The Role of PPAR-Gamma Agonists in Immunomodulation and Vascular Prevention in SLE (PPAR-SLE)
Phase: PHASE1
Conditions: Systemic Lupus Erythematosus
Sponsor: National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)

  
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CLINICAL RESEARCH PROTOCOL 
NATIONAL INSTITUTE OF ARTHRITIS AND MUSCULOSKELETAL AND SKIN DISEASES 
PROTOCOL NUMBER: 15-AR-0060 
PROTOCOL VERSION/TYPE: 27/ CR 
IRB CR Approved Date:  05/24/2021 
PROTOCOL STATUS: Open for Data/Specimen Analysis  
CR Expiration Date: 05/23/2022 
Z Number: ZIAAR041199 
 
PROTOCOL TITLE:   The role of PPAR-γ agonists in immunomodulation and vascular prevention in  
 
 
 
 
SLE   PPAR-SLE). 
 
SHORT TITLE:  PPAR-SLE 
IDENTIFYING WORDS: PPAR-SLE, Pioglitazone.  
Principal Investigator: 
Name, Degree 
Branch/Institute 
*Mariana J. Kaplan M.D. 
SAB/NIAMS 
 
ESTIMATED DURATION OF STUDY: 5 years 
 
START DATE: June 18th, 2015 
 
 
END DATE: June 18th, 2020 
 
NUMBER AND TYPE OF PATIENTS:  100 Lupus Patients 
Accrual Ceiling:   100 
 
Number 
Sex 
 
 
Age Range 
Lupus Patients: 
 100 
 
Females & Males   
≥18 ages 
 
 
 
 
PROJECT USES IONIZING RADIATION:  
    X   Research indicated 
RSC Approval Number: 2499       Expiration Date: 10-02-2017 
Protocol type: Phase I/II interventional study 
IND/IDE: IND waiver request was granted 
Sponsor:  NIAMS 
 

  
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1 
TABLE OF CONTENTS 
Title Page ........................................................................................................................................ 1 
1 
TABLE OF CONTENTS ............................................................................................ 2 
2 
LIST OF FIGURES ..................................................................................................... 4 
3 
LIST OF TABLES ...................................................................................................... 4 
4 
LIST OF ABBREVIATIONS ..................................................................................... 5 
5 
Précis ........................................................................................................................... 6 
6 
Background  information, scientific rationale and significance .................................. 6 
6.1 
Pathogenesis of SLE and unmet needs in the treatment of this disease ...................... 6 
6.2 
Vascular damage and premature atherosclerosis in SLE ............................................ 7 
6.3 
Mechanisms of premature CVD in SLE ...................................................................... 8 
6.4 
Current treatments and CVD in SLE ........................................................................... 8 
6.5 
PPAR-γ agonists as potential therapeutic targets in SLE ............................................ 9 
6.6 
Safety of PPAR agonists ........................................................................................... 11 
6.7 
PPAR agonists in SLE ............................................................................................... 14 
7 
Objectives .................................................................................................................. 16 
8 
Study Design and Methods ........................................................................................ 17 
8.1 
Proposed Surrogate Outcomes and Biomarkers ........................................................ 19 
 
Specific Aim 1: Effect of Pioglitazone on vascular function and cardiometabolic 
risk. ............................................................................................................................ 19 
 
Specific Aim 2:  Effect of pioglitazone on SLE disease activity .............................. 22 
 
Specific Aim 3: Assess the immunoregulatory role of pioglitazone in lymphoid and 
myeloid cell subsets in SLE ...................................................................................... 23 
9 
Inclusion and Exclusion criteria ................................................................................ 24 
9.1 
Study Population and Recruitment ............................................................................ 24 
9.2 
Inclusion Criteria ....................................................................................................... 24 
9.3 
Exclusion Criteria ...................................................................................................... 25 
9.4 
Screening and Randomization ................................................................................... 28 
9.5 
Study Visits ............................................................................................................... 29 
 
Baseline visit and 5-month +/- 7 days (post-washout) visit ...................................... 29 
 
Visits at months 1 (+/- 7 days) and 6 (+/- 7 days) ..................................................... 30 
 
Visits at 3  (+/- 7 days) and 8 months (+/- 7 days) .................................................... 30 
10 
Monitoring Subjects and Criteria for Withdrawal ..................................................... 30 
10.1 
Patient Withdrawal and Termination Criteria. .......................................................... 30 
10.2 
Study Completion Criteria ......................................................................................... 31 
10.3 
Results Given to Participants and Physicians ............................................................ 31 
10.4 
Blinding, Packaging, Labeling and Storage .............................................................. 32 
11 
Data Analysis ............................................................................................................ 32 
11.1 
Power and Sample Size ............................................................................................. 33 
11.2 
Data Management ...................................................................................................... 34 
11.3 
Study Timeline .......................................................................................................... 34 
12 
Human Subject Protection Issues .............................................................................. 34 
12.1 
Selection .................................................................................................................... 34 
 Human Participants Involvement and Characteristics ............................................... 35 
 Inclusion of Women, Minorities, and Children: ........................................................ 35 
12.2 
Benefits and Risks/Discomforts ................................................................................ 35 

  
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 Benefits ...................................................................................................................... 35 
 Potential Risks ........................................................................................................... 36 
 
Adverse Event UP Reporting .................................................................................... 40 
12.3.19 
Stopping Rules 
……………………………………………………………48 
12.4 
Compliance with Good Clinical Practices ................................................................. 49 
12.5 
Data Safety and Monitoring ...................................................................................... 49 
12.6 
Data Safety Monitoring Committee .......................................................................... 49 
12.7 
Research Use, Storage, and Disposition of Human SamplesIf , Specimens, or Data 51 
 Data Collection .......................................................................................................... 51 
12.8 
Remuneration ............................................................................................................ 52 
12.9 
Protocol Consent Processes and Documents ............................................................. 52 
13.  
Participation of NIH employees………………………………….……………………..53 
14.   
Associate Investigators                 ………………...........................................................54 
15. 
References ................................................................................................................. 54 
16. 
Appendices ................................................................................................................ 67 
1. 
American College of Rheumatology Revised Classification Criteria for Systemic 
Lupus Erythematosus (1A) and SLE-disease activity index. .................................... 68 
2. 
SELENA-SLEDAI ............................................................................................... 71-72 
3. 
BILAG 2004 .............................................................................................................. 72 
4. 
SLICC Classification Criteria for SLE ...................................................................... 74 
5. 
36-item Short Form Survey ....................................................................................... 75 
6. 
NIH Clinical Center guidelines for the management of allergic reactions ............... 80 
7. 
Physician Global Assessment (PGA) ........................................................................ 81 
8. 
Systemic Lupus International Collaborating Clincs/American College of ............... 82 
 
Rheumatology (SLICC/ACR) Damage Index ........................................................... 82 
9. 
Tabulation of Radiation Doses to Subjects ............................................................... 84 
 
 
 

  
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2 
LIST OF FIGURES 
Figure 1: Mechanisms of vascular damage/ atherosclerosis in SLE and potential role of PPAR-
 agonists in atherosclerosis prevention .........................................................................................16 
Figure 2: Overall Study Schematic .............................................................................................19 
 
3 
LIST OF TABLES 
Table 1: Three Pooled 16-to 26-Week Placebo-Controlled Clinical Trials of Pioglitazone 
Monotherapy: Adverse Events Reported at an Incidence > 5% and More Commonly in 
Patients Treated with Pioglitazone than in Patients Treated with Placebo .............................13 
Table 2: Adverse Event (AE) by Body System and Treatment in Pioglitazone Trial in RA 
patients N=143 ........................................................................................................................14 
Table 3: Study Visits and Procedures .........................................................................................27 
Table 4: Study Timeline ..............................................................................................................34 
Table 5: Adverse Event Association ...........................................................................................45 
Table 6: Severity Definitions ......................................................................................................43 
 
 
 

  
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4 
LIST OF ABBREVIATIONS 
Abbreviation 
Definition 
AE 
Adverse Event 
BILAG 
British Isles Lupus Assessment Group  
CAVI 
Cardio-Ankle Vascular Index 
CRP 
C-reactive Protein 
CV 
Cardiovascular 
CVD 
Cardiovascular Disease 
DAS-28 
Disease Activity Score in 28 Joints 
DM 
Diabetes Mellitus 
15-dpGJ2 
15-Deoxy-Delta-12,14-prostaglandin J2 
EPCs 
Endothelial Progenitor Cells 
ESR 
Erythrocyte Sedimentation Rate 
FDA 
Food and Drug Administration 
FDG 
Fluorodeoxyglucose 
HDL 
High Density Lipoprotein 
HRQOL 
Health Related Quality of Life 
IC 
Immune Complex 
ICAM-1 
Intercellular Adhesion Molecule-1 
IFNs 
Interferons 
iNOS 
Inducible Nitric Oxide Synthase 
LFTs 
Liver Function Tests 
MCP-1 
Monocyte Chemoattractant Protein-1 
MMF 
Mycophenolate Mofetil 
MMP 
Matrix Metalloproteinase 
NETs 
Neutrophil extracellular traps 
NYHA 
New York Heart Association 
NO 
Nitric Oxide 
PAI-1 
Plasminogen Activator Inhibitor 1 
PAT 
Pulse Applanation Tonometry 
PGA 
Physician Global Assessment 
piHDL 
Proinflammatory HDL 
PPAR 
Peroxisome Proliferator Associated Receptor 
PWV 
Pulse Wave Velocity 
RA 
Rheumatoid Arthritis 
RHI 
Reactive Hyperemia Index 
RH-PAT 
Reactive Hyperemia-Pulse Applanation Tonometry 
RXR 
Retinoid X Receptor 
SAEs 
Serious Adverse Events 
SF-36 
Short Form (36) Health Survey 
SLE 
Systemic Lupus Erythematosus 
TZD 
Thiazolidinedione 
VCAM-1 
Vascular Cellular Adhesion Molecule-1 

  
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5 
PRÉCIS  
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- (PPAR-). They have been proposed to have strong anti-
atherogenic and anti-inflammatory effects1 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 atherosclerosis2-4.  We 
recently identified the TZD pioglitazone as an effective drug in modulation of vascular function 
and disease activity in patients with rheumatoid arthritis5. 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 manifestations3, 6. 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- 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 
6 
BACKGROUND INFORMATION, SCIENTIFIC RATIONALE AND 
SIGNIFICANCE 
6.1 
Pathogenesis of SLE and unmet needs in the treatment of this disease 
SLE is a systemic autoimmune syndrome with pleiotropic clinical manifestations that primarily 
affects women of childbearing age. SLE is highly heterogeneous in its clinical presentation, 
which renders therapeutic interventions particularly challenging. The current management of 
patients with SLE is usually stratified by the degree of internal organ involvement; however, 
most treatment strategies include a variety of immunosuppressive medications that are limited 
both in their efficacy and by their potential toxicities. FDA-approved treatments for SLE include 
only hydroxychloroquine, corticosteroids, aspirin, and most recently, belimumab. Potentially 
devastating side effects of corticosteroids are well known and include infection, avascular 
necrosis, weight gain, osteoporosis, cataracts and development of diabetes. Although often 

  
7
beneficial for treatment of active disease, other immunosuppressive medications commonly used 
in SLE (azathioprine, mycophenolic acid (MMF), cyclophosphamide, etc.) are associated with 
multiple toxicities. Furthermore, despite the addition of these potentially toxic agents, SLE 
patients usually require continued treatment with corticosteroids. Thus, lupus patients are 
typically dependent indefinitely on corticosteroids and/or immunosuppressive agents for disease 
control even while developing cumulative toxicities from exposure to these drugs.  Clearly there 
is an unmet need for improved treatment of inflammation in this patient population7.  
Both innate and adaptive aberrant immune responses appear to play key roles in the loss of 
tolerance and the development of subclinical and clinical manifestations8. In SLE, genetic, 
environmental, hormonal, and various epigenetic and immunoregulatory factors act either 
sequentially or simultaneously on the immune system. This results in the generation of 
autoantibodies, immune complexes, autoreactive and inflammatory T cells, and inflammatory 
cytokines that initiate and amplify inflammation and damage to various organs9. Various 
cytokines have been proposed to play important pathogenic roles in SLE, including type I 
Interferons (IFNs), IL-6, IL-17, BLyS, IL-10 and TNF10. Various abnormalities in innate 
immune responses have been the focus of intense research in the last few years, including the 
role of aberrant cell death, neutrophil extracellular trap (NET) formation, and the interplay 
between lupus neutrophils and type I IFNs11, 12. Abnormalities in various subsets of T cells have 
been reported in SLE (including Teffector and Treg subsets), although the mechanism and 
functional consequences of such changes remain unclear. Th17 cells have been reported at 
increased frequency and detected at the site of end-organ damage in SLE, while serum levels of 
IL-17 are increased in SLE and correlate with disease activity10, 13. Treg cells are also altered in 
patients with SLE. Both human and murine studies have reported a deficiency in number and/or 
function of these cells, which act to suppress the activation of both T-helper cells and B cells. 
Treg cells isolated from patients with active SLE appear less effective at suppressing T cell 
proliferation and IFN-γ production in comparison with cells from healthy controls or patients 
with inactive lupus14.  
6.2 
Vascular damage and premature atherosclerosis in SLE 
While the life expectancy in lupus has significantly improved1, 2, the disease is associated with 
significant morbidity and increased mortality in significant part due to accelerated atherosclerotic 
vascular disease16, 17, 23.The risk of premature cardiovascular disease (CVD), especially in young 
women with SLE, is striking, and may be as high as 50-fold when compared to matched controls, 
depending on the study and outcome measure18. Atherosclerotic CVD develops or progresses in 
~10% of SLE patients/year during short-term follow-up19 and is one of the most common causes 
of death16, 20. As we now recognize SLE as an independent risk factor for premature CVD, the 
progressive nature of lupus vascular injury makes this population ideal for the study of 
mechanisms involved in endothelial dysfunction, a state wherein the vasodilatory, anticoagulant 
or anti-inflammatory properties of the endothelium are impaired and which predisposes to 
atherosclerosis development21. SLE patients without overt CVD display subclinical vascular 

  
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disease (endothelial dysfunction22, 23, arterial stiffness24 and coronary perfusion disturbances25) 
and increased subclinical atherosclerosis (carotid plaque and coronary calcification)26, 27. Many 
of these findings are not explained by traditional risk factors28. Further, while all-cause mortality 
in SLE has improved significantly with improved monitoring and immunosuppressive 
treatments, CVD remains a leading cause of death29. Indeed, advances in immunosuppression 
have decreased organ damage in lupus, but no drug to this date has proven to abrogate 
atherosclerosis development in SLE, and high uncertainty on how to reduce the enhanced CV 
risk remains. For example, steroids can induce hypertension, insulin resistance, and 
dyslipidemias30, but are anti-inflammatory and therefore may decrease CV complications26, 31. 
Antimalarials and mycophenolate mofetil (MMF) may have vasculoprotective effects32, 33, but 
their role in atherosclerosis prevention is unclear. These observations indicate that novel 
adjuvant therapies that target inflammation, immune dysregulation and metabolic abnormalities 
without significant side effects are a significant priority in SLE. 
6.3 
Mechanisms of premature CVD in SLE 
Although T and B cells are indispensable for lupus pathogenesis, it is still unclear if they play a 
major role in lupus CVD. In contrast, links between innate immunity, SLE, and CVD are 
myriad12, with proposed significant roles for type I IFNs, platelets and neutrophil NETs among 
others. We have proposed that type I IFNs promote an imbalance of vascular damage and repair, 
triggered in part by impairment in the phenotype and function of cells crucial for vasculogenesis 
including endothelial progenitor cells (EPCs). Furthermore, type I IFNs promote atherogenesis, 
recruit macrophages to plaque and induce platelet activation34, 35. In addition, there is a high 
prevalence of metabolic syndrome, insulin resistance and dyslipidemia in human and murine 
SLE36 and in murine lupus these metabolic abnormalities may precede the development of overt 
autoimmunity37.  
High-density lipoprotein (HDL)  function is not always accurately predicted by HDL cholesterol 
levels. The functions of HDL include reverse cholesterol transport and modulation of 
inflammation. In healthy individuals, in the absence of systemic oxidative stress and 
inflammation, HDL is anti-inflammatory. However, in those with chronic illnesses such as SLE 
characterized by systemic oxidative stress and inflammation, HDL may actually promote the 
inflammatory response38. Indeed, work from various groups including ours has shown that 
human and murine lupus are characterized by enhanced HDL oxidation and perturbed function 
and this has been associated with enhanced atherogenesis34. 
6.4 
Current treatments and CVD in SLE 
Corticosteroids, widely used as adjuvant treatment in SLE, likely have mixed effects on CVD. 
While there has long been evidence that duration of prednisone use can independently predict 
risk of CVD events, there is also evidence that, over time, more aggressive treatment with drugs 
like cyclophosphamide and corticosteroids, will correlate with reduced CVD burden19. In terms 
of drugs with a specific role in the treatment of the disease manifestations of SLE, two—the 

  
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antimalarials and MMF—have received the most attention for their potential cardioprotective 
benefits. It is still unclear the role that novel and potential biologics may have in modulating 
CVD in SLE. 
In recent years, there has also been increasing interest in whether drugs with defined roles in 
diseases like hypercholesterolemia and diabetes might have particular benefit in patients with 
SLE.  
6.5 
PPAR-γ agonists as potential therapeutic targets in SLE 
PPAR-γ agonists are members of the nuclear receptor superfamily of ligand-dependent 
transcription factors, expressed in various cells including adipocytes, vascular cells, antigen 
presenting cells and lymphocytes. PPAR- activation by agonists determines modulatory effects 
on different crucial cellular events such as growth factor release, cytokine production, cell 
proliferation and migration, extracellular matrix remodeling and cell cycle progression/ 
differentiation. In addition, PPAR- agonists have potent antioxidant effects39. PPAR- regulates 
gene expression by binding as a heterodimer to the retinoid X receptor (RXR). The PPAR-
/RXR heterodimer binds to sequence-specific PPAR response elements in the promoter region 
of target genes, acting as a transcriptional regulator40. PPAR- also functions in a DNA-binding-
independent manner to trans-repress various target genes. PPAR- activation by agonists 
determines modulatory effects on crucial cellular events: growth factor and cytokine production, 
cell proliferation, migration and differentiation, extracellular matrix remodeling and cell cycle 
progression. In addition, PPAR-/RXR complexes may cause functional inhibition by directly 
binding to transcription factors, preventing them from inducing gene transcription and may also 
inhibit phosphorylation and activation of several members of the MAPK family1. 
There are 2 isoforms of PPAR-: PPAR-1 and PPAR-2. Differential promoter usage and 
alternate splicing of the gene generates 3 mRNA isoforms. PPAR-1 and PPAR-3 mRNA both 
encode the PPAR-1 protein, which is expressed in most tissues, whereas PPAR-2 mRNA 
encodes PPAR-2 protein, which contains an additional 28 amino acids at the amino terminus 
and is specific to adipocytes40.  Once tissue injury and inflammatory responses ensue, there is 
upregulation of PPAR-. Activation of PPAR- (by endogenous or exogenous ligands) inhibits 
the activation of the transcription factors NF-κB, AP-1, NFAT, and STAT41.  This attenuates the 
formation of cytokines, chemokines, and adhesion molecules, reducing excessive inflammation 
and tissue injury. Ligands of PPAR- inhibit the expression of the pro-inflammatory cytokines 
IL-1β, IL-6, TNF-α and interferon (IFN)-; the chemokine monocyte chemoattractant protein-1 
(MCP-1); and the adhesion molecules intercellular adhesion molecule-1 (ICAM-1) and vascular 
cell adhesion molecule-1 (VCAM-1). In addition, other important mediators of inflammatory 
responses and/or pro-thrombotic cascades such as inducible nitric oxide (NO) synthase (iNOS), 
COX-2, CD40 ligand, plasminogen activator-I (PAI-I), and MMPs 9 and 1 are inhibited by these 
compounds1, 42-46.  Furthermore, within a week of treatment with exogenous PPAR- agonists, 
CRP levels decrease by 30% in patient groups, whereas the reduction produced by statins is only 

  
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14%47, 48. There are a number of endogenous ligands of PPAR-, including eicoisanoids (such as 
the PGD2 metabolite 15-deoxy-delta prostaglandin J2 (15d-PGJ2)) and long-chain 
polyunsaturated fatty acids. In addition, various synthetic PPAR- agonists have been developed 
or are under development. The most widely used belong to the TZD or glitazone class of anti-
diabetic drugs. The 2 currently available TZDs, pioglitazone and rosiglitazone, are used alone or 
in combination with other oral anti-diabetic agents for type 2 DM1. While PPAR- agonists have 
potent insulin-sensitizing effects, numerous reports indicate that the therapeutic benefits these 
drugs may go far beyond their use in DM. 
Emerging evidence indicates that the PPAR signaling pathways play critical roles in the 
regulation of a variety of biological processes within the CV system49 and that PPAR-  agonists 
inhibit the expression of genes that contribute to atherogenesis.  PPAR- isoforms have been 
characterized in multiple vascular cell types and prevent in vitro vascular smooth muscle cell 
growth50-52 and inflammatory responses, suggesting a role in vascular remodeling and 
atherosclerosis. Furthermore, TZDs can improve many atherosclerosis risk factors by lowering 
triglycerides, elevating HDL cholesterol and decreasing levels of biomarkers that are crucial in 
atherosclerosis development53. The positive lipid effects are significantly more prominent for 
pioglitazone than for rosiglitazone and rosiglitazone can have deleterious lipid effects; therefore, 
pioglitazone might be a better drug for atherosclerosis prevention54.  
With regards to vasculogenesis, TZDs upregulate both number and functional capacity of EPCs 
and prevent apoptosis of these cells in mice and humans55. Reduction of EPC apoptosis by TZD 
may be a potentially beneficial mechanism for patients with vascular diseases. TZDs can restore 
vasodilator responses, improve endothelial function and suppress atherosclerosis progression in 
various animal models of vascular injury56,57. These compounds also have potent antioxidant 
activity and an ability to inhibit LDL oxidation, further decreasing atherosclerotic risk58.  In 
clinical studies, TZDs can inhibit CIMT59 ameliorate endothelial dysfunction, and inhibit 
restenosis after cardiac stent60 in patients with DM independent of glucose control61. 
Pioglitazone decreases visceral and abdominal fat content and blood pressure, and reduces 
systemic vascular resistance in diabetics62. TZDs also ameliorate markers of endothelial 
activation and improve endothelial function in non-diabetic patients with coronary artery 
disease63, 64; in non-diabetics with the metabolic syndrome64 in patients with HIV65, RA5, and 
hypertension66; and in renal transplant recipients67. In nondiabetic patients with CV risk factors, 
pioglitazone treatment enhances insulin sensitivity, decreases C-reactive protein (CRP), and 
improves endothelial vasodilator function68. Therefore, TZDs might also be effective anti-
atherogenic strategies in non-diabetics with other increased risk factors for atherosclerosis.  
Current evidence suggests that atherosclerosis prevention induced by these compounds is not 
only due to the amelioration of systemic metabolic risk factors for atherogenesis but also to 
downmodulation of inflammatory events that occur within the artery wall69, 70.  Indeed, in a 
recent study, pioglitazone was found to counteract the deleterious effects of TNF-α on the 

  
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vascular endothelium, further supporting its putative role in inflammatory conditions associated 
with increased CV risk71. Studies suggest that short-term (3 weeks) treatment with TZDs can 
promote significant improvement in endothelial function in healthy subjects72. Regarding lipid 
control, data on file from Takeda Pharmaceuticals shows that a 30 mg dose of pioglitazone for 
26 weeks results in triglyceride lowering of 9.6%, HDL increase of 12%, and a neutral effect on 
LDL and total cholesterol (www.takeda.com). Low HDL cholesterol is increasingly recognized 
as a CV risk factor at any given level of total cholesterol or LDL73. Thus the HDL elevating 
properties of TZD therapy may further add to their putative CV benefits. Importantly, a report of 
5238 diabetic patients with macrovascular disease has shown that pioglitazone significantly 
reduces CV morbidity and mortality74. Also, treatment of type 2 DM with 45 mg daily 
pioglitazone exerts powerful effects on endothelial function beyond metabolic control75. This 
was the dose we used in our RA cohort, where we found significant improvements in arterial 
stiffness, metabolic parameters and disease activity5. 
6.6 
Safety of PPAR agonists 
Regarding safety, recent meta-analyses and observational studies have indicated that 
rosiglitazone may increase the risk of ischemic CV events and heart failure in DM and the 
elderly, whereas the association of pioglitazone with these complications is less clear76. Ongoing 
studies are assessing rosiglitazone’s effect in CV event prevention in patients with CVD 
history77. There is significant debate regarding the role of rosiglitazone or other TZDs in CV 
complications, particularly in insulin-dependent DM, heart failure and morbid obesity78. Overall, 
MI and stroke in DM have been significantly reduced by pioglitazone.  However, TZDs are 
contraindicated in New York Heart Association Class III or IV heart failure. 
Pioglitazone can cause decreases in hemoglobin and hematocrit of 2-4%.  These reductions may 
be due to an increase in plasma volume and usually pose only minor risk. While pioglitazone is 
typically not associated with hepatic toxicity or liver function test (LFT) elevations, the 
pioglitazone package insert states there are post marketing reports of hepatic failure and that 
causality cannot be excluded; Medwatch report states there is an association with hepatitis, 
hepatic enzyme elevations to 3 or more times the upper limit of normal.  Pioglitazone is 
structurally related to troglitazone (no longer marketed), which has been associated with 
idiosyncratic hepatotoxicity and rare cases of liver failure, liver transplants, and death. In a 
recent study of non-diabetics treated with pioglitazone for similar periods of time to what is 
proposed for our study, no changes in LFTs were observed68.  
Similarly in diabetics with a mean duration of diabetes of 9.5 years, an increased incidence of 
bone fracture was noted in female patients taking TZDs. There is significant debate regarding 
which patients on PPAR-gamma agonists are at increased risk for fracture. For example, a recent 
study reported that over 1 year, treatment with pioglitazone 30  mg/day did not produce 
consistent effects on either bone mineral density or bone turnover in people with type 2 DM 
(T2DM) or glucose intolerance79 while another study showed decreases in bone density at 
around 33 months of similar treatment80 . The majority of fractures observed in female patients 

  
12
have been nonvertebral fractures including lower limb and distal upper limb. In diabetics, 
postmenopausal women taking TZDs and the subset of men taking both loop diuretics and TZDs 
were at increased risk for fractures. In postmenopausal women, risk was associated with higher 
TZD dose. No difference between rosiglitazone and pioglitazone was apparent81. The effects of 
TZDs on bone appear related, in part, to induction of osteocyte apoptosis82.  
Preclinical and clinical trial data, and results from observational studies suggest an increased risk 
of bladder cancer in pioglitazone users. The observational data further suggest that the risk 
increases with duration of use83. It has been suggested that patients with bladder cancer (current 
or previous) should not use pioglitazone. No studies have been published regarding cancer risk 
with pioglitazone in nondiabetics. A recent meta-analysis of 215,142 of patients with T2DM on 
pioglitazone revealed a hazard ratio of 1.03(95% CI 0.84-1.26) for patients treated with 
pioglitazone for less than 12 months. The hazard ratio increased to 1.44(95% CI 1.19-1.74) for 
patients using pioglitazone for more than 24 months.  The p-value for interaction was 0.04, 
suggesting a significant interaction between duration of pioglitazone use and incidence of 
bladder cancer. However there was no interaction between cumulative dosage of pioglitazone 
and incidence of bladder cancer (p-value for interaction=0.19). The number needed to harm 
(NNH) was 20903 suggesting that more than 20,000 patients needed to be treated for one case of 
bladder cancer to develop.  Use of pioglitazone in patients with SLE and those with history of 
treatment with cyclophosphamide has not been studied extensively. In their report of 30 SLE 
patients treated with pioglitazone for 3 months Posadas-Romero et. al. have not reported any 
increased incidence of bladder cancer98. Of note, diabetes may increase the risk of bladder 
cancer, with varying risk ratios across different duration of diabetes, and glycemic control may 
also have an impact on the development of cancer through mechanisms related to metabolic 
changes, accumulation of advanced glycation end-products and increased oxidative stress. As 
PPAR agonists are usually used as second- or third-line drugs for glycemic control, their use may 
indicate a poor glycemic condition for a long duration before their use. Many of the previous 
observational studies could not adequately address the potential confounding effects of diabetes 
duration and glycemic control in data collection and analyses. As such, randomized clinical trials 
are needed to assess if there is truly an increased risk in diabetics exposed to long-term 
pioglitazone and whether this applies to other patient populations. 
Over 8500 patients with DM have been treated with pioglitazone in controlled clinical trials. 
Over 6000 patients have been treated for 6 months or longer and over 3000 patients have 
received the drug for at least 2 years. The overall incidence and adverse events reported in 
placebo controlled clinical trials are shown in the table below. The incidence of withdrawals was 
similar for patients treated with placebo (2.8%) or pioglitazone (3.3%). 
 
 

  
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Table 1: 
Three Pooled 16-to 26-Week Placebo-Controlled Clinical Trials of 
Pioglitazone Monotherapy: Adverse Events Reported at an Incidence > 
5% and More Commonly in Patients Treated with Pioglitazone than in 
Patients Treated with Placebo 
  
% OF PATIENTS 
PLACEBO 
N=259 
ACTOS  
N=606 
Upper Respiratory Tract Infection 
8.5 
13.2 
Headache 
6.9 
9.1 
Sinusitis 
4.6 
6.3 
Myalgia 
2.7 
5.4 
Pharyngitis 
0.8 
5.1 
*(Source http://www.rxlist.com/actos-drug/side-effects-interactions.htm) 
 
As mentioned above, our group recently completed a randomized, placebo-controlled, crossover 
trial on the effect of pioglitazone on endothelial function and disease activity in RA, another 
inflammatory disease associated to enhanced CV risk. One hundred forty-three non-diabetic 
adult RA patients (76.2% female, age 55.2 ± 12.1 [mean ± SD]) on stable RA standard of care 
treatment were enrolled in a randomized, double-blind placebo controlled crossover trial of 
45 mg daily pioglitazone versus placebo, with a 3-month duration/arm and a 2-month washout 
period. Pulse wave velocity of the aorta (PWV), brachial artery flow mediated dilatation, 
nitroglycerin mediated dilatation, microvascular endothelial function (reactive hyperemia index 
[RHI]), and circulating biomarkers of inflammation, insulin resistance, and atherosclerosis risk 
all were quantified. RA disease activity was assessed with the 28-Joint Count Disease Activity 
Score (DAS-28), CRP and the Short Form (36) Health Survey quality of life questionnaire. 
When added to standard of care RA treatment, pioglitazone significantly decreased aortic 
stiffness, while conduit and small vessel function remained unchanged when compared to 
placebo. Further, pioglitazone significantly reduced RA disease activity and CRP levels while 
improving lipid profiles. The drug was well-tolerated5. In this cohort of patients with overall low 
Framingham risk factors and preserved heart function, markers of target organ function, 
including LFTs and CBC, were not different between treatment versus placebo groups at the end 
of the study. There were more adverse events while on the active treatment group, and these 
consisted primarily of expected side effects related to this drug class such as weight gain, lower 
extremity edema, and dyspnea (see table below). Of the 16 serious adverse events (SAEs) in the 
trial, only one was probably related to the study drug. This was a case of lower extremity edema 
and chest pain that resolved with discontinuation of the study drug. There were 5 other SAEs 
considered to be not related to the study drug (dyspnea and chest pain, tachycardia and elevated 
blood pressure, low potassium and sodium, hip fracture, and intracranial bleed; n=1 each). The 
study drug was discontinued only for the case of dyspnea with chest pain, and all resolved. The 
remainder of the SAEs were considered “definitely not” related to the study drug. 

  
14
 
Table 2: 
Adverse Event (AE) by Body System and Treatment in Pioglitazone Trial in RA 
patients N=143 
Body System 
Placebo 
(n=127) 
Treatment 
(n=129) 
P Value 
Body as a whole 
3 (2.36%) 
5 (3.87%) 
0.72 
Cardiovascular 
4 (3.15%) 
8 (6.25%) 
0.25 
Edema 
0 (0.00%) 
6 (4.65%) 
NA 
Hemic and lymphatic 
0 (0.00%) 
1 (3.87%) 
NA 
Infection 
5 (3.94%) 
5 (3.87%) 
1.00 
Metabolic and nutritional 
3 (2.36%) 
4 (3.10%) 
1.00 
Musculoskeletal 
5 (3.94%) 
8 (6.25%) 
0.57 
Nervous system 
2 (1.57%) 
4 (3.1%) 
0.68 
Respiratory 
1 (0.79%) 
6 (4.65%) 
0.12 
Skin and appendages 
4 (3.15%) 
3 (2.33%) 
0.72 
Total number of AEs 
27 (21.26%) 
50 (38.75%) 
0.003 
Total number of subjects 
with at least one AE 
23 (18.11%) 
39 (30.23%) 
0.028 
 
6.7 
 PPAR agonists in SLE 
As mentioned above, both murine and human studies in SLE support the notion that PPAR-γ 
agonists may be beneficial in this disease and represent an important potential molecular target 
for vascular dysfunction improvement in SLE (Figure 1). Rosiglitazone and pioglitazone 
improve disease activity in the MRL/lpr land gld/ApoE-/-lupus mouse model2 with decreases in 
autoAbs and renal inflammation and spleen size2. Rosiglitazone also decreases hypertension and 
renal injury in lupus-prone NZB/W F1 mice4. A beneficial effect of TZDs in renal injury in other 
conditions has been well-documented 84, 85. We have reported that pioglitazone decreases renal 
inflammation in NZB/W F1 mice86. Kidneys from pioglitazone-treated mice showed significant 
decreases in immune complex (IC) deposition and in mesangial expansion, endocapillary 
hypercellularity, renal T cell infiltration and renal expression of proinflammatory molecules 
including TNF and IL-17. While renal function did not differ between treatment groups in the 
NZB/W mice, our results indicate that further exploring pioglitazone as adjuvant therapy when 
combined with other treatments targeting SLE activity is warranted, given the potential positive 
effects on organ damage prevention. These results indicate that TZDs significantly modulate 
inflammatory responses in SLE and may decrease tissue damage. There is also recent evidence 
that pioglitazone can downmodulate the proinflammatory effects of type I IFNs on myeloid cells 
and this may be particularly relevant in SLE pathogenesis, given evidence from our group and 
others that aberrant neutrophils may play key roles in lupus pathogenesis and its associated 
vascular disease as mentioned above89 
Similar to what we reported in murine EPCs3, when human EPCs are treated with pioglitazone, 
there is a significant improvement in their capacity to differentiate into mature ECs after 2 weeks 

  
15
in culture. In contrast, rosiglitazone-treated lupus EPCs  do not show improvement in their 
differentiation capacity (unpublished observations). This further supports testing pioglitazone as 
the TZD of choice in SLE due to its beneficial effects on vasculogenesis. IFN-α is known to be 
antiangiogenic and we recently begun to characterize the pathways by which it suppresses EPC 
differentiation and function90.  We have performed gene array expression studies on control and 
lupus circulating EPCs exposed to proangiogenic stimuli for 72 hours, then left untreated or 
treated for 6 hours with recombinant IFN-α90. We identified that IFN-α induces a strong 
antiangiogenic signature in control and lupus EPCs. One of the most significant changes 
included repression of various genes involved in PPAR-γ signaling in both SLE and control 
EPCs. This indicates a potential mechanism by which type I IFNs may interfere with vascular 
repair, through downregulation of pathways crucial in endothelial health, and further supports 
testing PPAR agonists in CV prevention in SLE. Interestingly, the level of PPAR-γ repression by 
IFN-α was significantly more pronounced in SLE EPCs than in control cells, suggesting that the 
former may be more sensitive to the effects of type I IFNs91.  
In a recent small clinical trial in 30 young female lupus patients, pioglitazone administration over 
three months improved HDL levels, insulin resistance, and HDL size, while decreasing markers 
of inflammation such as CRP and serum amyloid A; specific markers of endothelial function 
were not considered, neither was the effect on SLE disease activity92. 
We therefore propose that these agonists may particularly benefit SLE patients by suppressing 
inflammatory and immunologic pathways that promote premature atherosclerosis and internal 
organ damage. Identifying pioglitazone’s role in SLE may support an eventual paradigm shift in 
standard of care for these patients to include therapy with PPAR-γ agonists for treatment and 
prevention of endothelial injury, atherosclerosis and CV events in this disease and, potentially, in 
individuals with other systemic autoimmune diseases associated with premature CVD.  

