Effect of COMT genetic polymorphisms on response to propranolol therapy in TMD

COMT 基因多态性对 TMD 普萘洛尔治疗反应的影响

• 批准号: 9014580
• 负责人: Samuel Arbes
• 金额: $ 6.62万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-12 至 2017-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9014580
• 关键词: Adrenergic Agents; Adrenergic Antagonists; Adrenergic Receptor; Adrenergic beta-Antagonists; Adverse event; Affect; Affective; Analgesics; Case Report Form; Catechol O-Methyltransferase; Catecholamines; Caucasians; Characteristics; Chronic; Clinical; Clinical Trials; Clinical trial protocol document; Code; Consent Forms; Development; Disease; Dopamine; Dose; Emotional; Enrollment; Enzymes; Epinephrine; Evaluation; Facial Pain; Female; Fibromyalgia; Funding; Genes; Genetic Polymorphism; Genetic Research; Genotype; Goals; Grant; Haplotypes; Health; Heating; Investigation; Maintenance; Manuals; Masks; Measures; Medicine; Methods; Methyltransferase Gene; Modeling; Multicenter Trials; Musculoskeletal Pain; National Institute of Dental and Craniofacial Research; Norepinephrine; Outcome; Pain; Pain intensity; Patients; Perception; Persistent pain; Pharmaceutical Preparations; Pharmacogenetics; Phase; Phase II Clinical Trials; Physical Function; Pilot Projects; Placebo Control; Placebos; Procedures; Propranolol; Protocols documentation; Randomized; Randomized Clinical Trials; Reporting; Risk; Sampling; Sensory; Severities; Stimulus; Subgroup; Symptoms; Temporomandibular Joint; Temporomandibular Joint Disorders; Temporomandibular joint disorder pain; Therapeutic; Translating; U-Series Cooperative Agreements; Variant; Woman; adrenergic; beta-adrenergic receptor; clinical practice; diaries; experience; follow-up; genetic predictors; genetic variant; impression; improved; indexing; men; personalized intervention; pressure; randomized trial; response; satisfaction; treatment duration; treatment response

DESCRIPTION (provided by applicant): This U01 application seeks funds for 3 years to conduct a Phase II clinical trial that will evaluate the efficacy of the non-selective Beta-adrenergic antagonist, propranolol, compared to placebo, for treatment of pain in patients with temporomandibular disorder (TMD). TMD, one of the most common chronic musculoskeletal pain conditions, is ineffectively treated. Growing evidence suggests that pain states are enhanced by diminished activity of catechol-O-methyltransferase (COMT; an enzyme that metabolizes catecholamines), which results in elevated levels of catecholamines and increased activity of Beta 2/3-adrenergic receptors. Three common haplotypes in the COMT gene have been associated with pain modulation and the risk of developing TMD. In a pilot study of TMD patients, we found that analgesic efficacy of propranolol varied according to polymorphisms in the COMT gene. We now propose to conduct a Phase II randomized, masked, placebo-controlled, parallel assignment clinical trial of propranolol (LA 60 mg twice daily). The primary objective is to evaluate the efficacy of propranolol in reducing pain in TMD patients; a secondary objective will determine if propranolol efficacy varies according to patients' COMT diplotype. We will enroll 200 Caucasian female TMD patients, genotyped for COMT polymorphisms. This trial will consist of a 1-week baseline phase, a 10-week treatment phase, and a 1-week follow-up. The primary endpoint will be a weekly mean pain index, calculated as a product of the pain intensity score multiplied by the pain duration score from a Daily Symptom Diary. Patient pain ratings, responses to heat and pressure stimuli, physical function, emotional function, global improvement, occurrence of symptoms and adverse events, and use of rescue medication will be measured as secondary endpoints. Statistical analysis will evaluate three trial hypotheses: 1) propranolol is efficacious compared with placebo in reducing the pain index, 2) efficacy of propranolol varies according to patients' COMT polymorphism, and 3) propranolol is efficacious in improving secondary endpoints. Continuous measures will be analyzed in the "intent-to-treat" sample using methods for mixed-model repeated measures, with the baseline scores as covariates. Sensitivity analyses will be conducted with the per-protocol sample. Under an R34 grant, we have created the protocol, informed consent forms, the Manual of Procedures, case report forms, and study plans needed for the proposed clinical trial. The proposed study will generate new evidence about treating pain through previously unexploited pharmacologic targets (e.g., Beta-adrenergic receptors). The study offers potential for a genetically-tailored pharmacogenetic approach for TMD treatment and may explain variability of treatment responses to Beta-blockers when used to treat other diseases.

描述(申请人提供)：这份U01申请申请寻求为期3年的资金，以进行第二阶段临床试验，该试验将评估非选择性β-肾上腺素能拮抗剂心得安与安慰剂相比治疗颞颌关节紊乱(TMD)患者疼痛的疗效。TMD是最常见的慢性肌肉骨骼疼痛之一，治疗效果不佳。越来越多的证据表明，儿茶酚氧甲基转移酶(COMT；一种代谢儿茶酚胺的酶)活性降低会导致儿茶酚胺水平升高和β2/3肾上腺素能受体活性增加，从而增强疼痛状态。COMT基因中有三种常见的单倍型与疼痛调节和发生TMD的风险有关。在对TMD患者的初步研究中，我们发现心得安的止痛效果因COMT基因的多态而不同。我们现在建议进行普萘洛尔(LA 60 mg，每日两次)的随机、掩蔽、安慰剂对照、平行分配的II期临床试验。主要目的是评估心得安对TMD患者的止痛效果；次要目标是确定心得安的疗效是否因患者的COMT二倍型而异。我们将招募200名高加索女性TMD患者，进行COMT基因多态分型。这项试验将包括1周的基线阶段、10周的治疗阶段和1周的随访。主要终点将是每周平均疼痛指数，计算方法为疼痛强度分数乘以每日症状日记中的疼痛持续时间分数。患者疼痛评级、对高温和压力刺激的反应、身体功能、情感功能、整体改善、症状和不良事件的发生以及抢救药物的使用将被衡量为次要终点。统计分析将评估三个试验假设：1)心得安在降低疼痛指数方面与安慰剂相比有效，2)心得安的疗效因患者的COMT基因多态性而异，以及3)心得安在改善次要终点方面有效。将使用混合模型重复测量的方法，以基线分数为协变量，在“意向治疗”样本中分析连续测量。将对每个方案的样本进行敏感性分析。在R34的拨款下，我们已经创建了拟议的临床试验所需的方案、知情同意书、程序手册、病例报告表和研究计划。这项拟议的研究将为通过以前未开发的药理靶点(例如，β-肾上腺素能受体)治疗疼痛提供新的证据。这项研究为治疗TMD提供了一种基因定制的药物遗传学方法的可能性，并可能解释用于治疗其他疾病时对Beta受体阻滞剂的治疗反应的变异性。