Long-term Safety Study of Alogliptin Used in Combination With α-glucosidase Inhibitor in Participants With Type 2 Diabetes in Japan

A Long-term, Open-label Extension Study to Investigate the Long-term Safety of SYR-322 When Used in Combination With α-glucosidase Inhibitor in Subjects With Type 2 Diabetes in Japan

Status

Completed

Phases

Phase 2Phase 3

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT01263509

Enrollment

179

Registered

2010-12-20

Start date

2007-06-30

Completion date

2008-10-31

Last updated

2012-02-03

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Type 2 Diabetes Mellitus

Keywords

Diabetes Mellitus - Type 2, Diabetes Mellitus, Drug Therapy

Brief summary

The purpose of this study was to evaluate the long-term safety and efficacy of alogliptin and an α-glucosidase inhibitor administered once daily (QD) or three times daily (TID) for 40 consecutive weeks in participants who completed a phase 2/3 α-glucosidase inhibitor add on study.

Detailed description

Both insulin hyposecretion and insulin-resistance are considered to be involved in the development of type 2 diabetes mellitus. Takeda is developing SYR-322 (alogliptin) for the improvement of glycemic control in patients with type 2 diabetes mellitus. Alogliptin is an inhibitor of the dipeptidyl peptidase IV (DPP-IV) enzyme. DPP-IV is thought to be primarily responsible for the degradation of 2 peptide hormones released in response to nutrient ingestion. It is expected that inhibition of DPP-IV will improve glycemic control in patients with type 2 diabetes. To evaluate the long-term safety and efficacy of alogliptin and an α-glucosidase inhibitor, this extension study was administered for 40 consecutive weeks (52 weeks from the start of treatment in the phase 2 dose-ranging study) to participants who completed a phase 2/3 α-glucosidase inhibitor add on study 322/CCT-003 (NCT01263483).

Interventions

DRUGAlogliptin and voglibose

Alogliptin 12.5 mg, tablets, orally, once daily and voglibose 0.2 mg, tablets, orally, three times daily for up to 40 weeks.

Study design

Allocation

RANDOMIZED

Intervention model

PARALLEL

Primary purpose

TREATMENT

Masking

NONE

Eligibility

Sex/Gender

ALL

Age

33 Years to 85 Years

Healthy volunteers

Inclusion criteria

* Had completed the phase 2 dose-ranging study (i.e., the subject had completed the study visit at Week 12).

Exclusion criteria

* Had clinical manifestations of hepatic impairment (e.g., an aspartate aminotransferase or alanine aminotransferase value 2.5 times or more of the upper reference limit at Week 8 of treatment in the phase 2 dose-ranging study). * Had clinical manifestations of renal impairment (e.g., a creatinine value of 2 mg/dL or more at Week 8 of treatment in the phase 2 dose-ranging study).

Design outcomes

Primary

Measure	Time frame	Description
Number of Participants With Adverse Events.	52 Weeks.	A treatment-emergent adverse event (TEAE) is defined as an adverse event with an onset that occurs after receiving study drug and within 30 days after receiving the last dose of study drug. A TEAE may also be a pre-treatment adverse event or a concurrent medical condition diagnosed prior to the date of first dose of study drug, which increases in intensity after the start of dosing. Adverse events data with onset occurring more than 30 days after last dose of study drug (AE start date - last dose date \>30) will be listed, but not included in the summary tables below.

