Conditions: Dermatitis, Atopic Eczema
Keywords: Topical Corticosteroids Cyclosporine
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 331
Healthy volunteers: no

Brief summary:
The main purpose of this study is to evaluate the efficacy of lebrikizumab compared with placebo in participants not adequately controlled with cyclosporine or for whom cyclosporine is not medically advisable up to Week 16.

Detailed description:

Arms:
arm 1: Lebrikizumab administered subcutaneously (SC), participants will receive 2 injections of lebrikizumab 250 mg at Baseline and Week 2, followed by 1 injection of lebrikizumab 250 milligram (mg) once every two weeks (Q2W) in the induction period up to week 16. Participants who received lebrikizumab 250 mg Q2W during the Induction Period will continue to receive lebrikizumab 250 mg Q2W during the Maintenance Period. In order to maintain the double blind, participants from the lebrikizumab 250 mg Q2W arm will be administered a second injection of blinded placebo during Week 16 and Week 18. From Week 20 up to Week 52, all participants will receive 1 injection of lebrikizumab 250 mg Q2W in Open-label maintenance period. arm 2: Lebrikizumab-matching Placebo administered SC, 250 mg dose, Q2W in the induction period for 16 weeks. Participants will receive 2 injections of lebrikizumab 250 mg at Week 16 and Week 18 followed by 1 injection of lebrikizumab 250 mg Q2W from Week 20 up to Week 52 in Open-label maintenance period.

Interventions: intervention 1: Lebrikizumab intervention 2: Lebrikizumab-matching Placebo
Intervention descriptions: intervention 1: Lebrikizumab solution for injection administered subcutaneously. intervention 2: Matching Placebo solution for injection administered subcutaneously.

Protocol document:
Prot_000.pdf: 
Clinical Trial M-17923-30
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ALMIRALL, S.A.
Clinical Trial Protocol M-17923-30
Clinical Trial Protocol Title:
A Randomised, Double-Blind, Placebo-Controlled 
Phase 3 Clinical Trial to Assess the Efficacy and 
Safety of Lebrikizumab in Combination With Topical 
Corticosteroids in Adult and Adolescent Patients With 
Moderate-To-Severe Atopic Dermatitis That Are Not 
Adequately Controlled With Cyclosporine or For 
Whom Cyclosporine is Not Medically Advisable.
Short Protocol Title:
Efficacy and safety of lebrikizumab in patients with 
atopic dermatitis (AD) not adequately controlled or 
non-eligible for cyclosporine
Investigational Medicinal 
Product(s):
Lebrikizumab
Indication:
Atopic Dermatitis
Development Phase:
Phase 3
Final Protocol Version Date:
3.0, 22 August 2022
Amendment(s)
Number:
Global 
Amendment 2
Date:
22 August 2022
Number:
Global 
Amendment 1
Date:
13 December 
2021
EudraCT Number:
2021-002967-23
Sponsor:
Almirall, S.A.
Ronda General Mitre, 151
08022 Barcelona, Spain
This document is confidential. It contains proprietary information of Almirall, S.A. 
that may not be used, divulged, published, or disclosed without the prior consent of 
Almirall, S.A.


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Pr ot oc ol A me n d me nt S u m m ar y of C h a n ges
A me n d me nt 
N o.
D ate
S u m m ar y of C h a n ges
R ati o n ale
T his a me n d me nt pr o vi des a n 
u p date d trial desi g n of t he 
3 6- wee k o pe n-la bel 
Mai nte na nce Peri o d, w hic h 
will n o w ha ve o ne treat me nt 
ar m o nl y (e ver y 2 wee ks 
re gi me n). U p date d t he 
statistical a nal ysis pla n 
acc or di n gl y. Re m o ve d e ver y 4 
wee ks re gi me n a n d relate d 
details.
Li mite d a bilit y t o c ollect 
i nsi g hts t hat w o ul d reflect 
cli nical practice a n d li mite d 
c urre nt u n dersta n di n g of w hic h 
patie nts ca n be nefit fr o m e ver y 
4 wee ks d osi n g.
A d de d bl o o d sa m ple a n d uri ne 
sa m ple (f or hae mat ol o g y, 
bi oc he mistr y, a n d uri nal ysis) 
at Wee k 3 2 d uri n g t he 
Mai nte na nce Peri o d a n d 
u p date d e n d p oi nts 
acc or di n gl y. 
T o m ore a p pr o priatel y m o nit or 
t he safet y of patie nts d uri n g t he 
Mai nte na nce Peri o d.
A d de d Treat me nt Satisfacti o n 
Q uesti o n naire f or Me dicati o n-
9 ite ms assess me nts at 
Baseli ne d uri n g t he I n d ucti o n 
Peri o d.
T o e val uate patie nt’s last 
treat me nt.
A d de d t hat p h ot o gra p h y will 
be c ollecte d f or t he patie nts 
w h o c o nse nt at selecte d sites.
A d de d clarificati o n f or t he 
c ollecti o n of p h ot o gra p h y.
Gl o bal 
A me n d me nt 1
1 3 
Dece m ber 
2 0 2 1
S h orte ne d t he fasti n g peri o d, 
alc o h ol c o ns u m pti o n a n d 
stre n u o us p h ysical acti vit y 
fr o m 1 2 t o 8 h o urs.
U p date d base d o n U nite d 
Ki n g d o m E ur o pea n C o m m u nit y 
rec o m me n dati o n.
C CI


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Amendment 
No.
Date
Summary of Changes
Rationale
Post-last dose follow-up 
period reviewed and increased 
from 12 to 18 weeks. Added 
urine pregnancy test follow-up 
every 4 weeks after last dose.
Consistent with lebrikizumab 
elimination half-life time (t1/2).
Removed urine pregnancy test 
from Screening.
To perform only serum 
beta-human chorionic 
gonadotropin at Screening.
Updated number of trial 
centres and countries.
To add additional trial centres.
Added upadacitinib and 
tralokinumab to sentence 
about newly approved 
treatments in background 
section.
To update recently approved 
new treatments for moderate-to-
severe atopic dermatitis.
Added statement about drug 
accountability if injection is 
done at home by patient or 
their caregiver.
To monitor patient compliance.
Added statement that topical 
therapy, including TCS, 
should not be applied before 
the patient has undergone all 
study procedures and clinical 
evaluations on days of study 
visits.
To perform skin assessments 
properly.
Updated assessment of 
comorbidities in medical 
history.
To further understand the 
impact of patient comorbidities 
in the efficacy or safety of 
lebrikizumab.
Added section on COVID-19.
COVID-19-related measures 
per regulatory guidance.
Removed Appendices 2 to 17 
(efficacy and PRO scales; 
Fitzpatrick skin phototype 
scale).
To provide follow-up form 
separately to the sites.
Nonsubstantial changes for 
administrative, typographical, 
and/or grammatical corrections 
throughout the document.
Global 
Amendment 2
10 August 
2022
This amendment provides an 
update to the biostatistical 
portions, including:


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Amendment 
No.
Date
Summary of Changes
Rationale
-
Change of focus for 
primary analysis to 
Overall Population 
(instead of Dupilumab 
Naïve)
-
Because of the results 
of Phase III study 
(ADhere) with the 
dupilumab naïve 
population, which did 
not confirm the initial 
assumptions for the 
study sample size 
calculation.
-
Estimand framework 
amended to match that 
of Phase III 
Lebrikizumab study
-
To provide a 
comparable framework 
to the Phase III studies 
(Advocate 1 and 
Advocate 2).
-
Odds ratio added to 
CMH analyses 
-
To provide a more 
complete assessment of 
response (in addition to 
risk difference)
-
QoL analyses split out 
to provide clearer 
definition of analyses
-
For clarity
-
Missing data 
Section 11.10 updated 
in line with Phase III 
Lebrikizumab study, 
corresponding to 
updates to estimands 
framework.
-
To provide a 
comparable framework 
to the Phase III studies 
(Advocate 1 and 
Advocate 2).
Nonsubstantial changes for 
administrative, typographical, 
and/or grammatical corrections 
throughout the document.


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S p o ns or Si g n at ures
Cli nic al Tri al Pr ot oc ol Title:
A  Ra n d o mise d,  D o u ble- Bli n d,  Place b o- C o ntr olle d 
P hase  3  Cli nical  Trial  t o  Assess  t he  Efficac y  a n d 
Safet y of Le bri kiz u ma b i n C o m bi nati o n Wit h T o pical 
C ortic oster oi ds  i n  A d ult  a n d  A d olesce nt  Patie nts 
Wit h  M o derate- T o- Se vere  At o pic  Der matitis  T hat 
Are N ot A de q uatel y C o ntr olle d Wit h C ycl os p ori ne or 
F or W h o m C ycl os p ori ne is N ot Me dicall y A d visa ble.
Tri al C o de:
M- 1 7 9 2 3- 3 0
T he  i n di vi d uals  si g ni n g  t his  cli nical  trial  pr ot oc ol  declare  t hat  t he y  ha ve  re vie we d  it  f or 
c o m plete ness, acc urac y. T he y are res p o nsi ble f or t he trial a n d a gree t o c o n d uct it i n a d here nce 
t o t he prese nt d oc u me nt, a n y a me n d me nts, t o I nter nati o nal C o u ncil f or Har m o nisati o n (I C H) 
g ui deli nes  f or  c urre nt  G o o d  Cli nical  Practice  ( G C P),  a n d  t o  l ocal  re g ulat or y  re q uire me nts, 
w here ver a p plica ble.
S p o ns or
Al mirall, S. A.
R o n da Ge neral Mitre, 1 5 1
0 8 0 2 2 Barcel o na, S pai n
F u ncti o n al R ole
N a me
T his d oc u me nt w as si g ne d electr o nic ally i n t he e D M S R & D syste m.
M a nifest ati o n of t he e-si g n at ures is av ail a ble at t he e n d of t his d oc u me nt w hic h are e q uiv ale nt t o 
h a n d writte n si g n at ures.
P P D
P P D
P P D
P P D
P P D
P P D


Cli nic al Tri al M- 1 7 9 2 3- 3 0
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6/ 1 0 2
Pri nci p al I n vesti g at or Si g n at ure
Cli nic al Tri al Pr ot oc ol Title:
A  Ra n d o mise d,  D o u ble- Bli n d,  Place b o- C o ntr olle d 
P hase  3  Cli nical  Trial  t o  Assess  t he  Efficac y  a n d 
Safet y of Le bri kiz u ma b i n C o m bi nati o n Wit h T o pical 
C ortic oster oi ds  i n  A d ult  a n d  A d olesce nt  Patie nts 
Wit h  M o derate- T o- Se vere  At o pic  Der matitis  T hat 
Are N ot A de q uatel y C o ntr olle d Wit h C ycl os p ori ne or 
F or W h o m C ycl os p ori ne is N ot Me dicall y A d visa ble.
Tri al C o de:
M- 1 7 9 2 3- 3 0
T he  i n di vi d ual  si g ni n g  t his  cli nical  trial  pr ot oc ol  declares  t hat  he/s he  has  re vie we d  it  f or 
c o m plete ness, acc urac y. He/s he is res p o nsi ble f or t he trial a n d a grees t o c o n d uct it i n a d here nce 
t o  t he  prese nt  d oc u me nt,  a n y  a me n d me nts,  t o  I C H  G C P  g ui deli nes,  a n d  t o  l ocal  re g ulat or y 
re q uire me nts, w here ver a p plica ble.
Pri nci p al I n vesti g at or
R ole
N a me
Si g n at ure
D ate
Pri nci pal 
I n vesti gat or
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1
Protocol Synopsis
Title:
A Randomised, Double-Blind, Placebo-Controlled Phase 3 Clinical Trial to Assess the 
Efficacy and Safety of Lebrikizumab in Combination With Topical Corticosteroids in Adult 
and Adolescent Patients With Moderate-To-Severe Atopic Dermatitis That Are Not 
Adequately Controlled With Cyclosporine or For Whom Cyclosporine is Not Medically 
Advisable.
Short Title:
Efficacy and safety of lebrikizumab in patients with atopic dermatitis (AD) not adequately 
controlled or non-eligible for cyclosporine.
Investigators:
A Principal Investigator will be designated at each participating clinical trial centre, and a 
Coordinating Investigator will be nominated among the participating sites. The name, address, 
and affiliation of each Principal Investigator and the Coordinating Investigator will be detailed 
in the final clinical study report.
Trial Centres:
This is an international multicentre study. The study is planned to be conducted at 
approximately 81 centres in approximately 9 countries within Europe, including the United 
Kingdom, Italy, France, Spain, Germany, the Netherlands, Belgium, Austria, and Poland.
Study Duration:
The duration of the entire study from first patient, first visit to last patient, last visit is 
anticipated to be approximately 24 months.
Duration of Treatment:
The duration of each patient’s treatment is up to 52 weeks. The study has 2 treatment periods: 
a 16-week double-blind Induction Period followed by a 36-week open-label Maintenance 
Period.
Duration of Patients’ Participation in the Trial:
The total duration of each patient’s participation in the trial, including Screening, treatment, 
and follow-up periods, is estimated at a maximum of 72 weeks (up to 4 weeks of Screening, 
52 weeks of treatment [last dose given at Week 50], and 18 weeks of post-last dose safety 
follow-up).
Phase of Development:
This is a phase 3 trial.


Cli nic al Tri al M- 1 7 9 2 3- 3 0
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R ati o n ale:
At o pic  der matitis  is  a  c hr o nic  i nfla m mat or y  heter o ge ne o us  s ki n  dis or der  c haracterise d  b y 
rec urre nt ecze mat o us lesi o ns, i nte nse itc h, a n d s ki n pai n (e g, disc o mf ort or s ore ness). A D is 
o ne of t he m ost c o m m o n i nfla m mat or y s ki n dis or ders, affecti n g u p t o 2 0 % of c hil dre n a n d 1 0 % 
of a d ults i n hi g h-i nc o me c o u ntries. 1
T he use of le bri kiz u ma b f or A D is s u p p orte d b y n u mer o us precli nical st u dies de m o nstrati n g 
t hat A D is c haracterise d b y t he i ncrease d e x pressi o n of i nterle u ki n (I L)- 1 3 i n s ki n. M ore o ver, 
3  cli nical  trials  (s u m marise d  i n Secti o n  5. 1. 4 )  wit h  le bri kiz u ma b  de m o nstrate d  si g nifica nt 
cli nical be nefit i n patie nts wit h A D.
Le bri kiz u ma b  is  a  h u ma nise d  m o n ocl o nal  i m m u n o gl o b uli n  (I g)  G 4  a nti b o d y  w hic h  bi n ds 
s pecificall y t o s ol u ble h u ma n I L- 1 3 wit h hi g h affi nit y a n d p ote ntl y i n hi bits I L- 1 3 si g nalli n g 
t hr o u g h t he I L- 4 R α/I L- 1 3 R α 1 c o m ple x. A p hase 3 pr o gra m me is c urre ntl y o n g oi n g ai me d at 
c o nfir mi n g safet y a n d efficac y of le bri kiz u ma b i n patie nts wit h m o derate-t o-se vere A D w h o 
are ca n di dates f or s yste mic t hera p y.
T he c urre nt st u d y ai ms t o e val uate t he efficac y a n d safet y of le bri kiz u ma b wit h c o nc o mita nt 
t o pical  c ortic oster oi ds  ( T C S)  i n  patie nts  wit h  A D  a n d  a  hist or y  of  i na de q uate  res p o nse  or 
i nt olera nce t o c ycl os p ori ne A ( Cs A), or Cs A- naï ve patie nts f or w h o m Cs A treat me nt is n ot 
me dicall y a d visa ble.
O bjecti ves:
T his st u d y is desi g ne d t o e val uate efficac y a n d safet y of le bri kiz u ma b wit h c o nc o mita nt T C S 
t hr o u g h Wee k 5 2 i n a d ults a n d a d olesce nts (a ge d ≥1 2 t o < 1 8 years a n d wei g hi n g ≥4 0 k g) wit h 
m o derate-t o-se vere  A D,  w h o  are  n ot  a de q uatel y  c o ntr olle d  wit h  c ycl os p ori ne  or  f or  w h o m 
c ycl os p ori ne is n ot me dicall y a d visa ble .
Pri mar y

T o e val uate t he efficac y of le bri kiz u ma b c o m pare d wit h place b o i n patie nts n ot a de q uatel y 
c o ntr olle d wit h c ycl os p ori ne or f or w h o m c ycl os p ori ne is n ot me dicall y a d visa ble u p t o 
Wee k 1 6.
Sec o n dar y

T o  e val uate  t he  efficac y  i n  patie nts  n ot  a de q uatel y  c o ntr olle d  wit h  c ycl os p ori ne  or  f or 
w h o m c ycl os p ori ne is n ot me dicall y a d visa ble bet wee n Wee k 1 6 u p t o Wee k 5 2;

T o e val uate t he safet y a n d t olera bilit y of le bri kiz u ma b i n patie nts n ot a de q uatel y c o ntr olle d 
wit h c ycl os p ori ne or f or w h o m c ycl os p ori ne is n ot me dicall y a d visa ble u p t o Wee k 1 6;

T o e val uate t he safet y a n d t olera bilit y of le bri kiz u ma b i n patie nts n ot a de q uatel y c o ntr olle d 
wit h c ycl os p ori ne or f or w h o m c ycl os p ori ne is n ot me dicall y a d visa ble u p t o Wee k 6 8.
Tri al Desi g n:
T his  is  a ra n d o mise d,  d o u ble- bli n d,  place b o-c o ntr olle d,  parallel- gr o u p  st u d y,  7 2 wee ks  i n 
d urati o n ( u p t o 4 wee ks of Scree ni n g, 5 2 wee ks of treat me nt [last d ose gi ve n at Wee k 5 0], a n d 
C CI


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18 weeks of post-last dose safety follow-up). The study is designed to confirm the efficacy and 
safety of lebrikizumab administered concomitantly with TCS in adolescents and adults with 
moderate-to-severe AD not adequately controlled with cyclosporine or for whom cyclosporine 
is not medically advisable.
The study has 2 treatment periods: a 16-week double-blind Induction Period followed by a 
36-week open-label Maintenance Period. The study will be double-blind until Week 18 and 
open-label from Week 20 onward. The patients who received placebo during the Induction 
Period will receive loading doses of lebrikizumab at Weeks 16 and 18. To maintain blinding at 
Weeks 16 and 18, all patients will receive 2 injections at Weeks 16 and 18 (either 2 injections 
of lebrikizumab or 1 injection of lebrikizumab and 1 injection of placebo). From Week 20 
onward, all patients will receive 1 injection of lebrikizumab 250 mg every 2 weeks (Q2W).
Number of Patients:
A sufficient number of patients will be screened to randomise approximately 312 patients with 
moderate-to-severe AD.
Trial Population:
Eligible adult and adolescent (aged ≥12 to <18 years and weighing ≥40 kg) patients with 
moderate-to-severe AD for at least 1 year, defined according to the Hanifin and Rajka Criteria,2 
an Eczema Area and Severity Index score (EASI) of ≥16, an Investigator Global Assessment 
(IGA) score of ≥3 and a body surface area (BSA) affected by AD of ≥10% will be enrolled 
(adolescent patients aged ≥12 to <18 years will make up 12.5% of the overall population 
compared to adults aged ≥18 years). Eligible patients must have documented history of 
inadequate response to treatment with topical AD medication within 6 months before 
Screening, documented history of inadequate response or intolerance to CsA, or CsA-naïve 
patients for whom CsA treatment is not medically advisable. Patients with previous exposure 
to dupilumab, including suboptimal responses (eg, persistence of itch despite treatment with 
dupilumab, flare-up days before the next dupilumab dose) may be included in the study with a 
washout period of 8 weeks before Baseline. During this washout period, patients may be 
allowed to use TCS, which will need to be stopped at least 1 week before Baseline. The 
enrolment of this subpopulation of patients will be limited to a maximum of 60 enrolled 
patients. All other enrolled patients must be naïve to IL-4 or IL-13 blocking antibodies.
Test Investigational Medicinal Product, Dosage, and Mode of Administration:
Substance code/name:
Lebrikizumab
Administration route:
Subcutaneous (SC)
Unit dose/strength:
Each prefilled syringe is intended for a single 2 mL dose 
(250 mg)
Dosage form:
Solution 
for 
injection 
containing 
125 
mg/mL 
lebrikizumab. Supplied as a sterile prefilled syringe with 
a pre-assembled needle safety device (PFS-NSD).
Frequency:
During the 16-week Induction Period and 36-week 
Maintenance Period, 250 mg lebrikizumab Q2W (with 
loading doses of 500 mg [2 syringes] given at Baseline 
and Week 2 during Induction Period, and at Week 16 and 
Week 18 during the Maintenance Period for patients who 


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received placebo during the Induction Period). After 
completion of the Week 16 visit, patients will enter the 
Maintenance Period:

Patients who received lebrikizumab 250 mg Q2W 
during the Induction Period will continue to receive 
lebrikizumab 250 mg Q2W during the Maintenance 
Period

Patients who received placebo Q2W during 
Induction Period will start receiving lebrikizumab 
250 mg Q2W (with loading doses at Week 16 and 
Week 18) during the Maintenance Period.
Placebo Product, Dosage, and Mode of Administration:
Substance code/name:
The placebo solution is identical in appearance and 
volume to the active solution except that it does not 
contain lebrikizumab
Administration route:
SC
Unit dose/strength:
Each prefilled syringe is intended for a single 2 mL dose
Dosage form:
Solution for injection, containing the same excipients as 
the respective active lebrikizumab. Supplied as a sterile 
prefilled syringe with a PFS-NSD
Frequency:
Placebo will be administered during the initial 16-week 
period (and at Weeks 16 and 18, if applicable) to 
maintain blinding. Placebo will be administered Q2W 
(loading dose, 2 syringes, will be given at Baseline and 
Week 2) 
To allow patients in the placebo arm to receive lebrikizumab loading doses during the 
Maintenance Period, the blinding will be maintained in Week 16 and Week 18. In order to 
maintain the double-blind, patients from the lebrikizumab 250 mg Q2W arm will be 
administered a second injection of blinded placebo during Week 16 and Week 18. From Week 
20 onwards, all patients will receive 1 injection of lebrikizumab 250 mg Q2W. Therefore, the 
study will be open-label from Week 20 onward.
Methodology:
Trial visits and assessments will be performed in accordance with the Schedule of Assessments 
(Table 1).
Statistical Methods
Sample Size Calculation
The study is designed to gain an estimate of the effect of study treatment in the patient 
population of adults and adolescent patients not adequately controlled with cyclosporine or for 
whom cyclosporine is not medically advisable. The sample size for this study has been 
estimated to allow power enough to show efficacy in the overall study population for the 
primary and key secondary endpoints.


Cli nic al Tri al M- 1 7 9 2 3- 3 0
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I n t he o verall p o p ulati o n, a t otal sa m ple size of 3 1 2 patie nts, i n a 2: 1 rati o ( 2 0 8 le bri kiz u ma b 
ar m a n d 1 0 4 place b o ar m) will pr o vi de m ore t ha n 9 5 % n o mi nal p o wer t o detect a statisticall y 
si g nifica nt differe nce of 2 5 % ( 5 5 % le bri kiz u ma b ar m vers us 3 0 % place b o ar m) i n t he pri mar y 
st u d y  e n d p oi nt:  pr o p orti o n  of  patie nts  ac hie vi n g  E A SI  7 5  at  Wee k  1 6.  As  refere nce  a n d 
c o nsi deri n g  i n de pe n de nce  bet wee n  varia bles,  t his  sa me  sa m ple  size  will  pr o vi de  m ore  t ha n 
9 0 %  o verall  p o wer  t o  als o  detect  a  differe nce  of  1 8 %  ( 3 0 %  le bri kiz u ma b  ar m  vers us  1 2 % 
place b o  ar m)  i n  t he  pr o p orti o n  of  patie nts  ac hie vi n g  I G A  ( 0/ 1)  at  Wee k  1 6  a n d  of  3 4 % 
differe nces  ( 4 3 %  le bri kiz u ma b  ar m  vers us  9 %  place b o  ar m)  i n  t he  pr o p orti o n  of  patie nts 
ac hie vi n g a 4- p oi nt pr urit us n u merical rati n g scale ( N R S) decrease fr o m Baseli ne at Wee k 1 6.
A nal ysis P o p ulati o ns:
T he f oll o wi n g a nal ysis sets are defi ne d:

T he F ull A nal ysis Set ( F A S) i ncl u des all ra n d o mise d patie nts. Patie nts will be a nal yse d 
u n der t he treat me nt gr o u p as ra n d o mise d.

T he Per Pr ot oc ol A nal ysis Set ( P P S) i ncl u des all ra n d o mise d patie nts w h o recei ve at 
least o ne d ose of t he st u d y dr u g, ha ve at least o ne p ost- Baseli ne E A SI assess me nt, a n d 
a d diti o nall y f or w h o m t here are n o i m p orta nt pr ot oc ol de viati o ns affecti n g efficac y at 
Wee k 1 6. Patie nts will be a nal yse d u n der t he treat me nt gr o u p as ra n d o mise d.

T he Safet y A nal ysis Set ( S A F) i ncl u des all ra n d o mise d patie nts w h o recei ve at least 
1 d ose of t he st u d y dr u g. Patie nts will be a nal yse d u n der t he treat me nt gr o u p act uall y 
recei ve d.
T he mai n a nal ysis of all t he efficac y varia bles will be perf or me d o n t he F A S p o p ulati o n. T he 
pri mar y a n d ke y sec o n dar y efficac y varia bles will als o be a nal yse d f or t he o verall p o p ulati o n 
usi n g t he P P S p o p ulati o n t o assess t he r o b ust ness of t he fi n di n gs fr o m t he F A S p o p ulati o n. All 
safet y a nal yses will be c o n d ucte d usi n g t he S A F p o p ulati o n.
Statistical A nal ysis
St u d y res ults will be deli vere d i n 2 parts: t he first res ults deli ver y will be pr o vi de d after t he 
first data base l oc k, o nce all patie nts ha ve c o m plete d t he I n d ucti o n Peri o d or disc o nti n ue d st u d y 
bef ore t his p oi nt, a n d t he sec o n d res ults deli ver y will be pr o vi de d after sec o n d data base l oc k, 
at  t he  e n d  of  t he  st u d y  ( E O S),  o nce  all  patie nts  ha ve  c o m plete d  t he  st u d y,  or  disc o nti n ue d 
bef ore E O S.
Acc or di n gl y, 2 differe nt data base l oc ks will be perf or me d, a n d 2 differe nt cli nical st u d y re p orts 
will be ge nerate d.
All e n d p oi nts descri be d i n Secti o n 6  will als o be a nal yse d b y pre vi o us e x p os ure t o d u pil u ma b 
( Yes/ N o) as 
De m o gra p hics a n d Baseli ne C haracteristics
A p pr o priate  descri pti ve  statistics  will  be  use d  t o  s u m marise  de m o gra p hic  a n d  baseli ne 
c haracteristics, i ncl u di n g b ut n ot li mite d t o se x, a ge, re gi o n, race, hei g ht, wei g ht, b o d y mass 
i n de x  ( B MI),  s ki n  t y pe  ( Fitz patric k  scale3),  a n d  pri or  use  of  d u pil u ma b.  F or  stratificati o n 
fact ors, b ot h t he fact or as ra n d o mise d a n d t he act ual fact or will be s u m marise d, if differe nces 
e xist. Me dical hist or y i nf or mati o n will be prese nte d i n a b y- patie nt listi n g.
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Efficacy Analysis
The primary efficacy endpoint, EASI 75 at Week 16, will be analysed by means of a Cochran-
Mantel-Haenszel (CMH) model adjusted by country, age (adolescents/adults), prior use of 
dupilumab (yes/no), and baseline severity of disease (IGA=3/IGA=4). If the model does not 
converge, country will be removed as an adjusting factor. The estimate of the adjusted common 
risk difference, with corresponding Mantel-Haenszel-Sato (Sato 1989)58 adjusted 2-sided 95% 
confidence interval (CI) and p-value will be presented. Additionally, the CMH adjusted odds 
ratio along with the 95% two-sided asymptotic CI will be presented in a similar manner to the 
primary analyses. The primary analysis will be based on the Full Analysis Set (FAS) which 
was defined as all randomized patients. When analysing the dupilumab naïve and previously 
exposed populations, the factor for prior use of dupilumab will be removed from the CMH 
adjustment.
Further details on sensitivity and supportive measures, including descriptions of all estimands, 
intercurrent events (ICEs) and handling approaches are included in Section 11.8.1.1. Details 
regarding imputation of missing data are included in Section 11.10. 
Key secondary efficacy endpoints will be analysed in the same manner as the primary efficacy 
endpoint, on the same main and second estimands.
The binary secondary and other efficacy endpoints will be analysed using the same 
methodology as described above for the primary efficacy endpoint using only the main 
estimand.
Continuous secondary and other efficacy endpoints assessed at multiple post-Baseline visits 
during the Induction Period will be analysed for the main and second estimands for continuous 
endpoints by means of a mixed effect model for repeated measures (MMRM). More details are 
given in Section 11.8.1.1.
Time-to-event (TTE) endpoints will be analysed using Kaplan-Meier survival analysis 
methods. If available, for descriptive purposes, the estimate of the median time-to-event (in 
weeks) and the 2-sided 95% CI will be presented. A comparison of the survival distribution 
curves for the 2 treatment groups will be made by means of the log-rank test. The Cox 
proportional hazards model will be used to estimate the hazard ratio and its 95% CI of 
lebrikizumab compared with placebo at the respective time point. The main Cox proportional 
hazards model will include treatment group, with country, age, baseline disease severity, and 
previous exposure to dupilumab (when the overall population is analysed) as factors. 
Quality of Life (QoL) endpoints of Total DLQI and CDLQI will be analysed in the same way 
as the continuous other secondary efficacy endpoints occurring at multiple post-Baseline visits, 
on the overall population. DLQI-R, RECAP, TSQM-9, and WHO-5 will all be analysed 
descriptively on the overall population. Any individual components related to QoL scoring will 
also be analysed descriptively for the overall population.
All efficacy and QoL variables for the Maintenance Period will be analysed by means of 
descriptive statistics and presented by treatment group as randomised during the Induction 
Period.


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Cli nic al Tri al Pr ot oc ol Versi o n N o. 3. 0 2 2 A u g ust 2 0 2 2
S R D- 0 0 0 2 1 7 8 v 5. 0
C O N FI D E N TI A L
1 3/ 1 0 2
Safet y A nal ysis
T he a nal yses of safet y a n d t olera bilit y o utc o mes will be perf or me d o n t he S A F.
Safet y o utc o mes i ncl u de A Es, vital si g ns (i ncl u di n g b o d y te m perat ure, res pirat or y rate, p ulse, 
a n d s yst olic a n d diast olic bl o o d press ure), p h ysical e xa mi nati o ns (i ncl u di n g a p plicati o n site 
reacti o ns), a n d cli nical la b orat or y assess me nts ( hae mat ol o g y, c he mistr y pa nel, uri ne testi n g, 
a n d uri ne pre g na nc y test f or w o me n of c hil d beari n g p ote ntial).
All re p orte d A Es will be c o de d usi n g t he m ost rece nt versi o n of t he Me dical Dicti o nar y f or 
Re g ulat or y Acti vities. Details o n t he a nal ysis of safet y a n d t olera bilit y e n d p oi nts are pr o vi de d 
i n Secti o n 1 1. 8. 4.
I nteri m A nal ysis
N o i nteri m a nal yses are pla n ne d.
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Study Procedures
Screening
Induction Perioda
Study visit
1
2
3
4
5b
6
7b
8
9b
10
Day/Week (W)
W -4 to Day -1
Day 1-Baseline
W2
W4
W6
W8
W10
W12
W14
W16c
Visit windowd
 
 
±3d
±3d
±3d
±3d
±3d
±3d
±3d
±3d
POEM, RECAPi
X
X
X
X
X
DLQI or CDLQI, DLQI-Ri
X
X
X
 
X
 
X
 
X
WHO-5i
X
X
TSQM-9i
X
X
Photographyl
 
X
X
X 
 
X
 
 
 
X
Training autoinjection
 
 
 X
X 
 
 
 
 
 
Administer study drug and Product Complaint reporting
 
X
X
X
X
X
X
X
X
X
Assess treatment compliancem
X
X
X
X
X
X
X
X
Abbreviations: AE = adverse event; aPTT = activated partial thromboplastin time; BMI = body mass index; BSA = body surface area; CDLQI = Children Dermatology Life 
Quality Index; d = day; DLQI = Dermatology Life Quality Index; DLQI-R = DLQI-Relevant; EASI = Eczema Area and Severity Index; eDiary = electronic diary; HIV = 
human immunodeficiency virus; hCG = human chorionic gonadotropin; IGA = Investigator's Global Assessment; INR = International Normalised Ratio; NRS = Numerical 
Rating Scale; POEM = Patient-Oriented Eczema Measure; PT = Prothrombin time; Q2W = every 2 weeks; RECAP = Recap of Atopic Eczema; SCORAD = Scoring Atopic 
Dermatitis; TCS = topical corticosteroids; TSQM-9 = Treatment Satisfaction Questionnaire for Medication-9 items; W = week; WHO-5 = World Health Organisation-Five 
Well-Being Index; WOCBP = women of childbearing potential.
a.
A safety follow-up will occur 18 weeks after last dose of study medication (including both end-of-treatment period or after early termination).
b.
Visits shaded in blue may be conducted remotely or on-site, per preference of the study site or patient. W68 will be on-site for WOCBP only.
c.
For patients who received placebo during the Induction Period, loading doses of lebrikizumab will be given at W16 and W18 during the Maintenance Period. In order 
to maintain the double-blind, patients from the lebrikizumab 250 mg Q2W arm will be administered a second injection of blinded placebo during W16 and W18. From 
W20 onwards, all patients will receive 1 injection of lebrikizumab 250 mg Q2W.
d.
Visit window for patient-reported outcomes is -3 days during Induction Period and -5 days during Maintenance Period.
e.
For adults, height should only be captured at Screening. For adolescents, height should only be captured at Screening and Week 52.
f.
Patients should attend the visit fasted. Patients should not eat or drink anything except water for 8 hours before sample collection. Alcohol consumption will not be 
permitted for at least 8 hours before visits. Strenuous physical activity should be avoided for at least 8 hours before a visit.
g.
The contraception check is to confirm that contraception, if required, is used consistently and correctly.
h.
Serum beta-hCG at Screening. Urine pregnancy test at all other identified visits. If required per local regulations and/or institutional guidelines, pregnancy testing can 
occur at other times during the study treatment period. For WOCBP, urine pregnancy tests will be conducted every 4 weeks after last dose of study medication (W54, 
W58, and W62) and at W68. Male subjects engaged in a relationship with a WOCBP must be contacted every 4 weeks after last dose of study medication (W54, W58, 
and W62) and at W68 to ensure respect of the contraception.
i.
Patient-reported outcomes and quality of life measurements should all be completed before other study assessments. Assessments/procedures should be conducted in 
the following order: 1) patient-reported outcomes; 2) Investigator assessments and other efficacy assessments; 3) safety and laboratory assessments (including sample 


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collection for biomarkers); and 4) administration of study drug. Completed eDiary entries for Pruritus NRS and sleep-loss scales are needed for a minimum of 4 out 
of 7 days in the week preceding randomisation visit.
j.
To be performed daily up to W2, weekly from W2 to W16, and every 2 weeks from W16 onward.
k.
To be performed daily up to W2, weekly from W2 to W16, and every 4 weeks from W16 onward.
l.
For patients who consent at selected sites.
m.
Compliance assessment for study drug, TCS, as well as accountability.






Cli nic al Tri al M- 1 7 9 2 3- 3 0
Cli nic al Tri al Pr ot oc ol Versi o n N o. 3. 0 2 2 A u g ust 2 0 2 2
S R D- 0 0 0 2 1 7 8 v 5. 0
C O N FI D E N TI A L
1 9/ 1 0 2
2
T a ble of C o nte nts
Pr ot oc ol A me n d me nt S u m m ary of C h a n ges ............................................................................ 2
S p o ns or Si g n at ures ................................................................................................................... 5
Pri nci p al I nvesti g at or Si g n at ure .............................................................................................. 6
1 
Pr ot oc ol Sy n o psis ................................................................................................. 7
2 
T a ble of C o nte nts ............................................................................................... 1 9
T a ble of Fi g ures ...................................................................................................................... 2 2
T a ble of T a bles ........................................................................................................................ 2 2
3 
List of A b brevi ati o ns .......................................................................................... 2 3
4 
S p o ns or, I nvesti g at or(s) a n d Tri al A d mi nistr ative Str uct ure ........................... 2 6
4. 1 
S p o ns or........................................................................................................................... 2 6
4. 2 
I n vesti g at or(s)................................................................................................................ 2 6
4. 3  
A d mi nistr ati ve Str uct ure ............................................................................................. 2 6
5 
I ntr o d ucti o n........................................................................................................ 2 6
5. 1 
B ac k gr o u n d I nf or m ati o n.............................................................................................. 2 6
5. 1. 1 
I n dicati o n........................................................................................................................................ 2 6
5. 1. 2  
Mec ha nis m of Acti o n ..................................................................................................................... 2 7
5. 1. 4 
Cli nical St u dies .............................................................................................................................. 2 9
5. 2 
S u m m ar y of t he K n o w n P ote nti al Ris ks a n d Be nefits............................................... 3 2
5. 3 
Scie ntific R ati o n ale f or t he Tri al ................................................................................. 3 2
6  
O bjectives a n d E n d p oi nts................................................................................... 3 2
7 
Tri al Desi g n a n d R ati o n ale................................................................................ 3 6
7. 1 
Tri al Desi g n ................................................................................................................... 3 6
7. 2 
Tri al R ati o n ale .............................................................................................................. 3 9
7. 2. 1 
Rati o nale f or Trial Desi g n.............................................................................................................. 3 9
7. 2. 2 
Rati o nale f or Trial P o p ulati o n........................................................................................................ 4 0
7. 2. 3 
Rati o nale f or Trial D ose a n d Re gi me n........................................................................................... 4 0
7. 2. 4 
Rati o nale f or Trial Assess me nts..................................................................................................... 4 1
8 
Selecti o n of t he Tri al P o p ul ati o n a n d Wit h dr a w al of P atie nts......................... 4 2
8. 1  
N u m ber of P atie nts ....................................................................................................... 4 2
8. 2 
I ncl usi o n Criteri a .......................................................................................................... 4 2
8. 3 
E xcl usi o n Criteri a ......................................................................................................... 4 3
8. 3. 1 
Patie nt Wit h dra wal......................................................................................................................... 4 5
8. 3. 2 
St u d y Dr u g Disc o nti n uati o n........................................................................................................... 4 6
8. 4 
Scree n F ail ures .............................................................................................................. 4 6
8. 4. 1 
Patie nt Re place me nt Criteria.......................................................................................................... 4 6
8. 5 
Ter mi n ati o n of t he Tri al............................................................................................... 4 7
8. 5. 1 
E n d of Trial Defi niti o n................................................................................................................... 4 7
8. 5. 2 
C o m plete d Patie nt Defi niti o n......................................................................................................... 4 7
8. 5. 3 
Pre mat ure Trial Ter mi nati o n.......................................................................................................... 4 7
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9
Treatments ..........................................................................................................48
9.1
Identity of Trial Investigational Medicinal Product(s)..............................................48
9.2
Packaging and Labelling..............................................................................................49
9.3
Shipment, Storage, and Accountability ......................................................................49
9.4
Treatment Administration...........................................................................................50
9.5
Treatment Compliance.................................................................................................50
9.6
Methods for Assigning Patients to Treatment Groups..............................................51
9.6.1
Patient Identification ......................................................................................................................51
9.6.2
Randomisation................................................................................................................................51
9.7
Blinding..........................................................................................................................52
9.8
Unblinding by the Investigator....................................................................................52
9.9
Pre-trial, Concomitant, and Post-trial Medications/Therapy...................................53
9.9.1
Pre-trial Medications......................................................................................................................53
9.9.2
Concomitant Medications ..............................................................................................................54
9.9.3
Prohibited Concomitant Medications.............................................................................................55
9.9.4
Rescue Treatment for Atopic Dermatitis .......................................................................................56
9.9.5
Post-trial Medications ....................................................................................................................56
10
Trial Procedures and Assessments ....................................................................56
10.1
General Conditions of the Trial...................................................................................56
10.2
Patients General Conditions During the Trial...........................................................57
10.2.1
Instructions for Male Patients ........................................................................................................58
10.3
Scheduled Activities and Trial Visits ..........................................................................58
10.3.1
Screening Period ............................................................................................................................58
10.3.2
Treatment Period............................................................................................................................58
10.3.3
End-of-Treatment...........................................................................................................................59
10.3.4
Follow-up Period............................................................................................................................59
10.3.5
Unscheduled and Repeated Tests...................................................................................................59
10.4
Efficacy Assessments ....................................................................................................59
10.4.1
Eczema Area and Severity Index Score.........................................................................................59
10.4.2
Investigator Global Assessment.....................................................................................................60
10.4.3
Body Surface Area .........................................................................................................................60
10.4.4
Scoring Atopic Dermatitis..............................................................................................................60
10.4.5
Pruritus Numerical Rating Scale....................................................................................................61
10.4.6
Sleep-Loss Scale ............................................................................................................................61
10.4.7
Skin Pain NRS................................................................................................................................61
10.4.8
Patient-Oriented Eczema Measure.................................................................................................61
10.4.9
Dermatology Life Quality Index....................................................................................................62
10.4.10 Dermatology Life Quality Index-Relevant ....................................................................................62
10.4.11 World Health Organisation - Five Well-Being Index....................................................................62
10.4.12 Recap of Atopic Eczema................................................................................................................62
10.4.13 Treatment Satisfaction Questionnaire for Medication-9 Items (TSQM-9)....................................62
10.5
Safety and Tolerability Assessments...........................................................................62
10.5.1
Adverse Events...............................................................................................................................62
10.5.2
Medical History, Physical Examinations, and Vital Signs ............................................................63
10.5.3
Laboratory Testing.........................................................................................................................63
10.6
Adverse Events..............................................................................................................64
10.6.1
Definitions......................................................................................................................................64
10.6.2
Reporting of Adverse Events .........................................................................................................66
10.6.3
Recording of Adverse Events.........................................................................................................67
10.6.4
Reporting of Serious Adverse Events ............................................................................................67


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C O N FI D E N TI A L
2 1/ 1 0 2
1 0. 6. 5 
S us pecte d U ne x pecte d Seri o us A d verse Reacti o ns ....................................................................... 6 8
1 0. 6. 6 
F oll o w- u p of A d verse e ve nts/ Seri o us A d verse E ve nts .................................................................. 6 9
1 0. 6. 7  
O ver d ose ........................................................................................................................................ 6 9
1 0. 6. 8 
Pre g na ncies .................................................................................................................................... 7 0
1 0. 6. 9  
U n bli n di n g f or Safet y Reas o ns ...................................................................................................... 7 0
1 0. 6. 1 0 Pr o d uct C o m plai nts ........................................................................................................................ 7 0
1 0. 7  
Ot her Assess me nts ........................................................................................................ 7 1
1 0. 7. 2 
P h ot o gra p h y ................................................................................................................................... 7 2
1 1 
St atistics .............................................................................................................. 7 2
1 1. 1 
S a m ple Size C alc ul ati o n ............................................................................................... 7 2
1 1. 2 
Str uct ure a n d Met h o d ol o g y of t he St atistic al A n al ysis ............................................. 7 2
1 1. 3  
A n al ysis P o p ul ati o ns..................................................................................................... 7 3
1 1. 4  
Descri pti ve St atistics..................................................................................................... 7 3
1 1. 5 
P atie nt Dis p ositi o n ........................................................................................................ 7 3
1 1. 6  
De m o gr a p hic a n d B aseli ne C h ar acteristics................................................................ 7 3
1 1. 7 
E n d p oi nts ....................................................................................................................... 7 4
1 1. 8 
St atistic al Met h o ds........................................................................................................ 7 4
1 1. 8. 1  
A nal ysis of Efficac y ....................................................................................................................... 7 4
1 1. 8. 2  
A nal ysis of Q ualit y of Life E n d p oi nts ........................................................................................... 7 9
1 1. 8. 3  
A nal yses of E n d p oi nts Relate d t o t he Sec o n dar y O bjecti ve ( Fr o m Wee k 1 6 t o Wee k 5 2)........... 7 9
1 1. 8. 4  
A nal ysis of Safet y a n d T olera bilit y E n d p oi nts .............................................................................. 7 9
1 1. 1 0  
H a n dli n g of Missi n g D at a............................................................................................. 8 0
1 1. 1 1  
M ulti plicit y Str ate g y ..................................................................................................... 8 1
1 1. 1 2 
I nteri m A n al ysis ............................................................................................................ 8 1
1 2  
D at a H a n dli n g, Pr ocessi n g, a n d Rec or d Kee pi n g ............................................ 8 1
1 2. 1  
D at a C ollecti o n .............................................................................................................. 8 2
1 2. 1. 1 
I de ntificati o n of t he Trial Data S o urces ......................................................................................... 8 2
1 2. 1. 2 
Electr o nic Case Re p ort F or ms ....................................................................................................... 8 3
1 2. 1. 3 
Patie nt Diar y................................................................................................................................... 8 3
1 2. 2  
D at a M a n a ge me nt a n d Q u alit y C o ntr ol ..................................................................... 8 4
1 2. 3 
I n vesti g at or’s a n d Tri al M aster Files.......................................................................... 8 5
1 2. 4  
D oc u me nts a n d Rec or d Kee pi n g ................................................................................. 8 5
1 3  
Q u ality C o ntr ol a n d Q u ality Ass ur a nce ............................................................ 8 6
1 3. 1 
Tr ai ni n g of St aff............................................................................................................ 8 6
1 3. 2  
M o nit ori n g ..................................................................................................................... 8 6
1 3. 3 
I ns pecti o ns a n d A u dits ................................................................................................. 8 7
1 4 
Et hics .................................................................................................................. 8 7
1 4. 1  
Res p o nsi bilities.............................................................................................................. 8 7
1 4. 2 
P atie nt I nf or m ati o n a n d I C F/I A F ............................................................................... 8 8
1 4. 3 
I n de pe n de nt Et hics C o m mittee or I nstit uti o n al Re vie w B o ar d Re vie w .................. 8 8
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14.4
Patient Data Protection ................................................................................................89
15
Financing and Insurance ..................................................................................89
16
Publication Policy ..............................................................................................89
17
Other Practical Considerations .........................................................................90
17.1
Investigator’s Brochure................................................................................................90
17.2
Final Clinical Trial Report...........................................................................................90
17.3
Protocol Amendments ..................................................................................................90
17.4
Protocol Deviations.......................................................................................................90
17.5
COVID-19......................................................................................................................91
18
References...........................................................................................................92
19
List of Appendices ..............................................................................................96
Table of Figures
Figure 1
Lebrikizumab Phase 3 Study Design Schematic...............................................39
Table of Tables
Table 1.
Schedule of Assessments (SoA) .........................................................................14
Table 2.
Main Objectives and Related Endpoints ...........................................................32
Table 3. 
Secondary Objectives and Related Endpoints...................................................34
Table 4.
Dosing Schedule During Maintenance Period .................................................37
Table 5.
Prior Treatment Exclusions...............................................................................54
Table 6.
Instruction for Use of Concomitant Medication...............................................55
Table 7.
Investigator Global Assessment.........................................................................60
Table 8.
Laboratory Testing Parameters .........................................................................64
Table 9.
Main Estimand for Primary and Key Secondary Efficacy Analyses ...............75
Table 10.
Handling of ICEs for the Primary Efficacy Endpoint and Key Secondary 
Endpoints (for the Main and Second Estimands) ...........................................75
Table 11.
Sensitivity Analysis.............................................................................................77
Table 12.
Handling of ICEs for the Continuous Secondary Efficacy and Other Efficacy 
Endpoints ..........................................................................................................77
Table 13.
Data Imputation Methods..................................................................................80


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3
List of Abbreviations
AD
atopic dermatitis 
AE
adverse event
AESI
adverse event of special interest
ALCOA+
Attributable, legible, contemporaneous, original, accurate, 
complete, consistent, enduring, and available
BOCF
Baseline Observation Carried Forward
BSA
Body Surface Area
CI
Confidence interval 
CDLQI
Children’s Dermatology Life Quality Index
CMH
Cochran Mantel Haenszel
CRA
Clinical Research Associate
CRO
Clinical Research Organisation
CsA
Cyclosporine A
CSR
clinical study report
DLQI
Dermatology Quality of Life Index
DLQI-R 
DLQI-Relevant 
DM
Data Management
DMP
Data Management Plan
EASI
Eczema Area and Severity Index Score 
EASI 50
50% reduction from baseline in the EASI score
EASI 75
75% reduction from baseline in the EASI score
EASI 90
90% reduction from baseline in the EASI score
eCRF
Electronic Case Report Form 
eDiary
electronic diary
EMA
European Medicines Agency
EOS
end of study
EU
European Union
FAS
Full analysis set
GCP
Good Clinical Practice
GMP
Good Manufacturing Practice
HIV
Human Immunodeficiency Virus
IAF
Informed Assent Form
IB
Investigator’s Brochure
ICE
Intercurrent Event
ICF
Informed Consent Form
ICH
International Conference on Harmonisation
IEC
Independent Ethics Committee


