the PK parameter AUC(0 -24): AUC(0- 24,ss)/AUC(0 -24), Day 1, on the original scale

17. Average Concentration (Css,av) of PBTZ169 [Up to 72 hours after the last drug administration]

    Average steady-state concentration in the dosing interval following multiple dosing was evaluated as the ratio AUC0 24/τ (τ = the dosing interval)

18. Fluctuations (%) in the Dosing Interval [Up to 72 hours after the last drug administration]

    Fluctuations (%) in the dosing interval after multiple dosing ((Cmax - Cmin) × 100%/Css,av)

19. Total (Plasma) Clearance (Clt) of PBTZ169 [24 hours after the first drug administration]

    Clt/F (apparent total clearance following single and multiple oral administration) was calculated using the following formula: Cl_t/F=D/AUC where D is the daily dose of the drug.

20. Total (Plasma) Clearance (Clt) of PBTZ169 [24 hours after the last drug administration]

    Clt/F (apparent total clearance following single and multiple oral administration) was calculated using the following formula: Cl_t/F=D/AUC where D is the daily dose of the drug.

21. Volume of Distribution (Vd) of PBTZ169 [Up to 72 hours after the last drug administration]

    Distribution volume Vd for a dosing interval of 72 hours after the last dose

22. Plasma Half-life Time (T1/2) of PBTZ169 [24 hours after the fist drug administration]

23. Plasma Half-life Time (T1/2) of PBTZ169 [24 hours after the last drug administration]

24. Elimination Constant (Kel) of PBTZ169 [24 hours after the first drug administration]

    Apparent terminal elimination rate constant was evaluated based on the regressional dependence of log-transformed concentrations ln(C) on time for the terminal log- linear part of the concentration-time curve.

25. Elimination Constant (Kel) of PBTZ169 [72 hours after the last drug administration]

    Apparent terminal elimination rate constant was evaluated based on the regressional dependence of log-transformed concentrations ln(C) on time for the terminal log- linear part of the concentration-time curve.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 65 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Written informed consent received from a volunteer

• Men and women aged 18 to 65 years, inclusive

• The first-diagnosed active pulmonary tuberculosis, confirmed by characteristic radiographic changes (infiltration, dissemination, destruction) during radiography or computed tomography of chest organs, without damage to other organs or with the defeat of one or more of the following organs: larynx, trachea, bronchi, lymph nodes

• The amount of sputum given by the patient is sufficient for carrying out the analyzes provided for by the protocol, but not less than 4-5 ml at the screening

• The presence of acid-fast mycobacteria in the sputum according to the results of microscopy of smears (1+ and more using the method of microscopy with luminescent dye staining according to the Order of the Ministry of Health of the Russian Federation of March 21, 2003 No. 109, the last edition) and the detection of the DNA of mycobacteria of tuberculosis by the results of molecular genetic methods of diagnosis

• Body weight not less than 51 kg

• Body mass index of 18.5-25 kg/m2

• Ability, according to investigators opinion, to comply with all requirements of the protocol

• 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

Exclusion Criteria:

• Extrapulmonary localization of tuberculosis

• Presence of resistance to rifampicin and / or isoniazid in the study of sputum samples using molecular genetic methods

• Admission of any anti-tuberculosis drugs from the moment of diagnosis of tuberculosis to the moment of inclusion in the study

• The presence of absolute indications for surgical treatment of tuberculosis at the time of screening

• Positive tests for serological markers of syphilis or HIV infection during screening; active hepatitis or decompensated hepatic cirrhosis

• Aggravated allergic history, including presence of at least one episode of drug allergy

• The values of renal and / or hepatic parameters according to laboratory analyzes (taking into account the range of normal laboratory values):

• Aspartate aminotransferase (AST) level > 2.0 x upper limit of the norm

• Alanine aminotransferase (ALT) level > 2.0 x upper limit of norm

• General bilirubin level > 1.5 x upper limit of norm

• Creatinine level > 1.5 x upper limit of norm

• Individual drug components intolerance

• Presence in the anamnesis of malignant neoplasms, except for basal cell skin cancer

• The presence of severe chronic somatic diseases in the stage of decompensation, including diseases of the cardiovascular, bronchopulmonary, neuroendocrine system, ear, nose and throat (ENT) organs, the gastrointestinal tract, liver, kidneys, blood, skin, or any other somatic or mental diseases that, according to the researcher, prevent the patient from entering the study

• Gastrointestinal surgeries (except for appendectomy performed not less than 1 year before screening)

• Mental illness that may interfere with the patient's compliance with the protocol

• Diabetes mellitus

• Acute viral and bacterial infections at the time of enrollment or within 2 weeks before enrollment

• Alcoholism (except in cases when the patient is able, in the opinion of the researcher, to refrain from taking alcohol during the period of participation in the study), drug addiction, abuse of medicines

• Positive tests for narcotic and psychotropic agents

• Regular admission or use (including externally) of any hormonal medicines lasting more than 1 week less than 30 days before screening (with the exception of oral hormonal contraceptives and intrauterine spirals containing hormones)

• Use of cytostatic drugs less than 30 days before screening

• Multiple admission of drugs with the described in the instructions for medical use adverse events related to nervous system, hemodynamic and hepatic functions with frequencies "very frequent" (≥10%) and "often" (≥1% and <10%) less than 21 days before screening

• Pregnancy or lactation period

• Planned conception or sperm donation during the study after the test drug administration or during 3 months after the last date of drug administration

• Participation in other clinical studies of drugs within less than 3 months before the screening

Contacts and Locations

Locations

No locations specified.

