Exploratory/Developmental Study of Pharmacogenetic Smoking Cessation Therapy

描述（由申请人提供）：本探索性发展研究的主要目的是为未来的R01进行戒烟的药物遗传学（PGx）随机对照试验奠定基础-包括以患者为中心的有效遗传反馈（GF）动机增强干预。进行可行性试验的理由有三点。首先，来自多个研究的汇总数据证实了以下观察结果的重复性：低活性多巴胺能遗传变异（如ANKK1/“DRD2”Taq1A A1等位基因）与更高的尼古丁替代疗法（NRT）疗效相关，高活性变异（如Taq1A A2等位基因）与更高的安非他酮缓释（BUP）戒烟疗效相关。其次，PGx戒烟疗法目前直接销售给吸烟者，没有前瞻性试验的安全性和有效性证据。最后，到目前为止，唯一发表的关于GF对戒烟PGx治疗的心理和行为影响的研究都是在非临床环境中进行的假设病例研究。因此，我们的跨学科团队拥有PGx、临床试验、生物标志物信息激励增强、定性方法和生物医学伦理学方面的专业知识，提出以下具体目标：目标1：开展形成性研究，以扩展的平行过程模型为基础，开发和完善多组分戒烟干预的临床方案，包括PGx治疗和GF。我们将通过对20名非裔美国人和欧洲裔吸烟者的形成性访谈来调整、试点测试和完善基于理论的PGx戒烟干预措施。目标2：进行一项混合方法可行性试验，将寻求治疗的吸烟者随机分为PGx联合GF治疗和PGx不加GF治疗戒烟，以检查新制定的方案在初级保健环境中的可行性，并表征其心理和行为影响：吸烟者（N = 100）将被随机分为GF vs.不GF，所有人将接受动机性访谈（标准护理/SC）和PGx治疗。我们将评估GF对复发时间、药物依从性的影响，并对过程、认知、心理和行为结果进行综合评估。最后，我们将综合定量和定性数据来修订方案，产生假设，并估计后续R01提交的效应大小。我们假设，在接受PGx和SC的吸烟者中，基因反馈的增加将与复发时间和药物依从性增加有关；我们将探讨GF是否能提高自我效能感、戒烟信心以及在治疗期间和治疗结束时从基线到随访评估对戒烟的感知控制。公共卫生相关性：该项目的结果将支持我们开展一项大规模、随机的前瞻性基因定制戒烟疗法临床试验的能力，该试验将作为R01提案提交。这些结果将有助于将回顾性研究中不断增长的药物遗传信息转化为最终目标，即开发基于证据的、以患者为中心的、个性化的戒烟疗法，以提高疗效，同时最大限度地降低不良心理或行为后果的风险。

DESCRIPTION (provided by applicant): The major purpose of this exploratory developmental study will be to lay the groundwork for a future R01 to conduct a pharmacogenetic (PGx) randomized controlled trial of smoking cessation - incorporating a patient- centered and effective genetic feedback (GF) motivational enhancement intervention. The rationale for conducting a feasibility trial is three-fold. First, converging data from multiple studies demonstrate replication of the observation that low activity dopaminergic genetic variants (e.g., ANKK1/ "DRD2" Taq1A A1 alleles) are associated with greater nicotine replacement therapy (NRT) efficacy and higher activity variants (e.g., Taq1A A2 alleles) are associated with greater sustained-release bupropion (BUP) efficacy for smoking cessation. Secondly, PGx smoking cessation therapies are currently directly marketed to smokers without evidence of safety and efficacy from prospective trials. Finally, to date, the only published studies of the psychological and behavioral impact of GF for smoking cessation PGx therapies have used hypothetical case studies in non- clinical settings. Therefore, our transdisciplinary team with expertise in PGx, clinical trials, biomarker-informed motivational enhancement, qualitative methods, and biomedical ethics, proposes the following specific aims: Aim 1: Conduct formative research to develop and refine a clinical protocol for a multi-component smoking cessation intervention, grounded in the extended parallel process model, consisting of PGx treatment and GF: We will adapt, pilot-test, and refine a theoretically-grounded PGx smoking cessation intervention using formative interviews of 20 African-American and European-ancestry smokers. Aim 2: Conduct a mixed-methods feasibility trial randomizing treatment-seeking smokers to PGx treatment combined with GF vs. PGx treatment without GF for smoking cessation to examine the feasibility of the newly developed protocol in a primary care setting and characterize its psychological and behavioral impact: Smokers (N = 100) will be randomized to GF vs. no GF and all will receive motivational interviewing (standard care/SC) and PGx treatment. We will assess the impact of GF on time to relapse, medication adherence, and a comprehensive assessment battery of process and cognitive, psychological, and behavioral outcomes. Finally, we will synthesize quantitative and qualitative data to revise protocols, generate hypothesizes, and estimate effect sizes for a follow-up R01 submission. We hypothesize that amongst smokers receiving PGx and SC, the addition of genetic feedback will be associated with increased time to relapse and medication adherence; and we will explore whether or not GF enhances self-efficacy, smoking cessation confidence, and perceived control over smoking cessation from baseline to follow-up assessments during treatment and at the end of treatment. PUBLIC HEALTH RELEVANCE: The results from this project will support our ability to conduct a large-scale, randomized clinical trial of prospective genetically tailored smoking cessation therapies, to be submitted as an R01 proposal. These results will facilitate the translation of the growing body of pharmacogenetic information from retrospective studies toward the ultimate goals of developing evidence-based, patient-centered, personalized smoking cessation therapies that enhance efficacy while minimizing the risk of adverse psychological or behavioral outcomes.