A MULTICENTER STUDY EVALUATING THE EFFICACY AND SAFETY OF BOTOX<

评估 BOTOX 功效和安全性的多中心研究<

• 批准号: 7606657
• 负责人: Neal Hermanowicz
• 金额: $ 0.04万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-12-01 至 2007-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7606657
• 关键词: Acetylcholine; Affect; Area; Back Pain; Botox; Botulinum Toxin Type A; Calcitonin Gene-Related Peptide; Cervical Dystonia; Chronic; Chronic Daily Headaches; Chronic Headaches; Classification; Clinic; Clinical; Complex; Computer Retrieval of Information on Scientific Projects Database; Condition; Data; Disease; Dose; Double-Blind Method; Effectiveness; End Point; Epidemiologic Studies; Evaluation; FOS gene; Fire - disasters; Formalin; Frequencies; Funding; Gene Expression; General Population; Glutamates; Grant; Head and neck structure; Headache; Headache Disorders; Hour; Immediate-Early Genes; Injection of therapeutic agent; Institution; International; Label; Measures; Medical; Migraine; Modeling; Multicenter Studies; Muscle; Muscle Contraction; Myofascial Pain Syndromes; Neck Pain; Neurologic; Neuromuscular Junction; Neurons; Neurotoxins; Neurotransmitters; Numbers; Pain; Patients; Personal Satisfaction; Pharmaceutical Preparations; Phase; Phase II Clinical Trials; Phase III Clinical Trials; Placebos; Population; Prevention; Program Development; Prophylactic treatment; Proteins; Protocols documentation; Purpose; Quality of life; Range; Rattus; Recurrence; Reporting; Research; Research Personnel; Resources; Role; Safety; Site; Societies; Source; Spasm; Specific qualifier value; Stimulus; Striated Muscles; Substance P; Symptoms; Syndrome; Tension Headache; Testing; Toxin; Treatment Protocols; United States National Institutes of Health; Week; Whiplash Injuries; afferent nerve; authority; base; central sensitization; day; design; experience; medical specialties; neuromuscular activity; neurotransmitter release; prevent; response

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Headache is a common neurological symptom in clinical practice. In 1 year most of the US population will have a headache and over 5% will seek medical aid (Silberstein Silberstein, 1990). Headaches are either episodic (less than 15 headache days/month) or chronic (greater than or equal to 15 headache days/month) (Headache Classification Subcommittee of the International Headache Society, revised 2004 [ICHD-II]). Recurrent headaches (HA) can be symptoms of a chronic primary headache disorder. Primary chronic daily headache (CDH) is a syndrome characterized by HA not attributable to a secondary disorder, which last more than 4 hours/day and occur 16 or more days/month (Bigal et al, 2004; Silberstein and Lipton, 2001). Chronic daily headache is a heterogeneous disorder, affecting approximately 4% to 5% of the general population (based on global epidemiological studies; Castillo et al, 1999; Scher et al, 1998; Wang et al, 2000) and is the most common headache seen in headache specialty clinics. More than 90% of CDH patients initially report episodic HA (Silberstein and Lipton, 2000). Patients in whom episodic migraines have progressed into CDH are described as having "transformed migraine" (Silberstein it al, 1994). Most patients with CDH report their role functioning and well-being as frequently and severely impaired (Holroyd et al, 2000), highlighting the importance of this group of headaches on quality of life (Monzon and Lainez, 1998; Wang et al, 2001). Very few studies have evaluated HA prophylactic treatment in patients with CDH. To date, no drug has received regulatory authority approval for the prophylaxis of headaches in migraine patients with transformed migraine. There appears to be a large unmet medical need in this debilitated patient population. Botulinum Toxin Type A Purified Neurotoxin Complex (BOTOX) therapy has been reported to alleviate pain associated with various conditions with or without concomitant excess muscle contractions (Aoki, 2001). This includes cervical dystonia, spasticity, tension-associated HA, chronic whiplash-associated neck pain, myofascial pain, migraine prophylaxis, and back pain. The toxin is known to inhibit the release of the neurotransmitter, acetylcholine, at the neuromuscular junction, thereby inhibiting striated muscle contractions. In the majority of pain syndromes where Botulinum Toxin Type A Purified Neurotoxin Complex (Botox) has been studied inhibiting muscle spasms has been identified to be an important component of its activity. However, the reduction of pain often occurs before the decrease in muscle contractions suggesting that Botulinum Toxin Type A Purified Neurotoxin Complex (Botox) has a more complex mechanism of action that initially hypothesized (Aoki, 2003). Current data suggests an antinociceptive effect of Botulinum Toxin Type A Purified Neurotoxin Complex (Botox) that is separate from its neuromuscular activity. Botulinum Toxin Type A Purified Neurotoxin Complex (Botox) appears to act both peripherally and centrally on sensory nerves. The hypothesis that Botulinum Toxin Type A Purified Neurotoxin Complex (Botox) medicates an antinociceptive activity peripherally is supported by its inhibition of neurotransmitters such as glutamate (CUI et al, 2004), calcitonin gene-related peptide (CGRP) (Purkiss et al, 2000; Welch et al, 2000), and substance P (Durham et al, 2004). An indirect reduction of central sensitization is supported by studies investigating the stimulation of the immediate early gene, c-fos, using the formalin-challenged rat model. In these studies activation of the c-fos gene and expression of its protein product, Fos, indicate rapid neuronal firing in response to stimuli. Botulinum Toxin Type A Purified Neurotoxin Complex (Botox) treatment reduced Fos expression after formalin challenge in a dose-dependent manner indicating an indirect central effect in reducing pain (Cui et al, 2002). Early phase 2 Botulinum Toxin Type A Purified Neurotoxin Complex (Botox) studies evaluated 2 distinct patient populations: episodic migraine and chronic tension type headache (CTTH). Concurrent with the early phase 2 trials was growing clinical experience with Botulinum Toxin Type A Purified Neurotoxin Complex (Botox) has a HA preventative treatment in those patients who had failed, or who were intolerant to, other conventional preventative HA medications (Blumenfeld, 2003; Brin et al, 2000; Mathew it al, 2003). As a result, Allergan imitated and completed a comprehensive exploratory phase 2 development program that included 2 studies in migraine patients with > 16 headache days during a 4 week baseline period (Study Reports 191622-038 & 191622-039). The actual number of units and injection sites investigators' used in the phase 2 studies, as well as the efficacy and safety profiles were reviewed to determine the dosing for this study. The exploratory phase 2 studies have identified a specific patient population, dose, treatment regimen and efficacy endpoint that await confirmation in pivotal phase 3 trials. The total dose, muscles to be injected, dose and number of injection sites per muscle specified in this study are based on an evaluation of the exploratory phase 2 studies. Dose range studied for 191622-038 and 105-260 U and the range studied for 191622-039 was 75U, 150U and 225U. This protocol is therefore designed to confirm the efficacy and safety of Botulinum Toxin Type A Purified Neurotoxin Complex (Botox) in migraine patients with 15 or more headache days during a 28 day baseline period. The purpose of this study is to investigate whether injections of Botulinum Toxin Type A Purified Neurotoxin Complex (BOTOX) into specific muscle areas in the head and neck are effective and safe for preventing headaches in migraine patients with 15 or more headache days per 4-week period. This study will further test the safety and effectiveness of Botulinum Toxin Type A Purified Neurotoxin Complex (Botox) as a headache prevention treatment in migraine patients. The study data will be used to develop a better understanding of diseases capable of being treated with Botulinum Toxin Type A Purified Neurotoxin Complex (Botox). The clinical hypothesis is that Botulinum Toxin Type A Purified Neurotoxin Complex (Botox) is more effective than placebo as measured by the difference between treatment groups in the change form baseline in the frequency of headaches. And that Botulinum Toxin Type A Purified Neurotoxin Complex (Botox) has an acceptable safety profile. The objectives of the Double-blind Phase is to evaluate the efficacy and safety of Botulinum Toxin Type A Purified Neurotoxin Complex (Botox) compared with placebo as a HA prophylaxis in migraine subjects with 15 or more headache days per 4 week period. The objective of the Open-Label Phase is to evaluate the long-term safety of Botulinum Toxin Type A Purified Neurotoxin Complex (Botox) as headache prophylaxis in migraine subjects with 15 or more headache days per 4-week period.

该副本是利用众多研究子项目之一 由NIH/NCRR资助的中心赠款提供的资源。子弹和 调查员（PI）可能已经从其他NIH来源获得了主要资金， 因此可以在其他清晰的条目中代表。列出的机构是 对于中心，这不一定是调查员的机构。 头痛是临床实践中常见的神经系统症状。 在1年内，美国大多数人口都会头痛，超过5％的人会寻求医疗援助（Silberstein Silberstein，1990年）。 头痛要么是情节性（小于15个头痛的天气）或慢性（大于或等于15个头痛天/月）（国际头痛协会的头痛分类小组委员会，修订了2004年[iChd-ii]）。 复发性头痛（HA）可能是慢性原发性头痛障碍的症状。 原发性慢性每日头痛（CDH）是一种综合征，其特征是HA并非归因于次要疾病，该疾病持续超过4小时，并且发生了16天或更长时间/月/更长时间（Bigal等，2004； Silberstein and Lipton，2001）。 慢性每日头痛是一种异质性疾病，影响了大约4％至5％的普通人群（基于全球流行病学研究； Castillo等，1999； Scher等，1998； Wang等，2000），是头痛专业诊所中最常见的头痛。 超过90％的CDH患者最初报告了发作性HA（Silberstein and Lipton，2000）。 发作性偏头痛已发展为CDH的患者被描述为“转变为偏头痛”（Silberstein IT AL，1994）。 大多数患有CDH的患者报告的角色功能和幸福感频繁且严重受损（Holroyd等，2000），强调了这组头痛对生活质量的重要性（Monzon和Lainez，1998； Wang等，2001）。 很少有研究评估了CDH患者的HA预防治疗。 迄今为止，尚无药物获得监管机构的批准，以预防偏头痛偏头痛患者的头痛。 在这个虚弱的患者人群中，似乎有很大的未满足医疗需求。 据报道，肉毒杆菌毒素A型纯化的神经毒素复合物（肉毒杆菌毒素）疗法可以减轻与有或不同时过量肌肉收缩的各种疾病相关的疼痛（Aoki，2001）。 这包括宫颈肌张力障碍，痉挛，张力相关的HA，慢性鞭打相关的颈部疼痛，肌筋膜疼痛，预防偏头痛和背痛。 已知毒素可以抑制神经肌肉连接处神经递质乙酰胆碱的释放，从而抑制横纹肌收缩。 在大多数疼痛综合症中，已经研究了肉毒杆菌毒素型纯化的神经毒素复合物（肉毒杆菌毒素），抑制肌肉痉挛是其活性的重要组成部分。 然而，疼痛的减轻通常发生在肌肉收缩减少之前，表明肉毒杆菌毒素型纯化的神经毒素复合物（Botox）具有更复杂的作用机制，最初假设（Aoki，2003）。 当前的数据表明，肉毒杆菌毒素型纯化的神经毒素复合物（肉毒杆菌毒素）的抗伤害感受作用，该作用与其神经肌肉活性分开。 肉毒杆菌毒素A型纯化的神经毒素复合物（肉毒杆菌毒素）似乎在外围和集中作用于感觉神经。 肉毒杆菌毒素A型纯化的神经毒素复合物（肉毒杆菌毒素）药物的假说通过抑制神经递质（如谷氨酸）（Cui等，2004），钙蛋白基因基因基因基因相关的肽（CGRP）（CGRP）（2000 purkiss et al，2000; 2000; 2000; 2000; 2000;等，2004）。 使用福尔马林挑战的大鼠模型研究了刺激刺激早期基因C-FOS的刺激的研究支持了中央敏化的间接降低。 在这些研究中，C-FOS基因的激活及其蛋白产物的表达FOS表明响应刺激的快速神经元放电。 肉毒杆菌毒素A型纯化的神经毒素复合物（肉毒杆菌毒素）治疗以剂量依赖性的方式降低了FOS表达，这表明减轻疼痛的间接中心作用（Cui等，2002）。 早期2阶段肉毒杆菌毒素A型纯化的神经毒素复合物（Botox）研究评估了2种不同的患者人群：情节性偏头痛和慢性张力类型头痛（CTTH）。 与早期第二阶段试验的同时同时使用的是肉毒固醇毒素型纯化的神经毒素复合物（肉毒杆菌毒素）的临床经验，对那些失败或对其他常规预防性HA药物的患者进行了HA预防治疗（Blumenfeld，Blumenfeld，2003; Brin等，2000; Mathew; Mathew It，al al al al al al al al an al al al an al al an al an al al an al al an al an al an al al an al al an al a al al a al al al al a al al a al al a al a al a al a al a al a a; blumens overal iT，; 结果，Allergan模仿并完成了一项全面的探索性阶段2开发计划，其中包括在4周基线期间对偏头痛患者进行的2项研究（研究报告191622-038＆191622-039）。 审查了2阶段研究中使用的单位和注射地点的实际数量，以及审查了疗效和安全概况，以确定本研究的剂量。 探索性2期研究确定了特定的患者人群，剂量，治疗方案和疗效终点，该终点在关键第三阶段试验中等待确认。 本研究中指定的每个肌肉的总剂量，要注射的肌肉，剂量和注射部位的数量基于对探索性2期研究的评估。 研究了19162-038和105-260 U的剂量范围，191622-039研究的范围为75U，150U和225U。 因此，该方案旨在确认肉毒杆菌毒素型纯化的神经毒素复合物（Botox）在28天基线期间患有15或更多头痛的偏头痛患者中的疗效和安全性。 这项研究的目的是研究对头部和颈部特定肌肉区域的肉毒杆菌毒素型神经毒素复合物（肉毒杆菌毒素）的注射是否有效且安全，可防止每4周的头痛15或更多头痛的偏头痛患者的头痛。 这项研究将进一步测试肉毒杆菌毒素型纯化的神经毒素复合物（肉毒杆菌毒素）作为偏头痛患者的头痛治疗的安全性和有效性。 该研究数据将用于对能够用肉毒杆菌毒素型纯化的神经毒素复合物（Botox）治疗的疾病更好地理解。 临床假设是，肉毒杆菌毒素A型纯化的神经毒素复合物（肉毒杆菌毒素）比安慰剂更有效，因为在头痛的频率下，治疗组基线中的治疗组之间的差异来衡量。 肉毒杆菌毒素A型纯化的神经毒素复合物（肉毒杆菌毒素）具有可接受的安全性。 双盲阶段的目标是评估肉毒杆菌毒素A型纯化的神经毒素络合物（肉毒杆菌毒素）的功效和安全性，而安慰剂作为偏头痛受试者的HA预防，每4周的头痛天数为15或更多。 开放标签期的目的是评估肉毒杆菌毒素型纯化的神经毒素复合物（肉毒杆菌毒素）作为偏头痛受试者的头痛预防的长期安全性，每4周的头痛天数为15个或更多。