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Mallinckrodt Pharmaceuticals, Inc Investigational New Drug Protocol Mallinckrodt Pharmaceuticals, Inc Protocol CNS-HYD201US Intrathecal Hydromorphone Version: 5.0 MALLINCKRODT PHARMACEUTICALS, INC INVESTIGATIONAL NEW DRUG PROTOCOL INTRATHECAL HYDROMORPHONE HCL 10 MG/ML PROTOCOL NUMBER CNS-HYD201US VERSION 5.0 DATED 01 AUGUST 2016 AMENDMENT REVISING PRIOR VERSION 4.0 DATED 24 JUNE 2016 A Controlled, Two-Arm, Parallel Group, Randomized Withdrawal Study To Assess The Safety And Efficacy Of Hydromorphone Hydrochloride Delivered By Intrathecal Administration Using A Programmable Implantable Pump SPONSOR: MALLINCKRODT PHARMACEUTICALS INC 675 MCDONNELL BLVD HAZELWOOD, MO 63042 USA CONFIDENTIAL 01 August 2016 1 CONFIDENTIAL Mallinckrodt Pharmaceuticals, Inc Protocol CNS-HYD201US Intrathecal Hydromorphone Version: 5.0 SUMMARY OF CHANGES FROM VERSION 4.0 TO VERSION 5.0 DATED 01 AUGUST 2016 This protocol amendment was required (1) to correctly specify a dose titration up to 10 mg/day rather than 5 mg/day and (2) to further clarify the handling of subjects who are dropped or otherwise go off study prior to the 5-week randomized withdrawal period. These and other changes are listed below: 1. Version is changed from v4.0 to v5.0 and protocol re-dated as appropriate. Title page, headers and footers are revised appropriately. 2. The Protocol Synopsis, Dosage & Regimen Section was corrected to specify a 0.1 mg/day to 10 mg/day dosage based on dose titration, rather than 0.1 mg/day to 5 mg/day. 3. The Protocol Synopsis, Study Visit Schedule Section, last paragraph, was revised to include those subjects who go off study prior to randomization, since the protocol defines treatment failures as those subjects who fail after randomization. 4. Section 1.3.3, 4th paragraph, was corrected to specify dose titration up to 10 mg/day rather than 5 mg/day. 5. Section 1.4 Study Rationale, final paragraph, is revised to include those subjects who do not enter the 5-week randomized withdrawal period. 6. Section 3.1, Description of Trial Design, third paragraph on pg 34, is revised to add text concerning those subjects who were dropped prior to randomization. These subjects will complete the study visit that they are on, go directly into CNS-HYD202US and complete scales there at the Screening and Baseline Visit, since they will not have a Day 119 or treatment failure visit that will carry over. 7. Section 3.5.1.2, 12-Week Open-Label Treatment Phase, last paragraph, was revised to clarify the situation of subjects discontinuing prior to randomization and not rolling over into the CNS-HYD202US trial. 8. Appendix Table A-2, footnote ‘e’ is revised to include subjects who are dropped prior to randomization. 9. Minor edits were made as necessary to correct spelling, capitalization, grammar or format errors. 01 August 2016 2 CONFIDENTIAL Mallinckrodt Pharmaceuticals, Inc Protocol CNS-HYD201US Intrathecal Hydromorphone Version: 5.0 Table of Contents LIST OF IN-TEXT TABLES................................................................................................. 6 LIST OF APPENDICES........................................................................................................ 6 LIST OF ABBREVIATIONS ................................................................................................ 7 1.0 INTRODUCTION..................................................................................................... 18 1.1 Background ........................................................................................................... 18 1.2 Nonclinical Assessments........................................................................................ 19 1.2.1 Pharmacology................................................................................................. 19 1.2.2 Toxicology ..................................................................................................... 20 1.3 Clinical Experience................................................................................................ 21 1.3.1 Overview of Clinical Pharmacology ............................................................... 21 1.3.2 Overview of Clinical Pharmacology ............................................................... 22 1.3.3 Overview of Efficacy and Safety .................................................................... 24 1.4 Study Rationale ..................................................................................................... 27 2.0 PURPOSE AND STUDY OBJECTIVES .................................................................. 29 2.1 Purpose.................................................................................................................. 29 2.2 Study Objectives.................................................................................................... 30 2.2.1 Primary Objective........................................................................................... 30 2.2.2 Secondary Objective ....................................................................................... 30 3.0 STUDY DESIGN...................................................................................................... 30 3.1 Description of Trial Design.................................................................................... 30 3.2 Study Endpoints..................................................................................................... 34 3.2.1 Primary Endpoint............................................................................................ 34 3.2.2 Secondary Endpoints ...................................................................................... 34 3.3 Diagnosis of Granuloma ........................................................................................ 35 3.3.1 Treatment of Granuloma................................................................................. 35 3.4 Measures to Minimize Bias.................................................................................... 36 3.4.1 Blinding.......................................................................................................... 36 3.4.2 Randomization/Assignment to Study Drug ..................................................... 36 3.5 Study Drugs........................................................................................................... 37 3.5.1 Rationale for Doses and Dosing Regimen ....................................................... 37 3.5.2 Dose Interruption............................................................................................ 40 01 August 2016 3 CONFIDENTIAL Mallinckrodt Pharmaceuticals, Inc Protocol CNS-HYD201US Intrathecal Hydromorphone Version: 5.0 3.6 Concomitant Medications ...................................................................................... 40 3.6.1 Prior and Concomitant Medications ................................................................ 40 3.6.2 Prohibited Concomitant Medications .............................................................. 41 3.7 Nonpharmacologic Interventions ........................................................................... 41 3.8 Duration of Therapy............................................................................................... 41 3.9 Procedures for Monitoring Subject Compliance ..................................................... 41 4.0 STUDY POPULATION............................................................................................ 42 4.1 Inclusion Criteria ................................................................................................... 42 4.2 Exclusion Criteria .................................................................................................. 42 5.0 SAFETY ASSESSMENTS ....................................................................................... 43 5.1 Collection of Adverse Events Data......................................................................... 43 5.2 Physical Examinations and Medical History .......................................................... 44 5.2.1 Complete Physical Examination...................................................................... 44 5.2.2 Medical History, Pump Implantation and Surgical History.............................. 44 5.3 Clinical Laboratory Testing and ECGs................................................................... 44 5.4 Vital Signs............................................................................................................. 45 5.5 Documentation of Concomitant Medications ......................................................... 45 6.0 PHARMACOKINETICS .......................................................................................... 45 7.0 PHARMACODYNAMICS ....................................................................................... 45 8.0 EFFICACY ............................................................................................................... 45 9.0 STUDY VISITS........................................................................................................ 46 9.1 Screening............................................................................................................... 46 9.2 Baseline Evaluations.............................................................................................. 47 9.3 Dose Conversion and Optional Titration Period ..................................................... 47 9.4 Continuous Dosing Period (Day 1 to Day 83) ........................................................ 48 9.5 Randomized Withdrawal and Efficacy Evaluation Period
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