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

这项二期临床试验于2013年11月15日启动，我们成功招募和治疗了18名重症眼部GVHD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。 我们招募了18名患者，其中10名患者完成了6个月的交叉研究阶段(阶段1和阶段2)，并在研究的非掩蔽开放标签阶段3中使用了实际的自体血清滴眼液。在完成了第一阶段和第二阶段的10人中，有9人确信，由于其中一种滴眼液的症状明显缓解，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)。在第三阶段，使用开放标签的染料滴剂，他们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EASE的生产得以顺利进行，尽管FDA要求的要求很复杂，而且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一次性使用的未保存的滴剂，这些滴剂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药房不得不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。 一名患者病情严重，患有严重的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，但在那里患上了肺炎，并在睡梦中去世。 另一名慢性GVHD患者在参加研究后，在开始使用自体血清滴眼液之前，患上了肺部真菌感染，病情严重。他成功地接受了抗真菌治疗，康复并完成了6个月的交叉试验。当他肺部真菌感染复发并去世时，他正在研究的张开手臂中使用自体血清眼药水。 这两名患者显示了这些骨髓移植患者是多么虚弱，以及他们如何会因GVHD而出现多器官并发症。 不幸的是，2015年6月1日，FDA搁置了这项研究，就像许多其他使用NIH CC复方药房来制定试验药物和治疗的NIH临床研究一样，因为在组成试验药物的实验室中发现了两瓶受污染的白蛋白(与自体血清滴眼液无关)。按照FDA的要求，所有研究参与者都被指示停止使用眼药水，并将所有未使用的眼药水退回NIH CC药房。由于找不到其他药店立即按照FDA要求的、NEI(未保存和冷冻的血清滴眼液的一次性滴剂)可以接受的方式继续配制研究眼药水，并且由于患者已经停止滴眼治疗一个多月，根据数据和安全监测委员会(DSMC)的建议，NEI被迫停止并于2015年7月终止研究。在这一点上，10名患者已经完成了6个月的主要交叉试验，这些患者的数据正在分析中，并将在获得DSMC批准的情况下报告。 在结束这项研究进行安全性和有效性评估之前，我们最后一次看了所有患者。我们在2015年底完成了这项工作。我们目前正在继续对完成交叉研究的10名患者的结果进行分析和解释。我们正在编写这项研究的报告，以便出版。 最后注意：导致FDA关闭NIH复方药房的无关白蛋白小瓶污染案件中的一种污染物是一种真菌，它被证明是一种不同于导致我们一名患者死于肺部感染的微生物(如上所述)。

This Phase 2 clinical trial was activated on November 15, 2013 and we successfully recruited and treated 18 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). The patient is then provided with the actual ASED (Open label phase 3) until the completion and termination of the study. We recruited 18 patients, out of which number 10 patients completed the 6 month cross over study phases (Phases 1 and 2) and used the actual autologous serum eye drops in the unmasked, open label Phase 3 of the study). 9 out of the 10 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. In Phase 3, using the open label ASED dye drops, they claimed 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 allowed for smooth production of the ASED inspite of the complex requirements required by the FDA and the often very poor health of the GVHD patients. One important feature of the FDA approved study was the use of non-preserved ASED in single use dropperrettes which were frozen and used only once after thawing, and then discarded, to avoid spoilage as well as contamination. Since 4 such dropperrettes were used every day, the NIH Pharmacy had 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 severe 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 while there and passed away in her sleep. Another chronic GVHD patient became very ill with a fungal lung infection after he had enrolled in the study but before he started using the autologous serum eye drops. He was successfully treated with an anti-fungal, recovered and completed the 6 month cross over trial. He was using the autologous serum eye drops in the open arm of the study when he had a recurrence of the fungal lung infection and passed away. These 2 patients show how frail these Bone Marrow Transplantation patients are, and how they can develop multi-organ complications from GVHD. Unfortunately, on June 1, 2015, the FDA placed the study on clinical hold, like many other NIH clinical studies that used the NIH CC Compounding Pharmacy to formulate the trial medications and treatment, due to the discovery of 2 contaminated vials of albumin (unrelated to the autologous serum eye drops) in the laboratory making up the trial medications. As required by the FDA, all study participants were instructed to stop using the eye drops and return all unused eye drops back to the NIH CC Pharmacy. Since no other pharmacy could be located right away to continue making up the study eye drops in the same way as required by the FDA and which was acceptable to the NEI (single use dropperrettes for the non-preserved and frozen serum eye drops), and since patients had stopped the eye drop treatment for over a month, upon recommendation of the Data and Safety Monitoring Committee (DSMC), the NEI was forced to discontinue and terminate the study in July 2015. At this point, 10 patients had completed the 6 month main cross over Trial and the data from these patients is being analyzed and will be reported with approval by the DSMC. We saw all the patients one final time before closing the study for safety and efficacy review. We completed this by the end of 2015. We are currently continuing the analysis and interpretation of results on the 10 patients who completed the cross over study. We are in the process of writing up the report on this study for publication. One final note: one contaminant in the non-related albumin vial contamination case which caused the FDA to shut down the NIH Compounding Pharmacy was a fungus, which was shown to be a different organism to that which caused the demise of one of our patients from a lung infection (recounted above).