Statin Monotherapy for Treatment of Endocrine Metabolic Disease Risk
Statin Monotherapy for Treatment of Endocrine Metabolic Disease Risk
Rationale: After having a spinal cord injury (SCI), people develop changes in their body
 composition that influences their long-term health. Individuals with paralysis after SCI will
 have large declines in their bone density ant increases in fat mass which increases their
 risk of fracture and heart disease. Therapies to prevent SCI-related changes in body
 composition and their health effects are needed. Drugs known as "statins" used often to
 reduce high cholesterol, may help to reduce bone loss and inflammation.

 Hypothesis: Among adults with SCI for a long time, treatment with a drug named Rosuvastatin
 or a sugar pill, with supplements (coenzyme Q10, calcium and vitamin D), for twelve months
 can decrease their endocrine metabolic disease risk by increasing bone density and reducing
 inflammation.

 Study Design: A clinical trial will be conducted in Toronto, Ontario and Miami, Florida.
 Subjects will get statin therapy or placebo (sugar pill) by chance. Study subjects and
 research staff will not know whether they are taking the study drug or a sugar pill until
 after the study

 Subjects: Fifty-four adults (age 18-60 years) with a long-term SCI and no movement below
 their level of injury.

 Treatment: Subjects will be prescribed Rosuvastatin 10 mg daily or a sugar pill. In addition,
 all subjects will receive 100 mg of Co-Q10 daily, calcium carbonate 1250 mg and, vitamin D
 2,000 IU once a day.

 Data Collected: Subjects' bone density will be collected at the start and end of the study.
 Change in bone density between the two groups will be compared to see if one is better. Blood
 samples will be collected quarterly to make sure subjects are safe and do not develop
 problems with their liver or muscles and to measure the effects of the study drugs on
 inflammation throughout the body.

 Clinical Implications: Statins may be safe and effective therapy for adults living with SCI
 who are at increased risk of endocrine metabolic disease as they age.
Rationale: Individuals with motor-complete spinal cord injury (SCI) undergo dramatic changes
 in body composition in the first 18 months post-injury, including declines in bone mineral
 density (BMD) that increase lower-extremity fragility fracture risk, and increases in fat
 mass that increase cardio-metabolic disease (CMD) risk. While statins are an effective
 treatment for dyslipidemia, research evidence suggests additional pleiotropic effects on bone
 through promotion of osteogenesis, suppression of osteoblast apoptosis, and inhibition of
 osteoclastogenesis. There are currently no effective therapies to treat sublesional
 osteoporosis (SLOP) and reduce the risk of fragility fractures in individuals with SCI.

 Hypothesis: Twelve months of statin therapy with concurrent coenzyme Q10 (CoQ10), to reduce
 risk of statin neuromyotoxicity, and standard care (calcium 1250mg OD and vitamin D3 2000IU
 OD) will be superior to placebo with CoQ10 and standard care, for augmenting knee region BMD
 and reducing inflammatory stress (hs-CRP), thereby reducing endocrine metabolic disease risk.

 Objective: To determine the safety and efficacy of statin therapy for augmenting distal
 femoral BMD among adults with chronic motor-complete SCI in Toronto, Ontario and Miami,
 Florida.

 Study Design: Multi-centre, double-blind, randomized controlled Phase II safety and efficacy
 trial.

 Subjects: Consenting men and premenopausal women (N=54, age 18-60 yrs) with chronic (≥2
 years) spinal cord injury with a neurological level between C1-T10 and an AIS category of
 A/B.

 Intervention: Rosuvastatin 10 mg po daily at night versus placebo for 12 months. All subjects
 will receive osteoporosis standard care (calcium carbonate 1250mg po daily and vitamin D3
 2000 IU po daily) to maintain bone mass and CoQ10 100mg po daily to prevent statin-induced
 myopathy.

 Outcomes: Primary safety outcomes: i) establish the safety of rosuvastatin in chronic SCI by
 reporting the frequency of myotoxicity and type II diabetes onset; ii) frequency and mean
 duration of liver transaminase elevations in the rosuvastatin and placebo groups. Primary
 efficacy outcome: measure the mean between group absolute changes in distal femur areal BMD
 (aBMD, g/cm2) from baseline to one year. Secondary efficacy outcomes: will examine the mean
 absolute changes from baseline in: i) volumetric BMD (vBMD, g/cm3); ii) markers of bone
 turnover - Bone Specific Alkaline Phosphatase (BALP), telopeptide (CTX), Sclerostin and RANK
 Ligand (RANK-L); iii) serum inflammatory markers including high sensitivity C-reactive
 Protein (hs-CRP), Interleukin-1ß (IL-1ß). interleukin-6 (IL-6), tumor necrosis factor - alpha
 (TNF-alpha), erythrocyte sedimentation rate (ESR); and, iv) lipid profile; low density
 lipoprotein cholesterol (LDL), high density lipoprotein cholesterol (HDL), triglycerides, and
 total cholesterol Clinical Implications: Should rosuvastatin prove to be safe and efficacious
 for reducing endocrine metabolic disease risk for adults with chronic SCI, the results will
 advance the health of people with SCI by reducing the frequency and severity of heart disease
 and fracture as they age, with a single intervention.
Inclusion Criteria:

 -  Adult (age 18-60 years)

 -  Motor complete SCI (C1-T10 AIS A/B)

 -  2 years post-injury

 -  Have a telephone, and ability to attend the study visits

 -  Able to take oral medications and swallow independently

 -  Can provide free and informed consent

 -  Ability to understand instructions in English

 -  May report current use of oral alendronate 10mg daily or 70mg weekly or risedronate
 5mg daily, 30mg weekly or 150mg monthly

 Exclusion Criteria:

 These criteria are intended to exclude those in whom; Rosuvastatin would be unsafe,
 DXA/pQCT measurement or biomarker assessment would be invalid, or in whom other co-morbid
 health conditions may confound the study results. Exclusion criteria include:

 -  Current and/or one year prior to enrolment treatment with any statin such as
 atorvastatin, fluvastatin, lovastatin, pitavastatin, pravastatin, simvastatin and
 rosuvastatin.

 -  Current treatment with IV bisphosphonate, denosumab, recombinant PTH, ovarian hormone
 therapy, an oral contraceptive, Immunosuppressants (Including Cyclosporine) and
 fusidic acid.

 -  Known allergy to Rosuvastatin, lactose powder, CoQ10, calcium carbonate, vitamin D2
 and vitamin D3, or any other ingredient found in rosuvastatin, placebo or study
 supplements.

 -  History of Paget's disease, osteomalacia, steroid induced osteoporosis, or untreated
 parathyroid or untreated thyroid disease.

 -  Subjects with history of stage 4 chronic kidney disease. (124)

 -  Current Weight ≥136 kg.

 -  Bilateral knee region metal implants (hardware), history of bilateral knee region
 contracture >30 degrees, fracture or any other bilateral knee region pathology which
 would preclude accurate DXA assessment of one limb.

 -  Post-menopausal women (absence of menses for a minimum of 1 year).

 -  Women with amenorrhea due to bilateral surgical removal of the ovaries and/or uterus
 (women with amenorrhea due to spinal cord injury are able to participate).

 -  Pregnancy or lactation.

 -  Female of child-bearing potential who is engaged in active heterosexual relations and
 is not using appropriate birth control methods. Appropriate methods of birth control
 will include: surgical sterilization at least 6 months prior to using study drug or
 sexual activity restricted to a vasectomized partner, barrier contraception with a
 condom or diaphragm in conjunction with spermicidal gel in use at least 30 days prior
 to using study drug OR sexual abstinence as a lifestyle.

 -  History of liver disease or abnormal Aspartate Aminotransferase (AST) or Alanine
 Aminotransferase (ALT), ≥1.5 times the upper limit of the normal reference range at
 enrolment.

 -  History of symptomatic hypocalcemia or hypophosphatemia.

 -  Concurrent treatment with prednisone (>7.5mg/day for 90 days).

 -  Vitamin D deficiency (Serum Vitamin D level <75nmol/L) after completing 8 to 12 weeks
 of treatment for Vitamin D deficiency as per the Vitamin D correction protocol
 (Appendix Page 1).

 -  History of heart attack or stroke.

 -  Untreated hypertension defined as: elevated BP above (135/85mmHg) assessed with an
 automated blood pressure cuff at 3 distinct time points in a 7-10 day period.(125,
 126)

 -  Current alcohol or street drug abuse.

 -  Any illness or condition interfering with the trial conduct or subject safety.