Clinical trial NCT04575090
Conditions: Statin-related Muscle Pain Muscle Aches Muscle Weakness Muscle Cramp Muscle Stiffness
Sponsor: University of Texas Southwestern Medical Center
Start date: 2016-03-05; Completion date: 2021-06-23
Enrollment: 8 participants; Allocation: NON_RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Roughly 5-10% of statin-treated patients report muscle pain, aches, weakness, cramps, stiffness, or "heaviness" - typically occurring symmetrically in the legs. For healthcare providers, the major diagnostic challenge is to unambiguously link these symptoms to statin use, especially since some patients can have normal serum creatine kinase (CK) levels despite demonstrable weakness and muscle biopsy proven statin-induced myopathy .

No well accepted, standardized, or Food and Drug Administration (FDA)-endorsed diagnostic method exists for statin-induced muscle injury. This lack of an objective diagnostic methodology blocks vertical advancement of the field.

The successful completion of this project will develop in vivo techniques that will provide insight into how statins affect muscle metabolism and help establish a methodology to objectively diagnose muscle injury due to statins. The development of an MRS technique will allow for in-vivo analyses and the data accumulated here will serve as preliminary data for futher extramural funding of studies with much larger sample sizes. Ultimately, this focus of research will lead to improved diagnosis and treatment of patients with statin-related muscle complaints, which is central to obtaining the cardiovascular risk reduction from lipid-lowering drugs.

Detailed description:
The goal of the first study will be to generate hypothesis regarding the long-term effects of statin in muscles by studying 7T MRS findings in patients who are currently experiencing statin-related muscle complaints or who have a history of severe reactions to statins (i.e. rhabdomyolysis, anti-HMGCR-associated autoimmune myopathy, or CK elevation \> 10 times the upper limit of normal). We anticipate enrolling roughly 5 such patients. The protocol involves a single visit for a blood draw and MRS of calf muscle. The data will be compared to historical controls provided by the Advanced Imaging Research Center.

Second, we will study the effect of short-term statin administration in 5 patients with a history of statin related muscle complaints and 5 controls with no statin related muscle complaints . Controls will be matched for age, weight, and body mass index. Patients will undergo a wash-out of lipid lowering drugs followed by a challenge with simvastatin 40 mg daily (similar to a statin withdrawal and rechallenge). We chose simvastatin since it is the most common statin that caused myopathy according to our preliminary data (as well as most other published reports). Each patient will have 5 visits. The screening visit will involve a review of inclusion/exclusion criteria, blood draw, questionnaire, and instructions to withhold all lipid lowering drugs until visit 1. Any patient with known antibodies to HMGCR will be excluded from the remainder of the study.

Visit 1 will occur 2 weeks after stopping all lipid lowering drugs. A minimum 2 week period off lipid lowering drugs is required to allow clearance of any medication from the systemic circulation. Patients will undergo MRS of the calf muscle and a blood draw. Patients will then start simvastatin 40 mg daily.

Arms: arm 1: Patients in substudy 1 will be identified by the PI from the clinic as individuals who are currently experiencing statin related muscle complaints or who have had severe reactions to statins in the past. There is going to be only one visit which will last for apprximately 3.5 hrs. Subjects will have height, weight and vitals measured. They will be asked pain and and demographic questionnaire. They will have their blood draw and will undergo MRS. arm 2: Subjects with statin related muscle complaints were enrolled in this arm and will have 3 visits. First visit is screening visit which will last for about 2 hrs and the next 2 visits will last for about 3.5 hrs. The screening visit will occur 2 weeks prior to visit 1.

Subjects will have height, weight and vitals measured. They will be asked pain and and demographic questionnaire. They will have their blood draw and will undergo MRS.

Some volunteers who do/do not regularly exercise or are/are not active in sports may be asked to exercise prior to the MRS. This exercise may be in the form of hand grasps, toe-raises, bicycling on a stationary bike or walking on a treadmill. Exercise will be limited to up to one hour, during which time the subject's vital signs and blood oxygenation will be monitored. During the scan, the subject's heart rate and respiratory rate may be monitored arm 3: Subjects with no statin related muscle complaints were enrolled in this arm and will have 3 visits. First visit is screening visit which will last for about 2 hrs and the next 2 visits will last for about 3.5 hrs. The screening visit will occur 2 weeks prior to visit 1.

Subjects will have height, weight and vitals measured. They will be asked pain and and demographic questionnaire. They will have their blood draw and will undergo MRS.

Some volunteers who do/do not regularly exercise or are/are not active in sports may be asked to exercise prior to the MRS. This exercise may be in the form of hand grasps, toe-raises, bicycling on a stationary bike or walking on a treadmill. Exercise will be limited to up to one hour, during which time the subject's vital signs and blood oxygenation will be monitored. During the scan, the subject's heart rate and respiratory rate may be monitored
Interventions: intervention 1: Simvastatin
Intervention descriptions: intervention 1: Simvastatin 40 mg daily.

Protocol documents:
Prot_SAP_000.pdf: 
Official title: 7 Tesla MRS to Study Statin-Related Muscle Complaints 
NCT number: NCT04575090 
IRB Approval date: February 14, 2017 


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The University of Texas Southwestern Medical Center at Dallas 
Institutional Review Board 
 
Protocol  
 
Title: 7 Tesla MRS to Study Statin-Related Muscle Complaints 
 
1. Introduction and Purpose: Roughly 5-10% of statin-treated patients report muscle pain, aches, 
weakness, cramps, stiffness, or “heaviness” - typically occurring symmetrically in the legs1. For 
healthcare providers, the major diagnostic challenge is to unambiguously link these symptoms to 
statin use, especially since some patients can have normal serum creatine kinase (CK) levels despite 
demonstrable weakness and muscle biopsy proven statin-induced myopathy 2.  
 
The 2103 American College of Cardiology and American Heart Association (ACC/AHA) Blood 
Cholesterol Guidelines committee advocates statin withdrawal and rechallenge as a way to establish 
a causal relationship between muscle pain symptoms and statin therapy 3. This challenge involves 
stopping the statin for 2 weeks to see if the symptoms go away, then restarting the statin to see if the 
symptoms return. As long as patients are not under conditions of severe acute vascular stress (e.g. 
acute coronary syndrome, ischemic stroke, or major vascular surgery), short-term withholding of statin 
therapy is generally regarded as safe 4. 
 
 
Several issues limit widespread use of statin withdrawal and challenge as recommended by the 
ACC/AHA committee. First, health-care providers lack an evidence-based standardized protocol, 
making the process more of an art rather than a science. Second, the sensitivity and specificity 
remains unknown. In at least 2 studies, placebo-treated patients develop muscle complaints during 
controlled withdrawals and rechallenges 1, 5. Third, the outcome, self-reported muscle issues, remains 
subjective. No biomarker or imaging technique exists. 
 
No well accepted, standardized, or Food and Drug Administration (FDA)-endorsed diagnostic method 
exists for statin-induced muscle injury. This lack of an objective diagnostic methodology blocks 
vertical advancement of the field. For example, clinical investigations cannot enroll patients without 
using subjective inclusion criteria. In the clinical setting, health care providers have little insight into 
whether to try switching statins – and thus risking further muscle injury – or switch to non-statin lipid 
lowering drugs. Payers hesitate to approve new expensive non-statin lipid lowering drugs (e.g. 
PCSK9 inhibitors) based on subjective complaints of non-specific muscle symptoms. Studies of 
mitochondrial dysfunction, thought to be related to the mechanism of statin-induced muscle injury, 
have been limited to preexisting cell lines 6, animal models, or ex-vivo human experiments with small 
sample sizes 6, 7 (mostly because such studies require invasive muscle biopsies). 
 
UT Southwestern has one of the few available 7 Tesla (7T) magnetic resonance imaging (MRI) and 
magnetic resonance spectroscopy (MRS) instruments. The 7T MRS can detect ATP synthesis rates in 
human skeletal muscle as well as study intramyocellular lipids, carnitine and acetylcarnitine in the 
trimethylamine signals after exercise, lactate dynamics, and phosphorus metabolite kinetic 
exchanges. Compared to 3 Tesla and 1.5 Tesla, 7T offers much higher detection sensitivity and 
increased spectral resolution.  Patients’ scan times are short and the data quality better. 7T also helps 
identify small metabolite changes that otherwise are difficult to observe at lower fields. 
 
The central hypothesis of this proposal is that statin-induced myopathy causes changes in 
muscle metabolism that can be detected by a 7 Tesla MRS. 
 
The successful completion of this project will develop in vivo techniques that will provide insight into 
how statins affect muscle metabolism and help establish a methodology to objectively diagnose 
muscle injury due to statins. The development of an MRS technique will allow for in-vivo analyses and 
the data accumulated here will serve as preliminary data for futher extramural funding of studies with 


Main Protocol v1.0, Jan16 
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much larger sample sizes. Ultimately, this focus of research will lead to improved diagnosis and 
treatment of patients with statin-related muscle complaints, which is central to obtaining the 
cardiovascular risk reduction from lipid-lowering drugs.  
 
 
2. Background: The first case of statin-induced muscle injury occurred soon after the discovery of 
statins by Drs. Akira Endo and Masao Kuroda in Japan. They administered high doses of mevastatin 
to a 17-year-old girl with homozygous familial hypercholesterolemia 8 and noted “a side effect 
(muscular weakness at the proximal parts of the extremities with a rise of serum creatine 
phosphokinase, glutamate-pyruvate transaminase and glutamate-oxaloacetate transaminase 
activity).”  They also noted “these side effects completely disappeared within two weeks after 
withdrawal of the drug.” With lower doses of the mevastatin, “the side effects were no longer 
experienced.” In 1988, the New England Journal of Medicine published the first cases of 
rhabdomyolysis with statins: in two separate reports (one from UT Southwestern Medical Center), five 
cardiac transplant patients were described as developing rhabdomyolysis after taking lovastatin 9, 10. 
 
Despite awareness of statin-induced muscle injury, the exact pathology at the level of skeletal muscle 
remains unclear. Several contributing factors have been investigated without clear evidence of 
causality.  
 
Muscle biopsy studies have varied findings, although most recent investigations suggest decreased 
mitochondrial function. It remains unclear why mitochondrial content decreases. Most published 
studies imply decreased Coenzyme Q10, an intermediate in the cholesterol synthesis pathway that is 
decreased with statin use. Yet interventional studies with CoQ10 supplements have yielded conflicting 
results for improving statin-related muscle complaints 11, 12. Within mitochondria, changes in complex 
1 and complex III have imply altered oxidative phosphorylation 7.  
 
Genetic studies have linked statin-induced myopathy to genes involved in drug metabolism without 
providing much insight into the pathology at the level of the muscle. The best studied of these genes 
is solute carrier organic anion transporter family member 1B1 (SLCO1B1), which encodes for 
OATP1B1. A recent genome wide association study identified an association of simvastatin-related 
muscle injury and the nonsynonymous rs4149056 single-nucleotide polymorphism (SNP) in SLCO1B1 
13 in patients enrolled in a clinical trial of simvastatin 40 mg vs simvastatin 80 mg daily. More than 
60% of myopathy patients had the minor C allele (odds ratio 4.3 for one C allele and 17.4 for both C 
alleles). However, our preliminary data (see below) ascertained from clinic patients (rather than 
patients enrolled in clinical trials) failed to identify this SNP as a risk factor for statin-related muscle 
complaints. 
 
A small subset of patients with statin-related muscle complaints develop antibodies to 3-hydroxy-3-
methlyglutaryl coenzyme A reductase (HMGCR)14. The estimated incidence of anti-HMGCR-
associated autoimmune myopathy is 2 per million per year. Such patients have muscle weakness that 
continues even after statins are withheld and responds to treatment with immunosuppressive therapy. 
Such patients should not be rechallenged with statins. 
 
Three prior studies utilizing MRS have been published 15-17, none in the past 5 years and none with a 
7 T MR system. Results have been variable - likely related to small sample sizes and differing 
inclusion criteria – but have established that statins induce muscle changes detectable by MRS 
techniques.  
 
Most recently, Wu et al studied 3T MRS findings in the posterior calf of 10 subjects (no control group 
was included and only 4 of whom had any history of statin induced muscle complaints) before and 
after 4 weeks of statin therapy 17. They observed an increase in metabolic recover time from 28.1 
seconds to 55.4 seconds (p = 0.02) as measured by changes in phosphocreatine peaks before, 
during, and after exercise. These findings imply impairment in mitochondrial oxidative metabolism. An 


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older study, done on forearm flexor muscles with a 4.7 T MRS, found no difference in 
phosphocreatine peaks in 7 patients with a history of statin-induced rhabdomyolysis (not on statins at 
the time of the study) compared to 7 control patients on statins without any muscle complaints 16. 
Rather, the study found a slower rate of pH recovery (10.3 vs 15.7 mM H+/minute, p < 0.05), which 
the authors related to possible statin-induced defects in ion transport.  Finally, Slade et al studied 3T 
MRS findings in the anterior tibialis muscle of 10 statin users (without any history of statin related 
muscle complaints) compared to 10 controls and found that the phosphodiester peaks were 57% 
higher in statin users, implying increased cell membrane turnover similar to muscular dystrophies 15. 
 
Preliminary Data: As part of an ongoing study of a familial hypercholesterolemia (FH) cohort, we 
studied statin-related muscle complaints in 278 FH patients recruited from lipid clinics in the Dallas, 
TX area (manuscript in submission). Statin-induced myopathy occurred in 36% (n = 97). One patient 
had a reported history of statin-induced rhabdomyolysis and 2 patients had elevations in CK that were 
clearly linked to statin use. Simvastatin was the most common statin linked to muscle complaints, and 
the risk of myopathy was associated with age (OR 1.6, [95% CI 1.2, 2.2]), BMI in non-African-
Americans (0.90 [0.83, 0.97]), and hypertension (0.4, [0.2, 0.9]). In patients who were unable to 
reestablish statin therapy, LDL-C levels remained markedly elevated (“eventually tolerant” 127 
vs.”never tolerant” 192 mg/dL, p < 0.001).  
 
SLCO1B1 rs4149056 genotyping revealed 224 wild-type patients (TT), 48 heterozygotes (TC), and 
one homozygote (CC). The variant C allele was not associated with the risk of statin-induced 
myopathy (OR 0.70, [95% CI 0.37, 1.33]). 
 
3. Concise Summary of Project: 
 
We plan to do 2 substudies, running concurrently, in this proposal. In each one, visits will be for 
approximately 3.5 hours.  A written informed consent will be taken from all subjects. All visits will be to 
the Advanced Imaging Research Center at UT Southwestern for study procedures (blood testing and 
MRI/MRS). Urine pregnancy test will be collected in women of childbearing potential. Muscle pain will 
be evaluated with a pain assessment scale. All patients will be counseled to not alter exercise habits 
or diets for the duration of the study. 
  
The goal of the first study will be to generate hypothesis regarding the long-term effects of statin in 
muscles by studying 7T MRS findings in patients who are currently experiencing statin-related muscle 
complaints or who have a history of severe reactions to statins (i.e. rhabdomyolysis, anti-HMGCR-
associated autoimmune myopathy, or CK elevation > 10 times the upper limit of normal). We 
anticipate enrolling roughly 5 such patients. The protocol involves a single visit for a blood draw and 
MRS of calf muscle. The data will be compared to historical controls provided by the Advanced 
Imaging Research Center. 
 
Table 1: Substudy 1 Procedures 
 
Visit 1 
7T MRS 
X 
Blood Draw 
X 
Pain Assessment 
X 
 
Second, We plan to study the effect of short-term statin administration in 5 patients with a history of 
statin related muscle complaints (currently do not suffer related muscle pain) and 5 controls with no 
statin related muscle complaints (Table 2). Controls will be matched for age, weight, and body mass 
index. Patients will undergo a wash-out of lipid lowering drugs followed by a challenge with 
simvastatin 40 mg daily (similar to a statin withdrawal and re challenge). We chose simvastatin since 
it is the most common statin that caused myopathy according to our preliminary data (as well as most 
other published reports).  
 
Each patient will have 5 visits.   


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The screening visit will involve a review of inclusion/exclusion criteria, blood draw, questionnaire, and 
instructions to withhold all lipid lowering drugs until visit 1. Any patient with known antibodies to 
HMGCR will be excluded from the remainder of the study. 
Visit 1 will occur 2 weeks after stopping all lipid lowering drugs. A minimum 2 week period off lipid 
lowering drugs is required to allow clearance of any medication from the systemic circulation.  
Patients will undergo MRS of the calf muscle and a blood draw. Patients will then start simvastatin 40 
mg daily.  
Visit 2 will occur 1 week after starting simvastatin and will get MRS and blood draw. 
Visit 3 will occur 2 weeks after starting simvastatin and will get MRS and blood draw. 
Visit 4 will occur 4 weeks after starting simvastatin and will get MRS and blood draw. 
 
Even though most patients note the reappearance of muscle symptoms within the first week of the 
rechallenge period, we have extended the study to 4 weeks. During this 4 week time period we will 
capture all the metabolic and chemical changes and will be able to correlate better with the statin 
induced myopathy. These serial MRS scans will allow us to collect data on when abnormal MRS 
signals start to appear.  This data will serve as pilot data that will allow us to better design future 
studies. 
 
For safety purposes, if patients develop muscle symptoms during the simvastatin rechallenge, they 
will come for a study visit immediately so that an MRS can be done. Then, they will stop the 
simvastatin.  
Table 2: Sub Study 2 
Procedures 
 
Screening 
Visit 1 
Visit 2 
Visit 3 
Visit 4 
7TMRS 
 
X 
X 
X 
X 
Blood Draw 
X 
X 
X 
X 
X 
Pain Assessment 
X 
X 
X 
X 
X 
Start Simvastatin 
40 mg daily 
 
X 
X 
X 
X 
 
 
 
 
4. Study Procedures: 
 
The following procedures will be performed: 
 
Demographic Characteristics, Health History, and Physical Examination 
Subjects will be asked to complete a questionnaire on demographic characteristics and will also be 
asked questions about their medical and medication history, as well as, general physical activity level.  
The subject will also have their height, weight and vital signs measured. 
 
Blood Draw 
The following will be tested:   
 
Serum: chemistry, renal, liver, & thyroid function tests, lipid panel, lactate, CK, HMGCR 
antibodies 
 
Whole blood: CBC w/ differential, estimated sedimentation rate, Hemoglobin A1C  
 
Urine: pregnancy tests in females if indicated.   
 
Genetic Testing: Two aliquots will be used for DNA extraction. 
 
Magnetic Resonance Spectroscopy (MRS) of Calf Muscle 
Subjects enrolled in the study will undergo magnetic resonance spectroscopy (MRS) of calf muscles 
in a high field magnet. The Advanced Imaging Research Center at UT Southwestern now has 7T 


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systems for human experiments. While conventional MR techniques will be used, some MR 
parameters will vary. Compared to 3T and 1.5T, 7T offers much higher detection sensitivity and 
increased spectral resolution.  Patients’ scan times are short and the data quality better. Seven Tesla 
also helps identify small metabolite changes that otherwise are difficult to observe at lower fields.  All 
tests performed will be within the recommended operating conditions deemed to be a non-significant 
risk by the Food and Drug Administration (FDA). 
 
The subject will be screened for metal in or on their body using a standard MR screening form.  Any 
female of childbearing age will be screened for potential pregnancy. The subject will then remove all 
metal from their body and change into a gown or scrubs prior to admittance to the 7T MR 
environment. Some metabolites are better detected after exercise.  Some volunteers who do/do not 
regularly exercise or are/are not active in sports may be asked to exercise prior to the MRS.  This 
exercise may be in the form of hand grasps, toe-raises, bicycling on a stationary bike or walking on a 
treadmill.  Exercise will be limited to up to one hour, during which time the subject’s vital signs and 
blood oxygenation will be monitored. During the scan, the subject’s heart rate and respiratory rate 
may be monitored.  Calibration and set up of the scanner takes approximately 20 minutes.  This is 
done when the subject is in the scanner; therefore, the time in the scanner for the subject will be 
approximately a total of 2 hours, after which time the subject will be free to leave.   
 
 
5. Sub-Study Procedures: Not applicable. 
 
6. Criteria for Inclusion of Subjects: 
 
Inclusion criteria for substudy 1 include: 
 
1.) Adults, age 18 years or older  
2.) One of the following: 
a. Patients who are currently taking a statin and experiencing muscle pain, aches, 
weakness, cramps, stiffness, or “heaviness” in the legs. Since the MRI/MRS studies 
will be limited to calves, patient will have to have leg symptoms to qualify, or 
b. Patients with HMGCR antibodies, or 
c. Patients with a history of statin-induced CK elevation of > 10 times the upper limit of 
normal, or 
d. Patients with a history of statin-induced rhabdomyolysis 
3.) Subjects should be willing to participate under the conditions described in the informed 
consent form (ICF) and must be able to sign the ICF and applicable HIPAA forms.  
4.) Ability to exercise without physical restrictions. 
 
 
Inclusion criteria for substudy 2 include: 
 
1.) Adults, age 18 years or older  
2.) Patients who report complaints of statin-related muscle pain, aches, weakness, cramps, 
stiffness, or “heaviness” in the legs. Since the MRI/MRS studies will be limited to calves, 
patient will have to have leg symptoms to qualify. 
3.) Subjects should be willing to participate under the conditions described in the informed 
consent form (ICF) and must be able to sign the ICF and applicable HIPAA forms.  
4.) Ability to exercise without physical restrictions. 
 
 
7. Criteria for Exclusion of Subjects: 
 
Exclusion criteria for substudy 1 include: 


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1.) Any patients with underlying non-statin related muscle disorders such as inflammatory 
myopathy or myotonic dystrophy.  
2.) Presence of any clinically significant uncontrolled endocrine disease known to influence serum 
lipids or lipoproteins. Note: patients on thyroid replacement therapy can be included if the 
dosage of thyroxine has been stable for 6 weeks prior to the first study visit and thyroid-
stimulating hormone (TSH) level is within the normal range. 
3.) Conditions of severe acute vascular stress (e.g. acute coronary syndrome, ischemic stroke, or 
major vascular surgery) within 3 months prior to the first study visit. 
4.) History of rheumatological disease associated with symptoms that may be confounded with 
statin-related muscle complaints, e.g. rheumatoid arthritis 
5.) Diagnosis of fibromyalgia 
6.) Pregnant or breast-feeding women. The effects of high magnetic fields on a fetus are 
unknown. 
7.) Any person with implanted metal, because of MR safety.  This will include exclusion for 
vascular clips, surgical clips, prosthetic valves, pacemakers, otologic implants, etc.  
8.) Use of any active investigational drugs within 1 month or 5 half-lives, whichever is longer. 
 
Exclusion criteria for substudy 2 include: 
 
1.) Patients on the following drugs for which the FDA has issues restrictions for using simvastatin 
40 mg daily do to an increased risk of severe muscle injury: itraconazole, posaconazole, 
ketoconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, nefazodone, 
gemfibrozil, cyclosporine, danazol, amiodarone, amlodipine, ranolazine, and verapamil.  
2.) Patient who drink large quantities of grapefruit juice (> 1 quart daily) 
3.) Patients with muscle-related pain that is not related to statin-use (e.g. muscle aches from 
strain or trauma) or remains unexplained. 
4.) Any patients with underlying non-statin related muscle disorders such as inflammatory 
myopathy or myotonic dystrophy.  
5.) Presence of any clinically significant uncontrolled endocrine disease known to influence serum 
lipids or lipoproteins. Note: patients on thyroid replacement therapy can be included if the 
dosage of thyroxine has been stable for 6 weeks prior to the first study visit and thyroid-
stimulating hormone (TSH) level is within the normal range. 
6.) Conditions of severe acute vascular stress (e.g. acute coronary syndrome, ischemic stroke, or 
major vascular surgery) within 3 months prior to the first study visit. 
7.) 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, or allergic reactions to statins. 
8.) History of rheumatological disease associated with symptoms that may be confounded with 
statin-related muscle complaints, e.g. rheumatoid arthritis 
9.) Diagnosis of fibromyalgia 
10.) 
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. 
11.) 
Pregnant or breast-feeding women. The effects of high magnetic fields on a fetus are 
unknown. 
12.) 
Any person with implanted metal, because of MR safety.  This will include exclusion for 
vascular clips, surgical clips, prosthetic valves, pacemakers, otologic implants, etc.  
13.) 
Use of any active investigational drugs within 1 month or 5 half-lives, whichever is 
longer. 
14.) 
Antibodies to HGMCR detected in the blood drawn from the screening visit. 
 
8. Sources of Research Material: 
 


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Research material will consist of demographic questionnaires and medical history, blood and urine 
specimens, physical examination, and MRS results.  
 
9. Recruitment Methods and Consenting Process: 
 
The study subjects will be recruited from the lipid clinics at Parkland Health and Hospital Systems and 
UT Southwestern Medical Center. We will also advertise the study among local physicians. We will 
post the study on our website and at clinicaltrials.gov.  
 
Interested subjects will contact the Research Coordinator for more information regarding the study.  
The Research Coordinator will screen the potential subject according to Inclusion/Exclusion Criteria 
listed above. Both genders as well as minorities will be actively recruited for participation in this study. 
An approved HIPAA Waiver of Authorization will allow subjects to contact the research coordinator or 
other investigators for more information regarding study activities and eligibility screening. Subjects 
will participate after the purpose and benefits of the study are explained by physicians or nurses (i.e., 
Research Coordinator) associated with the study and signatures on applicable consent forms are 
obtained.  The informed consent process will include a review of a detailed list of potential adverse 
reactions. The informed consent process will be documented in the subject’s research chart.  All 
subjects will receive a copy of their signed ICF and HIPAA forms.  Subjects will be paid $100 for each 
study visit that involves MRS. $100 for Substudy 1 and $400 for Substudy 2. 
 
 
10. Potential Risks: 
 
Loss of Confidentially: Potential risks include the possible violation of the patient’s privacy, since 
medical history will be used as a source of data.  
 
Genetic testing: DNA will be collected and stored for potential future studies. Genetic testing carries 
the risk of revealing family links, or information about disease risks, which if revealed, could impact 
employment or insurance. This risk is minimized by the use of a separate genetic consent which is not 
kept with the ordinarily accessed hospital chart. 
 
Risks of Blood Drawing:  Phlebotomy carries the rare to occasional minimal risk of discomfort, 
hematoma, infection, fainting and/or vasovagal response. 
 
Withdrawing Lipid Lowering Therapy: Patients will stop all lipid lowering therapy for several weeks, 
resulting in an increase in cholesterol. As long as patients are not under conditions of severe acute 
vascular stress (e.g. acute coronary syndrome, ischemic stroke, or major vascular surgery), short-
term withholding of lipid lowering therapy is generally regarded as safe. Patients will still get long-term 
benefits of cholesterol lowering (i.e. reduction and risk of atherosclerotic cardiovascular disease). 
 
Statin-induced Muscle Injury:  In substudy 2, patients will be administered a statin, increasing their risk 
of muscle injury. Such statin challenges, however, are common in clinical practice, and in several 
published clinical trials, seem to be overall safe. We have taken several measure to minimize this risk: 
excluding patients with a history of severe muscle injury from statins (e.g. rhabdomyolysis or CK 
elevations > 10 times the upper limit of normal); excluding patients on drugs that interact with statins 
and increase the risk of muscle injury; excluding any patients with antibodies to HMGCR; and 
minimizing the time of the statin exposure. 
 
Magnetic Field:  This procedure is experimental and the long-term risks of the high magnetic field are 
unknown.  Exposure to high magnetic fields may have effects on the normal electrical activity of the 
body including changes in nerve and heart function. Changes in the heart rate or rhythm could occur. 
Blood pressure, temperature, and pulse rate may change. Studies with an 8 Tesla MRI have not 
shown any significant effects. 


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A subject may feel dizzy when moving the head quickly while in the magnetic field. This is a relatively 
frequent sensation, perhaps occurring in 30% or more of subjects. In studies at 8 Tesla, 1 subject out 
of 200 has vomited as the result of being in the magnet.  A relatively common sensation is a metallic 
taste in the mouth while entering or exiting the scanner.  A subject might see tiny light flashes similar 
to those that occur when you rub your eyes in the dark. This is less common and has no known 
harmful effects. Claustrophobia (uneasiness at being in a confined space) is a common 
contraindication in any MRI procedure at any magnetic field strength (tesla). 
 
