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Study Protocol Drug Substance Anifrolumab (MEDI-546) Study Code D3461C00008 Version 1.0 Date 20 Sep 2016

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Study Protocol Drug Substance Anifrolumab (MEDI-546) Study Code D3461C00008 Version 1.0 Date 20 Sep 2016 Clinical Study Protocol Drug Substance Anifrolumab (MEDI-546) Study Code D3461C00008 Version 1.0 Date 20 Sep 2016 A Multicenter, Randomized, Double-blind, Placebo-controlled, Phase 2 Study Characterizing the Pharmacokinetics, Pharmacodynamics, and Safety of Anifrolumab following subcutaneous administration in Adult Systemic Lupus Erythematosus Subjects with Type I Interferon test high result and active skin manifestations Sponsor: AstraZeneca AB, 151 85 Södertälje, Sweden 1 (131) VERSION HISTORY Version 1.0, 20 Sep 2016 Initial creation 2 (131) This submission document contains confidential commercial information, disclosure of which is prohibited without providing advance notice to AstraZeneca and opportunity to object. This Clinical Study Protocol has been subject to a peer review according to AstraZeneca Standard procedures. The clinical study protocol is publicly registered and the results are disclosed and/or published according to the AstraZeneca Global Policy on Bioethics and in compliance with prevailing laws and regulations. 3 (131) PROTOCOL SYNOPSIS A Multicenter, Randomized, Double-blind, Placebo-controlled, Phase 2 Study Characterizing the Pharmacokinetics, Pharmacodynamics, and Safety of Anifrolumab following subcutaneous administration in Adult Systemic Lupus Erythematosus Subjects with Interferon type I test high result and active skin manifestations Study site(s) and number of subjects planned Approximately 32 subjects are planned to be randomized from approximately 15 sites in 4-5 countries. Study period Phase of development Estimated date of first subject enrolled Q4 2016 Phase 2 Estimated date of last subject completed Q4 2018 Phase 2 Study design This is a Phase 2, multicentre, double-blind, randomized, placebo-controlled study characterizing the pharmacokinetics, pharmacodynamics, and safety of two fixed doses of anifrolumab administered as Subcutaneous (SC) injections in adult type I Interferon (IFN) test -high Systemic Lupus Erythematosus (SLE) subjects with active skin manifestations while receiving Standard of Care (SOC) treatment. The study will be double-blind until primary analysis performed after all subjects have completed Week 12. Thereafter, the sponsor will be unblinded while investigators and subjects will remain blinded throughout the remainder of the study. Approximately 32 subjects will be randomized to one of the four treatment groups in a 3:1:3:1 ratio receiving: x anifrolumab at a fixed dose of 150mg as added to SOC, given Q2W as one SC injection in a volume of 1mL (12 subjects); x placebo as added to SOC, given Q2W as one SC injection in a volume of 1mL (4 subjects); x anifrolumab at a fixed dose of 300mg as added to SOC, given Q2W as two SC injections in a volume of 1mL each (12 subjects) or 4 (131) Clinical Study Protocol Synopsis Drug Substance Anifrolumab (MEDI-546) Study Code D3461C00008 Version 1.0 Date 20 Sep 2016 x placebo as added to SOC, given Q2W as two SC injections in a volume of 1mL each (4 subjects). The study is blinded with respect to anifrolumab or placebo but not for dose since treatments will be given as one or two SC injections depending on dose level. Objectives Primary Objective: Outcome Measures: To characterize the PK and PD of 150 mg Anifrolumab concentrations and PK parameters and 300 mg anifrolumab administered as SC including maximum concentration (Cmax) after first injections Q2W as measured by anifrolumab dose and trough concentration (Ctrough) after subsequent concentrations, PK parameters, dosing 21-gene type I IFN PD signature and 21-gene type 1 IFN PD signature and neutralization neutralisation ratio at Week 12 ratio (relative to baseline) Secondary Objectives: Outcome Measure : To characterize the safety and tolerability of Adverse events (AE); serious adverse events (SAEs); anifrolumab when SC administered for a 52 adverse events of special interest (AESIs) including Week treatment period herpes zoster, influenza, opportunistic infections, non-opportunistic serious infections, tuberculosis (TB), malignancies, non-SLE related vasculitis, anaphylaxis, and major adverse cardiovascular events (MACE); laboratory variables; physical examinations; vital signs; and ECG To characterize the immunogenicity of Anti-drug antibodies (ADA) anifrolumab when administered SC for a 52 Week treatment period Exploratory Objectives: Outcome Measure: To characterize the efficacy of SC Proportion of subjects achieving 50% improvement administered anifrolumab on SLE skin in CLASI activity score from baseline to Week 12 manifestations as measured by the change in and week 52 Cutaneous Lupus erythematosus disease Area and Severity Index (CLASI) activity score from baseline To explore the effects of SC administered 21-gene type I IFN and other pathway-related gene anifrolumab on type I IFN and other pathway- expression in skin tissue at baseline and at Week 12 related gene expression in skin tissue (optional part of study) 5 (131) Clinical Study Protocol Synopsis Drug Substance Anifrolumab (MEDI-546) Study Code D3461C00008 Version 1.0 Date 20 Sep 2016 Target subject population Adult SLE subjects with active skin manifestations defined as CLASI activity score 10 while receiving SOC treatment at a stable dose will be recruited for the study. Only type I IFN test-high subjects will be eligible to allow evaluation of changes in the 21-gene type I IFN PD signature. Duration of treatment The study includes: x A screening period of up to 30 days; x A treatment period of 52 weeks; x A follow-up period of 8 weeks Investigational product (IP) will be administered at study visits from Week 0 to Week 50 (a total of 26 doses) during the treatment period and the last follow-up visit will be 10 weeks after the last IP dose. The approximate total study length will be 15 months. The treatment period will be double-blind up until the data base lock for the primary analysis performed after all subjects have completed Week 12. At this time point Sponsor will be unblinded whereas investigators and subjects will remain blinded throughout the entire study. Investigational product, dosage and mode of administration Anifrolumab in two fixed doses or placebo will be added to SOC treatment and administered as SC injections Q2W. x Anifrolumab 150 mg Q2W given as one SC injection (=1 mL) x Anifrolumab 300 mg Q2W given as two SC injections (=2 × 1 mL) x Placebo Q2W given as one SC injection (=1 mL) x Placebo Q2W given as two SC injections (=2 × 1 mL) Statistical methods There is no formal power calculation as there will be no hypothesis testing, and the data collected in this study will be used to inform the design of further development. Subjects will be randomized at a ratio of 3:1 to receive active:placebo treatment (12 subjects on active and 4 subjects on placebo) for the two dosing levels. This gives a total study population of 32 subjects. CCI CCI 6 (131) Clinical Study Protocol Synopsis Drug Substance Anifrolumab (MEDI-546) Study Code D3461C00008 Version 1.0 Date 20 Sep 2016 CCI Two data base locks and analyses are planned for the study, i.e., the main analysis after all randomized subjects complete Week 12 or discontinue the study prior to Week 12, and the “end of extension”-analysis that take place once all subjects have completed Week 60 or discontinued the study prior to Week 60. The full analysis set will be used as the primary population for reporting PD, efficacy and safety data. This comprises of all subjects randomized into the study who receive at least 1 dose of IP and did not discontinue IP, and will be analyzed according to randomized treatment (modified Intention-To-Treat). All subjects who received anifrolumab and who had at least 1 quantifiable serum PK observation post first dose, will be included in the PK analysis dataset. All PK summaries will be based on this analysis set. Descriptive statistics (number, mean, standard deviation [SD], median, minimum, maximum, and coefficient of variance [%CV]) will be provided by dose level for continuous variables, and counts and percentages will be presented for categorical variables. The primary characterization of the effect of anifrolumab on the 21-gene type I IFN PD signature will be carried out through the individual and median 21-gene type 1 IFN signature scores and neutralization ratios at Week 12. The PD gene signature will also be explored over time. The primary characterization of anifrolumab PK will be done by descriptive statistics of the derived PK parameters. 7 (131) Clinical Study Protocol Drug Substance Anifrolumab (MEDI-546) Study Code D3461C00008 Version 1.0 Date 20 Sep 2016 TABLE OF CONTENTS PAGE TITLE PAGE ........................................................................................................... 1 VERSION HISTORY .............................................................................................. 2 PROTOCOL SYNOPSIS ......................................................................................... 4 TABLE OF CONTENTS ......................................................................................... 8 LIST OF ABBREVIATIONS AND DEFINITION OF TERMS .......................... 15 1. INTRODUCTION ................................................................................................. 18 1.1 Background ............................................................................................................ 18 1.2 Rationale for study population, study design, and dosing ..................................... 19 1.2.1 Rationale for study population and study design ..................................................
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