16.1 9 Documentation of Statistical Methods€¦ · This statistical analysis plan (SAP) describes the statistical analysis to be completed by the AbbVie Clinical Statistics Department

RisankizumabM15-993 Clinical Study ReportR&D/17/0073

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16.1__9 Documentation of Statistical Methods

16.1__9.1 Statistical Analysis Plan

Risankizumab (ABBV-066)M15-993 – Statistical Analysis PlanVersion 1.0 – 14 December 2016

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1.0 Title Page

Statistical Analysis Plan

Study M15-993

A phase II, multicenter, randomized, double-blind, multiple dose, placebo-controlled, parallel-group

study to evaluate the efficacy, pharmacokinetics, and safety of risankizumab, an IL-23 p19 antagonist monoclonal antibody, in patients with moderately to severely active Crohn's disease, who are naïve to, or

were previously treated with anti-TNF therapy

Date: 14 December 2016


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2.0 Table of Contents

1.0 Title Page ..................................................................................12.0 Table of Contents.....................................................................23.0 Introduction .............................................................................63.1 Changes from the Previous SAP Versions................................................. 6

4.0 Study Objectives, Design and Procedures.............................74.1 Objectives .................................................................................................. 7

4.2 Design Diagram ......................................................................................... 8

4.3 Sample Size.............................................................................................. 14

5.0 Analysis Populations .............................................................175.1 Definition for Analysis Populations......................................................... 17

5.2 Variables Used for Stratification of Randomization................................ 18

6.0 Analysis Conventions ............................................................186.1 Statistical Significance............................................................................. 18

6.2 Definition of Baseline .............................................................................. 18

6.2.1 Definition of Period 1 Baseline................................................................ 18

6.2.2 Definition of Period 2/Period 3 Baseline ................................................. 19

6.3 Definition of Rx Days (Days Relative to the First Dose of Study Drug) ........................................................................................................ 19

6.3.1 Rx Days.................................................................................................... 19

6.4 Definition of Final Observation ............................................................... 19

6.5 Definition of Analysis Windows ............................................................. 19

6.6 Missing Data Handling ............................................................................ 23

6.7 Dealing with Multiple Measurements Collected on the Same Day......... 25

7.0 Demographics, Baseline Characteristics, Medical History, and Previous/Concomitant Medications ..............25

7.1 Demographic and Baseline Characteristics ............................................. 25

7.1.1 Analysis of Demographic Data and Baseline Characteristics.................. 27

7.2 Medical/Surgical History ......................................................................... 28

7.2.1 Medical History ....................................................................................... 28

7.3 Prior and Concomitant Medications ........................................................ 28

7.3.1 Reporting Special Medications ................................................................ 29


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7.4 Protocol Deviation ................................................................................... 30

8.0 Patient Disposition.................................................................309.0 Study Drug Exposure and Compliance...............................319.1 Study Drug Exposure ............................................................................... 31

9.2 Study Drug Compliance........................................................................... 32

9.2.1 Intravenous Therapy ................................................................................ 32

9.2.2 Subcutaneous Therapy ............................................................................. 32

10.0 Efficacy Analysis....................................................................3210.1 General Considerations ............................................................................ 32

10.2 Primary Efficacy Analyses....................................................................... 32

10.3 Second Efficacy Analyses........................................................................ 33

10.4 Exploratory Efficacy Analyses ................................................................ 34

10.5 Handling of Multiplicity .......................................................................... 36

10.6 Efficacy Subgroup Analysis .................................................................... 36

11.0 Safety Analysis .......................................................................3811.1 General Considerations ............................................................................ 38

11.2 Analysis of Adverse Events ..................................................................... 38

11.2.1 Treatment-Emergent Adverse Events ...................................................... 38

11.2.1.1 Adverse Event Overview ......................................................................... 39

11.2.1.2 Adverse Events by System Organ Class and Preferred Term.................. 40

11.2.1.3 Adverse Events by Maximum Severity ................................................... 40

11.2.1.4 Adverse Events by Maximum Relationship ............................................ 41

11.2.1.5 Adverse Events by "Reasonably Possibly Related" Relationship ........... 41

11.2.1.6 Serious Adverse Events (Including Deaths) and Adverse Events Leading to Study Drug Discontinuation .................................................. 42

11.2.1.7 Frequent (> 5%) Adverse Events by Preferred Term in Decreasing Frequency................................................................................................. 42

11.2.1.8 Reasonably Possibly Related Adverse Events by System Organ Class and Preferred Term......................................................................... 42

11.2.1.9 Adverse Events of Special Interests......................................................... 42

11.2.1.10 Adverse Events by 100 Patient Years ...................................................... 42

11.2.1.11 Listing of Adverse Events........................................................................ 43

11.3 Analysis of Laboratory Data .................................................................... 43


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11.3.1.1 Analysis for Potentially Clinically Significant Laboratory Values ......... 44

11.4 Analysis of Vital Signs and Weight......................................................... 44

11.4.1 Variables and Criteria Defining Abnormality.......................................... 44

11.4.2 Statistical Methods................................................................................... 45

11.5 Analysis for Other Safety Variables ........................................................ 45

11.6 Safety Subgroup Analysis........................................................................ 45

12.0 Appendix.................................................................................4612.1 Stool Consistency Calculation ................................................................. 46

12.2 Crohn's Disease Activity Index (CDAI) .................................................. 47

12.3 Patient Reported Outcome (PRO-2) ........................................................ 50

12.4 Crohn's Disease Endoscopic Index of Severity (CDEIS) ........................ 51

12.5 Simple Endoscopic Score – CD (SES-CD).............................................. 53

12.6 Bristol Stool Chart ................................................................................... 53

12.7 Time to Flare/Time to CDAI ≥ 150 ......................................................... 54

12.8 Inflammatory Bowel Disease Questionnaire (IBDQ).............................. 54

12.9 Isolated Ileatis .......................................................................................... 55

12.10 Important Protocol Violations.................................................................. 56

12.11 Adverse Events of Special Interest .......................................................... 60

13.0 References...............................................................................60

List of Tables

Table 1. Power and Sample Size for the Superiority Test of Clinical Remission and Mucosal Healing at Week 12 .......................................... 16

Table 2. Windows for All Protocol-Specified Visits, Using for Study Drug Administration, Vital Signs, Hematology Lab Values, CDAI, Review Patient Diary, and Fistula Exam ................................................. 21

Table 3. Analysis Windows for All Protocol-Specified Visits at Weeks 0, 2, 4, 8, 14, 18, 22, 26, 34, 42, 50 and 52, Using for Pregnancy Test........................................................................................................... 22

Table 4. Analysis Windows for All Protocol-Specified Visits at Weeks 0, 12, 26, and 52, Using for Ileocolonoscopy and IBDQ............................. 22

Table 5. Analysis Windows for All Protocol-Specified Visits at Weeks 0, 12, 26, and 52, Using for Ileocolonoscopy and IBDQ............................. 23


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Table 6. Rules for Prior and Concomitant Medication Classification ................... 29

Table 7. Criteria for Potentially Clinically Significant Vital Sign Findings.......... 45

List of Figures

Figure 1. Overview of Trial Design .......................................................................... 8


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3.0 Introduction

This statistical analysis plan (SAP) describes the statistical analysis to be completed by

the AbbVie Clinical Statistics Department for Study M15-993 (BI Trial No. 1311.6)

Amendment 7 dated 13 November 2015. It provides details to further elaborate statistical

methods as outlined in the protocol and describes analysis conventions to guide the

statistical programming work.

This analysis plan describes the primary and secondary efficacy analyses as well as the

safety analysis for the double-blind Intravenous therapy period, open-label intravenous

therapy/wash-out period, and open-label subcutaneous therapy period.

This document describes the analysis of data except pharmacokinetic, pharmacogenetic,

and selected biomarkers which will be analyzed separately. It takes into account ICH

Guidelines E3 and E9.

Unless noted otherwise, all analyses will be performed using SAS version 9.2 or later

(SAS Institute Inc., Cary, NC 27513) under the UNIX operating system.

3.1 Changes from the Previous SAP Versions

Boehringer Ingelheim Pharma GmbH & Co. KG (BIP) and AbbVie S.A.R.L. (AbbVie)

have entered into an agreement whereby AbbVie will take on the responsibilities for the

development and commercialization of risankizumab (BI 655066/ABBV-066).

The current SAP has adapted the final version of the TSAP developed by Boehringer

Ingelheim (BI), which was dated on 12 August 2015. AbbVie analysis conventions are

applied, and additional exploratory analyses are added.

The statistical analysis plans of the planned interim analyses (1 and 2) were describpted in

the Section 9.6 of the final version of the TSAP developed by Boehringer Ingelheim (BI),

dated on 12 August 2015.


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4.0 Study Objectives, Design and Procedures

4.1 Objectives

This study is to evaluate the efficacy, pharmacokinetics, and safety of risankizumab

(ABBV-066), an IL-23 p19 antagonist monoclonal antibody, in patients with moderately

to severely active Crohn's Disease, who are naïve to, or were previously treated with anti-

TNF therapy. The objectives of this study are listed below.

The primary objective is:

● To evaluate efficacy of risankizumab in inducing clinical remission, defined as

CDAI < 150, after 12 weeks of treatment.

The secondary objectives are:

● To evaluate efficacy of risankizumab in inducing endoscopic response, clinical

response, mucosal healing, and deep remission.

● To evaluate safety of risankizumab.

● To explore the pharmacokinetics and pharmacodynamics of risankizumab

therapy in Crohn's disease.

The exploratory objectives are:

● To evaluate the efficacy of risankizumab in achieving corticosteroid free

remission.

● To evaluate the effect of risankizumab on abdominal pain, stool frequency,

stool consistency, fistula response, number of Crohn's Disease related

hospitalizations or surgeries, and quality of life.

● To evaluate the effect of risankizumab on disease related biomarkers,

including CRP, calprotectin and lactoferrin, and correlate with clinical

parameters.


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4.2 Design Diagram

This is a Phase 2, proof of concept, multi-center, randomized, double-blind, placebo-

controlled, parallel-group -dose-ranging study of risankizumab, an IL-23 p19 antagonist

monoclonal antibody, in patients with moderately to severely active CD.

The trial consists of the following periods:

1. screening period of up to a maximum of 4 weeks

2. 12-week blinded intravenous therapy period (Period 1)

3. 14-week (or longer) open label intravenous therapy/wash-out period (Period 2)

4. 26-week subcutaneous therapy period (Period 3)

5. 15-week follow up period

The schematics of the overall study design are shown in Figure 1.

Figure 1. Overview of Trial Design


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Approximately 240 patients are planned to be screened and approximately 120 patients

with moderate to severe CD and mucosal ulcers detected on ileocolonoscopy are to be

randomized in a ratio of 1:1:1 to one of the 3 following treatment groups in Period 1 and

stratified according to previous experience with anti-TNF therapy (naïve vs. experienced).

1. Group 1: Placebo IV (n = 40)

2. Group 2: Risankizumab 200 mg IV (n = 40)

3. Group 3: Risankizumab 600 mg IV (n = 40)

Each treatment group receives the corresponding dose of risankizumab or placebo by IV

infusion at Week 0, Week 4, and Week 8. At Week 12, patients are evaluated for deep

remission, defined as reaching clinical remission (CDAI < 150) and endoscopic remission

(CDEIS ≤ 4, or for patients with initial isolated ileitis CDEIS ≤ 2) confirmed by central

independent reviewer(s). The scheduled activities for Period 1 are shown in Flow

Chart A.

Treatment and number of patients in Period 2 will be determined by the outcome at

Week 12.

● Patients who are in deep remission at Week 12 will stop medication, and will

enter a wash-out period until Week 26.

In case of a disease flare during this period (including visit E1), defined as an increase of

CDAI ≥ 70 points compared to Week 12 and a CDAI of 220 or greater, the investigator

will perform an ileocolonoscopy within 2 weeks.

○ If the CDEIS is ≤ 4 (in patients with initial ileitis ≤ 2), patients will

continue on wash-out until Week 26.

○ If the CDEIS is > 4 (in patients with initial ileitis > 2), patients will receive

open-label intravenous induction therapy (3 doses separated by 4 Week

intervals) with 600 mg of risankizumab, as described in Flow Chart B.


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● Patients who do not achieve deep remission at Week 12 will receive open label

intravenous induction therapy (3 doses separated by 4-week intervals) with

600 mg of risankizumab.

The scheduled activities for Period 2 and 3 are shown in Flow Chart B. Patients who are

in clinical remission at visit E1, irrespective of their Week 12 outcome and Period 2

treatment, will enter Period 3 (open label subcutaneous period) and will receive

4 injections of risankizumab (180 mg SC) separated by 8-week intervals.

Ileocolonoscopy will be performed for all patients at screening, Week 12 and at the end of

Period 3 to evaluate endoscopic response/remission, and to provide mucosal biopsy

specimens for molecular pharmacodynamic assessments pre and post treatment. Patients

who experience a flare after achieving deep remission at Week 12 will also be required to

undergo ileocolonoscopy and will receive open-label re-induction therapy only if their

CDEIS is > 4 (in patients with initial ileitis > 2) confirmed by central independent

reviewer(s). All colonoscopies will be videotaped with the use of a standard protocol and

interpreted by an independent reviewer(s), who will be unaware of study-group

assignments and the timing of the procedure. Patients participating in the study will

consent to undergo up to 4 colonoscopies.

Permitted concomitant medications are continued stable dosing of oral 5-aminosalicylate

(5-ASA) compounds, immunomodulators (azathioprine [AZA], 6-mercaptopurine

[6-MP], and methotrexate [MTX]), oral corticosteroids, and antibiotics. Doses of these

medications should remain stable through Week 52 with the exception of patients

receiving oral corticosteroids who are in clinical remission at or after Week 12, for whom

the daily dose of corticosteroid should be tapered by the investigator.


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4.3 Sample Size

Sample size is estimated for Period 1 of the trial based on assumption that there is a 21%

difference between risankizumab (using pooled data from both dose groups) and placebo


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for Week 12 clinical remission. Alpha is set at 2-sided 0.1. A sample size of 40 patients

for each active regimen and 40 patients for the placebo regimen is selected. Table 1

provides the estimated power for projected treatment differences.

A difference of 20% is supported by previous trial data in similar populations with other

biologic therapies. Assuming a decreased placebo response in patients with

endoscopically confirmed active disease, larger differences can be expected. With 30%

response to risankizumab and 21% difference, the power is 82%. Power is estimated in

the range from 77% to 93%.


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Table 1. Power and Sample Size for the Superiority Test of Clinical Remission and Mucosal Healing at Week 12

Induction Phase

Risankizumab Risankizumab Placebo Difference Randomization2-Sided Type I

ErrorTotal

Sample Size Dropout Power

Clinical remission rate at Week 12

30% 10% 20%

2:1 (1:1:1) 0.1 120 0%

77%

30% 5% 25% 96%

30% 6% 24% 93%

30% 8% 22% 87%

30% 9% 21% 82%

29% 9% 20% 79%

Mucosal healing rate at Week 12 25% 5% 20% 87%

Note: The ratio of active drug to placebo for power analysis is 2:1.


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5.0 Analysis Populations

5.1 Definition for Analysis Populations

Intent-to-Treat Population

The Intent-to-Treat (ITT) Population includes all randomized subjects regardless whether

they received any study drug or not.

Period 1 Full Analysis Set Population

The Period 1 Full Analysis Set (FAS-P1) population includes all randomized subjects who

have taken at least one dose of study drug in the double-blind IV period (Period 1). For

the FAS-P1 analysis set, subjects are assigned to a treatment group based on the

randomization schedule, regardless of the treatment actually received. This population

will be used for all efficacy analysis for the double-blind IV period and baseline

demographic and characteristics analyses.



have taken at least one dose of study drug in the open-label IV period (Period 2), or the

subjects who are in deep remission at Week 12. For the FAS-P2 analysis set, subjects will

be analyzed by the initial randomization treatment group. This population will be used for

all efficacy analysis for the open-label IV period (Period 2).



have taken at least one dose of study drug in the open-label SC period (Period 3). For the

FAS-P3 analysis set, subjects will be analyzed by the initial randomization treatment

group. This population will be used for all efficacy analysis for the open-label SC period

(Period 3).


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Safety Population

The Safety population will include all subjects who take at least one dose of study drug

during the study. For the safety analysis set, subjects are assigned to a treatment group

based on the treatment actually received, regardless the treatment randomized.

5.2 Variables Used for Stratification of Randomization

At Baseline, eligible patients will be randomized to three parallel groups with 200 mg IV

and 600 mg IV dose of risankizumab treatments or placebo in a 1:1:1 ratio.

Randomization will be stratified with respect to prior anti-TNF therapy (naïve or

experienced).

6.0 Analysis Conventions

6.1 Statistical Significance

Unless otherwise specified, statistical tests will be 2-sided for all analyses and the null

hypothesis will be rejected at the significance level of α = 0.10. P-values will be rounded

to four decimal places before assessing statistical significance. In this Phase 2 proof of

concept study, no adjustment for multiple comparisons for efficacy analyses will be made.

6.2 Definition of Baseline

This section provides the definition of baseline in this study unless otherwise specified in

the individual sections.

6.2.1 Definition of Period 1 Baseline

The baseline value for Period 1 (DB IV period) will be the last measurement taken prior

to the first dose DB IV drug. If multiple measurements are recorded on the same day, the

measurement recorded at the latest time prior to dosing will be used as baseline.


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6.2.2 Definition of Period 2/Period 3 Baseline

For patients randomized to active drug, the baseline measurement will be the same as the

one used for Period 1. For patients initially randomized to placebo, the baseline

measurement will be the last one recorded prior to the administration of active drug at

Week 14.

6.3 Definition of Rx Days (Days Relative to the First Dose of Study Drug)

6.3.1 Rx Days

The Rx Day is calculated as the event date minus the date of first dose of study drug plus

1 when the time point of interest is after the date of first dose of study drug, or the event

date minus the date of first dose of study drug when the time point of interest is prior to

the date of first dose of study drug. It provides a quantitative measure of days between

the time point of interest and the first dose date. The day of the first dose of study drug is

defined as Rx Day 1, while the day prior to the first study drug dose is defined as Rx

Day –1 (there is no Rx Day 0).

6.4 Definition of Final Observation

The final observation for each subject by period will be defined as the last non-missing

post-baseline value collected no more than 70 days after the last dose of the study drug

within each period. Any data collected beyond 70 days after the last dose of study drug

within each period will not be used for analysis but will be displayed in the data listings.

6.5 Definition of Analysis Windows

Since subjects do not always adhere to the study visit schedule, the following rules will be

applied to assign actual visits to protocol-specified visits including early termination

visits. For each study visit mentioned in the protocol, a nominal or target day will be

selected to represent the corresponding visit along with a window around the target day.

Windows will be selected in a non-overlapping fashion so that a date collected on the case

report form (CRF) does not correspond to multiple visit windows. Moreover, windows


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will not discard any post-baseline measurement recorded on the CRF. If a subject had

2 or more actual visits in one visit window, the visit closest to the target will be used as

the study visit for that window. If two visits are equidistant from the target day, then the

later visit will be used for reporting.

The visit window (week and nominal day) displayed here apply only for patients who do

not achieve deep remission at Week 12 where visit R0 (Flow Chart B) corresponds to

visit 6 (Flow Chart A). For patients who achieve deep remission at Week 12 and

experience flare after Week 12, visit R0 will correspond to the visit when the

ileocolonoscopy is performed to confirm if the endoscopic criterion (CDEIS > 4, or > 2

for patients with isolated ileitis) is met before starting the second course of intravenous

therapy (open-label therapy in Period 2). Thus, all future displayed visit window times in

such patients will be shifted by the time between Week 12 and the confirmation of the

flare by endoscopy.

The visit windows and the target/nominal day for each study visit are shown in Table 2.


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Table 2. Windows for All Protocol-Specified Visits, Using for Study Drug Administration, Vital Signs, Hematology Lab Values, CDAI, Review Patient Diary, and Fistula Exam

Period Protocol Specified Visit Week Lower Bound Nominal Day Upper Bound

1 0 –999 1a

1

1 2 2 15 22

1 4 23 29 43

1 8 44 57 71

1 12 72 85 92

2 14 93 99 113

2 18 114 127 141

2 22 142 155 169

2 26 170 183 211

3 34 212 239 267

3 42 268 295 323

3 50 324 351 358

3 52 359 365 9999b

a. Day of first dose of study drug.

b. Minimum of Day 9999 and last dose date + 70 days.

The visit windows presented in Table 2 will be used for assessments done at all protocol-

specified visits for study drug administration, vital signs, hematology lab values, CDAI,

review patient diary, and fistula exam.


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Table 3. Analysis Windows for All Protocol-Specified Visits at Weeks 0, 2, 4, 8, 14, 18, 22, 26, 34, 42, 50 and 52, Using for Pregnancy Test


1 0 –999 1a

1

1 4 23 29 43

1 8 44 57 78

2 14 79 99 113

2 18 114 127 141

2 22 142 155 169

2 26 170 183 211

3 34 212 239 267

3 42 268 295 323

3 50 324 351 9999b



The visit windows presented in Table 3 will be used for assessments done at Weeks 0, 4,

8, 14, 18, 22, 26, 34, 42, and 50 for pregnancy test.

Table 4. Analysis Windows for All Protocol-Specified Visits at Weeks 0, 12, 26, and 52, Using for Ileocolonoscopy and IBDQ


1 0 –999 1a

1

1 12 2 85 134

2 26 135 183 274

3 52 275 365 9999b




26 and 52 for ileocolonoscopy and IBDQ.


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Table 5. Analysis Windows for All Protocol-Specified Visits at Weeks 0, 12, 26, and 52, Using for Ileocolonoscopy and IBDQ


1 0 –999 1a

1

1 4 2 29 43

1 8 44 57 71

1 12 72 85 106

2 18 107 127 155

2 26 156 183 211

3 34 212 239 295

3 50 296 351 358

3 52 359 365 9999b




8, 12, 18, 26, 34, 50 and 52 for CRP, fecal calprotectin and lactoferrin.

6.6 Missing Data Handling

Missing data imputation will be done only for efficacy variables (categorical and

continuous variables). For the analysis other than efficacy, no imputation will be done for

missing values.

Last Observation Carried Forward (LOCF) Approach

The LOCF rule will be used to impute missing continuous efficacy data. Baseline and

Pre-Baseline values will not be used to impute the missing Post-Baseline values. Missing

values after Study Day 1 will be imputed using the latest non-missing value after Day 1

and prior to the missing value. If there are no non-missing values after Baseline, then the

LOCF value will be missing. If a subject early drops out, the data will be imputed using

LOCF only for the period which the subject started.


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Non-Responder Imputation (NRI)

The NRI approach is used for binary efficacy variables. These variables can take values

of 'Achieved' or 'Not Achieved' or may be missing for any reason including

discontinuation from study. According to the NRI imputation approach, all missing

values will be considered as 'Not Achieved.' If a subject early drops out, the data will be

imputed using NRI only for the period which the subject started.

Observed Case (OC)

Observed case analysis will be performed, i.e., missing values will not be imputed. An

analysis using only the observed data will be performed as a sensitivity analysis for

primary and secondary efficacy endpoints.

Imputation of Missing Dates

For Baseline, efficacy, and safety parameters, if the day and/or month are missing, the

following conventions will be used to impute the missing dates:

● 01 for missing start day

● End of month for missing end day

● January 1st for missing start month

● December 31st for missing end month

In case of partially missing AE start and stop dates, the dates will be imputed by

comparing to first dose date of study medication so than the corresponding AEs will be

made treatment-emergent whenever possible. If the start date of an AE is partially

missing and the month is the same as the start date of a new therapy, the AE will be made

treatment emergent to the new therapy.

In case of missing or partially missing study drug dosing dates, the dates will not be

imputed. Subjects will be treated as not receiving dose on that date.


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6.7 Dealing with Multiple Measurements Collected on the Same Day

For efficacy related analysis, if multiple measurements for a particular parameter are

collected on the same day for the same subject, the average of those measurements will be

used in analyses.

For safety related analysis, if multiple measurements are made for a particular laboratory

or vital sign parameter on the same day for the same subject, the average of the values

will be used in the analyses. For summaries and listings for shift from baseline and

potentially significant values, average of the multiple measurements will not be used. All

values will be considered in the analyses.

7.0 Demographics, Baseline Characteristics, Medical History, and Previous/Concomitant Medications

7.1 Demographic and Baseline Characteristics

The following demographic and baseline characteristics, as measured at baseline of the

study, will be summarized.

Demographics

● Age (years)

● Age category [< 40, 40 to < 65, 65 to < 75, ≥ 75 years]

● Sex [male/female]

● Race [American Indian/Alaska Native, Asian, Black or African American,

Native Hawaiian or Other Pacific Islander, White, Multiple]

● Ethnicity [Hispanic/Latino, Non-Hispanic/Latino]

● Country

Tobacco/Nicotine and Alcohol Use

● Tobacco/Nicotine Use [currently smokes, ex-smoker, never smoked,

unknown]


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● Alcohol Use [drinks (no interference), drinks (possible interference), non-

drinker, unknown]

Vital Signs

● Systolic and diastolic blood pressure (mmHg)

● Pulse (bpm)

● Body temperature (°C)

● Body weight (kg) – overall and by sex

● Body weight category (< 60 kg, ≥ 60 kg)

● Height (cm)

● Body Mass Index (kg/m2)

● BMI Category

○ Underweight [< 18.5 kg/m2]

○ Normal [≥ 18.5 and < 25 kg/m2]

○ Overweight [≥ 25 and < 30 kg/m2]

○ Obese [≥ 30 kg/m2]

Tuberculosis (TB) Screening Tests and Other Screening Tests

● QuantiFERON-TB Gold Test

○ Result [Positive, Negative, Indeterminate]

● Pregnancy test [Positive, Negative]

● Hepatitis B/C testing

● HIV

Patient Reported Outcomes at Baseline

● PRO-2 score (defined as the sum of the weighted subscores of stool frequency

and abdominal pain from the CDAI)

● IBDQ score

● Average Daily Stool Frequency


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● Average Daily Abdominal Pain

Other Assessments at Baseline

● CDAI

● SES-CD

● CDEIS

● Bristol Stool Chart Score

● Crohn's Disease Duration (years)

● Stool calprotectin

● Stool Lactoferrin

● Baseline corticosteroid use (yes, no)

Programming note: Use ATC code ATC3 contains 'CORTICOSTEROIDS.'

● TNF antagonist history

○ Patient ever received anti-TNF therapy (yes, no)

○ Patient nonresponsive to anti-TNF therapy during induction therapy (yes,

no)

○ Patient nonresponsive to anti-TNF therapy during maintenance therapy

(yes, no)

○ Patient was intolerant to anti-TNF therapy (yes, no)

● CRP

● Frequency distribution of draining fistulas

7.1.1 Analysis of Demographic Data and Baseline Characteristics

Demographic and Baseline characteristics will be summarized with descriptive statistics

for the FAS-P1 population. The number of non-missing observations, mean, standard

deviation, median, minimum and maximum will be summarized for continuous variables.

Categorical or discrete variables will be summarized by counts and percentages for the

FAS-P1 population.


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In general, continuous variables will be analyzed using analysis of variance with treatment

group as factor. Categorical variable will be analyzed using Chi-square of Fisher's exact

test if ≥ 20% of the cells have expected cell count < 5.

7.2 Medical/Surgical History

7.2.1 Medical History

Medical/Surgical history data will be summarized using body systems and

conditions/diagnoses as captured on the CRF for the Period 1 FAS Population. The body

systems will be presented in alphabetical order and the conditions/diagnoses will be

presented in alphabetical order within each body system. The number and percentage of

subjects with a particular condition/diagnosis will be summarized for each treatment

group and overall. Subjects reporting more than one condition/diagnosis within a body

system will be counted only once for that body system. No statistical comparison will be

performed on medical history.

7.3 Prior and Concomitant Medications

The number and percent of subjects who received a prior or concomitant medication listed

below will be tabulated by the generic name assigned by the most current version of the

World Health Organization (WHO) Drug Dictionary in alphabetical order for prior and

concomitant medications, respectively.

A prior medication is defined as any medication taken prior to the first dose of study drug

and collected in the CRF. A concomitant medication is defined as any medication other

than study drug and the rescue medication that (1) was started prior to the first dose of

study drug and continued to be taken after the first dose of study drug or (2) was started

after the first dose of study drug, but was not started after the last dose of study drug. A

particular medication will be classified as "prior" or "concomitant" or "both" according to

the rules provided in Table 6, where "FD" is the date of the first dose of study drug and

"LD" is the date of last dose of study drug plus 105 days.


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Crohn's disease specific immunomodulators at any time prior to Baseline will be

tabulated.

7.4 Protocol Deviation

A list of important protocol deviations is given in Appendix Section 12.10. Number and

percentage of subjects reported with at least 1 of the following protocol deviation

categories will be provided:

● Inclusion/exclusion criteria deviations

● Developed withdrawal criteria/was not withdrawn

● Received wrong treatment or incorrect dose

● Received excluded concomitant treatment

8.0 Patient Disposition

The number of subjects will be tabulated by country, investigator site and overall for the

following sets: Period 1 FAS population, Period 2 FAS population, Period 3 FAS

population, Safety population, subjects who completed study by period, and subjects who

prematurely discontinued for study drug by period, for each treatment group and overall,

as appropriate.

In addition, the number and percentage of subjects who discontinued study drug will be

summarized by reason for each treatment group, the pooled risankizumab dose groups,

and overall. All reasons and primary reasons for discontinuation of study drug will be

summarized as recorded on the eCRF by the following categories:

● Adverse event (AE)

● Protocol violation

● Lost to follow-up

● Withdrew by subject

● Lack of efficacy


31

● Other

Subjects may have more than one reason for discontinuing study drug, but they will be

counted once for the total number of discontinuations. Subjects have only one primary

reason for discontinuing study drug or discontinuing from the study.

9.0 Study Drug Exposure and Compliance

9.1 Study Drug Exposure

For the safety population, the duration of exposure to study drug will be summarized for

each treatment group, and the pooled risankizumab dose groups. Duration of exposure is

defined for each subject as number of days since first dose of study drug through the last

study drug dose date +105 days. Study drug dose date refers to recorded dates of

injections of study drug.

For each treatment group, the pooled risankizumab dose groups and total, the duration of

exposure will be summarized by the number of subjects treated, as well as the mean,

standard deviation, median, minimum and maximum values. In addition, the number and

percentage of subjects exposed to study drug will be summarized for the following

exclusive duration intervals:

● 1 – 28 days

● 29 – 56 days

● 57 – 84 days

● 85 – 126 days

● 127 – 154 days

● 155 – 182 days

● 183 – 238 days

● 239 – 294 days

● 295 – 350 days

● > 350 days


32

9.2 Study Drug Compliance

The treatment compliance (%) of risankizumab dose information will be summarized for

safety population:

9.2.1 Intravenous Therapy

● Total number of infusions received

● Average actual volume infused

● Average infusion duration (hours)

● Cumulative risankizumab dose (mg)

9.2.2 Subcutaneous Therapy

● Total number of injection received

● Cumulative risankizumab dose (mg)

10.0 Efficacy Analysis

10.1 General Considerations

For all efficacy endpoints, the descriptive statistics will be provided by period and by

treatment group that the subjects were initially randomized to. The statistics include

number of observations, mean, standard deviation, minimum, median, and maximum for

continuous variables; and number and percent for discrete variables.

The population for analysis will depend on to which period the efficacy variables belong.

Generally, the FAS-P1 is the analysis population for variables in Period 1, the FAS-P2 is

the analysis population for variables in Period 2, and the FAS-P3 is the analysis

population for variables in Period 3.

10.2 Primary Efficacy Analyses

This section provides the details of the primary efficacy analysis for the study.


33

Primary Efficacy Variable

● Clinical remission at Week 12, defined as a CDAI < 150

Statistical Method for the Primary Efficacy Analysis

The proportions of patients in clinical remission at Week 12 will be estimated and tested

between placebo and the combination of risankizumab 200 mg IV and 600 mg IV with the

use of the Cochran-Mantel-Haenszel risk difference estimate (CMH) test, stratified by the

randomization factors of naïve or experienced to anti-TNF therapy with weights proposed

by Greenland & Robins.

Pairwise comparisons of the three treatment arms will be conducted using the same

methods as the primary analysis. There will be no adjustments for multiplicity, nominal

p-values will be provided.

10.3 Second Efficacy Analyses

This section provides the details of the secondary efficacy analysis for the study.

Secondary Efficacy Variables

● Clinical response at Week 12, defined by either a CDAI < 150 or a CDAI

reduction from baseline of at least 100 points

● CDEIS remission, defined as a CDEIS of 4 or less at Week 12 (for patients

with initial isolated ileitis a CDEIS of 2 or less)

● CDEIS response at Week 12, defined as ≥ 50% reduction from baseline

● Mucosal healing, using CDEIS defined as the absence of mucosal ulceration at

Week 12, i.e., ulceration sub-score (deep ulceration, superficial ulceration,

ulcerated stenosis) is 0.

● Deep remission, defined as clinical remission and CDEIS remission at

Week 12.


34

Statistical Method for the Secondary Efficacy Analysis

All the binary secondary endpoints at Week 12 will be estimated and tested between

Placebo and the combination of 200 mg IV and 600 mg IV with the use of the Cochran-

Mantel-Haenszel risk difference estimate (CMH) test, stratified by the randomization

factors of naïve or experienced to anti-TNF therapy with weights proposed by Greenland

& Robins.

Pairwise comparisons of the three treatment arms will be conducted using the same

methods as the primary analysis. There will be no adjustments for multiplicity, nominal

p-values will be provided.

10.4 Exploratory Efficacy Analyses

This section provides the details of the exploratory efficacy analysis for the study.

Exploratory Efficacy Variables

● Boolean remission at Week 12, defined as abdominal pain daily average score

through week of 1 or less and stool frequency daily average score of 3 or less.

