Clinical trial NCT02455336
Conditions: Spinal Cord Injury Dyslipidemia
Keywords: tetraplegia paraplegia hypertriglyceridemia hyperlipidemia peroxisome proliferator-activated receptor alpha
Sponsor: VA Office of Research and Development
Start date: 2015-05-18; Completion date: 2018-08-01
Enrollment: 23 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Cardiovascular disease-related morbidity in persons with spinal cord injury (SCI) occurs earlier in life, at a greater prevalence than that of the general population, and is the primary cause of death after the first year of injury. During the chronic phase of SCI, a characteristic dyslipidemia emerges, which is characterized by low serum high density lipoprotein cholesterol (HDL-C) concentrations, with values often qualifying to be an independent risk factor for coronary artery disease, and elevations in serum triglycerides (TG). Serum low density lipoprotein cholesterol concentrations in those with SCI are usually similar to those of the general population. The current proposal in persons with SCI aims to determine the safety and efficacy of short-term fenofibrate treatment, an anti-lipid medication whose primary action lowers serum TG and raises serum HDL-C levels.

Detailed description:
Although considered a modifiable risk factor for coronary artery disease (CAD) in the general population, the magnitude of physical activity required to promote cardiorespiratory fitness and a clinically meaningful change in blood-derived biomarkers of CAD is not achievable in those with a severe physical disability, such as with immobilizing paralysis from spinal cord injury (SCI). During the chronic phase of SCI, a characteristic dyslipidemia emerges, with mean serum high density lipoprotein cholesterol (HDL-C) concentrations \<40 mg/dl, a threshold level for HDL-C that is appreciated to be an independent risk factor for CAD, elevations in triglycerides (TG) to concentrations at, or near, target values for the general population that trigger clinical intervention, and low density lipoprotein cholesterol (LDL-C) concentrations that are within the normal range. It should not be a surprise that cardiovascular disease (CVD)-related morbidity in persons with SCI occurs earlier in life, at a greater prevalence than that of the general population, and is the primary cause of death after the first year of injury. Population-based epidemiological studies are unavailable for clinical guidance because of the relatively low incidence rates for SCI. Clinical target values used to initiate treatment in the general population may be inappropriate in those with SCI because of their unique pathophysiology. In the absence of significant physical activity and lifestyle modifications, it would seem that appropriate pharmaceutical options are needed to properly manage markers of CVD-related risk in persons with SCI. To date, there is limited empirical evidence to support the use of lipid-lowering treatments in persons with SCI.

Fenofibrate is a fibric acid derivate that activates peroxisome proliferator-activated receptor and lipoprotein lipase, leading to enhanced elimination of TG from plasma. In clinical trials where fenofibrate was used as a monotherapy, serum TG concentrations fell 41-53%, very low density lipoprotein (VLDL) fell 38-52%, LDL-C decreased 6-20%, and HDL-C improved by as much as 20%. In consideration for the nature of dyslipidemia in persons with SCI, fenofibrate appears to be an appropriate first-line agent for treatment in this cohort, especially because most of those with SCI have LDL values that are within the clinically acceptable range. In the general population, standard clinical practice for lipid-lowering treatment with fenofibrate monotherapy follows a known and clinically accepted timeline to monitor safety and to determine therapeutic efficacy. It is recommended that, if after 2 months of continuous therapy there are no beneficial changes to the lipoprotein profile, that treatment be discontinued (i.e., non-responders). Similarly, several large clinical trials have demonstrated that the peak therapeutic effects of fenofibrate are observed after 12-16 weeks of treatment (i.e., responders). The proposed study will test the efficacy of administering fenofibrate to persons with SCI, a severely immobilized cohort that does not have established clinical practice guidelines to treat dyslipidemia and appears to have unique considerations that may be hypothesized to call for a more disease-specific approach for care. If successful, the treatment will reduce clinical markers of CVD-related risk by modifying the concentration and number of particles that are known to contribute to incident cardiac events and mortality. It is anticipated that the insight gained from this investigation will provide clinicians with a proof-of-concept for instituting appropriate use of lipid lowering agents to treat the dyslipidemia that has been well described in persons with SCI.

Arms: arm 1: Subjects with adverse TG concentrations (i.e., paraplegia: \>/=135 mg/dl; tetraplegia \>/=115 mg/dl) will be randomized to receive once daily fenofibrate therapy (i.e., 145 mg) for 4 months arm 2: Subjects with adverse TG concentrations (i.e., paraplegia: \>/=135 mg/dl; tetraplegia \>/=115 mg/dl) will be randomized to receive no therapy for 4 months
Interventions: intervention 1: Fenofibrate intervention 2: No intervention
Intervention descriptions: intervention 1: Fenofibrate is a peroxisome proliferator-activated receptor alpha agonist that is demonstrated to reduce triglyceride concentrations in the blood. intervention 2: A cohort of participants will be randomized to receive no study drug, but will engage in study encounters.

Protocol documents:
Prot_SAP_000.pdf: 
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An Open Label Safety and Efficacy Trial of Fenofibrate in Persons with SCI 
 
Lay Abstract 
Cardiovascular disease-related morbidity in persons with spinal cord injury (SCI) occurs 
earlier in life, at a greater prevalence than that of the general population, and is the primary 
cause of death after the first year of injury.  During the chronic phase of SCI, a characteristic 
dyslipidemia emerges, which is characterized by low serum high density lipoprotein 
cholesterol (HDL-C) concentrations, with values often qualifying to be an independent risk 
factor for coronary artery disease, and elevations in serum triglycerides (TG). Serum low 
density lipoprotein cholesterol concentrations in those with SCI are usually similar to those of 
the general population. The current proposal in persons with SCI aims to determine the safety 
and efficacy of short-term fenofibrate treatment, an anti-lipid medication whose primary 
action lowers serum TG and raises serum HDL-C levels. 
 
Scientific Abstract   
Although considered a modifiable risk factor for coronary artery disease (CAD) in the 
general population, the magnitude of physical activity required to promote cardiorespiratory 
fitness and a clinically meaningful change in blood-derived biomarkers of CAD is not 
achievable in those with a severe physical disability, such as with immobilizing paralysis from 
spinal cord injury (SCI).  During the chronic phase of SCI, a characteristic dyslipidemia 
emerges, with mean serum high density lipoprotein cholesterol (HDL-C) concentrations <40 
mg/dl, a threshold level for HDL-C that is appreciated to be an independent risk factor for 
CAD, elevations in triglycerides (TG) to concentrations at, or near, target values for the general 
population that trigger clinical intervention, and low density lipoprotein cholesterol (LDL-C) 
concentrations that are within the normal range.  It should not be a surprise that 
cardiovascular disease (CVD)-related morbidity in persons with SCI occurs earlier in life, at a 
greater prevalence than that of the general population, and is the primary cause of death after 
the first year of injury. Population-based epidemiological studies are unavailable for clinical 
guidance because of the relatively low incidence rates for SCI.  Clinical target values used to 
initiate treatment in the general population may be inappropriate in those with SCI because of 
their unique pathophysiology.  In the absence of significant physical activity and lifestyle 
modifications, it would seem that appropriate pharmaceutical options are needed to properly 
manage markers of CVD-related risk in persons with SCI.  To date, there is limited empirical 
evidence to support the use of lipid-lowering treatments in persons with SCI. 
Fenofibrate is a fibric acid derivate that activates peroxisome proliferator-activated 
receptor α and lipoprotein lipase, leading to enhanced elimination of TG from plasma.  In 
clinical trials where fenofibrate was used as a monotherapy, serum TG concentrations fell 41-
53%, very low-density lipoprotein (VLDL) fell 38-52%, LDL-C decreased 6-20%, and HDL-C 
improved by as much as 20%.  In consideration for the nature of dyslipidemia in persons with 


