Genetically Informed Smoking Cessation Trial

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以用于优化戒烟药物治疗，以提高疗效、药物依从性和减少副作用。吸烟是可预防的死亡和残疾的主要原因，而戒烟可以扭转死亡的风险。然而，尽管有戒烟药物，但戒烟失败是常见的，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。这一挑战可以通过基于个体遗传标记的个性化医疗来改进当前的治疗方法，以最大限度地提高疗效并减少副作用来解决。我们最近的研究表明，尼古丁受体基因CHRNA5改变了对尼古丁替代疗法（NRT）的反应，这在荟萃分析中得到了证实。我们新的初步数据表明，CHRNA5可能是一个有用的药物选择标志物，因为CHRNA5变异rs16969968 AA/GA基因型患者可能受益于NRT，而GG基因型患者（对NRT反应较差）可能受益于varenicline，这是一种成本较高且使用限制的药物。同样，尼古丁代谢基因CYP2A6等其他遗传变异也会改变对NRT的反应。目前没有足够的证据支持基于基因型的戒烟治疗的临床应用，因为这些发现是基于对不同试验的回顾性药理学分析，这些试验具有明显不同的安慰剂和咨询效果大小和不同的设计。对于临床转化，我们需要对最先进的干预措施进行面对面的比较，使用当前研究涉及的关键基因型，以及对副作用/依从性的有效评估。我们提出了一项前瞻性、基于基因型的分层随机试验，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（联合NRT[贴片和含片]，伐尼克兰和安慰剂，为期3个月）。利用首席研究员对现有基因型戒烟的观察性遗传随访研究，本研究采用基于受试者戒烟相关基因型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（NRT、伐尼克兰与安慰剂联合用药）对戒断的影响。在目的2中，我们将确定CHRNA5基因型是否预测药物依从性和副作用。在目标3中，我们将结合多种基因型和其他预测因子，以开发戒烟成功的临床治疗分配算法。本提案是一项创新的戒烟试验，利用现有的基因型吸烟者和基于基因型的随机化设计来建立证据基础，以支持基于基因型的算法，该算法可以在疗效、副作用、依从性方面优化戒烟药物治疗，并提高整体戒烟成功率。这项工作可以改善医生对吸烟患者的护理，全面成功戒烟，预防癌症、心脏和肺部疾病。

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.