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| ID | Type | Description | Link |
|---|---|---|---|
| R56DK078645 | U.S. NIH Grant/Contract | View source |
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| Name | Class |
|---|---|
| American Diabetes Association | OTHER |
| National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) | NIH |
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Diabetes is increasingly common among youth, forecasting early complications. Type 1 (T1D) cause early heart disease, shortening lifespan despite modern improvements in control of blood sugars and other risk factors for heart disease. Poor insulin action, otherwise known as insulin resistance (IR), is the main factor causing heart disease in type 2 diabetes (T2D), but the cause of increased heart disease in T1D is unclear. IR may contribute to heart disease in T1D as in T2D, as the investigators and others have found the presence of IR in T1D. Much less is known about IR in T1D, but a better understanding of its role in T1D is critical to understanding causes of heart disease in T1D. The investigators long-term goal is to understand the early causes of heart disease in diabetes so that we can prevent it. The investigators unique initial findings suggest that even reasonably well-controlled, normal weight, T1D youth are IR. The IR appears directly related to the heart, blood vessel, and exercise defects, but in a pattern that appears very different from T2D. The goals of this study are to determine the unique heart, blood vessel and insulin sensitivity abnormalities in T1D youth, and determine whether metformin improves these abnormalities. A clear understanding of these factors will help determine the causes, and what treatments could help each abnormality.
Hypothesis 1: Metformin will improve insulin function and mitochondrial function in T1D.
Hypothesis 2: Metformin will improve vascular and cardiac function in T1D.
All measures will be performed twice, before and after a 3-month randomized, placebo-controlled design where subjects are randomized to either metformin or placebo. The independent impact of insulin action as well as glucose levels, BMI, T1D duration, and gender on baseline outcomes and the impact of changes in insulin action, glucose levels and BMI on response to metformin will also be examined to help customize future strategies to prevent heart disease in T1D. This study will advance the field by providing new information about the role of poor insulin action in the heart disease of T1D, and whether improving insulin action in T1D is helpful. If a focus on directly improving insulin action in T1D youth is supported by our studies, the clinical approach to T1D management may significantly change.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Metformin | Experimental | Metformin will be given at a dose of 1000 mg twice a day orally for three months to assess changes in insulin resistance compared to placebo. |
|
| Placebo | Placebo Comparator | Placebo will be given at a dose of 1000 mg twice a day orally for three months to assess changes in insulin resistance compared to metformin. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Metformin | Drug |
| ||
| Placebo |
| Measure | Description | Time Frame |
|---|---|---|
| Change in Insulin Sensitivity | Hypothesis 1: Metformin will improve insulin function in Type 1 Diabetes. Insulin function will be measured using a euglycemic-hyperinsulinemic clamp procedure at both baseline and after 3 months of treatment. A clamp measures insulin sensitivity. A higher number indicates a better outcome; a lower number indicates a worse outcome. | Baseline, Month 3 |
| Measure | Description | Time Frame |
|---|---|---|
| Change in ADP Time Constant | Hypothesis 1b: Metformin will improve mitochondrial function in Type 1 Diabetes. 31Phosphorus magnetic resonance spectroscopy (MRS) was used before, during, and after 90 seconds of near-maximal isometric exercise of the calf muscle for post-exercise muscle mitochondrial function. ADP time constant is the time for conversion of ADP → ATP and is a measure of muscle mitochondrial health (energy metabolism). A faster recovery is a better outcome; a slower recovery is a worse outcome. |
| Measure | Description | Time Frame |
|---|---|---|
| Change in Brachial Artery Distensibility | Hypothesis 2a: Metformin will improve peripheral arterial stiffness in Type 1 Diabetes via Dynapulse. Peripheral arterial stiffness is measured by the distensibility of the arterial wall. Increased arterial stiffness results from reduced elasticity of the arterial wall. A higher result is a better outcome. | Baseline, Month 3 |
Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Kristen Nadeau, MD, MS | University of Colorado/Children's Hospital Colorado | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Children's Hospital Colorado and University of Colorado Denver Health Sciences Center | Aurora | Colorado | 80045 | United States |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 33402367 | Derived | Tommerdahl KL, Baumgartner K, Schafer M, Bjornstad P, Melena I, Hegemann S, Baumgartner AD, Pyle L, Cree-Green M, Truong U, Browne L, Regensteiner JG, Reusch JEB, Nadeau KJ. Impact of Obesity on Measures of Cardiovascular and Kidney Health in Youth With Type 1 Diabetes as Compared With Youth With Type 2 Diabetes. Diabetes Care. 2021 Mar;44(3):795-803. doi: 10.2337/dc20-1879. Epub 2021 Jan 5. | |
| 30566007 | Derived | Bjornstad P, Schafer M, Truong U, Cree-Green M, Pyle L, Baumgartner A, Garcia Reyes Y, Maniatis A, Nayak S, Wadwa RP, Browne LP, Reusch JEB, Nadeau KJ. Metformin Improves Insulin Sensitivity and Vascular Health in Youth With Type 1 Diabetes Mellitus. Circulation. 2018 Dec 18;138(25):2895-2907. doi: 10.1161/CIRCULATIONAHA.118.035525. |
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Three (3) enrolled participants decided against participation in the study before randomization occurred.