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SCI, fenofibrate appears to be an appropriate first-line agent for treatment in this cohort, 
especially because most of those with SCI have LDL values that are within the clinically 
acceptable range.  In the general population, standard clinical practice for lipid-lowering 
treatment with fenofibrate monotherapy follows a known and clinically accepted timeline to 
monitor safety and to determine therapeutic efficacy.  It is recommended that, if after 2 months 
of continuous therapy there are no beneficial changes to the lipoprotein profile, that treatment 
be discontinued (i.e., non-responders).  Similarly, several large clinical trials have 
demonstrated that the peak therapeutic effects of fenofibrate are observed after 12-16 weeks of 
treatment (i.e., responders).  The proposed study will test the efficacy of administering 
fenofibrate to persons with SCI, a severely immobilized cohort that does not have established 
clinical practice guidelines to treat dyslipidemia and appears to have unique considerations 
that may be hypothesized to call for a more disease-specific approach for care.  If successful, 
the treatment will reduce clinical markers of CVD-related risk by modifying the concentration 
and number of particles that are known to contribute to incident cardiac events and mortality.  
It is anticipated that the insight gained from this investigation will provide clinicians with a 
proof-of-concept for instituting appropriate use of lipid lowering agents to treat the 
dyslipidemia that has been well described in persons with SCI.   
Goals and Objectives 
In individuals with spinal cord injury (SCI): 
Primary Aim:   
1. To determine the efficacy of fenofibrate monotherapy after 2 months of treatment to 
improve the lipoprotein profile; a successful response will be defined as a 25% reduction in the 
serum TG concentration at 2 months.  This approach will permit the determination of the 
percent of subjects who show drug efficacy (i.e., responders) versus those who are non-
responders after 2 months of treatment, when drug administration will be discontinued if 
therapeutic efficacy is deemed suboptimal. 
 
2. To determine the efficacy of fenofibrate monotherapy to lower TG concentration at 4 months 
of treatment, when the peak therapeutic efficacy to drug treatment has been reported to occur.  
Lipid profiles will be performed in the drug responder and control groups. 
 
Secondary Aim: To describe the effects of fenofibrate monotherapy on lipoprotein particle 
number and size by nuclear magnetic resonance spectroscopy performed in non-responders 
and responders at 2 months of treatment, when drug treatment will be discontinued for lack of 
efficacy to agent. Lipids in responders and control groups will be studied by NMR 
spectroscopy at 4 months of treatment, which will be at the termination of the proposed 
treatment period. 
 


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Tertiary Aim: To determine the safety of fenofibrate monotherapy. Documentation and 
description of adverse events will be obtained in subjects who have received drug treatment 
compared to events occurring in the control group. 
 
Target Population  
It is estimated that approximately 100 participants with SCI will be screened to identify 30 
eligible and appropriate SCI participants (i.e., 20 treatment, 10 control) who will agree to 
participate in the study (Screening data from BAU-11-075 will be used to minimize the number 
of procedures performed, if it is not older than 45 days). To be considered eligible for the 
study, participants must meet the following eligibility criteria: 
 
Inclusion Criteria: 
(1) Male or female, age 21 to 69;  
(2) Chronic (e.g., duration of injury at least 6 months), stable SCI (regardless of level of 
neurological lesion); 
(3) American Spinal Injury Association Impairment Scale (AIS) designation of A, B or C; and  
(4) TG concentration ≥135 mg/dl (paraplegia) or ≥115 mg/dl (tetraplegia). 
 
Exclusion Criteria (These exclusion criteria were carefully chosen to minimize subject risk and/or 
confounding factors that are known to affect study endpoints): 
(1) Acute illness or infection;  
(2) Reduced kidney function (by glomerular filtration rate (GFR <60 ml/min) or liver function 
tests (LFTs ≥2.5 times above the upper limit of normal) as determined by test results at 
screening and any time point of the study;  
(3) Current pharmacological treatment with: HMG-CoA reductase inhibitors (statins), or any 
other hypolipidemic agent; anti-coagulant therapy; cyclosporine; or any other medications 
known to effect the TG concentration (i.e., β-blockers, thiazides or estrogen);  
(4) Hypersensitivity to fenofibrate;  
(5) Existing diagnosis of atherosclerosis, congestive heart failure, or recent history of 
myocardial infarction (i.e., ≤12 months);  
(6) Pregnancy or women who may become pregnant during the course of the study, or those 
who are nursing;  
(7) Diminished mental capacity; and 
(8) Inability or unwillingness of subject to provide informed consent. 
(9) Existing diagnosis of diabetes mellitus, or the results from screening blood tests indicate 
that diabetes mellitus is present (and perhaps undiagnosed); laboratory thresholds for 
exclusion will be as follows: HbA1C ≥6.5% and fasting plasma glucose is >126 mg/dl; 


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(10) Frequent alcohol consumption greater than 1 drink per day (one drink per day defined as 
½ ounce of absolute alcohol that is = to one 1.5 ounce of 80 proof alcohol = one 12 ounce can of 
beer = one 4 ounce glass of wine). 
 
Participant Recruitment  
Potential participants will be recruited in accordance with local regulatory guidelines.  The 
study coordinator will use a variety of methods to approach potential participants, including 
referrals from clinical staff, in-person contact at clinic visits, telephone calls, and placement of 
IRB approved flyers in authorized locations. For those participants who have previously 
signed consent document for a prior study and have requested to be contacted for future 
research studies, these individuals will be contacted for participation in our proposed study. 
Eligible participants will be enrolled after satisfying study inclusion/exclusion criteria.  To 
offset the level of inconvenience and perceived risk of the study procedures, remuneration in 
the amount of $50 will be provided for successful completion of the screening visit, months 1, 
2, 3 and follow-up;  subjects will receive $100 for completion of baseline and month 4 visits.  
Thus a subject who completes all study visits will receive $450 for participating in the 6 month 
study.  In the event that an individual performs only the screening visit, discontinues from 
participation, or is withdrawn, they will be provided partial remuneration commensurate with 
their length of participation.   
Methods  
 
The proposed investigation is an open-label, parallel-group intervention and 
randomized trial to determine the safety and efficacy of fenofibrate monotherapy on the 
lipoprotein profile in persons with SCI.  A screening visit will be performed in up to 100 
persons with SCI to identify 30 subjects who have adverse TG concentrations (i.e., paraplegia:  
≥135 mg/dl; tetraplegia ≥115 mg/dl).  After a baseline evaluation, a comprehensive medical 
history review and intake interview will be performed to identify demographic information, 
current health status, medications and lifestyle habits (i.e., smoking, alcohol consumption, 
recreational drug use, physical activity habits, diet etc.).   Twenty subjects with adverse TG 
concentrations will be randomized to receive once daily fenofibrate therapy (i.e., 145 mg) for 4 
months (dispensed by the research pharmacy of the James J. Peters VA Medical Center) and 
the remaining 10 subjects with adverse TG concentrations will receive no treatment and will 
serve as control subjects.  All subjects will complete monthly follow-up visits for the study 
period, which also includes a 1-month post-treatment visit.  If after 2 months of continuous 
fenofibrate treatment a subject does not demonstrate an improvement of ≥25% in TG 
concentration, then he/she will be discontinued from the study drug under appropriate 
supervision and terminated from the study.  For those who respond to fenofibrate treatment, 
he/she will continue on treatment for an additional 2 months. 
 
The primary study outcome will be to determine the efficacy of treatment on the serum 
lipoprotein profile (i.e., TG, HDL-C, LDL-C, total cholesterol), and the secondary study 


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outcome will be the lipoprotein particle number and size by NMR (i.e., HDL, LDL and VLDL 
subfractions). Liver (enzymes: AST, ALT, GGT) and kidney function (i.e., glomerular filtration 
rate) tests, and a complete blood count (CBC) with differential will be performed at all study 
visits, from blood samples, respectively, to monitor subject safety (Table 2).  To facilitate our 
understanding of the relationship between metabolic parameters, body composition and 
primary study outcome measurements associated with treatment efficacy, a 2 hour oral 
glucose tolerance test, and a total body dual energy x-ray absorptiometry (DXA) scan will be 
performed to quantify total body fat mass and fat-free mass at baseline, as well as to determine 
visceral adipose tissue volume (enCoreTM software (Lunar iDXA, platform version 13.6, 
General Electric Medical Systems, Madison, WI) at baseline and at 4 months.  In addition, all 
subjects who enter the trial as a treatment or control subject will receive dietetic counseling at 
baseline and at 2 months. Study support staff will perform phone calls twice a month to 
monitor drug compliance and direct concerns to the study physician during intervals when 
there may be noncompliance with scheduled study follow-up visits.  Thus, the proposed 
research investigation incorporates and follows best practices for the clinical treatment and 
utility of fenofibrate monotherapy in persons with dyslipidemia. 
 
