Newcastle Clinical Trials Unit, Newcastle University, Newcastle upon Tyne, UK.
Population Health Sciences Institute, Newcastle University, Newcastle upon Tyne, UK.
BMJ Open. 2024 Jun 12;14(6):e079158. doi: 10.1136/bmjopen-2023-079158.
Severe Graves' disease is a life-changing condition with poor outcomes from currently available treatments. It is caused by directly pathogenic thyroid-stimulating hormone receptor-stimulating antibodies (TRAb), which are secreted from plasma cells. The human anti-CD38 monoclonal antibody daratumumab was developed to target plasma cells which express high levels of CD38, and is currently licensed for treatment of the plasma cell malignancy, myeloma. However, it can also deplete benign plasma cells with the potential to reduce TRAb and alter the natural history of severe Graves' disease. This study aims to establish proof of concept that daratumumab has efficacy in patients with severe Graves' disease and will provide important data to inform a choice of dosing regimen for subsequent trials.
The Graves-PCD trial aims to determine if daratumumab modulates the humoral immune response in patients with severe Graves' disease, and if so, over what time period, and to find an optimal dose. It is a single-blinded, randomised, dose-finding, adaptive trial using four different doses of daratumumab or placebo in 30 adult patients. Part 1 of the trial is dose-finding and, following an interim analysis, in part 2, the remaining patients will be randomised between the chosen dose(s) from the interim analysis or placebo. The primary outcome is the percentage change in serum TRAb from baseline to 12 weeks.
The trial received a favourable ethical opinion from London-Hampstead Research Ethics Committee (reference 21/LO/0449). The results of this trial will be disseminated at international meetings, in the peer-reviewed literature and through partner patient group newsletters and presentations at patient education events.
ISRCTN81162400.
严重 Graves 病是一种改变生活的疾病，目前可用的治疗方法效果不佳。它是由直接致病的促甲状腺激素受体刺激抗体（TRAb）引起的，这些抗体是由浆细胞分泌的。人源抗 CD38 单克隆抗体达雷妥尤单抗被开发用于靶向表达高水平 CD38 的浆细胞，目前被批准用于治疗浆细胞恶性肿瘤多发性骨髓瘤。然而，它也可以耗尽良性浆细胞，从而有可能降低 TRAb 并改变严重 Graves 病的自然病程。本研究旨在证实达雷妥尤单抗对严重 Graves 病患者有效，并为后续试验的剂量方案选择提供重要数据。
Graves-PCD 试验旨在确定达雷妥尤单抗是否能调节严重 Graves 病患者的体液免疫反应，如果可以，其作用持续时间以及最佳剂量。这是一项单盲、随机、剂量发现、适应性试验，将 30 名成年患者分为四组，分别接受不同剂量的达雷妥尤单抗或安慰剂治疗。试验的第一部分是剂量发现，在中期分析后，第二部分将根据中期分析选择的剂量或安慰剂对其余患者进行随机分组。主要终点是从基线到 12 周时血清 TRAb 的百分比变化。
该试验得到了伦敦-汉普斯特德伦理委员会的有利伦理意见（参考号 21/LO/0449）。该试验的结果将在国际会议上、同行评议文献中以及通过合作伙伴患者群体的通讯和患者教育活动的演讲中进行传播。
ISRCTN81162400。