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Ig
Immunoglobulin 
IGA
Investigator’s Global Assessment
IL
Interleukin
IMP
investigational medicinal product
IV
intravenous
IWRS
interactive web response system
JAK
Janus kinase
MCMC MI
Markov Chain Monte-Carlo Multiple Imputation
MMRM
Mixed Effect Model for Repeated Measures
NRI
Non-responder imputation
NRS
Numerical Rating Scale 
OR
Odds Ratio
PK
pharmacokinetic
POEM
Patient-Oriented Eczema Measure 
PPS
Per Protocol (Analysis) Set
PRO
Patient-Reported Outcome
PT
preferred term
Q2W
Every 2 weeks 
Q4W
Every 4 weeks 
QoL
Quality of life
RECAP
Recap of atopic eczema
RNA
ribonucleic acid
SAE
Serious adverse event
SAF
Safety Analysis Set
SAP
Statistical Analysis Plan
SC
Subcutaneous
SCORAD
Scoring Atopic Dermatitis 
SD
Standard Deviation
SFU
Safety follow-up
SoA
Schedule of Assessments
SOP
standard operating procedure
SUSAR
suspected unexpected serious adverse reaction
t1/2
half-life
TCS
Topical corticosteroids 
TSQM-9
Treatment Satisfaction Questionnaire for Medication-9 items
TEAE
Treatment-emergent adverse event
Th1
type 1/T-helper
Th2
Type 2/T-helper 
US
United States


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WHO-5
World Health Organisation - Five Well-Being Index
WOCBP
Women of childbearing potential


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4
S p o ns or,  I n vesti g at or(s)  
a n d  
Tri al  
A d mi nistr ati ve 
Str uct ure
4. 1 
S p o ns or
Al mirall S. A. ( Le gal e ntit y)
Ge neral Mitre, 1 5 1
0 8 0 2 2 Barcel o na, S pai n
Al mirall Researc h a n d De vel o p me nt Ce ntre:
La ureà Mir ó, 4 0 8- 4 1 0
0 8 9 8 0 Sa nt Feli u de Ll o bre gat
Barcel o na, S pai n
4. 2 
I n vesti g at or(s)
A  Pri nci pal  I n vesti gat or  will  be  desi g nate d  at  eac h  partici pati n g  cli nical  trial  ce ntre  a n d  a 
C o or di nati n g  I n vesti gat or  will  be  n o mi nate d  fr o m  a m o n g  t he  partici pati n g  sites.  T he  na me, 
a d dress, a n d affiliati o n of eac h Pri nci pal I n vesti gat or a n d t he C o or di nati n g I n vesti gat or will be 
detaile d i n t he fi nal cli nical st u d y re p ort ( C S R).
4. 3  
A d mi nistr ati ve Str uct ure
Me dical E x pert a p p oi nte d b y t he S p o ns or f or t his trial:
5
I ntr o d ucti o n
Le bri kiz u ma b is bei n g de vel o pe d f or patie nts wit h m o derate-t o-se vere at o pic der matitis ( A D) 
i na de q uatel y  c o ntr olle d  b y  t o pical  t hera pies  w h o  are  ca n di dates  f or  s yste mic  t hera p y.  A 
s u m mar y  o n  t he  i n dicati o n,  mec ha nis m  of  acti o n,  a n d  c o m plete d  n o ncli nical  a n d  cli nical 
st u dies is pr o vi de d bel o w. A detaile d descri pti o n of t he c he mistr y, p har mac ol o g y, efficac y, a n d 
safet y of le bri kiz u ma b is pr o vi de d i n t he I n vesti gat or’s Br oc h ure (I B).
5. 1 
B ac k gr o u n d I nf or m ati o n
5. 1. 1 
I n dic ati o n
A D  is  a  c hr o nic  i nfla m mat or y  heter o ge ne o us  s ki n  dis or der  c haracterise d  b y  rec urre nt 
ecze mat o us lesi o ns, i nte nse itc h, a n d s ki n pai n (e g, disc o mf ort or s ore ness). A D is o ne of t he 
m ost c o m m o n i nfla m mat or y s ki n dis or ders, affecti n g u p t o 2 0 % of c hil dre n a n d 1 0 % of a d ults 
i n hi g h-i nc o me c o u ntries.1
A D feat ures acti vati o n of t y pe 2/ T- hel per ( T h 2) i m m u ne res p o nses a n d a n altere d s ki n barrier 
a n d s ki n micr o bi o me. 4- 7 Ge netic st u dies of A D 8 -1 1 ha ve s h o w n t hat ge nes e nc o di n g f or t y pe 2 
c yt o ki nes i n v ol ve d i n t he re g ulati o n of t he i m m u ne s yste m (i nterle u ki n [I L]- 4, I L- 5, a n d I L- 1 3) 
are str o n gl y ass ociate d wit h t he de vel o p me nt of A D. 1 2 -1 5 T y pe 2 c yt o ki nes i ncrease e pi der mal 
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thickening, sensitisation, inflammation, and pruritus and decrease the expression of 
antimicrobial peptides and the barrier proteins filaggrin, loricrin, and involucrin. IL-13 in 
particular can reduce epithelial integrity and barrier function through downregulation of 
filaggrin, loricrin, and involucrin16 and can act on keratinocytes in the skin to downregulate 
their differentiation.17 IL-13 also induces T-cell chemoattractants that mediate T-cell 
infiltration into AD lesions18 and may also induce IL-5 expression and eosinophil infiltration 
through the induction of eosinophil chemoattractants.19 Increased expression of IL-13 has 
consistently been reported in AD skin lesions and is associated with disease severity.20-26 The 
ubiquitous presence of IL-13 in the skin of patients with AD supports the evaluation of anti-IL-
13 therapies in patients with AD.
In many patients, treatment with topical corticosteroids (TCS) provides some measure of 
symptomatic relief but does not always adequately control the disease. For patients with 
inadequate response or intolerance to topical therapies, guidelines recommend systemic 
immunosuppressants (eg, cyclosporine A [CsA], corticosteroids, methotrexate, azathioprine, 
or mycophenolate-mofetil), although these treatments show variable efficacy/effectiveness and 
tolerability and may be complicated by adverse effects and adverse medication interactions 
both in the short and long term.27-31 Phototherapy is also recommended, but cannot be used as 
long-term treatment and has risks including burning, skin ageing, adverse medication 
interactions, and skin cancer.
Unlike other systemic immunosuppressants, CsA is approved in EU countries for severe AD 
when systemic therapy is required. CsA suppresses type 1/T-helper (Th1), Th2, and types 17 
and 22 T-helper (Th17/22) cells, affecting both humoral and cellular immune responses.32,33 
Although off-label use beyond 1 year has been reported, long-term use of CsA (eg, beyond 1 
year), as may be required in AD given the chronicity of the disease, is limited by risk of side 
effects.34-36 Side effects associated with CsA include hypertension, nephrotoxicity, and 
subjective side effects (eg, headache, paraesthesia in fingers and toes, fatigue). Its use is also 
limited by contraindications because of other medical conditions or concomitant therapies. 
Dupilumab, an anti-IL-4R monoclonal antibody, was approved in 2017 for the treatment of 
adult and adolescent patients with moderate-to-severe AD.37 More recently, a number of new 
treatments for moderate-to-severe AD have been authorised in Europe, namely baricitinib and 
upadacitinib (both oral Janus kinase [JAK] inhibitors) and tralokinumab (anti–IL-13 
monoclonal antibody for subcutaneous injection). However, significant unmet medical needs 
remain because of the chronicity and heterogeneity of the disease, and patients who are not 
able to achieve and maintain optimal long-term disease control are in need of new treatment 
options.
The current study aims to evaluate the efficacy and safety of lebrikizumab with concomitant 
TCS in patients with AD and a history of inadequate response or intolerance to CsA, or 
CsA-naïve patients for whom CsA treatment is not medically advisable.
5.1.2
Mechanism of Action
Lebrikizumab is a humanised monoclonal immunoglobulin (Ig) G4 antibody that binds 
specifically to soluble human IL-13 with high affinity and potently inhibits IL-13 signalling 
through the IL-4Rα/IL-13Rα1 complex, thereby preventing the downstream effects of IL-13 
with high potency. Blockade of IL-13 signalling is expected to be of benefit in diseases in 
which IL-13 is a key contributor to the disease pathogenesis.


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5. 1. 3  
N o ncli nic al St u dies
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5.1.4
Clinical Studies
The safety and efficacy of lebrikizumab has been assessed in 3 completed clinical studies in 
patients with AD.
5.1.4.1
Efficacy
5.1.4.1.1 Study J2T-DM-KGAF/AD01
Study AD01 was a randomised, double-blind, placebo-controlled, dose-ranging study to 
evaluate efficacy and safety of lebrikizumab monotherapy in adult patients (aged ≥18 years) 
with moderate-to-severe AD. The study consisted of a treatment period (16 weeks) and a 
follow-up period (16 weeks). Patients were randomised to 1 of 4 treatment groups (in a 3:3:3:2 
ratio):

lebrikizumab 125 mg every 4 weeks (Q4W) (with a loading dose of 250 mg)

lebrikizumab 250 mg Q4W (with a loading dose of 500 mg)

lebrikizumab 250 mg Q2W (with a loading dose of 500 mg on Day 1 and Week 2), or

placebo Q2W.
The study treatment was administered subcutaneously. Patients discontinued use of TCS at 
least 7 days before enrolment and used an emollient twice daily during the 7 days before study 
start as well as throughout study participation. The primary endpoint was the percent change 
in the Eczema Area and Severity Index (EASI) score at Week 16. Key secondary endpoints 
were the proportion of patients at Week 16 who:

had an Investigator Global Assessment (IGA) score of 0 (clear) or 1 (almost clear) and 
a ≥2-point reduction

had a ≥4-point change on the pruritus numerical rating scale (NRS)

achieved a 90% reduction from Baseline in the EASI score (EASI 90)

achieved a 75% reduction from Baseline in the EASI score (EASI 75), and

achieved a 50% reduction from Baseline in the EASI score (EASI 50).
Key efficacy results were as follows:

All 3 lebrikizumab groups showed statistically significantly greater reductions from 
Baseline in EASI score at Week 16 (primary endpoint) than the placebo group, 
indicating greater improvement in the extent/severity of AD with lebrikizumab than 
with placebo.

The responses for the primary and secondary endpoint measures showed greater 
improvement with increasing dose.

Statistically significantly greater proportions of patients in each of the lebrikizumab 
250 mg Q4W and 250 mg Q2W groups achieved EASI 50, EASI 75, or EASI 90 at 
Week 16 than the placebo group.

A statistically significantly greater proportion of patients in each of the lebrikizumab 
250 mg Q4W and 250 mg Q2W groups had both an IGA score of 0 or 1 and a ≥2-point 
improvement in IGA score at Week 16 than the placebo group.




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pr o gra m me i ncl u de 2 5 0 m g le bri kiz u ma b Q 2 W f or i n d ucti o n a n d eit her 2 5 0 m g le bri kiz u ma b 
Q 2 W  or  2 5 0  m g  le bri kiz u ma b  Q 4 W  as  mai nte na nce  treat me nt.  A  l oa di n g  d ose  of  5 0 0  m g 
le bri kiz u ma b at first a n d sec o n d d osi n g is als o bei n g use d. A t otal of 9 2 9 a d ult patie nts a n d 
2 5 5 a d olesce nt patie nts ha ve bee n e nr olle d i n t he p hase 3 st u dies t o date.
5. 1. 4. 2 
S afet y
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5.2
Summary of the Known Potential Risks and Benefits
Treatment options are limited for patients with moderate-to-severe AD whose disease cannot 
be adequately controlled with topical medications. Results of previous clinical studies have 
demonstrated a clinically significant effect of lebrikizumab on signs and symptoms of AD. On 
the basis of on cumulative safety data, the safety profile of lebrikizumab in the ongoing phase 
3 programme has been shown to comprise largely predictable AEs that are mainly non-serious 
and is consistent with the safety profile reported in the phase 2 studies. Refer to Section 5.1.4.2 
for details on the currently available information about the potential risks of lebrikizumab.
In this study, lebrikizumab will be administered in addition to standard therapy with TCS; 
therefore, patients who are randomised into the placebo arm will receive standard of care 
therapy and will be switched to lebrikizumab treatment after the initial 16 weeks of treatment. 
Additionally, TCS dosing can be adjusted to the patient’s condition at the Investigator’s 
discretion to prevent or treat flares. Patients who may be at higher risk of complications, such 
as those with a recent history of severe or recurring infections (in particular endoparasitic 
infection), immunosuppression, or positive viral serology results, will not be allowed to enter 
the study.
Further information regarding the preclinical and clinical characteristics, summary of the 
known potential risks and benefits, as well as reasonably expected AEs of the product under 
investigation are well described in the IB.
5.3
Scientific Rationale for the Trial
The use of lebrikizumab for AD is supported by numerous preclinical studies demonstrating 
that AD is characterised by the increased expression of IL-13 in skin. Moreover, 3 clinical trials 
(summarised in Section 5.1.4) with lebrikizumab demonstrated significant clinical benefit in 
patients with AD.
This trial is part of a phase 3 programme of lebrikizumab in adults and adolescents with 
moderate-to-severe AD. Cyclosporine is currently approved in the EU for treatment of severe 
AD. This trial aims to assess the response to lebrikizumab treatment in patients who have failed 
prior treatment with cyclosporine or who have medical contraindications to receive such 
treatment.
Additional detailed discussion of the lebrikizumab studies is provided in the lebrikizumab IB.
6
Objectives and Endpoints
Table 2 and Table 3 outline the objectives and corresponding endpoints that are to be assessed 
in the trial.
Table 2. Main Objectives and Related Endpoints
Main Objective
Endpoints
To evaluate the efficacy of lebrikizumab 
compared with placebo in patients not 
adequately controlled with cyclosporine or for 
whom cyclosporine is not medically advisable 
up to Week 16
Primary Endpoint: Percentage of patients 
achieving EASI 75 (≥75% reduction from 
Baseline in EASI score) at Week 16.


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Sec o n d ar y E n d p oi nts:

Perce nta ge of patie nts ac hie vi n g I G A 0/ 1 
a n d 2- p oi nt i m pr o ve me nt at Wee k 1 6. a

Perce nta ge of patie nts ac hie vi n g a 4- p oi nt 
i m pr o ve me nt Pr urit us N R S at Wee k 1 6.a

Perce nta ge of patie nts ac hie vi n g E A SI 9 0 at 
Wee k 1 6.

Perce nta ge of patie nts ac hie vi n g E A SI 7 5, 
E A SI 9 0 a n d E A SI 5 0 ( b y visit u p t o Wee k 
1 6)

C ha n ge fr o m Baseli ne B S A b y visit u p t o 
Wee k 1 6

C ha n ge fr o m Baseli ne S C O R A D b y visit u p 
t o Wee k 1 6

C ha n ge fr o m Baseli ne Pr urit us N R S b y visit 
u p t o Wee k 1 6

C ha n ge fr o m Baseli ne slee p l oss b y visit u p 
t o Wee k 1 6

C ha n ge fr o m Baseli ne P O E M b y visit u p t o 
Wee k 1 6

C ha n ge fr o m Baseli ne D L QI/ C D L QI b y 
visit u p t o Wee k 1 6

Perce nta ge of patie nts ac hie vi n g a 4- p oi nt 
i m pr o ve me nt D L QI/ C D L QI b y visit u p t o 
Wee k 1 6

Pr o p orti o n of T C S-free da ys fr o m Baseli ne 
b y visit u p t o Wee k 1 6

Ti me t o T C S-free use ( da ys) u p t o Wee k 1 6

C ha n ge fr o m Baseli ne S ki n Pai n N R S b y 
visit u p t o Wee k 1 6

Perce nta ge of patie nts ac hie vi n g a 4- p oi nt 
i m pr o ve me nt S ki n Pai n N R S at Wee k 1 6.
E x pl or at or y E n d p oi nts:
C CI


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A b bre viati o ns: B S A = b o d y s urface area; C D L QI = C hil dre n Der mat ol o g y Life Q ualit y I n de x; D L QI = Der mat ol o g y Life 
Q ualit y I n de x; D L QI- R = Der mat ol o g y Life Q ualit y I n de x- Rele va nt; E A SI = Ecze ma Area a n d Se verit y I n de x; 
I G A = I n vesti gat or’s Gl o bal Assess me nt; N R S = n u merical rati n g scale; P O E M = Patie nt- Orie nte d Ecze ma Meas ure; 
R E C A P = reca p of at o pic ecze ma; S C O R A D = Se verit y Sc ori n g of At o pic Der matitis; T C S = t o pical c ortic oster oi ds; 
T S Q M- 9 = Treat me nt Satisfacti o n Q uesti o n naire f or Me dicati o n- 9 ite ms; W H O- 5 = W orl d Healt h Or ga nisati o n- Fi ve Well-
Bei n g I n de x.
arelates t o ke y sec o n dar y e n d p oi nts. W hile t he sa m ple size is ali g ne d wit h t he pri mar y e n d p oi nt, t hese e n d p oi nts are als o of 
i nterest i n t he fi nal o utc o mes of t he st u d y. T he sa m ple size is a p pr o priatel y ali g ne d wit h t he pri mar y a n d ke y sec o n dar y 
e n d p oi nts.
T a ble 3.  Sec o n d ar y O bjecti ves a n d Rel ate d E n d p oi nts
Sec o n d ar y O bjecti ves
E n d p oi nts
T o  e val uate  t he  efficac y  i n  patie nts  n ot 
a de q uatel y c o ntr olle d wit h c ycl os p ori ne or f or 
w h o m c ycl os p ori ne is n ot me dicall y a d visa ble 
bet wee n Wee k 1 6 u p t o Wee k 5 2.

Perce nta ge of patie nts ac hie vi n g E A SI 7 5, 
E A SI 9 0, E A SI 5 0 ( b y visit, bet wee n Wee k 
1 6 a n d Wee k 5 2)

Perce nta ge of patie nts ac hie vi n g I G A 0/ 1 
a n d 2- p oi nt i m pr o ve me nt ( b y visit, bet wee n 
Wee k 1 6 a n d Wee k 5 2).

Perce nta ge of patie nts ac hie vi n g a 4- p oi nt 
i m pr o ve me nt Pr urit us N R S ( b y visit, 
bet wee n Wee k 1 6 a n d Wee k 5 2).

C ha n ge fr o m Baseli ne B S A ( b y visit, 
bet wee n Wee k 1 6 a n d Wee k 5 2).

C ha n ge fr o m Baseli ne S C O R A D ( b y visit, 
bet wee n Wee k 1 6 a n d Wee k 5 2).

C ha n ge fr o m Baseli ne Pr urit us N R S ( b y 
visit, bet wee n Wee k 1 6 a n d Wee k 5 2).

C ha n ge fr o m Baseli ne slee p l oss ( b y visit, 
bet wee n Wee k 1 6 a n d Wee k 5 2).

C ha n ge fr o m Baseli ne P O E M ( b y visit, 
bet wee n Wee k 1 6 a n d Wee k 5 2).

C ha n ge fr o m Baseli ne D L QI/ C D L QI ( b y 
visit, bet wee n Wee k 1 6 a n d Wee k 5 2).

Perce nta ge of patie nts ac hie vi n g a 4- p oi nt 
i m pr o ve me nt i n D L QI/ C D L QI ( b y visit, 
bet wee n Wee k 1 6 a n d Wee k 5 2).

Pr o p orti o n of T C S-free da ys fr o m Baseli ne 
( b y visit, bet wee n Wee k 1 6 a n d Wee k 5 2)

Ti me t o T C S-free use ( da ys)

C ha n ge fr o m Baseli ne S ki n Pai n N R S ( b y 
visit, bet wee n Wee k 1 6 a n d Wee k 5 2)

Perce nta ge of patie nts ac hie vi n g a 4- p oi nt 
i m pr o ve me nt S ki n Pai n N R S ( b y visit, 
bet wee n Wee k 1 6 a n d Wee k 5 2).
E x pl or at or y E n d p oi nts:
C CI


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S afet y a n d T oler a bilit y E n d p oi nts
I nci de nce of A Es u p t o a n d i ncl u di n g Wee k 1 6. 
A Es i ncl u des T E A Es, S A Es, Relate d T E A Es, 
Relate d S A Es, T E A Es lea di n g t o st u d y treat me nt 
disc o nti n uati o n, A E SIs a n d Deat hs.
O bser ve d res ults a n d c ha n ges fr o m Baseli ne i n 
La b orat or y Res ults ( Hae mat ol o g y, C he mistr y a n d 
Uri nal ysis) t o Wee k 1 6.
O bser ve d res ults a n d c ha n ges fr o m Baseli ne i n 
Vital Si g ns Res ults t o Wee ks 2, 4, 8, 1 2 a n d 1 6.
T o  e val uate  t he  safet y  a n d  t olera bilit y  of 
le bri kiz u ma b  i n  patie nts  n ot  a de q uatel y 
c o ntr olle d  wit h  c ycl os p ori ne  or  f or  w h o m 
c ycl os p ori ne is n ot me dicall y a d visa ble u p t o 
Wee k 1 6
Perce nta ge of patie nts wit h a b n or malities i n 
p h ysical e xa mi nati o n at Wee k 1 6.
I nci de nce of A Es u p t o a n d i ncl u di n g Wee k 6 8. 
A Es i ncl u des T E A Es, S A Es, Relate d T E A Es, 
Relate d S A Es, T E A Es lea di n g t o st u d y treat me nt 
disc o nti n uati o n, A E SIs a n d Deat hs.
O bser ve d res ults a n d c ha n ges fr o m Baseli ne i n 
La b orat or y Res ults ( Hae mat ol o g y, C he mistr y a n d 
Uri nal ysis) t o Wee ks 3 2 a n d 5 2.
O bser ve d res ults a n d c ha n ges fr o m Baseli ne i n 
Vital Si g ns Res ults t o Wee ks 2 0, 2 4, 2 8, 3 2, 3 6, 
4 0, 4 4, 4 8 a n d 5 2.
T o e val uate t he safet y a n d t olera bilit y of 
le bri kiz u ma b i n patie nts n ot a de q uatel y 
c o ntr olle d wit h c ycl os p ori ne or f or w h o m 
c ycl os p ori ne is n ot me dicall y a d visa ble u p t o 
Wee k 6 8
Perce nta ge of patie nts wit h a b n or malities i n 
p h ysical e xa mi nati o n at Wee ks 3 2 a n d 5 2.
E x pl or at or y O bjecti ves
Ot her E n d p oi nts
A b bre viati o ns: A E = a d verse e ve nt; A E SI = a d verse e ve nt of s pecial i nterest; B S A = b o d y s urface area; C D L QI = C hil dre n 
Der mat ol o g y Life Q ualit y I n de x; D L QI = Der mat ol o g y Life Q ualit y I n de x; D L QI- R = Der mat ol o g y Life Q ualit y I n de x-
Rele va nt; E A SI = Ecze ma Area a n d Se verit y I n de x; I G A = I n vesti gat or’s Gl o bal Assess me nt; N R S = n u merical rati n g scale; 
P O E M = Patie nt- Orie nte d Ecze ma Meas ure; R E C A P = reca p of at o pic ecze ma; S A E = seri o us a d verse e ve nt; 
S C O R A D = Se verit y Sc ori n g of At o pic Der matitis; T C S = t o pical c ortic oster oi ds; T E A E = treat me nt-e mer ge nt a d verse 
e ve nt; T S Q M- 9 = Treat me nt Satisfacti o n Q uesti o n naire f or Me dicati o n- 9 ite ms; W H O- 5 = W orl d Healt h Or ga nisati o n- Fi ve 
Well- Bei n g I n de x.
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7
Trial Design and Rationale
7.1
Trial Design
This is a randomised, double-blind, placebo-controlled, parallel-group study, 72 weeks in 
duration (up to 4 weeks of Screening, 52 weeks of treatment [last dose given at Week 50], and 
18 weeks of post-last dose safety follow-up [SFU]). The study is designed to confirm the 
efficacy and safety of lebrikizumab administered concomitantly with TCS in adolescents and 
adults with moderate-to-severe AD not adequately controlled with cyclosporine or for whom 
cyclosporine is not medically advisable.
The study has 2 treatment periods: a 16-week double-blind Induction Period followed by a 
36-week open-label Maintenance Period. The study will be double-blind until Week 18 and 
open-label from Week 20 onward. The patients who received placebo during the Induction 
Period will receive loading doses of lebrikizumab at Weeks 16 and 18. To maintain blinding at 
Weeks 16 and 18, all patients will receive 2 injections at Weeks 16 and 18 (either 2 injections 
of lebrikizumab or 1 injection of lebrikizumab and 1 injection of placebo) (
Table 4). From Week 20 onward, all patients will receive 1 injection of lebrikizumab 250 mg 
Q2W.
Study results will be delivered in 2 parts: the first results delivery will be provided after the 
first database lock, once all patients have completed the Induction Period or discontinued study 
before this point, and the second results delivery will be provided after second database lock, 
at the end of the study (EOS), once all patients have completed the study, or discontinued 
before EOS.
Accordingly, 2 different database locks will be used, and 2 different CSRs will be generated; 
one to cover the Induction Period, and the other to cover all data up to EOS. The first analysis 
will report the Induction Period only, and the second analysis will report all data up to EOS.
Eligible adult and adolescent (aged ≥12 to <18 years and weighing ≥40 kg) patients with 
moderate-to-severe AD for at least 1 year, defined according to the Hanifin and Rajka Criteria, 
2 an EASI score of ≥16, an IGA score of ≥3 and a body surface area (BSA) affected by AD of 
≥10% will be enrolled (adolescent patients aged ≥12 to <18 years will make up 12.5% of the 
overall population compared to adults aged ≥18 years). Eligible patients must have a 
documented history of inadequate response to treatment with topical AD medication within 
6 months before Screening, documented history of inadequate response or intolerance to CsA, 
or CsA-naïve patients for whom CsA treatment is not medically advisable. Patients with 
previous exposure to dupilumab, including suboptimal responses (eg, persistence of itch 
despite treatment with dupilumab, flare-up days before the next dupilumab dose) may be 
included in the study with a washout period of 8 weeks before Baseline. During this washout 
period, patients may be allowed to use TCS, which will need to be stopped at least 1 week 
before Baseline. The enrolment of such subpopulation of patients will be limited to a maximum 
of 60 enrolled patients. All other enrolled patients must be naïve to IL-4 or IL-13 blocking 
antibodies.
The total duration of each patient’s participation in the trial, including Screening, treatment, 
and follow-up periods, is estimated to be a maximum of 72 weeks (up to 4 weeks of Screening, 
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After providing informed consent form (ICF)/informed assent form (IAF), patients will be 
assessed for study eligibility at the Screening visit. Patients will undergo Screening within 
4 weeks before randomisation.
During the 16-week Induction Period, 312 patients will be randomised 2:1 to either 250 mg 
lebrikizumab (loading dose of 500 mg given at Baseline and Week 2) or placebo by SC 
injection Q2W. Randomisation will be stratified by previous use of dupilumab, age (adolescent 
patients aged ≥12 to <18 years will make up 12.5% of the overall population compared to adults 
aged ≥18 years) and baseline disease severity (IGA 3 versus 4). During the first 4 weeks of 
treatment as well as at Week 8, Week 12, Week 16, and Week 18 study drug injection will be 
administered in the clinic. Patients will have the option to self-administer study drug or get it 
administered by a caregiver outside the study site during weeks in which no on-site clinic visit 
is scheduled from Week 4 onward according to Table 1. Patients (and/or caregivers) will be 
trained on injecting study drug until competency has been demonstrated.
In case a patient is not willing to self-inject, their caregiver is not willing to do the injection, or 
the patient or caregiver does not demonstrate appropriate ability to do the injection, the clinic 
staff may administer all study drug injections throughout the study at the clinic.
All enrolled patients are required to start treatment with mid- or low-potency TCS at Baseline 
and continue it throughout the study as described in Section 9.9.2.
After completion of the Week 16 visit, patients will enter the Maintenance Period:

Patients who received lebrikizumab 250 mg Q2W during the Induction Period will continue 
to receive lebrikizumab 250 mg Q2W during the Maintenance Period

Patients who received placebo Q2W during the Induction Period will receive lebrikizumab 
250 mg Q2W during the Maintenance Period
Patients who received placebo during the Induction Period will receive loading doses of 
lebrikizumab (500 mg) at Weeks 16 and 18 during the Maintenance Period.
To allow patients in the placebo arm to receive these lebrikizumab loading doses during the 
Maintenance Period, the blinding will be maintained at Week 16 and Week 18. Therefore, the 
study will be open-label from Week 20 onward, as summarised in 
Table 4.
Table 4.
Dosing Schedule During Maintenance Period
Randomised at 
Baseline to
Double-blind Dose at 
Week 16
Double-blind Dose at 
Week 18
Open-label 
Treatment 
After Week 20
250 mg lebrikizumab 
SC injection
1 injection of 250 mg 
lebrikizumab
1 injection of placebo
1 injection of 250 mg 
lebrikizumab
1 injection of placebo
1 injection of 
lebrikizumab 
250 mg Q2W
Placebo SC injection
2 injections of 250 mg 
lebrikizumab
2 injections of 250 mg 
lebrikizumab
1 injection of 
lebrikizumab 
250 mg Q2W
Abbreviations: Q2W = every 2 weeks; SC = subcutaneous.
Patients who do not achieve EASI 50 for at least 2 consecutive visits assessed at Weeks 24, 28, 
32, 36, 40, 44, or 48 will be discontinued from the study.


Cli nic al Tri al M- 1 7 9 2 3- 3 0
Cli nic al Tri al Pr ot oc ol Versi o n N o. 3. 0 2 2 A u g ust 2 0 2 2
S R D- 0 0 0 2 1 7 8 v 5. 0
C O N FI D E N TI A L
3 8/ 1 0 2
Safet y, la b orat or y, a n d cli nical assess me nts will be perf or me d as s pecifie d i n t he Sc he d ule of 
Assess me nt ( S o A) ( Ta ble 1 ).
Efficac y will be meas ure d as f oll o ws:

Cli nical si g ns: E A SI sc ore, I G A sc ore, B S A affecte d b y A D lesi o ns

Cli nical si g ns a n d patie nt re p orte d s y m pt o ms: S C O R A D sc ore

A D  Patie nt  Re p orte d  S y m pt o ms:  Pr urit us  N R S,  Slee p-l oss  scale,  S ki n  Pai n  N R S, 
Patie nt- Orie nte d Ecze ma Meas ure ( P O E M).

Q ualit y of life ( Q o L) a n d i m pact of disease: Der mat ol o g y Life Q ualit y I n de x ( D L QI) 
or  C hil dre n's  Der mat ol o g y  Life  Q ualit y  I n de x ( C D L QI),  D L QI- Rele va nt  ( D L QI- R), 
W orl d Healt h Or ga nisati o n- Fi ve Well- Bei n g I n de x ( W H O- 5), Reca p of At o pic Ecze ma 
( R E C A P), a n d Treat me nt Satisfacti o n Q uesti o n naire f or Me dicati o n- 9 ite ms ( T S Q M-
9).
Safet y  will  be  assesse d  b y  m o nit ori n g  A Es,  ser u m  c he mistr y,  hae mat ol o g y  a n d  uri nal ysis 
la b orat or y test res ults, p h ysical e xa mi nati o n res ults, a n d vital si g ns.
Bl o o d  sa m ples  will  be  c ollecte d  at  Baseli ne  a n d  Wee k  1 6  t o  assess  bi o mar kers,  
 
.
P h ot o gra p hs of lesi o ns will be o btai ne d fr o m a s u bset of patie nts partici pati n g i n t his st u d y as 
o utli ne d i n t he P h ot o gra p h y Ma n ual. T he p h ot o gra p hs s h o ul d n ot o nl y i ncl u de t he lesi o n(s) b ut 
als o a greater b o d y area a n d t he u p per a n d l o wer b o d y, i ncl u di n g t he face, li m bs, a n d ha n ds 
( bac k a n d pal ms).
Patie nts c o m pleti n g t he st u d y treat me nt a n d patie nts w h o ter mi nate earl y will u n der g o a S F U 
visit a p pr o xi matel y 1 8 wee ks after t he last st u d y dr u g i njecti o n. F or patie nts w h o c o m plete t he 
st u d y, t he last d ose of treat me nt will occ ur at Wee k 5 0. T heref ore, t he S F U visit will occ ur at 
Wee k 6 8.
T he E O S is defi ne d as t he date of t he last visit of t he last patie nt i n t he st u d y s h o w n i n t he S o A 
(Ta ble 1 ).
T he trial desi g n is re prese nte d sc he maticall y i n Fi g ure 1 .
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Figure 1
Lebrikizumab Phase 3 Study Design Schematic
Abbreviations: D = day; dupi = dupilumab; EASI = Eczema Area and Severity Index Score; LD = loading dose; 
LEB = lebrikizumab; Q2W = every 2 weeks, SC = subcutaneous; W = week.
7.2
Trial Rationale
7.2.1
Rationale for Trial Design
The design for the Induction and Maintenance Periods for this trial is similar to the design used 
in the other lebrikizumab phase 3 trials and is commonly used in AD trials.
This study will enrol adult and adolescent patients with moderate-to-severe AD whose AD is 
not adequately controlled with cyclosporine or for whom cyclosporine is not medically 
advisable and therefore for whom a systemic treatment such as lebrikizumab may therefore be 
appropriate.
The Induction Period of the study has a double-blind, placebo-controlled design to guarantee 
an unbiased assessment of the primary and secondary efficacy variables at Week 16 in 
comparison with placebo. A duration of 16 weeks of placebo treatment is deemed acceptable 
in this patient population, also considering that all patients will receive background TCS 
therapy at a dosage that can be adapted based on the patient’s needs.
Starting from Week 16, all patients will receive the active drug. From Week 20 onward, the 
study will have an open-label design to give patients randomised to placebo the opportunity to 
receive lebrikizumab treatment and to assess long-term efficacy and safety of lebrikizumab 
while adapting or discontinuing concomitant TCS therapy. Discontinuing patients who do not 
achieve or maintain a clinical response during the Maintenance Period will ensure that patients 
are not unnecessarily given treatment that is not effective.
TCS are the first-line anti-inflammatory treatment, even for patients treated with systemic 
therapies. For this reason, this study will assess the efficacy of lebrikizumab in combination 
with background mid or low-potency TCS, forced at Baseline and during the Induction Period, 
and used as determined appropriate by the Investigator from Week 16 onward.


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7.2.2
Rationale for Trial Population
In this phase 3 study, adolescent patients (aged ≥12 to <18 years weighing ≥40 kg) will be 
included and will receive the same doses of lebrikizumab described above for adults 
(adolescent patients aged ≥12 to <18 years will make up 12.5% of the overall population 
compared to adults aged ≥18 years). The justification for this approach is as follows:
Both adults and adolescent patients have similar disease characteristics, typified by prominent 
type 2 skin inflammation and similar clinical manifestations. In addition, both groups tend to 
have similar efficacy outcomes in response to therapies, including dupilumab39,40. 
Pharmacokinetic (PK) modelling and simulations of lebrikizumab dosing (population PK 
modelling of pooled data from 2259 adult patients with asthma and a subsequent external 
posterior predictive check with lebrikizumab PK data from the DRM06-AD01 trial in adult 
patients with AD) revealed similar kinetics for adults and adolescent patients, aged 12 to 
<18 years. The maximal exposures are predicted to be slightly (≤35%) higher in adolescent 
patients than in adults for any given dose because of the lower adolescent weight ranges and 
lebrikizumab exposure dependence on weight; however, the safety profile in adolescent 
patients, based on the exposure-response relationship analysis and on partial extrapolation, is 
comparable to that observed in adults.
A subpopulation of patients previously exposed to dupilumab will be enrolled in the study with 
a maximum of 60 patients randomised. Patients may have discontinued dupilumab for any of 
the following reasons:

lack or loss of efficacy or suboptimal response (ie, persistence of itch despite treatment 
with dupilumab, flare-up days before the next dupilumab dose)

side effects or any other safety reasons

end of participation in a dupilumab clinical trial

end of reimbursement for dupilumab by National Health Services or health insurances

personal decision
The enrolment of patients with prior exposure to dupilumab will serve to explore the extent 
and duration of response to lebrikizumab treatment in this subpopulation of patients within a 
randomised, placebo-controlled trial.
7.2.3
Rationale for Trial Dose and Regimen
The dosing regimen of a 500 mg loading dose at Baseline and Week 2, followed by 250 mg of 
lebrikizumab Q2W was selected for the lebrikizumab phase 3 programme based on an 
evaluation of safety, efficacy, and PK data from the clinical trials (see Section 5.1.4).
For the Maintenance Period, all patients will receive lebrikizumab 250 mg Q2W, because of 
the limited ability to collect insights that would reflect clinical practice and limited current 
understanding of which patients can benefit from Q4W dosing. Dosing flexibility data will not 
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Additionally, the DRM06-AD03 PK study conducted in healthy adults demonstrated that a 
single SC injection of 2-mL (250 mg) of lebrikizumab delivered comparable levels of 
lebrikizumab as did 2 SC injections of 1-mL (125 mg). This study simulated the conditions 
under which study drug will be administered in phase 3, further supporting the dose and 
treatment regimen for phase 3 trials, lebrikizumab 250 mg Q2W with loading doses of 500 mg 
given at Baseline and Week 2, and at Week 16 and Week 18 during the Maintenance Period 
for patients who received placebo during the Induction Period.
7.2.4
Rationale for Trial Assessments
The efficacy assessments conducted in this study include clinician’s and patient’s reported 
outcome that have been validated and extensively employed in patients with AD.4,41 The 
majority of assessments discussed below are also being employed in the other phase 3 trials of 
lebrikizumab. The frequency of assessments is deemed adequate to properly monitor 
development and achievement of response in terms of efficacy measures and QoL changes 
during the Induction Period, and the maintenance of a stable response over the Maintenance 
Period.
EASI, BSA, and IGA scores allow for evaluation of disease severity and extent as well as the 
physician’s overall judgment at Screening and after study treatment. Achievement of EASI 75 
response or IGA assessment of 0 or 1 are both response criteria used as primary or key 
secondary end points to confirm success of treatment in AD clinical trials. The SCORAD is a 
validated composite measure developed by the European Task Force of Atopic Dermatitis 
(ETFAD) that incorporates both objective physician’s and subjective patient’s assessments. 
POEM is a validated measure that uses patient-reported outcomes (PROs) specifically designed 
to measure AD severity from the patient’s perspective.38
All pruritus entries will be recorded daily in the patient’s diary from Week 0 to Week 2, weekly 
from Week 2 to Week 16 of the Induction Period, and every 2 weeks during the Maintenance 
Period.
All skin pain and sleep loss entries will be recorded daily in the patient’s diary from Week 0 to 
Week 2, weekly from Week 2 to Week 16 of the Induction Period, and every 4 weeks during 
the Maintenance Period.
The RECAP is a newly designed patient questionnaire designed to capture AD control as 
experienced by the patient.42
QoL related to the patient’s AD condition will be assessed by administration of the DLQI (adult 
or paediatric version [eg, the CDLQI] depending on the age of the patient), which is commonly 
used in AD clinical trials and often also in dermatology clinical practice.43 The WHO-5 is a 
validated questionnaire measuring current positive mental well-being.44 The scale has adequate 
validity both as a Screening tool for depression and as an outcome measure in clinical trials 
and has been widely used in clinical trials of any type of therapeutic indications. Depression 
has been associated with AD.45
The TSQM-9 is a reliable and valid instrument to assess patients' satisfaction with medication. 
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Safety assessments including AEs, safety laboratory test results (haematology, chemistry, and 
urinalysis), vital signs, and physical examination findings will be performed at Screening visit 
to confirm eligibility criteria and at scheduled visits throughout the trial.
A predose blood sample will be collected at the Baseline visit for a biomarker analysis to 
characterise the enrolled patients with AD and explore any potential association with response 
to study treatment. Additionally, a predose blood sample will be collected at Week 16 to 
explore the potential biomarkers modification after treatment.
8
Selection of the Trial Population and Withdrawal of 
Patients
Study Investigators will review patient history and Screening test results at the Screening and 
Baseline visits to determine whether the patient meets all inclusion and none of the exclusion 
criteria to qualify for randomisation in the study. All Screening activities must be completed 
and reviewed before the patient is randomised
Prospective approval of protocol deviations to recruitment and enrolment criteria, also known 
as protocol waivers or exemptions, are not permitted.
8.1
Number of Patients
A sufficient number of patients will be screened to randomise approximately 312 patients with 
moderate-to-severe AD.
For details on the sample size determination, refer to Section 11.1.
8.2
Inclusion Criteria
Patients eligible for inclusion in this trial must fulfil all of the following criteria:
1. Adults and adolescents (aged ≥12 to <18 years at the time of ICF/IAF and weighing ≥40 
kg)
2. Chronic AD (according to Hanifin and Rajka Criteria2) that has been present for ≥1 year 
before the Screening visit
3. EASI score ≥16 at the Baseline Visit
4. IGA score ≥3 (moderate) (scale of 0 [clear] to 4 [severe]) at the Baseline visit
5. ≥10% BSA of AD involvement at the Baseline visit
6. Documented history by a physician of an inadequate response to existing topical 
medications within 6 months before Screening, defined as: inability to achieve good disease 
control (eg, not able to achieve IGA ≤2) after use of at least a mid-potency TCS for at least 
4 weeks, or for the maximum duration recommended by the product prescribing 
information (eg, 14 days for high/very-high-potency TCS), whichever is shorter
7. Documented history by a physician of either:
a) No previous CsA exposure and not currently a candidate for CsA treatment because of
i.
medical contraindications (eg, uncontrolled hypertension on medication), or
ii.
use of prohibited concomitant medications (eg, statins, digoxin, macrolide 
antibiotics, barbiturates, anti-seizure drugs, nonsteroidal anti-inflammatory 


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drugs, diuretics, angiotensin-converting-enzyme inhibitors, St John’s Wort, 
etc.), or
iii.
increased susceptibility to CsA-induced renal damage (elevated creatinine) 
and/or liver damage (elevated function tests results), or
iv.
increased risk of serious infections, or
v.
hypersensitivity to CsA active substance or excipients
OR:
b) Previous exposure to CsA; CsA treatment should not be continued or restarted because 
of
i.
intolerance and/or unacceptable toxicity (eg, elevated creatinine, elevated liver 
function test results, uncontrolled hypertension, paraesthesia, headache, nausea, 
hypertrichosis); or
ii.
requirement for CsA at doses or durations beyond those specified in the 
prescribing information or inadequate response
8. Completed electronic diary (eDiary) entries for pruritus and sleep-loss for a minimum of 4 
of 7 days before randomisation
9. Willing and able to comply with all clinic visits and study-related procedures and 
questionnaires
10. For women of childbearing potential: agree to remain abstinent (refrain from heterosexual 
intercourse) or to use a highly effective contraceptive method during the treatment period 
and for at least 18 weeks after the last dose of lebrikizumab or placebo

NOTE: A woman of childbearing potential (WOCBP) is defined as a postmenarcheal 
woman, who has not reached a postmenopausal state (≥ 12 continuous months of 
amenorrhea with no identified cause other than menopause), and has not undergone 
surgical sterilisation (removal of ovaries and/or uterus)

NOTE: The following contraceptive methods are highly effective: combined (oestrogen 
and progestogen containing) hormonal contraception (oral, intravaginal, transdermal) 
associated with inhibition of ovulation, progestogen-only hormonal contraception (oral, 
injectable, implantable) associated with inhibition of ovulation, intrauterine device, 
intrauterine hormone-releasing system, bilateral tubal occlusion, vasectomised partner, 
or sexual abstinence. The reliability of sexual abstinence should be evaluated in relation 
to the duration of the clinical trial and the preferred and usual lifestyle of the patient. 
Periodic abstinence (eg, calendar, ovulation, symptothermal, or post ovulation 
methods) and withdrawal are not acceptable methods of contraception
11. Male patients must agree to use an effective barrier method of contraception during the 
study and for a minimum of 18 weeks following the last dose of study drug if sexually 
active with a WOCBP
12. Patient must provide signed ICF. Adolescent patients must also provide separate informed 
assent to enrol in the study and sign and date either a separate IAF or the ICF signed by the 
parent/legal guardian (as appropriate based on local regulations and requirements)
8.3
Exclusion Criteria
Patients fulfilling any of the following criteria are not eligible for inclusion in this trial:
1. Participation in a prior lebrikizumab clinical study


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2. Treatment with IL-4 or IL-13 antagonists biological therapies before the Baseline visit. 
Exception: previous treatment with dupilumab will be allowed in a subset of patients 
(please see Section 7.2.2 for the definition of this subpopulation). A washout of at least 8 
weeks before the Baseline visit will be required for this subpopulation
3. Treatment with TCS within 1 week before the Baseline visit
4. Treatment with topical calcineurin inhibitors, phosphodiesterase-4 inhibitors such as 
crisaborole, or cannabinoids within 2 week before the Baseline visit
5. Treatment with any of the following agents within 4 weeks before the Baseline visit:
a.
Immunosuppressive/immunomodulating 
drugs 
(eg, 
systemic 
corticosteroids, 
cyclosporine, mycophenolate-mofetil, interferon-γ, JAK inhibitors, azathioprine, 
methotrexate, etc.)
b. Phototherapy and photochemotherapy (PUVA) for AD
6. Treatment with the following before the Baseline visit:
a.
An investigational drug within 8 weeks or within 5 half-lives (if known), whichever is 
longer;
b. B cell-depleting biologics, including but not limited to rituximab, within 6 months;
c.
Other biologics within 16 weeks or 5 half-lives (if known), whichever is longer
7. Treatment with a live (attenuated) vaccine within 12 weeks of the Baseline visit, planned 
during the study, or 18 weeks after the study treatment is discontinued
8. History of anaphylaxis as defined by the Sampson criteria47
9. Regular use (more than 2 visits per week) of a tanning booth/parlour within 4 weeks of the 
Screening visit
10. Uncontrolled chronic disease that might require bursts of oral corticosteroids, eg, co-
morbid severe uncontrolled asthma (defined by an Asthma Control Questionnaire-5 score 
≥1.5 or a history of ≥2 asthma exacerbations within the last 12 months requiring systemic 
[oral and/or parenteral] corticosteroid treatment or hospitalisation for >24 hours)
11.  Have had any of the following types of infection within 3 months of Screening or develop 
any of these infections before randomisation:
a.
Serious (requiring hospitalisation, and/or IV or equivalent oral antibiotic treatment);
b. Opportunistic (as defined in Winthrop et al. 2015). NOTE: Herpes zoster is considered 
active and ongoing until all vesicles are dry and crusted over;
c.
Chronic (duration of symptoms, signs, and/or treatment of 6 weeks or longer);
d. Recurring (including, but not limited to herpes simplex, herpes zoster, recurring 
cellulitis, chronic osteomyelitis)
12. Have a current or chronic infection with hepatitis B virus
13. Have a current infection with hepatitis C virus (ie, positive for hepatitis C RNA)
14. Have known liver cirrhosis and/or chronic hepatitis of any aetiology
15. Diagnosed active endoparasitic infections or at high risk of these infections
16. Known or suspected history of immunosuppression, including history of invasive 
opportunistic infections (eg, tuberculosis, histoplasmosis, listeriosis, coccidioidomycosis, 


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pneumocystosis, and aspergillosis) despite infection resolution: or unusually frequent, 
recurrent, or prolonged infections, per the Investigator’s judgment
17. History of HIV infection or positive HIV serology at Screening
18. In the Investigator’s opinion, any clinically significant laboratory test results from the 
chemistry, haematology, or urinalysis tests obtained at the Screening visit
19. Presence of skin comorbidities that may interfere with study assessments
20. History of malignancy, including mycosis fungoides, within 5 years before the Screening 
visit, except completely treated in situ carcinoma of the cervix, completely treated and 
resolved nonmetastatic squamous or basal cell carcinoma of the skin with no evidence of 
recurrence in the past 12 weeks
21. Severe concomitant illness(es) that in the Investigator’s judgment would adversely affect 
the patient’s participation in the study. Any other medical or psychological condition that 
in the opinion of the Investigator may suggest a new and/or insufficiently understood 
disease, may present an unreasonable risk to the study patient because of his/her 
participation in this clinical trial, may make patient’s participation unreliable, or may 
interfere with study assessments
22. Pregnant or breastfeeding women, or women planning to become pregnant or breastfeed 
during the study
23. Have had an important side effect to TCS (eg, intolerance to treatment, hypersensitivity 
reactions, significant skin atrophy, and systemic effects), as assessed by the Investigator or 
treating physician that would prevent further use
8.3.1
Patient Withdrawal
The Investigator will make reasonable efforts to keep each patient in the study. However, 
patients may withdraw or be withdrawn from the study for the following reasons:

Voluntary withdrawal of consent to participate in the study participation, at any time

In the opinion of the Investigator, continued participation in the study is not in the best 
interest of the patient

Serious protocol violation or procedure prohibited by the protocol

Lost to follow-up
Before being withdrawn, patients will be requested to attend an end-of-treatment visit. All 
information, including the reason for being withdrawn will be recorded in the patient’s study 
records and in the electronic case report form (eCRF).
A patient will be considered lost to follow-up if he or she repeatedly fails to return for scheduled 
visits and is unable to be contacted by the study site. 2 documented attempts (eg, telephone 
contact, emails) to contact the patient must be documented in a patient’s study records for all 
patients who are believed to be lost to follow-up. All attempts should be documented in the 
subject’s medical records. If it is determined that the subject has died, the site will use locally 
permissible methods to obtain the date and cause of death.


