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Glycemic Control and Complications in Diabetes Mellitus Type 2 (VADT)

This study has been completed.
Sponsor:
Collaborators:
SmithKline Beecham
Information provided by (Responsible Party):
Department of Veterans Affairs
ClinicalTrials.gov Identifier:
NCT00032487
First received: March 21, 2002
Last updated: March 7, 2014
Last verified: March 2014
  Purpose

This study is a prospective, 2-arm, randomized controlled trial to determine whether glycemic control, achieved through intensification of treatment, is effective in preventing clinical macrovascular complications in patients with type 2 DM who are no longer responsive to oral agents alone. The study consists of a two-year accrual period and five years of follow-up (7 years total) of 1700 patients across 20 centers. We have powered the study to detect a 21% reduction in the primary event rate. Additional study goals are to determine whether the expenditures, discomfort, and adverse effects associated with intensive intervention are justified in terms of their clinical benefits, considering both macrovascular and microvascular complications.


Condition Intervention Phase
Type 2 Diabetes Mellitus
Drug: Insulin
Drug: Glimepiride
Drug: Rosiglitazone
Drug: Metformin
Phase 3

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: CSP #465 - Glycemic Control and Complications in Diabetes Mellitus Type 2 (VADT)

Resource links provided by NLM:


Further study details as provided by Department of Veterans Affairs:

Primary Outcome Measures:
  • Primary Major Macrovascular Events [ Time Frame: Post baseline time to the first major macrovascular event up to 82 months ] [ Designated as safety issue: No ]
    Myocardial infarction (MI), intervention for coronary artery or Peripheral Vascular Disease (PVD), severe inoperable Coronary Artery Disease (CAD), new or worsening Congestive Heart Failure (CHF), stroke, Cardiovascular (CV) death, or amputation for ischemic gangrene.


Secondary Outcome Measures:
  • Secondary Endpoint [ Time Frame: Post baseline time to first event up to 82 months ] [ Designated as safety issue: No ]
    New or worsening angina, new transient ischemic attack (TIA), new intermittent claudication or critical limb ischemia with Doppler evidence or total mortality.


Enrollment: 1791
Study Start Date: December 2000
Study Completion Date: May 2008
Primary Completion Date: May 2008 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Active Comparator: Standard glycemic control
Standard glycemic control to maintain HbA1c between 8.0-9.0%. Metformin 500 mg Rosiglitazone 4 mg Glimepiride 2 mg Insulin 1 unit 9 lbs
Drug: Insulin
Insulin (intermediate or long-lasting) in a.m. 1 unit 9 lbs Arm 1 Insulin (intermediate or long-lasting) in a.m. 1 unit 9 lbs, add one injection of insulin Arm 2
Other Names:
  • Lantus,
  • NovoLog (aspart),
  • Novopen,
  • NPH,
  • Novolin R,
  • Lente
Drug: Glimepiride
Glimepiride 2 mg Arm 1 Glimepiride 8 mg Arm 2
Other Name: Amaryl
Drug: Rosiglitazone
Rosiglitazone 4 mg Arm 1 Rosiglitazone 4 mg bid Arm 2
Other Name: Avandia
Drug: Metformin
Metformin 500 mg (go up to 1000 mg) Arm 1 Metformin 500 mg (go up to 2000 mg) Arm 2
Other Names:
  • Fortamet,
  • Glucophage,
  • Glucophage XR,
  • Riomet,
  • Glumetza
Experimental: Intensive glycemic control
Intensive glycemic control lower HbA1c below 6.0%. Metformin 500 mg (go up to 2000 mg) Rosiglitazone 4 mg bid Glimepiride 8 mg Insulin 1 unit 9 lbs add one injection to Arm 1
Drug: Insulin
Insulin (intermediate or long-lasting) in a.m. 1 unit 9 lbs Arm 1 Insulin (intermediate or long-lasting) in a.m. 1 unit 9 lbs, add one injection of insulin Arm 2
Other Names:
  • Lantus,
  • NovoLog (aspart),
  • Novopen,
  • NPH,
  • Novolin R,
  • Lente
Drug: Glimepiride
Glimepiride 2 mg Arm 1 Glimepiride 8 mg Arm 2
Other Name: Amaryl
Drug: Rosiglitazone
Rosiglitazone 4 mg Arm 1 Rosiglitazone 4 mg bid Arm 2
Other Name: Avandia
Drug: Metformin
Metformin 500 mg (go up to 1000 mg) Arm 1 Metformin 500 mg (go up to 2000 mg) Arm 2
Other Names:
  • Fortamet,
  • Glucophage,
  • Glucophage XR,
  • Riomet,
  • Glumetza

