Abbreviated Title: AFED for the treatment of Ocular GVHD Version Date: 12SEP2017 Principal Investigator: Daniel Couriel, MD A RANDOMIZED, DOUBLE-BLINDED, PLACEBO-CONTROLLED STUDY FOR THE TREATMENT OF OCULAR CHRONIC GRAFT- VERSUS-HOST DISEASE (GVHD) WITH AMNIOTIC FLUID EYE DROPS (AFED) IRB # 103515 NCT # HCI-17-HEM-19 Principal Investigator Daniel Couriel, MD, MS Division of Hematology & Hematologic Malignancies Huntsman Cancer Institute - University of Utah 2000 Circle of Hope, Salt Lake City, UT 84112 [email protected] Sub-Investigators Catherine Lee, MD Division of Hematology & Hematologic Malignancies Huntsman Cancer Institute - University of Utah 2000 Circle of Hope Salt Lake City, UT 84112 [email protected] Michael Boyer, MD Department of Pediatrics, Primary Children’s Hospital Division of Hematology & Hematologic Malignancies Huntsman Cancer Institute - University of Utah 1950 Circle of Hope Salt Lake City, UT 84112 [email protected] Vedran Radjocic, MD Division of Hematology & Hematologic Malignancies Huntsman Cancer Institute - University of Utah 2000 Circle of Hope, Room 4246 Salt Lake City, UT 84112 [email protected] Axel Zander, MD Division of Hematology & Hematologic Malignancies Huntsman Cancer Institute - University of Utah 2000 Circle of Hope Salt Lake City, UT 84112 [email protected] Abbreviated Title: AFED for the treatment of Ocular GVHD Version Date: 12SEP2017 Sub-Investigators John Phillips, PhD Division of Hematology and Hematologic Malignancies University of Utah School of Medicine 5C330 SOM, 30 N. 1900 E. Salt Lake City UT 84132 [email protected] JoAnna Reems, PhD Cell Therapy & Regenerative Medicine University of Utah Health Sciences 675 Arapeen Drive, Suite 300 Salt Lake City, Utah 84108 [email protected] Jan Pierce, MBA Cell Therapy & Regenerative Medicine University of Utah Health Sciences 675 Arapeen Drive, Suite 300 Salt Lake City, Utah 84108 [email protected] Susan Schulman HSEB Clinical Skills Center 26 S 2000 E RM 3550 Salt Lake City, UT 84112 [email protected] Ophthalmology Dix Pettey John A Moran Eye Center 65 N Mario Capecchi Salt Lake City, UT 84132 [email protected] Statistician Ken Boucher, PhD Huntsman Cancer Institute 2000 Circle of Hope, Room: 4245 Salt Lake City, UT 84112 [email protected] Investigational agent IND Number Exempt Page 2 of 38 Abbreviated Title: AFED for the treatment of Ocular GVHD Version Date: 12SEP2017 TABLE OF CONTENTS TABLE OF CONTENTS ................................................................................................................ 3 LIST OF ABBREVIATIONS ......................................................................................................... 5 PROTOCOL SIGNATURE ............................................................................................................ 8 STUDY SUMMARY...................................................................................................................... 9 1. OBJECTIVES ........................................................................................................................ 11 1.1. Primary Objective .......................................................................................................... 11 1.1.1.2. Changes in the ophthalmologic performance of patients (dry eye symptoms). ...... 11 1.2. Secondary Objectives ..................................................................................................... 11 2. BACKGROUND AND RATIONALE ................................................................................. 12 2.1. Chronic GVHD .............................................................................................................. 12 2.2. Amniotic Fluid ............................................................................................................... 12 3. DRUG INFORMATION ....................................................................................................... 15 3.1. Description ..................................................................................................................... 15 3.2. Potential Side Effects and Hazards ................................................................................ 15 3.3. Lot Information .............................................................................................................. 15 4. STUDY DESIGN .................................................................................................................. 16 4.1. Description ..................................................................................................................... 16 4.2. Number of Patients ......................................................................................................... 16 4.3. Number of Study Centers ............................................................................................... 16 4.4. Study Duration ............................................................................................................... 16 5. ELIGIBILITY CRITERIA .................................................................................................... 17 5.1. Inclusion Criteria ............................................................................................................ 17 5.2. Exclusion Criteria ........................................................................................................... 17 6. TREATMENT PLAN............................................................................................................ 18 6.1. Administration Schedule ................................................................................................ 18 6.2. Treatment Information ................................................................................................... 18 6.3. Prohibited Concomitant Medications ............................................................................. 19 6.4. Duration of Therapy ....................................................................................................... 19 7. TOXICITIES AND DOSEAGE MODIFICATION.............................................................. 20 8. CALENDAR ......................................................................................................................... 21 Page 3 of 38 Abbreviated Title: AFED for the treatment of Ocular GVHD Version Date: 12SEP2017 9. CRITERIA FOR EVALUATION OF ENDPOINTS ............................................................ 21 9.1. Primary Objective: Clinical Effects ............................................................................... 21 Parameter d measures the changes in the ophthalmologic performance of patients ................. 22 9.1.2. Definition of Clinical Response ................................................................................. 22 9.2. Secondary Objectives ..................................................................................................... 22 10. STATISTICAL CONSIDERATIONS............................................................................... 23 11. REGISTRATIONS GUIDELINES ................................................................................... 23 12. DATA SUBMISSION SCHEDULE ................................................................................. 24 13. ETHICAL AND REGULATORY CONSIDERATIONS ................................................. 24 13.1. Informed Consent ....................................................................................................... 24 13.2. Institutional Review .................................................................................................... 24 13.3. Data and Safety Monitoring Plan ............................................................................... 24 13.4. Adverse Events / Serious Adverse Events .................................................................. 25 13.5. SAE Reporting Requirements .................................................................................... 26 13.6. Protocol Amendments ................................................................................................ 27 13.7. Protocol Deviations .................................................................................................... 27 13.8. FDA Annual Reporting .............................................................................................. 28 13.9. Clinical Trials Data Bank ........................................................................................... 28 13.10. Record Keeping .......................................................................................................... 28 14. REFERENCES .................................................................................................................. 29 APPENDIX A Patient Instructions and Dosing Diary ................................................................. 31 APPENDIX B FACT-G Quality of Life Questionnaire ............................................................... 33 APPENDIX C Health Care Provider Global Rating of Chronic GVHD ...................................... 35 APPENDIX D Ocular Rating of GVHD (Eye Score) .................................................................. 36 APPENDIX E Patient Global Rating of GVHD ........................................................................... 37 APPENDIX F Dry Eye Severity Grading Scheme ....................................................................... 38 Page 4 of 38 Abbreviated