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

February 28, 2017 updated by: VA Office of Research and Development

CSP #465 - Glycemic Control and Complications in Diabetes Mellitus Type 2 (VADT)

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.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

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.

Study Type

Interventional

Enrollment (Actual)

1791

Phase

  • Phase 3

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

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

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

40 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

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

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
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:
  • Lente
Drug: Glimepiride
Glimepiride 2 mg Arm 1 Glimepiride 8 mg Arm 2
Other Names:
  • Amaryl
Drug: Rosiglitazone
Rosiglitazone 4 mg Arm 1 Rosiglitazone 4 mg bid Arm 2
Other Names:
  • Avandia
Drug: Metformin
Metformin 500 mg (go up to 1000 mg) Arm 1 Metformin 500 mg (go up to 2000 mg) Arm
Other Names:
  • 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:
  • Lente
Drug: Glimepiride
Glimepiride 2 mg Arm 1 Glimepiride 8 mg Arm 2
Other Names:
  • Amaryl
Drug: Rosiglitazone
Rosiglitazone 4 mg Arm 1 Rosiglitazone 4 mg bid Arm 2
Other Names:
  • Avandia
Drug: Metformin
Metformin 500 mg (go up to 1000 mg) Arm 1 Metformin 500 mg (go up to 2000 mg) Arm
Other Names:
  • Glumetza

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Primary Major Macrovascular Events
Time Frame: Post baseline time to the first major macrovascular event up to 82 months
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.
Post baseline time to the first major macrovascular event up to 82 months

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Secondary Endpoint
Time Frame: Post baseline time to first event up to 82 months
New or worsening angina, new transient ischemic attack (TIA), new intermittent claudication or critical limb ischemia with Doppler evidence or total mortality.
Post baseline time to first event up to 82 months

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

VA Office of Research and Development

Collaborators

National Eye Institute (NEI)
SmithKline Beecham

Investigators

  • Study Chair: Carlos Abraira, MD, Miami VA Healthcare System, Miami, FL
  • Study Chair: William Duckworth, MD, Phoenix VA Health Care System, Phoenix, AZ

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

December 1, 2000

Primary Completion (Actual)

May 30, 2008

Study Completion (Actual)

May 30, 2008

Study Registration Dates

First Submitted

March 21, 2002

First Submitted That Met QC Criteria

March 21, 2002

First Posted (Estimate)

March 22, 2002

Study Record Updates

Last Update Posted (Actual)

March 30, 2017

Last Update Submitted That Met QC Criteria

February 28, 2017

Last Verified

February 1, 2017

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • 465 (BMT CTN)

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

NO

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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