Study Protocol

Official Title: A Single-Center, Multiple-Dose, Randomized, Double-Blind, Placebo- Controlled, Positive-Controlled, Crossover Study to Investigate the Effect of Balovapton on the Qtc Interval in Healthy Subjects NCT Number: NCT03808298 Document Date: Protocol Version 3: 23-April-2019 PROTOCOL TITLE: A SINGLE-CENTER, MULTIPLE-DOSE, RANDOMIZED, DOUBLE-BLIND, PLACEBO- CONTROLLED, POSITIVE-CONTROLLED, CROSS- OVER STUDY TO INVESTIGATE THE EFFECT OF BALOVAPTAN ON THE QTC INTERVAL IN HEALTHY SUBJECTS PROTOCOL NUMBER: WP40734 VERSION NUMBER: V3.0 EUDRACT NUMBER: NA IND NUMBER: 116483 TEST PRODUCT: Balovaptan (RO5285119) MEDICAL MONITOR: , MD SPONSOR: F. Hoffmann-La Roche Ltd DATE FINAL: See electronic date stamp below FINAL PROTOCOL APPROVAL Approver's Name Title Date and Time (UTC) Company Signatory 23-Apr-2019 06:19:00 CONFIDENTIAL This clinical study is being sponsored globally by F. Hoffmann-La Roche Ltd of Basel, Switzerland. However, it may be implemented in individual countries by Roche’s local affiliates, including Genentech, Inc. in the United States. The information contained in this document, especially any unpublished data, is the property of F. Hoffmann-La Roche Ltd (or under its control) and therefore is provided to you in confidence as an investigator, potential investigator, or consultant, for review by you, your staff, and an applicable Ethics Committee or Institutional Review Board. It is understood that this information will not be disclosed to others without written authorization from Roche except to the extent necessary to obtain informed consent from persons to whom the drug may be administered. Balovaptan —F. Hoffmann-La Roche Ltd Protocol WP40734, Version 3.0 Document Date of Issue Approver(s) Summary of Changes Original Oct-23-2018 Not Applicable Protocol Protocol v2.0 See date Changes in wording regarding intensive PK sampling for Amendment 1 stamp on the balovaptan and moxifloxacin outlined in Administrative and cover page. letter from Nov-13-2018 incorporated. Administrative Reference to balovaptan sampling on Day 16 have been letter 1, Nov- removed. 13-2018 The 1.25 h time point for PK sampling and ECG readings has been changed to 1.0 h post-dose. This information has been updated in Appendices and protocol text. Section 4.4 has been edited to clarify that concomitant therapy should be captured from 30 days prior to initiation of study drug. The text in Section 4.4.2 regarding prohibited therapies has been edited for clarity. Text in Section 4.4.4 has been edited to remove the statement “Subjects should have fasted for at least 8 hours prior to the screening visit, each admission to the CRU, and the Follow up visit” as it redundant with the collection description in Section 4.5.5.1. Text has been added to Section 4.4 to clarify that the clinical site is not required to track subject’s fluid intake. In Section 4.5.3 Physical Examinations the phrase “Any abnormality identified” has been updated to read “Any clinically significant abnormalities identified” Instructions for collection and handling of PK samples in Section 4.5.5.2 has been updated. Text reading safety ECG readings in Section 4.5.6.1 has been edited for clarity. Section 4.6.1 has been edited for clarity regarding assessments for subjects who withdraw or are terminated from the study early. Text regarding ECG extraction on consecutive days has been edited throughout the document to clarify that when a reading is taken on consecutive days (Day 2 and Day 15) the 24 h time point can be taken from the 3 pre- dose Holter extractions. Text regarding analysis of samples for cardiac biomarkers has been edited to indicate that samples will be taken but only analyzed for specific subjects on request. Text in Section 5.3.1 has been modified to make it consistent with Section 5.4.2.1 and Appendix 2 clarifying that only SAE’s will be recorded prior to study drug administration. Section 6.7.2 has been edited to make text consistent with ECG extraction time points throughout protocol. TQT exclusion criteria #3 and #7 have been edited to clarify that criteria should be assessed at both Screening Balovaptan —F. Hoffmann-La Roche Ltd 2/Protocol WP40734, Version 3.0 TABLE OF CONTENTS PROTOCOL ACCEPTANCE FORM .................................................................. 10 PROTOCOL SYNOPSIS .................................................................................... 11 1. BACKGROUND .......................................................................................... 23 1.1 Autism Spectrum Disorder..................................................... 23 1.2 Pre-Clinical Background on Balovaptan ................................ 23 1.2.1 Previous and Ongoing Clinical Studies.................................. 25 1.2.1.1 Clinical Pharmacology ........................................................... 25 1.2.1.2 Safety .................................................................................... 26 1.3 Study Rationale and Benefit-Risk Assessment...................... 28 2. OBJECTIVES AND ENDPOINTS ............................................................... 28 3. STUDY DESIGN ......................................................................................... 31 3.1 Description of the Study......................................................... 31 3.2 End of Study and Length of Study ......................................... 35 3.3 Rationale for Study Design .................................................... 35 3.3.1 Rationale for Balovaptan and Moxifloxacin Dose and Schedule......................................................................... 35 3.3.1.1 Balovaptan............................................................................. 35 3.3.1.2 Moxifloxacin........................................................................... 36 3.3.2 Rationale for Study Population .............................................. 36 3.3.3 Rationale for Transthoracic Doppler- Echocardiogram and Ambulatory Blood Pressure Monitoring.............................................................................. 37 4. MATERIALS AND METHODS .................................................................... 37 4.1 Subjects................................................................................. 37 4.1.1 Inclusion Criteria.................................................................... 37 4.1.2 Exclusion Criteria................................................................... 38 4.2 Method of Treatment Assignment and Blinding ..................... 41 4.2.1 Treatment Assignment........................................................... 41 4.2.2 Blinding.................................................................................. 42 Balovaptan —F. Hoffmann-La Roche Ltd 4/Protocol WP40734, Version 3.0 4.3 Study Treatment and Other Treatments Relevant to the Study Design ............................................................... 42 4.3.1 Study Treatment Formulation, Packaging, and Handling ................................................................................ 43 4.3.1.1 Balovaptan and Placebo........................................................ 43 4.3.1.2 Moxifloxacin Active Control and Placebo............................... 43 4.3.2 Study Treatment Dosage, Administration, and Compliance............................................................................ 43 4.3.2.1 Balovaptan and Placebo........................................................ 43 4.3.2.2 Moxifloxacin (Active Control) and Placebo ............................ 44 4.3.3 Investigational Medicinal Product Accountability ................... 44 4.4 Concomitant Therapy, Prohibited Food, and Additional Restrictions ........................................................... 45 4.4.1 Permitted Therapy ................................................................. 45 4.4.2 Prohibited Therapy ................................................................ 45 4.4.3 Prohibited Food ..................................................................... 46 4.4.4 Additional Restrictions/Considerations .................................. 46 4.4.4.1 Herbal Therapies ................................................................... 47 4.5 Study Assessments ............................................................... 47 4.5.1 Informed Consent Forms and Screening Log........................ 47 4.5.2 Medical History, Concomitant Medication, and Demographic Data................................................................. 47 4.5.3 Physical Examinations........................................................... 47 4.5.4 Vital Signs.............................................................................. 48 4.5.5 Laboratory, Genotyping, and Pharmacokinetic Samples................................................................................. 48 4.5.5.1 Laboratory Samples .............................................................. 48 4.5.5.2 Pharmacokinetic Samples ..................................................... 49 4.5.5.3 Optional Samples for Genetic Analyses ................................ 49 4.5.6 Electrocardiograms................................................................ 50 4.5.6.1 12-lead Safety Electrocardiograms........................................ 50 4.5.6.2 Cardiodynamic ECG Evaluation ............................................ 51 4.5.7 Transthoracic-Doppler Echocardiography ............................. 53 4.5.8 Ambulatory Blood Pressure Monitoring ................................. 54 4.5.9

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