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| ID | Title | Description |
|---|---|---|
| FG000 | Metformin | Metformin will be given at a dose of 1000 mg twice a day orally for three months to assess changes in insulin resistance compared to placebo. Metformin |
| FG001 | Placebo | Placebo will be given at a dose of 1000 mg twice a day orally for three months to assess changes in insulin resistance compared to metformin. Placebo |
| Title | Milestones | Reasons Not Completed | ||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
|
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| ID | Title | Description |
|---|---|---|
| BG000 | Metformin | Metformin will be given at a dose of 1000 mg twice a day orally for three months to assess changes in insulin resistance compared to placebo. Metformin |
| BG001 | Placebo |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Mean |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | ||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | Change in Insulin Sensitivity | Hypothesis 1: Metformin will improve insulin function in Type 1 Diabetes. Insulin function will be measured using a euglycemic-hyperinsulinemic clamp procedure at both baseline and after 3 months of treatment. A clamp measures insulin sensitivity. A higher number indicates a better outcome; a lower number indicates a worse outcome. | Metformin group: 1 participant lost to follow-up, 1 IV access problem Placebo group: 2 lost to follow-up, 2 IV access problems | Posted | Mean | Standard Deviation | (mg/kg/min)/(insulin) | Baseline, Month 3 |
|
3 months
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Metformin | Metformin will be given at a dose of 1000 mg twice a day orally for three months to assess changes in insulin resistance compared to placebo. Metformin |
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| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Gastrointestinal Side Effects | Gastrointestinal disorders | Systematic Assessment | nausea, diarrhea, reduced appetite, stomach pain |
Results may not apply to prepubertal youth. Treatment duration limited to 3 months. MRI unavailable during scanner replacement. Lacked measure to monitor BGs during vascular assessments. Not all females studied in traditional follicular phase.
| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Dr. Kristen J Nadeau | University of Colorado Denver/Children's Hospital Colorado | 720-777-2855 | Kristen.Nadeau@childrenscolorado.org |
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot_SAP | Yes | Yes | No | Study Protocol and Statistical Analysis Plan | Sep 9, 2016 | Dec 5, 2019 | Prot_SAP_000.pdf |
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| ID | Term |
|---|---|
| D003922 | Diabetes Mellitus, Type 1 |
| D003920 | Diabetes Mellitus |
| D007333 | Insulin Resistance |
| ID | Term |
|---|---|
| D044882 | Glucose Metabolism Disorders |
| D008659 | Metabolic Diseases |
| D009750 | Nutritional and Metabolic Diseases |
| D004700 | Endocrine System Diseases |
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| ID | Term |
|---|---|
| D008687 | Metformin |
| ID | Term |
|---|---|
| D001645 | Biguanides |
| D006146 | Guanidines |
| D000578 | Amidines |
| D009930 | Organic Chemicals |
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|
| Baseline, Month 3 |
| Change in Pulse Wave Velocity (PWV) | Hypothesis 2a: Metformin will improve central vascular function in Type 1 Diabetes via pulse wave velocity (PWV) by MRI. PWV is a measure of central arterial stiffness. A lower value indicates a better outcome. | Baseline, Month 3 |
| Change in Central Arterial Intimal Medial Thickness (cIMT) | Hypothesis 2a: Metformin will improve central vascular function in Type 1 Diabetes via central arterial intimal medial (cIMT) thickness by carotid ultrasound. cIMT is a measure used to diagnose the extent of carotid atherosclerotic vascular disease. The test measures the thickness of the inner two layers of the carotid artery-the intima and media. A lower result is a better outcome. | Baseline, Month 3 |
| Change in Mitral Valve E/A Ratio by Echocardiogram | Hypothesis 2b: Metformin will improve cardiac function in Type 1 Diabetes by echocardiogram. Mitral Valve E/A ratio is the ratio of early (E) to late (A) ventricular filling velocities. Ideal myocardial tissue relaxation is indicated by a ratio of >0.8 and <2.0. | Baseline, Month 3 |
| Change in Aortic Wall Sheer Stress (WSS) | Hypothesis 2a: Metformin will improve central vascular function in Type 1 Diabetes via Aortic Wall Sheer Stress (WSS) by MRI. WSS is a measure of central arterial stiffness. A lower value indicates a better outcome. | Baseline, Month 3 |
Placebo will be given at a dose of 1000 mg twice a day orally for three months to assess changes in insulin resistance compared to metformin.
