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Preferred Treatment of Type 1.5 Diabetes

Sponsor
University of Washington (Other)
Overall Status
Completed
CT.gov ID
NCT00194896
Collaborator
Seattle Institute for Biomedical and Clinical Research (Other), GlaxoSmithKline (Industry)
64
Enrollment
1
Location
2
Arms
106
Duration (Months)
0.6
Patients Per Site Per Month

Study Details

Study Description

Brief Summary

The purpose of this research was to test whether one treatment was superior over another in the management of type 1.5 diabetes. Specifically we tested recently diagnosed antibody positive type 2 diabetic patients to determine whether treatment with rosiglitazone results in greater preservation of beta cell function compared to treatment with glyburide.

Condition or Disease Intervention/Treatment Phase
N/A

Detailed Description

Type 1 diabetes and Type 2 diabetes have different underlying pathophysiologic processes. The disease process in classical Type 1 diabetes is an autoimmune destruction of the pancreatic beta cells. In contrast, the disease process in classical Type 2 diabetes is not autoimmune in nature, a decreased sensitivity to insulin action is central to the disease process, and a poorly understood but non-inflammatory beta cell lesion occurs which diminishes insulin secretion. In clinical practice, the diagnosis of Type 1 versus Type 2 diabetes is made phenotypically using variables such as age at onset, apparent abruptness of onset of hyperglycemia, presence of ketosis, degree of obesity (especially central and intra abdominal), prevalence of other autoimmune diseases, and apparent need for insulin replacement. This clinical distinction of Type 1 versus Type 2 diabetes is recognized to be imperfect.

There is also a third group of individuals, who phenotypically are usually like classic Type 2 diabetics but who are positive for one or more of the autoantibodies commonly seen in the Type 1 disease process, namely islet cell antibodies (ICA) and/or insulin autoantibodies (IAA) and/or autoantibodies to glutamic acid decarboxylase (GAD Ab) and/or autoantibodies to the tyrosine phosphatase islet cell autoantibody 512 (IA 2 Ab).

These patients, autoantibody positive [Ab(+)] Type 2 or Type 1.5 diabetes, were the focus of our study. Compared to antibody negative Type 2 diabetics, patients with Type 1.5 diabetes have a more rapid decline in beta cell function, fail sulfonylurea therapy and require insulin therapy earlier (4-13).

Hypothesis: Rosiglitazone treatment will ameliorate or slow the underlying disease process in antibody positive Type 2 diabetes.

Patients meeting the inclusion criteria came in for a baseline visit. The nature of the study was explained and informed consent obtained. A fasting blood sample was obtained for autoantibodies, glucose, C peptide of proinsulin molecule (C-peptide), glycosylated hemoglobin (HbA1c), genetic typing, and T lymphocyte (T cell) responses to islet antigens. The beta cell function test was performed. Patients were then randomized to either rosiglitazone or glyburide.

All patients were encouraged to perform self blood glucose monitoring twice per day, before breakfast and before dinner. The treatment goals for all patients was the same: before breakfast and before dinner blood sugar levels between 90-130 milligrams per deciliter (mg/dI) and HbA1c of less then 7% without severe hypoglycemia. Patients unable to reach goal with monotherapy had metformin (initially) or acarbose (secondarily) added, as there is no evidence to suggest that either affect beta-cell function.

The rosiglitazone treatment group commenced therapy with 4 milligram (mg) once per day and increased to twice per day if adequate glycemic control was not achieved. For glyburide, therapy was initiated with 2.5 mg in the morning or the patient was maintained on the dose they had been receiving prior to starting the study. The starting dose was raised by 2.5 mg in the evening and further up to a maximum of 10 mg twice a day if necessary to achieve desired glycemic control.

If adequate control, HbA1c less than 7%, was not achieved on glyburide or rosiglitazone monotherapy, metformin was added and the dose gradually increased as needed and tolerated to a maximum of 1000 mg twice daily. If necessary, acarbose was also used up to a maximum dose of 100 mg thrice daily as needed and tolerated.

After initiation of the study, patients were seen at 1 month and then every 3 months for up to 3 years. Those patients randomized to rosiglitazone had the liver enzyme alanine transaminase (ALT) monitored every 2 months. In addition, telephone contact was utilized to achieve and maintain glycemic goals. Each participant was followed for up to 3 years. Drs. Chiu and Palmer coordinated the study. If the patient and his/her private physician prefer, the treatment protocol was implemented by the patient's private physician.

Study Design

Study Type:
Interventional
Actual Enrollment :
64 participants
Allocation:
Randomized
Intervention Model:
Parallel Assignment
Masking:
None (Open Label)
Primary Purpose:
Treatment
Official Title:
Rosiglitazone Intervention Study in Patients With Type 1.5 Diabetes
Study Start Date :
Feb 1, 2000
Actual Primary Completion Date :
Sep 1, 2008
Actual Study Completion Date :
Dec 1, 2008

Arms and Interventions

Arm Intervention/Treatment
Active Comparator: rosiglitazone

Rosiglitazone is an oral antidiabetic agent which acts primarily by increasing insulin sensitivity. The rosiglitazone treatment group commenced therapy with 4 mg once per day and increase to twice per day if adequate glycemic control was not achieved.

Drug: rosiglitazone
Tablet taken orally at a dosage of 4 mg once per day and increase to twice per day if adequate glycemic control was not achieved. Study drug was taken up to 3 years.
Other Names:
  • Avandia

    		•
    Active Comparator: glyburide

    Glyburide is a sulfonylurea. Glyburide therapy was initiated with 2.5 mg in the morning or the patient was maintained on the dose they had been receiving prior to starting the study. This starting dose was raised by 2.5 in the evening and further up to a maximum of 10 mg twice a day if necessary to achieve desired glycemic control.

    Drug: glyburide
    Tablet taken orally, initially 2.5 mg in the morning or dose subject received prior to starting the study. Dosage was increased by 2.5 mg in the evening up to a maximum of 10 mg twice a day if necessary to achieve desired glycemic control. Study drug was taken up to 3 years.

    Outcome Measures

    Primary Outcome Measures

    1. Changes in Beta Cell Function Assessed by Fasting and Stimulated C-peptide Measured at 36 Months. [36 months]

      Changes in beta cell function assessed by fasting and stimulated C-peptide measured at 36 months.

    Secondary Outcome Measures

    1. Patients Positive for T Cell Responses to Islet Proteins at 36 Months. [36 months]

      Number of participants positive for T cell reactivity to islet proteins at 36 months.

    Eligibility Criteria

    Criteria

    Ages Eligible for Study:
    35 Years to 69 Years
    Sexes Eligible for Study:
    All
    Accepts Healthy Volunteers:
    No
    Inclusion Criteria:

    • Age at onset of diabetes - 35-69 years old.

    • No history of ketonuria or ketoacidosis.

    • Not requiring insulin to achieve glycemic control.

    • Not receiving more than two oral hypoglycemic agents.

    • Not taking a thiazolidinedione agent.

    • HbA1c in established patients (on an oral hypoglycemia agent for over 4 months) of greater than 6% and under 10%.

    • Fasting c-peptide greater than or equal to 0.8 ng/ml.

    • Women must be either post-menopausal or on adequate birth control (i.e. oral contraceptives, tubal ligation, hysterectomy, condoms, or diaphragm) or use abstinence.

    Exclusion Criteria:

    • Patients with history of chronic pancreatitis or other secondary causes of diabetes.

    • Patients receiving systemic corticosteroids.

    • Patients with severe systemic illness (e.g. recent MI, CHF or cerebral vascular disease).

    • Creatinine greater than 1.4 or liver enzymes greater than 2 times the upper limits of normal.

    • Not able to adhere to the protocol.

    Contacts and Locations

    Locations

    Site City State Country Postal Code
    1 DVA Puget Sound Health Care System Seattle Washington United States 98108

    Sponsors and Collaborators

    • University of Washington
    • Seattle Institute for Biomedical and Clinical Research
    • GlaxoSmithKline

    Investigators

    • Principal Investigator: Jerry P Palmer, MD, Seattle Institute for Biomedical & Clinical Research, University of Washington, DVA Puget Sound Health Care System

    Study Documents (Full-Text)

    None provided.

    More Information

    Publications

    Responsible Party:
    University of Washington
    ClinicalTrials.gov Identifier:
    NCT00194896
    Other Study ID Numbers:
    • 16707-D
    • 496539-188;
    • 16707D
    First Posted:
    Sep 19, 2005
    Last Update Posted:
    Mar 29, 2018
    Last Verified:
    Mar 1, 2018
    Keywords provided by University of Washington
    type 2 diabetes mellitus
    autoantibodies
    islet proteins
    rosiglitazone
    glyburide
    c-peptide
    Additional relevant MeSH terms:
    Diabetes Mellitus
    Diabetes Mellitus, Type 2
    Latent Autoimmune Diabetes in Adults
    Rosiglitazone
    Glyburide

    Study Results

    Participant Flow

    Recruitment Details Recruited through endocrinology physicians.
    Pre-assignment Detail
    Arm/Group Title Rosiglitazone Autoantibody Positive Rosiglitazone Autoantibody Negative Glyburide Autoantibody Positive Glyburide Autoantibody Negative
    Arm/Group Description Rosiglitazone is an oral antidiabetic agent which acts primarily by increasing insulin sensitivity. The rosiglitazone treatment group commenced therapy with 4 milligram (mg) once per day and increase to twice per day if adequate glycemic control was not achieved. Autoantibody positive for one or multiple islet autoantibodies. These autoantibodies include insulin autoantibodies(IAA), islet cell autoantibodies (ICA), glutamic acid decarboxylase (GAD),and/or islet cell autoantibodies 512 (IA2). Rosiglitazone is an oral antidiabetic agent which acts primarily by increasing insulin sensitivity. The rosiglitazone treatment group commenced therapy with 4 mg once per day and increase to twice per day if adequate glycemic control was not achieved. Autoantibody negative for insulin autoantibodies (IAA), islet cell autoantibodies (ICA), glutamic acid decarboxylase (GAD), and islet cell autoantibodies 512 (IA2). Glyburide is a sulfonylurea. Glyburide therapy was initiated with 2.5 mg in the morning or the patient was maintained on the dose they had been receiving prior to starting the study. This starting dose was raised by 2.5 in the evening and further up to a maximum of 10 mg twice a day if necessary to achieve desired glycemic control. Autoantibody positive for one or multiple islet autoantibodies. These autoantibodies include insulin autoantibodies(IAA), islet cell autoantibodies (ICA), glutamic acid decarboxylase (GAD), islet cell autoantibodies 512 (IA2). Glyburide is a sulfonylurea. Glyburide therapy was initiated with 2.5 mg in the morning or the patient was maintained on the dose they had been receiving prior to starting the study. This starting dose was raised by 2.5 in the evening and further up to a maximum of 10 mg twice a day if necessary to achieve desired glycemic control. Autoantibody negative for insulin autoantibodies (IAA), islet cell autoantibodies (ICA), glutamic acid decarboxylase (GAD), and islet cell autoantibodies 512 (IA2).
    Period Title: Overall Study
    STARTED 15 15 13 21
    COMPLETED 4 10 7 9
    NOT COMPLETED 11 5 6 12

    Baseline Characteristics

    Arm/Group Title Rosiglitazone Autoantibody Positive Rosiglitazone Autoantibody Negative Glyburide Autoantibody Positive Glyburide Autoantibody Negative Total
    Arm/Group Description Rosiglitazone is an oral antidiabetic agent which acts primarily by increasing insulin sensitivity. The rosiglitazone treatment group commenced therapy with 4 milligram (mg) once per day and increase to twice per day if adequate glycemic control was not achieved. Autoantibody positive for one or multiple islet autoantibodies. These autoantibodies include insulin autoantibodies(IAA), islet cell autoantibodies (ICA), glutamic acid decarboxylase (GAD),and/or islet cell autoantibodies 512 (IA2). Rosiglitazone is an oral antidiabetic agent which acts primarily by increasing insulin sensitivity. The rosiglitazone treatment group commenced therapy with 4 mg once per day and increase to twice per day if adequate glycemic control was not achieved. Autoantibody negative for insulin autoantibodies (IAA), islet cell autoantibodies (ICA), glutamic acid decarboxylase (GAD), and islet cell autoantibodies 512 (IA2). Glyburide is a sulfonylurea. Glyburide therapy was initiated with 2.5 mg in the morning or the patient was maintained on the dose they had been receiving prior to starting the study. This starting dose was raised by 2.5 in the evening and further up to a maximum of 10 mg twice a day if necessary to achieve desired glycemic control. Autoantibody positive for one or multiple islet autoantibodies. These autoantibodies include insulin autoantibodies(IAA), islet cell autoantibodies (ICA), glutamic acid decarboxylase (GAD), islet cell autoantibodies 512 (IA2). Glyburide is a sulfonylurea. Glyburide therapy was initiated with 2.5 mg in the morning or the patient was maintained on the dose they had been receiving prior to starting the study. This starting dose was raised by 2.5 in the evening and further up to a maximum of 10 mg twice a day if necessary to achieve desired glycemic control. Autoantibody negative for insulin autoantibodies (IAA), islet cell autoantibodies (ICA), glutamic acid decarboxylase (GAD), and islet cell autoantibodies 512 (IA2). Total of all reporting groups
    Overall Participants 15 15 13 21 64
    Age (Count of Participants)
    <=18 years
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    Between 18 and 65 years
    14
    93.3%
    13
    86.7%
    12
    92.3%
    18
    85.7%
    57
    89.1%
    >=65 years
    1
    6.7%
    2
    13.3%
    1
    7.7%
    3
    14.3%
    7
    10.9%
    Age (years) [Mean (Standard Deviation) ]
    Mean (Standard Deviation) [years]
    55.4
    (8.8)
    56.4
    (8.7)
    53.7
    (9)
    57.5
    (6.9)
    55.8
    (1.6)
    Sex: Female, Male (Count of Participants)
    Female
    4
    26.7%
    4
    26.7%
    2
    15.4%
    8
    38.1%
    18
    28.1%
    Male
    11
    73.3%
    11
    73.3%
    11
    84.6%
    13
    61.9%
    46
    71.9%
    Region of Enrollment (participants) [Number]
    United States
    15
    100%
    15
    100%
    13
    100%
    21
    100%
    64
    100%

    Outcome Measures

    1. Primary Outcome
    Title Changes in Beta Cell Function Assessed by Fasting and Stimulated C-peptide Measured at 36 Months.
    Description Changes in beta cell function assessed by fasting and stimulated C-peptide measured at 36 months.
    Time Frame 36 months

    Outcome Measure Data

    Analysis Population Description
    Analysis per protocol
    Arm/Group Title Rosiglitazone Autoantibody Positive Rosiglitazone Autoantibody Negative Glyburide Autoantibody Positive Glyburide Autoantibody Negative
    Arm/Group Description Rosiglitazone is an oral antidiabetic agent which acts primarily by increasing insulin sensitivity. The rosiglitazone treatment group commenced therapy with 4 milligram (mg) once per day and increase to twice per day if adequate glycemic control was not achieved. Autoantibody positive for one or multiple islet autoantibodies. These autoantibodies include insulin autoantibodies(IAA), islet cell autoantibodies (ICA), glutamic acid decarboxylase (GAD),and/or islet cell autoantibodies 512 (IA2). Rosiglitazone is an oral antidiabetic agent which acts primarily by increasing insulin sensitivity. The rosiglitazone treatment group commenced therapy with 4 mg once per day and increase to twice per day if adequate glycemic control was not achieved. Autoantibody negative for insulin autoantibodies (IAA), islet cell autoantibodies (ICA), glutamic acid decarboxylase (GAD), and islet cell autoantibodies 512 (IA2). Glyburide is a sulfonylurea. Glyburide therapy was initiated with 2.5 mg in the morning or the patient was maintained on the dose they had been receiving prior to starting the study. This starting dose was raised by 2.5 in the evening and further up to a maximum of 10 mg twice a day if necessary to achieve desired glycemic control. Autoantibody positive for one or multiple islet autoantibodies. These autoantibodies include insulin autoantibodies(IAA), islet cell autoantibodies (ICA), glutamic acid decarboxylase (GAD), islet cell autoantibodies 512 (IA2). Glyburide is a sulfonylurea. Glyburide therapy was initiated with 2.5 mg in the morning or the patient was maintained on the dose they had been receiving prior to starting the study. This starting dose was raised by 2.5 in the evening and further up to a maximum of 10 mg twice a day if necessary to achieve desired glycemic control. Autoantibody negative for insulin autoantibodies (IAA), islet cell autoantibodies (ICA), glutamic acid decarboxylase (GAD), and islet cell autoantibodies 512 (IA2).
    Measure Participants 15 15 13 21
    Fasting C-peptide
    -0.4
    (1.0)
    -1.4
    (1.6)
    0.1
    (1.2)
    0.3
    (1.1)
    Glucagon Stimulated C-peptide
    -0.6
    (1.6)
    -2.8
    (2.5)
    3.1
    (12.1)
    0.3
    (2.2)
    2. Secondary Outcome
    Title Patients Positive for T Cell Responses to Islet Proteins at 36 Months.
    Description Number of participants positive for T cell reactivity to islet proteins at 36 months.
    Time Frame 36 months

