7T Magnetic Resonance Spectroscopy and Skeletal Muscle Biopsy Findings in Statin Associated Adverse Muscle Events

7T Magnetic Resonance Spectroscopy and Skeletal Muscle Biopsy Findings in Statin

Over 40 million Americans take statins to reduce their risk of atherosclerotic cardiovascular disease (ASCVD). Unfortunately, 10 to 20% stop taking them due to statin-associated muscle symptoms (e.g. pain, aches, weakness, cramps, or stiffness) (1, 2). The pathophysiology of these statin-associated muscle symptoms (SAMS) has remained elusive. Consequently, no objective diagnostic method exists, causing confusion for patient and providers since muscle symptoms can often be multifactorial.

Study Overview

• Status: Terminated
• Conditions: Muscle Cramp; Statin Adverse Reaction; Weakness, Muscle; Ache
• Intervention / Treatment: Drug: Simvastatin 40mg

Detailed Description

The overall objectives of this project are to identify the underlying cause of SAMS and establish an in-vivo imaging technique to detect SAMS. The central hypothesis of this pro-posal is that statins directly inhibit mitochondrial function in SAMS patients. Our rationale is based on our own preliminary data indicating that simvastatin - the most common statin to cause SAMS - can directly inhibit oxidative phosphorylation (OXPHOS) in mice. Since such changes can be detected in vivo in humans utilizing 31P magnetic resonance spectroscopy (MRS) techniques, the investigators will use a state-of-the art 7 Tesla (7T) MRS instrument to study the so-leus muscles of SAMS patients. Additionally, the investigators will validate the MRS findings by doing func-tional studies in muscle biopsy specimens.

The investigators propose double-blind randomized, placebo-controlled pilot study in 15 SAMS pa-tients and 15 controls. Study participants will be treated with simvastatin 40 mg daily or place-bo for 10 weeks. The investigators will perform 7T MRS of soleus muscles at randomization and either at first complaint of muscle symptoms or at the end of 10 weeks if no muscle symptoms occur, whichever occurs first. Quadriceps muscle biopsies will also be done immediately following the second MRS scan.

• Study Type: Interventional
• Enrollment (Actual): 3
• Phase: Phase 4

Contacts and Locations

Study Locations

• United States
  • Texas
    • Dallas, Texas, United States, 75390
      • UT Southwestern Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 80 years (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion

• Adults, age > 18 ys or < 80 yrs. Patients reporting complaints of statin-associated muscle symptoms, aches, weakness, cramps, or stiffness in the legs.

Exclusion Criteria

• Patient who drink large quantities of grapefruit juice (> 1 quart daily).
• Patients on the following drugs for which the FDA has issued restrictions for using simvastatin 40 mg daily do to an increased risk of severe muscle injury such as itraconazole, posaconazole, ketoconazole, erythromycin, clarithromycin, telithromycin, HIV-1 protease inhibitors, nefazodone, gemfibrozil, cyclosporine, danazol, amiodarone, amlodipine, ranolazine, and verapamil.
• Patients with muscle-related pain that is not related to statin-use (e.g. muscle aches from strain or trauma) or remains unexplained.
• Any patients with underlying non-statin related muscle disorders.
• Presence of any clinically significant uncontrolled endocrine disease known to influence serum lipids or lipoproteins.
• Conditions of severe acute vascular stress (acute coronary syndrome, ischemic stroke, or major vascular surgery) within prior 3 months.
• Any patients with a history of severe or life-threatening reactions to statins including rhabdomyolysis (defined as evidence of organ damage with CK >10,000 IU/L), CK elevation > 10 times the upper limit of normal, cognitive decline, transaminitis, or allergic reactions.
• History of fibromyalgia or rheumatologic disease with symptoms that may be confounded with statin-related muscle complaints.
• Patients unable to maintain their current activity level or planning to increase their activity level (e.g. new exercise regimen). Such changes may have acute effects on muscle metabolism.
• Pregnant or breast-feeding women. Statins are teratogenic, and the effects of high magnetic fields on a fetus are unknown.
• Women of reproductive age not on effective contraception. Adequate contraceptive measures include intrauterine device (IUD); bilateral tubal ligation; condom or diaphragm plus either contraceptive sponge, foam or jelly.
• Any person with implanted metal, because of MRS safety.
• Use of any active investigational drugs within 1 month or 5 half-lives, whichever is longer.
• History of antibodies to HMGCoA.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: BASIC_SCIENCE
• Allocation: RANDOMIZED
• Interventional Model: SINGLE_GROUP
• Masking: TRIPLE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
PLACEBO_COMPARATOR: Placebo; Following the baseline period, subject will be randomized to receive either simvastatin or an identical placebo at a dose of 40 mg/day for a period of 10 weeks.	Drug: Simvastatin 40mg; 40mg oral daily for 10 weeks
ACTIVE_COMPARATOR: Simvastatin 40mg; Following the baseline period, subject will be randomized to receive either simvastatin or an identical placebo at a dose of 40 mg/day for a period of 10 weeks.	Drug: Simvastatin 40mg; 40mg oral daily for 10 weeks

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
The Mitochondrial Changes In Muscles During Statin Use	Study participants being treated with Simvastatin 40mg daily, or placebo for 10 weeks. Investigators will isolate mitochondrial from muscle biopsy sample and compare mitochondrial oxygen consumption rates, ultrastructural changes, and gene expression	10 weeks

Collaborators and Investigators

• Sponsor: University of Texas Southwestern Medical Center

Study record dates

Study Major Dates

• Study Start (ACTUAL): August 17, 2018
• Primary Completion (ACTUAL): December 20, 2021
• Study Completion (ACTUAL): December 20, 2021

Study Registration Dates

• First Submitted: January 31, 2019
• First Submitted That Met QC Criteria: August 7, 2020
• First Posted (ACTUAL): August 11, 2020

Study Record Updates

• Last Update Posted (ESTIMATE): February 14, 2023
• Last Update Submitted That Met QC Criteria: January 23, 2023
• Last Verified: January 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Nervous System Diseases; Neurologic Manifestations; Musculoskeletal Diseases; Muscular Diseases; Neuromuscular Manifestations; Muscle Weakness; Spasm; Muscle Cramp; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antimetabolites; Anticholesteremic Agents; Hypolipidemic Agents; Lipid Regulating Agents; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Simvastatin
• Other Study ID Numbers: STU 072016-015

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