  
16
 
Figure 1: 
Mechanisms of vascular damage/ atherosclerosis in SLE and potential role of 
PPAR- agonists in atherosclerosis prevention 
Predisposition to vascular damage in SLE is likely mediated by multiple pathways including abnormal vascular 
repair; enhanced endothelial apoptosis through a variety of mechanisms (cytokines such as type I IFNs, 
autoAbs, cell-mediated cytotoxicity, NETs, traditional risk factors); prothrombotic and metabolic 
abnormalities including increased piHDL. This leads to blood vessel damage,  NO, increased platelet 
aggregation and smooth muscle proliferation, all of which can lead to endothelial dysfunction and premature 
atherosclerosis. Further, inflammation triggers insulin resistance that also contributes to endothelial 
dysfunction. PPAR- agonists may prevent this complication by blocking the majority of these harmful 
pathways. 
 
7 
OBJECTIVES  
The major goal of the proposed research is to assess the effect of a targeted pharmacotherapeutic 
intervention – the administration of the PPAR- agonist pioglitazone – in SLE on: 
a) vascular endothelial function (primary endpoint), a predictor of CV risk 
b)  SLE disease activity (secondary endpoint).  
This randomized clinical trial, with a modest sample size, can both serve as a “proof of concept” 
study for the potential utility of TZDs in SLE, and inform us on which surrogate outcomes or 
biomarkers may be useful in future lupus studies aimed at CV/immunomodulatory outcomes. 
Aim 1:  To conduct a randomized, double-blind, placebo controlled, crossover, proof-of-concept 
clinical trial in adult SLE patients comparing the effects of pioglitazone vs. placebo on vascular 
endothelial function and blood vessel inflammation. Primary outcome measures will be large 
IFN-α 
SLE 
APC/NeutrophilActivation
Increases in:  
 proinflammatory HDL IFN-α, 
MCP-1, PAI1/TPA, tissue 
factor, homocysteine 
PPAR-γ 
EPC function 
Promotes EPC function 
Endothelial damage/apoptosis  
↓NO, ↑free radicals  
↑platelet aggregation 
↑collagen breakdown 
Smooth muscle proliferation 
Endothelial 
dysfunction 
Atherosclerosis 
PPAR-γ 
PPAR-γ 
 
 
         
 
 
        Blood  
 
 
        vessel 
Bone Marrow 
Insulin resistance 
PPAR-γ 
Θ
Θ
Θ 
PPAR-γ 
Θ 
 

  
17
vessel arterial stiffness, measured either by cardio-ankle vascular index (CAVI) or pulse wave 
velocity (PWV, assessed by Sphygmocor) (both tests to assess large vessel arterial stiffness), and 
assessment of microvascular peripheral arterial tone (PAT). Secondary outcome measures of 
atherosclerosis risk and metabolic disturbances will include proinflammatory HDL (piHDL) 
levels and HDL cargo, lipoprotein function, lipid profile and insulin resistance and EPC 
phenotype and function. In addition, modulation of arterial inflammation will be assessed in a 
subset of patients by neck to groin fluorodeoxyglucose positron emission tomography CT (FDG 
PET/CT). 
Hypothesis 1: Endothelial function and arterial compliance will significantly improve in 
SLE patients treated with pioglitazone when compared to placebo, while arterial 
inflammation will decrease. 
Hypothesis 2: Pioglitazone will alter HDL cargo function, decrease proinflammatory 
HDL levels and insulin resistance, and improve markers of vascular repair in SLE. 
Aim 2:  To assess the ability of pioglitazone to reduce SLE disease activity, when added to 
standard lupus care, as assessed by the SLEDAI-2K disease activity index (SLEDAI-2K), lack of 
A or B flares on the British Isles Lupus Activity Group (BILAG 2004) score, and physician’s 
global assessment (PGA) (See Appendix sections 2,3,7). Serological markers of SLE activity and 
various cytokines considered important in lupus pathogenesis will also be quantified. 
Hypothesis 3: SLE Disease activity will decrease in SLE patients when treated with 
pioglitazone vs. placebo. 
Aim 3:  To investigate the role of in vivo administration of PPAR-γ agonists in modulating 
aberrant immune responses in SLE. These will include lymphocyte phenotype and function, 
autoantibody and cytokine production and myeloid cell phenotype and functional abnormalities.  
Hypothesis 4: Pioglitazone will normalize innate and adaptive immune responses in SLE. 
8 
STUDY DESIGN AND METHODS  
This will be a single-center, randomized, double-blind, placebo-controlled, crossover, proof-of-
concept treatment trial enrolling 100 SLE patients including replacements due to screen failures 
and withdrawals.  If a patient drops out of the study before completion both arms, another patient 
may be enrolled so that up to 75 patients complete the study. They will be treated for 3 months 
with 45 mg daily pioglitazone or placebo, undergo an 8 week washout period, then undergo 
crossover to the other arm for 3 additional months. Throughout the study, functional, anatomical 
and blood biomarkers of vascular damage, atherosclerosis risk and SLE activity will be 
collected. Pioglitazone has been chosen over rosiglitazone because it appears to have a 
significantly better safety profile regarding CV effects and lipid profile alterations93, based on 
our experience in the rheumatoid arthritis (RA) trial5 and  the small pilot study published by 

  
18
another group that showed improvement in some metabolic parameters in SLE92, as well as our 
preliminary data which indicate improvement of vasculogenesis by pioglitazone but not 
rosiglitazone94 in human SLE.  We also have significant experience using this drug due to the 
recently completed clinical trial in RA3. The dose and study time period have been selected based 
on pioglitazone’s macrovascular protective effects74 and to allow detection of meaningful 
changes in endothelial function and disease activity, respectively. This is also based on the dose 
and study time period used in the RA trial, which showed significant effects on arterial stiffness, 
metabolic parameters, inflammatory markers and RA disease activity5.  
TZD studies indicate improvements on endothelial function from within a few weeks to a couple 
of months. Previous crossover studies assessing pioglitazone’s role in endothelial function, 
insulin resistance and inflammation have used treatments from 6-12 weeks with washout periods 
of 4-6 weeks68, 72, 95. In our studies in RA, 3 months was sufficient to observe significant 
improvements in arterial compliance and disease activity5. These washout periods appeared 
sufficient to avoid carryover effects and, indeed, in the RA trial we found no evidence of 
carryover effect after the same washout period5. Carryover issues will also be addressed by 
randomizing the sequence of placebo and pioglitazone treatment. Previous studies did not reveal 
that the sequence (i.e. placebo followed by pioglitazone vs. pioglitazone followed by placebo) 
had any effect on the observations68. The study will take approximately 5 years to complete. 
Figure 2 represents the study sequence. 

  
19
 
 
 
 
 
 
Figure 2: 
Overall Study Schematic 
 
 
8.1 
Proposed Surrogate Outcomes and Biomarkers 
 Specific Aim 1: Effect of Pioglitazone on vascular function and cardiometabolic risk. 
a) Vascular function and vascular inflammation. 
SLE patients demonstrate endothelial dysfunction independent of Framingham risk factors 
and in the setting of subclinical CVD 22, 23. Endothelial dysfunction is an early event in 
atheroma development and a trigger of CV events96. PPAR- agonists reverse endothelial 
dysfunction in other diseases61, 64, 98, and pioglitazone improves endothelial function in 
murine lupus99. 
Arterial compliance/CAVI and PWV: Arterial stiffening is caused by structural and/or 
functional changes within the major conduit artery walls, resulting in increases in pulse 
wave velocity, with important hemodynamic consequences100.  SLE patients without overt 
atherosclerosis have increased arterial stiffness24, 101-103, indicating it may be a sensitive 
marker of early CV dysfunction and increased risk and a target of treatment efficacy. In 
 
Placebo Arm: ( 
3 months) 
Screen 
Baseline 
Randomize 
Treatment Arm: 
Pioglitazone 
 ( 3 months) 
Crossover 
Placebo Arm: ( 
3 months) 
Crossover 
Treatment Arm: 
Pioglitazone 
 ( 3 months) 
 Washout 
 (2 months) 
Screen Visit 
Eligibility 
Baseline Visit 
Randomization 
Month 1 Visit 
Safety labs 
Month 3 Visit 
Begin Washout 
Month 5 Visit 
Start crossover 
Month 6 Visit 
Safety labs 
Month 8 Visit 
End Crossover 

  
20
RA, arterial compliance can improve after 12 weeks of etanercept104, suggesting that short-
term treatment of inflammatory processes may improve vascular compliance. In animal 
models and humans with other disease states, PPAR- agonists significantly improve 
arterial compliance during short duration trials 105-108.  In our pioglitazone trial in RA, 
arterial stiffness as assessed by PWV was significantly improved in patients on the 
pioglitazone arm when compared to placebo arm5. CAVI is an index reflecting the stiffness 
of the artery from the heart to ankles; it increases with atherosclerosis progression108.  An 
advantage of CAVI over other tests that assess vascular stiffness is that it is not 
significantly affected by changes in blood pressure. CAVI has been widely applied 
clinically to assess arterial stiffness in subjects with known CVD, as well as those at risk 
(hypertensive patients, diabetics, the elderly, and the obese). CAVI has also been utilized in 
studying normal individuals to assess their potential risks of developing CVD109. Changes 
in CAVI have been observed when measures to decrease CVD risk factors have been 
implemented110-112.  Specifically for SLE, a small study recently showed that CAVI is 
increased in SLE patients when compared to age- and sex-matched controls113. Similarly, 
PWV assessment using a Sphygmocor device is a non-invasive, reliable measurement to 
assess vascular compliance and was used in our RA trial5. Either of these two tests will be 
used in this trial, depending on which machine will be me more readily available once 
these studies are initiated. 
Pulse wave analysis (SphygmoCor): SphygmoCor is a set of non-invasive tools used to 
determine central blood pressures and arterial stiffness. It (1) derives the pressure wave 
from the ascending aorta to the carotid artery and (2) gives an accurate measurement of 
pressure at the heart, brain, and kidneys. However, it cannot be used on patients who may 
suffer from heart arrhythmias or arterial stenosis.  
The SphygmoCor consists of the following:  
SphygmoCor Px Pulse Wave Analysis System – a diagnostic tool to measure central blood 
pressure 
SphygmoCor Pulse Wave Analysis System – an algorithm used to determine central aortic 
pressure and visualize ventricular- vascular interactions  
SphygmoCor Pulse Wave Velocity System- a tool that derives a pressure pulse waveform 
using the pressure tonometer and an ECG signal simultaneously. Arterial tonometry uses a 
pressure sensor to detect the speed of a pulse wave and may indicate a problem in the 
arteries.    
SphygmoCor Pulse Wave Monitoring System– a tool that provides an estimated pressure 
waveform from the ascending aorta. 

  
21
PAT: The Endopat2000 device measures finger microvascular endothelial function in a 
fully-automated fashion before and after reactive hyperemia (RH-PAT). RH-PAT response 
is independently predicted by traditional and novel CV risk factors114. PAT test is operator-
independent, with higher inter-day reproducibility than US conduit studies115. PAT 
dysfunction occurs in SLE in association with IFN signatures116. While pioglitazone did not 
modulate PAT in RA patients5, it will be important to establish the role of this drug in 
microvascular function in SLE. Finger PAT signal is recorded by non-invasive, modified 
plethysmography-based probes, then to digital media. PAT software calculates various 
outcomes, the main one being the RH-PAT index=ratio of average RH-PAT PWA in a 
finger of the occluded arm for a 60 second period beginning 1 minute after blood pressure 
cuff-release, compared to average PWA during the 210 second-long baseline pre-occluded 
period. The ratio is normalized to the PAT index in the control arm. 
To simplify, we will refer to the CAVI, PWV and EndoPAT tests as “vascular function 
studies”. 
Assessment of vascular inflammation using [18F]-2-fluoro-2-deoxy-D-glucose (FDG) 
imaging using positron-emission tomography (PET)/computed tomography (CT)): FDG-
PET/CT enables highly precise, novel measurements of inflammatory activity including 
vascular, visceral, and whole body inflammation in vivo. The range of applications for 
FDG-PET imaging has been expanded to include the evaluation of activity of 
atherosclerotic plaque.   Importantly, in diabetics or patients with glucose intolerance, 
pioglitazone attenuated left main trunk inflammation in a glucose-lowering independent 
manner when examined after 4 months of treatments_9_References4. This will be 
performed in a subset of 30 patients given the logistics of scheduling imaging studies at the 
Clinical Center. 
b) Metabolic parameters and vasculogenesis profile 
Insulin resistance: This is an important CV risk factor117-119 and a significant proportion of 
SLE patients exhibit this abnormality120, 121. Homeostatic measurements like the HOMA 
calculation allow for an easy assessment of insulin resistance122, 123.  In lupus-prone mice, 
pioglitazone induced significant changes in insulin resistance. Furthermore, in the RA trial, 
3 months of pioglitazone changes led to substantial improvements in this parameter, as 
assessed by HOMA2 calculations5. 
piHDL and lipids: Patients with active SLE exhibit a proatherogenic lipid profile with low 
HDL, high triglycerides and dysfunctional HDL124. Pioglitazone improves lipid profiles 
l125, 126 in DM, in non-diabetics and in murine SLE86. We will monitor lipid profile, 
oxidized HDL and cholesterol efflux activity of HDL from all subjects ex vivo before and 
after therapy. HDL oxidation and proteome profiles will be determined by MS in a subset 
of patients in the trial, NMR to assess lipoprotein particles will also be performed. These 

  
22
studies will identify whether pioglitazone treatment improves HDL oxidation, remodels 
HDL proteome and renders the lipoprotein more functional.  
EPC numbers and function: As SLE EPCs are decreased in number and display decreased 
function, and pioglitazone has been shown to have positive effects on vasculogenesis, we 
will quantify EPC numbers and function as previously described by our group, at various 
time-points35. 
 Specific Aim 2:  Effect of pioglitazone on SLE disease activity 
In clinical trials, the main methods to assess SLE activity are the SLEDAI-2K and the 
BILAG 2004. The investigators on this study have significant expertise in the use of these 
tools and have participated in clinical trials that used both methods to score disease activity. 
a) –SLEDAI 2K: This validated scoring system  is a modification of the original SLEDAI-
2K  system to reflect persistent, active disease in those descriptors that had previously only 
considered new or recurrent occurrences5, The score can be between 0-105.  It is based on 
the presence of 24 descriptors in nine organ systems over the preceding 30 days. 
Descriptors are documented as present or absent. Each descriptor has a weighted score. 
Higher scores represent higher disease activity.(see Appendix).  
b) Lack of A or B flares on BILAG 2004: The BILAG 2004 assesses SLE activity based 
upon the premise of “intention to treat”129, 130. It has been widely used and is well 
validated (sensitivity 87%, specificity 99%, and positive predictive value of at least 80%). 
Within each organ/system, a combination of answers provides an activity score from A 
(very active) to E (not or never active) (see Appendix 3). Recent trials have modified 
BILAG 2004’s use to only the presence or absence of an A or B flare during the 
observation period as an outcome measure, thus incorporating BILAG’s sensitivity to 
flares in individual organ systems with the SLEDAI-2K. For the proposed study, the 
clinical disease activity endpoints will be patients achieving SLEDAI-2K improvement + 
absence of a BILAG 2004 A or B flare +improvement in PGA (see Appendix 3 and 7). 
There are eight systems: general, mucocutaneous, neurological, musculoskeletal, 
cardiorespiratory, vasculitis, renal and hematological. A score is calculated for each 
system depending on the clinical features present and whether they are new, worse, the 
same or improving in the last 4 weeks compared with previously. The most severe features 
in each system, which are deemed to require high dose steroids (prednisolone >20 mg 
daily or equivalent) and/or cytotoxic agents, characterize an A score. One or more features 
may have to be present to score an A, depending on the system.  More moderate disease 

  
23
items that would be considered appropriate to treat with lower dose steroids, antimalarials 
or non-steroidal anti-inflammatory drugs (NSAIDs) contribute to a B score. Mild 
symptomatic features that require just symptomatic therapy, for example with analgesics 
and NSAIDs, can only contribute to a C score. If there are no current symptoms but the 
system has previously been involved then a D is recorded. If the system has never been 
involved, it is scored E 
c)  Health Related Quality of Life Questionnaire (HRQOL) (SF-36) and physician global 
assessment (PGA): This is a widely used tool to assess HRQOL with prior successful 
application in SLE131, 132. SF-36 assesses physical wellness, social and emotional well 
being and overall sense of mental health131. Completion takes 5-15 minutes (see Appendix 
5). 
d)  Other: At each visit, C3, C4, anti-dsDNA, CRP and sedimentation rate will be 
quantified. 
 Specific Aim 3: Assess the immunoregulatory role of pioglitazone in lymphoid and 
myeloid cell subsets in SLE 
We propose to investigate the effects of pioglitazone on intracellular signaling molecules, 
serum cytokines and peripheral blood gene expression as a measure of biological effects 
that can potentially be used as outcome measures to power for larger trials. At each visit, 
serum and plasma will be saved for quantification of putative biomarkers of disease activity 
and vascular damage in all patients.  We will assess the effects of oral pioglitazone on 
immune cell phenotype and function.  Some of the proposed studies include:  
• Alteration in the “interferon signature”, “T cell signature” and the “granulocyte 
signature” in PBMCs using RNA seq or Affymetrix (to be performed by Center for 
Human Immunology);  
• Alteration in peripheral blood immune cell populations with special attention to 
CD4+, CD25+, Foxp3+ regulatory subsets and Th17 cells, monocyte subsets and a 
subset of aberrant neutrophils present in lupus patients (low-density granulocytes).  
• Measures of serum cytokines and chemokines: this will include Th1, Th2 and Th17 
markers, type I IFNs and myeloid cell-relevant cytokines such as IL-6, Il-8, MCP-1, 
IL-1beta. 
• Levels of autoantibodies (anti-dsDNA, ENA-Abs, APL Abs) and total IgG 
Some of the studies will be performed by the Center for Human Immunology (NIH) and others 
will be performed by Dr. Kaplan’s laboratory. 

  
24
9 
INCLUSION AND EXCLUSION CRITERIA 
 
9.1 
Study Population and Recruitment 
Patients 18 years old or older who fulfill revised SLE American College of Rheumatology 
(ACR) and 2012 Systemic Lupus International Collaborating Clinics (SLICC) criteria ( 1 and 4)  
will be recruited from the Outpatient Rheumatology Clinic of the Clinical Center at the NIH or 
the NIAMS Community Health Center, from referrals for treatment and/or second opinion, by 
advertising the study to rheumatologists within the larger DC area, and by direct advertising 
through publications of patient advocate organizations, such as the Arthritis Foundation, the 
Lupus Foundation, Lupus Research Institute, Alliance for Lupus Research, the American 
College of Rheumatology meeting, and in the news outlets. These documents will be sent to 
IRB for approval before being used. 
Patients will be considered enrolled once they have signed consent. 
9.2 
Inclusion Criteria 
1. 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. 
2. Meet revised ACR criteria and 2012 SLICC criteria for SLE and have: a) a baseline 
SLEDAI-2K ≥ 4 and <20 or a clinical SLEDAI-2K ≥ 2 (not considering anti-dsDNA or 
complement levels) and b) lack of BILAG A flare at baseline (See Appendix 3). 
3. 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. 
4. Allowed concomitant lupus-related medications 
Antimalarials,  
Prednisone ≤ 20mg daily or equivalent doses of other corticosteroids;  
Immunosuppressants:  

  
25
Mycophenolate mofetil, up to 3000 mg/day,  
Methotrexate, up to 30 mg/week,  
Azathioprine, up to 3 mg/kg/day,  
Leflunomide, up to 20 mg/day,  
Cyclosporine, up to 5 mg/kg/day 
Tacrolimus, up to 0.1 mg/kg/day 
NSAIDS and aspirin 
 
Note: While it would be highly desirable to maintain corticosteroid dosage at constant 
level for trial duration, it is impractical to anticipate that all patients with active SLE can 
be maintained without therapy modification for an 8-month period. Because 
corticosteroids are acceptable agents for treatment of the vast majority of minor lupus 
flares, and patients with major flares (BILAG 2004 A or recent change in medications) 
will be excluded, this will provide standardized treatment across study population that 
can be easily analyzed. An increase in prednisone dose of less than or equal to 10 mg/day  
from their prednisone dose at study entry will be permitted during the trial for increased 
disease activity with a standardized taper allowable in small monthly decrements to the 
patient’s baseline dose or 5 mg/day, whichever is less.  
 
9.3 
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.  See more details of information about the 46 days 
screening window period in section 9.4 Screening and Randomization, line 9-10.   
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.  

  
26
10. Receipt of any investigational new drug or device within 30 days prior to screening or 5 
half-lives of the agent (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 criteria96: 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 

  
27
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. 
Study Visits and Procedures 
Table 3: 
Study Visits and Procedures 
Procedure 
Screen 
Baseline 
Month 1 
Month 3 
Month 5 
Month 6 
Month 8 
Unscheduled 
visit  
Consent and 
Randomization. 
Eligibility 
Questionnaire 
X 
 
 
 
 
 
 
 
Medical History, 
Physical Exam 
including vital signs, 
SLEDAI-2K 
X 
 
 
 
 
 
 
 
Presenting Symptoms-
Abbreviated Medical 
History 
 
X 
X 
X 
X 
X 
X 
 
X 
Physical Exam 
including vital signs  
 
X 
X 
X 
X 
X 
X 
X 
BILAG 2004, 
SLEDAI-2K ,PGA, 
SF36 
 
X 
 
X 
X 
 
X 
 
Blood Draw: insulin, 
glucose, lipids, EPCs, 
C3, C4, autoAbs, 
piHDL, cytokines, 
CRP, ESR , Aim 3 labs, 
Acute care panel, 
Lymphocyte 
Phenotyping TBNK, 
lipoprotein profile, 
Urinalysis (includes 
microscopic), p/c ratio.  
 
X 
 
X 
X 
 
X 
 
 
 
X 
Blood Draw: safety labs 
(CBC, LFTS, 
pregnancy tests in 
women of childbearing 
potential) 
 
X 
X 
X 
X 
X 
X 
 
X 
Screening   labs and 
imaging. Blood draw:       
(pregnancy test, lipids, 
glucose, LFTs, CBC, 
Anti-ds-DNA, C3, C4, 
Urinalysis (includes 
microscopic), p/c ratio, 
Infectious disease 
X 
 
 
 
 
 
 
 

  
28
testing ), 
Echocardiogram (if it 
has not been obtained 
within the last 6 
months) and DEXA 
scan (postmenopausal  
women without DEXA 
scan in the last year) 
Vascular function 
Studies  
 
       X 
 
      X 
     X 
 
     X 
 
Dispense Drug 
 
X 
 
 
X 
 
 
 
AE Review  
 
 
X 
X 
X 
X 
X 
X 
Drug Accountability 
 
 
 
X 
 
 
X 
 
Health lifestyle 
Counseling (PRN) 
 
 
X 
 
X 
X 
 
X 
 
 
Urine analysis 
X 
 
 
 
 
 
X 
X 
PET-CT (subset of 
patients) 
 
X 
 
X 
 
 
 
 
 
9.4 
Screening and Randomization  
Subjects will review and sign informed consent document, and medical history, physical exam, 
disease activity (SLEDAI-2K), screening labs and echocardiogram will be performed.  
Echocardiogram will not be performed if patient is rescreened within 6 months and previous 
result is normal or if patient had normal Echocardiogram within 6 months prior to screening. 
Routine laboratory data obtained within 30 days of the screening visit under the natural history 
protocol 94-AR-0066 can be used for screening.  Screening labs will include infectious disease 
testing for HIV, Hepatitis B, Hepatitis C and Tuberculosis if they have not been obtained within 
the last 6 months.  As mentioned above, postmenopausal women without a DEXA scan in the 
last year will undergo a DEXA scan to assess eligibility.  The window between screening and 
baseline must be less than 46 days, otherwise subjects will need to be rescreened regarding labs.   
Inclusion/Exclusion Criteria will be signed off based on screening labs and assessment.  Patients 
who meet these criteria will be randomized to a sequence of active drug followed by placebo, or 
placebo followed by active drug in a 1:1 allocation ratio. Randomization and drug/placebo 
allocation will be done by the NIH clinical center research pharmacy after screening visit.   
We will test Urinalysis (includes microscopic) on Screening and Month 8 visits on all patients.   
If patients have evidence of microscopic hematuria > 20 RBCs/uL(excluding normal 
menstruation cycle)  it will be repeated twice at one month ( +/- 7 days) intervals and if RBCs 

  
29
are consistently more than 20 RBCs/uL then Urology consult will be placed.  The following 
algorithm will be put in place, per recommendations by the Urology service at NCI: 
1. Question patient about macroscopic hematuria > 20 RBCs/uL times 3 results.   
a. If YES → Urology consult → Cytology 
i. If abnormal cytology → Cystoscopy → FISH @ Mayo Labs for  genetic 
changes for bladder cancer detection 
ii. If normal cytology → Nothing 
9.5 
Study Visits 
 Baseline visit and 5-month +/- 7 days (post-washout) visit  
a. Baseline visit will include medical history. The baseline and 5-month (post-washout) visits will 
consist of a physical exam, and blood draw for biomarkers (Table 3). SF-36, PGA, disease 
activity (BILAG 2004, SLEDAI-2K) and vascular measurements will be determined and 
subjects will be issued a 3-month supply of blinded study drug or placebo with instructions. The 
first week of each treatment arm, patients will take two 15 mg capsules of pioglitazone daily (30 
mg total daily dose) and, if no significant side effects develop (primarily fluid retention), will 
increase to three 15 mg capsules (45 mg total daily dose).  Subjects will be instructed to follow 
the same titration for the placebo arm.  Patients will be called prior to increasing the dose to 45 
mg to question patients about rapid weight gain (>5 pounds in a week), significant edema or 
other side effects.  Patients will be called 1-2 weeks after increasing dose to 45 mg daily to 
assess tolerability. If 45 mg dose is not well tolerated but the 30 mg dose is well tolerated, dose 
will be decreased back to 30 mg daily for duration of trial.  PET/CT exams will be performed in 
15 patients initially randomized to placebo and 15 patients initially randomized to pioglitazone 
and the investigators will be blinded to this. PET/CT studies will only be performed at baseline 
and month 3.  Subjects can opt out of the PET/CT scan and still participate in the study. Patients 
will be asked to participate at baseline until we reach 15 patients/group.  If a patient is found to 
have an acute infection at the baseline visit, they will be given antibiotics and their next visit 
will be scheduled for no more than 4 weeks later, at which time they will start the study 
medication. We will repeat only baseline clinical labs at this extra visit; we will not repeat 
PET/CT, vascular function studies or research sample collection. If a patient has an abnormal 
lab result at the baseline visit that requires a repeat, the patients next visit will be scheduled no 
more than 4 weeks later, at which time if the abnormal lab has improved or normalized they will 

  
30
start the study medication. We will not repeat PET/CT, vascular function studies or research 
sample collection. If any subjects are enrolled in our Natural History of SLE Protocol (94-AR-
0066) and have undergone a research-indicated PET/CT scan as part of that study within the 6 
months prior to their baseline visit, we will use that data for their baseline values and will only 
perform the PET/CT scan at the month 3 visit. 
 Visits at months 1 (+/- 7 days) and 6 (+/- 7 days) 
Visits at months 1 and 6 are safety visits after study drug initiation. Only liver function tests 
(LFTS), complete blood count (CBC) and pregnancy test (in women of child-bearing potential) 
will be obtained. Adverse events will be assessed/reviewed.  Abbreviated medical history and a 
physical exam will be performed to assess any changes in medical conditions or medications. If 
feasible, blood may be obtained at a local lab and results faxed to NIH and a phone call from the 
research coordinator or investigators will assess adverse events. 
 Visits at 3 (+/- 7 days) and 8 months (+/- 7 days) 
Subjects will undergo a physical exam and blood will be drawn for biomarkers and safety labs. 
SF-36, PGA, disease activity and vascular measurements will be obtained. Abbreviated medical 
history will be performed to assess any changes in medical conditions or medications. Any 
leftover study drug will be collected and drug accountability performed. No additional study 
drug will be dispensed at these visits. PET exams will be performed in 15 patients initially 
randomized to placebo and 15 patients initially randomized to pioglitazone and the investigators 
will be blinded to this. PET studies will only be performed at baseline and month 3. A urine 
analysis will be obtained at the end of the study to assess for hematuria.  
The minimum time between baseline and visit 3-month and between visit 5 month and visit 8 
month will be 75 days and the maximum 105 days. Overall, total study duration will not exceed 
9 months (+/- 1 month). 
 
 Unscheduled Visits  
Subjects will undergo a physical exam and abbreviated medical history will be performed to assess any 
changes in medical conditions or medications.  Reason for the visit will be assessed related to AE, flare or 
study unrelated procedure/visit.  Blood may be drawn for clinical and safety labs when deemed 
appropriate by the study investigator. We may also perform a urine test called urine analysis.   Research 
blood may also be drawn for biomarkers as needed.  
10 MONITORING SUBJECTS AND CRITERIA FOR WITHDRAWAL 
10.1 Patient Withdrawal and Termination Criteria. 
Subjects will be informed that they may withdraw or be excluded from the study at any time.  
Our intention is to maintain stable doses of immunosuppression and antimalarials for the 

  
31
duration of the trial. On occasion, doses are adjusted to treat SLE activity. While not ideal, we 
anticipate that over the duration of 8 months, outside providers may want to adjust or add new 
immunosuppressive therapy. In the event of these changes, each of these instances will be 
reviewed by the Principal Investigator to determine continuation or withdrawal from the trial to 
maintain scientific integrity.  
The following conditions will require the discontinuation of study agent: 
1. Subjects may voluntarily withdraw at any point 
2. Flares not responding to the treatment above or if, in the opinion of the responsible 
investigator, the subject needs immediate immunosuppressive therapy that is not 
allowed in the protocol 
3. Any Grade 4 adverse event that is unexpected and at least possibly, probably or 
definitely related to study drug 
4. More than 1 “no-show” for a visit  
5. Becoming pregnant after baseline visit. The subject will be followed for the outcome of 
the pregnancy. 
6. Any other reason that, in the opinion of the responsible investigator, poses unacceptable 
risk to the subject. 
7. Nevertheless, LFTs will be monitored on all patients at each study visit and those 
patients with LFTs >2x upper limit at Screening visit will be excluded. If during the 
trial, LFTs increase to > than 3x fold the upper limit of normal (ULN), levels will be 
rechecked within 36 hours and if elevation >3 ULN persists and there are not alternative 
etiologies, therapy will be discontinued. If LFTs are elevated >2 but < 3x ULN (after 
confirming within 48 hours), we will investigate etiology of liver enzyme elevation and 
cautiously reinitiate therapy if alternative etiology is found. For patients with NAFLD 
that are enrolled, based on recent clinical trials that have been published (Cusi K et 
al.Annals of Internal Medicine 2016) assessing  the role of long-term pioglitazone 
treatment for nonalcoholic steatohepatitis, we will include only patients that have LFTs 
< 3 times ULN. If there is an increase to >3 times ULN once study drug starts during 
monitoring (confirmed within 24 hours), drug will be stopped. 
 
