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A Randomized, Double Blind, Placebo-Controlled Study to Assess A Randomized, Double Blind, Placebo-Controlled Study to Assess Efficacy, Safety and Tolerability of ISIS 304801 in Patients with Partial Lipodystrophy with an Open-Label Extension Principal Investigator: *Rebecca J. Brown, M.D., M.H.Sc. Associate Investigators: Monica Skarulis, M.D. *Phillip Gorden, M.D. Robert Shamburek, M.D. *Elaine Cochran, M.S.N., C.R.N.P. *Megan Startzell, R.N., M.P.H. Ahmed Gharib, M.D. Theo Heller, M.D. Christopher Koh, M.D., M.H.Sc. Marissa Lightbourne, M.D. (NICHD) Non-Investigator Research Staff: Michelle Ashmus, BSN, RN Non-NIH Collaborators: Elif, Oral, M.D. (Metabolism, Endocrinology, and Diabetes at the University of Michigan) Abhimanyu Garg, M.D. (University of Texas Southwestern) Stephen O’Rahilly, M.D. (Univ. of Cambridge, Metabolic Research Labs, UK) Robert Semple, M.D. (Univ. of Cambridge, UK) David Savage, M.D. (Univ. of Cambridge, UK) Morey W. Haymond, MD (Baylor College of Medicine) Shaji K. Chacko, Ph.D. (Baylor College of Medicine) Robert E. Eckel, M.D., Ph.D. (University of Colorado Anschutz Medical Campus) Kimberley D. Bruce, Ph.D. (University of Colorado Anschutz Medical Campus) Masami Murakami, M.D. (Gunma University Graduate School of Medicine; Japan) Katsuyuki Nakajima, Ph.D. (Gunma University Graduate School of Medicine; Japan) *Indicates those who are allowed to obtain informed consent Protocol Overview Protocol Title: A Randomized, Double Blind, Placebo-Controlled Study to Assess Efficacy, Safety and Tolerability of ISIS 304801 in Patients with Partial Lipodystrophy with an Open-Label Extension Abbreviated Title: ApoC-III ASO in lipodystrophy IRB: NIDDK/NIAMS Research Type: Phase II Clinical Trial Multi-site Collaboration: No Intramural Collaboration: No 1 CR 2019 version (IRB approved 9/24/2019) 16-DK-0038 Submitted to IRB: Ionizing Radiation Use: Research Indicated (X-rays, e.g., CT; radioisotope, e.g. PET; etc.) Investigational New Drug/Device: Yes Patient Self-Referral Allowed: Yes List Protocol On Web: Yes Is tissue being collected for research Yes purposes: Conflict of Interest The protocol involves no drugs/devices/products that may lead to payments and/or royalties to be paid to the investigators or the NIH. The investigators have no equity, consultative, or other financial relationship with a non-NIH source related to this protocol which might be considered a conflict of interest. Time Frame Start Date: 12/1/2015 End Date: 4/30/2020 2 CR 2019 version (IRB approved 9/24/2019) 16-DK-0038 Submitted to IRB: Table of Contents Contents Table of Contents _____________________________________________ 3 Precis – Abstract _____________________________________________ 6 STUDY GLOSSARY ____________________________________________ 7 1. Study Objectives ___________________________________________ 9 1.1 Primary Objective _______________________________________________ 9 1.2 Secondary/Tertiary Objectives _____________________________________ 9 2. Introduction ______________________________________________ 9 2.1 Lipodystrophy __________________________________________________ 9 2.2 Therapeutic Rationale __________________________________________ 11 2.3 ISIS 304801 __________________________________________________ 13 2.3.1 Mechanism of Action __________________________________________________________ 13 2.3.2 Chemistry __________________________________________________________________ 13 2.3.3 Preclinical Experience _________________________________________________________ 14 2.3.4 Clinical Experience ___________________________________________________________ 15 2.4 Rationale for Dose and Schedule of Administration ____________________ 16 3. Subject Eligibility Assessment and Enrollment ____________________ 17 3.1 Inclusion Criteria ______________________________________________ 17 3.2 Exclusion Criteria ______________________________________________ 18 4. Study Design _____________________________________________ 20 4.1 Design/Randomization __________________________________________ 20 4.2 Outcome Measures _____________________________________________ 21 4.2.1 Primary outcome: ____________________________________________________________ 21 4.2.2 Secondary outcomes: _________________________________________________________ 21 4.2.3 Tertiary/Exploratory outcomes: _________________________________________________ 21 5. Statistical Considerations ___________________________________ 22 5.1 Sample Size Justification ________________________________________ 22 5.2 Statistical Methods for Data Analysis _______________________________ 24 6. Experimental Plan _________________________________________ 25 6. 