Title: A Phase 1, Randomized, Double-Blind, Placebo ...

1 This may include, but is not limited to, redaction of the following: Title: A Phase 1, Randomized, Double-Blind, Placebo -Controlled, Safety, Tolerability andPharmacokinetic Study of Escalating Single and Multiple Doses of TAK-653 in HealthySubjectsNCT Number: NCT02561156 Protocol Approve Date: 24 March 2017 Certain information within this protocol has been redacted (ie, specific content is masked irreversibly from view with a black/blue bar) to protect either personally identifiable information or company confidential information. Named persons or organizations associated with the information, such as scales or coding systems, which are considered confidential information under prior agreements with license information as needed to protect confidentiality of Takeda or partners, personalinformation, or to otherwise protect the integrity of the clinical PAGECONFIDENTIALPROTOCOL AMENDMENTA Phase 1, Randomized, Double-Blind, Placebo -Controlled, Safety, Tolerability and Pharmacokinetic Study of Escalating Single and Multiple Doses of TAK-653 in Healthy SubjectsPhase 1 TAK-653 Escalating Single and Multiple Dose Study in Healthy SubjectsSponsor:Takeda Development Centre Europe AldwychLondon, WC2B 4 AEUnited KingdomStudy Number:TAK-653-1001 IND Number:Not ApplicableEudraCT Number:2015-002268-17 Compound:TAK-653 Date:24 March 2017 Amendment Number.

2 06 Amendment History:DateAmendment NumberAmendment TypeRegion23 June 2015 Initial ProtocolNot applicableUnited Kingdom26 August 20151 NonsubstantialUnited Kingdom29 March 20162 SubstantialUnited Kingdom01 April 20163 SubstantialUnited Kingdom28 June 20164 SubstantialUnited Kingdom06 January 20175 SubstantialUnited Kingdom24 March 20176 SubstantialUnited KingdomCONFIDENTIAL PROPERTY OF TAKEDAThis document is a confidential communication of Takeda. Acceptance of this document constitutes the agreement by the recipient that no information contained herein will be published or disclosed without written authorization from Takeda except to the extent necessary to obtain informed consent from those persons to whom the drug may be administered. Furthermore, the information is only meant for review and compliance by the recipient, his or her staff, and applicable institutional review committee and regulatory agencies to enable conduct of the No.

3 TAK-653-1001 Page 2 of 126 Protocol Incorporating Amendment No. 0624 March Investigators will be provided with emergency medical contact information cards to be carried by each advice on protocol procedures should be obtained through the monitor assigned to the study site. Information on service providers is given in Section relevant guidelines should be provided to the Type / RoleContactSerious adverse event and pregnancy reportingPharmacovigilance Takeda Development Centre Europe Ltd. Email: (preferred method of reporting) Fax: + (44) 207 242 1820 Medical Monitor(medical advice on protocol and compound)Takeda Development Centre Europe : MobileEmail: Responsible Medical Officer (carries overall responsibility for the conduct of the study)Takeda Development Centre Europe :MobileEmail: PPDPPDPPDPPDTAK-653 Study No.

4 TAK-653-1001 Page 3 of 126 Protocol Incorporating Amendment No. 0624 March OF TAKEDAThis study will be conducted with the highest respect for the individual participants in accordance with the requirements of this clinical study protocol and also in accordance with the following:!The ethical principles that have their origin in the Declaration of Helsinki.!International Council for Harmonisation E6 Good Clinical Practice Consolidated Guideline.!All applicable laws and regulations, including, without limitation, data privacy laws, clinical trial disclosure laws, and The responsible Takeda medical officer and other signatories are shown below. Electronic signatures are located on the last page of the No. TAK-653-1001 Page 4 of 126 Protocol Incorporating Amendment No. 0624 March 2017 CONFIDENTIALINVESTIGATOR AGREEMENT I confirm that I have read and that I understand this protocol, the Investigator s Brochure, and any other product information provided by the sponsor.

5 I agree to conduct this study in accordance with the requirements of this protocol and also to 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 Council for Harmonisation, E6 Good Clinical Practice: Consolidated Guideline.!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.!Appendix D Responsibilities of the further authorize that my personal information may be processed and transferred in accordance with the uses contemplated in Appendix Fof this No. TAK-653-1001 Page 5 of 126 Protocol Incorporating Amendment No.

6 0624 March Amendment 06 Summary of ChangesRationale for Amendment 06 This document describes the changes in reference to the protocol incorporating Amendment No. 06. The primary reasons for Protocol Amendment are to increase the approximate total number of subjects to be enrolled and to revise the parameters for dose escalation decisions, given the available nonclinical monkey toxicity data and favorable preliminary safety/tolerability and pharmacokinetic (PK) data for cohorts that have completed dosing to date. Minor grammatical, editorial, and formatting changes are included for clarification purposes specific descriptions of text changes and where the changes are located, see Appendix H. Changes in Amendment 061. The approximate total number of subjects to be enrolled in the study has been The nonclinical basis used to support dose escalation decisions has been The summary of the 13-week repeat-dose monkey toxicity data has been A summary of the 13-week repeat-dose rat toxicity data has been A summary of preliminary blinded safety/tolerability and PK data has been added for completed single-rising dose (SRD) Cohorts 1 to 5 and SRD/multiple-rising dose (MRD)

7 Cohorts 1 and The need for an independent medical reviewer from the sponsor to endorse dose escalation decisions has been Text has been added to clarify that study drug related central nervous system disorders/adverse events may result in the stopping of dose escalation or study drug Change in peripheral levels of the biomarker after dosing has been included as an endpoint for all cohorts (rather than just for SRD/MRD Cohort 3).9. An additional blood sample collection at 168 hours postdose has been included for SRD Cohort 6 onward in Part Text was clarified to indicate that TAK-653 and the only will be measured in if Text has been added to indicate that screening data for subjects who have undergone general screening procedures (ie, panel screening) before the effective date of this protocol amendment may be used to assess subject eligibility for enrollment in this The responsibilities of the investigator have been revised to reflect the updated International Council for Harmonisation E6(R2) Good Clinical Practice Consolidated Procedures for bioanalytical and pharmacogenomic sample collecting, processing, and shipping have been removed and referenced to the laboratory manual The sponsor signatories for this protocol have been No.

8 TAK-653-1001 Page 6of 126 Protocol Incorporating Amendment No. 0624 March 2017 CONFIDENTIALTABLE OF Amendment 06 Summary of REFERENCE of Abbreviations .. for the Proposed OBJECTIVES Objective .. Endpoints .. DESIGN AND 1: 2: for Study Design, Dose, and Mitigation .. Termination or Suspension of Study or Investigational for Premature Termination or Suspension of the No. TAK-653-1001 Page 7of 126 Protocol Incorporating Amendment No. 0624 March for Premature Termination or Suspension of Investigational Sites .. for Premature Termination or Suspensionof the Study or the Participation of Investigational AND DISCONTINUATION/WITHDRAWALOF Criteria .. Criteria .. Medications, Dietary , Fluid, and Activity for Discontinuation or Withdrawal of a for Discontinuation or Withdrawal of a TRIAL MATERIAL Medication and Form, Manufacturing, Packaging, and and Drug Assignment and Dispensing Code Creation and Drug Blind and Destruction of Sponsor-Supplied Consent Informed Consent , Medical History, and Medication History Examination , Height, and Sign of Concomitant of Concurrent Medical for Clinical Laboratory and Pregnancy Avoidance No.

9 TAK-653-1001 Page 8 of 126 Protocol Incorporating Amendment No. 0624 March ECG Procedure .. Safety EEG Pharmacogenomic Sample Collection (all Cohorts).. and RNA Pharmacokinetic Sample of Plasma and Urine for Pharmacokinetic of .. Methods .. Pharmacokinetic Pharmacodynamic Sample Pharmacodynamic Documentation of Screen Documentation of Assessment of Suicidal Ideation and Subject Treatment of Observations and Screening .. Check-In Treatment Study Exit .. Early Termination .. Follow-up End-of-Trial Volume .. EVENTS AND ADVERSE .. Additional Points to Consider for PTEs and No. TAK-653-1001 Page 9 of 126 Protocol Incorporating Amendment No. 0624 March Adverse Events of Special Interest .. Severity of PTEs and AEs .. Causality of Relationship to Study Start.

10 Concerning Study Drug .. Collection and Reporting of and AE Collection Period .. and AE Reporting .. Collection and Reporting of Reporting of Abnormal Liver Function of SAEs .. Safety Reporting to Investigators, IEC, and Regulatory HANDLING AND (Electronic).. and Analytical Analysis Analysis of Demographics and Other Baseline Pharmacokinetic in Plasma, Urine, and .. Parameters .. Pharmacodynamic Safety Analysis .. Laboratory No. TAK-653-1001 Page 10 of 126 Protocol Incorporating Amendment No. 0624 March EEGs .. Analysis and Criteria for Early of Sample CONTROL AND QUALITY Monitoring Visits .. Assurance Audits and Regulatory Agency ASPECTS OF THE Approval .. Information, Informed Consent, and Subject , Disclosure, and Clinical Trial Registration Publication and Clinical Trial Clinical Trial Results and Compensation for OF IN-TEXT TABLEST able of SRD Dose of SRD/MRD Dose Medications and Dietary for Vital Signs Laboratory Tests.