10.2 Study Completion Criteria 
A subject is considered to have completed the study when he/she has completed 8 months in the 
trial and received both treatment arms of the study. Enrolled subjects who withdraw from the 
trial prior to receiving study agent or who only complete one arm will be replaced; however, 
patients who complete only one arm will still be included in analysis. 
10.3 Results Given to Participants and Physicians 
Clinically relevant results will be transmitted to patients as part of this protocol.  Participants are 
encouraged to remain in contact with the responsible investigators   regarding advances in the 
field, and will be invited to enroll in pertinent future studies.  Participants may request research 
publications resulting from this protocol.  Medical care after study completion will occur with 

  
32
the primary treating physician and rheumatologist. Results of tests will be shared with the 
medical provider and patient if consider medically/clinically relevant. 
10.4 Blinding, Packaging, Labeling and Storage 
Study agent (15 mg pioglitazone or placebo) will be packaged in identical vials each containing 
300 capsules. Both study agents will be blinded using identical-looking capsules prepared by a 
vetted vendor selected by the NIH Pharmaceutical Development Service (PDS). Each vial will 
be labeled with a treatment number specific to the subject. A 300 capsule (one vial) supply of 
study agent will be given to each subject at enrollment at the baseline visit and at month 5.  The 
amount of study agent dispensed will be sufficient to last from baseline to month 3, and from 
month 5 to month 8.  The randomization code will be provided by the Clinical Center Research 
Pharmacy, as mentioned above.  Emergency unblinding will occur in the case of a serious 
adverse event (SAE) that is considered potentially secondary to the drug. Unblinding will be 
performed by PDS. Only the pharmacists will be unblinded throughout the trial.  The subjects, 
the investigators, and the study site staff will remain blinded to study medication assignment 
during the entire study period. Compliance with study treatment and pill counts will be 
performed by the research nurse/study coordinator and this information will be provided to PDS 
as well. 
11 DATA ANALYSIS 
 
The study measures the primary and secondary outcome variables at 4 time periods in each 
subject. We will begin with a univariate investigation of the outcomes to check for outliers and 
distributional properties followed by an assessment for carryover effects. The analysis of the 
study will be conducted using a 2-period cross-over model by comparing matched pair 
differences for the subjects in the first sequence with those in the second sequence. We expect 
this analysis will indicate no difference between the groups. If we find no carry over effect the 
modeling will continue without controlling for sequence. If we do find a sequence effect we will 
account for it in our models. The analysis will be based on a repeated measures analysis 
accounting for treatment and period effects and incorporating the two baseline measures. We 
will use a generalized linear model and a Generalized Estimating Equations (GEE) framework 
with two dummy variables, one indicating treatment condition and the other indicating the 
baseline condition (the omitted or the reference condition is Placebo). We will use an 
unstructured covariance matrix and robust standard errors. The primary parameter of interest is 
the regression coefficient for the treatment condition (a contrast between the placebo and 
pioglitazone). This approach is attractive because it can handle non-normal and categorical 
outcomes. The analysis is robust to model mis-specification154. 
The approach used in testing the hypothesis under the three specific aims will be similar. For 
Specific Aim 1, we will perform a separate analysis for each outcome variable: 
CAVI/Sphygmocor, PAT and FDG/CT. We will also perform secondary analysis using serum 
and cellular CV biomarkers. Our first analysis will be a randomization based analysis with no 

  
33
covariates other than treatment and period effects. There are several confounding variables, 
especially medications that could contribute towards the variation in the outcome. We will 
expand the regression models by including them as predictors. If the number of confounding 
variables is large, we will use investigate a propensity score matching analysis. For Specific 
Aim 2, we will define a dichotomous clinical endpoint measuring lupus disease activity. 
Patients achieving an improvement of the SLEDAI-2K by 20%, a significant improvement in 
PGA and the absence of a BILAG 2004 A or B flare will be considered to have improved. 
Others will be defined as not having improved. The analysis for this score will be similar to the 
one proposed for Specific Aim 1.  A GEE model will be used to assess treatment differences. 
We will also investigate the separate effects of each of these measures. The same approach used 
in Aim 1 will be taken for confounding variables using regression or propensity score 
adjustment. We will begin the investigation of Aim 3, assessment of innate and adaptive 
immune abnormalities in SLE, with a graphical analysis of the variables. We use multivariate 
methods to determine good summary measures of the various factors and compare the two 
treatments using the same models as defined for Aims 1 and 2.  
Our primary analysis will be performed as an intent-to-treat analysis. If the subjects providing 
complete data are systematically different from those who dropped out, then the estimates based 
only on completers will be biased. We will investigate adjusting for differences in the 
populations who are completers and noncompleters and will consider multiple imputation to 
impute the missing values. Before the database is locked and final analysis performed, 
violations will be assessed on a case-by-case basis by the PI to determine if the medication 
change was such that it would adversely affect the study results.  If changes may adversely 
affect data interpretation, subjects will be dropped from final analysis. A post hoc analysis of 
disease activity, measured by SLEDAI-2K, will be adjusted for burst steroids in excess of that 
permitted by the protocol. Analysis of prednisone doses, daily and cumulative will also be 
included. 
11.1 Power and Sample Size  
We arrived at sample size based on previous publications for arterial stiffness and vascular 
dysfunction observed in SLE92, 101-103 as well as on our recently completed RA trial. To achieve 
this sample size, we will be recruiting 100 patients, assuming a 20% or more dropout rate (see 
below).  The actual analysis will be more powerful and will use data on all subjects including 
those who provide partial information. Based on our previous experience with the CV lupus 
cohort and on published literature on cross-over designs using pioglitazone to measure CV 
markers in other populations, we estimate our dropout rate to be between 3-20%. We have then 
projected a 20% drop-out rate that includes both drop-outs, as well as the few people who are 
deemed protocol violators because of significant changes in immunosuppressive or vascular 
medications. This sample will give us power to detect moderate standardized differences for the 
other variables measured in this study. As this is a “proof of concept” study, we estimate it is 

  
34
important to detect at least moderate differences in outcome for them to be clinically 
meaningful. 
11.2 Data Management 
The primary source data for the study will be maintained by NIH Clinical Research Information 
System (CRIS) and the NIH Clinical Trials Database (CTDB), with subject surveys and interval 
questionnaires administered by the secure Clinical Trials Survey System (CTSS). Study data 
and outcomes will be monitored by a Data Safety Monitoring Committee (DSMC) consisting of 
NIH staff not affiliated with the study who will meet every 6 months and review un-blinded 
data. Possible adverse outcomes of treatment will be as per NIH and GCP monitoring 
guidelines. An IND waiver request was granted by FDA for this study. 
11.3 Study Timeline 
Table 4: 
Study Timeline 
Time Period 
Year 1 
Year 2 
Year 3 
Year 4 
Year 5 
 
Q 
1/2 
Q 
3/4 
Q 
1/2 
Q 
3/4 
Q 
1/2 
Q 
3/4 
Q 
1/2 
Q 
3/4 
Q 
1/2 
Q 
3/4 
Finalize Protocol CRFs 
X 
 
 
 
 
 
 
 
 
 
Submit IRB   
X 
 
 
 
 
 
 
 
 
 
Finalize SOPs 
X 
 
 
 
 
 
 
 
 
 
Build Database 
X 
X 
 
 
 
 
 
 
 
 
Pilot Test CRFs and Database 
X 
X 
 
 
 
 
 
 
 
 
Recruit Participants 
 
X 
X 
X 
X 
X 
X 
X 
 
 
Conduct Study Visits 
 
 
 
X 
X 
X 
X 
X 
 
 
Interim Analysis  
 
 
 
 
X 
 
X 
 
 
 
DSMC Reviews  
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Clean Data and Lock Database 
 
 
 
 
 
 
 
 
X 
 
Analysis and Publication 
 
 
 
 
 
 
 
 
 
X 
 
 
12 HUMAN SUBJECT PROTECTION ISSUES 
12.1 Selection 
 
 

  
35
 Human Participants Involvement and Characteristics  
For the purposes of this study, human participants will undergo physical examination and 
questionnaire completion, CAVI, Endopat, FDG PET CT and DXA scan (a subset of subjects), 
blood draws, Echocardiogram, and exposure to study drug (pioglitazone and placebo).  There 
will be no involvement of fetuses, neonates, children, pregnant women, prisoners, or 
institutionalized individuals.  Women of childbearing potential will be included, but risk 
reduction measures (including required contraception and pregnancy testing) are in place to 
protect them.  
 Inclusion of Women, Minorities, and Children: 
12.1.2.1 Women 
Women and men with SLE will be recruited into this study.  Research consistently shows that 
women are 7-10 times more likely to develop SLE than men. For this reason, we expect 
approximately 80-90% of participants to be female.  Based on the past record of the 
investigative team and the SLE natural history protocol, we believe specialized outreach for the 
recruitment of women will not be necessary.  
12.1.2.2 Inclusion of Minorities 
No ethnic groups will be excluded from this protocol.  All participants must have a diagnosis of 
SLE.  Research reviews indicate an increased risk for SLE development in African-Americans 
and Hispanics. Targeted enrollment rates will be based on data from the natural history protocol 
of SLE at NIH.   Based on the past record of the investigative team, we expect that minorities 
will be recruited in adequate numbers.  However, the PI will monitor recruitment progress on an 
annual basis, and will implement outreach strategies if enrollment falls short of targets.  
Outreach strategies include recruiting participants from physician offices in the area that service 
a predominance of minority patients.  
12.1.2.3 Inclusion of Children 
Children will be excluded from this study as pioglitazone is not approved in children and the 
proposed vascular tests have not been validated in children. 
12.1.2.3 Inclusion of NIH employees 
NIH employees are allowed to participate if they fulfill criteria. NIH employees who become 
subjects will be protected, as specified in SOP14F 
12.2 Benefits and Risks/Discomforts 
 
 Benefits 
The knowledge to be gained may result in better, more focused treatment approaches, 
implemented earlier in the course of disease, to reduce cardiovascular morbidity and mortality 
associated with SLE and other inflammatory autoimmune diseases. This would directly benefit 
future patients and greatly improve our understanding of these debilitating comorbidities.   

  
36
This study will provide important preliminary information about the effect of PPAR pathways 
in SLE patients and may contribute to a better understanding of the pathophysiology of SLE. 
Patients will benefit from comprehensive clinical exams and laboratory tests during the trial, as 
well as assessment of CV risk and thorough evaluation by experts in SLE. Otherwise, there may 
be no direct benefits to participants. The study agent is not expected to be associated with the 
most common toxicities of therapies commonly used in the treatment of SLE, such as severe 
immunosuppression, myelosuppression, or amenorrhea. This study involves more than minimal 
risk.  
 Potential Risks 
12.2.2.1 Blood Draws 
The risks of venous puncture include the occurrence of discomfort and/or bruising at the site of 
puncture. Less commonly, there may be formation of a small blood clot or swelling of the 
surrounding area as well as bleeding from the puncture site. Syncope and local infection may 
occur. These are minor risks. 
12.2.2.2 Physical Exam and Questionnaire-based Data Collection 
Some participants may experience discomfort or frustration these procedures. However, the 
risks for the participants are felt to be similar to those encountered in a standard physical 
examination. Breach of confidentiality and the possible discomfort associated with being asked 
personal questions about health history and the completion of questionnaires pose minimal 
risks.  Risks due to physical exam and questionnaire-based data collection are considered 
negligible. 
12.2.2.3 Vascular Function Studies 
No complications are expected from these procedures. Minor discomfort from the use of blood 
pressure cuffs may be experienced and is similar to having one’s blood pressure checked. 
12.2.2.4 FDG/PET/CT 
The NIH Clinical Center PET department uses only commercially available FDG.  
The effective radiation dose from 10 mCi FDG is approximately 0.62 rem.  Thus the total 
radiation from one FDG scan and a transmission CT scan is 1.32 rem. In addition to any 
radiation concern, there could be psychological distress caused by an incidental finding of 
asymmetric FDG uptake that would likely necessitate additional investigation to exclude cancer 
or other lesions (see below).  
Additional minimal risks include bleeding or bruising at the venous site of FDG administration.  
We have provided radiation dosimetry at the end of this protocol. This procedure will not be 
performed more often than twice per patient during the 8 month duration of this trial and will be 
performed in 30 out of the 70 patients. Overall, minimum exposure will be 0 rem/year (only 

  
37
vascular function tests but no imaging) and maximum exposure will be 2.64 rem/year, which is 
within the annual exposure limits.  
Participants may experience mild claustrophobia from the PET CT.  The participant will be able 
to notify the technician throughout the scan if he/she needs to come out of the scanner. 
 
12.2.2.5 Incidental Findings 
Incidental findings from imaging studies of coronary disease, obstructive or non-obstructive, 
will be reported to the subject’s referring physician.  This protocol will follow the NIH Clinical 
Center Guidelines for Management of Small Pulmonary Nodules Detected on CT Scans.  The 
literature has noted incidental findings on PET/CT scans to include neoplastic and non-
neoplastic lesions.  We have broadened our findings to include non-neoplastic and also 
inflammatory lesions such as lymph nodes as well as solitary pulmonary nodules.  Neoplastic 
findings include cancer of the colon, lung and soft tissue (sarcoma); however, except for lung 
cancer, these other 2 cancer types have not been highly detected by PET/CT.  Information 
regarding incidental findings is explained in the informed consent to help the subjects 
understand that these findings will be included on their report, sent to their physician, and may 
require clinical testing as a follow up to define the abnormality.  Prior to sending report, the 
investigators will provide dedicated follow up time with subjects to inform them of findings and 
as needed, will provide consult with appropriate medical personnel. 
12.2.2.6 Study Drug  
Participants will be randomized to pioglitazone or placebo and all patients will at some point 
receive pioglitazone given the crossover nature of trial.  Risks of pioglitazone use in this 
population (i.e. non-diabetic) are as follows:  
• Decreases in hemoglobin and hematocrit of 2-4%.  These reductions may be due to an 
increase in plasma volume and usually pose only minor risk. CBC will be monitored on 
all patients at each study visit. 
• Mild to moderate edema.  Pioglitazone is contraindicated in patients with NYHA Class 
III or IV cardiac failure.  In diabetics, concern over the use of rosiglitazone and 
worsening CV outcomes is still a matter of debate but a black box has been included in 
the medication guide describing a risk for congestive heart failure exacerbation in 
individuals taking TZDs. For our study, all patients will undergo a baseline 
echocardiogram and will be excluded for an ejection fraction <45% and/or evidence of 
NYHA class II-IV. 
• Hepatic effects.  Pioglitazone can cause decreases in hemoglobin and hematocrit of 2-
4%.  These reductions may be due to an increase in plasma volume and usually pose 
only minor risk. While pioglitazone is typically not associated with hepatic toxicity or 
liver function test (LFT) elevations, the pioglitazone package insert states there are post 
marketing reports of hepatic failure and that causality cannot be excluded; Medwatch 
report states there is an association with hepatitis, hepatic enzyme elevations to 3 or 
more times the upper limit of normal.  Pioglitazone is structurally related to troglitazone 

  
38
(no longer marketed), which has been associated with idiosyncratic hepatotoxicity and 
rare cases of liver failure, liver transplants, and death. In a recent study of non-diabetics 
treated with pioglitazone for similar periods of time to what is proposed for our study, 
no changes in LFTs were observed68.  Similarly, in our RA study, we did not detect any 
significant LFT abnormalities, even in those patients concomitantly taking methotrexate. 
Nevertheless, LFTs will be monitored on all patients at each study visit and those 
patients with LFTs >2x upper limit at Screening visit will be excluded. If during the 
trial, LFTs increase to > than 3x fold the upper limit of normal (ULN), levels will be 
rechecked within 36 hours and if elevation >3 ULN persists and there are not alternative 
etiologies, therapy will be discontinued. If LFTs are elevated >2 but < 3x ULN (after 
confirming within 48 hours), we will investigate etiology of liver enzyme elevation and 
cautiously reinitiate therapy if alternative etiology is found. For patients with NAFLD 
that are enrolled, based on recent clinical trials that have been published (Cusi K et 
al.Annals of Internal Medicine 2016) assessing  the role of long-term pioglitazone 
treatment for nonalcoholic steatohepatitis, we will include only patients that have LFTs 
< 3 times ULN. If there is an increase to >3 times ULN once study drug starts during 
monitoring (confirmed within 24 hours), drug will be stopped. 
• Interaction with hormonal contraceptives may reduce the effectiveness of hormonal 
contraception. Patients will be required to also use a barrier method during the trial if 
they are taking oral contraceptives. 
• The most common side effects reported were upper respiratory tract infection, sinusitis, 
pharyngitis, headache, myalgia, and tooth disorder.   
• Very rarely, pioglitazone may be associated with sporadic, transient elevations in CPK 
levels, which have been self-resolving. 
• Small weight gains (<5 kg) are associated with pioglitazone use, usually with more 
prolonged use than the treatment course we are proposing. Weight and edema will be 
monitored closely and patients will be instructed to notify investigators if weight is 
gained or edema or dyspnea develop. 
• An increased incidence of bone fracture was noted in female patients taking TZDs. 
During a mean follow-up of 34.5 months, the incidence of bone fracture in females was 
5.1% (44/870) for pioglitazone versus 2.5% (23/905) for placebo. This difference was 
noted after the first year of treatment and remained during the course of the study. No 
increase in fracture rates was observed in men treated with pioglitazone 1.7% (30/1735) 
versus placebo 2.1% (37/1728). Given the short duration of the trial, we will not assess 
the effect of this drug on bone metabolism. Given that the mechanism of bone fractures 
with TZDs is considered different than the one associated with corticosteroid use, we 
will not change inclusion/exclusion criteria based on medication use. In female patients, 
attention will be given to assessing and maintaining bone health according to current 
standards of care and in communication with treating rheumatologist. As mentioned in 
the exclusion criteria, we will exclude postmenopausal women who have a DXA scan 
showing a T score worse than -2.5, unless they are willing to begin a bisphosphonate by 
visit day 1. 
• As mentioned above, there have been data suggesting an increase in bladder cancer in 
diabetics that have been on TZDs for > 2 years. Given the short duration of this trial, no 
significant concerns are present. Nevertheless, we will exclude patients who have 
received cyclophosphamide over the last year, whoever developed hemorrhagic cystitis, 

  
39
or those with a previous history of bladder cancer, or with a history of hematuria not 
explained by another cause. 
 