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8.3.2
Study Drug Discontinuation
Study drug must be permanently discontinued for patients who experience the following:

AE, laboratory abnormality or intercurrent illness for which continued treatment, in the 
opinion of the Investigator, would affect assessments of clinical status or patient safety 
to a significant degree

TEAEs that are clinically significant, deemed persistent, and that, in the opinion of the 
Investigator, continued treatment would affect assessments of clinical status or patient 
safety to a significant degree

Unacceptable toxicity

Pregnancy

Use of systemic rescue medication as outlined in Section 9.9.3

No response to treatment as specified in Section 7.1
Patients who permanently discontinue study drug will be requested to:

perform all the end-of-treatment visit assessments at their next scheduled site visit

perform a SFU visit approximately 18 weeks after the last study drug injection, except 
for patients receiving systemic rescue medication as per Section 9.9.4.
All information, including the reason for permanent discontinuation of study drug will be 
recorded in the patient’s study records and in the eCRF.
8.4
Screen Failures
Screen failures are defined as participants who consent to participate in the clinical trial but are 
not subsequently randomly assigned to trial intervention/entered in the trial. A minimal set of 
screen failure information is required to be entered into the database to ensure transparent 
reporting of screen failure participants to meet the Consolidated Standards of Reporting Trials 
publishing requirements and to respond to queries from Competent Authorities. Minimal 
information includes demography, screen failure reason, eligibility criteria, and any SAE 
observed. In case of a Screening laboratory value abnormality, the test can be repeated once 
within the original Screening time window, if the Investigator believes there is a reasonable 
possibility that the subject would be eligible if re-tested.
Individuals who do not meet the criteria for participation in this trial (eg, screen failures) may 
be rescreened once. At the time of rescreening, the individual must sign a new ICF/IAF and 
repeat all Screening procedures.
8.4.1
Patient Replacement Criteria
Patients who withdraw from the trial at any time after randomisation will not be replaced.


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8.5
Termination of the Trial
8.5.1
End of Trial Definition
The “end of trial” is defined as the date when all patients randomised in the trial complete 
follow-up contact (either Treatment Completers or those Prematurely Discontinued), or are lost 
to follow-up and have not been able to be contacted, and will be communicated to Competent 
Authorities and the independent ethics committee (IEC) in due time according to local 
regulations.
8.5.2
Completed Patient Definition
A patient attending the Week 16 visit will be considered a completer of the Induction Period.
A patient receiving the last study drug dose planned in the protocol will be considered a 
treatment completer, even in the absence of completing the SFU visit.
8.5.3
 Premature Trial Termination
The Sponsor has the right to terminate the study at any time.
The entire study will be stopped if:

Evidence has emerged that, in the collective opinion of the Investigators at each site 
with the concurrence of the Sponsor, or in the sole opinion of the Sponsor, continuation 
of the study is unnecessary or unethical

The stated objectives of the study are achieved

The Sponsor discontinues the development of the study for any reason (eg, lack of 
patient enrolment or non-compliance with clinical trial protocol, regulation, or good 
clinical practice [GCP] guidelines).
All data available for the patient at the time of study discontinuation must be recorded in the 
patient’s records and the eCRF.
Certain additional circumstances may require the premature termination of the trial, including:

The Investigator/Coordinating Investigator and the Sponsor feel that the type, number, 
and/or severity of AEs justify discontinuation of the trial

The Sponsor considers the applied doses of the study drug to be no longer relevant.

Data not known before becoming available that raise concern about the safety of the 
study drug so that continuation would pose potential risks to the patient
If the trial is terminated or suspended, the Sponsor will promptly inform the Investigators and 
the Competent Authorities. The Independent Ethics Committee (IEC) should be promptly 
informed and provided the reason(s) for the termination or suspension by the 
Investigator/Sponsor, as specified by the applicable regulatory requirement(s).
Should the study be terminated, the decision and reason will be communicated in writing by 
the Sponsor to the Investigator with a request that all patients be discontinued. Patients should 
be scheduled for an end-of-treatment visit.


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T he I n vesti gat or will i nf or m t he patie nts a n d will c ollect a n d kee p all t he data u p t o t he date of 
disc o nti n uati o n. Sa m ples retrie ve d u p t o t he date of trial ter mi nati o n will be a nal yse d as per 
pr ot oc ol.
If t he trial is pre mat urel y ter mi nate d or s us pe n de d, trial res ults will be re p orte d acc or di n g t o 
t he re q uire me nts o utli ne d i n t his pr ot oc ol as far as a p plica ble.
T he  Cli nical  Data  I nterc ha n ge  Sta n dar ds  C o ns orti u m  criteria  s h o ul d  be  f oll o we d  w hile 
rec or di n g t he patie nt trial disc o nti n uati o n reas o ns.
9
Tre at me nts
9. 1 
I de ntit y of Tri al I n vesti g ati o n al Me dici n al Pr o d uct(s)
I n vesti gati o nal me dici nal pr o d uct (I M P) ma n ufact uri n g, la belli n g, pac ka gi n g, a n d release will 
be i m ple me nte d f oll o wi n g g o o d ma n ufact uri n g practice ( G M P) g ui deli nes.
Test I n vesti g ati o n al Me dici n al Pr o d uct
S u bst a nce C o de/ N a me
Le bri kiz u ma b
R o ute of A d mi nistr ati o n
S u bc uta ne o us 
D os a ge F or m
S ol uti o n  f or  i njecti o n,  c o ntai ni n g  1 2 5  
m g/ m L 
le bri kiz u ma b. S u p plie d as a sterile prefille d s yri n ge wit h 
a pre-asse m ble d nee dle safet y de vice ( P F S- N S D)
U nit D ose/ Stre n gt h
Eac h prefille d s yri n ge is i nte n de d f or a si n gle 2 m L d ose 
( 2 5 0 m g)
P ac k a gi n g Descri pti o n
W hite f ol di n g cart o n wit h partiti o n ( 1 6 7 × 5 4 × 4 0 m m)
Pl ace b o I n vesti g ati o n al Me dici n al Pr o d uct
S u bst a nce C o de/ N a me
T he  place b o  s ol uti o n  is  i de ntical  i n  a p peara nce  a n d 
v ol u me  t o  t he  acti ve  s ol uti o n  e xce pt  t hat  it  d oes  n ot 
c o ntai n le bri kiz u ma b
R o ute of A d mi nistr ati o n
S u bc uta ne o us
D os a ge F or m
S ol uti o n f or i njecti o n, c o ntai ni n g t he sa me e xci pie nts as 
t he res pecti ve acti ve le bri kiz u ma b. S u p plie d as a sterile 
C CI


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prefille d  s yri n ge  wit h  a  pre-asse m ble d  nee dle  safet y 
de vice ( P F S- N S D)
U nit D ose/ Stre n gt h
Eac h prefille d s yri n ge is i nte n de d f or a si n gle 2 m L d ose
P ac k a gi n g Descri pti o n
W hite f ol di n g cart o n wit h partiti o n ( 1 6 7 × 5 4 × 4 0 m m)
9. 2 
P ac k a gi n g a n d L a belli n g
Pac ka gi n g a n d la belli n g of I M P will be pr o vi de d b y t he S p o ns or a n d will c o m pl y wit h A n ne x 
1 3 of t he E U G M P re g ulati o ns a n d l ocal re g ulat or y re q uire me nts.
U p o n recei pt of t he st u d y dr u g b y t he cli nical researc h or ga nisati o n ( C R O), it will be i ns pecte d 
a n d c o u nte d b y t he res p o nsi ble p har macist. All st u d y dr u gs will be la belle d a p pr o priatel y.
9. 3 
S hi p me nt, St or a ge, a n d Acc o u nt a bilit y
O nl y  partici pa nts  e nr olle d  i n  t he  trial  ( or  pare nts/care gi vers,  if  a p plica ble)  ma y  recei ve  t he 
st u d y dr u g a n d o nl y a ut h orise d site staff ma y s u p pl y or a d mi nister t he st u d y dr u g. O n-site, all 
dr u g s u p plies m ust be st ore d i n a sec ure, e n vir o n me ntall y c o ntr olle d, m o nit ore d ( ma n ual or 
a ut o mate d) area i n acc or da nce wit h t he la belle d st ora ge c o n diti o ns, wit h access li mite d t o t he 
I n vesti gat or a n d a ut h orise d site staff.
T he  I n vesti gat or,  t he  trial  staff,  i nstit uti o n,  or  t he  hea d  of  t he  me dical  i nstit uti o n  ( w here 
a p plica ble) is res p o nsi ble f or cli nical st u d y dr u g or T C S s u p plies acc o u nta bilit y, rec o nciliati o n, 
a n d rec or d mai nte na nce (ie, recei pt, rec o nciliati o n, a n d fi nal dis p ositi o n rec or ds), f oll o wi n g 
S p o ns or’s i nstr ucti o ns. T he I n vesti gat or a n d trial staff m ust a d here t o G C P g ui deli nes, as well 
as l ocal or re gi o nal re q uire me nts. U n der n o circ u msta nces will t he I n vesti gat or all o w t he st u d y 
dr u g t o be use d ot her t ha n as directe d b y t his pr ot oc ol. Cli nical st u d y dr u g or T C S s u p plies will 
be  dis pe nse d  o nl y  b y  a n  a p pr o priatel y  q ualifie d  pers o n  a n d  will  n ot  be  dis pe nse d  t o  a n y 
i n di vi d ual w h o is n ot e nr olle d i n t he trial, u nless t he i n di vi d ual is t he pare nt or care gi ver of a n 
a d olesce nt partici pa nt.
St u d y  dr u g  is  t o  be  st ore d  u n der  refri gerate d  c o n diti o ns  ( 2° C  t o  8° C)  a n d  pr otecte d  fr o m 
e xcessi ve li g ht a n d heat. St u d y dr u g s h o ul d n ot be fr oze n, s ha ke n or st ore d at r o o m te m perat ure. 
Te m perat ure e xc ursi o ns o utsi de of 2° C t o 8° C m ust be re p orte d t o t he S p o ns or or t he desi g nee. 
Patie nts m ust re p ort t he date t hat t he st u d y dr u g is ta ke n o ut of t he refri gerat or a n d t he date of 
a d mi nistrati o n.
T he I n vesti gat or or desi g nee will c o nfir m recei pt of t he st u d y dr u g, will verif y t he c o n diti o n 
u n der w hic h t he dr u g was recei ve d a n d will verif y t he c o nte nts of t he s hi p me nt i m me diatel y 
u p o n recei pt of t he pr o d uct.
C CI


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The TCS must be stored according to leaflet instructions.
Used medication can be thrown away into special containers for injectable and medical waste, 
and empty boxes have to be stored for final accountability. If injection is done at home by the 
patient or their caregiver, the used syringes must be returned to the site in their respective 
original containers. Site personnel will then verify patient home compliance and dispose of the 
used medication into special containers for injectable and medical waste. Unused medication 
will be returned to the Sponsor or designee, where the remaining medication will be destroyed 
according to standard operating procedures (SOPs). Sites may destroy unused medication as 
long as, before destruction, it has been verified and documented that the site has appropriate 
facilities and written procedures to dispose of clinical trial materials. Retention drug samples 
will be kept by the Sponsor during the trial and until it is legally required after trial completion. 
Further guidance and information for the final disposition of unused trial interventions are 
outlined in the Investigator’s Drug Manual and/or Pharmacy Manual.
9.4
Treatment Administration
Treatment will begin on Day 1, after confirmation of patient eligibility and collection of all 
predose samples and assessments.
During the 16-week Induction Period, patients will receive either 250 mg lebrikizumab 
(loading dose of 500 mg given at Baseline and Week 2) or placebo by SC injection Q2W. The 
study drug injection will be administered in the clinic during the first 4 weeks of treatment as 
well as at Weeks 8, 12, 16, and 18. Patients will have the option to self-administer the study 
drug or get it administered by a caregiver outside of the study site during weeks in which no 
on-site clinic visit is scheduled from Week 4 onward according to Table 1. Patients (and/or 
caregivers) will be trained on study drug storage requirements, and on injecting study drug 
until competency has been demonstrated. After completion of the Week 16 visit, patients will 
enter the Maintenance Period:

Patients who received lebrikizumab 250 mg Q2W during the Induction Period will 
continue to receive lebrikizumab 250 mg Q2W during the Maintenance Period

Patients who received placebo Q2W during the Induction Period will start receiving 
lebrikizumab 250 mg Q2W (with loading doses at Week 16 and Week 18) during the 
Maintenance Period
To allow patients in the placebo arm to receive these loading doses during the Maintenance 
Period, blinding will be maintained at Week 16 and Week 18. In order to maintain the double-
blind, patients from the lebrikizumab 250 mg Q2W arm will be administered a second injection 
of blinded placebo during Week 16 and Week 18. From Week 20 onwards, all patients will 
receive 1 injection of lebrikizumab 250 mg Q2W. Therefore, the study will be open-label from 
Week 20 onward. Please see the Pharmacy Manual for details on SC injection site management.
9.5
Treatment Compliance
Study drug compliance will be assessed by counting returned used or unused prefilled syringes. 
A patient will be considered compliant with the dosing regimen if the patient received ≥75% 
of the expected number of injections while enrolled in the study. Deviation(s) from the 
prescribed dosage regimen should be recorded in the eCRF.


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Patie nts will be i nstr ucte d t o ret ur n all use d a n d u n use d T C S me dicati o n (t u bes) t o t he st u d y 
site f or acc o u nta bilit y p ur p oses. I nf or mati o n o n t he areas w here T C S was a d mi nistere d as well 
as t he t y pe of T C S will als o be c ollecte d. T he I n vesti gat or m ust kee p a n acc urate rec or d of t he 
n u m ber of t u bes recei ve d, dis pe nse d/ use d, a n d ret ur ne d b y patie nts. T he S p o ns or or desi g nee 
will pr o vi de f or ms t o facilitate i n ve nt or y c o ntr ol. All acc o u nta bilit y f or ms a n d treat me nt l o gs 
m ust be retai ne d i n t he I n vesti gat or’s per ma ne nt st u d y file, a n d t hese rec or ds m ust be a vaila ble 
f or i ns pecti o n at a n y ti me b y t he S p o ns or, its desi g nees, or b y re g ulat or y a ge ncies.
T he d osi n g l o gs f or eac h patie nt will be ke pt d uri n g t he trial. T he Cli nical Researc h Ass ociate 
( C R A)/ M o nit or will re vie w treat me nt c o m plia nce d uri n g m o nit ori n g site visits.
9. 6  
Met h o ds f or Assi g ni n g P atie nts t o Tre at me nt Gr o u ps
9. 6. 1 
P atie nt I de ntific ati o n
T o pr otect t he patie nt’s i de ntit y a n d data c o nfi de ntialit y, eac h patie nt will be i de ntifie d i n t he 
trial wit h 1 u ni q ue patie nt u ni q ue i de ntifier. At Scree ni n g, t he i nteracti ve we b res p o nse s yste m 
(I W R S) will assi g n a u ni q ue patie nt i de ntificati o n n u m ber t o t he patie nt, k n o w n as t he patie nt 
n u m ber. T his n u m ber will be ass ociate d wit h t he patie nt t hr o u g h o ut t he st u d y. E ver y patie nt 
w h o  si g ns  a n  I C F/I A F  m ust  be  e ntere d  i nt o  t he  I W R S,  re gar dless  of  eli gi bilit y,  t o  o btai n  a 
patie nt n u m ber. T his 1 1- di git n u m ber will c o nsist of a 3- di git c o u ntr y-s pecific c o de, f oll o we d 
b y a 5- di git site i de ntificati o n, a n d a 3- di git n u m ber assi g ne d se q ue ntiall y wit hi n eac h site t o 
eac h patie nt, starti n g at 0 0 1.
T he site n u m ber will be pre deter mi ne d, b ut t he se q ue ntial patie nt n u m ber is deter mi ne d w he n 
e nteri n g t he patie nt i n electr o nic data ca pt ure ( E D C). T he site staff m ust e nter t he patie nt details 
i n E D C u p o n si g ni n g t he I C F/I A F. At eac h site, t he first patie nt is assi g ne d patie nt n u m ber 0 0 1, 
a n d s u bse q ue nt patie nts are assi g ne d c o nsec uti ve n u m bers.
O nce assi g ne d t o a patie nt, t he patie nt n u m ber will n ot be re use d. T he patie nt n u m ber will be 
use d t o i de ntif y t he patie nt t hr o u g h o ut t he trial.
9. 6. 2  
R a n d o mis ati o n
Patie nts w h o meet all criteria f or e nr ol me nt will be assi g ne d a ra n d o misati o n n u m ber t hr o u g h 
t he I W R S, i n acc or da nce wit h t he ra n d o misati o n c o de ge nerate d b y t he a ut h orise d pers o n nel 
at 
 O nce a ra n d o misati o n n u m ber is all ocate d t o a patie nt, it ma y n ot be assi g ne d 
t o a n ot her patie nt e ve n if t he f or mer disc o nti n ue d t he st u d y.
Eli gi ble  patie nts  will  be  e nr olle d  a n d  ra n d o mise d  2: 1  o n  St u d y  Da y  1  t o  eit her  2 5 0  m g 
le bri kiz u ma b  (l oa di n g  d ose  of  5 0 0  m g  gi ve n  at  Baseli ne  a n d  Wee k  2)  or  place b o  b y  S C 
i njecti o n Q 2 W. Ra n d o misati o n will be stratifie d b y pri or use of d u pil u ma b, a ge (a d olesce nt 
patie nts a ge d ≥1 2 t o < 1 8 years will ma ke u p 1 2. 5 % of t he o verall p o p ulati o n c o m pare d t o a d ults 
a ge d ≥1 8 years), a n d baseli ne disease se verit y (I G A 3 vers us 4).
Ra n d o misati o n data will be ke pt strictl y c o nfi de ntial, accessi ble o nl y t o a ut h orise d pers o ns, 
u ntil t he ti me of u n bli n di n g of t he all ocate d treat me nt of all trial patie nts after data base l oc k. 
W he n t he trial is c o m plete d a n d t he data verifie d a n d l oc ke d, t he ra n d o misati o n c o des will be 
ma de a vaila ble f or data a nal ysis.
P P D


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T he I n vesti gat or or his/ her dele gate will c o ntact t he I W R S after c o nfir mi n g t hat t he patie nt 
f ulfils all t he i ncl usi o n criteria a n d d oes n ot meet a n y of t he e xcl usi o n criteria. T he I W R S will 
assi g n  a  ra n d o misati o n  n u m ber  t o  t he  patie nt,  w hic h  will  be  use d  t o  li n k  t he  patie nt  t o  a 
treat me nt ar m a n d will s pecif y u ni q ue me dicati o n pac k n u m bers f or t he first pac ka ges of trial 
treat me nt.
9. 7 
Bli n di n g
T he  1 6- wee k  I n d ucti o n  Peri o d  is  a  d o u ble- bli n d  treat me nt  peri o d.  W hile  t he  Mai nte na nce 
Peri o d is ge nerall y o pe n-la bel, t he Wee ks 1 6 a n d 1 8 d oses will re mai n bli n de d s o as t o all o w 
f or patie nts i n t he place b o ar m t o recei ve a bli n de d l oa di n g d ose bef ore recei vi n g mai nte na nce 
o pe n-la bel le bri kiz u ma b d uri n g t he Mai nte na nce Peri o d (fr o m Wee k 2 0 o n war d).
Acti ve a n d place b o me dicati o n will be s u p plie d i n i n di vi d ual cart o n b o xes c o ntai ni n g 1 s yri n ge 
eac h. Le bri kiz u ma b s yri n ges ca n n ot be disti n g uis he d vis uall y fr o m place b o s yri n ges, as t he y 
ha ve  a n  i de ntical  a p peara nce  a n d  c o m p o ne nts,  i ncl u di n g  t he  s yri n ge,  nee dle  safet y  de vice, 
f ol di n g cart o n, a n d la bels.
A  me dicati o n  n u m beri n g  s yste m  will  be  use d  i n  la belli n g  bli n de d  st u d y  dr u g.  Lists  li n ki n g 
me dicati o n n u m bers wit h pr o d uct l ot n u m bers will be mai ntai ne d b y t he gr o u ps ( or c o m pa nies) 
res p o nsi ble f or st u d y dr u g pac ka gi n g. T o mai ntai n t he bli n d, t hese lists will n ot be accessi ble 
t o i n di vi d uals i n v ol ve d i n st u d y c o n d uct.
N o st u d y site pers o n nel, patie nts, S p o ns or pers o n nel, or S p o ns or desi g nees will be u n bli n de d 
t o treat me nt assi g n me nt t hr o u g h o ut t he st u d y u nless u n bli n di n g is re q uire d. If a n I n vesti gat or 
bec o mes u n bli n de d t o a gi ve n patie nt’s st u d y treat me nt, t hat patie nt will be disc o nti n ue d fr o m 
t he st u d y u nless t here are et hical reas o ns f or t hat patie nt n ot t o be disc o nti n ue d; a p pr o val fr o m 
t he S p o ns or’s me dical m o nit or m ust be o btai ne d i n s uc h i nsta nces.
I n  t he  e ve nt  t hat  e mer ge nc y  u n bli n di n g  is  re q uire d  f or  a  gi ve n  patie nt  beca use  of  A Es  or 
c o ncer ns f or t he patie nt’s safet y or well- bei n g, t he I n vesti gat or ma y brea k t he ra n d o misati o n 
c o de  f or  t he  patie nt  via  t he  I W R S,  b y  w hic h  s yste m  t he  u n bli n di n g  will  be  ca pt ure d.  T he 
I n vesti gat or is res p o nsi ble f or n otif yi n g t he me dical m o nit or a n d/ or S p o ns or of s uc h a n e ve nt 
as s o o n as p ossi ble. F urt her details are pr o vi de d i n Secti o n 9. 8  bel o w.
T he S p o ns or, C R O/ ve n d ors i n v ol ve d i n t he cli nical c o n d uct of t he trial, t he I n vesti gat ors, trial 
site pers o n nel, a n d patie nts will be bli n de d t o t he treat me nt t hat is assi g ne d t o eac h patie nt.
9. 8  
U n bli n di n g b y t he I n vesti g at or
W he ne ver  t he  mai nte na nce  of  t he  safet y  a n d  well- bei n g  of  t he  patie nt  –  as  assesse d  b y  t he 
I n vesti gat or, re q uires t he k n o wle d ge of t he i nf or mati o n o n t he a d mi nistere d st u d y dr u g, t he 
I n vesti gat or s hall brea k t he bli n d. Als o, i n t he case of a n u ni nte n de d pre g na nc y of a patie nt or 
t he fe male part ner of a patie nt partici pati n g i n t he trial, t he I n vesti gat or c o ul d brea k t he bli n d.
I n case of a n y d o u bt, t he I n vesti gat or s h o ul d c o ntact t he S p o ns or/ Me dical M o nit or fr o m  
 
t o e val uate w het her t he bli n d s h o ul d be br o ke n.
T he  I n vesti gat or  will  call/access  t he  I W R S  i n dicati n g  t he  trial  patie nt  c o ncer ne d.  A 
c o nfir mati o n f or m will be se nt t o t he I n vesti gat or s pecif yi n g t he treat me nt assi g ne d, w hic h will 
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be retai ne d i n t he I n vesti gat or’s file. T he S p o ns or/
 P har mac o vi gila nce U nit m ust 
be i m me diatel y i nf or me d of a n y u n bli n di n g.
T he I W R S will be pr o gra m me d wit h bli n d- brea ki n g i nstr ucti o ns. I n case of a n e mer ge nc y, t he 
I n vesti gat or  has  t he  s ole  res p o nsi bilit y  f or  deter mi ni n g  if  u n bli n di n g  of  a  partici pa nt’s 
treat me nt assi g n me nt is warra nte d. Partici pa nt safet y m ust al wa ys be t he first c o nsi derati o n i n 
ma ki n g  s uc h  a  deter mi nati o n.  If  t he  I n vesti gat or  deci des  t hat  u n bli n di n g  is  warra nte d,  t he 
I n vesti gat or s h o ul d ma ke e ver y eff ort t o c o ntact t he S p o ns or bef ore u n bli n di n g a partici pa nt’s 
treat me nt  assi g n me nt  u nless  t his  c o ul d  dela y  e mer ge nc y  treat me nt  of  t he  partici pa nt.  If  a 
partici pa nt’s treat me nt assi g n me nt is u n bli n de d, t he S p o ns or m ust be n otifie d wit hi n 2 4 h o urs 
after brea ki n g t he bli n d. T he date a n d reas o n t hat t he bli n d was br o ke n m ust be rec or de d i n t he 
s o urce d oc u me ntati o n, as a p plica ble.
9. 9 
Pre-tri al, C o nc o mit a nt, a n d P ost-tri al Me dic ati o ns/ T her a p y
9. 9. 1 
Pre-tri al Me dic ati o ns
T o e ns ure pr o per was h o ut a n d re vie w of pr o hi bite d me dicati o ns, a n y pr o hi bite d treat me nt or 
treat me nt re q uiri n g a was h o ut peri o d (as o utli ne d i n Ta ble 5 , a n d Secti o n 9. 9. 2 ) ta ke n b y patie nt 
bef ore si g ni n g t he I C F be rec or de d i n t he e C R F (i n Pre vi o us a n d C o nc o mita nt Me dicati o n).
A c o m plete c o nc o mita nt A D t hera p y hist or y a n d reas o n f or disc o nti n uati o n (if a p plica ble) will 
be rec or de d i n t he e C R F.
A n y me dicati o n ta ke n f or me dical reas o ns ( mai nl y diseases c o nc o mita nt wit h st u die d disease) 
bef ore trial e ntr y, will be c o nti n ue d at t he sa me d ose a n d u n der t he sa me c o n diti o ns d uri n g t he 
e ntire e x peri me ntal p hase of t he trial. See Secti o n 8. 3  a n d Ta ble 5  f or bac k gr o u n d t hera pies 
t hat are n ot per mitte d i n t his trial.
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Table 5.
Prior Treatment Exclusions
Drug Class
Washout Period
IL-4 or IL-13 antagonists
N/A (not allowed)a
TCS
1 weeks
Topical calcineurin inhibitors
2 weeks
Phosphodiesterase-4 inhibitors (eg, crisaborole)
2 weeks
Cannabinoids
2 weeks
Immunosuppressive/immunomodulating 
drugs 
(eg, 
systemic corticosteroids, cyclosporine, mycophenolate-
mofetil, 
IFN-γ, 
JAK 
inhibitors, 
azathioprine, 
methotrexate)
4 weeks
Phototherapy and photochemotherapy (PUVA)
4 weeks
Investigational drugs
8 weeks or 5 half-lives (if known), 
whichever is longer
B cell-depleting biologics, including but not limited to 
rituximab
6 months
Other biologics
16 weeks or 5 half-lives (if known), 
whichever is longer
Live (attenuated) vaccine
12 weeks
Abbreviations: IFN = interferon; IL = interleukin; JAK = Janus kinase; PUVA = psoralen and ultraviolet A; 
TCS = topical corticosteroids.
aPrior treatment with dupilumab will be allowed in a subset of patients. A washout of at least 8 weeks before the 
Baseline visit will be required for this subpopulation.
9.9.2
Concomitant Medications
All medications (including prescription and non-prescription drugs, vitamins, and dietary 
supplements) taken after the patient signs initial ICF but before enrolment will be recorded in 
the eCRF as taken during the Screening Period. Thereafter, all nonstudy medications taken 
during the patient’s participation in the study must be recorded, including the dose and regimen, 
start and stop dates, and indication.
At the Investigator’s discretion, nonmedical topical moisturizers may be prescribed for the 
proper care and treatment of the patient, and TCS are required concomitant medications; 
administration is summarised in Table 6.


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Table 6.
Instruction for Use of Concomitant Medication
Concomitant Medication
Instructions for Use
Non-medicated topical 
moisturizer
Applied a stable dose at least BID for ≥7 days before the Baseline 
visit.
TCS
All patients must use concomitant TCS.
At Baseline (Week 0, Visit 2) and until Week 16, all eligible 
patients will apply mid-potency TCS and low-potency TCS.
Medium-potency TCS should be applied at least once daily to 
affected areas until lesions are under control (clear or almost clear). 
Patients should then switch to low-potency TCS and treat 
previously affected areas OD for 7 days and then stop.
Low-potency TCS may be used from the Baseline visit in place of 
mid-potency TCS on areas of thin skin (face, neck, folds, and 
genital areas) and areas with skin atrophy. If lesions reappear 
during the course of the study, the patients should resume the OD 
applications of mid-potency TCS or low-potency TCS as described 
above.
For patients whose lesions persist or worsen despite the use of 
emollients and low- and/or mid-potency TCS and/or patients who 
require daily applications on large surfaces, topical rescue with 
high- or very high-potency TCS may be considered for topical 
rescue with high- or very high-potency TCS.
On the days of study visits, topical therapy, including TCS, should 
not be applied before the patient has undergone all study procedures 
and clinical evaluations including adequate assessment of skin 
dryness.
From Week 16 to Week 52, TCS use will be at Investigator 
discretion and considered normal practice rather than an 
intercurrent event.
Inhaled corticosteroids and 
bronchodilators 
To control asthma.
Abbreviations: BID = twice daily; OD, once daily; TCS = topical corticosteroids.
The use of TCS is prohibited for at least 1 week before the Baseline visit. A mid-potency TCS, 
triamcinolone acetonide 0.1% cream, and a low-potency TCS, hydrocortisone 1% cream (for 
use on sensitive skin areas), will be provided by the Sponsor or clinical site during the Induction 
Period only. The use of concomitant medications for other medical conditions (eg, 
hypertension, diabetes, acute infections) is permitted during this study.
9.9.3
Prohibited Concomitant Medications
The introduction of medications or therapies for other medical conditions known to have an 
effect on AD are not permitted during the study. These may include but are not limited to the 
list of medication as outlined in Table 5 and below:

The use of systemic corticosteroids for the treatment of AD is prohibited and requires 
permanent discontinuation of the Investigational Product. If a systemic corticosteroid is 
used for the treatment of AEs (eg, worsening of existing condition, such as asthma 
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
Acute infections can be treated with systemic antibiotics, use of which must be recorded 
in the eCRF. However, chronic treatment with systemic antibiotics is not permitted.

The use of a tanning booth/parlour is not permitted during the trial.

Cannabinoid treatments for AD are prohibited.
9.9.4
Rescue Treatment for Atopic Dermatitis
If medically necessary (eg, to control intolerable AD symptoms), high-potency TCS or 
systemic treatments (eg, oral corticosteroids, phototherapy) may be used.
Patients using high-potency TCS will continue treatment with lebrikizumab and should 
continue to attend all study visits and be assessed for safety and efficacy according to the SoA.
Study drug must be permanently discontinued for patients receiving systemic rescue treatment 
as outlined in Section 9.9.3.
9.9.5
Post-trial Medications
Once the last dose of study drug is taken (eg, the last visit at which the patient takes IMP 
[Week 50]) and related trial measurements are completed (Week 52), patients should continue 
to take their usual medications, also allowed during the trial, and may resume other medications 
that were interrupted before trial enrolment as deemed appropriate by the Investigator.
The study drug is for experimental use only, and there are other therapies available to treat the 
disease.
Only concomitant medication associated with AEs will be captured between the last IMP 
administration and last phone contact/visit (between Week 50 and Week 68). From Week 52 
onward, medications to treat AD will be recorded in the eCRF.
10
Trial Procedures and Assessments
10.1
General Conditions of the Trial
Informed consent must be obtained before performing any procedure related to the trial. This 
can be done at any time before the Screening visit. ICF/IAF must be signed after the patient 
has received sufficient information about the trial and after he/she has had the opportunity to 
ask any questions and consider other treatment options. Participation in the trial must be 
documented in the patient´s medical records and a copy of the ICF/IAF will be given to the 
patient.
Trial visits will be scheduled in the morning whenever possible. At the scheduled protocol 
visits, IMP dosing must occur while being witnessed by the research personnel at the clinic to 
ensure the proper IMP application, as well as the correct timing of activities to occur before 
and after dosing.
Trial visit dates must be scheduled with respect to the randomisation visit day. To adapt 
appointments to local holidays, patient´s availability, or site internal organisation needs, a time 
window of ±3 days is allowed for visits during the Screening Period, Induction Period, and a 
time window of ±5 days is allowed for the SFU visit and visits during the Maintenance Period. 
PROs must be completed prior to other study-related activities. Therefore, the visit window for 


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P R Os is - 3 da ys d uri n g I n d ucti o n Peri o d a n d - 5 da ys d uri n g Mai nte na nce Peri o d. Please c o ntact 
t he C R A or 
 Me dical M o nit or f or a d vice i n case of e xce pti o nal sit uati o ns.
T he st u d y dr u g s h o ul d be a d mi nistere d after all ot her pr oce d ures a n d assess me nts ha ve bee n 
c o m plete d at a p plica ble visits.
P R Os  will  be  assesse d  at  t he  start  of  t he  visit  bef ore  a n y  ot her  assess me nts  or  pr oce d ures. 
Assess me nts  or  pr oce d ures  s h o ul d  be  c o n d ucte d  i n  t he  f oll o wi n g  or der:  1)  P R Os;  2) 
I n vesti gat or assess me nts a n d ot her efficac y assess me nts; 3) safet y a n d la b orat or y assess me nts 
(i ncl u di n g sa m ple c ollecti o n f or bi o mar kers); a n d 4) a d mi nistrati o n of st u d y dr u g.
Vital si g ns s h o ul d be assesse d bef ore bl o o d sa m pli n g.
La b orat or y  tests  will  be  perf or me d  usi n g  t he  e q ui p me nt  pr o vi de d  b y  t he  S p o ns or  f or  trial 
p ur p oses  t hr o u g h  a  s pecialise d  pr o vi der,  w h o  will  perf or m  ce ntralise d  assess me nt  a n d 
re p orti n g.
O pti mall y, t he e val uati o ns f or eac h patie nt (re vie w of treat me nt c o m plia nce, etc) s h o ul d be 
perf or me d b y t he sa me I n vesti gat or t hr o u g h o ut t he trial t o a v oi d i nter-assess or bias. I n a d diti o n, 
a p plica ble  q uesti o n naires  a n d  assess me nts  a d mi nistrati o n  will  be  perf or me d  b y  a n  assess or 
w h o is trai ne d a n d certifie d b y t he S p o ns or or dele gate as a p pr o priate.
A n  o ver vie w  of  t he  trial  is  pr o vi de d  i n  t he  S o A  ( Ta ble 1 ),  w hic h  s u m marises  t he  trial 
pr oce d ures t o be perf or me d at eac h visit. I n di vi d ual trial pr oce d ures are descri be d bel o w.
1 0. 2 
P atie nts Ge ner al C o n diti o ns D uri n g t he Tri al
After t he Scree ni n g e val uati o n a n d w hile n ot at t he researc h site, patie nts will mai ntai n n or mal 
dail y acti vities, f oll o wi n g t he i nstr ucti o ns of t he I n vesti gat or. Patie nts will be as ke d t o a d here 
as m uc h as p ossi ble t o t he f oll o wi n g ge neral re q uire me nts:

D o  n ot  d o nate  bl o o d  fr o m  t he  Scree ni n g  visit  t o  1  m o nt h  after  t he  sc he d ule d  f oll o w- u p 
c o ntact.

Kee p re g ular ni g ht/ da y s hifts.

Atte n d  visits  at  w hic h  hae mat ol o g y/c he mistr y  sa m ples  are  t o  be  c ollecte d  u n der  fasti n g 
c o n diti o ns.

Alc o h ol  c o ns u m pti o n  will  n ot  be  per mitte d  f or  at  least  8  h o urs  bef ore  visits  at  w hic h 
hae mat ol o g y/c he mistr y sa m ples are t o be c ollecte d.

N o use of har d dr u gs or ot her pr o hi bite d s u bsta nces.

D o  n ot  u n der g o  hazar d o us  p h ysical  acti vities  be y o n d  t he  patie nt’s  re g ular  practice. 
Stre n u o us p h ysical acti vit y s h o ul d be a v oi de d f or at least 8 h o urs bef ore visits at w hic h 
hae mat ol o g y/c he mistr y sa m ples are t o be c ollecte d.

C o ntrace pti o n, if assi g ne d, is use d c o nsiste ntl y a n d c orrectl y as o utli ne d i n Secti o n 8. 2.

Fe male partici pa nts will i nf or m t he st u d y staff of a n y c ha n ges i n c hil d beari n g p ote ntial.

O n t he da ys of st u d y visits, t o pical t hera p y, i ncl u di n g T C S, s h o ul d n ot be a p plie d bef ore 
t he patie nt has u n der g o ne all st u d y pr oce d ures a n d cli nical e val uati o ns i ncl u di n g a de q uate 
assess me nt of s ki n dr y ness.
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Any event likely to interfere with the objectives of the trial will be communicated to the 
Investigator and reported without delay to the Sponsor.
10.2.1
Instructions for Male Patients
Male patients must agree to use an effective barrier method of contraception during the study 
and for a minimum of 18 weeks after the last dose of study drug if sexually active with a 
WOCBP.
10.3
Scheduled Activities and Trial Visits
10.3.1
Screening Period
The Screening Period will start with the Screening visit and continue until randomisation. The 
ICF/IAF must be signed before any trial-related procedures are performed.
Before signature of the ICF/IAF, Investigators will evaluate eligibility of patients for entry in 
the trial by comparing past and current medical status, as documented in the patient’s medical 
records, to the trial’s inclusion/exclusion criteria.
Eligible patients will receive a detailed description of all activities and requirements before 
signing the ICF/IAF to ensure their understanding and compliance with sample collection, 
clinical examination, and eDiary completion requirements
Patients who require a washout period from prohibited concomitant treatments should be seen 
and sign the ICF/IAF before the Screening visit to ensure the necessary washout period is met 
as required based on the type of background therapy taken. No trial assessments will be 
performed on that date and the Screening visit will be scheduled according to the washout 
length required for the specific medication stopped.
The Screening visit and assessments will be performed in accordance with the schedule detailed 
in Table 1.
10.3.2
Treatment Period
Treatment period visits and assessments will be performed in accordance with the SoA detailed 
in Table 1. See Sections 10.4 and Section 10.5 for details on the efficacy and safety 
assessments, respectively.
The trial visits cannot be repeated or skipped but may be postponed (if not started yet) within 
the time windows allowed in this protocol, in case of:

technical problems with the equipment necessary for the visit

any AEs that impede the conduct of the visit

the intake of any prohibited medication, to reach the washout length required in the specific 
prohibited medication section of the protocol, as long as the delay fits the protocol-allowed 
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10.3.3
End-of-Treatment
End-of-treatment visit and assessments will be performed in accordance with the SoA detailed 
in Table 1, after the last study drug administration (for completed patients) or premature 
discontinuation visit (when applicable).
10.3.4
Follow-up Period
A follow-up visit and assessments will be performed in accordance with the SoA detailed in 
Table 1, after the last study drug administration (for completed patients) or premature 
discontinuation visit (when applicable).
10.3.5
Unscheduled and Repeated Tests
Unscheduled Tests
As deemed necessary by the Investigator, additional safety test(s) can be performed at any time 
during the trial to follow-up with the progress of any clinically relevant abnormal finding, 
investigate any potential new AE, etc. These additional tests outside of the initial schedule of 
the trial will be considered "unscheduled tests" and will not be associated with any trial visit.
Repeated Tests
Any safety test may be repeated at the Investigator’s discretion under either of the following 
situations:

When there is any kind of problem with the first test (ie, blood sample haemolysed, 
presence of artefacts). The Investigator should repeat the individual test as soon as 
possible.

At the Screening visit, any individual test(s) may be reasonably repeated before 
randomisation to confirm the eligibility criteria (eg, laboratory sample when there is any 
clinically significant abnormality).
The new test will be considered a “re-test” and will be identified with the same visit ID as the 
first attempt.
10.4
Efficacy Assessments
Each patient’s AD will be assessed as specified in the SoA (Table 1). Whenever possible, the 
same assessor should perform all assessments on a given patient during the course of the study. 
The Sponsor or delegate will administer training on the required efficacy assessments, and 
details on the specific instruments and training given will be recorded in the study training 
materials. If a parent or caregiver helps an adolescent patient complete an assessment or 
questionnaire, they must not influence or question the response given by the adolescent patient 
with AD. This requirement should be communicated to the parent or caregiver during training 
on eDiary completion.
10.4.1
Eczema Area and Severity Index Score
The EASI is used to assess the severity and extent of AD; it is a composite index with scores 
ranging from 0 to 72, with higher values indicating more severe and or extensive disease.48 The 
severity of erythema, induration/papulation, excoriation, and lichenification will be assessed 


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by the Investigator or trained designee on a scale of 0 (absent) to 3 (severe) for each of the 4 
body areas: head/neck, trunk, upper limbs, and lower limbs, with half points allowed. In 
addition, the extent of AD involvement in each of the 4 body areas will be assessed as a 
percentage by body area of head/neck, trunk, upper limbs, and lower limbs, and converted to a 
score of 0 to 6. Assessors must be trained and certified by the Sponsor or delegate before 
conducting this assessment.
10.4.2
Investigator Global Assessment
The IGA is an instrument used to globally rate the severity of the patient’s AD. It is based on 
a 5-point scale ranging from 0 (clear) to 4 (severe), and a score is selected using descriptors that 
best describe the overall appearance of the lesions at a given time point. Assessors must be trained 
and certified by the Sponsor or delegate before conducting this assessment.
Table 7.
Investigator Global Assessment
Score
Grade
Definition
0
Clear
Minor, residual discolouration; no erythema or 
induration/papulation; no oozing/crusting; no oedema.
1
Almost clear
Trace, faint-pink erythema with barely perceptible 
induration/papulation and no oozing/crusting; no oedema.
2
Mild
Faint-pink erythema with papulation and oedema perceptible 
upon palpation and no oozing/crusting; minimal induration.
3
Moderate
Pink-red erythema with definite oedema of skin papules and 
plaques; there may be some oozing/crusting; palpable induration.
4
Severe
Deep/bright red erythema with significant swelling and obvious 
raised borders of papules and plaques with oozing/crusting; 
significant induration.
10.4.3
Body Surface Area
The BSA assessment estimates the extent of disease or skin involvement with respect to AD 
and is expressed as a percentage of total body surface. BSA will be determined by the 
Investigator or designee using the patient palm = 1% BSA rule. Assessors must be trained and 
certified by the Sponsor or delegate before conducting this assessment.
10.4.4
Scoring Atopic Dermatitis
The SCORAD is a validated clinical tool for assessing the extent and intensity of AD.38 There 
are 3 components to the assessment:

The AD surface involvement is assessed as the proportion of involved surface area 
segment by segment by applying the rule of 9s (eg, 50% of the right leg = 4.5) and 
reported as the sum of all areas, with a score ranging from 0 to 100.

The intensity part of the SCORAD consists of 6 items: erythema, oedema, 
oozing/crusting, excoriation, lichenification, and dryness. Each item is graded is 
graded as follows: none (0), mild (1), moderate (2), or severe (3) (for a maximum 
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
Subjective assessment of itch and of sleeplessness is recorded for each symptom 
using a visual analog scale (VAS), where 0 is no itch (or sleeplessness) and 10 is 
the worst imaginable itch (or sleeplessness), for a maximum possible score of 20.
The SCORAD Index formula is: A/5 + 7B/2 + C. In this formula “A” is defined as the extent 
(0-100), “B” is defined as the intensity (0-18), and “C” is defined as the subjective symptoms 
(0-20). The maximum score of the SCORAD Index is 103.
Assessments will be reported by the clinician and the patient (VAS only), as outlined in the 
SoA (Table 1).
Assessors must be trained and certified by the Sponsor or delegate before conducting this 
assessment.
10.4.5
Pruritus Numerical Rating Scale
The Pruritus NRS is an 11-point scale used by patients to rate their worst itch severity over the 
past 24 hours, with 0 indicating “No itch,” and 10 indicating “Worst itch imaginable.”49 
Assessments will be recorded by the patient using an eDiary, as outlined in the SoA (Table 1).
The Baseline Pruritus NRS will be determined based on the average of daily Pruritus NRS 
scores during the 7 days immediately before Baseline. A minimum of 4 daily scores out of the 
7 days immediately before Baseline is required for this calculation.
10.4.6
Sleep-Loss Scale
Sleep loss will be assessed by all patients using a PRO instrument. Patients (and if applicable, 
with help of parents/caregiver if required) will rate their sleep on a 5-point Likert scale (with 
scores ranging from 0 [not at all] to 4 [unable to sleep at all]). Assessments will be recorded by 
the patient using an eDiary, as outlined in the SoA (Table 1).
10.4.7
Skin Pain NRS
The Skin Pain NRS is a patient-administered, validated, 11-point horizontal scale anchored at 
0 and 10, with 0 representing “no pain” and 10 representing “worst pain imaginable.” Overall 
severity of a patient’s skin pain is indicated by selecting the number that best describes the 
worst level of skin pain in the past 24 hours.”50 Assessments will be recorded by the patient 
using an eDiary, as outlined in the SoA (Table 1).
The Baseline Skin Pain NRS will be determined based on the average daily Skin Pain NRS 
scores during the 7 days before Baseline. A minimum of 4 daily scores out of the 7 days before 
Baseline is required for this calculation.
10.4.8
Patient-Oriented Eczema Measure
The POEM is a 7-item, validated questionnaire completed by the patient (and, if applicable, 
with help of parents/caregiver if required) to assess disease symptoms.51 Patients are asked to 
respond to questions on skin dryness, itching, flaking, cracking, sleep loss, bleeding, and 
weeping. All answers carry equal weight, with a total possible score ranging from 0 to 28 
(answers scored as: No days = 0; 1-2 days = 1; 3-4 days = 2; 5-6 days = 3; every day = 4). 
A high score is indicative of a poor QoL. POEM responses will be captured using an eDiary, 
as outlined in the SoA (Table 1).


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10.4.9
Dermatology Life Quality Index
The DLQI is a 10-item validated questionnaire completed by the patient or caregiver used to 
assess the impact of skin disease on the patient’s QoL during the previous week.52 The 10 
questions cover the following topics: symptoms, embarrassment, shopping and home care, 
clothes, social and leisure, sport, work or study, close relationships, sex, and treatment. Each 
question is scored from 0 to 3 (“not at all,” “a little,” “a lot,” and “very much”), giving a total 
score ranging from 0 to 30. A high score is indicative of a poor QoL. DLQI responses will be 
captured as outlined in the SoA (Table 1).
Adolescents younger than age of 16 years will use the CDLQI, which is based on a set of 
10 questions different from those of the DLQI.53
10.4.10
Dermatology Life Quality Index-Relevant
The DLQI-R is a recently developed scoring tool that adjusts the total score of the DLQI 
questionnaire for the number of not relevant responses indicated by a patient.54-56
10.4.11
World Health Organisation - Five Well-Being Index
The WHO-5 assessment is a self-reported measure of current mental well-being covering 5 
positively worded items, related to positive mood (good spirits, relaxation), vitality (being 
active and waking up fresh and rested), and general interests (being interested in things).44 Each 
item is rated on 6-point Likert scale, ranging from 0 (at no time) to 5 (all of the time). The raw 
scores are transformed to a score ranging from 0 to 100, with lower scores indicating worse 
well-being. WHO-5 responses will be captured from the patient as outlined in the SoA 
(Table 1).
10.4.12
Recap of Atopic Eczema
The RECAP is a 7-item patient-reported instrument to capture eczema control, over the 
previous week.57 Each item is scored on a 5-point Likert scale, ranging from 0 (very good) to 
4 (very bad). A higher score indicates worse eczema control. RECAP responses will be 
captured from the patient as outlined in the SoA (Table 1).
10.4.13
Treatment Satisfaction Questionnaire for Medication-9 Items 
(TSQM-9)
The TSQM-9 is a 9-item measure that assesses the most common dimensions patients use to 
evaluate their medication (ie, global satisfaction, effectiveness, and convenience).46 The results 
for each scale are presented from 0 to 100, where higher scores represent better satisfaction. 
TSQM-9 responses will be captured from the patient as outlined in the SoA (Table 1).
10.5
Safety and Tolerability Assessments
10.5.1
Adverse Events
See Section 10.6 for AE definitions and reporting requirements.


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10.5.2
Medical History, Physical Examinations, and Vital Signs
10.5.2.1 Medical History
A detailed medical history will be obtained by the Investigator or qualified designee at the 
Screening visit and recorded in the eCRF. The medical history will include immunisation 
records (for adolescent patients) and clinically relevant medical conditions or surgeries, 
including more specific information on a history of conjunctivitis and herpes infection/zoster. 
Information on the patient’s AD (years since AD was diagnosed, anatomical areas affected by 
AD) and comorbidities (past history of asthma, allergic rhinitis/hay fever, conjunctivitis, food 
allergies, alopecia areata, prurigo nodularis, chronic hand eczema, herpes zoster [shingles], 
chickenpox [varicella-zoster], herpes simplex [eczema herpeticum, labialis (oral), genital], and 
eosinophilic esophagitis) will be collected and include the date of onset, extent of involvement, 
and past treatments for AD (and main reason for discontinuation) as well as comorbidities.
Patient medical history should include information on clinically significant personal history, 
including identification of major cardiovascular risk factors, current and past smoking history, 
current alcohol use, and past history of infections, malignancies, and major cardiovascular 
conditions.
10.5.2.2 Physical Examinations
A complete physical examination will include, at a minimum, assessments of the 
cardiovascular, respiratory, gastrointestinal and neurological systems. Height and weight will 
also be measured and recorded.to allow calculation of body mass index. For this, patients 
should be in light indoor clothes without shoes. Specific head and neck lesions will be assessed 
at Baseline, Week 16, Week 32 and Week 52.
10.5.2.3 Vital Signs
Measurement of vital signs will include systolic and diastolic blood pressure (mmHg), pulse, 
respiratory rate (breaths per minute), and body temperature (°C). Measurements of systolic and 
diastolic blood pressure will be carried out after at least 5 minutes of resting in the supine 
position and always on the same arm. If there is any suspicion of an unreliable measurement, 
blood pressure will be measured again. The value obtained from the repeated measurement will 
be considered as definitive and should be recorded in the eCRF.
Significant findings that are observed after the patient has signed the ICF/IAF and that meet 
the definition of an AE must also be recorded in the eCRF.
10.5.3
Laboratory Testing
Blood and urine will be collected from each patient as specified in the SoA (Table 1) or as 
clinically indicated. Routine laboratory assessments will be analysed at a designated central 
laboratory (see Section 4.3). Tests to be performed are detailed in Table 8.


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Table 8.
Laboratory Testing Parameters
Assessment
Specific Tests
Haematology
Haematocrit, haemoglobin, erythrocytes (red blood cells count), mean 
corpuscular volume, Mean corpuscular haemoglobin, Mean corpuscular 
haemoglobin concentration, leucocytes (white blood cells count), 
differential blood count (absolute and percentage of neutrophils, 
lymphocytes, monocytes, eosinophils and basophils), thrombocytes 
(platelet count)
Coagulation 
At Screening only: Prothrombin time, activated partial thromboplastin 
time, and International Normalised Ratio
Blood chemistry
Electrolytes: Sodium, potassium, chloride, calcium, inorganic phosphate
Enzymes: alanine aminotransferase, aspartate aminotransferase, alkaline 
phosphatase, gamma-glutamyl transferase, and lactate dehydrogenase
Substrates: Total cholesterol, triglycerides, urea, creatinine, total bilirubin, 
total protein, albumin, uric acid, and blood urea nitrogen
Serology 
At Screening only: Hepatitis B surface antigen, Hepatitis B core antibody, 
Ig antibodies, anti-hepatitis C virus antibodies, and HIV I/II antibodies and 
antigen (serum)
Urinalysis
Dipstick measurements will be performed at the trial site* and will include: 
specific gravity, pH, blood, leucocytes, protein, glucose, bilirubin, 
urobilinogen, ketones and nitrites
*If relevant abnormalities are detected (eg, > ++ positive result in 
dipstick), the urine sample will be sent to the central laboratory for 
analysis.
Pregnancy Testing
A serum beta-hCG test will be performed in all women of childbearing 
potential at Screening. All pre-menopausal women who are not sterile at 
Screening will also have a urine pregnancy test performed locally at all 
visits. Any woman with a confirmed positive pregnancy test during 
Screening is not eligible for randomisation.
A positive urine pregnancy test during the treatment period of the trial 
requires a serum beta-hCG test to confirm the result.
Abbreviations: hCG = human chorionic gonadotropin; HIV = Human Immunodeficiency Virus; Ig = 
Immunoglobulin.
Blood and urine samples for laboratory testing will be collected in appropriate sampling tubes 
at scheduled time highlighted in the SoA (Table 1).
10.6
Adverse Events
The Investigator will closely monitor any AE and will adopt the necessary clinical measures to 
ensure the safety of the patient.
10.6.1
Definitions
Adverse Event
An AE is defined as any untoward medical occurrence in a clinical trial participant, regardless 
of the administration of the IMP and its causal relationship to it.


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A n  A E  ca n  t heref ore  be  a n y  u nfa v o ura ble  a n d  u ni nte n de d  me dical  occ urre nce  d uri n g  t he 
patie nt’s partici pati o n i n t he trial, i ncl u di n g deteri orati o n of a pre-e xisti n g me dical c o n diti o n, 
a n  a b n or mal  val ue  i n  a  la b orat or y  assess me nt,  or  a n  a b n or mal  fi n di n g  i n  t he  p h ysical 
e xa mi nati o n.
A Es m ust be te m p orall y ass ociate d wit h t he patie nt’s partici pati o n i n t he trial; ie, occ ur after 
t he patie nts si g ns t he I C F/I A F. At t he ti me of t he occ urre nce of a n A E, t he a d mi nistrati o n of 
t he I M P d oes n ot nee d t o ha ve bee n i nitiate d yet. If i nitiate d, it d oes n ot necessaril y nee d t o 
ha ve a p ositi ve ca usal relati o ns hi p t o t he e ve nt.
A d verse E ve nts of S peci al I nterest
T he  f oll o wi n g T E A Es are bei n g desi g nate d as A d verse E ve nts of S pecial I nterest ( A E SI):

c o nj u ncti vitis

her pes i nfecti o n or z oster
T he I n vesti gat or m ust re p ort a n y A E SIs wit hi n 4 8 h o urs fr o m t he m o me nt s he/ he first lear ns 
of it t o t he S p o ns or/
 p har mac o vi gila nce u nit. A d diti o nal data will be c ollecte d 
f or  A E SIs  d uri n g  t he  treat me nt  a n d  f oll o w- u p  p hases.  A  s pecific  f oll o w- u p  f or m  f or 
c o nj u ncti vitis  will  be  pr o vi de d  t o  t he  site.  Patie nt  rec or ds  will  i ncl u de  a n y  f oll o w- u p 
i nf or mati o n re gar di n g t hese A E SIs.
Seri o us A d verse E ve nt
A n S A E is a n A E, t hat falls i nt o 1 or m ore of t he f oll o wi n g cate g ories:

res ults i n deat h

is life-t hreate ni n g (ie, a n e ve nt t hat, i n t he vie w of t he I n vesti gat or, places t he patie nt at 
i m me diate ris k of deat h fr o m t he e ve nt as it occ urre d.) It d oes n ot mea n t hat t he e ve nt mi g ht 
h y p ot heticall y ha ve ca use d deat h if it were m ore se vere or ha d laste d l o n ger

re q uires i n- patie nt h os pitalisati o n or pr ol o n gs e xisti n g h os pitalisati o n

res ults i n persiste nt or si g nifica nt disa bilit y or i nca pacit y

is a c o n ge nital a n o mal y or birt h defect

is  a n y  ot her  me dicall y  i m p orta nt  e ve nt  t hat  ma y  je o par dise  t he  patie nt  or  ma y  re q uire 
i nter ve nti o n t o pre ve nt o ne of t he ot her a b o ve o utc o mes
Me dical a n d scie ntific j u d g me nt s h o ul d be e xercise d i n deci di n g w het her or n ot ot her sit uati o ns 
s h o ul d  be  c o nsi dere d  seri o us  reacti o ns,  s uc h  as  i m p orta nt  me dical  e ve nts  t hat  mi g ht  n ot  be 
i m me diatel y life-t hreate ni n g or d o n ot res ult i n deat h or h os pitalisati o n, b ut ma y je o par dise t he 
patie nt or ma y re q uire i nter ve nti o n t o pre ve nt o ne of t he ot her o utc o mes liste d i n t he defi niti o n 
a b o ve,  s h o ul d  als o  be  c o nsi dere d  seri o us.  T hese  are  c o nsi dere d  “ ot her  i m p orta nt  Me dical 
e ve nts.”
H os pitalisati o n is defi ne d as a n o ver ni g ht sta y at t he h os pital or e mer ge nc y r o o m.
Pr ol o n gati o n  of  h os pitalisati o n  is  defi ne d  as  a n y  e xte nsi o n  of  a n  i n- patie nt  h os pitalisati o n 
be y o n d t he sta y a ntici pate d/re q uire d i n relati o n t o t he ori gi nal reas o n f or t he i nitial a d missi o n, 
as deter mi ne d b y t he I n vesti gat or or treati n g p h ysicia n.
P P D


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1 0. 6. 2  
Re p orti n g of A d verse E ve nts
A Es eit her re p orte d b y t he patie nt or o bser ve d b y t he I n vesti gat or m ust be rec or de d o n t he A E 
pa ge of t he e C R F a n d s h o ul d be descri be d i n t he f oll o wi n g ma n ner:

T he nat ure of t he A E will be descri be d i n precise, sta n dar d me dical ter mi n ol o g y (ie, n ot 
necessaril y t he e xact w or ds use d b y t he patie nt). If k n o w n, a s pecific dia g n osis s h o ul d be 
rec or de d i nstea d of listi n g si g ns a n d s y m pt o ms (e g, aller gic c o ntact der matitis).

T he d urati o n of t he A E will be descri be d b y t he start date a n d e n d date.

T he i nte nsit y of t he A E will be descri be d i n ter ms of mil d, m o derate or se vere acc or di n g t o 
t he I n vesti gat or’s cli nical j u d g me nt. A n d assi g n t o 1 of t he f oll o wi n g cate g ories:
o
Mil d : A ware ness of e ve nt, s y m pt o ms or si g ns, b ut easil y t olerate d (acce pta ble).
o
M o der ate : S ufficie nt disc o mf ort a n d i nterferes wit h us ual acti vit y ( dist ur bi n g).
o
Se vere : I nca pacitati n g wit h i na bilit y t o d o n or mal dail y li vi n g acti vities or si g nifica ntl y 
affects cli nical stat us, a n d warra nts i nter ve nti o n ( u nacce pta ble).

T he ca usal relati o ns hi p of t he e ve nt t o t he use of t he I M P will be descri be d as:
o
N ot rel ate d : E ve nt or la b orat or y test res ult a b n or malit y, defi nitel y n ot relate d t o st u d y 
dr u g, or as relate d t o a n ot her dr u g, c he mical, or u n derl yi n g disease.
o
U nli kel y rel ate d : E ve nt or la b orat or y test res ult a b n or malit y, wit h a ti me relati o ns hi p t o 
st u d y dr u g a d mi nistrati o n t hat ma kes a relati o ns hi p i m pr o ba ble; disease or ot her dr u gs, 
c he micals or u n derl yi n g disease pr o vi de pla usi ble e x pla nati o ns.
o
P ossi bl y  rel ate d :  E ve nt  or  la b orat or y  test  res ult  a b n or malit y  wit h  a  reas o na ble  ti me 
relati o ns hi p t o st u d y dr u g a d mi nistrati o n; c o ul d als o be e x plai ne d b y u n derl yi n g disease 
or ot her dr u gs or c he micals; i nf or mati o n o n dr u g wit h dra wal ma y be lac ki n g or u nclear.
o
Rel ate d : E ve nt or la b orat or y test res ult a b n or malit y wit h a reas o na ble ti me relati o ns hi p 
t o st u d y dr u g a d mi nistrati o n, u nli kel y t o be attri b ute d t o u n derl yi n g disease or ot her dr u gs 
or c he micals; res p o nse t o wit h dra wal cli nicall y reas o na ble ( p ositi ve dec halle n ge).
P ossi bl y relate d a n d relate d ter ms will be c o nsi dere d “relate d” f or re p orti n g p ur p oses. If t he 
e ve nts are assesse d as u nli kel y relate d or n ot relate d t o t he s us pect I M P, t he e ve nt d oes n ot 
q ualif y f or re p orti n g p ur p oses. I n t he a bse nce of i nf or mati o n o n ca usalit y fr o m t he re p orti n g 
I n vesti gat or, 
 will i m me diatel y c o ntact t he re p orti n g I n vesti gat or t o re q uest a 
ca usalit y assess me nt. T he case will be u p date d wit h t he f oll o w- u p i nf or mati o n a n d re p orte d 
acc or di n gl y. If n o ca usalit y is pr o vi de d b y t he I n vesti gat or, t he S p o ns or assess me nt will be 
c o nsi dere d f or s u b missi o n p ur p oses.

T he o utc o me of t he e ve nt will be descri be d as:
o
Rec o vere d/res ol ve d
o
Rec o veri n g/res ol vi n g
o
Rec o vere d/res ol ve d wit h se q uelae
o
N ot rec o vere d/ n ot res ol ve d
o
Fatal
o
U n k n o w n

T he acti o n ta ke n o n t he st u d y dr u g will be ca pt ure d as:
P P D


Cli nic al Tri al M- 1 7 9 2 3- 3 0
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o
Dr u g wit h dra w n
o
N ot a p plica ble
A Es will be c ollecte d o nl y o nce wit h its ma xi m u m se verit y, e xce pt w he n t he A E starte d bef ore 
first I M P a d mi nistrati o n, persiste d after it a n d w orse ne d i n se verit y a n y ti me after first I M P 
a d mi nistrati o n. I n t his latter case, t he A E will be c ollecte d wit h eac h res pecti ve se verit y. T he 
A E ter m rec or de d m ust be e xactl y t he sa me i n t he differe nt ti me p oi nts w here A E is re p orte d 
i n t he e C R F.
1 0. 6. 3  
Rec or di n g of A d verse E ve nts
A Es will be c ollecte d fr o m t he si g nat ure of t he I C F/I A F u p t o 1 8 wee ks after last st u d y dr u g 
a d mi nistrati o n. A n y A E re p orte d b y t he patie nt fr o m t he last trial c o ntact (f oll o w- u p tele p h o ne 
c o ntact or visit) u ntil Wee k 6 8, s h o ul d be c ollecte d i n t he e C R F.
Me dical dis or ders prese nt at t he ti me t he patie nt si g ns t he I C F/I A F t hat are part of t he patie nt’s 
me dical hist or y will o nl y be c o nsi dere d A Es if t he y w orse n after t his ti me.
A b n or malities  detecte d  bef ore  I M P  a d mi nistrati o n  d uri n g  p h ysical  e xa mi nati o n,  la b orat or y 
tests, or ot her safet y assess me nts will n ot be c o nsi dere d A Es if alrea d y k n o w n as part of t he 
me dical hist or y or i n relati o n t o pri or me dical c o n diti o ns a n d will be rec or de d o n t he e C R F or 
case  re p ort  f or m  me dical  hist or y/ p h ysical  e xa mi nati o n  f or m/ pa ge.  H o we ver,  a b n or malities 
detecte d i n Scree ni n g/ Baseli ne tests t hat are n ot part of t he patie nt’s me dical hist or y will be 
c o nsi dere d A Es.
A b n or malities  ( ne wl y  occ urri n g  or  w orse ni n g  of  pre vi o usl y  k n o w n  a b n or malities)  detecte d 
after  I M P  a d mi nistrati o n  d uri n g  p h ysical  e xa mi nati o n,  la b orat or y  tests,  or  ot her  safet y 
assess me nts,  t hat  are  c o nsi dere d  cli nicall y  rele va nt  b y  t he  I n vesti gat or,  t hat  re q uire  a n 
i nter ve nti o n or a dia g n ostic test, or ma y res ult i n I M P disc o nti n uati o n s h o ul d be re p orte d as 
A Es.
Re p orte d  ter ms  s h o ul d  acc uratel y  c haracterise  t he  A E.  W he n  a  patie nt  e x perie nces  a n 
u ns pecifie d i nj ur y or si g ns a n d s y m pt o ms, a n acti ve i n vesti gati o n s h o ul d be c o n d ucte d t o reac h 
a fi nal dia g n osis. Disease dia g n osis w o ul d be t he preferre d re p orte d ter m.
A Es will be elicite d b y as ki n g t he patie nts n o n-lea di n g q uesti o ns (e g, " H o w d o/ di d y o u feel?) 
a n d b y c ollecti n g A Es s p o nta ne o usl y, as re p orte d b y t he patie nt t o t he I n vesti gat or or desi g nee.
All A Es elicite d b y t he I n vesti gat or d uri n g t he defi ne d A E c ollecti o n peri o d m ust be rec or de d 
o n t he e C R F. I n a d diti o n, w he n a n A E meets t he criteria of seri o us ness (ie, it is a n S A E), it 
m ust als o be rec or de d o n t he S A E f or m a n d re p orte d f oll o wi n g t he defi ne d ti meli nes i n Secti o n  
1 0. 6. 4 .
1 0. 6. 4  
Re p orti n g of Seri o us A d verse E ve nts
Seri o us a d verse e ve nts will be c ollecte d fr o m si g nat ure of I C F/I A F u p t o 1 8 wee ks after last 
st u d y dr u g a d mi nistrati o n.
T he I n vesti gat or m ust re p ort a n y S A E wit hi n 2 4 h o urs fr o m t he m o me nt s he/ he first lear ns of 
it t o t he S p o ns or/
 p har mac o vi gila nce u nit o n a S A E re p ort f or m. T his re p orti n g 
will ta ke place re gar dless of w het her t he I n vesti gat or c o nsi ders t he e ve nt t o be ca usall y relate d 
P P D


Cli nic al Tri al M- 1 7 9 2 3- 3 0
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S R D- 0 0 0 2 1 7 8 v 5. 0
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t o  t he  I M P(s),  t o  a n y  ot her  me dici nal  pr o d uct(s),  t o  t he  cli nical  trial  pr oce d ure,  or  t o  a n y 
i nter ve nti o n u n der g o ne b y t he patie nt.
Ori gi nal re p orts are t o be ke pt b y t he I n vesti gat or i n t he I n vesti gat or’s file.
T he trial ce ntre m ust tra ns mit t he S A E re p ort f or m a n d pre g na nc y f or m t o t he f oll o wi n g S A E 
e mail or fa x n u m ber: dr u g.s afet y.ser vices @ al mir all.c o m or + 3 4 9 3 2 9 1 2 8 2 9
C o ntact details a n d s pecific i nstr ucti o ns o n t he fl o w of t he S A E will be pr o vi de d t o all sites b y 
t he C R O.
T he mi ni m u m i nf or mati o n t hat m ust be i ncl u de d i n t he i nitial re p ort is:

A n e ve nt meeti n g t he criteria of S A E

A q ualifia ble re p orter, defi ne d as a n I n vesti gat or of t his trial or his/ her dele gate

A q ualifie d patie nt, defi ne d as a patie nt w h o has c o nse nte d t o partici pate i n t his trial

A s us pect me dici nal pr o d uct

T he I n vesti gat or’s ca usalit y assess me nt
U nless  t he  S A E  has  bee n  s ufficie ntl y  d oc u me nte d  i n  t he  i nitial  re p ort,  t he  I n vesti gat or  will 
pr o vi de  all  a vaila ble  a d diti o nal  i nf or mati o n  i n  f oll o w- u p  re p orts  b y  usi n g  a  ne w  f or m  a n d 
a d heri n g t o t he sa me r o uti n g a n d ti me fra mes as defi ne d f or t he i nitial re p ort. T his pr ocess will 
be c o nti n ue d u ntil t he e ve nt has bee n f ull y d oc u me nte d a n d re p orte d.
A n e ve nt re p orte d t o t he S p o ns or/
 p har mac o vi gila nce u nit t hat d oes n ot meet t he 
S A E criteria s hall be n ullifie d b y t he I n vesti gat or b y f or war di n g a f oll o w- u p re p ort.
A re g ulat or y re p ort of t he S A E ( de pe n di n g o n t he l ocal re q uire me nts) will be pr o d uce d b y t he 
S p o ns or/
 p har mac o vi gila nce u nit a n d s u b mitte d t o t he C o m pete nt A ut h orities, 
I E C, a n d/ or I n vesti gat ors, w he n a p plica ble acc or di n g t o l ocal re g ulati o ns.
S A Es N O T c o nsi dere d re p orta ble t o t he S p o ns or will be:

H os pitalisati o n f or a treat me nt/s ur gical pr oce d ure t hat was electi ve or pre- pla n ne d f or 
a pre-e xisti n g c o n diti o n t hat di d n ot w orse n d uri n g t he partici pati o n i n t he trial

E ve nts t hat res ult i n h os pital sta ys f or o bser vati o n of < 2 4 h o urs a n d t hat d o n ot re q uire 
a t hera pe utic i nter ve nti o n/treat me nt (e g, a n e mer ge nc y r o o m visit f or hae mat uria t hat 
res ults i n a dia g n osis of c ystitis a n d disc har ge t o h o me o n oral a nti bi otics)
1 0. 6. 5 
S us pecte d U ne x pecte d Seri o us A d verse Re acti o ns
A Es t hat meet all of t he f oll o wi n g criteria will be classifie d as s us pecte d u ne x pecte d seri o us 
a d verse  reacti o ns  ( S U S A Rs)  a n d  re p orte d  t o  t he  a p pr o priate  re g ulat or y  a ut h orities  i n 
acc or da nce wit h a p plica ble re g ulat or y re q uire me nts f or e x pe dite d re p orti n g:

seri o us

u ne x pecte d (ie, t he e ve nt is n ot c o nsiste nt wit h t he safet y i nf or mati o n)

t here is at least a reas o na ble p ossi bilit y t hat t here is a ca usal relati o ns hi p bet wee n t he 
e ve nt a n d t he st u d y treat me nt
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The Investigator will assess whether an event is causally related to study treatment. The 
Sponsor (or designee) will consider the Investigator’s assessment and determine whether the 
event meets the criteria for being reportable as a 7-day or 15-day safety report. SUSARs that 
are fatal or life-threatening must be reported to the regulatory authorities and the IEC (where 
required) within 7 days after the Sponsor (or designee) has first knowledge of them, with a 
follow-up report submitted within a further 8 calendar days. Other SUSARs must be reported 
to the relevant regulatory authorities and the IECs within 15 calendar days after the Sponsor 
(or designee) first has knowledge of them.
The Sponsor (or designee) is responsible for reporting SUSARs and any other events required 
to be reported in an expedited manner to the regulatory authorities and for informing 
Investigators of reportable events, in compliance with applicable regulatory requirements 
within specific timeframes. Investigators will notify the relevant IECs of reportable events 
within the applicable timeframes.
10.6.6
Follow-up of Adverse events/Serious Adverse Events
All AEs/SAEs that are still present after the last study drug administration (including AEs that 
have led to premature discontinuation), will be followed-up for at least 2 weeks after the last 
study drug administration for AEs and 4 weeks after the last study drug administration for 
SAEs, unless otherwise specified in the protocol, by means of a follow-up contact or visit 
(whichever is considered more appropriate by the Investigator). SAEs and non-serious AEs of 
special interest, will be followed until the event is resolved, stabilised, otherwise explained, or 
the participant is lost to follow-up. AEs still ongoing after that time point, will be evaluated by 
the Investigator and treated and followed until the symptom(s) return to normal or to clinically 
acceptable levels, as judged by the Investigator. The same timeframes will apply for AEs from 
Screening failures that are ongoing at the time the patient is withdrawn from the trial.
Additional safety data collected after the follow-up contact/visit to follow-up the ongoing AE 
will not be included in the clinical database, if this was already locked; therefore, the clinical 
database lock will not be delayed because of this situation. Any SAE will be followed up if 
needed after clinical database lock and the information will be only stored in the safety 
database.
10.6.7
Overdose
If an overdose (defined as any dose higher than doses described in this protocol) leads to an 
AE, the AE will be recorded in the eCRF.
In addition, if the overdose leads to an AE meeting the criteria of seriousness (ie, an SAE), the 
SAE form will be completed with all the available information and reported within the same 
timeframe and following the same routing as for a SAE (see Section 10.6.4). The patient must 
be followed up and the Investigator will make every effort to obtain information on how the 
overdose was managed, any treatment administered and the final outcome. This follow-up 
information will be reported, following the same procedure and timeframes as for the initial 
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1 0. 6. 8 
Pre g n a ncies
I n vesti gat ors  m ust  i nstr uct  fe male  patie nts  t o  i nf or m  t he m  i m me diatel y  if  t he y  bec o me 
pre g na nt d uri n g t he trial a n d u p t o 1 8 wee ks after last I M P d ose.
I n  case  of  pre g na nc y  d uri n g  t he  partici pati o n  i n  t he  trial,  t he  patie nt  will  be  i m me diatel y 
c o nsi dere d f or pre mat ure disc o nti n uati o n.
All pre g na ncies be gi n ni n g d uri n g t he patie nt’s partici pati o n i n t he trial or u p t o 1 8 wee ks after 
last I M P a d mi nistrati o n, w hic h c o me t o t he k n o wle d ge of t he I n vesti gat or, after t he cli nical 
trial  ter mi nati o n  will  be  re p orte d  t o  t he  S p o ns or/
  p har mac o vi gila nce  u nit  as 
t hr o u g h o ut t he trial.
T he  I n vesti gat or  m ust  c o m plete  a  st u d y-s pecific  pre g na nc y  f or m  u p o n  c o nfir mati o n  of  a 
pre g na nc y a n d se n d it t o t he S p o ns or/
 p har mac o vi gila nce u nit wit hi n 2 4 h o urs 
of  c o nfir mati o n  of  t he  pre g na nc y.  Pre g na nc y  is  n ot  itself  a n  A E  or  S A E;  h o we ver, 
mater nal/fetal c o m plicati o ns or a b n or malities will be rec or de d as A Es or S A Es, as a p pr o priate.
T he  I n vesti gat or  will  f oll o w  t he  pre g na nc y  u ntil  c o m pleti o n  or  u ntil  pre g na nc y  ter mi nati o n 
a n d, i n t he case of a li ve- b or n offs pri n g, t he f oll o w- u p peri o d will be dee me d t o ha ve e n de d 
w he n  t he  healt h  stat us  of  t he  c hil d  has  bee n  deter mi ne d  o n  its  birt h  or  after  a n  a p pr o priate 
peri o d  p ost- deli ver y  c o nsi dere d  necessar y  t o  m o nit or  t he  de vel o p me nt  of  t he  ne w- b or n  is 
c o m plete d.
T he s u bject will be as ke d t o pr o vi de i nf or mati o n o n t he o utc o me of t he pre g na nc y, i ncl u di n g 
pre mat ure ter mi nati o n s h o ul d t he case arise. S p o nta ne o us miscarria ge, de vel o p me ntal dela y, 
fetal  deat h,  S A E  i n  a  ne o nate  a n d  c o n ge nital  a b n or malities  will  be  re p orte d  as  S A Es.  T he 
I n vesti gat or will i nf or m t he S p o ns or/
 p har mac o vi gila nce u nit of t he o utc o me as 
a f oll o w- u p t o t he i nitial pre g na nc y f or m. All pre g na ncies s h o ul d be re p orte d t o t he S p o ns or 
a n d, w he n a p plica ble, t o t he et hics c o m mittee.
All pre g na ncies i n t he fe male part ners of male s u bjects recei vi n g at least o ne a d mi nistrati o n of 
t he st u d y dr u g will be rec or de d fr o m first d ose t o 1 8 wee ks after last I M P d ose. I n vesti gat ors 
m ust  i nstr uct  male  s u bjects  t o  i nf or m  t he m  i m me diatel y  if  t heir  fe male  part ner  bec o mes 
pre g na nt d uri n g t he trial a n d u p t o 1 8 wee ks after last I M P d ose.
1 0. 6. 9  
U n bli n di n g f or S afet y Re as o ns
F or a n y u n bli n di n g d o ne b y I n vesti gat or, please refer t o  Secti o n 9. 8.
Acc or di n g t o p har mac o vi gila nce le gislati o n t he S p o ns or’s C or p orate Dr u g Safet y De part me nt 
ca n  brea k  t he  bli n d  of  s pecific  patie nt  f or  re g ulat or y  re p orti n g  p ur p oses  (ie,  s us pecte d 
u ne x pecte d seri o us a d verse reacti o n [ S U S A R] case). U n bli n di n g will be d o ne acc or di n g t o t he 
a p plica ble S O P.
1 0. 6. 1 0 Pr o d uct C o m pl ai nts
A pr o d uct c o m plai nt is a n y writte n, electr o nic, or oral c o m m u nicati o n t hat alle ges deficie ncies 
relate d t o t he i de ntit y, q ualit y, d ura bilit y, relia bilit y, safet y, effecti ve ness or perf or ma nce of a 
trial  i nter ve nti o n.  T he  S p o ns or  c ollects  pr o d uct  c o m plai nts  o n  i n vesti gati o nal  pr o d ucts  a n d 
dr u g deli ver y s yste ms use d i n cli nical st u dies i n or der t o e ns ure t he safet y of st u d y partici pa nts, 
P P D
P P D
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m o nit or  q ualit y,  a n d  t o  facilitate  pr ocess  a n d  pr o d uct  i m pr o ve me nts.  Partici pa nts  will  be 
i nstr ucte d t o c o ntact t he I n vesti gat or as s o o n as p ossi ble if he or s he has a c o m plai nt or pr o ble m 
wit h t he i n vesti gati o nal pr o d uct or dr u g deli ver y s yste m s o t hat t he sit uati o n ca n be assesse d.
Ti me Peri o d f or Detecti n g Pr o d uct C o m pl ai nts:

Pr o d uct c o m plai nts t hat res ult i n a n a d verse e ve nt will be detecte d, d oc u me nte d, a n d 
re p orte d t o t he S p o ns or d uri n g all peri o ds of t he st u d y i n w hic h t he dr u g is use d.

If t he I n vesti gat or lear ns of a n y pr o d uct c o m plai nt at a n y ti me after a partici pa nt has 
bee n disc har ge d fr o m t he st u d y, a n d s uc h i nci de nt is c o nsi dere d reas o na bl y relate d t o a 
dr u g pr o vi de d f or t he st u d y, t he I n vesti gat or will pr o m ptl y n otif y t he S p o ns or.
Pr o m pt Re p orti n g of Pr o d uct C o m pl ai nts t o S p o ns or:

Pr o d uct  c o m plai nts  will  be  re p orte d  t o  t he  S p o ns or  wit hi n  2 4  h o urs  after  t he 
I n vesti gat or bec o mes a ware of t he c o m plai nt.

T he Pr o d uct C o m plai nt F or m will be se nt t o t he S p o ns or.
F oll o w- u p of Pr o d uct C o m pl ai nts:

F oll o w- u p  a p plies  t o  all  partici pa nts,  i ncl u di n g  t h ose  w h o  disc o nti n ue  st u d y 
i nter ve nti o n.

T he I n vesti gat or is res p o nsi ble f or e ns uri n g t hat f oll o w- u p i ncl u des a n y s u p ple me ntal 
i n vesti gati o ns  as  i n dicate d  t o  el uci date  t he  nat ure  a n d/ or  ca usalit y  of  t he  pr o d uct 
c o m plai nt.

Ne w or u p date d i nf or mati o n will be rec or de d o n t he ori gi nall y c o m plete d f or m wit h all 
c ha n ges si g ne d a n d date d b y t he I n vesti gat or a n d s u b mitte d t o t he S p o ns or
1 0. 7  
Ot her Assess me nts
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All e n d p oi nts descri be d i n Secti o n 6  will als o be a nal yse d b y pre vi o us e x p os ure t o d u pil u ma b 
( Yes/ N o) as
1 1. 3  A n al ysis P o p ul ati o ns
T he f oll o wi n g a nal ysis sets are defi ne d:

T he F ull A nal ysis Set ( F A S) i ncl u des all ra n d o mise d patie nts. Patie nts will be a nal yse d 
u n der t he treat me nt gr o u p as ra n d o mise d.

T he Per Pr ot oc ol A nal ysis Set ( P P S) i ncl u des all ra n d o mise d patie nts w h o recei ve at 
least o ne d ose of t he st u d y dr u g, ha ve at least o ne p ost- Baseli ne E A SI assess me nt, a n d 
a d diti o nall y f or w h o m t here are n o i m p orta nt pr ot oc ol de viati o ns affecti n g efficac y at 
Wee k 1 6. Patie nts will be a nal yse d u n der t he treat me nt gr o u p as ra n d o mise d.

T he Safet y A nal ysis Set ( S A F) i ncl u des all ra n d o mise d patie nts w h o recei ve at least 
1 d ose of t he st u d y dr u g. Patie nts will be a nal yse d u n der t he treat me nt gr o u p act uall y 
recei ve d.
T he precise reas o ns f or e xcl u di n g patie nts fr o m t he P P S p o p ulati o n, a n d ot her pre- defi ne d data 
ha n dli n g iss ues will be f ull y defi ne d a n d d oc u me nte d i n t he c orres p o n di n g Bli n d Data Re vie w 
Meeti n g ( B D R M) re p orts, fi nalise d bef ore u n bli n di n g of t he st u d y.
T he mai n a nal ysis of all t he efficac y varia bles will be perf or me d o n t he F A S p o p ulati o n. T he 
pri mar y a n d ke y sec o n dar y efficac y varia bles will als o be a nal yse d f or t he o verall p o p ulati o n 
usi n g t he P P S p o p ulati o n t o assess t he r o b ust ness of t he fi n di n gs fr o m t he F A S p o p ulati o n. All 
safet y a nal yses will be c o n d ucte d usi n g t he S A F p o p ulati o n.
1 1. 4  
Descri pti ve St atistics
S u m mar y statistics will be prese nte d b y st u d y peri o d a n d treat me nt gr o u p. T he I n d ucti o n a n d 
Mai nte na nce  Peri o ds  will  be  re p orte d  se paratel y.  Cate g orical  varia bles  will  be  s u m marise d 
wit h c o u nts ( n) a n d perce nta ges ( %) a n d will be ta b ulate d b y treat me nt a n d/ or o verall w here 
a p pr o priate.  F or  c o nti n u o us  varia bles,  t he  n u m ber  of  n o n- missi n g  o bser vati o ns  ( n),  mea n, 
sta n dar d de viati o n, sta n dar d err or of t he mea n, me dia n, first a n d t hir d q uartiles, mi ni m u m a n d 
ma xi m u m  will  be  ta b ulate d  b y  treat me nt  a n d/ or  o verall.  W he n  a p plica ble,  t hese  s u m maries 
will be pr o vi de d b y visit a n d ti me p oi nt of assess me nt. T he 9 5 % CI ar o u n d t he mea n ma y als o 
be prese nte d i n descri pti ve statistics as a p pr o priate f or s pecific e n d p oi nts of i nterest.
1 1. 5 
P atie nt Dis p ositi o n
T he n u m ber of patie nts i ncl u de d i n eac h a nal ysis set a n d t he reas o ns f or disc o nti n uati o n will 
be s u m marise d usi n g descri pti ve statistics b y st u d y peri o d a n d treat me nt gr o u p. I n a d diti o n, 
patie nts’ stat us wit h re gar d t o st u d y treat me nt wit hi n eac h st u d y peri o d a n d f oll o w- u p will als o 
be s u m marise d b y st u d y peri o d a n d treat me nt gr o u p. S u m maries of dis p ositi o n will be base d 
o n all patie nts e nr olle d, re gar dless of ra n d o misati o n.
1 1. 6  
De m o gr a p hic a n d B aseli ne C h ar acteristics
T he trial p o p ulati o n will be descri be d usi n g de m o gra p hic a n d baseli ne c haracteristics rec or de d 
d uri n g  bef ore  t he  first  st u d y  dr u g  a d mi nistrati o n.  A nal yses  of  de m o gra p hic  a n d  baseli ne 
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c haracteristics  will  be  base d  o n  t he  F A S;  a d diti o nal  p o p ulati o ns  ma y  be  a nal yse d  as 
a p pr o priate.
A p pr o priate  descri pti ve  statistics  acc or di n g  t o Secti o n  1 1. 4   will  be  use d  t o  s u m marise 
de m o gra p hic a n d Baseli ne c haracteristics, i ncl u di n g b ut n ot li mite d t o se x, a ge, re gi o n, race, 
hei g ht,  wei g ht,  b o d y  mass  i n de x  ( B MI),  s ki n  t y pe  ( Fitz patric k  scale 3) a n d  pri or  use  of 
d u pil u ma b. F or stratificati o n fact ors, b ot h t he fact or as ra n d o mise d a n d t he act ual fact or will 
be  s u m marise d,  if  differe nces  e xist.  Me dical  hist or y  i nf or mati o n  will  be  prese nte d  i n  a 
b y- patie nt listi n g. N o statistical tests will be perf or me d. F ull details of t he s u m maries t o be 
pr o d uce d will be pr o vi de d i n t he S A P.
1 1. 7 
E n d p oi nts
See Secti o n 6 f or t he f ull list of o bjecti ves a n d st u d y e n d p oi nts. Descri pti o ns of t he esti ma n ds 
f or t he st u d y are i ncl u de d i n Secti o n 1 1. 8. 1. 1 .
1 1. 8 
St atistic al Met h o ds
T he  statistical  a p pr oac h  f or  t he  a nal ysis  of  pri mar y  a n d  sec o n dar y  efficac y  e n d p oi nts  is 
descri be d  bel o w.  T he  f ull  statistical  met h o d ol o g y  t o  be  a p plie d  f or  pri mar y  a n d  sec o n dar y 
e n d p oi nts, a n d a d diti o nal e n d p oi nts will be detaile d i n t he S A P.
As disc usse d i n Secti o n 7. 1 , st u d y res ults will be deli vere d i n 2 parts: t he first res ults deli ver y 
will be pr o vi de d after t he first data base l oc k, o nce all patie nts ha ve c o m plete d t he I n d ucti o n 
Peri o d or disc o nti n ue d st u d y bef ore t his p oi nt, a n d t he sec o n d res ults deli ver y will be pr o vi de d 
after  sec o n d  data base  l oc k,  at  t he  E O S,  o nce  all  patie nts  ha ve  c o m plete d  t he  st u d y,  or 
disc o nti n ue d  bef ore  E O S.  T he  first  a nal ysis  will  re p ort  t he  I n d ucti o n  Peri o d  o nl y,  a n d  t he 
sec o n d a nal ysis will re p ort all data u p t o E O S.
1 1. 8. 1  
A n al ysis of Effic ac y
T he pri mar y a nal yses f or efficac y will be base d o n t he F A S. F urt her m ore, t he pri mar y a n d  ke y 
sec o n dar y  efficac y  varia bles  will  be  als o  a nal yse d  f or  t he  o verall  p o p ulati o n  usi n g  t he  P P S 
p o p ulati o n  t o  assess  t he  r o b ust ness  of  t he  fi n di n gs  fr o m  t he  F A S  p o p ulati o n.  Refer  t o 
Secti o n 1 1. 3  f or details of t he s pecific a nal yses t o be c o n d ucte d u n der t he P P S p o p ulati o n. As 
, all efficac y e n d p oi nts will be a nal yse d as well b y pre vi o us e x p os ure t o d u pil u ma b 
( Yes/ N o).
1 1. 8. 1. 1 Pri m ar y Effic ac y A n al ysis ( O ver all P o p ul ati o n)
A. Pri m ar y a n d Ke y Sec o n d ar y Effic ac y E n d p oi nts
T he pri mar y efficac y a nal ysis will be base d o n t he mai n esti ma n d f or t he o verall p o p ulati o n 
( F A S).  T he  o bjecti ves,  varia bles  a n d  p o p ulati o n-le vel  s u m mar y  meas ures  f or  t he  mai n 
esti ma n d f or t he pri mar y efficac y e n d p oi nt a n d ke y sec o n dar y e n d p oi nts is pr o vi de d i n Ta ble 9 .
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Table 9.
Main Estimand for Primary and Key Secondary Efficacy Analyses
Objectives/Treatment 
Condition of Interest
Variable/Outcome Assessed
Population-Level Summary 
Measure
To evaluate the efficacy of 
lebrikizumab compared with 
placebo in patients not 
adequately controlled with 
cyclosporine or for whom 
cyclosporine is not medically 
advisable up to Week 16 (ie, 
at the end of the Induction 
Period).
Title: EASI 75, IGA(0/1) and 
2pt improvement, 4pt 
improvement in Pruritus NRS 
Description: Patient 
achieving: EASI 75: ≥75% 
reduction in EASI score from 
Baseline, IGA: IGA score of 0 
or 1 with 2pt improvement 
from Baseline, Pruritus NRS: 
4pt improvement from 
Baseline
Time Frame: 16 weeks 
Population: Adult and Adolescent 
Patients with Moderate-To-Severe 
AD that are not Adequately 
Controlled with Cyclosporine or for 
whom Cyclosporine is not Medically 
Advisable.
Measure: Difference between 
treatments (lebrikizumab minus 
placebo) in proportion of subjects 
achieving EASI 75, IGA criteria, 
pruritus NRS criteria at Week 16
Abbreviations: AD = atopic dermatitis; EASI = Eczema Area and Severity Index (score).
Intercurrent Events (ICEs) for the Primary and Key Efficacy Endpoints:
The following ICEs are envisioned during the study, to be considered up to and including the 
Week 16 assessment:
a) ICE1: Patient prematurely discontinues study treatment due to reasons other than lack 
of efficacy prior to Week 16.
b) ICE2: Patient prematurely discontinues study treatment due to lack of efficacy prior to 
Week 16.
c) ICE3: Patient receives rescue medication prior to Week 16 (either allowed or 
prohibited) for treatment of AD, as per Section 9.9.
Further ICEs may be added as appropriate, for example to describe the effects of COVID on 
the response observed if applicable. The full list of ICEs will be detailed in the SAP.
For supportive analyses, a second estimand will be used.
The ICEs will be handled using the following approaches to be applied under the main and 
second estimands (Table 10):
Table 10.
Handling of ICEs for the Primary Efficacy Endpoint and Key 
Secondary Endpoints (for the Main and Second Estimands)
Analysis Strategy for ICEs
Treatment Discontinuation due to:
Estimand
ICE1: Reasons Other 
than Lack of Efficacy
ICE2: Lack of 
Efficacy
ICE3: Rescue or 
Prohibited Meds for 
Treatment of AD
Main Estimand 
(Hybrid)
Hypothetical Strategy: 
Set to missing
Composite Strategy: 
Set to baseline
Composite Strategy: 
Set to baseline


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Analysis Strategy for ICEs
Treatment Discontinuation due to:
Estimand
ICE1: Reasons Other 
than Lack of Efficacy
ICE2: Lack of 
Efficacy
ICE3: Rescue or 
Prohibited Meds for 
Treatment of AD
Second Estimand: 
Categorical Endpoints 
(Composite)
Composite Strategy: 
Set to non-responder
Composite Strategy: 
Set to non-responder
Composite Strategy: 
Set to non-responder
Abbreviations: AD = atopic dermatitis; ICE = intercurrent event.
Details on missing data imputation are described in Section 11.10. 

Main Estimand (Hybrid):
o
The approach for the main estimand is a hybrid estimand representing the 
primary clinical question of interest: what is the difference between treatment 
conditions, ie, Lebrikizumab vs Placebo, in the target patient population, in 
successful responses after 16 weeks achieved without use of rescue medication 
and if all patients continued with treatment except those who discontinued due 
to lack of efficacy?

Second Estimand:
o
The second estimand for categorical endpoints is a composite estimand 
representing the supportive clinical question of interest: what is the difference 
between treatment conditions in the target patient population, in successful 
responses after 16 weeks achieved without use of rescue medication or 
treatment discontinuation?
The complementary estimand approach here allows for an estimate of the effects of the 
different events to be ascertained.
Statistical Hypotheses:
The statistical hypotheses to be tested for the main estimand are:

H0: PLebrikizumab – Pplacebo = 0

H1: PLebrikizumab – Pplacebo ≠ 0,
where PLebrikizumab refers to the proportion of patients receiving lebrikizumab, and Pplacebo refers 
to the proportion of patients receiving placebo that achieve EASI 75 at Week 16. The testing 
procedure will thus be 2-sided. Confirmatory testing is conducted using the main estimand.
Analysis Model:
The primary and key secondary endpoints (for the main and second estimands) will be analysed 
by means of a Cochran-Mantel-Haenszel (CMH) model adjusted by country, age 
(adolescents/adults), prior use of dupilumab (yes/no), and baseline severity of disease 
(IGA=3/IGA=4). The FAS will be the primary analysis set; if the model does not converge, 
country will be removed as an adjusting factor. The estimate of the adjusted common risk 
difference, with corresponding Mantel-Haenszel-Sato (Sato 1989)58 adjusted 2-sided 95% CI 
and p-value will be presented. Additionally, the CMH adjusted odds ratio along with the 95% 
two-sided asymptotic CI will be presented. 


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For analyses using multiple imputation, the analysis will be conducted on the complete dataset, 
for each imputation separately. Modelled results will be combined using Rubin’s rule (PROC 
MIANALYZE) for tabulation.
Sensitivity Analysis for the Primary and Key Secondary Efficacy Endpoints:
The following sensitivity analysis will also be conducted for the main and second estimands 
of the primary and key secondary efficacy endpoints, on the overall population:
Table 11.
Sensitivity Analysis
Analysis Set
Modelling Method
Estimand and Data Handling
Sensitivity Analysis Conducted on Main and Second Estimands
PPS
CMH model adjusted by 
country, and stratification 
factors used in the 
randomisation (age, previous 
use of dupilumab, and baseline 
severity of disease, as per 
primary analysis).
As per main and second 
estimands
Abbreviations: CMH = Cochran-Mantel-Haenszel; PPS = Per Protocol Set.
Additional subgroup analyses based on baseline characteristics will be presented as appropriate 
using forest plots.
All inferential analyses of the primary and key secondary efficacy endpoints, including 
multiple imputation approaches, will be conducted during the Induction Period only (eg, up to 
and including Week 16). During the Maintenance Period, only descriptive analyses will be 
performed for efficacy. The handling of estimands as detailed above will also only apply up to 
and including Week 16. After this point, data will only be analysed as observed.
B. All Other Secondary and Other Efficacy Endpoints
All binary other secondary and other efficacy endpoints will be analysed using the same 
methodology as described above for the primary efficacy endpoint using only the main 
estimand. Sensitivity analyses based on the PPS population will not be conducted for these 
endpoints.
Continuous other secondary endpoints assessed at multiple post-Baseline visits during the 
Induction Period will be analysed on the following estimands (Table 12):
Table 12.
Handling of ICEs for the Continuous Secondary Efficacy and Other 
Efficacy Endpoints
Analysis Strategy for ICEs
Treatment Discontinuation due to:
Estimand
ICE1: Reasons Other 
than Lack of Efficacy
ICE2: Lack of 
Efficacy
ICE3: Rescue or 
Prohibited Meds for 
Treatment of AD
Main Estimand 
(Hybrid)
Hypothetical Strategy: 
Set to missing
Composite Strategy: 
Set to baseline
Composite Strategy: 
Set to baseline


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A n al ysis Str ate g y f or I C Es
Tre at me nt Disc o nti n u ati o n d ue t o:
Esti m a n d
I C E 1: Re as o ns Ot her 
t h a n L ac k of Effic ac y
I C E 2: L ac k of 
Effic ac y
I C E 3: Resc ue or 
Pr o hi bite d Me ds f or 
Tre at me nt of A D
Sec o n d Esti ma n d: 
C o nti n u o us E n d p oi nts 
( H y p ot hetical)
H y p ot hetical Strate g y: 
Set t o missi n g
H y p ot hetical Strate g y: 
Set t o missi n g
H y p ot hetical Strate g y: 
Set t o missi n g
– A b bre viati o n: I C E = i nterc urre nt e ve nt; A D = at o pic der matitis.
T he mai n a n d sec o n d esti ma n ds will be a nal yse d b y mea ns of a mi xe d effect m o del f or re peate d 
meas ures ( M M R M) i ncl u di n g t he baseli ne val ue as a c o variate, a n d a dj usti n g b y t he fact ors of 
c o u ntr y,  a ge  (a d olesce nts/a d ults),  baseli ne  se verit y  of  disease  (I G A = 3/I G A = 4),  pre vi o us 
e x p os ure  t o  d u pil u ma b  ( yes/ n o,  w he n  t he  o verall  p o p ulati o n  is  a nal yse d),  a n d  visit  a n d 
treat me nt- visit i nteracti o n. A restricte d ma xi m u m li keli h o o d met h o d will be s pecifie d, al o n g 
wit h a n u nstr uct ure d c o varia nce matri x. Esti mates of t he L S Mea ns f or eac h of t he 2 treat me nt 
gr o u ps at eac h visit u p t o a n d i ncl u di n g Wee k 1 6, al o n g wit h t he differe nce bet wee n treat me nts 
i n L S Mea ns, 2-si de d 9 5 % CI, a n d p- val ue f or t he differe nce will be prese nte d. 
Missi n g data will be ha n dle d as per Ta ble 1 3 .
F or all c o nti n u o us sec o n dar y efficac y e n d p oi nts descri be d a b o ve, i n case of n o n-c o n ver ge nce, 
t he c o u ntr y fact or will be re m o ve d fr o m t he m o del. 
Ti me-t o-e ve nt  ( T T E)  e n d p oi nts  will  be  a nal yse d  o n  t he  sec o n d  esti ma n d  f or  c o nti n u o us 
e n d p oi nts usi n g Ka pla n- Meier s ur vi val a nal ysis met h o ds. If a vaila ble, f or descri pti ve p ur p oses, 
t he esti mate of t he me dia n ti me-t o-e ve nt (i n wee ks) a n d t he 2-si de d 9 5 % CI will be prese nte d. 
A c o m paris o n of t he s ur vi val distri b uti o n c ur ves f or t he 2 treat me nt gr o u ps will be ma de b y 
mea ns of t he l o g-ra n k test. T he C o x pr o p orti o nal hazar ds m o del will be use d t o esti mate t he 
hazar d rati o a n d its 9 5 % CI of le bri kiz u ma b c o m pare d wit h place b o  at t he res pecti ve ti me p oi nt. 
T he  mai n  C o x  pr o p orti o nal  hazar ds  m o del  will  i ncl u de  treat me nt  gr o u p,  wit h  c o u ntr y,  a ge, 
baseli ne disease se verit y a n d pre vi o us e x p os ure t o d u pil u ma b ( w he n t he o verall p o p ulati o n is 
a nal yse d) as fact ors. T he pr o p orti o nal hazar d ass u m pti o n will be e val uate d o n all fact ors (ie, 
treat me nt a n d stratificati o n fact ors) b y gra p hical i ns pecti o n of t he Sc h oe nfel d resi d uals a n d b y 
Gra m bsc h a n d T her nea u test as well.  C o u ntr y ma y be re m o ve d fr o m t he m o del as a p pr o priate, 
si milar t o t he ot her a nal yses of efficac y. Beca use of t he fact t hat t he I n d ucti o n a n d Mai nte na nce 
Peri o ds will be re p orte d se paratel y, T T E e n d p oi nts will be a nal yse d at 2 se parate ti me p oi nts: 
i nitiall y u p t o a n d i ncl u di n g Wee k 1 6, a n d t he n se paratel y f or t he w h ole st u d y, i nc or p orati n g 
b ot h t he I n d ucti o n a n d Mai nte na nce Peri o ds.
All  efficac y  varia bles  f or  t he  Mai nte na nce  Peri o d  will  be  a nal yse d  b y  mea ns  of  descri pti ve 
statistics prese nte d b y treat me nt gr o u p as ra n d o mise d d uri n g t he I n d ucti o n Peri o d.
1 1. 8. 1. 2 S u b gr o u p  Effic ac y  A n al yses  ( D u pil u m a b  N aï ve  a n d  P atie nts 
Pre vi o usl y E x p ose d t o D u pil u m a b)
T he  sa me  a nal yses  descri be d  f or  t he  Pri mar y  efficac y  a nal yses  ( Secti o n  1 1. 8. 1. 1 )  will  be 
perf or me d i n eac h of t he t w o s u b gr o u ps descri be d, f or  
p ur p oses.
All efficac y varia bles f or t he Mai nte na nce Peri o d f or s u b gr o u p a nal yses will be a nal yse d b y 
mea ns of descri pti ve statistics prese nte d b y treat me nt gr o u p as ra n d o mise d d uri n g t he I n d ucti o n 
C CI


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Period, in the same way as for the primary and secondary efficacy analyses on the overall 
population.
11.8.2
Analysis of Quality of Life Endpoints
The Quality of Life (QoL) endpoints of Total DLQI and CDLQI will be analysed in the same 
way as the continuous other secondary efficacy endpoints occurring at multiple post-Baseline 
visits on the overall population.
DLQI-R, RECAP, TSQM-9, and WHO-5 will all be analysed descriptively on the overall 
population. Any individual components related to QoL scoring will also be analysed 
descriptively for the overall population.
All QoL endpoints and related individual components will also be analysed descriptively for 
the Maintenance Period, presented by treatment group as randomised during the Induction 
Period.
11.8.3
Analyses of Endpoints Related to the Secondary Objective (From 
Week 16 to Week 52)
All variables described in Table 3 from Section 6 will be analysed by means of descriptive 
statistics overall and separately, considering the arm where they were randomized during the 
induction period. More detailed description will be provided in the SAP.
11.8.4
Analysis of Safety and Tolerability Endpoints
The analyses of safety and tolerability outcomes will be performed on the SAF. Safety 
outcomes include AEs, vital signs (including body temperature, respiratory rate, pulse, and 
systolic and diastolic blood pressure), physical examinations (including application site 
reactions), and clinical laboratory assessments (haematology, chemistry panel, urine testing, 
and urine pregnancy test for WOCBP).
Baseline will be defined as the latest value before IMP administration on Day 1 of the study. 
In case of missing predose values, the value at Screening will be regarded as the Baseline value. 
For the follow-up visit the comparisons will be performed against Screening values.
Safety variables:

AEs will be summarised as an overall proportion of patients with at least one AE, 
proportion of patients with at least one SAE, proportion of patients with at least one 
severe AE, proportion of patients with at least one related AE, proportion of patients 
with at least one AE leading to treatment or study discontinuation. Each patient will 
contribute only once (eg, the first occurrence) to each of the rates, regardless of the 
number of occurrences (events) the subject experiences.

Treatment-emergent AEs will be summarised and tabulated by System Organ Class and 
PT, by severity (mild, moderate, severe), by seriousness, by action taken with the study 
drug (continued, interrupted or discontinued), by outcome (Recovered/resolved, 
Recovering/resolving, Recovered/resolved with sequelae, Not recovered/not resolved, 
Fatal, unknown), by relationship to study product (not related, unlikely related, possibly 
related, and related), and for AEs of clinical interest.


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
A n A E will be c o nsi dere d a T E A E if it was n ot prese nt bef ore t he first d ose of st u d y 
dr u g or was prese nt bef ore t he first d ose of st u d y dr u g b ut i ncrease d i n se verit y d uri n g 
t he treat me nt peri o d. A n y e ve nt wit h a missi n g o nset date will be i ncl u de d as a T E A E.

Deat hs a n d S A Es will be liste d b y s u bject.

Cli nical La b orat or y Tests: La b orat or y para meters will be s u m marise d usi n g descri pti ve 
statistics at Baseli ne a n d at eac h s u bse q ue nt pre- defi ne d ti me p oi nt b y treat me nt gr o u p. 
I n  a d diti o n,  s hift  ta bles  (ie,  l o w- n or mal- hi g h  at  Baseli ne  vers us  l o w- n or mal- hi g h  at 
f oll o w- u p  i n  a  3- b y- 3  c o nti n ge nc y  ta ble)  will  be  pr o vi de d  t o  assess  c ha n ges  i n 
la b orat or y val ues fr o m Baseli ne t o f oll o w- u p i n eac h treat me nt gr o u p a n d o verall.

Ot her Safet y Meas ures: Vital si g ns, p h ysical e xa mi nati o ns, l ocal s ki n reacti o ns, a n d, if 
a p plica ble,  A E SIs,  a n d  pre g na nc y  test  res ults  will  be  liste d  a n d  s u m marise d 
descri pti vel y .
Descri pti ve statistics will be use d t o s u m marise st u d y a n d treat me nt c o m plia nce.
Pri or a n d c o nc o mita nt me dicati o n i nf or mati o n will be prese nte d i n a b y- patie nt listi n g.
1 1. 9  
A n al ysis of Bi o m ar kers
1 1. 1 0  
H a n dli n g of Missi n g D at a
E ver y eff ort will be ma de t o pre ve nt patie nts wit h dra wi n g fr o m t he st u d y, a n d f or patie nts w h o 
per ma ne ntl y disc o nti n ue st u d y dr u g (a n d are n ot l ost t o f oll o w- u p), e ver y eff ort will be ma de 
t o c o nti n ue t o c ollect data after disc o nti n uati o n as o utli ne d i n Secti o n 8. 3. 2 . W here missi n g 
data e xist f or pri mar y a n d ke y sec o n dar y efficac y e n d p oi nts at a mi ni m u m, i m p utati o n will 
occ ur.
W here  t he  e n d p oi nt  is  a  bi nar y  or  cate g orical  o utc o me,  t he  i m p utati o n  will  occ ur  o n  t he 
bi nar y/cate g orical o utc o me. 
T he f oll o wi n g data i m p utati o n met h o ds will be e m pl o ye d:
T a ble 1 3.  
D at a I m p ut ati o n Met h o ds 
Esti m a n d
H a n dli n g Str ate g y: I m p ut ati o n
Pri m ar y a n d Ke y Sec o n d ar y Effic ac y E n d p oi nts
Mai n Esti ma n d

C o m p osite Strate g y: Set t o baseli ne ( B O C F)
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Estimand
Handling Strategy: Imputation

Hypothetical Strategy: Set to missing and impute with Markov Chain 
Monte-Carlo (MCMC) multiple imputation (MI)

Missing data not affected by ICE: MCMC MI
Second Estimand: 
Categorical Endpoints

Composite Strategy: Set to non-responder (NRI)

Missing data not affected by ICE: NRI
Other Secondary and Other Efficacy Endpoints
Estimand for 
Categorical Endpoints

As per main estimand for primary and key secondary efficacy 
endpoints
Main Estimand for 
Continuous Endpoints

As per main estimand for primary and key secondary efficacy 
endpoints
Second Estimand for 
Continuous Endpoints

Hypothetical strategy: Set to missing and do not impute (MMRM)

Missing data not affected by ICE: do not impute (MMRM)
Abbreviations: BOCF = Baseline-Observation-Carried-Forward; ICE = Intercurrent Event; MCMC = Markov-
Chain Monte-Carlo; MI = Multiple Imputation; NRI = Non-Responder Imputation; MMRM, Mixed Effect Model 
for Repeated Measures.
Where imputation occurs, imputation will be based on the overall population, and subsequent 
subgroup analyses (dupilumab naïve and previously exposed to dupilumab) will utilise these 
imputed data, selecting only the required patients for the analysis.
Where missing data are to be imputed for efficacy using the approaches above, a summary 
table by visit of the frequency and type of missing data will be presented.
The number of imputations and the seed to be used, plus any further details required, will be 
detailed in the SAP.
11.11
Multiplicity Strategy
No control for multiplicity between the primary and secondary variables will be taken into 
account. Please see Section 11.8.1.1 for the strategy of analysis for the primary and key 
secondary efficacy endpoints.
11.12
Interim Analysis
No interim analyses are planned.
12
Data Handling, Processing, and Record Keeping
The Investigator will conduct the trial in accordance with the protocol and International 
Council for Harmonisation (ICH) E6 GCP guidelines. In addition to the routine monitoring 
procedures, training records should be in place to ensure Investigators and CROs understand 
the data processing in any of the computerised systems to be used to ensure the confidence in 
the reliability, quality, and integrity of the patient data.
Sponsors, CROs, and other authorised personnel can view the trial data elements in the eCRF 
before and after the clinical Investigator(s) has electronically signed the completed eCRF. 
Reviewing trial data dynamically will allow early detection of trial-related problems (eg, safety 
concerns, protocol deviations) and problems with conducting the trial (eg, missing data, data 
discrepancies).
According to the eCRF entry guidelines, eCRFs must be completed for each patient by 
qualified and authorised personnel. Any data entry and corrections made on the eCRF must 


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ha ve a res pecti ve a u dit trail w here t he c orrecti o n is date d, t he i n di vi d ual ma ki n g t he c orrecti o n 
is i de ntifie d, t he reas o n f or t he c ha n ge is state d, a n d t he ori gi nal data are n ot o bsc ure d. O nl y 
data re q uire d b y t he pr ot oc ol f or t he p ur p oses of t he trial s h o ul d be c ollecte d.
A list of all a ut h orise d data ori gi nat ors (ie, pers o ns, s yste ms, de vices, a n d i nstr u me nts) s h o ul d 
be de vel o pe d a n d mai ntai ne d b y 
 a n d ma de a vaila ble at eac h cli nical site
T he e C R F is a n a u dita ble electr o nic rec or d of i nf or mati o n re p orte d t o t he S p o ns or o n eac h trial 
patie nt,  acc or di n g  t o  t his  cli nical  i n vesti gati o n  pr ot oc ol.  T he  e C R F  e na bles  cli nical 
i n vesti gati o n  data  t o  be  s yste maticall y  ca pt ure d,  re vie we d,  ma na ge d,  st ore d,  a nal yse d,  a n d 
re p orte d.
1 2. 1  
D at a C ollecti o n
1 2. 1. 1 
I de ntific ati o n of t he Tri al D at a S o urces
S o urce data i ncl u des all i nf or mati o n i n ori gi nal rec or ds a n d certifie d c o pies of ori gi nal rec or ds 
of  cli nical  fi n di n gs,  o bser vati o ns,  or  ot her  acti vities  i n  a  cli nical  i n vesti gati o n  use d  f or 
rec o nstr ucti n g a n d e val uati n g t he i n vesti gati o n.
W he n a de vice or i nstr u me nt is t he data ori gi nat or (e g, bl o o d press ure m o nit ori n g de vice or 
gl uc o meter)  a n d  data  are  a ut o maticall y  tra ns mitte d  directl y  t o  t he  e C R F,  t he  e C R F  is  t he 
s o urce.
Access t o s o urce data is critical t o t he re vie w a n d i ns pecti o ns of cli nical i n vesti gati o ns. S o urce 
data s h o ul d be attri b uta ble, le gi ble, c o nte m p ora ne o us, ori gi nal, acc urate, c o m plete, c o nsiste nt, 
e n d uri n g,  a n d  a vaila ble  ( A L C O A +)  a n d  m ust  meet  t he  re g ulat or y  re q uire me nts  f or 
rec or d kee pi n g.
T he trial data s o urces are o utli ne d bel o w:

Si g ne d I C Fs/I A Fs

Patie nt me dical rec or ds will i ncl u de: A D dia g n osis a n d i ncl usi o n/e xcl usi o n criteria 
a ge, ge n der, p h ysical e xa mi nati o n, pre vi o us me dicati o n, ori gi nal or certifie d c o p y of a 
la b orat or y re p orts, i nstr u me nt pri nt o ut, trial pr o gress n otes of t he p h ysicia n, reas o n f or 
wit h dra wal, d ose, c o ntrace pti o n met h o ds, c ha n ge i n c hil d beari n g p ote ntial)

Efficac y assess me nts - Cli nical si g ns: E A SI, I G A, B S A; Cli nical si g ns a n d Patie nt 
Re p orte d S y m pt o ms: S C O R A D; A D Patie nt Re p orte d S y m pt o ms: Pr urit us N R S, 
Slee p-l oss scale, S ki n Pai n N R S, P O E M; Q o L a n d i m pact of disease: D L QI/ C D L QI, 
D L QI- R, W H O- 5, R E C A P, a n d T S Q M- 9.

Safet y assess me nts – A Es, vital si g ns, p h ysical e xa mi nati o ns, cli nical la b orat or y 
assess me nts ( hae mat ol o g y, c oa g ulati o n, ser ol o g y, c he mistr y, uri nal ysis, a n d 
ser u m/ uri ne pre g na nc y test f or W O C B P).


I ma ges - p h ot o gra p hs of u p per a n d l o wer b o d y i ncl u di n g face, ha n ds, a n d li m bs fr o m a 
s u bset of patie nts

Patie nt e- diaries

e C R F
C CI
P P D


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1 2. 1. 2 
Electr o nic C ase Re p ort F or ms
T o c o m pl y wit h t he re q uire me nt t o mai ntai n acc urate case hist ories I n vesti gat ors s h o ul d re vie w 
a n d electr o nicall y si g n t he c o m plete d e C R F f or eac h patie nt bef ore t he data are arc hi ve d or 
s u b mitte d. Use of electr o nic si g nat ures m ust c o m pl y wit h part 1 1 ( 2 1 C F R part 1 1).
F or trial data ele me nts tra nscri be d fr o m pa per or electr o nic t o t he e C R F, t he electr o nic or pa per 
d oc u me nts fr o m w hic h t he data ele me nts are tra nscri be d are t he s o urce.
T hese data m ust be mai ntai ne d b y t he I n vesti gat ors a n d a vaila ble t o t he m o nit or or i ns pect or if 
re q ueste d (e g, a n ori gi nal or certifie d c o p y of a la b orat or y re p ort, i nstr u me nt pri nt o ut, pr o gress 
n otes of t he p h ysicia n, t he trial patie nt’s h os pital c hart(s), n urses’ n otes.
Direct E ntr y of D at a I nt o t he e C R F
T he direct e ntr y of data ca n eli mi nate err ors b y n ot usi n g a pa per tra nscri pti o n ste p bef ore e ntr y 
i nt o t he e C R F. F or t he f oll o wi n g data ele me nts, t he e C R F is t he s o urce:
1. I ncl usi o n a n d e xcl usi o n criteria c o nfir mati o n
2. E A SI,  I G A,  B S A,  a n d  S C O R A D  f or  I n vesti gat or;  S C O R A D,  Pr urit us  N R S,  Slee p- L oss 
Scale, S ki n Pai n N R S, P O E M, D L QI/ C D L Q 1, W H O- 5, T S Q M- 9 a n d R E C A P f or s u bjects
N ote:  Ce ntral  la b orat or y  p ortal  is  t he  s o urce  f or  la b orat or y  res ults  a n d  t he  p h ot o gra p h y 
ve n d or p ortal is t he s o urce f or p h ot o gra p hs.
3. Ra n d o misati o n n u m ber
4.  Uri ne pre g na nc y test res ults
F or t he a b o ve trial data ele me nts, t he e C R F is t he s o urce. If a pa per tra nscri pti o n ste p is use d, 
t he n  t he  pa per  d oc u me ntati o n  s h o ul d  be  retai ne d  a n d  ma de  a vaila ble  f or  m o nit ori n g  or 
i ns pecti o n.
Direct data e ntr y s h o ul d be i n c o m plia nce wit h A L C O A +. I n case trial data ca n n ot be e ntere d 
at t he ti me t he patie nt visit, e g, la b orat or y tests res ults, t he n I n vesti gat ors are re q ueste d t o ma ke 
t heir e ntries at t he ti me w he n t he re p ort wit h t he res ults is recei ve d.
All n o n-case re p ort f or m e ntere d e xter nal data (ie, i ma ges, bi o mar kers, etc.) will n ot be l oa de d 
i nt o  t he  e C R F,  b ut  it  will  be  i nte grate d  i n  S A S  datasets  a n d  rec o ncile d  fre q ue ntl y  wit h  t he 
e C R F data b y 
 Data Ma na ge me nt ( D M).
T he s o urce data verificati o n will be perf or me d b y 
 C R A ( m o nit or) acc or di n g t o 
t he re q uire me nts s pecifie d i n t he M o nit ori n g Pla n.
At  t he  trial  e n d, 
  will  ge nerate  1  certifie d  “tr ue  c o p y”  of  t he  c o m plete d  case 
re p ort f or m at t he site a n d will se n d t o t he I n vesti gat or(s) t hat c o p y certificati o n t o get her wit h 
t he c o m plete d e C R Fs (i n p orta ble d oc u me nt f or mat [ P D F]) fr o m all patie nts e nr olle d at his or 
her l ocati o n.
1 2. 1. 3 
P atie nt Di ar y
A m o bile a p plicati o n na me d t he St u d y A p p will be use d d uri n g t he st u d y. Researc h pers o n nel 
will be i nstr ucte d o n t he use of t he St u d y A p p i n or der t hat t he y f urt her i nstr uct t he patie nts at 
P P D
P P D
P P D


Cli nic al Tri al M- 1 7 9 2 3- 3 0
Cli nic al Tri al Pr ot oc ol Versi o n N o. 3. 0 2 2 A u g ust 2 0 2 2
S R D- 0 0 0 2 1 7 8 v 5. 0
C O N FI D E N TI A L
8 4/ 1 0 2
t he Scree ni n g visit a n d as ma n y ti mes as dee me d necessar y. Patie nts will als o recei ve writte n 
i nstr ucti o ns o n t he St u d y A p p use a n d re mi n ders, i ncl u di n g b ut n ot li mite d t o, c o m plete t he 
q uesti o n naires a n d diar y d uri n g t he st u d y, a n d treat me nt d osi n g
T he St u d y A p p data will be a vaila ble f or t he site i n real ti me t hr o u g h t he St u d y A p p a d mi n 
p ortal. T he site will be a ble t o f oll o w t he pr o gress a n d c o m plia nce of t he patie nt.
W he n  a n  i nstr u me nt  is  use d  b y  a  patie nt  or  I n vesti gat or  t o  tra ns mit  patie nt  data  ele me nts 
directl y t o t he e C R F, t he patie nt or I n vesti gat or is t he data ori gi nat or a n d t he e C R F is t he s o urce 
of data. If a pr ocess is use d b y w hic h t he patie nt or I n vesti gat or uses t he i nstr u me nt t o tra ns mit 
data t o a tec h n ol o g y ser vice pr o vi der data base, t he ser vice pr o vi der data base is t he s o urce.
T he St u d y A p p will all o w patie nts c o m pleti n g t he P R O q uesti o n naires a n d a diar y. T he patie nts 
will  be  as ke d  t o  ha ve  t he  St u d y  A p p  o n  t heir  o w n  m o bile  p h o ne.  T here  will  als o  be  t he 
p ossi bilit y t o pr o vi de patie nts wit h a m o bile p h o ne, if necessar y.
F or t his st u d y, eac h patie nt will c o m plete t he f oll o wi n g P R Os t hr o u g h t he e P R O m o d ule:

S C O R A D ( o nl y t h ose q uesti o ns a d dresse d t o patie nts)

Pr urit us N R S

Slee p-l oss

S ki n pai n N R S

D L QI or C D L QI

W H O- 5

R E C A P

T S Q M- 9

P O E M
Patie nts will als o rec or d use of T C S a n d st u d y dr u g i nta kes i n t he Patie nt Diar y as a p plica ble.
T he St u d y A p p rec or di n g will be tra nsferre d t o t he data base.
T he St u d y A p p will w or k acr oss all s mart p h o nes.
At  t he  st u d y  e n d  t he  I n vesti gat or  will  recei ve  a  C D/ D V D/ U S B  dri ve  wit h  t he  m o bile 
a p plicati o n data (i n P D F f or mat) fr o m t he patie nts e nr olle d at his/ her l ocati o n. T he I n vesti gat or 
will kee p t his C D wit h t he rest of t he ori gi nal data f or as l o n g as re q uire d b y l ocal re g ulati o ns. 
T he m o bile a p plicati o n files are rele va nt d oc u me ntati o n f or re gistrati o n.
T he m o bile a p p data is t he s ole pr o pert y of t he S p o ns or a n d s h o ul d n ot be a vaila ble i n a n y f or m 
t o  t hir d  parties  wit h o ut  t he  writte n  per missi o n  of  t he  S p o ns or,  e xce pt  t o  a ut h orise 
re prese ntati ves of a p pr o priate C o m pete nt A ut h orities.
1 2. 2  
D at a M a n a ge me nt a n d Q u alit y C o ntr ol
D M of t he trial will be perf or me d b y t he 
 D M de part me nt a n d s u per vise d b y t he 
S p o ns or’s D M de part me nt, acc or di n g t o t he S p o ns or a n d 
 S O Ps.
P P D
P P D


Cli nic al Tri al M- 1 7 9 2 3- 3 0
Cli nic al Tri al Pr ot oc ol Versi o n N o. 3. 0 2 2 A u g ust 2 0 2 2
S R D- 0 0 0 2 1 7 8 v 5. 0
C O N FI D E N TI A L
8 5/ 1 0 2
T o facilitate t he c ollecti o n of acc urate a n d c o m plete data, 
 will tar get t he ris ks 
ass ociate d t o critical trial data a n d will be d oc u me nte d i nt o t he Data Ma na ge me nt Pla n ( D M P) 
a n d t he M o nit ori n g Pla n.
I n vesti gat ors  will  res p o n d  wit hi n  4 8  h o urs  or  less  as  per  t he  D M  d oc u me nts  t o  a n y  critical 
q uer y ge nerate d b y t he D M gr o u p or a n y data ris k i n dicat or re p orte d.
Mai n D M acti vities a n d pr oce d ures will be acc uratel y descri be d i n t he D M P, create d b y  
 
 a n d se nt t o t he S p o ns or f or re vie w.
Data base c hec ks a n d listi n gs will be pr o gra m me d b y t he C R O, acc or di n g t o t he Data Vali dati o n 
Pla n  d oc u me nt  pr o vi de d  i n  t he  D M P.  Data base  c hec ks  a n d  listi n gs  pr o gra m mi n g  will  be 
a p pr o priatel y vali date d b y t he C R O.
Rec o nciliati o n  of  trial  data  a n d  S A Es  bet wee n  Cli nical  a n d  Dr u g  Safet y  data bases  will  be 
perf or me d  b y 
  i n  o n g oi n g  basis  a n d  bef ore  data base  s oft  l oc k  at  t he  C R O. 
Pr oce d ures t o be f oll o we d will be detaile d i n t he D M P.
E nc o di n g of s pecific data will be carrie d o ut b y t he C R O. F or t his trial, me dical hist or y, A Es, 
a n d  c o nc o mita nt  me dicati o ns  (i ncl u di n g  resc ue  me dicati o ns)  will  be  c o de d;  t he  Me dical 
Dicti o nar y  f or  Re g ulat or y  Acti vities  a n d  W H O- D R U G  E n ha nce d  dicti o naries  will  be  use d, 
versi o n n u m ber of eac h dicti o nar y will be d oc u me nte d i n t he D M P.
A Q ualit y C o ntr ol c hec k t o e ns ure t he acc urac y of t he data will be d o ne b y t he C R O, w he n 
data is clea ne d o n a n o n g oi n g basis a n d j ust bef ore t he data base l oc k. S pecificati o ns of t he 
Q ualit y C o ntr ol c hec k will be f o u n d i n t he D M P.
A n a u dit trail will be mai ntai ne d t o pr otect t he a ut he nticit y a n d i nte grit y of t he cli nical data.
1 2. 3 
I n vesti g at or’s a n d Tri al M aster Files
T he I n vesti gat or's file a n d S p o ns or Trial Master File will c o ntai n all trial d oc u me nts i n dicate d 
i n t he I C H G C P g ui deli nes a n d l ocal re g ulati o ns.
At t he trial e n d t he I n vesti gat or will recei ve o ne C D/ D V D/ U S B dri ve wit h t he E D C data, as 
well  as  o ne  C D/ D V D/ U S B  dri ve  wit h  t he  electr o nic  Patie nt  Diar y  data  fr o m  t he  patie nts 
e nr olle d at his/ her l ocati o n. T he I n vesti gat or will kee p t hese i n t he I n vesti gat or’s file.
T he S p o ns or’s Trial Master File will c o ntai n at a mi ni m u m all d oc u me nts i n dicate d i n t he I C H 
G C P g ui deli nes. T he d oc u me nts nee de d i n t he S p o ns or’s file ( ori gi nals a n d c o pies) ge nerate d 
or o btai ne d b y 
will be se nt t o t he S p o ns or f oll o wi n g a de q uate ti me p oi nts a n d 
i n t he f or mat defi ne d b y t he S p o ns or.
All rec or ds m ust be st ore d i n a sec ure facilit y pr otecte d fr o m fire, fl o o d a n d u na ut h orise d access 
w here t he y ma y be rea dil y accesse d i n t he e ve nt of a n a u dit or i ns pecti o n.
1 2. 4  
D oc u me nts a n d Rec or d Kee pi n g
T he  I n vesti gat or  s h o ul d  retai n  c o ntr ol  of  t he  rec or ds  (ie,  c o m plete d  a n d  si g ne d  e C R F  or 
certifie d c o p y of t he e C R F). T he I n vesti gat or ma y be re q ueste d b y i ns pect ors wit h access t o t he 
rec or ds t hat ser ve as t he electr o nic s o urce data.
P P D
P P D
P P D
P P D


Cli nic al Tri al M- 1 7 9 2 3- 3 0
Cli nic al Tri al Pr ot oc ol Versi o n N o. 3. 0 2 2 A u g ust 2 0 2 2
S R D- 0 0 0 2 1 7 8 v 5. 0
C O N FI D E N TI A L
8 6/ 1 0 2
W he n data ele me nts are tra nscri be d fr o m pa per s o urces i nt o a n e C R F, t he I n vesti gat or m ust 
als o retai n t he pa per s o urces, or certifie d c o pies, f or later re vie w. Ot her rec or ds (electr o nic a n d 
pa per) re q uire d t o c orr o b orate data i n t he e C R F ma y als o be re q ueste d d uri n g a n i ns pecti o n.
All trial data (i ncl u di n g electr o nic data), all har d c o pies i ncl u di n g pr ot oc ol, c o nse nt f or ms, case 
re p ort f or ms, q ueries a n d pri nt o uts, a n d all esse ntial d oc u me nts relati n g t o t he c o n d uct of t he 
cli nical trial will be st ore d at t he researc h site f or a peri o d of 2 5 years after c o m pleti o n of t he 
trial, u nless ot her wise c o m m u nicate d i n writi n g b y t he S p o ns or.
C R Os/ ve n d ors will st ore t he data bases, i ncl u di n g a u dit trails a n d relate d d oc u me ntati o n, f or a 
peri o d of 2 5 years after c o m pleti o n of t he trial, u nless l ocal re g ulati o ns or i nstit uti o nal p olicies 
re q uire  a  l o n ger  rete nti o n  peri o d.  N o  rec or ds  ma y  be  destr o ye d  d uri n g  t he  rete nti o n  peri o d 
wit h o ut t he writte n a p pr o val of t he S p o ns or. N o rec or ds ma y be tra nsferre d t o a n ot her l ocati o n 
or part y wit h o ut writte n n otificati o n t o t he S p o ns or.
1 3
Q u alit y C o ntr ol a n d Q u alit y Ass ur a nce
1 3. 1 
Tr ai ni n g of St aff
D uri n g t he set- u p p hase of t he trial, a p pr o priate kic k- off meeti n gs will be perf or me d bet wee n 
t he S p o ns or a n d 
a n d/ or ve n d ors (e g, e C R F, la b orat ories), t o trai n 
 
staff o n trial pr oce d ures.
A n  I n vesti gat ors’  meeti n g  will  be  perf or me d,  i ncl u di n g  trai ni n g  o n  G C P  pr oce d ures,  trial 
pr ot oc ol, efficac y a n d safet y assess me nts, la b orat or y pr oce d ures, e C R F c o m pleti o n, usa ge of 
a n y s pecific de vice a n d a n y ot her a p plica ble pr ocess/ pr oce d ure/ met h o d as a p plica ble.
A n i nitiati o n visit will be perf or me d at eac h site b y t he trial C R A desi g nate d b y 
 
t o  assess  w het her  all  t he  material  a n d  s u p plies  (e g,  case  re p ort  f or m,  I M P)  arri ve d  i n  g o o d 
c o n diti o ns a n d t o trai n t he site staff f or pr ot oc ol c o m plia nce.
A p pr o priate Trial Ma n uals will be pr o vi de d t o t he researc h sites as writte n hel p t o s u p p ort all 
trai ni n gs o n all trial pr oce d ures (e g, la b orat or y sa m ples, e C R F).
1 3. 2  
M o nit ori n g
T he  trial  will  be  m o nit ore d  b y 
  acc or di n g  t o  t he  details  s pecifie d  i n  t he 
M o nit ori n g Pla n.
T he trial C R A(s) will c o n d uct m o nit ori n g visits acc or di n g t o a pre-a gree d sc he d ule a n d wit h 
e n o u g h fre q ue nc y t o perf or m s o urce data verificati o n, c hec k t he acc urac y of e ntries o n t he case 
re p ort  f or ms,  t he  a d here nce  t o  t he  pr ot oc ol  a n d  t o  G o o d  Cli nical  Practice,  t he  pr o gress  of 
e nr ol me nt a n d t o e ns ure t hat trial me dicati o n is bei n g st ore d, dis pe nse d, a n d acc o u nte d f or, 
acc or di n g t o s pecificati o ns a n d re p ort a n y de viati o n as s o o n as p ossi ble t o t he Cli nical Trial 
Ma na ger. T he sc he d ule ca n a da pt t o m o nit ori n g w or kl oa d a n d/ or pre vaili n g circ u msta nces at 
t he site.
Sta n dar d m o nit ori n g re p orts will be pr o d uce d b y t he trial C R A(s) after eac h visit a n d file d i n 
t he Trial Master File. Ke y trial pers o n nel m ust be a vaila ble t o assist t he C R A(s) d uri n g t hese 
visits.
P P D
P P D
P P D
P P D


Cli nic al Tri al M- 1 7 9 2 3- 3 0
Cli nic al Tri al Pr ot oc ol Versi o n N o. 3. 0 2 2 A u g ust 2 0 2 2
S R D- 0 0 0 2 1 7 8 v 5. 0
C O N FI D E N TI A L
8 7/ 1 0 2
T he  I n vesti gat or  m ust  als o  kee p  t he  ori gi nal  I C F/I A F  si g ne d  b y  t he  patie nt  ( or 
pare nts/care gi vers, if a p plica ble) a n d mai ntai n s o urce d oc u me nts f or eac h patie nt i n t he trial, 
case a n d visit n otes me dical rec or ds, all i nf or mati o n o n case re p ort f or ms m ust be tracea ble t o 
t hese s o urce d oc u me nts i n t he patie nt´s file.
A  cl ose  o ut  visit  t o  s ol ve  pe n di n g  iss ues  a n d  t o  a gree  o n  t he  s hi p me nt  of  re mai ni n g  trial 
materials t o t he S p o ns or (e C R F/case re p ort f or ms a n d ot her data s o urce, me dicati o n) will be 
perf or me d b y t he trial C R A o nce all patie nts ha ve c o m plete d t he trial.
1 3. 3 
I ns pecti o ns a n d A u dits
T he trial site, trial pr ocesses, C R O, pr o vi ders a n d/ or trial d oc u me nts ma y be s u bject t o Q ualit y 
Ass ura nce a u dits b y t he S p o ns or ( or a ut h orise d part ner c o m pa nies) as well as i ns pecti o n b y t he 
a p pr o priate  C o m pete nt  A ut h orities  d uri n g  t he  trial  or  after  trial  c o m pleti o n.  A u dits  a n d 
i ns pecti o ns ma y i ncl u de, b ut are n ot li mite d t o, dr u g s u p pl y, prese nce of re q uire d d oc u me nts, 
I C F/I A F  pr ocess,  me dical  rec or ds,  ge neral  pr ot oc ol  c o m plia nce  a n d  c o m paris o n  of  data 
rec or de d o n t he e C R F a n d q ueries a gai nst s o urce d oc u me nts. I n vesti gat or will e ns ure direct 
access t o s o urce me dical rec or ds f or i ns pecti o n a n d a u dit p ur p oses.
1 4
Et hics
T his trial will be c o n d ucte d i n acc or da nce wit h t he rec o m me n dati o ns g ui di n g p h ysicia ns i n 
bi o me dical researc h i n v ol vi n g h u ma n patie nts a d o pte d b y t he 1 8t h W orl d Me dical Asse m bl y 
of Helsi n ki ( 1 9 6 4), as a me n de d i n F ortaleza, Brazil ( 2 0 1 3), as well as i n c o m plia nce wit h I C H 
G C P g ui deli nes, a n d l ocal la ws of t he c o u ntries i n w hic h t he trial ce ntres are l ocate d.
1 4. 1  
Res p o nsi bilities
T he  I n vesti gat or  is  res p o nsi ble  f or  c o n d ucti n g  t he  trial  i n  acc or da nce  wit h  t he  pr oce d ures 
descri be d i n t his pr ot oc ol. All t he pers o n nel i n v ol ve d i n t he cli nical trial will be f ull y i nf or me d 
a b o ut t he dr u g a n d t he nat ure of t he trial a n d will be patie nt t o pr ot oc ol pr oce d ures c o ncer ni n g 
t heir d uties i n t he trial.
T he  I n vesti gat or, 
  / ve n d ors  a n d  t he  S p o ns or  s h o ul d  e ns ure  t hat  all  w or k  a n d 
ser vices  descri be d  herei n,  or  i nci de ntal  t o  t h ose  descri be d  herei n,  s hall  be  c o n d ucte d  i n 
acc or da nce t o t he hi g hest sta n dar ds of G o o d Cli nical Practice (I C H G C P g ui deli nes) a n d l ocal 
re g ulati o ns.
T he I n vesti gat or, 
 a n d t he S p o ns or will w or k acc or di n g t o t he I C H g ui deli nes, 
t he 2 1 C F R of t he E ur o pea n Directi ve 2 0 0 1/ 2 0/ E C .
T he  I n vesti gat or  s hall  a d mi nister  t he  trial  me dicati o n  t o  patie nts  u n der  his  or  her  pers o nal 
s u per visi o n  or  u n der  t he  s u per visi o n  of  a n y  c o-I n vesti gat or  re p orti n g  t o  hi m/ her  w h o  are 
i de ntifie d  i n  t he  dele gati o n  of  res p o nsi bilities  a n d  si g nat ures  l o g.  T he  I n vesti gat or  a n d 
desi g nees will be res p o nsi ble f or t he patie nt’s c o m plia nce t hr o u g h o ut t he trial.
At  t he  c o m pleti o n  of  treat me nt  ( or  pre mat ure  disc o nti n uati o n)  patie nts  will  be  i nstr ucte d  t o 
res u me t he me dicati o n t he y were ta ki n g bef ore starti n g t he cli nical trial, or a n y ot her as dee me d 
a p pr o priate b y t he I n vesti gat or. Me dical care after disc har ge fr o m t he trial s h o ul d be pr o vi de d 
b y t he patie nt's fa mil y practiti o ner or s pecialist t hat us uall y treats his/ her c o n diti o n
P P D
P P D


Cli nic al Tri al M- 1 7 9 2 3- 3 0
Cli nic al Tri al Pr ot oc ol Versi o n N o. 3. 0 2 2 A u g ust 2 0 2 2
S R D- 0 0 0 2 1 7 8 v 5. 0
C O N FI D E N TI A L
8 8/ 1 0 2
1 4. 2 
P atie nt I nf or m ati o n a n d I C F/I A F
Patie nts will be i nf or me d b y t he I n vesti gat or i n detail of t he c haracteristics of t he dr u g t o be 
a d mi nistere d,  t he  nat ure  of  t he  cli nical  i n vesti gati o n,  t he  ris ks  a n d  t he  disc o mf ort  t hat  ca n 
reas o na bl y be e x pecte d as a res ult of t heir partici pati o n a n d t he uses of t he data, as descri be d 
i n t he Patie nt I nf or mati o n S heet.
T he patie nts will be i nf or me d t hat t he y are free t o wit h dra w t heir c o nse nt a n d s us pe n d t heir 
partici pati o n i n t he trial at a n y ti me wit h n o pe nalt y or l oss of be nefits t o w hic h t he patie nt is 
ot her wise  e ntitle d.  A d mi nistrati o n  of  t he  dr u g  ma y  be  i nterr u pte d,  a n d  a  patie nt  wit h dra w n 
fr o m t he trial at t he discreti o n of t he I n vesti gat or. T he I n vesti gat or s h o ul d j ustif y his decisi o n 
i n t he patie nt's e C R F.
A n y patie nt c o nsi dere d b y t he I n vesti gat or t o be s uita ble f or i ncl usi o n m ust d oc u me nt his or 
her willi n g ness t o partici pate i n t he trial b y gi vi n g his or her I C F/I A F i n writi n g bef ore starti n g 
a n y  trial  pr oce d ure  b y  si g ni n g  t he  I C F/I A F,  w hic h  m ust  be  date d  b y  t he  patie nt  a n d  t he 
I n vesti gat or.  At  s uc h  ti me  t he  patie nt  m ust  be  gi ve n  a de q uate  ti me  t o  u n dersta n d  t he 
i nf or mati o n  pr o vi de d  a n d  as k  q uesti o ns,  if  re q uire d.  A  c o p y  of  t he  si g ne d  I C F/I A F  will  be 
gi ve n t o t he patie nt. T he ori gi nal s hall be ke pt o n file b y t he I n vesti gat or. A n y ne w rele va nt 
i nf or mati o n t hat bec o mes a vaila ble d uri n g t he trial will be pr o vi de d t o t he patie nt.
T he Patie nt I nf or mati o n S heet a n d I C F/I A F will i ncl u de all ele me nts re q uire d acc or di n g t o t he 
a p plica ble  le gislati o n.  T hese  d oc u me nts  or  a n y  m o dificati o n  will  ha ve  bee n  a ut h orise d  b y 
Al mirall, S. A. a n d a p pr o ve d b y t he rele va nt I E C bef ore use.
After t he c o m pleti o n of t he trial, la y s u m maries s u m marisi n g mai n res ults fr o m t he trial will 
be ma ke a vaila ble f or patie nts.
1 4. 3 
I n de pe n de nt  Et hics  C o m mittee  or  I nstit uti o n al  Re vie w  B o ar d 
Re vie w
T his  pr ot oc ol,  patie nt  i nf or mati o n,  a n d  t he  i nf or me d  c o nse nt  a n d  asse nt  f or m  s h o ul d  be 
s u b mitte d  t o  a n  I E C  f or  re vie w  a n d  a p pr o val.  N otificati o n  i n  writi n g  of  a p pr o val  m ust  be 
o btai ne d fr o m t he I E C b y t he I n vesti gat or bef ore i nitiati o n of patie nt e nr ol me nt.
T he  S p o ns or  or 
  m ust  pr o m ptl y  re p ort  t o  t he  I E C  all  c ha n ges  i n  researc h 
( pr ot oc ol a me n d me nts) a n d will n ot ma ke s uc h c ha n ges wit h o ut I E C a p pr o val e xce pt w here 
necessar y  t o  eli mi nate  a p pare nt  i m me diate  hazar ds  t o  t he  trial  patie nts  or  a d mi nistrati ve 
c ha n ges.
S A Es reas o na bl y relate d t o t he st u d y dr u g will be c o m m u nicate d b y t he I n vesti gat or/ 
 
 t o t he I E C.
Wit hi n  1  year  after  c o m pleti o n  of  t he  trial,  t he  res p o nsi ble  pers o n  acc or di n g  t o  l ocal 
re g ulati o ns, (I n vesti gat or/
 will se n d t o t he I E C a n d t o t he C o m pete nt A ut h orit y 
a brief s u m mar y e x plai ni n g t he res ults o btai ne d i n t he trial.
T he I n vesti gat or/
are re q uire d t o mai ntai n acc urate a n d c o m plete rec or ds of all 
writte n  c orres p o n de nce  se nt  t o  a n d  recei ve d  fr o m  t he  I E C,  a n d  m ust  a gree  t o  s hare  t hese 
d oc u me nts a n d a n y re p orts wit h t he S p o ns or.
P P D
P P D
P P D
P P D


Cli nic al Tri al M- 1 7 9 2 3- 3 0
Cli nic al Tri al Pr ot oc ol Versi o n N o. 3. 0 2 2 A u g ust 2 0 2 2
S R D- 0 0 0 2 1 7 8 v 5. 0
C O N FI D E N TI A L
8 9/ 1 0 2
1 4. 4 
P atie nt D at a Pr otecti o n
T he trial patie nts s hall be i nf or me d b y t he I n vesti gat or t hat c o m plete c o nfi de ntialit y will be 
mai ntai ne d c o ncer ni n g t heir i de ntit y. O n e C R Fs/ E D C a n d all trial data rec or ds (e g, electr o nic 
patie nt diar y), patie nts will be i de ntifie d o nl y b y t he assi g ne d patie nt i de ntificati o n n u m ber a n d 
year of birt h.
A si g ne d writte n I C F/I A F si g nifies t he e x plicit acce pta nce b y t he i n di vi d ual t hat data fr o m t he 
trial will be a vaila ble t o t he I n vesti gat or a n d his/ her staff, t he a ut h orise d re prese ntati ves of t he 
S p o ns or a n d, if re q uire d, b y t he I E C a n d C o m pete nt A ut h orities. H o we ver, all data c o ntai ne d 
i n t he patie nt’s me dical hist or y will be c o nsi dere d as c o nfi de ntial. T he S p o ns or will treat data 
acc or di n g t o pers o nal data Re g ulati o n ( E U) 2 0 1 6/ 6 7 9, a n d a n y ot her a p plica ble nati o nal a n d 
i nter nati o nal re g ulati o n.
All cli nical trial fi n di n gs a n d d oc u me nts will be re gar de d as c o nfi de ntial. T he I n vesti gat or a n d 
me m bers  of  his/ her  researc h  tea m  m ust  n ot  discl ose  s uc h  i nf or mati o n  wit h o ut  pri or  writte n 
a p pr o val fr o m t he S p o ns or.
1 5
Fi n a nci n g a n d I ns ur a nce
T he S p o ns or will set u p a c o ntract wit h t he 
 wit h t he ec o n o mic as pects f or trial 
f u n di n g.
All  patie nts  recr uite d  will  ha ve  a n  i ns ura nce  p olic y  pr o vi de d  b y  t he  S p o ns or  t o  c o ver  a n y 
p ossi ble ris k res ulti n g fr o m t heir partici pati o n i n t he cli nical trial.
E xce pt  i n  t he  pr o ve n  case  of  cli nical  mal practice,  t he  i ns ura nce  c o m pa n y  will  i n de m nif y 
a gai nst  a n y  clai m  or  clai ms  ma de  b y  patie nts  or  t heir  de pe n de nts  w hic h  ma y  res ult  fr o m 
a d mi nistrati o n of t he I M P.
1 6
P u blic ati o n P olic y
T he S p o ns or will discl ose cli nical trials i n a ma n ner c o nsiste nt wit h a p plica ble nati o nal la ws 
a n d r ules g o ver ni n g pers o nal data pri vac y a n d pr otecti o n of i ntellect ual pr o pert y ri g hts. Cli nical 
trials will be re gistere d, a n d res ults discl ose d b y mea ns of rec o g nise d p u blic data bases, s uc h as 
cli nicaltrials. g o v i n t he U S a n d E u dra C T i n t he E ur o pea n U ni o n.
T he I n vesti gat or u n dersta n ds a n d acce pts t hat his/ her na me a n d trial ce ntre ma y be discl ose d 
i n t he c o nte xt of t his nati o nal or i nter nati o nal le gislati o n.
All  t he  i nf or mati o n  relate d  t o  t his  cli nical  trial  is  c o nsi dere d  strictl y  c o nfi de ntial  a n d  is  t he 
pr o pert y of t he S p o ns or. T his i nf or mati o n will n ot be gi ve n t o a t hir d part y wit h o ut t he writte n 
c o nse nt of t he S p o ns or.
B y si g ni n g t his trial pr ot oc ol, t he I n vesti gat or affir ms t o t he S p o ns or t hat he/s he will mai ntai n 
i n c o nfi de nce all i nf or mati o n f ur nis he d t o hi m/ her or res ulti n g fr o m t his trial. T he I n vesti gat or 
will o nl y di v ul ge s uc h i nf or mati o n as ma y be necessar y t o t he I E C, t he me m bers of t he staff 
a n d t he patie nts w h o are i n v ol ve d i n t his trial.
All rele va nt as pects re gar di n g p u blicati o n will be part of t he c o ntract ( or si milar d oc u me nt) 
bet wee n t he S p o ns or a n d C R O.
P P D


Cli nic al Tri al M- 1 7 9 2 3- 3 0
Cli nic al Tri al Pr ot oc ol Versi o n N o. 3. 0 2 2 A u g ust 2 0 2 2
S R D- 0 0 0 2 1 7 8 v 5. 0
C O N FI D E N TI A L
9 0/ 1 0 2
I n all cases, t he trial res ults s hall be re p orte d i n a n o bjecti ve, acc urate, bala nce d, a n d c o m plete 
ma n ner, wit h a disc ussi o n of t he stre n gt hs a n d li mitati o ns of t he trial. All a ut h ors will be gi ve n 
t he rele va nt statistical ta bles, fi g ures, a n d re p orts nee de d t o s u p p ort t he pla n ne d p u blicati o n.
P u blicati o n a n d/ or prese ntati o n w het her c o m plete or partial, of a n y part of t he data or res ults 
of  t his  trial  will  n ot  be  all o we d  u ntil  gl o bal  p u blicati o n  a n d  trial  res ults  discl os ure  b y  t he 
S p o ns or as per E ur o pea n Me dici nes A ge nc y/ or U S F o o d a n d Dr u g A d mi nistrati o n re g ulat or y 
c o m plia nce  o bli gati o ns,  a n d  o nl y  after  m ut ual  a gree me nt  bet wee n  t he  I n vesti gat or  a n d  t he 
S p o ns or.
1 7
Ot her Pr actic al C o nsi der ati o ns
1 7. 1 
I n vesti g at or’s Br oc h ure
T he I B c o ntai ns a s u m mar y of t he precli nical a n d cli nical. T he sa me c o nfi de ntialit y pr oce d ures 
a p pl y as f or t he I B a n d pr ot oc ol.
T he I B will be i ncl u de d i n t he I n vesti gat or’s file. T he I n vesti gat or will si g n a recei pt f or m.
1 7. 2 
Fi n al Cli nic al Tri al Re p ort
T he C S R will be writte n b y 
 f oll o wi n g t he I C H g ui deli nes re q uire me nts. It will 
be  a p pr o ve d  a n d  si g ne d  b y  t he  Pri nci pal/ C o or di nati n g  I n vesti gat ors  a n d  t he  S p o ns or’s 
re prese ntati ves acc or di n g t o i nter nal S O Ps.
T he C S R will be a u dite d b y 
a n d/ or t he S p o ns or bef ore iss ui n g t he fi nal versi o n.
Fi nal versi o n of electr o nic C S R will be e- p u blis he d ( h y perli n k, b o o k mar ks, etc.) i ncl u di n g all 
a p pe n dices acc or di n g t o I C H G ui deli nes.
T he s u m mar y of t he C S R will be se nt t o all t he I n vesti gat ors partici pati n g i n t he cli nical trial 
as well as t o t he I E Cs a n d/ or C o m pete nt A ut h orities acc or di n g t o t he l ocal re g ulati o n.
1 7. 3 
Pr ot oc ol A me n d me nts
M o dificati o ns of t he ori gi nal pr ot oc ol are referre d t o as “a me n d me nts” t o t he trial pr ot oc ol. 
M o dificati o ns of t he ori gi nal pr ot oc ol ma y o nl y be ma de wit h t he S p o ns or’s a p pr o val. 2 t y pes 
of a me n d me nt ma y be pr o d uce d:

S u bsta ntial A me n d me nts (relate d t o t he safet y or p h ysical or me ntal i nte grit y of t he patie nts, 
scie ntific val ue of t he trial, c o n d uct or ma na ge me nt of t he trial or t he q ualit y or safet y of 
a n y I M P use d) m ust be n otifie d t o t he I E C a n d/ or C o m pete nt A ut h orities a n d a p pr o ve d b y 
t he m bef ore i m ple me ntati o n.

N o ns u bsta ntial  A me n d me nts  d o  n ot  re q uire  n otificati o n  b ut  s h o ul d  be  rec or de d  a n d  be 
a vaila ble o n re q uest f or i ns pecti o n at t he trial site a n d/ or S p o ns or pre mises as a p pr o priate.
1 7. 4 
Pr ot oc ol De vi ati o ns
A n y pr ot oc ol de viati o ns d uri n g t he c o n d uct of t he trial will be rec or de d b y C R A/ M o nit ors as 
detecte d or deri ve d fr o m data c ollecte d i n t he cli nical data base.
P P D
P P D


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Relevant deviations will be promptly reported to the Sponsor after detection. Important 
protocol deviations will be included in the corresponding listing of the CSR.
Additionally, protocol deviations will be reported to the IECs and/or Competent Authorities 
according to the local regulation in each country.
17.5
COVID-19
Given the current COVID-19 pandemic, per regulatory guidance, a listing of patients either 
experiencing COVID-19 or at least possibly affected by COVID-19–related measures will be 
produced where applicable. In addition, a COVID-19 Visit Impact CRF has been included. 
Further details relating to additional populations and subgroup analyses, handling of protocol 
deviations, handling of missing data (including use of virtual assessments and/or switches from 
local to centralised labs), and any other considerations related to COVID-19 and related 
measures will be detailed further in the SAP, to be finalised before unmasking.


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18
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treatment of atopic eczema (atopic dermatitis) in adults and children: part I. 
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42. Howells LM, Chalmers JR, Gran S, et al. Development and initial testing of a new 
instrument to measure the experience of eczema control in adults and children: recap of 
atopic eczema (RECAP). Br J Dermatol. 2020;183(3):524-536. doi:10.1111/bjd.18780
43. Barrett A, Hahn-Pedersen J, Kragh N, Evans E, Gnanasakthy A. Patient-reported outcome 
measures in atopic dermatitis and chronic hand eczema in adults. Patient. 
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44. Topp CW, Østergaard SD, Søndergaard S, Bech P. The WHO-5 Well-Being Index: a 
systematic review of the literature. Psychother Psychosom. 2015;84(3):167-176. 
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45. Schonmann Y, Mansfield KE, Hayes JF, et al. Atopic eczema in adulthood and risk of 
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2020;8(1):248-257. doi:10.1016/j.jaip.2019.08.030
46. Bharmal M, Payne K, Atkinson MJ, Desrosiers M-P, Morisky DE, Gemmen E. 
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48. Hanifin JM, Thurston M, Omoto M, Cherill R, Tofte SJ, Graeber M. The eczema area and 
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49. Phan NQ, Blome C, Fritz F, Gerss J, Reich A, Ebata T, et al. Assessment of pruritus 
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J, Wyrwich KW, Eichenfield LF, Abetz-Webb L, Silverberg JI. Exploring content and 
psychometric validity of newly developed assessment tools for itch and skin pain in 
atopic dermatitis. J Patient Rep Outcomes. 2019 Jul 16; 3:42
51. Centre of Evidence Based Dermatology. POEM — Patient Oriented Eczema Measure. 
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52. Finlay, AY and Khan, GK 1994. Dermatology Life Quality Index (DLQI)--a simple 
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19
List of Appendices
Appendix 1. Hanifin/Rajka Diagnostic Criteria for Atopic Dermatitis
Appendix 2. Provisions for Changes in Study Conduct During Exceptional 
Circumstances 


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Appendix 1. Hanifin/Rajka Diagnostic Criteria for Atopic Dermatitis
To establish a diagnosis of atopic dermatitis, the patient requires the presence of at least 3 
“basic features” and 3 or more minor features listed below.
Basic Features
Must have 3 or more basic features:

Pruritus

Typical morphology and distribution

Flexural lichenification or linearity in adults

Chronic of chronically-relapsing dermatitis

Personal or family history of atopy (asthma, allergic rhinitis, atopic dermatitis)
Minor Features
Plus, 3 or more minor features:

Xerosis

Ichthyosis, palmar hyperlinearity, or keratosis pilaris

Immediate (type 1) skin-test reactivity

Elevated serum IgE

Early age of onset

Tendency toward cutaneous infections (especially Staph. Aureus and Herpes 
simplex)/impaired cell-mediated immunity

Tendency toward non-specific hand or foot dermatitis

Nipple eczema

Cheilitis

Recurrent conjunctivitis

Dennie-Morgan infraorbital fold

Keratoconus

Anterior subcapsular cataracts

Orbital darkening

Facial pallor/facial erythema

Pityriasis alba

Anterior neck folds

Itch when sweating

Intolerance to wool and lipid solvents

Perifollicular accentuation

Food intolerance

Course influenced by environmental or emotional factors

White dermographism/delayed blanch


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Appendix 2. Provisions for Changes in Study Conduct During Exceptional 
Circumstances
Implementation of this appendix
The changes to procedures described in this appendix are temporary measures intended to be 
used only during specific time periods as directed by the Sponsor in partnership with the 
Investigator.
Exceptional circumstances
Exceptional circumstances are rare events that may cause disruptions to the conduct of the 
study. Examples include pandemics or natural disasters. These disruptions may limit the ability 
of the Investigators, participants, or both to attend on-site visits or to conduct planned study 
procedures.
Implementing changes under exceptional circumstances
In an exceptional circumstance, after receiving the Sponsor’s written approval, sites may 
implement changes if permitted by local regulations.
After approval by local Ethical Review Boards (ERBs), regulatory bodies and any other 
relevant local authorities, implementation of these exceptional circumstance changes will not 
typically require additional notification to these groups, unless they have specific conditions in 
which notification is required. To protect the safety of study participants, urgent changes may 
be implemented before approval but need to be reported as soon as possible. All approvals 
must be retained in the study records.
If the Sponsor grants written approval for changes in study conduct, the Sponsor will also 
provide additional written guidance, if needed.
Considerations for making a change
The prevailing consideration for making a change is ensuring the safety of study participants. 
Additional important considerations for making a change are compliance with Good Clinical 
Practice, enabling participants to continue safely in the study and maintaining the integrity of 
the study.
Informed Consent
Additional consent/assent from the participant will be obtained, as applicable, and/or as 
required by ERB’s and local regulations. Assent will also be obtained to the same parameters, 
with consent for participants reaching the legal age for consent during the trial for continued 
participation, for:

participation in remote visits, as defined in Section “Remote Visits,”

a change in the method of study drug administration,

dispensation of additional study drug during an extended treatment period,

alternate delivery of study drug and ancillary supplies, and


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
provision of their personal or medical information required before implementation of 
these activities.
Changes in Study Conduct During Exceptional circumstances
Changes in study conduct not described in this appendix, or not consistent with applicable local 
regulations, are not allowed.
The following changes in study conduct will not be considered protocol deviations.
1. Remote visits
The study site should capture specific explanation for any missing data and other protocol 
deviations in source documents. While protocol deviations may be unavoidable in an 
exceptional circumstance, documentation of protocol deviations and missing data will be 
important for data analysis.
The following visits cannot be conducted remotely because efficacy or safety assessments must 
be performed in person at these visits:

Screening

Baseline (Day 1), and

Week 16.
Regardless of the type of remote visits implemented, the protocol requirements regarding the 
reporting of adverse events (AEs), serious adverse events (SAEs), and product complaints 
remain unchanged. Furthermore, every effort should be made to enable participants to return 
to on-site visits as soon as reasonably possible, while ensuring the safety of both the 
participants and the site staff.
Telemedicine: Telephone or technology-assisted virtual visits, or both, are acceptable to 
complete appropriate assessments. Assessments to be completed in this manner include, but 
are not limited to:

AE and SAE reports

concomitant medications

Dermatology Life Quality Index/Children’s Dermatology Life Quality Index 
(DLQI/CDLQI)

compliance with the participant eDiary, and

self-administration of study drug, if needed, and recording the self-administration 
details in the Study Drug Administration Log. Before administering study drug at 
home, participants and/or parents or caregivers will be adequately trained on at home 
study drug administration; see also the section “Study drug and ancillary supplies 
(including participant diaries)” below.
Mobile healthcare: Healthcare visits may be performed by a mobile healthcare provider at 
locations other than the study site, when participants cannot travel to the site because of an 
exceptional circumstance, if written approval is provided by the Sponsor. Procedures 
performed at such visits include, but are not limited to:

taking blood samples


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
collecting urine samples for pregnancy testing

assessing the amount of the topical corticosteroid (TCS) use

conducting physical assessments

administering patient-reported outcomes

administering study drug, and

collecting health information.
2. Local laboratory testing option
Local laboratory testing may be conducted in lieu of central laboratory testing. However, 
central laboratory testing must be retained for the following samples:

Pharmacokinetic

Immunogenicity

Testosterone

Oestradiol
The local laboratory must be qualified in accordance with applicable local regulations. 
Clinically significant laboratory findings will be reported as an AE in the AE electronic case 
report form (eCRF).
3. Study drug and ancillary supplies (including participant diaries)
When a participant is unable to go to the site to receive study supplies during normal on-site 
visits, the site should work with the Sponsor to determine appropriate actions. These actions 
may include:

asking the participant to go to the site and receive study supplies from site staff

without completion of a full study visit,

asking the participant’s parent/caretaker or designee to go to the site and receive study 
supplies on a participant’s behalf,

arranging delivery of study supplies, and

working with the Sponsor to determine how study drug that is typically administered 
on site will be administered to the participant; for example, self-administered or 
administered during a mobile healthcare visit.

returning the TCS tubes to the study staff
These requirements must be met before action is taken:

Participants or their parents/caregivers are appropriately trained on at home 
administration of the study drug (unless they have already received that training); the 
mobile healthcare provider will observe the participant or caregiver administer the 
study drug for the first time.
o
If the study drug is administered at home, participants or their 
parents/caregivers will need to record the details about the injections in the 
patient diary (regardless of whether the at home study drug administration is 
done by the participant him-/herself, caregiver, or mobile healthcare provider). 
For the at home administration information under exceptional circumstances, 
the Study Drug Administration Log will be used.


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
Alternate delivery of study drug should be performed in a manner that does not 
compromise treatment blinding and ensures product integrity. The existing protocol 
requirements for product accountability remain unchanged, including verification of 
participant’s receipt of study supplies.

When delivering supplies to a location other than the study site (eg, participant’s 
home), the Investigator, Sponsor, or both should ensure oversight of the shipping 
process to ensure accountability and product quality (that is, storage conditions 
maintained and intact packaging upon receipt).

Instructions may be provided to the participant and the participant’s parent/caregiver 
or designee on the final disposition of any unused or completed study supplies.
Unless the study drug is self-administered by the trained participants or their 
parents/caregivers, only authorised study personnel may supply, prepare, or administer study 
drug during a mobile healthcare visit.
4. Screening Period guidance
If the study Screening window exceeds 4 weeks because of the exceptional circumstances, the 
participant would be considered a screen failure and documented as such in the eCRF. The 
participant may be rescreened once. If rescreening is required more than once, it must first be 
approved by the Sponsor.
The Screening procedures per the Schedule of Visits and Procedures in the protocol should be 
followed to ensure participant eligibility for the study. Before rescreening, the participant must 
sign a new ICF/IAF and receive a new identification number.
5. Adjustments to visit windows
Whenever possible and safe to do so, as determined by the Investigator’s discretion, 
participants should complete the usual Schedule of Visits and Procedures. To maximise the 
possibility that these visits can be conducted as on-site visits, the windows for visits may be 
adjusted, upon further guidance from the Sponsor. This minimises missing data and preserves 
the intended conduct of the study.
This table describes the allowed adjustments to visit windows. Subsequent dosing should be a 
minimum of 7 days apart if the visit window is expanded because of exceptional circumstances.
Visit
Tolerance
Weeks 2 through 14
±7 days
Week 16
-7/+14 days
Week 68 (18-week SFU)
-7/+14 days
For participants whose visits have extended windows, additional study drug may need to be 
provided to avoid interruption and maintain overall integrity of the study.
Documentation


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Changes to study conduct will be documented:

Sites will identify and document the details of how participants, visits types, and 
conducted activities were affected by exceptional circumstances. Dispensing/shipment 
records of study drug and relevant communications, including delegation, should be 
filed with site study records.

Source documents generated at a location other than the study site should be part of 
the Investigator’s source documentation and should be transferred to the site in a 
secure and timely manner.


E L E C T R O NI C S I G N A T U R E S
Si g ne d b y
Me a ni n g of Si g n at ure
Ser ver D ate
( d d- M M M- y y y y H H: m m ‘ G M T’ Z)
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3 0- A u g- 2 0 2 2 0 9: 5 1 G M T + 0
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3 1- A u g- 2 0 2 2 1 2: 4 7 G M T + 0
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P ati e nt s Wit h M o d er at e- T o- S e v er e At o pi c D er m atiti s T h at Ar e N ot A d e q u at el y C o ntr oll e d Wit h 
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t hi s d o c u m e nt c o n stit ut e s a gr e e m e nt b y t h e r e ci pi e nt t h at n o i nf or m ati o n c o nt ai n e d h er ei n will b e 
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t hi s d o c u m e nt m a y b e di s cl o s e d t o a p pr o pri at e I n stit uti o n al R e vi e w B o ar d a n d Et hi c s C o m mitt e e s or d ul y 
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s h o ul d b e n otifi e d pr o m ptl y. 
 
 
 
 
 
 
 
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R e vi si o n Hi st or y 
V er si o n # 
D at e 
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D o c u m e nt O w n er 
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a c c or di n g t o L o c al pr ot o c ol a m e n d m e nt 4 f or 
G er m a n y. S e cti o n s t h at h a v e b e e n c h a n g e d ar e: 
2. 2 Ti mi n g s of A n al y s e s, 3. St u d y O bj e cti v e s a n d 
E n d p oi nt s, 4. 1. 4. E xt e n si o n P eri o d f or G er m a n y 
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M ai nt e n a n c e P eri o d h a s b e e n c orr e ct e d. 
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f or tr e at m e nt c o m pli a n c e c al c ul ati o n h a s b e e n 
a d d e d f or cl arit y. 
It h a s b e e n s p e cifi e d t h at t h e a n al y s e s of t h e 
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b a s e d o n t h o s e p ati e nt s wit hi n F A S w h o h a d a 
b a s eli n e N R S pr urit u s s c or e m or e or e q u al t h a n 4, 
t h at t h e a n al y s e s of t h e e n d p oi nt 4 p oi nt N R S S ki n 
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f o ot n ot e t o t h e T a bl e i n s e cti o n 9. 6 M ai nt e n a n c e 
P eri o d ( a n d E xt e n si o n p eri o d f or p ati e nt s fr o m 
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Fi n all y i n s e cti o n 1 0. 1, t h e w or di n g of T E A E 
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i n fr e q u e n c y” si n c e fr e q u e n c y i s n ot n e e d e d t o t a k e 
i nt o a c c o u nt f or t h e T E A E d eri v ati o n. 
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I c o nfir m t h at I h a v e r e vi e w e d t hi s d o c u m e nt a n d a gr e e wit h t h e c o nt e nt. 
 
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El e ctr o ni c all y si g n e d b y: 
R e a s o n: I a m t h e a ut h or
D at e: M ar 2 3, 2 0 2 3 0 7: 3 1 G M T + 9
M ar 2 3, 2 0 2 3
El e ctr o ni c all y si g n e d b y: 
R e a s o n: I a m t h e r e vi e w er
D at e: M ar 2 3, 2 0 2 3 0 9: 2 1 G M T + 1
M ar 2 3, 2 0 2 3
El e ctr o ni c all y si g n e d b y: 
R e a s o n: I a m t h e r e vi e w er
D at e: M ar 2 3, 2 0 2 3 0 9: 2 3 G M T
M ar 2 3, 2 0 2 3
El e ctr o ni c all y si g n e d b y: 
R e a s o n: I a m t h e a p pr o v er
D at e: M ar 2 3, 2 0 2 3 1 6: 5 1 G M T + 1
M ar 2 3, 2 0 2 3
P P D
P P D
P P
D
P P D
P P D
P P D
P P D
P P
D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
C CI
P P D


St ati sti c al A n al y si s Pl a n f or I nt er v e nti o n al St u di e s  
S p o n s or: A L MI R A L L, S. A.; Pr ot o c ol N o.: M- 1 7 9 2 3- 3 0 
 
 
T hi s d o c u m e nt i s c o nfi d e nti al. 
S A P t e xt V er si o n: S A P t e xt v 2. 0 2 2 M A R 2 0 2 3 
C o ntr oll e d D o c u m e nt I D:  
, Eff e cti v e D at e 3 1- A u g- 2 0 2 0 
Fili n g r e q uir e m e nt s: T M F  
 
P a g e 4  of 7 3  
I N T E R N AL U S E 
T a bl e of C o nt e nt s 
R e vi si o n Hi st or y .......................................................................................................................... 2  
A p pr o v al s  .................................................................................................................................. 3 
 
Gl o s s ar y of A b br e vi ati o n s ................................................................................................... 8  
 
P ur p o s e ............................................................................................................................ 1 1  
 
St u d y O bj e cti v e s a n d E n d p oi nt s ....................................................................................... 1 2  
 
St u d y D e si g n .................................................................................................................... 1 6  
 
A n al y si s S et s .................................................................................................................... 2 2  
 
E sti m a n d s a n d D at a H a n dli n g f or Effi c a c y A n al y s e s ........................................................ 2 3  
1. 
2. 
2. 1. 
R e s p o n si biliti e s ... ................................ .................................................................. 1 1 
2. 2. 
Ti mi n g s of A n al y s e s .............................................................................................. 1 1 
3. 
4. 
4. 1. 
Bri ef D e s cri pti o n ................................................................................. .................. 1 6 
4. 1. 1. 
S cr e e ni n g p eri o d ........................................................ ......... ................................. 1 6 
4. 1. 2. 
B a s eli n e a n d D o u bl e- Bli n d e d I n d u cti o n P eri o d ( w e e k O t o w e e k 1 6) .................. 1 6 
4. 1. 3. 
M ai nt e n a n c e P eri o d ( w e e k 1 6 t o w e e k 5 2) .......................................................... 1 6 
4. 1. 4. 
E xt e n si o n P eri o d f or G er m a n y a c c or di n g t o Pr ot o c ol A m e n d m e nt 4 .................. 1 6 
4. 1. 5. 
S af et y F oll o w- u p Vi sit .......................................................................................... 1 6 
4. 2. 
P ati e nt S el e cti o n ................................................................................................... 1 7 
4. 2. 1. 
I n cl u si o n Crit eri a ................................ .. .. .. .. .. .................. ...................................... 1 7 
4. 2. 2. 
E x cl u si o n Crit eri a .......................... ........................................... ....... .. .. ................. 1 7 
4. 3. 
D et er mi n ati o n of S a m pl e Si z e ............................................................................... 1 7 
4. 4. 
Tr e at m e nt A s si g n m e nt a n d Bli n di n g ..................................................................... 1 7 
4. 5. 
A d mi ni str ati o n of St u d y M e di c ati o n ........... ............................................................ 1 8 
4. 6. 
St u d y Pr o c e d ur e s a n d Fl o w c h art .............................. ................. ............... ............ 1 9 
5. 
5. 1. 
F ull A n al y si s S et ..................................................................................... .. ............ 2 2 
5. 2 . 
S af et y A n al y si s S et ............................................................................................... 2 2 
5. 3. 
P er Pr ot o c ol S et. ....................... .. ..... .. ................................................................... 2 2 
5. 4 . 
Pr ot o c ol D e vi ati o n s ............................................................................................... 2 2 
6. 
6. 1 . 
Pri m ar y Effi c a c y A n al y si s ( O v er all P o p ul ati o n) ...................................................... 2 3 
6. 1. 1. 
Pri m ar y a n d K e y S e c o n d ar y Effi c a c y E n d p oi nt s ............................. .. .................. 2 3 
6. 1. 2. 
All Ot h er S e c o n d ar y a n d Ot h er Effi c a c y E n d p oi nt s ............................................. 2 4 
C CI


St ati sti c al A n al y si s Pl a n f or I nt er v e nti o n al St u di e s  
S p o n s or: A L MI R A L L, S. A.; Pr ot o c ol N o.: M- 1 7 9 2 3- 3 0 
 
 
T hi s d o c u m e nt i s c o nfi d e nti al. 
S A P t e xt V er si o n: S A P t e xt v 2. 0 2 2 M A R 2 0 2 3 
C o ntr oll e d D o c u m e nt I D: 
, Eff e cti v e D at e 3 1- A u g- 2 0 2 0 
Fili n g r e q uir e m e nt s: T M F  
 
P a g e 5  of 7 3  
I N T E R N AL U S E 
 
G e n er al A s p e ct s f or St ati sti c al A n al y si s ........................................................................... 2 8  
 
D e m o gr a p hi c, Ot h er B a s eli n e C h ar a ct eri sti c s a n d M e di c ati o n ......................................... 3 3  
6. 2. 
S u b gr o u p Effi c a c y A n al y s e s ( D u pil u m a b N a Y v e a n d P ati e nt s Pr e vi o u sl y E x p o s e d t o 
D u pil u m a b) ..................................................................................... ...................... 2 5 
6. 3. 
I m p ut ati o n Pr o c e s s f or E sti m a n d H a n dli n g a n d Mi s si n g D at a .................. ..... ........ 2 5 
6. 3. 1. 
G e n er al M ulti pl e I m p ut ati o n A p pr o a c h ......................................... ....................... 2 6 
6. 3. 2. 
N o nr e s p o n d er I m p ut ati o n .................................................................................... 2 7 
6. 3. 3. 
Mi x e d- eff e ct s M o d el f or R e p e at e d M e a s ur e s ....................................... ............... 2 7 
7. 
7. 1. 
G e n er al M et h o d s ..................................... ............................................................. 2 8 
7. 2. 
K e y D efi niti o n s ...................................................................... ............ .................... 2 8 
7. 2. 1. 
Fir st D o s e D at e .................................................................................................... 2 8 
7. 2. 2. 
L a st D o s e D at e .................................................................................................... 2 8 
7. 2 .3. 
St u d y D a y ........................................................................ .... .... ............................. 2 8 
7. 2 .4. 
B a s eli n e a n d C h a n g e fr o m B a s eli n e ... .. .. ..................................................... ....... 2 8 
7. 3. 
Mi s si n g D at a ......................................................................................................... 2 9 
7. 3. 1. 
P arti al or Mi s si n g E v e nt D at e s ...... .................................. .. ................................... 2 9 
7. 3. 2. 
A d v er s e E v e nt s .................................................................... ........ ........ ................ 2 9 
7. 3. 3. 
Pri or/ C o n c o mit a nt M e di c ati o n s ............................................................. ............... 3 0 
7. 4 . 
Vi sit Wi n d o w s ................... .. ................ ........ ...................... .. .................................. 3 0 
7. 5. 
A dj u st m e nt s f or C o v ari at e s ......... ...................................................................... .. .. 3 1 
7. 6. 
S u b gr o u p s .......................................................................................................... .. 3 1 
7. 7. 
G e n er al C o n si d er ati o n s f or Effi c a c y d uri n g I n d u cti o n P eri o d ................................. 3 1 
7. 8. 
G e n er al C o n si d er ati o n s f or Effi c a c y d uri n g M ai nt e n a n c e P eri o d ........................... 3 1 
7. 9. 
C o ntr ol f or m ulti pli cit y .................................. ................................ .. .. ...................... 3 2 
8. 
8. 1. 
P ati e nt Di s p o siti o n a n d Wit h dr a w al s ......... ..... .. .. .. ............................................ ..... 3 3 
8. 2. 
Pr ot o c ol D e vi ati o n s ............................................................................................... 3 3 
8. 3 . 
D e m o gr a p hi c a n d B a s eli n e C h ar a ct eri sti c s ........................................................... 3 3 
8. 4. 
M e di c al Hi st or y a n d C o n c o mit a nt Di s e a s e s .................................... .......... ...... .. .. .. 3 4 
8. 5 . 
Ot h er B a s eli n e C h ar a ct eri sti c s ....................................................... ....................... 3 4 
8. 6. 
M e di c ati o n ............................................................................................................ 3 4 
8. 6. 1. 
Pri or M e di c ati o n .......................... ......................................................................... 3 4 
8. 6. 2. 
C o n c o mit a nt M e di c ati o n ....................................................................... ............... 3 4 
C CI


St ati sti c al A n al y si s Pl a n f or I nt er v e nti o n al St u di e s  
S p o n s or: A L MI R A L L, S. A.; Pr ot o c ol N o.: M- 1 7 9 2 3- 3 0 
 
 
T hi s d o c u m e nt i s c o nfi d e nti al. 
S A P t e xt V er si o n: S A P t e xt v 2. 0 2 2 M A R 2 0 2 3 
C o ntr oll e d D o c u m e nt I D:  
, Eff e cti v e D at e 3 1- A u g- 2 0 2 0 
Fili n g r e q uir e m e nt s: T M F  
 
P a g e 6  of 7 3  
I N T E R N AL U S E 
 
Effi c a c y ............................................................................................................................ 3 7  
 S af et y ............................................................................................................................... 5 5  
 C h a n g e s fr o m A n al y si s Pl a n n e d i n Pr ot o c ol ..................................................................... 6 0  
 R ef er e n c e Li st .................................................................................................................. 6 1  
 Pr o gr a m mi n g C o n si d er ati o n s ........................................................................................... 6 2  
9. 
1 0 . 
1 1 . 
1 2 . 
1 3 . 
8. 6. 3. 
P o st M e di c ati o n ................................................................................... .......... .. ..... 3 4 
8. 6. 4. 
R e s c u e M e di c ati o n ................. ............................................................................. 3 5 
8. 7. 
E xt e nt of E x p o s ur e ... ............. ......................................... ...................................... 3 5 
8. 8. 
Tr e at m e nt C o m pli a n c e .......................................................................................... 3 6 
9. 1. 
St ati sti c al H y p ot h e s e s ........................................................................................... 3 7 
9. 2. 
D efi niti o n s f or Effi c a c y E n d p oi nt s .......................................................................... 3 7 
9. 3. 
A n al y si s of t h e Pri m ar y a n d K e y S e c o n d ar y Effi c a c y E n d p oi nt s .......................... . 4 7 
9. 4. 
A n al y si s of all Ot h er S e c o n d ar y a n d Ot h er Effi c a c y E n d p oi nt .............................. . 4 8 
9. 5. 
S u b gr o u p Effi c a c y A n al y s e s ( D u pil u m a b N a'i v e a n d P ati e nt s Pr e vi o u sl y E x p o s e d t o 
D u pil u m a b) ................................................................................... ..... ................... 4 9 
9. 6. 
S u m m ar y of t h e St ati sti c al Effi c a c y A n al y si s t o b e p erf or m e d wit h I n d u cti o n p eri o d 
d at a ...................................................................................................................... 4 9 
9. 7. 
M ai nt e n a n c e P eri o d ( a n d E xt e n si o n P eri o d f or P ati e nt s fr o m G er m a n y) A n al y s e s 5 4 
1 0 .1. 
A d v er s e E v e nt s ..................................................................................................... 5 5 
1 0. 2. 
L a b or at or y E v al u ati o n s ......................................................................................... 5 6 
1 0. 3 . Vit al Si g n s ............................................................................................................. 5 6 
1 0. 4. 
P h y si c al E x a mi n ati o n ............................................................................................ 5 7 
1 0. 5. 
S p e ci al S af et y T o pi c s i n cl u di n g A d v er s e E v e nt s of S p e ci al l nt er e st ...................... 5 7 
1 0. 5. 1. 
E o si n o p hili a a n d E o si n o p hil- R el at e d Di s or d er s .................................... ............... 5 7 
1 0. 5. 2. 
I nf e cti o n s, I n cl u di n g H er p e s I nf e cti o n s a n d R el e v a nt P ar a siti c I nf e cti o n s .......... 5 7 
1 0. 5. 3 . 
C o nj u n cti viti s ........................................................................................................ 5 8 
1 0. 5. 4. 
H y p er s e n siti vit y ................................................... ............................................... .. 5 8 
1 0. 5. 5. 
I nj e ctio n Si t e R e a cti o n s (I S R) .............................................................................. 5 8 
1 0. 5. 6. 
M ali g n a n ci e s ........................................................................................................ 5 9 
1 0. 5. 7. 
At o pi c D er m atiti s E x a c er b ati o n ............................................................................ 5 9 
1 3. 1 . G e n er al C o n si d er ati o n s .............................................................................. ........ .. 6 2 
1 3 . 2. T a bl e , Fi g ur e , a n d Li sti n g F or m at ......................................................................... 6 2 
C CI


St ati sti c al A n al y si s Pl a n f or I nt er v e nti o n al St u di e s  
S p o n s or: A L MI R A L L, S. A.; Pr ot o c ol N o.: M- 1 7 9 2 3- 3 0 
 
 
T hi s d o c u m e nt i s c o nfi d e nti al. 
S A P t e xt V er si o n: S A P t e xt v 2. 0 2 2 M A R 2 0 2 3 
C o ntr oll e d D o c u m e nt I D: 
, Eff e cti v e D at e 3 1- A u g- 2 0 2 0 
Fili n g r e q uir e m e nt s: T M F  
 
P a g e 7  of 7 3  
I N T E R N AL U S E 
 Q u alit y C o ntr ol ................................................................................................................. 6 7  
 A p p e n di c e s ...................................................................................................................... 6 8  
 
1 4. 
1 5. 
1 3. 2. 1. 
G e n er al ................................................................................................................ 6 2 
1 3. 2. 2. 
H e a d er s ................................................................................................................ 6 2 
1 3. 2. 3. 
Di s pl a y Titl e s ........................................................................................................ 6 3 
1 3. 2. 4. 
C ol u m n H e a d er s .................................................................................................. 6 3 
1 3. 2. 5. 
B o d y of t h e D at a Di s pl a y ..................................................................................... 6 3 
1 3. 2. 6. 
F o ot n ot e s ............................................................................................................. 6 5 
C CI


St ati sti c al A n al y si s Pl a n f or I nt er v e nti o n al St u di e s  
S p o n s or: A L MI R A L L, S. A.; Pr ot o c ol N o.: M- 1 7 9 2 3- 3 0 
 
 
T hi s d o c u m e nt i s c o nfi d e nti al. 
S A P t e xt V er si o n: S A P t e xt v 2. 0 2 2 M A R 2 0 2 3 
C o ntr oll e d D o c u m e nt I D: 
, Eff e cti v e D at e 3 1- A u g- 2 0 2 0 
Fili n g r e q uir e m e nt s: T M F  
 
P a g e 8  of 7 3  
I N T E R N AL U S E 
  
Gl o s s ar y of A b br e vi ati o n s 
A b br e vi ati o n 
D e s cri pti o n 
A E 
A d v er s e E v e nt 
A D 
At o pi c d er m atiti s 
A E SI 
A d v er s e E v e nt s of S p e ci al I nt er e st 
A T C 
A n at o mi c al T h er a p e uti c C h e mi c al 
B O C F 
B a s eli n e- O b s er v ati o n- C arri e d- F or w ar d 
B S A 
B o d y S urf a c e Ar e a 
CI 
C o nfi d e n c e I nt er v al 
C D L QI 
C hil dr e n’ s D er m at ol o g y Lif e Q u alit y I n d e x 
C M H 
C o c hr a n- M a nt el- H a e n s z el 
C R F 
C a s e R e p ort F or m 
C s A 
C y cl o s p ori n e A 
C S R 
Cli ni c al st u d y r e p ort 
C T C A E 
C o m m o n T er mi n ol o g y Crit eri a f or A d v er s e E v e nt s 
C V 
C o effi ci e nt of V ari ati o n 
D L QI 
D er m at ol o g y Lif e Q u alit y I n d e x 
D L QI- R 
D L QI- R el e v a nt 
E A SI 
E c z e m a Ar e a a n d S e v erit y I n d e x ( s c or e) 
E A SI 5 0 
5 0 % r e d u cti o n fr o m b a s eli n e i n t h e E A SI s c or e 
E A SI 7 5 
7 5 % r e d u cti o n fr o m b a s eli n e i n t h e E A SI s c or e 
E A SI 9 0 
9 0 % r e d u cti o n fr o m b a s eli n e i n t h e E A SI s c or e 
F D A 
F o o d a n d Dr u g A d mi ni str ati o n 
G C P 
G o o d Cli ni c al Pr a cti c e 
I C E 
I nt er c urr e nt E v e nt 
I C H 
I nt er n ati o n al C o nf er e n c e o n H ar m o ni z ati o n 
I G A 
I n v e sti g at or’ s Gl o b al A s s e s s m e nt 
I S R 
I nj e cti o n sit e r e a cti o n 
M a x 
M a xi m u m 
M C M C MI  
M ar k o v C h ai n M o nt e- C arl o M ulti pl e I m p ut ati o n 
M M R M 
Mi x e d Eff e ct M o d el f or R e p e at e d M e a s ur e s 
1. 
C CI


St ati sti c al A n al y si s Pl a n f or I nt er v e nti o n al St u di e s  
S p o n s or: A L MI R A L L, S. A.; Pr ot o c ol N o.: M- 1 7 9 2 3- 3 0 
 
 
T hi s d o c u m e nt i s c o nfi d e nti al. 
S A P t e xt V er si o n: S A P t e xt v 2. 0 2 2 M A R 2 0 2 3 
C o ntr oll e d D o c u m e nt I D:  
, Eff e cti v e D at e 3 1- A u g- 2 0 2 0 
Fili n g r e q uir e m e nt s: T M F  
 
P a g e 9  of 7 3  
I N T E R N AL U S E 
A b br e vi ati o n 
D e s cri pti o n 
M e d D R A 
M e di c al Di cti o n ar y f or R e g ul at or y A cti viti e s 
Mi n 
Mi ni m u m 
N/ A 
N ot A p pli c a bl e 
N A 
N ot A p pli c a bl e 
N M S C 
N o n- m el a n o m a s ki n c a n c er 
N RI 
N o n-r e s p o n d er i m p ut ati o n 
OI 
O p p ort u ni sti c i nf e cti o n 
O R 
O d d s R ati o 
P O E M 
P ati e nt- Ori e nt e d E c z e m a M e a s ur e 
P P S 
P er Pr ot o c ol S et 
P R O 
P ati e nt- R e p ort e d O ut c o m e 
P T 
Pr ef err e d T er m 
Q C 
Q u alit y C o ntr ol 
Q 2 W 
E v er y 2 w e e k s 
Q 4 W 
E v er y 4 w e e k s 
Q o L 
Q u alit y of lif e 
R E C A P 
R e c a p of at o pi c e c z e m a 
S A E 
S eri o u s A d v er s e E v e nt 
S A F 
S af et y A n al y si s S et 
S A P 
St ati sti c al A n al y si s Pl a n 
S C 
S u b c ut a n e o u s 
S C O R A D  
S c ori n g At o pi c D er m atiti s 
S D 
St a n d ar d D e vi ati o n 
S E 
St a n d ar d Err or 
SI 
St a n d ar d I nt er n ati o n al S y st e m of U nit s 
S O C 
S y st e m Or g a n Cl a s s 
S O P 
St a n d ar d O p er ati n g Pr o c e d ur e 
S U S A R 
S u s p e ct e d U n e x p e ct e d S eri o u s A d v er s e R e a cti o n s 
T E A E 
Tr e at m e nt- E m er g e nt A d v er s e E v e nt 
T F L 
T a bl e, Fi g ur e a n d Li sti n g 
W H O- 5 
W orl d H e alt h Or g a ni z ati o n – Fi v e W ell- B ei n g I n d e x 
C CI


St ati sti c al A n al y si s Pl a n f or I nt er v e nti o n al St u di e s  
S p o n s or: A L MI R A L L, S. A.; Pr ot o c ol N o.: M- 1 7 9 2 3- 3 0 
 
 
T hi s d o c u m e nt i s c o nfi d e nti al. 
S A P t e xt V er si o n: S A P t e xt v 2. 0 2 2 M A R 2 0 2 3 
C o ntr oll e d D o c u m e nt I D:  
, Eff e cti v e D at e 3 1- A u g- 2 0 2 0 
Fili n g r e q uir e m e nt s: T M F  
 
P a g e 1 0  of 7 3  
I N T E R N AL U S E 
A b br e vi ati o n 
D e s cri pti o n 
W O C B P 
W o m e n of c hil d b e ari n g p ot e nti al 
 
C CI


St ati sti c al A n al y si s Pl a n f or I nt er v e nti o n al St u di e s  
S p o n s or: A L MI R A L L, S. A.; Pr ot o c ol N o.: M- 1 7 9 2 3- 3 0 
 
 
T hi s d o c u m e nt i s c o nfi d e nti al. 
S A P t e xt V er si o n: S A P t e xt v 2. 0 2 2 M A R 2 0 2 3 
C o ntr oll e d D o c u m e nt I D: 
 Eff e cti v e D at e 3 1- A u g- 2 0 2 0 
Fili n g r e q uir e m e nt s: T M F  
 
P a g e 1 1  of 7 3  
I N T E R N AL U S E 
  
P ur p o s e 
T h e p ur p o s e of t hi s st ati sti c al a n al y si s pl a n ( S A P) i s t o e n s ur e t h at t h e d at a li sti n g s, s u m m ar y t a bl e s a n d 
fi g ur e s w hi c h will b e pr o d u c e d, a n d t h e st ati sti c al m et h o d ol o gi e s w hi c h will b e u s e d, ar e c o m pl et e a n d 
a p pr o pri at e t o all o w v ali d c o n cl u si o n s r e g ar di n g t h e st u d y o bj e cti v e s. 
2. 1.  
R e s p o n si biliti e s 
 will p erf or m t h e st ati sti c al a n al y s e s a n d i s r e s p o n si bl e f or t h e pr o d u cti o n a n d q u alit y 
c o ntr ol of all t a bl e s, fi g ur e s a n d li sti n g s . 
2. 2.  
Ti mi n g s of A n al y s e s 
St u d y r e s ult s will b e d eli v er e d i n 4  p art s:  
T h e fir st r e s ult s d eli v er y will b e pr o vi d e d aft er t h e fir st d at a b a s e l o c k, o n c e all p ati e nt s h a v e c o m pl et e d 
t h e I n d u cti o n P eri o d or di s c o nti n u e d st u d y b ef or e t hi s p oi nt,   
T h e s e c o n d r e s ult s d eli v er y will b e pr o vi d e d aft er s e c o n d d at a b a s e l o c k, o n c e all p ati e nt s h a v e c o m pl et e d 
w e e k 5 2, or di s c o nti n u e d b ef or e t hi s p oi nt, a n d  
T h e t hir d r e s ult s d eli v er y will b e pr o vi d e d aft er t h e t hir d d at a b a s e l o c k, at t h e e n d of t h e st u d y, o n c e all 
p ati e nt s ( e x cl u di n g t h o s e p ati e nt s w h o j oi n e d t h e G er m a n e xt e n si o n) h a v e c o m pl et e d t h e st u d y i n cl u di n g 
f oll o w- u p ( w e e k 6 8) or di s c o nti n u e d b ef or e t hi s p oi nt. 
Fi n all y, t h e f o urt h d eli v er y will b e pr o vi d e d aft er t h e G er m a n e xt e n si o n c o m pl eti o n ( a c c or di n g t o L o c al 
Pr ot o c ol A m e n d m e nt n u m b er 4 f or G er m a n y ( d at e d 2- F e b- 2 0 2 3)). 
A c c or di n gl y, 4 diff er e nt d at a b a s e l o c k s will b e p erf or m e d. A f ull C S R i n cl u di n g I n d u cti o n P eri o d a n d 
M ai nt e n a n c e P eri o d, a n d a n a d d e n d u m w hi c h will al s o c o v er t h e f oll o w- u p st arti n g aft er w e e k 5 2 u ntil 
w e e k 6 8 pl u s t h e G er m a n e xt e n si o n p eri o d.   
2. 
C CI
P P D


St ati sti c al A n al y si s Pl a n f or I nt er v e nti o n al St u di e s  
S p o n s or: A L MI R A L L, S. A.; Pr ot o c ol N o.: M- 1 7 9 2 3- 3 0 
 
 
T hi s d o c u m e nt i s c o nfi d e nti al. 
S A P t e xt V er si o n: S A P t e xt v 2. 0 2 2 M A R 2 0 2 3 
C o ntr oll e d D o c u m e nt I D:  
, Eff e cti v e D at e 3 1- A u g- 2 0 2 0 
Fili n g r e q uir e m e nt s: T M F  
 
P a g e 1 2  of 7 3  
I N T E R N AL U S E 
  
St u d y O bj e cti v e s a n d E n d p oi nt s 
T h e 2 t a bl e s b el o w o utli n e t h e o bj e cti v e s a n d c orr e s p o n di n g e n d p oi nt s. 
M ai n O bj e cti v e  
E n d p oi nt s  
T o e v al u at e t h e effi c a c y of l e bri ki z u m a b 
c o m p ar e d wit h pl a c e b o i n p ati e nt s n ot 
a d e q u at el y c o ntr oll e d wit h c y cl o s p ori n e or f or 
w h o m c y cl o s p ori n e i s n ot m e di c all y a d vi s a bl e 
u p t o W e e k 1 6 
Pri m ar y E n d p oi nt:   
P er c e nt a g e of p ati e nt s a c hi e vi n g E A SI 7 5 ( ≥7 5 % 
r e d u cti o n fr o m B a s eli n e i n E A SI s c or e) at W e e k 1 6. 
S e c o n d ar y E n d p oi nt s:  
-  
P er c e nt a g e of p ati e nt s a c hi e vi n g I G A 0/ 1 a n d 
2- p oi nt i m pr o v e m e nt at W e e k 1 6 a . 
-  
P er c e nt a g e of p ati e nt s a c hi e vi n g a 4- p oi nt 
i m pr o v e m e nt Pr urit u s N R S at W e e k 1 6 a. 
-  
P er c e nt a g e of p ati e nt s a c hi e vi n g I G A 0/ 1 a n d 
2- p oi nt i m pr o v e m e nt b y w e e k u p t o W e e k 1 6. 
-  
P er c e nt a g e of p ati e nt s a c hi e vi n g a 4- p oi nt 
i m pr o v e m e nt Pr urit u s N R S b y w e e k u p t o 
W e e k 1 6. 
-  
P er c e nt a g e of p ati e nt s a c hi e vi n g E A SI 7 5, 
E A SI 9 0 a n d E A SI 5 0 ( b y w e e k u p t o W e e k 
1 6)  
-  
P er c e nt a g e of p ati e nt s a c hi e vi n g a 4- p oi nt 
i m pr o v e m e nt D L QI/ C D L QI b y w e e k u p t o 
W e e k 1 6  
-  
P er c e nt a g e of p ati e nt s a c hi e vi n g a 4- p oi nt 
i m pr o v e m e nt S ki n P ai n N R S at W e e k 1 6. 
-  
C h a n g e fr o m B a s eli n e B S A b y w e e k u p t o 
W e e k 1 6  
-  
C h a n g e fr o m B a s eli n e S C O R A D b y w e e k u p 
t o W e e k 1 6  
-  
C h a n g e fr o m B a s eli n e Pr urit u s N R S b y w e e k 
u p t o W e e k 1 6  
-  
C h a n g e fr o m B a s eli n e sl e e p l o s s b y w e e k u p 
t o W e e k 1 6  
-  
C h a n g e fr o m B a s eli n e P O E M b y w e e k u p t o 
W e e k 1 6  
-  
C h a n g e fr o m B a s eli n e D L QI/ C D L QI b y w e e k 
u p t o W e e k 1 6  
-  
C h a n g e fr o m B a s eli n e S ki n P ai n N R S b y 
w e e k u p t o W e e k 1 6  
-  
Pr o p orti o n of T C S-fr e e d a y s fr o m B a s eli n e b y 
w e e k u p t o W e e k 1 6 
-  
Ti m e t o T C S-fr e e u s e ( d a y s) u p t o W e e k 1 6  
 
 
E x pl or at or y E n d p oi nt s:  
3. 
C CI
C CI


St ati sti c al A n al y si s Pl a n f or I nt er v e nti o n al St u di e s  
S p o n s or: A L MI R A L L, S. A.; Pr ot o c ol N o.: M- 1 7 9 2 3- 3 0 
 
 
T hi s d o c u m e nt i s c o nfi d e nti al. 
S A P t e xt V er si o n: S A P t e xt v 2. 0 2 2 M A R 2 0 2 3 
C o ntr oll e d D o c u m e nt I D:  
, Eff e cti v e D at e 3 1- A u g- 2 0 2 0 
Fili n g r e q uir e m e nt s: T M F  
 
P a g e 1 3  of 7 3  
I N T E R N AL U S E 
 
S e c o n d ar y O bj e cti v e s  
E n d p oi nt s  
T o e v al u at e t h e effi c a c y i n p ati e nt s n ot 
a d e q u at el y c o ntr oll e d wit h c y cl o s p ori n e or f or 
w h o m c y cl o s p ori n e i s n ot m e di c all y a d vi s a bl e 
b et w e e n W e e k 1 6 u p t o W e e k 5 2. 
-  
P er c e nt a g e of p ati e nt s a c hi e vi n g I G A 0/ 1 a n d 
2- p oi nt i m pr o v e m e nt ( b y w e e k, b et w e e n 
W e e k 1 6 a n d W e e k 5 2).  
-  
P er c e nt a g e of p ati e nt s a c hi e vi n g a 4- p oi nt 
i m pr o v e m e nt Pr urit u s N R S ( b y w e e k, 
b et w e e n W e e k 1 6 a n d W e e k 5 2).  
-  
P er c e nt a g e of p ati e nt s a c hi e vi n g E A SI 7 5, 
E A SI 9 0, E A SI 5 0 ( b y w e e k, b et w e e n W e e k 
1 6 a n d W e e k 5 2)  
-  
P er c e nt a g e of p ati e nt s a c hi e vi n g a 4- p oi nt 
i m pr o v e m e nt i n D L QI/ C D L QI ( b y w e e k, 
b et w e e n W e e k 1 6 a n d W e e k 5 2).  
-  
P er c e nt a g e of p ati e nt s a c hi e vi n g a 4- p oi nt 
i m pr o v e m e nt S ki n P ai n N R S ( b y w e e k, 
b et w e e n W e e k 1 6 a n d W e e k 5 2). 
-  
C h a n g e fr o m B a s eli n e B S A ( b y w e e k, 
b et w e e n W e e k 1 6 a n d W e e k 5 2).  
-  
C h a n g e fr o m B a s eli n e S C O R A D ( b y w e e k, 
b et w e e n W e e k 1 6 a n d W e e k 5 2).  
-  
C h a n g e fr o m B a s eli n e Pr urit u s N R S ( b y 
w e e k, b et w e e n W e e k 1 6 a n d W e e k 5 2).  
-  
C h a n g e fr o m B a s eli n e sl e e p l o s s ( b y w e e k, 
b et w e e n W e e k 1 6 a n d W e e k 5 2).  
-  
C h a n g e fr o m B a s eli n e P O E M ( b y w e e k, 
b et w e e n W e e k 1 6 a n d W e e k 5 2).  
-  
C h a n g e fr o m B a s eli n e D L QI/ C D L QI ( b y w e e k, 
b et w e e n W e e k 1 6 a n d W e e k 5 2).  
-  
C h a n g e fr o m B a s eli n e S ki n P ai n N R S ( b y 
w e e k, b et w e e n W e e k 1 6 a n d W e e k 5 2)  
-  
Pr o p orti o n of T C S-fr e e d a y s fr o m B a s eli n e 
( b y w e e k, b et w e e n W e e k 1 6 a n d W e e k 5 2)  
-  
Ti m e t o T C S-fr e e u s e ( d a y s)  
-  
 
 
E x pl or at or y E n d p oi nt s:  
 
S af et y a n d T ol er a bilit y E n d p oi nt s 
T o e v al u at e t h e s af et y a n d t ol er a bilit y of 
l e bri ki z u m a b i n p ati e nt s n ot a d e q u at el y 
-  
I n ci d e n c e of A E s u p t o a n d i n cl u di n g W e e k 
1 6. A E s i n cl u d e s T E A E s, S A E s, R el at e d 
C CI
C CI
C CI


St ati sti c al A n al y si s Pl a n f or I nt er v e nti o n al St u di e s  
S p o n s or: A L MI R A L L, S. A.; Pr ot o c ol N o.: M- 1 7 9 2 3- 3 0 
 
 
T hi s d o c u m e nt i s c o nfi d e nti al. 
S A P t e xt V er si o n: S A P t e xt v 2. 0 2 2 M A R 2 0 2 3 
C o ntr oll e d D o c u m e nt I D:  
 Eff e cti v e D at e 3 1- A u g- 2 0 2 0 
Fili n g r e q uir e m e nt s: T M F  
 
P a g e 1 4  of 7 3  
I N T E R N AL U S E 
c o ntr oll e d wit h c y cl o s p ori n e or f or w h o m 
c y cl o s p ori n e i s n ot m e di c all y a d vi s a bl e u p t o 
W e e k 1 6 
 
T E A E s, R el at e d S A E s, T E A E s l e a di n g t o 
st u d y tr e at m e nt di s c o nti n u ati o n, A E SI s a n d 
D e at h s. 
-  
O b s er v e d r e s ult s a n d c h a n g e s fr o m B a s eli n e 
i n L a b or at or y R e s ult s ( H a e m at ol o g y, 
C h e mi str y a n d Uri n al y si s) t o W e e k 1 6. 
-  
O b s er v e d r e s ult s a n d c h a n g e s fr o m B a s eli n e 
i n Vit al Si g n s R e s ult s t o W e e k s 2, 4, 8, 1 2 
a n d 1 6.  
-  
P er c e nt a g e of p ati e nt s wit h a b n or m aliti e s i n 
p h y si c al e x a mi n ati o n at W e e k 1 6. 
T o e v al u at e t h e s af et y a n d t ol er a bilit y of 
l e bri ki z u m a b i n p ati e nt s n ot a d e q u at el y 
c o ntr oll e d wit h c y cl o s p ori n e or f or w h o m 
c y cl o s p ori n e i s n ot m e di c all y a d vi s a bl e u p t o 
W e e k 5 2/ 6 8 
-  
I n ci d e n c e of A E s u p t o a n d i n cl u di n g W e e k 
5 2/ 6 8. A E s i n cl u d e s T E A E s, S A E s, R el at e d 
T E A E s, R el at e d S A E s, T E A E s l e a di n g t o 
st u d y tr e at m e nt di s c o nti n u ati o n, A E SI s a n d 
D e at h s. 
-  
O b s er v e d r e s ult s a n d c h a n g e s fr o m B a s eli n e 
i n L a b or at or y R e s ult s ( H a e m at ol o g y, 
C h e mi str y a n d Uri n al y si s) t o W e e k s 3 2 a n d 
5 2.  
-  
O b s er v e d r e s ult s a n d c h a n g e s fr o m B a s eli n e 
i n Vit al Si g n s R e s ult s t o W e e k s 2 0, 2 4, 2 8, 
3 2, 3 6, 4 0, 4 4, 4 8 a n d 5 2.  
-  
P er c e nt a g e of p ati e nt s wit h a b n or m aliti e s i n 
p h y si c al e x a mi n ati o n at W e e k s 3 2 a n d 5 2. 
F or p ati e nt s e nt eri n g t h e E xt e n si o n P eri o d, t o 
e v al u at e t h e l o n g-t er m effi c a c y, s af et y, a n d 
t ol er a bilit y of l e bri ki z u m a b i n p ati e nt s n ot 
a d e q u at el y c o ntr oll e d wit h c y cl o s p ori n e or f or 
w h o m c y cl o s p ori n e i s n ot m e di c all y a d vi s a bl e 
u p t o e n d of tri al i n G er m a n y ( a c c or di n g t o 
l o c al pr ot o c ol a m e n d m e nt 4 f or G er m a n y) 
-  
P er c e nt a g e of p ati e nt s a c hi e vi n g E A SI 7 5, 
E A SI 9 0, E A SI 5 0; I G A 0/ 1 a n d 2- p oi nt 
-  
I m pr o v e m e nt, a n d 4- p oi nt i m pr o v e m e nt 
Pr urit u s N R S b y vi sit. 
-  
C h a n g e fr o m B a s eli n e i n B S A, S C O R A D, 
Pr urit u s N R S, sl e e p l o s s, D L QI/ C D L QI, a n d 
S ki n P ai n N R S b y vi sit. 
-  
P er c e nt a g e of p ati e nt s a c hi e vi n g a 4- p oi nt 
i m pr o v e m e nt i n D L QI/ C D L QI b y vi sit. 
I n ci d e n c e of A E s b y vi sit. A E s i n cl u d e s 
T E A E s, S A E s, R el at e d T E A E s, R el at e d 
S A E s, 
-  
T E A E s l e a di n g t o st u d y tr e at m e nt 
di s c o nti n u ati o n, A E SI s a n d D e at h s. 
-  
O b s er v e d r e s ult s a n d c h a n g e s fr o m B a s eli n e 
i n L a b or at or y R e s ult s ( H a e m at ol o g y, 
C h e mi str y a n d Uri n al y si s) b y vi sit. 
-  
O b s er v e d r e s ult s a n d c h a n g e s fr o m B a s eli n e 
i n Vit al Si g n s R e s ult s b y vi sit. 
-  
P er c e nt a g e of p ati e nt s wit h a b n or m aliti e s i n 
p h y si c al e x a mi n ati o n b y vi sit. 
E x pl or at or y O bj e cti v e s  
Ot h er E n d p oi nt s  
C CI
C CI


St ati sti c al A n al y si s Pl a n f or I nt er v e nti o n al St u di e s  
S p o n s or: A L MI R A L L, S. A.; Pr ot o c ol N o.: M- 1 7 9 2 3- 3 0 
 
 
T hi s d o c u m e nt i s c o nfi d e nti al. 
S A P t e xt V er si o n: S A P t e xt v 2. 0 2 2 M A R 2 0 2 3 
C o ntr oll e d D o c u m e nt I D:  
, Eff e cti v e D at e 3 1- A u g- 2 0 2 0 
Fili n g r e q uir e m e nt s: T M F  
 
P a g e 1 5  of 7 3  
I N T E R N AL U S E 
a r el at e s t o K e y s e c o n d ar y e n d p oi nt s . W hil e t h e s a m pl e si z e i s ali g n e d wit h t h e pri m ar y e n d p oi nt, t h e s e e n d p oi nt s 
ar e al s o of i nt er e st i n t h e fi n al o ut c o m e s of t h e st u d y. T h e s a m pl e si z e i s a p pr o pri at el y ali g n e d wit h t h e pri m ar y a n d 
k e y s e c o n d ar y e n d p oi nt s. 
C CI
C CI


St ati sti c al A n al y si s Pl a n f or I nt er v e nti o n al St u di e s  
S p o n s or: A L MI R A L L, S. A.; Pr ot o c ol N o.: M- 1 7 9 2 3- 3 0 
 
 
T hi s d o c u m e nt i s c o nfi d e nti al. 
S A P t e xt V er si o n: S A P t e xt v 2. 0 2 2 M A R 2 0 2 3 
C o ntr oll e d D o c u m e nt I D:  
, Eff e cti v e D at e 3 1- A u g- 2 0 2 0 
Fili n g r e q uir e m e nt s: T M F  
 
P a g e 1 6  of 7 3  
I N T E R N AL U S E 
  
St u d y D e si g n 
4. 1.  
Bri ef D e s cri pti o n 
T hi s i s a r a n d o mi s e d, d o u bl e- bli n d, pl a c e b o- c o ntr oll e d, p ar all el- gr o u p st u d y, 7 2 w e e k s i n d ur ati o n ( u p t o 4 
w e e k s of S cr e e ni n g, 5 2 w e e k s of tr e at m e nt [l a st d o s e gi v e n at W e e k 5 0], a n d 1 8 w e e k s of p o st-l a st d o s e 
s af et y f oll o w- u p). T h e st u d y i s d e si g n e d t o c o nfir m t h e effi c a c y a n d s af et y of l e bri ki z u m a b a d mi ni st er e d 
c o n c o mit a ntl y wit h T C S i n a d ol e s c e nt s a n d a d ult s wit h m o d er at e-t o- s e v er e A D n ot a d e q u at el y c o ntr oll e d 
wit h c y cl o s p ori n e or f or w h o m c y cl o s p ori n e i s n ot m e di c all y a d vi s a bl e. 
 
T h e st u d y h a s 2 tr e at m e nt p eri o d s: a 1 6- w e e k d o u bl e- bli n d I n d u cti o n P eri o d f oll o w e d b y a 3 6- w e e k o p e n-
l a b el M ai nt e n a n c e P eri o d. T h e st u d y will b e d o u bl e- bli n d u ntil W e e k 1 8 a n d o p e n-l a b el fr o m W e e k 2 0 
o n w ar d.  
 
S cr e e ni n g p eri o d  
T h e S cr e e ni n g P eri o d will st art wit h t h e S cr e e ni n g vi sit a n d c o nti n u e u ntil r a n d o mi s ati o n. El e ctr o ni c di ar y 
c oll e cti o n will b e gi n at s cr e e ni n g. 
 
B a s eli n e a n d D o u bl e- Bli n d e d I n d u cti o n P eri o d ( w e e k 0 t o w e e k 1 6) 
At b a s eli n e vi sit ( D a y 1), p ati e nt s w h o m e et t h e st u d y eli gi bilit y crit eri a will b e 2: 1 r a n d o ml y a s si g n e d t o 
t h eir i n d u cti o n tr e at m e nt s wit h str atifi c ati o n b a s e d o n pr e vi o u s u s e of d u pil u m a b ( Y e s / N o), a g e 
( a d ol e s c e nt p ati e nt s ≤1 2 t o < 1 8 v er s u s a d ult s ≥1 8 y e ar s) a n d b a s eli n e di s e a s e s e v erit y (I G A 3/ I G A 4).  
T h e tr e at m e nt gr o u p s i n t h e Bli n d e d I n d u cti o n P eri o d ar e: 
-  
L e bri ki z u m a b 2 5 0 m g e v er y 2 w e e k s ( Q 2 W): 5 0 0 m g l e bri ki z u m a b a d mi ni st er e d at B a s eli n e a n d 
W e e k 2 (l o a di n g d o s e) 
-  
Pl a c e b o b y S u b c ut a n e o u s ( S C) i nj e cti o n Q 2 W 
 
M ai nt e n a n c e P eri o d ( w e e k 1 6 t o w e e k 5 2) 
T h e p ati e nt s w h o r e c ei v e d pl a c e b o d uri n g t h e I n d u cti o n P eri o d will r e c ei v e l o a di n g d o s e s of l e bri ki z u m a b 
at W e e k s 1 6 a n d 1 8. T o m ai nt ai n bli n di n g at W e e k s 1 6 a n d 1 8, all p ati e nt s will r e c ei v e 2 i nj e cti o n s at 
W e e k s 1 6 a n d 1 8 ( eit h er 2 i nj e cti o n s of l e bri ki z u m a b or 1 i nj e cti o n of l e bri ki z u m a b a n d 1 i nj e cti o n of 
pl a c e b o). Fr o m W e e k 2 0 o n w ar d, all p ati e nt s will r e c ei v e o p e n l a b el 1 i nj e cti o n of l e bri ki z u m a b 2 5 0 m g 
e v er y 2 w e e k s ( Q 2 W).  
 
E xt e n si o n P eri o d f or G er m a n y a c c or di n g t o Pr ot o c ol A m e n d m e nt 4  
A c c or di n g t o L o c al pr ot o c ol a m e n d m e nt 4 f or G er m a n y ( d at e d 2- F e b- 2 0 2 3), E xt e n si o n P eri o d tr e at m e nt 
d ur ati o n i s a mi ni m u m of 6 m o nt h s ( 2 4 w e e k s) f oll o wi n g W e e k 5 2 a n d u ntil l e bri ki z u m a b i s c o m m er ci all y 
a v ail a bl e i n G er m a n y. M ai nt e n a n c e d o s e c h a n g e d t o o n c e e v er y 4 w e e k s ( Q 4 W) d uri n g t h e E xt e n si o n 
P eri o d, wit h r et ur n t o o n c e e v er y 2 w e e k s ( Q 2 W) all o w e d at t h e I n v e sti g at or’ s di s cr eti o n. 
 
S af et y F oll o w- u p Vi sit 
P ati e nt s w h o t er mi n at e e arl y fr o m t h e st u d y or d o n ot e nr oll i n t h e l o n g-t er m e xt e n si o n st u d y, will u n d er g o 
a f oll o w -u p vi sit a p pr o xi m at el y 1 8 w e e k s ( 4 w e e k s f or p ati e nt s i n G er m a n y w h o j oi n e d E xt e n si o n p eri o d) 
aft er t h e l a st st u d y dr u g i nj e cti o n. 
4. 
4. 1. 1. 
4. 1. 2. 
4. 1. 3. 
4. 1. 4. 
4. 1. 5. 
C CI


St ati sti c al A n al y si s Pl a n f or I nt er v e nti o n al St u di e s  
S p o n s or: A L MI R A L L, S. A.; Pr ot o c ol N o.: M- 1 7 9 2 3- 3 0 
 
 
T hi s d o c u m e nt i s c o nfi d e nti al. 
S A P t e xt V er si o n: S A P t e xt v 2. 0 2 2 M A R 2 0 2 3 
C o ntr oll e d D o c u m e nt I D:  
, Eff e cti v e D at e 3 1- A u g- 2 0 2 0 
Fili n g r e q uir e m e nt s: T M F  
 
P a g e 1 7  of 7 3  
I N T E R N AL U S E 
4. 2.  
P ati e nt S el e cti o n 
A s uffi ci e nt n u m b er of p ati e nt s will b e s cr e e n e d t o r a n d o mi s e a p pr o xi m at el y 3 1 2 p ati e nt s wit h m o d er at e-
t o- s e v er e A D. 
A d ol e s c e nt p ati e nt s ( a g e d ≥1 2 t o < 1 8 y e ar s w ei g hi n g ≥4 0 k g) will b e i n cl u d e d a n d will r e c ei v e t h e s a m e 
d o s e s of l e bri ki z u m a b a s f or a d ult s ( a d ol e s c e nt p ati e nt s a g e d ≥1 2 t o < 1 8 y e ar s will m a k e u p 1 2. 5 % of t h e 
o v er all p o p ul ati o n c o m p ar e d t o a d ult s a g e d ≥1 8 y e ar s).  
 
I n cl u si o n Crit eri a 
P ati e nt s eli gi bl e f or i n cl u si o n i n t hi s tri al m u st f ulfil all crit eri a d e s cri b e d i n s e cti o n 8. 2 of pr ot o c ol. 
 
E x cl u si o n Crit eri a 
P ati e nt s f ulfilli n g a n y of t h e crit eri a d e s cri b e d i n s e cti o n 8. 3 of pr ot o c ol ar e n ot eli gi bl e f or i n cl u si o n i n t hi s 
tri al. 
4. 3.  
D et er mi n ati o n of S a m pl e Si z e 
T h e st u d y i s d e si g n e d t o g ai n a n e sti m at e of t h e eff e ct of st u d y tr e at m e nt i n t h e p ati e nt p o p ul ati o n of 
a d ult s a n d a d ol e s c e nt p ati e nt s n ot a d e q u at el y c o ntr oll e d wit h c y cl o s p ori n e or f or w h o m c y cl o s p ori n e i s 
n ot m e di c all y a d vi s a bl e. T h e s a m pl e si z e f or t hi s st u d y h a s b e e n e sti m at e d t o all o w p o w er e n o u g h t o 
s h o w effi c a c y i n t h e o v er all st u d y p o p ul ati o n f or t h e pri m ar y a n d k e y s e c o n d ar y e n d p oi nt s. 
A t ot al s a m pl e si z e of 3 1 2 p ati e nt s, i n a 2: 1 r ati o ( 2 0 8 l e bri ki z u m a b ar m a n d 1 0 4 pl a c e b o ar m) will pr o vi d e 
m or e t h a n 9 5 % n o mi n al p o w er t o d et e ct a st ati sti c all y si g nifi c a nt diff er e n c e of 2 5 % ( 5 5 % l e bri ki z u m a b 
ar m v er s u s 3 0 % pl a c e b o ar m) i n t h e pri m ar y st u d y e n d p oi nt: pr o p orti o n of p ati e nt s a c hi e vi n g E A SI 7 5 at 
W e e k 1 6. A s r ef er e n c e a n d c o n si d eri n g i n d e p e n d e n c e b et w e e n v ari a bl e s, t hi s s a m e s a m pl e si z e will al s o 
pr o vi d e m or e t h a n 9 0 % o v er all p o w er t o al s o d et e ct a diff er e n c e of 1 8 % ( 3 0 % l e bri ki z u m a b ar m v er s u s 
1 2 % pl a c e b o ar m) i n t h e pr o p orti o n of p ati e nt s a c hi e vi n g I G A ( 0/ 1) at W e e k 1 6 a n d of 3 4 % diff er e n c e s 
( 4 3 % l e bri ki z u m a b ar m v er s u s 9 % pl a c e b o ar m) i n t h e pr o p orti o n of p ati e nt s a c hi e vi n g a 4- p oi nt pr urit u s 
n u m eri c al r ati n g s c al e ( N R S) d e cr e a s e fr o m B a s eli n e at W e e k 1 6. A t w o- si d e d t y p e o n e err or of 5 % h a s 
b e e n a s s u m e d.  
4. 4.  
Tr e at m e nt A s si g n m e nt a n d Bli n di n g 
T h e 1 6- w e e k I n d u cti o n P eri o d i s a d o u bl e- bli n d tr e at m e nt p eri o d. W hil e t h e M ai nt e n a n c e P eri o d i s 
g e n er all y o p e n-l a b el, t h e W e e k s 1 6 a n d 1 8 d o s e s will r e m ai n bli n d e d s o a s t o all o w f or p ati e nt s i n t h e 
pl a c e b o ar m t o r e c ei v e a bli n d e d l o a di n g d o s e b ef or e r e c ei vi n g m ai nt e n a n c e o p e n-l a b el l e bri ki z u m a b 
d uri n g t h e M ai nt e n a n c e P eri o d (fr o m W e e k 2 0 o n w ar d).  
A cti v e a n d pl a c e b o m e di c ati o n will b e s u p pli e d i n i n di vi d u al c art o n b o x e s c o nt ai ni n g 1 s yri n g e e a c h. 
L e bri ki z u m a b s yri n g e s c a n n ot b e di sti n g ui s h e d vi s u all y fr o m pl a c e b o s yri n g e s, a s t h e y h a v e a n i d e nti c al 
a p p e ar a n c e a n d c o m p o n e nt s, i n cl u di n g t h e s yri n g e, n e e dl e s af et y d e vi c e, f ol di n g c art o n, a n d l a b el s.  
A m e di c ati o n n u m b eri n g s y st e m will b e u s e d i n l a b elli n g bli n d e d st u d y dr u g. Li st s li n ki n g m e di c ati o n 
n u m b er s wit h pr o d u ct l ot n u m b er s will b e m ai nt ai n e d b y t h e gr o u p s ( or c o m p a ni e s) r e s p o n si bl e f or st u d y 
dr u g p a c k a gi n g. T o m ai nt ai n t h e bli n d, t h e s e li st s will n ot b e a c c e s si bl e t o i n di vi d u al s i n v ol v e d i n st u d y 
c o n d u ct.  
N o st u d y sit e p er s o n n el, p ati e nt s, S p o n s or p er s o n n el, or S p o n s or d e si g n e e s will b e u n bli n d e d t o 
4. 2. 1. 
4. 2. 2. 
C CI


St ati sti c al A n al y si s Pl a n f or I nt er v e nti o n al St u di e s  
S p o n s or: A L MI R A L L, S. A.; Pr ot o c ol N o.: M- 1 7 9 2 3- 3 0 
 
 
T hi s d o c u m e nt i s c o nfi d e nti al. 
S A P t e xt V er si o n: S A P t e xt v 2. 0 2 2 M A R 2 0 2 3 
C o ntr oll e d D o c u m e nt I D:  
, Eff e cti v e D at e 3 1- A u g- 2 0 2 0 
Fili n g r e q uir e m e nt s: T M F  
 
P a g e 1 8  of 7 3  
I N T E R N AL U S E 
tr e at m e nt a s si g n m e nt t hr o u g h o ut t h e st u d y u nl e s s u n bli n di n g i s r e q uir e d. If a n I n v e sti g at or b e c o m e s 
u n bli n d e d t o a gi v e n p ati e nt’ s st u d y tr e at m e nt, t h at p ati e nt will b e di s c o nti n u e d fr o m t h e st u d y u nl e s s 
t h er e ar e et hi c al r e a s o n s f or t h at p ati e nt n ot t o b e di s c o nti n u e d; a p pr o v al fr o m t h e S p o n s or’ s m e di c al 
m o nit or m u st b e o bt ai n e d i n s u c h i n st a n c e s. 
I n t h e e v e nt t h at e m er g e n c y u n bli n di n g i s r e q uir e d f or a gi v e n p ati e nt b e c a u s e of A E s or c o n c er n s f or t h e 
p ati e nt’ s s af et y or w ell- b ei n g, t h e I n v e sti g at or m a y br e a k t h e r a n d o mi s ati o n c o d e f or t h e p ati e nt vi a t h e 
I W R S, b y w hi c h s y st e m t h e u n bli n di n g will b e c a pt ur e d. T h e I n v e sti g at or i s r e s p o n si bl e f or n otif yi n g t h e 
m e di c al m o nit or a n d/ or S p o n s or of s u c h a n e v e nt a s s o o n a s p o s si bl e. T h e S p o n s or, C R O/ v e n d or s 
i n v ol v e d i n t h e cli ni c al c o n d u ct of t h e tri al, t h e I n v e sti g at or s, tri al sit e p er s o n n el, a n d p ati e nt s will b e 
bli n d e d t o t h e tr e at m e nt t h at i s a s si g n e d t o e a c h p ati e nt.  
4. 5.  
A d mi ni str ati o n of St u d y M e di c ati o n 
Tr e at m e nt will b e gi n o n D a y 1, aft er c o nfir m ati o n of p ati e nt eli gi bilit y a n d c oll e cti o n of all pr e d o s e s a m pl e s 
a n d a s s e s s m e nt s. D uri n g t h e 1 6- w e e k I n d u cti o n P eri o d, p ati e nt s will r e c ei v e eit h er 2 5 0 m g l e bri ki z u m a b 
(l o a di n g d o s e of 5 0 0 m g gi v e n at B a s eli n e a n d W e e k 2) or pl a c e b o b y S C i nj e cti o n Q 2 W. T h e st u d y dr u g 
i nj e cti o n will b e a d mi ni st er e d i n t h e cli ni c d uri n g t h e fir st 4 w e e k s of tr e at m e nt a s w ell a s at W e e k s 8, 1 2, 
1 6, a n d 1 8. P ati e nt s will h a v e t h e o pti o n t o s elf- a d mi ni st er t h e st u d y dr u g or g et it a d mi ni st er e d b y a 
c ar e gi v er o ut si d e of t h e st u d y sit e d uri n g w e e k s i n w hi c h n o o n- sit e cli ni c vi sit i s s c h e d ul e d fr o m W e e k 4 
o n w ar d. P ati e nt s ( a n d/ or c ar e gi v er s) will b e tr ai n e d o n st u d y dr u g st or a g e r e q uir e m e nt s, a n d o n i nj e cti n g 
st u d y dr u g u ntil c o m p et e n c y h a s b e e n d e m o n str at e d. Aft er c o m pl eti o n of t h e W e e k 1 6 vi sit, p ati e nt s will 
e nt er t h e M ai nt e n a n c e P eri o d: 
-  
P ati e nt s w h o r e c ei v e d l e bri ki z u m a b 2 5 0 m g Q 2 W d uri n g t h e I n d u cti o n P eri o d will c o nti n u e t o 
r e c ei v e l e bri ki z u m a b 2 5 0 m g Q 2 W d uri n g t h e M ai nt e n a n c e P eri o d  
-  
P ati e nt s w h o r e c ei v e d pl a c e b o Q 2 W d uri n g t h e I n d u cti o n P eri o d will st art r e c ei vi n g l e bri ki z u m a b 
2 5 0 m g Q 2 W ( wit h l o a di n g d o s e s at W e e k 1 6 a n d W e e k 1 8) d uri n g t h e M ai nt e n a n c e P eri o d T o 
all o w p ati e nt s i n t h e pl a c e b o ar m t o r e c ei v e t h e s e l o a di n g d o s e s d uri n g t h e M ai nt e n a n c e P eri o d, 
bli n di n g will b e m ai nt ai n e d at W e e k 1 6 a n d W e e k 1 8. I n or d er t o m ai nt ai n t h e d o u bl e bli n d, 
p ati e nt s fr o m t h e l e bri ki z u m a b 2 5 0 m g Q 2 W ar m will b e a d mi ni st er e d a s e c o n d i nj e cti o n of 
bli n d e d pl a c e b o d uri n g W e e k 1 6 a n d W e e k 1 8. Fr o m W e e k 2 0 o n w ar d s, all p ati e nt s will r e c ei v e 1 
i nj e cti o n of l e bri ki z u m a b 2 5 0 m g Q 2 W. T h er ef or e, t h e st u d y will b e o p e n-l a b el fr o m W e e k 2 0 
o n w ar d. Pl e a s e s e e t h e P h ar m a c y M a n u al f or d et ail s o n S C i nj e cti o n sit e m a n a g e m e nt. 
C CI


St ati sti c al A n al y si s Pl a n f or I nt er v e nti o n al St u di e s  
S p o n s or: A L MI R A L L, S. A.; Pr ot o c ol N o.: M- 1 7 9 2 3- 3 0 
 
 
T hi s d o c u m e nt i s c o nfi d e nti al. 
S A P t e xt V er si o n: S A P t e xt v 2. 0 2 2 M A R 2 0 2 3 
C o ntr oll e d D o c u m e nt I D: 
 Eff e cti v e D at e 3 1- A u g- 2 0 2 0 
Fili n g r e q uir e m e nt s: T M F  
 
P a g e 1 9  of 7 3  
I N T E R N AL U S E 
4. 6.  
St u d y Pr o c e d ur e s a n d Fl o w c h art 
 
 
 
Sc ree ni n g a n d I n d u cti o n Pe ri o d 
S t u dy P r o c e d u r es 
Sc. ree n i ng 
In d u ct i o n P c r i o dJ; 
St u d y visil 
I 
2 
3 
4 
5• 
6 
7• 
8 
9• 
l O 
D a y/ W e c k ( W) 
W- 4 l o Da y- I  
Da y I- B as eli n e 
\ V 2 
W 4 
\ V 6 
W 8 
W I  O 
W l 2 
Wl 4 
\ Vl 6' 
Visit wi n d o w d 
± 3 d 
±'.I d 
; c J d ctl d 
B d 
;cJ d 
;t3 d 
ctl d 
Virt ual visit (as per patie nt a n d l n vcsti gal or pr ef er e n c e) 
a 
a 
w 
l nfo m 1e d c o n.se n t f or m/inf o m 1c d asse nt f or m 
X 
Fit z p atri c k s c ale 
X 
I ncl usi o n a n d e xcl usi o n critrri a 
X 
X 
D c m o gr a p bi cs a n d m e di c a l hist or y 
X 
X 
R e vi e w of im m u nis ati o n rec or d (f or a d ol es c e nts) 
X 
R a n d o mis ati o n 
X 
Vita l si g ns 
X 
X  
X  
X  
X 
X 
X 
P h ysic al e x a min a ti o n a n d he ig ht, wci g ht .1 a n d B M l m c as u r e m c nl 
x• 
X 
A Es 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Pri or a n d c o nc o m ita nl me dic ati o ns/t her a p ies 
X 
X  
X  
X  
X  
X  
X  
X 
X 
X 
S er ol o g y ( H N, he patitis B a n d C) a n d c o a g u lati o n ( a P TI, P T , I N R) 
X 
H ae m at o lo g y a n d c hc m istr yr 
X 
X 
Uri n al ysis 
X 
X 
P r e g n a n c y test a n d c o nt r a c e pti o n c h e c k s 
x• 
x• 
X' 
X' 
x• 
X' 
Pr c d o s c bi o m ar k crs bl o o d sa m ple 
X 
X 
IG A , E A SI, a n d B S A; 
X 
X  
X  
X  
X 
X 
X 
S C O R A D ; 
X 
X 
X 
D is pc nsc c Di ar y 
X 
T r ai n/ c h e c k u n derst a n d i n g of r e c o r di n g d at a i n t he c D iar y 
X 
X 
X 
X 
X 
X  
X 
X 
X  
X 
Pr urit us N R S " , Slee p -l oss s c ale'-', S ki n Pai n N R S u, 
X 
x, 
xj 
Xi 
)(I 
x, 
Xi 
Xi 
X J 
Xi 
P O E M. R E C A P' 
X 
X  
X 
X 
X 
D L QI or C D L Ql , D L Q I- R; 
X  
X  
X  
X 
X 
X 
W H 0 - 5• 
X 
X 
T S Q M- 9; 
X 
X 
P h ol o gr a p b y' 
X  
X  
X  
X 
X 
Tr ai n i n g a u toi njccti o n 
X 
X 
A d mi nist e r stu d y dr u g a n d Pr o d uct C o m pl ai n t re p orti n g 
X  
X  
X  
X  
X  
X  
X  
X  
X 
Ass ess tre at me n t c o m pli a n cc m 
X  
X  
X  
X 
X 
X  
X  
X 
A b b re vi ati o ns: A E = a d v e rs e e ve nt;, a PT T = acti v ate d p arti al t hr n m b o plasti n ti me; B Ml = b o d y m ass i n de x; B S A = b o d y s urf ace are a ; C D L QI = C h il dre n Der m at o l o g y Lif e 
Q u alit y I nde .,; d = d a y ;  DL Q I = D er m a tol o g y Lif e Q ual it y I n de x ; D L Q I- R = D L QI -Rcle va n l: E A S I = Ecze ma Arca a o d S e v erit y In de x; c D i ar y = el e ctr o ni c di ar y ; HI V = 
h u m a n i m m u n o deficie nc y vir us ; h C G = h u m a n c h ori o nic g o n:i d otr o p i n; I G A = l n vcsti g at or'.s Gl o b al Assess me nt ; (N R = l ntcr n ati o m 1l N o ml.l lisc d R ati o; N R S = N u meric al 
Rati n g Scale ; PO E M = P atie n t-Ori e nt e d Ecze ma M e as ur e ; P T = Pr ot hr o m bi n ti m e; Q 2 W = e ver y 2 wee ks ; R E C A P = Reca p of Al o pic Ecze ma; S C O R A D = S c ori n g At o pic 
D c n n atitis: T C S = to pi c a l c orti c ost er oi ds ; T S Q M - 9 = Tr e at m e nt S atisf a cti o n Q u est io n nai re f or M c di c ati o n- 9 ite ms ; W = wee k ; W H O- 5 = W or l d Hea lt h Or g a nis ati o n -Fi v e 
Well -B ei n g I n de x ; W O C B P = w o me n of c h ild b e ari n g p olc n tial. 
b. 
.. 
A saJ'ct y f oll o w-u p will o c c ur 1 8 wee ks afler lasl d os e of slu d y me dicati o n (i n cl u di n g b o th e n d - of-treat me nt peri o d or aft er e arl y lc m,i n ati o n . 
Visits s h a d ed i n bl ue ma y be c o n d u ct e d re m ote l y or o n -si te, pe r p n:fcrc ncc of t he st u d y site or patie nt. W 6 8 wi ll be o n -site f or W O C B P o n l y. 
F or p a tie nts w h o recei ve d pl ace b o d uri n g t he In d uct io n P eri o d , lo a d i ng d oses of lc bri kiz u m a b wi U be gi ve n at \ V 16 a n d WI 8 d uri n g the M ai nte n a nce Peri o d. I n or der 
t o mai ntai n t h e d o u ble -bli n d, p ati e nts fr o m t h e lc bri kiz u ma b 2 5 0 m g Q 2 W ar m will be a d mi nist er e d a sec o n d i njecti o n of bli n de d pl a c e b o d uri n g W 16 a n d WI 8. Fr o m 
W 2 0 o n w a rds, a ll p ati e nts wi ll recei ve I i njecti on ofl c b ri kiz u mab 2 5 0 m g Q 2 W . 
Visit wi n d o w f or p at ie nt-re p orte d o utc o mes is - 3 dil. ys d uri n g l n d ucti o n Peri o d a n d - 5 d a ys d uri ng M ai nte n a nce Peri o d. 
F or a d ul ts, br i g h t s h o ul d o nl y be c a pt ur e d at Scree ni n g. F or a d olesce n ts, hei g ht s h o ul d o nl y b e c a pt ur e d at S cr e e ni n g a n d Wec k 5 2 . 
P atie nts s h o ul d a tte n d t he visi t f as te d . Pa tie n ts s h o ul d n ot c al or dri n k a n ytl 1 in g e xce pt w ater f or 8 ho urs bef ore s a m ple. c oll e c tio n . Alc o h o l c o ns u m pti o n will n o t be 
p c n nitt c d f or at least 8 h o ws bef ore vis its. Stre n u o us p h ysical a cti vit y s h o ul d be a v oi de d f or al leas t 8 h o urs b ef o re a vis it. 
T he c o n trace pti o n c hec k is l o c o nfir m t h at c o nt r a c e p ti o n, if re q uire d ~ is use d c o nsist e ntl y a n d c orrectl y . 
Scr u m b ct a -h C G at Scree ni n g. Uri n e pre g n a n c y tes t at all ot h e r i dc n tjfi e d visits . If re q uire d per loc al re g u lati o ns a n d/ o r instit u ti o n al g ui d eli n es , pr q ,r n a nc y testi n g c a n 
occ ur at ot her ti mes d uri n g t he st u d y tre at me nt pe ri o d . F or \V O C B P . uri ne pr e g n a nc y tests wi ll be c o n d ucte d e ver y 4 w e e ks afler last d o s e of stu d y me dic ati o n (\ 1/ 5 4, 
W 5 8, a n d W 6 2) a n d at W 6 8. Male s u bj e cts e n g a g e d i n a relati o ns hi p wit h a W O C B P m ust be c o ntacte d e ver y 4 w e e ks aft er lasl d os e of st ud y me dicati o n ( W 5 4. W 5 8. 
a n d W 6 2) a n d at W 6 8 t o e ns u re res p e ct of t he c o nt race pti o n. 
P atie nt -re p orte d o ut c o m es a n d q u ality of life m e as u r e m e nts s ho ul d a ll be c o m ple te d bef ore ot her st u dy assess me nts . Ass es sm e nt s/pr oce d ure s s h o ul d be c o n d ucte d i n 
t he f oll o wi n g or der. l) p atie nt -re p o rte d o ut c o m es ; 2) I n vesti g at or assess me nts a n d ot her effi c a c y assess me nts ; 3) s afe ty a n d la b o r ator y ass css m c nt,o;; (i n cl udi n g s a m p l e 
c oll e cti o n f or bi o m ar k ers) ; a n d 4) a d m inistr a ti o n of st u dy dr u g . C o m pl ete d c D iar y e ntri es f or Pr ur it us R S a n d sl e e p- loss s c al es arc n e e d e d f or a mi ni m u m of 4 o ut 
of 7 d a ys i n t he w e e k prece di n g r a n d o mis ati o n visi t. 
T o be p crf o n n c d da il y u p t o W 2 , w e e kl y fr o m W 2 t o WI 6 , a n d e v er y 2 w e e ks fr o m Wl 6 o n w ar d . 
T o b e perf o m 1e d d ail y u p l o W 2, w e e kl y fr o m W 2 l o WI 6 , a n d e v er y 4 wee ks fr o m Wl 6 o n wa r d. 
F o r p ati e nts w h o c o ns e nt at se lecte d si tes. 
C o m pl ian ce ass ess m e n t f or st ud y dr u g , TC S , as well as acc o u nta bili 1 y . 
C CI


St ati sti c al A n al y si s Pl a n f or I nt er v e nti o n al St u di e s  
S p o n s or: A L MI R A L L, S. A.; Pr ot o c ol N o.: M- 1 7 9 2 3- 3 0 
 
 
T hi s d o c u m e nt i s c o nfi d e nti al. 
S A P t e xt V er si o n: S A P t e xt v 2. 0 2 2 M A R 2 0 2 3 
C o ntr oll e d D o c u m e nt I D:  
, Eff e cti v e D at e 3 1- A u g- 2 0 2 0 
Fili n g r e q uir e m e nt s: T M F  
 
P a g e 2 0  of 7 3  
I N T E R N AL U S E 
 
 
 
l\il aint e n a n ce P e l'i o d a n d S afe h ' F o llo w- u p 0 
S afet y 
St u d y Pr o c e d u .-es 
:\f ai nle u a n c e Pea ·io d 
F o llo w 
- u p 
Yi sif>, A 
St u d y visi t 
II 
12 
1 3 • 
1 4 
1 s• 
1 6 
1 1• 
1 8 
1 9• 
2 0 
2 1b 
2 2 
2 3 b 
2 4 
2 5 b 
2 6 
2J b 
2 8 
2 9 b 
D a y /W e e k ( W) 
W I
S < 
W 2 0 
W 2 2 
W 2 4 
W 2 6  W 2 8  W 3 0 
W 3 2 
W 3 4 
W 3 6 
\ V 3 8  \ V 4 0 \ V 42 
\ V 4 4 \ V 4 6 \ V 4 8 \ V S 0 W S 2/ 
W 6 8• 
E o T 
Visit wi n d o",c 1 
± S d 
± S d 
± S d 
± S d 
± 5 d 
± S d 
± S d 
± S d 
± S d 
± S d 
± Sd 
± S d 
± S d  
± S d 
± Sd 
± 5 d 
± S d 
± S d 
± S d 
Virt u al vis it ( as p er p ati e nt a n d 
a 
a 
a 
a 
a 
a 
a 
a 
a 
I nv es ti ut or or ef er e n c e) 
Vi tal sig ns 
X  
X  
X 
X 
X  
X 
X 
X 
X 
P h ysi c al e x a mi n ati o n , h ei g ht , 
X 
x• 
weisz ht , B MI 
A Es 
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X 
Pri or a n d c o n c o mit a nt 
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X 
m e di c a ti o ns/t h er a oi es 
H a e m at ol o g y , c h e mistr yr 
X 
X 
U ri nal ysis 
X 
X 
Pr e g n a n c y tes t, c o n tr a c e ptio n 
x• 
x• 
x• 
x• 
x• 
x• 
x• 
x• 
x• 
x• 
c h e c k' 
! G A, EA SI , B S A' 
X  
X  
X 
X 
X  
X  
X  
X 
X 
S C O R A D ; 
X 
X 
Tr ai n/ c h e c k u n d erst a n di n g of 
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X 
X 
X  
X  
X  
X  
X 
re c or d i ne: d at a i n t he e Di ar v 
Pr urit us N R SiJ 
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X 
S ki n P ai n N R Sl, k , Sl e e p- loss s c a le i. 
X  
X  
X 
X 
X  
X  
X  
X 
X 
' 
E- Di ar y : P O E M. R E C A P • 
X 
X 
D L QI or C D L Q I. D L QI - R' 
X 
X 
X 
\ V H O- S; 
X 
X 
S a fe t y 
St u d y P r o c e d ur e.5 
:\f aiu t e n a u c e P e 1i o d 
F o llo w 
- u p 
, .isit',ll 
St u d y vis it 
1 1 
12 
1 3 • 
1 4 
1s• 
1 6 
1 1 • 
1 8 
1 9• 
2 0 
2 1• 
2 2 
2 3• 
2 4 
2s• 
2 6 
2 1• 
2 8 
2 9• 
D a y/ W e c k ( W) 
W I S' 
W 2 0 W 2 2 W 2 4 
W 2 6 
W 2 8 W 3 0 
W 3 2 
\ V 3 4 W 3 6  W 3 8 
\ V 4 0 \ V 42 
\ V 4 4 \ V 4 6 \ V 48  W S 0 
W S 2/ 
W 6 8' 
E o T 
Visit wi n d o " ,ct 
± S d 
± S d  ± S d 
± S d  
± S d 
± S d 
± S d 
± S d 
± S d 
± S d  
± S d 
± S d 
± S d  
± S d 
± 5 d 
± S d 
± S d 
± S d 
± S d 
T S Q M- 9; 
X 
X 
P h o 1 o gr a p h y' 
X 
X 
A d mi nis ter s t u dy dr u g a n d Pr o d u c t 
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X 
C o m ol ai nt re o o rti n2 
Ass ess tr e at m e nt c o m p lia nce m 
X  
X  
X  
X  
X 
X 
X 
X 
X  
X  
X 
X 
X  
X  
X  
X  
X 
A b b re vi ati o ns : A E = a d v ers e e v e nt ; B MI = b o d y m ass m d e x ; B S A = b o d y s urf a c e ar e a ; C D L QI = Cl u l dr e n D er m at ol o g y Li fe Q u aht y I nd e x ; d = d a y ; D L QI =  D e nn a tol o g y 
Lif e Q u al it y I n d e x; D L QI - R = D L QI -R el c v a n t; E A SI =  E c z e m a Ar e a a n d S e v erit y I n d e x; e D iar y = el e ctr o ni c di ar y ; E o T = e n d - of-tr e at m e nt; HI V = h u m a n i m m u n o d efi ci e n c y 
vir us ; h C G = H u m a n c h ori o nic g o n a d otr o pi n ; I G A = I n v estig a t or's Gl o b a l Ass ess m e nt; N R S = N u m eri c al R at i ng Sca le; P O E M = Pa ti e nt- Ori e nt e d E c z e m a M e as ur e ; Q 2 W  = 
e v er y 2 w e e ks ; R E C A P = R e c a p of At o p ic E c z e m a ; S C O R A D = S c ori n g At o pi c D er m at itis; T C S =  t o pi c a l c o rtic ost er o i ds; T S Q M - 9 = Tr e at m e nt S a tisf a cti o n Q u est i on n air e 
f or M e di c ati o n- 9 it e ms; W = w e e k ; W H O- 5 = W o rld H e alt h Or g a nis ati o n- Fi v e W ell- B ei n g I n de x ; W O C B P = w o m e n of c h il d b e ari ng p ot e nti al. 
, _ 
A s af et y f ollo w- u p will o c c ur 1 8 w e e ks aft er last d os e o f st u d y m e di c ati o n (i n clu di n g b ot h e n d- of-tr e at m e n t p eri o d or aft er e ar l y t er mi n ati o n), e x c e p t f or p ati e nts w h o 
c o nt in u e tr e at m e nt i n t h e E xt e n si o n P eri o d . 
b. 
V isits s h a d e d i n bl u e m a y b e c o n d u ct e d r e m ot ely or o n-s ite, p er pr ef er e n c e of th e st u d y sit e or p a ti e nt. W 6 8 will b e o n -site f or W O C B P o nl y . 
F or p ati e nts w h o r e c eiv e d pl a c e b o d uri n g t h e I n du cti o n P eri o d, lo a di n g d os es of l e bri ki z u m a b w ill b e gi v e n at W 1 6 a n d W t 8 d uri n g t h e M ai n te n a n c e P eri o d . I n or d er 
t o m ai nt ai n t h e d o u b le- bli n d, p a tie nts fr o m t h e l e bri. ki z u m a b 2 5 0 m g Q 2 W ar m wi ll b e a d mi nist er e d a s e c o nd i nj ecti on o f bli n d e d pl a c e b o d uri n g Wl 6 a n d W I S. Fr o m 
W 2 0 o n w ar ds, all p ati e nts will re c ei v e 1 i nje cti o n ofl e bril ci z u m a b 2 5 0 m g Q 2 W . 
4 
V isit wi n d o w f or p a tie nt-r e p orte d o ut c o m es is - 3 da ys d uri n g I nd uc ti o n P eri o d a n d - 5 d a ys d uri n g M ai nt e n a n c e P eri o d . 
F or ad ults , h ei g ht s h o ul d o nl y b e c a pt ur e d at s cr e eni n g. F or a d oles c e nts , h ei g ht s h o u l d o nl y b e c a p t ur e d at s cr e e ni n g a n d W e e k 5 2 . 
P at ient s  sh o u l d att e n d t h e vis it f ast ed. P at ie nts s h o ul d n ot c at or dri n k a n yt hi n g e x c e pt w at er f or 8 h o urs b ef or e s am pl e c o ll ec ti o n. Al c o h ol c o ns u m pti o n will n ot b e 
p er mitt e d f or at le as t 8 h o ur s b ef or e visi ts. Str e n u o us p h ys ic a l a cti vit y sh o u l d b e a v oi d e d f or at le ast 8 h o urs b ef or e a vis it. 
" 
T h e c o ntr a c e p ti on c h e c k is t o c o ufi n u t h at c o ntr a c e p ti on. if r e q uir e d, is us e d c o nsist e ntl y a n d c orr e c tly. 
b.. 
S cr u m B et a- h C G at S cr e e ni n g . Uri ne pr e g n a n c y tes t at all ot h er i d e ntifi e d vis its. If r e q uir e d p er lc x:a l r e g ul ati ons a n d.f or i nstit uti on al g ui d eli n es , pr e g n a n c y tes ti ng c a n 
o c c u r at ot h er ti m es d u ri n g t h e st u d y tr e at m e nt p eri o d . F or W O C B P , uri n e pr e g n a n c y t ests will b e c o n d u ct e d e v er y 4 w e e ks aft er last d os e of st ud y m e di c ati o n ( W 54, 
W 5 8 , a n d W 6 2) a n d at W 6 8. M al e s u bj e c ts e n g a g e d i n a r el ati o ns hi p w it h a W O C B P m u s t b e c o n tac t e d e v er y 4 w e e ks aft er last d os e of s n 1 d y m e di c at i o n ( W 54, W 5 8 , 
a n d W 6 2) a n d at W 6 8 t o e ns ur e r es p e ct of t h e c o nt r a c e pti o n. 
P ati e nt -r e p ort e d o ut c o m es a n d q u alit y of lif e m e as ur e m e nts s h o u l d all b e c o m pl et e d b ef or e ot h er st u d y ass ess m e nts . Ass ess m e nts/ pr o c e d ur es s h o u l d b e c o n d u ct e d i n 
t h e f ollo wi n g or d er :  1) p a ti e nt•r e p ort e d o u tc o m es ; 2) I nv es ti gat or ass ess m e nts a n d ot h er effi c a c y ass ess m e n ts; 3) s a f et y a n d la b or a tor y ass ess m e n t s (i n clu di n g s a m pl e 
c o lle c ti o n f or bi o m ar k crs) ; a n d 4) a d mi nistr ati o n of s t u d y dr u g . C o m pl et e d e Di ar y e ntri es f or Pr uri.t u s N R S a n d sl e e p-loss s c a les ar e n e e d e d f or a mi n im u m of 4 o ut 
of 7 d a ys i n t he w e e k pr e c e di n g r a n d o mis atio n visit. 
T o b e p erf o m 1 e d d ail y u p t o W 2 , w e e kl y fr o m W 2 t o Wl 6
, a u d e v er y 2 w e e k s fr o m Wl 6 o n w ar d . 
T o b e p erf or m e d d ail y u p t o W 2 , w e e kl y fr o m W 2 t o Wl 6
, a u d e v er y 4 w e e ks fr o m Wl 6 o n w ar d. 
F o r p ati e n ts w h o c o ns e n t at s e l ec t e d si tes . 
m. 
C o m p li a n c e ass ess m e nt f or st u dy dr u g , T C S , as w e ll as a c c o w u a b ilit y. 
o. 
O nl y a p p li c a bl e t o p ati e nt s w h o d o n ot e nt er th e E xt e n s i on P eri o d 
C CI


St ati sti c al A n al y si s Pl a n f or I nt er v e nti o n al St u di e s  
S p o n s or: A L MI R A L L, S. A.; Pr ot o c ol N o.: M- 1 7 9 2 3- 3 0 
 
 
T hi s d o c u m e nt i s c o nfi d e nti al. 
S A P t e xt V er si o n: S A P t e xt v 2. 0 2 2 M A R 2 0 2 3 
C o ntr oll e d D o c u m e nt I D:  
, Eff e cti v e D at e 3 1- A u g- 2 0 2 0 
Fili n g r e q uir e m e nt s: T M F  
 
P a g e 2 1  of 7 3  
I N T E R N AL U S E 
O nl y f or G er m a n E xt e nsi o n acc or di n g t o L oc al Pr ot oc ol A m e n d m e nt 4 f or G er m a n y 
 
