NIRS to Diagnose SAMS

Study Overview: Forty patients with possible SAMS will be recruited from the Cholesterol
Management Center at Hartford Hospital, advertisements and contact with physicians' offices.
Subjects will be withdrawn from all statin lipid lowering medications for at least 4 weeks.
Subjects will then undergo baseline testing (tissue oxygenation will be measured using NIRS
during a short handgrip exercise protocol) 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 of muscle pain and administer the Brief Pain Inventory (BPI). NIRS measurements will
be repeated and treatment (simvastatin or placebo) will be stopped after 2 months or after
subjects have experienced muscle symptoms continuously for one week. After 4 weeks washout,
subjects will again be randomized to simvastatin or placebo treatment and the monitoring and
measurement processes will be repeated (see study schematic below). Those patients developing
muscle symptoms during statin treatment but not during placebo treatment will be considered
to have confirmed SAMS. Investigators hypothesize that patients with confirmed SAMS will be
distinguished from all other patients with reduced tissue oxygenation during simvastatin
treatment relative to placebo, demonstrating efficacy of NIRS as a clinical tool that can be
eventually used for the diagnosis and ultimately treatment of SAMS.

Study Subjects: Statin myopathic symptoms have been poorly defined in the medical literature.
For the purpose of this study, investigators will use similar criteria as the previous CoQ10
in Statin Myopathy Study when recruiting eligible subjects. Subjects will be considered to
have had prior statin related complaints and recruited for participation in the study if the
following occurred: 1) They developed new myalgia, cramps, or muscle aching during statin
treatment; 2) The symptoms resolved within 4 weeks of stopping the statin; 3) The identical
symptoms recurred during repeat statin exposure. Investigators will recruit men and women ≥40
yrs of age, since older age is a risk factor for SAMS and 25% of U.S. adults ≥40 yrs report
statin use. Investigators will enroll equal numbers of men and women to improve the
generalizability of the results. Investigators will not exclude individuals with diagnosed
coronary artery disease, peripheral vascular disease, or an elevated CK off treatment<10
upper normal limit (UNL) because spontaneous elevations in CK levels are normal in the
general population. During the study, subjects will be contacted by phone weekly to inquire
about muscle complaints using the Brief Pain Inventory (Short Form) (BPI-SF). Results will be
recorded on paper forms and entered into the database. After 1 week of persistent symptoms or
as soon as possible if the patient has intolerable symptoms, the subject will undergo NIRS
testing and be taken off study drug. 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 4
weeks washout and move on to the crossover phase. Subjects will be reimbursed $200 for study.

Inclusion Criteria:

- Subjects >40 years of age, equal numbers of age, with a prior history of
statin-associated muscle symptoms (SAMS). Subjects will be considered to have had
prior statin related complaints and recruited for participation in the study if the
following occurred: 1) They developed new pain, cramps, or muscle aching during statin
treatment; 2) The symptoms resolved within 4 weeks of stopping the statin; 3) The
identical symptoms recurred during repeat statin exposure.

Exclusion Criteria:

Subjects who have had cancer within 5 years of entry, have hepatic disease (ALT > 2 times
normal) or renal disease (creatinine > 2 mg/L) since these patients may require more
careful monitoring during the study and would be best managed in a totally clinical setting

- Subjects presently treated with other medications known to alter statin metabolism;

- Subjects with hypo- or hyperthyroidism defined as a TSH > 5 or <0.01 IU/L since these
conditions are known to be associated with statin intolerance and muscle weakness,
respectively;1,2

- Subjects with hepatic dysfunction evidenced by a baseline alanine aminotransferase
(ALT) level > 2 UNL;1,2

- Subjects with renal dysfunction defined as a baseline creatinine > 2mg/dl;

- Subjects with physical disabilities prohibiting the handgrip protocol;

- Women who are pregnant as determined by a urine pregnancy test using an Accutest Early
Pregnancy Test Kit, or who are trying to become pregnant, and/or who have not been
using a form of birth control for at least the last 3 months, since the impact of
statins on pregnancy-related outcomes has not been well studied;1

- Subjects who regularly use corticosteroids or other drugs known to affect skeletal
muscle metabolism or regularly have intramuscular injections that will affect CK
levels.

Subjects who are unwilling to limit their alcohol intake to an average of two or less
drinks daily.