Statin Monotherapy for Treatment of Endocrine Metabolic Disease Risk
Kata kunci
Abstrak
Deskripsi
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.
tanggal
| Terakhir Diverifikasi: | 09/30/2018 |
| Pertama Dikirim: | 04/02/2017 |
| Perkiraan Pendaftaran Telah Dikirim: | 04/09/2017 |
| Pertama Diposting: | 04/13/2017 |
| Pembaruan Terakhir Dikirim: | 10/29/2018 |
| Pembaruan Terakhir Diposting: | 10/31/2018 |
| Tanggal Mulai Studi Sebenarnya: | 02/25/2018 |
| Perkiraan Tanggal Penyelesaian Utama: | 11/30/2020 |
| Perkiraan Tanggal Penyelesaian Studi: | 11/30/2020 |
Kondisi atau penyakit
Intervensi / pengobatan
Drug: Rosuvastatin
Drug: Placebo
Dietary Supplement: Coenzyme Q10
Dietary Supplement: Calcium Carbonate
Dietary Supplement: Vitamin D
Tahap
Kelompok Lengan
| Lengan | Intervensi / pengobatan |
|---|---|
| Active Comparator: Rosuvastatin | Drug: Rosuvastatin 10mg Rosuvastatin, daily for 12 months |
| Placebo Comparator: Placebo | Drug: Placebo Placebo, daily for 12 months |
Kriteria kelayakan
| Usia yang Layak untuk Belajar | 18 Years Untuk 18 Years |
| Jenis Kelamin yang Layak untuk Belajar | All |
| Menerima Relawan Sehat | Iya |
| Kriteria | 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. |
Hasil
Ukuran Hasil Utama
1. Change from Baseline in areal BMD of the knee region [Baseline and 12 months (or study completion)]
Ukuran Hasil Sekunder
1. Change from Baseline in Low density lipoprotein cholesterol (LDL) [Baseline and 12 months (or study completion)]
2. Change from Baseline in high density lipoprotein cholesterol (HDL) [Baseline and 12 months (or study completion)]
3. Change from Baseline in triglycerides (TG) [Baseline and 12 months (or study completion)]
4. Change from Baseline in total cholesterol [Baseline and 12 months (or study completion)]
5. Change from Baseline in High sensitivity C-reactive Protein (hsCRP) [Baseline and 12 months (or study completion)]
6. Change from Baseline in Interleukin-1ß (IL-1ß) [Baseline and 12 months (or study completion)]
7. Change from Baseline in interleukin-6 (IL-6) [Baseline and 12 months (or study completion)]
8. Change from Baseline in tumor necrosis factor - alpha (TNF-alpha) [Baseline and 12 months (or study completion)]
9. Change from Baseline in erythrocyte sedimentation rate (ESR) [Baseline and 12 months (or study completion)]
10. Change from Baseline in Bone Specific Alkaline Phosphatase (BALP) [Baseline, 6 months and 12 months (or study completion)]
11. Change from Baseline in C-telopeptide (CTX) [Baseline, 6 months and 12 months (or study completion)]
12. Change from Baseline in Sclerostin [Baseline, 6 months and 12 months (or study completion)]
13. Change from Baseline in RANK Ligand (RANK-L) [Baseline, 6 months and 12 months (or study completion)]
14. Change from Baseline in volumetric BMD of the tibia (pQCT) [Baseline and 12 months (or study completion)]
15. Change from Baseline in volumetric BMD of the tibia (HR-pQCT) [Baseline and 12 months (or study completion)]
Ukuran Hasil Lainnya
1. Changes in visceral adipose tissue [Baseline and 12 months (or study completion)]
2. Changes in lean mass [Baseline and 12 months (or study completion)]
3. Changes in aortic arterial stiffness [Baseline and 12 months (or study completion)]
