Effect of Food on the Pharmacokinetics of Single Oral Dose Administration of a Fixed-Dose Combination of SYR-322 and Metformin Hydrochloride in Healthy Adult Male Subjects

Phase 3

Completed

• Conditions: Clinical Pharmacology
• Interventions: Drug: SYR-322-MET

• Registration Number: NCT02276274
• Lead Sponsor: Takeda

Brief Summary

This is a randomized, open-label, crossover study to determine the effect of food when a combination tablet of SYR-322 and metformin hydrochloride ( hereinafter referred to as SYR-322-MET tablet) is orally administered under fasting conditions in the morning or after breakfast in Japanese healthy adult male subjects.

Detailed Description

The primary objective of this clinical trial is to determine the effect of food on the pharmacokinetics of single oral dose administration of SYR-322-MET tablets in Japanese healthy adult male subjects

Study Timeline

• Study Start: 2014-06
• Primary Completion: 2014-06
• Study Completion: 2014-06
• Study First Submitted: 2014-06-26
• Study First Submitted QC: 2014-10-27
• Study First Posted: 2014-10-28
• Results First Submitted: 2015-06-04
• Results First Submitted QC: 2015-06-04
• Results First Posted: 2015-06-29
• Status Verified: 2023-08
• Last Update Submitted: 2023-08-29
• Last Update Posted: 2023-09-21

Recruitment & Eligibility

• Status: COMPLETED
• Sex: Male
• Target Recruitment: 12

Inclusion Criteria

1. In the opinion of the investigator or subinvestigator, the subject is capable of understanding and complying with protocol requirements.
2. The subject signs and dates a written, informed consent form prior to the initiation of any study procedures.
3. The subject is a Japanese healthy adult male.
4. The subject is aged 20 to 35 years, inclusive, at the time of informed consent.
5. The subject has a body weight of 50 kg or more with a BMI of ≥18.5 kg/m2 and <25.0 kg/m2 at screening.

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Exclusion Criteria

1. The subject has received any investigational compound within 16 weeks (112 days) prior to the start of study drug administration in Period 1.
2. The subject has received SYR-322 or metformin hydrochloride in a previous clinical study or as a therapeutic agent.
3. The subject is an immediate family member, study site employee, or is in a dependant relationship with a study site employee who is involved in the conduct of this study (eg, spouse, parent, child, sibling) or may consent under duress.
4. The subject has uncontrolled, clinically significant neurologic, cardiovascular, pulmonary, hepatic, renal, metabolic, gastrointestinal, urologic, or endocrine disease or other abnormality, which may impact the ability of the subject to participate or potentially confound the study results.
5. The subject has a known hypersensitivity to drugs.
6. The subject has a positive urine drug result for drugs of abuse (defined as any illicit drug use) at screening.
7. The subject has a history of drug abuse or history of alcohol abuse within 2 years prior to the screening visit or unwilling to agree to abstain from alcohol and drugs throughout the study.
8. Subject has taken any excluded medication, supplements, or food products during the time periods listed in the Excluded Medications and Dietary Products table.
9. Subject has evidence of current cardiovascular, central nervous system, hepatic, hematopoietic disease, renal dysfunction, metabolic or endocrine dysfunction, serious allergy, asthma, hypoxemia, hypertension, seizures, or allergic skin rash. There is any finding in the subject's medical history, physical examination, or safety laboratory tests giving reasonable suspicion of a disease that would contraindicate taking DPP-4 inhibitors or biguanides, or a similar drug in the same class, or that might interfere with the conduct of the study. This includes, but is not limited to, peptic ulcer disease, seizure disorders, and cardiac arrhythmias.
10. The subject has current or recent [within 24 weeks (168 days) prior to the initiation of study treatment in Period 1] gastrointestinal disease that would be expected to influence the absorption of drugs (i.e., a history of malabsorption, esophageal reflux, peptic ulcer disease, erosive esophagitis, frequent [more than once per week] occurrence of heartburn, or any surgical intervention [e.g., cholecystectomy]).
11. The subject has a history of cancer.
12. The subject has a positive test result for hepatitis B surface antigen (HBsAg), hepatitis C antibody (HCV), human immunodeficiency virus (HIV) antibody/antigen, or serological reactions for syphilis at screening.
13. The subject has poor peripheral venous access.
14. The subject has undergone whole blood collection of at least 200 mL within 4 weeks (28 days) or at least 400 mL within 12 weeks (84 days) prior to the start of study medication administration Period 1.
15. The subject has undergone whole blood collection of at least 800 mL in total within 52 weeks (364 days) prior to the start of study medication administration in Period 1.
16. The subject has undergone blood component collection within 2 weeks (14 days) prior to the start of study medication administration in Period 1.
17. The subject has a screening or prior to the start of study medication administration on Day 1 in Period 1 hemoglobin level <12.5 g/dL.
18. The subject has a screening or prior to the start of study medication administration on Day 1 in Period 1 abnormal (clinically significant) 12-lead ECG.
19. Subject has abnormal screening or prior to the start of study medication administration on Day 1 in Period 1 laboratory values that suggest a clinically significant underlying disease or subject with the following lab abnormalities: ALT and/or AST >1.5 the upper limits of normal.
20. Subject who, in the opinion of the investigator, is unlikely to comply with the protocol or is unsuitable for any other reason.