  Hide Detailed Description

Detailed Description:

Primary Hypothesis: Intensive glycemic control reduces major macrovascular morbidity and mortality compared to standard glycemic control in type 2 diabetics who have failed simple therapy.

Secondary Hypotheses: Intensive glycemic control, compared to standard glycemic control, reduces other macrovascular morbidity and total mortality.

Intervention: The intervention is tight glycemic control, aiming at normalization of HbA1c. This will be achieved through stepped care therapy, using all categories of tools available to most diabetologists. These categories include: patient education of diabetes control (e.g. diet, exercise, etc.), oral diabetes medications, and insulin. All drugs to be used are approved. Specific agents will be used within the different classes to promote consistency across sites.

The comparison is standard control, aiming at HbA1c of 8 - 9%. The same agents will be used, but at reduced doses.

The general approach to the stepped care treatment protocol is to treat both groups with the same agents, but at different intensities (doses) (taking into account intolerance/contraindications). The sequence of steps is shown below.

STEP 1: Either Metformin (obese) or Glimepiride (lean)in combination with Rosiglitazone STEP 2: Insulin STEP 3: Increase doses in STEPS 1,2 in the Standard group. Since the Intensive group is already at maximal doses of oral agents, they will intensify insulin and may add Acarbose/Miglitol.

STEP 4: For standard, proceed as in STEP 3 for Intensive; Intensives will use multiple daily injection (MDI) of insulin STEP 5: "Tool Box": Miscellaneous agents, tailored to the individual patient.

Primary Outcomes: Time to one of the following major macrovascular events: myocardial infarction, stroke, new or worsening congestive heart failure, amputation for ischemic gangrene, invasive intervention for coronary artery or peripheral vascular disease, inoperable coronary artery disease, or cardiovascular death.

Secondary Outcomes: Angina, transient ischemic attack, intermittent claudication, critical limb ischemia, and total mortality.

Study Abstract: A quarter of the patients treated by the Department of Veterans Affairs (VA) Health Administration have type 2 diabetes mellitus (DM). The costs of care for the treatment of patients with type 2 DM are extremely high, both in treatment expenditures for the metabolic disorder and for the care of end-organ complications. Although patients initially respond to diet and oral agent treatment, most eventually need insulin to near-normalize their glucose level, as the disease is characterized by progressive loss of insulin secretory capacity.

After several clinical trials in both type 1 and type 2 DM, there is a reasonable certainty that about half of the incidence and rate of progression of indicators of microvascular complications (retinopathy, nephropathy, and neuropathy) can be prevented or delayed by achieving and maintaining near-normalization of glycemic levels. Consequently, there has been a uniform trend in recent guidelines to advise a near-normalization of glycemic levels in both type 1 and type 2 DM. Note, however, that the clinical consequences of microvascular deterioration are dependent not only on glycemic levels but also on the duration of the disease. With the early onset of diabetes typical in type 1 patients, there is sufficient time for development of clinical microvascular complications, and prevention of these complications is a goal of treatment in type 1 diabetics. In contrast, the prevalence of hard clinical endpoints indicative of microangiopathy, such as renal failure or blindness, is very low in patients in whom the disease is diagnosed after the 5th decade, the greatest age of prevalence of patients with type 2 DM in this country. Furthermore, microvascular complications can be minimized by the well-established benefits of blood pressure and lipid control, as well as by therapeutic intervention (photocoagulation, cataract extraction). Since the costs and efforts necessary to reach near-normal levels of glycemia are very high, there is a need to determine the cost/benefit ratios of such expenditures in the population subject to type 2 diabetes, namely patients in their 6th to 8th decades of life.

In contrast with the late and relatively infrequent appearance of clinical endpoints of microangiopathy, macrovascular complications (i.e., coronary heart disease and peripheral vascular disease) are responsible for the overwhelming majority of the mortality, morbidity and treatment costs in the American population of type 2 diabetics, even more so in the older VA diabetic population. In the recently concluded United Kingdom Prospective Diabetes Study (UKPDS) on type 2 DM, macrovascular mortality was 70 times higher than that of microvascular mortality. Intervention studies to determine the effect of rigorous glycemic control on these macrovascular events are inconclusive and contradictory. Intensive treatment in patients who are newly diagnosed has failed to demonstrate a beneficial effect of tight control on cardiovascular complications. The few studies conducted in later stages of the disease (i.e., in patients requiring insulin treatment, alone or in combination with oral agents) have been conflicting and indeterminate.

The decision on intensity of treatment is further compromised by current recommendations to attenuate glycemic control goals, especially when usage of insulin is required, both in patients with the common comorbidities of overweight or preexisting cardiovascular disease, and in those in the later decades of life. These concerns are based on fears that intensive insulin treatment might be associated with weight gain, increased cardiovascular risk factors (hypertriglyceridemia, dyslipidemia, hyperinsulinemia, and insulin resistance), and adverse effects of recurrent hypoglycemic events. The prevalent level of glycemic control in insulin-treated type 2 diabetics is relatively poor, likely due to a combination of practical difficulties and the uncertainties of what are the safe and effective glycemic goals. There is no long-term study currently being done in the high-risk population typical of the patient population in the VA. Before the Department of Veterans Affairs devotes considerable resources to a widespread intervention (a quarter of patients) that may be of little value, and might even be counterproductive, a trial to determine the value of the intervention is mandated. It is expected that CSP #465 will provide the scientific data on which the VA can base clinical treatment of Type II diabetes.

CSP #465 is a prospective, 2-arm, randomized controlled trial to determine whether glycemic control, achieved through intensification of treatment, is effective in preventing clinical macrovascular complications in patients with type 2 DM who are no longer responsive to oral agents alone. The study consists of a two-year accrual period and five years of follow-up (7 years total) of 1700 patients across 20 centers. We have powered the study to detect a 25% reduction in the primary event rate. Additional study goals are to determine whether the expenditures, discomfort, and adverse effects associated with intensive intervention are justified in terms of their clinical benefits, considering both macrovascular and microvascular complications.

Main Manuscript:Duckworth W, Abraira C, Moritz T, Reda D, Emanuele N et al., VADT investigators: Glucose Control and Complications in the VA Diabetes Trial (VADT). N Eng J of Med 360:129-139, 2009.

  Eligibility

Ages Eligible for Study:   40 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Patients with type 2 DM who are no longer responsive to maximum dose of one or more oral agents.

Exclusion Criteria:

  • Angina pectoris, Canadian Class I-II,
  • congestive heart failure, Class III-IV,
  • stroke, incapacitating or in last 6 months,
  • Myocardial infarction (MI) or invasive cardiovascular procedure within the past six months,
  • ongoing diabetic gangrene,
  • BMI > 40,
  • hemoglobinopathy that interferes with A1c monitoring,
  • serum creatinine > 1.6 mg/dL,
  • fasting C-peptide < 0.21 pmol/ml,
  • Alanine Amino Transaminase (ALT) > 3 times normal or serum bilirubin > 1.9 mg/dL,
  • malignancy or noncardiac life-threatening diseases making life expectancy < 5 years,
  • autonomic neuropathy,
  • symptomatic pancreatic insufficiency (endocrine or exocrine),
  • recurrent seizures within the past year,
  • hypopituitarism,
  • pregnancy, lactation, or planning a pregnancy,
  • active psychosis or substance abuse,
  • lack of access to a person who can assist or be called in an emergency,
  • underlying conditions that in the site PI's judgment may prevent adherence to protocol,
  • current participation in another clinical trial.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00032487

