Statin Monotherapy for Treatment of Endocrine Metabolic Disease Risk (RoBaCO)

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

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.

Study Overview

• Status: Active, not recruiting
• Conditions: Metabolic Syndrome; Osteoporosis; Spinal Cord Injuries
• Intervention / Treatment: Drug: Rosuvastatin Calcium; Dietary supplement: Coenzyme Q10; Dietary supplement: Calcium Carbonate; Dietary supplement: Vitamin D; Drug: Placebo Oral Tablet

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 8
• Phase: Phase 2

Contacts and Locations

Study Locations

• Canada
  • Ontario
    • Toronto, Ontario, Canada, M4G 3V9
      • University Health Network - Toronto Rehab Lyndhurst Centre
• United States
  • Florida
    • Miami, Florida, United States, 33136
      • University of Miami Miller School of Medicine

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years to 58 years (Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Placebo	Dietary supplement: Coenzyme Q10; 100mg CoQ10, daily for 12 months; Dietary supplement: Calcium Carbonate; 1250mg Calcium Carbonate, daily for 12 months; Dietary supplement: Vitamin D; 2000IU Vitamin D, daily for 12 months; Drug: Placebo Oral Tablet; Placebo, daily for 12 months
Active Comparator: Rosuvastatin	Drug: Rosuvastatin Calcium; 10mg Rosuvastatin, daily for 12 months; Dietary supplement: Coenzyme Q10; 100mg CoQ10, daily for 12 months; Dietary supplement: Calcium Carbonate; 1250mg Calcium Carbonate, daily for 12 months; Dietary supplement: Vitamin D; 2000IU Vitamin D, daily for 12 months

What is the study measuring?

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)

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Changes in visceral adipose tissue	Whole Body DXA assessment of body composition	Baseline and 12 months (or study completion)
Changes in lean mass	Whole Body DXA assessment of body composition	Baseline and 12 months (or study completion)
Changes in aortic arterial stiffness	Assessment of Aortic Pulse Wave Velocity (aPWV)	Baseline and 12 months (or study completion)

Collaborators and Investigators

• Sponsor: Dr. B. Catharine. Craven
• Collaborators: University Health Network, Toronto; University of Miami; Toronto Rehabilitation Institute; The Craig H. Neilsen Foundation; Rick Hansen Institute
• Investigators: Principal Investigator: B. Catharine Craven, BA, MD, FRCPC, MSc, Toronto Rehabilitation Institute - UHN

Study record dates

Study Major Dates

• Study Start (Actual): February 26, 2018
• Primary Completion (Anticipated): December 1, 2022
• Study Completion (Anticipated): December 1, 2022

Study Registration Dates

• First Submitted: April 3, 2017
• First Submitted That Met QC Criteria: April 10, 2017
• First Posted (Actual): April 14, 2017

Study Record Updates

• Last Update Posted (Actual): October 20, 2021
• Last Update Submitted That Met QC Criteria: October 19, 2021
• Last Verified: October 1, 2021

More Information

Terms related to this study

• Keywords: Spinal Cord Injury; Osteoporosis; Cardiometabolic Syndrome
• Additional Relevant MeSH Terms: Glucose Metabolism Disorders; Metabolic Diseases; Central Nervous System Diseases; Nervous System Diseases; Wounds and Injuries; Musculoskeletal Diseases; Trauma, Nervous System; Spinal Cord Diseases; Insulin Resistance; Hyperinsulinism; Bone Diseases; Bone Diseases, Metabolic; Metabolic Syndrome; Osteoporosis; Spinal Cord Injuries; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antimetabolites; Gastrointestinal Agents; Micronutrients; Anticholesteremic Agents; Hypolipidemic Agents; Lipid Regulating Agents; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Vitamins; Bone Density Conservation Agents; Calcium-Regulating Hormones and Agents; Antacids; Vitamin D; Rosuvastatin Calcium; Calcium; Calcium, Dietary; Calcium Carbonate; Coenzyme Q10; Ubiquinone
• Other Study ID Numbers: 2016-350642

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No