Role of PPAR-y Agonists in Immunomodulation and Vascular Prevention in SLE (PPAR-SLE)

Phase 1

Completed

Conditions: Systemic Lupus Erythematosus

Interventions: Radiation: PET/CT
Drug: Pioglitazone
Drug: Placebo

Registration Number: NCT02338999

Lead Sponsor: National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)

Brief Summary: Background:

- Lupus causes a person s immune system to attack the body. It can cause blood vessel problems, heart attack, or stroke. Researchers want to see if the drug pioglitazone may help.

Objectives:

- To see how well pioglitazone improves blood vessel function and decreases blood vessel inflammation. To study its effect on lupus symptoms.

Eligibility:

- Adults at least 18 years old with lupus.

Design:

* Participants will be screened with medical history, heart test, and blood and urine tests. They may have a bone density test.

* Visit 1:

* Participants will have:

* Physical exam and blood drawn.

* Peripheral Arterial Tonometry (Endopat). A cup will be placed on the finger and a pressure cuff on the arm.

* Cardio-ankle vascular index (CAVI) and/or Sphygmocor. Electrodes will be placed on both wrists, a microphone on the chest, and a blood pressure cuff on each arm and leg. Another test will involve placing a small device on a fingertip.

* 18-Fluorodeoxyglucose (FDG) positron emission tomography/computerized tomography (PET/CT) (some participants). A radioactive sugar will be injected into a small plastic tube in an arm vein. Participants will lie on a bed that moves in and out of a scanner that takes pictures.

* Participants will get a 3-month-supply of the study drug or placebo. After 1 week, their dose may increase.

* After those 3 months, they will not take either drug for 8 weeks. Then they will switch and take the other drug for 3 months.

* Participants will have 6 more visits over 8 months after Visit 1. Tests from Visit 1 may be repeated. They may have a urine test.

Detailed Description: Systemic lupus erythematosus (SLE) is an autoimmune disease of unclear cause that affects primarily women of childbearing age. Patients with lupus have a significantly increased risk of developing complications of their blood vessels due to accelerated hardening of the arteries (atherosclerosis). These complications include heart attacks and stroke. No drug to date has proven to prevent this type of complication in lupus and premature vascular disease significantly impacts the quality of life of these patients and enhances their risk of death.

The thiazolidinediones (TZD) are a class of drugs approved for the treatment of patients with type 2 diabetes mellitus (DM); they belong to the family of drugs that activate the peroxisome proliferator-activated receptor-gamma (PPAR-gamma). They have been proposed to have strong anti-atherogenic and anti-inflammatory effects even in patients without diabetes. Recent work from our group and others indicates that TZDs significantly improve vascular damage, dysfunction of blood vessels and disease activity in mouse models of lupus and abrogate atherosclerosis. We recently identified the TZD pioglitazone as an effective drug in modulation of vascular function and disease activity in patients with rheumatoid arthritis. In addition, we have found in mouse models of lupus and in in vitro experiments with human lupus cells, that pioglitazone has important roles in modulating immune function and vascular manifestations. Furthermore, this drug is not immunosuppressive, adding an additional advantage when compared to other medications used in this disease.

We propose that TZDs could significantly improve blood vessel function and play a role in atherosclerosis prevention in human SLE, in addition to modifying lupus disease activity. The major goal of the proposed research is to assess the effects of the PPAR-gamma agonist pioglitazone in SLE on vascular function and inflammation and on SLE disease activity. The results of the study may lead to the characterization of a new therapeutic target with dual effects on lupus and its associated blood vessel damage

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 88

Inclusion Criteria

Not provided

Exclusion Criteria

Not provided

Study & Design

Study Type: INTERVENTIONAL

Study Design: CROSSOVER

Arm && Interventions

Group	Intervention	Description
Pioglitazone, then placebo	PET/CT	Treatment with pioglitazone up to 45 mg orally daily for three months. Followed by a two-month washout period before cross over to placebo orally daily for three months. A randomly selected subset of subjects underwent optional FDG-PET/CT for measurement of inflammatory activity in the blood vessels.
Pioglitazone, then placebo	Placebo	Treatment with pioglitazone up to 45 mg orally daily for three months. Followed by a two-month washout period before cross over to placebo orally daily for three months. A randomly selected subset of subjects underwent optional FDG-PET/CT for measurement of inflammatory activity in the blood vessels.
Placebo, then Pioglitazone	PET/CT	Treatment with placebo orally daily for three months. Followed by a two-month washout period before cross over to pioglitazone up to 45 mg daily orally for an additional three months. A randomly selected subset of subjects underwent optional FDG-PET/CT for measurement of inflammatory activity in the blood vessels.
Placebo, then Pioglitazone	Placebo	Treatment with placebo orally daily for three months. Followed by a two-month washout period before cross over to pioglitazone up to 45 mg daily orally for an additional three months. A randomly selected subset of subjects underwent optional FDG-PET/CT for measurement of inflammatory activity in the blood vessels.
Pioglitazone, then placebo	Pioglitazone	Treatment with pioglitazone up to 45 mg orally daily for three months. Followed by a two-month washout period before cross over to placebo orally daily for three months. A randomly selected subset of subjects underwent optional FDG-PET/CT for measurement of inflammatory activity in the blood vessels.
Placebo, then Pioglitazone	Pioglitazone	Treatment with placebo orally daily for three months. Followed by a two-month washout period before cross over to pioglitazone up to 45 mg daily orally for an additional three months. A randomly selected subset of subjects underwent optional FDG-PET/CT for measurement of inflammatory activity in the blood vessels.

