SENolytics to Improve Osteoporosis Therapy: a Randomised Controlled Clinical Trial The SENIOR Trial
试验速览
- 阶段
- 2 期
- 状态
- 进行中（未招募）
- 入组人数
- 120
- 试验地点
- 1
- 主要终点
- Bone resorption marker CTX
研究概览
简要总结
This randomised clinical trial aims to study osteoporosis as a disease of accelerated skeletal aging caused by the accumulation of senescent cells within the skeleton and investigate the effects and safety of senolytics and antioxidant therapy on bone.
详细描述
Background, hypothesis, and aim:
Evidence suggests that it is feasible to alleviate chronic age-related disorders by targeting the biology of aging. Recent studies implicate cellular senescence at the nexus of skeletal aging, suggesting that selectively eliminating senescent cells may emerge as a conceptually novel approach to manage the enormous problem of age-related bone loss. In addition, previous studies have demonstrated that antioxidants inhibit cellular senescence. The aim of this randomised clinical trial is to study osteoporosis as a disease of accelerated skeletal aging caused by accumulation of senescent cells within the skeleton and investigate the effects and safety of senolytics and antioxidant therapy on bone.
The main trial endpoint is the percent change in circulating marker of bone resorption (CTX) measured at baseline and at week 21. Secondary endpoints are the changes in bone resorption marker tartrate resistant acid phosphatase (TRAcP) and bone formation markers (PINP, osteocalcin, and bone alkaline phosphatase) measured at baseline and at 21 weeks.
Trial design:
The study design is a randomised controlled open-label clinical trial. Study participants will be randomised 1:1:1 to one of three treatment groups, that will include either,
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Single (Outcomes Assessor)
入排标准
- 年龄范围
- 60 Years 至 90 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Men and women (menopause > 5 years and FSH and LH in the postmenopausal range) aged 60-90 years with increased fracture risk according to WHO 10 years absolute Fracture Risk Assessment Tool (FRAX)
- •Osteopenia (ICD10 DM858A) based on a T-score ≤ -1 to -2.5 at the total hip/femoral neck, or lumbar spine, with or without a fragility fracture at any time (excluding hip and vertebral fractures within the last 2 years)
- •osteoporosis (ICD10 DM819) based on a T-score between ≥-3 and ≤ -2.5, which includes candidates suitable for conventional osteoporosis therapies, but who prefer to participate in the trial, despite being candidates for conventional osteoporosis therapy, or candidates which cannot be treated with conventional therapies due to contraindications
- •Ability to provide informed consent
排除标准
- •DXA of hip or spine not possible e.g., due to a prosthesis
- •Inability to provide fasting blood samples
- •Primary hyperparathyroidism
- •Vitamin D deficiency (<50 nM) (re-test after substitution acceptable)
- •Known disorders affecting bone metabolism, e.g., uncontrolled thyrotoxicosis, chronic kidney disease defined as eGFR <30 or liver dysfunction, rheumatism, celiac disease/malabsorption, hypogonadism, severe COPD, hypopituitarism, Cushing's disease, uncontrolled diabetes (HbA1c > 58 mmol/mol).
- •Antiresorptive or bone anabolic drugs for the last 2 years (5 years if treated with zoledronic acid)
- •Concomitant treatments known to influence bone metabolism e.g., glucocorticoids (systemic treatments), anabolic steroids, etc.
- •Subjects taking the following other drugs if they cannot be held for at least 2 days before and during administration of D+Q: digoxin, lithium, all statins, repaglidine, bosentan, gemfibrozil, olmesartan, enalapril, valsartan, methotrexate, corticosteroids, eluxadoline, eltrombopag, nitroglycerin, pioglitazone, glyburide, enzalutamide, ezetimibe, colchicine, imatinib, cyclosporine, tacrolimus, sirolimus, carbamazepine, flecainide, phenytoin, phenobarbital, rifampicin, theophylline, warfarin, heparin, clopidogrel, celecoxib, desipramine, thioridazine, venlafaxine, tizanidine, atomoxetine, voriconazole, citalopram, diazepam, escitalopram, propranolol, clozapine, cyclobenzaprine, mexiletine, olanzapine, ondansetron
- •Subjects taking medications that are sensitive to substrates or substrates with a narrow therapeutic range for CYP3A4, CYP2C8, CYP2C9, or CYP2D6 or strong inhibitors or inducers of CYP3A4 (e.g., cyclosporine, tacrolimus or sirolimus). If antifungals are necessary from an infectious disease perspective, then they will be allowed only if the levels are therapeutic.
- •Subjects taking proton pump inhibitors and unwilling to discontinue therapy for two days before and during the study drug dosing periods.
- •Anti-arrhythmic medications known to cause QTc prolongation
- •Tyrosine kinase inhibitor therapy
- •Subjects with an abnormal Complete Blood Count (clinically insignificant changes would be acceptable based on the judgement of the investigators)
- •Subjects on antiplatelet agents (Clopidogrel; Dipyridamole + ASA; ASA, Ticagrelor; Prasugrel; Ticlopidine or other) who are unable or unwilling to reduce or hold therapy prior to and during the study drug dosing periods and collection of bone biopsies. Subjects may continue their previous regimen between study drug dosing periods.
- •Known allergy to dasatinib, quercetin, or nicotinamide riboside
- •Subjects taking the following antimicrobial agents: Aminoglycosides, Azole antifungals (fluconazole, miconazole, voriconazole, itraconazole), Macrolides (clarithromycin, erythromycin), antivirals (nelfinavir, indinavir, saquinavir, ritonavir, elbasvir/grazoprevir)
- •Presence of any condition the Investigator believes would place the subject at risk or would preclude the subject from successfully completing all aspects of the trial e.g., heart failure, malignancy etc.
- •QTc >470 msec
- •Inability to take oral medication
- •The study will exclude subjects with inability to speak and understand Danish and with inability to cooperate
研究组 & 干预措施
Nicotinamide Riboside (NR)
The participants will receive treatment with 1g Nicotinamide Riboside (oral) daily for 20 weeks
干预措施: Nicotinamide Riboside 1g (oral) (Dietary Supplement)
Control
The participants in the Control group, will not receive any treatment for 20 weeks.
Dasatinib plus Quercetin (DQ)
Study participants will receive a combination of 100 mg/d dasatinib (oral) for two consecutive days and 1.250 mg/d quercetin (oral) for three consecutive days followed by 25 days without treatment, with treatment being repeated every 4 weeks for a total of 20 weeks (i.e., 5 times)
干预措施: Quercetin 1.250 mg (oral) (Dietary Supplement)
Dasatinib plus Quercetin (DQ)
Study participants will receive a combination of 100 mg/d dasatinib (oral) for two consecutive days and 1.250 mg/d quercetin (oral) for three consecutive days followed by 25 days without treatment, with treatment being repeated every 4 weeks for a total of 20 weeks (i.e., 5 times)
干预措施: Dasatinib 100 Mg Oral Tablet (Drug)
结局指标
主要结局
Bone resorption marker CTX
时间窗: Baseline, week 5, week 13, week 21
Change in circulating marker of bone resorption C-terminal telopeptide of type I collagen (CTX) at 21 weeks.
次要结局
- Bone resorption marker TRAcP(Baseline, week 5, week 13, week 21)
- Bone formation markers (PINP, osteocalcin, and bone alkaline phosphatase)(Baseline, week 5, week 13, week 21)