Official Title: A MULTICENTER, OPEN-LABEL, PHASE III CLINICAL TRIAL TO EVALUATE THE EFFICACY, SAFETY, AND PHARMACOKINETICS OF SUBCUTANEOUS ADMINISTRATION OF EMICIZUMAB IN HEMOPHILIA A PEDIATRIC PATIENTS WITH INHIBITORS NCT Number: NCT02795767 Document: PROTOCOL Version & Date: Version 4: 01 September 2017 PROTOCOL TITLE: A MULTICENTER, OPEN-LABEL, PHASE III CLINICAL TRIAL TO EVALUATE THE EFFICACY, SAFETY, AND PHARMACOKINETICS OF SUBCUTANEOUS ADMINISTRATION OF EMICIZUMAB IN HEMOPHILIA A PEDIATRIC PATIENTS WITH INHIBITORS PROTOCOL NUMBER: BH29992 VERSION NUMBER: 4 EUDRACT NUMBER: 2016-000073-21 IND NUMBER: 122954 TEST PRODUCT: Emicizumab (RO5534262) MEDICAL MONITOR: M.D., M.A.S. SPONSOR: F. Hoffmann-La Roche Ltd and Chugai Pharmaceutical Co. Ltd. DATE FINAL: 20 January 2016 DATES AMENDMED: Version 2: 12 July 2016 Version 3: 8 December 2016 Version 4: See electronic date stamp below. PROTOCOL AMENDMENT APPROVAL Approver's Name Title Date and Time (UTC) Company Signatory 01-Sep-2017 18:27:12 CONFIDENTIAL F. Hoffmann-La Roche Ltd of Basel, Switzerland, and Chugai Pharmaceutical Co. Ltd.* of Tokyo, Japan, will act as co-sponsors of this global study. However, it may be implemented in individual countries by Roche’s local affiliates, including Genentech, Inc. in the United States, or Chugai Pharmaceutical Co. Ltd.* in South Korea, Taiwan, and Japan. The information contained in this document, especially any unpublished data, is the property of F. Hoffmann-La Roche Ltd (or under its control) and therefore is provided to you in confidence as an investigator, potential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. *Chugai will act as the Sponsor only in South Korea, Taiwan, and Japan. The specific details of the legal/regulatory entity within the relevant country are provided within the clinical trial agreement with the Investigator/Institution and the Clinical Trial Application with the Competent Authority. Emicizumab—F. Hoffmann-La Roche Ltd Protocol BH29992, Version 4 PROTOCOL AMENDMENT, VERSION 4: RATIONALE Protocol BH29992 has been primarily amended to evaluate additional emicizumab dosing schedules and to update safety information. Changes to the protocol, along with a rationale for each change, are summarized below: Two cohorts (designated as Cohorts B and C; patients 211 years of age) have been added to the study to investigate additional less frequent emicizumab dosing schedules (every 2 weeks [Q2W] and every 4 weeks [Q4W]), which would allow the option to select a preferred schedule, while still delivering the same cumulative dose (Sections 1.3, 3.3.1, 3.3.1.1, and 6.9.1.1). The addition of these cohorts is reflected throughout the protocol (Sections 16). Recent safety findings of thrombotic microangiopathy (TMA) observed in Study BH29884 have been added (Sections 1.2, 3.1, and 5.1.1.4). Clarification regarding laboratory monitoring of coagulation status after any bypassing agent use has been added. Laboratory monitoring is to be done after any use of a bypassing agent, and not only after use of a bypassing agent to treat breakthrough bleeds (Section 5.1.2). An exclusion criterion has been added for patients who are unable to or unwilling to receive blood or blood products (or any standard-of-care treatment for a life-threatening condition). This criterion has been added in context of a fatal outcome from a life-threatening rectal hemorrhage in Study BH29884 in a patient who declined receipt of blood and blood products (Sections 4.3 and 5.1.1.4). The up-titration schema has been modified with removal of the 2.25-mg/kg once weekly (QW) dosing level. This is based on an interim data review characterizing exposure at 1.5 mg/kg QW in patients 212 years of age to be similar to adolescent/adult patients (Section 4.5.2). As such, the up-titration dose will be the same used in adolescent/adult patients (3 mg/kg QW). A new safety risk associated with emicizumab has been added as follows: Life-threatening bleeding due to unreliable standard coagulation tests and inhibitors assays in the setting of emicizumab Coagulation laboratory tests (including, but not limited to, aPTT, one-stage FVIII activity, and FVIII inhibitor measurement by Bethesda assay) are not reliable and are impacted by the presence of emicizumab and, therefore, are not reflecting the patient’s underlying hemostatic status accurately (Section 5.1.1.5). The reporting of the term “sudden death” has been updated to also require the presumed cause of death (Section 5.3.5.8). Event reporting for hospitalization has been clarified (Section 5.3.5.11). The process for reviewing and handling protocol