● PRO-2 clinical remission, defined as weighted total (weekly) AP + SF ≤ 75, at

Week 12, Week 26 and Week 52 respectively.

● PRO-2 clinical response, defined as weighted total (weekly) AP + SF decrease

from baseline of 50 points or more, at Week 12, Week 26 and Week 52

respectively.

● Change from baseline in CDAI by period and visit.

● Change from baseline in PRO-2 score by period and visit.

● SES-CD response, defined as ≥ 50% reduction from baseline, at Week 12,

Week 26 and Week 52 respectively.

● SES-CD remission, defined as a score of 4 or less (for patients with initial

isolated ileitis a score of 2 or less) and at least a 2 point reduction from

baseline and no subscore > 1 in any individual variable, at Week 12, Week 26

and Week 52 respectively.

● Change from baseline in CDEIS by period and visit.


35

● Change from baseline in SES-CD by period and visit.

● Reduction of at least 75% in CDEIS at Week 12

● Reduction of at least 75% in SES-CD at Week 12

● Time to flare for those who achieve deep remission and stop medication at

Week 12. Change from baseline in stool frequency by visit based on patient

diary.

● Stool consistency by visit based on patient diary.

● Change from baseline in abdominal pain scores by visit based on the patient

diary and scored, on a numeric rating scale from 0 (no pain) to 10 (worst

possible pain).

● Change from baseline in IBDQ scores by visit.

● Change from baseline in CRP, stool calprotectin and lactoferrin profile by

visit.

● Frequency distribution of subjects who are in clinical remission and on

corticosteroids at the beginning of Period 2/Visit R0.

● Reduction in the number of draining fistulas in patients with draining fistulas

at baseline by visit.

● CDAI clinical response, defined by either a CDAI < 150 or a CDAI reduction

from baseline of at least 100 points, at Week 26 and Week 52 respectively.

● CDAI clinical remission, defined as CDAI < 150, at Week 26 and Week 52

respectively.

● CDEIS remission, at Week 26 and 52 respectively.

● CDEIS response, at Week 26 and Week 52 respectively.

● Mucosal healing, at Week 26 and Week 52 respectively.

● Deep remission, at Week 26 and Week 52 respectively.

Statistical Method for the Exploratory Efficacy Analysis

Boolean remission at Week 12, Week 26 and Week 52 will be analyzed in a similar

fashion to the primary endpoint. The change from baseline in CDEIS and SES-CD at

Week 26 of the active treatments (combination of 200 mg IV and 600 mg IV) and placebo


36

will be analyzed using non-parametric (Wilcoxon Rank Sum) methods in order to perform

a pairwise median comparison of the two combined active drug doses versus placebo.

Except for the aforementioned endpoints, the rest will be analyzed descriptively by

treatment group and by period. For all periods (1, 2, and 3), the endpoints will be

analyzed by the treatment group subjects were initially randomized to.

The analyses beyond Week 12 will not include subjects who achieved deep remission at

Week 12. Subjects who achieve deep remission at Week 12 will be analyzed

descriptively using patient profiles.

Correlation at baseline, Week 12, and EOT will be reported between abdominal pain,

stool frequency, general well-being and CDAI score using Pearson's rho with

corresponding confidence interval.

Stool Consistency will be listed and tabulated in order to analyze the frequency

distribution of the number of days during which subjects had a score (Bristol stool scale)

of 6 or 7.

The analysis of time to flare will be performed using product limit method. The median

time-to-event and its 95% CI, if applicable, will be provided for Period 1 FAS population

who has deep remission at Week 12. Flare is defined as an increase of CDAI score

≥ 70 points compared to Week 12 and a CDAI score of 220 or greater. Similarly, the time

to CDAI ≥ 150 will also be provided for those who achieve clinical remission at Week 26.

10.5 Handling of Multiplicity

There will be no adjustment for multiple comparisons between the two combined active

drug dose groups and placebo on the efficacy variables.

10.6 Efficacy Subgroup Analysis

The primary endpoint, proportion of patients in clinical remission at Week 12, will be

analyzed in the subgroups of subjects naïve to, or previously treated with anti-TNF


37

therapy. The subgroup analysis will be performed in a similar fashion to the primary

endpoint. Other subgroups are defined below.

Patients with Baseline SF ≥ 4 or AP ≥ 2


● Percent of patients with average daily SF ≤ 2.8 and AP ≤ 1 and both not worse

than baseline at Week 12, Week 26 and Week 52

Patients with Baseline SF ≥ 4 or AP ≥ 2, and Baseline SES-CD, Excluding the Presence of Narrowing Component, ≥ 6 (≥ 4 for Subjects with Initial Isolated Ileitis)


● Percent of patients with average daily SF ≤ 2.8 and AP ≤ 1 and both not worse

than baseline at Week 12 and Week 52

● Percent of patients with ≥ 65% decrease in average daily SF or ≥ 35% decrease

in average daily AP and both not greater than baseline, or achievement of

revised clinical remission (average daily SF ≤ 2.8 and AP ≤ 1 and both not

worse than baseline) at Week 12 and Week 52

● Percent of patients with ≥ 30% decrease in average daily SF or ≥ 30% decrease

in average daily AP and both not greater than baseline, or achievement of

revised clinical remission (average daily SF ≤ 2.8 and AP ≤ 1 and both not

worse than baseline) at Week 12 and Week 52

● Percent of patients with SES-CD remission (defined as SES-CD ≤ 4 (for

patients with initial isolated ileitis a score of 2 or less) and at least a 2 point

reduction from baseline and no subscore > 1 in any individual variable) at

Weeks 12 and Week 52

● Percent of patients with SES-CD response (≥ 50% decrease in SES-CD from

BL) at Week 12 and Week 52


38

11.0 Safety Analysis

11.1 General Considerations

Safety analyses will include reporting of adverse events, laboratory, and vital signs

measurements. All safety analyses will be performed on the Safety Population, which

includes all subjects who received at least one dose of study medication during the study.

The baseline for safety analysis will be treatment dependent. For the Period 1 analysis,

the baseline is defined as the last available measurement before study drug administration

for all subjects. Starting from Period 2, the baseline for subjects initially randomized to

Risankizumab will remain the same. However, the baseline for subjects initially

randomized to placebo will be redefined as the last available measurement before

first dose of Risankizumab administration. In cases of repeated measurements performed

for the same visit, the last observation will be used for tabulation.

The following summary statistics will be presented for subjects who have both baseline

and post-baseline values for laboratory parameters and vital signs: the mean value at

Baseline and at each respective protocol specified visit, and the mean, standard deviation

and median for changes from Baseline. Categorical data will be summarized using

frequencies and percentages. The number of non-missing values will be given.

11.2 Analysis of Adverse Events

11.2.1 Treatment-Emergent Adverse Events

Treatment-emergent AEs are defined as events that begin or worsen either on or after the

first dose of the study medication and within 105 days after the last dose of the study

drug.

Events where the onset date is the same as the study drug start date are assumed to be

treatment-emergent, unless the study drug start time and the adverse event start time are

collected and the adverse event start time is prior to the study drug start time. If an

incomplete onset date was collected for an adverse event, the event will be assumed to be


39

treatment-emergent unless there is other evidence that confirms that the event was not

treatment-emergent (e.g., the event end date was prior to the study drug start date).

The analyses of adverse events will be descriptive in nature. All analyses of AEs will be

based on the number of patients with AEs (not the number of AEs).

Treatment labels for the safety analyses will be assigned accounting for the three periods:

a. Period 1 will consist of three treatment labels: Placebo, Risankizumab 200 mg IV,

Risankizumab 600 mg IV

b. Period 2 will consist of one treatment label: Risankizumab 600 mg IV

c. Period 3 will consist of one treatment label: Risankizumab 180 mg SC

Any AEs occurring during the study will be assigned to Risankizumab for the duration of

the trial with the following exception: AEs occurring during Period 1 in subjects taking

Placebo will be assigned to Placebo.

Summary of AEs will be done for the subjects who have taken at least one dose of

Risankizumab during the administration of Risankizumab.

11.2.1.1 Adverse Event Overview

The number and percentage of subjects experiencing TEAEs will be summarized for the

following AE categories.

● Any treatment-emergent adverse event.

● Any treatment-emergent adverse event that was rated as related to study drug

by the investigator.

● Any treatment-emergent severe adverse event.

● Any treatment-emergent serious adverse event.

● Any treatment-emergent adverse event leading to discontinuation of study

drug.

● Any treatment-emergent adverse event leading to death.


40

● Any treatment-emergent adverse event of special interest.

