Long-term Safety Study of Alogliptin Used in Combination With Sulfonylurea or Metformin in Participants With Type 2 Diabetes in Japan

A Long-term, Open-label Extension Study to Investigate the Long-term Safety of Alogliptin When Used in Combination With Sulfonylurea or Metformin in Subjects With Type 2 Diabetes in Japan

Status

Completed

Phases

Phase 2Phase 3

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT01318135

Enrollment

576

Registered

2011-03-18

Start date

2009-01-31

Completion date

2010-04-30

Last updated

2012-08-16

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

To evaluate the efficacy and safety of alogliptin administered as an add-on to sulfonylurea (glimepiride) or metformin, once daily (QD), twice daily (BID) or three times daily (TID).

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. This was a phase 2/3, multicenter, open-label study, in participants who had completed the core phase 2/3 sulfonylurea add-on study (SYR-322/CCT-005; NCT01318083) or the core phase 2/3 metformin add-on study (SYR-322/CCT-006; NCT01318109) to evaluate the safety and efficacy of alogliptin administered as an add-on to a sulfonylurea (glimepiride) or metformin continuously for 40 weeks (52 weeks from the start of study treatment with alogliptin in the core phase 2/3 sulfonylurea add-on study or the core phase 2/3 metformin add-on study).

Interventions

DRUGAlogliptin and glimepiride

Alogliptin 12.5 mg, tablets, orally, once daily and sulfonylurea 1, 2, 3, 4, 5 or 6 mg, tablets, orally, once or twice daily for up to 52 weeks.

DRUGAlogliptin and metformin

Alogliptin 12.5 mg, tablets, orally, once daily and metformin 500 mg, tablets, orally, twice daily or metformin 750 mg, tablets, orally, three times daily for up to 52 weeks.

Study design

Allocation

RANDOMIZED

Intervention model

PARALLEL

Primary purpose

TREATMENT

Masking

NONE

Eligibility

Sex/Gender

ALL

Age

20 Years to 64 Years

Healthy volunteers

Inclusion criteria

Common criteria that applied to participants completing both the core phase 2/3 sulfonylurea add-on study and those completing the core phase 2/3 metformin add-on study: 1. Had completed the core phase 2/3 sulfonylurea add-on study or the core phase 2/3 metformin add-on study. 2. Was capable of understanding and complying with protocol requirements. 3. Signed a written informed consent form prior to the initiation of any study procedure.

Exclusion criteria

Common criteria that applied to participants completing both the core phase 2/3 sulfonylurea add-on study and those completing the core phase 2/3 metformin add-on study: 1. With clinical manifestation of hepatic impairment (eg, an aspartate aminotransferase or alanine aminotransferase value of 2.5 times or more of the upper reference limit at Week 8 of the core phase 2/3 sulfonylurea add-on study or the core phase 2/3 metformin add-on study). 2. With clinical manifestation of renal impairment (eg, a creatinine value of 1.5 times or more of the upper reference limit at Week 8 of the core phase 2/3 sulfonylurea add-on study or the core phase 2/3 metformin add-on study). 3. With serious cardiac disease, cerebrovascular disorder, or serious pancreatic or hematological disease (eg, a subject who requires hospital admission). Criteria that applied only to participants completing the core phase 2/3 metformin add-on study: 1\. With history or symptoms of lactic acidosis.

Design outcomes

Primary

Measure	Time frame	Description
Number of Participants With Adverse Events.	52 Weeks.	Treatment-emergent adverse events (TEAE) are defined as any unfavorable and unintended sign, symptom or disease temporally associated with the use of a medicinal product reported from first dose of study drug through 30 days after receiving the last dose of study drug. A TEAE may also be a pretreatment adverse event or a concurrent medical condition diagnosed prior to the date of first dose of study drug that increases in severity after the start of dosing.

Secondary

Measure	Time frame	Description
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 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 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 final visit and glycosylated hemoglobin collected at baseline.
Change From Baseline in Fasting Blood Glucose (Week 8).	Baseline and Week 8.	The change between the value of fasting blood glucose collected at week 8 and baseline.
Change From Baseline in Fasting Blood Glucose (Week 12).	Baseline and Week 12.	The change between the value of fasting blood glucose collected at week 12 and baseline.
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 Fasting Blood Glucose (Week 20).	Baseline and Week 20.	The change between the value of fasting blood glucose collected at week 20 and baseline.
Change From Baseline in Fasting Blood Glucose (Week 24).	Baseline and Week 24.	The change between the value of fasting blood glucose collected at week 24 and baseline.
Change From Baseline in Fasting Blood Glucose (Week 28).	Baseline and Week 28.	The change between the value of fasting blood glucose collected at week 28 and baseline.
Change From Baseline in Fasting Blood Glucose (Week 32).	Baseline and Week 32.	The change between the value of fasting blood glucose collected at week 32 and baseline.
Change From Baseline in Fasting Blood Glucose (Week 36).	Baseline and Week 36.	The change between the value of fasting blood glucose collected at week 36 and baseline.
Change From Baseline in Fasting Blood Glucose (Week 40).	Baseline and Week 40.	The change between the value of fasting blood glucose collected at week 40 and baseline.
Change From Baseline in Fasting Blood Glucose (Week 44).	Baseline and Week 44.	The change between the value of fasting blood glucose collected at week 44 and baseline.
Change From Baseline in Fasting Blood Glucose (Week 48).	Baseline and Week 48.	The change between the value of fasting blood glucose collected at week 48 and baseline.
Change From Baseline in Fasting Blood Glucose (Week 52).	Baseline and Week 52.	The change between the value of fasting blood glucose collected at week 52 and baseline.
Change From Baseline in Fasting Blood Glucose (Final Visit).	Baseline and Final Visit (up to Week 52).	The change between the value of fasting blood glucose collected at final visit and baseline.
Change From Baseline in Blood Glucose Measured by the Meal Tolerance Test (Week 12).	Baseline and Week 12.	The change between the value of blood glucose measured by the meal tolerance test collected at week 12 and blood glucose measured by the meal tolerance test collected at baseline. Meal tolerance test measures blood glucose through blood samples drawn before a meal and at 2 hours after the start of the meal.
Change From Baseline in Blood Glucose Measured by the Meal Tolerance Test (Week 24).	Baseline and Week 24.	The change between the value of blood glucose measured by the meal tolerance test collected at week 24 and blood glucose measured by the meal tolerance test collected at baseline. Meal tolerance test measures blood glucose through blood samples drawn before a meal and at 2 hours after the start of the meal.
Change From Baseline in Blood Glucose Measured by the Meal Tolerance Test (Week 52).	Baseline and Week 52.	The change between the value of blood glucose measured by the meal tolerance test collected at week 52 and blood glucose measured by the meal tolerance test collected at baseline. Meal tolerance test measures blood glucose through blood samples drawn before a meal and at 2 hours after the start of the meal.
Change From Baseline in Blood Glucose Measured by the Meal Tolerance Test (Final Visit).	Baseline and Final Visit (up to Week 52).	The change between the value of blood glucose measured by the meal tolerance test collected at final visit and blood glucose measured by the meal tolerance test collected at baseline. Meal tolerance test measures blood glucose through blood samples drawn before a meal and at 2 hours after the start of the meal.
Change From Baseline in Fasting Blood Glucose (Week 16).	Baseline and Week 16.	The change between the value of fasting blood glucose collected at week 6 and baseline.

Participant flow

Recruitment details

Participants enrolled at 58 investigative sites in Japan from 06 January 2009 to 23 January 2010.

Pre-assignment details

Participants who had completed a core phase 2/3 glimepiride (SYR-322/CCT-005; NCT01318083) or metformin (SYR-322/CCT-006; NCT01318109) add-on study were enrolled in one of four, once daily (QD) or twice-daily (BID) treatment groups. Five participants completed OCT-005 study without receiving the study drug.

Participants by arm

Arm	Count
Alogliptin 12.5 mg QD and Glimepiride 1- 6 mg QD or BID Alogliptin 12.5 mg, tablets, orally, once daily and sulfonylurea 1, 2, 3, 4, 5 or 6 mg, tablets, orally, once or twice daily for up to 52 weeks.	150
Alogliptin 25 mg QD and Glimepiride 1 - 6 mg QD or BID Alogliptin 25 mg, tablets, orally, once daily and sulfonylurea 1, 2, 3, 4, 5 or 6 mg, tablets, orally, once or twice daily for up to 52 weeks.	152
Alogliptin 12.5 mg QD and Metformin 500 mg BID or 750 mg TID Alogliptin 12.5 mg, tablets, orally, once daily and metformin 500 mg, tablets, orally, twice daily or metformin 750 mg, tablets, orally, three times daily for up to 52 weeks.	142
Alogliptin 25 mg QD and Metformin 500 mg BID or 750 mg TID Alogliptin 25 mg, tablets, orally, once daily and metformin 500 mg, tablets, orally, twice daily or metformin 750 mg, tablets, orally, three times daily for up to 52 weeks.	145
Total	589

Withdrawals & dropouts

Period	Reason	FG000	FG001	FG002	FG003	FG004	FG005	FG006	FG007
Enrolled - Long-Term Extension Study	Adverse Event	1	0	0	0	0	0	0	0
Enrolled - Long-Term Extension Study	Treatment Complications	1	0	0	0	0	0	0	0
Entered - Long-Term Extension Study	Adverse Event	9	3	4	3	4	2	0	0
Entered - Long-Term Extension Study	Lack of Efficacy	5	7	2	3	2	2	1	1
Entered - Long-Term Extension Study	Protocol Violation	1	1	0	0	1	0	0	0
Entered - Long-Term Extension Study	Use of Excluded Medications	0	0	0	0	0	0	0	1
Entered - Long-Term Extension Study	Withdrawal by Subject	2	2	2	1	2	0	0	1

Baseline characteristics

Characteristic	Alogliptin 12.5 mg QD and Glimepiride 1- 6 mg QD or BID	Alogliptin 25 mg QD and Glimepiride 1 - 6 mg QD or BID	Alogliptin 12.5 mg QD and Metformin 500 mg BID or 750 mg TID	Alogliptin 25 mg QD and Metformin 500 mg BID or 750 mg TID	Total
Age, Customized ≤ 64 years	93 participants 9.5	105 participants 8.92	142 participants 8.12	145 participants 8.41	485 participants
Age, Customized ≥ 65 years	57 participants	47 participants	0 participants	0 participants	104 participants
Sex: Female, Male Female	53 Participants	52 Participants	46 Participants	44 Participants	195 Participants
Sex: Female, Male Male	97 Participants	100 Participants	96 Participants	101 Participants	394 Participants

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk	EG002 affected / at risk	EG003 affected / at risk
deaths Total, all-cause mortality	— / —	— / —	— / —	— / —
other Total, other adverse events	116 / 150	134 / 152	108 / 142	113 / 145
serious Total, serious adverse events	16 / 150	3 / 152	7 / 142	5 / 145

Outcome results

Primary

Number of Participants With Adverse Events.

Treatment-emergent adverse events (TEAE) are defined as any unfavorable and unintended sign, symptom or disease temporally associated with the use of a medicinal product reported from first dose of study drug through 30 days after receiving the last dose of study drug. A TEAE may also be a pretreatment adverse event or a concurrent medical condition diagnosed prior to the date of first dose of study drug that increases in severity after the start of dosing.

Time frame: 52 Weeks.

Population: Full Analysis Set was defined as the population of participants randomized in the core phase 2/3 SYR-322/CCT-005 (NCT01318083) or SYR-322/CCT-006 (NCT01318109) add-on studies and received at least 1 dose of the investigational products (SYR-322DB in combination with glimepiride or metformin) for the treatment period were identified for analysis.

Arm	Measure	Group	Value (NUMBER)
Alogliptin 12.5 mg QD and Glimepiride 1- 6 mg QD or BID	Number of Participants With Adverse Events.	Serious Adverse Event	16 participants
Alogliptin 12.5 mg QD and Glimepiride 1- 6 mg QD or BID	Number of Participants With Adverse Events.	Other Adverse Event (≥3% Frequency Threshold)	116 participants
Alogliptin 25 mg QD and Glimepiride 1 - 6 mg QD or BID	Number of Participants With Adverse Events.	Other Adverse Event (≥3% Frequency Threshold)	134 participants
Alogliptin 25 mg QD and Glimepiride 1 - 6 mg QD or BID	Number of Participants With Adverse Events.	Serious Adverse Event	3 participants
Alogliptin 12.5 mg QD and Metformin 500 mg BID or 750 mg TID	Number of Participants With Adverse Events.	Serious Adverse Event	7 participants
Alogliptin 12.5 mg QD and Metformin 500 mg BID or 750 mg TID	Number of Participants With Adverse Events.	Other Adverse Event (≥3% Frequency Threshold)	108 participants
Alogliptin 25 mg QD and Metformin 500 mg BID or 750 mg TID	Number of Participants With Adverse Events.	Serious Adverse Event	5 participants
Alogliptin 25 mg QD and Metformin 500 mg BID or 750 mg TID	Number of Participants With Adverse Events.	Other Adverse Event (≥3% Frequency Threshold)	113 participants

Secondary

Change From Baseline in Blood Glucose Measured by the Meal Tolerance Test (Final Visit).

The change between the value of blood glucose measured by the meal tolerance test collected at final visit and blood glucose measured by the meal tolerance test collected at baseline. Meal tolerance test measures blood glucose through blood samples drawn before a meal and at 2 hours after the start of the meal.

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