Clinical trial NCT04174937: PA Tolerability, Safety and Pharmacokinetics in Healthy Volunteers
Official title: A Randomized, Placebo-controlled Study of the Tolerability, Safety and Pharmacokinetics of PA in Healthy Volunteers
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Infections, Respiratory
Keywords: Safety
Iodine complex
Pharmacokinetics
Antibiotic potentiator
Lead sponsor: Scientific Center for Anti-infectious Drugs, Kazakhstan
Sponsor class: INDUSTRY
Collaborators: name: Institute Of Cardiology & Internal Diseases, Kazakhstan
name: Al-Farabi Kazakh National University (KazNU)
First posted: 2019-11-22
Enrollment: 72
Sex: MALE
Minimum age (years): 18
Maximum age (years): 55
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: OTHER

Brief summary: This is a first-in-human (FIH) study to explore the safety, tolerability and pharmacokinetics of PA after oral ascending dose administration to healthy male volunteers.

Detailed description: The first-in-human dose (FHD) trial is a randomized, double-blind, placebo-controlled, dose-escalation trial assessing safety, tolerability and pharmacokinetics (PK) of single and multiple oral doses of PA in healthy male subjects.

The study consists of two stages: single dose administration and multiple dose administration.

The single dose administration stage includes 5 cohorts, multiple dose administration stage includes at least 4 cohorts (groups). Each cohort includes 8 subjects (6 active drugs and 2 placebos). Cohorts intake ascending doses of study drug. The dose of 1st cohort is 1,0 mg/ml, the doses for the following cohorts will be estimated by the Data Monitoring Committee based on pharmacokinetics and safety results of previous group.

For each subject study includes screening period, one baseline period on Day -1, a treatment period (1 day - at single dose stage; 14 days - at multiple dose stage), followed by safety, PK, assessments up to 72-96 hours post dose. Follow-up visits will take place on Day 7 ; 30; 60 (single dose stage) and 30; 60; 90 (multiple dose stage).

Eligibility criteria: Inclusion Criteria:

* Age 18 to 55 years
* Body mass index 16 to 30
* Subjects should be in good physical and mental health based on medical history, clinical examination and laboratory investigations
* Subjects should have signed informed consent prior to screening and the clinical study after they have read and understood the objective, conduct, risks related to the study, and their rights as study participants
* Subjects should have signed informed consent for being tested for HIV
* Subjects should have signed informed consent to be tested for alcoholemia, use of cannabinoids, cocaine, morphine, benzodiazepines, barbiturates and amphetamine

Exclusion Criteria:

* Subjects should not have evidence of any physical and/or mental health issues at screening and/or results of any clinical, laboratory and/or technical procedures at screening outside of the normal range
* Subjects should not be taking any concomitant medication
* Subjects should not have a history of allergies, hypersensitivity or intolerance to iodine or iodide or to medicines containing iodine such as contrast media used for radiologic examinations
* Subjects should not have a history of addiction or abuse of drugs or alcohol
* Subjects should not be in a position of subordination or other dependence on persons involved in the study such as sponsor, investigators, or any other person or institution interested in its results
* Subjects should not be members of the armed forces or prison inmates
* Subjects should not have positive serology for Hepatitis B, Hepatitis C or HIV
* Subjects should not have any apparent functional and/or physical defects which may or interfere with the study or distort results

Primary outcomes:
measure: Adverse Events (AE)
timeFrame: Adverse event reporting will be performed throughout the trial from the Screening visit until the Final visit (up to 90 days)
Secondary outcomes:
measure: Area under plasma concentration time curve (AUC∞)
timeFrame: Blood collections at the following time points: before drug intake (two points - 1 day and 10 min), and 5 min, 15 min, 30 min, and 1, 1.5; 2; 3; 6; 9; 12; 15; 24; 48 and 72 hours after study drug administration
measure: Maximum concentration of drug in the blood (Cmax)
timeFrame: Blood collections at the following time points: before drug intake (two points - 1 day and 10 min), and 5 min, 15 min, 30 min, and 1, 1.5; 2; 3; 6; 9; 12; 15; 24; 48 and 72 hours after study drug administration
measure: Time to reach maximum drug concentration (Tmax)
timeFrame: Blood collections at the following time points: before drug intake (two points - 1 day and 10 min), and 5 min, 15 min, 30 min, and 1, 1.5; 2; 3; 6; 9; 12; 15; 24; 48 and 72 hours after study drug administration
measure: Half-life time (T1/2)
timeFrame: Blood collections at the following time points: 5 min, 15 min, 30 min, and 1, 1.5; 2; 3; 6; 9; 12; 15; 24; 48 and 72 hours after study drug administration
measure: Total clearance (СL)
timeFrame: Blood collections at the following time points: before drug intake (two points - 1 day and 10 min), and 5 min, 15 min, 30 min, and 1, 1.5; 2; 3; 6; 9; 12; 15; 24; 48 and 72 hours after study drug administration
measure: Mean residence time of drug (MRT)
timeFrame: Blood collections at the following time points: before drug intake (two points - 1 day and 10 min), and 5 min, 15 min, 30 min, and 1, 1.5; 2; 3; 6; 9; 12; 15; 24; 48 and 72 hours after study drug administration
measure: Drug excretion (%)
timeFrame: Urine samples taken during 0-96 h after drug intake
measure: Volume of distribution (Vλz)
timeFrame: Blood collections at the following time points: 5 min, 15 min, 30 min, and 1, 1.5; 2; 3; 6; 9; 12; 15; 24; 48 and 72 hours after study drug administration
measure: Drug elimination rate constant (Lambda-z (λz))
timeFrame: 0-72 hours
measure: Accumulation index (Rac)
timeFrame: Blood sampling at multiple dosing: Day 1-17
measure: Change in thyroid stimulating hormone (TSH)
timeFrame: Screening visit; Single dose intake: Day 1 - before and 12 hours after dose; Day 2; Day 3; Day 60. Multiple dose intake: Day 1 - before and 12 hours after dosing; Days 2;3;5;9;14;17;30;60;90
measure: Change in total triiodothyronine (TT3)
timeFrame: Screening visit; Single dose intake: Day 1 - before and 12 hours after dose; Day 2; Day 3; Day 60. Multiple dose intake: Day 1 - before and 12 hours after dosing; Days 2;3;5;9;14;17;30;60;90
measure: Change in free triiodothyronine (FT3)
timeFrame: Screening visit; Single dose intake: Day 1 - before and 12 hours after dose; Day 2; Day 3; Day 60. Multiple dose intake: Day 1 - before and 12 hours after dosing; Days 2;3;5;9;14;17;30;60;90
measure: Change in total thyroxine (TT4)
timeFrame: Screening visit; Single dose intake: Day 1 - before and 12 hours after dose; Day 2; Day 3; Day 60. Multiple dose intake: Day 1 - before and 12 hours after dosing; Days 2;3;5;9;14;17;30;60;90
measure: Change in free thyroxine (FT4)
timeFrame: Screening visit; Single dose intake: Day 1 - before and 12 hours after dose; Day 2; Day 3; Day 60. Multiple dose intake: Day 1 - before and 12 hours after dosing; Days 2;3;5;9;14;17;30;60;90
measure: Change in anti-thyroglobulin antibody
timeFrame: Screening visit; Single dose intake: Day 1 - before and 12 hours after dose; Day 2; Day 3; Day 60. Multiple dose intake: Day 1 - before and 12 hours after dosing; Days 2;3;5;9;14;17;30;60;90
measure: Change in anti-thyroid peroxidase antibody
timeFrame: Screening visit; Single dose intake: Day 1 - before and 12 hours after dose; Day 2; Day 3; Day 60. Multiple dose intake: Day 1 - before and 12 hours after dosing; Days 2;3;5;9;14;17;30;60;90
measure: Change from baseline in thyroid ultrasound
timeFrame: Screening visit; Final visit (Day 60 - at Single dose intake; Day 90 - at Multiple dose intake)
measure: Change from baseline in electrocardiogram (ECG)
timeFrame: Screening visit; before dose (Day -1); Day 1 - after dose (4 hours); Final visit (Day 60). Multiple dose intake: before dose (Day -1); Day 1 and 15 - 4 hours after dose; Final visit (Day 90).
measure: Change in Respiratory Rate
timeFrame: every visit up to 90 days
measure: Change in Heart Rate
timeFrame: every visit up to 90 days
measure: Change in Blood Pressure
timeFrame: every visit up to 90 days
measure: Change in Body Temperature
timeFrame: every visit up to 90 days
measure: Symptoms of musculoskeletal system
timeFrame: From baseline till the last visit (daily during hospital stay, every visit in follow-up period - up to 90 days)
measure: Symptoms of cardiovascular system
timeFrame: From baseline till the last visit (daily during hospital stay, every visit in follow-up period - up to 90 days)
measure: Symptoms of lymphatic system
timeFrame: From baseline till the last visit (daily during hospital stay, every visit in follow-up period - up to 90 days)
measure: Symptoms of nervous system
timeFrame: From baseline till the last visit (daily during hospital stay, every visit in follow-up period - up to 90 days)
measure: Symptoms of Respiratory system
timeFrame: From baseline till the last visit (daily during hospital stay, every visit in follow-up period - up to 90 days)
measure: Symptoms of Gastrointestinal system
timeFrame: From baseline till the last visit (daily during hospital stay, every visit in follow-up period - up to 90 days)
measure: Symptoms of urinary system
timeFrame: From baseline till the last visit (daily during hospital stay, every visit in follow-up period - up to 90 days)
measure: Symptoms of Endocrine system
timeFrame: From baseline till the last visit (daily during hospital stay, every visit in follow-up period - up to 90 days)
measure: Symptoms of Skin and subcutaneous tissue
timeFrame: From baseline till the last visit (daily during hospital stay, every visit in follow-up period - up to 90 days)
measure: Change in Alanine transaminase (ALT)
timeFrame: Single dose intake: Screening visit; before dose (Day -1); Day 1 - after dose (3 hours); Days 2;7;30;60. Multiple dose intake: Screening visit; before dose (Day -1); Days 1; 3;10;14-after dose (3 hours); Days 17;30;60;90
measure: Change in Aspartate aminotransferase (AST)
timeFrame: Single dose intake: Screening visit; before dose (Day -1); Day 1 - after dose (3 hours); Days 2;7;30;60. Multiple dose intake: Screening visit; before dose (Day -1); Days 1; 3;10;14-after dose (3 hours); Days 17;30;60;90
measure: Change in Bilirubin / bilirubin fractions
timeFrame: Single dose intake: Screening visit; before dose (Day -1); Day 1 - after dose (3 hours); Days 2;7;30;60. Multiple dose intake: Screening visit; before dose (Day -1); Days 1; 3;10;14-after dose (3 hours); Days 17;30;60;90
measure: Change in Creatinine
timeFrame: Single dose intake: Screening visit; before dose (Day -1); Day 1 - after dose (3 hours); Days 2;7;30;60. Multiple dose intake: Screening visit; before dose (Day -1); Days 1; 3;10;14-after dose (3 hours); Days 17;30;60;90
measure: Change in Alkaline phosphatase
timeFrame: Single dose intake: Screening visit; before dose (Day -1); Day 1 - after dose (3 hours); Days 2;7;30;60. Multiple dose intake: Screening visit; before dose (Day -1); Days 1; 3;10;14-after dose (3 hours); Days 17;30;60;90
measure: Change in Blood Urea Nitrogen
timeFrame: Single dose intake: Screening visit; before dose (Day -1); Day 1 - after dose (3 hours); Days 2;7;30;60. Multiple dose intake: Screening visit; before dose (Day -1); Days 1; 3;10;14-after dose (3 hours); Days 17;30;60;90
measure: Change in Uric acid
timeFrame: Single dose intake: Screening visit; before dose (Day -1); Day 1 - after dose (3 hours); Days 2;7;30;60. Multiple dose intake: Screening visit; before dose (Day -1); Days 1; 3;10;14-after dose (3 hours); Days 17;30;60;90
measure: Change in Alpha-amylase (α-amylase)
timeFrame: Single dose intake: Screening visit; before dose (Day -1); Day 1 - after dose (3 hours); Days 2;7;30;60. Multiple dose intake: Screening visit; before dose (Day -1); Days 1; 3;10;14-after dose (3 hours); Days 17;30;60;90
measure: Change in Serum total protein
timeFrame: Single dose intake: Screening visit; before dose (Day -1); Day 1 - after dose (3 hours); Days 2;7;30;60. Multiple dose intake: Screening visit; before dose (Day -1); Days 1; 3;10;14-after dose (3 hours); Days 17;30;60;90
measure: Change in Albumin level in blood
