Clinical trial NCT04370431: A Study of TTYP01 in Healthy Adult Subjects
Official title: A Phase I, Single Center, Randomized, Single-Ascending Dose, Pharmacokinetic and Safety Study (Part A), Bioavailability Comparison Study (Part B) and Food Effect Study (Part C) in Healthy Adult Subjects.
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Healthy Adult Subjects
Lead sponsor: Shanghai Auzone Biological Technology Co., Ltd.
Sponsor class: INDUSTRY
Collaborators: name: TIGERMED AUSTRALIA PTY LIMITED
name: CMAX Clinical Research Pty Ltd
First posted: 2020-05-01
Enrollment: 72
Sex: ALL
Minimum age (years): 18
Maximum age (years): 40
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: This is integrated Phase 1, Single centre, Randomized study will be conducted in 3 parts, each with a specific primary objective:

Part A: To characterise the safety and tolerability of TTYP01 in healthy adult subjects; Part B: To evaluate the bioavailability of TTYP01 tablets in healthy adult subjects; Part C: To characterise the food effect of TTYP01 tablets in healthy adult subjects under the fasted or fed condition.

The secondary objectives of the study are to evaluate the pharmacokinetic (PK) profiles of TTYP01 tablets in healthy adult subjects, and the effects of gender on the PK of TTYP01 tablets in healthy adults. In Part A of the study, a total of 32 healthy adult subjects will be enrolled over four consecutive cohorts (8 per cohort), with participants receiving a single dose of TTYP01 at one of four levels (60, 120, 10 or 240 mg), to assess the PK and safety of TTYP01. In Part B, 16 healthy adults will be randomized into 2 groups, and the comparison of the PK of edaravone (TTYP01 and intravenous (IV) edaravone) will be evaluated using a randomized, open-label, four-period crossover design under fasted conditions. In the first crossover period, subjects will receive a single fixed dose of TTYP01 followed by the alternate IV dose after completion of the washout phase, and in the second crossover period, subjects will receive a higher fixed dose of TTYP01 followed by the alternate IV dose after completion of the washout phase. In Part C, 18 healthy subjects will be enrolled to evaluate the effect of food on the PK of TTYP01 using a randomized, open-label, two-period cross-over design. Participants will be randomized into two groups and administered a fixed dose of TTYP01 on Day 1 (Period 1) under the fed conditions and the second dosing day (Period 2) under the fasted conditions, while the other group being administered a fixed dose of TTYP01 on Day 1 (Period 1) under the fasted conditions and the second dosing day (Period 2) under the fed conditions.


Eligibility criteria: Inclusion Criteria:

* Age between 18 and 40, inclusive;
* Non-smokers, ex-smokers and moderate smokers will be included. "A moderate smoker is defined as someone smoking 5 cigarettes or less per day, an ex-smoker is someone who completely stopped smoking for at least 3 months.";
* If female, must be of non-childbearing potential (defined as either surgically sterilized or at least 1 year postmenopausal) or must agree to use a clinically acceptable method of contraception (e.g., oral, intrauterine device \[IUD; diaphragm\], injectable, transdermal or implantable contraception) or abstinence, for at least 1 month prior to randomization, during the study and 3 month following completion of the study. Females of childbearing potential must have a negative serum human chorionic gonadotropin (hCG) pregnancy test at screening;
* Body Mass Index (BMI) of 18 to 30 kg/m2, inclusive; and a total body weight \>50 kg at screening for male subjects, total body weight \> 45 kg for female subjects;
* Female subjects of child bearing potential and all male participants who have not had a vasectomy must use effective contraception during the study
* Ability to understand and willingness to sign a written informed consent form (the consent form must be signed by the subject prior to any study-specific procedures), and evidence of a personally signed and dated informed consent document indicating that the subject has been informed of all pertinent aspects of the study;
* Willingness and ability to comply with study procedures and follow-up examination.
* Adequate organ function as evidenced by the following peripheral blood counts or serum chemistry values within 28 days before randomization:

  1. Hemoglobin greater than or equal to 9 g/dL
  2. Neutrophil count (ANC) greater than or equal to 1,500/microL
  3. Platelet count greater than or equal to 100,000/microL
  4. Serum creatinine less than or equal to 1.5 mg/dL (less than or equal to 132.6 micromol/L) and creatinine clearance greater than or equal to 60 ml/min
  5. Creatine phosphokinase (CPK) less than or equal to 2x upper limit of normal (ULN)
  6. Hepatic function variables:

