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: 8672553
• 负责人: Samuel Arbes
• 金额: $ 117.57万
• 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/8672553
• 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; Caucasoid Race; 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; 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 variant; impression; improved; indexing; men; 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，用于开展II期临床试验，该试验将评估非选择性β -肾上腺素能拮抗剂心得安与安慰剂相比治疗颞下颌紊乱（TMD）患者疼痛的疗效。TMD是最常见的慢性肌肉骨骼疼痛之一，目前治疗效果不佳。越来越多的证据表明，由于儿茶酚- o -甲基转移酶（COMT，一种代谢儿茶酚胺的酶）活性降低，导致儿茶酚胺水平升高，β 2/3-肾上腺素能受体活性增加，疼痛状态得以增强。COMT基因的三种常见单倍型与疼痛调节和TMD发病风险有关。在一项针对TMD患者的初步研究中，我们发现心得安的镇痛效果根据COMT基因的多态性而变化。我们现在建议进行一项随机、屏蔽、安慰剂对照、平行分配的心得安（LA 60 mg，每日两次）II期临床试验。主要目的是评价心得安减轻TMD患者疼痛的疗效；第二个目的是确定心得安的疗效是否因患者的COMT双型而异。我们将招募200名高加索女性TMD患者，对COMT多态性进行基因分型。该试验将包括1周的基线期、10周的治疗期和1周的随访期。主要终点将是每周平均疼痛指数，由疼痛强度评分乘以每日症状日记中的疼痛持续时间评分计算得出。患者疼痛评分、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抢救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)心得安与安慰剂相比在减轻疼痛指数方面有效；2)心得安的疗效因患者COMT多态性而异；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方法对“治疗意向”样本中的连续测量进行分析，以基线得分为协变量。敏感性分析将对每个方案的样本进行。在R34授权下，我们制定了方案、知情同意书、程序手册、病例报告表和拟议临床试验所需的研究计划。提出的研究将产生新的证据，通过以前未开发的药理学靶点（例如，β -肾上腺素能受体）治疗疼痛。该研究为TMD治疗提供了基因定制药物遗传学方法的潜力，并可能解释β受体阻滞剂用于治疗其他疾病时治疗反应的可变性。