Sponsors and Collaborators

• Nearmedic Plus LLC
• OCT LLC

Investigators

None specified.

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Jul 20, 2017

More Information

Publications

None provided.

• Responsible Party: Nearmedic Plus LLC
• ClinicalTrials.gov Identifier: NCT03334734
• Other Study ID Numbers: PBTZ169-A15-C2A-1
• First Posted: Nov 7, 2017
• Last Update Posted: Mar 9, 2020
• Last Verified: Feb 1, 2020

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by Nearmedic Plus LLC: Tuberculosis; PBTZ169; antimycobacterial
• Additional relevant MeSH terms: Tuberculosis; Isoniazid; Macozinone

Study Results

Participant Flow

Arm/Group Title	PBTZ169, 160 mg	PBTZ169, 320 mg	PBTZ169, 640 mg	Isoniazid, 600 mg
Arm/Group Description	2 capsules 80 mg of PBTZ169 once a day for 14 days PBTZ169: Once a day for 14 days	4 capsules 80 mg of PBTZ169 once a day for 14 days PBTZ169: Once a day for 14 days	8 capsules 80 mg of PBTZ169 once a day for 14 days PBTZ169: Once a day for 14 days	2 tablets 300 mg of Isoniazid once a day for 14 days Isoniazid: Once a day for 14 days
Period Title: Overall Study
STARTED	4	4	7	1
COMPLETED	4	4	5	1
NOT COMPLETED	0	0	2	0

Baseline Characteristics

Arm/Group Title	PBTZ169, 160 mg	PBTZ169, 320 mg	PBTZ169, 640 mg	Isoniazid, 600 mg	Total
Arm/Group Description	2 capsules 80 mg of PBTZ169 once a day for 14 days PBTZ169: Once a day for 14 days	4 capsules 80 mg of PBTZ169 once a day for 14 days PBTZ169: Once a day for 14 days	8 capsules 80 mg of PBTZ169 once a day for 14 days PBTZ169: Once a day for 14 days	2 tablets 300 mg of Isoniazid once a day for 14 days Isoniazid: Once a day for 14 days	Total of all reporting groups
Overall Participants	4	4	7	1	16
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	49.0 (13.0)	48.8 (10.7)	43.7 (14.8)	41.0 (0)	46.1 (12.3)
Sex: Female, Male (Count of Participants)
Female	0 0%	0 0%	2 28.6%	0 0%	2 12.5%
Male	4 100%	4 100%	5 71.4%	1 100%	14 87.5%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%	0 0%	0 0%
Asian	0 0%	0 0%	0 0%	0 0%	0 0%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%	0 0%	0 0%
Black or African American	0 0%	0 0%	0 0%	0 0%	0 0%
White	4 100%	4 100%	7 100%	1 100%	16 100%
More than one race	0 0%	0 0%	0 0%	0 0%	0 0%
Unknown or Not Reported	0 0%	0 0%	0 0%	0 0%	0 0%
Region of Enrollment (participants) [Number]
Russia	4 100%	4 100%	7 100%	1 100%	16 100%

Outcome Measures

1. Primary Outcome

Title	Early Bactericidal Activity (0-14)
Description	Early bactericidal activity 14 days from the monotherapy start date (EBA 0-14): agar inoculation, the mean of two measurements at the Visit
Time Frame	14 days after the onset of monotherapy

Outcome Measure Data

Analysis Population Description

FAS

Arm/Group Title	PBTZ169, 160 mg	PBTZ169, 320 mg	PBTZ169, 640 mg	Isoniazid, 600 mg
Arm/Group Description	2 capsules 80 mg of PBTZ169 once a day for 14 days PBTZ169: Once a day for 14 days	4 capsules 80 mg of PBTZ169 once a day for 14 days PBTZ169: Once a day for 14 days	8 capsules 80 mg of PBTZ169 once a day for 14 days PBTZ169: Once a day for 14 days	2 tablets 300 mg of Isoniazid once a day for 14 days Isoniazid: Once a day for 14 days
Measure Participants	4	4	7	1
Mean (Standard Deviation) [CFU per 1 mL of sputum]	0.061 (0.085)	0.015 (0.025)	0.071 (0.126)	0.237 (0)