Placebo
| BG002 | Total | Total of all reporting groups |
| years |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Ethnicity (NIH/OMB) | Count of Participants | Participants |
|
| Race (NIH/OMB) | Count of Participants | Participants |
|
| Placebo |
Placebo will be given at a dose of 1000 mg twice a day orally for three months to assess changes in insulin resistance compared to metformin. Placebo |
|
|
|
| Secondary | Change in ADP Time Constant | Hypothesis 1b: Metformin will improve mitochondrial function in Type 1 Diabetes. 31Phosphorus magnetic resonance spectroscopy (MRS) was used before, during, and after 90 seconds of near-maximal isometric exercise of the calf muscle for post-exercise muscle mitochondrial function. ADP time constant is the time for conversion of ADP → ATP and is a measure of muscle mitochondrial health (energy metabolism). A faster recovery is a better outcome; a slower recovery is a worse outcome. | 22 participants had both pre/post MRS data | Posted | Median | Inter-Quartile Range | seconds (s) | Baseline, Month 3 |
|
|
|
|
| Secondary | Change in Pulse Wave Velocity (PWV) | Hypothesis 2a: Metformin will improve central vascular function in Type 1 Diabetes via pulse wave velocity (PWV) by MRI. PWV is a measure of central arterial stiffness. A lower value indicates a better outcome. | Number of participants analyzed differs from participant flow numbers because the institution's MRI scanner was unavailable during replacement. | Posted | Mean | Standard Deviation | m/s | Baseline, Month 3 |
|
|
|
|
| Secondary | Change in Central Arterial Intimal Medial Thickness (cIMT) | Hypothesis 2a: Metformin will improve central vascular function in Type 1 Diabetes via central arterial intimal medial (cIMT) thickness by carotid ultrasound. cIMT is a measure used to diagnose the extent of carotid atherosclerotic vascular disease. The test measures the thickness of the inner two layers of the carotid artery-the intima and media. A lower result is a better outcome. | Metformin: 1 lost to follow-up Placebo: 2 lost to follow-up | Posted | Mean | Standard Deviation | mm | Baseline, Month 3 |
|
|
|
|
| Secondary | Change in Mitral Valve E/A Ratio by Echocardiogram | Hypothesis 2b: Metformin will improve cardiac function in Type 1 Diabetes by echocardiogram. Mitral Valve E/A ratio is the ratio of early (E) to late (A) ventricular filling velocities. Ideal myocardial tissue relaxation is indicated by a ratio of >0.8 and <2.0. | Metformin: 2 lost to follow-up Placebo: 2 lost to follow-up, 1 echocardiogram not performed | Posted | Mean | Standard Deviation | ratio | Baseline, Month 3 |
|
|
|
|
| Secondary | Change in Aortic Wall Sheer Stress (WSS) | Hypothesis 2a: Metformin will improve central vascular function in Type 1 Diabetes via Aortic Wall Sheer Stress (WSS) by MRI. WSS is a measure of central arterial stiffness. A lower value indicates a better outcome. | Number of participants analyzed differs from participant flow numbers because the institution's MRI scanner was unavailable during replacement. | Posted | Mean | Standard Deviation | dyne/cm2 | Baseline, Month 3 |
|
|
|
|
| Other Pre-specified | Change in Brachial Artery Distensibility | Hypothesis 2a: Metformin will improve peripheral arterial stiffness in Type 1 Diabetes via Dynapulse. Peripheral arterial stiffness is measured by the distensibility of the arterial wall. Increased arterial stiffness results from reduced elasticity of the arterial wall. A higher result is a better outcome. | Metformin: 1 lost to follow-up Placebo: 2 lost to follow-up | Posted | Mean | Standard Deviation | %/mmHg | Baseline, Month 3 |
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|
|
|
| 0 |
| 25 |
| 0 |
| 25 |
| 10 |
| 25 |
| EG001 | Placebo | Placebo will be given at a dose of 1000 mg twice a day orally for three months to assess changes in insulin resistance compared to metformin. Placebo | 0 | 23 | 0 | 23 | 2 | 23 |
|
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| D001327 | Autoimmune Diseases |
| D007154 | Immune System Diseases |
| D006946 | Hyperinsulinism |