SALTIRE II: Bisphosphonates and RANKL Inhibition in Aortic Stenosis
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 入组人数
- 152
- 试验地点
- 1
- 主要终点
- Change in aortic valve calcium score
研究概览
简要总结
Aortic stenosis is a condition whereby one of the heart valves (aortic valve) becomes narrowed, due to calcium deposition, over time. This can lead to chest pain, heart failure and sudden death. It is the commonest valve disease requiring surgery in the developed world and as the population becomes increasingly older, it is predicted that the prevalence of aortic stenosis will double in the next 20 years. Currently the only treatment is replacement of the aortic valve. Whilst this is excellent treatment, not everyone is suitable for it.
The primary objective of our study is to determine whether 2 drugs used in the treatment of osteoporosis (a condition of bone thinning) can halt/retard the progression of aortic stenosis. This is on the basis that studies have suggested that altered regulation of calcium metabolism may be an important mechanism perpetuating the disease. Both drugs work by reducing calcium release into the bloodstream from bones and therefore calcification of the aortic valve.
150 patients will therefore be randomly allocated to either of the trial drugs which are denosumab,the bisphosphonate (alendronic acid), or a placebo.
Positron Emission Tomography (PET) scanning is a technique where biochemically active molecules are injected and are taken up at sites of ongoing calcification activity where they emit radiation and can be detected by the PET scanner. We have previously shown that this technique can demonstrate areas of newly developing calcification on an aortic valve.
We therefore propose that patients receiving bisphosphonates or denosumab will have reduced evidence of active calcification and slower progression of their disease at two years as assessed by Echocardiography (ultrasound) and a change in their calcium score (quantity of calcium on the aortic valve measured using Computed Tomography [CT] ).
The data from this study will then be used to design a larger trial.
详细描述
BACKGROUND Aortic Stenosis is a common cause of valvular heart disease in which the valve cusps become progressively calcified. The only available treatment is aortic valve replacement and previous attempts at providing medical therapies to modify the disease process have proved unsuccessful.
Pathophysiology of Aortic Stenosis. The initiating event is believed to be caused by mechanical damage to the cells lining the valve in a process similar to that which occurs in atherosclerosis. However the propagating mechanism is more likely to be that of active calcification. In support of this, a growing body of pre-clinical and clinical data indicates that treatments for osteoporosis, which work by preventing the breakdown of bone and therefore calcium release into the blood, can reduce calcium deposition (calcification) of the blood vessels. These agents therefore hold considerable promise as novel therapies for aortic stenosis.
Denosumab in Aortic Stenosis Denosumab is a drug which prevents bone cells called osteoclasts from breaking down bone and releasing calcium into the blood. For this reason it is used to treat osteoporosis. It works on a specific pathway which we believe to be important in regulating calcium release from bone. Mice engineered with defects within this pathway were found to have increased bone breakdown and blood vessel calcification. Furthermore there have been two studies to assess the role of this pathway in patients with aortic valve disease. Both studies have also demonstrated altered regulation within this pathway
Bisphosphonates in Aortic Stenosis Bisphosphonates are a group of drugs widely used for the treatment of osteoporosis and also prevent bone breakdown by osteoclasts. They have also been shown to have important cardiovascular effects with a consistent reduction in calcification of blood vessels and the aortic valve. This in part appears to be a consequence of their inhibition of bone breakdown but also by reducing the production of key inflammatory substances implicated in the early stages of aortic stenosis. We plan on using alendronic acid which is a bisphosphonate commonly used in the management of osteoporosis.
PET CT scanning in Aortic Stenosis. 18F-NaF (Sodium Fluoride) is biochemical compound which preferentially binds to regions of newly developing calcification and emits radiation. When used in combination with Computed Tomography (CT) it enables it to be localized. This way we are able to identify areas of newly developing calcification on an aortic valve.
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
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
入排标准
- 年龄范围
- 50 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •age >50 years
- •peak aortic jet velocity of >2.5 m/s on Doppler echocardiography
- •grade 2-4 calcification of the aortic valve on echocardiography
排除标准
- •Anticipated or planned aortic valve surgery in the next 6 months,
- •Life expectancy <2 years,
- •Inability to undergo scanning
- •Treatment for osteoporosis with bisphosphonates or denosumab.
- •Long-term corticosteroid use.
- •Abnormalities of the oesophagus or conditions which delay oesophageal/gastric emptying,
- •Inability to sit or stand for at least 30 minutes, 9) Known allergy or intolerance to alendronate or denosumab, or any of their excipients, 10) Hypocalcaemia, 11) Maintenance calcium supplementation, 12) Dental extraction within 6 months, 13) History of osteonecrosis of the jaw, 14) Major or untreated cancers, 15) Poor dental hygiene, 16) Women of child-bearing potential who have experienced menarche, are pre-menopausal, have not been sterilised or who are currently pregnant, 17) Women who are breastfeeding, 18) Renal failure (estimated glomerular filtration rate of <30 mL/min), 19) Allergy or contraindication to iodinated contrast, 20) Inability or unwilling to give informed consent, 21) Likelihood of non-compliance to treatment allocation or study protocol
研究组 & 干预措施
Alendronic Acid
50 patients will receive once weekly Alendronic Acid tablets (70mg).
干预措施: Alendronic Acid (Drug)
Alendronic Acid placebo
25 patients will receive alendronic acid placebo tablets.
干预措施: Alendronic Acid Placebo (Drug)
Denosumab
50 patients will receive 6 monthly denosumab injections
干预措施: Denosumab (Drug)
Denosumab Placebo
25 patients will receive a 6 monthly placebo injection.
干预措施: Denosumab Placebo (Drug)
结局指标
主要结局
Change in aortic valve calcium score
时间窗: Measured at Baseline, 6 months and 2 years
The change in calcium score will be assessed using computed tomography and is an assessment of disease severity.
次要结局
- Change in aortic valve 18F-NaF uptake(Measured at baseline and 6 months)
- Change in quality of life determined by Short Form 36 Questionnaire(Measured at baseline and 2 years)
- Change in aortic-jet velocity(Measured at baseline, 6, 12, 18 and 24 months)
- Change in thoracic aortic and coronary artery calcium score(Measured at baseline and 2 years)
- Change in thoracic spine bone mineral density(Measured at baseline and 2 years)