Preliminary Safety Study of Botulinum Toxin for Treatment of Myofascial TMJD Pain

肉毒毒素治疗肌筋膜下颌关节疼痛的初步安全性研究

• 批准号: 9113560
• 负责人: KAREN G. RAPHAEL
• 金额: $ 92.98万
• 依托单位: NEW YORK UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-08-01 至 2018-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9113560
• 关键词: Address; Adopted; Adverse effects; Adverse event; Alveolar; Animals; Benefits and Risks; Bone Density; Botox; Botulinum Toxins; Clinical; Clinical Trials; Controlled Clinical Trials; Data; Diagnostics Research; Double-Blind Method; Evaluation; Frequencies; Funding; Grant; Health; Human; Image; Injection of therapeutic agent; Joints; Label; Literature; Low Dose Radiation; Mandible; Mandibular Condyle; Masticatory muscles; Maxilla; Modeling; Morphology; Muscle; Muscle function; Myofascial Pain Syndromes; Myopathy; National Institute of Dental and Craniofacial Research; Neurotoxins; Oryctolagus cuniculus; Osteopenia; Pain; Pain Research; Pain intensity; Pain management; Patients; Phase; Placebo Control; Randomized; Randomized Controlled Clinical Trials; Research; Risk; Role; Running; Safety; Saline; Sample Size; Sampling; Serious Adverse Event; Temporomandibular Joint; Tooth structure; Translating; Translational Research; Weight-Bearing state; arthropathies; base; bone; bone quality; cohort; cone-beam computed tomography; density; falls; follow-up; human data; human subject; imaging modality; innovation; meetings; novel therapeutics; phase 2 study; preclinical study; response; safety study; temporalis muscle

DESCRIPTION (provided by applicant): Botox(R) (Botulinum Toxin A; BTA), the most potent neurotoxin known to humankind, is widely used to treat myofascial temporomandibular muscle and joint disorders (TMJD), even though efficacy and safety of this off-label use are largely untested. Injection of BTA into masticatory muscles represents its first use in muscles acting on a load-bearing joint, and introduces potential for unknown adverse effects on bone resulting from diminished load. Our long-term aim is to conduct a Phase II randomized controlled clinical trial to evaluate efficacy with a properly sized sample, and assess a previously unexamined risk of BTA injections: disuse osteopenia in the TMJ, suggested by disturbing findings from the animal literature which show major reductions in volume and density of the mandibular condyle and alveolar region after a single masseter injection of BTA in rabbits. Because extrapolation of these data to humans suggests major safety risks, the FDA has asked for an Investigative New Drug (IND) application before proceeding with the RCCT, including data showing that BTA is "reasonably safe" for use in this patient group and with this mode of administration. No such human data exist. Thus, the main aim of this R01 grant is to provide the first evaluation of bone-related risks of BTA when injected into masticatory muscles of human subjects. We adopt an innovative naturalistic approach that avoids the "Catch-22" introduced by needing safety data to do an RCCT about safety, through four studies. First, we will compare bone quality in approximately15 patients before and after they have received a minimum of three BTA treatments, similar to a traditional Phase I approach. Second, we will compare bone quality in cohorts of 100 myofascial TMJD patients that have elected (or not) to receive at least three cycles of BTA injections in the masticatory muscles. Third, we will compare condylar volume of each of these cohorts to a reference group of historical controls. Fourth, we will assess reasons for discontinuation among a small sample of myofascial TMJD patients who have elected to have one or two treatment cycles of BTA for myofascial pain, to assess the potential role of adverse events in early discontinuation. Our safety assessment falls into two domains. (a) One is translational research based assessment, using innovative imaging methods to assess markers of mandibular bone quality. In particular, we will use a low-radiation dose cone beam CT to derive images from which precise estimates of bone density and volume can be made. (b) The second safety domain is the relative frequency of traditional clinical adverse events (AEs) and serious adverse events (SAEs), with special focus on potential bone-related AEs. Results from this study will provide: (1) actionable data on bone- related safety concerns raised in preclinical studies and now translated to humans, and (2) necessary material to submit an FDA IND application that would permit a Phase II study to evaluate risk and benefit of BTA for treatment of TMJD pain.

描述（由申请人提供）：肉毒杆菌毒素(R)（肉毒杆菌毒素A； BTA）是人类已知的最有效的神经毒素，广泛用于治疗肌筋膜颞下颌肌和关节疾病（TMJD），尽管这种标签外使用的有效性和安全性在很大程度上未经测试。将BTA注射到咀嚼肌中代表了其首次在肌肉中用于承重关节，并引入了由于负荷减少而对骨骼产生未知不良影响的可能性。我们的长期目标是开展一项II期随机对照临床试验，通过适当大小的样本来评估疗效，并评估以前未检查过的注射BTA的风险：颞下颌关节的废弃性骨质减少，这是由动物文献中令人不安的发现所提示的，这些发现显示，在兔子中单次咬肌注射BTA后，下颌髁和牙槽区体积和密度显著减少。由于将这些数据外推到人类身上表明存在重大的安全风险，FDA要求在进行RCCT之前提交一份调查性新药（IND）申请，其中包括显示BTA在该患者组和这种给药模式下使用“合理安全”的数据。没有这样的人类数据存在。因此，这项R01拨款的主要目的是首次评估将BTA注射到人类受试者的咀嚼肌时与骨骼相关的风险。我们采用了一种创新的自然主义方法，通过四项研究，避免了需要安全数据来做关于安全的随机对照试验的“第22条军规”。首先，我们将比较大约15名患者接受至少三次BTA治疗前后的骨质量，这与传统的I期方法类似。其次，我们将比较100名选择（或不选择）接受至少三个周期咀嚼肌BTA注射的肌筋膜TMJD患者的骨质量。第三，我们将每个队列的髁突体积与历史对照参照组进行比较。第四，我们将评估一小部分肌筋膜颞下颌关节痛患者停药的原因，这些患者选择接受一到两个治疗周期的BTA治疗肌筋膜疼痛，以评估不良事件在早期停药中的潜在作用。我们的安全评估分为两个领域。(a)一个是基于转化研究的评估，使用创新的成像方法来评估下颌骨质量的标志物。特别是，我们将使用低辐射剂量锥束CT来获得图像，从中可以精确估计骨密度和体积。(b)第二个安全领域是传统临床不良事件（ae）和严重不良事件（sae）的相对频率，特别关注潜在的骨相关不良事件。该研究的结果将提供：(1)临床前研究中提出的骨相关安全问题的可操作数据，现在已转化为人类；(2)提交FDA IND申请所需的材料，以允许进行II期研究，评估BTA治疗颞下颌关节疼痛的风险和益处。