Overall, given the short duration of exposure to pioglitazone (3 months), we do not expect 
repercussions on bone health, bladder or adverse CV outcomes.  
12.2.2.7 Echocardiogram:  
No side effects are associated with echocardiogram. 
12.2.2.8 DXA scan: 
The exposure to radiation is minimal from this procedure. No side effects are otherwise expected 
and this will only be performed in postmenopausal subjects that have not undergone a DXA scan 
over the last year. 
12.3 ADVERSE EVENT AND UNANTICIPATED PROBLEM REPORTING: 
The Principal Investigator will be responsible for detecting, documenting, and reporting AEs and 
SAEs in accordance with the protocol, IRB requirements, and federal regulations. 
12.3.1 Definitions: 
12.3.2 Adverse Event: 
An adverse event (AE) is any unfavorable and unintended diagnosis, symptom, sign (including 
an abnormal laboratory finding), syndrome, or disease that either occurs during the study, having 
been absent at baseline, or if present at baseline, appears to worsen.  All AEs will be graded for 
intensity (severity) and relationship to study drug. 
12.3.3 Unanticipated Problem: 
The Office for Human Research Protections considers unanticipated problems to be any incident, 
experience, or outcome that meets all of the following criteria: 
• Is unexpected in terms of nature, severity, or frequency given a) the research procedures 
that are described in the IRB-approved research protocol and informed consent, and 
b) the characteristics of the subject population being studied; 
• Is related or possibly related to participation in the research (possibly related means there 
is a reasonable possibility that the incident, experience, or outcome may have been 
caused by the procedures involved in the research); and 
• Places subjects or others at a greater risk for physical, psychological, economic, or social 
harm than was previously known or recognized. 

  
40
An incident, experience, or outcome that meets the 3 criteria above will generally warrant 
consideration of substantive changes in order to protect the safety, welfare, or rights of subjects 
or others.  Examples of corrective actions or substantive changes that might need to be 
considered in response to an unanticipated problem include the following: 
• Changes to the research protocol initiated by the investigator prior to obtaining IRB 
approval to eliminate apparent immediate hazards to subjects. 
• Modification of inclusion or exclusion criteria to mitigate the newly identified risks. 
• Implementation of additional procedures for monitoring subjects. 
• Suspension of enrollment of new subjects. 
• Suspension of research procedures in currently enrolled subjects. 
• Modification of informed consent documents to include a description of newly 
recognized risks. 
• Provision of additional information about newly recognized risks to previously enrolled 
subjects. 
Per the definition, only a subset of AEs would be further characterized as unanticipated 
problems.  Additionally, there are other sorts of events that, while not AEs, would also be 
characterized as unanticipated problems (e.g., contaminated study drug). 
12.3.4 Serious Adverse Event: 
A serious adverse event (SAE) is defined as any untoward medical occurrence that: 
• Results in death, 
• Is life-threatening (defined as a subject at immediate risk of death at the time of the event; 
it does not apply to an AE which hypothetically might have caused the death if it were 
more severe), 
• Requires or prolongs hospitalization (i.e. the AE required at least a 24-hour inpatient 
hospitalization or prolonged a hospitalization beyond the expected length of stay; 
hospitalizations for elective medical/surgical procedures, scheduled treatments, or routine 
check-ups are not SAEs by this criterion), 
• Results in a congenital anomaly or birth defect (i.e., an adverse outcome in a child or 
fetus of a patient exposed to the trial drug prior to conception or during pregnancy), 
• Causes a persistent or significant disability/incapacity (i.e. the AE resulted in a 
substantial disruption of the patient’s ability to carry out normal life functions), or 

  
41
• Is any other condition that, in the judgment of the investigator, represents a 
significant hazard or it does not meet any of the above serious criteria but may 
jeopardize the patient and may require medical or surgical intervention to prevent 
one of the outcomes listed above. 
12.3.5 Medical Events Not Qualifying as Adverse Events or Serious Adverse Events: 
Signs and symptoms of pre-existing medical conditions will not be recorded or reported as AEs 
or SAEs, unless they represent a clinically significant change from the baseline disease status 
documented at the Pre-screening Visit.  In addition, hospitalization for elective procedures or 
surgeries will not be considered SAEs, nor will inpatient hospitalizations for convenience. 
12.3.6 Clinical Laboratory Test Results Not Qualifying as Adverse Events or Serious 
Adverse Events: 
A clinically significant laboratory result that is present at baseline and does not change 
significantly during the study will not be reported as an AE or SAE.  The clinical significance of 
a change in a laboratory result will be determined by the investigator. 
The Principal Investigator or designated AI will evaluate all clinical laboratory and imaging 
results for clinically significant abnormalities and document the evaluation in the medical record 
and case report form. A laboratory abnormality will be documented as an adverse event using the 
following criteria:  
• The abnormality is not already encompassed by a reported adverse event (e.g., 
elevated AST need not be reported as an AE if Liver Failure has already been 
reported as an AE). 
• The abnormality is considered clinically significant by the Investigator.  
Clinically significant lab abnormality is defined as meeting the following: 
o Necessitates study drug dosing modification (i.e., dose reduction, 
interruption or discontinuation); and/or 
o Requires a therapeutic intervention (e.g., concomitant medication, blood 
transfusion or dialysis); and 
o Is unexplainable by the patient’s current and past medical conditions 
The Principal Investigator will follow significant abnormalities until they return to baseline or 
stabilize. 
 

  
42
12.3.7 Lupus Flare: 
A lupus flare is any significant worsening of the signs, symptoms and laboratory test 
abnormalities associated with lupus. Any increase in the SLEDAI 2K index of 3 or more will be 
considered as a SLE flare. 
12.3.8 Reporting of Adverse Events, Unanticipated Problems and Protocol Deviations:  
12.3.8.1 
Intensity of Adverse Event: 
The intensity (severity) of AEs and SAEs will be graded according to a descriptive scale based 
on the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE), 
Version 4.0.  If AEs and SAEs is not available at CTCAE, it will be graded according to below 
chart.  
Severity Definitions 
Grade 
Definition 
       1. Mild: 
Causing no limitation of usual activity 
2. Moderate: 
Causing some limitations of usual activities 
3. Severe: 
Causing inability to carry out usual activities 
4. Life Threatening: 
Patient was at immediate risk of death from the event  
 
For lupus flares, we will use the following criteria based on validated activity scores: (changes 
are points increased compared to baseline visit) 
Increase in SLEDAI 2K: 2-4:  Mild 
Increase in SLEDAI2K: 5-8: Moderate 
Increase in SLEDAI 2K: > 9: Severe 

  
43
12.3.8.2 
Relationship to Study Drug and Procedures: 
For all AEs and SAEs, the investigator will provide his/her best estimate of the causal 
relationship between the event and study drug, and the causal relationship between the event and 
study procedures.  The degree of certainty about causality will be graded according to the criteria 
in Table. 5.  
 
 
Table 5. 
Relatedness of Adverse Event to Intervention 

  
44
Causality 
Description 
Not Related Category 
Unknown 
Not enough information exists for the assessment of causality at the time 
of occurrence. 
Unrelated 
Adverse event is clearly due to extraneous causes (e.g., underlying 
disease, environment) 
Related Category 
Unlikely 
(must have at least 2) 
1) does not have temporal relationship to intervention  
2) could readily have been produced by the subject’s clinical state  
3) could have been due to environmental or other interventions   
4) does not follow a known pattern of response to intervention  
5) does not reappear or worsen with reintroduction of intervention 
Possible 
(must have at least 2) 
1) has a reasonable temporal relationship to intervention  
2) could not readily have been produced by the subject’s clinical state 
3) could not readily have been due to environmental or other interventions 
4) follows a known pattern of response to intervention 
Probable 
(must have at least 3) 
1) has a reasonable temporal relationship to intervention  
2) could not readily have been produced by the subject’s clinical state or 
have been due to environmental or other interventions 
3) follows a known pattern of response to intervention 
4) disappears or decreases with reduction in dose or cessation of 
intervention 
Definite 
(must have all 4) 
1) has a reasonable temporal relationship to intervention  
2) could not readily have been produced by the subject’s clinical state or 
have been due to environmental or other interventions 
3) follows a known pattern of response to intervention 
4) disappears or decreases with cessation of intervention and recurs with 
re-exposure 
 

  
45
12.3.8.3 
Expectedness of Adverse Events: 
For purposes of regulatory reporting, the medically responsible investigator will determine 
whether an AE or SAE is expected or unexpected.  Expected adverse events are those 
adverse events that are listed or characterized in the Package Insert or in the Physicians’ 
Desk Reference.  
Unexpected adverse events are those not listed in the Package Insert (P.I.) or Physicians’ 
Desk Reference (PDR), published medical literature, protocol, and informed consent 
document or not identified.  This includes adverse events for which the specificity or 
severity is not consistent with the description in the P.I., PDR, published medical literature, 
protocol and informed consent.  For example, under this definition, hepatic necrosis would 
be unexpected if the P.I. only referred to elevated hepatic enzymes or hepatitis. 
For consistency of labeling and categorizing adverse events, the NCI CTCAE, Version 4.0 
will be used in this study.   
12.3.9 Procedures for Reporting 
Serious adverse events, unexpected AEs, and unanticipated problems will be reported to the IRB, 
NIAMS Clinical Director, and DSMC according to the NIH-OHSRP SOP 16, “Reporting 
Requirements for Unanticipated Problems, Adverse Events and Protocol Deviations.”  All patients 
who receive at least one dose or part of a dose of the trial medication (pioglitazone), whether 
withdrawn prematurely or not, will be included in the safety analyses. All data relating to safety 
will be listed and summarized separately for the treatment period and for the entire study. All 
safety reports will be reviewed by the Principal Investigator. 
12.3.10 
Reporting Timeline:  
Adverse events, protocol deviations, unanticipated problems (UP), Unanticipated Adverse 
Device Effects (UADEs), serious adverse events, sponsor and serious, are defined as described 
in NIH HRPP SOP 16 (“Reporting Requirements for Unanticipated Problems, Adverse Events 
and Protocol Deviations.”). All adverse events occurring during the study, including those 
observed by or reported to the research team, will be recorded. Serious unanticipated problems 
and serious protocol deviations, will be reported to the IRB, DSMC and Clinical Director as 
soon as possible but not more than 7 days after the PI first learns of the event. Not serious 
unanticipated problems will be reported to the IRB, DSMC and Clinical Director as soon as 
possible but not more than 14 days after the PI first learns of the event. Not serious protocol 

  
46
deviations will be reported to the IRB as soon as possible but not more than 14 days after the 
PI first learns of the event. 
Deaths will be reported to the Clinical Director, DSMC and IRB within 7 days after the PI first 
learns of the event. 
12.3.11  Reporting of Non-Serious Protocol Deviations: 
Non-serious protocol deviations will only be reported to the IRB (within 14 days after the PI first 
learns of the event) if they represent a departure from NIH policies for the conduct of human 
subjects research, adversely affect the health care of the subject(s) or compromise the 
interpretation or integrity of the research.  Non-serious protocol deviations that result from normal 
subject scheduling variations or technical issues associated with sampling that does not impact the 
health of the subject or the interpretation of the study data will not be reported. 
12.3.12  Reporting of Adverse Events: 
The PI is responsible for summarizing all serious adverse events and adverse events at least 
possibly related to the research procedure and interventions at the time of Continuing 
Review.   
12.3.13  Reporting of Deaths: 
All deaths that have occurred among study participants since the previous review will be 
summarized at the time of continuing review.   
12.3.14 Reporting Waivers: 
Waiver of Reporting to the IRB of anticipated minor protocol deviations, adverse events and 
deaths due to underlying disease or population under study unless determined to be an 
Unanticipated Problem. 
• Non-unanticipated problems (UP)/ adverse events will not be reported to the IRB unless 
they occur at a rate greater than that known to occur in patients with SLE. If events are 
occurring substantially more frequent that would be anticipated in typically treated 
patients with SLE, they will also be reported to IRB. The following anticipated adverse 
events will not be reported to the IRB unless they occur at a severity greater than that 
known to occur in patients taking pioglitazone: lower extremity edema, decrease in Hb 
which is less than 1.5 g/dl, weight gain <5 pounds/week. Examples of expected adverse 
events include those events detailed in the Investigator’s protocol for pioglitazone and 

  
47
in the pioglitazone drug insert.  No more than a total gain of 15% weight gain if 
associated with signs and symptoms of volume overload such as shortness of breath 
on exertion, paroxysmal nocturnal dyspnea or elevated jugular venous pressure will be 
allowed for the total duration of the study.  If patient gained weight during study due 
to other reasons such as lifestyle changes or increase in Prednisone dose or other 
specific reasons and the patient is not at risk of health compromising condition, these 
reasons will be documented in CRIS and will not be reported as Unanticipated 
Problems. Patient will be advised to lose weight through NIH nutrition consults or 
exercising. If the rate of these events exceeds the rate specified in the protocol or 
investigator’s brochure the events will be classified and reported as though they are 
Unanticipated Problems.  
12.3.15 Adverse Event, Protocol deviation and Unanticipated Problem Assessment and 
Follow-up: 
In the event of an adverse event, protocol deviation and unanticipated problem the first concern 
will be for the safety of the patients.  Investigators are required to collect and document all adverse 
events (AEs), protocol deviations and unanticipated problems.  At each study visit, the Principal 
Investigator will inquire about the occurrence of AE/SAEs since the last visit, and review any 
protocol deviations and unanticipated problems. Adverse events (including SAEs), protocol 
deviations, and unanticipated problems may be discovered through any of these methods:  
• Observing the subject.  
• Questioning the subject in an objective manner.  
• Receiving an unsolicited complaint from the subject.  
• Review of all source documentation related to study procedures; abnormal values or results 
from clinical or laboratory evaluations (including, but not limited to, radiographs, 
ultrasounds, or electrocardiograms) can also indicate adverse events. 
Events will be followed for outcome information until they return to baseline or stabilize.  Study-
related AEs will be followed and/or treated at the NIH until resolution or stabilization of the AE, 
after which the subject will be referred to a physician(s) outside of the NIH for care and follow-
up. 

  
48
12.3.16 Adverse Event Recording: 
Adverse events will be monitored throughout this study, and these events will be recorded on the 
appropriate AE eCRF at each visit after starting study medication.  The record for each event 
will include the following information: 
• Description of the event. 
• Onset and stop dates of the event. 
• Seriousness of event. 
• Intensity (or severity) of the event. 
• Action taken because of the event. 
• Relationship of the event to study drug and/or study procedure. 
• Outcome of the event. 
• Expectedness of the event. 
12.3.17  Pregnancy Reporting and Follow-up: 
This study includes pregnancy information as safety data and pregnancies will be recorded if 
they begin any time after enrollment. Information about any pregnancy should be reported 
promptly to the NIH NIAMS/NIDDK IRB, NIAMS Clinical Director, and DSMC on the same 
timeline as a SAE. All pregnancies identified during the study must be followed to conclusion 
and the outcome of each must be reported. The investigator should be informed immediately of 
any pregnancy in a study subject or a partner of a study subject. A pregnant subject should be 
instructed to stop taking study medication. The investigator will refer patient to High-risk 
Obstetrics for counseling and follow-up.  Pioglitazone has a pregnancy risk factor Category C; 
there are no adequate and well controlled studies in pregnant women.  Animal studies show 
increased rates of post-implantation loss, delayed development, reduced fetal weights, and 
delayed parturition at doses 10 to 40 times the maximum recommended human dose (Label, 
2013).  Monitoring of the pregnant subject should continue until the conclusion of the pregnancy, 
and a follow-up Pregnancy Monitoring form detailing the outcome of the pregnancy should be 
submitted to the IRB. When possible, similar information should be obtained for a pregnancy 
occurring in a partner of a study subject. Information requested about the delivery will include:  
• Subject’s enrollment ID  
• Gestational age at delivery  

  
49
• Birth weight, length, and head circumference  
• Gender  
• Appearance, pulse, grimace, activity, and respiration (APGAR) score at 1 minute, 5 
minutes, and 24 hours after birth, if available   
• Any abnormalities.  
Should the pregnancy result in a congenital abnormality or birth defect, an SAE also must 
be submitted to the NIH NIAMS/NIDDK IRB using the SAE reporting procedures 
described above.  
12.3.18  Lost to follow up patient reporting:  
After three attempts to contact the patient via phone, a certified letter will be sent to notify him 
or her that they have been withdrawn from the study. 
12.3.19   Stopping Rules:  
If any of the involved entities believes there is any evidence of a pattern of unanticipated AEs 
(regardless of causality) or SAEs an unscheduled independent third party review by the DSMC 
will be requested.  Based on the conclusions of the review, the PI will either terminate the study 
or modify the protocol.  Additional stopping rules may be set at any time by the IRB or DSMC.  
Due to the interventional nature of the protocol, we expect to work closely with an assigned 
DSMC. 
12.3 Compliance with Good Clinical Practices  
This trial will be conducted in compliance with the protocol, current GCPs recommended by the 
International Conference on Harmonization (ICH) and the applicable regulatory requirements 
for participating institutions. These include the tenets of the Declaration of Helsinki and review 
and approval by the appropriate ethics review committee or IRBs of participating organizations.  
12.4 Data Safety and Monitoring  
The study will be conducted according to Good Clinical Practice (GCP) guidelines, the Manual 
of Procedures (MOP), U.S. 21 CFR Part 50 – Protection of Human Subjects, 21CFR312 subpart 
D and Part 56 – Institutional Review Boards.  
 
12.5 Data Safety Monitoring Committee 
The NIAMS DSMC will have safety oversight responsibilities for the study.  DSMC will be 
comprised of 3 members after discussion with NIAMS Clinical Director. The DSMC Chair will 
not be affiliated to NIAMS. 

  
50
Approximately twice a year (as mentioned in section 11.2), the DSMC will review data related 
to enrollment progress, study implementation, subject safety, and protocol violations.  The 
CTDB will generate reports that compile all newly submitted and accumulated AEs, SAEs, 
toxicities, pregnancies, and concomitant medications. Subsequent review of periodic reports 
will be performed by the Principal Investigator.  
The DSMC will also consider current information from other sources on the biology of the 
disease and the subject population under study.  Based on these reviews, the DSMC will make 
recommendations to the Principal Investigator and the NIAMS Clinical Director concerning the 
continuation, modification, or termination of the study.  The DSMC will also meet ad hoc if 
relevant issues arise that require committee review.  
The Principal Investigator will be responsible for reporting incidents of non-compliance to the 
NIH IRB (in compliance with regulations on the protection of human subjects and institutional 
policy and procedures) and responsible for securing compliance.  
Clinical monitoring for this study will be based on a clinical monitoring plan developed by 
Leidos Biomedical Research, Inc., Clinical Monitoring Research Program, Clinical Trials 
Management team in collaboration with the principal investigator. The purposes of the clinical 
monitoring activities are: 
 1) To verify the existence of signed informed consent documents and documentation of the ICF 
process for each monitored subject;  
2) To verify the prompt and accurate recording of all monitored data points, and prompt 
reporting of all SAEs;  
3) To compare abstracted information with individual subjects’ records and source documents 
(subjects’ charts, laboratory analyses and test results, physicians’ progress notes, nurses’ notes, 
and any other relevant original subject information); and  
4) To help ensure investigators are in compliance with the protocol. 
The monitors also will inspect the clinical site regulatory files to ensure that regulatory 
requirements (Office for Human Research Protections-OHRP) and applicable guidelines (ICH-
GCP) are being followed.  
During the monitoring visits, the investigator (and/or designee) and other study personnel will 
be available to discuss the study progress and monitoring visit. 
The Clinical Monitoring Plan will specify the frequency, procedures, and levels of monitoring 
activities. Some monitoring activities will be performed remotely (e.g., review of regulatory 
documents), while others will take place on site (e.g., verification of study databases against 
source documentation). 

  
51
The staff from Leidos Biomedical Research Inc. CMRP/CTM will conduct the monitoring 
activities and provide the follow-up letters describing the findings.  The frequency of reporting 
for monitoring activities will be specified in the monitoring plan.  The Principal Investigator 
will receive copies of the final follow-up letters.  
12.6 Research Use, Storage, and Disposition of Human Samples If, Specimens, or Data 
 
 Data Collection 
Study staff will complete electronic case report forms (eCRFs) that will be compiled and stored 
in a computerized central database CTDB.  Security of the database system is maintained 
through an application firewall, military grade encryption and SSL certificates, removal of 
personal identifiers consistent with HIPAA requirements (45 C.F.R. 164.514(a),(b)&(c)). 
Research samples collected from subjects consenting to this protocol will be stored in locked 
secure freezers belonging to NIAMS.  The freezers are located in Building 10 at the NIH. 
Samples will be kept indefinitely unless there is a significant justification for destroying them.  
The Principal Investigator will report to the Institutional Review Board (IRB) the loss or 
destruction of samples collected under this protocol. 
All samples will be coded and will not have personal identifiers.  The codes for identifiers will 
be contained in a secure electronic database (CTDB) and a subject code log that is maintained in 
secure research files.  An electronic record log with identifiers of all collected research 
specimens will be kept.  These will be stored in either research charts or on secure NIH 
computers.   
If coded samples are shared with collaborators within or outside the NIH in the future, tech 
transfer agreements, MTAS or CRADAS will be obtained and an amendment will be submitted 
to IRB to describe the nature of this collaboration. Currently, we do not have any planned 
collaborations. Samples will be stored in the NIAMS and may be used by the investigators in 
this proposal for studies in the pathogenesis of SLE.  Approval from the IRB will be obtained 
prior to any research use of stored samples beyond the scope of this study. 
All patient samples will be coded and used for research purposes without sharing identifying 
information and all collaborators will follow federal rules for clinical research. 
The investigators will retain all study-related records for at least 3 years after discontinuation of 
the study.  Some of the research data might be maintained indefinitely for research purposes. 
Research records and all source documents will be kept in locked cabinets or rooms, and 
computer research databases will be stored in a secure, password-protected environment, per 
standard NIH policies.  Only study investigators and participating research personnel will have 
access to the data. 
The site investigators are required to keep accurate records to ensure the conduct of the study is 
fully documented. The period of record retention should be consistent with the record retention 

  
52
policies of the sponsoring agency or applicable regulatory agencies. Medical and research 
records will be maintained in the strictest confidence. However, as a part of the quality 
assurance and legal responsibilities of an investigation, Principal investigator must permit 
authorized representatives of the IND sponsor (if applicable), Leidos, CTDB at the NIH and 
health authorities to examine (and when required by applicable law, to copy) clinical records for 
the purposes of quality assurance reviews, audits, and evaluation of the study safety and 
progress. Unless required by the laws permitting copying of records, only the coded identity 
associated with documents or other subject data may be copied (obscuring any personally 
identifying information). Authorized representatives as noted above are bound to maintain the 
strict confidentiality of medical and research information that may be linked to identified 
individuals. Participating sites will normally be notified in advance of auditing visits.  
Study staff will complete electronic case report forms (eCRFs) via a web-based electronic data 
capture (EDC) system (Clinical Trials Database, CTDB) that is compliant with Part 11 Title 21 
of the Code of Federal Regulations.  Subject’s electronic medical records in the Clinical 
Research Information System (CRIS) will be used as source documents for these eCRFs. 
CRFs and subject questionnaire data will be kept in the CTDB database.   
The data will be further validated via a series of manual edit checks, and all relevant data 
queries will be raised and resolved on an ongoing basis. Complete, clean data will be frozen to 
prevent further inadvertent modifications. All discrepancies will be reviewed and any resulting 
queries will be resolved with the investigators and amended in the database. All elements of 
data entry (i.e., time, date, verbatim text, and the person performing the data entry) will be 
recorded in an electronic audit trail to allow all data changes in the database to be monitored and 
maintained in accordance with federal regulations.  
12.7 Remuneration 
Patients will be offered remuneration as follows: 
$60/visit for screening, baseline, month 3, month 5 and month 8 visits. 
$30/visit for safety visits at months 1 and 6. 
$150/ FDG/PET CT scan. 
 
 Travel costs may be covered as per the current NIH/NIAMS policy. 
12.8 Protocol Consent Processes and Documents 
 
The principles of informed consent in the current edition of the Declaration of Helsinki, as well 
as compliance with all IRB requirements, will be implemented in the study, before any 
protocol-specified procedures are carried out. A standard consent form for subject participation 
will be provided with the protocol to the IRB and Office of Protocol Services (OPS) of the NIH. 
Any modifications to the standard information in the template will require review and approval 
by the IRB. All subjects will receive a consent form that will include the purposes, procedures, 
benefits, and potential hazards of the study.  This information will be reviewed with the subject 

  
53
by either the principal or a qualified associate investigator. All prospective subjects will be 
given ample time to read the consent form, and ask questions, before signing.  
The consent documents will be translated into Spanish. For Spanish speaking subjects the 
consent will be explained by the PI/AI through an interpreter. Subjects who are unable to read 
and/or understand English or Spanish will be given a short consent form in their native 
language, if available.  The short consent form will be explained to the subject through an 
interpreter.  The NIH IRBs will review and approve the short consent form process for non-
English-speaking subjects.  If these approaches are not satisfactory, the subject will be excluded 
from the study because of an inability to understand the consent.  All subjects will be informed 
of their right to withdraw from the study. Translated documents must be certified to contain the 
complete descriptions provided in the English version of the document. 
Short Form Consent Process: 
 
We anticipate the enrollment of Spanish speaking subjects into this study for which English 
consents have been fully translated. If there is unexpected enrollment of a research participant 
for which there is no translated extant IRB-approved consent document, the Principal 
Investigator and/or those authorized to obtain informed consent will use the short form consent 
process as described in MAS Policy M77-2, NIH SOP 12, and 45 CFR 46.117 (b) (2). The 
summary that will be used is the English version of the extant IRB-approved consent document. 
We request prospective IRB approval of the use of the short form consent process for up to a 
maximum of 5 requests (either for individual participants or families of participants) in a given 
language, and will notify the IRB at the time of continuing review of the frequency of the use of 
the short form. Should we reach the threshold of 5 subjects and/or families speaking a single 
language, we will request an additional use of the short form from the IRB and will notify the 
Board that we plan to have any consent documents frequently used with that population 
translated into the language(s) they speak. 
 
For inclusion in the study, each subject will be required to sign the consent form.  The original 
forms will become part of the permanent medical record and kept on file in the subject’s study 
chart, available for inspection by regulatory authorities, both federal and institutional, as well as 
the monitoring entity, Leidos Biomedical Research, Inc. Copies will be provided to the subjects. 
The fact that informed consent was obtained prior to the initiation of study procedures will be 
documented in the subject’s medical or research record. 
 
 

  
54
13. Participation of NIH employees: 
We anticipate eligible NIH employees may participate in this study.  We will follow the 
Guidelines for the Inclusion of Employees in NIH Research Studies and will give each employee 
a copy of the “NIH information sheet on Staff Research Participation” as per NIH SOP 14F, 
“Research Involving NIH Staff as Subjects.” If the employee is within the same branch, section, 
or unit such that the individual obtaining consent is a supervisor then independent monitoring of 
the consent process through Clinical Center Department of Bioethics Consultation Service will 
be requested. Study staff will be trained that communication of any personal or medical 
information about an NIH employee), including the fact that they are participating in this study, 
should be restricted to those investigators who need to know this information, and such 
information will not be discussed with anyone outside of the study without permission from the 
subject. 
We will discuss the following applicable safeguards to the eligible NIH employee : 
- 
Unbiased participation for protocol integrity and participant risk assessment. 
- 
Ensure there is no perceived workplace pressure or expectation on either participation or 
deciding not to participate on the protocol in regards to a benefit or adverse effect on their 
NIH employment or staff position.   
- 
Protection of privacy and confidentiality will be maintained, but also with acknowledgement 
of the limits due to sensitive information that may be in their NIH file.   
- 
Discussion of time commitments of the study and compensation in accordance with NIH 
policy 2300-630-3, Leave Policy for NIH Employees Participating in NIH Medical Research 
Studies. 
 
14. ASSOCIATE INVESTIGATORS 
1.  Dr. Thomas: Associate Investigator. 
Role: Dr. Thomas will be referring subjects to the NIH clinical center for possible 
participation in the protocol. He will not be involved in consenting subjects or any other 
research procedures or analyses.  He will not be receiving any identifiable research 
samples from the study on the subjects he refers to the NIH. However, as he is the 
primary physician listed in CRIS he would get progress notes and clinical labs from 
subject’s visit to the NIH clinical center. 
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Takahashi M, Takahara A. Evaluation of blood pressure control using a new arterial stiffness 
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Fleck PR. Effects of pioglitazone on lipid and lipoprotein profiles in patients with type 2 
diabetes and dyslipidaemia after treatment conversion from rosiglitazone while continuing 
stable statin therapy. Diab Vasc Dis Res. 2006;3:39-44 
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postprandial increases in glucose and triglyceride levels and on oxidative stress in japanese 
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systemic lupus erythematosus. Arthritis Rheum. 2008;59:181-185 
 
 
 
 

  
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16. APPENDICES 
1. American College of Rheumatology Revised Classification Criteria for Systemic 
Lupus Erythematosus (1A) and SLE-disease activity index. 
1A. ACR Revised Classification Criteria for SLE 
Criteria 
Definition 
Malar rash 
Fixed erythema, flat or raised, over the malar eminences, tending to spare 
the nasolabial folds 
: pDiscoid rash Erythematous raised patches with adherent keratotic scaling and follicular 
plugging; atrophic scarring occurs in older lesions 
Photosensitivity Skin rash as a result of unusual reaction to sunlight, by patient history or 
physician observation 
Oral ulcers 
Oral or nasopharyngeal ulceration, usually painless, observed by a 
physician 
Arthritis 
Nonerosive arthritis involving two or more peripheral joints, characterized 
by tenderness, swelling, or effusion 
Serositis 
   a.     Pleuritis—convincing history of pleuritic pain or rub heard by a 
physician or evidence of pleural effusion or 
   b.    Pericarditis—documented by ECG or rub or evidence of 
pericardial effusion 
Renal disorder 
   a.     Persistent proteinuria >0.5 g/day >3+ if quantitation is not 
performed or 
   b.    Cellular casts—may be red blood cell, hemoglobin, granular 
tubular, or mixed 
Neurologic 
disorder 
   a.     Seizures—in the absence of offending drugs or known metabolic 
derangements (e.g., uremia, acidosis, or electrolyte imbalance) or 

  
69
Criteria 
Definition 
   
b.    Psychosis—in the absence of offending drugs or known 
metabolic derangements (e.g., uremia, acidosis, or electrolyte 
imbalance) 
Hematologic 
disorder 
   a.     Hemolytic anemia with reticulocytosis, or 
   b.    Leukopenia—<4000/mm3, or 
   c.     Lymphopenia—<1500/mm3, or 
   d.    Thrombocytopenia—<100,000/mm3 in the absence of offending 
drugs 
Immunologic 
disorder 
   a.     Anti-DNA—antibody to native DNA in abnormal titer, or 
   b.    Anti-Sm—presence of antibody to Sm nuclear antigen, or 
   
c.     Positive finding of antiphospholipid antibodies based on (1) 
abnormal serum concentration of IgG or IgM anticardiolipin 
antibodies, (2) positive test result for lupus anticoagulant using a 
standard method, or (3) false-positive serologic test for syphilis 
known to be positive for at least 6 mo and confirmed by 
Treponema pallidum immobilization or fluorescent treponemal 
antibody absorption test 
ANA 
Abnormal titer of ANA by immunofluorescence or equivalent assay at any 
point in time and in the absence of drugs known to be associated with 
drug-induced lupus syndrome 
 
 
 

  
70
2A. SLEDAI-2K disease activity questionnaire: 
For an item to be scored the indicated weight, the manifestation must have been  
present in the past 10 days. 
 
 
SLEDAI 2K 
Descriptor 
Definition 
Weight 
SCORE 
8 
 
 
Seizure 
Recent onset, exclude metabolic, infectious or drug causes. 
8 
 
 
Psychosis 
Altered ability to function in normal activity due to severe disturbance in 
the perception of reality.  Include hallucinations, incoherence, marked 
loose associations, impoverished thought content, marked illogical 
thinking, bizarre, disorganized, or catatonic behavior.  Exclude uremia 
and drug causes 
8 
 
 
Organic brain syndrome 
Altered mental function with impaired orientation, memory, or other 
intellectual function, with rapid onset and fluctuating clinical features, 
inability to sustain attention to environment, plus at least 2 of the 
following:  perceptual disturbance, incoherent speech, insomnia or 
daytime drowsiness, or increased or decreased psychomotor activity.  
Exclude metabolic, infectious, or drug causes. 
8 
 
 
Visual disturbance 
Retinal changes of SLE.  Include cytoid bodies, retinal hemorrhages, 
serous exudate or hemorrhages in the choroid, or optic neuritis.  
Exclude hypertension, infection, or drug causes. 
8 
 
 
Cranial nerve disorder 
New onset of sensory or motor neuropathy involving cranial nerves. 
8 
 
 
Lupus headache 
 
Severe, persistent headache;  may be migrainous, but must be 
nonresponsive to narcotic analgesia. 
8 
 
 
CVA 
New onset of cerebrovascular accident(s).  Exclude arteriosclerosis. 
8 
 
 
Vasculitis 
Ulceration, gangrene, tender finger nodules, periungual infarction, 
splinter hemorrhages, or biopsy or angiogram proof of vasculitis. 
4 
 
 
Arthritis 
> 2 joints with pain and signs of inflammation (i.e., tenderness, swelling 
or effusion). 
4 
 
 
Myositis 
Proximal muscle aching/weakness, associated with elevated creatine 
phosphokinase/aldolase or electromyogram changes or a biopsy 
showing myositis. 
4 
 
 
Urinary casts 
Heme-granular or red blood cell casts. 
4 
 
 
Hematuria 
>5 red blood cells/high power field.  Exclude stone, infection  or other 
cause. 
4 
 
 
Proteinuria 
>0.5 gram/24 hours 

  
71
4 
 
 
Pyuria 
>5 white blood cells/high power field.  Exclude infection. 
2 
 
 
Rash 
Inflammatory type rash. 
2 
 
 
Alopecia 
Abnormal, patchy or diffuse loss of hair. 
2 
 
 
Mucosal ulcers 
Oral or nasal ulcerations. 
2 
 
 
Pleurisy 
Pleuritic chest pain with pleural rub or effusion, or pleural thickening. 
2 
 
 
P 
Pericarditis 
Pericardial pain with at least 1 of the following:  rub, effusion, or 
electrocardiogram or echocardiogram confirmation. 
2 
 
 
Low complement 
Decrease in CH50, C3, or C4 below the lower limit of normal for testing 
laboratory 
2 
 
 
Increased DNA binding 
Increased DNA binding by Farr assay above normal range for testing 
laboratory. 
1 
 
 
Fever 
>38o C. Exclude infectious cause. 
1 
 
 
Thrombocytopenia 
<100,000 platelets / x109/L, exclude drug causes. 
1 
 
 
Leukopenia 
< 3,000 white blood cells / x109/L, exclude drug causes.  
 
