Genetically Informed Smoking Cessation Trial

基因知情戒烟试验

• 批准号: 8835537
• 负责人: Li-Shiun Chen
• 金额: $ 68.42万
• 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/8835537
• 关键词: Abstinence; Address; Adherence; Adverse effects; Adverse event; Algorithms; Biological Markers; Carbon Monoxide; Cessation of life; Clinical; Clinical Treatment; Clinical Trials Design; Combination Medication; Counseling; Data; Dependence; Development; Ensure; Equilibrium; Failure; Genes; Genetic; Genetic Markers; Genetic Models; Genetic Variation; Genotype; Goals; Grouping; Health; Heart; Hybrids; Individual; Intervention; Link; Lung diseases; Measures; Medicine; 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; Translations; Trees; Variant; Withholding Treatment; Work; base; cancer prevention; cost; cytochrome P-450 CYP2A6 (human); design; disability; evidence base; follow-up; head-to-head comparison; improved; innovation; medication compliance; modifiable risk; mortality; nicotine replacement; non-genetic; primary outcome; prospective; public health relevance; response; smoking cessation; success; 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）：我们的总体目标是确定是否可以使用遗传标记来优化戒烟药物疗法以提高功效，药物依从性并降低副作用。吸烟是可预防死亡和残疾的主要原因，戒烟会逆转死亡的风险。但是，尽管可用的戒烟药物，但戒烟失败还是很常见的，这些药物与不同的疗效，副作用，依从性，使用限制和成本有关。可以通过基于个体遗传标记的个性化医学来改善当前治疗方法来解决这一挑战，以最大程度地提高功效并最大程度地减少副作用。我们最近的工作表明，在荟萃分析中，复制了烟碱受体基因CHRNA5改变对尼古丁替代疗法（NRT）的反应。我们的新初步数据表明，CHRNA5可能是药物选择的有用标志物，因为患有CHRNA5变体RS16969968 AA/GA基因型的患者可能会受益于NRT，而NRT和GG基因型（赋予NRT反应不佳）的患者可能会受益于Varenicline，具有更高的成本和限制性的药物。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。当前，没有足够的证据支持基于基因型的戒烟治疗的临床使用，因为这些发现基于回顾性的药物遗传学分析，对不同试验和辅导效果尺寸明显不同和不同设计。对于临床翻译，我们需要头部比较最先进的干预措施，使用当前研究涉及的关键基因型的使用以及对副作用/依从性的有效评估。我们提出了第一个基于基因型的分层随机试验，以比较720名患有已知基因型的吸烟者中两种最有效的戒烟药物（组合NRT [Patch and Lozenge]，Varenicline与安慰剂3个月）。该研究利用主要研究者的观察性遗传随访研究，以现有基因型戒烟，使用基于受试者的相关基因型用于戒烟的分层随机试验设计。具体而言，在AIM 1中，我们将确定CHRNA5基因型是否会调节药物（组合NRT，Varenicline，vs.安慰剂）对禁欲的影响。在AIM 2中，我们将确定CHRNA5基因型是否预测药物依从性和副作用。在AIM 3中，我们将合并多种基因型和其他预测因子，以开发临床治疗分配算法以进行停止成功。该提案是一项创新的吸烟戒烟试验，利用现有的基因型吸烟者和基于基因型的随机化设计，以建立证据基础，以支持基于基因型的算法，该算法可以优化戒烟药物治疗，以效果，副作用，依从性，并提高吸烟限制。这项工作可以改善对吸烟，整体戒烟成功以及预防癌症，心脏和肺部病的患者的护理。