2. Primary Outcome

Title	Early Bactericidal Activity (0-14)
Description	Early bactericidal activity 14 days from the monotherapy start date (EBA 0-14): PCR, the mean of two measurements at the Visit
Time Frame	14 days after the onset of monotherapy

Outcome Measure Data

Analysis Population Description

FAS

Arm/Group Title	PBTZ169, 160 mg	PBTZ169, 320 mg	PBTZ169, 640 mg	Isoniazid, 600 mg
Arm/Group Description	2 capsules 80 mg of PBTZ169 once a day for 14 days PBTZ169: Once a day for 14 days	4 capsules 80 mg of PBTZ169 once a day for 14 days PBTZ169: Once a day for 14 days	8 capsules 80 mg of PBTZ169 once a day for 14 days PBTZ169: Once a day for 14 days	2 tablets 300 mg of Isoniazid once a day for 14 days Isoniazid: Once a day for 14 days
Measure Participants	4	4	7	1
Mean (Standard Deviation) [cell count per 1 mL of sputum]	0.038 (0.081)	-0.014 (0.048)	0.097 (0.136)	-0.099 (0)

3. Secondary Outcome

Title	Early Bactericidal Activity (0-2)
Description	EBA (0-2): agar inoculation, the mean of two measurements at the Visit
Time Frame	2 days after the onset of monotherapy

Outcome Measure Data

Analysis Population Description

FAS

Arm/Group Title	PBTZ169, 160 mg	PBTZ169, 320 mg	PBTZ169, 640 mg	Isoniazid, 600 mg
Arm/Group Description	2 capsules 80 mg of PBTZ169 once a day for 14 days PBTZ169: Once a day for 14 days	4 capsules 80 mg of PBTZ169 once a day for 14 days PBTZ169: Once a day for 14 days	8 capsules 80 mg of PBTZ169 once a day for 14 days PBTZ169: Once a day for 14 days	2 tablets 300 mg of Isoniazid once a day for 14 days Isoniazid: Once a day for 14 days
Measure Participants	4	4	7	1
Mean (Standard Deviation) [CFU per 1 mL of sputum]	0.496 (0.615)	0.124 (0.095)	-0.003 (0.452)	-0.243 (0)

4. Secondary Outcome

Title	Early Bactericidal Activity (0-7)
Description	EBA (0-7): agar inoculation, the mean of two measurements at the Visit
Time Frame	7 days after the onset of monotherapy

Outcome Measure Data

Analysis Population Description

FAS

Arm/Group Title	PBTZ169, 160 mg	PBTZ169, 320 mg	PBTZ169, 640 mg	Isoniazid, 600 mg
Arm/Group Description	2 capsules 80 mg of PBTZ169 once a day for 14 days PBTZ169: Once a day for 14 days	4 capsules 80 mg of PBTZ169 once a day for 14 days PBTZ169: Once a day for 14 days	8 capsules 80 mg of PBTZ169 once a day for 14 days PBTZ169: Once a day for 14 days	2 tablets 300 mg of Isoniazid once a day for 14 days Isoniazid: Once a day for 14 days
Measure Participants	4	4	7	1
Mean (Standard Deviation) [CFU per 1 mL of sputum]	0.078 (0.136)	0.026 (0.069)	0.064 (0.102)	0.090 (0)

5. Secondary Outcome

Title	Early Bactericidal Activity (0-2)
Description	EBA (0-2): PCR, the mean of two measurements at the Visit
Time Frame	2 days after the onset of monotherapy

Outcome Measure Data

Analysis Population Description

FAS

Arm/Group Title	PBTZ169, 160 mg	PBTZ169, 320 mg	PBTZ169, 640 mg	Isoniazid, 600 mg
Arm/Group Description	2 capsules 80 mg of PBTZ169 once a day for 14 days PBTZ169: Once a day for 14 days	4 capsules 80 mg of PBTZ169 once a day for 14 days PBTZ169: Once a day for 14 days	8 capsules 80 mg of PBTZ169 once a day for 14 days PBTZ169: Once a day for 14 days	2 tablets 300 mg of Isoniazid once a day for 14 days Isoniazid: Once a day for 14 days
Measure Participants	4	4	7	1
Mean (Standard Deviation) [cell count per 1 mL of sputum]	-0.110 (0.872)	0.007 (0.084)	0.085 (0.397)	0.627 (0)

6. Secondary Outcome

Title	Early Bactericidal Activity (0-7)
Description	EBA (0-7): PCR, the mean of two measurements at the Visit
Time Frame	7 days after the onset of monotherapy

Outcome Measure Data

Analysis Population Description

FAS

Arm/Group Title	PBTZ169, 160 mg	PBTZ169, 320 mg	PBTZ169, 640 mg	Isoniazid, 600 mg
Arm/Group Description	2 capsules 80 mg of PBTZ169 once a day for 14 days PBTZ169: Once a day for 14 days	4 capsules 80 mg of PBTZ169 once a day for 14 days PBTZ169: Once a day for 14 days	8 capsules 80 mg of PBTZ169 once a day for 14 days PBTZ169: Once a day for 14 days	2 tablets 300 mg of Isoniazid once a day for 14 days Isoniazid: Once a day for 14 days
Measure Participants	4	4	7	1
Mean (Standard Deviation) [cell count per 1 mL of sputum]	-0.044 (0.076)	-0.004 (0.081)	0.116 (0.186)	-0.408 (0)

7. Secondary Outcome

Title	Peak Plasma Concentration (Сmax) of PBTZ169
Description	Peak plasma concentration (Сmax) of PBTZ169 for multiple dosing
Time Frame	Up to 72 hours after the last drug administration

Outcome Measure Data

Analysis Population Description

PKA: the pharmacokinetic analysis population for multiple dosing comprised all patients participating in the PK study who had received at least one dose of the study drug PBTZ169, provided that data on study drug concentration (with at least one measurement above BLQ) was available.

Arm/Group Title	PBTZ169, 160 mg	PBTZ169, 320 mg	PBTZ169, 640 mg
Arm/Group Description	2 capsules 80 mg of PBTZ169 once a day for 14 days PBTZ169: Once a day for 14 days	4 capsules 80 mg of PBTZ169 once a day for 14 days PBTZ169: Once a day for 14 days	8 capsules 80 mg of PBTZ169 once a day for 14 days PBTZ169: Once a day for 14 days
Measure Participants	4	4	7
Mean (Standard Deviation) [ng/ml]	34.4714 (18.6498)	122.0135 (96.3347)	101.3818 (31.3830)

8. Secondary Outcome

Title	Minimal Plasma Concentration (Сmin) of PBTZ169
Description	Minimal plasma concentration (Сmin) of PBTZ169: concentration measurement following single dosing
Time Frame	for single dosing , Day 1 (24 h after 1st dose of PBTZ169)

Outcome Measure Data

Analysis Population Description

PKA

Arm/Group Title	PBTZ169, 160 mg	PBTZ169, 320 mg	PBTZ169, 640 mg
Arm/Group Description	2 capsules 80 mg of PBTZ169 once a day for 14 days PBTZ169: Once a day for 14 days	4 capsules 80 mg of PBTZ169 once a day for 14 days PBTZ169: Once a day for 14 days	8 capsules 80 mg of PBTZ169 once a day for 14 days PBTZ169: Once a day for 14 days
Measure Participants	4	4	7
Mean (Standard Deviation) [ng/ml]	0.4985 (0.4475)	0.2678 (0.3375)	1.0275 (0.9101)

9. Secondary Outcome

Title	Residual Concentration (Ctrough) of PBTZ169
Description	Residual concentration (Ctrough) of PBTZ169, measured 24 hours after the first dose administration, prior to the last dose, and 24 hours after the last dose
Time Frame	Up to 72 hours after the last drug administration

Outcome Measure Data

Analysis Population Description

PKA

Arm/Group Title	PBTZ169, 160 mg	PBTZ169, 320 mg	PBTZ169, 640 mg
Arm/Group Description	2 capsules 80 mg of PBTZ169 once a day for 14 days PBTZ169: Once a day for 14 days	4 capsules 80 mg of PBTZ169 once a day for 14 days PBTZ169: Once a day for 14 days	8 capsules 80 mg of PBTZ169 once a day for 14 days PBTZ169: Once a day for 14 days
Measure Participants	4	4	7
24 hours after the first dose (Ctrough_SD24)	0.7835 (0.6820)	1.4116 (1.2712)	1.8712 (0.9453)
prior to the last dose (Ctrough_MD0)	2.1610 (1.6332)	4.9505 (1.4050)	18.2674 (27.2441)
24 hours after the last dose (Ctrough_MD24)	1.4207 (1.0145)	2.9274 (1.4535)	5.2710 (2.5201)

10. Secondary Outcome

Title	Minimal Plasma Concentration (Сmin) of PBTZ169
Description	Minimal plasma concentration (Сmin) of PBTZ169: multiple dosing
Time Frame	Up to 72 hours after the last drug administration

Outcome Measure Data

Analysis Population Description

PKA

Arm/Group Title	PBTZ169, 160 mg	PBTZ169, 320 mg	PBTZ169, 640 mg
Arm/Group Description	2 capsules 80 mg of PBTZ169 once a day for 14 days PBTZ169: Once a day for 14 days	4 capsules 80 mg of PBTZ169 once a day for 14 days PBTZ169: Once a day for 14 days	8 capsules 80 mg of PBTZ169 once a day for 14 days PBTZ169: Once a day for 14 days
Measure Participants	4	4	5
Mean (Standard Deviation) [ng/ml]	1.4207 (1.0145)	3.3889 (2.0001)	4.9322 (2.4003)

11. Secondary Outcome

Title	Time to Reach Maximum Concentration (Tmax) of PBTZ169
Description	Time to reach maximum concentration (Tmax) of PBTZ169 after single oral administration in different doses
Time Frame	for single dosing , Day 1 (24 h after 1st dose of PBTZ169)