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: CROSSOVER

Arm && Interventions

Group	Intervention	Description
Fasted dosing followed by fed dosing	SYR-322-MET	Oral administration
Fed dosing followed by fasted dosing	SYR-322-MET	Oral administration

Primary Outcome Measures

Name	Time	Method
AUC (0-72): Area Under the Plasma Concentration-time Curve From Time 0 to 72 Hours Postdose for Unchanged SYR-322 (SYR-322Z)	3 hours prior to administration (predose) and 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, and 72 hours postdose	AUC (0-72) is measure of area under the curve from time 0 to 72 hours post dose.
AUC (0-tlqc): Area Under the Plasma Concentration-time Curve From Time 0 to the Time of the Last Quantifiable Concentration for SYR-322Z	3 hours prior to administration (predose) and 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, and 72 hours postdose	AUC (0-tlqc) is a measure of total plasma exposure to the drug from Time 0 to Time of the Last Quantifiable Concentration (AUC \[0-tlqc\]).
Cmax: Maximum Observed Plasma Concentration for SYR-322Z	3 hours prior to administration (predose) and 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, and 72 hours postdose	Maximum observed plasma concentration (Cmax) is the peak plasma concentration of a drug after administration, obtained directly from the plasma concentration-time curve.
Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for SYR-322Z	3 hours prior to administration (predose) and 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, and 72 hours postdose	Tmax: Time to reach the maximum plasma concentration (Cmax), equal to time (hours) to Cmax.
AUC (0-inf): Area Under the Plasma Concentration-time Curve From Time 0 to Infinity for SYR-322Z	3 hours prior to administration (predose) and 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, and 72 hours postdose	AUC (0-inf) is a measure of total plasma exposure to the drug from time zero extrapolated to infinity.
Apparent Terminal Elimination Rate Constant (λz) for SYR-322Z	3 hours prior to administration (predose) and 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, and 72 hours postdose	Terminal elimination rate constant, calculated as the negative of the slope of the log-linear regression of the natural logarithm concentration-time curve during the terminal phase.
Mean Residence Time (MRT) for SYR-322Z	3 hours prior to administration (predose) and 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, and 72 hours postdose	Mean residence time (MRT) calculated as area under the first moment plasma concentration-time curve (AUMC \[0-inf\]) divided by AUC (0-inf). (AUMC \[0-inf\]) is the area under the first moment plasma concentration-time curve from time 0 to infinity.
MRT (0-tlqc): Mean Residence Time From Time 0 to Time of the Last Quantifiable Concentration (Tlqc) for SYR-322Z	3 hours prior to administration (predose) and 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, and 72 hours postdose	MRT (0-tlqc) is a measure of the mean residence time from time 0 to time of the last quantifiable concentration (tlqc) calculated as MRT (0-tlqc) =AUMC (0-tlqc)/AUC (0-tlqc). AUMC (0-tlqc) is the area under the first moment plasma concentration-time curve from time 0 to time of the last quantifiable concentration (tlqc), calculated using the linear trapezoidal rule.
AUC (0-72): Area Under the Plasma Concentration-time Curve From Time 0 to 72 Hours Post Dose for SYR-322 Metabolites M-I and M-II	3 hours prior to administration (predose) and 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, and 72 hours postdose	AUC (0-72) is measure of area under the curve from time 0 to 72 hours post dose.
AUC (0-tlqc): Area Under the Plasma Concentration-time Curve From Time 0 to the Time of the Last Quantifiable Concentration for SYR-322 Metabolites M-I and M-II	3 hours prior to administration (predose) and 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, and 72 hours postdose	AUC (0-tlqc) is a measure of total plasma exposure to the drug from Time 0 to Time of the Last Quantifiable Concentration (AUC \[0-tlqc\]).
MRT (0-tlqc): Mean Residence Time From Time 0 to Time of the Last Quantifiable Concentration (Tlqc) for SYR-322 Metabolites M-I and M-II	3 hours prior to administration (predose) and 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, and 72 hours postdose	MRT (0-tlqc) is a measure of the mean residence time from time 0 to time of the last quantifiable concentration (tlqc) calculated as MRT (0-tlqc) =AUMC (0-tlqc)/AUC (0-tlqc). AUMC (0-tlqc) is the area under the first moment plasma concentration-time curve from time 0 to time of the last quantifiable concentration (tlqc), calculated using the linear trapezoidal rule.
