Healthy
Conditions
Brief summary
The purpose of this study is to investigate the bioequivalence of 2 tablets of SYR-472 25 milligram (mg) and 1 tablet of SYR-472 50 mg administered to healthy adult males.
Detailed description
Bioequivalence of 2 SYR-472 25 mg tablets and 1 SYR-472 50 mg tablet administered to healthy adult males will be investigated in a randomized, open-label, crossover study.
Interventions
DRUGSYR-472
SYR-472 25mg, 50mg
Sponsors
Takeda
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
MALE
Age
20 Years to 35 Years
Healthy volunteers
Yes
Inclusion criteria
1. Participants who understand the outline of the clinical study and are capable of complying with their responsibilities as participants, as judged by the investigator or sub investigator. 2. Participants who can sign and date the informed consent form before the initiation of the study procedure. 3. Healthy Japanese adult males. 4. Participants who are 20 to 35 years of age at the time of informed consent. 5. Participants who weigh 50.0 kilogram (kg) or more with a body mass index (BMI) of 18.5 to less than 25.0 kilogram per square meter (kg/m\^2) in the screening period.
Exclusion criteria
1. Participants who were administered any investigational product within 16 weeks (112 days) before the start of the study drug administration in stage 1. 2. Participants who have received SYR-472 in the past. 3. Employees of the study site, their family members, those who are in a dependency relationship with employees of the study site involved in the conduct of the study (for example \[e.g.\], spouse, parents, children, brothers and sisters), and those who might be coerced to consent to participate in the study. 4. Participants who have poorly controlled, clinically significant abnormalities of the nervous system, cardiovascular system, lung, liver, kidneys, metabolism, gastrointestinal system, urinary system, or endocrinological system, which possibly may affect study participation or study results. 5. Participants who have a positive urine drug test in the screening period. 6. Participants who need to use drugs or foods listed in the table of prohibited concomitant drugs and foods. 7. Participants who have a history of hypersensitivity or allergy to drugs (including SYR-472 and its ingredients). 8. Participants who currently have or recently had (within the past 6 months) gastrointestinal disease that may affect drug absorption (malabsorption, esophageal reflux, peptic ulcer disease, erosive esophagitis, frequent \[at least once a week\] heartburn, surgical intervention \[e.g., cholecystectomy\]). 9. Participants with a past history of cancer. 10. Participants who are positive for any of the following during the screening period: hepatitis B virus surface antigen (HBsAg), antibody against hepatitis C virus (HCV), human immunodeficiency virus (HIV) antigen, anti-HIV antibody, or serological test for syphilis. 11. Participants with difficulty having blood collected from a peripheral vein. 12. Participants who donated 200 milliliter (mL) or more of whole blood within the 4 weeks (28 days) or 400 mL or more of whole blood within the 12 weeks (84 days) before starting the study drug administration in stage 1. 13. Participants who donated a total of 800 mL or more of whole blood within the 52 weeks (364 days) before starting the study drug administration in stage 1. 14. Participants who donated blood components within the 2 weeks (14 days) before starting the study drug administration in stage 1. 15. Participants who show clinically significant abnormalities in electrocardiogram (ECG) during the screening period or on Day 1 (before the study drug administration). 16. Participants who have laboratory test abnormalities suggestive of a clinically significant primary disease or who have abnormal values in any of the following parameters: alanine aminotransferase (ALT) or aspartate serum transaminase AST exceeding 1.5 times the upper limit of the normal range. 17. Participants who are unlikely to comply with the study protocol or are ineligible for the study for any other reason, as judged by the investigator or sub investigator.
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| AUC(0-168): Area Under the Plasma Concentration-Time Curve From Time 0 to 168 Hours Postdose for Unchanged SYR-472 (SYR-472Z) | Day 1: pre dose (within 3 hours prior to dosing), and at multiple time points (up to 168 hours) post dose in each period |
| Cmax: Maximum Observed Plasma Concentration for SYR-472Z | Day 1: pre dose (within 3 hours prior to dosing), and at multiple time points (up to 168 hours) post dose in each period |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| MRT: Mean Residence Time From Time Zero to Infinity for SYR-472Z | Day 1: pre dose (within 3 hours prior to dosing), and at multiple time points (up to 168 hours) post dose in each period | — |
| Apparent Terminal Elimination Rate Constant (λz) for SYR-472Z | Day 1: pre dose (within 3 hours prior to dosing), and at multiple time points (up to 168 hours) post dose in each period | — |
| Number of Participants Reporting One or More Treatment-Emergent Adverse Events (TEAEs) | Day 1 of Period 1 up to the day of hospital discharge (Day 29) in Period 2 | Collection of AEs commenced from the time that the participant was first administered study drug in Period 1 (Day 1). Routine collection of AEs continued until the end (hospital discharge) of Period 2 (Day 29). |
| AUC(0-inf): Area Under the Plasma Concentration-Time Curve From Time 0 to Infinity for SYR-472Z | Day 1: pre dose (within 3 hours prior to dosing), and at multiple time points (up to 168 hours) post dose in each period | — |
| Number of Participants With TEAEs Related to Body Weight | Day 1 of Period 1 up to the day of hospital discharge (Day 29) in Period 2 | — |
| Number of Participants With TEAEs Categorized Into Investigations System Organ Class (SOC) Related to Laboratory Values | Day 1 of Period 1 up to the day of hospital discharge (Day 29) in Period 2 | — |
| Number of Participants Who Had Abnormal and Clinically Significant 12-lead Electrocardiograms (ECG) Findings After Study Drug Administration | Baseline up to 7 days after the last dose of study drug (Day 8) in each period | Participants whose results of electrocardiograms were judged as abnormal and clinically significant by investigator after study drug administration were counted in this measure. |
| Number of Participants With TEAEs Related to Vital Signs | Day 1 of Period 1 up to the day of hospital discharge (Day 29) in Period 2 | — |
| Tmax: Time to Reach the Cmax for SYR-472Z | Day 1: pre dose (within 3 hours prior to dosing), and at multiple time points (up to 168 hours) post dose in each period | — |
Countries
Japan
Participant flow
Recruitment details
Participants took part in the study at 1 investigative site in Japan from 04 March 2015 to 08 April 2015.
Pre-assignment details
Healthy male participants were enrolled in 1 of the 2 treatment sequences in either Period 1 or 2: Group A: 25 milligram (mg) tablet in Period 1 followed by 50 mg tablet in Period 2, Group B: 50 mg tablet in Period 1 followed by 25 mg tablet in Period 2.
Participants by arm
| Arm | Count |
|---|---|
| SYR-472 25 mg + SYR-472 50 mg SYR-472 25 mg, 2 tablets, orally, on Day 1 of the first intervention period (8 days), followed by at least 13 days washout period, followed by SYR-472 50 mg, tablet, orally on Day 1 of the second intervention period (8 days). | 12 |
| SYR-472 50 mg + SYR-472 25 mg SYR-472 50 mg, 1 tablet, orally, on Day 1 of the first intervention period (8 days), followed by at least 13 days washout period, followed by SYR-472 25 mg, 2 tablets, orally on Day 1 of the second intervention period (8 days). | 12 |
| Total | 24 |
Baseline characteristics
| Characteristic | Total | SYR-472 25 mg + SYR-472 50 mg | SYR-472 50 mg + SYR-472 25 mg |
|---|---|---|---|
| Age, Continuous | 23.0 Years STANDARD_DEVIATION 2.93 | 23.7 Years STANDARD_DEVIATION 2.64 | 22.3 Years STANDARD_DEVIATION 3.17 |
| Alcohol Classification Drinks a Few Days per Month | 11 participants | 7 participants | 4 participants |
| Alcohol Classification Drinks a Few Days per Week | 7 participants | 2 participants | 5 participants |
| Alcohol Classification Never Drunk | 6 participants | 3 participants | 3 participants |
| Body Mass Index (BMI) | 21.37 kilogram per square meter (kg/m^2) STANDARD_DEVIATION 1.894 | 21.69 kilogram per square meter (kg/m^2) STANDARD_DEVIATION 1.866 | 21.05 kilogram per square meter (kg/m^2) STANDARD_DEVIATION 1.948 |
| Caffeine Classification Caffeine Consumer | 6 participants | 4 participants | 2 participants |
| Caffeine Classification Caffeine Non-Consumer | 18 participants | 8 participants | 10 participants |
| Height | 172.4 centimeter (cm) STANDARD_DEVIATION 7.06 | 172.0 centimeter (cm) STANDARD_DEVIATION 6.93 | 172.8 centimeter (cm) STANDARD_DEVIATION 7.48 |
| Region of Enrollment Japan | 24 participants | 12 participants | 12 participants |
| Sex: Female, Male Female | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Male | 24 Participants | 12 Participants | 12 Participants |
| Smoking Classification Current Smoker | 9 participants | 5 participants | 4 participants |
| Smoking Classification Ex-Smoker | 1 participants | 0 participants | 1 participants |
| Smoking Classification Never Smoked | 14 participants | 7 participants | 7 participants |
| Weight | 63.65 kilogram (kg) STANDARD_DEVIATION 7.972 | 64.51 kilogram (kg) STANDARD_DEVIATION 9.707 | 62.79 kilogram (kg) STANDARD_DEVIATION 6.087 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 0 / 24 | 0 / 24 |
| serious Total, serious adverse events | 0 / 24 | 0 / 24 |
Outcome results
Primary
AUC(0-168): Area Under the Plasma Concentration-Time Curve From Time 0 to 168 Hours Postdose for Unchanged SYR-472 (SYR-472Z)
Time frame: Day 1: pre dose (within 3 hours prior to dosing), and at multiple time points (up to 168 hours) post dose in each period
Population: The PK analysis set included all participants who received study drug, satisfied the minimum requirements of the protocol with no significant deviations, and were assessable for PK.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| SYR-472 25 mg | AUC(0-168): Area Under the Plasma Concentration-Time Curve From Time 0 to 168 Hours Postdose for Unchanged SYR-472 (SYR-472Z) | 2733 nanogram hour per milliliter(ng*hr/mL) | Standard Deviation 445.48 |
| SYR-472 50 mg | AUC(0-168): Area Under the Plasma Concentration-Time Curve From Time 0 to 168 Hours Postdose for Unchanged SYR-472 (SYR-472Z) | 2780 nanogram hour per milliliter(ng*hr/mL) | Standard Deviation 437.95 |
Comparison: The 2-sided 90% confidence interval for the difference between the products (2 tablets of SYR-472 25 mg, 1 tablet of SYR-472 50 mg) was determined from the ANOVA model with the natural logarithms of the AUC(0-168) as a dependent variable, and product, group and period as fixed effects.90% CI: [-0.0344, 0.0004]
Primary
Cmax: Maximum Observed Plasma Concentration for SYR-472Z
Time frame: Day 1: pre dose (within 3 hours prior to dosing), and at multiple time points (up to 168 hours) post dose in each period
Population: The PK analysis set included all participants who received study drug, satisfied the minimum requirements of the protocol with no significant deviations, and were assessable for PK.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| SYR-472 25 mg | Cmax: Maximum Observed Plasma Concentration for SYR-472Z | 196.5 nanogram per milliliter(ng/mL) | Standard Deviation 54.034 |
| SYR-472 50 mg | Cmax: Maximum Observed Plasma Concentration for SYR-472Z | 223.6 nanogram per milliliter(ng/mL) | Standard Deviation 67.2 |
Comparison: The 2-sided 90% confidence interval for the difference between the products (2 tablets of SYR-472 25 mg, 1 tablet of SYR-472 50 mg) was determined from the ANOVA model with the natural logarithms of the Cmax as a dependent variable, and product, group and period as fixed effects.90% CI: [-0.2177, -0.0406]
Secondary
Apparent Terminal Elimination Rate Constant (λz) for SYR-472Z
Time frame: Day 1: pre dose (within 3 hours prior to dosing), and at multiple time points (up to 168 hours) post dose in each period
Population: The PK analysis set included all participants who received study drug, satisfied the minimum requirements of the protocol with no significant deviations, and were assessable for PK.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| SYR-472 25 mg | Apparent Terminal Elimination Rate Constant (λz) for SYR-472Z | 0.01399 per hour(hr-1) | Standard Deviation 0.0036008 |
| SYR-472 50 mg | Apparent Terminal Elimination Rate Constant (λz) for SYR-472Z | 0.01254 per hour(hr-1) | Standard Deviation 0.0028378 |
Comparison: The 2-sided 90% confidence interval for the difference between the products (2 tablets of SYR-472 25 mg, 1 tablet of SYR-472 50 mg) was determined from the ANOVA model with the natural logarithms of the λz as a dependent variable, and product, group and period as fixed effects.90% CI: [0.0235, 0.1963]
Secondary
AUC(0-inf): Area Under the Plasma Concentration-Time Curve From Time 0 to Infinity for SYR-472Z
Time frame: Day 1: pre dose (within 3 hours prior to dosing), and at multiple time points (up to 168 hours) post dose in each period
Population: The PK analysis set included all participants who received study drug, satisfied the minimum requirements of the protocol with no significant deviations, and were assessable for PK.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| SYR-472 25 mg | AUC(0-inf): Area Under the Plasma Concentration-Time Curve From Time 0 to Infinity for SYR-472Z | 2829 ng*hr/mL | Standard Deviation 466.32 |
| SYR-472 50 mg | AUC(0-inf): Area Under the Plasma Concentration-Time Curve From Time 0 to Infinity for SYR-472Z | 2889 ng*hr/mL | Standard Deviation 454.46 |
Comparison: The 2-sided 90% confidence interval for the difference between the products (2 tablets of SYR-472 25 mg, 1 tablet of SYR-472 50 mg) was determined from the ANOVA model with the natural logarithms of the AUC(0-inf) as a dependent variable, and product, group and period as fixed effects.90% CI: [-0.0362, -0.0058]
Secondary
MRT: Mean Residence Time From Time Zero to Infinity for SYR-472Z
Time frame: Day 1: pre dose (within 3 hours prior to dosing), and at multiple time points (up to 168 hours) post dose in each period
Population: The PK analysis set included all participants who received study drug, satisfied the minimum requirements of the protocol with no significant deviations, and were assessable for PK.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| SYR-472 25 mg | MRT: Mean Residence Time From Time Zero to Infinity for SYR-472Z | 32.52 hr | Standard Deviation 4.7575 |
| SYR-472 50 mg | MRT: Mean Residence Time From Time Zero to Infinity for SYR-472Z | 33.07 hr | Standard Deviation 4.8613 |
Comparison: The 2-sided 90% confidence interval for the difference between the products (2 tablets of SYR-472 25 mg, 1 tablet of SYR-472 50 mg) was determined from the ANOVA model with the natural logarithms of the MRT as a dependent variable, and product, group and period as fixed effects.90% CI: [-0.0504, 0.0169]
Secondary
Number of Participants Reporting One or More Treatment-Emergent Adverse Events (TEAEs)
Collection of AEs commenced from the time that the participant was first administered study drug in Period 1 (Day 1). Routine collection of AEs continued until the end (hospital discharge) of Period 2 (Day 29).
Time frame: Day 1 of Period 1 up to the day of hospital discharge (Day 29) in Period 2
Population: The safety analysis set included all participants who received study drug.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| SYR-472 25 mg | Number of Participants Reporting One or More Treatment-Emergent Adverse Events (TEAEs) | 0 participants |
| SYR-472 50 mg | Number of Participants Reporting One or More Treatment-Emergent Adverse Events (TEAEs) | 0 participants |
Secondary
Number of Participants Who Had Abnormal and Clinically Significant 12-lead Electrocardiograms (ECG) Findings After Study Drug Administration
Participants whose results of electrocardiograms were judged as abnormal and clinically significant by investigator after study drug administration were counted in this measure.
Time frame: Baseline up to 7 days after the last dose of study drug (Day 8) in each period
Population: The safety analysis set included all participants who received study drug.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| SYR-472 25 mg | Number of Participants Who Had Abnormal and Clinically Significant 12-lead Electrocardiograms (ECG) Findings After Study Drug Administration | 0 participants |
| SYR-472 50 mg | Number of Participants Who Had Abnormal and Clinically Significant 12-lead Electrocardiograms (ECG) Findings After Study Drug Administration | 0 participants |
Secondary
Number of Participants With TEAEs Categorized Into Investigations System Organ Class (SOC) Related to Laboratory Values
Time frame: Day 1 of Period 1 up to the day of hospital discharge (Day 29) in Period 2
Population: The safety analysis set included all participants who received study drug.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| SYR-472 25 mg | Number of Participants With TEAEs Categorized Into Investigations System Organ Class (SOC) Related to Laboratory Values | 0 participants |
| SYR-472 50 mg | Number of Participants With TEAEs Categorized Into Investigations System Organ Class (SOC) Related to Laboratory Values | 0 participants |
Secondary
Number of Participants With TEAEs Related to Body Weight
Time frame: Day 1 of Period 1 up to the day of hospital discharge (Day 29) in Period 2
Population: The safety analysis set included all participants who received study drug.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| SYR-472 25 mg | Number of Participants With TEAEs Related to Body Weight | 0 participants |
| SYR-472 50 mg | Number of Participants With TEAEs Related to Body Weight | 0 participants |
Secondary
Number of Participants With TEAEs Related to Vital Signs
Time frame: Day 1 of Period 1 up to the day of hospital discharge (Day 29) in Period 2
Population: The safety analysis set included all participants who received study drug.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| SYR-472 25 mg | Number of Participants With TEAEs Related to Vital Signs | 0 participants |
| SYR-472 50 mg | Number of Participants With TEAEs Related to Vital Signs | 0 participants |
Secondary
Tmax: Time to Reach the Cmax for SYR-472Z
Time frame: Day 1: pre dose (within 3 hours prior to dosing), and at multiple time points (up to 168 hours) post dose in each period
Population: The PK analysis set included all participants who received study drug, satisfied the minimum requirements of the protocol with no significant deviations, and were assessable for PK.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| SYR-472 25 mg | Tmax: Time to Reach the Cmax for SYR-472Z | 1.5000 hour(hr) |
| SYR-472 50 mg | Tmax: Time to Reach the Cmax for SYR-472Z | 1.000 hour(hr) |
Comparison: The 2-sided 90% confidence interval for the difference between the products (2 tablets of SYR-472 25 mg, 1 tablet of SYR-472 50 mg) was determined from the ANOVA model with Tmax as a dependent variable, and product, group and period as fixed effects.90% CI: [-0.1452, 0.8952]