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

自体血清滴眼液治疗造血干细胞移植 (HSCT) 患者严重眼部慢性移植物抗宿主病 (GVHD) 的随机、对照、双盲临床试验

• 批准号: 9362422
• 负责人: Manuel B Datiles
• 金额: $ 39.36万
• 依托单位: NATIONAL EYE INSTITUTE
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/9362422
• 关键词: Albumins; Amendment; Anemia; Antifungal Agents; Artificial Tears; Autologous; Back; Blood; Blood Banks; Bone Marrow Transplantation; Case Study; Cells; Chronic Disease; Chronic Granulomatous Disease; Clinical; Clinical Research; Clinical Trials; Collaborations; Complex; Contact Lenses; Controlled Clinical Trials; Cross-Over Studies; Cross-Over Trials; Cyclosporine; Data; Disease; Drops; Dry Eye Syndromes; Dyes; Enrollment; Eye; Eyedrops; FDA approved; Freezing; Future; Genetic Crossing Over; HIV; Health; Hematopoietic Neoplasms; Hematopoietic Stem Cell Transplantation; Home environment; Infection; Laboratories; Life; Lung; Mainstreaming; Malignant Neoplasms; Masks; Medicine; Methods; Monitor; Ointments; Organ; Organism; Outpatients; Participant; Patients; Pharmaceutical Preparations; Pharmacy facility; Phase; Phase II Clinical Trials; Placebo Control; Placebos; Pneumonia; Process; Production; Protocols documentation; Publications; Publishing; Quality of life; Randomized; Recommendation; Recruitment Activity; Recurrence; Reporting; Running; Safety; Series; Serum; Sickle Cell Anemia; Sleep; Solid Neoplasm; South America; Stem cell transplant; Steroids; Symptoms; Time; Transfusion; Transplant Recipients; United States National Institutes of Health; Vial device; Visit; Work; Writing; arm; chronic graft versus host disease; cost; design; eye dryness; fungus; graft vs host disease; leukemia; open label; phase 3 study; prevent; reduce symptoms; safety study; success; sunglasses

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).

该2期临床试验于2013年11月15日启动，我们成功招募并治疗了18例严重眼GVHD患者。该研究设计为双掩模、安慰剂对照和随机6个月的交叉研究，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液再使用3个月（第二阶段）。然后为患者提供实际的ASED（开放标签阶段3），直到研究完成和终止。