     1. Total bilirubin ≤ 1.5x ULN
     2. Total alkaline phosphatase (ALP) ≤ 1.5x ULN, or if \> 1.5x ULN, then ALP liver fraction or 5' nucleotidase must be ≤1x ULN
     3. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) must be ≤ 2.5x ULN

Exclusion Criteria:

* Evidence or history of clinically significant hematological, renal, endocrine, pulmonary, gastrointestinal, cardiovascular, hepatic, psychiatric, neurologic, or allergic disease.
* Subjects with a history of hypersensitivity to edaravone or any of the inactive ingredients of the formulation (such as sulfite and sodium bisulfite).
* Subjects with PR \>240 msec, QRS =120 msec, or QTcF \>450 msec for male \& QTcF \>470 msec for female on the screening or Day -1 ECG, or any clinically significant electrocardiographic abnormality in the opinion of the investigator.
* Male subjects with partners currently pregnant; male subjects able to father children who are unwilling or unable to use a highly effective method of contraception as outlined in this protocol for the duration of the study and for at least 3 months after the last dose of investigational product.
* Female subjects currently pregnant or lactating; female subjects able to bear children or of child bearing potential who are unwilling or unable to use a highly effective method of contraception as outlined in this protocol for the duration of the study and for at least 3 months after the last dose of investigational product.
* Subjects whose urine drug/alcohol screening was positive at the time of screening and/or on Day-1.
* Subjects having difficulty in swallowing pills/tablets.
* Subjects smoking \> 5 cigarettes per day within 3 months prior to the screening visit.
* Subjects unwilling or unable to comply with the Lifestyle Guidelines described in the protocol.
* Subjects who are investigational site staff members directly involved in the conduct of the studies and their family members, site staff members otherwise supervised by the Investigator, or subjects who are the sponsors' employees directly involved in the conduct of the studies.
* Evidence of any severe acute or chronic medical or psychiatric condition or laboratory abnormality that may increase the risk associated with study participation or investigational product administration or may interfere with the interpretation of study results and, in the judgment of the investigator, would make the subject inappropriate for entry into this trial.
* Subjects who have participated in another clinical trial less than 3 months before or donated his/her blood in a quantity greater than 200 milliliters (mL) within 1 month of the screening period of this clinical trial.

Primary outcomes:
measure: Adverse events
timeFrame: until the last follow-up visit, up to 4 weeks
measure: change in hemoglobin (g/L)
timeFrame: up to 6 days post each dose
measure: change in hematocrit (ratio)
timeFrame: up to 6 days post each dose
measure: change in red blood cell count (cells x 10^12/L)
timeFrame: up to 6 days post each dose
measure: change in white blood cell (WBC) count (cells x 10^9/L)
timeFrame: up to 6 days post each dose
measure: change in platelet count (cells x 10^9/L)
timeFrame: up to 6 days post each dose
measure: change in total neutrophils count (cells x 10^9/L)
timeFrame: up to 6 days post each dose
measure: change in lymphocytes count (cells x 10^9/L)
timeFrame: up to 6 days post each dose
measure: change in monocytes count (cells x 10^9/L)
timeFrame: up to 6 days post each dose
measure: change in eosinophils count (cells x 10^9/L)
timeFrame: up to 6 days post each dose
measure: change in basophils count (cells x 10^9/L)
timeFrame: up to 6 days post each dose
measure: change in serum sodium (mmol/L)
timeFrame: up to 6 days post each dose
measure: change in serum potassium (mmol/L)
timeFrame: up to 6 days post each dose
measure: change in serum chloride (mmol/L)
timeFrame: up to 6 days post each dose
measure: change in serum calcium (mmol/L)
timeFrame: up to 6 days post each dose
measure: change in serum glucose (mmol/L)
timeFrame: up to 6 days post each dose
measure: change in serum urea (mmol/L)
timeFrame: up to 6 days post each dose
measure: change in serum creatinine (umol/L)
timeFrame: up to 6 days post each dose
measure: change in serum total bilirubin (umol/L)
timeFrame: up to 6 days post each dose
measure: change in aspartate aminotransferase (AST) (U/L)
timeFrame: up to 6 days post each dose
measure: change in alanine aminotransferase (ALT) (U/L)
timeFrame: up to 6 days post each dose
measure: change in alkaline phosphatase (ALP) (U/L)
timeFrame: up to 6 days post each dose
measure: change in serum creatine kinase (CK) (U/L)
timeFrame: up to 6 days post each dose
measure: change in serum albumin (g/L)
timeFrame: up to 6 days post each dose
measure: change in serum phosphate (mmol/L)
timeFrame: up to 6 days post each dose
measure: change in serum lipase (U/L)
timeFrame: up to 6 days post each dose
measure: change in serum total protein (g/L)
timeFrame: up to 6 days post each dose
measure: change in urine pH
timeFrame: up to 6 days post each dose
measure: change in urine specific gravity
timeFrame: up to 6 days post each dose
measure: change in urine glucose
timeFrame: up to 6 days post each dose
measure: change in urine protein
timeFrame: up to 6 days post each dose
measure: change in urine ketones
timeFrame: up to 6 days post each dose
measure: change in urine blood
timeFrame: up to 6 days post each dose
measure: change in urine casts
timeFrame: up to 6 days post each dose
measure: change in urine crystals
timeFrame: up to 6 days post each dose
measure: change in urine epithelial cells
timeFrame: up to 6 days post each dose
measure: change in urine bacteria (cfu/L)
timeFrame: up to 6 days post each dose
measure: change in urine red blood cells (Cells x 10^9/L)
timeFrame: up to 6 days post each dose
measure: change in urine white blood cells (Cells x 10^9/L)
timeFrame: up to 6 days post each dose
measure: change in systolic blood pressure (mmHg)
timeFrame: up to 6 days post each dose
measure: change in diastolic blood pressure (mmHg)
timeFrame: up to 6 days post each dose
measure: change in pulse rate (bpm)
timeFrame: up to 6 days post each dose
measure: change in body temperature (celsius)
timeFrame: up to 6 days post each dose
measure: Change in QT intervals (msec)
timeFrame: up to 6 days post each dose
measure: Change in RR intervals (msec)
timeFrame: up to 6 days post each dose
measure: Change in PR intervals (msec)
timeFrame: up to 6 days post each dose
measure: Change in QRS duration (msec)
timeFrame: up to 6 days post each dose
measure: Change in corrected QTcF (msec)
timeFrame: up to 6 days post each dose
measure: clinically significant abnormality in brief physical examinations
timeFrame: up to 6 days post each dose
Secondary outcomes:
measure: Maximum observed plasma concentration (Cmax)
timeFrame: up to 24 hours post each dose
measure: Time of maximum plasma concentration (Tmax)
timeFrame: up to 24 hours post each dose
measure: Area under the plasma concentration-time curve from time-zero extrapolated to infinite time (AUC0-inf)
timeFrame: up to 24 hours post each dose
measure: Area under the plasma concentration-time curve from time-zero to the time of the last measurable concentration (AUC0-last)
timeFrame: up to 24 hours post each dose
measure: The ratio of area under the plasma concentration-time curve from time-zero to the time of the last measurable concentration (AUC0-last) extrapolated to AUC0-inf over AUC0-inf (% AUCex)
timeFrame: up to 24 hours post each dose
measure: Apparent volume of distribution (Vd/F)
timeFrame: up to 24 hours post each dose
measure: Terminal half-life(T1/2)
timeFrame: up to 24 hours post each dose
measure: Apparent oral clearance (CL/F)
timeFrame: up to 24 hours post each dose
measure: Mean retention time (MRT)
timeFrame: up to 24 hours post each dose
measure: Lambda z - the reciprocal of elimination rate constant (λz)
timeFrame: up to 24 hours post each dose
measure: Fabs-bioavailability value (Fabs)
timeFrame: up to 24 hours post each dose
Other outcomes:
Locations:
city: Adelaide
country: Australia
facility: CMAX Clinical Research Pty Ltd
state: South Australia
Study officials:
affiliation: Royal Adelaide Hospital
name: Sepehr Shakib, MD
role: PRINCIPAL_INVESTIGATOR
References: