CLINICAL ASSESSMENT OF HYPERSENSITIVITY TO ISONIAZID AND RIFAPENTINE IN STUDY 26

该子项目是利用NIH/NCRR资助的中心赠款提供的资源的许多研究子项目之一。子项目和研究者（PI）可能从另一个NIH来源获得主要资金，因此可以在其他CRISP条目中表示。所列机构为中心，不一定是研究者所在机构。目的：主要目的是研究在接受异烟肼900 mg+利福喷丁900 mg每周一次或异烟肼300 mg每日一次治疗的患者中发生的可能的抗体介导的超敏反应/流感样疾病，有时伴有低血压。次要目的是评估与低血压、荨麻疹-血管性水肿或急性支气管痉挛相关的过敏综合征患者的血清类胰蛋白酶水平。 研究报告：两个治疗组中没有超敏反应综合征体征或症状的患者将在服用任何研究药物前的基线和治疗12周后再次采集10 cc血液。将血液采集到血清分离管中，并进行处理，以储存和运输至方案指定的机构（约翰霍普金斯DACI参考实验室）。同意参加子研究的对照组将在研究入组后首次访视时和服用任何药物前进行知情同意过程。 方法：研究设计是嵌套在多中心、前瞻性、随机、开放标签III期临床试验中的病例对照研究，该试验比较了两种治疗方案对潜伏性结核感染的有效性：“每周利福喷丁/异烟肼治疗3个月与每日异烟肼治疗9个月治疗潜伏性结核感染的有效性和耐受性研究”（TB Trials Consortium Study 26）。病例和对照组将从试验参与者中招募，这些参与者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。对于该子研究，病例是任一治疗组中符合潜在超敏反应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受试者。将使用对照血清将药物特异性免疫应答的频率和强度与观察到的临床超敏反应综合征联系起来。在研究26中，预计发生超敏反应综合征的患者数量相对较少。为了在病例数较少的情况下获得足够的把握度，将采用1：4的病例对照比。 临床相关性：通过使用间歇性方案（每周一次或两次）而不是每日治疗方案，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良好，但间歇性利福平与似乎是免疫介导的超敏反应综合征的发生相关。这种超敏反应综合征可由以下流感样症状中的任何一种（单独或组合）组成：发热、寒战、昏厥、头痛、肌痛和关节痛。异烟肼也可引起过敏反应，但其特征为发热、皮疹、淋巴结病和血管炎。很少，INH可以引起流感样综合征。迄今为止，研究26中的两种方案总体耐受性良好，但部分患者可能发生超敏反应。尚不清楚该反应是否归因于异烟肼、利福喷丁或两者。因此，本研究建议更详细地评估这种可能的超敏反应综合征。

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.