University of Texas Medical Branch Porphyria Laboratory and Center Protocol: Panhematin™ Prevention Study Date: June 18, 2019 Version: 7 IND 13,929 Clinical Study Protocol Safety and Efficacy of Panhematin™ for Prevention of Acute Attacks of Porphyria Trial phase: II This document is confidential and was prepared by and is the property of The University of Texas Medical Branch. Access to and reproduction of this document by permission only. Page 1 University of Texas Medical Branch Porphyria Laboratory and Center Protocol: Panhematin™ Prevention Study Date: June 18, 2019 Version: 7 IND 13,929 Table of Contents 1. Introduction ....................................................................................................... 5 1.1 Description of acute porphyrias and current treatment ................................. 5 1.2 Description of the drug under study ............................................................... 12 1.3 Rationale for this clinical trial .......................................................................... 13 2. Objectives ........................................................................................................ 14 2.1 Endpoints. .......................................................................................................... 15 3. Trial Design ...................................................................................................... 15 3.1 Type of Trial ....................................................................................................... 15 3.2 Rationale for the trial design ............................................................................ 17 3.3 Treatment of Subjects and Rationale for Treatment ..................................... 17 4. Trial Population ............................................................................................... 18 4.1 Number of patient and sites ............................................................................. 18 4.2 Recruitment of Subjects ................................................................................... 19 4.3 Inclusion Criteria ............................................................................................... 19 4.4 Exclusion Criteria .............................................................................................. 22 4.5 Withdrawal Criteria ............................................................................................ 22 4.6 Subject Replacement ........................................................................................ 23 5. Study materials ............................................................................................... 23 5.1 Study drug reconstitution and administration............................................... 23 5.2 Placebo preparation and administration ........................................................ 25 5.3 Timing of administration of Panhematin™ or placebo ................................. 26 5.4 Glucose administration .................................................................................... 26 5.5 Blinding .............................................................................................................. 26 5.6 Treatment of acute attacks during the study ................................................. 27 5.7 Randomization ................................................................................................... 27 This document is confidential and was prepared by and is the property of The University of Texas Medical Branch. Access to and reproduction of this document by permission only. Page 2 University of Texas Medical Branch Porphyria Laboratory and Center Protocol: Panhematin™ Prevention Study Date: June 18, 2019 Version: 7 IND 13,929 6. Methods and Assessments ........................................................................... 28 6.1 Visit Procedures ................................................................................................ 28 6.1.1 Visit 1 – Screening and Enrollment .................................................................................... 28 6.1.2 Visit 2: ..................................................................................................................................... 29 6.1.3 Visit 3, 4, etc. ......................................................................................................................... 30 6.2 Assessments for Efficacy................................................................................. 30 6.2.1 Clinical improvement ............................................................................................................ 30 6.2.2 Biochemical measures of improvement ............................................................................. 30 6.3 Safety Assessment............................................................................................ 30 6.3.1 Symptoms .............................................................................................................................. 30 6.3.2 Physical Examination ........................................................................................................... 30 6.3.3 Blood counts and chemistries ............................................................................................. 31 6.3.4 Urinalysis ................................................................................................................................ 31 6.3.5 Pregnancy test ...................................................................................................................... 31 6.3.6 Adverse Events ..................................................................................................................... 31 7. Adverse Events ............................................................................................... 31 7.1 Definitions (ICH) ................................................................................................ 31 8. Case Report Forms ......................................................................................... 32 8.1 Rules for Completing CRFs ............................................................................. 32 8.2 Corrections to CRFs.......................................................................................... 33 8.3 CRF Review and Data Entry ............................................................................. 33 9. Monitoring Procedures .................................................................................. 33 10. Data Management ....................................................................................... 34 11. Evaluability of Subjects for Analysis ....................................................... 35 12. Statistical Analyses .................................................................................... 35 12.1 Purposes ............................................................................................................ 35 12.2 Variables for statistical analyses .................................................................... 35 12.2.1 Efficacy variables ............................................................................................................. 35 12.2.2 Safety variables ................................................................................................................ 36 12.3 Statistical Methods ............................................................................................ 36 This document is confidential and was prepared by and is the property of The University of Texas Medical Branch. Access to and reproduction of this document by permission only. Page 3 University of Texas Medical Branch Porphyria Laboratory and Center Protocol: Panhematin™ Prevention Study Date: June 18, 2019 Version: 7 IND 13,929 12.4 Sample size determination ............................................................................... 36 12.5 Interim analyses ................................................................................................ 37 13. Ethical considerations ................................................................................ 37 13.1 Assessment of Risks ........................................................................................ 37 13.2 Assessment of benefits .................................................................................... 40 13.3 Research consent .............................................................................................. 40 13.4 Institutional Review Boards ............................................................................. 40 13.5 Regulatory Authorities ...................................................................................... 41 14. Premature Termination of the Trial ........................................................... 41 15. Deviations from the Protocol..................................................................... 41 16. Essential Documents .................................................................................. 41 17. Reports and Publication ............................................................................. 42 18. Retention of Clinical Trial Documents ..................................................... 42 19. Indemnity Statement ................................................................................... 42 20. Quality Control and Quality Assurance ................................................... 42 21. References cited.........................................................................................