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（由申请人提供）：该U01申请寻求3年的资金进行II期临床试验，该试验将评估非选择性β-肾上腺素能拮抗剂普萘洛尔的疗效，与安慰剂相比，用于治疗颞下颌疾病（TMD）患者的疼痛。 TMD是最常见的慢性肌肉骨骼疼痛条件之一，是无效治疗的。越来越多的证据表明，疼痛态通过儿茶酚-O-甲基转移酶的活性降低（COMT；一种代谢儿茶酚胺的酶），从而导致儿茶酚胺水平升高和β2/3-肾上腺素能受体的活性增加。 COMT基因中的三种常见单倍型与疼痛调节和发展TMD的风险有关。在一项针对TMD患者的试点研究中，我们发现普萘洛尔的镇痛功效因COMT基因的多态性而有所不同。现在，我们建议进行II期随机，掩盖，安慰剂对照的，并行分配的临床试验（每天两次LA 60 mg）。主要目的是评估普萘洛尔在减轻TMD患者疼痛方面的疗效；次要目标将根据患者的COMT外交类型确定普萘洛尔疗效是否有所不同。我们将招募200名高加索女性TMD患者，该患者针对COMT多态性。该试验将包括一个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，以每日症状日记中的疼痛持续时间评分乘以疼痛持续时间评分的产物。患者疼痛评分，对热量和压力刺激的反应，身体功能，情绪功能，全球改善，症状和不良事件的发生以及使用救援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）与安慰剂减少疼痛指数相比，普萘洛尔是有效的，2）普萘洛尔的疗效根据患者的COMT多态性而变化，而3）普萘洛尔在改善次要端点方面有效。使用混合模型重复测量方法的方法将在“意图对治疗”样本中分析连续措施，基线得分作为协变量。敏感性分析将使用每项协议样本进行。根据R34赠款，我们创建了协议，知情同意书，程序手册，案例报告表和拟议临床试验所需的研究计划。拟议的研究将通过以前未开发的药理靶标（例如β-肾上腺素能受体）来生成有关治疗疼痛的新证据。该研究为TMD治疗提供了遗传学的药物遗传学方法的潜力，并可以解释用于治疗其他疾病时对β受体阻滞剂的可变性。