Cmax: Maximum Observed Plasma Concentration for SYR-322 Metabolites M-I and M-II	3 hours prior to administration (predose) and 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, and 72 hours postdose	Maximum observed plasma concentration (Cmax) is the peak plasma concentration of a drug after administration, obtained directly from the plasma concentration-time curve.
Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for SYR-322 Metabolites M-I and M-II	3 hours prior to administration (predose) and 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, and 72 hours postdose	Tmax: Time to reach the maximum plasma concentration (Cmax), equal to time (hours) to Cmax.
AUC (0-inf): Area Under the Plasma Concentration-time Curve From Time 0 to Infinity for SYR-322 Metabolites M-I and M-II	3 hours prior to administration (predose) and 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, and 72 hours postdose	AUC (0-inf) is a measure of total plasma exposure to the drug from time zero extrapolated to infinity.
Apparent Terminal Elimination Rate Constant (λz) for SYR-322 Metabolites M-I and M-II	3 hours prior to administration (predose) and 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, and 72 hours postdose	Terminal elimination rate constant, calculated as the negative of the slope of the log-linear regression of the natural logarithm concentration-time curve during the terminal phase.
Terminal Phase Elimination Half-life (T1/2) for SYR-322 Metabolites M-I and M-II	3 hours prior to administration (predose) and 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, and 72 hours postdose	Terminal phase elimination half-life (T1/2) is the time required for half of the drug to be eliminated from the plasma.
Terminal Phase Elimination Half-life (T1/2) for SYR-322Z	3 hours prior to administration (predose) and 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, and 72 hours postdose	Terminal phase elimination half-life (T1/2) is the time required for half of the drug to be eliminated from the plasma.
Apparent Clearance After Extra Vascular Administration (CL/F) for SYR-322Z	3 hours prior to administration, and at 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48 and 72 hours after administration	CL/F is apparent clearance of the drug from the plasma, calculated as the drug dose divided AUC (0-inf), expressed in liter/hour (L/hr).
Mean Residence Time (MRT) for SYR-322 Metabolites M-I and M-II	3 hours prior to administration (predose) and 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, and 72 hours postdose	Mean residence time (MRT) calculated as area under the first moment plasma concentration-time curve (AUMC \[0-inf\]) divided by AUC (0-inf). AUMC (0-inf) is the area under the first moment plasma concentration-time curve from time 0 to infinity.
AUC (0-48): Area Under the Plasma Concentration-time Curve From Time 0 to 48 Hours Postdose for Metformin	3 hours prior to administration (predose) and 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 36, and 48 hours postdose	AUC (0-48) is measure of area under the curve from time 0 to 48 hours post dose.
AUC (0-tlqc): Area Under the Plasma Concentration-Time Curve From Time 0 to the Time of the Last Quantifiable Concentration for Metformin	3 hours prior to administration (predose) and 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 36, and 48 hours postdose	AUC (0-tlqc) is a measure of total plasma exposure to the drug from Time 0 to Time of the Last Quantifiable Concentration (AUC \[0-tlqc\]).
MRT (0-tlqc): Mean Residence Time From Time 0 to Time of the Last Quantifiable Concentration (Tlqc) for Metformin	3 hours prior to administration (predose) and 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 36, and 48 hours postdose	MRT (0-tlqc) is a measure of the mean residence time from time 0 to time of the last quantifiable concentration (tlqc) calculated as MRT (0-tlqc) =AUMC (0-tlqc)/AUC (0-tlqc). AUMC (0-tlqc) is the area under the first moment plasma concentration-time curve from time 0 to time of the last quantifiable concentration (tlqc), calculated using the linear trapezoidal rule.
Cmax: Maximum Observed Plasma Concentration for Metformin	3 hours prior to administration (predose) and 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 36, and 48 hours postdose	Maximum observed plasma concentration (Cmax) is the peak plasma concentration of a drug after administration, obtained directly from the plasma concentration-time curve.
Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for Metformin	3 hours prior to administration (predose) and 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 36, and 48 hours postdose	Tmax: Time to reach the maximum plasma concentration (Cmax), equal to time (hours) to Cmax.
AUC (0-inf): Area Under the Plasma Concentration-time Curve From Time 0 to Infinity for Metformin	3 hours prior to administration (predose) and 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 36, and 48 hours postdose	AUC (0-inf) is a measure of total plasma exposure to the drug from time zero extrapolated to infinity.
Apparent Terminal Elimination Rate Constant (λz) for Metformin	3 hours prior to administration (predose) and 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 36, and 48 hours postdose	Terminal elimination rate constant, calculated as the negative of the slope of the log-linear regression of the natural logarithm concentration-time curve during the terminal phase.
Terminal Phase Elimination Half-life (T1/2) for Metformin	3 hours prior to administration (predose) and 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 36, and 48 hours postdose	Terminal phase elimination half-life (T1/2) is the time required for half of the drug to be eliminated from the plasma.
Apparent Clearance After Extra Vascular Administration (CL/F) for Metformin	3 hours prior to administration (predose) and 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 36, and 48 hours postdose	CL/F is apparent clearance of the drug from the plasma, calculated as the drug dose divided AUC (0-inf), expressed in L/hr.
Mean Residence Time (MRT) for Metformin	3 hours prior to administration (predose) and 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 36, and 48 hours postdose	Mean residence time (MRT) calculated as area under the first moment plasma concentration-time curve (AUMC \[0-inf\]) divided by AUC (0-inf). AUMC (0-inf) is the area under the first moment plasma concentration-time curve from time 0 to infinity.
Urinary Excretion Ratio of SYR-322Z From 0 to 12 Hours Postdose	0 to 12 hours postdose	Cumulative urinary excretion ratio of unchanged SYR-322 was calculated as the percentage of SYR-322 dose.
Urinary Excretion Ratio of SYR-322Z From 0 to 24 Hours Postdose	0 to 24 hours postdose	Cumulative urinary excretion ratio of unchanged SYR-322 was calculated as the percentage of SYR-322 dose.
Urinary Excretion Ratio of SYR-322Z From 0 to 48 Hours Postdose	0 to 48 hours postdose	Cumulative urinary excretion ratio of unchanged SYR-322 was calculated as the percentage of SYR-322 dose.
CLr: Renal Clearance of SYR-322Z	3 hours prior to administration (predose) and 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, and 72 hours postdose	CLr is a measure of apparent clearance of the drug from the urine. The clearance is the rate at which waste substances are cleared from the blood.
Urinary Excretion Ratio of SYR-322Z From 0 to 72 Hours Postdose	0 to 72 hours postdose	Cumulative urinary excretion ratio of unchanged SYR-322 was calculated as the percentage of SYR-322 dose.
Urinary Excretion Ratio of Metformin From Time 0 to 12 Hours Postdose	0 to 12 hours postdose	Cumulative urinary excretion ratio of metformin was calculated as the percentage of metformin dose.
Urinary Excretion Ratio of SYR-322 Metabolites M-I and M-II From 0 to 12 Hours Postdose	0 to 12 hours postdose	Cumulative urinary excretion ratio of SYR-322 metabolites M-I and M-II was calculated as the percentage of SYR-322 dose.
Urinary Excretion Ratio of SYR-322 Metabolites M-I and M-II From 0 to 24 Hours Postdose	0 to 24 hours post dose	Cumulative urinary excretion ratio of SYR-322 metabolites M-I and M-II was calculated as the percentage of SYR-322 dose.
Urinary Excretion Ratio of SYR-322 Metabolites M-I and M-II From 0 to 48 Hours Postdose	0 to 48 hours postdose	Cumulative urinary excretion ratio of SYR-322 metabolites M-I and M-II was calculated as the percentage of SYR-322 dose.
Urinary Excretion Ratio of SYR-322 Metabolites M-I and M-II From 0 to 72 Hours Postdose	0 to 72 hours postdose	Cumulative urinary excretion ratio of SYR-322 metabolites M-I and M-II was calculated as the percentage of SYR-322 dose.
Urinary Excretion Ratio of Metformin From 0 to 24 Hours Postdose	0 to 24 hours postdose	Cumulative urinary excretion ratio of metformin was calculated as the percentage of metformin dose.
Urinary Excretion Ratio of Metformin From 0 to 48 Hours Postdose	0 to 48 hours postdose	Cumulative urinary excretion ratio of metformin was calculated as the percentage of metformin dose.
CLr: Renal Clearance of Metformin	3 hours prior to administration (predose) and 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 36, and 48 hours postdose	CLr is a measure of apparent clearance of the drug from the urine.

