Clinical trial NCT00760344: Efficacy and Safety of SYR-472 in Subjects With Type 2 Diabetes Mellitus
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 type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Diabetes Mellitus
Keywords: Glucose Metabolism Disorder
Dysmetabolic Syndrome
Type II Diabetes
Diabetes Mellitus, Lipoatrophic
Dyslipidemia
Drug Therapy
Lead sponsor: Takeda
Sponsor class: INDUSTRY
First posted: 2008-09-26
Enrollment: 386
Sex: ALL
Minimum age (years): 18
Maximum age (years): 80
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

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.

Eligibility criteria: 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.

Primary outcomes:
measure: Change from baseline in glycosylated hemoglobin
timeFrame: Week 12 or Final Visit
Secondary outcomes:
measure: Change from baseline in glycosylated hemoglobin
timeFrame: Weeks 4, 8 and 12 or Final Visit.
measure: Change from baseline in fasting plasma glucose
timeFrame: Weeks 1, 2, 4, 8, and 12 or Final Visit
measure: Change from baseline in 1,5-Anhydroglucitol
timeFrame: Weeks 2, 4, 8, and 12 or Final Visit.
measure: Change from baseline in Proinsulin
timeFrame: Weeks 4, 8, and 12 or Final Visit.
measure: Change from baseline in Insulin
timeFrame: Weeks 4, 8, and 12 or Final Visit.
measure: Change from baseline in Proinsulin/insulin ratio
timeFrame: Weeks 4, 8, and 12 or Final Visit.
measure: Change from baseline in C-peptide
timeFrame: Weeks 4, 8, and 12 or Final Visit.
measure: Change from baseline in Homeostasis model assessment of insulin resistance.
timeFrame: Weeks: 4, 8, and 12 or Final Visit.
measure: Change from baseline in Homeostasis model assessment of beta-cell function.
timeFrame: Weeks 4, 8, and 12 or Final Visit.
measure: Incidence of marked hyperglycemia (fasting plasma glucose greater than or equal to 200 mg/dL [11.10 mmol/L]).
timeFrame: Weeks 4, 8 and 12 or Final Visit.
measure: Incidence of rescue.
timeFrame: Weeks 1, 2, 4, 8, and 12 or Final Visit.
measure: Clinical response endpoint incidence of glycosylated hemoglobin less than or equal to 6.5%.
timeFrame: Week 12 or Final Visit
measure: Clinical response endpoint incidence of glycosylated hemoglobin less than or equal to 7.0%.
timeFrame: Week 12 or Final Visit
measure: Change from baseline in Fasting lipids (triglycerides, total cholesterol, high-density lipoprotein cholesterol and low-density lipoprotein cholesterol).
timeFrame: Weeks 4, 8, and 12 or Final Visit.
measure: Body weight.
timeFrame: Weeks 4, 8, and 12 or Final Visit.
Other outcomes:
Locations:
city: Birmingham
country: United States
state: Alabama
city: Mobile
country: United States
state: Alabama
city: Montgomery
country: United States
state: Alabama
city: Phoenix
country: United States
state: Arizona
city: Tempe
country: United States
state: Arizona
city: Tucson
country: United States
state: Arizona
city: Anderson
country: United States
state: Arkansas
city: Little Rock
country: United States
state: Arkansas
city: Pine Bluff
country: United States
state: Arkansas
city: Carmichael
country: United States
state: California
city: Chino
country: United States
state: California
city: Long Beach
country: United States
state: California
city: Los Angeles
country: United States
state: California
city: Los Gatos
country: United States
state: California
city: Orange
country: United States
state: California
city: Pico Rivera
country: United States
state: California
city: Rolling Hills Estates
country: United States
state: California
city: Roseville
country: United States
state: California
city: Rowland Heights
country: United States
state: California
city: Sacramento
country: United States
state: California
city: Santa Ana
country: United States
state: California
city: Stockton
country: United States
state: California
city: Torrance
country: United States
state: California
city: Arvada
country: United States
state: Colorado
city: Colorado Springs
country: United States
state: Colorado
city: Highlands Ranch
country: United States
state: Colorado
city: Avon
country: United States
state: Connecticut
city: Rocky Hill
country: United States
state: Connecticut
city: Newark
country: United States
state: Delaware
city: Aventura
country: United States
state: Florida
city: Edgewater
country: United States
state: Florida
city: Hollywood
country: United States
state: Florida
city: Jacksonville
country: United States
state: Florida
city: Kissimmee
country: United States
state: Florida
city: Merritt Island
country: United States
state: Florida
city: Miami
country: United States
state: Florida
city: New Port Richey
country: United States
state: Florida
city: Ocala
country: United States
state: Florida
city: Pembroke Pines
country: United States
state: Florida
city: Tampa
country: United States
state: Florida
city: Zanesville
country: United States
state: Florida
city: Atlanta
country: United States
state: Georgia
city: Roswell
country: United States
state: Georgia
city: Waycross
country: United States
state: Georgia
city: Idaho Falls
country: United States
state: Idaho
city: Chicago
country: United States
state: Illinois
city: Avon
country: United States
state: Indiana
city: Fort Wayne
country: United States
state: Indiana
city: Des Moines
country: United States
state: Iowa
city: Waterloo
country: United States
state: Iowa
city: Topeka
country: United States
state: Kansas
city: Wichita
country: United States
state: Kansas
city: Crestview
country: United States
state: Kentucky
city: Oxon Hill
country: United States
state: Maryland
city: Detroit
country: United States
state: Michigan
city: Troy
country: United States
state: Michigan
city: Olive Branch
country: United States
state: Mississippi
city: Kansas City
country: United States
state: Missouri
city: St. Louis
country: United States
state: Missouri
city: Omaha
country: United States
state: Nebraska
city: Las Vegas
country: United States
state: Nevada
city: West Caldwell
country: United States
state: New Jersey
city: Wildwood Crest
country: United States
state: New Jersey
city: Albuquerque
country: United States
state: New Mexico
city: East Islip
country: United States
state: New York
city: Lewiston
country: United States
state: New York
city: New York
country: United States
state: New York
city: North Massapequa
country: United States
state: New York
city: Wantagh
country: United States
state: New York
city: Hickory
country: United States
state: North Carolina
city: Statesville
country: United States
state: North Carolina
city: Tabor City
country: United States
state: North Carolina
city: Bismarck
country: United States
state: North Dakota
city: Cincinnati
country: United States
state: Ohio
city: Columbus
country: United States
state: Ohio
city: Mason
country: United States
state: Ohio
city: Wadsworth
country: United States
state: Ohio
city: Norman
country: United States
state: Oklahoma
city: Oklahoma City
country: United States
state: Oklahoma
city: Tulsa
country: United States
state: Oklahoma
city: Eugene
country: United States
state: Oregon
city: Medford
country: United States
state: Oregon
city: Bensalem
country: United States
state: Pennsylvania
city: Connellsville
country: United States
state: Pennsylvania
city: Philadelphia
country: United States
state: Pennsylvania
city: Pittsburgh
country: United States
state: Pennsylvania
city: Shippensburg
country: United States
state: Pennsylvania
city: Charleston
country: United States
state: South Carolina
city: Greer
country: United States
state: South Carolina
city: North Myrtle Beach
country: United States
state: South Carolina
city: Chattanooga
country: United States
state: Tennessee
city: Memphis
country: United States
state: Tennessee
city: New Tazewell
country: United States
state: Tennessee
city: Carrolton
country: United States
state: Texas
city: Dallas
country: United States
state: Texas
city: Georgetown
country: United States
state: Texas
city: Houston
country: United States
state: Texas
city: Killeen
country: United States
state: Texas
city: San Antonio
country: United States
state: Texas
city: Salt Lake City
country: United States
state: Utah
city: Spanish Fork
country: United States
state: Utah
city: Richmond
country: United States
state: Virginia
city: Suffolk
country: United States
state: Virginia
city: Virginia Beach
country: United States
state: Virginia
city: Spokane
country: United States
state: Washington
city: Zapopan
country: Mexico
state: Jalisco
city: Monterrey
country: Mexico
state: Nuevo Leon
city: Mexico DF
country: Mexico
city: Monterrey
country: Mexico
city: Nezahualcoyotl
country: Mexico
city: Puebla
country: Mexico
city: Veracruz
country: Mexico
Study officials:
affiliation: Takeda
name: VP Biological Sciences
role: STUDY_DIRECTOR
References: