Conditions: Diabetes Mellitus, Type II
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 10
Healthy volunteers: no

Brief summary:
Diabetic complications affecting the eyes, kidneys, and nerves are difficult to arrest once in progress. Recent evidence that fenofibrate confers a robust yet unexpected benefit in diabetic retinopathy offers an important translational research opportunity. The investigator's global proteomic study will provide new clues as to how fenofibrate protects vulnerable tissues, and will spur discovery of targets for new therapeutic interventions.

Detailed description:

Arms:
arm 1: Single arm. Participants will take study medication

Interventions: intervention 1: Fenofibrate
Intervention descriptions: intervention 1: 40 patients (20 males and 20 females) aged 18-70 years, with type 2 diabetes and triglycerides \>150 mg/dL will be recruited. They will have a physical exam and blood draw at visit 1. Participants will receive 160 mg fenofibrate to be taken orally daily for six weeks. They will return for a second visit after 6 weeks and have blood draw as follow up.

Protocol document:
ICF_002.pdf: 
 
 








 
 






 
 


 
 


 
 


 
 

Prot_001.pdf: 
 
 
 
PROTOCOL TITLE: Fenofibrate in Type 2 Diabetes- Novel Biomarkers and 
Mechanisms 
NCT03829514 
IRB approval date (most recent version): 11/14/2019 
     


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PROTOCOL TITLE: Fenofibrate in Type 2 Diabetes- Novel Biomarkers and 
Mechanisms 
 
PRINCIPAL INVESTIGATOR: Timothy J. Lyons, MD 
 


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1.0 
Objectives / Specific Aims 
Fenofibrate, a safe and long-established lipid-lowering agent, was recently discovered to 
have unexpected yet dramatic therapeutic effects on diabetic retinopathy (DR) in two large 
clinical trials (1,2). Intriguingly, the retinal benefits were independent of plasma lipids, 
suggesting novel mechanisms of action. Furthermore, evidence indicates that fenofibrate’s 
beneficial effects extend to many other microvascular complications of diabetes.  
Our aims are: 1) to recruit a cohort of 40 well-characterized fenofibrate-naïve patients with 
type 2 diabetes who will receive oral fenofibrate 160 mg/day for six weeks; this work will 
establish a clinical sample repository, collected immediately prior to and after treatment, to 
enable us to 2) characterize the global plasma proteome before and after fenofibrate 
treatment and future follow-up studies. We expect to gain novel insights into the systemic 
effects of fenofibrate on the pathophysiologic processes that drive diabetic vascular 
complications. This will generate new hypotheses about the common root causes of diabetic 
complications and complement data being accrued in ongoing studies of retinopathy, 
nephropathy, atherosclerosis, and complications of pregnancy that integrate human data with 
and animal/cellular model systems. The ultimate translational impact of the work will be the 
development of proactive means to block a range of complications early in their evolution, 
either through the development of more selective targeted therapies, and/or finding new 
disease indications for existing drugs.   
To translate this into new preventive and/or therapeutic measures, we hypothesize: 1) that 
fenofibrate has mechanisms of action beyond PPARα agonism that attenuate microvascular 
complications of diabetes; and 2) that observable treatment-induced changes in the 
constituents of plasma will reflect the underlying effects of the drug on target tissues.  
 
2.0 
Background 
Work in my laboratory is directed at improving our understanding of the vascular 
complications of diabetes, and our work relates to vascular disease in general (i.e. to 
cardiovascular, cerebrovascular, and peripheral vascular disease).   
The complications of diabetes, which range from well-recognized conditions such as DR, to 
less obvious ones such as hepatic steatosis and fibrosis, remain challenging and without truly 
satisfactory therapies. For example, DR is a leading cause of blindness worldwide, and with 
the ongoing epidemic of diabetes, promises to constitute a major global health problem for 
the foreseeable future. Current standard of care includes anti-VEGF antibodies and steroids 
(both via invasive intraocular injection), laser photocoagulation, and vitrectomy, all of which 
are useful only in the late stages of the disease. By that time, irreversible retinal damage has 
occurred, and some therapies actually involve further retinal destruction. Similar 
considerations apply to diabetic renal disease and neuropathy. Such 'crisis management' is 
necessary and valuable, but it would be vastly preferable to stop complications at an earlier 
stage using a convenient, safe, orally available drug. The recent discovery that fenofibrate is 
beneficial for DR and other microvascular complications (1,2) brings hope, and 
tantalizingly, the drug’s efficacy across different complications suggests unrecognized 
common disease pathways (3-7). Still, the lack of correlation between its microvascular 
protective effects and its lipid-lowering activity raises questions (1,2). Presumably, the 
relevant mechanism(s) of action are unique to fenofibrate, a PPARα agonist, and not shared 
with either PPARγ agonists, e.g. rosiglitazone and pioglitazone, that enhance insulin 
sensitivity, or HMG-CoA reductase inhibitors (statins), that lower lipid levels by 


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upregulating hepatic LDL receptors. It is also unclear whether the benefits of fenofibrate are 
mediated via PPARα or some novel mechanisms of action (8-13). In fact, recent data from 
our group using a human retinal pigment epithelial (RPE) barrier model showed that 
fenofibrate, but not other PPARα agonists (WY14643, gemfibrozil, bezafibrate), attenuated 
the toxic effects of oxidized LDL on barrier integrity (14). Thus, fenofibrate may or may not 
be the answer, but it certainly provides important clues, and our lack of understanding of its 
systemic effects on the diabetic milieu is a barrier to the development of new treatments. 
Discovery of the mechanisms and pathways of action could yield a new generation of drugs 
that can protect multiple tissues from the effects of diabetes, blocking disease development 
proactively instead of reacting to end-stage complications. 
 
3.0 
Intervention to be studied  
Fibrates belong to a class of drugs that exert their effects by activating peroxisome 
proliferator activated receptor α (PPARα) (15). These drugs reduce the concentration of 
plasma triglyceride (TG) by 30-50% and raise the level of high-density lipoprotein 
cholesterol (HDL-C) by 2-20% (15-17). The first member of the class, clofibrate, was 
introduced in the 1960’s and became available in the US in 1967 (18). Fenofibrate (the 
original generic name of which was procetofene), a third-generation fibrate, was introduced 
in clinical practice in 1975 (19). Fenofibrate is now one of the most commonly prescribed 
fibrates worldwide, indicated for the treatment of hypercholesterolemia, combined 
dyslipidemia, remnant hyperlipidemia, endogenous hyperlipidemia (hypertriglyceridemia) 
and mixed hyperlipidemia (Friedrickson type IIa, IIb, III, IV, and V dyslipidemia, 
respectively) (19). 
 
Fenofibrate is FDA-approved for oral administration. The primary indication is for use in 
adult patients with hypercholesterolemia or mixed dyslipidemia. The standard dose of 
fenofibrate, 160 mg/day that was used in the ACCORD study (2) will be replicated in the 
current study. Fenofibrate is not FDA approved for the treatment of diabetic retinopathy.  
 
4.0 
Study Endpoints (if applicable) 
 
Specific endpoints have not been predetermined. 
 
5.0 
Inclusion and Exclusion Criteria/ Study Population 
Type 2 diabetes is highly prevalent in our endocrine clinic population and recruitment of 
sufficient numbers of volunteer subjects should be easily achieved. We anticipate recruitment 
of subjects to occur over six months, such that all study samples will be available for LC-
MS/MS analysis within eight months of start-up. We have a long track record of collaboration 
with the SCTR NEXUS facility, e.g. through DCCT/EDIC, and are familiar with their policies 
and procedures. While our sample size is adequate for discovery research related to the 
systemic effects of fenofibrate treatment, any human study of outcomes would require a much 
larger cohort and longer period of follow-up. All subjects will be screened by their provider 
to ensure the eligibility for the study according to the criteria outlined below. 
 
 
 
Inclusion criteria: 
 
• Male or female aged ≥18 and ≤ 70 years 


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• Type 2 diabetes of at least one year’s duration; stable glycemic 
control (no more than 1.0% change in HbA1c in the previous six 
months, but no limit on HbA1c) 
• Triglycerides >150 mg/dL (in the previous six months) 
 
Exclusion criteria: 
 
• Previous use of Fenofibrate or other fibrates 
• Pregnancy/lactation 
• Active malignancy 
• Recent cardiac event or congestive heart failure 
• Active liver disease (LFT’s > 2x’s normal value) 
• Significant renal impairment (serum creatinine > 2mg/dl) 
• Current warfarin use 
 
6.0 
Number of Subjects 
For this study, 40 patients (20 males and 20 females) aged 18-70 years, matching the ethnic 
composition representative of the demographics of SC, will be recruited from the cohort 
attending our Endocrinology Clinics at MUSC.   
7.0 
Setting 
Participants will be recruited and consented at MUSC’s Endocrinology clinic. Procedures 
at both visits will be performed at SCTR NEXUS nursing clinic.  
 
8.0 
Recruitment Methods 
Participants will be approached by their treating physician (in this case either the PI or one of 
the co-investigators) from the patients attending the MUSC Endocrinology clinics. 
Advertisements will be placed in MUSC Endocrinology clinics and MUSC elevators. 
ResearchMatch.org will be utilized as a recruitment tool for this protocol.  ResearchMatch.org 
is a national electronic, web-based recruitment tool that was created through the Clinical & 
Translational Science Awards Consortium in 2009. 
 
9.0 
Consent Process 
Potential participants will be identified by treating physicians (PI/Co-PI’s) from the patients 
attending the MUSC Endocrinology clinics. The PI and/or IRB-approved personnel will 
explain the nature of the study to individuals who meet criteria. Individuals who take part in 
this study must choose to participate voluntarily and must provide signed consent. Potential 
participants will be provided IRB-approved consent forms, the opportunity to read it, and 
the opportunity to ask questions. They will be consented before undergoing any study-
related procedures. They will be encouraged to take time to discuss study participation with 
family and friends. Once the informed consent form is signed, participants will be actively 
enrolled in the study.  


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By an analogous process, written permission will be obtained for the HIPAA document. IRB 
approved personnel will give a copy of the signed informed consent form and the HIPAA 
form, to the participant.  Informed consent forms will be signed, and copies distributed as 
usual (PI files and to the participant), with strict regard for confidentiality.  
 
10.0 Study Design / Methods 
 
Regularly scheduled Endocrinology clinic visit: 
• If participants qualify and agree to participate, they will be provided an informed consent 
form, and a HIPAA form and provided the opportunity to sign agreement to participate.  
• Visit one will then be scheduled for participants at the SCTR NEXUS clinic by the 
research coordinator.  
• Participants will be instructed on fasting protocol following consent process and prior to 
visit one. 
Visit 1: 
• Upon arrival at the SCTR NEXUS clinic, a physical examination will be performed by 
either the PI or co-investigators. Clinical data will be recorded to include demographic 
information, diabetes complication status and medications, and anthropometric 
information. 
• Women of childbearing potential will have urine β-HCG measured (+pregnancy 
outcome is criteria for exclusion) and will be required to use the following as acceptable 
methods for birth control throughout the study: 1) barrier methods including male and 
female condoms, diaphragm, cervical cap and contraceptive sponge, 2) hormonal 
methods including birth control pills, vaginal ring (NuvaRing), contraceptive implant 
(Nexplanon), contraceptive injection (Depo-Provera) and birth control patch, 3) 
intrauterine devices (IUDs) such as the copper IUD (ParaGard) and the hormonal IUD 
(Mirena, Skyla, Kyleena, others), 4) sterilization to include tubal ligation or the Essure 
system for women, and vasectomy for men, or 5) avoiding sexual activity that could 
cause you to become pregnant. 
• Fasting blood (80ml) will be obtained for baseline labs (BUN, Cr, urine microalbumin, 
LFTs, CPK, Lipid Profile, HbA1c, TSH, C-peptide) and processed to yield heparin, 
EDTA, and citrate-plasma, serum, and pellets (sufficient for all planned analyses). A 
timed morning urine sample will be collected with the volume recorded. Samples will 
be stored in ultra-low freezers for proteomics and subsequent confirmatory assays (by 
ELISA). 
• Participants will then be given the study medication (160 mg fenofibrate to be taken 
orally daily for six weeks) by the research physician. As well, they will receive 
instruction on possible side effects and proper protocol for reporting unexpected 
symptoms. 
• Following venipuncture, participants will be given a choice of breakfast foods from 
which to choose by the IRB approved personnel and a place to eat.   
• Participants will receive a gift card at the completion of visit one in the amount of $25.  
• Participants will be scheduled for visit 2 in six weeks. 
Visit 2: 
• Upon arrival at the SCTR NEXUS clinic, a physical examination will be performed by 
either the PI or co-investigators. Clinical data will be recorded to include demographic 
information, and medications, and anthropometric information. 
• Fasting blood (80ml) will be obtained for follow-up labs (BUN, Cr, urine microalbumin, 
LFTs, CPK, Lipid Profile, HbA1c, TSH, C-peptide) and processed to yield heparin, 


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EDTA, and citrate-plasma, serum, and pellets (sufficient for all planned analyses). A 
timed morning urine sample will be collected with the volume recorded. Samples will be 
stored in ultra-low freezers for proteomics and subsequent confirmatory assays (by 
ELISA). 
• Participants will then undergo an assessment of adverse events and study drug 
compliance, which will be determined by pill count. 
• Following venipuncture, participants will be given a choice of breakfast foods from 
which to choose by the IRB approved personnel and a place to eat.   
• Participants will receive a gift card at the completion of visit two in the amount of $25.  
• The plasma proteomic signature will be generated by LC-MS/MS (n=80 proteomes) of 
each subject before and after fenofibrate treatment. Bioinformatic approaches will then 
be employed based on geneset enrichment analysis to identify the biological 
processes/signaling networks impacted by treatment. 
 