 
TOTAL SCORE:   ______________ 
 
 

  
72
3. BILAG SCORE. 
BILAG 2004: The scoring system for the BILAG index of disease activity is based upon the principle of 
the physician's intention to treat. There are eight systems: general, mucocutaneous, neurological, 
musculoskeletal, cardiorespiratory, vasculitis, renal and haematological. A score is calculated for each 
system depending on the clinical features present and whether they are new, worse, the same or 
improving in the last 4 weeks compared with previously. The most severe features in each system, which 
are deemed to require high dose steroids (prednisolone >20 mg daily or equivalent) and/or cytotoxic 
agents, characterize an A score. One or more features may have to be present to score an A, depending 
on the system  More moderate disease items that would be considered appropriate to treat with lower 
dose steroids, antimalarials or non-steroidal anti-inflammatory drugs (NSAIDs) contribute to a B score. 
Mild symptomatic features that require just symptomatic therapy, for example with analgesics and 
NSAIDs, can only contribute to a C score. If there are no current symptoms but the system has previously 
been involved then a D is recorded. If the system has never been involved, it is scored E 

  
73
 

  
74
5. SLICC Classification Criteria for SLE 
Requirements: 4 or more criteria (at least 1 clinical and 1 laboratory criteria) 
OR biopsy-proven lupus nephritis with positive ANA or anti-DNA. 
 
Clinical Criteria                    
Immunologic Criteria 
1. Acute Cutaneous Lupus        
1. ANA 
2. Chronic Cutaneous Lupus     
2. Anti-DNA 
3. Oral or nasal ulcers               
3. Anti-Sm 
4. Non-scarring alopecia           
4. Antiphospholipid Ab 
5. Arthritis                                 
5. Low complement (C3, C4, CH50) 
6. Serositis                                 
6. Direct Coombs  
7. Renal 
8. Neurologic 
9. Hemolytic Anemia 
10. Leukopenia 
11. Thrombocytopenia (<100,000) 
 
 
 
 
 
 
 

  
75
6. 36-item Short Form Survey 
Medical Outcomes Study:  36-Item Short Form Survey Instrument 
 
1. In general, would you say 
your health is: 
Excellent 
1 
Very good  
2 
Good 
3 
Fair 
4 
Poor 
5 
2. Compared to one year ago, 
how would your rate your health in general now? 
Much better now than one year ago 
1 
Somewhat better now than one year ago 
2 
About the same 
3 
Somewhat worse now than one year ago 
4 
Much worse now than one year ago 
5 
The following items are about activities you might do during a typical day. Does your health 
now limit you in these activities? If so, how much? 
(Circle One Number on Each Line) 
 
Yes, 
Limited a 
Lot  
Yes, Limited 
a Little  
No, Not 
limited at All  

  
76
3. Vigorous activities, such as running, lifting 
heavy objects, participating in strenuous sports 
[1]  
[2]  
[3]  
4. Moderate activities, such as moving a table, 
pushing a vacuum cleaner, bowling, or playing 
golf 
[1]  
[2]  
[3]  
5. Lifting or carrying groceries 
[1]  
[2]  
[3]  
6. Climbing several flights of stairs 
[1]  
[2]  
[3]  
7. Climbing one flight of stairs 
[1] 
[2] 
[3] 
8. Bending, kneeling, or stooping 
[1] 
[2] 
[3] 
9. Walking more than a mile 
[1]  
[2]  
[3]  
10. Walking several blocks  
[1]  
[2]  
[3]  
11. Walking one block 
[1] 
[2] 
[3]  
12. Bathing or dressing yourself 
[1] 
[2] 
[3] 
During the past 4 weeks, have you had any of the following problems with your work or other 
regular daily activities as a result of your physical health? 
(Circle One Number on Each Line) 
 
Yes  No  
13. Cut down the amount of time you spent on work or other activities 
1  
2  
14. Accomplished less than you would like 
1  
2  
15. Were limited in the kind of work or other activities  
1  
2  
16. Had difficulty performing the work or other activities (for example, it took extra 
effort)  
1  
2  

  
77
During the past 4 weeks, have you had any of the following problems with your work or other 
regular daily activities as a result of any emotional problems (such as feeling depressed or 
anxious)? 
(Circle One Number on Each Line) 
 
Yes No 
17. Cut down the amount of time you spent on work or other activities 
1  
2  
18. Accomplished less than you would like 
1  
2  
19. Didn't do work or other activities as carefully as usual 
1  
2  
20. During the past 4 weeks, to what extent has your physical health or emotional problems 
interfered with your normal social activities with family, friends, neighbors, or groups? 
(Circle One Number) 
Not at all 1 
Slightly 2 
Moderately 3 
Quite a bit 4 
Extremely 5 
21. How much bodily pain have you had during the past 4 weeks? 
(Circle One Number) 
None 1 
Very mild 2 
Mild 3 
Moderate 4 
Severe 5 
Very severe 6 

  
78
22. During the past 4 weeks, how much did pain interfere with your normal work (including 
both work outside the home and housework)? 
(Circle One Number) 
Not at all 1 
A little bit 2 
Moderately 3 
Quite a bit 4 
Extremely 5 
These questions are about how you feel and how things have been with you during the past 4 
weeks. For each question, please give the one answer that comes closest to the way you have 
been feeling. 
How much of the time during the past 4 weeks . . . 
(Circle One Number on Each Line) 
 
All of 
the 
Time 
Most of 
the 
Time 
A Good 
Bit of the 
Time 
Some of 
the Time 
A Little 
of the 
Time 
None of 
the Time 
23. Did you feel full of pep? 
1  
2  
3  
4  
5  
6  
24. Have you been a very 
nervous person? 
1  
2  
3  
4  
5  
6  
25. Have you felt so down in 
the dumps that nothing could 
cheer you up? 
1  
2  
3  
4  
5  
6  
26. Have you felt calm and 
peaceful? 
1  
2  
3  
4  
5  
6  
27. Did you have a lot of 
energy? 
1  
2  
3  
4  
5  
6  

  
79
28. Have you felt 
downhearted and blue? 
1  
2  
3  
4  
5  
6  
29. Did you feel worn out? 
1  
2  
3  
4  
5  
6  
30. Have you been a happy 
person? 
1  
2  
3  
4  
5  
6  
31. Did you feel tired?  
1  
2  
3  
4  
5  
6  
32. During the past 4 weeks, how much of the time has your physical health or emotional 
problems interfered with your social activities (like visiting with friends, relatives, etc.)? 
(Circle One Number) 
All of the time 1 
Most of the time 2 
Some of the time 3 
A little of the time 4 
None of the time 5 
How TRUE or FALSE is each of the following statements for you. 
(Circle One Number on Each Line) 
 
Definitely 
True 
Mostly 
True  
Don't 
Know  
Mostly 
False  
Definitely 
False  
33. I seem to get sick a little 
easier than other people  
1  
2  
3  
4  
5  
34. I am as healthy as anybody 
I know  
1  
2  
3  
4  
5  
35. I expect my health to get 
worse  
1  
2  
3  
4  
5  
36. My health is excellent  
1  
2  
3  
4  
5  

  
80
7. NIH Clinical Center guidelines for the management of allergic reactions 
 
ANAPHYLAXIS TREATMENT MEDICATION DOSE GUIDELINES – PRIMARY 
THERAPY 
DRUG 
CONCENTRATION 
ADULT DOSE (1) 
PEDIATRIC DOSE 
(1,2,3) 
First-line Treatment 
EPINEPHRINE AUTO-
INJECTOR 
(EpiPen) 
1:1,000 
(0.3 MG Fixed Dose Inj) 
0.3 mg 
> 25 Kg (3) 
IM (4) 
MAY REPEAT q 5 to 
15 mins 
0.3 mg 
> 25 Kg (3) 
IM (4) 
MAY REPEAT q 5 to 
15 mins 
EPINEPHRINE AUTO-
INJECTOR Jr 
(EpiPen Jr.) 
1:2,000 
(0.15 MG Fixed Dose 
Inj) 
N/A 
0.15 mg 
10 to 25 Kg(3) 
IM (3) or SQ 
MAY REPEAT q 5 to 
15 mins 
EPINEPHRINE AMPULE 
1:1,000 
(1 mg/mL) 
0.2 to 0.5 mg per dose 
IM (4) or Subcutaneous 
MAY REPEAT q 5 to 
15 mins 
 
 
0.01 mg/Kg per dose 
IM (4) or Subcutaneous  
MAY REPEAT q 5 to 
15 mins 
 
MAX SINGLE DOSE 
0.5 mg (0.5 mL) 
1. The diagnosis and management of anaphylaxis practice parameter: 2010 Update.  J Allergy Clin Immunol 2010;126: 477-80. 
2. The Harriet Lane Handbook, 18th Edition 
3. This differs from the package insert recommendation as per Guidelines for the Diagnosis and Management of Food Allergy in the 
United States: Report of the NIAID-Sponsored Expert Panel.  J Allergy Clin Immunol 2010;126: S1 – S58. 
4. The intramuscular (IM) route is preferred.  Epinephrine absorption in adults: Intramuscular versus subcutaneous injection.  J 
Allergy Clin Immunol 2001;108:871-3. 
SEE REVERSE SIDE FOR ADJUNCTIVE THERAPY➔ 
Approved by P&T Committee on February 24, 2011.  Revised on XX/XX/2011 
 
--------------------------------------------------------------------------------------------------------------------------------------
---------- 
 

  
81
7. Physician Global Assessment (PGA) 
 
Mark an X on the line below to indicate disease activity (independent of patient’s self 
assessment): 
 
 
Very good                                                                                                            Very bad   
 
 
 
 
 
 
 

  
82
8. 
Systemic Lupus International Collaborating Clincs/American College of 
Rheumatology (SLICC/ACR) Damage Index 
 
Score Item 
 
Ocular (either eye, by clinical assessment) 
0,1 Any cataract ever 
0,1 Retinal change or optic atrophy 
 
Neuropsychiatric 
0,1 Cognitive impairment (e.g. memory deficit, difficulty with calculation, poor concentration, 
difficulty in spoken or written language, impaired performance level) OR major psychosis 
0,1 Seizures requiring therapy for 6 months 
0,1,2 Cerebrovascular accident ever (score 2 if >1) 
0,1 Cranial or peripheral neuropathy (excluding optic) 
0,1 Transverse myelitis 
 
Renal 
0,1 Estimated or measured glomerular filtration rate < 50% 
0,1 Proteinuria > 3.5g/24h 
or 3 OR End-stage renal disease (regardless of dialysis or transplantation) 
 
Pulmonary 
0,1 Pulmonary hypertension (right ventricular prominence, or loud P2) 
0,1 Pulmonary fibrosis (physical and radiograph) 
0,1 Shrinking lung (radiograph) 
0,1 Pleural fibrosis (radiograph) 
0,1 Pulmonary infarction (radiograph) 
 
Cardiovascular 
0,1 Angina OR coronary artery bypass 
0,1,2 Myocardial infarction ever (score 2 if > 1) 
0,1 Cardiomyopathy (ventricular dysfunction) 
0,1 Valvular disease (diastolic murmur or systolic murmur > 3/6) 
0,1 Pericarditis for 6 months, OR pericardectomy 
 
Peripheral vascular 
0,1 Claudication for 6 months 
0,1 Minor tissue loss (pulp space) 
0,1,2 Significant tissue loss ever (e.g. loss of digit or limb)(score 2 if > 1 site) 
0,1 Venous thrombosis with swelling, ulceration, OR venous stasis 
 
Gastrointestinal 
0,1,2 Infarction or resection of bowel below duodenum, spleen, liver or gallbladder ever, for any 
cause (score 2 if > 1 site) 

  
83
0,1 Mesenteric insufficiency 
0,1 Chronic peritonitis 
0,1 Stricture OR upper gastrointestinal tract surgery ever 
0,1 Chronic pancreatitis 
 
Musculoskeletal 
0,1 Muscle atrophy or weakness 
0,1 Deforming or erosive arthritis (including reducible deformities, excluding avascular necrosis) 
0,1 Osteoporosis with fracture or vertebral collapse (excluding avascular necrosis) 
0,1,2 Avascular necrosis (score 2 if > 1) 
0,1 Osteomyelitis 
0,1 Tendon rupture 
 
Skin 
0,1 Scarring chronic alopecia 
0,1 Extensive scarring of panniculum other than scalp and pulp space 
0,1 Skin ulceration (excluding thrombosis for > 6 months) 
0,1 Premature gonadal failure 
0,1 Diabetes (regardless of treatment) 
0,1,2 Malignancy (exclude dysplasia) (score 2 if >1 site) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

  
84
9. 
Tabulation of Radiation Doses to Subjects 
Radioactive Material or Procedure: F18FDG, 2 studies/duration of trial 
Administered quantity or view of exposure: 10mCi 
Subject Age: Adult   
 
 
  
ORGAN  
RADIATION DOSE (rem)  
Per single Administration         Per Year (12 mos.)  
Adrenals  
 0.48  
 0.96  
Brain  
0.70  
1.40  
Breasts  
0.34  
0.68 
Esophagus 1  
 0.44  
 0.88 
Gallbladder Wall  
 0.49  
 0.98 
GI-tract: Lower Large Intestine  
 0.51  
 1.01  
 Small Intestine  
 0.47  
 0.94  
 Stomach  
 0.47  
 0.94 
 Upper Large Intestine  
 0.46  
 1.84 
 Colon 2  
0.48  
0.96 
Heart Wall  
 2.20  
 4.40  
Kidneys  
 0.74  
 1.48  
Liver  
 0.58  
1.08  
Lungs  
 0.64  
 1.28  
Muscle  
 0.39  
 0.78  
Ovaries  
 0.53  
1.03  
Pancreas  
 0.96  
 1.92  
Red Marrow  
 0.47  
0 .94  
Bone Surfaces  
 0.41  
 0.82  
Skin  
 0.30  
 0.60 
Spleen  
 1.40  
 2.80  
Testes  
 0.41  
 0.82 
Thymus  
 0.44  
 0.88  
Thyroid  
 0.39  
 0.78  
Urinary Bladder Wall 3  
 3.20  
 6.40  
Lens of Eye4  
0.30  
0.60 
Uterus  
 0.62  
 1.24  
 
 EFFECTIVE DOSE  
 
 0.62  
 
 1.24  
NOTES:  
1. Since no dose is explicitly tabulated for esophagus, thymus dose is used (as per ICRP80)  
2. Colon Dose estimated by [0.57 (DoseULI) + 0.43 (DoseLLI)] (as per ICRP 80).  
3. Dynamic urinary bladder model used; void interval of 1.5 hours  
4. Lens of Eye Dose does not contribute to effective dose  
 
DOSIMETRY SOURCE: Coronado, L. (F-18)FDG Internal Radiation Dosimetry for use in Research Protocols, 10/30/91, NIH,RSB; 
updated to ICRP 103 by Corina Millo, May 2010 (note some remainder organs doses are not defined;10 are included)  
 

  
85
Radioactive Material or Procedure: attenuation whole body CT, mCT Siemens Biograph.  
Administered quantity or view of exposure: 120 kV, 92mA, pitch=0.8, collimation=19.2, 2 
scans/duration of trial (8 month trial). Subject Age: Adults 
 
  
ORGAN  
RADIATION DOSE (rem)  
Per single Administration     Per Year (12 mos.) 
Adrenals  
0.58  
1.16  
Brain  
0.68  
1.36  
Breasts  
0.56  
1.12  
Esophagus 1  
0.75  
1.50  
Gallbladder Wall  
0.62  
1.24  
GI-tract: Lower Large Intestine  
0.66  
1.32  
 Small Intestine  
0.58  
1.16  
 Stomach  
0.64  
1.28  
 Upper Large Intestine  
0.60  
1.20  
 Colon 2  
0.63  
1.26  
Heart Wall  
0.67  
1.34  
Kidneys  
0.67  
1.34  
Liver  
0.62  
1.24  
Lungs  
0.69  
1.38  
Muscle  
0.99  
1.98  
Ovaries  
0.59  
1.18  
Pancreas  
0.56  
1.12  
Red Marrow  
0.57  
1.14  
Bone Surfaces  
1.84  
3.68  
Skin  
0.93  
1.86  
Spleen  
0.60  
1.20  
Testes  
1.34  
2.68  
Thymus  
0.75  
1.50  
Thyroid  
1.00  
2.00  
Urinary Bladder Wall  
0.73  
1.46  
Lens of Eye3  
0.81  
1.62  
Uterus  
0.68  
1.36  
 
 EFFECTIVE DOSE  
 
0.70  
 
1.40  
  
DOSIMETRY SOURCE: CT dosimetry by Craig Baker, physicist, Aug. 2012, based on ICRP 103.  
1. Since no dose is explicitly tabulated for esophagus, thymus dose is used (as per ICRP80)  
2. Colon Dose estimated by [0.57 (DoseULI) + 0.43 (DoseLLI)] (as per ICRP 80).  
3. Lens of Eye Dose does not contribute to effective dose