  Hide Study Locations
Locations
United States, Arizona
Carl T. Hayden VA Medical Center
Phoenix, Arizona, United States, 85012
Southern Arizona VA Health Care System, Tucson
Tucson, Arizona, United States, 85723
United States, California
VA Central California Health Care System, Fresno
Fresno, California, United States, 93703
VA Medical Center, Long Beach
Long Beach, California, United States, 90822
VA San Diego Healthcare System, San Diego
San Diego, California, United States, 92161
United States, Florida
Miami VA Healthcare System, Miami, FL
Miami, Florida, United States, 33125
United States, Illinois
Edward Hines, Jr. VA Hospital
Hines, Illinois, United States, 60141-5000
United States, Indiana
Richard Roudebush VA Medical Center, Indianapolis
Indianapolis, Indiana, United States, 46202-2884
United States, Kentucky
VA Medical Center, Lexington
Lexington, Kentucky, United States, 40502
United States, Minnesota
VA Medical Center, Minneapolis
Minneapolis, Minnesota, United States, 55417
United States, Nebraska
VA Medical Center, Omaha
Omaha, Nebraska, United States, 68105-1873
United States, New Jersey
VA New Jersey Health Care System, East Orange
East Orange, New Jersey, United States, 07018
United States, Pennsylvania
VA Pittsburgh Health Care System
Pittsburgh, Pennsylvania, United States, 15240
United States, South Carolina
Ralph H Johnson VA Medical Center, Charleston
Charleston, South Carolina, United States, 29401-5799
United States, Tennessee
VA Medical Center
Nashville, Tennessee, United States, 37212-2637
United States, Texas
Michael E. DeBakey VA Medical Center (152)
Houston, Texas, United States, 77030
VA South Texas Health Care System, San Antonio
San Antonio, Texas, United States, 78229
United States, Virginia
Hunter Holmes McGuire VA Medical Center
Richmond, Virginia, United States, 23249
VA Medical Center, Salem VA
Salem, Virginia, United States, 24153
United States, Washington
VA Puget Sound Health Care System, Seattle
Seattle, Washington, United States, 98108
Puerto Rico
VA Medical Center, San Juan
San Juan, Puerto Rico, 00921
Sponsors and Collaborators
SmithKline Beecham
Investigators
Study Chair: Carlos Abraira, MD Miami VA Healthcare System, Miami, FL
Study Chair: William Duckworth, MD Carl T. Hayden VA Medical Center, Phoenix AZ
  More Information

Publications:

Additional publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: Department of Veterans Affairs
ClinicalTrials.gov Identifier: NCT00032487     History of Changes
Other Study ID Numbers: 465
Study First Received: March 21, 2002
Results First Received: September 10, 2013
Last Updated: March 7, 2014
Health Authority: United States: Federal Government
United States: Food and Drug Administration

Keywords provided by Department of Veterans Affairs:
DM
glycemic control
insulin
type 2 diabetes mellitus

Additional relevant MeSH terms:
Diabetes Mellitus
Diabetes Mellitus, Type 2
Endocrine System Diseases
Glucose Metabolism Disorders
Metabolic Diseases
Glimepiride
Insulin
Insulin, Globin Zinc
Metformin
Rosiglitazone
Anti-Arrhythmia Agents
Cardiovascular Agents
Hypoglycemic Agents
Immunologic Factors
Immunosuppressive Agents
Pharmacologic Actions
Physiological Effects of Drugs
Therapeutic Uses

ClinicalTrials.gov processed this record on November 25, 2014