Outcome Measure Data

Analysis Population Description

PKA

Arm/Group Title	PBTZ169, 160 mg	PBTZ169, 320 mg	PBTZ169, 640 mg
Arm/Group Description	2 capsules 80 mg of PBTZ169 once a day for 14 days PBTZ169: Once a day for 14 days	4 capsules 80 mg of PBTZ169 once a day for 14 days PBTZ169: Once a day for 14 days	8 capsules 80 mg of PBTZ169 once a day for 14 days PBTZ169: Once a day for 14 days
Measure Participants	4	4	7
Median (Full Range) [h]	1.250	2.250	2.000

12. Secondary Outcome

Title	Time to Reach Maximum Concentration (Tmax) of PBTZ169
Description	Time to reach maximum concentration (Tmax) of PBTZ169 after multiple oral administration in different doses
Time Frame	Up to 72 hours after the last drug administration

Outcome Measure Data

Analysis Population Description

PKA

Arm/Group Title	PBTZ169, 160 mg	PBTZ169, 320 mg	PBTZ169, 640 mg
Arm/Group Description	2 capsules 80 mg of PBTZ169 once a day for 14 days PBTZ169: Once a day for 14 days	4 capsules 80 mg of PBTZ169 once a day for 14 days PBTZ169: Once a day for 14 days	8 capsules 80 mg of PBTZ169 once a day for 14 days PBTZ169: Once a day for 14 days
Measure Participants	4	4	5
Median (Full Range) [h]	2.000	2.000	1.500

13. Secondary Outcome

Title	AUC(0-24)
Description	Area under the plasma concentration of PBTZ169 versus time curve in frames [0-24 hours]
Time Frame	Up to 24 hours after the first drug administration

Outcome Measure Data

Analysis Population Description

PKA

Arm/Group Title	PBTZ169, 160 mg	PBTZ169, 320 mg	PBTZ169, 640 mg
Arm/Group Description	2 capsules 80 mg of PBTZ169 once a day for 14 days PBTZ169: Once a day for 14 days	4 capsules 80 mg of PBTZ169 once a day for 14 days PBTZ169: Once a day for 14 days	8 capsules 80 mg of PBTZ169 once a day for 14 days PBTZ169: Once a day for 14 days
Measure Participants	4	4	7
Mean (Standard Deviation) [ng*h/ml]	93.604 (74.3008)	120.954 (44.7920)	237.153 (111.4025)

14. Secondary Outcome

Title	Peak Plasma Concentration (Сmax) of PBTZ169
Description	Peak plasma concentration (Сmax) of PBTZ169: concentration measurement following single dosing
Time Frame	for single dosing , Day 1 (24 h after 1st dose of PBTZ169)

Outcome Measure Data

Analysis Population Description

PKA: the pharmacokinetic analysis population for multiple dosing comprised all patients participating in the PK study who had received at least one dose of the study drug PBTZ169, provided that data on study drug concentration (with at least one measurement above BLQ) was available.

Arm/Group Title	PBTZ169, 160 mg	PBTZ169, 320 mg	PBTZ169, 640 mg
Arm/Group Description	2 capsules 80 mg of PBTZ169 once a day for 14 days PBTZ169: Once a day for 14 days	4 capsules 80 mg of PBTZ169 once a day for 14 days PBTZ169: Once a day for 14 days	8 capsules 80 mg of PBTZ169 once a day for 14 days PBTZ169: Once a day for 14 days
Measure Participants	4	4	7
Mean (Standard Deviation) [ng/ml]	24.6543 (18.8506)	35.5370 (23.4983)	79.6684 (49.1865)

15. Secondary Outcome

Title	AUC(0-24)
Description	Area under the plasma concentration of PBTZ169 versus time curve in frames [0-24 hours] for the last dosing (Day 14)
Time Frame	Up to 24 hours after the last drug administration

Outcome Measure Data

Analysis Population Description

PKA

Arm/Group Title	PBTZ169, 160 mg	PBTZ169, 320 mg	PBTZ169, 640 mg
Arm/Group Description	2 capsules 80 mg of PBTZ169 once a day for 14 days PBTZ169: Once a day for 14 days	4 capsules 80 mg of PBTZ169 once a day for 14 days PBTZ169: Once a day for 14 days	8 capsules 80 mg of PBTZ169 once a day for 14 days PBTZ169: Once a day for 14 days
Measure Participants	4	4	5
Mean (Standard Deviation) [ng*h/ml]	113.293 (73.9862)	349.308 (282.1627)	502.895 (167.7201)

16. Secondary Outcome

Title	AUC (0-t)
Description	Area under the plasma concentration of PBTZ169 versus time curve in frames [0-last concentration above lower limit of quantification (LLoQ)]
Time Frame	Up to 72 hours after the last drug administration

Outcome Measure Data

Analysis Population Description

PKA

Arm/Group Title	PBTZ169, 160 mg	PBTZ169, 320 mg	PBTZ169, 640 mg
Arm/Group Description	2 capsules 80 mg of PBTZ169 once a day for 14 days PBTZ169: Once a day for 14 days	4 capsules 80 mg of PBTZ169 once a day for 14 days PBTZ169: Once a day for 14 days	8 capsules 80 mg of PBTZ169 once a day for 14 days PBTZ169: Once a day for 14 days
Measure Participants	4	4	5
Mean (Standard Deviation) [ng*h/ml]	113.259 (73.9728)	356.170 (282.0489)	502.075 (168.5111)

17. Secondary Outcome

Title	AUC(0-∞) of PBTZ169
Description	Area under the plasma concentration versus time curve in frames [0-∞]
Time Frame	Up to 72 hours after the last drug administration

Outcome Measure Data

Analysis Population Description

PKA

Arm/Group Title	PBTZ169, 160 mg	PBTZ169, 320 mg	PBTZ169, 640 mg
Arm/Group Description	2 capsules 80 mg of PBTZ169 once a day for 14 days PBTZ169: Once a day for 14 days	4 capsules 80 mg of PBTZ169 once a day for 14 days PBTZ169: Once a day for 14 days	8 capsules 80 mg of PBTZ169 once a day for 14 days PBTZ169: Once a day for 14 days
Measure Participants	4	4	5
Mean (Standard Deviation) [ng*h/ml]	141.855 (87.0391)	412.819 (299.2734)	568.581 (189.4584)

18. Secondary Outcome

Title	Accumulation Ratios for the PK Parameters AUC(0 -24)
Description	Accumulation ratios for the PK parameter AUC(0 -24): AUC(0- 24,ss)/AUC(0 -24), Day 1, on the original scale
Time Frame	24 hours after the first and the last drug administration

Outcome Measure Data

Analysis Population Description

PKA

Arm/Group Title	PBTZ169, 160 mg	PBTZ169, 320 mg	PBTZ169, 640 mg
Arm/Group Description	2 capsules 80 mg of PBTZ169 once a day for 14 days PBTZ169: Once a day for 14 days	4 capsules 80 mg of PBTZ169 once a day for 14 days PBTZ169: Once a day for 14 days	8 capsules 80 mg of PBTZ169 once a day for 14 days PBTZ169: Once a day for 14 days
Measure Participants	4	4	5
Geometric Mean (90% Confidence Interval) [ratio]	1.50	2.35	2.74

19. Secondary Outcome

Title	Average Concentration (Css,av) of PBTZ169
Description	Average steady-state concentration in the dosing interval following multiple dosing was evaluated as the ratio AUC0 24/τ (τ = the dosing interval)
Time Frame	Up to 72 hours after the last drug administration

Outcome Measure Data

Analysis Population Description

PKA

Arm/Group Title	PBTZ169, 160 mg	PBTZ169, 320 mg	PBTZ169, 640 mg
Arm/Group Description	2 capsules 80 mg of PBTZ169 once a day for 14 days PBTZ169: Once a day for 14 days	4 capsules 80 mg of PBTZ169 once a day for 14 days PBTZ169: Once a day for 14 days	8 capsules 80 mg of PBTZ169 once a day for 14 days PBTZ169: Once a day for 14 days
Measure Participants	4	4	5
Mean (Standard Deviation) [ng/ml]	862.63 (606.973)	793.27 (212.270)	532.95 (325.436)

20. Secondary Outcome

Title	Fluctuations (%) in the Dosing Interval
Description	Fluctuations (%) in the dosing interval after multiple dosing ((Cmax - Cmin) × 100%/Css,av)
Time Frame	Up to 72 hours after the last drug administration

Outcome Measure Data

Analysis Population Description

PKA

Arm/Group Title	PBTZ169, 160 mg	PBTZ169, 320 mg	PBTZ169, 640 mg
Arm/Group Description	2 capsules 80 mg of PBTZ169 once a day for 14 days PBTZ169: Once a day for 14 days	4 capsules 80 mg of PBTZ169 once a day for 14 days PBTZ169: Once a day for 14 days	8 capsules 80 mg of PBTZ169 once a day for 14 days PBTZ169: Once a day for 14 days
Measure Participants	4	4	5
Mean (Standard Deviation) [% (ratio)]	32955.25 (18636.037)	24703.16 (19047.811)	16253.19 (7977.030)

21. Secondary Outcome

Title	Total (Plasma) Clearance (Clt) of PBTZ169
Description	Clt/F (apparent total clearance following single and multiple oral administration) was calculated using the following formula: Cl_t/F=D/AUC where D is the daily dose of the drug.
Time Frame	24 hours after the first drug administration

Outcome Measure Data

Analysis Population Description

PKA

Arm/Group Title	PBTZ169, 160 mg	PBTZ169, 320 mg	PBTZ169, 640 mg
Arm/Group Description	2 capsules 80 mg of PBTZ169 once a day for 14 days PBTZ169: Once a day for 14 days	4 capsules 80 mg of PBTZ169 once a day for 14 days PBTZ169: Once a day for 14 days	8 capsules 80 mg of PBTZ169 once a day for 14 days PBTZ169: Once a day for 14 days
Measure Participants	4	4	7
Mean (Standard Deviation) [L/h]	3293.80 (3329.026)	2375.06 (759.203)	2935.49 (1382.371)

22. Secondary Outcome

Title	Total (Plasma) Clearance (Clt) of PBTZ169
Description	Clt/F (apparent total clearance following single and multiple oral administration) was calculated using the following formula: Cl_t/F=D/AUC where D is the daily dose of the drug.
Time Frame	24 hours after the last drug administration

Outcome Measure Data

Analysis Population Description

PKA

Arm/Group Title	PBTZ169, 160 mg	PBTZ169, 320 mg	PBTZ169, 640 mg
Arm/Group Description	2 capsules 80 mg of PBTZ169 once a day for 14 days PBTZ169: Once a day for 14 days	4 capsules 80 mg of PBTZ169 once a day for 14 days PBTZ169: Once a day for 14 days	8 capsules 80 mg of PBTZ169 once a day for 14 days PBTZ169: Once a day for 14 days
Measure Participants	4	4	5
Mean (Standard Deviation) [L/h]	1393.31 (606.676)	1200.61 (899.707)	1259.77 (519.021)

23. Secondary Outcome

Title	Volume of Distribution (Vd) of PBTZ169
Description	Distribution volume Vd for a dosing interval of 72 hours after the last dose
Time Frame	Up to 72 hours after the last drug administration

Outcome Measure Data

Analysis Population Description

PKA

Arm/Group Title	PBTZ169, 160 mg	PBTZ169, 320 mg	PBTZ169, 640 mg
Arm/Group Description	2 capsules 80 mg of PBTZ169 once a day for 14 days PBTZ169: Once a day for 14 days	4 capsules 80 mg of PBTZ169 once a day for 14 days PBTZ169: Once a day for 14 days	8 capsules 80 mg of PBTZ169 once a day for 14 days PBTZ169: Once a day for 14 days
Measure Participants	4	4	5
Mean (Standard Deviation) [L]	4.7206 (3.0828)	14.5545 (11.7568)	20.9540 (6.9883)

24. Secondary Outcome

Title	Plasma Half-life Time (T1/2) of PBTZ169
Time Frame	24 hours after the fist drug administration

Outcome Measure Data

Analysis Population Description

PKA

Arm/Group Title	PBTZ169, 160 mg	PBTZ169, 320 mg	PBTZ169, 640 mg
Arm/Group Description	2 capsules 80 mg of PBTZ169 once a day for 14 days PBTZ169: Once a day for 14 days	4 capsules 80 mg of PBTZ169 once a day for 14 days PBTZ169: Once a day for 14 days	8 capsules 80 mg of PBTZ169 once a day for 14 days PBTZ169: Once a day for 14 days
Measure Participants	4	4	7
Mean (Standard Deviation) [h]	10.201 (4.6319)	16.469 (9.5669)	10.110 (2.1530)

25. Secondary Outcome

Title	Plasma Half-life Time (T1/2) of PBTZ169
Time Frame	24 hours after the last drug administration

Outcome Measure Data

Analysis Population Description

PKA

Arm/Group Title	PBTZ169, 160 mg	PBTZ169, 320 mg	PBTZ169, 640 mg
Arm/Group Description	2 capsules 80 mg of PBTZ169 once a day for 14 days PBTZ169: Once a day for 14 days	4 capsules 80 mg of PBTZ169 once a day for 14 days PBTZ169: Once a day for 14 days	8 capsules 80 mg of PBTZ169 once a day for 14 days PBTZ169: Once a day for 14 days
Measure Participants	4	4	5
Mean (Standard Deviation) [h]	15.524 (4.0037)	13.790 (2.3234)	8.883 (2.5338)

26. Secondary Outcome

Title	Elimination Constant (Kel) of PBTZ169
Description	Apparent terminal elimination rate constant was evaluated based on the regressional dependence of log-transformed concentrations ln(C) on time for the terminal log- linear part of the concentration-time curve.
Time Frame	24 hours after the first drug administration

Outcome Measure Data

Analysis Population Description

PKA

Arm/Group Title	PBTZ169, 160 mg	PBTZ169, 320 mg	PBTZ169, 640 mg
Arm/Group Description	2 capsules 80 mg of PBTZ169 once a day for 14 days PBTZ169: Once a day for 14 days	4 capsules 80 mg of PBTZ169 once a day for 14 days PBTZ169: Once a day for 14 days	8 capsules 80 mg of PBTZ169 once a day for 14 days PBTZ169: Once a day for 14 days
Measure Participants	4	4	7
Mean (Standard Deviation) [1/h]	0.0797 (0.0371)	0.0524 (0.0250)	0.0708 (0.0126)

27. Secondary Outcome

Title	Elimination Constant (Kel) of PBTZ169
Description	Apparent terminal elimination rate constant was evaluated based on the regressional dependence of log-transformed concentrations ln(C) on time for the terminal log- linear part of the concentration-time curve.
Time Frame	72 hours after the last drug administration

Outcome Measure Data

Analysis Population Description

PKA

Arm/Group Title	PBTZ169, 160 mg	PBTZ169, 320 mg	PBTZ169, 640 mg
Arm/Group Description	2 capsules 80 mg of PBTZ169 once a day for 14 days PBTZ169: Once a day for 14 days	4 capsules 80 mg of PBTZ169 once a day for 14 days PBTZ169: Once a day for 14 days	8 capsules 80 mg of PBTZ169 once a day for 14 days PBTZ169: Once a day for 14 days
Measure Participants	4	4	5
Mean (Standard Deviation) [1/h]	0.0470 (0.0123)	0.0515 (0.0098)	0.0828 (0.0211)

Adverse Events

Time Frame	Collection and evaluation of safety data started at the Screening Visit (Day -10 to -1) after signing the informed consent form and was continued till the last visit of the patient within the study (Day 21+1)
Arm/Group Title	PBTZ169, 160 mg		PBTZ169, 320 mg		PBTZ169, 640 mg		Isoniazid, 600 mg
Arm/Group Description	2 capsules 80 mg of PBTZ169 once a day for 14 days PBTZ169: Once a day for 14 days		4 capsules 80 mg of PBTZ169 once a day for 14 days PBTZ169: Once a day for 14 days		8 capsules 80 mg of PBTZ169 once a day for 14 days PBTZ169: Once a day for 14 days		2 tablets 300 mg of Isoniazid once a day for 14 days Isoniazid: Once a day for 14 days
All Cause Mortality
	PBTZ169, 160 mg		PBTZ169, 320 mg		PBTZ169, 640 mg		Isoniazid, 600 mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/4 (0%)		0/4 (0%)		0/7 (0%)		0/1 (0%)
Serious Adverse Events
	PBTZ169, 160 mg		PBTZ169, 320 mg		PBTZ169, 640 mg		Isoniazid, 600 mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/4 (0%)		0/4 (0%)		1/7 (14.3%)		0/1 (0%)
Gastrointestinal disorders
Spontaneously opened tuberculous paraproctitis	0/4 (0%)	0	0/4 (0%)	0	1/7 (14.3%)	1	0/1 (0%)	0
Other (Not Including Serious) Adverse Events
	PBTZ169, 160 mg		PBTZ169, 320 mg		PBTZ169, 640 mg		Isoniazid, 600 mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	3/4 (75%)		3/4 (75%)		2/7 (28.6%)		0/1 (0%)
Cardiac disorders
Sinus arrhythmia	1/4 (25%)	1	0/4 (0%)	0	0/7 (0%)	0	0/1 (0%)	0
Sinus tachycardia	0/4 (0%)	0	1/4 (25%)	1	1/7 (14.3%)	1	0/1 (0%)	0
Wandering atrial pacemaker	1/4 (25%)	1	0/4 (0%)	0	0/7 (0%)	0	0/1 (0%)	0
General disorders
Hyperthermia	1/4 (25%)	4	0/4 (0%)	0	0/7 (0%)	0	0/1 (0%)	0
Investigations
Fever	0/4 (0%)	0	0/4 (0%)	0	1/7 (14.3%)	1	0/1 (0%)	0
Metabolic disorders found in ECG	0/4 (0%)	0	1/4 (25%)	1	0/7 (0%)	0	0/1 (0%)	0
QTc elongation	0/4 (0%)	0	1/4 (25%)	1	1/7 (14.3%)	1	0/1 (0%)	0
QTc(F) shortening	0/4 (0%)	0	1/4 (25%)	1	0/7 (0%)	0	0/1 (0%)	0
Repolarization disturbances in the V1 lead in ECG	0/4 (0%)	0	0/4 (0%)	0	1/7 (14.3%)	2	0/1 (0%)	0
Reduced (+)T amplitude in standard leads	0/4 (0%)	0	0/4 (0%)	0	1/7 (14.3%)	2	0/1 (0%)	0
ESR over 2.5 x normal	0/4 (0%)	0	0/4 (0%)	0	1/7 (14.3%)	1	0/1 (0%)	0
Metabolism and nutrition disorders
Hyperglycemia	1/4 (25%)	1	0/4 (0%)	0	0/7 (0%)	0	0/1 (0%)	0
Vascular disorders
Hypotension	0/4 (0%)	0	0/4 (0%)	0	1/7 (14.3%)	1	0/1 (0%)	0

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The agreements between the Principal Investigators and the CRO restricts the PIs' rights to discuss or publish trial results after the trial is completed.