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，戒烟可逆转死亡风险。然而，戒烟失败是常见的，尽管可用的戒烟药物，这与不同的疗效，副作用，依从性，使用限制和成本。这一挑战可以通过基于个体遗传标记的个性化药物来改善目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。我们最近的工作表明，尼古丁受体基因CHRNA 5改变尼古丁替代疗法（NRT）的反应已在荟萃分析中得到复制。我们新的初步数据表明，CHRNA 5可能是药物选择的有用标志物，因为CHRNA 5变异rs 16969968 AA/GA基因型患者可能受益于NRT，GG基因型患者（对NRT反应差）可能受益于伐尼克兰，这是一种成本较高且使用限制的药物。同样，其他遗传变异（如尼古丁代谢基因CYP 2A 6）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物遗传学分析，这些试验具有显著不同的安慰剂和咨询效应量以及不同的设计。对于临床翻译，我们需要对最先进的干预措施进行头对头比较，使用当前研究涉及的关键基因型，并对副作用/依从性进行有效评估。我们提出了第一个，前瞻性，基于基因型的分层随机试验，比较两种最有效的戒烟药物（组合NRT [贴剂和锭剂]，伐尼克兰与安慰剂3个月）在720名已知基因型的吸烟者。利用主要研究者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，在目标1中，我们将确定CHRNA 5基因型是否会调节药物（NRT、伐尼克兰联合用药vs.安慰剂）对戒断的影响。在目标2中，我们将确定CHRNA 5基因型是否预测药物依从性和副作用。在目标3中，我们将纳入多个基因型和其他预测因素，以开发一种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，整体戒烟成功，预防癌症，心脏病和肺病。

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.