Carnitine for the Treatment of Atherosclerosis.

Phase 2

Completed

• Conditions: Metabolic Syndrome
• Interventions: Dietary Supplement: L-carnitine capsules; Dietary Supplement: Cellulose capsules

• Registration Number: NCT02117661
• Lead Sponsor: Dr. Amer Johri

Brief Summary

Obesity is one of the main causes of the metabolic syndrome, a condition which is becoming more common in Canada and worldwide. Metabolic syndrome is a name for a group of heart disease risk factors that occur together: obesity, diabetes, high blood pressure, and high cholesterol. These patients have a high risk of developing narrowing and blockages of blood vessels which occur when fat and cholesterol build up in the walls of blood vessels and form plaque. This is called atherosclerosis. Plaque buildup leads to stroke, heart attacks, and death. We do not understand the underlying mechanisms of the metabolic syndrome and we do not have a treatment for it. L-carnitine, a dietary supplement, has been shown to treat some components of the metabolic syndrome, but its benefit to reduce plaque in the blood vessels has never been studied. Recently there has been some controversy because a new study showed that L-carnitine could make heart disease worse in some patients. Our goal is to study whether supplementation with L-carnitine does in fact prevent or reduce buildup of plaque in blood vessels of patients with the metabolic syndrome. This novel therapy has the potential to decrease the burden of heart disease in obese and diabetic patients with the metabolic syndrome.

Detailed Description

Primary Question: Does L-carnitine (L-C) therapy slows down and/or regress atherosclerosis, as measured by total plaque volume (TPV) assessed by 3-dimensional (3D) carotid ultrasound in patients with metabolic syndrome? We hypothesize that L-C will regress atherosclerotic plaque formation.

To assess our primary outcome of L-C induced atherosclerosis regression, we anticipate a significant percent (%) difference in carotid total plaque volume (TPV) over six months of L-C treatment, compared to placebo. For our secondary outcome, we expect to show that L-C therapy compared to placebo, induces a reduction in the proportion of small-sized LDL and an increase in large LDL particles. As small dense LDL particles are more atherogenic than large buoyant ones, this would suggest a mechanism contributing to the atherosclerosis reduction induced by L-C therapy.

Study Timeline

• Study First Submitted: 2014-04-16
• Study First Submitted QC: 2014-04-17
• Study First Posted: 2014-04-21
• Study Start: 2015-01
• Primary Completion: 2017-07
• Status Verified: 2018-11
• Study Completion: 2019-05
• Last Update Submitted: 2020-06-24
• Last Update Posted: 2020-06-26

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 177

Inclusion Criteria

STEP 1: Initial screening; BP, weight and fasting blood samples will be obtained.

1. Men and women, >18 years, meeting the criteria for clinical diagnosis of MetS, according to the International Diabetes Federation (IDF) harmonized definition, where any 3 of the 5 following risk factors cut points constitutes a diagnosis of MetS:

   1. Elevated waist circumference: Population- and country-specific definitions; Health Canada recommends males 102 cm and women 88cm.
   2. Elevated triglycerides: 150 mg/dL (1.7 mmol/L).
   3. Reduced HDL: 40 mg/dL (1.0 mmol/L) in males; 50 mg/dL (1.3 mmol/L) in females or treated.
   4. Elevated BP: Systolic 130 and/or diastolic 85 mm Hg or treated.
   5. Elevated fasting glucose: 100 mg/dL (5.6 mmol/L), or HbA1c ≥6.2%, or treated.

2. Willing to provide informed consent. STEP 2: Baseline plaque volume ≥50 mm3 by 3D US, to ensure sufficient detectable plaque. This will be measured after consent (at Step 1), but prior to randomization/enrolment (Step 2).

Exclusion criteria:

1. Individuals who have had a change in statin and/or diabetes medication therapy or dosing in the last three months;
2. Who are actively having an unstable arrhythmia, angina or heart attack (untreated and/or unstable patients): symptomatic heart failure (NYHA 2 or greater); renal failure (GFR <50 mL/min/1.73m2);
3. Known severe abnormal blood biochemistries: Na <100 or >150 mmol/L, K <2 or >5 mmol/L, Total Serum Ca >3 mmol/L;
4. Known severe liver disease: AST >100 U/L, ALT >80 U/L, or a diagnosis of cirrhosis (Child Pugh Class A to C);
5. Known severe anemia: HgB <70 g/L;
6. Have endocrine disorders, e.g. Cushing's disease, hyper- or hypo-thyroidism;
7. Any condition expected to limit survival to less than six (6) months (ex. malignant tumor);
8. A condition limiting adherence to study procedure (i.e. alcoholism, drug addiction, known poor adherence, severe mental disorder);
9. Concomitant treatment with: anticonvulsants; L-C or derivatives; Acenocoumarol (Sintrom) and Warfarin (Coumadin) anticoagulants and vitamin K antagonists; >1g fish oil; and/or thyroid treatment;
10. A seizure disorder or at risk of seizure (CNS mass or medications that lower seizure threshold); receiving treatments for cancer or HIV infection (secondary L-C deficiency);
11. Currently pregnant or breastfeeding;
12. A history of allergy or intolerance to L-C or derivatives;
13. Vegetarians (do not eat animal flesh) due to potential for altered L-C metabolism;
14. Patients who have had a carotid surgery (ie. endarterectomy (CEA) or stent) or who are scheduled to receive carotid surgery during the trial.

Exclusion Criteria

Not provided

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
L-carnitine capsules	L-carnitine capsules	2000 mg daily (2x 500 mg capsules twice a day - BID) for six months
Cellulose capsules	Cellulose capsules	2x capsules twice a day - BID (4 total per day) for six months

Primary Outcome Measures

Name	Time	Method
Change in carotid Total Plaque Volume	Six months	Carotid 3D ultrasound scan

Secondary Outcome Measures

Name	Time	Method
Change in LDL size profile	Six months	Blood test

Trial Locations

Locations (2)

Queen's University, Cardiovascular Imaging Network at Queen's (CINQ), Kingston General Hospital; 🇨🇦 Kingston, Ontario, Canada

Robarts Institute, Stroke Prevention & Atherosclerosis Research Centre (SPARC); 🇨🇦 London, Ontario, Canada