A Study of TTYP01 in Healthy Adult Subjects

Healthy Adult Subjects Clinical Trial

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.

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT04370431
• Other study ID #: Auzone-01
• Status: Completed
• Phase: Phase 1
• Start date: April 24, 2020
• Est. completion date: January 8, 2021

Study information

• Verified date: March 2021
• Source: Auzone Biological Technology Pty Ltd
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 72
• Est. completion date: January 8, 2021
• Est. primary completion date: December 17, 2020
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: All
• Age group: 18 Years to 40 Years

Eligibility

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.

Related Conditions & MeSH terms

• Healthy Adult Subjects

Intervention

Drug:
• TTYP01 single ascending doses
TTYP01 (30 mg edaravone tablet) will be orally administrated at single ascending doses of 60 mg, 120 mg, 180 mg and 240 mg (n=6 per dose)
• Placebo
Placebo control for Part A of the study
• TTYP01, 60 mg
TTYP01 oral tablets (30 mg edaravone per tablet)
• TTYP01, 120 mg
TTYP01 oral tablets (30 mg edaravone per tablet)
• Radicut® (ampoule), 30 mg
An intravenous dose of edaravone injection, containing 30 mg edaravone in a 20 mL ampoule, will be administered at a dose of 30 mg over 30 minutes
• Radicut® (bag) , 60 mg
An intravenous dose of edaravone injection, containing 30 mg edaravone in a 100 mL injection bag, will be administered at a dose of 60 mg over 60 minutes
• TTYP01, up to 120 mg
TTYP01 oral tablets (30 mg edaravone per tablet). The fixed oral dose level of TTYP01 will depend on the results obtained in Part B of the study (no more than 120 mg)

Locations

Country	Name	City	State
Australia	CMAX Clinical Research Pty Ltd	Adelaide	South Australia

Sponsors (3)

Lead Sponsor	Collaborator
Auzone Biological Technology Pty Ltd	CMAX Clinical Research Pty Ltd, TIGERMED AUSTRALIA PTY LIMITED

Country where clinical trial is conducted

Australia, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Adverse events	Frequencies (number and percentage) of subjects with one or more AEs	until the last follow-up visit, up to 4 weeks
Primary	change in hemoglobin (g/L)	measured by hematology test	up to 6 days post each dose
Primary	change in hematocrit (ratio)	measured by hematology test	up to 6 days post each dose
Primary	change in red blood cell count (cells x 10^12/L)	measured by hematology test	up to 6 days post each dose
Primary	change in white blood cell (WBC) count (cells x 10^9/L)	measured by hematology test	up to 6 days post each dose
Primary	change in platelet count (cells x 10^9/L)	measured by hematology test	up to 6 days post each dose
Primary	change in total neutrophils count (cells x 10^9/L)	measured by hematology test	up to 6 days post each dose
Primary	change in lymphocytes count (cells x 10^9/L)	measured by hematology test	up to 6 days post each dose
Primary	change in monocytes count (cells x 10^9/L)	measured by hematology test	up to 6 days post each dose
Primary	change in eosinophils count (cells x 10^9/L)	measured by hematology test	up to 6 days post each dose
Primary	change in basophils count (cells x 10^9/L)	measured by hematology test	up to 6 days post each dose
Primary	change in serum sodium (mmol/L)	measured by serum chemistry	up to 6 days post each dose
Primary	change in serum potassium (mmol/L)	measured by serum chemistry	up to 6 days post each dose
Primary	change in serum chloride (mmol/L)	measured by serum chemistry	up to 6 days post each dose
Primary	change in serum calcium (mmol/L)	measured by serum chemistry	up to 6 days post each dose
Primary	change in serum glucose (mmol/L)	measured by serum chemistry	up to 6 days post each dose
Primary	change in serum urea (mmol/L)	measured by serum chemistry	up to 6 days post each dose
Primary	change in serum creatinine (umol/L)	measured by serum chemistry	up to 6 days post each dose
Primary	change in serum total bilirubin (umol/L)	measured by serum chemistry	up to 6 days post each dose
Primary	change in aspartate aminotransferase (AST) (U/L)	measured by serum chemistry	up to 6 days post each dose
Primary	change in alanine aminotransferase (ALT) (U/L)	measured by serum chemistry	up to 6 days post each dose
Primary	change in alkaline phosphatase (ALP) (U/L)	measured by serum chemistry	up to 6 days post each dose
Primary	change in serum creatine kinase (CK) (U/L)	measured by serum chemistry	up to 6 days post each dose
Primary	change in serum albumin (g/L)	measured by serum chemistry	up to 6 days post each dose
Primary	change in serum phosphate (mmol/L)	measured by serum chemistry	up to 6 days post each dose
Primary	change in serum lipase (U/L)	measured by serum chemistry	up to 6 days post each dose
Primary	change in serum total protein (g/L)	measured by serum chemistry	up to 6 days post each dose
Primary	change in urine pH	measured by urinalysis	up to 6 days post each dose
Primary	change in urine specific gravity	measured by urinalysis	up to 6 days post each dose
Primary	change in urine glucose	measured by urinalysis	up to 6 days post each dose
Primary	change in urine protein	measured by urinalysis	up to 6 days post each dose
Primary	change in urine ketones	measured by urinalysis	up to 6 days post each dose
Primary	change in urine blood	measured by urinalysis	up to 6 days post each dose
Primary	change in urine casts	measured by microscopic analysis, if any abnormalities in urinalysis are detected	up to 6 days post each dose
Primary	change in urine crystals	measured by microscopic analysis, if any abnormalities in urinalysis are detected	up to 6 days post each dose
Primary	change in urine epithelial cells	measured by microscopic analysis, if any abnormalities in urinalysis are detected	up to 6 days post each dose
Primary	change in urine bacteria (cfu/L)	measured by microscopic analysis, if any abnormalities in urinalysis are detected	up to 6 days post each dose
Primary	change in urine red blood cells (Cells x 10^9/L)	measured by microscopic analysis, if any abnormalities in urinalysis are detected	up to 6 days post each dose
Primary	change in urine white blood cells (Cells x 10^9/L)	measured by microscopic analysis, if any abnormalities in urinalysis are detected	up to 6 days post each dose
Primary	change in systolic blood pressure (mmHg)		up to 6 days post each dose
Primary	change in diastolic blood pressure (mmHg)		up to 6 days post each dose
Primary	change in pulse rate (bpm)		up to 6 days post each dose
Primary	change in body temperature (celsius)		up to 6 days post each dose
Primary	Change in QT intervals (msec)	Measured using a 12 Lead Electrocardiogram	up to 6 days post each dose
Primary	Change in RR intervals (msec)	Measured using a 12 Lead Electrocardiogram	up to 6 days post each dose
Primary	Change in PR intervals (msec)	Measured using a 12 Lead Electrocardiogram	up to 6 days post each dose
Primary	Change in QRS duration (msec)	Measured using a 12 Lead Electrocardiogram	up to 6 days post each dose
Primary	Change in corrected QTcF (msec)	Calculated using measurements by a 12 Lead Electrocardiogram	up to 6 days post each dose
Primary	clinically significant abnormality in brief physical examinations	clinically significant abnormality in skin, lungs, cardiovascular system, and abdomen (spleen and liver)	up to 6 days post each dose
Secondary	Maximum observed plasma concentration (Cmax)		up to 24 hours post each dose
Secondary	Time of maximum plasma concentration (Tmax)		up to 24 hours post each dose
Secondary	Area under the plasma concentration-time curve from time-zero extrapolated to infinite time (AUC0-inf)		up to 24 hours post each dose
Secondary	Area under the plasma concentration-time curve from time-zero to the time of the last measurable concentration (AUC0-last)		up to 24 hours post each dose
Secondary	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)		up to 24 hours post each dose
Secondary	Apparent volume of distribution (Vd/F)		up to 24 hours post each dose
Secondary	Terminal half-life(T1/2)		up to 24 hours post each dose
Secondary	Apparent oral clearance (CL/F)		up to 24 hours post each dose
Secondary	Mean retention time (MRT)		up to 24 hours post each dose
Secondary	Lambda z - the reciprocal of elimination rate constant (?z)		up to 24 hours post each dose
Secondary	Fabs-bioavailability value (Fabs)		up to 24 hours post each dose