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Official Title: a Phase III, Randomized, Double-Blind Placebo-Controlled Official Title: A Phase III, Randomized, Double-Blind Placebo-Controlled, Multicenter Study To Evaluate the Efficacy and Safety of Baloxavir Marboxil in Combination With Standard-of-Care Neuraminidase Inhibitor in Hospitalized Participants With Severe Influenza NCT Number: NCT03684044 Document Date: Protocol Version 2: 30-May-2019 PROTOCOL TITLE: A PHASE III, RANDOMIZED, DOUBLE-BLIND PLACEBO-CONTROLLED, MULTICENTER STUDY TO EVALUATE THE EFFICACY AND SAFETY OF BALOXAVIR MARBOXIL IN COMBINATION WITH STANDARD-OF-CARE NEURAMINIDASE INHIBITOR IN HOSPITALIZED PATIENTS WITH SEVERE INFLUENZA PROTOCOL NUMBER: CP40617 VERSION NUMBER: 2 EUDRACT NUMBER: 2018-001416-30 IND NUMBER: 126653 TEST PRODUCT: Baloxavir marboxil (RO7191686) MEDICAL MONITOR: M.D. SPONSOR: F. Hoffmann-La Roche Ltd DATE FINAL: Version 1: 17 July 2018 DATES AMENDED: Version 1 (VHP only): 27 November 2018 Version 2: See electronic date stamp below. FINAL PROTOCOL APPROVAL Approver's Name Title Date and Time (UTC) Company Signatory 30-May-2019 16:10:33 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 The information contained in this document, especially any unpublished data, is the property of F. Hoffmann-La Roche Ltd (or under its control) and therefore is provided to you in confidence as an investigator, potential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. Baloxavir Marboxil—F. Hoffmann-La Roche Ltd Protocol CP40617, Version 2 PROTOCOL AMENDMENT, VERSION 2: RATIONALE In addition to updates initiated in this Version 2, this amendment contains updates made in a Version 1 (VHP only) amendment approved on 27 November 2018 (applicable to countries under Voluntary Harmonization Procedure [VHP] only). Protocol Version 2 supersedes Protocol Version 1 and Version 1 VHP. Changes to the protocol are summarized below: The study sample size was change from approximately 240 to approximately 366 hospitalized adults and adolescent patients throughout the protocol. This change was based upon a blinded review of the time to clinical improvement (TTCI) data from patients recruited during the northern hemisphere 2018/2019 flu season and the incorporation of a planned futility interim analysis (see Section 6). The optional interim analysis was changed to a formal, pre-planned, unblinded, non-binding futility analysis. It will be conducted after approximately 65% of TTCI events and will be based on the TTCI and the Lan-DeMets Pocock beta spending function (Section 6.7.1). The endpoint “time to clinical response” was moved from an exploratory endpoint to an additional key secondary endpoint at the request of the FDA (Section 2). The palatability and acceptability endpoint was added to address a request from the European Medicines Agency (EMA) Pediatric Committee (PDCO) to assess the acceptability of the baloxavir marboxil granules for oral suspension formulation (Section 2, Section 4.5.15, Section 6.4.5, and Appendix 5). The number of sites to enroll patients was updated from approximately 215 global sites to 250 sites to allow for the increase in sample size (Section 3.1). Known hypersensitivity to baloxavir marboxil or the drug product excipients was added as an exclusion criterion (Section 4.1.2). A section was added to summarize post-marketing safety data that identified hypersensitivity reactions (i.e., anaphylaxis/anaphylactic reactions, angioedema, and urticaria) as adverse drug reactions during post-marketing use of baloxavir marboxil (Section 1.2.4). In the event of a anaphylaxis or other form of hypersensitivity reaction, advice that patients should be withdrawn from study treatment was included (Section 4.6.1). Other additions and clarifications: Summary information was added for intravenous zanamivir (Dectova), which recently received a positive opinion for use under exceptional circumstances from the EMA for the treatment of complicated and potentially life-threatening influenza A or B virus infection in adult and pediatric patients (Section 1.1). A section was added to summarize results from a Phase III, double-blind, randomized, placebo- and active-controlled study investigating baloxavir marboxil in patients at high risk of developing influenza-related complications (Section 1.2.3). Baloxavir Marboxil—F. Hoffmann-La Roche Ltd 2/Protocol CP40617, Version 2 The timing of the vital signs and assessments for National Early Warning Score 2 (NEWS2) was clarified, as indicated in the clarification letters sent to sites, to ensure all vital sign parameters and NEWS2 assessments are collected together and that assessment timepoints are spread throughout the study day to reflect the patient’s condition over the entire study day, where possible (Sections 4.5.4; Appendix 5 footnotes). The vitals sign data to be utilized during screening to calculate the NEWS2 score was clarified, as indicated in the clarification letters sent to sites, to ensure that all data collected closest to but before randomization should be used for the NEWS2 score calculation and assessment of patient eligibility (Section 4.5.6 and Appendix 3). Clarification was added that the modified intent-to-treat infected (mITTI) population would be used in efficacy analyses. Clarification was also added that full details of analysis methods will be contained within the Statistical Analysis Plan (Section 6.4). The following minor revisions were made for clarification or for consistency across sections/Schedule of Activities: – Study Treatment Preparation (Section 4.3.1.1): Text was aligned with Pharmacy Manual following protocol clarification letter. – Cautionary Therapy (Section 4.4.2): Dairy products and calcium-fortified beverages was added to the list of cautionary therapies. The word “oral” was added to laxatives and antacids for clarity. In addition, the phrase “where possible” was also added to match wording for this section (i.e., cautionary, not prohibited). – Pharmacokinetic Analyses (Section 6.6): The text was updated to describe how patients with 2 or 3 study treatment doses will be analyzed separately. It was also stated that population PK model outcomes would be reported in a separate report. – Schedule of Activities: The End of Study (EOS) column was moved so it is included under the Follow-Up Period heading for clarity. – Schedule of Activities: The timing of Visit 8 was clarified in a footnote to ensure that Visit 8 did not occur on the same day as Visit 7. – Other minor clarifications and corrections were made throughout the protocol for clarify, consistency, or to align text with clarification letters. These are indicated by italicized text. Updates in line with Xofluza® (baloxavir marboxil) approvals and documentation: Core Data Sheets (CDS), Investigator’s Brochure, Drug Safety Update Report (DSUR). Rationale for patient population (Section 3.3.2): Text was updated to align with approvals as well as current and potentially future Clinical Development Plan (CDP). Safety plan update (Section 5.1): Text was updated to align with the Sponsor’s documentation and approvals. Baloxavir Marboxil—F. Hoffmann-La Roche Ltd 3/Protocol CP40617, Version 2 The following updates were made to bring the protocol into alignment with recent updates to the company’s protocol model document: Text has been modified to account for the fact that special situations (i.e., accidental overdoses and medication errors) are not required to be reported within 24 hours (Sections 5.3.5.11 and 5.4). Note that serious adverse events associated with special situations are still required to be reported within 24 hours. Language has been updated to indicate that therapeutic or elective abortions are not considered adverse events unless performed because of an underlying maternal or embryofetal toxicity. In such cases, the underlying toxicity should be reported as a serious adverse event. Language has also been added to clarify that all abortions are to be reported on the paper Clinical Trial Pregnancy Reporting Form (Section 5.4.3.3). Language has been added for consistency with Roche's current data retention policy and to accommodate more stringent local requirements (if applicable) (Section 7.5). Language has been added to indicate that the study will comply with applicable local, regional, and national laws (Section 8.1). Language has been revised to clarify that data posting will not be limited to clinical trial registries and to clarify that redacted Clinical Study Reports are provided only if requirements of Roche's global policy on data sharing have been met (Section 9.5). The following updates were made in the Version 1 (VHP only) amendment per VHP request, except where noted, and are being carried forward into this Version 2 amendment: Known hypersensitivity to baloxavir marboxil or the drug product excipients has been added as an exclusion criterion (Section 4.1.2). The Medical Monitor has changed and updated contact information has been provided (Section 5.4.1). Language regarding written informed consent for adolescents unable to legally provide consent was revised to accommodate situations where a local regulatory
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