1 Diet ________________________________________________________ 25 6.2 Medications __________________________________________________ 25 6.2.1 Pre-study Medications _________________________________________________________ 25 6.2.2 ISIS 304801 ________________________________________________________________ 25 3 CR 2019 version (IRB approved 9/24/2019) 16-DK-0038 Submitted to IRB: 6.3 Study Procedures ______________________________________________ 26 6.3.1 Study Schedule ______________________________________________________________ 26 6.3.2 Prescreening ________________________________________________________________ 26 6.3.3 Initial Visit – Includes Screening (Week -1) and the first week of dosing (Week 1) _________ 27 6.3.4 In-person follow-up visits ______________________________________________________ 27 6.3.5 Home nurse visits ____________________________________________________________ 27 6.3.6 Telephone follow-up __________________________________________________________ 28 6.3.7 Post-Treatment ______________________________________________________________ 28 6.3.8 Follow-up Visits for Early Termination from Treatment Period _________________________ 28 6.3.9 Follow-up Visits for Early Termination from Post-Treatment Follow-up Period _____________ 29 6.3.10 End of Study _______________________________________________________________ 29 6.3.11 Post-Study Obligations _______________________________________________________ 29 6.4 Study Assessments _____________________________________________ 29 6.4.1 Patient Reported Outcomes ____________________________________________________ 29 6.4.2 Detailed Metabolic Phenotyping _________________________________________________ 29 6.4.3 Pharmacokinetic Analysis ______________________________________________________ 32 7. Human Subject Protection ___________________________________ 34 7.1 Data and Safety Monitoring Plan __________________________________ 34 7.1.1 Investigational New Drug application _____________________________________________ 35 7.1.2 Data and Safety Monitoring Board _______________________________________________ 35 7.1.3 Study monitoring ____________________________________________________________ 35 7.1.4 Adjudication Committees ______________________________________________________ 35 7.2 Adverse Events, Protocol Deviations, and Unanticipated Problems ________ 36 7.2.1 Definitions __________________________________________________________________ 36 7.2.2 Monitoring and Recording Adverse Events _________________________________________ 37 7.2.3 Evaluation of Adverse Events (Serious and Non-Serious) _____________________________ 37 7.3 Reporting ____________________________________________________ 39 7.4 Procedures for Handling Special Situations __________________________ 40 7.4.1 Contraception and Pregnancy ___________________________________________________ 40 7.4.2 Abnormalities of Laboratory Tests _______________________________________________ 41 7.4.3 Prescheduled or Elective Procedures or Routinely Scheduled Treatments ________________ 41 7.4.4 Dosing Errors _______________________________________________________________ 41 7.5 Safety Monitoring Rules _________________________________________ 42 7.5.1 Safety Monitoring Rules for Liver Chemistry Tests ___________________________________ 42 7.5.2 Safety Monitoring Rules for Renal Function ________________________________________ 43 7.5.3 Safety Monitoring Rules for Platelet Count Results __________________________________ 43 7.5.4 Safety Monitoring for Minor Bleeding Events _______________________________________ 43 7.5.5 Safety Monitoring for Constitutional Symptoms _____________________________________ 43 7.5.6 Safety Monitoring for LDL-C Elevations ___________________________________________ 44 7.5.7 Safety Monitoring Rule for Documented Severe Hypoglycemia _________________________ 44 7.5.8 Monitoring Rule for Hyperglycemia ______________________________________________ 45 7.5.9 Acute Pancreatitis ____________________________________________________________ 46 7.6 Stopping Rules ________________________________________________ 46 7.6.1 Stopping Rules for Liver Chemistry Elevations ______________________________________ 47 7.6.2 Stopping Rules for Renal Function Test Results _____________________________________ 47 7.6.3 Stopping Rule for Platelet Count Results __________________________________________ 47 7.6.4 Stopping Rule for Documented Severe Hypoglycemia ________________________________ 50 4 CR 2019 version (IRB approved 9/24/2019) 16-DK-0038 Submitted to IRB: 7.7 Adjustment of Dose and/or Treatment Schedule ______________________ 50 7.8 Withdrawal Criteria ____________________________________________ 50 7.9 Rationale for Subject Selection ___________________________________ 51 7.10 Risks/Benefits Analysis including Considerations of Alternatives to Participation _______________________________________________________________ 51 7.10.1 Benefits ___________________________________________________________________
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