Development and validation of a disease-relevant patient-reported outcome tool in light chain amyloidosis

摘要 轻链淀粉样变性（AL）是一种浆细胞疾病，其特征是不溶性原纤维 来自克隆轻链的沉积。这种疾病与高早期死亡率有关， 类似于多发性骨髓瘤的化疗健康状况的下降在AL中占主导地位， 签名功能介绍。即使化疗产生了成功的血液学反应， 患者可能继续经历与器官（例如心脏、肾、神经）功能障碍相关的症状， 这是由于治疗前原纤维的沉积。因此，PRO的测量，例如患者报告的疲劳 和身体功能，这是一个关键的，但利用不足，方面的总体结果评估的试验， AL疗法候选人为这个指导病人为导向的研究职业发展（K23）奖，博士。 Anita D 'Souza是一名血液学/肿瘤学培训的淀粉样蛋白专家， 制药商发起的临床试验。作为浆细胞疾病工作委员会的科学主任， NIH资助的国际血液和骨髓移植研究中心和数据和 D 'Souza博士是NIH资助的血液和骨髓移植临床试验网络的协调中心。 在浆细胞疾病的临床试验的开发和执行的职业生涯定位良好。她的职业目标 是进行以患者为中心的淀粉样蛋白临床研究，以患者的观点为标准， 临床试验的预期组成部分1）评估AL淀粉样变性的新治疗方法 和2） 使用PRO 症状监测和管理 .为了实现这一目标，D 'Souza博士需要教学培训， PRO方法中的导师制，以患者为中心的研究中的导师制，以及有效的 与患者和患者倡导者的接触。在此K23应用程序中，以及在提供此应用程序的上下文中， 培训和指导，我们建议开发和评估与AL相关的PRO工具（AL-PROfile）， 利用NIH PROMIS措施库中的项目。具体目标1将确定最相关的目标 通过文献回顾和定性研究， 与患者、患者权益维护者以及临床和研究专家进行访谈，从PROMIS中选择项目 项目库组成AL-PROfile，并确认认知访谈中的项目理解， 患者;目标2将评价AL-PROfile的心理测量特性，包括收敛性 判别效度、已知组效度、内部一致性、重测信度、 和响应性 目标3将在临床护理中纵向跟踪新诊断患者的PRO。D 'Souza博士 培训计划包括教学法，多学科团队的指导，以及将 使她能够增强她在AL临床试验方面的专业知识， 研究和专业。 这项工作将提供初步数据，以支持R 01提案， 一项随机、多中心临床试验，旨在检验AL-PROfile作为AL症状管理干预措施的效果 .

ABSTRACT Light chain amyloidosis (AL) is a plasma cell disorder characterized by organ dysfunction from insoluble fibril deposition derived from clonal light chains. The disease is associated with high early mortality and is treated with chemotherapies similar to multiple myeloma. Decline in health status is predominant in AL and often the signature feature at presentation. Even when chemotherapy produces a successful hematologic response, patients may continue to experience symptoms related to organ (e.g. cardiac, renal, neurologic) dysfunction, due to deposition of fibrils prior to therapy. Therefore, measurement of PROs, such as patient-reported fatigue and physical functioning, is a critical, yet underutilized, aspect of the overall outcomes assessment of trials of AL therapies. The candidate for this mentored patient-oriented research career development (K23) award, Dr. Anita D'Souza, is a hematology/oncology trained amyloid specialist with demonstrated success in conducting investigator-initiated clinical trials. As the Scientific Director of the Plasma Cell Disorders Working Committee in the NIH-funded Center for International Blood and Marrow Transplant Research and member of the Data and Coordinating Center for the NIH-funded Blood and Marrow Transplant Clinical Trials Network, Dr. D'Souza is well positioned for a career in developing and executing clinical trials in plasma cell disorders. Her career goal is to conduct patient-centered amyloid clinical research, where the patient's perspective is a standard and expected component of clinical trials 1) evaluating new treatments for AL amyloidosis and 2) using PROs for symptom monitoring and management . To accomplish this goal, Dr. D'Souza requires didactic training and mentorship in PRO methodology, mentorship in patient-centered research, and mentorship in effective engagement with patients and patient advocates. In this K23 application, and in the context of providing this training and mentorship, we propose to develop and evaluate a PRO tool relevant for AL (the AL-PROfile), utilizing items from the library of NIH PROMIS measures. Specific Aim 1 will determine the most relevant symptom and functioning domains for patient-centered AL research through literature review and qualitative interviews with patients, patient advocates, and clinical and research experts, select items from the PROMIS item libraries to comprise the AL-PROfile, and confirm item comprehension in cognitive interviews with patients; Aim 2 will evaluate the psychometric measurement properties of the AL-PROfile, including convergent and discriminant validity, known groups validity, internal consistency, test-retest reliability, and responsiveness to change; and Aim 3 will track PROs longitudinally in newly diagnosed patients in clinical care. Dr. D'Souza's training plan incorporates didactics, mentoring by a multi-disciplinary team, and research experience that will allow her to augment her expertise in AL clinical trials with a deeper understanding of patient-centered research and PROs. The work will provide preliminary data to support an R01 proposal to conduct a randomized, multicenter clinical trial to test the AL-PROfile as an intervention for symptom management in AL .