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

说明(申请人提供)：肉毒杆菌(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和关节紊乱(TMJD)，尽管这种非标签使用的有效性和安全性在很大程度上未经测试。将BTA注射到咀嚼肌肉中代表了它第一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，以评估适当大小的样本的疗效，并评估以前未被研究过的BTA注射的风险：动物文献中令人不安的发现表明，在兔单一咬肌注射BTA后，下颌骨髁突和牙槽骨区域的体积和密度显著减少。由于将这些数据外推到人体表明存在重大安全风险，FDA要求在继续进行随机对照试验之前申请研究新药(IND)，包括数据显示，BTA在该患者组和这种给药模式下使用是“合理安全的”。不存在这样的人类数据。因此，这项R01拨款的主要目的是对BTA注射到受试者咀嚼肌肉中时与骨骼相关的风险进行首次评估。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关于安全的RCCT所引入的“第22条军规”。首先，我们将比较大约15名患者在接受至少三次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名肌肉筋膜TMJD患者的骨质量，这些患者已经选择(或没有)接受至少三个周期的BTA咀嚼肌肉注射。第三，我们将把这些队列中每个人的髁突体积与历史对照的参照组进行比较。第四，我们将评估一小部分选择接受BTA治疗肌筋膜疼痛的小样本TMJD患者的停药原因，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的锥形束CT来获得图像，从中可以精确地估计骨密度和体积。(B)第二个安全领域是传统临床不良事件和严重不良事件的相对频率，特别是潜在的与骨骼相关的不良事件。这项研究的结果将提供：(1)在临床前研究中提出并现已转化为人类的与骨骼相关的安全问题的可操作数据，以及(2)提交FDA IND申请所需的材料，该申请将允许进行第二阶段研究，以评估BTA治疗TMJD疼痛的风险和益处。

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.