Table 2.  Table of Procedures  
Treatment 
Follow-Up 
  
Screening Baseline 
Month 1 
Month 2 
Month 3 
Month 4 
Post- 1 
month 
Safety Labs 
Liver and Kidney Function  
x 
x 
x 
x 
x 
x 
x 
CBC with Differential 
x 
x 
x 
x 
x 
x 
x 
Primary Study Outcomes 
Lipoprotein Concentrations 
x 
x 
x 
x 
x 
x 
x 
Lipoprotein Particle Number 
x 
x 
x 
x 
x 
x 
Additional Outcomes  
Fasting Insulin, Glucose and A1
x 
x 
x 
x 
x 
x 
x 
Oral Glucose Tolerance Test 
x 
x 
Body Composition Analysis 
x 
x 
ApoE blood genotyping 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Procedures 
Safety Labs: Serum blood specimen will be obtained for the determination of the glomerular 
filtration rate (GFR).  If at screening or during the trial, GFR is <60 ml/min, the potential subject 
will not be eligible to enroll in the study, or if the GFR should fall to <60 ml/min during the 
trial, the participant will be discontinued from study drug; renal function will be monitored 
for a period of at least 4 months after identifying a fall in creatinine clearance while on study 
drug.  Liver function tests [i.e., AST, ALT (<35 IU/L), GGT (elevated for respective age and 


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gender)] and complete blood count with differential (CBC with diff) will be obtained and 
evaluated for abnormal values.  If evidence for abnormal liver function (i.e., 2 standard 
deviations above the upper limit of normal) or infection (white blood cell >10,000 cells/ml), the 
subject will either be considered ineligible for the study at the time of screening or 
discontinued from study drug under appropriate supervision and monitored for a period of at 
least 4 months. These specimens will be processed by a commercial laboratory at the time of 
collection (LabCorp).  All safety labs will be reviewed by Dr. William A. Bauman (Co-
Investigator and study physician).  He will be responsible for the oversight of safety 
monitoring, eligibility and review of all laboratory data from screening and treatment.  
 
Primary Study Outcomes:  Venous blood samples will be obtained after an overnight fast 
(minimum 8 hours) for the determination of lipoprotein concentrations (i.e., HDL-C, LDL-C, 
VLDL-C, TG and total cholesterol) and lipoprotein particle number and size (i.e., mean size of 
HDL, LDL and VLDL particle; the number of HDL, LDL and VLDL for the respective sub-
fraction of small, medium and large particles).  Lipoprotein concentrations will be processed 
by a commercial laboratory at the time of collection (LabCorp).; lipoprotein particle number 
and size will be performed as a fee-for-service by Liposcience, Inc (Raleigh, NC, USA). 
 
Additional Outcomes:  To assist in the stratification of interventional outcomes, all participants 
who enter the study intervention (i.e., receive drug or serve as control), will provide a blood 
sample at the beginning of the treatment period so that their apolipoprotein E (ApoE) 
genotype can be determined by a commercial laboratory as a fee-for-service procedure 
(LabCorp).  Venous blood samples will be obtained after an overnight fast (minimum 8 hours) 
for the determination of fasting plasma insulin level and serum glucose concentration at each 
study visit once the trial begins.  For the oral glucose tolerance test, the participant will drink a 
glucose containing solution (i.e., 75 grams) over a 2-minute period.   Venous blood will be 
drawn from a catheter at time 0 (same blood sample just described) and 120 minutes later to 
determine plasma glucose and insulin levels.  These outcomes will be monitored for changes 
in glucose tolerance and insulin sensitivity that may be associated with fenofibrate treatment.  
The Core Laboratory of the Center of Excellence for the Medical Consequences of SCI will 
perform the glucose analyses (YSI 2300 STAT Plus, YSI Life Sciences, Yellow Springs, OH) and 
insulin assay by batch processing in duplicate by radioimmunoassay using techniques 
previously developed by our laboratory.58  For body composition analysis, subjects will be 
transferred from their wheelchair to a semi-padded scanner bed, where a DXA total body scan 
will be performed.  To determine fat mass and fat-free mass, the scan will expose subjects to a 
very low dose of radiation (i.e., approximately 1/5th of the radiation for a standard chest x-ray).  
The scan will take no more than 20 minutes to be performed and will only be performed twice 
during the study (Table 2).  Skinfold and Girth Circumference Measurements: a soft measuring 
tape will be used to measure various circumferences and lengths of each subject’s body, and a 


