Pharmacokinetics, Pharmacodynamics and Safety of Alogliptin in Children, Adolescents and Adults With Type 2 Diabetes Mellitus

Alogliptin is a selective, orally available inhibitor of dipeptidyl peptidase-4 being
developed by Takeda Global Research & Development Center, Inc. as a treatment for type 2
diabetes mellitus. Inhibition of dipeptidyl peptidase-4 (DPP-4) prolongs the action of 2
important incretin hormones, glucagon-like peptide-1 (GLP-1) and glucose-dependent
insulinotropic peptide (GIP). These hormones are responsible for increasing insulin
synthesis, regulating β-cell proliferation, inhibiting gastric emptying, and inhibiting
glucagon secretion.

To date, alogliptin has not been studied in participants less than 18 years of age. As with
adults, there is growing evidence of an increase in the prevalence of type 2 diabetes
mellitus in children and adolescents.

This study is designed to determine the pharmacokinetic, pharmacodynamic, and safety profile
of alogliptin in children and adolescents with type 2 diabetes mellitus. These profiles will
be compared with those of similarly matched adult subjects with type 2 diabetes mellitus.
Pharmacokinetic, pharmacodynamic and safety endpoints will be analyzed.

Inclusion criteria for children and adolescent participants (between 10 and 17 years of
age):

- Is capable of understanding an informed consent form (ICF) or assenting to
participate. The parent or legal guardian of the participant must be able to
understand and sign a written ICF prior to the initiation of any study procedures.

- Weighs at least 36 kg (79 pounds) and has a Screening Body Mass Index of at least 18
kg/m2.

- Participants must have a diagnosis of Type 2 Diabetes Mellitus (non-insulin
dependent) based on diagnostic criteria of the American Diabetes Association.
Criteria include:

- fasting plasma glucose level of greater than or equal to 126 mg/dL where
fasting is defined as no caloric intake for at least 8 hours, or

- 2-hour plasma glucose level of greater than or equal to 200 mg/dL during an oral
glucose tolerance test, or

- random plasma glucose level of greater than or equal to 200 mg/dL, or

- glycated Hemoglobin greater than or equal 6.5%.

- Diagnosis can be historical (documented), or subjects can be diagnosed for this
study.

- Subjects must have a fasting serum C-peptide concentration greater than or equal to
0.8 ng/mL (greater than or equal to 0.26 nmol/L) at Screening Visit only.

- Subjects may be taking concomitant metformin if the dose has been stable for at least
30 days prior to Day 1.

Inclusion criteria for gender and race matched adult participants (between 18 and 65 years
of age):

- Weighs at least 50 kg (110 pounds) and has a Screening Body Mass Index between 23
kg/m2 and 45 kg/m2 (except for Asian or Asian-descendant subjects for whom the range
is between 20 kg/m2 and 35 kg/m2), inclusive for gender and race matched Type 2
Diabetes Mellitus adult subjects only.

- Subjects must have a diagnosis of Type 2 Diabetes Mellitus (non-insulin dependent)
based on diagnostic criteria of the American Diabetes Association. Criteria include:

- Fasting plasma glucose level of greater than or equal to 126 mg/dL where fasting
is defined as no caloric intake for at least 8 hours, or

- 2-hour plasma glucose level of greater than or equal to 200 mg/dL during an oral
glucose tolerance test, or

- random plasma glucose level of greater than or equal to 200 mg/dL, or

- glycated Hemoglobin greater than or equal 6.5%.

- Diagnosis can be historical (documented) or subjects can be diagnosed for this study.

- May be taking concomitant metformin if the dose has been stable for at least 30 days
prior to Day 1.

- May be taking statin or antihypertensive drugs if the dose has been stable for at
least 30 days prior to Day 1.

Inclusion criteria for all participants:

- Female participants of childbearing potential and male subjects who are sexually
active agree to routinely use adequate contraception from Screening until 30 days
after receiving the dose of study drug.

- Must have a negative urine test result for selected substances of abuse (including
alcohol and cotinine) at Screening and Check-in (Day -1).

- Has clinical chemistry, hematology, and complete urinalysis (fasted for at least 8
hours) results within the reference range for the testing laboratory (except results
associated with Type 2 Diabetes Mellitus) unless the out-of-range results are deemed
not clinically meaningful by the investigator or sponsor.

- Has a negative test result for hepatitis B surface antigen (HBsAg) and hepatitis C
virus antibody (anti-HCV), and no known history of human immunodeficiency virus
(HIV).

Exclusion Criteria:

- Is currently participating in another investigational study or has taken an
investigational drug within 30 days prior to Day 1.

- Received alogliptin previously.

- Received or donated blood or blood products within 30 days prior to Screening or
plans to donate blood during the study.

- Has a known hypersensitivity to alogliptin or related compounds.

- Has a history of drug abuse or a history of alcohol abuse within 1 year prior to
study Day 1.

- Has had an acute, clinically significant illness (excluding Type 2 Diabetes Mellitus)
within 30 days prior to study Day 1.

- Has any other condition or prior therapy that, in the opinion of the investigator,
would make the subject unsuitable for the study.

- Has a history or clinical manifestations of significant metabolic (excluding Type 2
Diabetes Mellitus), hematologic, pulmonary, cardiovascular, gastrointestinal,
neurologic, hepatic, renal, urologic, immunologic, musculoskeletal or psychiatric
disorder.

- Has a hemoglobin value less than 12 g/dL.

- Has a systolic blood pressure greater than 140 mm Hg or has a diastolic blood
pressure greater than 90 mm Hg at Screening or Check-in (Day -1).

- Adult subject has an alanine aminotransferase or aspartate aminotransferase level
greater than 2 times the upper limit of normal active liver disease, or jaundice at
the Screening Visit or on Check-in (Day -1).

- Pediatric subject has an alanine aminotransferase or aspartate aminotransferase level
greater than 1.5 times the upper limit of normal at the Screening Visit or on
Check-in (Day -1).

- Has a serum creatinine level greater than 1.5 mg/dL.

- Has a creatinine clearance less than 50 mL/min (normalized to body surface area of
1.73 m2).

- Has a history of abdominal surgery (except laparoscopic cholecystectomy or
uncomplicated appendectomy) or thoracic or nonperipheral vascular surgery within 6
months prior to Day 1.

- Has a history or presence of a clinically significant abnormal 12-lead
Electrocardiogram result as determined by the investigator or Takeda Global Research
and Development at Screening or Check-in (Day -1).

- Has a history of cancer, other than basal cell carcinoma or Stage I squamous cell
carcinoma of the skin that has not been in remission for at least 5 years prior to
the first dose of study drug.

- If female, subject is pregnant or lactating or intending to become pregnant before,
during, or within 30 days after receiving study drug.

- If male, subject intends to impregnate others during the study or for 30 days after
receiving study drug.

- Has consumed or is unable to abstain from consumption of products containing alcohol,
caffeine, or xanthine, and food or beverages containing grapefruit juice or
Seville-type oranges within 72 hours prior to study Day 1 and for the duration of the
study.

- Used any tobacco (ie, nicotine) products within 6 weeks prior to study Day 1, and is
unwilling to abstain from these products for the duration of the study.

- Has used any nutraceutical preparations within 28 days prior to study Day 1.

- Is currently taking ketoconazole, fluconazole, gemfibrozil, rifampin or carbamazepine
or taken within 28 days prior to Check-in (Day -1).

- Has poor peripheral venous access.

- Has a medical history of clinical or laboratory evidence to indicate a diagnosis of
type 1 diabetes or secondary forms of diabetes including maturity-onset diabetes of
the young (MODY).