| ID | Type | Description | Link |
|---|---|---|---|
| R01HL075771 | U.S. NIH Grant/Contract | View source |
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| Name | Class |
|---|---|
| National Heart, Lung, and Blood Institute (NHLBI) | NIH |
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This trial will test the hypothesis that inflammation and insulin resistance contribute to reduced walking distance in subjects with intermittent claudication by impairing vascular reactivity and skeletal muscle metabolic function.
People with peripheral arterial disease (PAD), an important clinical manifestation of atherosclerosis, often suffer symptoms of intermittent claudication that impair their walking ability and adversely affect their quality of life. People with PAD are also at increased risk for adverse cardiovascular events, including myocardial infarction, stroke and death. Unfortunately, medical therapies directed to the functional and limb-threatening manifestations are limited. Little attention has been paid to the biologic processes that cause PAD, and to atherogenic mechanisms that may preferentially affect the peripheral circulation.
Vascular inflammation and insulin resistance are two important and interdependent conditions that are associated with atherosclerosis. Subjects in this trial (160 adults with stable intermittent claudication who are not taking insulin or insulin-sensitizing medications, such as thiazolidinediones) will be randomized in a placebo-controlled, parallel design manner, to atorvastatin 80 mg orally daily (to reduce inflammation) and pioglitazone 45 mg orally once daily (to improve insulin sensitivity). Forty healthy adult subjects, age and gender-matched to a subset of the study group, will be enrolled to serve as a control population. Primary and secondary study endpoints include: treadmill walking time, endothelium-dependent vasodilation, and insulin-mediated skeletal muscle glucose uptake.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Patients with PAD (Including diabetics) | Experimental | Randomized to either atorvastatin and pioglitazone, atorvastatin/placebo, pioglitazone/placebo, or placebo/placebo. |
|
| PAD (Excluding Diabetics) | Active Comparator | Randomized to either atorvastatin and pioglitazone, atorvastatin/placebo, pioglitazone/placebo, or placebo/placebo. |
|
| Healthy Controls | Active Comparator | Randomized to either atorvastatin and pioglitazone, atorvastatin/placebo, pioglitazone/placebo, or placebo/placebo. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| atorvastatin and pioglitazone | Drug | atorvastatin 80 mg orally once daily (to reduce inflammation) and pioglitazone 30 mg orally once daily (to improve insulin sensitivity) |
|
| Measure | Description | Time Frame |
|---|---|---|
| Lower Extremity Skeletal Muscle Glucose Uptake | Net calf skeletal muscle glucose uptake determined by Patlak modeling. | 60 minutes |
| Measure | Description | Time Frame |
|---|---|---|
| 'M' = Whole Body Insulin Sensitivity | A hyperinsulinemic-euglycemic clamp was performed prior to and during FDG-PET imaging to measure insulin sensitivity and to standardize metabolic conditions. Subjects were required to fast for 8 hours prior to the study. Patients were given a primed insulin infusion of 2 mU/kg/min. Serum glucose measurements were made at five-minute intervals from an arterialized venous sample achieved by placing the hand in a warming box at 50°C. Blood glucose levels are checked every 5 minutes and 20% dextrose infusion is adjusted to maintain a serum glucose level of approximately 80 mg/dL. Subjects were considered to have achieved steady state when the dextrose infusion rate required to maintain a serum glucose level of 80 mg/dL varied by no greater than 5%. To compute the steady-state glucose disposal rate, we averaged the glucose infusion rates over the last 20 minutes of the clamp and applied a "space correction" to account for small changes in serum glucose levels over that time period. |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Mark Creager, M.D. | Brigham and Women's Hospital | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Brigham & Women's Hospital | Boston | Massachusetts | 02115 | United States |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 25095746 | Derived | Pande RL, Brown J, Buck S, Redline W, Doyle J, Plutzky J, Creager MA. Association of monocyte tumor necrosis factor alpha expression and serum inflammatory biomarkers with walking impairment in peripheral artery disease. J Vasc Surg. 2015 Jan;61(1):155-61. doi: 10.1016/j.jvs.2014.06.116. Epub 2014 Aug 2. |
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| ID | Title | Description |
|---|---|---|
| FG000 | Healthy Controls | Healthy individuals, non-smokers, normal CV examination. Randomized to atorvastatin/pioglitazone, atorvastatin/placebo, placebo/pioglitazone, or placebo/placebo. |
| FG001 | Patients With PAD | Patients with PAD and stable intermittent claudication with a resting ABI of 0.90 or less. Randomized to atorvastatin/pioglitazone, atorvastatin/placebo, placebo/pioglitazone, or placebo/placebo. |
| FG002 | PAD (Excluding Patients With Diabetes) | Patients with PAD and stable intermittent claudication with a resting ABI of 0.90 or less. Excluding those patients with diabetes. Randomized to atorvastatin/pioglitazone, atorvastatin/placebo, placebo/pioglitazone, or placebo/placebo. |
| Title | Milestones | Reasons Not Completed | ||||||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
Baseline Characteristics were collected according to the clinical diagnosis of the patients and not according to randomization. Participants are grouped at Baseline regardless of randomization because we are measuring baseline characteristics that do not depend on which intervention they received.
