A Study of TTYP01 in Healthy Adult Subjects
Study Details
Study Description
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.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
|
Phase 1 |
Study Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Experimental: PartA: TTYP01 single ascending doses 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
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)
Other Names:
|
| Placebo Comparator: Part A: Placebo Placebo control for Part A of the study |
Drug: Placebo
Placebo control for Part A of the study
|
| Experimental: Part B: TTYP01 (oral edaravone) first then IV edaravone 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
TTYP01 oral tablets (30 mg edaravone per tablet)
Other Names:
Drug: TTYP01, 120 mg
TTYP01 oral tablets (30 mg edaravone per tablet)
Other Names:
Drug: 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
Other Names:
Drug: 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
Other Names:
|
| Experimental: Part B: IV edaravone first then TTYP01 (oral edaravone) 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
TTYP01 oral tablets (30 mg edaravone per tablet)
Other Names:
Drug: TTYP01, 120 mg
TTYP01 oral tablets (30 mg edaravone per tablet)
Other Names:
Drug: 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
Other Names:
Drug: 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
Other Names:
|
| Experimental: Part C: TTYP01: fasted dosing first then fed dosing 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
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)
Other Names:
|
| Experimental: Part C: TTYP01: fed dosing first then fasted dosing 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
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)
Other Names:
|
Outcome Measures
Primary Outcome Measures
- Adverse events [until the last follow-up visit, up to 4 weeks]
Frequencies (number and percentage) of subjects with one or more AEs
- change in hemoglobin (g/L) [up to 6 days post each dose]
measured by hematology test
- change in hematocrit (ratio) [up to 6 days post each dose]
measured by hematology test
- change in red blood cell count (cells x 10^12/L) [up to 6 days post each dose]
measured by hematology test
- change in white blood cell (WBC) count (cells x 10^9/L) [up to 6 days post each dose]
measured by hematology test
- change in platelet count (cells x 10^9/L) [up to 6 days post each dose]
measured by hematology test
- change in total neutrophils count (cells x 10^9/L) [up to 6 days post each dose]
measured by hematology test
- change in lymphocytes count (cells x 10^9/L) [up to 6 days post each dose]
measured by hematology test
- change in monocytes count (cells x 10^9/L) [up to 6 days post each dose]
measured by hematology test
- change in eosinophils count (cells x 10^9/L) [up to 6 days post each dose]
measured by hematology test
- change in basophils count (cells x 10^9/L) [up to 6 days post each dose]
measured by hematology test
- change in serum sodium (mmol/L) [up to 6 days post each dose]
measured by serum chemistry
- change in serum potassium (mmol/L) [up to 6 days post each dose]
measured by serum chemistry
- change in serum chloride (mmol/L) [up to 6 days post each dose]
measured by serum chemistry
- change in serum calcium (mmol/L) [up to 6 days post each dose]
measured by serum chemistry
- change in serum glucose (mmol/L) [up to 6 days post each dose]
measured by serum chemistry
- change in serum urea (mmol/L) [up to 6 days post each dose]
measured by serum chemistry
- change in serum creatinine (umol/L) [up to 6 days post each dose]
measured by serum chemistry
- change in serum total bilirubin (umol/L) [up to 6 days post each dose]
measured by serum chemistry
- change in aspartate aminotransferase (AST) (U/L) [up to 6 days post each dose]
measured by serum chemistry
- change in alanine aminotransferase (ALT) (U/L) [up to 6 days post each dose]
measured by serum chemistry
- change in alkaline phosphatase (ALP) (U/L) [up to 6 days post each dose]
measured by serum chemistry
- change in serum creatine kinase (CK) (U/L) [up to 6 days post each dose]
measured by serum chemistry
- change in serum albumin (g/L) [up to 6 days post each dose]
measured by serum chemistry
- change in serum phosphate (mmol/L) [up to 6 days post each dose]
measured by serum chemistry
- change in serum lipase (U/L) [up to 6 days post each dose]
measured by serum chemistry
- change in serum total protein (g/L) [up to 6 days post each dose]
measured by serum chemistry
- change in urine pH [up to 6 days post each dose]
measured by urinalysis
- change in urine specific gravity [up to 6 days post each dose]
measured by urinalysis
- change in urine glucose [up to 6 days post each dose]
measured by urinalysis
- change in urine protein [up to 6 days post each dose]
measured by urinalysis
- change in urine ketones [up to 6 days post each dose]
measured by urinalysis
- change in urine blood [up to 6 days post each dose]
measured by urinalysis
- change in urine casts [up to 6 days post each dose]
measured by microscopic analysis, if any abnormalities in urinalysis are detected
- change in urine crystals [up to 6 days post each dose]
measured by microscopic analysis, if any abnormalities in urinalysis are detected
- change in urine epithelial cells [up to 6 days post each dose]
measured by microscopic analysis, if any abnormalities in urinalysis are detected
- change in urine bacteria (cfu/L) [up to 6 days post each dose]
measured by microscopic analysis, if any abnormalities in urinalysis are detected
- change in urine red blood cells (Cells x 10^9/L) [up to 6 days post each dose]
measured by microscopic analysis, if any abnormalities in urinalysis are detected
- change in urine white blood cells (Cells x 10^9/L) [up to 6 days post each dose]
measured by microscopic analysis, if any abnormalities in urinalysis are detected
- 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) [up to 6 days post each dose]
Measured using a 12 Lead Electrocardiogram
- Change in RR intervals (msec) [up to 6 days post each dose]
Measured using a 12 Lead Electrocardiogram
- Change in PR intervals (msec) [up to 6 days post each dose]
Measured using a 12 Lead Electrocardiogram
- Change in QRS duration (msec) [up to 6 days post each dose]
Measured using a 12 Lead Electrocardiogram
- Change in corrected QTcF (msec) [up to 6 days post each dose]
Calculated using measurements by a 12 Lead Electrocardiogram
- clinically significant abnormality in brief physical examinations [up to 6 days post each dose]
clinically significant abnormality in skin, lungs, cardiovascular system, and abdomen (spleen and liver)
Secondary Outcome Measures
- 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]
Eligibility Criteria
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:
-
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.
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | CMAX Clinical Research Pty Ltd | Adelaide | South Australia | Australia | 5000 |
Sponsors and Collaborators
- Auzone Biological Technology Pty Ltd
- TIGERMED AUSTRALIA PTY LIMITED
- CMAX Clinical Research Pty Ltd
Investigators
- Principal Investigator: Sepehr Shakib, MD, Royal Adelaide Hospital
Study Documents (Full-Text)
None provided.More Information
Publications
None provided.- Auzone-01