Fenofibrate Treatment in SCI

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

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.

Study Overview

• Status: Completed
• Conditions: Dyslipidemia; Spinal Cord Injury
• Intervention / Treatment: Drug: Fenofibrate; Other: No intervention

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.

• Study Type: Interventional
• Enrollment (Actual): 23
• Phase: Phase 2; Phase 3

Contacts and Locations

Study Locations

• United States
  • New Jersey
    • West Orange, New Jersey, United States, 07052
      • Kessler Institute for Rehabilitation
  • New York
    • Bronx, New York, United States, 10468
      • James J. Peters VA Medical Center, Bronx, NY

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 21 years to 69 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

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

What is the study measuring?

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

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Adverse Event Profile	Documentation and description of adverse events will be obtained in subjects who have received drug treatment compared to events occurring in the control group.	4 months

Collaborators and Investigators

• Sponsor: VA Office of Research and Development
• Investigators: Principal Investigator: Michael F LaFountaine, EdD, James J. Peters Veterans Affairs Medical Center

Publications and helpful links

Helpful Links

• Click here for more information about this study: An Open Label Safety and Efficacy Trial of Fenofibrate in Persons with SCI

Study record dates

Study Major Dates

• Study Start (Actual): May 18, 2015
• Primary Completion (Actual): August 1, 2018
• Study Completion (Actual): August 1, 2018

Study Registration Dates

• First Submitted: May 14, 2015
• First Submitted That Met QC Criteria: May 22, 2015
• First Posted (Estimate): May 27, 2015

Study Record Updates

• Last Update Posted (Actual): June 26, 2019
• Last Update Submitted That Met QC Criteria: June 7, 2019
• Last Verified: May 1, 2019

More Information

Terms related to this study

• Keywords: hypertriglyceridemia; hyperlipidemia; tetraplegia; paraplegia; peroxisome proliferator-activated receptor alpha
• Additional Relevant MeSH Terms: Metabolic Diseases; Central Nervous System Diseases; Nervous System Diseases; Wounds and Injuries; Trauma, Nervous System; Spinal Cord Diseases; Lipid Metabolism Disorders; Dyslipidemias; Spinal Cord Injuries; Molecular Mechanisms of Pharmacological Action; Antimetabolites; Hypolipidemic Agents; Lipid Regulating Agents; Fenofibrate
• Other Study ID Numbers: B1925-P

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Undecided

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: Yes