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

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ClinicalTrials.gov Identifier: NCT03113994
Recruitment Status : Recruiting
First Posted : April 14, 2017
Last Update Posted : November 1, 2018
Sponsor:
Collaborators:
The Craig H. Neilsen Foundation
Toronto Rehabilitation Institute
University Health Network, Toronto
University of Miami
Rick Hansen Institute
Information provided by (Responsible Party):
Dr. B. Catharine. Craven, Toronto Rehabilitation Institute

Tracking Information
First Submitted Date  ICMJE April 3, 2017
First Posted Date  ICMJE April 14, 2017
Last Update Posted Date November 1, 2018
Actual Study Start Date  ICMJE February 26, 2018
Estimated Primary Completion Date December 2020   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: April 10, 2017)
Change from Baseline in areal BMD of the knee region [ Time Frame: Baseline and 12 months (or study completion) ]
Dual Xray Absorptiometry (DXA) Assessment of areal bone mineral density (aBMD) of the knee region
Original Primary Outcome Measures  ICMJE Same as current
Change History Complete list of historical versions of study NCT03113994 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: July 23, 2018)
  • Change from Baseline in Low density lipoprotein cholesterol (LDL) [ Time Frame: Baseline and 12 months (or study completion) ]
    Serum assessment of LDL
  • Change from Baseline in high density lipoprotein cholesterol (HDL) [ Time Frame: Baseline and 12 months (or study completion) ]
    Serum assessment of HDL
  • Change from Baseline in triglycerides (TG) [ Time Frame: Baseline and 12 months (or study completion) ]
    Serum assessment of TG
  • Change from Baseline in total cholesterol [ Time Frame: Baseline and 12 months (or study completion) ]
    Serum assessment of cholesterol
  • Change from Baseline in High sensitivity C-reactive Protein (hsCRP) [ Time Frame: Baseline and 12 months (or study completion) ]
    Serum assessment of hsCRP
  • Change from Baseline in Interleukin-1ß (IL-1ß) [ Time Frame: Baseline and 12 months (or study completion) ]
    Serum assessment of IL-1ß
  • Change from Baseline in interleukin-6 (IL-6) [ Time Frame: Baseline and 12 months (or study completion) ]
    Serum assessment of IL-6
  • Change from Baseline in tumor necrosis factor - alpha (TNF-alpha) [ Time Frame: Baseline and 12 months (or study completion) ]
    Serum assessment of TNF-alpha
  • Change from Baseline in erythrocyte sedimentation rate (ESR) [ Time Frame: Baseline and 12 months (or study completion) ]
    Serum assessment of ESR
  • Change from Baseline in Bone Specific Alkaline Phosphatase (BALP) [ Time Frame: Baseline, 6 months and 12 months (or study completion) ]
    Serum assessment of BALP
  • Change from Baseline in C-telopeptide (CTX) [ Time Frame: Baseline, 6 months and 12 months (or study completion) ]
    Serum assessment of CTX
  • Change from Baseline in Sclerostin [ Time Frame: Baseline, 6 months and 12 months (or study completion) ]
    Serum assessment of Sclerostin
  • Change from Baseline in RANK Ligand (RANK-L) [ Time Frame: Baseline, 6 months and 12 months (or study completion) ]
    Serum assessment of RANK-L
  • Change from Baseline in volumetric BMD of the tibia (pQCT) [ Time Frame: Baseline and 12 months (or study completion) ]
    Peripheral Quantitative Computed Tomography (pQCT) assessment - Toronto Site Only
  • Change from Baseline in volumetric BMD of the tibia (HR-pQCT) [ Time Frame: Baseline and 12 months (or study completion) ]
    High Resolution Peripheral Quantitative Computed Tomography (HR-pQCT) assessment - Toronto Site Only
Original Secondary Outcome Measures  ICMJE
 (submitted: April 10, 2017)
  • Change from Baseline in Low density lipoprotein cholesterol (LDL) [ Time Frame: Baseline and 12 months (or study completion) ]
    Serum assessment of LDL
  • Change from Baseline in high density lipoprotein cholesterol (HDL) [ Time Frame: Baseline and 12 months (or study completion) ]
    Serum assessment of HDL
  • Change from Baseline in triglycerides (TG) [ Time Frame: Baseline and 12 months (or study completion) ]
    Serum assessment of TG
  • Change from Baseline in total cholesterol [ Time Frame: Baseline and 12 months (or study completion) ]
    Serum assessment of cholesterol
  • Change from Baseline in High sensitivity C-reactive Protein (hsCRP) [ Time Frame: Baseline and 12 months (or study completion) ]
    Serum assessment of hsCRP
  • Change from Baseline in Interleukin-1ß (IL-1ß) [ Time Frame: Baseline and 12 months (or study completion) ]
    Serum assessment of IL-1ß
  • Change from Baseline in interleukin-6 (IL-6) [ Time Frame: Baseline and 12 months (or study completion) ]
    Serum assessment of IL-6
  • Change from Baseline in tumor necrosis factor - alpha (TNF-alpha) [ Time Frame: Baseline and 12 months (or study completion) ]
    Serum assessment of TNF-alpha
  • Change from Baseline in erythrocyte sedimentation rate (ESR) [ Time Frame: Baseline and 12 months (or study completion) ]
    Serum assessment of ESR
  • Change from Baseline in Bone Specific Alkaline Phosphatase (BALP) [ Time Frame: Baseline and 12 months (or study completion) ]
    Serum assessment of BALP
  • Change from Baseline in C-telopeptide (CTX) [ Time Frame: Baseline and 12 months (or study completion) ]
    Serum assessment of CTX
  • Change from Baseline in Sclerostin [ Time Frame: Baseline and 12 months (or study completion) ]
    Serum assessment of Sclerostin
  • Change from Baseline in RANK Ligand (RANK-L) [ Time Frame: Baseline and 12 months (or study completion) ]
    Serum assessment of RANK-L
  • Change from Baseline in volumetric BMD of the tibia (pQCT) [ Time Frame: Baseline, 6 months and 12 months (or study completion) ]
    Peripheral Quantitative Computed Tomography (pQCT) assessment - Toronto Site Only
  • Change from Baseline in volumetric BMD of the tibia (HR-pQCT) [ Time Frame: Baseline, 6 months and 12 months (or study completion) ]
    High Resolution Peripheral Quantitative Computed Tomography (HR-pQCT) assessment - Toronto Site Only
Current Other Pre-specified Outcome Measures
 (submitted: April 10, 2017)
  • Changes in visceral adipose tissue [ Time Frame: Baseline and 12 months (or study completion) ]
    Whole Body DXA assessment of body composition
  • Changes in lean mass [ Time Frame: Baseline and 12 months (or study completion) ]
    Whole Body DXA assessment of body composition
  • Changes in aortic arterial stiffness [ Time Frame: Baseline and 12 months (or study completion) ]
    Assessment of Aortic Pulse Wave Velocity (aPWV)
Original Other Pre-specified Outcome Measures Same as current
 
Descriptive Information
Brief Title  ICMJE Statin Monotherapy for Treatment of Endocrine Metabolic Disease Risk
Official Title  ICMJE The Efficacy and Safety of Rosuvastatin for Modifying Bone Mass and Cardiometabolic Disease Outcomes
Brief Summary

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

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  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Condition  ICMJE
  • Spinal Cord Injuries
  • Osteoporosis
  • Metabolic Syndrome
Intervention  ICMJE
  • Drug: Rosuvastatin Calcium
    10mg Rosuvastatin, daily for 12 months
  • Drug: Placebo Oral Tablet
    Placebo, 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
Study Arms  ICMJE
  • Active Comparator: Rosuvastatin
    Interventions:
    • Drug: Rosuvastatin Calcium
    • Dietary Supplement: Coenzyme Q10
    • Dietary Supplement: Calcium Carbonate
    • Dietary Supplement: Vitamin D
  • Placebo Comparator: Placebo
    Interventions:
    • Drug: Placebo Oral Tablet
    • Dietary Supplement: Coenzyme Q10
    • Dietary Supplement: Calcium Carbonate
    • Dietary Supplement: Vitamin D
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: April 10, 2017)
54
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE December 2020
Estimated Primary Completion Date December 2020   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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

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 an oral or 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.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years to 60 Years   (Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Masae Miyatani, PhD 416-597-3422 ext 6304 masae.miyatani@uhn.ca
Contact: Lindsie Blencowe, MSc 416-597-3422 ext 6301 lindsie.blencowe@uhn.ca
Listed Location Countries  ICMJE Canada,   United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03113994
Other Study ID Numbers  ICMJE 2016-350642
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
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
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Responsible Party Dr. B. Catharine. Craven, Toronto Rehabilitation Institute
Study Sponsor  ICMJE Dr. B. Catharine. Craven
Collaborators  ICMJE
  • The Craig H. Neilsen Foundation
  • Toronto Rehabilitation Institute
  • University Health Network, Toronto
  • University of Miami
  • Rick Hansen Institute
Investigators  ICMJE
Principal Investigator: B. Catharine Craven, BA, MD, FRCPC, MSc Toronto Rehabilitation Institute - UHN
PRS Account Toronto Rehabilitation Institute
Verification Date October 2018

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP