Statin Monotherapy for Treatment of Endocrine Metabolic Disease Risk

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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The Efficacy and Safety of Rosuvastatin for Modifying Bone Mass and Cardiometabolic Disease Outcomes

Conditions
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Spinal Cord Injuries, Osteoporosis, Metabolic Syndrome

Intervention / Treatment
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* Drug: Rosuvastatin Calcium
* Drug: Placebo Oral Tablet
* Dietary Supplement: Coenzyme Q10
* Dietary Supplement: Calcium Carbonate
* Dietary Supplement: Vitamin D


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 60 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Rosuvastatin<br> | Drug: Rosuvastatin Calcium<br>* 10mg Rosuvastatin, daily for 12 months<br>Dietary Supplement: Coenzyme Q10<br>* 100mg CoQ10, daily for 12 months<br>Dietary Supplement: Calcium Carbonate<br>* 1250mg Calcium Carbonate, daily for 12 months<br>Dietary Supplement: Vitamin D<br>* 2000IU Vitamin D, daily for 12 months<br>|
| Placebo Comparator: Placebo<br> | Drug: Placebo Oral Tablet<br>* Placebo, daily for 12 months<br>Dietary Supplement: Coenzyme Q10<br>* 100mg CoQ10, daily for 12 months<br>Dietary Supplement: Calcium Carbonate<br>* 1250mg Calcium Carbonate, daily for 12 months<br>Dietary Supplement: Vitamin D<br>* 2000IU Vitamin D, daily for 12 months<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change from Baseline in areal BMD of the knee region | Dual Xray Absorptiometry (DXA) Assessment of areal bone mineral density (aBMD) of the knee region | Baseline and 12 months (or study completion) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change from Baseline in Low density lipoprotein cholesterol (LDL) | Serum assessment of LDL | Baseline and 12 months (or study completion) | 
| Change from Baseline in high density lipoprotein cholesterol (HDL) | Serum assessment of HDL | Baseline and 12 months (or study completion) | 
| Change from Baseline in triglycerides (TG) | Serum assessment of TG | Baseline and 12 months (or study completion) | 
| Change from Baseline in total cholesterol | Serum assessment of cholesterol | Baseline and 12 months (or study completion) | 
| Change from Baseline in High sensitivity C-reactive Protein (hsCRP) | Serum assessment of hsCRP | Baseline and 12 months (or study completion) | 
| Change from Baseline in Interleukin-1ß (IL-1ß) | Serum assessment of IL-1ß | Baseline and 12 months (or study completion) | 
| Change from Baseline in interleukin-6 (IL-6) | Serum assessment of IL-6 | Baseline and 12 months (or study completion) | 
| Change from Baseline in tumor necrosis factor - alpha (TNF-alpha) | Serum assessment of TNF-alpha | Baseline and 12 months (or study completion) | 
| Change from Baseline in erythrocyte sedimentation rate (ESR) | Serum assessment of ESR | Baseline and 12 months (or study completion) | 
| Change from Baseline in Bone Specific Alkaline Phosphatase (BALP) | Serum assessment of BALP | Baseline, 6 months and 12 months (or study completion) | 
| Change from Baseline in C-telopeptide (CTX) | Serum assessment of CTX | Baseline, 6 months and 12 months (or study completion) | 
| Change from Baseline in Sclerostin | Serum assessment of Sclerostin | Baseline, 6 months and 12 months (or study completion) | 
| Change from Baseline in RANK Ligand (RANK-L) | Serum assessment of RANK-L | Baseline, 6 months and 12 months (or study completion) | 
| Change from Baseline in volumetric BMD of the tibia (pQCT) | Peripheral Quantitative Computed Tomography (pQCT) assessment - Toronto Site Only | Baseline and 12 months (or study completion) | 
| Change from Baseline in volumetric BMD of the tibia (HR-pQCT) | High Resolution Peripheral Quantitative Computed Tomography (HR-pQCT) assessment - Toronto Site Only | Baseline and 12 months (or study completion) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Spinal Cord Injury, Osteoporosis, Cardiometabolic Syndrome