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: 9020301
• 负责人: KAREN G. RAPHAEL
• 金额: $ 7.03万
• 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/9020301
• 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; Pharmaceutical Preparations; Phase; Placebo Control; Randomized; Randomized Controlled Clinical Trials; Relative (related person); 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; phase 2 study; preclinical study; response; safety study

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）：Botox（R）（肉毒杆菌毒素A; BTA）是人类已知的最有效的神经毒素，被广泛用于治疗肌筋膜颞下颌肌肉和关节疾病（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用于作用于承重关节的肌肉，并引入了因负荷减少而对骨骼产生未知不良影响的可能性。我们的长期目标是进行一项II期随机对照临床试验，以评估适当大小样本的疗效，并评估BTA注射的先前未检查的风险：TMJ中的废用性骨质减少，这是由动物文献中令人不安的发现提出的，这些发现显示在兔中单次咬肌注射BTA后，下颌骨髁突和牙槽区域的体积和密度显著降低。由于将这些数据外推到人类表明存在重大安全风险，因此FDA要求在进行RCCT之前进行研究性新药（IND）申请，包括显示BTA在该患者组和这种给药方式中使用“合理安全”的数据。没有这样的人类数据。 因此，该R 01资助的主要目的是首次评估BTA注入人类受试者咀嚼肌时的骨相关风险。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进行安全性RCCT的“Catch-22”。首先，我们将比较大约15名患者接受至少3次BTA治疗前后的骨质量，类似于传统的I期方法。其次，我们将比较100名肌筋膜TMJD患者的骨质量，这些患者选择（或不选择）在咀嚼肌中接受至少三个周期的BTA注射。第三，我们将这些队列中的每一个的髁突体积与历史对照的参考组进行比较。第四，我们将评估一小部分肌筋膜性TMJD患者的停药原因，这些患者选择了一个或两个治疗周期的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。我们的安全评估福尔斯分为两个领域。(a)一种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形束CT来获得图像，从中可以精确估计骨密度和体积。(b)第二个安全性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AE。本研究的结果将提供：（1）临床前研究中提出的骨相关安全性问题的可操作数据，目前已转化为人类，以及（2）提交FDA IND申请的必要材料，该申请将允许进行II期研究，以评价BTA治疗TMJD疼痛的风险和获益。