Secondary Outcome Measures

Name	Time	Method
Inhibition Rate of Dipeptidyl-peptidase-4 (DPP-4) Activity	3 hours prior to administration (predose) and 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8 and 24 hours postdose	DPP-4 activity and inhibition rate of DPP-4 activity was assessed from the plasma samples collected from the participants. Inhibition of DPP-4 enzyme was used to determine the antihyperglycemic activity of the investigational product.
DPP-4 Activity	3 hours prior to administration (predose) and 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8 and 24 hours postdose	DPP-4 activity was assessed from the plasma samples collected from the participants.
AUC (0-24): Area Under the Inhibition Rate of Plasma DPP-4 Activity-time Curve From Time 0 to 24 Hours	3 hours prior to administration (predose) and 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8 and 24 hours postdose	Area under the inhibition rate of plasma DPP-4 activity-time curve from time 0 to 24 hours was determined from the inhibition-time curve.
Emax: Maximum Inhibition Rate of Plasma DPP-4 Activity	3 hours prior to administration (predose) and 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8 and 24 hours postdose	Maximum inhibition rate of plasma DPP-4 activity was determined from the inhibition-time curve.
Tmax: Time to Reach Emax	3 hours prior to administration (predose) and 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8 and 24 hours postdose	Time to reach Emax for the first time was determined from the inhibition-time curve.
Number of Participants Reporting 1 or More Treatment-emergent Adverse Events	Baseline up to the day of discharge (Day 4) in the second intervention period	An Adverse Event (AE) is defined as any untoward medical occurrence in a clinical investigation participant administered a drug; it does not necessarily have to have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign (eg, a clinically significant abnormal laboratory finding), symptom, or disease temporally associated with the use of a drug, whether or not it is considered related to the drug. A treatment-emergent adverse event (TEAE) is defined as an adverse event with an onset that occurs after receiving study drug.
Number of Participants With Clinically Significant Change From Baseline in Vital Signs	3 hours prior to administration (predose) and 2, 24 and 72 hours postdose	Vital signs included body temperature (infra-axillary), supine blood pressure resting more than 5 minutes (systolic and diastolic \[Millimeters of mercury\]), respiratory rate and pulse (beats per minute). Clinically significant change in vital signs observed at any time point are reported.
Number of Participants With Significant Change From Baseline in Electrocardiograms	3 hours prior to administration (predose) and 2, 24 and 72 hours postdose	Clinically significant change in electrocardiograms observed at any time point are reported.
Number of Participants With Laboratory-related Treatment Emergent Adverse Events (TEAEs)	3 hours prior to administration (predose), 24 and 72 hours postdose	Laboratory assessments included hematology, serum chemistry and urinalysis. Any laboratory-related TEAE reported at any time point were reported in this measure.
Number of Participants With Clinically Significant Change From Baseline in Body Weight	3 hours prior to administration (predose), 24 and 72 hours postdose	Clinically significant change participant's body weight observed at any time point are reported.