Statin Myopathy Clinical Trial
Official title:
CoEnzyme Q10 in Statin Myopathy
Statins (such as simvastatin or Zocor) are the most effective and widely prescribed
medications to lower cholesterol levels and reduce the frequency of heart attacks, cardiac
deaths and strokes. Unfortunately, statins can cause muscle discomfort or pain called
"myalgia" in patients treated with these drugs. These symptoms often cause patients who need
these medications to stop taking the drug. The cause of statin muscle pain is not known, but
it is thought that a reduction of a vitamin-like substance called Coenzyme Q10 (CoQ10)
during statin treatment may play a role. CoQ10 is a vitamin like substance and is not a drug
approved and regulated by the Food and Drug Administration (FDA). This study will look at
the effects of CoQ10 supplements on individuals who develop muscle symptoms while on
simvastatin.
The investigators hope to test the hypothesis that CoQ10 supplementation compared to placebo
in patients with documented statin myalgia reduces the intensity of pain during statin
treatment.
Study Overview: We estimate, based on the calculations detailed below that 80 subjects with
documented statin myalgia will be required to test our hypothesis. Consequently, 135
patients with statin myopathic complaints will be recruited from the Cholesterol Management
Center at Hartford Hospital, newspaper and radio advertisements and contact with physicians'
offices. Subjects will be withdrawn from all lipid lowering medications for at least 4
weeks. Subjects will then have serum measured for baseline lipids, liver, kidney, and
thyroid function, creatine kinase (CK) and CoQ10 values and be randomized to treatment with
simvastatin 20 mg daily or matching placebo for up to 2 months. Subjects will be called
weekly to assess symptoms. Blood measurements will be repeated and treatment (simvastatin or
placebo) will stopped after 2 months or after subjects have experienced muscle symptoms
continuously for one week. After 4 weeks, subjects will cross over to the alternative
placebo or simvastatin treatment and the monitoring and measurement process will be
repeated. Those patients developing myalgia during statin treatment, but not during placebo,
will enter the CoQ10 study, again after 4 weeks off treatment. These subjects will have
serum lipids, liver, CK, vitamin D and CoQ10 levels measured, 4mL of blood sample will be
stored for future white blood cell analysis and they will undergo tests of muscle
performance and exercise capacity. They will then be randomized to placebo or CoQ10
treatment arms, "loaded" with placebo or CoQ10 to ensure adequate tissue levels for two
weeks, and then retreated with simvastatin 20 mg daily. Subjects will be called weekly to
inquire about muscle symptoms. Blood measurements will be repeated, another 4mL of blood
sample will be stored for future white blood cell analysis and treatment (simvastatin/CoQ10
or simvastatin/placebo) will be stopped after 2 months or after subjects have experienced
muscle symptoms continuously for one week. After 4 weeks subjects will cross over to the
alternative simvastatin/CoQ10 or simvastatin/placebo treatment and the monitoring and
measurement will be repeated. The primary endpoint will be the intensity of pain at eight
weeks, or after subjects have had continuous symptoms for a week (or less in the case of
intolerable symptoms), whichever comes first. We will also determine time in days to the
onset of repeat myopathic symptoms and measure muscle performance including skeletal muscle
strength and endurance and maximal aerobic exercise capacity using techniques used in our
present NIH funded research project The Effect of Statins on Skeletal Muscle Function (R01
HL081893). We will measure muscle strength, endurance and aerobic capacity because weakness
is a frequent, but largely unquantified, complaint among patients with statin myalgia and
its prevention with CoQ10 is therefore important. Also, some investigators have reported
changes in the rest and exercise respiratory exchange ratio (RER) with statin therapy
implying an alteration in cellular substrate metabolism with statins that may be influenced
by CoQ10 treatment.
Study Subjects: Subjects will be recruited from the Cholesterol Management Center, which
sees approximately 20 new patients weekly, the majority of whom have statin myalgia and who
are referred because of Dr. Thompson's expertise in this topic, via advertisements and by
physician contact by mail and email informing them of the study. Subjects will be reimbursed
$500 for their participation in the study.
