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A Phase 1, Bioequivalence Study of SYR-472 25mg and 50mg Tablets

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ClinicalTrials.gov Identifier: NCT02372097
Recruitment Status : Completed
First Posted : February 26, 2015
Results First Posted : May 13, 2016
Last Update Posted : May 13, 2016
Sponsor:
Information provided by (Responsible Party):
Takeda

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Crossover Assignment;   Masking: None (Open Label);   Primary Purpose: Treatment
Condition Healthy
Intervention Drug: SYR-472
Enrollment 24

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.
Arm/Group Title SYR-472 25 mg + SYR-472 50 mg SYR-472 50 mg + SYR-472 25 mg
Hide Arm/Group Description 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). 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).
Period Title: First Intervention Period (8 Days)
Started 12 12
Completed 12 12
Not Completed 0 0
Period Title: Wash Out Period (13 Days)
Started 12 12
Completed 12 12
Not Completed 0 0
Period Title: Second Intervention Period (8 Days)
Started 12 12
Completed 12 12
Not Completed 0 0
Arm/Group Title SYR-472 25 mg + SYR-472 50 mg SYR-472 50 mg + SYR-472 25 mg Total
Hide Arm/Group Description 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). 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). Total of all reporting groups
Overall Number of Baseline Participants 12 12 24
Hide Baseline Analysis Population Description
The pharmacokinetic (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.
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 12 participants 12 participants 24 participants
23.7  (2.64) 22.3  (3.17) 23.0  (2.93)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 12 participants 12 participants 24 participants
Female
0
   0.0%
0
   0.0%
0
   0.0%
Male
12
 100.0%
12
 100.0%
24
 100.0%
Region of Enrollment  
Measure Type: Number
Unit of measure:  Participants
Japan Number Analyzed 12 participants 12 participants 24 participants
12 12 24
Height  
Mean (Standard Deviation)
Unit of measure:  Centimeter (cm)
Number Analyzed 12 participants 12 participants 24 participants
172.0  (6.93) 172.8  (7.48) 172.4  (7.06)
Weight  
Mean (Standard Deviation)
Unit of measure:  Kilogram (kg)
Number Analyzed 12 participants 12 participants 24 participants
64.51  (9.707) 62.79  (6.087) 63.65  (7.972)
Body Mass Index (BMI)  
Mean (Standard Deviation)
Unit of measure:  Kilogram per square meter (kg/m^2)
Number Analyzed 12 participants 12 participants 24 participants
21.69  (1.866) 21.05  (1.948) 21.37  (1.894)
Smoking Classification  
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 12 participants 12 participants 24 participants
Never Smoked 7 7 14
Current Smoker 5 4 9
Ex-Smoker 0 1 1
Alcohol Classification  
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 12 participants 12 participants 24 participants
Drinks a Few Days per Week 2 5 7
Drinks a Few Days per Month 7 4 11
Never Drunk 3 3 6
Caffeine Classification  
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 12 participants 12 participants 24 participants
Caffeine Consumer 4 2 6
Caffeine Non-Consumer 8 10 18
1.Primary Outcome
Title AUC(0-168): Area Under the Plasma Concentration-Time Curve From Time 0 to 168 Hours Postdose for Unchanged SYR-472 (SYR-472Z)
Hide Description [Not Specified]
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
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
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/Group Title SYR-472 25 mg SYR-472 50 mg
Hide Arm/Group Description:
SYR-472 25 mg, 2 tablets, once orally, on Day 1 of either Period 1 or Period 2. A washout of 13 days was maintained between the two periods.
SYR-472 50 mg, tablet, once orally, on Day 1 of either Period 1 or Period 2. A washout of 13 days was maintained between the two periods.
Overall Number of Participants Analyzed 24 24
Geometric Mean (Standard Deviation)
Unit of Measure: nanogram hour per milliliter(ng*hr/mL)
2733  (445.48) 2780  (437.95)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection SYR-472 25 mg, SYR-472 50 mg
Comments 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.