                      
 
 
 
 
 
 
 
 
 
11.0 Collection and Banking (if applicable) 
For this work, fasting blood samples (80 ml) will be collected at each of two visits, and 
processed via centrifugation to yield heparin, EDTA, and citrate-plasma, serum, and pellets 
(sufficient for all planned analyses). A timed morning urine sample will be collected with 
the volume recorded. Samples will be alphanumerically coded and correlated to the stored 
samples. Codes have no association to the participant’s identity. Samples will be stored in 
ultra-low freezers for proteomics and subsequent confirmatory assays (by ELISA). Links to 
participant identity (including demographic and clinical information) will be accessible to 
the PI and research coordinator only and links will be destroyed at the study’s conclusion. 
Consent forms and any associated hard documents will be kept in a locked cabinet, in the 
locked office of the PI.  
Specimen/Banking for Future Use 
The samples will be stored in ultra-low freezers maintained by the Lyons lab on the 9th floor 
of the Clinical Science Building (CSB). The freezers are housed in room 912, which remains 
locked and accessible only to members of the Lyons lab. Samples will be alphanumerically 
coded and linked to clinically pertinent information. The samples will be stored indefinitely 
or until completely used. 
Future research may be conducted by Dr. Lyons or by other researchers who obtain IRB 
approval for their research. There is potential in the future for genetic analyses of samples 
and therefore the option to opt out will be made available to participants in the informed 
consent form.  
 


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12.0 Data Management  
Participants’ privacy will be protected via alpha-numeric coding of the data once obtained. 
Names of participants will not be entered in the database, instead they will be identified by 
assigned code. Information linking the code to the participant will be kept securely by the 
PI. There will be no link to the participant after study completion. The consent forms, which 
are the possible way to breach confidentiality, will be stored in the PI’s office as well in a 
secure location. All clinical data pertaining to the study will be stored online in REDCap. 
  
13.0 Provisions to Monitor the Data to Ensure the Safety of Subjects (if 
applicable) 
Adverse event (AE) reporting Adverse events anticipated in this study that involves a fasting 
blood draw and potential side effects of fenofibrate (for example myalgias, elevation of liver 
enzymes) are few.  Risks associated with drawing blood from the arm include momentary 
discomfort and/or bruising.  Infection, excess bleeding, clotting, or fainting is possible, 
although unlikely. 
Risk minimization These risks will be minimized by allowing only well-trained clinical 
research staff of the SCTR NEXUS facility to perform study procedures and testing 
according to standard practice, and by making sure study participants clearly understand 
study procedures before and during the study protocol.  
The blood draw will be performed with the subject resting and recumbent.  Adequate rest 
time will be provided after the blood draw to avoid a hypotensive response.  Breakfast will 
be provided at the end of blood draw. Participants will be instructed to report any concerning 
symptoms. If necessary, adverse events  will be reported to the PI and the IRB. Unanticipated 
non-serious adverse events must be reported from the investigator to the IRB no later than 
10 working days after the event or notification to the investigator that the event has occurred, 
and serious adverse events will be reported within 24 per MUSC IRB guidelines. In absence 
of moderate or serious adverse events, reports of study progress will be submitted to the IRB 
for review on an annual basis. 
The potential benefits of the research, which may include lowering of cholesterol and the 
identification of major new risk factors for complications of diabetes, are considered to 
outweigh the minimal risks involved. 
Monitoring of Study Implementation and Progress Periodic assessments will be performed 
to assess recruitment and retention of study participants, data quality, and risk-benefit ratio. 
The recruitment goal for this study is to recruit over the period of 6 months 40 (20 males and 
20 females) type 2 diabetic participants with elevated triglycerides. Data checks will be 
performed by Drs. Lyons and Leyva. If additional information regarding the study’s risk-
benefit ratio becomes available, the PI will be responsible for notifying the IRB, sponsor, 
and study participants, as indicated.  
A record will be kept of patients who were considered for enrollment but not enrolled e.g., 
patient screening log to establish that the participant population was selected without bias. 
 