Secondary

Measure	Time frame	Description
Change From Baseline in Glycosylated Hemoglobin (Week 8).	Baseline and Week 8.	The change in the value of glycosylated hemoglobin (the concentration of glucose bound to hemoglobin as a percent of the absolute maximum that can be bound) collected at week 8 and glycosylated hemoglobin collected at baseline.
Change From Baseline in Glycosylated Hemoglobin (Week 12).	Baseline and Week 12.	The change in the value of glycosylated hemoglobin (the concentration of glucose bound to hemoglobin as a percent of the absolute maximum that can be bound) collected at week 12 and glycosylated hemoglobin collected at baseline.
Change From Baseline in Glycosylated Hemoglobin (Week 16).	Baseline and Week 16.	The change in the value of glycosylated hemoglobin (the concentration of glucose bound to hemoglobin as a percent of the absolute maximum that can be bound) collected at week 16 and glycosylated hemoglobin collected at baseline.
Change From Baseline in Glycosylated Hemoglobin (Week 20).	Baseline and Week 20.	The change in the value of glycosylated hemoglobin (the concentration of glucose bound to hemoglobin as a percent of the absolute maximum that can be bound) collected at week 20 and glycosylated hemoglobin collected at baseline.
Change From Baseline in Fasting Plasma Glucose (Week 36).	Baseline and Week 36.	The change between the value of fasting plasma glucose collected at week 36 and fasting plasma glucose collected at baseline.
Change From Baseline in Glycosylated Hemoglobin (Week 24).	Baseline and Week 24.	The change in the value of glycosylated hemoglobin (the concentration of glucose bound to hemoglobin as a percent of the absolute maximum that can be bound) collected at week 24 and glycosylated hemoglobin collected at baseline.
Change From Baseline in Glycosylated Hemoglobin (Week 28).	Baseline and Week 28.	The change in the value of glycosylated hemoglobin (the concentration of glucose bound to hemoglobin as a percent of the absolute maximum that can be bound) collected at week 28 and glycosylated hemoglobin collected at baseline.
Change From Baseline in Glycosylated Hemoglobin (Week 32).	Baseline and Week 32.	The change in the value of glycosylated hemoglobin (the concentration of glucose bound to hemoglobin as a percent of the absolute maximum that can be bound) collected at week 32 and glycosylated hemoglobin collected at baseline.
Change From Baseline in Glycosylated Hemoglobin (Week 36).	Baseline and Week 36.	The change in the value of glycosylated hemoglobin (the concentration of glucose bound to hemoglobin as a percent of the absolute maximum that can be bound) collected at week 36 and glycosylated hemoglobin collected at baseline.
Change From Baseline in Glycosylated Hemoglobin (Week 40).	Baseline and Week 40.	The change in the value of glycosylated hemoglobin (the concentration of glucose bound to hemoglobin as a percent of the absolute maximum that can be bound) collected at week 40 and glycosylated hemoglobin collected at baseline.
Change From Baseline in Glycosylated Hemoglobin (Week 44).	Baseline and Week 44.	The change in the value of glycosylated hemoglobin (the concentration of glucose bound to hemoglobin as a percent of the absolute maximum that can be bound) collected at week 44 and glycosylated hemoglobin collected at baseline.
Change From Baseline in Glycosylated Hemoglobin (Week 48).	Baseline and Week 48.	The change in the value of glycosylated hemoglobin (the concentration of glucose bound to hemoglobin as a percent of the absolute maximum that can be bound) collected at week 48 and glycosylated hemoglobin collected at baseline.
Change From Baseline in Glycosylated Hemoglobin (Week 52).	Baseline and Week 52.	The change in the value of glycosylated hemoglobin (the concentration of glucose bound to hemoglobin as a percent of the absolute maximum that can be bound) collected at week 52 and glycosylated hemoglobin collected at baseline.
Change From Baseline in Glycosylated Hemoglobin (Final Visit).	Baseline and Final Visit (up to Week 52).	The change in the value of glycosylated hemoglobin (the concentration of glucose bound to hemoglobin as a percent of the absolute maximum that can be bound) collected at week 52 or final visit and glycosylated hemoglobin collected at baseline.
Change From Baseline in Fasting Plasma Glucose (Week 8).	Baseline and Week 8.	The change between the value of fasting plasma glucose collected at week 8 and fasting plasma glucose collected at baseline.
Change From Baseline in Fasting Plasma Glucose (Week 12).	Baseline and Week 12.	The change between the value of fasting plasma glucose collected at week 12 and fasting plasma glucose collected at baseline.
Change From Baseline in Fasting Plasma Glucose (Week 16).	Baseline and Week 16.	The change between the value of fasting plasma glucose collected at week 16 and fasting plasma glucose collected at baseline.
Change From Baseline in Fasting Plasma Glucose (Week 20).	Baseline and Week 20.	The change between the value of fasting plasma glucose collected at week 20 and fasting plasma glucose collected at baseline.
Change From Baseline in Fasting Plasma Glucose (Week 24).	Baseline and Week 24.	The change between the value of fasting plasma glucose collected at week 24 and fasting plasma glucose collected at baseline.
Change From Baseline in Fasting Plasma Glucose (Week 28).	Baseline and Week 28.	The change between the value of fasting plasma glucose collected at week 28 and fasting plasma glucose collected at baseline.
Change From Baseline in Fasting Plasma Glucose (Week 32).	Baseline and Week 32.	The change between the value of fasting plasma glucose collected at week 32 and fasting plasma glucose collected at baseline.
Change From Baseline in Fasting Plasma Glucose (Week 44).	Baseline and Week 44.	The change between the value of fasting plasma glucose collected at week 44 and fasting plasma glucose collected at baseline.
Change From Baseline in Fasting Plasma Glucose (Week 48).	Baseline and Week 48.	The change between the value of fasting plasma glucose collected at week 48 and fasting plasma glucose collected at baseline.
Change From Baseline in Fasting Plasma Glucose (Week 52).	Baseline and Week 52.	The change between the value of fasting plasma glucose collected at week 52 and fasting plasma glucose collected at baseline.
Change From Baseline in Fasting Plasma Glucose (Final Visit).	Baseline and Final Visit (up to Week 52).	The change between the value of fasting plasma glucose collected at week 52 or final visit and fasting plasma glucose collected at baseline.
Change From Baseline in Fasting C-peptide (Week 8).	Baseline and Week 8.	The change between the value of fasting C-peptide collected at week 8 and fasting C-peptide collected at baseline.
Change From Baseline in Fasting C-peptide (Week 12).	Baseline and Week 12.	The change between the value of fasting C-peptide collected at week 12 and fasting C-peptide collected at baseline.
Change From Baseline in Fasting C-peptide (Week 16).	Baseline and Week 16.	The change between the value of fasting C-peptide collected at week 16 and fasting C-peptide collected at baseline.
Change From Baseline in Fasting C-peptide (Week 20).	Baseline and Week 20.	The change between the value of fasting C-peptide collected at week 20 and fasting C-peptide collected at baseline.
Change From Baseline in Fasting C-peptide (Week 24).	Baseline and Week 24.	The change between the value of fasting C-peptide collected at week 24 and fasting C-peptide collected at baseline.
Change From Baseline in Fasting C-peptide (Week 28).	Baseline and Week 28.	The change between the value of fasting C-peptide collected at week 28 and fasting C-peptide collected at baseline.
Change From Baseline in Fasting C-peptide (Week 32).	Baseline and Week 32.	The change between the value of fasting C-peptide collected at week 32 and fasting C-peptide collected at baseline.
Change From Baseline in Fasting C-peptide (Week 36).	Baseline and Week 36.	The change between the value of fasting C-peptide collected at week 36 and fasting C-peptide collected at baseline.
Change From Baseline in Fasting C-peptide (Week 40).	Baseline and Week 40.	The change between the value of fasting C-peptide collected at week 40 and fasting C-peptide collected at baseline.
Change From Baseline in Fasting C-peptide (Week 44).	Baseline and Week 44.	The change between the value of fasting C-peptide collected at week 44 and fasting C-peptide collected at baseline.
Change From Baseline in Fasting C-peptide (Week 48).	Baseline and Week 48.	The change between the value of fasting C-peptide collected at week 48 and fasting C-peptide collected at baseline.
Change From Baseline in Fasting C-peptide (Week 52).	Baseline and Week 52.	The change between the value of fasting C-peptide collected at week 52 and fasting C-peptide collected at baseline.
Change From Baseline in Fasting C-peptide (Final Visit).	Baseline and Final Visit (up to Week 52).	The change between the value of fasting C-peptide collected at week 52 or final visit and fasting C-peptide collected at baseline.
Change From Baseline in Blood Glucose Measured by Meal Tolerance Testing (2-hr Postprandial Value) (Week 12).	Baseline and Week 12.	The change between the value of blood glucose collected at week 12 and blood glucose collected at baseline. Meal tolerance test measures blood glucose, insulin, C-peptide and glucagon through blood samples drawn before a meal and 2 hours after the start of the meal.
Change From Baseline in Blood Glucose Measured by Meal Tolerance Testing (2-hr Postprandial Value) (Week 24).	Baseline and Week 24.	The change between the value of blood glucose collected at week 24 and blood glucose collected at baseline. Meal tolerance test measures blood glucose, insulin, C-peptide and glucagon through blood samples drawn before a meal and 2 hours after the start of the meal.
Change From Baseline in Blood Glucose Measured by Meal Tolerance Testing (2-hr Postprandial Value) (Week 52).	Baseline and Week 52.	The change between the value of blood glucose collected at week 52 and blood glucose collected at baseline. Meal tolerance test measures blood glucose, insulin, C-peptide and glucagon through blood samples drawn before a meal and 2 hours after the start of the meal.
Change From Baseline in Blood Glucose Measured by Meal Tolerance Testing (2-hr Postprandial Value) (Final Visit).	Baseline and Final Visit (up to Week 52).	The change between the value of blood glucose collected at week 52 or final visit and blood glucose collected at baseline. Meal tolerance test measures blood glucose, insulin, C-peptide and glucagon through blood samples drawn before a meal and 2 hours after the start of the meal.
Change From Baseline in Blood Glucose Measured by Meal Tolerance Testing (AUC (0-2)) (Week 12).	Baseline and Week 12.	The change between the value of blood glucose collected at week 12 and blood glucose collected at baseline. Meal tolerance test measures blood glucose, insulin, C-peptide and glucagon through blood samples drawn before a meal and 2 hours after the start of the meal.
Change From Baseline in Blood Glucose Measured by Meal Tolerance Testing (AUC (0-2)) (Week 24).	Baseline and Week 24.	The change between the value of blood glucose collected at week 24 and blood glucose collected at baseline. Meal tolerance test measures blood glucose, insulin, C-peptide and glucagon through blood samples drawn before a meal and 2 hours after the start of the meal.
Change From Baseline in Blood Glucose Measured by Meal Tolerance Testing (AUC (0-2)) (Week 52).	Baseline and Week 52.	The change between the value of blood glucose collected at week 52 and blood glucose collected at baseline. Meal tolerance test measures blood glucose, insulin, C-peptide and glucagon through blood samples drawn before a meal and 2 hours after the start of the meal.
Change From Baseline in Blood Glucose Measured by Meal Tolerance Testing (AUC (0-2)) (Final Visit).	Baseline and Final Visit (up to Week 52).	The change between the value of blood glucose collected at week 52 or final visit and blood glucose collected at baseline. Meal tolerance test measures blood glucose, insulin, C-peptide and glucagon through blood samples drawn before a meal and 2 hours after the start of the meal.
Change From Baseline in Insulin Measured by Meal Tolerance Testing (AUC(0-2)) (Week 12).	Baseline and Week 12.	The change between the value of insulin collected at week 12 and insulin collected at baseline as measured by the meal tolerance test. Meal tolerance test measures blood glucose, insulin, C-peptide and glucagon through blood samples drawn before a meal and 2 hours after the start of the meal.
Change From Baseline in Insulin Measured by Meal Tolerance Testing (AUC(0-2)) (Week 24).	Baseline and Week 24.	The change between the value of insulin collected at week 24 and insulin collected at baseline as measured by the meal tolerance test. Meal tolerance test measures blood glucose, insulin, C-peptide and glucagon through blood samples drawn before a meal and 2 hours after the start of the meal.
Change From Baseline in Insulin Measured by Meal Tolerance Testing (AUC(0-2)) (Week 52).	Baseline and Week 52.	The change between the value of insulin collected at week 52 and insulin collected at baseline as measured by the meal tolerance test. Meal tolerance test measures blood glucose, insulin, C-peptide and glucagon through blood samples drawn before a meal and 2 hours after the start of the meal.
Change From Baseline in Insulin Measured by Meal Tolerance Testing (AUC(0-2)) (Final Visit).	Baseline and Final Visit (up to Week 52).	The change between the value of insulin collected at week 52 or final visit and insulin collected at baseline as measured by the meal tolerance test. Meal tolerance test measures blood glucose, insulin, C-peptide and glucagon through blood samples drawn before a meal and 2 hours after the start of the meal.
Change From Baseline in C-peptide Measured by Meal Tolerance Testing (AUC(0-2)) (Week 12).	Baseline and Week 12.	The change between the value of C-peptide collected at week 12 and C-peptide collected at baseline as measured by the meal tolerance test. Meal tolerance test measures blood glucose, insulin, C-peptide and glucagon through blood samples drawn before a meal and 2 hours after the start of the meal.
Change From Baseline in Fasting Plasma Glucose (Week 40).	Baseline and Week 40.	The change between the value of fasting plasma glucose collected at week 40 and fasting plasma glucose collected at baseline.
Change From Baseline in C-peptide Measured by Meal Tolerance Testing (AUC(0-2)) (Week 52).	Baseline and Week 52.	The change between the value of C-peptide collected at week 52 and C-peptide collected at baseline as measured by the meal tolerance test. Meal tolerance test measures blood glucose, insulin, C-peptide and glucagon through blood samples drawn before a meal and 2 hours after the start of the meal.
Change From Baseline in C-peptide Measured by Meal Tolerance Testing (AUC(0-2)) (Final Visit).	Baseline and Final Visit (up to Week 52).	The change between the value of C-peptide collected at week 52 or final visit and C-peptide collected at baseline as measured by the meal tolerance test. Meal tolerance test measures blood glucose, insulin, C-peptide and glucagon through blood samples drawn before a meal and 2 hours after the start of the meal.
Change From Baseline in Glucagon Measured by Meal Tolerance Testing (AUC (0-2)) (Week 12).	Baseline and Week 12.	The change between the value of glucagons collected at week 12 and glucagons collected at baseline. Meal tolerance test measures blood glucose, insulin, C-peptide and glucagon through blood samples drawn before a meal and 2 hours after the start of the meal.
Change From Baseline in Glucagon Measured by Meal Tolerance Testing (AUC (0-2)) (Week 24).	Baseline and Week 24.	The change between the value of glucagons collected at week 24 and glucagons collected at baseline. Meal tolerance test measures blood glucose, insulin, C-peptide and glucagon through blood samples drawn before a meal and 2 hours after the start of the meal.
Change From Baseline in Glucagon Measured by Meal Tolerance Testing (AUC (0-2)) (Week 52).	Baseline and Week 52.	The change between the value of glucagons collected at week 52 and glucagons collected at baseline. Meal tolerance test measures blood glucose, insulin, C-peptide and glucagon through blood samples drawn before a meal and 2 hours after the start of the meal.
Change From Baseline in Glucagon Measured by Meal Tolerance Testing (AUC (0-2)) (Final Visit).	Baseline and Final Visit (up to Week 52).	The change between the value of glucagons collected at week 52 or final visit and glucagons collected at baseline. Meal tolerance test measures blood glucose, insulin, C-peptide and glucagon through blood samples drawn before a meal and 2 hours after the start of the meal.
Change From Baseline in C-peptide Measured by Meal Tolerance Testing (AUC(0-2)) (Week 24).	Baseline and Week 24.	The change between the value of C-peptide collected at week 24 and C-peptide collected at baseline as measured by the meal tolerance test. Meal tolerance test measures blood glucose, insulin, C-peptide and glucagon through blood samples drawn before a meal and 2 hours after the start of the meal.

Participant flow

Recruitment details

Participants enrolled at 24 investigative sites in Japan from 06 June 2007 to 02 October 2008.

Pre-assignment details

Participants enrolled in one of 2, once-daily (QD) or three-times daily (TID) treatment groups. Analyses performed by treatment group or treatment dose in this study. All 213 participants randomized in the phase 2/3 α-glucosidase inhibitor (NCT01263483) study are included in the Full Analysis Set in this study, of which 179 randomized.

Participants by arm

Arm	Count
Alogliptin 12.5 mg QD and Voglibose 0.2 mg TID Alogliptin 12.5 mg, tablets, orally, once daily and voglibose 0.2 mg, tablets, orally, three times daily for up to 40 weeks.	108
Alogliptin 25 mg QD and Voglibose 0.2 mg TID Alogliptin 25 mg, tablets, orally, once daily and voglibose 0.2 mg, tablets, orally, three times daily for up to 40 weeks.	105
Total	213

Withdrawals & dropouts

Period	Reason	FG000	FG001	FG002	FG003
Entered - Long-Term Extension Study	Adverse Event	5	5	4	1
Entered - Long-Term Extension Study	Lack of Efficacy	1	4	1	0
Entered - Long-Term Extension Study	Participant Unavailability	1	1	0	0
Entered - Long-Term Extension Study	Poor Glycosylated Hemoglobin Control	0	0	0	1
Entered - Long-Term Extension Study	Withdrawal by Subject	1	2	0	0

Baseline characteristics

Characteristic	Alogliptin 12.5 mg QD and Voglibose 0.2 mg TID	Alogliptin 25 mg QD and Voglibose 0.2 mg TID	Total
Age, Customized ≤ 64 years	69 participants	53 participants	122 participants
Age, Customized ≥ 65 years	39 participants	52 participants	91 participants
Sex: Female, Male Female	44 Participants	38 Participants	82 Participants
Sex: Female, Male Male	64 Participants	67 Participants	131 Participants

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk
deaths Total, all-cause mortality	— / —	— / —
other Total, other adverse events	85 / 108	73 / 105
serious Total, serious adverse events	6 / 108	7 / 105

Outcome results

Primary

Number of Participants With Adverse Events.

A treatment-emergent adverse event (TEAE) is defined as an adverse event with an onset that occurs after receiving study drug and within 30 days after receiving the last dose of study drug. A TEAE may also be a pre-treatment adverse event or a concurrent medical condition diagnosed prior to the date of first dose of study drug, which increases in intensity after the start of dosing. Adverse events data with onset occurring more than 30 days after last dose of study drug (AE start date - last dose date \>30) will be listed, but not included in the summary tables below.

Time frame: 52 Weeks.

Population: Adverse Event Profile in the Safety Analysis Set

Arm	Measure	Group	Value (NUMBER)
Alogliptin 12.5 mg QD and Voglibose 0.2 mg TID	Number of Participants With Adverse Events.	Serious Adverse Event	6 participants
Alogliptin 12.5 mg QD and Voglibose 0.2 mg TID	Number of Participants With Adverse Events.	Serious Adverse Event Related to Study Drug	0 participants
Alogliptin 12.5 mg QD and Voglibose 0.2 mg TID	Number of Participants With Adverse Events.	Other Adverse Events (Incidence ≥3%)	85 participants
Alogliptin 25 mg QD and Voglibose 0.2 mg TID	Number of Participants With Adverse Events.	Serious Adverse Event	7 participants
Alogliptin 25 mg QD and Voglibose 0.2 mg TID	Number of Participants With Adverse Events.	Serious Adverse Event Related to Study Drug	1 participants
Alogliptin 25 mg QD and Voglibose 0.2 mg TID	Number of Participants With Adverse Events.	Other Adverse Events (Incidence ≥3%)	73 participants

Secondary

Change From Baseline in Blood Glucose Measured by Meal Tolerance Testing (2-hr Postprandial Value) (Final Visit).

The change between the value of blood glucose collected at week 52 or final visit and blood glucose collected at baseline. Meal tolerance test measures blood glucose, insulin, C-peptide and glucagon through blood samples drawn before a meal and 2 hours after the start of the meal.

Time frame: Baseline and Final Visit (up to Week 52).