Type of Statistical Test Non-Inferiority or Equivalence
Comments Two tablets of SYR-472 25 mg and 1 tablet of SYR-472 50 mg were considered bioequivalent if 90% CI of the mean differences of natural log-transformed AUC(0-168) of SYR-472Z was within the range of ln(0.80) to ln(1.25) or within the range of ln(0.9) to ln(1.11) and the results of dissolution test satisfied the requirement.
Method of Estimation Estimation Parameter Least square (LS) mean difference
Estimated Value -0.0170
Confidence Interval (2-Sided) 90%
-0.0344 to 0.0004
Estimation Comments [Not Specified]
2.Primary Outcome
Title Cmax: Maximum Observed Plasma Concentration for SYR-472Z
Hide Description [Not Specified]
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
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
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/Group Title SYR-472 25 mg SYR-472 50 mg
Hide Arm/Group Description:
SYR-472 25 mg, 2 tablets, once orally, on Day 1 of either Period 1 or Period 2. A washout of 13 days was maintained between the two periods.
SYR-472 50 mg, tablet, once orally, on Day 1 of either Period 1 or Period 2. A washout of 13 days was maintained between the two periods.
Overall Number of Participants Analyzed 24 24
Geometric Mean (Standard Deviation)
Unit of Measure: nanogram per milliliter(ng/mL)
196.5  (54.034) 223.6  (67.200)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection SYR-472 25 mg, SYR-472 50 mg
Comments 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.
Type of Statistical Test Non-Inferiority or Equivalence
Comments Two tablets of SYR-472 25 mg and 1 tablet of SYR-472 50 mg were considered bioequivalent if 90% CI of the mean differences of natural log-transformed Cmax of SYR-472Z was within the range of ln(0.80) to ln(1.25) or within the range of ln(0.9) to ln(1.11) and the results of dissolution test satisfied the requirement.
Method of Estimation Estimation Parameter LS mean difference
Estimated Value -0.1292
Confidence Interval (2-Sided) 90%
-0.2177 to -0.0406
Estimation Comments [Not Specified]
3.Secondary Outcome
Title AUC(0-inf): Area Under the Plasma Concentration-Time Curve From Time 0 to Infinity for SYR-472Z
Hide Description [Not Specified]
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
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
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/Group Title SYR-472 25 mg SYR-472 50 mg
Hide Arm/Group Description:
SYR-472 25 mg, 2 tablets, once orally, on Day 1 of either Period 1 or Period 2. A washout of 13 days was maintained between the two periods.
SYR-472 50 mg, tablet, once orally, on Day 1 of either Period 1 or Period 2. A washout of 13 days was maintained between the two periods.
Overall Number of Participants Analyzed 24 24
Geometric Mean (Standard Deviation)
Unit of Measure: ng*hr/mL
2829  (466.32) 2889  (454.46)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection SYR-472 25 mg, SYR-472 50 mg
Comments 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.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Method of Estimation Estimation Parameter LS mean difference
Estimated Value -0.0210
Confidence Interval 90%
-0.0362 to -0.0058
Estimation Comments [Not Specified]
4.Secondary Outcome
Title Tmax: Time to Reach the Cmax for SYR-472Z
Hide Description [Not Specified]
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
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
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/Group Title SYR-472 25 mg SYR-472 50 mg
Hide Arm/Group Description:
SYR-472 25 mg, 2 tablets, once orally, on Day 1 of either Period 1 or Period 2. A washout of 13 days was maintained between the two periods.
SYR-472 50 mg, tablet, once orally, on Day 1 of either Period 1 or Period 2. A washout of 13 days was maintained between the two periods.
Overall Number of Participants Analyzed 24 24
Median (Full Range)
Unit of Measure: hour(hr)
1.5000
(0.50 to 6.0)
1.000
(0.50 to 6.0)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection SYR-472 25 mg, SYR-472 50 mg
Comments 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.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Method of Estimation Estimation Parameter LS mean difference
Estimated Value 0.3750
Confidence Interval (2-Sided) 90%
-0.1452 to 0.8952
Estimation Comments [Not Specified]
5.Secondary Outcome
Title MRT: Mean Residence Time From Time Zero to Infinity for SYR-472Z
Hide Description [Not Specified]
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
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
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/Group Title SYR-472 25 mg SYR-472 50 mg
Hide Arm/Group Description:
SYR-472 25 mg, 2 tablets, once orally, on Day 1 of either Period 1 or Period 2. A washout of 13 days was maintained between the two periods.
SYR-472 50 mg, tablet, once orally, on Day 1 of either Period 1 or Period 2. A washout of 13 days was maintained between the two periods.
Overall Number of Participants Analyzed 24 24
Geometric Mean (Standard Deviation)
Unit of Measure: hr
32.52  (4.7575) 33.07  (4.8613)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection SYR-472 25 mg, SYR-472 50 mg
Comments 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.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Method of Estimation Estimation Parameter LS mean difference
Estimated Value -0.0168
Confidence Interval (2-Sided) 90%
-0.0504 to 0.0169
Estimation Comments [Not Specified]
6.Secondary Outcome
Title Apparent Terminal Elimination Rate Constant (λz) for SYR-472Z
Hide Description [Not Specified]
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
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
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/Group Title SYR-472 25 mg SYR-472 50 mg
Hide Arm/Group Description:
SYR-472 25 mg, 2 tablets, once orally, on Day 1 of either Period 1 or Period 2. A washout of 13 days was maintained between the two periods.
SYR-472 50 mg, tablet, once orally, on Day 1 of either Period 1 or Period 2. A washout of 13 days was maintained between the two periods.
Overall Number of Participants Analyzed 24 24
Geometric Mean (Standard Deviation)
Unit of Measure: per hour(hr-1)
0.01399  (0.0036008) 0.01254  (0.0028378)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection SYR-472 25 mg, SYR-472 50 mg
Comments 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.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Method of Estimation Estimation Parameter LS mean difference
Estimated Value 0.1099
Confidence Interval (2-Sided) 90%
0.0235 to 0.1963
Estimation Comments [Not Specified]
7.Secondary Outcome
Title Number of Participants Reporting One or More Treatment-Emergent Adverse Events (TEAEs)
Hide Description 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
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
The safety analysis set included all participants who received study drug.
Arm/Group Title SYR-472 25 mg SYR-472 50 mg
Hide Arm/Group Description:
SYR-472 25 mg, 2 tablets, once orally, on Day 1 of either Period 1 or Period 2. A washout of 13 days was maintained between the two periods.
SYR-472 50 mg, tablet, once orally, on Day 1 of either Period 1 or Period 2. A washout of 13 days was maintained between the two periods.
Overall Number of Participants Analyzed 24 24
Measure Type: Number
Unit of Measure: participants
0 0
8.Secondary Outcome
Title Number of Participants With TEAEs Related to Vital Signs
Hide Description [Not Specified]
Time Frame Day 1 of Period 1 up to the day of hospital discharge (Day 29) in Period 2
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
The safety analysis set included all participants who received study drug.
Arm/Group Title SYR-472 25 mg SYR-472 50 mg
Hide Arm/Group Description:
SYR-472 25 mg, 2 tablets, once orally, on Day 1 of either Period 1 or Period 2. A washout of 13 days was maintained between the two periods.
SYR-472 50 mg, tablet, once orally, on Day 1 of either Period 1 or Period 2. A washout of 13 days was maintained between the two periods.
Overall Number of Participants Analyzed 24 24
Measure Type: Number
Unit of Measure: participants
0 0
9.Secondary Outcome
Title Number of Participants With TEAEs Related to Body Weight
Hide Description [Not Specified]
Time Frame Day 1 of Period 1 up to the day of hospital discharge (Day 29) in Period 2
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
The safety analysis set included all participants who received study drug.
Arm/Group Title SYR-472 25 mg SYR-472 50 mg
Hide Arm/Group Description:
SYR-472 25 mg, 2 tablets, once orally, on Day 1 of either Period 1 or Period 2. A washout of 13 days was maintained between the two periods.
