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

NCT02338999 | Completed Phase 1 Results FDA Drug

• 2 other identifiers: 15006015-AR-0060
• Study Type: interventional
• Target: 88
• Locations: 1 country
• Sites: 1

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.

Conditions

Systemic Lupus Erythematosus

Keywords

Autoimmunity Pathogenesis; Atherosclerosis; Adult

Outcome Measures

Primary Outcomes (9)

• Change in Vascular Function and Cardiometabolic Risk as Measured by Left CAVI at Month 3

  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)

  3 months after start of first intervention (Baseline to 3 months)

• Change in Vascular Function and Cardiometabolic Risk as Measured by Left CAVI at Month 8

  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)

  3 months after start of second intervention (5 months to 8 months)

• Change in Vascular Function and Cardiometabolic Risk as Measured by Right CAVI at Month 3

  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)

  3 months after start of first intervention (Baseline to 3 months)

• Change in Vascular Function and Cardiometabolic Risk as Measured by Right CAVI at Month 8

  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)

  3 months after start of second intervention (5 months to 8 months)

• Change in Vascular Function and Cardiometabolic Risk as Measured by PWV at Month 3

  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).

  3 months after start of first intervention (Baseline to 3 months)

• Change in Vascular Function and Cardiometabolic Risk as Measured by PWV at Month 8

  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).

  3 months after start of second intervention (5 months to 8 months)

• Change in Vascular Function and Cardiometabolic Risk as Measured by RHI at Month 3

  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

  3 months after start of first intervention (Baseline to 3 months)

• Change in Vascular Function and Cardiometabolic Risk as Measured by RHI at Month 8

  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

  3 months after start of second intervention (5 months to 8 months)

• Effect of Pioglitazone on Vascular Inflammation and Cardiometabolic Risk as Measured by TBR Value at Month 3

  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.

  3 months after start of first intervention (Baseline to 3 months)

Study Arms (2)

Pioglitazone, then placebo

EXPERIMENTAL

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.

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

Placebo, then Pioglitazone

EXPERIMENTAL

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.

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

Interventions

PET/CT RADIATION

The combined PET/CT scans provide images that pinpoint the anatomic location of abnormal metabolic activity within the body.

Pioglitazone, then placebo; Placebo, then Pioglitazone

Pioglitazone DRUG

Increases insulin sensitivity in muscle and adipose tissue, and inhibits hepatic gluconeogenesis.

Pioglitazone, then placebo; Placebo, then Pioglitazone

Placebo DRUG

Pioglitazone, then placebo; Placebo, then Pioglitazone

Eligibility Criteria

• Age: 18 Years - 99 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• For females and males 18 years old or older: females should be on adequate contraception if they are of child-bearing potential, which should be documented by a clinician, unless patients or their spouse/partner(s) have previously undergone a sterilization procedure. Adequate contraception will be considered:
• Intrauterine device (IUD),
• Hormone implants,
• Injectable contraceptives,
• Oral contraceptives plus a barrier method (male condom, female condom or diaphragm),
• Abstinence, or
• A vasectomized partner.
• Meet revised ACR criteria and 2012 SLICC criteria for SLE and have: a) a baseline SLEDAI-2K greater than or equal to 4 and \<20 or a clinical SLEDAI-2K greater than or equal to 2 (not considering anti-dsDNA or complement levels) and b) lack of BILAG A flare at baseline.
• Stable doses of immunosuppressants and/or antimalarials for at least 3 months, and/or corticosteroids for at least 2 weeks. The prednisone dose may be increased after screening visit as long as the total dose is less than 20 mg of prednisone or equivalent per
• day and the subject is on stable dose for at least 2 weeks prior to their Day 1 visit. If on statins, should have been on stable doses for at least 6 months.
• Allowed concomitant lupus-related medications
• Antimalarials,
• Prednisone greater than or equal to 20mg daily or equivalent doses of other corticosteroids;
• Immunosuppressants:
• Mycophenolate mofetil, up to 3000 mg/day,

You may not qualify if:

• Pregnant or lactating women
• Expected need for major surgery during trial.
• Current or previous diagnosis of malignant disease, except for basal cell or squamous cell carcinoma of the skin with complete excision and clear borders or adequately treated in situ carcinoma of the cervix.
• Acute infections identified during screening that require antibiotics. These subjects would be eligible to participate following resolution of infection before Day 1 visit within the allowed 46 days screening period. The subject will re-screen if it extends beyond the
• allowed 46 days screening period.
• Chronic infections such as hepatitis B, hepatitis C, HIV or Tuberculosis.
• Current use of cyclophosphamide or having received cyclophosphamide within the last year.
• Prior history of hemorrhagic cystitis or hematuria while receiving cyclophosphamide that could not be explained by other causes.
• Current use (within 3 months) of tocilizumab, rituximab, belimumab, intravenous gammaglobulin or other biologic.
• History of poor compliance with medical care, study visits and/or medication use.
• Receipt of any investigational new drug or device within 30 days prior to screening or 5 half-lives of the agent \<TAB\>(whichever is longer), or any investigational new drug with known long-term effects.
• Pioglitazone is not recommended in patients with symptomatic heart failure. Patients with current heart failure (NYHA class II, III or IV) and/or a left ventricular ejection fraction of \<45% by echocardiogram at screening will be excluded.
• Significant impairment of major organ function (lung, heart, liver, kidney) or any condition that, in the opinion of the Investigator, would jeopardize the subject s safety following exposure to the study drug.
• Known hypersensitivity to TZDs
• Serum hepatic transaminase levels \> 2 times upper normal limit, or clinical evidence of active liver disease at screening. The only exception is patients with confirmed non-alcoholic fatty liver disease (NAFLD) where pioglitazone has been reported to have a therapeutic role.

Sponsors & Collaborators

• National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS): lead

Study Sites (1)

National Institutes of Health Clinical Center, 9000 Rockville Pike

Bethesda, Maryland, 20892, United States

Location

Related Publications (1)

• Hasni S, Temesgen-Oyelakin Y, Davis M, Chu J, Poncio E, Naqi M, Gupta S, Wang X, Oliveira C, Claybaugh D, Dey A, Lu S, Carlucci P, Purmalek M, Manna ZG, Shi Y, Ochoa-Navas I, Chen J, Mukherjee A, Han KL, Cheung F, Koroleva G, Belkaid Y, Tsang JS, Apps R, Thomas DE, Heller T, Gadina M, Playford MP, Li X, Mehta NN, Kaplan MJ. Peroxisome proliferator activated receptor-gamma agonist pioglitazone improves vascular and metabolic dysfunction in systemic lupus erythematosus. Ann Rheum Dis. 2022 Oct 12;81(11):1576-1584. doi: 10.1136/ard-2022-222658.

  PMID: 35914929 DERIVED

Related Links

• NIH Clinical Center Detailed Web Page

MeSH Terms

Conditions

Lupus Erythematosus, Systemic; Atherosclerosis

Interventions

Pioglitazone

Condition Hierarchy (Ancestors)

Connective Tissue Diseases; Skin and Connective Tissue Diseases; Autoimmune Diseases; Immune System Diseases; Arteriosclerosis; Arterial Occlusive Diseases; Vascular Diseases; Cardiovascular Diseases

Intervention Hierarchy (Ancestors)

Thiazolidinediones; Thiazoles; Sulfur Compounds; Organic Chemicals; Azoles; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds

Results Point of Contact

• Title: Kaplan, Mariana
• Organization: National Inst of Arthritis and Musculoskeletal and Skin Diseases

mariana.kaplan@nih.gov

+1 301 496 0517

Study Officials

• Mariana J Kaplan, M.D.

  National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, INVESTIGATOR
• Purpose: PREVENTION
• Intervention Model: CROSSOVER
• Sponsor Type: NIH
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: January 14, 2015
• First Posted: January 15, 2015
• Study Start: June 18, 2015
• Primary Completion: July 14, 2020
• Study Completion: July 14, 2020
• Last Updated: September 14, 2021
• Results First Posted: September 14, 2021

Record last verified: 2020-07-14

Locations

US (1)