14.0 Withdrawal of Subjects (if applicable) 
Participants may be discontinued from study treatment at any time. Specific reasons for 
discontinuation from this study are: 


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• Study treatment not tolerated and raising safety concerns. Non-toleration of study 
drug could include any symptoms of myalgia or at the investigator’s discretion. 
• Voluntary discontinuation by the participant who is at any time free to discontinue 
their participation in the study, without prejudice to further treatment. 
• Safety reasons as judged by the investigator. 
• Occurrence of an adverse event, which in the opinion of the investigator warrants the 
participant’s discontinuation.  
• If at any time the participant experiences unexplained muscle pain, tenderness or 
weakness, study medication should be discontinued.  
• Participant lost to follow-up. 
• Pregnancy. 
• Deterioration in the participant’s condition which in the opinion of the investigator 
warrants study medication withdrawal. 
Participants who discontinue will be asked the reason(s) for their discontinuation and the 
presence of any adverse events. The participant must return all unused investigational 
products to the investigator. The number of encapsulated tablets returned must be checked 
against the number dispensed to determine participant compliance.  
15.0 Risks to Subjects 
Potential risks are low and include: 
• Research records will be confidential. There is a small risk of loss of confidentiality, 
but records will be stored, locked in the PI’s office as a means of preventing this loss 
of confidentiality. 
• Hazards of venipuncture:  pain, bruising, inflammation or clot formation, syncope. 
Procedures for minimizing potential risks include the use of aseptic techniques for 
venipuncture, and drawing blood with subjects in the recumbent position.  Subjects 
will be provided explanation in advance about laboratory test procedures to be 
performed. The subject’s results will be known only to the investigators.   
• Fenofibrate use has been associated with an increased risk of muscle pain, abnormal 
results in tests of liver function and allergic reaction. Participants will be instructed 
on risks and provided protocol for reporting with medication administration. 
16.0 Potential Benefits to Subjects or Others 
Fenofibrate lowers triglyceride levels, and has been found to confer unrelated and 
unexpected therapeutic benefit on diabetic retinopathy in two large clinical trials on type 2 
diabetic subjects.   Additional clinical data suggest that fenofibrate has beneficial effects in 
diabetic nephropathy, limb ischemia, diabetic neuropathy, hepatic fibrosis, cancer, and other 
conditions.  However, these studies involve longer-term use of the drug, and there is no 
evidence that short-term use, as in the present study, will confer any benefit. 
 
17.0 Drugs or Devices (if applicable)  
All study medication will be procured from MUSC’s Pharmacy Distribution Center. It will 
be labeled, in its original packaging according to FDA standards, by the research 
coordinator. Medications will be stored securely at room temperature in the Lyons lab in a 
locked cabinet. All medications will be dispensed to participants by an IRB-approved, 


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licensed practitioner. All medication-related procedures will be recorded on a drug 
accountability form.  
 
 
 
 
References 
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Tse D, Williamson E, et al. (2007) Effect of fenofibrate on the need for laser treatment for diabetic 
retinopathy (FIELD study): a randomised controlled trial. Lancet. 370: 1687-1697.  
2. ACCORD Study Group; ACCORD Eye Study Group, Chew EY, Ambrosius WT, Davis MD, Danis 
RP, Gangaputra S, Greven CM, Hubbard L, Esser BA, Lovato JF, Perdue LH, Goff DC Jr, 
Cushman WC, Ginsberg HN, Elam MB, Genuth S, Gerstein HC, Schubart U, Fine LJ. (2010) 
Effects of medical therapies on retinopathy progression in type 2 diabetes. N Engl J Med. 363: 
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9. Miranda S, González-Rodríguez Á, García-Ramírez M, Revuelta-Cervantes J, Hernández C, Simó 
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10. Trudeau K, Roy S, Guo W, Hernández C, Villarroel M, Simó R, Roy S. (2011) Fenofibric acid 
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Invest Ophthalmol Vis Sci. 52: 6348-6354.  
11. Roy S, Kim D, Hernández C, Simó R, Roy S. (2015) Beneficial effects of fenofibric acid on 
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permeability associated with diabetic retinopathy. Exp Eye Res. 140: 124-129.  
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prevents retinal pigment epithelium disruption induced by interleukin-1β by suppressing AMP-
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13. Omae T, Nagaoka T, Tanano I, Kamiya T, Yoshida A. (2012) Fenofibrate, an anti-dyslipidemia 
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