Fenofibrate Treatment in SCI

Study Overview
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Brief Summary
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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
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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.

Official Title
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An Open Label Safety and Efficacy Trial of Fenofibrate in Persons With SCI

Conditions
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Spinal Cord Injury, Dyslipidemia

Intervention / Treatment
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* Drug: Fenofibrate
* Other: No intervention


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or female, age 21 to 69; Chronic (e.g., duration of injury at least 6 months), stable SCI (regardless of level of neurological lesion); American Spinal Injury Association Impairment Scale (AIS) designation of A, B or C; and TG concentration 135 mg/dl (paraplegia) or 115 mg/dl (tetraplegia). Exclusion Criteria: Acute illness or infection; Reduced kidney function (by glomerular filtration rate (GFR <60 ml/min) or liver function tests (LFTs 2.5 standard deviations above the upper limit of normal); 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., -blockers, thiazides or estrogen); Hypersensitivity to fenofibrate; Existing diagnosis of atherosclerosis, congestive heart failure, or recent history of myocardial infarction (i.e., 12 months); Pregnancy or women who may become pregnant during the course of the study, or those who are nursing; Diminished mental capacity; and Inability or unwillingness of subject to provide informed consent. 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.

Ages Eligible for Study
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Minimum Age: 21 Years
Maximum Age: 69 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Fenofibrate<br>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 | Drug: Fenofibrate<br>* Fenofibrate is a peroxisome proliferator-activated receptor alpha agonist that is demonstrated to reduce triglyceride concentrations in the blood.<br>|
| Other: No Intervention<br>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 | Other: No intervention<br>* A cohort of participants will be randomized to receive no study drug, but will engage in study encounters.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Triglyceride Concentration (Percent Change From Baseline) | 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. | two months from initiating drug treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Triglyceride Concentration (Percent Change From Baseline) | 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. | four months from initiating drug treatment | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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tetraplegia, paraplegia, hypertriglyceridemia, hyperlipidemia, peroxisome proliferator-activated receptor alpha