Phase 1 Bioavailability Study of SYR-322MET

An Open-Label, Single-dose, Randomized, Crossover Study to Determine the Bioavailability and Bioequivalence of Alogliptin 12.5 mg and Metformin 1000 mg When Administered as Individual Tablets and as a Fixed-Dose Combination Tablet Vipdomet (Alogliptin FDC With Metformin) in Russian Healthy Subjects

The purpose of this study is to determine the relative bioavailability of alogliptin 12.5 milligram (mg) and immediate-release metformin 1000 mg when administered as individual tablets and as a fixed-dose combination (FDC) product.

Study Overview

• Status: Completed
• Conditions: Healthy Volunteers
• Intervention / Treatment: Drug: Alogliptin; Drug: Metformin Hydrochloride; Drug: SYR-322MET

Detailed Description

The drug being tested in this study is called SYR-322MET (alogliptin 12.5 mg and metformin 1000 mg FDC tablet). SYR-322MET is being tested to assess whether its pharmacokinetic properties (how it is processed by the body) are affected when administered as a FDC compared to administration of alogliptin and metformin alone. This study will look at lab results in people who take SYR-322MET.

This crossover study will enroll approximately 24 participants. Participants will be randomly assigned (by chance, like flipping a coin) to one of two treatment sequences. All participants will receive both treatments over two periods; the order of receipt will be determined by the randomization code. All participants will receive the following study medications by the end of the study:

• Alogliptin 12.5 mg + Metformin 1000 mg as individual tablets
• SYR-322MET (alogliptin 12.5 mg and metformin 1000 mg fixed-dose combination [FDC] tablet)

This single center trial will be conducted in Russia. The overall time to participate in this study is up to 63 days. Participants will make multiple visits to the clinic including two 4-day periods of confinement to the clinic, and will be contacted by telephone 14 days after last dose of study drug for a follow-up assessment.

• Study Type: Interventional
• Enrollment (Actual): 24
• Phase: Phase 1

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 55 years (Adult)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. In the opinion of the investigator, the participant is capable of understanding and complying with protocol requirements.
2. Signs and dates a written, informed consent form and any required privacy authorization prior to the initiation of any study procedures including requesting that a participant fast for any laboratory evaluations.
3. Is a healthy male or female.
4. Is aged 18 to 55 years, inclusive, at the time of informed consent and first study medication dose.
5. Weighs at least 50 kilogram (kg) and has a body mass index (BMI) from 18.5 to 30.0 kilogram per square meter (kg/m^2), inclusive at Screening.
6. A male participant who is nonsterilized and sexually active with a female partner of childbearing potential agrees to use adequate contraception from signing of informed consent throughout the duration of the study and for 30 days after last dose.
7. A female participant of childbearing potential who is sexually active with a nonsterilized male partner agrees to use routinely adequate contraception from signing of informed consent and throughout the duration of the study and for 30 days after last dose.

Exclusion Criteria

1. Has received any investigational compound within 30 days prior to Check-in (Day-1).
2. Has received alogliptin or metformin hydrochloride (HCl) in a previous clinical study or as a therapeutic agent within 90 days prior to Check-in (Day-1).
3. Is an immediate family member, study site employee, or is in a dependent relationship with a study site employee who is involved in the conduct of this study (example, spouse, parent, child, sibling) or may consent under duress.
4. Has clinically significant history or current diagnosis of cardiovascular, respiratory, neurological, endocrine, hematopoietic, immune, urinary, genital, gastrointestinal, hepatic and psychiatric diseases.
5. Has fasting blood glucose lower than 3.88 millimoles per liter (mmol/L)
6. Has experienced acute infectious diseases within 4 weeks before screening.
7. Has a history of clinically significant allergic reactions or has a known hypersensitivity to any component of the formulation of alogliptin, metformin or related compounds.
8. Has a positive urine drug result for drugs of abuse (defined as any illicit drug use) or positive alcohol breath test at Screening or Check-in (Day -1).
9. Consumes over 10 drinks weekly (1 drink is equivalent to 0.5 liters of beer, 200 milliliter [mL] of dry wine or 50 mL of hard liquor) or has a history of alcoholism, drug and/or substance abuse.
10. Has taken any excluded medication, supplements, or food products during the time periods listed in the Excluded Medications and Dietary Products table, including intake of medicines with pronounced effects on blood circulation, liver function (barbiturates, omeprazole, cimetidine, etc.) within 2 months before Day -1 of Period 1.
11. If female, the participant is pregnant or lactating or intending to become pregnant before, during, or within 30 days after participating in this study; or intending to donate ova during such time period.
12. If male, the participant intends to donate sperm during the course of this study or for 12 weeks after the last dose of study medication.
13. If female, the subject is having unprotected sex with non-sterilized men within 30 days before the IMP administration.
14. Has current or recent (within 6 months) gastrointestinal disease that would be expected to influence the absorption of drugs (that is, a history of malabsorption, esophageal reflux, peptic ulcer disease, erosive esophagitis, frequent [more than once per week] occurrence of heartburn, or any surgical intervention.
15. Has non-standard diet (example, vegetarian or vegan) or lifestyle (including nighttime work, extreme physical activity such as weights lifting), which may interfere with the trial.
16. Has a history of cancer, except basal cell carcinoma which has been in remission for at least 5 years prior to Day 1 of Period 1.
17. Has a positive test result for hepatitis B surface antigen (HBsAg), hepatitis C virus (HCV) antibody, human immunodeficiency virus (HIV) antibody or syphilis at screening.
18. Has used nicotine-containing products (including but not limited to cigarettes, pipes, cigars, chewing tobacco, nicotine patch or nicotine gum) within 28 days prior to Check-in Day -1. Cotinine test is positive at Screening or Check-in (Day 1).
19. Has poor peripheral venous access.
20. Has donated or lost 450 mL or more of his or her blood volume (including plasmapheresis), or had a transfusion of any blood product within 30 days prior to Day 1 of Period 1.
21. Has abnormalities in routine physician examination, laboratory and/or ECG findings
22. Has a systolic blood pressure greater (>)130 millimeter of mercury (mm Hg) or less than (<)100 mm Hg , diastolic blood pressure >90 mm Hg or <70 mm Hg; heart rate <60 bpm or >80 bpm at screening (Day -28 to Day -2) or check-in to Period 1 (Day -1).
23. Has participated in any clinical study within 3 months before Day -1 of Period 1.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Sequence I: AB; SYR-322MET (alogliptin 12.5 mg and metformin 1000 mg) fixed-dose combination (FDC) tablets, orally, once, on Day 1 of Period 1, followed by a 7-day washout period, followed by alogliptin 12.5 mg tablets and metformin 1000 mg tablets, orally, once, on Day 1 of Period 2.	Drug: Alogliptin; Alogliptin 12.5 mg tablets; Other Names: Vipidia; Drug: Metformin Hydrochloride; Metformin hydrochloride 1000 mg tablets; Other Names: Glucophage; Drug: SYR-322MET; SYR-322MET (alogliptin 12.5 mg and metformin 1000 mg) fixed-dose combination (FDC) tablets
Experimental: Sequence II: BA; Alogliptin 12.5 mg tablets, orally and metformin 1000 mg tablets, orally, once, on Day 1 of Period 1, followed by a 7-day washout period, followed by SYR-322MET (alogliptin 12.5 mg and metformin 1000 mg) fixed-dose combination (FDC) tablets, orally, once, on Day 1 of Period 2.	Drug: Alogliptin; Alogliptin 12.5 mg tablets; Other Names: Vipidia; Drug: Metformin Hydrochloride; Metformin hydrochloride 1000 mg tablets; Other Names: Glucophage; Drug: SYR-322MET; SYR-322MET (alogliptin 12.5 mg and metformin 1000 mg) fixed-dose combination (FDC) tablets

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
AUC(0-tlqc): Area Under the Plasma Concentration-Time Curve From Time 0 to the Time of the Last Quantifiable Concentration for Alogliptin	(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]).	Day 1 predose and at multiple time points (up to 72 hours) post-dose.
Cmax: Maximum Observed Plasma Concentration for Alogliptin	Maximum observed plasma concentration (Cmax) is the peak plasma concentration of a drug after administration, obtained directly from the plasma concentration-time curve.	Day 1 predose and at multiple time points (up 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 Metformin	(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]).	Day 1 predose and at multiple time points (up to 72 hours) post-dose.
Cmax: Maximum Observed Plasma Concentration for Metformin	Maximum observed plasma concentration (Cmax) is the peak plasma concentration of a drug after administration, obtained directly from the plasma concentration-time curve.	Day 1 predose and at multiple time points (up to 72 hours) post-dose.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of Participants who Experience at Least one Post-dose Adverse Event (AE)	An 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 (example, 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.	Day 1 of Period 1 up to 30 days after the last dose of study medication (up to 38 days)
Percentage of Participants who Meet the Markedly Abnormal Criteria for Safety Laboratory Tests at Least Once Post Dose	Standard safety laboratory values (hematology and chemistry) will be collected throughout study and compared to pre-specified criteria for markedly abnormal values.	At Day 4 and Day 7 of Period 2
Percentage Of Participants who Meet the Markedly Abnormal Criteria for Vital Sign Measurements at Least Once Post Dose	Vital sign measurements will be collected throughout study and compared to pre-specified criteria for markedly abnormal values.	Day 1 up to Day 4 of each period
Percentage of Participants who Meet the Markedly Abnormal Criteria for Safety Electrocardiogram (ECG) Parameters at Least Once Post Dose	Standard 12-lead ECG measurements will be collected throughout the study and compared to pre-specified criteria for markedly abnormal values.	At Day 1 and Day 4 of each period

Collaborators and Investigators

• Sponsor: Takeda

Study record dates

Study Major Dates

• Study Start: April 1, 2016
• Primary Completion (Actual): April 1, 2016
• Study Completion (Actual): April 1, 2016

Study Registration Dates

• First Submitted: July 23, 2015
• First Submitted That Met QC Criteria: July 23, 2015
• First Posted (Estimate): July 24, 2015

Study Record Updates

• Last Update Posted (Estimate): October 5, 2016
• Last Update Submitted That Met QC Criteria: October 4, 2016
• Last Verified: October 1, 2016

More Information

Terms related to this study

• Keywords: Drug therapy
• Additional Relevant MeSH Terms: Hypoglycemic Agents; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Protease Inhibitors; Incretins; Dipeptidyl-Peptidase IV Inhibitors; Metformin; Alogliptin
• Other Study ID Numbers: SYR-322MET-1003; U1111-1168-6473 (Registry Identifier: WHO)