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set of skin calipers will be used to measure skin folds specifically located on the subject’s arms, 
legs, back, and trunk. The total time of this procedure will not exceed 10 minutes.  
 
Potential Risks 
The health risks associated with this research study are minimal in nature.  As with any 
investigational study, there may be adverse events or side effects that are currently unknown. 
In the case of a serious adverse event during the test, hospital emergency personnel will be 
summoned over telephone by study personnel.   The following list contains potential risks/and 
or discomfort related to study procedures: 
-Fenofibrate:  Common side effects for treatment include abdominal pain, skin rash, and 
nausea. Less common side effects include gas, bloating, change in bowel frequency and stool 
color. As mentioned previously participants are at risk to develop elevated and/or abnormal 
liver and kidney function from taking Fenofibrate. If abnormal levels become evident as 
indicated by safety monitoring labs taken at each time point, the subject will be discontinued 
from study drug and monitored on a monthly basis for up to four months or until liver 
function returns to normal. In addition, if the subject develops elevated and/or abnormal liver 
function results, they may experience the following: yellowing of eyes/skin, dark urine, 
pruritis, swelling, and headache.  
-Blood draw/catheter placement:  The subject may experience the feeling of being lightheaded, 
dizzy, blurry eyesight, nausea and/or syncope during the needle/catheter insertion.  There is 
also the potential risk of developing a bruise or infection at the site of skin puncture. 
-Oral glucose tolerance test:  In addition to the listed risks for blood draw/catheter placement, 
the ingestion of a large volume of glucose may cause some individuals to experience nausea. 
-Dual energy x-ray absorptiometry scans:  To complete the scan, participants will be asked to 
transfer from their wheelchair to the scanning bed.  This will be completed independently or 
with assistance from an overhead patient lift.  The scan will take approximately 15 minutes to 
complete during which the subject will be asked not to move.  Each dual energy x-ray 
absorptiometry scan will expose the subject to 8.62 µSv of radiation (i.e., equivalent to 1/5 of an 
average chest x-ray), thus each subject will receive 17.24 µSv for the two scans. 
 
Statistical Analyses 
Separate analysis of variance (ANOVA) will be performed to identify group differences 
(i.e., control, treatment) for baseline demographic data [e.g., age, height, weight, BMI, duration 
of injury (DOI)].  Pearson chi-square tests will be performed to identify differences for the 
number of enrolled participants in each group based on gender (e.g., male, female), injury 
level (e.g., paraplegia, tetraplegia), AIS level (e.g., A, B, C), and ethnicity (e.g., African 
American, White, Hispanic).  Separate 2 (group: treatment, control) X 3 (visit: baseline, Mo2, 
Mo4) mixed-model repeated measures ANOVA (RMANOVA) will be performed to determine 
if differences were present for serum lipoprotein profile [e.g., HDL-C, LDL-C, VLDL-C, TG, 
TC], glucose, insulin, and the TG/HDL-C, LDL-C/HDL-C and TC/HDL-C ratios. Separate 


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factorial ANOVA will be performed to identify the presence of group differences in the 
percent change from baseline to 2 and 4 months, respectively in the serum TG, HDL-C, and 
LDL-C.  The nature of significant group or time main effects will be explored with Tukey post 
hoc tests.  Although not part of the primary analysis, results from the venous blood samples at 
months 1 and 3 visits will be provided.  Statistical analyses will be completed using IBM SPSS 
Statistics 25 (IBM, Armonk, NY) and figures will be created with GraphPad Prism (version 8.0 
for Windows, GraphPad Software, San Diego, CA).  An a priori level of significance was set at 
p ≤ 0.05.