Long-term Safety of Alogliptin in Patients With Type 2 Diabetes Mellitus

Phase 3

Completed

• Conditions: Diabetes Mellitus
• Interventions: Drug: Alogliptin

• Registration Number: NCT00306384
• Lead Sponsor: Takeda

Brief Summary

The purpose of this study is to evaluate the long-term safety of alogliptin, once daily (QD), following participation in 1 of 7 controlled studies in patients with type 2 diabetes mellitus.

Detailed Description

SYR-322 (alogliptin) is an inhibitor of the dipeptidyl peptidase IV enzyme. Dipeptidyl peptidase IV is thought to be primarily responsible for the degradation of 2 peptide hormones released in response to nutrient ingestion, namely glucagon-like peptide-1 and glucose-dependent insulinotropic peptide. It is expected that inhibition of dipeptidyl peptidase IV will improve glycemic (glucose) control in patients with type 2 diabetes mellitus by prolonging the beneficial effects of glucagon-like peptide-1.

The rising incidence of type 2 diabetes mellitus and the limitations of the currently available treatments suggest the need for new therapies for glycemic control. Studies have been undertaken in humans that evaluated the effects of directly augmenting glucagon-like peptide-1 and glucose-dependent insulinotropic peptide levels and of inhibiting the activity of dipeptidyl peptidase IV.

This study is an extension of 7 controlled phase 3 studies of alogliptin. These phase 3 studies included 1 monotherapy study of alogliptin (SYR-322-PLC-010; NCT00286455); 4 placebo-controlled add-on studies of alogliptin, namely in combination with a sulfonylurea (SYR-322-SULF-007; NCT00286468), metformin (SYR-322-MET-008; NCT00286442), a thiazolidinedione (pioglitazone; SYR-322-TZD-009; NCT00286494), and insulin (SYR-322-INS-011; NCT00286429); 1 coadministration study with pioglitazone in combination with metformin (01-05-TL-322OPI-001; NCT00328627), and 1 coadministration study with pioglitazone (01-06-TL-322OPI-002; NCT00395512).

The end of treatment or early withdrawal visit from the preceding study will be the screening visit for this study, after which enrolled patients will be required to commit to approximately 22 additional visits at the study center.

Study Timeline

• Study Start: 2006-03
• Study First Submitted: 2006-03-21
• Study First Submitted QC: 2006-03-21
• Study First Posted: 2006-03-23
• Primary Completion: 2011-11
• Study Completion: 2011-11
• Status Verified: 2013-02
• Results First Submitted: 2013-02-17
• Results First Submitted QC: 2013-02-17
• Last Update Submitted: 2013-02-17
• Results First Posted: 2013-03-22
• Last Update Posted: 2013-03-22

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 3323

Inclusion Criteria

• Females of childbearing potential who are sexually active must agree to use adequate contraception, and can neither be pregnant nor lactating from Screening throughout the duration of the study.

• Type 2 diabetes mellitus and was enrolled in one of the following 7 controlled Phase III studies. The study will be open to all patients who completed one of these studies through the end-of-treatment visit:

  • SYR-322-PLC-010 - NCT00286455
  • SYR-322-SULF-007 - NCT00286468
  • SYR-322-MET-008 - NCT00286442
  • SYR-322-TZD-009 - NCT00286494
  • SYR-322-INS-011 - NCT00286429
  • 01-05-TL-322OPI-001 - NCT00328627
  • 01-06-TL-322OPI-002 - NCT00395512

• Alanine aminotransferase less than or equal to 3 times the upper limit of normal and serum creatinine less than or equal to 2.0 mg per dL.

• Able and willing to monitor own blood glucose concentrations with a home glucose monitor.

• No major illness or debility that in the investigator's opinion prohibits the patient from completing the study.

Exclusion Criteria

• The occurrence of any adverse event or condition during the controlled Phase III studies, which, in the opinion of the investigator, should exclude the patient from participating in the open-label extension.

• Is required to take or intends to continue taking any disallowed medication, any prescription medication, herbal treatment or over-the counter medication that may interfere with evaluation of the study medication, including:

  • Weight-loss drugs
  • Investigational antidiabetics, additional dipeptidyl peptidase-4 (DPP-4) and glucagon-like peptide-1 (GLP 1) inhibitors
  • Incretin Mimetics,
  • Oral or systemically injected glucocorticoids.

Exclusion Criteria

Not provided

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Alogliptin 12.5 mg	Alogliptin	Alogliptin 12.5 tablet, orally, once daily for up to 4 years.
Alogliptin 25 mg	Alogliptin	Alogliptin 25 mg tablet, orally, once daily for up to 4 years.

Primary Outcome Measures

Name	Time	Method
Percentage of Participants With Treatment-emergent Adverse Events (TEAEs)	4 years	Safety was assessed by physical examinations, clinical laboratory parameters, electrocardiogram (ECG) readings, vital sign measurements, oral temperature, and hypoglycemic events. Changes in laboratory values or ECG parameters were considered to be adverse events if they were judged to be clinically significant. A TEAE was any event that started on or after the first dose of open-label study drug and within 14 days after the last dose.

Secondary Outcome Measures

Name	Time	Method
Change From Baseline Over Time in Glycosylated Hemoglobin	Baseline and Month 3, 6, 9, 12, 15, 18, 21, 24, 27, 30, 33, 36, 39, 42 and 45.	The change from Baseline in glycosylated hemoglobin (HbA1c; the concentration of glucose bound to hemoglobin as a percent of the absolute maximum that can be bound) during the study. Endpoint was defined as the last postbaseline observation collected within 7 days after the last dose of open-label study drug.
Change From Baseline in Fasting Plasma Glucose	Baseline and Year 4	The change from Baseline in fasting plasma glucose (FPG) at the last post-baseline observation, collected within 7 days after the last dose of open-label study drug.
Percentage of Participants With Marked Hyperglycemia	Randomization up to 4 years.	Marked Hyperglycemia is defined as fasting plasma glucose greater than or equal to 200 mg/dL (≥11.10 mmol/L).; The Month 42 to Month 45 interval includes all marked hyperglycemic episodes occurring on or after Day 1247 (a 203-day visit window).
Change From Baseline in Proinsulin Level	Baseline and Year 4	Proinsulin is a precursor to insulin, and was measured as an indicator of pancreatic function. The change from Baseline in fasting proinsulin to the last post-baseline observation, collected within 7 days after the last dose of open-label study drug.; Note: A transcription error occurred in the reporting of 1 proinsulin value for a patient in the alogliptin 25 mg completed group, for whom a partial patient ID number was mistakenly entered as an end-of-treatment proinsulin level.
Change From Baseline in Insulin Level	Baseline and Year 4	The change from Baseline in fasting insulin at the last post-baseline observation, collected within 7 days after the last dose of open-label study drug.
Change From Baseline in C-peptide Level	Baseline and Year 4	C-peptide is a byproduct created when the hormone insulin is produced and is measured by a blood test. Change from Baseline to the last post-baseline observation, collected within 7 days after the last dose of open-label study drug.
Change From Baseline in Body Weight	Baseline and Year 4	Change from Baseline in body weight to the last post-baseline observation collected within 7 days after the last dose of open-label study drug.
Percentage of Participants With a Clinical Response	Weeks 2, 4, 8, 12, every 3 months up to 4 years, and 1 Day after final dose.	Clinical response was defined based on the absolute value of HbA1c meeting one of two clinical targets at any post-baseline visit: * HbA1c ≤6.5%; * HbA1c ≤7.0%.