Phase 2a Study of PBTZ169

Phase 2

Terminated

Conditions: Tuberculosis

Interventions: Drug: PBTZ169
Drug: Isoniazid

Registration Number: NCT03334734

Lead Sponsor: Nearmedic Plus LLC

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

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

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

Recruitment & Eligibility

Status: TERMINATED

Sex: All

Target Recruitment: 16

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

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
PBTZ169, 640 mg	PBTZ169	8 capsules 80 mg of PBTZ169 once a day for 14 days
PBTZ169, 320 mg	PBTZ169	4 capsules 80 mg of PBTZ169 once a day for 14 days
PBTZ169, 160 mg	PBTZ169	2 capsules 80 mg of PBTZ169 once a day for 14 days
Isoniazid, 600 mg	Isoniazid	2 tablets 300 mg of Isoniazid once a day for 14 days

Primary Outcome Measures

Name	Time	Method
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

Name	Time	Method
Plasma Half-life Time (T1/2) of PBTZ169	24 hours after the last drug administration
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
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)
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)
AUC (0-t)	Up to 72 hours after the last drug administration	Area under the plasma concentration of PBTZ169 versus time curve in frames \[0-last concentration above lower limit of quantification (LLoQ)\]
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
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
Early Bactericidal Activity (0-2)	2 days after the onset of monotherapy	EBA (0-2): PCR, the mean of two measurements at the Visit
Minimal Plasma Concentration (Сmin) of PBTZ169	Up to 72 hours after the last drug administration	Minimal plasma concentration (Сmin) of PBTZ169: multiple dosing
Early Bactericidal Activity (0-7)	7 days after the onset of monotherapy	EBA (0-7): PCR, the mean of two measurements at the Visit
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
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
AUC(0-∞) of PBTZ169	Up to 72 hours after the last drug administration	Area under the plasma concentration versus time curve in frames \[0-∞\]
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)
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.
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.