Clinical trial NCT03713632
Conditions: Hidradenitis Suppurativa
Keywords: acne inversa Hidradenitis suppurativa maladie de Verneuil inflammatory disease AIN457 AIN457M secukinumab HS lumps skin lesions
Sponsor: Novartis Pharmaceuticals
Start date: 2019-02-25; Completion date: 2022-07-19
Enrollment: 545 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study was to demonstrate superiority of secukinumab at Week 16, based on Hidradenitis Suppurativa Clinical Response (HiSCR) rates versus placebo, along with the maintenance of efficacy of secukinumab at Week 52 in subjects with moderate to severe HS. Moreover, this study assessed the safety and tolerability of secukinumab.

Detailed description:
This was a multicenter, randomized, double-blind, placebo-controlled, parallel group study with two secukinumab dose regimens in patients with moderate to severe HS. The study consisted of: screening (up to 4 weeks) treatment period 1 (16 weeks, active drug or placebo) and treatment period 2 (up to 1 year all patients on active drug); there was an optional extension study (NCT04179175). Adult males and females with moderate to severe HS were included, with a diagnosis of HS greater than 1 year prior to baseline. Dosing was once every 2 weeks, or once every 4 weeks via pre-filled syringe; periodic home-dosing is included.

In Treatment Period 1, participants were randomized to secukinumab Q2W, secukinumab Q4W, placebo Q2W or placebo Q4W in 1:1:0.5:0.5 ratio. In Treatment Period 2, at the Week 16 visit participants initially randomized to placebo were switched to one of the two active dose regimens (secukinumab Q2W or Q4W), while subjects randomized to secukinumab during Treatment Period 1 continued on the same dose.

Arms: arm 1: Secukinumab 300mg every 2 weeks arm 2: Secukinumab 300mg every 4 weeks arm 3: Placebo group to secukinumab 300mg every 2 weeks arm 4: Placebo group to secukinumab 300mg every 4 weeks
Interventions: intervention 1: Secukinumab intervention 2: Placebo
Intervention descriptions: intervention 1: Secukinumab 300mg every 2 or every 4 weeks intervention 2: Placebo 300mg every 2 or every 4 weeks

Protocol documents:
SAP_002.pdf: 


Novartis
For business use only
Page 2
SAP CSR3 week 52 DBL
AIN457M2302
Document History – Changes compared to previous final version of SAP
Date
Time 
point
Reason for 
update
Outcome for update
Section and title 
impacted (Current)


Novartis
For business use only
Page 3
SAP CSR3 week 52 DBL
AIN457M2302
Table of contents
Table of contents .................................................................................................................3
List of abbreviations............................................................................................................5
1
Introduction .........................................................................................................................7
1.1
Study design.............................................................................................................7
1.2
Study objectives, endpoints and estimands ...........................................................10
1.2.1
Estimand................................................................................................14
2
Statistical methods.............................................................................................................14
2.1
Data analysis general information .........................................................................14
2.1.1
Study Day 1 and other study days.........................................................15
2.1.2
Screening, baseline and post-baseline definitions.................................15
2.1.3
Day of last dose of study treatment.......................................................16
2.2
Analysis sets ..........................................................................................................16
2.3
Analysis period and treatment groups ...................................................................16
2.3.1
Final Week 52 analysis .........................................................................16
2.4
Patient disposition, demographics and other baseline characteristics ...................17
2.5
Treatments (study treatment, rescue medication, concomitant therapies, 
compliance)............................................................................................................20
2.5.1
Study treatment / compliance................................................................20
2.5.2
Prior and concomitant therapies............................................................23
2.6
Safety analyses.......................................................................................................24
2.6.1
Adverse events (AEs)............................................................................24
2.6.2
Deaths....................................................................................................25
2.6.3
Laboratory data .....................................................................................25
2.6.4
Other safety data ...................................................................................27
2.7
Pharmacokinetic endpoints....................................................................................28
2.8
PD and PK/PD analyses.........................................................................................28
2.9
Immunogenicity.....................................................................................................28
2.10
Resource utilization ...............................................................................................28
2.11
Patient-reported outcomes .....................................................................................29
2.12
Biomarkers.............................................................................................................31
2.13
Other Exploratory analyses....................................................................................31
2.14
Week 52 and Week 16 databases...........................................................................34
3
Sample size calculation .....................................................................................................34
4
Change to protocol specified analyses ..............................................................................36
5
Appendix ...........................................................................................................................36
5.1
Imputation rules.....................................................................................................36


Novartis
For business use only
Page 4
SAP CSR3 week 52 DBL
AIN457M2302
5.1.1
Study drug.............................................................................................36
5.1.2
AE date imputation ...............................................................................36
5.1.3
Concomitant medication date imputation .............................................37
5.1.4
First diagnosis date and Symptom(s) onset date imputation.................38
5.1.5
Other imputations..................................................................................38
5.2
AEs coding/grading ...............................................................................................38
5.3
Laboratory parameters derivations ........................................................................38
5.4
Statistical models...................................................................................................39
5.4.1
Analysis of continuous data ..................................................................39
5.4.2
Analysis of binary (and categorical) data..............................................39
5.4.3
Exposure-adjusted incidence rate and 100(1 - α)% confidence 
interval...................................................................................................40
5.5
Patient reported outcomes......................................................................................41
5.5.1
Dermatology Life Quality Index (DLQI)..............................................41
5.5.2
Modified Hidradenitis Suppurativa Score.............................................42
5.6
Rule of exclusion criteria of analysis sets..............................................................43
6
References .........................................................................................................................43


Novartis
For business use only
Page 5
SAP CSR3 week 52 DBL
AIN457M2302
List of abbreviations
AE
Adverse event
ALP
Alkaline Phosphatase
ALT
Alanine aminotransferase
AN
Abscesses and inflammatory nodules
AST
Aspartate aminotransferase
ATC
Anatomical Therapeutic Classification
COVID-19
Coronavirus disease of 2019
CM
Concomitant Medication
CRF
Case Report Form
CSR
Clinical Study report
CTCAE
Common Terminology Criteria for Adverse Events
DLQI
Dermatology Life Quality Index
DMC
Data Monitoring Committee 
EOT
End of Treatment
EQ-5D
EuroQol-5 Dimension
FAS
Full Analysis Set
GGT
Gamma-Glutamyl Transferase
HLT
High Level Term
HS
Hidradenitis suppurativa
HS-PGA
Hidradenitis Suppurativa Physician's Global Assessment
ICE
Intercurrent event
MedDRA
Medical Dictionary for Drug Regulatory Affairs
MAR
Missing at random
MELRM
Mixed Effect Logistic Regression Model
mHSS
modified  Hidradenitis  Suppurativa  Score
MMRM
Mixed Model for Repeated Measures
NRS
Numerical Rating Scale
PD
Pharmacodynamic(s)
PFS
Pre-filled syringe
PGI-c
Patient Global Impression of change
PGI-s
Patient Global Impression of severity
PK
Pharmacokinetics
PRO
Patient-reported Outcomes
QoL
Quality of Life
Q2W
Once every two weeks
Q4W
Once every four weeks
RAP
Report and Analysis Process
RDO
Retrieved drop-out
RMP
Risk management plan
SAP
Statistical Analysis Plan
SCC
Skin squamous cell carcinoma
S.C.
Subcutaneous


Novartis
For business use only
Page 6
SAP CSR3 week 52 DBL
AIN457M2302
SAE
Serious adverse event
SOC
System Organ Class
TS
Trial statistician
TFL
Tables, Figures, Listings
WHO
World Health Organization










Novartis
For business use only
Page 11
SAP CSR3 week 52 DBL
AIN457M2302
Objective(s)
Endpoint(s)
NRS30 is defined as at least a 30% 
reduction and at least 2 units reduction 
from baseline in Patient's Global 
Assessment of Skin Pain - at worst.
Exploratory objective(s)
Endpoint(s) for exploratory objective(s)

To evaluate the safety and tolerability of 
secukinumab over 52 weeks of treatment.

Clinical safety and tolerability 
assessments:

physical exams,

vital signs,

laboratory assessments,

AE monitoring

To explore the long-term effect of secukinumab 
with respect to HiSCR, AN count, proportion of 
subjects with flares, HS related skin pain up to 
52 weeks of treatment.

Achievement of clinical response as 
defined by HiSCR, HiSCR25, HiSCR50, 
HiSCR75, HiSCR90, HiSCR100.

Absolute/percent and percentage change 
from baseline in AN count, AN (0/1), 
AN25, AN 50, AN75, AN90, AN100 
response.

Flares.

Achievement of pain relief as defined by 
NRS30.

To evaluate the effect of secukinumab with 
respect to the following efficacy assessments:

Modified Hidradenitis Suppurativa Score 
(mHSS);

HS-Physician's Global Assessment (HS-
PGA);

Dermatology Life Quality Index (DLQI);

Health Status Questionnaire (EQ-5D-3L);

Patient Global Impression of severity 
(PGI-s);

Patient Global Impression of change (PGI-
c);

Work Productivity Activity Impairment 
(WPAI);

HS Symptom Diary

Inflammatory markers with respect to CRP 
and ESR
compared to placebo after 16 weeks and in the 
two secukinumab dose regimens up to 52 
weeks of treatment.

Absolute and percent change from 
baseline in modified Hidradenitis 
Suppurativa Score (mHSS).

HS-PGA response. HS-PGA response is 
defined as the achievement of at least a 
2-point reduction in HS-PGA score 
compared to baseline.

DLQI response and absolute/percent 
DLQI total score change from baseline.
DLQI response is defined as a decrease 
greater than 5.0 points from baseline in 
DLQI total score.

EQ-5D-3L Categories on Category 
questions and summary statistics on EQ -
5D -3L score questions.

Patient Global Impression of severity and 
change (PGI-s and PGI-c) categories.

Absolute and percent change from 
baseline in Work Productivity and Activity 
Impairment - Specific Health Problem 
(WPAI-SHP).

HS Symptom Diary items score change 
from baseline.


Novartis
For business use only
Page 12
SAP CSR3 week 52 DBL
AIN457M2302
Objective(s)
Endpoint(s)

Absolute and percent change from 
baseline in CRP and ESR.

To evaluate the pharmacokinetics of 
secukinumab in HS subjects.

AIN457 levels in serum

To assess the development of immunogenicity 
against secukinumab.

anti-AIN457 antibodies levels in serum

To explore the potential association of 
biomarker levels with secukinumab efficacy 
and safety by visit up to Week 52 (EOT2).
●To explore the efficacy 
of secukinumab compared to placebo with respect 
to HiSCR response after 16 weeks of treatment, 
and the sustained efficacy over time in bio-
naive patients.
● To explore the efficacy of secukinumab 
compared to placebo with respect to HiSCR 
response after 16 weeks of treatment and the 
sustained efficacy over time in patients with body 
weight lower and higher than 90 kg (<90 kg and 
≥90 kg).

Biomarkers in serum
● Achievement of HiSCR at Week 16 and up 
to Week 52 in bio-naive patients.
● Achievement of HiSCR at Week 16 and up 
to Week 52 in patients with body weight lower 
and higher than 90 kg (<90kg and ≥90kg).


Novartis
For business use only
Page 13
SAP CSR3 week 52 DBL
AIN457M2302


Novartis
For business use only
Page 14
SAP CSR3 week 52 DBL
AIN457M2302
1.2.1
Estimand
The estimand framework relating to the primary and secondary estimands are described in the 
Week 16 PEA SAP.
2
Statistical methods
2.1
Data analysis general information
Novartis will be performing the analysis. Statistical software SAS version 9.4 or later will be 
used.
Summary statistics for continuous variables will include N, mean, standard deviation, minimum, 
lower quartile, median, upper quartile, maximum. Summary statistics for discrete variables will 
be presented in contingency tables and will include absolute and relative frequencies. Unless 
otherwise stated, summary tables/figures/listings will be based on all subjects included in the 
population under consideration. 
Listings will be presented by treatment arms.
Footnotes will generally be provided for:

abbreviations used in the output; abbreviations used on several outputs, e.g. for listings in 
Appendix 16.2 can be presented on a separate page and do not have to be repeated as 
footnotes on each listing

sorting order of categories, e.g. for sorting within MedDRA (Medical Dictionary for 
Regulatory Activities) hierarchy levels

MedDRA version used for reporting of MedDRA coded data
Footnotes will generally NOT be given for

units displayed on the output


Novartis
For business use only
Page 15
SAP CSR3 week 52 DBL
AIN457M2302

interpretation of results (e.g., “odds ratio larger 1 favors active treatment”)

information that can be retrieved from the statistical section of the clinical study report 
(CSR) unless it is not identifiable from the output, e.g.

explanation of analysis model used unless results of more than one model are 
displayed in an output

derivations of variables (e.g. BMI will not be explained in a footnote)

information that will be provided in the clinical study protocol and/or methods section of 
the CSR (e.g. baseline definition if this is specified in the statistical section of the CSR)
2.1.1
Study Day 1 and other study days
Day 1 is the day of the first drug administration of the study treatment (or randomization day if 
there has been no drug administration).
All other study days will be labeled relative to Day 1. For event dates on or after Day 1, study 
day for an event date is calculated as Date of event – [Day 1] + 1, i.e., Day 2, Day 3, etc., will 
be one day, two days, etc., after Day 1, respectively. For event dates before Day 1, study day 
for an event date is calculated as Date of event – [Day 1], i.e., Day -1, Day -2, etc., will be one 
day, two days, etc., before Day 1, respectively. Duration of an event will be calculated as (Event 
end date – Event start date + 1).
The descriptor “Day 0” will not be used.
2.1.2
Screening, baseline and post-baseline definitions
Screening refers to any procedures (e.g., checking inclusion and exclusion criteria) performed 
prior to the first dose of study treatment. Per protocol, subject informed consent must be 
obtained prior to performing any study related activity. The date of signing informed consent is 
the start date of screening period. Any assessment obtained during the screening period will be 
labeled screening assessment. Assessments made on Day 1 may occur before or after the first 
dose.
Baseline definitions
For efficacy analyses, 

For HS Symptom Diary assessment and Patient’s Global assessment of Skin Pain, the 
average of the latest 7 assessments before the date of the first drug administration of the 
study treatment (or randomization date if there has been no drug administration) will be 
used as baseline. In case less than 4 diary entries prior to the first dose of the study 
treatment were available, baseline will be set to missing.

For all other efficacy assessments, baseline is the last assessment (including unscheduled 
visits) obtained (on or) before the day of the first drug administration of the study 
treatment (or randomization date if there has been no drug administration).
All assessments obtained after first dose (day) of study treatment are considered as post-baseline 
unless otherwise specified.


Novartis
For business use only
Page 16
SAP CSR3 week 52 DBL
AIN457M2302
For safety analyses, baseline is the last assessment (including unscheduled visits) obtained (on 
or) before the first dose (day) of study treatment. All assessments obtained after the first dose 
(day) of study treatment are considered as post-baseline unless otherwise specified.
Of note, baseline will be derived based on first dose day, exact dosing time is not considered.
2.1.3
Day of last dose of study treatment
The date of last dose will be collected via the CRF. 
The subject’s exposure will be calculated considering the last visit or the last dose + 84 days 
whichever occurs earlier.
2.2
Analysis sets
The following analysis sets will be used for the data analysis. 
The Randomized Analysis Set (RAN) consists of all randomized subjects. Subjects will be 
analyzed according to the treatment they are assigned to at randomization. Unless otherwise 
specified, misrandomized patients (mis-randomized in IRT) are excluded from the randomized 
set. 
Mis-randomized patients are patients who were screen-failures, but had been randomized by 
the investigator before eligibility was finally assessed, however had not been treated. 
Furthermore, all subjects with serious GCP violation at their site will be excluded from the 
randomized set.
The Full Analysis Set (FAS) consists of all subjects to whom study treatment has been assigned. 
Subjects will be analyzed according to the treatment assigned to at randomization. Mis-
randomized subjects (mis-randomized in IRT) and subjects with serious GCP violation at their 
site will be excluded from FAS. If the actual stratum is different to the assigned stratum in IRT, 
the actual stratum will be used in analyses.
The Safety Set (SAF) includes all subjects who received at least one dose of study treatment. 
Subjects will be analyzed according to the study treatment received. Treatment received is 
defined as the randomized/assigned treatment if the subject took at least one dose of that 
treatment or the first treatment received if the randomized/assigned treatment was never 
received (subject received the wrong treatment during the entire study). Mis-randomized 
subjects and subjects with serious GCP violation at their site will be excluded from the safety 
set.
2.3
Analysis period and treatment groups
2.3.1
Final Week 52 analysis
The efficacy and safety analyses will be conducted up to Week 52 or Week 60, when all subjects 
have completed the study.
The efficacy will be conducted using the following treatment groups: 


Novartis
For business use only
Page 17
SAP CSR3 week 52 DBL
AIN457M2302

AIN457 300mg Q2W (subjects randomized to secukinumab 300 mg every 2 weeks arm)

AIN457 300mg Q4W (subjects randomized to secukinumab 300 mg every 4 weeks arm)

PBO-AIN457 300mg Q2W (subjects randomized to placebo who switched to 
secukinumab 300 mg every 2 weeks arm at Week 16. Data is included after first intake of 
placebo.)

PBO-AIN457 300mg Q4W (subjects randomized to placebo who switched to 
secukinumab 300 mg every 4 weeks arm at Week 16. Data is included after first intake of 
placebo.)
The safety will be conducted using the following treatment groups:

AIN457 300mg Q2W (subjects randomized to secukinumab 300 mg every 2 weeks arm)

AIN457 300mg Q4W (subjects randomized to secukinumab 300 mg every 4 weeks arm)

Any AIN457 300mg Q2W (subjects randomized to secukinumab 300mg Q2W plus 
subjects randomized to placebo to secukinumab 300 mg every 2 weeks arm after their first 
intake of secukinumab)

Any AIN457 300mg Q4W (subjects randomized to secukinumab 300mg Q4W plus 
subjects randomized to placebo to secukinumab 300 mg every 4 weeks arm after their first 
intake of secukinumab)

Any AIN457 (this group combines the two groups “Any AIN457 300mg Q2W” and “Any 
AIN457 300mg Q4W”) 
The subjects randomized to placebo to secukinumab 300 mg every 2 weeks arm and placebo to 
secukinumab 300 mg every 4 weeks arm will be counted in placebo until the day before the 
first secukinumab dose. Subsequently, they will be counted in Any AIN457 300mg Q2W or 
Any AIN457 300mg Q4W, respectively. AEs that occur starting on the day of taking the first 
secukinumab dose will be counted in Any AIN457 300mg Q2W or Any AIN457 300mg Q4W; 
other assessments, (i.e. efficacy, lab assessments) collected on the day of taking the first 
secukinumab dose will be counted in the placebo group.
Safety tables related to exposure adjustment incident rate will also display the placebo 
treatement group.
2.4
Patient disposition, demographics and other baseline 
characteristics
Demographic and baseline characteristics will be summarized and listed based on the 
Randomized Analysis Set. The following background and demographic variables will be 
analyzed:


Novartis
For business use only
Page 18
SAP CSR3 week 52 DBL
AIN457M2302
Continuous variables:

Age 

Height

Weight

Body mass index (BMI)
Categorical variables:

Age categories (<20, [20, 30), [30, 50), ≥50)

Age categories (<30, [30, 40), [40, 65), ≥65)

Gender

Weight categories (<70 kg, [70 kg, 90 kg), ≥ 90kg)

Weight categories (<90 kg, ≥ 90kg)

Race

White

Black or African American

Asian

Native Hawaiian or Other Pacific Islander

American Indian or Alaska Native

Ethnicity

Hispanic or Latino

Not Hispanic or Latino

Not reported

Unknown

Smoking status at baseline

Region

Current antibiotic use (Yes/No) 
Hidradenitis suppurativa specific baseline characteristics and history of disease will be 
summarized: 
Continuous variables:

Baseline AN count

Baseline inflammatory nodule count

Baseline abscess count

Baseline draining fistula count

Baseline total fistulae count

Baseline NRS

Baseline Hidradentis Suppurativa Physician’s Global Assessment (HS-PGA)

Baseline modified  Hidradenitis  Suppurativa  Score (mHSS)

Baseline hsCRPBsl ESR


Novartis
For business use only
Page 19
SAP CSR3 week 52 DBL
AIN457M2302

Dermatology Life Quality Index (DLQI) total score

EuroQol-5 Dimension (EQ5D)

Time since diagnosis of HS

Time since HS symptom(s) onset
Categorical variables:

Baseline Hurley stage

Prior surgery for HS

Family history of HS

Previous exposure to systemic biologic therapy

Previous exposure to adalimumab

Previous exposure to systemic antibiotics

Previous exposure to non- biologic and non-antibiotic systemic therapy
Body Mass Index (BMI) will be calculated using the following formula:
BMI = (body weight in kilograms) / (height in meters)2
For BMI, height and body weight of the last value prior to first dose will be used as a baseline 
value. If there is no weight or height recorded prior to taking the study treatment, BMI will be 
missing. 
Time since diagnosis of hidradenitis suppurativa will be calculated using the following formula:
Time since diagnosis = (inform consent date – first diagnosis date + 1)/365.25
Time since disease duration (defined as onset of symptom) will be calculated using the 
following formula:
Time since onset = (inform consent date – Symptom(s) onset date + 1)/365.25
The first diagnosis date of hidradenitis suppurativa and hidradenitis suppurativa symptom(s) 
onset will be imputed according to the imputation rules in Section 5.1.4.
Unless otherwise specified, summary statistics will be presented for continuous variables for 
each treatment group in the randomized set. The number and percentage of subjects in each 
category will be presented for categorical variables for each treatment group in the randomized 
set.
Any condition entered on the Relevant medical history / current medical conditions CRF will 
be coded using the MedDRA dictionary. They will be summarized by System Organ Class 
(SOC) and Preferred Term (PT) of the MedDRA dictionary.
Patient disposition
The number and percentage of subjects in the Randomized Analysis Set who completed the 
entire treatment period and who discontinued the treatment prematurely (including the reason 
for discontinuation) will be presented for each treatment group. A listing will be also provided, 
and detail reason for discontinuation might be displayed if applicable.


Novartis
For business use only
Page 20
SAP CSR3 week 52 DBL
AIN457M2302
For each protocol deviation, the number and percentage of subjects for whom the deviation 
applies will be tabulated. All protocol deviations will be presented by PD category as well as 
by PD sub category (PD short description).
2.5
Treatments (study treatment, rescue medication, concomitant 
therapies, compliance)
2.5.1
Study treatment / compliance
The analysis of study treatment data will be based on the Safety Set.
The number of secukinumab and placebo doses will be summarized by treatment group by 
means of contingency tables.
The duration of exposure to study treatment will be summarized by treatment group. In addition, 
the number of subjects with exposure of at least certain period of time will be displayed using 
the following categories: “any exposure”, “≥ 1 week”, “≥ 2 week”, “≥ 3 week” , “≥ 4 weeks”, 
“≥ 8 weeks”, “≥ 12 weeks”, “≥ 16 weeks”,  “≥ 24 weeks”,  “≥ 32 weeks”, “≥ 40 weeks” and “≥ 
52 weeks”.
Duration of exposure will be defined as the time from first dose of study medication to the last 
dose plus 84 days or last visit (including follow-up visits) whichever occurs earlier, i.e., for 
subjects who discontinued or have their last visit earlier than 84 days, the end of study treatment 
exposure will be the date of the last study visit in the follow-up period or in the corresponding 
treatment period.
Duration of exposure (days) = min (end date, last dose date +84) – first dose date +1
Duration of exposure (years) = duration of exposure (days) / 365.25
Duration of exposure (100 subject years) = duration of exposure (years) / 100
2.5.1.1
Visit windows
Visit windows will be used for the data that is summarized by visit. They are based on the study 
evaluation schedule and comprise a set of days around the nominal visit day. For any assessment, 
there are the protocol defined scheduled visits around which visit windows were created to 
cover the complete range of days within the study. For subjects randomized to Placebo to 
secukinumab 300 mg every 2 weeks arm and Placebo to secukinumab 300 mg every 4 
weeks arm, the day of taking the first secukinumab dose will also need to be taken into visit 
window consideration. Further information will be found in Study Programming Dataset 
Specifications (PDS). The visit windows are shown in Table 2-1. In these tables, the days are 
counted since the first dose of study treatment (study day 1). These visit windows apply to 
measurements taken at every visit. For assessments collected less often different visit windows 
will be applied as detailed below.
When visit windows are used, all visits will be re-aligned, i.e. they will be mapped into one of 
the visit windows. E.g., if the Week 4 visit of a subject is delayed and occurs on Day 60 instead 
of on Day 29, it will be re-aligned to visit window Week 8. In the case of major deviations from 
the visit schedule, or due to unscheduled visits, several assessments of a subject may fall in a 


Novartis
For business use only
Page 21
SAP CSR3 week 52 DBL
AIN457M2302
particular visit window (either scheduled or unscheduled). Statistical approaches to handle 
multiple assessments in a given visit window are specified below.
Table 2-1
Assessment windows for scheduled visits for analyses based on the 
entire study period
Analysis Visit
Week
Scheduled Day
Visit Window
Baseline
BSL
1
-28 days to Day 1*
Week 1
1
8
Day 2-11
Week 2
2
15
Day 12-18
Week 3
3
22
Day 19-25
Week 4
4
29
Day 26-43
Week 8
8
57
Day 44-71
Week 12
12
85
Day 72-99
Week 16
16
113
Day 100-120
Week 18
18
127
Day 121-134
Week 20
20
141
Day 135-155
Week 24
24
169
Day 156-183
Week 28
28
197
Day 184-211
Week 32
32
225
Day 212-239
Week 36
36
253
Day 240-267
Week 40
40
281
Day 268-295
Week 44
44
309
Day 296-323
Week 48
48
337
Day 324-351
Week 52
52
365
Day 352-379
Follow up
60
421
Starting from day 380
* Baseline measurement before the first drug administration.
For HiSCR, HiSCR components inflammatory nodules, abscesses, draining fistulae, Flare and 
other lesion related assessments, Screening 1 visit, Screening 2 visit and baseline visit will be 
adjusted per below table
Analysis Visit
Week
Scheduled Day
Visit Window
Screening 1
-4
-21
-28 days to -14 days
Screening 2
-2
-7
-13 days to -1 days
Baseline
BSL
1
Day 1


Novartis
For business use only
Page 22
SAP CSR3 week 52 DBL
AIN457M2302
For parameters which are not collected at every visit (e.g. weight, laboratory parameters, DLQI), 
visit windows defined in and Table 2-1 will be combined. The following rules are used to 
determine the visit window for an applicable visit post baseline: “Lower limit” = “upper limit 
of prior applicable visit” + 1. “Upper limit” = “target day of current visit” + integer part of 
(“target day of next applicable visit” – “target day of current visit”)/2. For example, if a 
parameter is measured at Baseline, Week 12 and Week 28 only, Week 12 visit window will 
extend from Day 2 to Day 141 (combining Week 1 to Week 20 visit windows), Week 28 will 
extend from Day 142 to Day 379 (combining Week 24 to Week 52). If more than one 
assessment falls into the interval, the rules defined below are applied.
The analysis visit will be used for listing of visit and period for both safety and efficacy data. If 
a visit falls after the last visit window (after Day 379) it is not assigned to an analysis visit and 
will be listed under label “After Week 52”.
In case patients make use of the additional unscheduled visits for assessments other than the 
PGA of skin pain (NRS) before the Week 52 assessment (which were introduced due to the 
pandemic; see Section 1.1), the visit window for Week 52 and the follow-up period does not 
apply to these patients. The actual Week 52 visit will be taken for these patients as long as the 
time difference between this assessment and the last dosing is at most 4 weeks. The actual 
follow-up visit will be taken for these patients as long as the time difference between this 
assessment and the last dosing is at most 12 weeks.
For analysis of HS Symptom Diary assessment, Patient’s Global assessment of skin Pain, the 
weekly average HS Symptom component score and NRS from Baseline to Week 52 is 
calculated based on the 7 available daily scores: Baseline (Week 0) will be average of HS 
symptom Diary score from day -7 to day -1, Week 1 will be average of score from day 1 to day 
7, Week 2 will be average of score from day 8 to day 14 and so on. For any week with less than 
4 diary entries within the week, the weekly average component score will be recorded as 
missing.
2.5.1.2
Multiple assessments within visit windows
When there are multiple assessments in a particular visit window, the following rules are 
applied to select one value “representing” the subject in summary statistics in a visit window 
(see Table 2-2).
For baseline assessment definition see Section 2.1.2. For post-baseline visit windows the 
following applies (unless otherwise specified):

for quantitative variables, the closest to the scheduled day is chosen (if two assessments 
have the same distance, then the earlier one will be chosen); 

for qualitative variables, the worst record is selected. It is noted that in the analyses 
performed, worst case is always well defined (e.g., for urine protein values “+” and “++”, 
the worst case is defined as “++”),

in case qualitative variables are based on quantitative variables, e.g. DLQI response, the 
visit will be assigned to the quantitative variable, and this visit will be used for the derived 
qualitative variable. 


Novartis
For business use only
Page 23
SAP CSR3 week 52 DBL
AIN457M2302
Table 2-2
Rules for selecting values for analysis within a given visit window
Timing of 
measurement
Type of data
Rule
Baseline
All data
See Section 2.1.2
Post-baseline 
efficacy
All data except for PRO
e.g., HiSCR, HS-PGA
The measurement closest to the scheduled day will be 
used. In the event two measurements are taken equally 
apart (e.g., 1 day before target date and 1 day after), 
the earlier one will be used.
Post-baseline 
efficacy
PRO data
The measurement closest to the scheduled day will be 
used. In the event two measurements are taken equally 
apart (e.g., 1 day before target date and 1 day after), 
the earlier one will be used. For e-diary data, a cut-off at  
3:00 PM is used to define the start of a new day. 
Anything entered before that time (no later than 2:59 
PM) refers to the day before. If more than one 
measurement is taken on the same day (before the cut-
off), the latest one will be used.
Post-baseline 
safety
Summary visit 
information (e.g. 
laboratory values, vital 
signs, etc.)
The (non-missing) measurement closest to the 
scheduled day will be used. In the event two 
measurements are taken equally apart (e.g., 1 day 
before target date and 1 day after), the earlier one will 
be used.
Post-baseline 
safety 
Notable abnormalities 
(e.g. vitals signs) and 
CTCAE grades for 
laboratory values
The most extreme measurement in the window will be 
used. Note this means a subject can have a notably 
high and notably low measurement within an analysis 
period.
2.5.2
Prior and concomitant therapies
Medications will be identified using Novartis Drug and Therapy Dictionary (NovDTD) 
including Anatomical Therapeutic Chemical (ATC) code. Prior and concomitant treatments will 
be summarized by treatment group for the safety set unless otherwise specified. Concomitant 
treatments will be displayed for the Treatment Period. Also, prior and concomitant treatments 
will be listed.
Prior medications are defined as drugs taken and stopped prior to the first dose of study 
treatment. Any medication given at least once between the day of first dose of study treatment,
and within 84 days after last dose will be a concomitant medication, including those which were 
started before first dose of study treatment and continued into the Treatment Period. 
Prior or concomitant medication will be identified based on recorded or imputed start and end 
dates of medication taken. Medications collected in ‘Prior HS Medications’ CRF page are 
considered as prior medications. Therapies collected on ‘Prior HS non-drug therapy’ CRF page 
are considered as prior therapies. Further rules will be given in Section 5.1.3.
Prior and concomitant medications will be summarized by treatment group in separate tables. 
Medications will be presented in alphabetical order, by category and preferred term. Tables will 


Novartis
For business use only
Page 24
SAP CSR3 week 52 DBL
AIN457M2302
also show the overall number and percentage of subjects receiving at least one drug of a 
particular category and at least one drug in a particular preferred term. 
In addition, medical procedures and significant non-drug therapies as coded in MedDRA will 
be summarized.
Pain medication for HS (ibuprofen, tramadol and paracetamol) will be summarized by treatment 
group in separate tables. Medications will be presented in alphabetical order, by category and 
preferred term. Tables will also show the overall number and percentage of subjects receiving 
at least one drug of a particular category and at least one drug in a particular preferred term.
2.6
Safety analyses
All safety analyses will be based on the safety set. 
Analysis of adverse events will be based on treatment emergent events, which are defined as 
events started on or after the first dose of study treatment or events present prior to the first dose 
of study treatment  but increased in severity based on preferred term and on or before last dose 
+ 84 days.
Other safety variables will be evaluated based on on-treatment events, which are defined as any 
events that happened after first dose of study treatment and on or before last dose + 84 days.
Safety analysis will be performed on actual treatment and the entire study period.
2.6.1
Adverse events (AEs)
For adverse events and other binary safety variables crude and exposure time adjusted incidence 
rates will be derived as described below and summarized in Table 2-3.
All adverse events, serious adverse events will be listed with “treatment emergent” flag 
displayed.
Table 2-3
Overview of analyses on some safety endpoints
Analysis 
period
AEs & 
Risk management 
plans (RMP)
SAEs
AEs by 
severity
study treatment related 
AEs, death & other 
significant AEs
notables 
(lab/vitals)
Entire 
study 
period
• crude incidence
• exp.time 
adjusted 
incidence
• crude 
incidence
• exp.time 
adjusted 
incidence
• crude 
incidence
• crude incidence
• crude 
incidence
The crude incidence of treatment emergent adverse events will be summarized by primary 
System Organ Class (SOC) and Preferred Term (PT). Confidence intervals for the crude rate 
will be derived using the score method including continuity correction (Newcombe 1998) as 
described in Section 5.4.2.1.
Adverse events will be summarized by presenting, for each treatment group, the number and 
percentage of subjects having at least one AE, having an AE in each primary system organ class 
and having each individual AE (preferred term). Summaries will also be presented for AEs by 
severity. If a particular AE “severity” is missing, this variable will be listed as missing and 


Novartis
For business use only
Page 25
SAP CSR3 week 52 DBL
AIN457M2302
treated as missing in summaries. If a subject reported more than one adverse event with the 
same preferred term, the adverse event with the greatest severity will be presented. If a subject 
reported more than one adverse event within the same primary system organ class, the subject 
will be counted only once with the greatest severity at the system organ class level, where 
applicable. AEs by severity will be provided by SOC and AEs by severity and PTs may be 
provided if required at ad-hoc basis.
The most common adverse events reported (≥% in any treatment group by SOC and PT) will 
be presented in descending frequency according to its incidence in Any AIN457 group starting 
from the most common event. The threshold value  is set to 2 % but it may be updated 
following review of the dry run outputs.
Separate summaries will be provided for deaths, serious adverse events, other significant 
adverse events leading to discontinuation.
For the legal requirements of ClinicalTrials.gov and EudraCT, two required tables on treatment 
adverse events which are not serious adverse events with an incidence greater than 2% and on 
treatment serious adverse events and SAE suspected to be related to study treatment will be 
provided by system organ class and preferred term on the safety set population.
If for a same subject, several consecutive AEs (irrespective of study treatment causality, 
seriousness and severity) occurred with the same SOC and PT:

a single occurrence will be counted if there is ≤ 1 day gap between the end date of the 
preceding AE and the start date of the consecutive AE

more than one occurrence will be counted if there is > 1 day gap between the end date of 
the preceding AE and the start date of the consecutive AE
For occurrence, the presence of at least one SAE / SAE suspected to be related to study 
treatment / non SAE has to be checked in a block e.g., among AEs in a ≤ 1 day gap block, if at 
least one SAE is occurring, then one occurrence is calculated for that SAE.
The number of deaths resulting from SAEs suspected to be related to study treatment and SAEs 
irrespective of study treatment relationship will be provided by SOC and PT.
Algorithms for AE date imputations will be provided in Section 5.1.2.
2.6.2
Deaths
Separate summary and listing will be provided for deaths.
2.6.3
Laboratory data
The summary of laboratory evaluations will be presented for two groups of laboratory tests 
(hematology and serum chemistry). 
Descriptive summary statistics for the change from baseline for the entire study period will be 
presented by laboratory test and treatment group. Change from baseline will only be 
summarized for subjects with both baseline and post baseline values and will be calculated as:
change from baseline = post baseline value – baseline value


Novartis
For business use only
Page 26
SAP CSR3 week 52 DBL
AIN457M2302
All laboratory data will be listed with “on-treatment” flag displayed. In addition, Box and 
Whisker plots of hematology and serum chemistry will be provided for absolute values over 
time for Treatment period 1 and Entire study period.
For each parameter, the maximum change (maximum decrease and maximum increase) from 
baseline within Treatment Period will be summarized analogously. 
In addition, shift tables will be provided for all parameters to compare a subject’s baseline 
laboratory evaluation relative to the most extreme laboratory test value within a Treatment 
Period. For the shift tables, the normal laboratory ranges will be used to evaluate whether a 
particular laboratory test value is normal, low, or high (including category “high and low”). 
These summaries will be presented by laboratory test and treatment group. Subjects with 
abnormal laboratory values will be listed and values outside the normal ranges will be flagged.
The following laboratory parameters will be analyzed with respect to numerical Common 
Terminology Criteria for Adverse Events (CTCAE) grades, given in Table 2-4: hemoglobin, 
platelets, white blood cell count, neutrophils, lymphocytes, creatinine, total bilirubin (TBL), 
gamma-glutamyl 
transferase 
(GGT), 
alanine 
aminotransferase 
(ALT), 
aspartate 
aminotransferase (AST), alkaline phosphatase (ALP). CTCAE version 4.03 is implemented to 
be consistent with previous analyses.
The number and percentage of subjects with CTCAE grade newly occurring or worsening after 
baseline will be presented. These summaries will be split into hematology and chemistry.
Table 2-4
CTCAE grades for laboratory parameters to be analyzed
CTCAE v4.03 Term
Grade 1 
Grade 2 
Grade 3 
Grade 4 
HGB decreased 
(Anemia)
<LLN – 100 g/L
<100 – 80 g/L
<80 g/L
Life-threatening
consequences;
urgent
intervention
Platelet count
Decreased
<LLN – 75.0 x10e9 /L
<75.0 - 50.0 x10e9 /L
<50.0 – 25.0 x10e9 /L
<25.0 x 10e9 /L
White blood cell 
decreased
<LLN - 3.0 x 10e9 /L
<3.0 - 2.0 x 10e9 /L
<2.0 - 1.0 x 10e9 /L
<1.0 x 10e9 /L
Neutrophil count 
decreased
<LLN - 1.5 x 10e9 /L
<1.5 - 1.0 x 10e9 /L
<1.0 - 0.5 x 10e9 /L
<0.5 x 10e9 /L
Lymphocyte count 
decreased
<LLN - 0.8 x 10e9/L
<0.8 - 0.5 x 10e9 /L
<0.5 - 0.2 x 10e9 /L
<0.2 x 10e9 /L
Creatinine increased
>ULN - 1.5 x ULN
>1.5 - 3.0 x ULN
>3.0 - 6.0 x ULN
>6.0 x ULN
TBL increased
>ULN - 1.5 x ULN
>1.5 - 3.0 x ULN
>3.0 - 10.0 x ULN
>10.0 x ULN
GGT increased
>ULN - 2.5 x ULN
>2.5 - 5.0 x ULN
>5.0 - 20.0 x ULN
>20.0 x ULN
ALT increased
>ULN - 3.0 x ULN
>3.0 - 5.0 x ULN
>5.0 - 20.0 x ULN
>20.0 x ULN
AST increased
>ULN - 3.0 x ULN
>3.0 - 5.0 x ULN
>5.0 - 20.0 x ULN
>20.0 x ULN
ALP increased
>ULN - 2.5 x ULN
>2.5 - 5.0 x ULN
>5.0 - 20.0 x ULN
>20.0 x ULN
Shift tables will be presented comparing baseline laboratory result (CTCAE grade) with the 
worst results (expressed in CTCAE grade) during the treatment period analyzed. 


Novartis
For business use only
Page 27
SAP CSR3 week 52 DBL
AIN457M2302
The number and percentage of subjects with newly occurring liver enzyme abnormalities will 
also be summarized based on the event criteria given in Table 2-5.
Table 2-5
Liver-related events
Parameter
Criterion
ALT
>3xULN; >5xULN; >8xULN;>10xULN, >20xULN
AST
>3xULN; >5xULN; >8xULN; >10xULN; >20xULN
ALT or AST
>3xULN; >5xULN; >8xULN; >10xULN; >20XULN
TBL
>1xULN;>1.5xULN; >2xULN; >3xULN,
ALP
>1.5xULN;>2xULN; >3xULN; >5XULN
ALT or AST & 
TBL
ALT or AST>3xULN & TBL >1.5xULN;
ALT or AST>3xULN & TBL >2xULN;
ALT or AST >5xULN & TBL >2xULN;
ALT or AST >8xULN & TBL >2xULN;
ALT or AST >10xULN & TBL >2xULN;
ALT or AST >20xULN & TBL >2xULN;
ALP & TBL
ALP >3xULN & TBL >2XULN
ALP >5xULN & TBL >2xULN
ALT or AST & 
TBL & ALP
ALT or AST>3xULN & TBL >2xULN & ALP <2xULN  (Potential Hy’s Law)
Note: elevated ALP may suggest obstruction as a consequence of gall bladder or 
bile duct disease; ALP may also be increased in malignancy. FDA therefore terms 
Hy’s Law cases as indicators of pure hepatocellular injury. This does not mean 
that cases of ALT or AST >3xULN & TBL >2xULN & ALP >2xULN may not result 
in severe DILI.
ALT or AST>3xULN & TBL >2xULN & ALP <2xULN  (Potential Hy’s Law) or 
reported Hy’s Law case
Note: “Hy’s Law case” is a lower level term in MedDRA (10070546) and may be 
reported as AE.
For a combined criterion to be fulfilled, all conditions have to be fulfilled on the same visit. The 
criteria are not mutually exclusive, e.g., a subject with ALT = 6.42x ULN is counted for ALT  > 
3x ULN and ALT > 5x ULN.
For urinalysis, all parameters collected will be listed.
2.6.4
Other safety data
2.6.4.1
Vital signs
Analysis in vital sign measurement using descriptive summary statistics for the change from 
baseline for visits up to Week 52 will be performed by vital sign parameters and treatment group. 
Change from baseline will only be summarized for subjects with both baseline and post-baseline 
values and will be calculated as:
change from baseline = post-baseline value – baseline value


Novartis
For business use only
Page 28
SAP CSR3 week 52 DBL
AIN457M2302
All vital signs will be listed with “on-treatment” flag displayed. In addition, Box and Whisker 
plots of hematology and serum chemistry will be provided for absolute values over time for 
Treatment period 1 and Entire study period.
The number and percentage of subjects with newly occurring notable vital signs will be 
presented. Criteria for notable vital sign abnormalities are provided in Table 2-6 below. 
Table 2-6
Criteria for notable vital sign abnormalities
Vital sign (unit)
Notable abnormalities
Systolic blood pressure (mmHg)
>= 140 mmHg or < 90 mmHg
Diastolic blood pressure (mmHg)
>=90 mmHg or <60 mmHg
Pulse (bpm)
> 100 bpm or <60 bpm
2.7
Pharmacokinetic endpoints  
All subjects with quantifiable pharmacokinetic (PK) measurements of secukinumab will be 
included in the pharmacokinetic data analysis. 
Serum concentrations will be expressed in mass per volume units. All concentrations below the 
limit of quantification as well as missing data will be labeled as such in the concentration data 
listings. 
PK concentrations will be summarized by analysis visit and treatment group. In addition to 
mean, standard deviation (SD), coefficient of variation (CV), median and quartiles, the 
geometric mean and geometric coefficient of variation (CV) and n(log) will be presented. The 
formula for deriving the geometric mean and CV (%) is as following: 

CV (%) = (SD/mean)*100,

geometric mean = exp( (sum of log transformed data) / number of non-missing data points 
after log transformation),

geometric CV = sqrt( exp( variance of log-transformed data)-1)*100.

n(log) = number of non-missing data points after log transformation
In addition, sample number, concentration, sample date, sample time at pre-dose and minutes 
pre-dose will be listed by treatment sequence.
Values below lower limit of quantification/below detection limit will be imputed by 0.
2.8
PD and PK/PD analyses
This analysis will be reported separately. 
2.9
Immunogenicity
All immunogenicity results will be listed by treatment group, subject and visit/time.
2.10
Resource utilization
Data relating to resource utilization will be used for the purpose of economic evaluation and 
will be carried out and reported as a separate activity.


Novartis
For business use only
Page 29
SAP CSR3 week 52 DBL
AIN457M2302
2.11
Patient-reported outcomes
These analyses will use the FAS.
Dermatology Life Quality Index (DLQI)
The Dermatology Life Quality Index (DLQI) is a 10-item dermatology-specific HRQoL 
measure presented to each subject from the randomization to the study end. The instrument 
contains six subscales (i.e. symptoms and feeling, daily activities, leisure, work and school, 
personal relationships, treatment). For the DLQI, each of the 10 items is answered with the 
following response: “not at all,” “a little,” “a lot,” or “very much”. “not relevant” is also a valid 
response. Seven scores will be derived from the DLQI: the total score of each of the six 
subscales as well as the total score over all items. The higher the score, the more quality of life 
is impaired. The DLQI total score will be calculated by summing the score of each item 
resulting in a maximum of 30 and a minimum of 0. For details of DLQI scoring and 
interpretation please refer to Section 5.5.1.
Handling of missing values:

Step 1: if there is only one item with missing score at a visit, it will be imputed as 0 and 
the subscale including this item and also the total score will be calculated accordingly.

Step 2: If there are two or more items with missing scores at a visit, the scores for these 
two items will be missing, so is the subscale including this item and also the total score.
Summary statistics will be provided for absolute and percentage change from baseline of each 
of the six subscales as well as the total score by visit up to Week 52.
The DLQI scores as well as DLQI responders will be plotted over time. The median will be 
displayed for the DLQI score per visit and group. For DLQI responders, the rate will be 
calculated per visit and group and displayed as bar charts.
Work Productivity and Activity Impairment Questionnaire: Specific Health 
Problem (WPAI-SHP)
The WPAI-SHP has four subscales, which include Absenteeism, Presenteeism, Work 
Productivity Loss, and Activity Impairment.
The scores for these subscales are expressed as impairment percentages.
Questions:
1 = currently employed
2 = hours missed due to specified problem
3 = hours missed other reasons
4 = hours actually worked
5 = degree problem affected productivity while working
6 = degree problem affected regular activities
Scores: (Each of the below scores is multiplied by 100 to be expressed in percentages.)

Absenteeism is the percent work time missed due to problem: Q2/(Q2+Q4)

Presenteeism is the percent impairment while working due to problem: Q5/10




Novartis
For business use only
Page 31
SAP CSR3 week 52 DBL
AIN457M2302
2.12
Biomarkers
All biomarker data will be listed by treatment group, subject and visit. Summary statistics will 
be provided by treatment and visit. 
2.13
Other Exploratory analyses
Table 2-7 lists the primary, secondary and exploratory variables for this study. Unless otherwise 
specified in related sections, observed data will be used up to Week 52.
Table 2-7
Exploratory variables
Variable
Type
Model
Missing data 
handling
HiSCR over time 
exploratory
MELRM
descriptive
use observed data only
Flare over time 
exploratory
MELRM
Kaplan Meier
descriptive
use observed data only
AN count over time 
exploratory
MMRM
descriptive
use observed data only
AN50 over time 
exploratory
MELRM
descriptive
use observed data only
NRS30 over time 
exploratory
MELRM
descriptive
use observed data only
HiSCR25, HiSCR75, HiSCR90, 
HiSCR100 over time
exploratory
descriptive
use observed data only
AN25, AN50, AN75, AN90, AN100 AN 
0/1, AN0/1/2 over time
exploratory
descriptive
use observed data only
No increase in draining fistulae over time
exploratory
descriptive
use observed data only
No increase in abcesses over time
exploratory
descriptive
use observed data only
Inflammatory nodules, abcesses, 
draining fistulale change from baseline 
over time
exploratory
descriptive
use observed data only
DLQI total score and component score 
over time
exploratory
descriptive
use observed data only
WPAI-HS over time
exploratory
descriptive
use observed data only
HS-dairy over time
exploratory
descriptive
use observed data only
PGI-s and PGI-c over time
exploratory
descriptive
use observed data only
EQ-5D
exploratory
descriptive
use observed data only
Following analyses will use the FAS.
Hidradenitis Suppurativa Clinical Response (HiSCR) components and 
alternative definitions
The number and percentage of HiSCR subjects will be presented by visit up to Week 52 for 
each treatment group, where HiSCR is defined as at least a 50% decrease in Abscess and 
Inflammatory Nodule (AN) count with no increase in the number of abscesses and/or in the 


Novartis
For business use only
Page 32
SAP CSR3 week 52 DBL
AIN457M2302
number of draining fistulae compared to baseline. Observed values will be presented for data 
up to Week 52.
Figures will be provided displaying estimates for responder rates by treatment groups including 
confidence intervals. The below lesion information will be presented by visit up to Week /52 
for each treatment group. The number and percentage will be presented for subjects who 
achieved at least 25%, 50%, 75%, 90% and 100% reductions in the AN count relative to 
Baseline (AN25, AN50, AN75, AN90, AN100). Furthermore, the number and percentage will 
be presented for subjects who showed an AN count of either 0 or 1 (AN0/1) and for subjects 
who showed an AN count of either 0 or 1 or 2 (AN0/1/2).

The number and percentage will be presented for subjects with no increase in the number 
of abscesses. Furthermore, the number and percentage of subjects with no increase in 
draining fistulae will be presented.

Analogously, the number and percentage will be presented for subjects who achieved a 
slight modification of the HiSCR response: at least 25%, 75%, 90% and 100% reductions 
in the AN count with no increase in the number of abscesses and/or in the number of 
draining fistulae relative to baseline (HiSCR25, HiSCR75, HiSCR90, HiSCR100).

Summary statistics will be presented for absolute and percent change from baseline for    
number of inflammatory nodules/abscesses/AN counts/draining fistulae. The following 
visualizations will be provided: The number of inflammatory nodules/abscesses/AN 
counts/draining fistulae will be plotted over time. For this, the mean will be provided per 
visit and group. Furthermore, the relative change from baseline in AN counts to Week 52 
will be displayed per group using violin plots. Similarly, the absolute change from 
baseline in number of abscesses and draining fistulae to Week 52 will be displayed per 
group using violin plots.

A mixed effects logistic regression model (MELRM) will be fitted. The endpoint is 
HiSCR at all time points from Week 2 up to Week 52 and are included on the left hand 
side of the model as dependent variables. The covariates included as fixed effects are: 
treatment group, visit, baseline AN count and the interaction between visit and treatment 
group. An unstructured covariance structure will be applied. In case of non-convergence, 
alternative covariance structures will be considered. If additional convergence issues are 
encountered, then modifications to the model will be considered.
Percentage change from baseline in AN count
The mean change from baseline in AN count up to Week 52 will be presented for each treatment 
group. Observed values will be presented.
A mixed model for repeated measures (MMRM) will be fitted. The endpoint is percentage 
change from baseline in AN count and all time points from Week 2 up to Week 52 are included 
on the left hand side of the model as dependent variables. The covariates included as fixed 
effects are: treatment group, visit, baseline AN count and the interaction between visit and 
treatment group. An unstructured covariance structure will be applied. In case of non-
convergence, alternative covariance structures will be considered. If additional convergence 
issues are encountered, then modifications to the model will be considered.


Novartis
For business use only
Page 33
SAP CSR3 week 52 DBL
AIN457M2302
Achievement of AN50
The number and percentage of AN50 up to Week 52 will be presented for each treatment group. 
Observed values will be presented.
Figures will be provided displaying estimates for AN50 rates by treatment groups including 
confidence intervals. 
A similar MELRM analysis as described for HiSCR will be performed for this endpoint. The 
endpoint is the achievement of AN50 and all time points from Week 2 up to Week 52 are 
included on the left hand side of the model as dependent variables. The covariates included as 
fixed effects are: treatment group, visit, baseline AN count and the interaction between visit and 
treatment group. An unstructured covariance structure will be applied. In case of non-
convergence, alternative covariance structures will be considered. If additional convergence 
issues are encountered, then modifications to the model will be considered.
Flare 
The number and percentage of Flare up to Week 52 will be presented for each treatment group. 
Observed values will be presented.
Figures will be provided displaying estimates for flaring rates by treatment groups including 
confidence intervals.
A Kaplan-Meier (KM) analysis for the cumulative incidence of the Flare-free period up to Week 
52 will be presented for each treatment group. Observed values will be presented. Patients 
without Flare will be censored at the last known visit. Corresponding KM figures will also be 
provided.
A similar MELRM analysis as described for HiSCR will be performed for this endpoint.
rom Week 2 up to Week 52 are included on the left hand side of the model as dependent 
variables. The covariates included as fixed effects are: treatment group, visit, baseline AN count 
and the interaction between visit and treatment group. An unstructured covariance structure will 
be applied. In case of non-convergence, alternative covariance structures will be considered. If 
additional convergence issues are encountered, then modifications to the model will be 
considered.
Skin Pain/NRS30
The number and percentage of NRS30 responder subjects will be presented by visit up to Week 
52 for each treatment group observed values will be presented.
Figures will be provided displaying estimates for responder rates by treatment groups including 
confidence intervals.
A similar MELRM analysis as described for HiSCR will be performed for this endpoint.
The endpoint is the achievement of NRS30 and all time points for time windows from Week 2 
up to Week 52 are included on the left hand side of the model as dependent variables. The 
covariates included as fixed effects are: treatment group, visit, baseline NRS score and the 
interaction between visit and treatment group. An unstructured covariance structure will be 
applied. In case of non-convergence, alternative covariance structures will be considered. If 


Novartis
For business use only
Page 34
SAP CSR3 week 52 DBL
AIN457M2302
additional convergence issues are encountered, then modifications to the model will be 
considered.
Analyses will be performed at a study level and also pooling both studies.
Modified Hidradenitis Suppurativa Score
Summary statistics will be provided for absolute and percent change from baseline of modified 
Sartorius score by visit up to Week 52 for each treatment group.
HS-Physician's Global Assessment
The number and percentage of subjects who achieve HS-PGA response will be presented by 
visit up to Week 52 for each treatment group, where HS-PGA response is defined as the 
achievement of at least a 2-point reduction in HS-PGA score compared to baseline or the 
achievement of a “mild” status (defined as achieving an HS-PGA score of ≤ 2).
CRP and ESR
Summary statistics will be provided for absolute and percent change from baseline of CRP and 
ESR by visit up to Week 52 for each treatment group.
2.14
Week 52 and Week 16 databases
Any changes to the Week 16 PEA HiSCR responder status as a result of changes to baseline or 
Week 16 lesion counts will be listed and assessed for the impact on the PEA. Additionally, any 
changes to the AN50 responder status, NRS30 responder status, flare and percentage change 
from baseline in AN count will be listed.
Changes to the treatment termination reason will also be listed in a separate listing.
Further, any new SAEs with start date prior to the cut-off date of the Week 16 PEA iDBL will 
be listed. All SAEs related to the Week 16 analysis that have been recorded or modified after 
the cut-off date and the SAEs with changed preferred term with start date prior to the cut-off 
date will be included.  
3
Sample size calculation
Sample size requirements for this study are primarily driven by HiSCR at Week 16 endpoint. 
A 5% two-sided type-I-error rate will used to control for type-I-error. Two secukinumab doses 
will be tested versus placebo with respect to the primary endpoint (HiSCR at Week 16). The 
type-I-error will be split to 4% and 1% two-sided for secukinumab 300 mg Q2W vs. placebo 
and secukinumab 300 mg Q4W vs. placebo, respectively. Sample sizes will be based on this 
type-I-error assumption.
A total of 471 subjects was originally planned to be randomized to study drug in a 1:1:0.5:0.5 
ratio. A second study of identical design with the same sample size will be conducted in parallel. 
Both studies are independently powered to address the primary endpoint (HiSCR) and 
secondary endpoints of AN count and flare. The secondary endpoint of pain will be analyzed 
in the combined populations of both trials, provided the primary null-hypothesis can be rejected 
in both studies. All sample size calculations were done in nQuery Advisor 7.0.


Novartis
For business use only
Page 35
SAP CSR3 week 52 DBL
AIN457M2302
As discussed in Section 5 of the study protocol, to account for the disruptive impact of the 
COVID-19 pandemic on the conduct of the study since the release of protocol Amendment 01, 
the number of randomized subjects was increased to approximately 541 (15% increase from the 
original population of 471 subjects).
Primary endpoint
HiSCR: Based on adalimumab phase III placebo-controlled studies (PIONEER I and II, 
respectively, Kimball et al 2016), a placebo response rate of 30% is assumed. The total sample 
size of 471 subjects for this trial is sufficient to achieve 93% power for the demonstration of 
20% difference of secukinumab 300 mg Q2W over placebo based on the primary endpoint 
(HiSCR) when assuming a secukinumab response rate to be 50%. In regards to the comparison 
of secukinumab 300 mg Q4W to placebo, we achieve 83% power to show superiority. The 
sample size was further increased by 15% to 544 subjects to account for potential pandemic 
impact.
Secondary endpoints
The power mentioned for the Secondary endpoints is conditional on the successful rejection of 
the null hypothesis for the primary endpoint (HiSCR), and the testing procedures are defined in 
Section 2.8 in the week 16 PEA SAP.
Percentage change in AN count: based on adalimumab phase III placebo-controlled studies 
(PIONEER I and II, respectively, Kimball et al 2016), it is assumed that the difference between 
secukinumab and placebo is at least 18% in favor of secukinumab when considering the mean 
percentage change from baseline in AN count at Week 16. Although it is planned to use an 
ANCOVA model for the analysis, an approximate sample size can be based on a simple -test. 
A total sample size of 471 subjects is sufficient to achieve 92% power in secukinumab 300 mg 
Q2W vs. placebo and 81% power in secukinumab 300 mg Q4W vs. placebo when assuming a 
standard deviation of 46%. 
Flare: Based on adalimumab phase III placebo-controlled studies (PIONEER I and II, 
respectively, Kimball et al 2016), a placebo rate of 35% is assumed. A total sample size of 471 
subjects is sufficient to achieve 98% power for the demonstration of 20% difference of 
secukinumab 300 mg Q2W over placebo based on the second endpoint when assuming 
secukinumab 300 mg Q2W rate to be 15%. Assuming the same rate for secukinumab 300 mg 
Q4W, the sample size would be sufficient to achieve 92% power in a comparison of 
secukinumab 300 mg Q4W vs. placebo.
Pain: Based on adalimumab phase III placebo-controlled studies (PIONEER I and II, 
respectively, Kimball et al 2016), a placebo rate of 23% is assumed. Assuming 80% subjects 
are qualified to calculate Pain variable NRS30, a total sample size of 942 subjects across two 
studies is sufficient to achieve 85% power for the demonstration of 13% difference of 
secukinumab 300 mg Q2W over placebo based on the second endpoint when assuming the rate 
to be 36%. The sample size is also sufficient to achieve 70% power to demonstrate superiority 
of secukinumab 300 mg Q4W over placebo based on the same assumptions in regards to the 
rates of secukinumab and placebo as above.


Novartis
For business use only
Page 36
SAP CSR3 week 52 DBL
AIN457M2302
4
Change to protocol specified analyses
Response of HS-PGA is defined as the achievement of at least a 2-point reduction in HS-PGA 
score compared to baseline or the achievement of a “mild” status (defined as achieving an HS-
PGA score of ≤ 2). While in the Protocol it is defined as at least a 2-point reduction in HS-PGA 
score only.
5
Appendix
5.1
Imputation rules
5.1.1
Study drug
Any partial dates will be imputed as follows:
The earlier day will be taken from below

The last day in the month and 

The end day of the corresponding Treatment Period
5.1.2
AE date imputation
Impute AE end date:
1. If the AE end date ‘month’ is missing, the imputed end date should be set to the earliest of 
the (min (last visit date, last dose date + 84 days), 31DECYYYY, date of death). 
2. If the AE end date ‘day’ is missing, the imputed end date should be set to the earliest of 
the (min (last visit date, last dose date + 84 days), last day of the month, date of death). 
3. If AE ‘year’ is missing or AE is ongoing, the end date will not be imputed. 
Impute AE start date:
Before imputing AE start date, find the AE start reference date. 
1. If the (imputed) AE end date is complete and the (imputed) AE end date < treatment start 
date then AE start reference date = min(informed consent date, earliest visit date). 
2. Else AE start reference date = treatment start date 
1. If the AE start date ‘year’ value is missing, the date uncertainty is too high to impute a 
rational date. Therefore, if the AE year value is missing, the imputed AE start date is set to 
NULL. 
2. If the AE start date ‘year’ value is less than the treatment start date year value, the AE 
started before treatment. Therefore: 
If AE ‘month’ is missing, the imputed AE start date is set to the mid-year point 
(01JULYYYY). 
Else if AE ‘month’ is not missing, the imputed AE start date is set to the mid-month point 
(15MONYYYY). 
3. If the AE start date year value is greater than the treatment start date year value, the AE 
started after treatment. Therefore: 


Novartis
For business use only
Page 37
SAP CSR3 week 52 DBL
AIN457M2302
a. If the AE month is missing, the imputed AE start date is set to the year start point 
(01JANYYYY). 
b. Else if the AE month is not missing, the imputed AE start date is set to the later of 
(month start point (01MONYYYY), AE start reference date + 1 day). 
4. If the AE start date year value is equal to the treatment start date year value: 
a. And the AE month is missing the imputed AE start date is set to the AE reference 
start date + 1 day. 
b. Else if the AE month is less than the treatment start month, the imputed AE start date 
is set to the mid-month point (15MONYYYY). 
c. Else if the AE month is equal to the treatment start date month or greater than the 
treatment start date month, the imputed AE start date is set to the later of (month start 
point (01MONYYYY), AE start reference date + 1 day). 
If complete (imputed) AE end date is available and the imputed AE start date is greater than the 
(imputed) AE end date, then imputed AE start date should be set to the (imputed) AE end date.
5.1.3
Concomitant medication date imputation
Impute CM end date:
1. If CM end day is missing and CM month/year are non-missing then impute CM day as the 
minimum of treatment end date and the last day of the month. 
2. If CM end day/month are missing and CM year is non-missing then impute CM day as the 
minimum of treatment end date and the end of the year (31DECYYYY). 
3. If imputed CM end date is less than the CM start date, use the CM start date as the 
imputed CM end date. 
Impute CM start date:
1. If the CM start date year value is missing, the imputed CM start date is set to one day prior 
to treatment start date. 
2. If the CM start date year value is less than the treatment start date year value, the CM 
started before treatment. Therefore: 
a. If the CM month is missing, the imputed CM start date is set to the mid-year point 
(01JULYYYY). 
b. Else if the CM month is not missing, the imputed CM start date is set to the mid-
month point (15MONYYYY). 
3. If the CM start date year value is greater than the treatment start date year value, the CM 
started after treatment. Therefore: 
a. If the CM month is missing, the imputed CM start date is set to the year start point 
(01JANYYYY). 
b. Else if the CM month is not missing, the imputed CM start date is set to the month 
start point (01MONYYYY). 
4. If the CM start date year value is equal to the treatment start date year value: 
a. And the CM month is missing or the CM month is equal to the treatment start date 
month, then the imputed CM start date is set to one day prior treatment start date. 


Novartis
For business use only
Page 38
SAP CSR3 week 52 DBL
AIN457M2302
b. Else if the CM month is less than the treatment start date month, the imputed CM start 
date is set to the mid-month point (15MONYYYY). 
c. Else if the CM month is greater than the treatment start date month, the imputed CM 
start date is set to the month start point (01MONYYYY). 
If complete (imputed) CM end date is available and the imputed CM start date is greater than 
the (imputed) CM end date, then imputed CM start date should be set to the (imputed) CM end 
date. 
5.1.4
First diagnosis date and Symptom(s) onset date imputation
1. If the first diagnosis or Symptom onset day/ month are missing and the year is non-
missing:
a. If the year part of the date is equal to the year part of the inform consent date, then the 
imputed date is set to the year start point (01JANYYYY).
b. Otherwise the imputed date is set to the mid-year point (01JULYYYY).
2. If the first diagnosis or Symptom onset day is missing and the month/year are non-
missing:
a. If the month and year part of date is equal to the month and year part of the inform 
consent date, then the imputed date is set to the month start point (01MONYYYY).
b. Otherwise the imputed date is set to the mid-month point (15MONYYYY).
5.1.5
Other imputations
For laboratory test values below Lower Level of Quantification (LLQ) or above Upper Level 
of Quantification (ULQ) will be imputed as LLQ or ULQ value, respectively. The numerical 
part of the reported result will be treated as the actual LLQ or ULQ. These laboratory values 
will be displayed in listings using the standard unit with the reported sign (“<” or “>”).”
5.2
AEs coding/grading
Adverse events will be coded according to MedDRA dictionary. The MedDRA version used 
for reporting the adverse events will be described in a footnote.
5.3
Laboratory parameters derivations
The following criteria will be used to define expanded limits and notable abnormalities of key 
laboratory tests.
Liver Function and Related Variables
Alanine transaminase (ALT) (SGPT): > 3 x Upper Limit of Normal (ULN)
Aspartate transaminase (AST) (SGOT): > 3 x ULN
Total bilirubin: > 2 x ULN
Alkaline phosphatase: > 2.5 x ULN
Renal Function
Creatinine (serum): > 1.5 x ULN


Novartis
For business use only
Page 39
SAP CSR3 week 52 DBL
AIN457M2302
Hematology
Hemoglobin: ≥ 2 g/dl decrease from baseline
Platelet count: < Lower Limit of Normal (LLN)
White blood cell count: < 0.8 x LLN
Neutrophils: < 0.9 x LLN
Eosinophils: > 1.1 x ULN
Lymphocytes: > 1.1 x ULN
Urinalysis
Protein urine dipstick: ++*
* ++ is ≥ 100 mg/dl
5.4
Statistical models
5.4.1
Analysis of continuous data
Summary statistics (including N, mean, standard deviation, minimum, lower quartile, median, 
upper quartile, maximum) will be provided for continuous data by visit and treatment group. If 
applicable and not otherwise stated, means +/- SE will be plotted. If appropriate, summary 
statistics will also be derived for absolute and percentage changes from baseline.
5.4.1.1
Mixed Model for Repeated Measures (MMRM)
A mixed effects regression model will be fitted. The endpoint is continuous and its values at all 
time points from Week 2 up to Week 52 are included on the left hand side of the model as 
dependent variables. The covariates included as fixed effects are: treatment group, visit, 
baseline AN count and the interaction between visit and treatment group. An unstructured 
covariance structure will be applied. In case of non-convergence, alternative covariance 
structures will be considered. If additional convergence issues are encountered, then 
modifications to the model will be considered.
5.4.2
Analysis of binary (and categorical) data
5.4.2.1
Summary statistics for binary and categorical data
Summary statistics for discrete variables will be presented in contingency tables and will 
include absolute and relative frequencies. If applicable, confidence intervals will be derived as 
well based on the score method including continuity correction (Newcombe 1998):
With  as (1 −/2)-quantile of the standard normal distribution (SAS:  = PROBIT(1 −
/2),  as total number of subjects (i.e. number of subjects in the denominator), and  as 
estimated crude incidence (number of subjects with event / ) it is  = 1 −.
Then the lower limit is for  > 0 ( = 0 for  = 0):


Novartis
For business use only
Page 40
SAP CSR3 week 52 DBL
AIN457M2302
 = max
⎩
⎨
⎧
0,
2 + $ −1 −%$ −2 −1
 + 4( + 1)
2( + $)
⎭
⎬
⎫
,
and the upper limit is for  for  < 1 ( + = 1 for  = 1):
+ = min
⎩
⎨
⎧
1,
2 + $ + 1 + %$ + 2 −1
 + 4( −1)
2( + $)
⎭
⎬
⎫
.
Note: if  > 100 then  = 100 and if + < 100 then + = 100.
5.4.2.2
Mixed effects logistic regression model  (MELRM)
A mixed effects logistic regression model will be fitted. The endpoint is binary and all time
points from week 2 up to week 52 are included on the left hand side of the model as dependent 
variables. The covariates included as fixed effects are: treatment group, visit, baseline AN count
(or NRS for Skin Pain/NRS30) and the interaction between visit and treatment group. An 
unstructured covariance structure will be applied. In case of non-convergence, alternative 
covariance structures will be considered. If additional convergence issues are encountered, then 
modifications to the model will be considered.
5.4.3
Exposure-adjusted incidence rate and 100(1 - α)% confidence interval
It will be assumed that for each of n subjects in a clinical trial the time / (0 = 1, … , ) to the 
first occurrence of a certain treatment emergent event is observed, or if the event was not 
experienced, the (censored) time to the end of the observation period or last dose plus 84 days 
whichever occur earlier. The sequence of first occurrences of an event will be modeled to follow 
approximately a Poisson process with constant intensity 2. The rate parameter 2 will be 
estimated as 3 = 4/5, where 5 = ∑
/
7
/89
and 4 is the number of subjects with at least one 
event. Conditionally on 5, an exact 100(1 −)% confidence interval for a Poisson variable 
with parameter 25 and observed value 4 can be obtained based on (Garwood, 1936), from 
which an exact 100(1 −)% confidence interval for 3 = 4/5 will be derived as follows 
(Sahai, 1993; Ulm, 1990):
Lower confidence limit  =
:.;<=
>,>?
@
for 4 > 0, and = 0 otherwise;
Upper confidence limit + =
:.;<AB=
>,>?C>
@
.
where DE,F is the -th quantile of the Chi-square distribution with G degrees of freedom.


Novartis
For business use only
Page 41
SAP CSR3 week 52 DBL
AIN457M2302
The example below shows how this should be handled for cases where subjects switch 
treatment. In particular for summarizing ‘Any AIN’ as a group, one should take into 
consideration the sequence of treatments while calculating exposure time for subjects.
Table 5-1
Examples for calculating exposure time for incidence rates (IR)
1st 
treatment
1st exposure
2nd 
treatment
2nd 
exposure
Event days (in 
terms of study 
day)
Exposure for IR
Placebo
100 days
150 mg 
200 days
50 (1st trt)
110 (10 days 
into 2nd trt)
Placebo: 50 days 
(event)
150 mg: 10 days 
(event)
Any AIN: 10 days 
(event)
5.5
Patient reported outcomes  
5.5.1
Dermatology Life Quality Index (DLQI)
The DLQI is a 10-item general dermatology disability index designed to assess Health-related 
quality of life in adult subjects with skin diseases (e.g. Hidradenitis Suppurativa). The measure
is self-administered and includes six domains of symptoms and feelings, daily activities, leisure, 
work and school, personal relationships and treatment.
The scoring of each question is as follows:

Very much: Scored 3

A lot: Scored 2

A little: Scored 1

Not at all: Scored 0

Not relevant: Scored 0

Question unanswered: Scored 0

Question 7 “prevented work or studying”: Scored 3
The DLQI total score will be calculated by summing the score of each question resulting in a 
maximum of 30 and a minimum of 0. The higher the score, the more Quality of Life is impaired. 
Meaning of DLQI Scores:

0-1 = no effect at all on subject’s life

2-5 = small effect on subject’s life

6-10 = moderate effect on subject’s life

11-20 = very large effect on subject’s life

21-30 = extremely large effect on subject’s life
The DLQI will be analyzed under six headings as follows:

Symptoms and feelings: questions 1 and 2, score maximum 6

Daily activities: questions 3 and 4, score maximum 6


Novartis
For business use only
Page 42
SAP CSR3 week 52 DBL
AIN457M2302

Leisure: questions 5 and 6, score maximum 6

Work and school: question 7, score maximum 3

Personal relationships: questions 8 and 9: score maximum 6

Treatment: question 10, score maximum 3
Interpretation of incorrectly completed questionnaires:
There is a very high success rate of accurate completion of the DLQI. However, sometimes 
subjects do make mistakes.
1. If one question is left unanswered this is scored 0.
2. If two or more questions are left unanswered the questionnaire will not be scored.
3. If question 7 is answered “yes” this will be scored 3. If question 7 will be answered “no” 
or “not relevant” but then either “a lot” or “a little” is ticked this will then be scored 2 or 1, 
respectively.
4. If two or more response options are ticked, the response option with the highest score will 
be recorded.
5. If there is a response between two tick boxes, the lower of the two score options will be 
recorded.
6. If one item is missing from a two-item subscale that subscale will not be scored.
Of note, in situations where subjects responded to more questions than what was expected or 
required, the “most severe” answer was entered into the WriteResult (vendor for PRO data) 
database. In most cases the Self-Evident Corrections (SECs) were defined correctly, however, 
the SEC regarding question 7A/7B was not designed to select the “most severe” answer. This 
was confirmed with Novartis HEOR and communicated to the AIN team.
5.5.2
Modified Hidradenitis Suppurativa Score
Collect lesion counts in all affected anatomic regions:

Left axilla

Right axilla

Left groin

Right groin

Left gluteal

Right gluteal 

Other
For each anatomic region, calculate the regional Sartorius score as follows.
Regional Sartorius Score = Region
+ 1 * Total noduli (=AN counts)
+ 6 * Total draining fistulae
+ Distance
+ Separate,
Where


Novartis
For business use only
Page 43
SAP CSR3 week 52 DBL
AIN457M2302
Region =
3, if any lesion count in this anatomic region > 0
0, otherwise
Distance =
0, if no acitve lesions
1, if longest distance between two relevant lesions or size <5 cm
3, if longest distance between two relevant lesions or size 5-10 cm
9, if longest distance between two relevant lesions or size >10 cm
Separate = 
0, with separation by normal skin
9, without separation by normal skin
The total Modified Hidradenitis Suppurativa Score would be the sum of all affected regional 
Hidradenitis Suppurativa Scores.
In case subjects make mistakes leading to missing data in region, total noduli (AN count), total 
fistulae, distance, or separate, the regional Hidradenitis Suppurativa Score will be set to missing 
and the same will be done for the total Modified Hidradenitis Suppurativa Score except for the 
two cases below:

Total noduli is missing, region, total fistulae, distance, seperate is not missing, then noduli 
will be imputed as 0.

Total fistulae is missing, region, total noduli, distance, seperate is not missing, then 
fistulae will be imputed as 0.
5.6
Rule of exclusion criteria of analysis sets
Table 5-2 presents the rules of exclusion criteria of analysis sets.
Table 5-2
Subject Classification
Analysis Set
PD ID that
   
cause subjects to be excluded
Non-PD criteria that cause 
subjects to be excluded
RAN
INCL01*, M-OTH07
Not randomized/Mis-randomized
FAS
INCL01*, M-OTH07
Not in RAN;
SAF
INCL01*, M-OTH07
Not in RAN; No study drug taken
* Written informed consent must be obtained before any assessment is performed.
6
References
Bretz F, Maurer W, Xi D (2019) Replicability, reproducibility and multiplicity in drug 
development. CHANCE; 32(4):4-11.
Ratitch, B, Lipkovich, I, Shannon E et al (2018). Points to consider for analyzing efficacy 
outcomes in long‐term extension clinical trials. Pharm Stat; 17(6):685–700.
Carpenter JR, Roger JH, Kenward MG (2013) Analysis of longitudinal trials with protocol 
deviation: a framework for relevant, accessible assumptions, and inference via multiple 
imputation. J Biopharm Stat; 23(6):1352–71.


Novartis
For business use only
Page 44
SAP CSR3 week 52 DBL
AIN457M2302
Garwood, F (1936). Fiducial limits for the Poisson distribution. Biometrika, 46; 441–453.
Kimball AB, Okun MM, Williams DA, et al (2016) Two Phase 3 Trials of Adalimumab for 
Hidradenitis Suppurativa. N. Engl. J. Med; 375(5):422–34.
Little, RJA and Rubin DB (2002) Bayes and Multiple Imputation. In: Little RJA, Rubin DB. 
Statistical Analysis with Missing Data. 2nd ed; Hoboken: John Wiley & Sons, Inc. p. 200–20.
Newcombe RG (1998) Two-sided confidence intervals for the single proportion: comparison 
of seven methods. Stat Med; 17(8):857–72.
Rubin DB (1987) Multiple Imputation for Nonresponse in Surveys. New York: John Wiley & 
Sons, Inc.
Sahai H, Khurshid Anwer (1993). Confidence intervals for the mean of a poisson distribution: 
a review. Biom J, 35 (7); 857-867
Ulm K (1990). A simple method to calculate the confidence interval of a standard mortality 
ratio. American Journal of Epidemiology, 131(2); 373-375

Prot_000.pdf: 
Novartis Research and Development
AIN457
Clinical Trial Protocol CAIN457M2302
A randomized, double-blind, multicenter study assessing 
short (16 weeks) and long-term efficacy (up to 1 year), 
safety, and tolerability of 2 subcutaneous secukinumab 
dose regimens in adult patients with moderate to severe 
hidradenitis suppurativa (SUNRISE)
Document type:
Amended Protocol Version
EUDRACT number:
2018-002062-39
Version number:
02 (Clean)
Clinical trial phase:
III
Release date:
08-Jan-2021
Property of Novartis
Confidential
May not be used, divulged, published, or otherwise disclosed
without the consent of Novartis
Clinical Trial Protocol Template version 1.0 dated 01-Dec-2017


Novartis
Confidential
Page 2
Amended Protocol Version 02 (Clean)
Protocol No. CAIN457M2302
Table of contents
Table of contents .................................................................................................................2
List of tables ........................................................................................................................5
List of figures ......................................................................................................................6
List of abbreviations............................................................................................................7
Glossary of terms...............................................................................................................10
Amendment 2 (08-Jan-2021).............................................................................................12
Amendment 1 (17-Jun-2020) ............................................................................................14
Protocol summary..............................................................................................................16
1
Introduction .......................................................................................................................19
1.1
Background............................................................................................................19
1.2
Purpose ..................................................................................................................21
2
Objectives and endpoints...................................................................................................21
3
Study design ......................................................................................................................23
4
Rationale............................................................................................................................27
4.1
Rationale for study design .....................................................................................27
4.2
Rationale for dose/regimen and duration of treatment ..........................................28
4.3
Rationale for choice of control drugs (comparator/placebo).................................30
4.4
Purpose and timing of interim analyses/design adaptations..................................31
4.5
Risks and benefits..................................................................................................31
5
Population..........................................................................................................................32
5.1
Inclusion criteria ....................................................................................................32
5.2
Exclusion criteria...................................................................................................33
6
Treatment...........................................................................................................................35
6.1
Study treatment......................................................................................................35
6.1.1
Investigational and control drugs..........................................................35
6.1.2
Additional study treatments ..................................................................35
6.1.3
Treatment arms/group ...........................................................................35
6.1.4
Treatment duration................................................................................36
6.2
Other treatment(s)..................................................................................................36
6.2.1
Concomitant therapy.............................................................................36
6.2.2
Prohibited medication ...........................................................................37
6.2.3
Rescue medication ................................................................................39
6.3
Subject numbering, treatment assignment, randomization....................................39
6.3.1
Subject numbering ................................................................................39
6.3.2
Treatment assignment, randomization ..................................................40


Novartis
Confidential
Page 3
Amended Protocol Version 02 (Clean)
Protocol No. CAIN457M2302
6.4
Treatment blinding.................................................................................................40
6.5
Dose escalation and dose modification..................................................................41
6.5.1
Dose modifications................................................................................41
6.5.2
Follow-up for toxicities.........................................................................41
6.6
Additional treatment guidance...............................................................................41
6.6.1
Treatment compliance...........................................................................41
6.6.2
Recommended treatment of adverse events..........................................42
6.6.3
Emergency breaking of assigned treatment code..................................42
6.7
Preparation and dispensation.................................................................................42
6.7.1
Handling of study treatment and additional treatment..........................43
6.7.2
Instruction for prescribing and taking study treatment .........................43
7
Informed consent procedures ............................................................................................45
8
Visit schedule and assessments .........................................................................................46
8.1
Screening ...............................................................................................................52
8.1.1
Information to be collected on screening failures.................................52
8.2
Subject demographics/other baseline characteristics.............................................52
8.2.1
Demography..........................................................................................52
8.2.2
HS medical history/diagnosis................................................................52
8.2.3
Prior HS medications and therapy.........................................................52
8.2.4
Hurley stage ..........................................................................................52
8.2.5
Smoking History ...................................................................................53
8.2.6
Relevant medical history/current medical conditions...........................53
8.2.7
Prior and concomitant medications.......................................................53
8.2.8
Determination of the tuberculosis status...............................................53
8.3
Efficacy..................................................................................................................56
8.3.1
Hidradenitis Suppurativa Clinical Response (HiSCR) .........................56
8.3.2
Patient's Global Assessment of Skin Pain - NRS in the past 24 
hours......................................................................................................57
8.3.3
Modified Hidradenitis Suppurativa Score (mHSS)...............................57
8.3.4
HS-Physician’s Global Assessment (HS-PGA)....................................58
8.3.5
Dermatology life quality index (DLQI) ................................................58
8.3.6
Health Status Questionnaire (EQ-5D-3L).............................................59
8.3.7
Hidradenitis Suppurativa Symptom Diary............................................59
8.3.8
Patient Global Impression of severity (PGI-s)......................................60
8.3.9
Patient Global Impression of Change (PGI-c) ......................................60
8.3.10
Work Productivity and Activity Impairment Questionnaire: 
Specific Health Problem (WPAI-SHP).................................................60


Novartis
Confidential
Page 4
Amended Protocol Version 02 (Clean)
Protocol No. CAIN457M2302
8.3.11
Patient's lesion count.............................................................................60
8.3.12
Appropriateness of efficacy assessments..............................................60
8.4
Safety.....................................................................................................................61
8.4.1
Physical examination ............................................................................61
8.4.2
Vital signs..............................................................................................62
8.4.3
Height and weight .................................................................................62
8.4.4
Laboratory evaluations..........................................................................62
8.4.5
Pregnancy and assessments of fertility .................................................64
8.4.6
Appropriateness of safety measurements..............................................64
8.5
Additional assessments..........................................................................................65
8.5.1
Clinical Outcome Assessments (COAs) ...............................................65
8.5.2
Pharmacokinetics ..................................................................................65
8.5.3
Biomarkers............................................................................................66
8.5.4
Other Assessments ................................................................................68
9
Study discontinuation and completion ..............................................................................68
9.1
Discontinuation......................................................................................................68
9.1.1
Discontinuation of study treatment .......................................................68
9.1.2
Withdrawal of informed consent...........................................................69
9.1.3
Lost to follow-up...................................................................................70
9.1.4
Early study termination by the sponsor.................................................70
9.2
Study completion and post-study treatment ..........................................................70
10 Safety monitoring and reporting........................................................................................71
10.1
Definition of adverse events and reporting requirements......................................71
10.1.1
Adverse events ......................................................................................71
10.1.2
Serious adverse events ..........................................................................73
10.1.3
SAE reporting........................................................................................74
10.1.4
Pregnancy reporting ..............................................................................74
10.1.5
Reporting of study treatment errors including misuse/abuse................75
10.2
Additional Safety Monitoring................................................................................75
10.2.1
Data Monitoring Committee .................................................................75
10.2.2
Steering Committee...............................................................................75
11 Data Collection and Database management......................................................................76
11.1
Data collection.......................................................................................................76
11.2
Database management and quality control............................................................76
11.3
Site monitoring ......................................................................................................77
12 Data analysis and statistical methods ................................................................................78


Novartis
Confidential
Page 5
Amended Protocol Version 02 (Clean)
Protocol No. CAIN457M2302
12.1
Analysis sets ..........................................................................................................78
12.2
Subject demographics and other baseline characteristics......................................78
12.3
Treatments .............................................................................................................79
12.4
Analysis of the primary endpoint(s) ......................................................................79
12.4.1
Definition of primary endpoint(s).........................................................79
12.4.2
Statistical model, hypothesis, and method of analysis..........................79
12.4.3
Handling of missing values/censoring/discontinuations.......................80
12.4.4
Sensitivity and Supportive analyses......................................................81
12.5
Analysis of secondary endpoints ...........................................................................81
12.5.1
Efficacy and/or Pharmacodynamic endpoint(s)....................................81
12.5.2
Safety endpoints....................................................................................84
12.5.3
Pharmacokinetics ..................................................................................85
12.5.4
DNA......................................................................................................85
12.5.5
Biomarkers............................................................................................85
12.5.6
PK/PD relationships..............................................................................86
12.5.7
Patient reported outcomes.....................................................................86
12.6
Analysis of exploratory endpoints.........................................................................86
12.7
Interim analyses.....................................................................................................88
12.8
Sample size calculation..........................................................................................89
12.8.1
Primary endpoint(s)...............................................................................89
12.8.2
Secondary endpoint(s)...........................................................................89
13 Ethical considerations and administrative procedures ......................................................90
13.1
Regulatory and ethical compliance........................................................................90
13.2
Responsibilities of the investigator and IRB/IEC..................................................90
13.3
Publication of study protocol and results...............................................................90
13.4
Quality Control and Quality Assurance.................................................................91
14 Protocol adherence ............................................................................................................91
14.1
Protocol Amendments ...........................................................................................91
15 References .........................................................................................................................92
16 Appendices ........................................................................................................................95
16.1
Appendix 1: Clinically notable laboratory values and vital signs .........................95
16.2
Appendix 2: Blood samples collection..................................................................96
16.3
Appendix 3: Type I alpha for the pain hypothesis.................................................98
List of tables
Table 2-1
Objectives and related endpoints ..........................................................21
Table 6-1
Investigational and control drug............................................................35


Novartis
Confidential
Page 6
Amended Protocol Version 02 (Clean)
Protocol No. CAIN457M2302
Table 6-2
Prohibited medication ...........................................................................38
Table 8-1
Assessment Schedule ............................................................................48
Table 8-2
Hurley stages.........................................................................................53
Table 8-3
Modified Hidradenitis Suppurativa Score (mHSS)...............................57
Table 8-4
Hidradenitis Suppurativa Physician's Global Assessment Scale 
(HS-PGA)..............................................................................................58
Table 10-1
Guidance for capturing the study treatment errors including 
misuse/abuse .........................................................................................75
Table 16-1
Blood log: Time schedule for blood sampling......................................96
Table 16-2
Type I alpha for the pain hypothesis.....................................................98
List of figures
Figure 3-1
Study design..........................................................................................26
Figure 3-2
Study design in case of global health disruptive event .........................27
Figure 4-1
Predicted systemic exposure with 2 and 4 weeks dosing intervals 
during maintenance at the 300 mg dose level .......................................30
Figure 8-1
Tuberculosis screening flowchart .........................................................55
Figure 12-1
Testing strategy.....................................................................................83


Novartis
Confidential
Page 7
Amended Protocol Version 02 (Clean)
Protocol No. CAIN457M2302
List of abbreviations
A
abscess
AE
adverse event
ALT
alanine aminotransferase
ALP
Alkaline Phosphatase
AN
abscesses and inflammatory nodules
ANCOVA
analysis of covariance
AST
aspartate aminotransferase
BD-2
beta-defensin-2
CDS
core data sheet
CFR
Code of Federal Regulation
COAs
clinical outcome assessments
COVID-19
Corona Virus Disease 2019
CRP (hsCRP)
(high sensitivity) C-reactive protein
CSR
clinical study report
CTC
Common Toxicity Criteria
CTT
clinical trial team
CV
coefficient of variation
DF
Draining fistulae
DLQI
Dermatology Life Quality Index
DMC
Data Monitoring Committee
DNA
deoxyribonucleic acid
eCRF
electronic case report/record form
EDC
electronic data capture
ELISA
enzyme-linked immunosorbent assay
EMA
European Medicines Agency
EOT
end of treatment
EPAR
European public assessment report
EQ-5D
Euro-QoL (EQ-5D-3L) - standardized tool to assess quality of life in 3 levels
ESR
erythrocyte sedimentation rate
EU
European Union
F
fistulae
FAS
full analysis set
FDA
Food and Drug Administration
FSH
follicle-stimulating hormone
GCP
Good Clinical Practice
GGT
gamma glutamyl transferase
HbA1c
hemoglobin A1c
HDL
high density lipoprotein
HiSCR
Hidradenitis Suppurativa Clinical Response
HIV
human immunodeficiency virus
HRQoL
health-related quality of life
HS
hidradenitis suppurativa
HS-PGA
Hidradenitis Suppurativa Physician's Global Assessment
i.v.
intravenous
IB
Investigator’s Brochure
ICF
informed consent form


Novartis
Confidential
Page 8
Amended Protocol Version 02 (Clean)
Protocol No. CAIN457M2302
ICH
International Council for Harmonisation of Technical Requirements for Pharmaceuticals 
for Human Use
IEC
independent ethics committee
IFU
instructions for use
IG
immunogenicity
IgG1
immunoglobulin G1
IL-17A
interleukin-17A
IRB
institutional review board
IRT
interactive response technology
LDL
low density lipoprotein
LLN
lower limit of normal
LLOQ
lower limit of quantification
MedDRA
Medical Dictionary for Regulatory Activities
mHSS
modified Hidradenitis Suppurativa Score
MHRA
Medicines and Healthcare products Regulatory Agency
MMRM
mixed model repeated measures
mRNA
messenger RNA
N
inflammatory nodules
NRS
Numerical Rating Scale
PD
pharmacodynamic(s)
PFS
pre-filled syringe
PGI-c
Patient Global Impression of change
PGI-s
Patient Global Impression of severity
PK
pharmacokinetic(s)
PPD
purified protein derivative
PRO
patient reported outcome
PSUR
Periodic Safety Update Report
PTY
patient-treatment years
q2w
once every two weeks
q4w
once every four weeks
QFT
QuantiFERON® TB-Gold In-Tube assay
QoL
quality of life
RAS
randomized analysis set
RNA
ribonucleic acid
s.c.
subcutaneous
SAE
serious adverse event
SC
steering committee
SD
standard deviation
SGOT
serum glutamic oxaloacetic transaminase
SGPT
serum glutamic pyruvic transaminase
SUSAR
suspected unexpected serious adverse reactions
TB
tuberculosis
TNF-α
tumor necrosis factor-α
ULN
upper limit of normal
US
United States
VAS
visual analog scale
WBC
white blood cell(s)


Novartis
Confidential
Page 9
Amended Protocol Version 02 (Clean)
Protocol No. CAIN457M2302
WHO
World Health Organization
WPAI-SHP
Work Productivity and Activity Impairment Questionnaire: Specific Health Problem
β-hCG
β-human chorionic gonadotropin


Novartis
Confidential
Page 10
Amended Protocol Version 02 (Clean)
Protocol No. CAIN457M2302
Glossary of terms
Assessment
A procedure used to generate data required by the study
Cohort
A specific group of subjects fulfilling certain criteria
Control drug
A study drug used as a comparator to reduce assessment bias, preserve blinding of 
investigational drug, assess internal study validity, and/or evaluate comparative effects of 
the investigational drug.
Dosage
Dose of the study treatment given to the subject in a time unit (e.g. 100 mg once a day, 75 
mg twice a day)
Enrollment
Point/time of subject entry into the study at which informed consent must be obtained (i.e. 
prior to starting any of the procedures described in the protocol)
Epoch
Interval of time in the planned conduct of a study. An epoch is associated with a purpose 
(e.g. screening, randomization, treatment, follow-up), which applies across all arms of a 
study.
Estimand
A structured framework that translate the trial objective into a precise definition of the 
treatment effect that is to be estimated
Healthy volunteer
A person with no known significant health problems who volunteers to be a study 
participant 
Intercurrent 
events
Events occurring after treatment initiation that affect either the interpretation or the 
existence of the measurements associated with the clinical question of interest.
Investigational 
drug
The study drug whose properties are being tested in the study; this definition is consistent 
with US CFR 21 Section 312.3 and is synonymous with “investigational new drug” or 
“investigational medicinal product”.
Investigational 
treatment
All investigational drug(s) whose properties are being tested in the study as well as their 
associated treatment controls. This includes any placebos, any active controls, as well as 
approved drugs used outside of their indication/approved dosage or tested in a fixed 
combination. Investigational treatment generally does not include other treatments 
administered as concomitant background therapy required or allowed by the protocol 
when used within approved indication/dosage.
Part
A single component of a study which contains different objectives or populations within 
that single study. Common parts within a study are: a single dose part and a multiple dose 
part, or a part in patients with established disease and in those with newly-diagnosed 
disease.
Patient
An individual with the condition of interest
Period
A minor subdivision of the study timeline; divides phases into smaller functional segments 
such as screening, baseline, titration, washout, etc.
Premature 
subject 
withdrawal
Point/time when the subject exits from the study prior to the planned completion of all 
study drug administration and assessments; at this time all study drug administration is 
discontinued and no further assessments are planned.
Randomization 
number
A unique identifier assigned to each randomized subject, corresponding to a specific 
treatment arm assignment
Screen Failure
A subject who is screened but is not treated or randomized
Stage
A major subdivision of the study timeline; begins and ends with major study milestones 
such as enrollment, randomization, completion of treatment, etc.
Study completion
Point/time at which the subject came in for a final evaluation visit or when study drug was 
discontinued whichever is later.
Study drug 
discontinuation
Point/time when subject permanently stops taking study drug for any reason; may or may 
not also be the point/time of premature subject withdrawal.
Study 
drug/treatment
Any drug (or combination of drugs) administered to the subject as part of the required 
study procedures; includes investigational drug, active drug run-ins or background 
therapy.
Subject
An individual who has consented to participate in this study. The term Subject may be 
used to describe either a healthy volunteer or a patient.


Novartis
Confidential
Page 11
Amended Protocol Version 02 (Clean)
Protocol No. CAIN457M2302
Subject number
A unique number assigned to each subject upon signing the informed consent. This 
number is the definitive, unique identifier for the subject and should be used to identify the 
subject throughout the study for all data collected, sample labels, etc.
Variable
Information used in the data analysis; derived directly or indirectly from data collected 
using specified assessments at specified time-points.
Withdrawal of 
consent (WoC)
Withdrawal of consent from the study occurs only when a subject does not want to 
participate in the study any longer, and does not allow any further collection of personal 
data.


Novartis
Confidential
Page 12
Amended Protocol Version 02 (Clean)
Protocol No. CAIN457M2302
Amendment 2 (08-Jan-2021)
Amendment Rationale
The purpose of this amendment is to update the statistical analysis section including adjusting 
the split of the overall alpha level allocating 80to testing the high dose secukinumab regimen 
(300 mg q2w) versus placebo, revising the definition of the baseline for assessments and adding 
additional analyses as described below.
This change has been deemed necessary following the recently available results from study 
CAIN457A2324, conducted in patients affected by moderate to severe plaque psoriasis and 
body weight ≥90kg and treated with secukinumab 300 mg every four weeks (q4w) or every two 
weeks (q2w). The study CAIN457A2324 showed that in psoriasis patients who weigh ≥90kg, 
secukinumab 300 mg q2w demonstrates a better treatment effect, without altering the well 
characterized safety profile of secukinumab. Patients with Hidradenitis Suppurativa (HS) are 
generally heavier than patients with psoriasis (Storer et al 2018), and it seems reasonable to 
assume that the same weight-based response seen in psoriasis could apply to HS patients as 
well. These new findings, paired with the absence of safety concerns noted by the HS Data 
Monitoring Committee (DMC) when evaluating the 300 mg q2w data from the 
CAIN457M2301 and CAIN457M2302 studies (17-Jun-2020), and the safety profile seen in 
study CAIN457A2324, support the revision of the statistical analysis section.
In addition, this amendment introduces the value of the individual lesion count assessed at the 
baseline visit only to be used as ‘baseline’ in the statistical analyses, instead of the weighted 
average across the two screening visits and the baseline (randomization) visit. This change 
follows the guidance from the FDA advice letter on studies CAIN457M2301 and 
CAIN457M2302 dated 20-Aug-2019 stating: “As the treatment will be initiated at baseline and 
not at screening visits, for interpretation of study findings, we recommend that you use the 
assessments collected at the time of the baseline visit” and also guidance from the FDA advice 
letter on studies CAIN457M2301/M2302 dated 10-Nov-2020 “For interpretation of study 
findings, we maintain our recommendation that you use the assessments collected at 
the randomization visit as the baseline value”. The weighted average value will still be 
considered in sensitivity analyses.
In order to take into account the variability and the subjectivity of the Hidradenitis Suppurativa 
Clinical Response (HiSCR), the inter-rater variability when evaluating the draining fistulae and 
their longevity often requiring surgical excision (Revuz J 2009), a secondary endpoint 
evaluating only the abscesses and inflammatory nodules (AN) count has been added. Analyzing 
AN count on the original, continuous scale, enables a more sensitive and granular approach to 
summarizing the clinical effect of treatment (Kimball et al 2018).
Moreover, based on the evidence that biologic-naive (bio-naive) patients respond better to 
biologic therapies, including secukinumab, compared to those who are bio-experienced 
(Garcia-Montoya and Marzo-Ortega 2018), and considering that it is plausible to assume a dose-
response influenced by weight, the exploratory objective section has been updated to include a 
specific analysis to evaluate the benefit of secukinumab in the bio-naive population and in the 
patients with body weight above and below 90 kg. Furthermore, an exploratory objective related 


Novartis
Confidential
Page 13
Amended Protocol Version 02 (Clean)
Protocol No. CAIN457M2302
to C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR) has been added to explore
treatment effect with regard to inflammatory markers.
Lastly, as introduced in the previous Amendment 01, the number of patients to be randomized 
has been formally increased to account for the disruptive impact of the COVID-19 pandemic.
Changes to specific sections of the protocol are shown in the track changes version of the 
protocol using strike through red font for deletions and red underlined for insertions.
The major changes made to the protocol are listed below.

Section 2 and Table 2-1 have been updated with the addition of the reduction of AN count 
as secondary and exploratory endpoints, evaluation of inflammatory markers (ESR and 
CRP) and of the achievement of HiSCR in bio-naive patients, and in patients with body 
weight lower  and higher than 90 kg (90 kg and ≥90 kg) as exploratory subgroup 
analyses.

Section 3, Section 5 and Section 12.8 have been updated with the increase of the target 
population (approximately 541 patients). 

Section 4.2 Rationale for dose/regimen and duration of treatment and Section 4.5 have 
been updated including the available data from the recent CAIN457A2324 study.

Section 12.4.1 has been edited with updated baseline definition. 

Section 12.4.4 has been updated with additional sensitivity analysis for baseline and 
weighted baseline values

Section 12.5.1 and Appendix 16.3 have been modified to reflect the updated alpha 
allocation.

Section 12.6 has been updated with the pre-specified subgroup analyses.

Section 12.8, Section 12.8.1 Primary endpoint(s) and Section 12.8.2 have been updated 
with power calculations.
This protocol amendment also includes corrections of minor errors across sections of the 
protocol.
IRBs/IECs 
A copy of this amended protocol will be sent to the Institutional Review Board 
(IRBs)/Independent Ethics Committee (IECs) and Health Authorities. The changes described 
in this amended protocol require IRB/IEC and Health Authority approval according to local 
regulations prior to implementation. The changes herein affect the Informed Consent. Sites are 
required to update and submit for approval a revised Informed Consent that takes into account 
the changes described in this protocol amendment.


Novartis
Confidential
Page 14
Amended Protocol Version 02 (Clean)
Protocol No. CAIN457M2302
Amendment 1 (17-Jun-2020)
Amendment rationale 
The rationale for the amendment reflects the guidance released from several Health Authorities 
(FDA, EMA, MHRA) to introduce a level of flexibility in drug dispensation, protocol 
assessments and visit schedule if a major health care event requires it (i.e. COVID-19 
pandemic).
While adherence to protocol procedure and GCPs remains mandatory, Novartis has edited the 
wording in some sections of the protocol to allow the patients in the trial to continue treatment 
while being monitored for safety in these situations. 
These changes will reduce the risk of exposure for patients and site staff, and potentially the 
risk for transmission of infectious diseases (e.g. COVID-19). 
In addition, a ‘special scenario’ has been added to the study design to ensure a careful 
assessment of lesion count at Week 52, by allowing for the possibility to perform up to 3 
unscheduled visits. 
In case of a global health crisis impeding the patients (or the sites) to attend (or perform) 
Week 52 study visit on site, the patients in the study will be allowed to receive additional study 
treatment up to 12 weeks after Week 50, or until they can return to the study site to perform the 
Week 52 assessment (whichever occurs first). 
This additional, optional phase will permit the patients to be assessed for eligibility to roll over 
in the 4 years, long-term extension study. During this period, the patients will continue to be 
monitored for safety.
Changes to specific sections of the protocol are shown in the track changes version of the 
protocol using strike through red font for deletions and red underlined for insertions.
The major changes made to the protocol are listed below.

Section 3, Section 8 and Table 8-1 have been edited with the option of performing up to 3 
unscheduled visits if, in case of pandemic/epidemic health crisis, the patient cannot be 
assessed on site for the Week 52 lesion count. 

Section 3, Section 5, Section 12.4.3 and Section 12.8 have been modified to allow the 
recruitment of additional patients if missing data due to a global health event jeopardize 
the power of the predefined statistical tests. The number of patients that may be included 
to compensate the missing data is not expected to exceed 15% of the pre-planned 
population.

Section 3, Section 6.7, Section 6.7.2, Section 8, Section 8.3, Section 8.4 and Section 11.3 
have been modified to allow study drug shipment to subjects for home administration, as 
well as remote contact to collect safety information, remote site initiation visits or 
monitoring related activities in case of pandemic/epidemic events. 

Section 5.2 and Section 8.2.8 have been edited adding clarity on the process to assess the 
eligibility of patients with latent TB at screening.

Section 7 has been edited include the possibility for patients to provide their consent 
remotely, if appropriate.


Novartis
Confidential
Page 15
Amended Protocol Version 02 (Clean)
Protocol No. CAIN457M2302

Section 8.3.7 has been edited to clarify the mandatory completion of the HS Patients’ 
Diary in countries where available.
This protocol amendment also includes corrections of minor errors or inconsistencies across 
sections of the protocol and increase clarity of the text.
IRBs/IECs 
A copy of this amended protocol will be sent to the Institutional Review Board 
(IRBs)/Independent Ethics Committee (IECs) and Health Authorities. The changes described 
in this amended protocol require IRB/IEC and Health Authority approval according to local 
regulations prior to implementation.  
The changes herein affect the Informed Consent. Sites are required to update and submit for 
approval a revised Informed Consent that takes into account the changes described in this 
protocol amendment.


Novartis
Confidential
Page 16
Amended Protocol Version 02 (Clean)
Protocol No. CAIN457M2302
Protocol summary
Protocol number
CAIN457M2302
Full Title
A randomized, double-blind, multicenter study assessing short (16 weeks) and long-
term efficacy (up to 1 year), safety, and tolerability of 2 subcutaneous secukinumab 
dose regimens in adult patients with moderate to severe hidradenitis suppurativa
Brief title
Study of efficacy and safety of two secukinumab dose regimens in subjects with 
moderate to severe hidradenitis suppurativa
Sponsor and 
Clinical Phase
Novartis/Phase III
Investigation type
Drug
Study type
Interventional
Purpose and 
rationale
The purpose of this study is to demonstrate superiority of secukinumab at Week 16, 
based on HiSCR rates versus placebo, along with the maintenance of efficacy of 
secukinumab at Week 52 in subjects with moderate to severe HS. Moreover, this study 
will also assess the safety and tolerability of secukinumab.
Primary 
Objective(s) 
The primary objective of this study is to demonstrate the efficacy of secukinumab 
compared to placebo with respect to HiSCR after 16 weeks of treatment
Secondary 
Objectives
To demonstrate the efficacy of secukinumab compared to placebo with respect to:
●percentage change in AN count
● proportion of patients with HS flares
●proportion of patients with clinical response in HS related skin pain after 16 weeks of 
treatment
Study design
This is a multicenter, randomized, double-blind, placebo controlled, parallel group study 
with two secukinumab dose regimens in approximately 541 patients with moderate to 
severe HS. The study consists of: Screening (up to 4 weeks), Treatment Period 1 (16 
weeks) and Treatment Period 2 (36 weeks). Subjects who prematurely discontinue the 
study, or who complete the study and cannot or do not wish to continue in a planned 
optional extension study, will enter a post-treatment Follow-Up period (8 weeks).
Population
The study population will consist of a representative group of adult male and female 
subjects (≥ 18 years) with moderate to severe HS. It is aimed to randomize 
approximately 541 subjects in approximately 132 study sites worldwide. Up to 40% of 
the subjects will be allowed to enter the study on treatment with stable dose of 
antibiotics.
Key Inclusion 
criteria
1. Written informed consent must be obtained before any assessment is performed.
2. Male and female patients ≥ 18 years of age.
3. Diagnosis of HS ≥ 1 year prior to baseline.
4. Patients with moderate to severe HS defined as:
● A total of at least 5 inflammatory lesions, i.e. abscesses and/or inflammatory 
nodules
AND
● Inflammatory lesions should affect at least 2 distinct anatomic areas
5. Patients agree to daily use of topical over-the-counter antiseptics on the areas 
affected by HS lesions while on study treatment.


Novartis
Confidential
Page 17
Amended Protocol Version 02 (Clean)
Protocol No. CAIN457M2302
Key Exclusion 
criteria
1. Total fistulae count ≥ 20 at baseline.
2. Any other active skin disease or condition that may interfere with 
assessment of HS.
3- Active ongoing inflammatory diseases other than HS that require treatment 
with prohibited medications (see Table 6-2).
4. Use or planned use of prohibited treatment. Washout periods detailed in the 
protocol have to be adhered to (see Table 6-2).
5. History of hypersensitivity to any of the study drug constituents.
6. History of lymphoproliferative disease or any known malignancy or history of 
malignancy of any organ system treated or untreated within the past 5 years, 
regardless of whether there is evidence of local recurrence or metastases 
(except for skin Bowen’s disease, or basal cell carcinoma or actinic keratoses 
that have been treated with no evidence of recurrence in the past 12 weeks; 
carcinoma in situ of the cervix or non-invasive malignant colon polyps that have 
been removed).
7. Pregnant or lactating women.
Study treatment
● Secukinumab 300 mg solution for s.c. injection in a 2 ml PFS
● Placebo solution for s.c. injection in a 2 ml PFS
Efficacy 
assessments
Efficacy assessments related to the primary and secondary objectives include:
● Individual lesion count used for calculation of Hidradenitis Suppurativa Clinical 
Response (HiSCR) and HS flare
● Patient's Global Assessment of Skin Pain - NRS in the past 24 hours 
Key safety 
assessments
● Evaluation of all AEs and SAEs
● Physical examination
● Vital signs
● Laboratory evaluations (e.g. hematology, clinical chemistry, urinalysis)
● Immunogenicity (assessment of anti-AIN457 antibody development)
● Pregnancy
Other 
assessments
● Additional efficacy assessments linked to the exploratory objectives include: 
● Modified Hidradenitis Suppurativa Score (mHSS);
● HS-Physician's Global Assessment (HS-PGA);
● Dermatology Life Quality Index (DLQI);
● Health Status Questionnaire (EQ-5D-3L);
● Patient Global Impression of severity (PGI-s);
● Patient Global Impression of change (PGI-c);
● Work Productivity and Activity Impairment - Specific Health Problem (WPAI-SHP);
● HS Symptom Diary
● Exploratory biomarkers
● Pharmacokinetic parameter
Data analysis
The primary endpoint of the study is HiSCR at Week 16, defined as at least a 50% 
decrease in the Abscess and inflammatory Nodule (AN) count compared to baseline 
with no increase in the number of abscesses and/or in the number of draining fistulae 
from baseline to Week 16.
The secondary endpoints of this study are as follows:
● Percentage change from baseline in AN count at Week 16
● Flare over 16 weeks: Patients who experience at least one flare over 16 weeks. Flare 
is defined as at least a 25% increase in AN count with a minimum increase of 2 AN 
relative to baseline.
● Pain/NRS30 at Week 16: Patients achieving NRS30 at Week 16, among patients with 
baseline NRS ≥ 3. NRS30 is defined as at least a 30% reduction and at least 2 unit 
reduction from baseline in the Patient's Global Assessment of Skin Pain.
The statistical hypothesis for the primary endpoint being tested is that there is no 
difference in the proportion of HiSCR at Week 16 in any of the secukinumab regimens 
versus placebo regimen.
H1: secukinumab 300 mg q2w s.c. is not different to placebo regimen with respect to 
HiSCR after 16 weeks of treatment.
H2: secukinumab 300 mg q4w s.c. is not different to placebo regimen with respect to 


Novartis
Confidential
Page 18
Amended Protocol Version 02 (Clean)
Protocol No. CAIN457M2302
HiSCR after 16 weeks of treatment.
The primary analysis method will be logistic regression with treatment group, 
geographical region, Hurley stage, use of antibiotic, baseline body weight and baseline 
AN count as explanatory variables. Odds ratios will be computed for comparisons of 
secukinumab dose regimens versus placebo utilizing the logistic regression model 
fitted. In case of response rates of 0% or of 100% in one of the treatment groups, 
Fisher’s exact test will be applied. Risk difference and confidence intervals for risk 
difference will be provided.
The statistical hypotheses for the secondary endpoint being tested are that:
● there is no difference in mean of percentage change from baseline in AN count in any 
of the secukinumab regimens versus placebo regimen.
● there is no difference in the proportion of flare over 16 weeks in any of the 
secukinumab regimens versus placebo regimen
● there is no difference in the proportion of NRS30 at Week 16 in any of the 
secukinumab regimens versus placebo regimen
H3: secukinumab 300 mg q2w s.c. is not different to placebo regimen with respect to 
the percentage change from baseline in AN count at Week 16
H4: secukinumab 300 mg q4w s.c. is not different to placebo regimen with respect to 
the percentage change from baseline in AN count at Week 16
H5: secukinumab 300 mg q2w s.c is not different to placebo regimen with respect to 
flare over 16 weeks of treatment
H6: secukinumab 300 mg q4w s.c. is not different to placebo regimen with respect to 
flare over 16 weeks of treatment
H7: secukinumab 300 mg q2w s.c. is not different to placebo regimen with respect to 
NRS30 at Week 16
H8: secukinumab 300 mg q4w s.c. is not different to placebo regimen with respect to 
NRS30 at Week 16
For the secondary endpoint of percentage change in AN count from baseline to Week 
16, an analysis of covariance (ANCOVA) model will be fitted to estimate the treatment 
differences between the two secukinumab regimens and placebo with treatment group, 
baseline AN count, Hurley stage, use of antibiotic, geographical region and baseline 
body weight as covariates.
The analysis method for flare up to Week 16 and Pain/NRS30 at Week 16endpoints will 
be the logistic regression: with treatment group, Hurley stage, geographical region, use 
of antibiotic, baseline body weight and baseline AN counts as explanatory variables for 
flare endpoints; and with treatment group, Hurley stage, region, use of antibiotic, 
baseline body weight and baseline NRS as explanatory variables for pain endpoints. 
Odds ratios will be computed for comparisons of secukinumab dose regimens versus 
placebo utilizing the logistic regression model fitted. In case of response rates of 0% or 
of 100% in one of the treatment groups, Fisher’s exact test will be applied. Risk 
difference and confidence intervals for risk difference will be provided.
Key words
hidradenitis suppurativa, HS, IL-17A, monoclonal antibody, AIN457, secukinumab, 
HiSCR, pain, efficacy, safety


Novartis
Confidential
Page 19
Amended Protocol Version 02 (Clean)
Protocol No. CAIN457M2302
1
Introduction
1.1
Background
Hidradenitis suppurativa (HS), also called “acne inversa” or “maladie de Verneuil”, is a chronic, 
recurrent, and debilitating inflammatory skin condition that typically presents with deep, 
inflammatory, painful lesions in apocrine gland-bearing parts of the body. The most common 
areas 
affected 
are 
the 
axillae, 
the 
groin, 
and 
the 
anogenital 
region 
(Fimmel and Zouboulis 2010, Jemec 2012).
HS is currently considered an inflammatory disease of the pilosebaceous follicle with an 
underlying immune system imbalance that occurs in genetically predisposed individuals 
(Kelly et al 2014).
The disease starts after puberty and women are more frequently affected than men (3:1). Risk 
factors include obesity and smoking. Although epidemiological prevalence estimates vary 
widely (0.03 to 4.3%), and geographical differences exist, a prevalence of approximately 0.1 to 
1% is accepted by the scientific community (Deckers et al 2014, Garg et al 2017).
The clinical manifestations of HS are heterogeneous, but the disease tends to manifest with 
chronic, relapsing, deep, painful, inflammatory skin lesions, mostly inflammatory nodules and 
abscesses, leading to possible drainage and suppuration. Inflammatory lesions are complicated 
during disease progression by sinus tract formation and fistulization, and may lead to 
hypertrophic scarring with a possible impact on functional use.
HS is associated with pain, malodorous discharge from the wounds, and scarring, and it 
frequently has devastating psychosocial effects. HS is a profoundly debilitating disease with a 
high negative impact on quality of life (QoL), with multiple studies confirming that the impact 
is greater than that seen with other dermatologic diseases (Deckers and Kimball 2016). Patients 
with HS also often suffer from depression, social isolation, have an impaired sexual health, and 
may have difficulty performing their work duties (Deckers et al 2014, Janse et al 2017).
HS is difficult to treat. Official European treatment guidelines have only been developed in 
2015 and suggest that patients should be provided with adjuvant, medical and surgical therapy 
(Zouboulis et al 2015).
While topical antibiotics can be used for mild cases, long courses of multiple antimicrobial 
therapy are preferred for moderate to severe HS, generally with tetracyclines or a combination 
of clindamycin and rifampicin, which can be followed by maintenance with chronic antibiotic 
treatment
for 
months 
or 
even 
years
(Zouboulis et al 2015, Bettoli et al 2016, Dessinioti et al 2016).
However, it is widely recognized that HS is a chronic inflammatory condition, not an infectious 
disease (Jemec 2012). Therefore, anti-inflammatory agents are an alternative and probably 
more appropriate approach than antibiotics.
Over time, the consequence of chronic, recurrent, inadequately treated inflammation is 
irreversible fibrosis, which does not respond to medical therapy. Once lasting anatomical 
changes occur, the only therapeutic option to reduce the volume of fibrotic tissue and improve 
functionality in the areas of affected skin is surgery (Andersen and Jemec 2017).


Novartis
Confidential
Page 20
Amended Protocol Version 02 (Clean)
Protocol No. CAIN457M2302
In 2015, adalimumab (Humira®), a recombinant human monoclonal immunoglobulin G1 
(IgG1) antibody to soluble and membrane bound tumor necrosis factor α (TNF-α), received 
regulatory approval for the treatment of moderate to severe HS.
Efficacy has been seen with adalimumab, with Hidradenitis Suppurativa clinical response 
(HiSCR) response rates over placebo of approximately 16% (41.8% adalimumab vs 26% 
placebo) and 31% (58.9% adalimumab vs 27.6% placebo) as reported in PIONEER I and II 
studies, respectively (Kimball et al 2016). As captured in the adalimumab labels, adalimumab 
is associated with an increased safety risk for serious infections including tuberculosis (TB), 
invasive fungal infections and other opportunistic infections. An increased incidence of 
malignancies has also been reported with adalimumab.
There is an unmet need for systemic therapies that effectively reduce inflammation while having 
a favorable safety profile.
Secukinumab (AIN457) is a recombinant high-affinity fully human monoclonal anti-human 
interleukin-17A (IL-17A) antibody of the immunoglobulin G1 (IgG1)/kappa isotype. 
Secukinumab is selective for human IL-17A and potently neutralizes the bioactivity of this 
cytokine. IL-17A is the central cytokine in multiple autoimmune and inflammatory processes.
In HS, there is increasing scientific evidence to support the role of IL-17 in the pathogenesis of 
the disease:

Upregulation of mRNA for IL-17A in lesions of patients with HS and psoriasis, while 
levels in control and atopic dermatitis patients were not increased (Wolk et al 2011)

High levels of IL-17A or downstream markers are expressed in inflammatory HS lesions 
(Kelly et al 2015, Lima et al 2016): 

IL-17 producing cells are present in lesional and peri-lesional HS skin and may 
contribute to the initiation of inflammatory processes.

Massive influx of IL-17-expressing cells (neutrophils and/or T-lymphocytes) has been 
observed in deep dermal infiltrates.

Increased IL-17 serum levels have been observed in patients with HS; a tendency toward 
higher serum concentrations of IL-17 has been reported for patients with more advanced 
disease (Matusiak et al 2016).
Secukinumab is approved in more than 80 countries worldwide. The product is indicated for 
the treatment of moderate to severe plaque psoriasis, ankylosing spondylitis, psoriatic arthritis, 
non-radiographic axial spondyloarthritis, and is being evaluated in other inflammatory 
conditions such as juvenile idiopathic arthritis and pediatric psoriasis.
As of 25-Jun-2020, over 22,000 patients have received secukinumab in clinical studies at doses 
ranging from single and/or multiple doses of 0.1 mg/kg to 30 mg/kg intravenous (i.v.) and 25 
mg to 300 mg subcutaneous (s.c.) (Investigator's Brochure (IB) Edition 20, data cut-off 25–Jun-
2020). The cumulative patient exposure from post-marketing experience for all approved 
indications since the International Birth Date of the product is approximately 467,835 patient-
treatment years (PTY) (Periodic Safety Update Report (PSUR), data cut-off 25-Dec-2019). Full 
safety results including all reported adverse events (AEs) are currently available for completed 
studies across different indications. In general, these results show comparable numbers of AEs 
in subjects treated with secukinumab compared to placebo without indication of any specific 


Novartis
Confidential
Page 21
Amended Protocol Version 02 (Clean)
Protocol No. CAIN457M2302
organ toxicity. The Investigator’s Brochure (IB) provides a more detailed review of the pre-
clinical and clinical information on secukinumab.
In a case report by Thorlacius, substantial improvement was observed in the number of boils 
and pain severity in one patient with HS treated with secukinumab 300 mg every 4 weeks, after 
loading doses of 300 mg weekly for 4 weeks (Thorlacius et al 2017). A second case report 
described a patient treated with secukinumab who experienced significant improvement with 
secukinumab in a similar dosing regimen (Schuch et al 2018) further supporting that treatment 
with an anti-IL-17 antibody could be an effective therapy for HS. A third case report 
(Pandey et al 2018) described a patient with HS who responded to secukinumab treatment for 
a period of 6 months and was able to discontinue treatment after satisfactory improvement. The 
patient remained symptom free for three months following discontinuation, and began 
successful re-treatment with secukinumab after lesions reappeared. No unexpected safety 
signals were observed in all three patients.
Early clinical evidence of the effects of another Novartis anti-IL-17 antibody, CJM112, 
supports the potential of an anti-IL-17 antibody as an effective therapy for patients with HS. 
The results of a randomized, double-blind, placebo-controlled Phase 2 study in 66 patients with 
moderate to severe HS (study CCJM112X2202) showed a statistically significant increase in 
the responder rate (HS Physician's Global Assessment (HS-PGA) responder rate 32.3% vs 
12.5%, p = 0.028) at Week 16. Numerical decreases in inflammatory lesions were similar to 
that observed with adalimumab (-2.6 inflammatory lesions in CJM112 relative to placebo vs -
2.4 to -3.0 in adalimumab relative to placebo) (Novartis data on file).
Based on the available data, secukinumab has the potential to be an effective therapy for 
moderate to severe HS with efficacy at least similar to that of adalimumab, a better safety profile 
and sustained low immunogenicity supporting long-term treatment.
The aim of the present study is to assess the efficacy, safety, pharmacokinetics and tolerability
of two dose regimens of secukinumab in patients with moderate to severe HS.
1.2
Purpose
The purpose of this study is to demonstrate superiority of secukinumab at Week 16, based on 
HiSCR rates versus placebo, along with the maintenance of efficacy of secukinumab at 
Week 52 in subjects with moderate to severe HS. Moreover, this study will assess the safety 
and tolerability of secukinumab.
2
Objectives and endpoints
Table 2-1
Objectives and related endpoints
Objective(s)
Endpoint(s)
Primary objective(s)
Endpoint(s) for primary objective(s)
● To demonstrate the efficacy of secukinumab 
compared to placebo with respect to HiSCR after 
16 weeks of treatment.
● Achievement of HiSCR at Week 16. HiSCR is defined as 
at least a 50% decrease in Abscess and Inflammatory 
Nodule (AN) count with no increase in the number of 
abscesses and/or in the number of draining fistulae.


Novartis
Confidential
Page 22
Amended Protocol Version 02 (Clean)
Protocol No. CAIN457M2302
Objective(s)
Endpoint(s)
Secondary objective(s)
Endpoint(s) for secondary objective(s)
● To demonstrate the efficacy of secukinumab 
compared to placebo after 16 weeks of 
treatment with respect to AN count 
● To demonstrate the efficacy of secukinumab 
compared to placebo after 16 weeks of 
treatment with respect to:
● proportion of patients with HS flares
● proportion of patients with clinical response 
in HS related skin pain
● Percentage change from baseline in AN count at Week 
16.
● Flaring up to Week 16. Flare is defined as at least a 25% 
increase in AN count with a minimum increase of 2 AN 
relative to baseline.
● Achievement of NRS30 at Week 16, among subjects with 
baseline NRS ≥ 3. NRS30 is defined as at least a 30% 
reduction and at least 2 unit reduction from baseline in 
Patient's Global Assessment of Skin Pain - at worst.
Exploratory objective(s)
Endpoint(s) for exploratory objective(s)
● To evaluate the safety and tolerability of 
secukinumab over 52 weeks of treatment.
● Clinical safety and tolerability assessments:
● physical exams,
● vital signs,
● laboratory assessments,
● AE monitoring
● To explore the long-term effect of 
secukinumab with respect to HiSCR, AN count,
proportion of patients with flares, HS related skin 
pain up to 52 weeks of treatment.
● Achievement of clinical response as defined by HiSCR.
● Absolute and percentage change from baseline in AN 
count.
● Flares
● Achievement of pain relief as defined by NRS30.
● To evaluate the effect of secukinumab with 
respect to the following efficacy assessments:
● Modified Hidradenitis Suppurativa Score 
(mHSS);
● HS-Physician's Global Assessment (HS-
PGA);
● Dermatology Life Quality Index (DLQI);
● Health Status Questionnaire (EQ-5D-3L);
● Patient Global Impression of severity (PGI-
s);
● Patient Global Impression of change (PGI-
c);
● Work Productivity and Activity Impairment 
(WPAI);
● HS Symptom Diary;
● Inflammatory markers with respect to CRP 
and ESR 
compared to placebo after 16 weeks and in the 
two secukinumab dose regimens up to 52 weeks 
of treatment.
● Absolute and percent change from baseline in modified 
Hidradenitis Suppurativa Score (mHSS).
● HS-PGA response. HS-PGA response is defined as the 
achievement of at least a 2-point reduction in HS-PGA 
score compared to baseline.
● DLQI response and absolute/percent DLQI total score 
change from baseline.
DLQI response is defined as a decrease greater than 5.0 
points from baseline.
● EQ-5D-3L Categories on Category questions and 
summary statistics on EQ -5D -3L score questions.
● Patient Global Impression of severity and change (PGI-s 
and PGI-c) categories.
● Absolute and percent change from baseline in Work 
Productivity and Activity Impairment - Specific Health 
Problem (WPAI-SHP).
● HS Symptom Diary items score change from baseline.
● Absolute and percent change from baseline in CRP and 
ESR
● To evaluate the pharmacokinetics of 
secukinumab in HS patients.
● AIN457 levels in serum
● To assess the development of immunogenicity 
against secukinumab.
● anti-AIN457 antibodies levels in serum
● To explore the potential association of 
biomarker levels with secukinumab efficacy and 
safety by visit up to Week 52 visit (EOT2).
● Biomarkers in serum


Novartis
Confidential
Page 23
Amended Protocol Version 02 (Clean)
Protocol No. CAIN457M2302
Objective(s)
Endpoint(s)
●To explore the efficacy of secukinumab 
compared to placebo with respect to HiSCR 
response after 16 weeks of treatment  and the 
sustained efficacy over time in bio-naive 
patients.
● To explore the efficacy of secukinumab 
compared to placebo with respect to HiSCR 
response after 16 weeks of treatment and the 
sustained efficacy over time in patients with body 
weight lower and higher than 90 kg (90 kg and 
≥90 kg).
● Achievement of HiSCR at Week 16 and up to Week 52 in 
bio-naive patients.
● Achievement of HiSCR at Week 16 and up to Week 52 in 
patients with body weight lower and higher than 90 kg 
(90kg and ≥90kg).
3
Study design
This is a multicenter, randomized, double-blind, placebo controlled, parallel group study with 
two secukinumab dose regimens in approximately 541 patients with moderate to severe HS.
The study consists of: Screening (up to 4 weeks), Treatment Period 1 (16 weeks) and Treatment 
Period 2 (36 weeks). Subjects who prematurely discontinue the study, or who complete the 
study and cannot or do not wish to continue in a planned optional extension study, will need to 
complete a post-treatment Follow-Up period (8 weeks).
Safety, efficacy, biomarker and pharmacokinetic measurements of secukinumab will be 
assessed.
An outline of the study design is presented in Figure 3-1, and a detailed visit and assessment 
schedule is provided in Table 8-1.
Screening (Screening to Randomization)
A screening period of up to 4 weeks will be used to assess the subject´s eligibility and to 
washout and/or taper prohibited medication(s). Two screening visits will be performed: Visit 1 
(Day -28 to Day -14) and Visit 2 (Day -13 to Day -1). Subjects can be re-screened if the subject 
screen fails due to a transient medical condition or due to an insufficient prohibited medication 
washout period. Subjects can be re-screened only once and no study-related re-screening 
procedure should be performed prior to re-consenting the subject.
Important note:
In the event of a global health disruptive event, such as pandemic/epidemic affecting the ability 
of the patient or the site to adhere to protocol requirements and assessments, Investigators 
should only randomize patients if they expect them to be able to adhere to assessments and 
protocol-related activities. Evaluation of the eligibility of the subject should consider the ability 
to attend study visits and adhere to protocol assessments. If the latter is not anticipated, 
screening and randomization should not proceed, and re-screening (as allowable per protocol –
see above) should be considered when conditions allow for proper trial management.


Novartis
Confidential
Page 24
Amended Protocol Version 02 (Clean)
Protocol No. CAIN457M2302
Treatment Period 1 (Randomization to Week 16 pre-dose)
Treatment Period 1 covers the time from randomization (baseline) through Week 16 (prior to 
Week 16 dosing). At baseline, eligible subjects will be randomized at a 1:1:0.5:0.5 ratio to one 
of four treatment arms:

Secukinumab 300 mg every 2 weeks

Secukinumab 300 mg every 4 weeks

Placebo group to secukinumab 300 mg every 2 weeks

Placebo group to secukinumab 300 mg every 4 weeks
Approximately 180 patients will be randomized to each of the two secukinumab regimen arms 
and another 180 patients will be randomized to two placebo switching to secukinumab regimen 
arms. 
In the event of a global health disruptive event, such as pandemic/epidemic affecting the ability 
of the patient or the site to adhere to protocol requirements and assessments and therefore 
leading to a potential increase in the number of missing measurements, the Sponsor may 
consider recruiting additional patients to restore the sample size and maintain the pre-defined 
statistical power.
Randomization will be stratified by region, current antibiotic use and body weight. All subjects 
will receive a single s.c. injection of blinded study drug (active drug or placebo) once a week 
for four weeks (induction) at Baseline, Week 1, 2, 3 and 4. Thereafter, the frequency of study 
drug injections will be every 2 weeks for all subjects in order to maintain the treatment blind: 
either placebo (placebo to secukinumab arms), or secukinumab alternating with placebo every 
2 weeks (secukinumab 300 mg every 4 weeks arm) or secukinumab every 2 weeks 
(secukinumab 300 mg every 2 weeks arm). See Figure 3-1.
In Treatment Period 1, home administrations (H) of study drug are scheduled at Weeks 6, 10 
and 14.
Refer to Section 6.1.3 for further details on treatment arms.
Subjects who complete Treatment Period 1 will enter Treatment Period 2.
Treatment Period 2 (Week 16 post-dose to Week 52)
Treatment Period 2 is defined as the time from Week 16 (post-dose) through Week 52. From 
Week 16, all patients will receive secukinumab.
The Week 16 dose is the first dose of Treatment Period 2.
Subjects who were randomized to either of the two secukinumab regimens will continue on the 
same dose regimen. Subjects who were randomized to one of the two 'Placebo to secukinumab' 
regimens will receive either secukinumab 300 mg every 2 weeks or secukinumab 300 mg every 
4 weeks.
At Week 16, all subjects will receive a re-induction consisting of a single s.c. injection of 
blinded study drug (active drug or placebo) once a week for four weeks, at Week 16, 17, 18, 19 
and 20. Thereafter, all subjects will receive study drug injections every 2 weeks, either 


Novartis
Confidential
Page 25
Amended Protocol Version 02 (Clean)
Protocol No. CAIN457M2302
secukinumab alternating with placebo every 2 weeks (secukinumab 300 mg every 4 weeks arm) 
or secukinumab every 2 weeks (secukinumab 300 mg every 2 weeks arm) until Week 50.
Home administrations (H) of study drug are scheduled at Weeks 22, 26, 30, 34, 38, 42, 46 and 
50.
The planned end of Treatment Period 2 visit (EOT 2) will be performed at Week 52. At this 
visit, the site should call Interactive Response Technology (IRT) after performing the scheduled 
study assessments to record the completion of treatment period by subject(s). For subjects 
rolling over to the extension study, Week 52 will be the end of study visit; for subjects 
continuing to the Post-Treatment Follow-Up, the visit at Week 60 will be the end of study visit.
Subjects who discontinue study treatment prematurely for any reason other than withdrawal of 
informed consent before Week 52 should not be considered as discontinued from the study. 
Subjects should continue attending site visits for the study assessments. Subjects who are 
unwilling to continue attending further study visits after discontinuing the study drug, should 
attend the end of study visit. The End of Treatment visit (EOT 1 for discontinuation during 
Treatment Period 1 and EOT 2 for discontinuation during Treatment Period 2) which should be 
performed two weeks (where possible) after their last dose of study drug. After the EOT visit, 
subjects should enter the post-treatment Follow-Up period.
If the primary endpoint analysis conducted after all subjects complete Week 16 shows a positive 
benefit-risk for only one of the two dose regimens evaluated in the study (e.g. no significant 
effect on primary and secondary endpoints is observed for one of the proposed dose regimens), 
patients still participating in Treatment Period 2 will be transitioned to the dose regimen with 
positive benefit-risk. 
Post-Treatment Follow-Up (8 weeks)
Only subjects who prematurely discontinue study treatment in Treatment Periods 1 or 2 for any 
reason, or subjects who do not enroll in the planned extension study, will enter the Post-
Treatment Follow-Up and complete the Week 60 (F8) visit (see Table 8-1).


Novartis
Confidential
Page 26
Amended Protocol Version 02 (Clean)
Protocol No. CAIN457M2302
Figure 3-1
Study design
BSL: Baseline; EOT1/EOT2: End of Treatment 1/2; F8: End of Follow-up visit at Week 60;q2w: every 
two weeks; q4w: every four weeks. Treatment allocation for Placebo arm switching to secukinumab 
arms at Week 16 will be performed at the Randomization visit in 1:1 ratio and does not account for 
potential discontinuations during Treatment Period 1. Follow-up: only subjects who prematurely 
discontinue treatment during Treatment Period 1 or 2 or subjects who do not enroll in the extension 
study, will enter Follow-up.
In the event of a global health disruptive event, such as a pandemic/epidemic (e.g. COVID-19), that 
limits or prevents the conduct of site study visits per protocol, special effort should be made to conduct 
on-site visits for the EOT(s) visits, Week 16 and Week 52. If it is not feasible to conduct these visits on 
site, virtual visits, or visits to the patient´s home should be attempted.
Delay of Week 52 visit (special scenario) 
In the event Week 52 cannot be performed on-site as scheduled due to a global health disruptive 
event, such as a pandemic/epidemic (e.g. COVID-19), or to a delay of HAs/ECs approval of the 
extension protocol, an additional treatment period of up to a maximum of 12 weeks (i.e., up to 
6 doses, the frequency of study drug injections will remain every 2 weeks) could be considered 
to ensure therapeutic continuity for the patients until they are able to perform Week 52 visit on-
site, and then participate in  the long-term extension study. See Figure 3-2.


Novartis
Confidential
Page 27
Amended Protocol Version 02 (Clean)
Protocol No. CAIN457M2302
Figure 3-2
Study design in case of global health disruptive event
*UNS = Unscheduled; UNS1, UNS2 and UNS3 correspond to three possible additional IRT calls at 
which 2 doses will be dispensed.
4
Rationale
4.1
Rationale for study design
The double-blind, randomized, parallel-group, placebo-controlled design will enable the 
evaluation of the benefit-risk of the two proposed secukinumab dose regimens in an adequate 
and well-controlled setting.
The primary and secondary endpoints reflect the most important domains in HS as proposed by 
the scientific community (Thorlacius et al 2018). The primary endpoint used in this study, 
HiSCR, was developed and validated in the context of the development program of adalimumab 
in HS. The HiSCR is considered to be adequately described and validated for its intended 
purpose as the primary endpoint in pivotal studies and has already been the basis for the HA 
approval of adalimumab as a treatment for patients with moderate to severe 
HS (Humira (adalimumab) EPAR).
AN count, number of flares and reduction in skin pain are selected as secondary endpoints due 
to their impact on patient’s quality of life. These endpoints will provide complementary 
clinically relevant information not fully evaluated in the primary endpoint, HiSCR.


Novartis
Confidential
Page 28
Amended Protocol Version 02 (Clean)
Protocol No. CAIN457M2302
The primary endpoint will be evaluated at Week 16, which is the maximal acceptable duration 
of treatment exposure to placebo in this indication (see Section 4.3 for further rationale on the 
use of placebo). The total study duration including one year of treatment will allow for 
assessment of long-term safety and sustainability of the effect in the two dose regimens.
Adult subjects with moderate to severe HS will be included in the study. Moderate to severe 
HS will be defined as having at least 5 inflammatory lesions affecting at least 2 anatomical 
areas. This definition focuses on the degree and extent of inflammatory activity at baseline 
instead of using the level of scarring in the worst affected area as in the previously used Hurley 
Stages.
The proposed number of inflammatory lesions assures that patients would meet the definition 
of moderate to severe disease in the broadly used HS-PGA tool as proposed by Alavi 
(Alavi 2016). It is also in line with the proposed refined Hurley Staging (Horváth et al 2017), 
which proposes that selecting the population by requiring 5 inflammatory lesions in at least 2 
anatomical locations is the appropriate way to define patients with moderate to severe HS who 
should be candidates for treatment with biologic anti-inflammatory therapies. Using this 
definition for moderate to severe HS it is expected that the study will mainly include patients 
in Hurley stages II and III, but will still allow a small proportion of patients with highly 
inflammatory Hurley stage I to enter the study. Based on available data, it is expected that the 
proportion of Hurley stage I patients in the proposed studies will be less than 15% of the 
recruited patients in this study.
Patient's previous treatment failure to antibiotics is not a requirement to enter the study. It is 
expected that the majority of the patients entering the study would have previously received 
systemic antibiotics at least during the period since diagnosis (≥ 1 year).
Reflecting the clinical practice in many countries and the concern of exposing some patients to 
placebo for up to 16 weeks without anti-inflammatory therapy, this study allows a proportion 
of the patients to remain on a stable dose of systemic antibiotics during Treatment Period 1. It 
is usually not considered acceptable to maintain patients on systemic antibiotics if they have 
previously failed to respond to this treatment approach. It is expected that patients who 
previously failed to respond to systemic antibiotics will enter the study without chronic use of 
systemic antibiotics (non-antibiotic strata). Information on the previous use of systemic 
therapies will be collected at baseline and will support efficacy analysis based on previous 
antibiotic use.
Patients with 20 or more fistulas at baseline will not be eligible for the study as the high level 
of scarring expected in these patients could significantly impair the ability to accurately count 
the number of inflammatory lesions for the primary and secondary endpoint.
4.2
Rationale for dose/regimen and duration of treatment
Two secukinumab dosing regimens will be evaluated in this study:

Secukinumab 300 mg s.c. every 4 weeks

Secukinumab 300 mg s.c. every 2 weeks
Both dose regimens will start with an induction period consisting of 300 mg s.c. injections at 
Baseline, Weeks 1, 2, 3, and 4, followed by the maintenance treatment as described in Section 3. 


Novartis
Confidential
Page 29
Amended Protocol Version 02 (Clean)
Protocol No. CAIN457M2302
As clearly demonstrated in the development program for moderate to severe plaque psoriasis, 
it is expected that the induction period with weekly dosing during the first month will enable to 
quickly achieve effective drug concentrations and lead to a more rapid onset of clinical response.
Rationale for 300 mg s.c. every 4 weeks regimen
Secukinumab 300 mg s.c. with an initial weekly induction schedule up to 4 weeks followed by 
a s.c administration of every four weeks up to Week 48 is in line with the secukinumab Phase 
3 registration program and the approved product labelling for moderate to severe plaque 
psoriasis. Initial information from case reports shows a positive clinical response to treatment 
in 
patients 
with 
HS 
treated 
with 
the 
psoriasis 
therapeutic 
dose 
(Thorlacius et al 2017;
Schuch et al 2018). The demonstrated positive benefit-risk of the 
300 mg s.c. every 4 weeks regimen in psoriasis, another inflammatory dermatological disease, 
supported by case reports showing positive clinical effects in HS patients indicates the potential 
of this dose regimen to show a positive benefit-risk in HS and justifies further evaluation in this 
study.
Rationale for 300 mg s.c. every 2 weeks regimen
In addition to the psoriasis dose regimen, the second dose regimen will be evaluated to achieve 
a higher exposure for the following reasons:

Higher body weights are expected for this population compared to the psoriasis population 
(approximately 10 kg heavier weight for HS population in clinical trials 
(Kimball et al 2016)), thus potentially requiring higher doses to achieve adequate 
exposure. Secukinumab systemic exposure varies with body weight in an allometric 
relationship. For clearance, the allometric exponent was estimated to be close to 1; in 
other words, a doubling of body weight could lead to a nearly 2-fold increase in clearance 
and therefore reduced serum exposure (Bruin et al 2017). Therefore, evaluation of a 
dosing regimen with higher exposure than that resulting from the marketed regimen is 
appropriate in this heavier patient population.

Higher local exposure than in psoriasis might be needed for this disease with deep 
inflammatory subcutaneous lesions.

Clinical experience with adalimumab in HS supports a dosing regimen with higher 
exposure in HS than in psoriasis.
After the same induction period during the first month, considerably higher and more consistent 
systemic exposure can be achieved with a shortened dose interval (every 2 weeks) than can be 
reached with the 4 weeks interval (Figure 4-1).
Secukinumab 300 mg s.c. every 2 weeks has been tested in over 300 patients for at least 24 
weeks in completed clinical studies in uveitis and psoriasis. A safety profile in line with that of 
secukinumab 300 mg s.c. every 4 weeks has been observed.






Novartis
Confidential
Page 32
Amended Protocol Version 02 (Clean)
Protocol No. CAIN457M2302
Treatment with multiple high doses of secukinumab (10 mg/kg and 30 mg/kg i.v.) has been 
administered to more than 2000 patients, with the majority receiving 3 doses of 10 mg/kg i.v. 
over 1 month and 38 patients receiving monthly doses for at least 6 months. Treatment with 
high doses (monthly exposure on chronic doses being approximately 2-fold higher compared 
to 300 mg s.c. every 2 weeks dose) was associated with a numerical increase in infections 
compared to placebo, mainly due to more reports of non-serious upper respiratory tract 
infections, but also a few more individual reports of non-serious local fungal infections such as 
oral or vulvovaginal candidiasis. Otherwise, the safety profile was consistent with the known 
safety profile of secukinumab with the approved doses.
The recently completed randomized, double-blind, multicenter study CAIN457A2324 
(NCT03504852), evaluated the safety and efficacy of secukinumab 300 mg s.c. administered 
every 2 weeks (q2w) or every 4 weeks (q4w), in patients with psoriasis who weigh ≥90 kg. 
Study CAIN457A2324 showed that in psoriasis patients who weigh ≥90kg, secukinumab 
300 mg q2w demonstrates a better treatment effect. Whilst the efficacy data is not yet published 
at the time of release of protocol amendment 02, the analysis of the safety data did not 
demonstrate any new safety signals with the q2w regimen and showed an overall safety profile 
in line with what is already known.
The risk to subjects in this trial may be minimized by compliance with the eligibility criteria 
and study procedures, as well as close clinical monitoring, and periodic review of safety data 
by an independent DMC.
Based on all available data, and a positive benefit/risk ratio for the treatment of moderate to 
severe HS with secukinumab at doses 300 mg q4w and 300 mg q2w, it is appropriate to initiate 
study CAIN457M2302.
Additional information can be found in the IB for secukinumab.
5
Population
The study population will consist of a representative group of adult male and female patients (≥ 
18 years old) with moderate to severe HS. The study originally aimed to randomize 
approximately 471 patients in approximately 132 study sites worldwide. To account for the 
disruptive impact of the COVID-19 pandemic on the conduct of the study since the release of 
protocol amendment 01, the number of randomized patients was increased to approximately 
541 (15increase from the original population of 471 patients). Up to 40% of the patients will 
be allowed to enter the study on treatment with stable dose of antibiotics. Patients who drop out 
after they have been randomized will not be replaced.
In case of a global health disruptive event, such as pandemic/epidemic impacting the conduct 
of the trial, patients or sites may not be able to perform the assessments as per protocol, leading 
to a potential increase in the number of missing measurements. If the latter should affect the 
power of tests and the precision of estimates for this study, the Sponsor may consider recruiting 
additional patients to restore the sample size and maintain the pre-defined statistical power. 
5.1
Inclusion criteria
Patients eligible for inclusion in this study must meet all of the following criteria:


Novartis
Confidential
Page 33
Amended Protocol Version 02 (Clean)
Protocol No. CAIN457M2302
1. Written informed consent must be obtained before any assessment is performed.
2. Male and female patients ≥ 18 years of age.
3. Diagnosis of HS ≥ 1 year prior to baseline.
4. Patients with moderate to severe HS defined as:

A total of at least 5 inflammatory lesions, i.e. abscesses and/or inflammatory nodules
AND

Inflammatory lesions should affect at least 2 distinct anatomic areas
5. Patients agree to daily use of topical over-the-counter antiseptics on the areas affected by 
HS lesions while on study treatment.
5.2
Exclusion criteria
Patients meeting any of the following criteria are not eligible for inclusion in this study.
1. Total fistulae count ≥ 20 at baseline.
2. Any other active skin disease or condition that may interfere with assessment of HS.
3. Active ongoing inflammatory diseases other than HS that require treatment with prohibited 
medications (see Table 6-2).
4. Underlying conditions (including, but not limited to metabolic, hematologic, renal, hepatic, 
pulmonary, neurologic, endocrine, cardiac, infectious or gastrointestinal
such as 
inflammatory bowel disease) which in the opinion of the investigator significantly 
immunocompromises the patient and/or places the patient at unacceptable risk for receiving 
an immunomodulatory therapy.
5. Current severe progressive or uncontrolled diseases which renders the patient unsuitable for 
the trial or puts the patient at increased risk, including any medical or psychiatric condition 
which, in the Investigator’s opinion, would preclude the participant from adhering to the 
protocol or completing the study per protocol.
6. Use or planned use of prohibited treatment. Washout periods detailed in the protocol have 
to be adhered to (see Table 6-2).
7. For patients enrolling in the non-antibiotic strata: use of systemic antibiotics for the 
treatment of HS within 28 days before baseline.
For patients enrolling in the antibiotic strata: patients enter the study under concomitant 
treatment with systemic antibiotics (as per protocol) on a stable dose (defined as a dose or 
dose regimen that has not changed in the previous 28 days before baseline and is considered 
unlikely to change at least for the first 16 weeks during the study).
8. History of hypersensitivity to any of the study drug constituents.
9. Previous exposure to secukinumab (AIN457) or any other biologic drug directly targeting 
IL-17 A/F or the IL-17 receptor.
10. History of chronic or recurrent systemic infections or active systemic infections during the 
last two weeks (exception: common cold) prior to randomization.
11. Evidence of tuberculosis infection as defined by a positive QuantiFERON® TB-Gold test 
(QFT) at screening. Patients with a positive or indeterminate QFT test may participate in 
the study if a full tuberculosis work-up (according to local practice/guidelines) completed 
within 12 weeks prior to randomization, establishes conclusively that the patient has no 


Novartis
Confidential
Page 34
Amended Protocol Version 02 (Clean)
Protocol No. CAIN457M2302
evidence of active tuberculosis. Subjects positive for latent TB per work-up may be 
randomized to the trial if sufficient treatment has been initiated according to local routine 
clinical practice and was completed at least four weeks before randomization.
12. Medical history record of infection with human immunodeficiency virus (HIV), hepatitis B 
or C prior to randomization, except for hepatitis C successfully treated and cured.
13. History of lymphoproliferative disease or any known malignancy or history of malignancy 
of any organ system treated or untreated within the past 5 years, regardless of whether there 
is evidence of local recurrence or metastases (except for skin Bowen’s disease, or basal cell 
carcinoma or actinic keratoses that have been treated with no evidence of recurrence in the 
past 12 weeks; carcinoma in situ of the cervix or non-invasive malignant colon polyps that 
have been removed).
14. History or evidence of ongoing alcohol or drug abuse, which in the opinion of the 
investigator will prevent the patient from adhering to the protocol and completing the study.
15. Pregnant or lactating women.
16. Women of childbearing potential, defined as all women physiologically capable of 
becoming pregnant, unless they are using methods of contraception during the entire study 
or longer if required by locally approved prescribing information (e.g. in European Union 
(EU) 20 weeks).
Contraception methods include:

Total abstinence, when this is in line with the preferred and usual lifestyle of the patient. 
Periodic abstinence (e.g. calendar, ovulation, symptothermal, post-ovulation methods) 
and withdrawal are not acceptable methods of contraception.

Female sterilization (have had surgical bilateral oophorectomy with or without 
hysterectomy), total hysterectomy or bilateral tubal ligation at least six weeks before 
taking study treatment. In case of oophorectomy alone, only when the reproductive 
status of the woman has been confirmed by follow-up hormone level assessment.

Male sterilization (at least 6 months prior to screening). The vasectomized male partner 
should be the sole partner for that patient.

Barrier methods of contraception: Condom or Occlusive cap (diaphragm or 
cervical/vault 
caps). 
For 
United 
Kingdom: 
with 
spermicidal 
foam/gel/film/cream/vaginal suppository.

Use of oral (estrogen and progesterone), injected or implanted hormonal methods of 
contraception or other forms of hormonal contraception that have comparable efficacy 
(failure rate <1%), for example hormone vaginal ring or transdermal hormone 
contraception or placement of an intrauterine device (IUD) or intrauterine system (IUS).
In case of use of oral contraception, women should have been stable on the same pill for a 
minimum of 3 months before taking study treatment.
In case local regulations deviate from the contraception methods listed above, local 
regulations apply and will be described in the informed consent form (ICF).
Note: Women are considered post-menopausal and not of childbearing potential if they have 
had 12 months of natural (spontaneous) amenorrhea with an appropriate clinical profile (e.g. 
age appropriate, history of vasomotor symptoms) or have had surgical bilateral 
oophorectomy (with or without hysterectomy), total hysterectomy or bilateral tubal ligation 


Novartis
Confidential
Page 35
Amended Protocol Version 02 (Clean)
Protocol No. CAIN457M2302
at least six weeks prior to enrollment. In the case of oophorectomy alone, only when the 
reproductive status of the woman has been confirmed by follow-up hormone level 
assessment is she considered not of childbearing potential.
No additional exclusions may be applied by the investigator, in order to ensure that the study 
population will be representative of all eligible patients.
6
Treatment
6.1
Study treatment
6.1.1
Investigational and control drugs
Table 6-1
Investigational and control drug
Investigational/ 
Control Drug
(Name and 
Strength)
Pharmaceutical 
Dosage Form
Route of 
Administration
Blinding/volume
Sponsor
(global or local)
Secukinumab 300 
mg
Solution for 
injection
Subcutaneous Use
Double blinded 
subject packs; 2 ml 
pre-filled syringe
Sponsor (global)
Placebo
Solution for 
injection
Subcutaneous Use
Double blinded 
subject packs; 2 ml 
pre-filled syringe
Sponsor (global)
Novartis will supply the investigational therapy as follows:

Secukinumab 300 mg solution for sub-cutaneous injection in a 2 ml pre-filled syringe

Placebo solution for sub-cutaneous injection in a 2 ml pre-filled syringe
Each placebo pre-filled syringe contains a mixture of inactive excipients, matching the 
composition and the appearance of the secukinumab 300 mg dose.
Secukinumab and the secukinumab matching placebo will be labeled as “AIN457 300 mg / 
Placebo” (2 ml) to keep the blind. Subjects will be initially instructed about injections by site 
staff. They will also receive instructions on how to self-inject using the pre-filled syringe.
6.1.2
Additional study treatments
No additional treatment beyond investigational drug and control drug are included in this trial. 
Subjects are requested to use over-the-counter antiseptics according to eligibility criteria, 
Section 6.2.1 and Section 6.2.2. For rescue medication, see Section 6.2.3.
6.1.3
Treatment arms/group
At Baseline/Randomization visit, all eligible subjects will be randomized via Interactive 
Response Technology (IRT) in a 1:1:0.5:0.5 ratio to one of the following 4 treatment groups:
• Secukinumab 300 mg every 2 weeks group: subjects will receive a loading dose of 
secukinumab 300 mg once weekly for four weeks (at Randomization, Weeks 1, 2, 3 and 4), 
followed by secukinumab 300 mg every two weeks, starting at Week 6 and up to Week 


Novartis
Confidential
Page 36
Amended Protocol Version 02 (Clean)
Protocol No. CAIN457M2302
50. These subjects will receive two additional placebo injections at Weeks 17 and 19 to 
maintain the treatment blind during the re-induction.
• Secukinumab 300 mg every 4 weeks group: subjects will receive secukinumab 300 mg once 
weekly for four weeks (at Randomization, Weeks 1, 2, 3 and 4), followed by secukinumab 300 
mg every four weeks, starting at Week 8 and up to Week 48. In order to maintain the treatment 
blind, subjects in this group will also receive a placebo injection every 4 weeks starting at Week 
6, until Week 50. These subjects will receive three additional placebo injections at Weeks 17, 
18 and 19 to maintain the treatment blind during the re-induction.
• Placebo group to secukinumab 300 mg every 2 weeks: subjects will receive placebo once 
weekly for four weeks (at Randomization, Weeks 1, 2, 3 and 4), followed by placebo every two 
weeks, starting at Week 6 and up to Week 14. At Week 16, subjects will be switched from 
Placebo to Secukinumab 300 mg every 2 weeks. The subjects will receive secukinumab 300 
mg once weekly for four weeks (Weeks 16, 17, 18, 19 and 20), followed by secukinumab 300 
mg every two weeks, starting at Week 22 and until Week 50.
• Placebo group to secukinumab 300 mg every 4 weeks: subjects will receive placebo once 
weekly for four weeks (at Randomization, Weeks 1, 2, 3 and 4), followed by placebo every two 
weeks, starting at Week 6 and up to Week 14. At Week 16, subjects will be switched from 
Placebo to Secukinumab 300 mg every 4 weeks. The subjects will receive secukinumab 300 
mg once weekly for four weeks (Weeks 16, 17, 18, 19 and 20), followed by secukinumab 300 
mg every four weeks, starting at Week 24 and up to Week 48. To maintain the treatment blind, 
subjects will receive placebo alternating with secukinumab starting at Week 22 and up to Week 
50.
See Figure 3-1 for graphical representation of type of injection per treatment group and visit.
6.1.4
Treatment duration
The planned duration of treatment is 52 weeks. Subjects may be discontinued from treatment 
earlier due to unacceptable toxicity or at the discretion of the investigator or the subject. After 
completion of Treatment Period 2, subjects may continue treatment in a planned extension 
study or enter the 8-week post-treatment Follow-up in this study.
6.2
Other treatment(s)
6.2.1
Concomitant therapy
The investigator must instruct the subject to notify the study site about any new medications 
taken after enrolling in the study. All medications, procedures and significant non-drug 
therapies (including physical therapy and blood transfusions) administered after the subject was 
enrolled into the study must be recorded on the appropriate electronic case report/record form 
(eCRF).
Each concomitant drug must be individually assessed against all exclusion criteria/prohibited 
medication. If in doubt, the investigator should contact the Novartis medical monitor before 
randomizing a subject or allowing a new medication to be started.


Novartis
Confidential
Page 37
Amended Protocol Version 02 (Clean)
Protocol No. CAIN457M2302
6.2.1.1
Permitted concomitant therapy
Antiseptic Therapy
Subjects should be instructed to use daily topical over-the-counter antiseptics on the skin areas 
affected by HS lesions following the local standard practice.
Wound Care
Concomitant use of wound care dressings on HS wounds is allowed following the local standard 
practice.
6.2.1.2
Permitted concomitant therapy requiring caution and/or action
Antibiotics
Systemic antibiotics for the treatment of acute systemic infectious disease both related or 
unrelated to HS (e.g. pneumonia, cellulitis) are allowed as medically warranted during the study.
Systemic antibiotics for the treatment of HS are only allowed as rescue medication as described 
in Section 6.2.3 below.
For subjects entering the study in the antibiotic strata, treatment with the following tetracyclines 
on a stable dose is allowed in Treatment Period 1:

Tetracycline up to 500 mg twice a day

Minocycline up to 100 mg twice a day

Doxycycline up to 100 mg twice a day
Analgesics
Subjects will be required to wash out opioid analgesics (including tramadol) for 14 days prior 
to Baseline. This includes opioids for both HS-related pain and non-HS-related pain.
Subjects on a stable dose of a non-opioid analgesic ("as needed" is not considered stable) may 
continue the analgesic, provided the dose is stable for 14 days prior to Baseline and is 
anticipated to remain stable for at least 16 weeks of treatment.
In case a subject presents with uncontrolled pain related to HS during the study, 
ibuprofen and acetaminophen (paracetamol) are permitted. 
If HS-related pain is uncontrolled with ibuprofen or acetaminophen (paracetamol) at the 
maximal dose as per local label during the trial, subjects can be prescribed tramadol (at a dose 
of up to 100 mg orally every 4 hours), not to exceed 400 mg/24 hours.
Information on the concomitant use of analgesics should be recorded by the subject in the 
eDiary and reviewed by the investigator at the scheduled visits.
6.2.2
Prohibited medication
Use of the treatments displayed in Table 6-2 that could confound the efficacy assessment or 
could put the patient at an additional safety risk are not allowed during the study and wash-out 


Novartis
Confidential
Page 38
Amended Protocol Version 02 (Clean)
Protocol No. CAIN457M2302
periods for these treatments prior to randomization are indicated in the table. If the use of these 
treatments is required, then the subject should not be randomized.
The investigator should instruct the subject to notify the study site about any new treatments 
he/she takes after the start of study treatment. All prohibited medications and significant non-
drug therapies administered after the subject starts study treatment must be recorded in the 
eCRF.
If a prohibited treatment listed in Table 6-2 is used during the study, the subject should 
discontinue use of the prohibited treatment if he/she wishes to continue in the study. At the 
discretion of the investigator, if the subject’s use during the study of a prohibited treatment 
presents undue safety risk for the subject, the subject should be discontinued from study 
treatment.
Table 6-2
Prohibited medication
Medication
Prior to randomization
Use between 
randomization and last 
dose of study drug
Action taken
Prior treatment with 
secukinumab or other 
agents blocking IL-17 A/F 
or IL-17R
Not allowed
Not allowed
Subject not eligible
Systemic biological 
immunomodulating 
treatment (e.g. 
adalimumab, infliximab, 
ustekinumab, anakinra, 
natalizumab)
12 weeks wash-out 
period or 5 half-lives, 
whichever is longer
Not allowed
Discontinue use or 
discontinue study 
treatment
Systemic non-biologic 
immunomodulating 
treatment (e.g. 
methotrexate (MTX), 
cyclosporine A, retinoids, 
apremilast)
28 days wash-out period 
required
Not allowed
Discontinue use or 
discontinue study 
treatment
Topical antibiotic 
therapies for the 
treatment of HS
14 days wash-out period 
required
Not allowed until Week 
16
Discontinue use or 
discontinue study 
treatment if not medically 
warranted
Antibiotics for the 
treatment of HS (non-
antibiotic strata)
28 days wash-out period 
required
Not allowed until Week 
16, except for 
rescue treatment
Discontinue use or 
discontinue study 
treatment if not medically 
warranted
Systemic corticosteroids 
for the treatment of HS
28 days wash-out period 
required
Not allowed
Discontinue use of 
discontinue study 
treatment
Opioid analgesics
14 days wash-out period 
required
Not allowed
Discontinue use or 
discontinue study 
treatment
Surgeries for the 
treatment of HS other 
than allowed as rescue 
therapy
Not allowed within 6 
weeks prior to 
randomization
Not allowed until Week 
16
Discontinue study 
treatment


Novartis
Confidential
Page 39
Amended Protocol Version 02 (Clean)
Protocol No. CAIN457M2302
Medication
Prior to randomization
Use between 
randomization and last 
dose of study drug
Action taken
Live vaccines
Not allowed within 6 
weeks prior to 
randomization
Not allowed
Discontinue study 
treatment
Any investigational 
treatment or participation 
in any interventional trial
28 days or 5 half-lives 
(whichever is longer) 
wash-out period required
Not allowed
Discontinue study 
treatment
6.2.3
Rescue medication
Antibiotics
At Week 4, 8 and 12, if a subject experiences an increase in their AN count (for example, the 
total count is greater-than-or equal-to 150% of the weighted average of screening and baseline 
AN count (Section 12.4.1)) with a minimum increase of 3 lesions, oral antibiotics rescue 
medication can be used. This applies only to Treatment Period 1.
Subjects who qualify for rescue medication may initiate antibiotic treatment with minocycline 
or doxycycline up to 100 mg bid. The dosing regimen must remain stable until Week 16. Except 
for current antibiotic use strata, concomitant use of antibiotic therapy for treatment of HS is 
otherwise not allowed. However, antibiotics are permitted to treat an acute infection if 
medically warranted (Section 6.2.1.2). Rescue antibiotic therapy should be captured in the 
source and on the appropriate eCRF.
Lesion Intervention
In the event of an acutely painful single lesion that requires an immediate intervention, the 
investigator will be allowed to perform an unplanned surgery/intervention for lesion such as 
excision, drainage or intra-lesion steroid administration at any time.
Other HS related surgery is not allowed until after Week 16.
All study visit evaluations must take place before any interventions are performed.
6.3
Subject numbering, treatment assignment, randomization
6.3.1
Subject numbering
Each subject is identified in the study by a Subject Number (Subject No.), that is assigned when 
the patient is enrolled for screening and is retained for the subject throughout his/her 
participation in the trial. A new Subject No. will be assigned if the subject is rescreened. The 
Subject No. consists of the Center Number (Center No.) (as assigned by Novartis to the 
investigative site) with a sequential subject number suffixed to it, so that each subject 
participation is numbered uniquely across the entire database. Upon signing the informed 
consent form, the patient is assigned to the next sequential Subject No. available within the 
electronic data capture (EDC) system.
The investigator or his/her staff will contact the IRT and provide the requested identifying 
information for the subject to register them into the IRT.


Novartis
Confidential
Page 40
Amended Protocol Version 02 (Clean)
Protocol No. CAIN457M2302
If the subject fails to be treated for any reason, the IRT must be notified within 2 days that the 
subject was not treated. The reason for not being treated will be entered on the appropriate 
eCRF.
6.3.2
Treatment assignment, randomization
The investigator or his/her delegate will contact the IRT after confirming that the subject fulfills 
all the inclusion/exclusion criteria. The IRT will assign a randomization number to the subject, 
which will be used to link the subject to a treatment arm and will specify a unique medication 
number for the package of study drug to be dispensed to the subject. The randomization number 
will not be communicated to the investigator or his/her delegate.
The randomization numbers will be generated using the following procedure to ensure that 
treatment assignment is unbiased and concealed from subjects and investigator staff. A patient 
randomization list will be produced by the IRT provider using a validated system that automates 
the random assignment of patient numbers to randomization numbers. These randomization 
numbers are linked to the different treatment arms, which in turn are linked to medication 
numbers. A separate medication list will be produced by or under the responsibility of Novartis 
Clinical Drug Supply using a validated system that automates the random assignment of 
medication numbers to packs containing the investigational drug(s).
Randomization will be stratified by region, concomitant antibiotic use (Yes/No) and body 
weight (weight < 90kg / ≥ 90kg).
The randomization scheme for subjects will be reviewed and approved by a member of the 
Randomization Group.
6.4
Treatment blinding
This is a double blind study. Subjects, investigator staff, persons performing the assessments, 
and Novartis Clinical Trial Team (CTT) will remain blind to the identity of the treatment from 
the time of randomization until database lock, using the following methods:
1. Randomization data are kept strictly confidential until the time of unblinding, and will not be 
accessible by anyone else involved in the study with the following exceptions:

Specific vendors whose role in trial conduct requires their unblinding (e.g., IRT)

Drug Supply Management

The designated Novartis study team members involved in the primary endpoint analysis
2. The identity of the treatments will be concealed by the use of study treatment that are all 
identical in packaging, labeling, schedule of administration, appearance and schedule of 
administration.
The randomization codes associated with subjects from whom PK samples are taken will be 
disclosed to the bioanalyst and pharmacokineticist (if required at primary endpoint analysis) 
who will keep serum concentrations confidential until database lock.
For subjects, investigators/site personnel and Novartis personnel working directly with the sites, 
unblinding will occur in the case of subject emergencies (see Section 6.6.3), and at the 
conclusion of the study. The appropriate personnel from the study site and Novartis will assess 


Novartis
Confidential
Page 41
Amended Protocol Version 02 (Clean)
Protocol No. CAIN457M2302
whether the study treatment should be discontinued for any subject whose treatment code has 
been broken inadvertently for any reason.
At the time of a primary endpoint analysis after all subjects have completed Week 16, the 
designated Novartis personnel (e.g. biostatisticians and programmers involved in the analysis, 
key Global Team members) may have access to the unblinded results. Field monitors/clinical 
research associates will remain blinded until after final database lock. Subjects and site 
personnel directly involved in the conduct of the trial, i.e. investigator staff and persons 
performing the assessments, will remain blinded to individual treatment allocation until the 
conclusion of the study to ensure study integrity is maintained.
6.5
Dose escalation and dose modification
Investigational or other study treatment dose adjustments and/or interruptions are not permitted.
6.5.1
Dose modifications
Study treatment interruption is only permitted if, in the opinion of the investigator, a subject is 
deemed to be placed at a significant safety risk unless dosing is temporarily interrupted. In such 
cases, study treatment should be interrupted only during the time that this risk is present and 
ongoing. Study treatment can be restarted at the next scheduled visit after resolution of the 
safety risk.
These changes must be recorded on the appropriate eCRF.
6.5.2
Follow-up for toxicities
Not applicable.
6.6
Additional treatment guidance
6.6.1
Treatment compliance
All doses of study treatment administration will be recorded on the appropriate Dosage 
Administration Record eCRF page (visit specific and summary pages). For study treatment 
administration at home, the investigator must promote compliance by instructing the subject to 
administer the study treatment exactly as instructed and by stating that compliance is necessary 
for the subject’s safety and the validity of the study. The subject must also be instructed to 
contact the investigator if he/she is unable for any reason to administer the study treatment. 
Compliance will be assessed by the investigator and/or study personnel at each visit using empty 
medication packaging, pre-filled syringe (PFS) and information provided by the subject. This 
information should be captured in the source document at each visit. All study treatment 
dispensed and returned must be recorded in the Drug Accountability Log. Compliance will also 
be assessed and confirmed by a field monitor by drug accountability logs, by documentation
and information provided by IRT and by the qualified site personnel that is responsible for 
treatment dispensation, administration and accountability. Cross-checks should be performed 
for home administrations (H) and empty medication outer packing and patient's returned PFS 
should be collected for compliance checks by field monitors.


Novartis
Confidential
Page 42
Amended Protocol Version 02 (Clean)
Protocol No. CAIN457M2302
Pharmacokinetic parameters (measures of treatment exposure) will be determined in all subjects 
treated with secukinumab, as detailed in the Pharmacokinetics Section 8.5.2.
6.6.2
Recommended treatment of adverse events
Treatment for adverse events should follow general guidelines for standard-of-care, and is at 
the discretion of the investigator or treating physician. There are no specific treatment 
recommendations for adverse events that may possibly occur in this trial. Refer to the 
Investigator's Brochure for adverse events related to secukinumab.
6.6.3
Emergency breaking of assigned treatment code
Emergency code breaks must only be undertaken when it is required to in order to treat the 
subject safely. Most often, study treatment discontinuation and knowledge of the possible 
treatment assignments are sufficient to treat a study subject who presents with an emergency 
condition. Emergency treatment code breaks are performed using the IRT. When the 
investigator contacts the system to break a treatment code for a subject, he/she must provide the 
requested subject identifying information and confirm the necessity to break the treatment code 
for the subject. The investigator will then receive details of the investigational drug treatment 
for the specified subject and a fax or email confirming this information. The system will 
automatically inform the Novartis monitor for the site and the study team that the code has been 
broken.
It is the investigator’s responsibility to ensure that there is a dependable procedure in place to 
allow access to the IRT at any time in case of emergency. The investigator will provide:

protocol number

study drug name (if available)

subject number
In addition, oral and written information to the subject must be provided on how to contact the 
investigator's backup in cases of emergency, or when he/she is unavailable, to ensure that un-
blinding can be performed at any time.
Study treatment must be discontinued after emergency unblinding.
6.7
Preparation and dispensation
Investigator staff will identify the study medication kits to dispense to the subject by contacting 
the IRT and obtaining the medication number(s). The study medication has a 2-part label (base 
plus tear-off label), immediately before dispensing the medication kit to the subject, site 
personnel will detach the outer part of the label from the packaging and affix it to the source 
document.
In case of a major health care event (e.g., pandemic, epidemic) that limits or prevents on-site 
study visits, if required alternative ways to provide study drug may be implemented, including 
but 
not 
limited 
to 
shipping 
or 
home 
delivery 
for 
home 
administration. The 
shipment/provisioning should cover an adequate period, based on local situation and 
regulations. In this case, regular phone calls or virtual contacts (approximately every 4 weeks, 
prior to home administration, or more frequently if needed) will occur between the site and the 


Novartis
Confidential
Page 43
Amended Protocol Version 02 (Clean)
Protocol No. CAIN457M2302
subject for instructional purposes, safety monitoring and discussion on patient’s health status 
until the subject can again visit the site.
This is necessary to ensure that there are no safety concerns to the subject requiring treatment 
interruption or discontinuation.
The subjects will be supplied with material to document drug self-administration and to allow 
accountability of the study medication. At the site level, the agreement with/approval of the 
Principal Investigator, Ethics Committee/ Institutional Review Board (EC/IRB) and any other 
Board as appropriate should be in place to implement home delivery.
6.7.1
Handling of study treatment and additional treatment
6.7.1.1
Handling of study treatment
Study treatment must be received by a designated person at the study site, handled and stored 
safely and properly and kept in a secured location to which only the investigator and designated 
site personnel have access. Upon receipt, all study treatment must be stored according to the 
instructions specified on the labels. Clinical supplies are to be dispensed only in accordance 
with the protocol. Technical complaints are to be reported to the respective Novartis Country 
Organization (CO) Quality Assurance.
Medication labels will be in the local language and comply with the legal requirements of each 
country. They will include storage conditions for the study treatment but no information about 
the subject except for the medication number.
The investigator must maintain an accurate record of the shipment and dispensing of study 
treatment in a drug accountability log. Monitoring of drug accountability will be performed by 
monitors during site visits or remotely and at the completion of the trial. The subjects will record 
the date(s) of administration at home on a diary and will return the used medication and 
packaging at their next visit to the site. Site staff will record in the appropriate documents the 
dates of the administration. Detailed instructions will be provided separately. Subjects will be 
asked to return all unused study treatment and packaging at the end of the study or at the time 
of discontinuation of study treatment.
At the conclusion of the study, and as appropriate during the course of the study, the investigator 
will return all unused study treatment, packaging, drug labels, and a copy of the completed drug 
accountability log to the Novartis monitor or to the Novartis address provided in the investigator 
folder at each site.
6.7.1.2
Handling of additional treatment
Not applicable.
6.7.2
Instruction for prescribing and taking study treatment
Secukinumab solution for s.c. injection or placebo secukinumab solution (active or placebo, 
respectively) will be provided in pre-filled syringes (PFS).
Each subject will require one box with PFS per dose throughout the study:

One secukinumab 300 mg, 2ml PFS OR


Novartis
Confidential
Page 44
Amended Protocol Version 02 (Clean)
Protocol No. CAIN457M2302

One secukinumab placebo 300 mg, 2ml PFS.
All study treatment kits assigned to the subject by IRT during the study will be captured in the 
IRT system.
The first study treatment administration will occur at the baseline/randomization visit after the 
inclusion/exclusion criteria have been confirmed and all study scheduled assessments have been 
performed. All study assessments, including completion of Patient Reported Outcomes (PROs) 
and blood withdrawal, should be completed prior to the self-injection of study treatment.
All doses of study treatment (secukinumab and/or placebo) will be self-administered by the 
subject/ trained caregiver either at the study site after the study assessments for the visits have 
been completed or at home.
The first use at baseline and the Week 1 assessments of the self-injection will take place in the 
context of an observed assessment under the supervision of one site staff member. At the 
baseline visit, subjects will be instructed by the site staff on how to self-inject via the pre-filled 
syringe (Instructions for Use (IFU) containing detailed information about self-administration of 
study treatment should be provided to each subject at the beginning of the study). After 
providing detailed explanations/instructions, subjects will then be asked to raise any questions. 
Thereafter, they will proceed with self-injection. At Week 1, subjects will be asked to refer to 
the IFU and to proceed with self-injection of the actual study drug (i.e. without a detailed 
explanation/instruction on handling the syringe).
Home administrations (H) should be done at pre-defined visits (see Section 3). Home 
administration can be performed by the subject or trained caregiver. If the subject or caregiver 
is not able/confident to perform home administration, the subject will be allowed to return to 
the site for administration of the medication. However, during those visits no additional 
assessments will be required.
During home administrations, subjects will be instructed to contact the investigator/site staff in 
case they are experiencing any AE/SAEs or have any concerns.
In case of a major health care event (e.g., pandemic, epidemic) that limits or prevents on-site 
study visits, home administration of the study drug could be generally permitted. Home 
administration can be performed by the subject or a trained caregiver. Study participants or 
caregivers will be trained adequately on how to perform administrations of the study treatment, 
if not already trained. If the subject or caregiver is not trained for drug administration and 
cannot visit the site to undergo training, the site can consider providing suitable virtual training 
and oversight. A joint decision together with the subject or caregiver should be made as to 
whether this constitutes sufficient training and oversight.
Administration
The study treatment solution must be injected in non-affected areas of the skin.
Pre-filled syringes should be kept at 2 to 8°C (36°F and 46°F), never be frozen, and should be 
protected from light. Prior to administration, the boxes containing the pre-filled syringes should 
be allowed to adapt to room temperature unopened for about 30 to 45 minutes before 
administration. Used PFS (if according to the regulatory needs of the respective countries) 
should be stored in the original boxes and returned at the next site visit for reconciliation.


Novartis
Confidential
Page 45
Amended Protocol Version 02 (Clean)
Protocol No. CAIN457M2302
7
Informed consent procedures
Eligible subjects may only be included in the study after providing (witnessed, where required 
by law or regulation), IRB/IEC-approved informed consent.
If applicable, in cases where the subject's representative(s) gives consent (if allowed according 
to local requirements), the subject must be informed about the study to the extent possible given 
his/her understanding. If the subject is capable of doing so, he/she must indicate agreement by 
personally signing and dating the written informed consent document.
Informed consent must be obtained before conducting any study-specific procedures (e.g. all of 
the procedures described in the protocol). The process of obtaining informed consent must be 
documented in the subject source documents.
Novartis will provide to investigators in a separate document a proposed informed consent form 
that complies with the ICH GCP guidelines and regulatory requirements and is considered 
appropriate for this study. Any changes to the proposed consent form suggested by the 
investigator must be agreed by Novartis before submission to the IRB/IEC and a copy of the 
approved version must be provided to the Novartis monitor after IRB/IEC approval.
Information about common side effects already known about the investigational drug can be 
found in the Investigator's Brochure (IB) and CDS. This information will be included in the 
subject informed consent and should be discussed with the subject during the study as needed. 
Any new information regarding the safety profile of the investigational drug that is identified 
between IB updates will be communicated as appropriate, for example, via an investigator 
notification or an aggregate safety finding. New information might require an update to the 
informed consent and then must be discussed with the subject.
Women of child bearing potential must be informed that taking the study treatment may involve 
unknown risks to the fetus if pregnancy were to occur during the study and agree that in order 
to participate in the study they must adhere to the contraception requirements for the duration 
of the study. If there is any question that the subject will not reliably comply, they must not be 
entered in the study.
The study includes optional sub-study (biopsy sampling) / DNA component which requires a 
separate signature if the subject agrees to participate. It is required as part of this protocol that 
the Investigator presents this option to the subjects, as permitted by local governing regulations. 
The process for obtaining consent should be exactly the same as described above for the main 
informed consent.
Declining to participate in these optional assessments (DNA / biopsy sampling substudy) will 
in no way affect the subject’s ability to participate in the main research study.
A copy of the approved version of all consent forms must be provided to Novartis after IRB/IEC 
approval.
Subjects might be asked to complete an optional questionnaire to provide feedback on their 
clinical trial experience.
During a major health care disruption (e.g., pandemic, epidemic) that may challenge the ability 
to obtain a standard written informed consent due to limits that prevent an on-site visit, the 
Investigator may conduct the informed consent discussion remotely (e.g. telephone, 


Novartis
Confidential
Page 46
Amended Protocol Version 02 (Clean)
Protocol No. CAIN457M2302
videoconference). Guidance issued by local regulatory bodies on this aspect prevail and must 
be implemented and appropriately documented (e.g. the presence of an impartial witness, 
sign/dating separate ICFs by trial subject and person obtaining informed consent, etc).
8
Visit schedule and assessments
Table 8-1 lists all of the study visits and indicates with an “X” when the assessments are to be 
performed. An ‘S’ indicates the data for that assessment are in the source documents at the site.
Subjects should be seen for all visits on the designated day or as close as possible to the original 
planned visit schedule.
If for any reason the subject is a screen failure, the subject may be rescreened once only.
If a subject rescreens for the study, then the subject must sign a new ICF and be issued a new 
subject number prior to any screening assessment being conducted for the subject under the
new screening subject number. For all rescreened subjects, the investigator/qualified site staff 
will record if the subject was rescreened on the rescreening eCRF and the original screening 
number the subject was issued prior to the current screening number.
Informed Consent for a rescreened subject must be obtained prior to performing any study-
related assessment or collecting any data for the Screening Visit. For rescreening, all screening 
assessments must be performed as per protocol, except for the tuberculosis (TB) work up, if 
applicable, if performed not more than 12 weeks before randomization. However, the subject 
must repeat the QuantiFERON test performed by the central laboratory.
During the treatment periods, subjects may be seen at an unscheduled visit, e.g., if they 
experience deterioration of HS, or AEs that in the opinion of the investigator need intervention 
or repeated laboratory testing. The assessment(s) performed at an unscheduled visit are at the 
investigator’s discretion.
Subjects who discontinue study treatment will continue to be followed up for as long as possible, 
and efforts should be made so that subjects continue study visits as per the assessment schedule 
even if not on study drug. Special effort should be made up until Week 16 to ensure that those 
subjects who prematurely discontinue study treatment attend all scheduled visits.
Subjects who discontinue study treatment before completing the study and do not wish to attend 
site visits for assessments only should be scheduled for an end of study visit 2 weeks (wherever 
possible) after their last study treatment administration, at which time all the assessments listed 
for EOT 1 (Week 16)/EOT 2 (Week 52) will be performed. Subjects should then return to the 
study site 8 weeks after completing EOT visit at Week 60 Follow-Up visit for final safety and 
efficacy assessments.
If a subject refuses to return for these assessments or are unable to do so, every effort should be 
made to contact them or a knowledgeable informant by telephone or by sending appropriate 
correspondence (i.e. certified letter) immediately. At this contact, the safety (e.g., potential 
occurrence of AE or SAE) and the primary reason for a subject’s premature withdrawal should 
be determined.
At a minimum, subjects who pre-maturely discontinue the treatment will be contacted for safety 
evaluations during the 10 weeks following the last dose of study treatment, including final 


Novartis
Confidential
Page 47
Amended Protocol Version 02 (Clean)
Protocol No. CAIN457M2302
contact at the 10 week point. Documentation of attempts to contact the subject should be 
recorded in the subject record.
It is recommended that assessments be completed in the following order: PROs, Physician 
assessments, study visit procedures (e.g. laboratory and PK sample collection, vital signs 
measurements), study treatment administration.
In the event of a major health care event (e.g., pandemic, epidemic) that limits or prevents on-
site study visits, regular phone calls (approximately every 4 weeks or more frequently, if 
needed) will occur until the subject can again visit the site. Events qualifying for being reported 
in the case report form (e.g., AE, procedure) should be entered as appropriate. Special effort 
should be made to collect information related to EOT 1, (Week 16) and EOT 2 (Week 52) visits. 
If it is not feasible to conduct these visits on-site, phone calls should be attempted instead. 
Additional Unscheduled doses could be given at Home after Week 50 every 2 weeks for a 
maximum of 12 weeks until the subject is able to perform the Week 52 visit on-site.


Novartis
Confidential
Page 48
Amended Protocol Version 02 (Clean)
Protocol No. CAIN457M2302
Table 8-1
Assessment Schedule
Period
Screening
Treatment Period 1
Treatment Period 2
Post-Treatment 
Follow-Up
Visit Name
Screening 
1
Screening 
2
Baseline
Week 1
Week 2
Week 3
Week 4
Week 8
Week 12
Week 16 / 
EOT1
Week 17
Week 18
Week 19
Week 20
Week 24
Week 28
Week 32
Week 36
Week 40
Week 44
Week 48
UNS 1 to 3
Week 52 / 
EOT2
Week 60 / F8
Days
-28 to -14 -13 to -1
1
8
15
22
29
57
85
113
120 127 134 141 169 197 225 253 281 309 337
365
421
Obtain informed 
consent (ICF)
X
Demography
X
Inclusion / Exclusion 
criteria1
X
X
X
Washout evaluation / 
instruction
S
S
S
Relevant medical 
history / current 
medical condition
X
HS medical history 
and previous therapies 
X
Smoking history
X
Hurley stage
X
X
X
X
X
Prior / concomitant 
medications2
X
Update as necessary
Adverse Events3
X
Update as necessary
Physical Examination1
S
S
S
S
Body Height
X
Body Weight
X
X
X
X
X
X
Vital Signs
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Tuberculosis test
X
X


Novartis
Confidential
Page 49
Amended Protocol Version 02 (Clean)
Protocol No. CAIN457M2302
Period
Screening
Treatment Period 1
Treatment Period 2
Post-Treatment 
Follow-Up
Visit Name
Screening 
1
Screening 
2
Baseline
Week 1
Week 2
Week 3
Week 4
Week 8
Week 12
Week 16 / 
EOT1
Week 17
Week 18
Week 19
Week 20
Week 24
Week 28
Week 32
Week 36
Week 40
Week 44
Week 48
UNS 1 to 3
Week 52 / 
EOT2
Week 60 / F8
Days
-28 to -14 -13 to -1
1
8
15
22
29
57
85
113
120 127 134 141 169 197 225 253 281 309 337
365
421
Lesion count 
(physician)
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Flare assessment4
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Numerical Rating 
Scale for pain 
assessment5
Completed daily in the eDiary
Completed weekly in the eDiary
Modified Hidradenitis 
Suppurativa Score 
(mHSS)
X
X
X
X
HS-Physician's Global 
Assessment
X
X
X
X
X
X
X
X
Patient's Lesion Count Completed weekly in the eDiary
DLQI
X
X
X
X
X
X
X
EQ5D
X
X
X
X
X
X
X
Patient Global 
Impression of severity 
(PGI-s)
X
X
X
X
X
X
X
Patient Global 
Impression of change 
(PGI-c)
X
X
X
X
X
X
X
Work productivity 
Activity Impairment 
(WPAI)
X
X
X
X
X
X
HS Symptom Diary6
Completed daily in the eDiary
X
X
X
X
X
Hematology
X
X
X
X
X
X
X
X
X
X
X
X
X
Clinical Chemistry
X
X
X
X
X
X
X
X
X
X
X
X
X


Novartis
Confidential
Page 50
Amended Protocol Version 02 (Clean)
Protocol No. CAIN457M2302
Period
Screening
Treatment Period 1
Treatment Period 2
Post-Treatment 
Follow-Up
Visit Name
Screening 
1
Screening 
2
Baseline
Week 1
Week 2
Week 3
Week 4
Week 8
Week 12
Week 16 / 
EOT1
Week 17
Week 18
Week 19
Week 20
Week 24
Week 28
Week 32
Week 36
Week 40
Week 44
Week 48
UNS 1 to 3
Week 52 / 
EOT2
Week 60 / F8
Days
-28 to -14 -13 to -1
1
8
15
22
29
57
85
113
120 127 134 141 169 197 225 253 281 309 337
365
421
Fasting lipid panel
X
X
X
Urinalysis
X
X
X
Serum pregnancy test
X
Urine pregnancy test
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
Blood sample for 
pharmacokinetics
X
X
X
X
X
Blood sample for 
immunogenicity
X
X
X
X
Biomarker serum
X
X
X
Optional biopsy 
sample7
X
X
X
Optional DNA 
sampling8
X
Contact IRT
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
Randomization
X
Drug dispensation9
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Dose administration10
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Period 
completion/disposition 
form
X
X
X
Health care resource 
utilization
X
X
X
X
X
Trial Feedback 
Questionnaire 
(optional)
X
X
X


Novartis
Confidential
Page 51
Amended Protocol Version 02 (Clean)
Protocol No. CAIN457M2302
Period
Screening
Treatment Period 1
Treatment Period 2
Post-Treatment 
Follow-Up
Visit Name
Screening 
1
Screening 
2
Baseline
Week 1
Week 2
Week 3
Week 4
Week 8
Week 12
Week 16 / 
EOT1
Week 17
Week 18
Week 19
Week 20
Week 24
Week 28
Week 32
Week 36
Week 40
Week 44
Week 48
UNS 1 to 3
Week 52 / 
EOT2
Week 60 / F8
Days
-28 to -14 -13 to -1
1
8
15
22
29
57
85
113
120 127 134 141 169 197 225 253 281 309 337
365
421
X Assessment to be recorded in the clinical database or received electronically from a vendor
S Assessment to be recorded in the source documentation only
1 These assessments are source documentation only and will not be entered into the eCRF. However, data regarding to which inclusion/exclusion criteria are not met are 
captured on the Inclusion/Exclusion eCRF.
2 While all concomitant medications are recorded on eCRF, patients will record their daily analgesics use on eDiary. 
3 AEs /SAEs occurring after the patient has provided informed consent must be reported.
4 Occurrence of flare will be calculated from lesion count assessment and does not require any additional action from the site staff.
5 Subjects will complete the NRS skin pain assessment using eDiary. From Screening through Week 16, subjects will complete a daily diary of their skin pain. From Week 16 
through Week 52, subjects will complete skin pain assessments on a weekly basis.
6 Instruct the subject on the use of the patient eDiary. From Screening through Week 16, subject will complete the diary on a daily basis. From Week 16 through Week 52,
subjects will complete the diary at Week 20, 24, 28, 44, 52.
7 Optional biopsy sample must only be collected after separate informed consent is signed at sites participating in the lesion biopsy substudy
8 Optional blood sample for DNA sampling can only be collected after separate informed consent is signed
9 After all assessments are completed, study site personnel should access IRT and dispense study treatment
10 Home administrations will be performed at Weeks 6, 10, 14, 22, 26, 30, 34, 38, 42, 46 and 50. In case of a major global health event, additional home administrations can be 
performed between Week 50 and Week 52. Home administrations can be performed by subject or caregiver. If the subject or caregiver is not able/confident to perform home 
administration, the subject will be allowed to return to the site for administration of the medication. 


Novartis
Confidential
Page 52
Amended Protocol Version 02 (Clean)
Protocol No. CAIN457M2302
8.1
Screening
8.1.1
Information to be collected on screening failures
Patients who sign an informed consent but fail to be started on treatment for any reason will be 
considered a screen failure. For each subject who has signed informed consent and discontinued 
before entering the double-blind treatment period, IRT must be notified within 5 days and the 
reason for not being randomized will be entered on the disposition eCRF. In addition, the 
Screening visit date, the Demography eCRF, Informed Consent eCRF, Inclusion/Exclusion 
Criteria eCRF and Subject rescreening eCRF (for rescreened subjects) must be completed.
Adverse events that are not SAEs will be followed up by the investigator and collected only in 
the source data. However, serious adverse events should be recorded in the eCRF for any serious 
adverse event (SAEs) that occurred during the screening period. If consent was withdrawn 
during the screening period before the subject was randomized, complete the appropriate eCRF.
8.2
Subject demographics/other baseline characteristics
8.2.1
Demography
Subject demographics data will include: age, gender, race, and ethnicity.
8.2.2
HS medical history/diagnosis
The following information should be collected and entered in the relevant eCRF:

The date of first symptoms

The date of first diagnosis of HS

HS family history
8.2.3
Prior HS medications and therapy
Any treatments for HS since initial diagnosis (as determined through medical history records 
or through subject interview) prior to study entry will be collected and recorded in the eCRF 
(including previous use of antibiotics, non-biologic immunomodulators and biologic therapies), 
along with the duration of the prior therapy and the reason for discontinuation.
8.2.4
Hurley stage
The Hurley staging system is a severity scale that assesses both current activity and past scarring, 
ranging from isolated abscesses in the primary stage to coalescing lesions with scarring and 
sinus tracts in the tertiary stage (Table 8-2). Hurley stage will be recorded in eCRF.


Novartis
Confidential
Page 53
Amended Protocol Version 02 (Clean)
Protocol No. CAIN457M2302
Table 8-2
Hurley stages
Stage
Description
I
Abscess formation, single or multiple without sinus tracts and cicatrization/scarring
II
Recurrent abscesses with tract formation and cicatrization. Single or multiple, widely 
separated lesions
III
Diffuse or near-diffuse involvement, or multiple interconnected tracts and abscesses 
across entire area
8.2.5
Smoking History
The current and/or previous use of tobacco use will be recorded prior to randomization, as well 
as the estimated number of pack-years based on the approximate consumption per year.
8.2.6
Relevant medical history/current medical conditions
Relevant medical history and current medical conditions includes data prior to signing of the 
informed consent and should be recorded in the Medical History eCRF. Whenever possible, 
diagnoses and not symptoms should be recorded.
Significant findings that are observed after the subject has signed the ICF and that meet the 
definition of an AE must be recorded in the AE eCRF.
8.2.7
Prior and concomitant medications
Concomitant medications and prior medications taken over the 6 months preceding study 
enrollment for reasons other than HS will be captured at the screening visit, and updated as 
necessary in the relevant eCRF. In addition, information on the concomitant use of analgesics 
should be recorded by the subject in the eDiary and reviewed by the investigator at the 
scheduled visits.
8.2.8
Determination of the tuberculosis status
Determination of the tuberculosis (TB) status should be done at Screening and should be 
performed as defined by local guidelines. The TB status must be determined by medical history, 
signs, symptoms, TB testing (QuantiFERON-TB Gold assay). Any significant findings should 
be recorded in the eCRF.
QuantiFERON TB-Gold In-Tube assay
A QuantiFERON® TB-Gold In-Tube assay (QFT) to screen a population for latent tuberculosis 
infection (Doherty et al 2008) will be used at Screening to evaluate the subjects’ eligibility for 
the study. This blood-based assay is specific for Mycobacterium tuberculosis and is not 
influenced by previous Bacillus Calmette-Guérin vaccination or by exposure to other 
Mycobacteria species. Furthermore, this test, in contrast to the purified protein derivative (PPD) 
skin test, is also insensitive to a booster effect since the subject is not exposed to the vaccine. 
The assay measures the production of interferon-gamma and presents it relative to a negative 
and a positive control sample (Manuel and Kumar 2008). The QuantiFERON®-TB Gold assay 
test will be supplied by the central laboratory. Details on the collection, shipment of samples 
and reporting of results by the central laboratory are provided to investigators in the study-
specific Laboratory Manual.


Novartis
Confidential
Page 54
Amended Protocol Version 02 (Clean)
Protocol No. CAIN457M2302
The workflow of sample handling in case of positive or indeterminate test results is provided 
in Figure 8-1.

If the test result is negative, the subject may be randomized.

If the test result is positive, the investigator should perform a work-up for the test result as 
per local procedures. If a TB work-up was conducted prior to the screening of the subject, 
results of the work-up can be used to assess eligibility if the work-up was conducted 
within 12 weeks prior to randomization.

Subjects positive for latent TB per work-up may be randomized to the trial if 
sufficient treatment has been initiated according to local routine clinical practice and
completed at least four weeks before randomization.

Subjects positive for active TB per work-up are not eligible for the study.

Subjects negative for TB (no signs of latent or active TB) per work-up may be 
randomized to the trial.

If the test result is indeterminate, the investigator may repeat the test once or may 
proceed directly to perform the work-up for the test result as per local procedures. This 
action is at the discretion of the investigator. If a TB work-up was conducted prior to the 
screening of the subject, results of the work-up can be used to assess eligibility if the 
work-up was conducted within 12 weeks prior to randomization.

If the second test is negative, the subject may be randomized.

If the second test is positive, the investigator should perform work-up as per local 
guidelines. Subjects positive for latent TB per work-up may be randomized to the 
trial if sufficient treatment has been initiated according to local routine clinical 
practice and completed at least four weeks before randomization. Subjects positive 
for active TB per work-up are not eligible for the study. Subjects negative for TB (no 
signs of latent or active TB) per work-up may be randomized to the trial.

If the second test is again indeterminate, the investigator should perform follow-up 
for the test result as per local procedures. Subjects tested positive for latent TB per 
work- up may be randomized to the trial if sufficient treatment has been initiated 
according to local routine clinical practice. Subjects positive for active TB per work-
up are not eligible for the study. Subjects negative for TB per work-up (no signs of 
latent or active TB) may be randomized to the trial if the work-up was conducted 12 
within weeks prior to randomization.
If eligibility is being assessed with only 1 test result and a TB work-up (i.e., no second TB test 
will be performed), the TB test to assess eligibility must have been done via the central 
laboratory for the study within the Screening Epoch (within 4 weeks prior to randomization) 
and TB work-up will only be considered if it was completed within 12 weeks prior to 
randomization. Subjects positive for latent TB per work-up may be randomized to the trial if 
sufficient treatment has been initiated according to local routine clinical practice and completed 
at least four weeks before randomization. Subjects positive for active TB per work-up are not 
eligible for the study. Subjects negative for TB per work-up (no signs of latent or active TB) 
may be randomized to the trial.


Novartis
Confidential
Page 55
Amended Protocol Version 02 (Clean)
Protocol No. CAIN457M2302
Figure 8-1
Tuberculosis screening flowchart
The subject will not be eligible for randomization if "active tuberculosis is present" or if "latent 
tuberculosis is present and is untreated as per local guidelines". * If the first QuantiFERON® TB-Gold 
In-Tube assay (QFT) is indeterminate, the investigator may choose to perform a second QFT or refer 
the subject for tuberculosis workup per local guidelines. ** If the result of QFT is "positive" or the 
results of 2 sequential QFTs are "indeterminate", the subject must be referred to have a tuberculosis 
workup per local guidelines (if no workup within 12 weeks prior to randomization is available). 


Novartis
Confidential
Page 56
Amended Protocol Version 02 (Clean)
Protocol No. CAIN457M2302
8.3
Efficacy
Whenever possible, efficacy assessments for an individual subject should be performed by the 
same member of the study site staff throughout the study.
In 
the 
event 
of 
a 
pandemic/epidemic 
that limits 
or 
prevents 
on-site study 
visits, selected efficacy assessments (excluding lesion count) can alternatively be done via 
phone calls, virtual contacts or visits of site staff to the subject´s home, depending on local 
regulations and capabilities.
Efficacy assessments based on Patient Reported Outcomes (PROs) might alternatively be done 
remotely from the subject´s home (e.g. online or by telephone interview), depending on local 
regulations and technical capabilities.
8.3.1
Hidradenitis Suppurativa Clinical Response (HiSCR)
The HiSCR (Kimball et al 2014) is defined by the status of three types of lesions: abscesses 
(fluctuant, with or without drainage, tender or painful), inflammatory nodules (tender, 
erythematous, pyogenic granuloma lesion), and draining fistulas (sinus tracts, with 
communications to skin surface, draining purulent fluid). The definition of responders to 
treatment (HiSCR achievers) is:

at least a 50% reduction in abscesses and inflammatory nodules (ANs),

no increase in the number of abscesses, and

no increase in the number of draining fistulas from baseline.
The HiSCR will be derived from the individual lesion counts of abscesses, nodules and fistulae 
at scheduled visits as indicated in the assessments schedule and as such will not be recorded in 
the eCRF.
Individual lesion count
The HS affected areas e.g. right and left axillary (armpit), right and left gluteal ("buttock"), right 
and left inguinal-femoral (groin), perineal, pubic, sternal, right and left sub-mammary (breast) 
and others will be assessed by the physician for abscesses, inflammatory nodules, draining 
fistulas, total fistulas, and other lesions.
Whenever possible, the same physician should perform the lesion count throughout the study.
Inflammatory lesions, including abscesses, nodules, draining fistulae, total fistulae and other 
lesions will be counted by area.
Individual lesion counts will be performed for all lesions as outlined in the Table 8-1. The lesion 
count will include any existing and newly observed lesions and will be recorded in the eCRF. 
The HS lesions are defined as (Lipsker et al 2016; Zouboulis et al 2017):

Inflammatory nodules (N) that are typically raised, deep-seated, three-dimensional, round, 
tender, erythematous, infiltrated and possibly pyogenic granuloma lesions with a diameter 
of >10 mm

Abscesses (A) that are often inflammatory, painful, tender but fluctuating mass with a 
diameter of >10 mm, surrounded by an erythematous area; the middle of an abscess 
contains pus


Novartis
Confidential
Page 57
Amended Protocol Version 02 (Clean)
Protocol No. CAIN457M2302

Draining fistulae (DF); sinus tracts, raised, tender but fluctuating longitudinal mass of 
variable length and depth, with communications to skin surface, draining purulent fluid

Fistulae (F): total fistulae defined as sinus tracts, raised, tender but fluctuating 
longitudinal mass of variable length and depth, with communications to skin surface, both 
draining and non-draining purulent fluid.
8.3.2
Patient's Global Assessment of Skin Pain - NRS in the past 24 hours
The Patient's Global Assessment of Skin Pain - Numerical Rating Scale (NRS) in the past 24 
hours will be used to assess pain “at its worst” and the average skin pain due to HS in the last 
24 hours. The NRS is a segmented numeric version of the visual analog scale (VAS) in which 
a respondent selects a whole number (0–10 integers) that best reflects the intensity of their pain 
ranging from 0 (no skin pain) to 10 (skin pain as bad as you can imagine). Skin Pain will be 
collected as specified in the assessment schedule. To assess this, the patient should concentrate 
on the pain that his/her skin lesions generate. The Patient's Global Assessment of Skin Pain -
NRS will be completed by the subject using the eDiary device.
8.3.3
Modified Hidradenitis Suppurativa Score (mHSS)
The Hidradenitis Suppurativa Score (Sartorius score) has been developed specifically for HS to 
reflect disease severity and has since been used as a modified score (mHSS) in clinical trials 
(Sartorius et al 2009; Kimball et al 2012) with minor simplifications when compared to the 
original score. The same seven anatomical areas as the HS-PGA are used. The following is 
recorded by the dermatologist:

the anatomical regions involved: axilla, groin, gluteal (left ⁄right) or other region, 3 points 
per region;

the numbers and scores of lesions (inflammatory nodule or abcess - 1 point, draining 
fistula - 6 points) for each region;

the longest distance between two relevant lesions (inflammatory nodule, abscess or 
draining fistula), or size of lesion if single, in each region: < 5 cm, 1 point; 5–10 cm, 3 
points; > 10 cm, 9 points; and

whether all lesions in each region are separated by normal skin: yes, 0; no (= Hurley III), 9 
points.
Regional scores are added and summed up to the patient’s total score. The upper limit of the 
scale is open. Results will be recorded in the eCRF.
Table 8-3
Modified Hidradenitis Suppurativa Score (mHSS)
Area evaluated
Number
Multiplier
Anatomical region involved: axilla, 
groin, gluteal (for all left ⁄right 
location) or other region
Number of regions involved
x3 per each region
Number and severity of lesions
Inflammatory nodules and 
abscesses
Number of inflammatory nodules 
and abscesses
x1 per each inflammatory nodule 
or abscess
Draining fistulas
Number of draining fistulas
x6 per each fistula


Novartis
Confidential
Page 58
Amended Protocol Version 02 (Clean)
Protocol No. CAIN457M2302
Area evaluated
Number
Multiplier
The longest distance between 2 
relevant lesions or size of lesion (if 
single in each region).
Number of areas with the longest 
distance between 2 relevant 
lesions in each distance/size 
category
<5 cm: x1 
5-10 cm: x3 
> 10 cm: x9 
no active lesions: x0
Are all lesions clearly separated by 
normal skin?
Number of areas in each category: 
with and without separation by 
normal skin
Yes: x0
No: x9
TOTAL SUM
8.3.4
HS-Physician’s Global Assessment (HS-PGA)
The HS-PGA score is a static global severity 6-point scale used and described by Kimball 
(Kimball et al 2012) (Table 8-4). It will be completed at scheduled visits as indicated in the 
Assessments schedule (Table 8-1). For a significant clinical response, at least a 2 point reduction 
is expected. The HS affected regions (e.g. right and left axillary, right and left gluteal (buttock), 
perianal, right and left inguinal-femoral (groin), others such as sub-mammary) are assessed for 
abscesses, draining fistulas, inflammatory nodules, and non-inflammatory nodules and one 
global rating / score is assigned to each patient. The scores will be recorded in eCRF.
Table 8-4
Hidradenitis Suppurativa Physician's Global Assessment Scale (HS-
PGA)
Score
Rating
Description
0
Clear
0 abscesses, 0 draining fistulas, 0 inflammatory nodules, and 0 non-
inflammatory nodules
1
Minimal
0 abscesses, 0 draining fistulas, 0 inflammatory nodules, and presence 
of non-inflammatory nodules
2
Mild
0 abscesses, 0 draining fistulas, and 1-4 inflammatory nodules
or
1 abscess or draining fistula and 0 inflammatory nodules
3
Moderate
0 abscesses, 0 draining fistulas, and ≥5 inflammatory nodules
or
1 abscess or draining fistula and ≥1 inflammatory nodules
or
2-5 abscesses or draining fistulas and <10 inflammatory nodules
4
Severe
2-5 abscesses or draining fistulas and ≥10 inflammatory nodules
5
Very severe
>5 abscesses or draining fistulas
8.3.5
Dermatology life quality index (DLQI)
The Dermatology Life Quality Index (DLQI) is a 10-item general dermatology disability index 
designed to assess health-related quality of life (HRQoL) in adult subjects with skin diseases 
such as eczema, psoriasis, acne, and viral warts (Finlay and Khan 1994). The measure is self-
administered and includes domains of daily activities, leisure, personal relationships, symptoms 
and feelings, treatment, and work/school. The measure is widely used: it has been tested across 
32 different skin conditions and is available in 55 languages. The recall period is the last week, 
and the instrument requires 1 to 2 minutes for completion. Each item has four response 
categories ranging from 0 (not at all) to 3 (very much). “Not relevant” is also a valid response 
and is scored as 0. The DLQI total score is a sum of the 10 questions. Scores range from 0 to 




Novartis
Confidential
Page 60
Amended Protocol Version 02 (Clean)
Protocol No. CAIN457M2302
Subject eDiary training
At the initial study visit (Screening Visit 1), subjects will complete the initial eDiary training 
during which they will learn to use the eDiary’s protocol-specific and general features.
Subject and site training materials will be provided to the subjects and to the study sites.
8.3.8
Patient Global Impression of severity (PGI-s)
Patient Global Impression of severity (PGI-s) rates the severity of the current HS on a scale 
ranging from "none" to "very severe". The PGI-s is self-administered and is to be completed as 
per the assessment schedule on the electronic tablet at the investigational site. The PGI-s is 
based on the validated Clinical Global Impression of severity scale.
8.3.9
Patient Global Impression of Change (PGI-c)
The Patient Global Impression of change (PGI-c) is a patient-reported instrument that measures 
change in overall status on a scale ranging from one ("very much improved") to seven ("very 
much worse"). PGI-c rates the current HS symptoms as compared to the start of the study at 
visits indicated in the assessment schedule. The PGI-c is self-administered and is to be 
completed as per the assessment schedule on the electronic tablet at the investigational site. The 
PGI-c is based on the validated Clinical Global Impression of change scale.
8.3.10
Work Productivity and Activity Impairment Questionnaire: Specific 
Health Problem (WPAI-SHP)
The WPAI-SHP consists of six questions regarding current employment status, hours missed 
from routine work due to a disease/other reasons, the number of hours actually worked, and the 
degree to which HS affected productivity/regular activities over the past seven days. WPAI 
outcomes are expressed as impairment percentages, with higher numbers indicating greater 
impairment and less productivity, i.e. worse outcomes.
8.3.11
Patient's lesion count
This is a self-reported patient's assessed count of existing and new lesions in the HS affected 
areas. The Patient's lesion count will be implemented on the eDiary and will be assessed on a 
weekly basis.
8.3.12
Appropriateness of efficacy assessments
The primary and secondary endpoints reflect the most important domains in HS as proposed by 
the scientific community (Thorlacius et al 2018). The primary endpoint used in this study, 
HiSCR, was developed and validated as part of the development program of adalimumab in HS. 
The HiSCR is considered to be adequately described and validated for its intended purpose as 
the primary end-point in pivotal studies (Humira (adalimumab) EPAR).
The secondary endpoint definition of flare is based on physician lesion counts and has been 
previously used in clinical trials in HS. The secondary endpoint of efficacy assessment used for 
evaluation of pain relief (NRS) is standard recommended primary outcome measures for pain 
clinical trials, also supported by Food and Drug Administration (FDA) and European Medicines 
Agency (EMA) guidelines. As chronic pain interferes with daily activities and quality of life, 


Novartis
Confidential
Page 61
Amended Protocol Version 02 (Clean)
Protocol No. CAIN457M2302
additional patient reported outcome measures (PROs) of physical functioning and health-related 
quality of life (HRQoL) tools are recommended for assessing the patient’s perception of the 
impact of disease and treatment on daily life, physical, psychological and social functioning, 
and well-being. Therefore, DLQI, EQ-5D, PGI-s, PGI-c and WPAI are included as exploratory 
endpoints. These PROs are not disease specific, but applied conventionally in other chronic 
diseases. The HS-specific exploratory endpoints of HS-PGA and mHSS have been used in 
previous HS trials.
8.4
Safety
All blood draws and safety assessments should be done prior to study treatment administration. 
Appropriate safety assessments (e.g., evaluation of AEs and SAEs including injection site 
reactions) should be repeated after the dose is administered.
In case of a global health event (e.g. pandemic, epidemic) that limits or prevents on-site study 
visits, regular phone contacts or virtual calls, depending on feasibility and technical 
requirements, will occur (approximately every 4 weeks, prior to home administration, or more 
frequently if needed) for safety monitoring and discussion of the subject´s health status until 
the subject can again visit the site. Events qualifying for being reported in the case report form 
(e.g. AE, infection) should be entered as appropriate.
If
subjects cannot 
visit 
the 
site 
to have blood/urine samples drawn for 
central lab 
analysis, investigator may consider performing the safety lab tests locally, e.g. by the 
patient´s general practitioner, in case it is needed to check safety parameters.
If female subjects of child bearing potential cannot visit the site to have urine pregnancy tests 
done, urine pregnancy test kits may be shipped or provided directly to the subject (e.g. together 
with the study drug). After appropriate instruction, subjects should perform the urine pregnancy 
test at home and report the result to the site. It is important that subjects do the pregnancy 
test first and only if the test result is negative proceed with the administration of the study 
drug. A communication process should be established with the subject so that the site is 
informed of the pregnancy test results.
Alternatively, depending on local regulations and capabilities, study site staff may visit the 
subject at home to draw blood/ urine samples if needed. Sites should inform the Sponsor of 
proposed changes to sample management/ collection.
8.4.1
Physical examination
A physical examination, including general appearance, skin, neck, eyes, ears, nose, throat, lungs, 
heart, abdomen, back, lymph nodes, extremities, vascular and neurological systems will be 
performed as indicated in Table 8-1.
If necessary, based on medical history and/or symptoms, additional exams will be performed at 
the discretion of the investigator.
Whenever possible, assessments for an individual subject should be performed by the same 
member of the study site staff throughout the study.
Information for all physical examinations must be included in the source documentation at the 
study site. Significant findings that are present prior to the start of study treatment must be 


Novartis
Confidential
Page 62
Amended Protocol Version 02 (Clean)
Protocol No. CAIN457M2302
included in the Medical History eCRF. Significant findings made after signing informed 
consent which meet the definition of an Adverse Event must be recorded on the Adverse Event 
eCRF.
8.4.2
Vital signs
Vital signs (including blood pressure and pulse measurements) will be assessed at every 
scheduled visit as indicated in Table 8-1. Whenever possible, assessments should be performed 
by the same study site staff member throughout the study.
After the subject has been sitting for five minutes, with back supported and both feet placed on 
the floor, heart rate, systolic and diastolic blood pressure will be measured 
twice (measurements separated by 1 to 2 minutes) using a validated device, with an 
appropriately sized cuff. In case the cuff sizes available are not large enough for the subject’s 
arm circumference, a sphygmomanometer with an appropriately sized cuff may be used. 
Measurements will be recorded in the source documentation and the average of the two 
measurements will be entered on the Vital Signs eCRF.
No specific action is pre-defined within this protocol to respond to specific abnormal vital signs, 
as it will be decided by the investigator whether and which specific action needs to be taken to 
respond to any abnormal values, taking into account the overall status of the subject.
8.4.3
Height and weight
Height and body weight will be measured as indicated in Table 8-1.
Height in centimeters (cm) and body weight (to the nearest 0.1 kilogram (kg)) will be measured 
in indoor clothing, but without shoes. If possible, body weight assessments should be performed 
by the same study site staff member and using the same scale throughout the study. The body 
weight recorded at the Randomization visit will be used to stratify the subject population for 
randomization.
8.4.4
Laboratory evaluations
A central laboratory will be used for analysis of all specimens listed below, unless noted 
otherwise. Details on the collections, shipment of samples and reporting of results by the central 
laboratory are provided to investigators in the laboratory manual. Refer to the Laboratory 
Manual for identification of laboratory reference range values and the schema for notification 
of site staff and Novartis for out of range values.
Blood withdrawals and safety assessments should be done prior to study treatment 
administration and should be taken as shown in Table 8-1 and in Table 16-1.
Section 16.1 shows the extended laboratory ranges that are considered clinically notable. No 
specific action is pre-defined within this protocol to respond to specific abnormal laboratory 
values, as it will be decided by the investigator whether and which specific action needs to be 
taken to respond to any abnormal values, taking into account the overall status of the subject.


Novartis
Confidential
Page 63
Amended Protocol Version 02 (Clean)
Protocol No. CAIN457M2302
8.4.4.1
Hematology
Hemoglobin, hematocrit, red blood cell count, white blood cell count with differential 
(neutrophils including bands, lymphocytes, monocytes, eosinophils, basophils) and platelet 
count will be measured at all scheduled study visits as specified in Table 8-1.
8.4.4.1.1 Erythrocyte sedimentation rate (ESR)
The ESR test will be performed locally by unblinded person using the ESR Supplies kit 
provided by the central laboratory. A laboratory manual will be provided with detailed 
information on sample collection and handling. In order to preserve the blind, results of ESR 
will not be communicated to the other study site staff, including the investigator, or to Novartis 
during the study.
8.4.4.2
Clinical chemistry
Serum chemistry will include urea, creatinine, HbA1c, total bilirubin, AST (SGOT), ALT 
(SGPT), GGT, alkaline phosphatase, sodium, potassium, bicarbonate, calcium, phosphorous, 
total protein, albumin, lipase, amylase, and uric acid. Serum chemistry will be measured at all 
scheduled study visits as specified in Table 8-1.
8.4.4.2.1 Lipid panel
A lipid profile including High Density Lipoprotein (HDL), Low Density Lipoprotein (LDL), 
total cholesterol and triglycerides will be measured from a fasting blood sample as indicated in 
Table 8-1.
8.4.4.2.2 High sensitivity C-reactive protein
High sensitivity C-reactive protein (hsCRP) will be assessed centrally as part of the clinical 
chemistry panel as indicated in Table 8-1. In order to preserve the blind, results of hsCRP will 
not be communicated to the study site staff, including the investigator, or to Novartis during the 
study.
8.4.4.3
Local urinalysis
Dipsticks will be provided by the central laboratory to the study sites for local urinalysis 
assessments. Standard dipstick measurements for specific gravity, protein, glucose, pH, blood, 
urine blood dipstick (non-hemolyzed), urine blood dipstick (hemolyzed), bilirubin, ketones and 
WBC will be done at scheduled visits as indicated in Table 8-1. If the standard dipstick result 
is positive, microscopy assessments will be performed and recorded in the source data.
8.4.4.4
Immunogenicity
Blood samples for immunogenicity (IG, anti-secukinumab antibodies) will be taken pre-dose at 
the scheduled time points as indicated in Table 8-1. All blood samples (approximately 2 mL 
each) will be taken by direct venipuncture.
The blood sample will be allowed to clot at room temperature prior to harvesting of the serum. 
The serum will be obtained by centrifugation, split into 2 aliquots and then stored at 
approximately -70˚C to -20˚C prior to shipment on dry ice to the central laboratory.


Novartis
Confidential
Page 64
Amended Protocol Version 02 (Clean)
Protocol No. CAIN457M2302
For a detailed description of the blood sampling schema, including time points, refer to the 
Blood Log in Section 16.2, Table 16-1.
A laboratory manual will be provided by the central laboratory with detailed information on 
sample collection, sample handling and shipment.
The actual sample collection date and exact time of collection will be entered on the eCRF 
capturing blood collection for IG. Sampling problems will be noted in the ‘Reason sample not 
taken’ section of the eCRF. In case unscheduled IG samples are taken, there should always be 
matching PK samples taken as well.
Immunogenicity analytical method
An electrochemiluminescence-based method will be used for the detection of potential anti-
secukinumab antibody formation. A detailed description of the method to assess 
immunogenicity will be described in the bioanalytical raw data and in the respective 
Bioanalytical Data Report (BDR).
8.4.5
Pregnancy and assessments of fertility
All pre-menopausal women who are not surgically sterile will have pregnancy testing. 
Pregnancy tests will be performed in all women of childbearing potential (see Section 5.2 for 
definition of childbearing potential), as indicated in Table 8-1.
Any woman with a confirmed positive pregnancy test during screening is not eligible for 
randomization. A positive local urine pregnancy test during the treatment periods of the study 
requires immediate interruption of study treatment until a serum β-subunit of human chorionic 
gonadotropin (β-hCG) test is performed and found to be negative. If the serum β-hCG test is 
positive, the subject must be discontinued from the study treatment.
Assessments of fertility
Medical documentation of oophorectomy, hysterectomy, or bilateral tubal ligation must be 
retained as source documents. Subsequent hormone level assessment to confirm the woman is 
not of childbearing potential must also be available as source documentation in the following 
cases:
1. surgical bilateral oophorectomy without a hysterectomy
2. reported 12 months of natural (spontaneous) amenorrhea with an appropriate clinical 
profile.
In the absence of the above medical documentation, FSH testing is required of any female 
subject, regardless of reported reproductive/menopausal status at screening/baseline.
8.4.6
Appropriateness of safety measurements
The safety measures used in this study are reliable and relevant standard measures for a biologic 
immunomodulating agent in HS.


Novartis
Confidential
Page 65
Amended Protocol Version 02 (Clean)
Protocol No. CAIN457M2302
8.5
Additional assessments
8.5.1
Clinical Outcome Assessments (COAs)
The impact of HS on various aspects of subject’s health-related quality of life (HRQoL) will be 
assessed by the following and are described in Section 8.3:

Patient Global Assessment of Skin Pain (NRS)

Dermatology Life Quality Index (DLQI)

EuroQoL 9 Dimension Health Questionnaire - Health Status Questionnaire (EQ-5D-3L)

Patient Global Impression of severity (PGI-s)

Patient Global Impression of change (PGI-c)

Work Productivity Activity Impairment (WPAI)

HS Symptom Diary
All these questionnaires (except for questionnaires completed by subjects on the eDiary at home 
including Patient's Global Assessment of Pain NRS and HS Symptom Diary) should be 
completed by subjects before any study related clinical assessments by the investigator take 
place. Responses to HRQoLs will be collected as per the eCOA manual on eDiary or site pad.
All questionnaires will be completed in the language the respondent is most familiar with, at 
the scheduled visit before the subject sees the investigator for clinical assessments. The subject 
should be given sufficient space and time to complete the questionnaires. Before the investigator 
begins the clinical assessments, the study coordinator should check the questionnaires for 
completeness and encourage the subject to complete any missing responses.
After the investigator completes the clinical efficacy assessments (e.g. lesion count), the 
investigator will review and the examine questionnaires completed by the subject for responses 
that may indicate potential AEs or SAEs. The investigator should review not only the responses 
to the questions in the questionnaires but also for any unsolicited comments written by the 
subject. If AEs or SAEs are confirmed then the investigator must record the events as per 
instructions given in Section 10 of the protocol. The investigator/site staff should not encourage 
the subject to change the responses reported in the completed questionnaires.
8.5.2
Pharmacokinetics
Details on sample collection, numbering, processing and shipment can be found in the 
Laboratory Manual.
At all study sites, blood samples will be collected pre-dose for PK analysis at the scheduled 
visits as indicated in Table 8-1.
For a detailed description of the blood sampling schema, including time points, refer to the 
Blood Collection Log in Table 16-1.
Blood samples (approximately 2 ml, not less than 1.5 ml) will be collected into Serum Separator 
Tubes (SST). All blood samples will be taken by direct venipuncture. The blood sample will be 
allowed to clot over a minimum of 30 minutes at room temperature prior to harvesting of the 
serum. The serum will be obtained by centrifugation at approx. 2500 Revolutions Per Minutes 
(RPM) for 10 minutes. Thereafter, the serum samples will be placed on ice, split into 2 aliquots 






Novartis
Confidential
Page 68
Amended Protocol Version 02 (Clean)
Protocol No. CAIN457M2302
Laboratory Manual will contain detailed information on sample collection, handling, and 
shipment.
8.5.4
Other Assessments
8.5.4.1
Trial feedback questionnaire
This trial will include an option for subjects to complete an anonymized questionnaire, referred 
to as a ‘Trial Feedback Questionnaire’. This questionnaire will give subjects an opportunity to 
provide feedback on their clinical trial experience. Individual subject level responses will not 
be reviewed by investigators. Responses will be used by the sponsor (Novartis) to understand 
where improvements can be made in the clinical trial process. This questionnaire does not 
collect data about the subject's disease, symptoms, treatment effect or adverse events, and 
therefore is not considered trial data. Should any spontaneous information be collected about 
AEs, this will be transferred to the safety database.
8.5.4.2
Health Care Resource Utilization
Studies conducted in Canada and the United States have indicated the high economic impact of 
the disease both on a direct level (due to hospitalizations and emergency department visits) and 
on an indirect level (occupational disability). All-cause and HS-related outpatient visits, 
inpatient stays and emergency visits not planned per protocol will be collected to explore 
possible decreases in utilization of these resources. Health Care Resource Utilization will be 
entered on eCRF.
9
Study discontinuation and completion
9.1
Discontinuation
9.1.1
Discontinuation of study treatment
Discontinuation of study treatment for a subject occurs when study treatment is stopped earlier 
than the protocol planned duration, and can be initiated by either the subject or the investigator.
Subjects may voluntarily discontinue study treatment for any reason at any time.
The investigator must discontinue study treatment for a given subject if, he/she believes that 
continuation would negatively impact the subject's well-being.
Study treatment must be discontinued under the following circumstances:

Subject's wish

Withdrawal of consent

Pregnancy

Ongoing use of prohibited treatment as per the prohibited treatment Section 6.2.2

Any situation in which study participation might result in a safety risk to the subject

Following emergency unblinding


Novartis
Confidential
Page 69
Amended Protocol Version 02 (Clean)
Protocol No. CAIN457M2302

Emergence of the following adverse events: any adverse events that in the judgment of the 
investigator/qualified site staff, taking into account the subject’s overall status, prevent the 
subject from continuing study treatment (for example, sepsis)

Any laboratory abnormalities that in the judgment of the investigator/qualified site staff, 
taking into consideration the subject’s overall status, prevents the subject from continuing 
study treatment
If discontinuation of study treatment occurs, the investigator should make a reasonable effort 
to understand the primary reason for the subject’s premature discontinuation of study treatment 
and record this information in the eCRF.
Subjects who discontinue study treatment should NOT be considered withdrawn from the study 
UNLESS 
they 
withdraw 
their 
consent 
(see 
Withdrawal 
of 
Informed 
Consent, Section 9.1.2). Where possible, they should continue attending site visits for the 
assessments indicated in the assessment schedule (including efficacy assessments). If the 
subject does not wish to attend any further visits, the subject should return to the site after 
discontinuation of study drug, for an End of Treatment (EOT) visit and Follow-up visit (F8). 
Assessments detailed in the EOT and Follow-up visit (F8) in Table 8-1 should be completed 
and recorded in the eCRF. If the subject fails to return for these assessments for unknown 
reasons, every effort (e.g. telephone, e-mail, letter) should be made to contact the subject/pre-
designated contact as specified in the Lost to Follow-up section (Section 9.1.3). This contact 
should preferably be done according to the study visit schedule.
If the subject cannot or is unwilling to attend any visit(s), the site staff should maintain regular 
telephone contact with the subject, or with a person pre-designated by the subject. This 
telephone contact should preferably be done according to the study visit schedule.
The investigator must also contact the IRT to register the subject’s discontinuation from study 
treatment.
If discontinuation occurs because treatment code has been broken, please refer to Emergency 
breaking of treatment code section.
9.1.2
Withdrawal of informed consent
Subjects may voluntarily withdraw consent to participate in the study for any reason at any time. 
Withdrawal of consent occurs only when a subject:

Does not want to participate in the study anymore
and

Does not want any further visits or assessments
and

Does not want any further study related contacts
and

Does not allow analysis of already obtained biologic material
In this situation, the investigator should make a reasonable effort (e.g. telephone, e-mail, letter) 
to understand the primary reason for the subject’s decision to withdraw his/her consent and 
record this information.


Novartis
Confidential
Page 70
Amended Protocol Version 02 (Clean)
Protocol No. CAIN457M2302
Study treatment must be discontinued and no further assessments conducted, and the data that 
would have been collected at subsequent visits will be considered missing.
Further attempts to contact the subject are not allowed unless safety findings require 
communicating or follow-up.
All efforts should be made to complete the assessments prior to study withdrawal. A final 
evaluation at the time of the subject’s study withdrawal should be made as detailed in the 
assessment table.
Novartis will continue to retain and use all research results (data) that have already been 
collected for the study evaluation.
9.1.3
Lost to follow-up
For subjects whose status is unclear because they fail to appear for study visits without stating 
an intention to discontinue or withdraw, the investigator must show "due diligence" by 
documenting in the source documents steps taken to contact the subject, e.g. dates of telephone 
calls, registered letters, etc. A subject should not be considered as lost to follow-up until due 
diligence has been completed or until the end of the study.
9.1.4
Early study termination by the sponsor
The study can be terminated by Novartis at any time for any reason. This may include reasons 
related to the benefit/ risk assessment of participating in the study, practical reasons (including 
slow enrollment), or for regulatory or medical reasons. In taking the decision to terminate, 
Novartis will always consider the subject welfare and safety. Should early termination be 
necessary, subjects must be seen as soon as possible (and be provided instructions on when the 
subject should stop self-administration of study drug and come for a final visit) and treated as 
a prematurely withdrawn subject. The investigator may be informed of additional procedures 
to be followed in order to ensure that adequate consideration is given to the protection of the 
subject’s interests. The investigator or sponsor depending on the local regulation will be 
responsible 
for 
informing 
Institutional 
Review 
Board/Independent 
Ethics 
Committee (IRB/IEC) of the early termination of the trial.
9.2
Study completion and post-study treatment
Study completion is defined as when the last subject finishes their Study Completion visit, and 
any repeat assessments associated with this visit have been documented and followed-up 
appropriately by the Investigator, or in the event of an early study termination decision, the date 
of that decision.
A subject will be considered to have completed the study when she/he has completed the last 
visit planned in the protocol (visit at Week 52 or visit at Week 60 (F8)). The Study Completion 
visit for individual patient will be defined as:

Week 60 (F8) visit for subjects who prematurely discontinue study treatment in Treatment 
Periods 1 or 2 for any reason, or subjects who complete treatment period but do not enroll 
in the planned extension study

Week 52 visit for subjects continuing in the planned extension study


Novartis
Confidential
Page 71
Amended Protocol Version 02 (Clean)
Protocol No. CAIN457M2302
At the end of the study, patients who completed the core study treatment period are expected to 
benefit from study treatment based on the investigator's clinical judgement, and wish to 
participate will be eligible to continue into a planned extension study. The extension study is 
intended to collect further safety and efficacy data on secukinumab, provide continuous access 
to treatment for patients and evaluate the sustainability of the treatment effect after study drug 
discontinuation (in the randomized withdrawal part of this study).
The investigator must provide follow-up medical care for all subjects who are pre-maturely 
withdrawn from the study or do not continue in the extension study, or must refer them for 
appropriate ongoing care. This care may include use of long term antibiotics, surgical 
intervention and/or use of biologics.
10
Safety monitoring and reporting
10.1
Definition of adverse events and reporting requirements
10.1.1
Adverse events
An adverse event (AE) is any untoward medical occurrence (e.g., any unfavorable and 
unintended sign [including abnormal laboratory findings], symptom or disease) in a subject or 
clinical investigation subject after providing written informed consent for participation in the 
study. Therefore, an AE may or may not be temporally or causally associated with the use of a 
medicinal (investigational) product.
In addition, all reports of intentional misuse and abuse of the product are also considered an 
adverse event irrespective if a clinical event has occurred.
The investigator has the responsibility for managing the safety of individual subject and 
identifying adverse events.
Novartis qualified medical personnel will be readily available to advise on trial related medical 
questions or problems.
The occurrence of adverse events must be sought by non-directive questioning of the subject at 
each visit during the study. Adverse events also may be detected when they are volunteered by 
the subject during or between visits or through physical examination findings, laboratory test 
findings, or other assessments.
Adverse events must be recorded in the Adverse Events eCRF under the signs, symptoms or 
diagnosis associated with them, accompanied by the following information (as far as possible) 
(if the event is serious refer to Section 10.1.2):
1. The severity grade.

mild: usually transient in nature and generally not interfering with normal activities

moderate: sufficiently discomforting to interfere with normal activities

severe: prevents normal activities
2. Its relationship to the study treatment (suspected: Yes/No). If the event is due to lack of 
efficacy or progression of underlying illness (i.e. progression of the study indication), the 
assessment of causality will usually be ‘Not suspected’. The rationale for this guidance is 
that the symptoms of a lack of efficacy or progression of underlying illness are not caused 


Novartis
Confidential
Page 72
Amended Protocol Version 02 (Clean)
Protocol No. CAIN457M2302
by the trial drug, they happen in spite of its administration and/or both lack of efficacy and 
progression of underlying disease can only be evaluated meaningfully by an analysis of 
cohorts, not on a single subject.
3. Its duration (start and end dates) or if the event is ongoing, an outcome of not 
recovered/not resolved must be reported.
4. Whether it constitutes a serious adverse event (SAE - see Section 10.1.2 for definition of 
SAE) and which seriousness criteria have been met.
5. Action taken regarding with study treatment.
All adverse events must be treated appropriately. Treatment may include one or more of the 
following:

dose not changed

dose reduced/increased

drug interrupted/withdrawn
6. Concomitant medication or non-drug therapy given
7. Its outcome

not recovered/not resolved

recovered/resolved

recovered/resolved with sequelae

fatal

unknown
Conditions that were already present at the time of informed consent should be recorded in 
medical history of the subject.
Adverse events (including lab abnormalities that constitute AEs) should be described using a 
diagnosis whenever possible, rather than individual underlying signs and symptoms.
Adverse event monitoring should be continued for at least 10 weeks following the last dose of 
study treatment.
Once an adverse event is detected, it must be followed until its resolution or until it is judged to 
be permanent (e.g. Continuing at the end of the study), and assessment must be made at each 
visit (or more frequently, if necessary) of any changes in severity, the suspected relationship to 
the study drug, the interventions required to treat it, and the outcome.
Information about adverse drug reactions for the investigational drug can be found in the 
Investigator's Brochure (IB).
Abnormal laboratory values or test results constitute adverse events only if they fulfill at least 
one of the following criteria:

they induce clinical signs or symptoms

they are considered clinically significant

they require therapy
Clinically significant abnormal laboratory values or test results must be identified through a 
review of values outside of normal ranges/clinically notable ranges, significant changes from 


Novartis
Confidential
Page 73
Amended Protocol Version 02 (Clean)
Protocol No. CAIN457M2302
baseline or the previous visit, or values which are considered to be non-typical in subjects with 
the underlying disease. Alert ranges for laboratory and other test abnormalities are included 
in Section 16.1.
10.1.2
Serious adverse events
An SAE is defined as any adverse event [appearance of (or worsening of any pre-existing)] 
undesirable sign(s), symptom(s) or medical conditions(s) which meets any one of the following 
criteria:

fatal

life-threatening
Life-threatening in the context of a SAE refers to a reaction in which the subject was at risk of 
death at the time of the reaction; it does not refer to a reaction that hypothetically might have 
caused death if it were more severe (please refer to the ICH-E2D Guidelines).

results in persistent or significant disability/incapacity

constitutes a congenital anomaly/birth defect

requires inpatient hospitalization or prolongation of existing hospitalization, unless 
hospitalization is for:

routine treatment or monitoring of the studied indication, not associated with any 
deterioration in condition 

elective or pre-planned treatment for a pre-existing condition that is unrelated to the 
indication under study and has not worsened since signing the informed consent

social reasons and respite care in the absence of any deterioration in the subject’s 
general condition

treatment on an emergency outpatient basis for an event not fulfilling any of the 
definitions of a SAE given above and not resulting in hospital admission

is medically significant, e.g. defined as an event that jeopardizes the subject or may 
require medical or surgical intervention to prevent one of the outcomes listed above
Medical and scientific judgment should be exercised in deciding whether other situations should 
be considered serious reactions, such as important medical events that might not be immediately 
life threatening or result in death or hospitalization but might jeopardize the subject or might 
require intervention to prevent one of the other outcomes listed above. Such events should be 
considered as “medically significant”. Examples of such events are intensive treatment in an 
emergency room or at home for allergic bronchospasm, blood dyscrasias or convulsions that do 
not result in hospitalization or development of dependency or abuse (please refer to the ICH-
E2D Guidelines).
All malignant neoplasms will be assessed as serious under “medically significant” if other 
seriousness criteria are not met.
Any suspected transmission via a medicinal product of an infectious agent is also considered a 
serious adverse reaction.
All reports of intentional misuse and abuse of the product are also considered serious adverse 
event irrespective if a clinical event has occurred.


Novartis
Confidential
Page 74
Amended Protocol Version 02 (Clean)
Protocol No. CAIN457M2302
10.1.3
SAE reporting
To ensure subject safety, every SAE, regardless of causality, occurring after the subject has 
provided informed consent and until 10 weeks following the last administration of study 
treatment must be reported to Novartis safety within 24 hours of learning of its occurrence. 
Detailed instructions regarding the submission process and requirements are to be found in the 
investigator folder provided to each site.
1. Screen Failures (e.g. A subject who is screened but is not treated or randomized): SAEs 
occurring after the subject has provided informed consent until the time the subject is 
deemed a Screen Failure must be reported to Novartis
2. Randomized OR Treated Subjects: SAEs collected between time subject signs ICF until 
10 weeks after the subject has discontinued or stopped study treatment.
All follow-up information for the SAE including information on complications, progression of 
the initial SAE and recurrent episodes must be reported as follow-up to the original episode 
within 24 hours of the investigator receiving the follow-up information. An SAE occurring at a 
different time interval or otherwise considered completely unrelated to a previously reported 
one must be reported separately as a new event.
If the SAE is not previously documented in the Investigator’s Brochure or Package Insert (new 
occurrence) and is thought to be related to the study treatment, a CMO & PS Department 
associate may urgently require further information from the investigator for health authority 
reporting. Novartis may need to issue an Investigator Notification (IN) to inform all 
investigators involved in any study with the same study treatment that this SAE has been 
reported.
Suspected Unexpected Serious Adverse Reactions (SUSARs) will be collected and reported to 
the competent authorities and relevant ethics committees in accordance with EU Guidance 
2011/C 172/01 or as per national regulatory requirements in participating countries.
Any SAEs experienced after the 10 week period following the last administration of study 
treatment should only be reported to Novartis Safety if the investigator suspects a causal 
relationship to study treatment. Any SAEs reported up to the subject’s last visit will be reported 
in the AE eCRF. SAEs beyond that date will only be recorded in the Safety database.
10.1.4
Pregnancy reporting
If a female subject becomes pregnant, the study treatment should be stopped, and the subject 
must be asked to read and sign a pregnancy consent form to allow the Study Doctor to ask 
questions about her pregnancy. To ensure subject safety, each pregnancy occurring after signing 
the informed consent must be reported to Novartis within 24 hours of learning of its occurrence. 
The pregnancy should be followed up to determine outcome, including spontaneous or 
voluntary termination, details of the birth, and the presence or absence of any birth defects, 
congenital abnormalities, or maternal and/or newborn complications.
Pregnancy should be recorded and reported by the investigator to the Novartis Chief Medical 
Office and Patient Safety (CMO&PS). Pregnancy follow-up should be recorded on the same 
form and should include an assessment of the possible relationship to the study treatment any 
pregnancy outcome. Any SAE experienced during pregnancy must be reported.


Novartis
Confidential
Page 75
Amended Protocol Version 02 (Clean)
Protocol No. CAIN457M2302
10.1.5
Reporting of study treatment errors including misuse/abuse
Medication errors are unintentional errors in the prescribing, dispensing, administration or 
monitoring of a medicine while under the control of a healthcare professional, subject or 
consumer (European Medicines Agency definition).
Misuse refers to situations where the medicinal product is intentionally and inappropriately used 
not in accordance with the protocol.
Abuse corresponds to the persistent or sporadic, intentional excessive use of a medicinal product, 
which is accompanied by harmful physical or psychological effects.
Study treatment errors and uses outside of what is foreseen in the protocol will be collected in 
the DAR (dose administration record) eCRF irrespective of whether or not associated with an 
AE/SAE and reported to Safety only if associated with an SAE. Misuse or abuse will be 
collected and reported in the safety database irrespective of it being associated with an AE/SAE 
within 24 hours of Investigator’s awareness.
Table 10-1
Guidance for capturing the study treatment errors including 
misuse/abuse
Treatment error 
type
Document in Dose Administration 
(DAR) eCRF (Yes/No)
Document in AE 
eCRF
Complete SAE form
Unintentional study 
treatment error
Yes
Only if associated 
with an AE
Only if associated with an
SAE
Misuse/Abuse
Yes
Yes
Yes, even if not 
associated with a SAE
For more information on AE and SAE definition and reporting requirements, please see the 
respective sections.
10.2
Additional Safety Monitoring
Not applicable.
10.2.1
Data Monitoring Committee
This study will include a Data Monitoring Committee (DMC) that will function independently 
of all other individuals associated with the conduct of the clinical trial, including the site 
investigators participating in the study. The DMC will assess 
 
 the progress of a clinical trial, safety data, and critical efficacy variables, and it will 
recommend to the sponsor whether to continue, modify or terminate a trial.
Specific details regarding the composition, responsibilities, data monitoring and meeting 
frequency, and documentation of DMC reports, minutes, and recommendations will be 
described in a separate charter that is established between the sponsor and the DMC.
10.2.2
Steering Committee
A Steering Committee (SC) will be established comprising disease area experts, investigators 
participating in the trial, i.e. not being members of the DMC and Novartis representatives from 
the CTT.


Novartis
Confidential
Page 76
Amended Protocol Version 02 (Clean)
Protocol No. CAIN457M2302
The SC will ensure transparent management of the study according to the protocol by 
recommending and approving modifications as circumstances require. The SC will review 
protocol amendments as appropriate. Together with the clinical trial team, the SC will also 
develop recommendations for publication of study results. The details of the role of the steering 
committee will be defined in the Steering Committee Charter.
11
Data Collection and Database management
11.1
Data collection
All data should be recorded, handled and stored in a way that allows its accurate reporting, 
interpretation and verification.
Designated investigator staff will enter the data required by the protocol into the Electronic 
Case Report Forms (eCRF). The eCRFs have been built using fully validated secure web-
enabled software that conforms to 21 CFR Part 11 requirements, Investigator site staff will not 
be given access to the EDC system until they have been trained. Automatic validation programs 
check for data discrepancies in the eCRFs, allow modification and/or verification of the entered 
data by the investigator staff.
The investigator/designee is responsible for assuring that the data (entered into eCRF) is 
complete, accurate, and that entry and updates are performed in a timely manner. The 
Investigator must certify that the data entered are complete and accurate
After final database lock, the investigator will receive copies of the subject data for archiving 
at the investigational site.
11.2
Database management and quality control
Novartis personnel (or designated contract research organization (CRO)) will review the data 
entered by investigational staff for completeness and accuracy. Electronic data queries stating 
the nature of the problem and requesting clarification will be created for discrepancies and 
missing values and sent to the investigational site via the EDC system. Designated investigator 
site staff are required to respond promptly to queries and to make any necessary changes to the 
data.
Concomitant treatments and prior medications entered into the database will be coded using the 
World Health Organization (WHO) Drug Reference List, which employs the Anatomical 
Therapeutic Chemical classification system. Medical history/current medical conditions and 
adverse events will be coded using the Medical Dictionary for Regulatory Activities (MedDRA) 
terminology.
Laboratory samples will be processed centrally and the results will be sent electronically to 
Novartis (or a designated CRO).
Subjects will fill in their PRO data in a site based tablet. The system will be supplied by a 
vendor, who will also manage the database. The database will be sent electronically to Novartis 
personnel (or designated CRO).
Randomization codes and data about all study treatment (s) dispensed to the subject and all 
dosage changes will be tracked using an Interactive Response Technology (IRT). The system 


Novartis
Confidential
Page 77
Amended Protocol Version 02 (Clean)
Protocol No. CAIN457M2302
will be supplied by a vendor, who will also manage the database. The data will be sent 
electronically to Novartis (or a designated CRO) at specific timelines.
Each occurrence of a code break via IRT will be reported to the clinical team and monitor. The 
code break functionality will remain available until study shut down or upon request of Novartis.
Once all the necessary actions have been completed and the database has been declared to be 
complete and accurate, it will be locked and the treatment codes will be unblinded and made 
available for data analysis. Any changes to the database after that time can only be made after 
written agreement by Novartis development management.
DNA samples:
To maximize confidentiality, all samples and the information associated with the samples will 
be double-coded to prevent the exposure of the subject’s information and identity. This double-
coding process allows Novartis to go back and destroy the sample at the subject’s request. In 
addition, sample information is stored in one secured database while genetic data is stored in 
an independent secured database.
The use of DNA to search for biomarkers of disease and drug action is exploratory. Any results 
from this DNA study will not be placed in the subject’s medical records.
11.3
Site monitoring
Before study initiation, at a site initiation visit or at an investigator’s meeting, a Novartis 
representative will review the protocol and data capture requirements (i.e. eCRFs) with the 
investigators and their staff. During the study, Novartis employs several methods of ensuring 
protocol and GCP compliance and the quality/integrity of the sites’ data. The field monitor will 
visit the site to check the completeness of subject records, the accuracy of data capture / data 
entry, the adherence to the protocol and to Good Clinical Practice, the progress of enrollment, 
and to ensure that study treatment is being stored, dispensed, and accounted for according to 
specifications. Key study personnel must be available to assist the field monitor during these 
visits. Continuous remote monitoring of each site’s data may be performed by a centralized 
Novartis CRA organization. Additionally, a central analytics organization may analyze data & 
identify risks & trends for site operational parameters, and provide reports to Novartis clinical 
teams to assist with trial oversight.
The investigator must maintain source documents for each subject in the study, consisting of 
case and visit notes (hospital or clinic medical records) containing demographic and medical 
information, laboratory data, electrocardiograms, and the results of any other tests or 
assessments. All information on eCRFs must be traceable to these source documents in the 
subject’s file. The investigator must also keep the original informed consent form signed by the 
subject (a signed copy is given to the subject).
The investigator must give the monitor access to all relevant source documents to confirm their 
consistency with the data capture and/or data entry. Novartis monitoring standards require full 
verification for the presence of informed consent, adherence to the inclusion/exclusion criteria, 
documentation of SAEs, and of data that will be used for all primary variables. Additional 
checks of the consistency of the source data with the eCRFs are performed according to the 


Novartis
Confidential
Page 78
Amended Protocol Version 02 (Clean)
Protocol No. CAIN457M2302
study-specific monitoring plan. No information in source documents about the identity of the 
subjects will be disclosed.
In the event of a major health care disruption (e.g. pandemic, epidemic), requiring social 
distancing or limited travel/attendance to site, remote site initiation and monitoring could be 
considered.
12
Data analysis and statistical methods
Any data analysis carried out independently by the investigator should be submitted to Novartis 
before publication or presentation.
12.1
Analysis sets
The Randomized Analysis Set (RAS) consists of all randomized subjects. Subjects will be 
analyzed according to the treatment assigned to at randomization.
The Full Analysis Set (FAS) comprises all subjects to whom study treatment has been assigned. 
Subjects will be analyzed according to the treatment assigned to at randomization. Mis-
randomized subjects (mis-randomized in IRT) will be excluded from FAS. Mis-randomized 
subjects are defined as cases where IRT contacts were made by the site either prematurely or 
inappropriately prior to confirmation of the subject’s final randomization eligibility and no 
study medication was administered to the subject.
The Safety Set includes all subjects who received at least one dose of study treatment. Subjects 
will be analyzed according to the study treatment received, where treatment received is defined 
as the randomized/assigned treatment if the patient took at least one dose of that treatment or 
the first treatment received if the randomized/assigned treatment was never received.
For all analysis in Treatment Period 1, the Placebo group to secukinumab 300 mg every 2 weeks 
and Placebo group to secukinumab 300 mg every 4 weeks will be pooled together.
12.2
Subject demographics and other baseline characteristics
The analysis of subject demographics and other baseline characteristics data will be based on 
Randomized Analysis Set.
Demographics and baseline characteristics
Summary statistics will be presented for continuous demographic and baseline characteristic 
variables for each treatment group and for all subjects. The number and percentage of subjects 
in each category will be presented for categorical variables for each treatment group and for all 
subjects.
Medical history
Any condition entered as medical history or current medical conditions at baseline will be coded 
using the MedDRA dictionary. Medical history will be summarized by system organ class and 
preferred term in the MedDRA dictionary.


Novartis
Confidential
Page 79
Amended Protocol Version 02 (Clean)
Protocol No. CAIN457M2302
12.3
Treatments
The analysis of study treatment data will be based on the Safety Set.
The number of active and placebo injections will be summarized by treatment group by means 
of contingency tables.
The duration of exposure to study treatment will also be summarized by treatment group. In 
addition, the number of subjects with exposure of at least certain thresholds (e.g., any exposure, 
≥1 week, ≥2 weeks, ≥3 weeks, ≥4 weeks, ≥8 weeks, etc.) will be displayed.
Prior and concomitant treatments
Prior and concomitant treatments will be summarized by treatment group in separate tables for 
the Safety Set.
Prior treatments are defined as treatments taken and stopped prior to first dose of study 
treatment. Any treatment given at least once between the day of first dose of randomized study 
treatment and the last day of study visit will be a concomitant treatment, including those that 
were started pre-baseline and continued into the treatment period.
Treatments will be presented in alphabetical order, by ATC codes and main groups. Tables will 
also show the overall number and percentage of subjects receiving at least one treatment of a 
particular ATC code and at least one treatment in a particular anatomical main group.
In addition, medical procedures and significant non-drug therapies as coded in MedDRA will 
be summarized.
12.4
Analysis of the primary endpoint(s)
The primary aim of the study is to demonstrate the efficacy of two secukinumab regimens 
compared to placebo with respect to HiSCR after 16 weeks of treatment. The detailed definition 
and the justification of the corresponding primary Estimand, as well as the definition of the 
supplementary Estimands will be provided in the Statistical Analysis Plan.
12.4.1
Definition of primary endpoint(s)
The primary endpoint of the study is HiSCR at Week 16, defined as at least a 50% decrease in 
Abscess and inflammatory Nodule (AN) count compared to baseline with no increase in the 
number of abscesses and/or in the number of draining fistulas from baseline to Week 16. The 
baseline is defined as the last assessment (including unscheduled visits) obtained before/on the 
day of the first administration of the study treatment, or on the randomization date if there has 
been no drug administration.
The analysis of the primary endpoint will be based on the FAS.
12.4.2
Statistical model, hypothesis, and method of analysis
The statistical hypotheses for the primary endpoint being tested is that there is no difference in 
the proportion of HiSCR at Week 16 in any of the secukinumab regimens versus placebo 
regimen.
Let pj denote the proportion of HiSCR at Week 16 for treatment regimens j, j = 0, 1, 2 where


Novartis
Confidential
Page 80
Amended Protocol Version 02 (Clean)
Protocol No. CAIN457M2302

0 corresponds to placebo regimen,

1 corresponds to secukinumab 300 mg q2w s.c.,

2 corresponds to secukinumab 300 mg q4w s.c.,
In statistical terms, Hj: pj = p0, HAj : pj ≠ p0 for the jth secukinumab regimen, i.e.
H1: secukinumab 300 mg q2w s.c. is not different to placebo regimen with respect to HiSCR 
after 16 weeks of treatment.
H2: secukinumab 300 mg q4w s.c. is not different to placebo regimen with respect to HiSCR 
after 16 weeks of treatment.
The primary analysis method will be logistic regression with treatment group, geographical 
region, Hurley stage, use of antibiotic, baseline body weight and baseline AN counts as 
explanatory variables. Odds ratios will be computed for comparisons of secukinumab dose 
regimens versus placebo utilizing the logistic regression model fitted. In case of response rates 
of 0% or of 100% in one of the treatment groups, Fisher’s exact test will be applied. Risk 
difference and confidence intervals for risk difference will be provided.
The detailed testing strategy including the primary endpoint analysis is provided 
in Section 12.5. Efficacy of two secukinumab regimens compared to placebo with respect to 
HiSCR after 16 weeks of treatment could be demonstrated if H1 and/or H2 is/are rejected and 
the treatment effect is in favor of secukinumab.
12.4.3
Handling of missing values/censoring/discontinuations
Missing data for primary and secondary endpoints will be addressed using multiple imputation.
As these endpoints are binary outcomes derived from underlying continuous variables, the 
imputations will be performed on those continuous variables, from which the imputed binary 
outcomes will then be constructed. Subjects who discontinue from study treatment early will 
be encouraged to stay in the study and are considered as retrieved dropout (RDO) subjects. The 
analysis will account for different post-randomization events for missing data handling as 
follows:
Permanent discontinuation of study treatment due to AE (Adverse Event), LoE (Lack of 
Efficacy): If retrieved dropout data are available, these will be used for analysis. If no data was 
retrieved after study treatment discontinuation, missing data will be multiply imputed based on 
placebo arm data (Carpenter et al 2013). More details on the imputation model will be specified 
in the Statistical Analysis Plan prior to unblinding.
Permanent discontinuation of study treatment due to other reasons than AE (Adverse 
Event), LoE (Lack of Efficacy): If efficacy data collected after study treatment discontinuation 
are available (retrieved dropout), then the retrieved drop-out data will be excluded and missing 
data after study treatment discontinuation will be multiply imputed using the MAR (missing at 
random) assumption. In case of a major health event (e.g. pandemic/epidemic), the number of 
missing measurements may increase and the potential to recover information for the main 
endpoints from intermediate measurements that have been dropped from the visit schedule may 
decrease. This may affect the power of tests and the precision of estimates for this study.


Novartis
Confidential
Page 81
Amended Protocol Version 02 (Clean)
Protocol No. CAIN457M2302
Furthermore, the Sponsor might consider additional analyses to assess any potential impact of 
a major health event on our study results. Detailed information, including missing data handling 
plan and additional analysis will be specified in the Statistical Analysis Plan.
12.4.4
Sensitivity and Supportive analyses
Sensitivity analyses
To further support the primary estimand, sensitivity analyses will be considered in the way of 
varying assumptions about the missing outcomes between treatment arms.
Another sensitivity analysis will be performed where the baseline is defined as weighted 
average of first screening visit (with weight 1/6) and the second screening visit (with weight 
2/6) and the randomization visit (with weight 3/6). This weighted average is being used during 
the study to identify the need for rescue medication and it is also used at Week 52 to identify 
responders being randomized in the extension study.
Supportive analyses
A supplementary estimand, which is detailed in the Statistical Analysis Plan, and following 
analyses will also be done to support primary endpoints:

The number and percentage of subjects will be presented for proportions of subjects who 
achieved at least 50%, 75% and 100% reductions in the AN count relative to Baseline 
(AN50, AN75, AN100).

Summary statistics will be presented for absolute and percent change from Baseline in AN 
count.

Summary statistics will be presented for absolute and percent change from Baseline in 
number of abscesses.

Summary statistics will be presented for absolute and percent change from Baseline in 
number of inflammatory nodules.

Summary statistics will be presented for absolute and percent change from Baseline in 
number of draining fistulas.
12.5
Analysis of secondary endpoints
12.5.1
Efficacy and/or Pharmacodynamic endpoint(s)
The secondary endpoints of this study are planned as follow:

Percentage change from baseline in AN count at Week 16

Flare over 16 weeks: Patients who experience at least one flare over 16 weeks. Flare is 
defined as an at least a 25% increase in AN counts with a minimum increase of 2 AN 
relative to baseline.

Pain/NSR30 at Week 16: Patients achieving NRS30 at Week 16, among patients with 
baseline NRS ≥ 3. NRS30 is defined as at least 30% reduction and at least 2 unit reduction 
from baseline in Patient's Global Assessment of Skin Pain. NRS from baseline to Week 16 
is the weekly average score calculated based on the 7 available daily scores: Baseline 
(Week 0) will be average of NRS score from day -7 to day -1, week 1 will be average of 


Novartis
Confidential
Page 82
Amended Protocol Version 02 (Clean)
Protocol No. CAIN457M2302
score from day 1 to day 7, week 2 will be average of score from day 8 to day 14 and so 
on. For any week with less than 4 diary entries within the week, the weekly average will 
be recorded as missing.
For the secondary endpoint of percentage change in AN count from baseline to Week 16, an 
analysis of covariance (ANCOVA) model will be fitted to estimate the treatment differences 
between the two secukinumab regimens and placebo with treatment group, baseline AN count, 
Hurley stage, use of antibiotic, geographical region and baseline body weight as covariates.
The analysis method for both flare up to Week 16 and Pain/NRS30 at Week 16 will be the 
logistic regression: with treatment group, Hurley stage, geographical region, use of antibiotic, 
baseline body weight and baseline AN counts as explanatory variables for flare endpoints; and 
with treatment group, Hurley stage, region, use of antibiotic, baseline body weight and baseline 
NRS as explanatory variables for pain endpoints. Odds ratios will be computed for comparisons 
of secukinumab dose regimens versus placebo utilizing the logistic regression model fitted. In 
case of response rates of 0% or of 100% in one of the treatment groups, Fisher’s exact test will 
be applied. Risk difference and confidence intervals for risk difference will be provided.
Testing strategy
Two studies of identical design (CAIN457M2301 and CAIN457M2302) are planned, each with 
multiple endpoints. Primary endpoint, secondary endpoints percentage change from baseline in 
AN count at Week16 and flare over 16 weeks will be tested in each of the two studies separately. 
Pain/NSR30 at Week 16 will be tested using the combined data from the two studies. In order 
to control for the type-I error rate (“false positive rate”) at the level of the individual studies, 
and at the level of the combined dataset of both studies, the testing strategy illustrated in Figure 
12-1 below will be implemented.
The hypotheses included in the test procedure are listed below:
Primary endpoint (as described in Section 12.4):
H1(H'1): secukinumab 300 mg q2w s.c. is not different to placebo regimen with respect to 
HiSCR after 16 weeks of treatment.
H2(H'2): secukinumab 300 mg q4w s.c. is not different to placebo regimen with respect to 
HiSCR after 16 weeks of treatment.
Secondary endpoints:
H3(H'3): secukinumab 300 mg q2w s.c. is not different to placebo regimen with respect to 
percentage change from baseline in AN count at Week 16
H4(H'4): secukinumab 300 mg q4w s.c. is not different to placebo regimen with respect to 
percentage change from baseline in AN count at Week 16
H5(H'5): secukinumab 300 mg q2w s.c. is not different to placebo regimen with respect to flare 
over 16 weeks of treatment
H6(H'6): secukinumab 300 mg q4w s.c. is not different to placebo regimen with respect to flare 
over 16 weeks of treatment
H7: secukinumab 300 mg q2w s.c. is not different to placebo regimen with respect to NRS30 
at Week 16


Novartis
Confidential
Page 83
Amended Protocol Version 02 (Clean)
Protocol No. CAIN457M2302
H8: secukinumab 300 mg q4w s.c. is not different to placebo regimen with respect to NRS30 
at Week 16
Efficacy of two secukinumab regimens compared to placebo with respect to percentage change 
from baseline in AN count at Week 16 could be demonstrated if H3(H'3) and/or H4(H'4) is/are 
rejected and the treatment effect is in favor of Secukinumab. Efficacy of two secukinumab
regimens compared to placebo with respect to flare over 16 weeks could be demonstrated if 
H5(H'5) and/or H6(H'6) is/are rejected and the treatment effect is in favor of secukinumab.
Efficacy of two secukinumab regimens compared to placebo with respect to Pain/NSR30 at 
Week 16 could be demonstrated if H7 and/or H8 is/are rejected and the treatment effect is in 
favor of secukinumab.
Figure 12-1
Testing strategy
Testing procedure and type-I-error control in the planned submission includes studies 
CAIN457M2301 and CAIN457M2302 (both with identical design). Hypotheses can only be 
tested in the order as indicated by the arrows. The hypothesis H1 of the primary objective 
(HiSCR at Week 16) for the high dose secukinumab regimen (q2w) versus placebo will be 
tested at 4α/5 while the hypothesis H2 of the primary objective (HiSCR at Week 16) for the low 
dose secukinumab regimen (q4w) versus placebo will be tested at α/5 simultaneously. If at least 
one of H1 and/or H2 are/is rejected then H3 and/or H4 (percentage change from baseline in AN 
count at Week 16), is tested. If at least one of H3 and/or H4 are/is rejected, then the 
corresponding alpha will be passed to H5 and/or H6 (flare over 16 weeks) respectively. Once 
HiSCR, percentage change in AN count and flare hypotheses for a secukinumab regimen are 
rejected, the respective 4α/5 for the high dose and α/5 for the low dose can be passed on to the 
other regimen’s hypotheses, if they are not already rejected at the initial significance level (i.e.,
α/5 for the low dose and 4α/5 for the high dose). If both studies independently reject the primary 
null-hypothesis on the same secukinumab regimen (H1 and H'1, or H2 and H'2), then the
corresponding secukinumab regimen’s pain hypothesis (H7 or H8) can be tested. Additionally,


Novartis
Confidential
Page 84
Amended Protocol Version 02 (Clean)
Protocol No. CAIN457M2302
the significance level for the pain hypothesis can be passed from one dose regimen to the other
dose regimen if one pain dose regimen is rejected and the primary null-hypothesis on the two 
secukinumab regimen are all rejected. The initial significance level for pain hypothesis (H7 
and/or H8) is set to α-α2. The subtraction of α2 is to account for the maximum possible type I 
error to claim a success for HiSCR, percentage change in AN count and flare in both studies. 
Therefore, the type I error rate is controlled at level α for the submission on all hypothesis 
endpoints. The detailed information regarding the significance level of H7 and H8 can be found 
in Section 16.3 (Appendix 3: Type I alpha for the pain hypothesis). Under the global null 
hypothesis (i.e. no difference between secukinumab and placebo), the testing procedure 
outlined above controls the type I error rate (one-sided) at the study-level to <0.025, and at the 
submission level to <0.000625(=0.0252). Considering all possible configurations of true and 
false null hypotheses, the type I error control at the level of the submission is <0.000625 for the 
primary objectives, and <0.025 for all hypotheses (Bretz et al 2019).
12.5.2
Safety endpoints
All safety evaluations will be performed on the Safety set.
Adverse events
Treatment emergent AEs (events started after the first dose of study treatment and within 84 
days after last dose, or events present prior to the first dose of study treatment but increased in 
severity based on preferred term within 84 days after last dose) will be summarized. Only 
primary paths within MedDRA will be considered for AE reporting.
AEs will be summarized by presenting, for each treatment group, the number and percentage 
of subjects having any AE, having an AE in each primary system organ class and having each 
individual AE (preferred term). Summaries will also be presented for AEs by severity and for 
study treatment related AEs. If a subject reported more than one AE with the same preferred 
term, the AE with the greatest severity will be presented. If a subject reported more than one 
AE within the same primary system organ class, the subject will be counted only once with the 
greatest severity at the system organ class level, where applicable.
Confidence intervals for relative frequencies will be derived as well according to the score 
method including continuity correction by Newcombe (Newcombe 1998).
Separate summaries will be provided for death, SAE, other significant AEs leading to 
discontinuation and AEs leading to study treatment discontinuation.
A graphical display of relative frequencies within system organ classes will be presented.
Vital signs
Analysis of the vital sign measurements using summary statistics for the change from baseline 
for each post-baseline visit will be performed. These descriptive summaries will be presented 
by vital sign and treatment group. Change from baseline will only be summarized for subjects 
with both baseline and post-baseline values.


Novartis
Confidential
Page 85
Amended Protocol Version 02 (Clean)
Protocol No. CAIN457M2302
Clinical laboratory evaluations
The summary of laboratory evaluations will be presented for two groups of laboratory tests 
(hematology and serum chemistry). Descriptive summary statistics for the change from baseline 
to each study visit will be presented. These descriptive summaries will be presented by test 
group, laboratory test and treatment group. Change from baseline will only be summarized for 
subjects with both baseline and post baseline.
For each parameter, the maximum change from baseline within each study treatment period 
will be analyzed analogously.
In addition, shift tables will be provided for all parameters based on Common Toxicity grade 
Criteria (CTC). For these shift tables, the normal laboratory ranges will be used to evaluate 
whether a particular laboratory test value was normal, low, or high relative to the baseline value. 
These summaries will be presented by laboratory test and treatment group. Shifts will be 
presented for most extreme values post-baseline.
Immunogenicity
All immunogenicity results will be listed by treatment group, subject and visit/time.
Resource utilization
Data relating to resource utilization will be used for the purpose of economic evaluation and 
will be carried out and reported as a separate activity.
12.5.3
Pharmacokinetics
PK concentrations will be listed by treatment and subject and Cmin will be determined. 
Descriptive summary statistics will include mean (arithmetic and geometric), SD, and CV 
(arithmetic and geometric), median, minimum and maximum.
12.5.4
DNA
Exploratory DNA studies are designed to investigate the association between genetic factors 
(genotypes) and clinical assessments (phenotypes) which are collected during the clinical trial. 
Without prior evidence of a strong association, a number of possible associations are evaluated 
with exploratory analyses. A range of statistical tests are used for the analyses. Additional data, 
from other clinical trials, are often needed to confirm associations. Alternatively, if the number 
of subjects enrolled in the study is too small to complete proper statistical analyses, the data 
may be combined, as appropriate, with those from other studies to enlarge the dataset for 
analysis.
12.5.5
Biomarkers
All biomarker data will be listed by treatment group, subject and visit. Summary statistics will 
be provided by treatment and visit. The number of values outside of the limits of quantification 
will be reported in each table.
Exploratory biomarker assessments will be reported separately.


Novartis
Confidential
Page 86
Amended Protocol Version 02 (Clean)
Protocol No. CAIN457M2302
12.5.6
PK/PD relationships
The effect of the secukinumab serum concentration on HiSCR and other endpoints will be 
investigated if appropriate. Clinically important subject covariates, such as Hurley stage, 
geographical region, use of antibiotic, baseline body weight, age and baseline AN count will be 
investigated.
12.5.7
Patient reported outcomes
Please refer to Section 12.6 for the analysis method of Patient reported outcomes.
12.6
Analysis of exploratory endpoints
For the exploratory endpoints analyses, the estimates of the differences between secukinumab 
groups versus placebo group and the corresponding p-values for pairwise comparisons will not 
be adjusted for multiple comparisons as no formal confirmatory hypothesis tests are planned.
Subpopulation Analysis
The number and percentage of HiSCR responders in bio-naive patients will be presented by 
visit up to end of study for each treatment group. 
The number and percentage of HiSCR responders in patients with body weight lower and higher 
than 90kg (90kg and ≥90kg) will be presented by visit up to the end of study for each treatment 
group.
To allow for a pairwise comparison between the two secukinumab regimens and placebo at 
Week 16 in bio-naive patients, HiSCR at Week 16 will also be analyzed in bio-naive patients 
using logistic regression with treatment group, geographical region, Hurley stage, baseline AN 
count use of antibiotic, and baseline body weight as explanatory variables. Odds ratios will be 
computed for the comparison of secukinumab dose regimens versus placebo utilizing the 
logistic regression model fitted. In case of response rates of 0or of 100in one of the 
treatment groups, Fisher’s exact test will be applied. Risk difference and confidence intervals 
for risk difference will be provided.
The subgroup analysis of patients with bodyweight lower and higher than 90 kg (90kg and 
≥90kg) will be analyzed analogously to bio-naive patients.
Modified Hidradenitis Suppurativa Score
Summary statistics will be provided for absolute and percent change from baseline of modified 
Hidradenitis Suppurativa Score by visit up to end of study.
To allow for a pairwise comparison between two secukinumab regimens and placebo until 
Week 16, modified Hidradenitis Suppurativa Score up to Week 16 will also be analyzed using 
a MMRM with treatment group, the respective baseline value, Hurley stage, use of antibiotic, 
geographical region, baseline bodyweight, visit, baseline mHSS*visit interaction, and treatment 
group*visit as covariates, with unstructured covariance matrix.


Novartis
Confidential
Page 87
Amended Protocol Version 02 (Clean)
Protocol No. CAIN457M2302
HS-Physician's Global Assessment
HS-PGA responder will be analyzed using logistic regression with treatment group, Hurley 
stage, geographical region, use of antibiotic, baseline bodyweight, baseline HS-PGA as 
explanatory variables. Odds ratios will be computed for comparisons of secukinumab dose 
regimens versus placebo utilizing the logistic regression model fitted. In case of response rates 
of 0% or of 100% in one of the treatment groups, Fisher’s exact test will be applied. Risk 
difference and confidence intervals for risk difference will be provided. Multiple imputation 
will be applied in case of missing data and detail information will be specified in Statistical 
Analysis Plan.
Dermatology Life Quality Index (DLQI)
The Dermatology Life Quality Index (DLQI) is a 10-item dermatology-specific HRQoL 
measure presented to each subject from the randomization up to the study end. The instrument 
contains six functional scales (i.e. symptoms and feeling, daily activities, leisure, work and 
school, personal relationships, treatment). Each question is answered with the following 
response: “not at all,” “a little,” “a lot,” or “very much”. Seven scores will be derived from the 
DLQI: the total score of each of the six dimensions as well as the total score over all items. The 
higher the score, the more quality of life is impaired. The DLQI total score will be calculated 
by summing the score of each question resulting in a maximum of 30 and a minimum of 0.

DLQI responder: Decrease of ≥ 5.0 points on DLQI total score will be considered as 
responder and logistic regression will be utilized for analysis with treatment group, Hurley 
stage, geographical region, use of antibiotic, baseline bodyweight, baseline DLQI score as 
explanatory variables. Odds ratios and will be computed for comparisons of secukinumab 
dose regimens versus placebo utilizing the logistic regression model fitted. In case of 
response rates of 0% or of 100% in one of the treatment groups, Fisher’s exact test will be 
applied. Risk difference and confidence intervals for risk difference will be provided. 
Multiple imputation will be applied in case of missing data and detail information will be 
specified in Statistical Analysis Plan.

Summary statistics will be provided for absolute and percentage change from baseline of 
the total score of each of the six dimensions as well as the total score by visit up to the end 
of study for each treatment group.

To allow for a pairwise comparison between two secukinumab regimens and placebo until 
Week 16, DLQI score up to Week 16 will also be analyzed using a MMRM with treatment
group, the respective baseline value, Hurley stage, use of antibiotic, geographical region, 
baseline bodyweight, visit, baseline DLQI*visit interaction, and treatment group*visit as 
covariates, with unstructured covariance matrix.
Work Productivity and Activity Impairment (WPAI)
Summary statistics will be provided for absolute and percentage change from baseline of WPAI 
component scores by visit up to end of study.




Novartis
Confidential
Page 89
Amended Protocol Version 02 (Clean)
Protocol No. CAIN457M2302
At the End of Study, a final analysis of all data collected up to last study visit will be performed 
when all subjects have completed the last study visit.
12.8
Sample size calculation
Sample size requirements for this study are primarily driven by HiSCR at Week 16 endpoints. 
A 5% two-sided type-I-error rate will used to control for type I error. Two secukinumab doses 
will be tested versus placebo with respect to the primary endpoint (HiSCR at Week 16). The
type-I-error will be split to 4and 1% two-sided for secukinumab 300 mg q2w vs. placebo and 
secukinumab 300 mg q4w vs. placebo, respectively. Sample sizes will be based on this type-I-
error assumption.
A total of 471 patients was originally planned to be randomized to study drug in a 1:1:0.5:0.5 
ratio. A second study of identical design with the same sample size will be conducted in parallel. 
Both studies are independently powered to address the primary endpoint (HiSCR) and 
secondary endpoint on flare. The secondary endpoint on pain will be analyzed in the combined 
populations of both trials, provided the primary null-hypothesis can be rejected in both studies. 
All sample size calculations were done in nQuery Advisor 7.0.
As discussed in Section 5, to account for the disruptive impact of the COVID-19 pandemic on 
the conduct of the study since the release of protocol amendment 01, the number of randomized
patients was increased to approximately 541 (15% increase from the original population of 471 
patients). 
12.8.1
Primary endpoint(s)
HiSCR: Based on adalimumab phase III placebo-controlled studies (PIONEER I and II, 
respectively, Kimball et al 2016), a placebo response rate of 30% is assumed. The original total 
sample size of 471 patients for this trial is sufficient to achieve 93% power for the demonstration 
of 20% difference of secukinumab 300 mg q2w over placebo based on the primary endpoint 
(HiSCR) when assuming a secukinumab response rate to be 50%. In regards to the comparison 
of secukinumab 300 mg q4w to placebo, we achieve 83power to show superiority.
12.8.2
Secondary endpoint(s)
The power mentioned for the Secondary endpoints is conditional on the successful rejection of 
the null hypothesis for the primary endpoint (HiSCR), and the testing procedures are defined in 
Section 12.5.1.
Percentage change in AN count: based on adalimumab phase III placebo-controlled studies 
(PIONEER I and II, respectively (Kimball et al 2016), it is assumed that the difference between 
secukinumab and placebo is at least 18in favor of secukinumab when considering the mean 
percentage change from baseline in AN count at Week 16. Although it is planned to use a 
repeated measures model for the analysis, an approximate sample size can be based on a simple 
t-test. The original sample size of 471 patients is sufficient to achieve 92power in 
secukinumab 300 mg q2w vs. placebo and 81power in secukinumab 300 mg q4w vs. placebo 
when assuming a standard deviation of 46.
Flare: Based on adalimumab phase III placebo-controlled studies (PIONEER I and II, 
respectively, Kimball et al 2016), a placebo rate of 35% is assumed. The original sample size 


Novartis
Confidential
Page 90
Amended Protocol Version 02 (Clean)
Protocol No. CAIN457M2302
of 471 patients is sufficient to achieve 98% power for the demonstration of 20% difference of 
secukinumab 300 mg q2w over placebo based on the second endpoint when assuming 
secukinumab 300 mg q2w rate to be 15%. Assuming the same rate for secukinumab 300 mg 
q4w, the sample size would be sufficient to achieve 92power in a comparison of secukinumab 
300 mg q4w vs. placebo.
Pain: Based on adalimumab phase III placebo-controlled studies (PIONEER I and II, 
respectively, Kimball et al 2016), a placebo rate of 23% is assumed. Assuming 80% patients 
are qualified to calculate Pain variable NRS30, the original total sample size of 942 patients 
across two studies is sufficient to achieve 85% power for the demonstration of 13% difference 
of secukinumab 300 mg q2w over placebo based on the second endpoint when assuming the
rate to be 36%. The original sample size is also sufficient to achieve 70power to demonstrate 
superiority of secukinumab 300 mg q4w over placebo based on the same assumptions in regards 
to the rates of secukinumab and placebo as above.
13
Ethical considerations and administrative procedures
13.1
Regulatory and ethical compliance
This clinical study was designed and shall be implemented, executed and reported in accordance 
with the ICH Harmonized Tripartite Guidelines for Good Clinical Practice, with applicable 
local regulations (including European Directive 2001/20/EC, US CFR 21), and with the ethical 
principles laid down in the Declaration of Helsinki.
13.2
Responsibilities of the investigator and IRB/IEC
Before initiating a trial, the investigator/institution must obtain approval/favorable opinion from 
the Institutional Review Board/Independent Ethics Committee (IRB/IEC) for the trial protocol, 
written informed consent form, consent form updates, subject recruitment procedures (e.g., 
advertisements) and any other written information to be provided to subjects. Prior to study 
start, the investigator is required to sign a protocol signature page confirming his/her agreement 
to conduct the study in accordance with these documents and all of the instructions and 
procedures found in this protocol and to give access to all relevant data and records to Novartis 
monitors, auditors, Novartis/Quality Assurance representatives, designated agents of Novartis, 
IRBs/IECs, and regulatory authorities as required. If an inspection of the clinical site is 
requested by a regulatory authority, the investigator must inform Novartis immediately that this 
request has been made.
13.3
Publication of study protocol and results
The protocol will be registered in a publicly accessible database such as clinicaltrials.gov and 
as required in EudraCT. In addition, after study completion (defined as last patient last visit) 
and finalization of the study report the results of this trial will be submitted for publication and 
posted in a publicly accessible database of clinical trial results, such as the Novartis clinical trial 
results website and all required Health Authority websites (e.g. Clinicaltrials.gov, EudraCT 
etc.) .


Novartis
Confidential
Page 91
Amended Protocol Version 02 (Clean)
Protocol No. CAIN457M2302
For details on the Novartis publication policy including authorship criteria, please refer to the 
Novartis publication policy training materials that were provided at the trial investigator 
meetings.
13.4
Quality Control and Quality Assurance
Novartis maintains a robust Quality Management System (QMS) that includes all activities 
involved in quality assurance and quality control, to ensure compliance with written Standard 
Operating Procedures as well as applicable global/local GCP regulations and ICH Guidelines.
Audits of investigator sites, vendors, and Novartis systems are performed by auditors, 
independent from those involved in conducting, monitoring or performing quality control of the 
clinical trial. The clinical audit process uses a knowledge/risk based approach.
Audits are conducted to assess GCP compliance with global and local regulatory requirements, 
protocols and internal SOPs, and are performed according to written Novartis processes
14
Protocol adherence
This protocol defines the study objectives, the study procedures and the data to be collected on 
study participants. Additional assessments required to ensure safety of subjects should be 
administered as deemed necessary on a case by case basis. Under no circumstances including 
incidental collection is an investigator allowed to collect additional data or conduct any 
additional procedures for any purpose involving any investigational drugs under the protocol, 
other than the purpose of the study. If despite this interdiction prohibition, data, information, 
observation would be incidentally collected, the investigator shall immediately disclose it to 
Novartis and not use it for any purpose other than the study, except for the appropriate 
monitoring on study participants.
Investigators ascertain they will apply due diligence to avoid protocol deviations. If an 
investigator feels a protocol deviation would improve the conduct of the study this must be 
considered a protocol amendment, and unless such an amendment is agreed upon by 
Novartis and approved by the IRB/IEC and Health Authorities, where required, it cannot be 
implemented.
14.1
Protocol Amendments
Any change or addition to the protocol can only be made in a written protocol amendment that 
must be approved by Novartis, health authorities where required, and the IRB/IEC prior to 
implementation.
Only amendments that are required for subject safety may be implemented immediately 
provided the health authorities are subsequently notified by protocol amendment and the 
reviewing IRB/IEC is notified.
Notwithstanding the need for approval of formal protocol amendments, the investigator is 
expected to take any immediate action required for the safety of any subject included in this 
study, even if this action represents a deviation from the protocol. In such cases, Novartis should 
be notified of this action and the IRB/IEC at the study site should be informed according to 
local regulations.


Novartis
Confidential
Page 92
Amended Protocol Version 02 (Clean)
Protocol No. CAIN457M2302
15
References
References are available upon request
Alavi A (2016) Discussion: What Heals Hidradenitis Suppurativa: Surgery, 
Immunosuppression, or Both? Plast. Reconstr. Surg. p. 230S-1S.
Andersen RK, Jemec GBE (2017) Pathophysiology of Hidradenitis Suppurativa p. 19-26.
Bettoli V, Join-Lambert O, Nassif A (2016) Antibiotic Treatment of Hidradenitis Suppurativa. 
Dermatol Clin p. 81-9.
Bretz F, Maurer W, Xi D. (2019) Replicability, reproducibility and multiplicity in drug 
development. CHANCE. p.4-11.
Bruin G, Loesche C, Nyirady J, et al (2017) Population Pharmacokinetic Modeling of 
Secukinumab in Patients With Moderate to Severe Psoriasis. J Clin Pharmacol p. 876-885.
Carpenter JR, Roger JH, Kenward MG (2013) Analysis of longitudinal trials with protocol 
deviation: a framework for relevant, accessible assumptions, and inference via multiple 
imputation. J Biopharm Stat p. 1352-71.
Deckers IE, Kimball AB (2016) The Handicap of Hidradenitis Suppurativa. Dermatol Clin p. 
17-22.
Deckers IE, van der Zee HH, Prens EP (2014) Epidemiology of Hidradenitis Suppurativa: 
Prevalence, Pathogenesis, and Factors Associated with the Development of HS. p. 54-60.
Dessinioti C, Zisimou C, Tzanetakou V, et al (2016) Oral clindamycin and rifampicin 
combination therapy for hidradenitis suppurativa: a prospective study and 1-year follow-up. 
Clin. Exp. Dermatol. p. 852-857.
Doherty SD, Van Voorhees A, Lebwohl MG, et al (2008) National Psoriasis Foundation 
consensus statement on screening for latent tuberculosis infection in patients with psoriasis 
treated with systemic and biologic agents. J. Am. Acad. Dermatol. p. 209-17.
Fimmel S, Zouboulis CC (2010) Comorbidities of hidradenitis suppurativa (acne inversa). 
Dermatoendocrinol p. 9-16.
Finlay AY, Khan GK (1994) Dermatology Life Quality Index (DLQI)--a simple practical 
measure for routine clinical use. Clin. Exp. Dermatol. p. 210-6.
Garcia-Montoya and Marzo-Ortega (2018) The role of secukinumab in the treatment of 
psoriatic arthritis and ankylosing spondylitis. Ther Adv Musculoskelet Dis.Sep 6;10(9):169-
180.
Garg A, Kirby JS, Lavian J, et al (2017) Sex- and Age-Adjusted Population Analysis of 
Prevalence Estimates for Hidradenitis Suppurativa in the United States. JAMA Dermatol p. 
760-764.
Horváth B, Janse IC, Blok JL, et al (2017) Hurley Staging Refined: A Proposal by the Dutch 
Hidradenitis Suppurativa Expert Group. Acta Derm. Venereol. p. 412-413.
Humira (adalimumab) EPAR.


Novartis
Confidential
Page 93
Amended Protocol Version 02 (Clean)
Protocol No. CAIN457M2302
Janse IC, Deckers IE, van der Maten AD, et al (2017) Sexual health and quality of life are 
impaired in hidradenitis suppurativa: a multicentre cross-sectional study. Br. J. Dermatol. p. 
1042-1047.
Jemec GBE (2012) Clinical practice. Hidradenitis suppurativa. N. Engl. J. Med. p. 158-64.
Kelly G, Hughes R, McGarry T, et al (2015) Dysregulated cytokine expression in lesional and 
nonlesional skin in hidradenitis suppurativa. Br. J. Dermatol. p. 1431-9.
Kelly G, Sweeney CM, Tobin AM, et al (2014) Hidradenitis suppurativa: the role of immune 
dysregulation. Int. J. Dermatol. p. 1186-96.
Kimball AB, Ganguli A, Fleischer A (2018) Reliability of the hidradenitis suppurativa clinical 
response in the assessment of patients with hidradenitis suppurativa. J Eur Acad Dermatol 
Venereol. p. 2254-6.
Kimball AB, Jemec GBE, Yang M, et al (2014) Assessing the validity, responsiveness and 
meaningfulness of the Hidradenitis Suppurativa Clinical Response (HiSCR) as the clinical 
endpoint for hidradenitis suppurativa treatment. Br. J. Dermatol. p. 1434-42.
Kimball AB, Kerdel F, Adams D, et al (2012) Adalimumab for the treatment of moderate to 
severe Hidradenitis suppurativa: a parallel randomized trial. Ann. Intern. Med. p. 846-55.
Kimball AB, Okun MM, Williams DA, et al (2016) Two Phase 3 Trials of Adalimumab for 
Hidradenitis Suppurativa. N. Engl. J. Med. p. 422-34.
Lima AL, Karl I, Giner T, et al (2016) Keratinocytes and neutrophils are important sources of 
proinflammatory molecules in hidradenitis suppurativa. Br. J. Dermatol. p. 514-21.
Lipsker D, Severac F, Freysz M, et al (2016) The ABC of Hidradenitis Suppurativa: A 
Validated Glossary on how to Name Lesions. Dermatology (Basel) p. 137-42.
Manuel O, Kumar D (2008) QuantiFERON-TB Gold assay for the diagnosis of latent 
tuberculosis infection. Expert Rev. Mol. Diagn. p. 247-56.
Matusiak Ł, Szczęch J, Bieniek A, et al (2016) Increased interleukin (IL)-17 serum levels in 
patients with hidradenitis suppurativa: Implications for treatment with anti-IL-17 agents. J. 
Am. Acad. Dermatol. p. 670-675.
Newcombe RG (1998) Two-sided confidence intervals for the single proportion: comparison 
of seven methods. Stat Med p. 857-72.
Pandey K, Sekhri R, Sekhri V (2018) IL-17 inhibitor Secukinumab in refractory Hidradenitis 
Suppurativa: A case report.
Revuz J (2009) Hidradenitis Suppurativa J Eur Acad Dermatol Venereol.Sep23;(9):985-98.
Sartorius K, Emtestam L, Jemec GBE, et al (2009) Objective scoring of hidradenitis 
suppurativa reflecting the role of tobacco smoking and obesity. Br. J. Dermatol. p. 831-9.
Schuch A, Fischer T, Boehner A, et al (2018) Successful Treatment of Severe Recalcitrant 
Hidradenitis Suppurativa with the Interleukin-17A Antibody Secukinumab. Acta Derm. 
Venereol. p. 151-152.


Novartis
Confidential
Page 94
Amended Protocol Version 02 (Clean)
Protocol No. CAIN457M2302
Storer MA, Danesh MJ, Sandhu ME, et al (2018) An assessment of the relative impact of 
hidradenitis suppurativa, psoriasis, and obesity on quality of life. Int. J. Women's 
Dermatology 4; 198–202.
Thorlacius L, Ingram JR, Villumsen B, et al (2018) A Core Domain Set For Hidradenitis 
Suppurativa Trial Outcomes: An International Delphi Process. Br. J. Dermatol.
Thorlacius L, Theut Riis P, Jemec GBE (2017) Severe hidradenitis suppurativa responding to 
treatment with secukinumab: a case report. Br. J. Dermatol.
Wolk K, Warszawska K, Hoeflich C, et al (2011) Deficiency of IL-22 contributes to a chronic 
inflammatory disease: pathogenetic mechanisms in acne inversa. J. Immunol. p. 1228-39.
Zouboulis CC, Desai N, Emtestam L, et al (2015) European S1 guideline for the treatment of 
hidradenitis suppurativa/acne inversa. J Eur Acad Dermatol Venereol p. 619-44.
Zouboulis CC, Tzellos T, Kyrgidis A, et al (2017) Development and validation of the 
International Hidradenitis Suppurativa Severity Score System (IHS4), a novel dynamic 
scoring system to assess HS severity. Br. J. Dermatol. p. 1401-1409.


Novartis
Confidential
Page 95
Amended Protocol Version 02 (Clean)
Protocol No. CAIN457M2302
16
Appendices
16.1
Appendix 1: Clinically notable laboratory values and vital signs
The following criteria will be used to define expanded limits and notable abnormalities of key 
laboratory tests.
No specific action is pre-defined within this protocol to respond to specific abnormal laboratory 
values, as it will be decided by the investigator whether and which specific action needs to be 
taken to respond to any abnormal values, taking into account the overall status of the subject.
Liver Function and Related Variables
Alanine transaminase (ALT) (SGPT): > 3 x Upper Limit of Normal (ULN)
Aspartate transaminase (AST) (SGOT): > 3 x ULN
Total bilirubin: > 2 x ULN
Alkaline phosphatase (ALP): > 2.5 x ULN
Renal Function
Creatinine (serum): > 1.5 x ULN
Hematology
Hemoglobin: ≥ 2 g/dl decrease from baseline
Platelet count: < Lower Limit of Normal (LLN)
White blood cell count: < 0.8 x LLN
Neutrophils: < 0.9 x LLN
Eosinophils: > 1.1 x ULN
Lymphocytes: > 1.1 x ULN
Urinalysis
Protein urine dipstick: ++*
* ++ is ≥ 100 mg/dl


Novartis
Confidential
Page 96
Amended Protocol Version 02 (Clean)
Protocol No. CAIN457M2302
16.2
Appendix 2: Blood samples collection
Table 16-1
Blood log: Time schedule for blood sampling
Period
Visit Name
Hematology
Clinical 
Chemistry
Serum 
pregnancy test
Blood sample for PK
Blood sample 
for IG
Biomarker
TB test
Total 
volume 
(ml)
Volume (ml)
Volume (ml)
Volume (ml)
Dose Ref. 
ID#
Volume 
(ml)
Volume (ml)
Volume 
(ml)
Volume 
(ml)
Screening
Screening 1
4.8
3.5
2
4
14.3
Screening 2
0
Treatment 
Period 1
Baseline
4.8
5
1
2
2
15
28.8*
Week 1
0
Week 2
4.8
3.5
8.3
Week 3
0
Week 4
4.8
3.5
8.3
Week 8
4.8
3.5
8.3
Week 12
4.8
3.5
8.3
Week 16/EOT1
4.8
5
2
2
2
15
28.8
Treatment 
Period 2
Week 17
0
Week 18
4.8
3.5
8.3
Week 19
0
Week 20
4.8
3.5
8.3
Week 24
3
2
2
Week 28
4.8
3.5
8.3
Week 32
0
Week 36
0
Week 40
0
Week 44
4.8
3.5
8.3
Week 48
0
Week 52/EOT2
4.8
5
4
2
2
15
4
32.8


Novartis
Confidential
Page 97
Amended Protocol Version 02 (Clean)
Protocol No. CAIN457M2302
Period
Visit Name
Hematology
Clinical 
Chemistry
Serum 
pregnancy test
Blood sample for PK
Blood sample 
for IG
Biomarker
TB test
Total 
volume 
(ml)
Volume (ml)
Volume (ml)
Volume (ml)
Dose Ref. 
ID#
Volume 
(ml)
Volume (ml)
Volume 
(ml)
Volume 
(ml)
Post-
Treatment 
Follow-Up
Week 60
4.8
3.5
4
2
2
12.3
* For patients who sign optional DNA sampling ICF, 3 ml of blood will be additionally collected at baseline visit. # Dose reference IDs 1, 2 and 3 are
collected pre-dose; scheduled post-dose time points for dose reference ID 4 are collected 2 and 10 weeks post-last study dose.


Novartis
Confidential
Page 98
Amended Protocol Version 02 (Clean)
Protocol No. CAIN457M2302
16.3
Appendix 3: Type I alpha for the pain hypothesis
Pain will be analyzed based on pooled data.Detailed information are listed in below table:
Table 16-2
Type I alpha for the pain hypothesis
Scenario
Hypothesis rejected within two studies
Alpha for pooled pain
300q2
w
HiSCR
300q2w
AN 
count
300q2
w
Flare 
300q4w
HiSCR
300q4w
AN 
count
300q4w
Flare
300q2w
Pooled Pain
300q4w
Pooled 
Pain
H1, H'1
H3, H'3
H5, H'5
H2, H'2
H4,H'4
H6, H'6
H7
H8
1
Y
N
N
N
N
N
4α/5-α2
-
2
Y
Y
N
N
N
N
4α/5-α2
-
3
Y
Y
Y
N
N
N
4α/5-α2
-
4
N
N
N
Y
N
N
-
α/5-α2
5
N
N
N
Y
Y
N
-
α/5-α2
6
N
N
N
Y
Y
Y
-
α/5-α2
7
Y
N
N
Y
N
N
4α/5-α2
α/5-α2
8
Y
Y
N
Y
N
N
4α/5-α2
α/5-α2
9
Y
Y
Y
Y
N
N
4α/5-α2
α/5-α2
10
Y
N
N
Y
Y
N
4α/5-α2
α/5-α2
11
Y
Y
N
Y
Y
N
4α/5-α2
α/5-α2
12
Y
Y
Y
Y
Y
N
4α/5-α2
α/5-α2
13
Y
N
N
Y
Y
Y
4α/5-α2
α/5-α2
14
Y
Y
N
Y
Y
Y
4α/5-α2
α/5-α2
15
Y
Y
Y
Y
Y
Y
4α/5
α/5
For scenario 1, 2 and 3, where H1, H'1 are rejected, and H2, H'2 are not rejected, then H7 could 
be tested at level 4α/5-α2, and H8 cannot be tested.
For scenario 4, 5 and 6, where H2, H'2 are rejected, and H1, H'1 are not rejected, then H8 could 
be tested at level α/5-α2, and H7 cannot be tested.
For scenario 7 to 14, where H1, H'1, H2, H'2 are rejected, and at least one of the hypothesis H3, 
H'3, H4, H'4, H5, H'5 , H6, H'6 are not rejected, then H7 and H8 could be tested. Initially, H7 
is tested at level 4α/5-α2 and H8 is tested at level α/5-α2. If H7 (H8) is rejected, H8 (H7) can be 
tested at level α-2α2.
For scenario 15 where H1, H'1, H2, H'2, H3, H'3, H4, H'4, H5, H5’, H6, H6’ are all rejected, 
then H7 and H8 could be tested at level α. Initially, H7 is tested at level 4α/5 and H8 is tested 
at level α/5. If H7 (H8) is rejected, H8 (H7) can be tested at level α.
The subtraction of α2 would be subtracted in the initial significance level for pain hypothesis 
(H7 and/or H8) is to account for the maximum possible type I error to claim a success for 
HiSCR, AN count and/or Flare in both studies. Therefore, the type I error rate is controlled at 
level α for the submission on all hypothesis endpoints. Under the global null hypothesis (i.e. no 
difference between secukinumab and placebo), the testing procedure outlined above controls 


Novartis
Confidential
Page 99
Amended Protocol Version 02 (Clean)
Protocol No. CAIN457M2302
the type I error rate (one-sided) at the study-level to 0.025, and at the submission level to 
0.000625(0.0252). Considering all possible configurations of true and false null hypotheses, 
the type I error control at the level of the submission is 0.000625 for the primary objectives, 
and 0.025 for all hypotheses (Bretz et al 2019).