Study Definition of Statin-Related Myopathic Complaints: Statin myopathic symptoms have been
poorly defined in the medical literature. For the purpose of this study, subjects will be
considered to have had prior statin related complaints and recruited for participation in
the study if all of the following occur:
1. They developed new myalgia, cramps, or muscle aching during statin treatment;
2. The symptoms resolved within 4 weeks of stopping the statin. Subjects meeting these
criteria will be recruited into the study. To ensure that only patients with documented
statin myalgia are entered into the CoQ10 trial, all subjects with a history of statin
myalgia will be treated for up to 8 weeks with simvastatin 20 mg daily or placebo in a
double-blind, cross-over protocol.
Those developing statin myalgia only during simvastatin treatment will be advanced to the
CoQ10 trial.
Throughout the study, subjects will be contacted by phone weekly to inquire about muscle
complaints using the Brief Pain Inventory (Short Form) (BPI-SF) (18). Results will be
recorded on paper forms and entered into the database. During the phone contacts, subjects
with symptoms for statin myopathy will have a CK level determined within 72 hours and while
on study drug. If the CK is > 10 times upper limits of normal (UNL), the standard diagnosis
of myositis, and is unassociated with recent exercise, the drug will be stopped and the
subject will undergo prompt repeat testing and be removed from the study. If the CK is < 10
UNL, the drug will be continued until the subject has had symptoms for 1 week to document
that the symptoms are not transitory. After 1 week of persistent symptoms or as soon as
possible if the patient has intolerable symptoms, the subject will undergo final testing and
have completed the study. This reduces undue subject burden such that subjects do not have
to maintain statin treatment for multiple weeks with pain symptoms. Subjects who do not
report recurrent symptoms will be treated for 8 weeks, at which time they will undergo final
testing and have completed the study.
Justification of Primary Endpoint: We will examine the ability of CoQ10 to reduce the
intensity of pain because many patients would remain on statin therapy if the discomfort
were tolerable. Consequently, increasing pain tolerability is a key clinical measure. We
selected 8 weeks of therapy for the simvastatin vs placebo and CoQ10 vs placebo sections of
the study because in the largest clinical study, the median time to onset of myalgia in
statin naïve subjects was 1 month and statin rechallenge typically reproduces symptoms more
rapidly. Consequently, most subjects with true statin myalgia will have clearly developed
symptoms at or before 8 weeks, the point at which study procedures are completed, allowing
us to accurately assess the impact of CoQ10 on muscle pain intensity. Except for chronic
aspirin use, commonly recommended in patients at risk for heart disease, or in patients
chronically using pain medications even off statin therapy, over the counter pain medication
use for myalgic or myopathic symptoms will be prohibited during the study.
Study outline:
135 Subjects with Prior Statin Complaints:Stop Cholesterol Drugs for at least 4 Weeks
Run-In: Initial - Simvastatin or Placebo
1. Phlebotomy: Lipids1, ALT, creatinine, TSH, CK, CKMB, Vitamin D and CoQ10
2. Arterial Stiffness
3. FMD/Nitroglycerin administration
4. Simvastatin 20 mg for 8 weeks or Until Symptoms Persist for 1 Week or are Intolerable
5. Obtain lipids and CK
**4-week washout followed by crossover and repeat 1 - 5**
**4-Week Washout**
**100 Subjects Symptomatic on Statins Only(CoQ10 treatment phase)**:
1. Phlebotomy: Lipids, ALT, creatinine, CK, CKMB, Vitamin D and CoQ10, 4mL sample stored
for future white blood cell analysis
2. Baseline Strength and Exercise Performance Testing, Accelerometer, Pain Questionnaire
3. Randomization to Treatment: Placebo or 600 mg CoQ10
4. Load Subjects for 2 weeks on Treatment
Simvastatin 20mg + Placebo (N=50) or Simvastatin 20mg + CoQ10 (N=50)
Weekly phone calls: Pain Questionaires
At 8 Weeks or Until Symptoms Persist 1 Week or are Intolerable:
1. Phlebotomy: Lipids, ALT, creatinine, CK, CKMB and CoQ10, Vitamin D, 4mL sample stored
for future white blood cell analysis
2. Arterial stiffness
3. Strength and Exercise Performance Testing,Accelerometer, Pain Questionnaire
**4 week washout followed by crossover, repeat 1-4 and 1-3 above**
Weekly phone calls used to assess muscle symptoms and document myalgia
All visits include a Cognitive Failures Questionnaire.
;
Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Primary Purpose: Basic Science
| Status | Clinical Trial | Phase | |
|---|---|---|---|
| Completed |
NCT01259791 -
Evaluation of Patients With Statin Myopathy Using an N of 1 Trial Design
|
N/A |