Exposure to the rapidly changing magnetic fields could cause twitching of the subject’s muscles. This 
effect, known as peripheral nerve stimulation (PNS), is temporary. 
 
It is possible that radio frequency energy in a 7 Tesla MRI system may be absorbed in an unexpected 
manner by human subjects.  Local heating of the body may occur. 
 
As with all MRI, any metal in the body or in clothing represents a risk.  Metallic objects can be 
accelerated by the magnetic field and become dangerous. A metal implant or foreign object in the 
body could be displaced by the magnetic field. There can be increased heating near metal structures.  
 
Females: Risks to pregnant women and their fetuses are unknown at high magnetic field.  Females 
who are pregnant or breast-feeding cannot be a part of this study.  Females of childbearing age must 
agree to be tested for pregnancy prior to the MRI study. 
 
11. Subject Safety and Data Monitoring: 
All potential adverse events will be discussed with study participants.  Subjects will be informed of the 
voluntary nature of this research and will be in constant contact with the instrument operator should 
they desire to terminate the study for any reason.  To minimize dizziness, subjects will be moved 
slowly in and out of the magnet.  Earplugs and earmuffs will be provided to minimize discomfort of 
acoustic noise from the scanner sequences.  If a subject experiences muscle twitching, they will be 
asked to inform the operator and the study will be discontinued.  Additionally, if a subject states they 
feel an area of their body getting warm, they will be asked to notify the operator and the scan will be 
stopped.  All subjects will be carefully evaluated prior to entering the magnet to exclude metal objects 
in or on their body. A person with metal implants will be excluded from participation in the 7T scanner. 
Females of childbearing age will have a pregnancy test prior to any MR procedure. All subjects will 
complete a 24 hour post scan evaluation form.   
 
In the event of a medical emergency, the Aston Ambulatory Emergency Response Team, which 
consists of qualified medical personnel physically located in the UTSW north campus, may be 
contacted during ordinary work hours for emergency assistance.  
 
 
12. Procedures to Maintain Confidentiality: 
Confidentially will be maintained per HIPPA guidelines. Any information obtained in connection with 
this research that can be identified with a subject will remain confidential and will be disclosed with 
the permission of the subject or subject’s legal guardian. All individuals who have access to data 
obtained during this study will have approved human subjects protection training and will provide 
written assurance of compliance with the statements in the Belmont Report, 45 CFR 46, and Multiple 
Project Assurance M- 1304. The IRB may review research information if needed for auditing or other 
purposes that the IRB deems necessary. Data bases, research files and samples will include ID 
numbers only. All aliquots or derivatives of initial samples will be labeled with ID numbers only; no 
personal health information (PHI) will be included. The ID numbers will not be derived from PHI. 
Obtained data and subject identification information will be kept separate. All medical and biological 
information will be confidential and no disclosures of personal identity will be allowed unless 
specifically requested by the research subject or subject’s legal representative. The location of copies 


Main Protocol v1.0, Jan16 
Page 9 of 10 
of executed consent forms will be kept in a locked research office. The consent will be kept securely 
and separately from the subject’s medical chart. 
 
13. Potential Benefits: 
 
Knowledge gained by this project may lead to insight into how statins affect muscle metabolism as 
well as develop an objective methodology to diagnose statin-induced muscle injury.  Objective 
methodology would allow for not just definitive diagnoses in the clinical setting, but also would provide 
inclusion criteria for clinical trials or further studies of statin-related muscle injury. Understanding of 
statin induced muscle injury could help establish new therapies and strategies in prevention of statin 
related muscle injury. Ultimately, better understanding of statin-related muscle complaints would help 
tailor therapy and improve adherence, critical to reducing the burden of atherosclerotic cardiovascular 
disease. 
 
 
14. Biostatistics: Unpaired nonparametric tests will be used to compare data from both groups in 
substudy 2. P < 0.05 will be the significant threshold. 
 
 
 


Main Protocol v1.0, Jan16 
Page 10 of 10 
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