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）：本 U01 申请寻求为期 3 年的资金来进行 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与安慰剂相比，治疗颞下颌关节紊乱 (TMD) 患者疼痛的疗效。 TMD 是最常见的慢性肌肉骨骼疼痛疾病之一，但治疗效果不佳。越来越多的证据表明，儿茶酚-O-甲基转移酶（COMT；一种代谢儿茶酚胺的酶）活性降低会加剧疼痛状态，从而导致儿茶酚胺水平升高和 2/3-肾上腺素能受体活性增加。 COMT 基因中的三种常见单倍型与疼痛调节和发生 TMD 的风险有关。在一项针对 TMD 患者的初步研究中，我们发现普萘洛尔的镇痛功效根据 COMT 基因的多态性而变化。我们现在建议开展一项普萘洛尔（LA 60 mg，每日两次）的 II 期随机、隐蔽、安慰剂对照、平行分配临床试验。主要目的是评估普萘洛尔减轻 TMD 患者疼痛的功效；次要目标将确定普萘洛尔疗效是否根据患者的 COMT 双倍型而变化。我们将招募 200 名白人女性 TMD 患者，进行 COMT 多态性基因分型。该试验将包括 1 周基线阶段、10 周治疗阶段和 1 周随访阶段。主要终点是每周平均疼痛指数，计算为疼痛强度评分乘以每日症状日记中的疼痛持续时间评分的乘积。患者疼痛评级、对热和压力刺激的反应、身体功能、情绪功能、整体改善、症状和不良事件的发生以及救援药物的使用将作为次要终点进行测量。统计分析将评估三个试验假设：1) 与安慰剂相比，普萘洛尔在降低疼痛指数方面有效，2) 普萘洛尔的功效根据患者的 COMT 多态性而变化，3) 普萘洛尔在改善次要终点方面有效。将使用混合模型重复测量方法，以基线分数作为协变量，对“意向治疗”样本中的连续测量进行分析。将使用符合方案的样本进行敏感性分析。根据 R34 拨款，我们制定了拟议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。拟议的研究将产生关于通过以前未开发的药理靶点（例如β-肾上腺素能受体）治疗疼痛的新证据。该研究为 TMD 治疗提供了基因定制的药物遗传学方法的潜力，并可能解释用于治疗其他疾病时对 β 受体阻滞剂的治疗反应的变异性。