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

Sponsor

Takeda (Industry)

Overall Status

Completed

CT.gov ID

NCT00760344

Collaborator

(none)

386

Enrollment

112

Locations

Arms

Duration (Months)

3.4

Patients Per Site

0.3

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

The purpose of this study is to determine the efficacy and safety of SYR-472, once daily (QD), in subjects with type 2 diabetes mellitus who have not achieved glycemic control with diet and exercise, or by taking metformin.

Condition or Disease	Intervention/Treatment	Phase
Diabetes Mellitus	Drug: SYR-472 Drug: SYR-472 Drug: SYR-472 Drug: SYR-472 Drug: Placebo Drug: Sitagliptin	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 20 weeks.

Study Design

Study Type:

Interventional

Actual Enrollment :

386 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 Treatment With SYR-472 in Subjects With Type 2 Diabetes

Study Start Date :

Mar 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 3.125 mg QD (with lifestyle modification and/or metformin stable dose therapy)	Drug: SYR-472 SYR-472 3.125 mg, tablets, orally, once daily with lifestyle modification and/or metformin stable dose therapy for up to 12 weeks.
Experimental: SYR-472 12.5 mg QD (with lifestyle modification and/or metformin stable dose therapy)	Drug: SYR-472 SYR-472 12.5 mg, tablets, orally, once daily with lifestyle modification and/or metformin stable dose therapy for up to 12 weeks.
Experimental: SYR-472 50 mg QD (with lifestyle modification and/or metformin stable dose therapy)	Drug: SYR-472 SYR-472 50 mg, tablets, orally, once daily with lifestyle modification and/or metformin stable dose therapy for up to 12 weeks.
Experimental: SYR-472 100 mg QD (with lifestyle modification and/or metformin stable dose therapy)	Drug: SYR-472 SYR-472 100 mg, tablets, orally, once daily with lifestyle modification and/or metformin stable dose therapy for up to 12 weeks.
Placebo Comparator: Placebo QD (with lifestyle modification and/or metformin stable dose therapy)	Drug: Placebo SYR-472 placebo-matching tablets, orally, once daily with lifestyle modification and/or metformin therapy for up to 12 weeks.
Active Comparator: Sitagliptin 100 mg QD (with lifestyle modification and/or metformin stable dose therapy)	Drug: Sitagliptin Sitagliptin 100 mg, tablets, orally, once daily with lifestyle modification and/or metformin stable dose therapy for up to 12 weeks. Other Names: Januvia™

Outcome Measures

Primary Outcome Measures

Change from baseline in glycosylated hemoglobin [Week 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]
Change from baseline in 1,5-Anhydroglucitol [Weeks 2, 4, 8, and 12 or Final Visit.]
Change from baseline in Proinsulin [Weeks 4, 8, and 12 or Final Visit.]
Change from baseline in Insulin [Weeks 4, 8, and 12 or Final Visit.]
Change from baseline in Proinsulin/insulin ratio [Weeks 4, 8, and 12 or Final Visit.]
Change from baseline in C-peptide [Weeks 4, 8, and 12 or Final Visit.]
Change from baseline in Homeostasis model assessment of insulin resistance. [Weeks: 4, 8, and 12 or Final Visit.]
Change from baseline in Homeostasis model assessment of beta-cell function. [Weeks 4, 8, and 12 or Final Visit.]
Incidence of marked hyperglycemia (fasting plasma glucose greater than or equal to 200 mg/dL [11.10 mmol/L]). [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:

Had a historical diagnosis of type 2 diabetes mellitus.
Had 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.
If 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.
Had received no treatment with antidiabetic agents other than metformin within the 8 weeks prior to Screening.
The subject has an glycosylated hemoglobin concentration between 7.0% and 10.0%, inclusive, at Screening and at the Week -1 Visit.
Had a body mass index between 23 and 45 kg/m2.
A C-peptide concentration is greater than or equal to 0.8 ng/mL (greater than or equal to 0.26 nmol/L).
A fasting plasma glucose concentration is less than 275 mg/dL (less than 15.27 mmol/L) at Screening and at the Week -1 Visit.
If the subject regularly uses other non-excluded medications, he or she must be on a stable dose for at least the 4 weeks prior to Screening.
The subject has a systolic blood pressure reading of less than 160 mm Hg and a diastolic pressure reading of less than 100 mm Hg.
The subject has a hemoglobin value greater than or equal to 12 g/dL (greater than or equal to 120 g/L) for men and greater than or equal to 10 g/dL (greater than or equal to 100 g/L) for women.
Had an alanine aminotransferase level is less than or equal to 3 times the upper limit of normal.
A male subject has a serum creatinine value of less than 1.5 mg/dL (less than 133 μmol/L); a female subject has a serum creatinine value of less than 1.4 mg/dL (less than 124 μmol/L).
Had a urine albumin/creatinine ratio of less than 1000 μg/mg at Screening.
Had a thyroid-stimulating hormone level less than or equal to the upper limit of the normal range and the subject is clinically euthyroid.
A female subject of childbearing potential who is sexually active must agree to use adequate contraception, and must be neither pregnant nor lactating from Screening and throughout the duration of the study.
Was able and willing to monitor his or her own blood glucose concentrations with a home glucose monitor.
Had no major illness or debility that in the investigator's opinion prohibits the subject from completing the study.

Exclusion Criteria:

Was being concurrently treated with antidiabetic therapy other than metformin and lifestyle intervention.
Had 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.
Had a history of laser treatment for proliferative diabetic retinopathy within the 6 months prior to Screening.
Had a history of treated diabetic gastric paresis.
Had a New York Heart Association class III or IV heart failure regardless of therapy.
Had a history of coronary angioplasty, coronary stent placement or coronary bypass surgery, myocardial infarction, or stroke within the 6 months prior to Screening.
Had a history of hemoglobinopathy that may affect determination of glycosylated hemoglobin.
Had a history of infection with human immunodeficiency virus.
Had a history of a psychiatric disorder that in the investigator's opinion will affect the subject's ability to participate in the study.
Had a history of alcohol abuse (defined as regular or daily consumption of more than 4 alcoholic drinks per day) or substance abuse (defined as illicit drug use) within the 2 years prior to Screening.
Was 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:
Ingested or received systemically injected glucocorticoids within the 3 months prior to randomization.
Used prescription or over-the-counter weight-loss drugs within the 3 months prior to randomization.
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.
Had received previous treatment in an investigational study of SYR-472.
Had a known hypersensitivity to any compound related to SYR-472 or Sitagliptin.

Contacts and Locations

Locations

	City	State	Country
1	Birmingham	Alabama	United States
2	Mobile	Alabama	United States
3	Montgomery	Alabama	United States
4	Phoenix	Arizona	United States
5	Tempe	Arizona	United States
6	Tucson	Arizona	United States
7	Anderson	Arkansas	United States
8	Little Rock	Arkansas	United States
9	Pine Bluff	Arkansas	United States
10	Carmichael	California	United States
11	Chino	California	United States
12	Long Beach	California	United States
13	Los Angeles	California	United States
14	Los Gatos	California	United States
15	Orange	California	United States
16	Pico Rivera	California	United States
17	Rolling Hills Estates	California	United States
18	Roseville	California	United States
19	Rowland Heights	California	United States
20	Sacramento	California	United States
21	Santa Ana	California	United States
22	Stockton	California	United States
23	Torrance	California	United States
24	Arvada	Colorado	United States
25	Colorado Springs	Colorado	United States
26	Highlands Ranch	Colorado	United States
27	Avon	Connecticut	United States
28	Rocky Hill	Connecticut	United States
29	Newark	Delaware	United States
30	Aventura	Florida	United States
31	Edgewater	Florida	United States
32	Hollywood	Florida	United States
33	Jacksonville	Florida	United States
34	Kissimmee	Florida	United States
35	Merritt Island	Florida	United States
36	Miami	Florida	United States
37	New Port Richey	Florida	United States
38	Ocala	Florida	United States
39	Pembroke Pines	Florida	United States
40	Tampa	Florida	United States
41	Zanesville	Florida	United States
42	Atlanta	Georgia	United States
43	Roswell	Georgia	United States
44	Waycross	Georgia	United States
45	Idaho Falls	Idaho	United States
46	Chicago	Illinois	United States
47	Avon	Indiana	United States
48	Fort Wayne	Indiana	United States
49	Des Moines	Iowa	United States
50	Waterloo	Iowa	United States
51	Topeka	Kansas	United States
52	Wichita	Kansas	United States
53	Crestview	Kentucky	United States
54	Oxon Hill	Maryland	United States
55	Detroit	Michigan	United States
56	Troy	Michigan	United States
57	Olive Branch	Mississippi	United States
58	Kansas City	Missouri	United States
59	St. Louis	Missouri	United States
60	Omaha	Nebraska	United States
61	Las Vegas	Nevada	United States
62	West Caldwell	New Jersey	United States
63	Wildwood Crest	New Jersey	United States
64	Albuquerque	New Mexico	United States
65	East Islip	New York	United States
66	Lewiston	New York	United States
67	New York	New York	United States
68	North Massapequa	New York	United States
69	Wantagh	New York	United States
70	Hickory	North Carolina	United States
71	Statesville	North Carolina	United States
72	Tabor City	North Carolina	United States
73	Bismarck	North Dakota	United States
74	Cincinnati	Ohio	United States
75	Columbus	Ohio	United States
76	Mason	Ohio	United States
77	Wadsworth	Ohio	United States
78	Norman	Oklahoma	United States
79	Oklahoma City	Oklahoma	United States
80	Tulsa	Oklahoma	United States
81	Eugene	Oregon	United States
82	Medford	Oregon	United States
83	Bensalem	Pennsylvania	United States
84	Connellsville	Pennsylvania	United States
85	Philadelphia	Pennsylvania	United States
86	Pittsburgh	Pennsylvania	United States
87	Shippensburg	Pennsylvania	United States
88	Charleston	South Carolina	United States
89	Greer	South Carolina	United States
90	North Myrtle Beach	South Carolina	United States
91	Chattanooga	Tennessee	United States
92	Memphis	Tennessee	United States
93	New Tazewell	Tennessee	United States
94	Carrolton	Texas	United States
95	Dallas	Texas	United States
96	Georgetown	Texas	United States
97	Houston	Texas	United States
98	Killeen	Texas	United States
99	San Antonio	Texas	United States
100	Salt Lake City	Utah	United States
101	Spanish Fork	Utah	United States
102	Richmond	Virginia	United States
103	Suffolk	Virginia	United States
104	Virginia Beach	Virginia	United States
105	Spokane	Washington	United States
106	Zapopan	Jalisco	Mexico
107	Monterrey	Nuevo Leon	Mexico
108	Mexico DF		Mexico
109	Monterrey		Mexico
110	Nezahualcoyotl		Mexico
111	Puebla		Mexico
112	Veracruz		Mexico