timeFrame: Single dose intake: Screening visit; before dose (Day -1); Day 1 - after dose (3 hours); Days 2;7;30;60. Multiple dose intake: Screening visit; before dose (Day -1); Days 1; 3;10;14-after dose (3 hours); Days 17;30;60;90
measure: Change in Glucose level in blood
timeFrame: Single dose study:Screening visit; before dose (Day -1); Day 1 - after dose (3 hours); Days 2;7;30;60. Multiple dose study: Screening visit; before dose (Day -1); Days 1; 3;10;14-after dose (3 hours); Days 17;30;60;90
measure: Change in Total cholesterol
timeFrame: Single dose intake: Screening visit; before dose (Day -1); Day 1 - after dose (3 hours); Days 2;7;30;60. Multiple dose intake: Screening visit; before dose (Day -1); Days 1; 3;10;14-after dose (3 hours); Days 17;30;60;90
measure: Change in Potassium in blood
timeFrame: Single dose study:Screening visit; before dose (Day -1); Day 1 - after dose (3 hours); Days 2;7;30;60. Multiple dose study: Screening visit; before dose (Day -1); Days 1; 3;10;14-after dose (3 hours); Days 17;30;60;90
measure: Change in Serum calcium
timeFrame: Single dose intake: Screening visit; before dose (Day -1); Day 1 - after dose (3 hours); Days 2;7;30;60. Multiple dose intake: Screening visit; before dose (Day -1); Days 1; 3;10;14-after dose (3 hours); Days 17;30;60;90
measure: Change in Serum magnesium
timeFrame: Single dose intake: Screening visit; before dose (Day -1); Day 1 - after dose (3 hours); Days 2;7;30;60. Multiple dose intake: Screening visit; before dose (Day -1); Days 1; 3;10;14-after dose (3 hours); Days 17;30;60;90
measure: Change in erythrocytes number in blood
timeFrame: Single dose intake: Screening visit; before dose (Day -1); Day 1 - after dose (3 hours); Days 2;7;30;60. Multiple dose intake: Screening visit; before dose (Day -1); Days 1; 3;10;14-after dose (3 hours); Days 17;30;60;90
measure: Change in hemoglobin
timeFrame: Single dose intake: Screening visit; before dose (Day -1); Day 1 - after dose (3 hours); Days 2;7;30;60. Multiple dose intake: Screening visit; before dose (Day -1); Days 1; 3;10;14-after dose (3 hours); Days 17;30;60;90
measure: Change in leucocytes number in the blood
timeFrame: Single dose intake: Screening visit; before dose (Day -1); Day 1 - after dose (3 hours); Days 2;7;30;60. Multiple dose intake: Screening visit; before dose (Day -1); Days 1; 3;10;14-after dose (3 hours); Days 17;30;60;90
measure: Change in thrombocytes number in the blood
timeFrame: Single dose intake: Screening visit; before dose (Day -1); Day 1 - after dose (3 hours); Days 2;7;30;60. Multiple dose intake: Screening visit; before dose (Day -1); Days 1; 3;10;14-after dose (3 hours); Days 17;30;60;90
measure: Change in hematocrit
timeFrame: Single dose intake: Screening visit; before dose (Day -1); Day 1 - after dose (3 hours); Days 2;7;30;60. Multiple dose intake: Screening visit; before dose (Day -1); Days 1; 3;10;14-after dose (3 hours); Days 17;30;60;90
measure: Change in Erythrocyte Sedimentation Rate (ESR))
timeFrame: Single dose intake: Screening visit; before dose (Day -1); Day 1 - after dose (3 hours); Days 2;7;30;60. Multiple dose intake: Screening visit; before dose (Day -1); Days 1; 3;10;14-after dose (3 hours); Days 17;30;60;90
measure: Change in prothrombin index
timeFrame: Single dose intake: Screening visit; before dose (Day -1); Day 1 - after dose (3 hours); Days 2;7;30;60. Multiple dose intake: Screening visit; before dose (Day -1); Days 1; 3;10;14-after dose (3 hours); Days 15;16;17;30;60;90
measure: Change in activated partial thromboplastin time (aPTT)
timeFrame: Single dose intake: Screening visit; before dose (Day -1); Day 1 - after dose (3 hours); Days 2;7;30;60. Multiple dose intake: Screening visit; before dose (Day -1); Days 1; 3;10;14-after dose (3 hours); Days 15;16;17;30;60;90
measure: Change in prothrombin ratio
timeFrame: Single dose intake: Screening visit; before dose (Day -1); Day 1 - after dose (3 hours); Days 2;7;30;60. Multiple dose intake: Screening visit; before dose (Day -1); Days 1; 3;10;14-after dose (3 hours); Days 15;16;17;30;60;90
measure: Change in thrombin time
timeFrame: Single dose intake: Screening visit; before dose (Day -1); Day 1 - after dose (3 hours); Days 2;7;30;60. Multiple dose intake: Screening visit; before dose (Day -1); Days 1; 3;10;14-after dose (3 hours); Days 15;16;17;30;60;90