11.2.1.2 Adverse Events by System Organ Class and Preferred Term

The number and percentage of subjects experiencing TEAEs will be tabulated using

primary Medical Dictionary for Regulatory Activities (MedDRA) system organ classes

(SOCs) and preferred terms (PTs) for each treatment group according to Version 18.0 or

higher of the MedDRA coding dictionary. The SOCs will be presented in alphabetical

order, and the PTs will be presented in alphabetical order within each SOC.

A subject who reports more than 1 AE in different SOCs will be counted only once in the

overall total. A subject who reports 2 or more different PTs, which are in the same SOC,

will be counted only once in the SOC total. Subjects reporting more than 1 AE for a

given PT will be counted only once for that term (most severe incident for the severity

tables and most related incident for the relationship tables).

11.2.1.3 Adverse Events by Maximum Severity

TEAEs will also be summarized by maximum severity. If a subject has an AE with an

unknown severity, then the subject will be counted in the severity category of unknown,

even if the subject has another occurrence of the same event with a severity present. The

only exception is if the subject has another occurrence of the same AE with the most

extreme severity – severe. In this case, the subject will be counted under the severe

category.

National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events

(CTCAE) v4.03 will be used to report Adverse Event (including abnormal laboratory

findings) in this study. The severity of an AE will be tabulated by the scale of Grades 1

through 5:


41

Grade 1 Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; intervention not indicated.

Grade 2 Moderate; minimal, local or noninvasive intervention indicated; limiting age-appropriate instrumental ADL (refer to preparing meals, shopping for groceries or clothes, using the telephone, managing money, etc.).

Grade 3 Severe or medically significant but not immediately life-threatening; hospitalization or prolongation of hospitalization indicated; disabling; limiting self-care ADL (refer to bathing, dressing and undressing, feeding self, using the toilet, taking medications, and not bedridden).

Grade 4 Life-threatening consequences; urgent intervention indicated.

Grade 5 Death related to AE.

AEs with Grade 3 or higher will be listed and described in detail.

11.2.1.4 Adverse Events by Maximum Relationship

TEAEs will also be summarized by maximum relationship to Risankizumab and Placebo

separately, as assessed by the investigator. If a subject has an AE with an unknown

relationship, then the subject will be counted in the relationship category of "unknown,"

even if the subject has another occurrence of the same event with a relationship present.

The only exception is if the subject has another occurrence of the same AE with a

relationship assessment of related. In this case, the subject will be counted under the

related category.

11.2.1.5 Adverse Events by "Reasonably Possibly Related" Relationship

TEAEs will also be summarized by relationship defined by "reasonably possibly related"

to drug, as assessed by the investigator. If a subject has an AE with an unknown

relationship, then the subject will be counted in as 'related.'


42

11.2.1.6 Serious Adverse Events (Including Deaths) and Adverse Events Leading to Study Drug Discontinuation

All pre- and post-treatment serious adverse events (SAEs), deaths, and adverse events

leading to discontinuation of study drug will be listed. The number and percentage of

subjects experiencing SAEs (including deaths) and adverse events leading to

discontinuation of study drug will be tabulated according to the primary MedDRA SOC

and PT for each treatment group.

11.2.1.7 Frequent (> 5%) Adverse Events by Preferred Term in Decreasing Frequency

TEAEs occurring for more than 5% of the subjects in any of the treatment arms will be

summarized by MedDRA PT in decreasing frequency.

11.2.1.8 Reasonably Possibly Related Adverse Events by System Organ Class and Preferred Term

Reasonably possibly related TEAES will be summarized by MedDRA SOC and

MedDRA PT.

11.2.1.9 Adverse Events of Special Interests

The Adverse Events of Special Interests (AESI) categories are listed in Appendix 12.11.

These will be summarized and presented using primary MedDRA query and MedDRA

PT.

Additional AEs may be considered for tabulation/summary based on recommendations

from Clinical and Safety teams, as deemed appropriate.

11.2.1.10 Adverse Events by 100 Patient Years

TEAEs will be summarized by event rate per 100 subject years, defined as

YearsPatientTotal

TEAEsofNumber100


43

where total patient years is defined as the sum of the study drug exposure of all subjects,

as defined in an earlier section, normalized by 365.25, and rounded to 1 decimal place.

11.2.1.11 Listing of Adverse Events

The following additional summaries of AEs will be prepared.

● Listing of Subjects with Treatment-Emergent Adverse Event of Special

Interests

● Listing of Subjects with Pretreatment Serious Adverse Events

● Listing of Subjects with Treatment-Emergent Serious Adverse Events

● Listing of all adverse events that led to discontinuation of study drug.

● Listing of all deaths.

11.3 Analysis of Laboratory Data

Changes from Baseline in continuous laboratory parameters will be summarized by n,

mean, standard deviation, minimum value, median, and maximum value for each

treatment group.

Shift tables from Baseline to the final value (the last assessment during each treatment

period) according to the normal range will be provided for each hematology, clinical

chemistry parameter and urinalysis parameter. The laboratory data will be categorized as

low, normal, or high based on the normal ranges of the laboratory used in this study. The

shift tables will tabulate the number and percentage of subjects with Baseline values

below/within/above the normal range versus final values below/within/above the normal

range.

For selected laboratory parameter with Common Toxicity Criteria (CTC) a listing of all

subjects with any laboratory determinations meeting CTC Version 3.0 (or later) of

Grade ≥ 3 will be provided. For each of these subjects, the whole course of the parameter

will be listed. For subjects with laboratory values with CTC ≥ 3, all of the laboratory

parameters for those subjects will be listed.


44

11.3.1.1 Analysis for Potentially Clinically Significant Laboratory Values

The liver-specific laboratory tests include the serum glutamic pyruvic transaminase

(SGPT/ALT), serum glutamic-oxaloacetic transaminase (SGOT/AST), alkaline

phosphatase, and total bilirubin. Each of these laboratory values will be categorized as

follows:

● < 1.5 × ULN,

● ≥ 1.5 × ULN TO < 3 × ULN,

● ≥ 3 × ULN TO < 5 × ULN,

● ≥ 5 × ULN TO < 8 × ULN, and

● ≥ 8 × ULN.

where ULN is the upper normal limit.

A listing of potentially clinically significant liver function laboratory values will be

provided. The listing will include all subjects who met any of the following 4 criteria:

● ALT ≥ 2.5 × ULN, or

● AST ≥ 2.5 × ULN, or

● Alkaline phosphatase ≥ 2.5 × ULN, or

● Total bilirubin ≥ 1.5 × ULN.

11.4 Analysis of Vital Signs and Weight

11.4.1 Variables and Criteria Defining Abnormality

Vital sign variables include sitting systolic blood pressure, sitting diastolic blood pressure

and heart rate. The criteria for potentially clinically significant vital sign findings are

presented in Table 7.


45

Table 7. Criteria for Potentially Clinically Significant Vital Sign Findings

Vital Sign Category Criteria for Potential Clinically Significant Vital Signs

Systolic blood pressure (mmHg)

Low Value ≤ 90 mmHg and/or decrease ≥ 20 mmHg from Baseline

High Value ≥ 180 mmHg and/or increase ≥ 20 mmHg from Baseline

Diastolic blood pressure (mmHg)

Low Value ≤ 50 mmHg and/or decrease ≥ 15 mmHg from Baseline

High Value ≥ 100 mmHg and/or increase ≥ 15 mmHg from Baseline

Heart rate (bpm) Low Value ≤ 50 bpm and/or decrease ≥ 15 bpm from Baseline

High Value ≥ 120 bpm and/or increase ≥ 15 bpm from Baseline

11.4.2 Statistical Methods

The following summary statistics will be presented by treatment group: baseline mean,

the mean at each visit, mean change from baseline, standard deviation, median, minimum,

and maximum. The number and percentage of subjects meeting the criteria for potentially

clinically significant vital sign values will be summarized.

Vital sign results meeting the criteria for potentially clinically significant vital sign

findings will be identified in a listing.

11.5 Analysis for Other Safety Variables

Not applicable for the current planned analysis.

11.6 Safety Subgroup Analysis

Not applicable.


46

12.0 Appendix

12.1 Stool Consistency Calculation

Stool consistency is measured by the Bristol stool form (above). The Bristol Stool Form

Scale (BSFS) is an illustration of seven stool types that represent differing whole gut

transit times. The BSFS categorizes stool transit into three categories:

● slow (BSFS 1 – 2, hard and lumpy),

● normal (BSFS 3 – 5, smooth and soft, snake like), and

● fast (BSFS 6 – 7, fluffy, mushy, watery).

The categorization based on stool transit times are reflected in the table below.


47

For any given participant, we simply take the classification with the highest occurrence

over the given week.

Hence, for a given week, a participant's stool classification will fall under one of the

3 categories:

● Predominantly Hard

● Predominantly Normal

● Predominantly Fast

If there is a tie, we select the worse classification. We are using the following

assumptions.

