Clinical trial NCT03334734: Phase 2a Study of PBTZ169
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
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE2
Conditions: Tuberculosis
Keywords: Tuberculosis
PBTZ169
antimycobacterial
Lead sponsor: Nearmedic Plus LLC
Sponsor class: INDUSTRY
Collaborators: name: OCT LLC
First posted: 2017-11-07
Enrollment: 16
Sex: ALL
Minimum age (years): 18
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

Eligibility criteria: 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

Primary outcomes:
measure: Early Bactericidal Activity (0-14)
timeFrame: 14 days after the onset of monotherapy
measure: Early Bactericidal Activity (0-14)
timeFrame: 14 days after the onset of monotherapy
Secondary outcomes:
measure: Early Bactericidal Activity (0-2)
timeFrame: 2 days after the onset of monotherapy
measure: Early Bactericidal Activity (0-7)
timeFrame: 7 days after the onset of monotherapy
measure: Early Bactericidal Activity (0-2)
timeFrame: 2 days after the onset of monotherapy
measure: Early Bactericidal Activity (0-7)
timeFrame: 7 days after the onset of monotherapy
measure: Peak Plasma Concentration (Сmax) of PBTZ169
timeFrame: Up to 72 hours after the last drug administration
measure: Minimal Plasma Concentration (Сmin) of PBTZ169
timeFrame: for single dosing , Day 1 (24 h after 1st dose of PBTZ169)
measure: Residual Concentration (Ctrough) of PBTZ169
timeFrame: Up to 72 hours after the last drug administration
measure: Minimal Plasma Concentration (Сmin) of PBTZ169
timeFrame: Up to 72 hours after the last drug administration
measure: Time to Reach Maximum Concentration (Tmax) of PBTZ169
timeFrame: for single dosing , Day 1 (24 h after 1st dose of PBTZ169)
measure: Time to Reach Maximum Concentration (Tmax) of PBTZ169
timeFrame: Up to 72 hours after the last drug administration
measure: AUC(0-24)
timeFrame: Up to 24 hours after the first drug administration
measure: Peak Plasma Concentration (Сmax) of PBTZ169
timeFrame: for single dosing , Day 1 (24 h after 1st dose of PBTZ169)
measure: AUC(0-24)
timeFrame: Up to 24 hours after the last drug administration
measure: AUC (0-t)
timeFrame: Up to 72 hours after the last drug administration
measure: AUC(0-∞) of PBTZ169
timeFrame: Up to 72 hours after the last drug administration
measure: Accumulation Ratios for the PK Parameters AUC(0 -24)
timeFrame: 24 hours after the first and the last drug administration
measure: Average Concentration (Css,av) of PBTZ169
timeFrame: Up to 72 hours after the last drug administration
measure: Fluctuations (%) in the Dosing Interval
timeFrame: Up to 72 hours after the last drug administration
measure: Total (Plasma) Clearance (Clt) of PBTZ169
timeFrame: 24 hours after the first drug administration
measure: Total (Plasma) Clearance (Clt) of PBTZ169
timeFrame: 24 hours after the last drug administration
measure: Volume of Distribution (Vd) of PBTZ169
timeFrame: Up to 72 hours after the last drug administration
measure: Plasma Half-life Time (T1/2) of PBTZ169
timeFrame: 24 hours after the fist drug administration
measure: Plasma Half-life Time (T1/2) of PBTZ169
timeFrame: 24 hours after the last drug administration
measure: Elimination Constant (Kel) of PBTZ169
timeFrame: 24 hours after the first drug administration
measure: Elimination Constant (Kel) of PBTZ169
timeFrame: 72 hours after the last drug administration
Other outcomes:
Locations:
Study officials:
References: