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

基本信息

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
项目类别：
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

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

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项目摘要

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（R）（肉毒杆菌毒素A; BTA），是人类已知的最有效的神经毒素，被广泛用于治疗肌室颞下颌肌肉和关节疾病（TMJD），即使这种未标记使用的功效和安全性很大。将BTA注射到咀嚼肌肉中是其在作用于负荷关节的肌肉中的首次使用，并引入了因负荷减少而导致骨骼的不知情不良影响的潜力。我们的长期目的是进行II期随机对照临床试验，以评估适当尺寸的样本的功效，并评估先前未经检查的BTA注射风险：在TMJ中解雇骨质骨减少症，这表明了动物文献中的发现的发现，该发现表明，该动物文献的体积和bbular conder allve allve allve syse sings in singles singles singles in single syse sings in single syse by syse by。由于将这些数据推送到人类表明主要的安全风险，因此FDA在进行RCCT之前要求进行调查新药（IND）应用，包括数据表明BTA在该患者组中以及这种管理方式中使用了BTA“相当安全”。没有这样的人类数据。因此，该R01赠款的主要目的是在注射到人类受试者的咀嚼肌肉中时对BTA的骨相关风险进行首次评估。我们采用了一种创新的自然主义方法，该方法避免了通过需要安全数据来通过四项研究来对安全进行RCCT引入的“ CATCH-22”。首先，我们将在接受至少三种BTA治疗之前和之后的大约15名患者中比较骨质质量，类似于传统的I期方法。其次，我们将比较当选（或不）接受（或不）接受至少三个BTA注射的100例肌筋膜TMJD患者的骨骼质量。第三，我们将将这些队列的每个人的condoly体积与一组历史控制组进行比较。第四，我们将评估一小部分肌筋膜TMJD患者中停用的原因，这些患者选择有一个或两个BTA治疗周期以用于肌筋膜疼痛，以评估不良事件在早期中断中的潜在作用。我们的安全评估属于两个领域。（a）一种是基于转化研究的评估，使用创新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来得出图像，从中可以从中对骨密度和体积进行精确的估计。（b）第二安全域是传统临床不良事件（AES）和严重不良事件（SAE）的相对频率，特别关注潜在的与骨相关的AE。这项研究的结果将提供：（1）有关临床前研究提出的有关骨相关安全问题的可行数据，现在转化为人类，以及（2）提交FDA IND应用的必要材料，该应用将允许II期研究评估BTA治疗TMJD疼痛的风险和利益。