SYR-472 50 mg, tablet, once orally, on Day 1 of either Period 1 or Period 2. A washout of 13 days was maintained between the two periods.
Overall Number of Participants Analyzed 24 24
Measure Type: Number
Unit of Measure: participants
0 0
10.Secondary Outcome
Title Number of Participants With TEAEs Categorized Into Investigations System Organ Class (SOC) Related to Laboratory Values
Hide Description [Not Specified]
Time Frame Day 1 of Period 1 up to the day of hospital discharge (Day 29) in Period 2
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
The safety analysis set included all participants who received study drug.
Arm/Group Title SYR-472 25 mg SYR-472 50 mg
Hide Arm/Group Description:
SYR-472 25 mg, 2 tablets, once orally, on Day 1 of either Period 1 or Period 2. A washout of 13 days was maintained between the two periods.
SYR-472 50 mg, tablet, once orally, on Day 1 of either Period 1 or Period 2. A washout of 13 days was maintained between the two periods.
Overall Number of Participants Analyzed 24 24
Measure Type: Number
Unit of Measure: participants
0 0
11.Secondary Outcome
Title Number of Participants Who Had Abnormal and Clinically Significant 12-lead Electrocardiograms (ECG) Findings After Study Drug Administration
Hide Description 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
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
The safety analysis set included all participants who received study drug.
Arm/Group Title SYR-472 25 mg SYR-472 50 mg
Hide Arm/Group Description:
SYR-472 25 mg, 2 tablets, once orally, on Day 1 of either Period 1 or Period 2. A washout of 13 days was maintained between the two periods.
SYR-472 50 mg, tablet, once orally, on Day 1 of either Period 1 or Period 2. A washout of 13 days was maintained between the two periods.
Overall Number of Participants Analyzed 24 24
Measure Type: Number
Unit of Measure: participants
0 0
Time Frame Day 1 of Period 1 up to the day of hospital discharge (Day 29) in Period 2
Adverse Event Reporting Description At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
 
Arm/Group Title SYR-472 25 mg SYR-472 50 mg
Hide Arm/Group Description SYR-472 25 mg, 2 tablets, once orally, on Day 1 of either Period 1 or Period 2. A washout of 13 days was maintained between the two periods. SYR-472 50 mg, tablet, once orally, on Day 1 of either Period 1 or Period 2. A washout of 13 days was maintained between the two periods.
All-Cause Mortality
SYR-472 25 mg SYR-472 50 mg
Affected / at Risk (%) Affected / at Risk (%)
Total   --/--   --/-- 
Show Serious Adverse Events Hide Serious Adverse Events
SYR-472 25 mg SYR-472 50 mg
Affected / at Risk (%) Affected / at Risk (%)
Total   0/24 (0.00%)   0/24 (0.00%) 
Show Other (Not Including Serious) Adverse Events Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 0%
SYR-472 25 mg SYR-472 50 mg
Affected / at Risk (%) Affected / at Risk (%)
Total   0/24 (0.00%)   0/24 (0.00%) 
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
No publication related to study results will be made without Sponsor’s prior written approval. Any proposed publication or presentation will be submitted to Sponsor for review 60 days in advance of publication. Institution will remove Sponsor confidential information unrelated to study results. Sponsor can delay a proposed publication for an additional 60 days to preserve intellectual property.
Results Point of Contact
Name/Title: Medical Director
Organization: Takeda
Phone: +1-877-825-3327
Responsible Party: Takeda
ClinicalTrials.gov Identifier: NCT02372097     History of Changes
Other Study ID Numbers: SYR-472-1005
U1111-1167-0746 ( Other Identifier: WHO )
JapicCTI-152813 ( Registry Identifier: JapicCTI )
JapicCTI-R160849 ( Registry Identifier: JapicCTI )
First Submitted: February 20, 2015
First Posted: February 26, 2015
Results First Submitted: April 8, 2016
Results First Posted: May 13, 2016
Last Update Posted: May 13, 2016