CLINICAL ASSESSMENT OF HYPERSENSITIVITY TO ISONIAZID AND RIFAPENTINE IN STUDY 26

本子项目是利用由NIH/NCRR资助的中心赠款提供的资源的众多研究子项目之一。子项目和研究者（PI）可能已经从另一个NIH来源获得了主要资金，因此可以在其他CRISP条目中表示。列出的机构是中心的，不一定是研究者的机构。目的：主要目的是研究一种可能的抗体介导的过敏/流感样疾病，有时伴有低血压，发生在异烟肼900 mg加利福喷丁900 mg每周一次或异烟肼300 mg每天治疗的患者中。次要目的是评估与低血压、血管水肿或急性支气管痉挛相关的超敏综合征患者的血清胰蛋白酶水平。研究计划：两个治疗组中没有超敏综合征体征或症状的患者在服用任何研究药物前和治疗12周后均在基线时采集10cc血液。血液将在血清分离管中收集，处理后储存并运送到协议指定的设施（约翰霍普金斯大学DACI参考实验室）。同意参加子研究的对照者将在研究登记后和服用任何药物之前的第一次访问时接受知情同意程序。方法：该研究设计是一项多中心、前瞻性、随机、开放标签的III期临床试验中的病例对照研究，比较两种治疗方案对潜伏性结核感染的有效性：“每周一次利福喷丁/异烟肼治疗3个月与每天异烟肼治疗9个月的有效性和耐受性研究”（TB Trials Consortium study 26）。病例和对照将从试验参与者中招募，他们都是高风险结核菌素皮肤试验反应者，需要治疗潜伏感染以预防结核病。在本亚研究中，一个病例是任一治疗组中符合潜在超敏综合征定义的临床试验参与者。对照组为两个研究组中不符合病例定义的参与者。对照血清将用于将药物特异性免疫反应的频率和强度与观察到的临床超敏综合征联系起来。在研究26中，相对较少的患者预计会出现过敏综合征。为了在低病例数的情况下获得足够的功率，将实施1:4的病例控制比。临床意义：使用间歇治疗方案（每周一次或两次）代替每日治疗方案，使抗结核治疗的管理变得更加容易。虽然这些间歇性方案通常耐受性良好，但间歇性利福平与免疫介导的超敏综合征的发展有关。这种过敏综合征可由以下任何流感样症状组成，可单独出现或合并出现：发烧、寒战、头晕、头痛、肌痛和关节痛。异烟肼也可引起超敏反应，但其特点是发热、皮肤出疹、淋巴结病和血管炎。INH很少会引起流感样综合征。迄今为止，研究26中的两种方案总体耐受良好，但一些患者可能出现过敏反应。目前尚不清楚这种反应是由异烟肼、利福喷丁还是两者共同引起的。因此，本研究建议更详细地评估这种可能的超敏综合征。

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. OBJECTIVE: The primary objective is to investigate a possible antibody-mediated hypersensitivity/flu-like illness that is sometimes accompanied by hypotension, occurring in patients treated with isoniazid 900 mg plus rifapentine 900 mg once-weekly or with isoniazid 300 mg daily. The secondary objective is to assess serum tryptase levels in persons with hypersensitivity syndrome associated with hypotension, uticaria-angioedema, or acute bronchospasm. RESEARCH PLAN: Patients in both treatment arms who do not have signs or symptoms of the hypersensitivity syndrome will have 10 cc of blood obtained at baseline before taking any study drug and again after 12 weeks of treatment. The blood will be collected in a serum separator tube and processed for storage and shipment to the facility designated by protocol (Johns Hopkins DACI Reference Laboratory). Controls who agree to participate in the sub-study will undergo the informed consent process at the first visit after study enrollment and before taking any medication. METHODS: The study design is a case-control study nested within a multi-center, prospective, randomized, open-label phase III clinical trial comparing the effectiveness of two treatment regimens for latent tuberculosis infection: "A study of the effectiveness and tolerability of weekly rifapentine/isoniazid for three months versus daily isoniazid for nine months for the treatment of latent tuberculosis infection" (TB Trials Consortium Study 26). Cases and controls will be recruited from among trial participants who are all high-risk tuberculin skin-test reactors who require treatment of latent infection to prevent tuberculosis. For this sub-study, a case is a clinical trial participant in either treatment arm who meets the definition of potential hypersensitivity syndrome. Controls will be participants from both study arms who do not meet the case definition. Sera from controls will be used to relate the frequency and intensity of drug-specific immune responses to the observed clinical hypersensitivity syndromes. A relatively small number of patients are expected to develop hypersensitivity syndrome in Study 26. To achieve sufficient power with a low number of cases, a case-control ratio of 1:4 will be implemented. CLINICAL RELEVANCE: The administration of anti-tuberculosis therapy has been made easier by the use of intermittent regimens (once or twice-weekly) instead of daily treatment regimens. Although these intermittent regimens are generally well-tolerated, intermittent rifampin has been associated with the development of a hypersensitivity syndrome which appears to be immune-mediated. This hypersensitivity syndrome can consist of any of the following influenza-like symptoms, either alone or in combination: fever, shivering, faintness, headache, myalgia, and arthralgia. Isoniazid can also cause a hypersensitivity reaction, but it is characterized by fever, skin eruptions, lymphadenopathy, and vasculitis. Rarely, INH can cause a flu-like syndrome. To date, both regimens in Study 26 have been generally well tolerated but some patients may have developed a hypersensitivity reaction. It is unclear whether this reaction is attributable to isoniazid, rifapentine, or both. Therefore, this study proposes to assess this possible hypersensitivity syndrome in greater detail.