measure: Change of protein level in urine
timeFrame: Single dose intake: Screening visit; before dose (Day -1); Day 1 - after dose (3 hours); Days 2;7;30;60. Multiple dose intake: Screening visit; before dose (Day -1); Days 1; 3;10;14-after dose (3 hours); Days 17;30;60;90
measure: Change in Urinary glucose
timeFrame: Single dose intake: Screening visit; before dose (Day -1); Day 1 - after dose (3 hours); Days 2;7;30;60. Multiple dose intake: Screening visit; before dose (Day -1); Days 1; 3;10;14-after dose (3 hours); Days 17;30;60;90
measure: Hematuria
timeFrame: Single dose intake: Screening visit; before dose (Day -1); Day 1 - after dose (3 hours); Days 2;7;30;60. Multiple dose intake: Screening visit; before dose (Day -1); Days 1; 3;10;14-after dose (3 hours); Days 17;30;60;90
measure: Leucocyturia
timeFrame: Single dose intake: Screening visit; before dose (Day -1); Day 1 - after dose (3 hours); Days 2;7;30;60. Multiple dose intake: Screening visit; before dose (Day -1); Days 1; 3;10;14-after dose (3 hours); Days 17;30;60;90
measure: Ketonuria
timeFrame: Single dose intake: Screening visit; before dose (Day -1); Day 1 - after dose (3 hours); Days 2;7;30;60. Multiple dose intake: Screening visit; before dose (Day -1); Days 1; 3;10;14-after dose (3 hours); Days 17;30;60;90
measure: Change in urine pH
timeFrame: Single dose intake: Screening visit; before dose (Day -1); Day 1 - after dose (3 hours); Days 2;7;30;60. Multiple dose intake: Screening visit; before dose (Day -1); Days 1; 3;10;14-after dose (3 hours); Days 17;30;60;90
measure: Change in immunoglobulin A (IgA) level in blood
timeFrame: Single dose study: before dose (Day -1); Day 1 - after dose (3 hours); Day 2. Multiple dose study: before dose (Day -1) Days 14; 17; 30;60; 90
measure: Change in immunoglobulin M (IgM) level in blood
timeFrame: Single dose intake: before dose (Day -1); Day 1 - after dose (3 hours); Day 2. Multiple dose intake: before dose (Day -1) Days 14; 17; 30;60; 90
measure: Change in immunoglobulin G (IgG) level in blood
timeFrame: Single dose intake: before dose (Day -1); Day 1 - after dose (3 hours); Day 2. Multiple dose intake: before dose (Day -1) Days 14; 17; 30;60; 90
measure: Change in immunoglobulin E (IgE) level in blood
timeFrame: Single dose intake: Screening visit; Day 1 - after dose (3 hours); Day 2. Multiple dose intake: Screening visit; Days 14; 17; 30;60; 90
measure: Change in Rheumatoid factor
timeFrame: Single dose intake: Screening visit; Day 1 - after dose (3 hours); Day 2. Multiple dose intake: Screening visit; Days 14; 17; 30;60; 90
measure: Change in C-Reactive Protein
timeFrame: Single dose intake: Screening visit; Day 1 - after dose (3 hours); Day 2. Multiple dose intake: Screening visit; Days 14; 17; 30;60; 90
measure: Change in Antimitochondrial Antibody
timeFrame: Single dose intake: before dose (Day -1); Day 30; Day 60. Multiple dose intake: before dose (Day -1); Day 60; Day90
measure: Change in antinuclear antibody
timeFrame: Single dose intake: before dose (Day -1); Day 30; Day 60. Multiple dose intake: before dose (Day -1); Day 60; Day90
measure: Change from baseline in CD3+tcells
timeFrame: Single dose intake: before dose (Day -1); Day 1 - after dose (3 hours); Days 2; 17; 30; 60. Multiple dose intake: before dose (Day -1); Day 1; 14 - after dose (3 hours); Days 17;30;60;90
measure: Change from baseline in CD4+tcells
timeFrame: Single dose intake: before dose (Day -1); Day 1 - after dose (3 hours); Days 2; 17; 30; 60. Multiple dose intake: before dose (Day -1); Day 1; 14 - after dose (3 hours); Days 17;30;60;90
measure: Change from baseline in CD8+tcells
timeFrame: Single dose intake: before dose (Day -1); Day 1 - after dose (3 hours); Days 2; 17; 30; 60. Multiple dose intake: before dose (Day -1); Day 1; 14 - after dose (3 hours); Days 17;30;60;90
measure: Change from baseline in Ratio CD4/CD8
timeFrame: Single dose intake: before dose (Day -1); Day 1 - after dose (3 hours); Days 2; 17; 30; 60. Multiple dose intake: before dose (Day -1); Day 1; 14 - after dose (3 hours); Days 17;30;60;90
Other outcomes:
Locations:
city: Almaty
country: Kazakhstan
facility: Institute Of Cardiology & Internal Diseases
state: Almatinskaya
Study officials:
affiliation: JSC "Scientific Center for Anti-infectious Drugs"
name: Amirkan A Azembayev, PhD
role: STUDY_DIRECTOR
References: