Phase 2a Study of PBTZ169

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

Detailed Description
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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.

Official Title
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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

Conditions
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Tuberculosis

Intervention / Treatment
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* Drug: PBTZ169
* Drug: Isoniazid


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: PBTZ169, 160 mg<br>2 capsules 80 mg of PBTZ169 once a day for 14 days | Drug: PBTZ169<br>* Once a day for 14 days<br>|
| Experimental: PBTZ169, 320 mg<br>4 capsules 80 mg of PBTZ169 once a day for 14 days | Drug: PBTZ169<br>* Once a day for 14 days<br>|
| Experimental: PBTZ169, 640 mg<br>8 capsules 80 mg of PBTZ169 once a day for 14 days | Drug: PBTZ169<br>* Once a day for 14 days<br>|
| Active Comparator: Isoniazid, 600 mg<br>2 tablets 300 mg of Isoniazid once a day for 14 days | Drug: Isoniazid<br>* Once a day for 14 days<br>|

What is the study measuring?
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Primary Outcome Measures

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

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Early Bactericidal Activity (0-2) | EBA (0-2): agar inoculation, the mean of two measurements at the Visit | 2 days after the onset of monotherapy | 
| Early Bactericidal Activity (0-7) | EBA (0-7): agar inoculation, the mean of two measurements at the Visit | 7 days after the onset of monotherapy | 
| Early Bactericidal Activity (0-2) | EBA (0-2): PCR, the mean of two measurements at the Visit | 2 days after the onset of monotherapy | 
| Early Bactericidal Activity (0-7) | EBA (0-7): PCR, the mean of two measurements at the Visit | 7 days after the onset of monotherapy | 
| Peak Plasma Concentration (Сmax) of PBTZ169 | Peak plasma concentration (Сmax) of PBTZ169 for multiple dosing | Up to 72 hours after the last drug administration | 
| Minimal Plasma Concentration (Сmin) of PBTZ169 | Minimal plasma concentration (Сmin) of PBTZ169: concentration measurement following single dosing | for single dosing , Day 1 (24 h after 1st dose of PBTZ169) | 
| Residual Concentration (Ctrough) of PBTZ169 | 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 | Up to 72 hours after the last drug administration | 
| Minimal Plasma Concentration (Сmin) of PBTZ169 | Minimal plasma concentration (Сmin) of PBTZ169: multiple dosing | Up to 72 hours after the last drug administration | 
| Time to Reach Maximum Concentration (Tmax) of PBTZ169 | Time to reach maximum concentration (Tmax) of PBTZ169 after single oral administration in different doses | for single dosing , Day 1 (24 h after 1st dose of PBTZ169) | 
| Time to Reach Maximum Concentration (Tmax) of PBTZ169 | Time to reach maximum concentration (Tmax) of PBTZ169 after multiple oral administration in different doses | Up to 72 hours after the last drug administration | 
| AUC(0-24) | Area under the plasma concentration of PBTZ169 versus time curve in frames [0-24 hours] | Up to 24 hours after the first drug administration | 
| Peak Plasma Concentration (Сmax) of PBTZ169 | Peak plasma concentration (Сmax) of PBTZ169: concentration measurement following single dosing | for single dosing , Day 1 (24 h after 1st dose of PBTZ169) | 
| AUC(0-24) | Area under the plasma concentration of PBTZ169 versus time curve in frames [0-24 hours] for the last dosing (Day 14) | Up to 24 hours after the last drug administration | 
| AUC (0-t) | Area under the plasma concentration of PBTZ169 versus time curve in frames [0-last concentration above lower limit of quantification (LLoQ)] | Up to 72 hours after the last drug administration | 
| AUC(0-∞) of PBTZ169 | Area under the plasma concentration versus time curve in frames [0-∞] | Up to 72 hours after the last drug administration | 
| Accumulation Ratios for the PK Parameters AUC(0 -24) | Accumulation ratios for the PK parameter AUC(0 -24): AUC(0- 24,ss)/AUC(0 -24), Day 1, on the original scale | 24 hours after the first and the last drug administration | 
| Average Concentration (Css,av) of PBTZ169 | Average steady-state concentration in the dosing interval following multiple dosing was evaluated as the ratio AUC0 24/τ (τ = the dosing interval) | Up to 72 hours after the last drug administration | 
| Fluctuations (%) in the Dosing Interval | Fluctuations (%) in the dosing interval after multiple dosing ((Cmax - Cmin) × 100%/Css,av) | Up to 72 hours after the last drug administration | 
| Total (Plasma) Clearance (Clt) of PBTZ169 | 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. | 24 hours after the first drug administration | 
| Total (Plasma) Clearance (Clt) of PBTZ169 | 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. | 24 hours after the last drug administration | 
| Volume of Distribution (Vd) of PBTZ169 | Distribution volume Vd for a dosing interval of 72 hours after the last dose | Up to 72 hours after the last drug administration | 
| Plasma Half-life Time (T1/2) of PBTZ169 |  | 24 hours after the fist drug administration | 
| Plasma Half-life Time (T1/2) of PBTZ169 |  | 24 hours after the last drug administration | 
| Elimination Constant (Kel) of PBTZ169 | 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. | 24 hours after the first drug administration | 
| Elimination Constant (Kel) of PBTZ169 | 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. | 72 hours after the last drug administration | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Tuberculosis, PBTZ169, antimycobacterial