Supplementary Material for: Evidence-Based Use of Levothyroxine/Liothyronine Combinations in Treating Hypothyroidism: A Consensus Document

Background: Fourteen clinical trials have not shown a consistent benefit of combination therapy with levothyroxine (LT4) and liothyronine (LT3). Despite the publication of these trials, combination therapy is widely used and patients reporting benefit continue to generate patient and physician interest in this area. Recent scientific developments may provide insight into this inconsistency and guide future studies. Methods: The American Thyroid Association (ATA), British Thyroid Association (BTA), and European Thyroid Association (ETA) held a joint conference on November 3, 2019 (live-streamed between Chicago and London) to review new basic science and clinical evidence regarding combination therapy with presentations and input from 12 content experts. After the presentations, the material was synthesized and used to develop Summary Statements of the current state of knowledge. After review and revision of the material and Summary Statements, there was agreement that there was equipoise for a new clinical trial of combination therapy. Consensus Statements encapsulating the implications of the material discussed with respect to the design of future clinical trials of LT4/LT3 combination therapy were generated. Authors voted upon the Consensus Statements. Iterative changes were made in several rounds of voting and after comments from ATA/BTA/ETA members. Results: Of 34 Consensus Statements available for voting, 28 received at least 75% agreement, with 13 receiving 100% agreement. Those with 100% agreement included studies being powered to study the effect of deiodinase and thyroid hormone transporter polymorphisms on study outcomes, inclusion of patients dissatisfied with their current therapy and requiring at least 1.2 µg/kg of LT4 daily, use of twice daily LT3 or preferably a slow-release preparation if available, use of patient-reported outcomes as a primary outcome (measured by a tool with both relevant content validity and responsiveness) and patient preference as a secondary outcome, and utilization of a randomized placebo-controlled adequately powered double-blinded parallel design. The remaining statements are presented as potential additional considerations. Discussion: This article summarizes the areas discussed and presents Consensus Statements to guide development of future clinical trials of LT4/LT3 combination therapy. The results of such redesigned trials are expected to be of benefit to patients and of value to inform future thyroid hormone replacement clinical practice guidelines treatment recommendations.

背景：十四项临床试验并未显示出左甲状腺素（LT4）与三碘甲状腺原氨酸（LT3）联合疗法的持续益处。尽管已有这些试验的发表，联合疗法仍被广泛采用，且报告受益的患者持续引发患者及医师对该领域的关注。近期科学发展的新进展可能为这种不一致性提供洞见，并指导未来的研究。方法：美国甲状腺协会（ATA）、英国甲状腺协会（BTA）和欧洲甲状腺协会（ETA）于2019年11月3日联合举办了一场研讨会（芝加哥与伦敦之间进行现场直播），旨在回顾关于联合疗法的新基础科学和临床证据，并邀请了12位内容专家进行报告和意见反馈。在报告结束后，相关材料被综合整理，并用于制定当前知识状态的总结性声明。在材料及总结性声明的审查和修订过程中，各方达成共识，认为有必要进行一项新的联合疗法临床试验。基于对所讨论材料对LT4/LT3联合疗法未来临床试验设计影响的理解，形成了共识性声明。作者对共识性声明进行了投票。经过数轮投票及ATA/BTA/ETA成员的反馈后，对声明进行了迭代修改。结果：在34份可供投票的共识性声明中，28份至少获得了75%的同意票，其中13份获得了100%的同意票。获得100%同意的声明包括：研究设计旨在探究脱碘酶和甲状腺激素转运蛋白多态性对研究结果的影响，纳入对当前治疗方案不满意且每日至少需要1.2 µg/kg LT4的患者，使用每日两次的LT3或更佳的缓释制剂（如可用），将患者报告的结局作为主要结局（通过具有相关内容效度和反应性的工具进行测量）以及患者偏好作为次要结局，并采用随机、双盲、平行设计的充分随机对照试验。其余声明则作为潜在附加考虑因素进行展示。讨论：本文总结了讨论的领域，并提出了共识性声明，以指导LT4/LT3联合疗法未来临床试验的发展。预计这些重新设计的试验结果将对患者有益，并对指导未来甲状腺激素替代疗法的临床实践指南和治疗建议具有价值。