ARREST PAD (Peripheral Arterial Disease)

• Sponsor: Brigham and Women's Hospital (Other)
• Overall Status: Completed
• CT.gov ID: NCT00153166
• Collaborator: National Heart, Lung, and Blood Institute (NHLBI) (NIH)
• Enrollment: 76
• Location: 1
• Arms: 3
• Duration (Months): 95
• Patients Per Site Per Month: 0.8

Study Details

Study Description

Brief Summary

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.

Condition or Disease	Intervention/Treatment	Phase
Arterial Occlusive Disease; Intermittent Claudication; Insulin Resistance	Drug: atorvastatin and pioglitazone; Drug: atorvastatin/placebo; Drug: pioglitazone/placebo; Drug: placebo/placebo	Phase 2/Phase 3

Detailed Description

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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 76 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: The Contribution of Inflammation and Insulin Resistance to Intermittent Claudication
• Study Start Date: Jan 1, 2004
• Actual Primary Completion Date: Nov 1, 2010
• Actual Study Completion Date: Dec 1, 2011

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Patients with PAD (Including diabetics) Randomized to either atorvastatin and pioglitazone, atorvastatin/placebo, pioglitazone/placebo, or placebo/placebo.	Drug: atorvastatin and pioglitazone; atorvastatin 80 mg orally once daily (to reduce inflammation) and pioglitazone 30 mg orally once daily (to improve insulin sensitivity); Other Names: atorvastatin: lipitor pioglitazone: actos ; Drug: atorvastatin/placebo; atorvastatin 80 mg orally once daily and matching placebo orally twice daily; Other Names: atorvastatin: lipitor ; Drug: pioglitazone/placebo; pioglitazone 30 mg orally once daily and matching placebo orally once daily; Other Names: pioglitazone: actos ; Drug: placebo/placebo; placebo orally three times daily
Active Comparator: PAD (Excluding Diabetics) Randomized to either atorvastatin and pioglitazone, atorvastatin/placebo, pioglitazone/placebo, or placebo/placebo.	Drug: atorvastatin and pioglitazone; atorvastatin 80 mg orally once daily (to reduce inflammation) and pioglitazone 30 mg orally once daily (to improve insulin sensitivity); Other Names: atorvastatin: lipitor pioglitazone: actos ; Drug: atorvastatin/placebo; atorvastatin 80 mg orally once daily and matching placebo orally twice daily; Other Names: atorvastatin: lipitor ; Drug: pioglitazone/placebo; pioglitazone 30 mg orally once daily and matching placebo orally once daily; Other Names: pioglitazone: actos ; Drug: placebo/placebo; placebo orally three times daily
Active Comparator: Healthy Controls Randomized to either atorvastatin and pioglitazone, atorvastatin/placebo, pioglitazone/placebo, or placebo/placebo.	Drug: atorvastatin and pioglitazone; atorvastatin 80 mg orally once daily (to reduce inflammation) and pioglitazone 30 mg orally once daily (to improve insulin sensitivity); Other Names: atorvastatin: lipitor pioglitazone: actos ; Drug: atorvastatin/placebo; atorvastatin 80 mg orally once daily and matching placebo orally twice daily; Other Names: atorvastatin: lipitor ; Drug: pioglitazone/placebo; pioglitazone 30 mg orally once daily and matching placebo orally once daily; Other Names: pioglitazone: actos ; Drug: placebo/placebo; placebo orally three times daily

Outcome Measures

Primary Outcome Measures

1. Lower Extremity Skeletal Muscle Glucose Uptake [60 minutes]

   Net calf skeletal muscle glucose uptake determined by Patlak modeling.

Secondary Outcome Measures

1. 'M' = Whole Body Insulin Sensitivity [every 5 minutes for 20 minutes]

   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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 40 Years to 85 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes

Inclusion Criteria:

• symptomatic intermittent claudication for >= 6 months

• resting ankle/brachial index (ABI) <=0.90

• maximal treadmill walking time between 1-20 minutes

• = 20% decrease in ABI post treadmill exercise

• 4 week statin wash-out prior to initial study testing (if applicable)

Exclusion Criteria:

• myocardial infarction or coronary artery bypass surgery within past 6 months

• lower extremity revascularization (surgical or percutaneous) within past 6 months

• transient ischemic attack or ischemic stroke within past 6 months

• pregnancy

• uncontrolled hypertension (systolic pressure > 180mmHg and/or diastolic pressure > 100mmHg

• serum creatinine >2.5

• hepatic transaminases (AST, ALT) > 3x upper limit of normal (ULN)

• creatine kinase > 5x ULN

• known hypersensitivity to HMG-CoA reductase inhibitors

• insulin dependent Type 2 diabetes

• current treatment with thiazolidinedione

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Brigham & Women's Hospital	Boston	Massachusetts	United States	02115

Sponsors and Collaborators

• Brigham and Women's Hospital
• National Heart, Lung, and Blood Institute (NHLBI)

Investigators

• Principal Investigator: Mark Creager, M.D., Brigham and Women's Hospital

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Mark Alan Creager, MD, Principal Investigator, Brigham and Women's Hospital
• ClinicalTrials.gov Identifier: NCT00153166
• Other Study ID Numbers: 2003P-001501; R01HL075771; NCT00225940
• First Posted: Sep 12, 2005
• Last Update Posted: Sep 30, 2014
• Last Verified: Sep 1, 2014

• Keywords provided by Mark Alan Creager, MD, Principal Investigator, Brigham and Women's Hospital: peripheral arterial disease; intermittent claudication
• Additional relevant MeSH terms: Peripheral Arterial Disease; Intermittent Claudication; Arterial Occlusive Diseases; Insulin Resistance; Pioglitazone; Atorvastatin

Study Results

Participant Flow

Arm/Group Title	Healthy Controls	Patients With PAD	PAD (Excluding Patients With Diabetes)
Arm/Group Description	Healthy individuals, non-smokers, normal CV examination. Randomized to atorvastatin/pioglitazone, atorvastatin/placebo, placebo/pioglitazone, or placebo/placebo.	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.	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.
Period Title: Overall Study
STARTED	11	37	28
Received Atorvastatin and Pioglitazone	3	9	7
Received Atorvastatin and Placebo	2	9	7
Received Placebo and Pioglitazone	3	10	7
Received Placebo and Placebo	3	9	7
COMPLETED	11	37	28
NOT COMPLETED	0	0	0

Baseline Characteristics

Arm/Group Title	Healthy Controls	Patients With PAD	PAD Without Diabetes	Total
Arm/Group Description	Healthy individuals, non-smokers, normal CV examination.	Patients with PAD and stable intermittent claudication with a resting ABI of 0.90 or less.	Patients with PAD and stable intermittent claudication with a resting ABI of 0.90 or less. These patients do not have diabetes.	Total of all reporting groups
Overall Participants	11	37	28	76
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%	0 0%
Between 18 and 65 years	3 27.3%	6 16.2%	6 21.4%	15 19.7%
>=65 years	8 72.7%	31 83.8%	22 78.6%	61 80.3%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	60.5 (6)	66 (8.7)	64.6 (8.8)	64.2 (9.5)
Sex: Female, Male (Count of Participants)
Female	6 54.5%	6 16.2%	3 10.7%	15 19.7%
Male	5 45.5%	31 83.8%	25 89.3%	61 80.3%
Region of Enrollment (participants) [Number]
United States	11 100%	37 100%	28 100%	76 100%

Outcome Measures

1. Primary Outcome

Title	Lower Extremity Skeletal Muscle Glucose Uptake
Description	Net calf skeletal muscle glucose uptake determined by Patlak modeling.
Time Frame	60 minutes

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Healthy Controls	Patients With PAD	PAD (Excluding Diabetes)
Arm/Group Description	Healthy individuals, non-smokers, normal CV examination.	Patients with PAD and stable intermittent claudication with a resting ABI of 0.90 or less.	Patients with PAD and stable intermittent claudication with a resting ABI of 0.90 or less. These patients do not have diabetes.
Measure Participants	11	37	28
Mean (Standard Deviation) [umol/kg/min]	62.9 (21)	48.6 (15)	49.5 (3.1)

2. Secondary Outcome

Title	'M' = Whole Body Insulin Sensitivity
Description	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.
Time Frame	every 5 minutes for 20 minutes

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Healthy Controls	Patients With PAD	PAD (Excluding Diabetes)
Arm/Group Description	Healthy individuals, non-smokers, normal CV examination.	Patients with PAD and stable intermittent claudication with a resting ABI of 0.90 or less.	Patients with PAD and stable intermittent claudication with a resting ABI of 0.90 or less. These patients do not have diabetes.
Measure Participants	11	37	28
Median (Inter-Quartile Range) [mg/kg/min]	5.0	3.4	3.4

Adverse Events

Arm/Group Title	Received Atorvastatin/Pioglitazone		Received Atorvastatin/Placebo		Received Placebo/Pioglitazone		Received Placebo/Placebo
Arm/Group Description	Including healthy subjects and subjects with PAD		Including healthy subjects and subjects with PAD		Including healthy subjects and subjects with PAD		Including healthy subjects and subjects with PAD
All Cause Mortality
	Received Atorvastatin/Pioglitazone		Received Atorvastatin/Placebo		Received Placebo/Pioglitazone		Received Placebo/Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	Received Atorvastatin/Pioglitazone		Received Atorvastatin/Placebo		Received Placebo/Pioglitazone		Received Placebo/Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/19 (0%)		0/18 (0%)		0/20 (0%)		0/19 (0%)
Other (Not Including Serious) Adverse Events
	Received Atorvastatin/Pioglitazone		Received Atorvastatin/Placebo		Received Placebo/Pioglitazone		Received Placebo/Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/19 (0%)		0/18 (0%)		0/20 (0%)		0/19 (0%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT 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.