Clinical trial NCT02276274: 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
Official title: A Randomized, Open-label, Crossover Study to Determine the 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Clinical Pharmacology
Lead sponsor: Takeda
Sponsor class: INDUSTRY
First posted: 2014-10-28
Enrollment: 12
Sex: MALE
Minimum age (years): 20
Maximum age (years): 35
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Primary purpose: BASIC_SCIENCE

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

Eligibility criteria: 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.

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.

Primary outcomes:
measure: AUC (0-72): Area Under the Plasma Concentration-time Curve From Time 0 to 72 Hours Postdose for Unchanged SYR-322 (SYR-322Z)
timeFrame: 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
measure: AUC (0-tlqc): Area Under the Plasma Concentration-time Curve From Time 0 to the Time of the Last Quantifiable Concentration for SYR-322Z
timeFrame: 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
measure: Cmax: Maximum Observed Plasma Concentration for SYR-322Z
timeFrame: 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
measure: Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for SYR-322Z
timeFrame: 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
measure: AUC (0-inf): Area Under the Plasma Concentration-time Curve From Time 0 to Infinity for SYR-322Z
timeFrame: 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
measure: Apparent Terminal Elimination Rate Constant (λz) for SYR-322Z
timeFrame: 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
measure: Terminal Phase Elimination Half-life (T1/2) for SYR-322Z
timeFrame: 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
measure: Apparent Clearance After Extra Vascular Administration (CL/F) for SYR-322Z
timeFrame: 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
measure: Mean Residence Time (MRT) for SYR-322Z
timeFrame: 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
measure: MRT (0-tlqc): Mean Residence Time From Time 0 to Time of the Last Quantifiable Concentration (Tlqc) for SYR-322Z
timeFrame: 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
measure: 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
timeFrame: 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
measure: 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
timeFrame: 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
measure: 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
timeFrame: 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
measure: Cmax: Maximum Observed Plasma Concentration for SYR-322 Metabolites M-I and M-II
timeFrame: 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
measure: Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for SYR-322 Metabolites M-I and M-II
timeFrame: 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
measure: AUC (0-inf): Area Under the Plasma Concentration-time Curve From Time 0 to Infinity for SYR-322 Metabolites M-I and M-II
timeFrame: 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
measure: Apparent Terminal Elimination Rate Constant (λz) for SYR-322 Metabolites M-I and M-II
timeFrame: 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
measure: Terminal Phase Elimination Half-life (T1/2) for SYR-322 Metabolites M-I and M-II
timeFrame: 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
measure: Mean Residence Time (MRT) for SYR-322 Metabolites M-I and M-II
timeFrame: 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
measure: AUC (0-48): Area Under the Plasma Concentration-time Curve From Time 0 to 48 Hours Postdose for Metformin
timeFrame: 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
measure: AUC (0-tlqc): Area Under the Plasma Concentration-Time Curve From Time 0 to the Time of the Last Quantifiable Concentration for Metformin
timeFrame: 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
measure: MRT (0-tlqc): Mean Residence Time From Time 0 to Time of the Last Quantifiable Concentration (Tlqc) for Metformin
timeFrame: 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
measure: Cmax: Maximum Observed Plasma Concentration for Metformin
timeFrame: 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
measure: Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for Metformin
timeFrame: 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
measure: AUC (0-inf): Area Under the Plasma Concentration-time Curve From Time 0 to Infinity for Metformin
timeFrame: 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
measure: Apparent Terminal Elimination Rate Constant (λz) for Metformin
timeFrame: 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
measure: Terminal Phase Elimination Half-life (T1/2) for Metformin
timeFrame: 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
measure: Apparent Clearance After Extra Vascular Administration (CL/F) for Metformin
timeFrame: 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
measure: Mean Residence Time (MRT) for Metformin
timeFrame: 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
measure: Urinary Excretion Ratio of SYR-322Z From 0 to 12 Hours Postdose
timeFrame: 0 to 12 hours postdose
measure: Urinary Excretion Ratio of SYR-322Z From 0 to 24 Hours Postdose
timeFrame: 0 to 24 hours postdose
measure: Urinary Excretion Ratio of SYR-322Z From 0 to 48 Hours Postdose
timeFrame: 0 to 48 hours postdose
measure: Urinary Excretion Ratio of SYR-322Z From 0 to 72 Hours Postdose
timeFrame: 0 to 72 hours postdose
measure: Urinary Excretion Ratio of SYR-322 Metabolites M-I and M-II From 0 to 12 Hours Postdose
timeFrame: 0 to 12 hours postdose
measure: Urinary Excretion Ratio of SYR-322 Metabolites M-I and M-II From 0 to 24 Hours Postdose
timeFrame: 0 to 24 hours post dose
measure: Urinary Excretion Ratio of SYR-322 Metabolites M-I and M-II From 0 to 48 Hours Postdose
timeFrame: 0 to 48 hours postdose
measure: Urinary Excretion Ratio of SYR-322 Metabolites M-I and M-II From 0 to 72 Hours Postdose
timeFrame: 0 to 72 hours postdose
measure: Urinary Excretion Ratio of Metformin From Time 0 to 12 Hours Postdose
timeFrame: 0 to 12 hours postdose
measure: Urinary Excretion Ratio of Metformin From 0 to 24 Hours Postdose
timeFrame: 0 to 24 hours postdose
measure: Urinary Excretion Ratio of Metformin From 0 to 48 Hours Postdose
timeFrame: 0 to 48 hours postdose
measure: CLr: Renal Clearance of SYR-322Z
timeFrame: 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
measure: CLr: Renal Clearance of Metformin
timeFrame: 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
Secondary outcomes:
measure: Inhibition Rate of Dipeptidyl-peptidase-4 (DPP-4) Activity
timeFrame: 3 hours prior to administration (predose) and 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8 and 24 hours postdose
measure: DPP-4 Activity
timeFrame: 3 hours prior to administration (predose) and 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8 and 24 hours postdose
measure: AUC (0-24): Area Under the Inhibition Rate of Plasma DPP-4 Activity-time Curve From Time 0 to 24 Hours
timeFrame: 3 hours prior to administration (predose) and 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8 and 24 hours postdose
measure: Emax: Maximum Inhibition Rate of Plasma DPP-4 Activity
timeFrame: 3 hours prior to administration (predose) and 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8 and 24 hours postdose
measure: Tmax: Time to Reach Emax
timeFrame: 3 hours prior to administration (predose) and 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8 and 24 hours postdose
measure: Number of Participants Reporting 1 or More Treatment-emergent Adverse Events
timeFrame: Baseline up to the day of discharge (Day 4) in the second intervention period
measure: Number of Participants With Clinically Significant Change From Baseline in Vital Signs
timeFrame: 3 hours prior to administration (predose) and 2, 24 and 72 hours postdose
measure: Number of Participants With Clinically Significant Change From Baseline in Body Weight
timeFrame: 3 hours prior to administration (predose), 24 and 72 hours postdose
measure: Number of Participants With Significant Change From Baseline in Electrocardiograms
timeFrame: 3 hours prior to administration (predose) and 2, 24 and 72 hours postdose
measure: Number of Participants With Laboratory-related Treatment Emergent Adverse Events (TEAEs)
timeFrame: 3 hours prior to administration (predose), 24 and 72 hours postdose
Other outcomes:
Locations:
city: Fukuoka-shi
country: Japan
state: Fukuoka
Study officials:
affiliation: Takeda Pharmaceutical Company Limited (Japan)
name: General Manager
role: STUDY_DIRECTOR
References: