Efficacy of SYR-472 in Subjects With Type 2 Diabetes Mellitus

Sponsor

Takeda (Industry)

Overall Status

Completed

CT.gov ID

NCT00653185

Collaborator

(none)

369

Enrollment

Locations

Arms

Duration (Months)

4.2

Patients Per Site

0.4

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

The purpose of this study is to determine the efficacy, safety and tolerability of SYR-472, once daily (QD), in subjects with Type 2 Diabetes Mellitus.

Condition or Disease	Intervention/Treatment	Phase
Diabetes Mellitus	Drug: SYR-472 Drug: SYR-472 Drug: SYR-472 Drug: SYR-472 Drug: Placebo	Phase 2

Detailed Description

Type 2 diabetes mellitus is a complex metabolic disorder characterized by abnormal insulin secretion and glucose homeostasis, resulting from impaired pancreatic beta-cell function and insulin resistance in target tissues. The worldwide prevalence of type 2 diabetes mellitus is reaching epidemic proportions, and the total number of cases is expected to reach 221 million by 2010. The high incidence of the disease and its associated complications places a significant burden on healthcare systems.

The primary risk factor for the development of type 2 diabetes mellitus is obesity and its associated insulin resistance. Insulin resistance is characterized by an impaired response to the physiologic effects of insulin and leads to decreased cellular glucose uptake, increased hepatic gluconeogenesis, and a compensatory increase in insulin secretion that contributes to beta-cell exhaustion. Therefore in the insulin-resistant state, blood glucose and insulin levels are increased. The relationship between improved glycemic control in patients with type 2 diabetes mellitus and the delay or prevention of comorbidities has been reported in the Diabetes Control and Complications Trial and the United Kingdom Prospective Diabetes Study. Therefore, reduction of persistent hyperglycemia is the highest priority in treating this disease.

Diet and exercise are important and effective measures for maintaining glycemic control in individuals with insulin resistance, impaired glucose tolerance, and type 2 diabetes mellitus, particularly in the early stages of disease progression. In cases where diet and exercise alone fail to adequately maintain glycemic control, oral antidiabetic drugs are typically used. Combination oral therapy and eventually insulin are usually required to maintain lower blood glucose levels but can result in adverse effects including hypoglycemia and weight gain. Therefore, novel safe and effective antidiabetic therapies are needed.

Dipeptidyl peptidase-4 is a ubiquitous aminopeptidase that is widely expressed in many tissues; it is thought to be primarily responsible for the in vivo degradation of at least two gut-derived incretin hormones, namely glucagon-like peptide-1 and glucose-dependent insulinotropic peptide, which are both released in response to nutrient ingestion. Glucagon-like peptide-1 has been demonstrated to augment glucose-dependent insulin secretion; suppress glucagon release and hepatic gluconeogenesis; inhibit gastric emptying, and reduce appetite and food intake. Glucagon-like peptide-1 and glucose-dependent insulinotropic peptide also have been shown to promote insulin biosynthesis and stimulate beta cell proliferation and survival. Orally available inhibitors of dipeptidyl peptidase-4 activity have been developed that increase intact postprandial glucagon-like peptide-1 levels after oral administration.

SYR-472 is a selective inhibitor of dipeptidyl peptidase-4 in development to improve glycemic control in patients with type 2 diabetes mellitus. The aim of this study is to evaluate SYR-472 in subjects with type 2 diabetes mellitus who have not previously achieved adequate glycemic control with lifestyle modification (diet/exercise) or metformin antidiabetic monotherapy. Study participation is anticipated to be up to 14 weeks.

Study Design

Study Type:

Interventional

Actual Enrollment :

369 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)

Primary Purpose:

Treatment

Official Title:

A Phase 2, Double-Blind, Randomized, Placebo-Controlled, Parallel-Group, Multicenter Study to Evaluate Weekly Treatment With SYR-472 in Subjects With Type 2 Diabetes

Study Start Date :

May 1, 2007

Actual Primary Completion Date :

Mar 1, 2008

Actual Study Completion Date :

Mar 1, 2008

Arms and Interventions

Arm	Intervention/Treatment
Experimental: SYR-472 25 mg QD (with lifestyle modification and/or metformin therapy)	Drug: SYR-472 SYR-472 25 mg, tablets, orally, once daily and lifestyle modification and/or metformin for up to 12 weeks.
Experimental: SYR-472 50 mg QD (with lifestyle modification and/or metformin therapy)	Drug: SYR-472 SYR-472 50 mg, tablets, orally, once daily and lifestyle modification and/or metformin for up to 12 weeks.
Experimental: SYR-472 100 mg QD (with lifestyle modification and/or metformin therapy)	Drug: SYR-472 SYR-472 100 mg, tablets, orally, once daily and lifestyle modification and/or metformin for up to 12 weeks.
Experimental: SYR-472 200 mg QD (with lifestyle modification and/or metformin therapy)	Drug: SYR-472 SYR-472 200 mg, tablets, orally, once daily and lifestyle modification and/or metformin for up to 12 weeks.
Placebo Comparator: Placebo QD (with lifestyle modification and/or metformin therapy)	Drug: Placebo SYR-472 placebo-matching tablets, orally, once daily and lifestyle modification and/or metformin for up to 12 weeks.

Outcome Measures

Primary Outcome Measures

Change from baseline in glycosylated hemoglobin [Weeks 12 or Final Visit.]

Secondary Outcome Measures

Change from baseline in glycosylated hemoglobin [Weeks 4, 8, and 12 or Final Visit.]
Change from baseline in fasting plasma glucose [Weeks 1, 2, 4, 8, and 12 or Final Visit.]
1,5-Anhydroglucitol [Weeks 2, 4, 8, and 12 or Final Visit.]
Change in Proinsulin [Weeks 4, 8, and 12 or Final Visit.]
Change in Proinsulin/insulin ratio [Weeks 4, 8, and 12 or Final Visit.]
Change in baseline C-peptide [Weeks 4, 8, and 12 or Final Visit.]
Change from baseline in insulin [Weeks 4, 8, and 12 or Final Visit.]
Change in Homeostasis model assessment of beta cell function [Weeks 4, 8, and 12 or Final Visit.]
Change in Homeostasis model assessment of insulin resistance [Weeks 4, 8, and 12 or Final Visit]
Incidence of rescue [Weeks 1, 2, 4, 8, and 12 or Final Visit.]
Clinical response endpoint incidence of glycosylated hemoglobin less than or equal to 6.5% [Week 12 or Final Visit]
Clinical response endpoint incidence of glycosylated hemoglobin less than or equal to 7.0% [Week 12 or Final Visit]
Change from baseline in Fasting lipids (triglycerides, total cholesterol, high-density lipoprotein cholesterol and low-density lipoprotein cholesterol) [Weeks 4, 8, and 12 or Final Visit]
Body weight [Weeks 4, 8, and 12 or Final Visit.]

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 80 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Has a historical diagnosis of type 2 diabetes mellitus.
Has undergone less than 7 days of any antidiabetic therapy except lifestyle modification (diet/exercise) within 8 weeks prior to Screening; or has received metformin monotherapy for at least 8 weeks prior to Screening and maintained a stable daily dose of metformin for at least 12 weeks prior to randomization.
The subject receiving metformin monotherapy at randomization must have been at least 75% compliant with his or her regimen during the Run-in/Stabilization Period as determined by subject diary and investigator assessment.
Has received no treatment with antidiabetic agents other than metformin within the 8 weeks prior to Screening.
Has a glycosylated hemoglobin concentration between 7.0% and 10.0%, inclusive, at Screening and at the Week -1 Visit.
The subject's fasting C-peptide concentration is greater than or equal to 0.8 ng/mL.
Has a fasting plasma glucose concentration less than 275 mg/dL.
If regularly uses other non-excluded medications, must be on a stable dose for at least the 4 weeks prior to Screening.
Has a systolic blood pressure reading less than 160 mm Hg and a diastolic pressure reading less than 100 mm Hg.
Has a hemoglobin value greater than or equal to 12 g/dL for men and greater than or equal to 10 g/dL for women.
Has an alanine aminotransferase level is less than or equal to 3 times the upper limit of normal.
Males have a serum creatinine value less than 1.5 mg/dL; females have a serum creatinine value less than 1.4 mg/dL.
Has a urine albumin/creatinine ratio less than 1000 μg/mg.
Has a thyroid-stimulating hormone level less than or equal to the upper limit of the normal range and is clinically euthyroid.
Females must be not be pregnant or lactating, and must agree to use adequate contraception throughout the duration of the study.
Is able and willing to monitor his or her own blood glucose concentrations with a home glucose monitor.
Has no major illness or debility that in the investigator's opinion prohibits the subject from completing the study.

