A Pilot,Randomized Controlled-trial of Lipoprotein(a) Lowering for the Prevention of Aortic Valve Disease-translating Genomic Knowledge for Cardiovascular Prevention
试验速览
- 阶段
- 早期 1 期
- 状态
- 撤回
- 发起方
- 试验地点
- 3
- 主要终点
- Calcium score progression by cardiac CT in individuals randomized to niacin as compared to those randomized to placebo
研究概览
简要总结
Aortic valve disease is the most common form of heart valve disease and is a major burden to society. Aortic valve disease is also expected to become more prevalent with the aging of the Canadian population. Currently, over 1 million individuals in North America have aortic stenosis, which is a narrowing of the aortic valve, and leads to symptoms of heart failure and sometimes death. Valve replacement with its potential costs and complications remains the only avenue for treatment, once symptoms develop. Despite the major importance of this disease, there are currently no medical treatments to prevent the development of aortic stenosis.The lack of preventative treatments stems in large part to a poor understanding of the causes of this disease.
Using cutting-edge genetic technologies, the investigators have recently identified that individuals with a genetic predisposition to elevations in a type of cholesterol not normally screened, called lipoprotein(a), have a much higher risk of developing aortic valve disease. The investigators have also shown that lipoprotein(a) causes hardening of the valve, a very early sign of valve narrowing. The investigators plan to evaluate in a randomized controlled trial whether lowering this unusual form of cholesterol at an early stage of this disease could slow or stop the development of aortic valve narrowing
The investigators are currently proposing a pilot project to evaluate the feasibility of this type of study. If successful, our proposed treatment would be notable in two ways. First, it would represent the first medical treatment to prevent valve disease, which could lead to major reductions in the societal burden of this important disease. And second, it would herald a major success for genomic medicine as it would represent one of the first treatments borne from recent genetic studies. In these ways, our proposal could significantly impact the health of many Canadians while also highlighting the innovative research performed in Canada.
Recruitment (n=238) for this project will be from the echocardiography laboratories of McGill University affiliated hospitals. Individuals with aortic sclerosis or mild aortic stenosis (aortic valve area [AVA] >1.5 cm2, mean gradient [MG] < 25 mmHG) and high Lp(a) will be eligible for inclusion into this proposed study.
详细描述
Screening: Potentially eligible participants from the echocardiography laboratory will be screened by a member of the research team for inclusion and exclusion criteria and will be asked to review and sign a consent form that explains the study.
Run-in: Participants with elevated Lp(a) and normal liver and renal indices, that meet all other inclusion and exclusion criteria will be started on low dose niacin (500 mg/d) for a 6 week run-in phase prior to randomization to assess tolerability and compliance to the intervention. The niacin dose will be increased by 500 mg increments weekly, as tolerated, to a maximum of 1500 mg/day (Participants who remain compliant >85% (by pill count and self-report) and who tolerate at least 1500 mg/d of niacin for at least 2 weeks will then undergo randomization to 1500 mg/d of immediate release niacin or matching placebo.
Randomization: will be performed via an Internet website where each participant will be given a unique identifier that matches the allocated drug kit.Blocking using random blocks of 2 and 4 will ensure that similar numbers of patients are randomized to the two arms of the study at each of the study centers.
The study will be double blind - neither patients, physicians, nor study personnel will know which participants are receiving active treatment.
After a 6-week run-in phase, participants able to tolerate the intervention will be randomized 1:1 to niacin extended release or placebo. After randomization, the treatment phase will be for 2 years (104 weeks). Data will be collected during 5 visits: (i) Randomization visit; (ii) 6-month follow-up visit; (iii) 12-month follow-up visit; (iv) 18-month follow-up visit; (v)Final visit (24-month).
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Single Group
- 主要目的
- Prevention
- 盲法
- Double (Participant, Investigator)
入排标准
- 年龄范围
- 50 Years 至 85 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Age >50 years and < 85 years
- •Aortic sclerosis OR mild AS
- •Aortic sclerosis: diffuse of focal (at least 2 areas) thickening or calcification (highly echodense lesions) on aortic leaflets seen in at least 2 contiguous views with normal leaflet excursion and peak aortic jet velocity < 2 m/s.
- •Mild AS: peak aortic jet velocity 2-3 cm/s, AVA >1.5cm2, mean gradient <25 m
- •Elevated Lp(a) > 50 mg/dL (>80th percentile).
排除标准
- •Current use or documented indication for niacin therapy or known niacin allergy/intolerance
- •Bicuspid valve, unicuspid valve or other congenital cardiac anomaly (except patent foramen ovale)
- •Known renal disease or more than mild renal dysfunction (Creatinine > 150 mmol/L or Creatinine clearance < 60).
- •Major comorbidities limiting life expectancy to < 2 years
- •Unable or unwilling to complete follow-up visits to 2 year
- •Diagnosed hepatic failure, cirrhosis, hepatitis or history of hepatic impairment (AST or ALT levels ³ 2 times upper limit of normal)
- •Newly diagnosed (< 2 months) or poorly controlled diabetes
- •Gout or use of anti-hyperuricemic medications
研究组 & 干预措施
Extended release Niacin
Taking 1500-2000mg niacin daily
干预措施: Extended release Niacin (Drug)
No Naicin
Placebo Comparator arm will be taking 1500mg of placebo daily
干预措施: Placebo Comparator (Drug)
结局指标
主要结局
Calcium score progression by cardiac CT in individuals randomized to niacin as compared to those randomized to placebo
时间窗: 2 years
次要结局
- Mean change in Lp(a) levels between treatment arms(2 years)
研究者
George Thanassoulis
MD MSc FRCPC
McGill University Health Centre/Research Institute of the McGill University Health Centre