Genetically Informed Smoking Cessation Trial

基因知情戒烟试验

• 批准号: 9306808
• 负责人: Li-Shiun Chen
• 金额: $ 65.95万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-30 至 2019-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9306808
• 关键词: Abstinence; Address; Adherence; Adverse effects; Adverse event; Algorithms; Biological Markers; Carbon Monoxide; Cessation of life; Clinical; Clinical Treatment; Counseling; Data; Dependence; Development; Ensure; Failure; Follow-Up Studies; Genes; Genetic; Genetic Markers; Genetic Models; Genetic Variation; Genotype; Goals; Grouping; Health; Heart Diseases; Hybrids; Individual; Intervention; Link; Lung diseases; Measures; Meta-Analysis; Metabolism; Methods; Modeling; Nausea; Nicotine; Nicotine Dependence; Nicotinic Receptors; Other Genetics; Outcome; Participant; Patient Care; Patients; Pharmaceutical Preparations; Pharmacogenetics; Pharmacotherapy; Physicians; Placebo Control; Placebos; Principal Investigator; Randomized; Receptor Gene; Recommendation; Reporting; Research; Risk; Risk Factors; Severities; Side; Smoke; Smoker; Smoking; Socioeconomic Status; Testing; Time; Trees; Variant; Withholding Treatment; Work; base; cancer prevention; clinical translation; cost; design; disability; evidence base; head-to-head comparison; improved; innovation; medication compliance; modifiable risk; mortality; nicotine replacement; non-genetic; personalized medicine; primary outcome; prospective; public health relevance; randomized trial; response; smoking cessation; success; trial design; varenicline

DESCRIPTION (provided by applicant): Our overarching goal is to determine whether genetic markers can be used to optimize smoking cessation pharmacotherapy to enhance efficacy, medication adherence, and reduce side effects. Smoking is a leading cause of preventable death and disability, and smoking cessation reverses the risk of mortality. However, cessation failure is common despite available cessation medications, which are associated with different efficacy, side effects, adherence, use constraints, and costs. This challenge can be addressed by improving current treatments via personalized medicine based on individual genetic markers to maximize efficacy and minimize side effects. Our recent work suggesting that the nicotinic receptor gene CHRNA5 alters response to nicotine replacement therapy (NRT) has been replicated in a meta-analysis. Our new preliminary data suggest that CHRNA5 may be a useful marker for medication choice, because patients with CHRNA5 variant rs16969968 AA/GA genotypes may benefit from NRT and those with GG genotypes (conferring poor response to NRT) may benefit from varenicline, a medication with higher cost and use restrictions. Similarly, other genetic variation such as the nicotine metabolism gene CYP2A6 also alters response to NRT. Currently there is insufficient evidence to support the clinical use of genotype based smoking cessation treatment, because these findings are based on retrospective pharmacogenetic analyses of different trials with markedly different placebo and counseling effect sizes and dissimilar designs. For clinical translation, we need head to head comparison of state-of-the-art interventions, use of key genotypes implicated by current research, and valid assessments of side effects/ adherence. We propose a first, prospective, genotype-based stratified randomization trial to compare the two most effective smoking cessation medications (combination NRT [patch and lozenge], varenicline vs. placebo for 3 months) in 720 smokers with known genotypes. Leveraging the Principal Investigator's observational genetic follow-up study of smoking cessation with existing genotypes, this study uses a stratified randomization trial design based on a subject's pertinent genotype for smoking cessation. Specifically, in Aim 1, we will determine if CHRNA5 genotype moderates the effect of medication (combination NRT, varenicline, vs. placebo) on abstinence. In Aim 2, we will determine if CHRNA5 genotype predicts medication adherence and side effects. In Aim 3, we will incorporate multiple genotypes and other predictors in order to develop a clinical treatment assignment algorithm for cessation success. This proposal is an innovative smoking cessation trial leveraging existing genotyped smokers and a genotype-based randomization design to build the evidence base to support a genotype based algorithm that can optimize smoking cessation pharmacotherapy in terms of efficacy, side effects, adherence, and improve overall smoking cessation success. This work can result in improved physician care of patients who smoke, overall smoking cessation success, and prevention of cancer, heart, and lung disease.

描述（由申请人提供）：我们的首要目标是确定遗传标记是否可用于优化戒烟药物治疗，以提高疗效、药物依从性并减少副作用。吸烟是可预防的死亡和残疾的主要原因，戒烟可以逆转死亡风险。然而，尽管有可用的戒烟药物，但戒烟失败仍然很常见，这与不同的疗效、副作用、依从性、使用限制和成本有关。这一挑战可以通过基于个体遗传标记的个性化医疗改进当前的治疗方法来解决，以最大限度地提高疗效并最大限度地减少副作用。我们最近的研究表明烟碱受体基因 CHRNA5 改变了对尼古丁替代疗法 (NRT) 的反应，这一点已在荟萃分析中得到证实。我们的新初步数据表明，CHRNA5 可能是药物选择的有用标记，因为具有 CHRNA5 变异 rs16969968 AA/GA 基因型的患者可能会从 NRT 中受益，而具有 GG 基因型（对 NRT 反应较差）的患者可能会从伐尼克兰（一种具有更高的成本和使用限制。同样，其他遗传变异（例如尼古丁代谢基因 CYP2A6）也会改变对 NRT 的反应。目前没有足够的证据支持临床使用基于基因型的戒烟治疗，因为这些发现是基于对不同试验的回顾性药物遗传学分析，这些试验具有明显不同的安慰剂和咨询效果大小以及不同的设计。对于临床转化，我们需要对最先进的干预措施、当前研究涉及的关键基因型的使用以及副作用/依从性的有效评估进行直接比较。我们提出了第一个基于基因型的前瞻性分层随机试验，在 720 名已知基因型的吸烟者中比较两种最有效的戒烟药物（NRT [贴片和含片]组合、伐尼克兰与安慰剂 3 个月）。利用主要研究者对现有基因型戒烟的观察性基因随访研究，本研究采用基于受试者与戒烟相关的基因型的分层随机试验设计。具体来说，在目标 1 中，我们将确定 CHRNA5 基因型是否会调节药物（NRT 组合、伐尼克兰与安慰剂）对戒断的影响。在目标 2 中，我们将确定 CHRNA5 基因型是否可以预测药物依从性和副作用。在目标 3 中，我们将整合多种基因型和其他预测因子，以开发成功戒烟的临床治疗分配算法。该提案是一项创新的戒烟试验，利用现有基因型吸烟者和基于基因型的随机化设计来建立证据基础，以支持基于基因型的算法，该算法可以在功效、副作用、依从性和改善整体吸烟方面优化戒烟药物治疗戒断成功。这项工作可以改善医生对吸烟患者的护理，全面戒烟成功，并预防癌症、心脏病和肺病。