A Randomized, Controlled, Double-Masked, Clinical Trial of Autologous Serum Eye Drops for Severe Ocular Chronic Graft-versus-Host Disease (GVHD) in Hematopoietic Stem Cell Transplant (HSCT) Patients

这项2期临床试验于2013年11月15日启动，我们招募并治疗了11名严重眼部移植物抗宿主病患者。这项研究设计为一项双掩蔽、安慰剂对照的随机6个月交叉试验，其中安慰剂或自体血清滴眼液(ASED)使用3个月(第一阶段)，然后切换到另一种滴眼剂3个月(第二阶段)。然后，将向患者提供实际的ASD(开放标签阶段3)，直到研究完成和终止。4名患者已经完成了6个月的交叉研究阶段(阶段1和阶段2)，现在正在使用实际的自体血清滴眼液(无遮盖，开放标签的研究阶段3)。所有4名完成了第一阶段和第二阶段的人都确信，由于其中一种眼药水的症状明显缓解，他们在使用眼药水的头几周内知道自己处于哪一项研究中(无论是安慰剂还是非安慰剂)。现在，在第三阶段，使用开放标签的染料滴剂，他们现在声称主观上显著缓解了他们的干眼症状。 我们与输血医学部(也称为NIH血库)和NIH临床中心药房的密切合作使我们能够顺利生产EASE，尽管FDA提出了复杂的要求，GVHD患者的健康状况往往非常糟糕。FDA批准的这项研究的一个重要特征是使用未保存的保鲜液，这些液滴在解冻后只使用一次，然后丢弃，以避免变质和污染。由于每天使用4个这样的滴管，NIH药房必须为每个患者补充数千个这样的滴管。我们需要对议定书进行几次修改，进行调整，给NIH血库和药房更大的回旋余地，以延长滴眼剂生产中复杂步骤的窗口，并保持在FDA的要求之内。这对未来生产这些眼药水的所有血库和药店来说都是有用的信息。 一名病情严重的患者患有肺部移植物抗宿主病，在她可以开始ASED之前去世，但在她接受筛查和参加研究后去世。她去南美的家做了一次短暂的探望，但患上了肺炎，并在睡梦中去世。这显示了骨髓移植患者是多么虚弱，以及他们如何会出现移植物抗宿主病的多器官并发症。 综上所述，我们正在继续招募和治疗在这项临床试验中有严重干眼症状的严重眼部GVHD患者，并对最初几名患者的热情参与感到鼓舞。

This Phase 2 clinical trial was activated on November 15, 2013 and we have recruited and treated 11 patients with severe ocular GVHD. The study was designed to be a double masked, placebo controlled and randomized 6 month cross over study where either a placebo or the autologous serum eye drop (ASED) is used for 3 months (Phase 1), then switched to the other drop for another 3 months (Phase 2). Then the patient will be provided with the actual ASED (Open label phase 3) until the completion and termination of the study. 4 patients have completed the 6 month cross over study phases (Phases 1 and 2) and are now using the actual autologous serum eye drops (unmasked, open label Phase 3 of the study). All 4 who have completed Phases 1 and 2 are convinced that they knew which arm of the study they were in (whether placebo or ASED), within the first weeks of using the eye drops due to the marked relief from symptoms from one of the drops. Now in Phase 3, using the open label ASED dye drops, they now claim significant subjective relief of their dry eye symptoms. Our close collaboration with the Department of Transfusion Medicine (also called the NIH Blood Bank) and the NIH Clinical Center Pharmacy has allowed for smooth production of the ASED inspite of the complex requirements imposed by the FDA and the often very poor health of the GVHD patients. One important feature of the FDA approved study is the use of non- preserved ASED in dropperrettes which are frozen and used only once after thawing, and then discarded, to avoid spoilage as well as contamination. Since 4 such dropperrettes are used every day, the NIH Pharmacy has to make up thousands of such dropperrettes for every patient. We needed to make several amendments to refine the Protocol, to make adjustments and give more leeway for the NIH Blood Bank and Pharmacy to extend the windows for the complex steps in the production of the eye drops and stay within the requirements of FDA. This is helpful information for all blood banks and pharmacies that will be making these eye drops in the future. One patient who was very ill and suffered from GVHD of the lungs, passed away before she can start the ASED but after she was screened and enrolled in the study. She went for a short visit to her home in South America but developed pneumonia and passed away in her sleep. This shows how frail Bone Marrow Transplantation patients are, and how they can develop multi-organ complications from GVHD. In summary, we are continuing to recruit and treat severe ocular GVHD patients who have severe dry eye symptoms in this clinical trial and are encouraged by the enthusiastic participation of the first few patients.