Primary Outcome Measures

Name	Time	Method
Change in Vascular Function and Cardiometabolic Risk as Measured by Left CAVI at Month 3	3 months after start of first intervention (Baseline to 3 months)	Change in vascular function using non-invasive vascular tests, measuring vascular compliance - Cardio ankle vascular index (CAVI). CAVI is an index reflecting the stiffness of the artery from the heart to ankles; it increases with atherosclerosis progression. CAVI was measured using VaSera-1500A (Fukuda Denshi Co. Redmond, WA)
Change in Vascular Function and Cardiometabolic Risk as Measured by Left CAVI at Month 8	3 months after start of second intervention (5 months to 8 months)	Change in vascular function using non-invasive vascular tests, measuring vascular compliance - Cardio ankle vascular index (CAVI). CAVI is an index reflecting the stiffness of the artery from the heart to ankles; it increases with atherosclerosis progression. CAVI was measured using VaSera-1500A (Fukuda Denshi Co. Redmond, WA)
Change in Vascular Function and Cardiometabolic Risk as Measured by Right CAVI at Month 3	3 months after start of first intervention (Baseline to 3 months)	Change in vascular function using non-invasive vascular tests, measuring vascular compliance - Cardio ankle vascular index (CAVI). CAVI is an index reflecting the stiffness of the artery from the heart to ankles; it increases with atherosclerosis progression. CAVI was measured using VaSera-1500A (Fukuda Denshi Co. Redmond, WA)
Change in Vascular Function and Cardiometabolic Risk as Measured by Right CAVI at Month 8	3 months after start of second intervention (5 months to 8 months)	Change in vascular function using non-invasive vascular tests, measuring vascular compliance - Cardio ankle vascular index (CAVI). CAVI is an index reflecting the stiffness of the artery from the heart to ankles; it increases with atherosclerosis progression. CAVI was measured using VaSera-1500A (Fukuda Denshi Co. Redmond, WA)
Change in Vascular Function and Cardiometabolic Risk as Measured by PWV at Month 3	3 months after start of first intervention (Baseline to 3 months)	Change in vascular function using non-invasive vascular tests, measuring vascular compliance -Pulse, wave, velocity (PWV). The central aortic pressure PWV was determined by using the pressure tonometer and an EKG signal was used simultaneously to visualize ventricular-vascular interactions. It increases with atherosclerosis progression. Central aortic BP and stiffness were quantified using SphygmoCor CP system (AtCor Medical Pty Ltd.; New South Wales, Australia).
Change in Vascular Function and Cardiometabolic Risk as Measured by PWV at Month 8	3 months after start of second intervention (5 months to 8 months)	Change in vascular function using non-invasive vascular tests, measuring vascular compliance -Pulse, wave, velocity (PWV). The central aortic pressure PWV was determined by using the pressure tonometer and an EKG signal was used simultaneously to visualize ventricular-vascular interactions. It increases with atherosclerosis progression. Central aortic BP and stiffness were quantified using SphygmoCor CP system (AtCor Medical Pty Ltd.; New South Wales, Australia).
Change in Vascular Function and Cardiometabolic Risk as Measured by RHI at Month 3	3 months after start of first intervention (Baseline to 3 months)	Change in vascular function using non-invasive vascular tests, measuring vascular compliance -Reactive hyperemia index (RHI). RHI is a measure of endothelial dysfunction using noninvasive peripheral arterial tonometry (PAT). It is a ratio of the post-to-pre occlusion PAT amplitude of the tested arm, divided by the post-to-pre occlusion ratio of the control arm. RHI less than 1.67 is considered sign of endothelial dysfunction and RHI equal to or greater than 1.67 is considered normal function. The possible range of scores is 1 to 3. Increasing score indicates the improvement of coronary endothelial function
Change in Vascular Function and Cardiometabolic Risk as Measured by RHI at Month 8	3 months after start of second intervention (5 months to 8 months)	Change in vascular function using non-invasive vascular tests, measuring vascular compliance -Reactive hyperemia index (RHI). RHI is a measure of endothelial dysfunction using noninvasive peripheral arterial tonometry (PAT). It is a ratio of the post-to-pre occlusion PAT amplitude of the tested arm, divided by the post-to-pre occlusion ratio of the control arm. RHI less than 1.67 is considered sign of endothelial dysfunction and RHI equal to or greater than 1.67 is considered normal function. The possible range of scores is 1 to 3. Increasing score indicates the improvement of coronary endothelial function
Effect of Pioglitazone on Vascular Inflammation and Cardiometabolic Risk as Measured by TBR Value at Month 3	3 months after start of first intervention (Baseline to 3 months)	Change in vascular inflammation using non-invasive vascular test, measuring changes in target to blood pool ratio (TBR) value by positron emission tomography (PET) computerized tomography (CT). The higher the value, the higher the degree of vascular inflammation.