1. For a given week, the frequency of hard stools and fast stools shouldn't be equal.

2. There are no 3-way ties.

12.2 Crohn's Disease Activity Index (CDAI)

The Crohn's Disease Activity Index (CDAI) is a composite instrument that includes

patient symptoms evaluated over 7 days (abdominal pain, stool frequency and general

well-being), as well as physical and laboratory findings. These items are scored

individually, weighted, and do not contribute equally to the overall score. The CDAI is

derived from summing up the weighted individual scores of eight items as outlined below:


48

CDAI

Variable Description Weight

Number of liquid stools

Sum of 7 days 2

Abdominal pain Sum of 7 days ratings Range: 0 (none) to 3 (severe)

5

General well being Sum of 7 days ratings Range:0 (generally well) to 4 (terrible)

7

Extraintestinal complications

Number of listed complications

arthritis/arthralgia, iritis/uveitis, erythema nodosum, pyoderma gangrenosum, aphthous stomatitis, anal fissure/fistula/abscess, fever > 37.8°C

20

Antidiarrhoeal drugs

Use in previous 7 days 0 (no) or 1 (yes) 30

Abdominal mass 0 (no), 2 (questionable) or 5 (definite) 10

Hematocrit Expected minus observed hematocrit

Males: 47 minus observed Females: 42 minus observed

6

Body weight Observed/ideal ratio [1 – (observed/ideal)] × 100 1

CDAI ranges from 0 to 600 with higher scores indicating more severe disease. For the

calculation of CDAI and components at each visit, the following rules will be applied:

● The 7 most recent useable days out of the 14 days preceding the visit will be

used.

● If 7 useable days are not available, an average will be calculated based on the

number of days with available data as follows:

○ An average for the most recent 6 days will be calculated if data for only

6 days are available,





○ Data for days with missing diary entries will be imputed using the average

of the non-missing days, in order to calculate a CDAI and components

based on 7 days.


49

● If the minimum number of days of diary data (i.e., 4 days for CDAI and

components) are not available, then the subject's score for that visit will be

considered missing and NRI will be used for any endpoints relating to data for

this visit.

Programming Note:

From the diary, the sum of the number of liquid or soft stools each day for 7 days is

multiplied by 2. CDASH questions: CDAI0101, CDAI0102, CDAI0103, CDAI0104,

CDAI0105, CDAI0106, CDAI0107. The average score is taken, multiplied by 7 and

multiplied by 2.

From the diary, the abdominal pain, sum of seven daily ratings (0 = None

1 = Mild 2 = moderate 3 = severe) is multiplied by 5. CDASH questions: CDAI0108,

CDAI0109, CDAI0110, CDAI0111, CDAI0112, CDAI0113, CDAI0114. The average

score is taken, multiplied by 7 and multiplied by 5.

From the diary, the general well-being, sum of seven daily ratings (0 = generally well,

1 = slightly under par, 2 = poor, 3 = very poor, 4 = terrible) are multiplied 7. CDASH

questions: CDAI0115, CDAI0116, CDAI0117, CDAI0118, CDAI0119, CDAI0120,

CDAI0121. The average score is taken, multiplied by 7 and multiplied by 7.

From the investigator physical assessment, the number of listed complications:

1. Arthritis or arthralgia (CDAI0122).

2. Iritis or uveitis (CDAI0123).

3. Erythema nodosum, pyroderma gangrenosum or aphthous stomatitis (CDAI0124).

4. Anal fissure, fistula or abscess (CDAI0125).

5. Other fistula (CDAI0126).

6. Fever over 37.8°C [100°F] (CDAI0127).


50

The sum of the complication ratings will be used. This sum is multiplied by 20.

Use of diphenoxylate or loperamide for diarrhea (use of medications for diarrhoea) is

multiplied by 30. CDASH question: CDAI0128.

Abdominal mass (0 = no, 2 = questionable, 5 = definite) is multiplied by 10. CDASH

question: CDAI0129.

Hematocrit (males: 47-HCT [%], females: 42-HCT [%] is multiplied by 6. CDASH

question: CDAI0130.

Body weight (1-(current weight kg/standard ideal MetLife table weight kg)) multiplied by

100. CDASH question: CDAI0131. If the calculated value is less than –10 then the

value is set to –10.

The expected range is 0 to 600. The score is derived to the CDASH question CDAI0132.

The CDAI score is set to missing under the following conditions:

1. If there are less than 4 days of any diary data.

2. If any component other than the diary data is missing.

12.3 Patient Reported Outcome (PRO-2)

The PRO-2 is calculated based on the sum of the weighted patient-reported subscores of

CDAI for liquid or soft stool frequency [SF] plus abdominal pain [AP] in the 7 days prior

to the study visit. PRO-2 is calculated (as in the CDAI) by adding the values of the

summed stool frequency scores multiplied by 2 plus the summed abdominal pain scores

multiplied by 5.

The SF and AP score at an assessment visit will be the average of the daily values

reported during the 7 days preceding the scheduled assessment visit.


51

● If 7 days daily values are not available, an average will be calculated based on

the number of days with available data as follows:






4 days are available.

● If the minimum number of days of diary data (i.e., 4 days for SF and AP) are

not available, then the subject's score for that visit will be considered missing

and NRI will be used for any endpoints (e.g., clinical remission) relating to

data for this visit. Subjects who discontinue prior to the endpoint for any

reason will be considered as "not achieved" for clinical remission endpoint.

12.4 Crohn's Disease Endoscopic Index of Severity (CDEIS)

In all investigational sites, ileocolonoscopy/biopsy will be performed at baseline,

Week 12, Week 52, and in case of flare during the wash out period. Every effort should

be made for the patient to perform a final ileocolonoscopy/biopsy within 2 weeks

following the premature discontinuation visit. Lesions detected by ileocolonoscopy will

be scored by means of the validated Crohn's Disease Endoscopic Index of Severity

(CDEIS). The same endoscopist at the study site will complete the CDEIS for each

ileocolonoscopy immediately after the procedure. Investigators will record endoscopies

and send the videos to the central imaging laboratory. A central reading of endoscopies

will be performed by independent blinded reviewer(s) and the findings be scored using

both, the CDEIS and the SES-CD scores. In case of discrepancies between the local

endoscopic and central blinded reviewer, the centrally read scores will be used for

efficacy assessments and the trial report.


52

Scoring System for Crohn's Disease Endoscopic Index of Severity (CDEIS)

RectumSigmoid and Left Colon

Transverse Colon

Right Colon Ileum Total

Deep ulcerations (12 if present) Total 1

Superficial ulcerations (6 if present)

Total 2

Surface involved by disease (cm) Total 3

Surface involved by ulcerations (cm)

Total 4

Total 1 + Total 2 + Total 3 + Total 4 = Total A

Number of segments totally or partially explored N

Total A/n = Total B

If an ulcerated stenosis is present anywhere add 3 = C

If a nonulcerated stenosis is present anywhere add 3 = D

Total B + C + D = CDEIS

● If deep ulceration is present the value is 12. Sum the present values for

rectum, sigmoid and left colon, transverse colon, right colon and ileum.

● If superficial ulceration is present the value is 6. Sum the present values for

rectum, sigmoid and left colon, transverse colon, right colon and ileum.

● Sum the surface involved by the disease (cm from 0 – 10) for rectum, sigmoid

and left colon, transverse colon, right colon and ileum. The sum has

one decimal place.

● Sum the surface involved by ulcerations (cm from 0 – 10) for rectum, sigmoid

and left colon, transverse colon, right colon and ileum. The sum has

one decimal place.

● A is the sum of the sum for deep ulceration + sum for superficial ulceration +

sum for surface involved by disease + sum for surface involved by ulceration.

● n is the number of segments totally or partially explored.

● B is A/n.

● C if ulcerated stenosis is present anywhere add 3.

● D if non ulcerated stenosis is present anywhere add 3.


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The total score (CDEIS) is the sum of the sum for deep ulceration + sum for superficial

ulceration + sum for surgace involved by disease + sum for surface involved by ulceration

(for all examined segments) (CDEISCS2, CDEISCS3, CDEISCS4, CDEISCS5) divided

by the number of segments totally or partially explored (CDEISCS1) + 3 if ulcerated

stenosis (CDEISCS6) present + (> 0) for non-ulcerated stenosis (CDEISCS7) present

(> 0).

12.5 Simple Endoscopic Score – CD (SES-CD)

SES-CD is calculated based the sum of individual segment values for four endoscopic

variables (presence and size of ulcers, ulcerated surface, affected surface and presence of

narrowing). Each variable in each segment be scored 0 to 3 resulting in SES-CD values

ranging from 0 to 56 with higher scores indicating more severe disease.

12.6 Bristol Stool Chart

The average daily Bristol stool score will be calculated from the 7 days prior to visit.

If 7 days daily values are not available, an average will be calculated based on the number

of days with available data as follows:

● An average for the most recent 6 days will be calculated if data for only 6 days

are available,


are available,


54


are available.

If the minimum number of days of diary data (i.e., 4 days) are not available, then the

subject's score for that visit will be considered missing and NRI will be used for any

endpoints (e.g., clinical remission) relating to data for this visit. Subjects who discontinue

prior to endpoint for any reason will be considered as "not achieved" for clinical

remission endpoint.

12.7 Time to Flare/Time to CDAI ≥ 150

Flare is defined as an increase of CDAI ≥ 70 points compared to Week 12 and a CDAI of

220 or greater.

For Time to Flare:

Time to event [days] = (date of event) – (end date of blinded IV therapy) + 1.

For patients that were not observed to have event:

Time to event [censored] = minimum (Visit E1, date of last contact) – (end date of

blinded IV therapy) + 1.

For Time to CDAI ≥ 150:

Time to event [days] = (date of event) – (first dose date of subcutaneous therapy) + 1.

For patients that were not observed to have event:

Time to event [censored] = minimum (Visit E5, date of last contact) – (first dose date of

subcutaneous therapy) + 1.

12.8 Inflammatory Bowel Disease Questionnaire (IBDQ)

The IBDQ is a 32-item (ranges 1 – 7) self-report questionnaire for patients with IBD to

evaluate the patient reported outcomes across 4 dimensions: bowel symptoms (loose


55

stools, abdominal pain), systemic symptoms (fatigue, altered sleep pattern), social

function (work attendance, need to cancel social events), and emotional function (anger,

depression, irritability). The IBDQ total Score ranges from 32 to 224 with a higher score

indicating better outcome. The patient will complete the IBDQ as noted in the Flow

Chart A and Flow Chart B.

12.9 Isolated Ileatis

● For isolated ileitis in the analysis using CDEIS: Patients who have CDEIS = 0

in all segments other than ileum are considered to have isolated ileitis.

● For isolated ileitis in the analysis using SESCD: Patients who have

SESCD = 0 in all segments other than ileum are considered to have isolated

ileitis.

Programming notes: Patients who have a CDEIS < 7 will be considered to have isolated

ileitis and the appropriate cut-off will be used in order to establish the endoscopic

remission.


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12.10 Important Protocol Violations

Category/Code Description Example/CommentExcluded

FromEfficacy or Safety

Automatic/ Manual

A Entrance Criteria Not Met

A1.1 Disease severity or prior treatment for Crohn's disease not met

Inclusion Criteria 2, 3, 4, or 5 not met as specified in the protocol.

E/S Automatic

A1.2 Ineffective use of contraception

Inclusion Criterion 6 not met E/S Automatic and Manual

A1.3 Inability to understand informed consent

Inclusion Criterion 7 not met E/S Automatic and Manual

A2.1 Certain complications of Crohn's disease

Exclusion Criteria 1 – 3 met E/S Automatic and Manual

A2.2 Prohibited treatment or medical procedures

Exclusion Criteria 4, 6, 7, 8, 12, 15 met

E/S Automatic and Manual

A2.3 Pregnant or planning pregnancy

Exclusion Criteria 5 met E/S Automatic

A2.4 Certain prior or current infections or diseases

Exclusion Criteria 9, 11, 13, 14 met

E/S Automatic

A2.5 Violation of TB criteria


A2.6 Substance abuse Exclusion Criteria 17 met E/S Automatic

A2.7 Participation in another clinical trial

Exclusion Criteria 18 met E/S Automatic and Manual

A2.8 Lab results violation


A2.9 Hypersensitivity to investigational drug


A2.10 Patient clinically unable to successfully undergo study

Exclusion Criteria 21 met E/S Automatic and Manual


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Automatic/ Manual

B Informed Consent

B1 Informed consent not available/not done

Informed consent date missing All None Automatic and Manual

B2 Informed consent too late

Informed consent date was after Visit 2 date

None Automatic and Manual

C Trial Medication and Randomization

C1 Incorrect trial medication taken

C1.1 Incorrect trial medication taken during study

Any deviation. Check whether the medication packagesdispensed (med. numbers entered into RDC) has the correct content (to be seen from the med. number list that was the basis for packaging). If content was correct, the deviation will only be noted. Otherwise, the cases will be described individually and possibly excluded. In addition, check whether the dispensed packages match the randomized treatment of the patient (IVRS assignment). If not, and if treated consistently throughout the trial, analyze as treated.

E/S Manual

C1.2 Stopping rules for safety not followed correctly

Review AEs during MQRMs E/S Manual

C2 Randomization order not followed


58



Automatic/ Manual

C2.1 Error by the vendor who implemented the randomization scheme

E.g., the same randomization number was given to different patients or the assignment of duplicate medication numbers or incorrect medication numbers. Or wrong stratum. Verify by comparing the medication numbers and randomization numbers from IVRS. (In this study, the vendor Prometrika, will conduct a randomization check when approximately 50% have been randomized.)

E Manual

C3 Non-compliance with study medication

C3.1 Non-compliance with risankizumab 600 mg, 200 mg or Placebo

Since the site administers the treatment, noncompliance will be measured by a missed clinical visit.

Patient data will be considered evaluable for the primary endpoint as long as the patient receives at least one dose.

None Automatic

C3.2 Improper preparation or administration of risankizumab for IV infusion or SC injection

Create listing, decision at MQRM/BRPM, see CTP Section 5.2.6 and check comment in the eCRF. I.e., Infusion tubing set not flushed with dextrose solution, or, Exceed time limit – failure to complete infusion within 2 hours of end of preparation.

None Automatic

D Concomitant Medication

D1 Prohibited medication use before the treatment period of the trial

To be determined on a case by case basis.

E/S Automatic and Manual

D2 Prohibited medication use during the conduct of the trial

To be determined on a case by case basis.

E/S Manual


59



Automatic/ Manual

D2.1 Use of treatment in Table 4.2.2.1

Violation of Table 4.2.2.1 of CTP

E/S Manual

D3.1 Permitted use of concomitant treatment

Incorrect tapering of corticosteroids, see Section 4.2.2 of CTP.

E/S Manual

Manual IPVs checked via the IPV spreadsheet.

Note: Missing visits, evaluations, and tests will be considered missing data, not protocol deviations. All final

decisions as to whether any deviation is relevant will be taken at the BRPM.


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12.11 Adverse Events of Special Interest

Type of MedDRA Query

Broad or Narrow Search SMQ/CMQ Search Criteria

Drug induced liver injury (DILI)

SMQ Broad Hepatic failure, fibrosis and cirrhosis and other liver damage-related conditions

SMQ Broad Hepatitis, non-infectious

SMQ Broad Cholestasis and jaundice of hepatic origin

SMQ Broad Liver related investigations, signs and symptoms

SMQ Narrow Liver-related coagulation and bleeding disturbances

Infections CMQ "Infections"

Serious Infections CMQ "Infections" – Subset for SAEs

Opportunistic infections CMQ "Opportunistic infection"

Tuberculosis CMQ "Tuberculosis"

Fungal infections CMQ "Fungal infections"

Malignancies SMQ Narrow "Malignancies"

Systemic Hypersensitivity/Anaphylactic Reactions

SMQ Broad "Hypersensitivity""Anaphylactic reaction" "Angioedema"

Depression, Suicidal ideation and behavior (SIB)

SMQ Broad "Suicide/self-injury""Depression (excluding suicide and self-injury)"

Hepatic Disorder SMQ Narrow "Drug Related Hepatic Disorders"

Cardiac Arrhythmias SMQ Narrow "Torsade de pointes/QT Prolongation"

"Tachyarrhythmias"

13.0 References

1. Greenland S, Robins JM. Estimation of a common effect parameter from sparse

follow-up data. Biometrics. 1985;41(1):55-68.


61

2. Trial Statistical Analysis Plan, Protocol 1311.6 (Including Protocol

Amendment c01651690-13). A phase II, multicenter, randomized, double-blind,

multiple dose, placebo-controlled, parallel-group study to evaluate the efficacy,

pharmacokinetics, and safety of BI 655066, an IL-23 p19 antagonist monoclonal

antibody, in patients with moderately to severely active Crohn's disease, who are

naïve to, or were previously treated with anti-TNF therapy. 12 August 2015

SIGNED.

Documents

16.1 9 Documentation of Statistical Methods€¦ · This statistical analysis plan (SAP) describes the statistical analysis to be completed by the AbbVie Clinical Statistics Department