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Statistical Analysis Plan Version 3 I1F-MC-RHCD Statistical Analysis Plan Version 3 Multicenter, Double-Blind, Randomized, Placebo-Controlled Study to Evaluate Safety, Tolerability, and Efficacy of Ixekizumab in Patients from 6 to Less than 18 Years of Age with Moderate-to-Severe Plaque Psoriasis. NCT03073200 Approval Date: 26-Jun-2019 I1F-MC-RHCD Statistical Analysis Plan Version 3 Page 1 1. Statistical Analysis Plan: I1F-MC-RHCD: A Multicenter, Double-Blind, Randomized, Placebo-Controlled Study to Evaluate Safety, Tolerability, and Efficacy of Ixekizumab in Patients from 6 to Less than 18 Years of Age with Moderate-to-Severe Plaque Psoriasis Confidential Information The information contained in this document is confidential and the information contained within it may not be reproduced or otherwise disseminated without the approval of Eli Lilly and Company or its subsidiaries. Note to Regulatory Authorities: This document may contain protected personal data and/or commercially confidential information exempt from public disclosure. Eli Lilly and Company requests consultation regarding release/redaction prior to any public release. In the United States, this document is subject to Freedom of Information Act (FOIA) Exemption 4 and may not be reproduced or otherwise disseminated without the written approval of Eli Lilly and Company or its subsidiaries. Ixekizumab (LY2439821) Pediatric Psoriasis Study I1F-MC-RHCD is a Phase 3, multicenter, randomized, double-blind, placebo- controlled study, examining the effects of ixekizumab versus placebo on PASI 75 and sPGA in subjects from 6 to <18 years of age with moderate to severe plaque psoriasis (PASI ≥12, sPGA ≥3, BSA ≥10%) at screening and baseline. Eli Lilly and Company Indianapolis, Indiana USA 46285 Protocol I1F-MC-RHCD (Phase 3) Statistical Analysis Plan Version 1 electronically signed and approved by Lilly: 06-June- 2017 Statistical Analysis Plan Version 2 electronically signed and approved by Lilly: 18- March-2019 Statistical Analysis Plan Version 3 electronically signed and approved by Lilly on date provided below. Approval Date: 26-Jun-2019 GMT LY2439821 I1F-MC-RHCD Statistical Analysis Plan Version 3 Page 2 2. Table of Contents Section Page 1. Statistical Analysis Plan: I1F-MC-RHCD: A Multicenter, Double- Blind, Randomized, Placebo-Controlled Study to Evaluate Safety, Tolerability, and Efficacy of Ixekizumab in Patients from 6 to Less than 18 Years of Age with Moderate-to-Severe Plaque Psoriasis.........................................1 2. Table of Contents................................................................................................................2 3. Revision History .................................................................................................................8 4. Study Objectives ...............................................................................................................10 5. Study Design.....................................................................................................................12 5.1. Summary of Study Design............................................................................................12 5.2. Determination of Sample Size ......................................................................................18 5.2.1. Clinical Protocol RHCD.......................................................................................18 5.2.2. Protocol Addendum RHCD(2) .............................................................................18 5.3. Method of Assignment to Treatment ............................................................................19 5.3.1. Clinical Protocol RHCD.......................................................................................19 5.3.2. Protocol Addendum RHCD(2) .............................................................................19 6. A Priori Statistical Methods ..............................................................................................20 6.1. General Considerations ................................................................................................20 6.1.1. Analysis Population .............................................................................................20 6.1.2. Baseline Definition ..............................................................................................23 6.1.3. Analysis Methods.................................................................................................24 6.1.3.1. Double-Blind Treatment Period (Period 2): Main Protocol..........................................................................................................24 6.1.3.2. Double-Blind Treatment Period (Period 2): Protocol Addendum(2) .................................................................................................25 6.1.3.3. Combined Treatment Periods..........................................................................25 6.1.3.4. Double-Blind Randomized Withdrawal Period (Period 4)...............................25 6.2. Adjustments for Covariates ..........................................................................................26 6.3. Handling of Dropouts or Missing Data.........................................................................26 6.3.1. Nonresponder Imputation (NRI)...........................................................................26 6.3.2. Last Observation Carried Forward (LOCF) ..........................................................26 6.4. Multicenter Studies ......................................................................................................27 6.5. Multiple Comparisons/Multiplicity...............................................................................27 6.6. Use of an “Efficacy Subset” of Patients........................................................................27 6.7. Patient Disposition .......................................................................................................27 6.8. Patient Characteristics ..................................................................................................28 LY2439821 I1F-MC-RHCD Statistical Analysis Plan Version 3 Page 3 6.8.1. Demographics and Baseline Characteristics..........................................................28 6.8.2. Historical Illnesses and Preexisting Conditions ....................................................30 6.9. Treatment Compliance .................................................................................................31 6.10. Previous and Concomitant Therapy..............................................................................32 6.10.1. Previous Therapy .................................................................................................32 6.10.2. Concomitant Therapy...........................................................................................32 6.11. Efficacy Analyses ........................................................................................................34 6.11.1. Co-Primary Outcome and Primary Analysis Methodology ...................................45 6.11.2. Gated Secondary Efficacy Analyses .....................................................................45 6.11.3. Additional Analyses of the Co-Primary Outcome.................................................45 6.11.4. Other Secondary Efficacy Analyses .....................................................................45 6.12. Health-Outcome/Quality-of-Life Analyses ...................................................................47 6.13. Pharmacokinetic/Pharmacodynamic Methods...............................................................53 6.14. Safety Analyses............................................................................................................53 6.14.1. Extent of Exposure...............................................................................................54 6.14.2. Adverse Events ....................................................................................................55 6.14.3. Deaths, Other Serious Adverse Events, and Other Notable Adverse Events ....................................................................................................57 6.14.3.1. Special Safety Topics including Adverse Events of Special Interest ...............................................................................................58 6.14.4. Clinical Laboratory Evaluation.............................................................................67 6.14.4.1. Leukocytes (White Blood Cells [WBCs]) and Platelets...................................68 6.14.4.2. Neutrophil Follow-Up ....................................................................................69 6.14.5. Vital Signs and Other Physical Findings...............................................................69 6.14.6. Standardized Growth............................................................................................72 6.14.7. Children’s Depression Rating Scale, Revised (CDRS-R)......................................72 6.14.8. Columbia-Suicide Severity Rating Scale (C-SSRS)..............................................73 6.14.9. Tanner Stage Scale...............................................................................................74 6.14.10. Immunization.......................................................................................................74 6.14.11. Immunogenicity...................................................................................................74 6.14.11.1.
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