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Protocol No. AKB-6548-CI-0021 Vadadustat Original Protocol (Version 1) 1 SIGNATURE PAGES 1.1 Protocol Approval Medical Research Akebia Therapeutics, Inc. Confidential 23 May 2016; Page 2 Akebia Therapeutics, Inc. Protocol No. AKB-6548-CI-0021 Vadadustat Original Protocol (Version 1) 1.2 Investigator Agreement I confirm that I have read and that I understand this protocol, any amendments to the protocol (if applicable, a history of protocol changes are appended at the end of this document), the Investigator’s Brochure, and other product information provided by the Sponsor. I agree to conduct this study in accordance with the requirements of this protocol and also protect the rights, safety, privacy, and well-being of study subjects in accordance with the following: • The ethical principles that have their origin in the Declaration of Helsinki. • International Conference on Harmonization Guidance for Industry, Good Clinical Practice E6. • All applicable laws and regulations, including, without limitation, data privacy laws and regulations. • Regulatory requirements for reporting serious adverse events defined in this protocol. • Terms outlined in the Clinical Study Site Agreement. Signature of Investigator Date Investigator Name (print or type) Investigator’s Title Phone Number Full Address Confidential 23 May 2016; Page 3 Akebia Therapeutics, Inc. Protocol No. AKB-6548-CI-0021 Vadadustat Original Protocol (Version 1) TABLE OF CONTENTS 1 SIGNATURE PAGES .................................................................................................. 2 1.1 Protocol Approval .................................................................................................... 2 1.2 Investigator Agreement ............................................................................................ 3 TABLE OF CONTENTS ......................................................................................................... 4 LIST OF TABLES ................................................................................................................... 7 LIST OF FIGURES ................................................................................................................. 7 2 PROTOCOL SYNOPSIS .............................................................................................. 8 3 LIST OF ABBREVIATIONS ..................................................................................... 14 4 BACKGROUND ........................................................................................................ 16 4.1 Proposed Indication of Renal Anemia ................................................................... 16 4.2 Available Therapies for Anemia in Patients with CKD ......................................... 17 4.3 Hypoxia-Inducible Factor ...................................................................................... 17 4.4 Description and Mechanism of Action of Vadadustat ........................................... 18 4.5 Summary of Clinical Experience ........................................................................... 19 4.6 Ethno-Bridging Data from a Study of Healthy Japanese and Caucasian Volunteers ................................................................................................................................ 20 4.7 Potential Benefits and Risks ................................................................................... 22 5 STUDY OBJECTIVES AND ENDPOINTS .............................................................. 22 5.1 Primary Objective and Endpoint ............................................................................ 22 5.2 Secondary Objectives and Endpoints ..................................................................... 22 6 STUDY DESIGN ........................................................................................................ 23 6.1 Study Design .......................................................................................................... 23 6.2 Study Duration ....................................................................................................... 25 6.3 Rationale for Study Design .................................................................................... 25 6.4 Dose Justification ................................................................................................... 26 7 SELECTION AND WITHDRAWAL OF SUBJECTS .............................................. 27 7.1 General Criteria ...................................................................................................... 27 7.2 Inclusion Criteria .................................................................................................... 27 7.3 Exclusion Criteria ................................................................................................... 27 7.4 Retesting and Rescreening ..................................................................................... 29 7.4.1 Retesting ............................................................................................................ 29 7.4.2 Rescreening ....................................................................................................... 29 7.5 Study Completion, Study Termination, and Individual Study Site Termination ... 29 7.5.1 Study Completion .............................................................................................. 29 7.5.2 Study Termination ............................................................................................. 30 7.5.3 Individual Study Site Termination .................................................................... 30 7.6 Subject Completion and Individual Subject Discontinuation ................................ 30 Confidential 23 May 2016; Page 4 Akebia Therapeutics, Inc. Protocol No. AKB-6548-CI-0021 Vadadustat Original Protocol (Version 1) 7.6.1 Subject Completion ........................................................................................... 30 7.6.2 Conditions and Documentation of Individual Subject Study Drug Discontinuation .................................................................................................. 30 7.6.3 Individual Subject Discontinuation during the Primary Efficacy Period or Blinded Dose Adjustment and Data Cleaning Period ....................................... 31 7.6.4 Individual Subject Discontinuation during the Open-Label Extension Period . 31 8 STUDY DRUGS AND TREATMENT OF SUBJECTS ............................................ 31 8.1 Study Drugs ............................................................................................................ 31 8.1.1 Formulation ....................................................................................................... 31 8.1.2 Storage and Accountability ............................................................................... 32 8.1.3 Dispensing of Study Drugs ................................................................................ 32 8.1.4 Product Accountability and Destruction ........................................................... 32 8.2 Treatment of Subjects ............................................................................................. 33 8.2.1 Dosing Instructions ............................................................................................ 33 8.2.2 Randomization ................................................................................................... 33 8.2.3 Blinding During the Primary Efficacy Period and Breaking the Blind ............. 34 8.2.4 Study Drug Administration during the Primary Efficacy Period ...................... 34 8.2.5 Study Drug Administration during the Blinded Dose Adjustment and Data Cleaning Period ................................................................................................. 35 8.2.6 Vadadustat Administration during the Open-Label Extension Period .............. 36 8.2.7 Dose Adjustment Guidelines ............................................................................. 36 8.2.8 Rescue Therapy Guidelines ............................................................................... 37 8.2.9 Oral Iron
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