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

Exclusion Criteria

• •1. Pregnant or lactating women
• •2. Expected need for major surgery during trial.
• •3. 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.
• •4. 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.
• •5. Chronic infections such as hepatitis B, hepatitis C, HIV or Tuberculosis.
• •6. Current use of cyclophosphamide or having received cyclophosphamide within the last year.
• •7. Prior history of hemorrhagic cystitis or hematuria while receiving cyclophosphamide that could not be explained by other causes.
• •8. Current use (within 3 months) of tocilizumab, rituximab, belimumab, intravenous gammaglobulin or other biologic.
• •9. History of poor compliance with medical care, study visits and/or medication use.
• •10. 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.
• •11. 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.
• •12. 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.
• •13. Known hypersensitivity to TZDs
• •14. 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.
• •15. Diagnosis of DM or meeting DM criteria at screening visit, as established by new classification criteria: Patients with diabetes are excluded because diabetes by itself will induce profound changes in endothelial function and we want to assess the effects of PPAR agonists in vascular risk beyond changes in insulin resistance.
• •16. Known latex allergy for EndoPAT test
• •17. Patients with severe Raynaud's phenomenon, history of finger ulcers or finger gangrene will not undergo Endopat testing.
• •18. Patients with severe SLE at baseline, as quantified as SLEDAI-2K \>20.
• •19. Patients with active lupus nephritis or active CNS lupus at baseline even if SLEDAI-2K \<20. Active disease will be considered as CNS or renal disease that require aggressive immunosuppression. Active CNS disease will be diagnosed based on clinical presentation and physical exam, exclusion of other conditions that could explain symptomatology and, when warranted, ancillary tests (imaging) that support the diagnosis.
• •Patients that are not on induction therapy for lupus nephritis and have chronic (more than 6 months), stable proteinuria \<750 mg/gram in protein:creatinine ratio but otherwise considered to have no evidence of active lupus nephritis (e.g. no cellular casts and stable serum creatinine \< 2 mg/dL) over the last 6 months, will be included in the study.
• •In selected patients with potentially confounding clinical factors, consults will be requested to help clarify the nature of any underlying renal disease that may affect inclusion.
• •20. Postmenopausal women who have not undergone a DEXA scan over the last year will undergo a DEXA scan at screening. Patients with a better than -2.5 will be included. Postmenopausal women who have undergone a DEXA scan during the last year and have a T score better than -2.5 will be included without repeating the DEXA scan prior to enrollment. If the T score is worse than -2.5, they will be excluded from participating unless the subject is willing to begin appropriate treatment for osteoporosis by Visit Day 1. Postmenopausal women who have undergone a DEXA scan during the last year, have a T score worse than -2.5 and are not on bisphosphonates or other appropriate therapy will be excluded.