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| ID | Title | Description |
|---|---|---|
| BG000 | Healthy Controls | Healthy individuals, non-smokers, normal CV examination. |
| BG001 | Patients With PAD | Patients with PAD and stable intermittent claudication with a resting ABI of 0.90 or less. |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Categorical | Count of Participants |
| 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 | Lower Extremity Skeletal Muscle Glucose Uptake | Net calf skeletal muscle glucose uptake determined by Patlak modeling. | Baseline Characteristics were collected according to the clinical diagnosis of the patients and not according to randomization. Participants were grouped at Baseline and are presented here irrespective of randomization because the primary intention was to compare the different types of patients regardless of interventions received. | Mean | Standard Deviation | umol/kg/min | 60 minutes |
|
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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 | Received Atorvastatin/Pioglitazone | Including healthy subjects and subjects with PAD |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Mark Creager | Brigham and Women's Hospital | 617-732-5267 | mcreager@partners.org |
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| ID | Term |
|---|---|
| D001157 | Arterial Occlusive Diseases |
| D007383 | Intermittent Claudication |
| D007333 | Insulin Resistance |
| D058729 | Peripheral Arterial Disease |
| ID | Term |
|---|---|
| D014652 | Vascular Diseases |
| D002318 | Cardiovascular Diseases |
| D016491 | Peripheral Vascular Diseases |
| D012816 | Signs and Symptoms |
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| ID | Term |
|---|---|
| D000069059 | Atorvastatin |
| D000077205 | Pioglitazone |
| ID | Term |
|---|---|
| D011758 | Pyrroles |
| D001393 | Azoles |
| D006573 | Heterocyclic Compounds, 1-Ring |
| D006571 | Heterocyclic Compounds |
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|
| atorvastatin/placebo | Drug | atorvastatin 80 mg orally once daily and matching placebo orally twice daily |
|
|
| pioglitazone/placebo | Drug | pioglitazone 30 mg orally once daily and matching placebo orally once daily |
|
|
| placebo/placebo | Drug | placebo orally three times daily |
|
| every 5 minutes for 20 minutes |
| BG002 | PAD Without Diabetes | Patients with PAD and stable intermittent claudication with a resting ABI of 0.90 or less. These patients do not have diabetes. |
| BG003 | Total | Total of all reporting groups |
| Participants |
|
| Age, Continuous | Mean | Standard Deviation | years |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Region of Enrollment | Number | participants |
|
| OG002 | PAD (Excluding Diabetes) | Patients with PAD and stable intermittent claudication with a resting ABI of 0.90 or less. These patients do not have diabetes. |
|
|
| Secondary | 'M' = Whole Body Insulin Sensitivity | A hyperinsulinemic-euglycemic clamp was performed prior to and during FDG-PET imaging to measure insulin sensitivity and to standardize metabolic conditions. Subjects were required to fast for 8 hours prior to the study. Patients were given a primed insulin infusion of 2 mU/kg/min. Serum glucose measurements were made at five-minute intervals from an arterialized venous sample achieved by placing the hand in a warming box at 50°C. Blood glucose levels are checked every 5 minutes and 20% dextrose infusion is adjusted to maintain a serum glucose level of approximately 80 mg/dL. Subjects were considered to have achieved steady state when the dextrose infusion rate required to maintain a serum glucose level of 80 mg/dL varied by no greater than 5%. To compute the steady-state glucose disposal rate, we averaged the glucose infusion rates over the last 20 minutes of the clamp and applied a "space correction" to account for small changes in serum glucose levels over that time period. | Baseline Characteristics were collected according to the clinical diagnosis of the patients and not according to randomization. Participants were grouped at Baseline and are presented here irrespective of randomization because the primary intention was to compare the different types of patients regardless of interventions received. | Median | Inter-Quartile Range | mg/kg/min | every 5 minutes for 20 minutes |
|
|
|
| 0 |
| 19 |
| 0 |
| 19 |
| EG001 | Received Atorvastatin/Placebo | Including healthy subjects and subjects with PAD | 0 | 18 | 0 | 18 |
| EG002 | Received Placebo/Pioglitazone | Including healthy subjects and subjects with PAD | 0 | 20 | 0 | 20 |
| EG003 | Received Placebo/Placebo | Including healthy subjects and subjects with PAD | 0 | 19 | 0 | 19 |
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| D013568 | Pathological Conditions, Signs and Symptoms |
| D006946 | Hyperinsulinism |
| D044882 | Glucose Metabolism Disorders |
| D008659 | Metabolic Diseases |
| D009750 | Nutritional and Metabolic Diseases |
| D050197 | Atherosclerosis |
| D001161 | Arteriosclerosis |
| D006538 |
| Heptanoic Acids |
| D005227 | Fatty Acids |
| D008055 | Lipids |
| D045162 | Thiazolidinediones |
| D013844 | Thiazoles |
| D013457 | Sulfur Compounds |
| D009930 | Organic Chemicals |