Exclusion Criteria

Is being concurrently treated with antidiabetic therapy other than metformin and lifestyle intervention.
Has a history of cancer, other than squamous cell or basal cell carcinoma of the skin that has not been in full remission for at least 5 years prior to Screening.
Has a history of laser treatment for proliferative diabetic retinopathy within the 6 months prior to Screening.
Has a history of treated diabetic gastric paresis.
Has New York Heart Association class III or IV heart failure regardless of therapy.
Has a history of coronary angioplasty, underwent coronary stent placement or coronary bypass surgery, or suffered a myocardial infarction, or stroke within the 6 months prior to Screening.
Has a history of any hemoglobinopathy that may affect determination of glycosylated hemoglobin.
Has a history of infection with human immunodeficiency virus.
Has a history of a psychiatric disorder that in the investigator's opinion will affect the subject's ability to participate in the study.
Has ingested or received systemically injected glucocorticoids within the 3 months prior to randomization. Inhaled corticosteroids are allowed.
Has used prescription or over-the-counter weight-loss drugs within the 3 months prior to randomization.
Has received any investigational drug within the 30 days prior to Screening or has received an investigational antidiabetic drug within the 3 months prior to Screening.
Has received previous treatment in an investigational study of SYR-472.
Has a known hypersensitivity to any compound related to SYR-472.

Contacts and Locations

Locations

	City	State	Country
1	Birmingham	Alabama	United States
2	Mobile	Alabama	United States
3	Montgomery	Alabama	United States
4	Pell City	Alabama	United States
5	Tallassee	Alabama	United States
6	Sierra Vista	Arizona	United States
7	Fountain Valley	California	United States
8	Los Angeles	California	United States
9	National City	California	United States
10	Pismo Beach	California	United States
11	Clearwater	Florida	United States
12	North Miami Beach	Florida	United States
13	Ocoee	Florida	United States
14	Orlando	Florida	United States
15	Plantation	Florida	United States
16	Dawsonville	Georgia	United States
17	Gainesville	Georgia	United States
18	Naperville	Illinois	United States
19	Elkhart	Indiana	United States
20	Indianapolis	Indiana	United States
21	Slidell	Louisiana	United States
22	Taunton	Massachusetts	United States
23	Ann Arbor	Michigan	United States
24	Great Falls	Montana	United States
25	Scottsbluff	Nebraska	United States
26	Las Vegas	Nevada	United States
27	Brooklyn	New York	United States
28	Charlotte	North Carolina	United States
29	Shelby	North Carolina	United States
30	Sparta	North Carolina	United States
31	Fargo	North Dakota	United States
32	Bensalem	Ohio	United States
33	Dayton	Ohio	United States
34	Kettering	Ohio	United States
35	Central Point	Oregon	United States
36	Altoona	Pennsylvania	United States
37	Providence	Rhode Island	United States
38	Clemson	South Carolina	United States
39	Columbia	South Carolina	United States
40	Greer	South Carolina	United States
41	Rapid City	South Dakota	United States
42	Cleveland	Tennessee	United States
43	Kingsport	Tennessee	United States
44	Arlington	Texas	United States
45	Fort Worth	Texas	United States
46	North Richland Hills	Texas	United States
47	San Antonio	Texas	United States
48	Spring	Texas	United States
49	Sugarland	Texas	United States
50	Hampton	Virginia	United States
51	Richmond	Virginia	United States
52	Santiago		Chile
53	Temuco		Chile
54	Ostrava		Czech Republic
55	Prague		Czech Republic
56	Guatemala		Guatemala
57	Quetzaltenango		Guatemala
58	Eger		Hungary
59	Szentes		Hungary
60	Riga		Latvia
61	Sigulda		Latvia
62	Valmiera		Latvia
63	Kaunas		Lithuania
64	Kedainiai		Lithuania
65	Klaipeda		Lithuania
66	Vilnius		Lithuania
67	Ponce		Puerto Rico
68	Alba Iulia		Romania
69	Baia Mare		Romania
70	Bihor		Romania
71	Brasov		Romania
72	Bucharest		Romania
73	Constanta		Romania
74	Ploiesti		Romania
75	Satu Mare		Romania
76	Targoviste		Romania
77	Kemerovo		Russian Federation
78	Moscow		Russian Federation
79	St. Petersburg		Russian Federation
80	Ufa		Russian Federation
81	Volgograd		Russian Federation
82	Yaroslavl		Russian Federation
83	Banska Bystrica		Slovakia
84	Bratislava		Slovakia
85	Presov		Slovakia
86	Kharkiv		Ukraine
87	Vinnytsya		Ukraine