deviations has been updated per internal standard operating procedures (Section 9.2). Emicizumab—F. Hoffmann-La Roche Ltd 2/Protocol BH29992, Version 4 Additional minor changes have been made to improve clarity, consistency, and alignment with the other emicizumab protocols. Substantive new information appears in italics. This amendment represents cumulative changes to the original protocol. Emicizumab—F. Hoffmann-La Roche Ltd 3/Protocol BH29992, Version 4 PROTOCOL AMENDMENT, VERSION 4: SUMMARY OF CHANGES PROTOCOL TITLE The protocol title has been revised as follows: A SINGLE-ARM, MULTICENTER, OPEN-LABEL, PHASE III CLINICAL TRIAL TO EVALUATE THE EFFICACY, SAFETY, AND PHARMACOKINETICS OF ONCE WEEKLY SUBCUTANEOUS ADMINISTRATION OF EMICIZUMAB IN HEMOPHILIA A PEDIATRIC PATIENTS WITH INHIBITORS PROTOCOL SYNOPSIS The protocol synopsis has been updated to reflect the changes to the protocol, where applicable. SECTION 1.2: BACKGROUND ON EMICIZUMAB Clinical Studies … Two severe adverse events were observed: appendicitis and mesenteric hematoma. Both events were considered to be serious adverse events and not related to emicizumab administration. In the Phase I/II Studies ACE001JP and ACE002JP, no thrombotic microangiopathy (TMA), thromboembolic adverse events, or systemic hypersensitivity reactions have been reported in any dosing cohort thus far, including those patients who required concomitant FVIII concentrates or bypassing agent therapy to treat bleeds. In the ongoing Phase III Study BH29884 (adolescent and adult patients with hemophilia A with FVIII inhibitors), as of November April 20176, TMA thrombotic microangiopathy (TMA; atypical hemolytic uremic syndrome [aHUS]) was observed in 32 patients receiving emicizumab and bypassing agents; and 32 cases of serious thromboembolic events were observed in 2 patients receiving emicizumab and bypassing agents. For more details refer to Sections 5.1.1.3 and 5.1.1.4. SECTION 1.3: STUDY RATIONALE AND BENEFIT–RISK ASSESSMENT … In these studies, no thromboembolic or systemic hypersensitivity adverse events were observed; however, in the ongoing Phase III Study BH29884,32 cases of TMA (aHUS) and 2 3 serious thromboembolic events were observed in patients on emicizumab who received bypassing agents for the treatment of breakthrough bleeds. Three Four out of these 54 patients have fully recovered and the fourth patient’s condition has improved, and 1 patient died due to severe rectal bleeding (see Sections 5.1.1.3 and 5.1.1.4). This current study is designed to evaluate the efficacy, safety, and pharmacokinetics of emicizumab administered subcutaneously initially once weekly (QW) in pediatric patients with hemophilia A with FVIII inhibitors. Following review of data in adult and adolescent patients with hemophilia A from two ongoing Phase III studies Emicizumab—F. Hoffmann-La Roche Ltd 4/Protocol BH29992, Version 4 evaluating emicizumab at 3 mg/kg every 2 weeks (Q2W; BH30071) and 6 mg/kg every 4 weeks (Q4W; BO39182), this study will open two additional non-randomized cohorts to investigate Q2W and Q4W regimens in pediatric patients (see Section 3.3.1). SECTION 2: OBJECTIVES AND ENDPOINTS The objectives of the study are to investigate (with no formal hypothesis testing) the efficacy, safety, and pharmacokinetics of once weekly SC administration of emicizumab administered at 1.5 mg/kg QW, 3 mg/kg Q2W, and 6 mg/kg Q4W in pediatric patients with hemophilia A and FVIII inhibitors who are currently receiving treatment with bypassing agents. A total of approximately 80 patients are planned: approximately 60 patients in Cohort A (1.5 mg/kg QW) and approximately 10 patients each in Cohort B (3 mg/kg Q2W) and Cohort C (6 mg/kg Q4W). At least 20 pPatients younger than 12 years old of age and up to 60 patients are planned for enrollment, with allowance of patients 1217 years of age who weigh 40 kg at the time of informed consent to further evaluate dosing of emicizumab in patients 40 kg. Of note, enrollment in Cohort A may be left open exclusively for patients 2 years of age until approximately 5 such patients have been enrolled. SECTION 2.1: EFFICACY OBJECTIVES The endpoints will be analyzed separately for the three cohorts: Cohort A (1.5 mg/kg QW), Cohort B (3 mg/kg Q2W), and Cohort C (6 mg/kg Q4W), and overall as appropriate. The efficacy objectives for this study are as follows: To evaluate the clinical effect of prophylactic emicizumab on the number of bleeds over time (i.e., bleed rate) * To evaluate the efficacy in reducing the number of bleeds over time compared with the patient's historical bleed rate (intra-patient comparison, Cohort A