The Use of Low-Dose Carvedilol to Improve Hypoglycemia Awareness in Patients with T1DM NCT03538015 Document Date: 10/10/2019 Protocol Title: The Use of Low-Dose Carvedilol to Improve Hypoglycemia Awareness in Patients with T1DM Version Date: October 10, 2019 Principal Investigator: Owen Chan The Use of Low-Dose Carvedilol to Improve Hypoglycemia Awareness in Patients with T1DM IRB #00108879 Principal Investigator Owen Chan, Ph.D. Associate Professor 15 North 2030 East EIHG Building 533, Rm 2420B Salt Lake City, UT 84112 Tel: (801) 585-0444 Fax: (801) 585-0956 Email: [email protected] Sub-investigator(s) Matthew Wahl, M.D. Simon J. Fisher, MD, PhD Funding Organization Juvenile Diabetes Research Foundation Investigational Agent Carvedilol IND Number [IND number issued by FDA, if applicable] Page 1 of 36 Protocol Title: The Use of Low-Dose Carvedilol to Improve Hypoglycemia Awareness in Patients with T1DM Version Date: October 10, 2019 Principal Investigator: Owen Chan TABLE OF CONTENTS LIST OF ABBREVIATIONS ............................................................................................................................... 5 STATEMENT OF COMPLIANCE ...................................................................................................................... 6 STUDY SUMMARY ......................................................................................................................................... 7 STUDY SCHEMA ............................................................................................................................................. 9 1. OBJECTIVES ......................................................................................................................................... 10 1.1 Primary Objectives and Endpoints .............................................................................................. 10 1.2 Secondary Objectives and Endpoints .......................................................................................... 10 2 BACKGROUND ..................................................................................................................................... 10 3 DRUG INFORMATION .......................................................................................................................... 14 4 STUDY DESIGN..................................................................................................................................... 16 4.1 Description .................................................................................................................................. 16 4.2 Dose Limiting Toxicity ................................................................................................................. 16 4.3 Number of Subjects ..................................................................................................................... 16 4.4 Number of Study Centers............................................................................................................ 16 4.5 Study Duration ............................................................................................................................ 16 5 ELIGIBILITY CRITERIA ......................................................................................................................... 167 5.1 Inclusion Criteria ....................................................................................................................... 177 5.2 Exclusion Criteria ......................................................................................................................... 17 6 TREATMENT PLAN ............................................................................................................................. 188 6.1 Administration Schedule ............................................................................................................. 18 6.2 Treatment (include name of each treatment as section header) ............................................. 188 6.2.1 How Supplied, Stored, Packaged and Labeled .................................................................. 188 6.2.2 Preparation and Administration ......................................................................................... 18 6.2.3 Accountability and Compliance ........................................................................................ 188 6.3 Duration of Therapy .................................................................................................................. 188 7 TOXICITIES AND DOSE MODIFICATION ............................................................................................. ..20 7.1 Dose Modification ....................................................................................................................... 20 7.2 Supportive Care ........................................................................................................................... 20 8 STUDY CALENDAR ............................................................................................................................. 211 9 STUDY PROCEDURES ........................................................................................................................... 22 9.1 Informed Consent ....................................................................................................................... 22 Page 2 of 36 Protocol Title: The Use of Low-Dose Carvedilol to Improve Hypoglycemia Awareness in Patients with T1DM Version Date: October 10, 2019 Principal Investigator: Owen Chan 9.2 Study Entrance Criteria ............................................................................................................... 22 9.3 Demographics and Medical History ............................................................................................ 22 9.4 Laboratory Variables ................................................................................................................... 22 9.4.1 Hematology and Clinical Chemistries.................................................................................. 22 9.4.2 Urinalysis ............................................................................................................................. 23 9.4.3 Pregnancy Testing ............................................................................................................... 23 9.4.4 Specimen Collection, Preparation, Storage and Shipping .................................................. 23 9.5 Physical Examination ................................................................................................................... 23 9.6 Vital Signs .................................................................................................................................... 23 9.7 Electrocardiogram ....................................................................................................................... 23 9.8 Continuous Glucose Monitor (CGM) ........................................................................................... 23 9.9 Concurrent Medications ............................................................................................................. 23 9.9.1 Prohibited Concurrent Medications ................................................................................... 23 9.10 The Clamp Procedure…………………………………………………………………………………………………………….24 9.11 Efficacy Measurements ............................................................................................................... 25 9.11.1 Primary Objective Assessment ............................................................................................ 26 9.11.2 Secondary Objective Assessment ....................................................................................... 26 9.12 Safety Measurements ................................................................................................................. 27 9.12.1 Adverse Events .................................................................................................................... 27 9.12.2 Serious Adverse Events ....................................................................................................... 28 9.12.3 Serious Adverse Event Reporting Requirements ................................................................ 28 9.12.4 Reporting of Pregnancy ....................................................................................................... 29 9.13 Study Halting Rules ..................................................................................................................... 29 10 STATISTICAL CONSIDERATIONS ....................................................................................................... 29 11 DATA HANDLING AND RECORD KEEPING ....................................................................................... 30 11.1 Records Retention ....................................................................................................................... 30 11.2 Disclosure and Publication Policy ............................................................................................... 30 12 ETHICAL AND REGULATORY CONSIDERATIONS .............................................................................. 30 12.1 Institutional Review .................................................................................................................... 30 12.2 Data and Safety Monitoring Plan ...............................................................................................