A Study of TTYP01 in Healthy Adult Subjects

Study Overview
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Brief Summary
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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.

Official Title
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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.

Conditions
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Healthy Adult Subjects

Intervention / Treatment
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* Drug: TTYP01 single ascending doses
* Drug: Placebo
* Drug: TTYP01, 60 mg
* Drug: TTYP01, 120 mg
* Drug: Radicut® (ampoule), 30 mg
* Drug: Radicut® (bag) , 60 mg
* Drug: TTYP01, up to 120 mg


Participation Criteria
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Eligibility Criteria
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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: Hemoglobin greater than or equal to 9 g/dL Neutrophil count (ANC) greater than or equal to 1,500/microL Platelet count greater than or equal to 100,000/microL 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 Creatine phosphokinase (CPK) less than or equal to 2x upper limit of normal (ULN) Hepatic function variables: Total bilirubin ≤ 1.5x ULN Total alkaline phosphatase (ALP) ≤ 1.5x ULN, or if > 1.5x ULN, then ALP liver fraction or 5' nucleotidase must be ≤1x ULN 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.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 40 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: PartA: TTYP01 single ascending doses<br>In Part A: a single-ascending-dose (SAD) escalation study with four consecutive cohorts, single ascending doses of TTYP01 (60, 120, 180 and 240 mg) will be orally administrated. | Drug: TTYP01 single ascending doses<br>* 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)<br>* Other names: edaravone tablet;|
| Placebo Comparator: Part A: Placebo<br>Placebo control for Part A of the study | Drug: Placebo<br>* Placebo control for Part A of the study<br>|
| Experimental: Part B: TTYP01 (oral edaravone) first then IV edaravone<br>Randomized, Open-label, Four-period and Crossover design. A single dose of edaravone in each treatment period. Period 1: 60 mg oral edaravone tablet (TTYP01); Period 2: 30 mg IV edaravone (Radicut® ampoule), Period 3: 120 mg oral edaravone tablet (TTYP01); Period 4: 60 mg IV edaravone (Radicut® bag). Each dose will be spearated by a minimum of 7 days washout period. | Drug: TTYP01, 60 mg<br>* TTYP01 oral tablets (30 mg edaravone per tablet)<br>* Other names: Edaravone tablet;Drug: TTYP01, 120 mg<br>* TTYP01 oral tablets (30 mg edaravone per tablet)<br>* Other names: Edaravone tablet;Drug: Radicut® (ampoule), 30 mg<br>* 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<br>* Other names: Edaravone injection;Drug: Radicut® (bag) , 60 mg<br>* 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<br>* Other names: Edaravone injection;|
| Experimental: Part B: IV edaravone first then TTYP01 (oral edaravone)<br>Randomized, Open-label, Four-period and Crossover design. A single dose of edaravone in each treatment period. Period 1: 30 mg IV edaravone (Radicut® ampoule); Period 2: 60 mg oral edaravone tablet (TTYP01); Period 3: 60 mg IV edaravone (Radicut® bag); Period 4: 120 mg oral edaravone tablet (TTYP01). Each dose will be spearated by a minimum of 7 days washout period. | Drug: TTYP01, 60 mg<br>* TTYP01 oral tablets (30 mg edaravone per tablet)<br>* Other names: Edaravone tablet;Drug: TTYP01, 120 mg<br>* TTYP01 oral tablets (30 mg edaravone per tablet)<br>* Other names: Edaravone tablet;Drug: Radicut® (ampoule), 30 mg<br>* 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<br>* Other names: Edaravone injection;Drug: Radicut® (bag) , 60 mg<br>* 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<br>* Other names: Edaravone injection;|
| Experimental: Part C: TTYP01: fasted dosing first then fed dosing<br>Randomized, open-Label, Two-period and Crossover design. A fix oral dose of TTYP01 tablet in each treatment period. Period 1: under fasted condition; Period 2: under fed condition. Each dose will be spearated by a minimum of 7 days washout period. | Drug: TTYP01, up to 120 mg<br>* 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)<br>* Other names: Edaravone tablet;|
| Experimental: Part C: TTYP01: fed dosing first then fasted dosing<br>Randomized, open-Label, Two-period and Crossover design. A fix oral dose of TTYP01 tablet in each treatment period. Period 1: under fed condition; Period 2: under fasted condition. Each dose will be spearated by a minimum of 7 days washout period. | Drug: TTYP01, up to 120 mg<br>* 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)<br>* Other names: Edaravone tablet;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Adverse events | Frequencies (number and percentage) of subjects with one or more AEs | until the last follow-up visit, up to 4 weeks | 
| change in hemoglobin (g/L) | measured by hematology test | up to 6 days post each dose | 
| change in hematocrit (ratio) | measured by hematology test | up to 6 days post each dose | 
| change in red blood cell count (cells x 10^12/L) | measured by hematology test | up to 6 days post each dose | 
| change in white blood cell (WBC) count (cells x 10^9/L) | measured by hematology test | up to 6 days post each dose | 
| change in platelet count (cells x 10^9/L) | measured by hematology test | up to 6 days post each dose | 
| change in total neutrophils count (cells x 10^9/L) | measured by hematology test | up to 6 days post each dose | 
| change in lymphocytes count (cells x 10^9/L) | measured by hematology test | up to 6 days post each dose | 
| change in monocytes count (cells x 10^9/L) | measured by hematology test | up to 6 days post each dose | 
| change in eosinophils count (cells x 10^9/L) | measured by hematology test | up to 6 days post each dose | 
| change in basophils count (cells x 10^9/L) | measured by hematology test | up to 6 days post each dose | 
| change in serum sodium (mmol/L) | measured by serum chemistry | up to 6 days post each dose | 
| change in serum potassium (mmol/L) | measured by serum chemistry | up to 6 days post each dose | 
| change in serum chloride (mmol/L) | measured by serum chemistry | up to 6 days post each dose | 
| change in serum calcium (mmol/L) | measured by serum chemistry | up to 6 days post each dose | 
| change in serum glucose (mmol/L) | measured by serum chemistry | up to 6 days post each dose | 
| change in serum urea (mmol/L) | measured by serum chemistry | up to 6 days post each dose | 
| change in serum creatinine (umol/L) | measured by serum chemistry | up to 6 days post each dose | 
| change in serum total bilirubin (umol/L) | measured by serum chemistry | up to 6 days post each dose | 
| change in aspartate aminotransferase (AST) (U/L) | measured by serum chemistry | up to 6 days post each dose | 
| change in alanine aminotransferase (ALT) (U/L) | measured by serum chemistry | up to 6 days post each dose | 
| change in alkaline phosphatase (ALP) (U/L) | measured by serum chemistry | up to 6 days post each dose | 
| change in serum creatine kinase (CK) (U/L) | measured by serum chemistry | up to 6 days post each dose | 
| change in serum albumin (g/L) | measured by serum chemistry | up to 6 days post each dose | 
| change in serum phosphate (mmol/L) | measured by serum chemistry | up to 6 days post each dose | 
| change in serum lipase (U/L) | measured by serum chemistry | up to 6 days post each dose | 
| change in serum total protein (g/L) | measured by serum chemistry | up to 6 days post each dose | 
| change in urine pH | measured by urinalysis | up to 6 days post each dose | 
| change in urine specific gravity | measured by urinalysis | up to 6 days post each dose | 
| change in urine glucose | measured by urinalysis | up to 6 days post each dose | 
| change in urine protein | measured by urinalysis | up to 6 days post each dose | 
| change in urine ketones | measured by urinalysis | up to 6 days post each dose | 
| change in urine blood | measured by urinalysis | up to 6 days post each dose | 
| change in urine casts | measured by microscopic analysis, if any abnormalities in urinalysis are detected | up to 6 days post each dose | 
| change in urine crystals | measured by microscopic analysis, if any abnormalities in urinalysis are detected | up to 6 days post each dose | 
| change in urine epithelial cells | measured by microscopic analysis, if any abnormalities in urinalysis are detected | up to 6 days post each dose | 
| change in urine bacteria (cfu/L) | measured by microscopic analysis, if any abnormalities in urinalysis are detected | up to 6 days post each dose | 
| 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 | 
| 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 | 
| change in systolic blood pressure (mmHg) |  | up to 6 days post each dose | 
| change in diastolic blood pressure (mmHg) |  | up to 6 days post each dose | 
| change in pulse rate (bpm) |  | up to 6 days post each dose | 
| change in body temperature (celsius) |  | up to 6 days post each dose | 
| Change in QT intervals (msec) | Measured using a 12 Lead Electrocardiogram | up to 6 days post each dose | 
| Change in RR intervals (msec) | Measured using a 12 Lead Electrocardiogram | up to 6 days post each dose | 
| Change in PR intervals (msec) | Measured using a 12 Lead Electrocardiogram | up to 6 days post each dose | 
| Change in QRS duration (msec) | Measured using a 12 Lead Electrocardiogram | up to 6 days post each dose | 
| Change in corrected QTcF (msec) | Calculated using measurements by a 12 Lead Electrocardiogram | up to 6 days post each dose | 
| 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 Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum observed plasma concentration (Cmax) |  | up to 24 hours post each dose | 
| Time of maximum plasma concentration (Tmax) |  | up to 24 hours post each dose | 
| Area under the plasma concentration-time curve from time-zero extrapolated to infinite time (AUC0-inf) |  | up to 24 hours post each dose | 
| 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 | 
| 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 | 
| Apparent volume of distribution (Vd/F) |  | up to 24 hours post each dose | 
| Terminal half-life(T1/2) |  | up to 24 hours post each dose | 
| Apparent oral clearance (CL/F) |  | up to 24 hours post each dose | 
| Mean retention time (MRT) |  | up to 24 hours post each dose | 
| Lambda z - the reciprocal of elimination rate constant (λz) |  | up to 24 hours post each dose | 
| Fabs-bioavailability value (Fabs) |  | up to 24 hours post each dose |