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title Rosiglitazone Autoantibody Positive Rosiglitazone Autoantibody Negative Glyburide Autoantibody Positive Glyburide Autoantibody Negative
    Arm/Group Description Rosiglitazone is an oral antidiabetic agent which acts primarily by increasing insulin sensitivity. The rosiglitazone treatment group commenced therapy with 4 milligram (mg) once per day and increase to twice per day if adequate glycemic control was not achieved. Autoantibody positive for one or multiple islet autoantibodies. These autoantibodies include insulin autoantibodies(IAA), islet cell autoantibodies (ICA), glutamic acid decarboxylase (GAD),and/or islet cell autoantibodies 512 (IA2). Rosiglitazone is an oral antidiabetic agent which acts primarily by increasing insulin sensitivity. The rosiglitazone treatment group commenced therapy with 4 mg once per day and increase to twice per day if adequate glycemic control was not achieved. Autoantibody negative for insulin autoantibodies (IAA), islet cell autoantibodies (ICA), glutamic acid decarboxylase (GAD), and islet cell autoantibodies 512 (IA2). Glyburide is a sulfonylurea. Glyburide therapy was initiated with 2.5 mg in the morning or the patient was maintained on the dose they had been receiving prior to starting the study. This starting dose was raised by 2.5 in the evening and further up to a maximum of 10 mg twice a day if necessary to achieve desired glycemic control. Autoantibody positive for one or multiple islet autoantibodies. These autoantibodies include insulin autoantibodies(IAA), islet cell autoantibodies (ICA), glutamic acid decarboxylase (GAD), islet cell autoantibodies 512 (IA2). Glyburide is a sulfonylurea. Glyburide therapy was initiated with 2.5 mg in the morning or the patient was maintained on the dose they had been receiving prior to starting the study. This starting dose was raised by 2.5 in the evening and further up to a maximum of 10 mg twice a day if necessary to achieve desired glycemic control. Autoantibody negative for insulin autoantibodies (IAA), islet cell autoantibodies (ICA), glutamic acid decarboxylase (GAD), and islet cell autoantibodies 512 (IA2).
    Measure Participants 4 10 7 9
    Number [participants]
    1
    (0) 6.7%
    2
    (0) 13.3%
    2
    (0) 15.4%
    3
    (0) 14.3%

    Adverse Events

    Time Frame Adverse event data was collected during the period the research subjects were actively participating in the study. This time period was between February 3, 2000 through September 8, 2008.
    Adverse Event Reporting Description
    Arm/Group Title Rosiglitazone Autoantibody Positive Rosiglitazone Autoantibody Negative Glyburide Autoantibody Positive Glyburide Autoantibody Negative
    Arm/Group Description Rosiglitazone is an oral antidiabetic agent which acts primarily by increasing insulin sensitivity. The rosiglitazone treatment group commenced therapy with 4 milligram (mg) once per day and increase to twice per day if adequate glycemic control was not achieved. Autoantibody positive for one or multiple islet autoantibodies. These autoantibodies include insulin autoantibodies(IAA), islet cell autoantibodies (ICA), glutamic acid decarboxylase (GAD),and/or islet cell autoantibodies 512 (IA2). Rosiglitazone is an oral antidiabetic agent which acts primarily by increasing insulin sensitivity. The rosiglitazone treatment group commenced therapy with 4 mg once per day and increase to twice per day if adequate glycemic control was not achieved. Autoantibody negative for insulin autoantibodies (IAA), islet cell autoantibodies (ICA), glutamic acid decarboxylase (GAD), and islet cell autoantibodies 512 (IA2). Glyburide is a sulfonylurea. Glyburide therapy was initiated with 2.5 mg in the morning or the patient was maintained on the dose they had been receiving prior to starting the study. This starting dose was raised by 2.5 in the evening and further up to a maximum of 10 mg twice a day if necessary to achieve desired glycemic control. Autoantibody positive for one or multiple islet autoantibodies. These autoantibodies include insulin autoantibodies(IAA), islet cell autoantibodies (ICA), glutamic acid decarboxylase (GAD), islet cell autoantibodies 512 (IA2). Glyburide is a sulfonylurea. Glyburide therapy was initiated with 2.5 mg in the morning or the patient was maintained on the dose they had been receiving prior to starting the study. This starting dose was raised by 2.5 in the evening and further up to a maximum of 10 mg twice a day if necessary to achieve desired glycemic control. Autoantibody negative for insulin autoantibodies (IAA), islet cell autoantibodies (ICA), glutamic acid decarboxylase (GAD), and islet cell autoantibodies 512 (IA2).
    All Cause Mortality
    Rosiglitazone Autoantibody Positive Rosiglitazone Autoantibody Negative Glyburide Autoantibody Positive Glyburide Autoantibody Negative
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total / (NaN) / (NaN) / (NaN) / (NaN)
    Serious Adverse Events
    Rosiglitazone Autoantibody Positive Rosiglitazone Autoantibody Negative Glyburide Autoantibody Positive Glyburide Autoantibody Negative
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 1/15 (6.7%) 2/15 (13.3%) 0/13 (0%) 3/21 (14.3%)
    Cardiac disorders
    Atrial Fibrillation 0/15 (0%) 0 1/15 (6.7%) 1 0/13 (0%) 0 0/21 (0%) 0
    Heart Attack 0/15 (0%) 0 0/15 (0%) 0 0/13 (0%) 0 1/21 (4.8%) 1
    Endocrine disorders
    Cholecystitis 0/15 (0%) 0 1/15 (6.7%) 1 0/13 (0%) 0 0/21 (0%) 0
    General disorders
    Death 1/15 (6.7%) 1 0/15 (0%) 0 0/13 (0%) 0 0/21 (0%) 0
    Vascular disorders
    Stroke 0/15 (0%) 0 0/15 (0%) 0 0/13 (0%) 0 2/21 (9.5%) 2
    Other (Not Including Serious) Adverse Events
    Rosiglitazone Autoantibody Positive Rosiglitazone Autoantibody Negative Glyburide Autoantibody Positive Glyburide Autoantibody Negative
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 0/15 (0%) 0/15 (0%) 1/13 (7.7%) 1/21 (4.8%)
    Endocrine disorders
    Hypoglycemia 0/15 (0%) 0 0/15 (0%) 0 1/13 (7.7%) 1 1/21 (4.8%) 1

    Limitations/Caveats

    Small numbers based on high drop out of participants.

    More Information

    Certain Agreements

    All Principal Investigators ARE employed by the organization sponsoring the study.

    There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

    Results Point of Contact

    Name/Title Jerry P. Palmer, MD
    Organization University of Washington
    Phone 206-764-2495
    Email jpp@u.washington.edu
    Responsible Party:
    University of Washington
    ClinicalTrials.gov Identifier:
    NCT00194896
    Other Study ID Numbers:
    • 16707-D
    • 496539-188;
    • 16707D
    First Posted:
    Sep 19, 2005
    Last Update Posted:
    Mar 29, 2018
    Last Verified:
    Mar 1, 2018