E xt e ns i o n P el'i o d a n d S a fet v F oll o w -u p Vis it f ol' P a tie n ts w h o E nt e 1· t he E xt e n s i o n P el'i o d 
St u d y P .- oced u .-es 
E xt e nsi o n P e ri o d 
S afet y f o Uo w -u p Y isit' 
St u d y Vis it 
E X T 1° 
E X T 2 
E X T 3  
E X T 4 • 
E X T 5• 
E X T 6' " 
E X T S F U 
Ti mi n g (w e e ks ) r el ativ e t o W e e k 5 2 ( Visit 2 8) 
0 t o S 4 
> 4 t o 6 
( 4 we e ks after las t 
Ti mi n g (w e e k s) r el ativ e t o E X T I ,~si t 
l eb ri ki z u ma b d ose) 
+ 12 
+ 2 4 
+ 3 6  
+ 4 8 
+ 6 0 
V isit wi n d o w d 
N A 
N A 
±! 0 d 
±! 0 d  
± ! 0 d 
±! 0 d 
±! 0 d 
+ ! 0 d 
Vit al sig ns 
X  
X  
X  
X  
X  
X 
X 
P h ys ica l ex a mi n a tio n, h e i g ht, w ei g h t, B MI • 
X  
X  
X  
X  
X  
X 
X 
A Es 
X  
X  
X  
X  
X  
X  
X 
X 
C o n c o mit a nt me d ic atio n s/t her a pi es 
X  
X  
X  
X  
X  
X  
X 
X 
H a em at ol o g y , c h e mistr y ' 
X 
X 
X 
X 
Ur i nalysis 
X 
X 
X 
X 
Pr e g n a n c y tes t, c o ntr ac e pt i o n c h cc ks. h 
x• 
X  
X  
X  
X  
X  
X 
X 
!G A , E A SI, B S A 
X  
X  
X  
X  
X  
X 
X 
S C O R A D 
X 
X 
X 
X 
Pr uri t us N R Sij 
X  
X  
X  
X  
X  
X 
X 
S ki n Pa i n N R S "' . Sl e e p- loss s c ale I,• 
X  
X  
X  
X  
X  
X 
X 
E- D iar y: P O E M , R E C A P' 
X 
X  
X  
X  
X 
X 
D L QI or C D L QI , D L QI - R1 
X 
X  
X  
X  
X 
X 
W H O- 5 1 
X 
X 
X  
X 
X 
X 
T S Q M- 9
1 
X 
X  
X  
X  
X 
X 
P h ot o gr a p h y" 
X 
X 
X 
A d mi nister / Dis p e ns e s ni d y dr u g a n d Pr o d u ct C o m pl ai n t re p o rti ng <,' 
X  
X  
X  
X  
X  
X  
X 
Ass ess tre at me n t c o m pl i a ncc m 
X  
X 
X  
X 
X 
X 
A b br e vi a ti ons : A E = a d v ers e e v e nt ; B MI = b o d y m ass w d e x ; B S A = b o d y s urf a c e area .; CD L QI = C hil dr e n D er m a t olo g y Lif e Q u a lit y I n de x ; d = d a y ; DL QI = D er m at o lo g y 
Lif e Q u a lit y I n de x; D L QI - R  = D L QI - R clc v a n t;  EA S I = E c z e m a Ar c a  a n d S e v erit y I n de x ; c D i ar y = el ec tro ni c  di ar y; E o T =  e n d - of-tre a t me n t; ! GA = I nv es tiga t or's Gl o b al 
Ass ess m e nt ; N R S = 
u m e ric a l R ati n g S c a le; P O E M = P at ie nt- Orie n te d E c z e m a M e as ur e ; Q2 W = e v er y 2 w e e ks ; R E C A P = R eca p of At o p ic E c z e m a ; S C O R A D = S c o ri ng 
At o pi c Der m a titis; T C S = t o pic al c o rti c os ter o ids ; T S Q M- 9 = Tr c a bll c n t S a tisf acti on Q u est i on n a ire f or Mc di c ati o n- 9 ite ms ; W = wee k; W H O - 5 = W o rld H e a lt h O r g a nis a tio n-
F i v e W e ll- B ei ng I n de x; W O C B P = w o m e n of c hi l db e ari n g p o te n tial. 
A s a fet y f ollo w- u p a n d f u1al assess me nt vis it wi ll occ ur 4 w ee ks after t he las t dose of sr ud y m e d ic a tio n i n p at ie nts w h o ent er t he E xt e ns io n P eri o d . 
b. 
A fter t he E X T 6 vis it, a n y su b seq u e n t visit(s) w ill be c o n d u cte d e ver y 1 2 wee ks u nti l lc bri kiz u m a b is c o m m erc i ally a v a ila ble i n Ger m a n y a n d E X T 3 vis it assess me n ts 
will b e p erf or m e d at a n y of t h ose s ubse q u e nt visit(s), e x c e p t hacr ua t olo g y , c h e mistr y , a n d uri n a lys is a n d p h ot o gr a p h y w hi c h wi ll be p e rfor m e d e v er y 2 4 w e e ks . 
B e gi n ni n g at W e c k 5 2 ( or wit hi n 8 w e e ks of t he las t d os e of lc bri ki z u m a b i n t he M a i nte n a n c e Pe rio d [ Wec k 5 0]) , p a tie nts e n teri n g t he E xt e ns i o n Perio d w ill b e trea te d 
wit h lc bri ki zu ma b 2 5 0 m g e v er y 4  w e e ks ( Q4 W) , f or at leas t 6 m o ut h s ( 2 4 w e e ks) . A c c or d i n g t o t h e I nv es tig at or ' s ju d ge me n t, t he lc bri ki z u m a b d osi n g fre q u e n c y 
d uri n g the E xt e ns i o n Peri o d m a y be i ncre ase d t o Q 2 W at a n y ti me i n p a tie n ts n o t mai n tai ni n g cl i nic a l be ne fit b ut m a y not t here a fter be d ecre ase d ag a i n to Q 4 W. 
d. 
Vi sit wi n d o w f or p at ient -re p orte d o ut c o m es is - 1 0 d a ys d uri n g E x te nsi o n Peri o d . 
f or a d u lts, hei g h t is o nl y c a p t ure d at scre e ni n g . 
Alc o hol c o ns u m p ti o n w ill n o t be pe n ni ne d f or at le as t 8 h o urs bef o re visits . Stren uo us p h ys ic a l ac tivi t y s h o ul d be a v oi de d f or at le ast 8 ho urs bef o re a visi t. 
" 
T h e c o ntr ace p tio n c hec k is to c o n fi n n t hat c o n tr ace ptio n, if re q uire d, is use d c o n siste n tly a n d c o rrec tly. 
h. 
Uri ne pr e g n an c y tes t f or \ VO C B P d uri n g t he Ext e nsi o n P eri o d . If re quire d per loc a l re g u l atio ns a n d/ o r i nstit uti o n al g u i del i nes , pre g n a nc y testi n g c a n occ u r at o t he r 
ti mes d u ri n g t he st udy tre at me nt peri o d . M ale s ubjects e n g a ge d i n a rel a tio ns hip wi t h a \ VO C B P m u st be c o nt ac te d 4 wee ks afte r las t dose of st udy me d ic atio n i n t he 
Ext e ns i on Peri o d t o e ns ur e res pec t of t he c o n trace p ti o n. 
P a tie nt -re p o rte d o utc o m es an d q u ali t y of life me as ure me nt s s ho u l d all be c o m pl ete d be f ore o t her st udy assess me n ts. Assess me n ts/p r oce d ures s houl d be c o n d uc te d i n 
t h e f ollo w i n g or d er:  I) pa tic nt-rc p o n c d o u t c o m es; 2) I nves tiga t or assess me nts a n d ot h er effic a c y ass ess m e nt s; 3) safet y a n d lab or a tor y ass ess m e nts (i nclu di n g sa mpl e 
c o llecti o n f or bi o mar k crs) ; a n d 4) a dmi n istr ati o n of s t u dy dr u g. 
T o be per f or me d e v er y 2 w e e ks d uri n g t he E xt e ns i o n Peri o d . 
11• 
To be p crf o n u e d e ver y 4 wee ks d uri n g t he E xt e ns io n Peri o d . 
S u ffici ent d m g is d is pe nse d t o c o v e r i nj e ctio ns t hro u g h ne xt vis it. 
m. 
C o m pl i a nce assess me nt f or st u dy dr u g as w e ll as acc o u nt a b ilit y. 
T he st u dy will c o n cl u d e w he n a ll p at ie nts e n teri n g t he Ext e nsi o n P eri o d h a ve bee n tre ate d f or at le as t 6 m o nt h s ( 2 4 wee ks) , or di s c onti n u e d p ri or t o t his p o i nt, a n d 
lc brilciz u m a b is c o m merc i ally a v ail a b le i n G er m a n y . T h eref o re, a gi ve n p at ient m a y h a ve m ore t h a n 3 s ite vis its d uri n g t he Exte ns io n Peri o d . 
P at ie nts w ho c o m ple te \Vee k 5 2 of t he M ai n te n a nc e P eri o d will be gi ve n t he o p p ort u nit y to c o nti n ue lebri k iz u m a b tre at me nt i n the Ext e nsi o n P eri o d. T h e first visi t i n 
the E xt e nsi o n P eri o d ( E X T I. ic st art of tre a t me n t i n t he E x te ns io n P eri o d) m a y c o i ncide wi t h t he Wec k 5 2 vis it of t he M ai n te n a nce P er io d o r t he first Ext e ns io n Peri o d 
visi t m a y occ ur u p to 8 wee ks fr o m th e las t d ose a d mi nis tra tio n i n the M a i nte n a nce Peri o d ( V/ee k 5 0) . If t he g a p bet w ee n t he W ee k 5 2 vis it a n d t he first E xt e ns i o n 
P eri o d visi t ( EX T I) is Ot o :52 w e e ks (ic, u p t o 4 we e ks aft e r t he W e c k 5 0 lcbr i ki z w n a b d o s e), t he n effi c a c y a n d safet y ass ess m e nt s ( e x c e pt pr e g n a n c y test i ng) d o n ot 
n e e d t o be re p e a te d a n d t hes e ass ess m e nts will b e ta ke n fro m t he W e c k 5 2 vis it. Pr e g n a n c y testi n g m us t be re p e a t e d i n w o m e n of c hil d bea ri ng p o te n tial ( WO C B P ), 
u nl ess t he Wec k 
5 2 visi t c oin ci des wit h t he first Ext e nsi on P eri o d vis it. If the g a p bet wee n t he \ Vcc k 5 2 vis it a n d t he E X T 1 vis it is > 2 to !: 6 w ee ks { E X T 1 yel l o w 
sha d e d area , i c, > 4 t o ~ 8 w e e ks aft er t he We c k 5 0 lcbr i ki z w n a b d ose) , t he n ef ficac y a n d safet y ass ess m e n ts m us t be re peate d at t he E X T I visit. 
P· 
Gr e en s ha d e d E X T 4. E X T 5, a n d E X T 6 vis its arc ap pli c a bl e o nl y to p at ie n ts  w h o c o nti n u e tre a t me n t be y o n d E X T 3 e it her b ec a use n o t all p a tie nts e n teri n g t he 
E xt e nsi o n P eri o d h a ve h a d at l e ast 6 mo nt hs ( 2 4 wee ks) of tre at me nt or le bri.z u m a b is not ye t c o m me rci ally a v ail a b le i n G er m a n y a n d , t heref ore , t he Exte nsi o n P eri o d 
has n ot y e t c o d e d . 
q. 
F o r p a tie n ts wh o c o nse n t at selecte d sites . 
C CI


St ati sti c al A n al y si s Pl a n f or I nt er v e nti o n al St u di e s  
S p o n s or: A L MI R A L L, S. A.; Pr ot o c ol N o.: M- 1 7 9 2 3- 3 0 
 
 
T hi s d o c u m e nt i s c o nfi d e nti al. 
S A P t e xt V er si o n: S A P t e xt v 2. 0 2 2 M A R 2 0 2 3 
C o ntr oll e d D o c u m e nt I D:  
, Eff e cti v e D at e 3 1- A u g- 2 0 2 0 
Fili n g r e q uir e m e nt s: T M F  
 
P a g e 2 2  of 7 3  
I N T E R N AL U S E 
  
A n al y si s S et s 
T hr e e diff er e nt st ati sti c al a n al y si s s et s h a v e b e e n d efi n e d i n t hi s st u d y:  
5. 1.  
F ull A n al y si s S et 
T h e F ull A n al y si s S et ( F A S) will i n cl u d e all r a n d o mi s e d p ati e nt s. P ati e nt s will b e a n al y s e d u n d er t h e 
tr e at m e nt gr o u p a s r a n d o mi s e d. T h e F A S will b e u s e d f or all a n al y s e s of effi c a c y e n d p oi nt s a s w ell a s f or 
d e m o gr a p hi c s a n d b a s eli n e c h ar a ct eri sti c s. 
5. 2.  
S af et y A n al y si s S et  
T h e S af et y A n al y si s S et ( S A F) will i n cl u d e all r a n d o mi s e d p ati e nt s w h o r e c ei v e at l e a st 1 d o s e of t h e 
st u d y dr u g. P ati e nt s will b e a n al y s e d u n d er t h e tr e at m e nt gr o u p a ct u all y r e c ei v e d. T h e S A F will b e u s e d 
f or all a n al y s e s of s af et y e n d p oi nt s.  
5. 3.  
P er Pr ot o c ol S et  
T h e P er Pr ot o c ol S et ( P P S) will i n cl u d e all r a n d o mi s e d p ati e nt s w h o r e c ei v e at l e a st o n e d o s e of t h e 
st u d y dr u g, h a v e at l e a st o n e p o st- B a s eli n e E A SI a s s e s s m e nt, a n d a d diti o n all y f or w h o m t h er e ar e n o 
i m p ort a nt pr ot o c ol d e vi ati o n s aff e cti n g effi c a c y at W e e k 1 6. P ati e nt s will b e a n al y s e d u n d er t h e tr e at m e nt 
gr o u p a s r a n d o mi s e d.  
T h e pr e ci s e r e a s o n s f or e x cl u di n g p ati e nt s fr o m t h e P P S p o p ul ati o n, a n d ot h er pr e- d efi n e d d at a h a n dli n g 
i s s u e s will b e f ull y d efi n e d a n d d o c u m e nt e d i n t h e c orr e s p o n di n g Bli n d D at a R e vi e w M e eti n g ( B D R M) 
r e p ort s, fi n ali s e d b ef or e u n bli n di n g of t h e st u d y.  
5. 4.  
Pr ot o c ol D e vi ati o n s 
A n y pr ot o c ol d e vi ati o n s d uri n g t h e c o n d u ct of t h e tri al will b e r e c or d e d b y C R A/ M o nit or s a s d et e ct e d or 
d eri v e d fr o m d at a c oll e ct e d i n t h e cli ni c al d at a b a s e. Pr ot o c ol d e vi ati o n s ar e c at e g ori z e d a s n o n-i m p ort a nt 
or i m p ort a nt a n d fi n ali z e d d uri n g B D R M b ef or e d at a b a s e l o c k. 
Pr ot o c ol d e vi ati o n s aff e cti n g pri m ar y effi c a c y will b e d efi n e d a n d r e vi e w e d b ef or e t h e B D R M a n d cl o s e d 
d uri n g t h e B D R M, t o b e h el d ( wit h r e p ort fi n ali z e d) b ef or e d at a b a s e l o c k. 
All p ati e nt s e nr oll e d (t h o s e w h o si g n e d t h e i nf or m c o n s e nt) will b e d e s cri b e d i n t h e s u m m ari e s of p ati e nt 
di s p o siti o n, a n d will b e u s e d will b e u s e d f or s o m e p ati e nt li sti n g s.  
 
5. 
C CI


St ati sti c al A n al y si s Pl a n f or I nt er v e nti o n al St u di e s  
S p o n s or: A L MI R A L L, S. A.; Pr ot o c ol N o.: M- 1 7 9 2 3- 3 0 
 
 
T hi s d o c u m e nt i s c o nfi d e nti al. 
S A P t e xt V er si o n: S A P t e xt v 2. 0 2 2 M A R 2 0 2 3 
C o ntr oll e d D o c u m e nt I D:  
, Eff e cti v e D at e 3 1- A u g- 2 0 2 0 
Fili n g r e q uir e m e nt s: T M F  
 
P a g e 2 3  of 7 3  
I N T E R N AL U S E 
  
E sti m a n d s a n d D at a H a n dli n g f or Effi c a c y A n al y s e s 
A s di s c u s s e d i n Pr ot o c ol S e cti o n 1 1. 8. 1, t h e pri m ar y a n al y s e s f or effi c a c y will b e b a s e d o n t h e F A S. 
F urt h er m or e, t h e pri m ar y a n d k e y s e c o n d ar y effi c a c y v ari a bl e s will b e al s o a n al y s e d f or t h e o v er all 
p o p ul ati o n u si n g t h e P P S p o p ul ati o n t o a s s e s s t h e r o b u st n e s s of t h e fi n di n g s fr o m t h e F A S p o p ul ati o n. A s 
, all effi c a c y e n d p oi nt s will b e a n al y s e d a s w ell b y pr e vi o u s e x p o s ur e t o d u pil u m a b ( Y e s/ N o). 
6. 1.  
Pri m ar y Effi c a c y A n al y si s ( O v er all P o p ul ati o n) 
 
Pri m ar y a n d K e y S e c o n d ar y Effi c a c y E n d p oi nt s 
T h e pri m ar y effi c a c y a n al y si s will b e b a s e d o n t h e m ai n e sti m a n d f or t h e o v er all p o p ul ati o n ( F A S). T h e 
o bj e cti v e s, v ari a bl e s a n d p o p ul ati o n-l e v el s u m m ar y m e a s ur e s f or t h e m ai n e sti m a n d f or t h e pri m ar y 
effi c a c y e n d p oi nt a n d k e y s e c o n d ar y e n d p oi nt s i s pr o vi d e d i n t a bl e b el o w: 
O bj e cti v e s/ Tr e at m e nt 
C o n diti o n of I nt er e st  
V ari a bl e/ O ut c o m e A s s e s s e d  
P o p ul ati o n- L e v el S u m m ar y M e a s ur e  
T o e v al u at e t h e effi c a c y of 
l e bri ki z u m a b c o m p ar e d wit h 
pl a c e b o i n p ati e nt s n ot 
a d e q u at el y c o ntr oll e d wit h 
c y cl o s p ori n e or f or w h o m 
c y cl o s p ori n e i s n ot m e di c all y 
a d vi s a bl e u p t o W e e k 1 6 (i e, 
at t h e e n d of t h e I n d u cti o n 
P eri o d). 
Titl e : E A SI 7 5, I G A( 0/ 1) a n d 2 pt 
i m pr o v e m e nt, 4 pt i m pr o v e m e nt 
i n Pr urit u s N R S  
D e s cri pti o n : P ati e nt a c hi e vi n g: 
E A SI 7 5: ≥7 5 % r e d u cti o n i n 
E A SI s c or e fr o m B a s eli n e, I G A: 
I G A s c or e of 0 or 1 wit h 2 pt 
i m pr o v e m e nt fr o m b a s eli n e, 
Pr urit u s N R S: 4 pt i m pr o v e m e nt 
fr o m b a s eli n e 
Ti m e Fr a m e : 1 6 w e e k s  
P o p ul ati o n : A d ult a n d A d ol e s c e nt 
P ati e nt s wit h M o d er at e- T o- S e v er e A D 
t h at ar e n ot A d e q u at el y C o ntr oll e d wit h 
C y cl o s p ori n e or f or w h o m C y cl o s p ori n e 
i s n ot M e di c all y A d vi s a bl e. 
M e a s ur e : Diff er e n c e b et w e e n 
tr e at m e nt s (l e bri ki z u m a b mi n u s 
pl a c e b o) i n pr o p orti o n of p ati e nt s 
a c hi e vi n g E A SI 7 5, I G A crit eri a, 
pr urit u s N R S crit eri a at W e e k 1 6 
A b br e vi ati o n s: A D = at o pi c d er m atiti s; E A SI = E c z e m a Ar e a a n d S e v erit y I n d e x ( s c or e); I G A = I n v e sti g at or Gl o b al A s s e s s m e nt; N R S 
= N u m eri c al R ati n g S c al e. 
T h e f oll o wi n g I C E s ar e e n vi si o n e d d uri n g t h e st u d y, t o b e c o n si d er e d u p t o a n d i n cl u di n g t h e W e e k 1 6 
a s s e s s m e nt: 
a)  I C E 1: P ati e nt pr e m at ur el y di s c o nti n u e s st u d y tr e at m e nt d u e t o r e a s o n s ot h er t h a n l a c k of effi c a c y 
pri or t o W e e k 1 6. 
b)  I C E 2: P ati e nt pr e m at ur el y di s c o nti n u e s st u d y tr e at m e nt d u e t o l a c k of effi c a c y pri or t o W e e k 1 6. 
c)  I C E 3:  P ati e nt  r e c ei v e s  r e s c u e  m e di c ati o n  pri or  t o  W e e k  1 6  ( eit h er  all o w e d  or  pr o hi bit e d)  f or 
tr e at m e nt of A D 
Tr e at m e nt di s c o nti n u ati o n d u e t o p a n d e mi c will b e tr e at e d u n d er t h e s a m e i nt er c urr e nt e v e nt a s tr e at m e nt 
di s c o nti n u ati o n d u e t o r e a s o n s ot h er t h a n l a c k of effi c a c y. I nt er mitt e nt mi s si n g a s s e s s m e nt d u e t o 
p a n d e mi c a n d/ or r el at e d r e stri cti o n s will b e tr e at e d t h e s a m e a s a n y ot h er i nt er mitt e nt mi s si n g v al u e s. 
D et ail s of h o w mi s si n g d at a will b e h a n dl e d f or effi c a c y ar e d e s cri b e d i n S e cti o n 6. 3 . 
F or s u p p orti v e a n al y s e s a s e c o n d e sti m a n d will b e u s e d. 
6. 
6. 1. 1. 
C CI
C CI


St ati sti c al A n al y si s Pl a n f or I nt er v e nti o n al St u di e s  
S p o n s or: A L MI R A L L, S. A.; Pr ot o c ol N o.: M- 1 7 9 2 3- 3 0 
 
 
T hi s d o c u m e nt i s c o nfi d e nti al. 
S A P t e xt V er si o n: S A P t e xt v 2. 0 2 2 M A R 2 0 2 3 
C o ntr oll e d D o c u m e nt I D:  
, Eff e cti v e D at e 3 1- A u g- 2 0 2 0 
Fili n g r e q uir e m e nt s: T M F  
 
P a g e 2 4  of 7 3  
I N T E R N AL U S E 
T h e I C E s will b e h a n dl e d u si n g t h e f oll o wi n g a p pr o a c h e s t o b e a p pli e d u n d er t h e m ai n a n d s e c o n d 
e sti m a n d s. 
 
 
E sti m a n d 
A n al y si s Str at e g y f or I C E s  
Tr e at m e nt Di s c o nti n u ati o n d u e t o:  
 
I C E 3: R e s c u e or 
Pr o hi bit e d M e d s f or 
Tr e at m e nt of A D  
I C E 1: R e a s o n s Ot h er 
t h a n L a c k of Effi c a c y 
I C E 2: L a c k of 
Effi c a c y 
M ai n E sti m a n d 
( H y bri d) 
H y p ot h eti c al Str at e g y: 
S et t o mi s si n g 
C o m p o sit e Str at e g y: 
S et t o b a s eli n e 
C o m p o sit e Str at e g y: 
S et t o b a s eli n e 
S e c o n d E sti m a n d: 
C at e g ori c al E n d p oi nt s 
( C o m p o sit e) 
C o m p o sit e Str at e g y: 
S et t o n o n-r e s p o n d er 
C o m p o sit e Str at e g y: 
S et t o n o n-r e s p o n d er 
C o m p o sit e Str at e g y: 
S et t o n o n-r e s p o n d er 
A b br e vi ati o n: I C E = i nt er c urr e nt e v e nt; A D = at o pi c d er m atiti s. 
D et ail s o n mi s si n g d at a i m p ut ati o n ar e d e s cri b e d i n S e cti o n エラー
エラー! 参照元が見つかりません。
参照元が見つかりません。.  
M ai n E sti m a n d ( H y bri d): 
  
T h e a p pr o a c h f or t h e m ai n e sti m a n d i s a h y bri d e sti m a n d r e pr e s e nti n g t h e pri m ar y cli ni c al q u e sti o n 
of i nt er e st: w h at i s t h e diff er e n c e b et w e e n tr e at m e nt c o n diti o n s, i e, L e bri ki z u m a b v s Pl a c e b o, i n t h e 
t ar g et p ati e nt p o p ul ati o n, i n s u c c e s sf ul r e s p o n s e s aft er 1 6 w e e k s a c hi e v e d wit h o ut u s e of r e s c u e 
m e di c ati o n a n d if all p ati e nt s c o nti n u e d wit h tr e at m e nt e x c e pt t h o s e w h o di s c o nti n u e d d u e t o l a c k 
of effi c a c y ? 
S e c o n d E sti m a n d: 
  
T h e  s e c o n d  e sti m a n d  f or  c at e g ori c al  e n d p oi nt s  i s  a  c o m p o sit e  e sti m a n d  r e pr e s e nti n g  t h e 
s u p p orti v e cli ni c al q u e sti o n of i nt er e st: w h at i s t h e diff er e n c e b et w e e n tr e at m e nt c o n diti o n s i n t h e 
t ar g et p ati e nt p o p ul ati o n, i n s u c c e s sf ul r e s p o n s e s aft er 1 6 w e e k s a c hi e v e d wit h o ut u s e of r e s c u e 
m e di c ati o n or tr e at m e nt di s c o nti n u ati o n ? 
T h e c o m pl e m e nt ar y e sti m a n d a p pr o a c h h er e all o w s f or a n e sti m at e of t h e eff e ct s of t h e diff er e nt e v e nt s 
t o b e a s c ert ai n e d. 
 
All Ot h er S e c o n d ar y a n d Ot h er Effi c a c y E n d p oi nt s 
All bi n ar y ot h er s e c o n d ar y a n d ot h er effi c a c y e n d p oi nt s will b e a n al y s e d u si n g t h e s a m e m et h o d ol o g y a s 
d e s cri b e d i n  S e cti o n 6. 1. 1 f or t h e pri m ar y effi c a c y e n d p oi nt u si n g o nl y t h e m ai n e sti m a n d. S e n siti vit y 
a n al y s e s b a s e d o n t h e P P S p o p ul ati o n will n ot b e c o n d u ct e d f or t h e s e e n d p oi nt s. 
C o nti n u o u s ot h er s e c o n d ar y e n d p oi nt s a s s e s s e d at m ulti pl e p o st- b a s eli n e vi sit s d uri n g t h e I n d u cti o n 
P eri o d will b e a n al y s e d o n t h e f oll o wi n g e sti m a n d s: 
 
 
E sti m a n d 
A n al y si s Str at e g y f or I C E s  
Tr e at m e nt Di s c o nti n u ati o n d u e t o:  
 
I C E 3: R e s c u e or 
Pr o hi bit e d M e d s f or 
Tr e at m e nt of A D  
I C E 1: R e a s o n s Ot h er 
t h a n L a c k of Effi c a c y 
I C E 2: L a c k of 
Effi c a c y 
M ai n E sti m a n d 
( H y bri d) 
H y p ot h eti c al Str at e g y: 
S et t o mi s si n g 
C o m p o sit e Str at e g y: 
S et t o b a s eli n e 
C o m p o sit e Str at e g y: 
S et t o b a s eli n e 
S e c o n d E sti m a n d: 
C o nti n u o u s E n d p oi nt s 
( H y p ot h eti c al) 
H y p ot h eti c al Str at e g y: 
S et t o mi s si n g 
H y p ot h eti c al Str at e g y: 
S et t o mi s si n g 
H y p ot h eti c al Str at e g y: 
S et t o mi s si n g 
A b br e vi ati o n: I C E = i nt er c urr e nt e v e nt; A D = at o pi c d er m atiti s. 
6. 1. 2. 
C CI


St ati sti c al A n al y si s Pl a n f or I nt er v e nti o n al St u di e s  
S p o n s or: A L MI R A L L, S. A.; Pr ot o c ol N o.: M- 1 7 9 2 3- 3 0 
 
 
T hi s d o c u m e nt i s c o nfi d e nti al. 
S A P t e xt V er si o n: S A P t e xt v 2. 0 2 2 M A R 2 0 2 3 
C o ntr oll e d D o c u m e nt I D:  
, Eff e cti v e D at e 3 1- A u g- 2 0 2 0 
Fili n g r e q uir e m e nt s: T M F  
 
P a g e 2 5  of 7 3  
I N T E R N AL U S E 
 
6. 2.  
S u b gr o u p Effi c a c y A n al y s e s ( D u pil u m a b N aï v e a n d P ati e nt s Pr e vi o u sl y E x p o s e d t o 
D u pil u m a b) 
T h e s a m e e sti m a n d s a s p er S e cti o n 6. 1  will al s o b e c o n d u ct e d f or t h e s u b gr o u p a n al y s e s, f or  
 
p ur p o s e s. 
6. 3.  
I m p ut ati o n Pr o c e s s f or E sti m a n d H a n dli n g a n d Mi s si n g D at a 
I m p ut ati o n f or mi s si n g d at a will o c c ur f or pri m ar y a n d k e y s e c o n d ar y effi c a c y e n d p oi nt s. 
W h er e t h e e n d p oi nt i s a bi n ar y or c at e g ori c al o ut c o m e, t h e i m p ut ati o n will o c c ur o n t h e bi n ar y/ c at e g ori c al 
o ut c o m e.  
T h e f oll o wi n g d at a i m p ut ati o n m et h o d s will b e e m pl o y e d: 
E sti m a n d  
H a n dli n g Str at e g y: I m p ut ati o n  
Pri m ar y a n d K e y  S e c o n d ar y Effi c a c y E n d p oi nt s  
M ai n E sti m a n d 
  
C o m p o sit e Str at e g y: S et t o b a s eli n e ( B O C F) 
  
H y p ot h eti c al  Str at e g y:  S et  t o  mi s si n g  a n d  i m p ut e  wit h  M ar k o v C h ai n 
M o nt e- C arl o ( M C M C) m ulti pl e i m p ut ati o n ( MI) 
 
Mi s si n g d at a n ot aff e ct e d b y I C E: M C M C MI  
S e c o n d E sti m a n d: 
C at e g ori c al E n d p oi nt s  
  
C o m p o sit e Str at e g y: S et t o n o n-r e s p o n d er ( N RI) 
 
Mi s si n g d at a n ot aff e ct e d b y I C E: N RI  
Ot h er S e c o n d ar y a n d Ot h er Effi c a c y E n d p oi nt s  
E sti m a n d f or 
C at e g ori c al E n d p oi nt s  
  
A s  p er  m ai n  e sti m a n d  f or  pri m ar y  a n d  k e y  s e c o n d ar y  effi c a c y 
e n d p oi nt s 
M ai n E sti m a n d f or 
C o nti n u o u s E n d p oi nt s  
  
A s  p er  m ai n  e sti m a n d  f or  pri m ar y  a n d  k e y  s e c o n d ar y  effi c a c y 
e n d p oi nt s 
S e c o n d E sti m a n d f or 
C o nti n u o u s E n d p oi nt s  
  
H y p ot h eti c al str at e g y: S et t o mi s si n g a n d d o n ot i m p ut e ( M M R M) 
 
Mi s si n g d at a n ot aff e ct e d b y I C E: d o n ot i m p ut e ( M M R M)  
A b br e vi ati o n s: I C E = I nt er c urr e nt E v e nt; M C M C = M ar k o v- C h ai n M o nt e- C arl o; MI = M ulti pl e I m p ut ati o n; B O C F, B a s eli n e-
O b s er v ati o n- C arri e d- F or w ar d; N RI = N o n- R e s p o n d er I m p ut ati o n; M M R M, Mi x e d Eff e ct M o d el f or R e p e at e d M e a s ur e s. 
W h er e i m p ut ati o n o c c ur s, i m p ut ati o n will b e b a s e d o n t h e o v er all p o p ul ati o n, a n d s u b s e q u e nt s u b gr o u p 
a n al y s e s ( d u pil u m a b n aï v e a n d pr e vi o u sl y e x p o s e d t o d u pil u m a b) will utili s e t h e s e i m p ut e d d at a, 
s el e cti n g o nl y t h e r e q uir e d p ati e nt s f or t h e a n al y si s. 
W h er e mi s si n g d at a ar e t o b e i m p ut e d f or effi c a c y u si n g t h e a p pr o a c h e s a b o v e, a s u m m ar y t a bl e b y w e e k 
of t h e fr e q u e n c y a n d t y p e of mi s si n g d at a will b e pr e s e nt e d. 
G e n er al MI A p pr o a c h ( S e cti o n 6. 3. 1 ) will b e u s e d f or 
-  
M ai n e sti m a n d of t h e pri m ar y a n d k e y s e c o n d ar y effi c a c y e n d p oi nt s 
-  
M ai n e sti m a n d f or c at e g ori c al ot h er s e c o n d ar y effi c a c y e n d p oi nt s 
-  
C o nti n u o u s Ot h er S e c o n d ar y Effi c a c y E n d p oi nt s  
N o n- R e s p o n d er I m p ut ati o n A p pr o a c h ( S e cti o n 6. 3. 2 ) will b e u s e d f or t h e S e c o n d e sti m a n d of t h e pri m ar y 
a n d k e y s e c o n d ar y effi c a c y e n d p oi nt s. 
C CI
C CI


St ati sti c al A n al y si s Pl a n f or I nt er v e nti o n al St u di e s  
S p o n s or: A L MI R A L L, S. A.; Pr ot o c ol N o.: M- 1 7 9 2 3- 3 0 
 
 
T hi s d o c u m e nt i s c o nfi d e nti al. 
S A P t e xt V er si o n: S A P t e xt v 2. 0 2 2 M A R 2 0 2 3 
C o ntr oll e d D o c u m e nt I D:  
, Eff e cti v e D at e 3 1- A u g- 2 0 2 0 
Fili n g r e q uir e m e nt s: T M F  
 
P a g e 2 6  of 7 3  
I N T E R N AL U S E 
Mi x e d M o d el f or R e p e at e d M e a s ur e s a n al y s e s ( S e cti o n 6. 3. 3 ) will b e p erf or m e d o n s e c o n d e sti m a n d f or 
c o nti n u o u s ot h er s e c o n d ar y effi c a c y e n d p oi nt s. 
 
G e n er al M ulti pl e I m p ut ati o n A p pr o a c h  
T h e pri m ar y m et h o d of i m p ut ati o n f or mi s si n g d at a will b e MI ( M ulti pl e I m p ut ati o n); t h e MI pr o c e d ur e of t h e 
S A S s y st e m will b e u s e d t o g e n er at e s et s of d at a wit h mi s si n g v al u e s i m p ut e d fr o m o b s er v e d d at a. T ot al 
E A SI s c or e will b e i m p ut e d i n t hi s m a n n er.  
F or t h e i m p ut ati o n of t h e pri m ar y e n d p oi nt, w h er e a MI a p pr o a c h i s d e s cri b e d, t h e c o nti n u o u s E A SI s c or e 
b et w e e n 0 a n d 7 2 will b e m ulti pl e i m p ut e d, a n d s u b s e q u e ntl y t h e ( p er c e nt a g e) c h a n g e fr o m b a s eli n e will 
b e c al c ul at e d f or e a c h i m p ut ati o n i n or d er t o d eri v e t h e c at e g ori c al o ut c o m e of E A SI 7 5. T h e n u m b er of 
i m p ut ati o n s  will  b e  1 0 0  f or  t h e  MI  st e p,  r e pr e s e nti n g  t h e  s et  of  1 0 0  pl a u si bl e  v al u e s  o bt ai n e d  fr o m  a 
pr e di cti o n m o d el b a s e d  pri m aril y o n o b s er v e d d at a. T h e n u m b er of i m p ut ati o n s a n d/ or b ur n-i n it er ati o n s 
m a y b e i n cr e a s e d if t h er e ar e c o n v er g e n c e i s s u e s. 
N ot e  t h at  all  p ati e nt s  i n  t h e  F A S  will  b e  i n cl u d e d  i n  t h e  i m p ut ati o n  st e p s  b el o w.  A s  pr e vi o u s  d u pil u m a b 
e x p o s ur e i s o n e of t h e str atifi c ati o n f a ct or s t o b e i n cl u d e d i n t h e MI m o d el s, i m p ut ati o n will b e i n p art b a s e d 
o n t hi s f a ct or. F or a n al y si s, t h e s p e cifi c p o p ul ati o n will t h e n b e s el e ct e d fr o m t hi s t ot al p o ol of F A S p ati e nt s 
wit h c o m pl et e d at a.  
T h e f ull MI a p pr o a c h will c o m pri s e st e p s a s f oll o w s: 
  
C o m p o sit e  V ari a bl e  Str at e g y  St e p  ( 1  i m p ut ati o n):  A n y  mi s si n g  d at a  t o  b e  h a n dl e d  u si n g  a 
c o m p o sit e v ari a bl e str at e g y will b e i m p ut e d u si n g a B O C F a p pr o a c h. 
  
M ulti pl e i m p ut ati o n St e p ( 1 0 0 i m p ut ati o n s): Aft er s etti n g t o mi s si n g a n y d at a t o b e h a n dl e d u si n g a 
h y p ot h eti c al str at e g y, i m p ut e a n y mi s si n g d at a wit h a M ar k o v C h ai n M o nt e- C arl o ( M C M C) m ulti pl e 
i m p ut ati o n a p pr o a c h. 
  
C o m bi ni n g  St e p:  R u bi n’ s  r ul e  ( S A S  P R O C  MI A N A L Y Z E)  i s  u s e d  t o  c o m bi n e  t h e  1 0 0  p oi nt 
e sti m at e s a n d st a n d ar d err or s, i n or d er t o pr o vi d e a si n gl e p oi nt e sti m at e, c o nfi d e n c e i nt er v al a n d 
p- v al u e t h at c a n b e c o m p ar e d t o t h e r e s p e cti v e n ull h y p ot h e s e s t o pr o vi d e r ej e cti o n or a c c e pt a n c e. 
6. 3. 1. 1.  
B O C F A p pr o a c h f or C o m p o sit e V ari a bl e H a n dli n g Str at e g y 
M o n ot o n e mi s si n g d at a i m pl e m e nti n g t h e c o m p o sit e v ari a bl e str at e g y will b e i m p ut e d u si n g a B O C F 
a p pr o a c h, w h er e b y a n y mi s si n g d at a o c c urri n g o n or aft er I C E of d e at h will b e si n g ul arl y i m p ut e d u si n g 
t h e a v ail a bl e b a s eli n e r e s ult f or t h e p ati e nt. If n o o b s er v e d b a s eli n e r e s ult i s i m m e di at el y a v ail a bl e, t h e n 
t h e i m p ut e d v al u e fr o m St e p 1 will b e u s e d a n d c arri e d f or w ar d. 
6. 3. 1. 2.  
M ar k o v C h ai n M o nt e- C arl o ( M C M C) 
A n y p ati e nt wit h mi s si n g d at a f or E A SI s c or e will b e m ulti pl e i m p ut e d u si n g a M C M C a p pr o a c h, wit h m ulti pl e 
c h ai n s, i n cl u di n g f a ct or s f or st u d y tr e at m e nt, str atifi c ati o n f a ct or s, b a s eli n e E A SI s c or e, a n d bi n ar y v ari a bl e s 
f or I C E o c c urr e n c e at t h e vi sit. At t hi s p oi nt, 1 0 0 i m p ut ati o n s will b e a v ail a bl e f or t h e pri m ar y e sti m a n d. 
E x a m pl e S A S s y nt a x i s a s f oll o w s: 
6. 3. 1. 
C CI
C CI


St ati sti c al A n al y si s Pl a n f or I nt er v e nti o n al St u di e s  
S p o n s or: A L MI R A L L, S. A.; Pr ot o c ol N o.: M- 1 7 9 2 3- 3 0 
 
 
T hi s d o c u m e nt i s c o nfi d e nti al. 
S A P t e xt V er si o n: S A P t e xt v 2. 0 2 2 M A R 2 0 2 3 
C o ntr oll e d D o c u m e nt I D:  
, Eff e cti v e D at e 3 1- A u g- 2 0 2 0 
Fili n g r e q uir e m e nt s: T M F  
 
P a g e 2 7  of 7 3  
I N T E R N AL U S E 
6. 3. 1. 3.  
C o m bi ni n g St e p ( R u bi n’ s R ul e) 
S A S Pr o c MI A N A L Y Z E will b e u s e d t o c o m bi n e t h e 1 0 0 p oi nt e sti m at e s ( p er e sti m a n d) f or t h e diff er e n c e i n 
p er c e nt a g e of p ati e nt s a c hi e vi n g E A SI 7 5 r e s p o n s e at W e e k 1 6 b et w e e n tr e at m e nt s a n d st a n d ar d err or s, 
all o wi n g a p pr o pri at e st ati sti c al i nf er e n c e a s d e s cri b e d b el o w: 
 
N o nr e s p o n d er I m p ut ati o n  
T h e n o nr e s p o n d er i m p ut ati o n ( N RI) m et h o d will b e u s e d t o h a n dl e mi s si n g d at a r el ati v e t o t h e s u p p orti v e 
e sti m a n d  f or  bi n ar y/ c at e g ori c al  e n d p oi nt s  ( c o m p o sit e).  P ati e nt s  w h o  r e c ei v e  r e s c u e  m e di c ati o n  or 
di s c o nti n u e tr e at m e nt, will b e s et t o n o n-r e s p o n s e s u b s e q u e nt t o t hi s ti m e t hr o u g h W e e k 1 6. I nt er mitt e nt 
mi s si n g v al u e s will al s o b e s et t o n o n-r e s p o n s e.  
T h e n o nr e s p o n d er i m p ut ati o n ( N RI) m et h o d i m p ut e s mi s si n g v al u e s a s n o n-r e s p o n d er s a n d c a n b e j u stifi e d 
b a s e d o n t h e c o m p o sit e str at e g y (I C H E 9 R 1) f or h a n dli n g i nt er c urr e nt e v e nt s. I n t hi s str at e g y p ati e nt s ar e 
d efi n e d a s r e s p o n d er s o nl y if t h e y m e et t h e cli ni c al r e q uir e m e nt s f or r e s p o n s e at t h e pr e d efi n e d ti m e A N D 
t h e y  r e m ai n  o n  t h e  a s si g n e d  st u d y  tr e at m e nt  (i e  n ot  u si n g  r e s c u e  m e di c ati o n s  a n d  n ot  h a vi n g  mi s si n g 
v al u e s d u e t o ot h er r e a s o n s). F aili n g eit h er crit eri a b y d efi niti o n m a k e s t h e m n o nr e s p o n d er s.  
R a n d o mi z e d p ati e nt s wit h o ut at l e a st 1 p o st- b a s eli n e o b s er v ati o n will al s o b e d efi n e d a s n o nr e s p o n d er s 
f or all vi sit s f or t h e N RI a n al y si s.  
 
Mi x e d- eff e ct s M o d el f or R e p e at e d M e a s ur e s  
Mi x e d M o d el f or R e p e at e d M e a s ur e s a n al y s e s will b e p erf or m e d o n c o nti n u o u s e n d p oi nt s t o miti g at e t h e 
i m p a ct of mi s si n g d at a. T hi s a p pr o a c h a s s u m e s mi s si n g o b s er v ati o n s ar e mi s si n g- at-r a n d o m 
( mi s si n g n e s s i s r el at e d t o o b s er v e d d at a) a n d b orr o w s i nf or m ati o n fr o m p ati e nt s i n t h e s a m e tr e at m e nt 
ar m t a ki n g i nt o a c c o u nt b ot h t h e mi s si n g n e s s of d at a t hr o u g h t h e c orr el ati o n of t h e r e p e at e d 
m e a s ur e m e nt s. 
W h e n M M R M i s u s e d, t h e m o d el i n cl u d e s tr e at m e nt, b a s eli n e v al u e, vi sit, t h e i nt er a cti o n of t h e b a s eli n e 
v al u e- b y- w e e k, t h e i nt er a cti o n of tr e at m e nt- b y- w e e k, a n d t h e str atifi c ati o n f a ct or s m e nti o n e d i n S e cti o n 
7. 5  a s fi x e d f a ct or s. 
E x a m pl e S A S s y nt a x i s a s f oll o w s: 
6. 3. 2. 
6. 3. 3. 
C CI
C CI
C CI


St ati sti c al A n al y si s Pl a n f or I nt er v e nti o n al St u di e s  
S p o n s or: A L MI R A L L, S. A.; Pr ot o c ol N o.: M- 1 7 9 2 3- 3 0 
 
 
T hi s d o c u m e nt i s c o nfi d e nti al. 
S A P t e xt V er si o n: S A P t e xt v 2. 0 2 2 M A R 2 0 2 3 
C o ntr oll e d D o c u m e nt I D:  
, Eff e cti v e D at e 3 1- A u g- 2 0 2 0 
Fili n g r e q uir e m e nt s: T M F  
 
P a g e 2 8  of 7 3  
I N T E R N AL U S E 
  
G e n er al A s p e ct s f or St ati sti c al A n al y si s 
7. 1.  
G e n er al M et h o d s 
  U nl e s s ot h er wi s e s p e cifi e d, s u m m ari e s will b e pr e s e nt e d b y st u d y p eri o d, b y tr e at m e nt gr o u p a n d 
o v er all.  
  C o nti n u o u s v ari a bl e s will b e s u m m ari z e d u si n g t h e n u m b er of o b s er v ati o n s ( n), m e a n, st a n d ar d 
d e vi ati o n ( S D), st a n d ar d err or of m e a n, m e di a n, fir st a n d t hir d q u artil e s, mi ni m u m a n d m a xi m u m. 
C at e g ori c al v ari a bl e s will b e s u m m ari z e d u si n g n u m b er of o b s er v ati o n s ( n) a n d p er c e nt a g e s ( %) of 
p ati e nt s. T h e 9 5 % CI ar o u n d t h e m e a n m a y al s o b e pr e s e nt e d i n d e s cri pti v e st ati sti c s a s 
a p pr o pri at e f or s p e cifi c e n d p oi nt s of i nt er e st. 
  All r el e v a nt p ati e nt d at a will b e i n cl u d e d i n li sti n g s. All p ati e nt s e nt er e d i nt o t h e d at a b a s e will b e 
i n cl u d e d i n p ati e nt d at a li sti n g s 
7. 2.  
K e y D efi niti o n s 
 
Fir st D o s e D at e 
Fir st d o s e d at e i s d efi n e d a s t h e d a y of fir st d o s e of st u d y tr e at m e nt r e c ei v e d aft er r a n d o mi z ati o n. 
 
L a st D o s e D at e 
L a st d o s e d at e i s d efi n e d a s d a y of t h e l a st d o s e of st u d y tr e at m e nt.   
F or p ati e nt s o n g oi n g f or t h e tr e at m e nt p eri o d at ti m e of a n al y si s pri or t o d at a b a s e l o c k, t h e l a st d o s e d at e 
i s t h e d at e of t h e m o st r e c e nt st u d y vi sit w h er e st u d y dr u g w a s a d mi ni st er e d i n t h e d at a b a s e f or t h e p ati e nt. 
 
St u d y D a y 
T h e st u d y d a y i s d et er mi n e d r el ati v e t o t h e d at e of fir st d o s e of st u d y tr e at m e nt, u nl e s s ot h er wi s e s p e cifi e d.  
T h e d a y of t h e fir st d o s e of st u d y tr e at m e nt i s d efi n e d a s st u d y d a y 1.  T h e d a y pri or t o t h e fir st d o s e of 
st u d y tr e at m e nt i s st u d y d a y - 1.  T h er e i s n o st u d y d a y 0. 
F or e v e nt s t h at o c c ur b ef or e t h e fir st d o s e of st u d y tr e at m e nt,  
st u d y d a y = d at e of t h e e v e nt – fir st d o s e d at e;  
f or e v e nt s t h at o c c ur o n or aft er t h e fir st d o s e of st u d y tr e at m e nt,  
st u d y d a y = d at e of t h e e v e nt – fir st d o s e d at e + 1. 
 
B a s eli n e a n d C h a n g e fr o m B a s eli n e  
F or all c h a n g e fr o m b a s eli n e v ari a bl e s, t h e b a s eli n e i s d efi n e d a s t h e l a st n o n- mi s si n g a s s e s s m e nt pri or t o 
or o n t h e d a y of r a n d o mi z ati o n, a n d m u st b e pri or t o t h e fir st a d mi ni str ati o n of st u d y tr e at m e nt, i n cl u di n g 
s c h e d ul e d  a n d  u n s c h e d ul e d  vi sit s,  u nl e s s  ot h er wi s e  s p e cifi e d.    H e n c e,  c h a n g e  fr o m  b a s eli n e  =  p o st-
b a s eli n e v al u e – b a s eli n e v al u e.  
T h e  b a s eli n e  v al u e  f or  a n al y s e s  of  q u alit ati v e  p ar a m et er s  ( e. g.,  n or m al/ a b n or m al)  i s  d efi n e d  a s  t h e  l a st 
e v al u ati o n  pri or  t o  or  o n t h e  d a y  of r a n d o mi z ati o n,  a n d  m u st b e pri or  t o t h e fir st  a d mi ni str ati o n of st u d y 
tr e at m e nt. 
7. 
7. 2. 1. 
7. 2. 2. 
7. 2. 3. 
7. 2. 4. 
C CI


St ati sti c al A n al y si s Pl a n f or I nt er v e nti o n al St u di e s  
S p o n s or: A L MI R A L L, S. A.; Pr ot o c ol N o.: M- 1 7 9 2 3- 3 0 
 
 
T hi s d o c u m e nt i s c o nfi d e nti al. 
S A P t e xt V er si o n: S A P t e xt v 2. 0 2 2 M A R 2 0 2 3 
C o ntr oll e d D o c u m e nt I D:  
, Eff e cti v e D at e 3 1- A u g- 2 0 2 0 
Fili n g r e q uir e m e nt s: T M F  
 
P a g e 2 9  of 7 3  
I N T E R N AL U S E 
T h e b a s eli n e v al u e f or t h e P R O q u e sti o n n air e s a n d di ar y will b e t h e a v er a g e of t h e 7 d a y s b ef or e st arti n g 
st u d y tr e at m e nt.  
7. 3.  
Mi s si n g D at a 
Mi s si n g d at a i m p ut ati o n r ul e s f or effi c a c y d at a ar e s p e cifi e d i n S e cti o n エラー
エラー! 参照元が見つかりません。
参照元が見つかりません。. 
All ot h er mi s si n g d at a n ot c o v er e d h er e will n ot b e i m p ut e d. A n al y s e s will b e p erf or m e d c o n si d eri n g all d at a 
o b s er v e d f or t h e r e s p e cti v e a n al y si s s et s.  
 
P arti al or Mi s si n g E v e nt D at e s 
All p arti al or mi s si n g d at e s will b e pr e s e nt e d i n t h e d at a li sti n g s a s t h e y ar e r e c or d e d o n t h e el e ctr o ni c C a s e 
R e p ort F or m ( e C R F). T h e a n al y si s d at a s et will fl a g w h er e d a y, m o nt h or y e ar h a s b e e n i m p ut e d f or a n al y si s 
st art or st o p d at e. 
 
A d v er s e E v e nt s 
F or t h e p ur p o s e of a s s e s si n g w h et h er a n A E i s tr e at m e nt e m er g e nt, if a n A E h a s a c o m pl et el y mi s si n g st art 
a n d st o p d at e, it will b e c o n si d er e d tr e at m e nt e m er g e nt; if t h e st o p d at e i s n ot mi s si n g, b ut t h e st art d at e i s 
c o m pl et el y mi s si n g, it will b e c o n si d er e d tr e at m e nt e m er g e nt u nl e s s t h e st o p d at e o c c ur s pri or t o t h e fir st 
d o s e of st u d y dr u g.  
F or p ur p o s e of c al c ul ati o n of d ur ati o n of A E, if a c o m pl et el y mi s si n g st art a n d st o p d at e o c c ur s t h e n it will 
b e c o n si d er e d t o h a v e st art e d o n t h e d at e of fir st d o s e a n d st o p p e d at t h e d at e of st u d y t er mi n ati o n. If st o p 
d at e i s pr e s e nt, a n d st art d at e i s c o m pl et el y mi s si n g, t h e st art d at e will b e i m p ut e d wit h t h e d at e of fir st d o s e 
of st u d y dr u g u nl e s s t h e st o p d at e o c c ur s pri or t o fir st d o s e of st u d y dr u g; i n t hi s c a s e t h e st art d at e will b e 
i m p ut e d wit h t h e d at e of fir st d o s e of st u d y dr u g. If st art d at e i s pr e s e nt a n d a c o m pl et el y mi s si n g st o p d at e 
o c c ur s, it will b e c o n si d er e d t o h a v e st o p p e d at t h e d at e of st u d y t er mi n ati o n f or t h e p ati e nt.  
F or a s s e s si n g tr e at m e nt e m er g e n c e or f or c al c ul ati o n of d ur ati o n of A E, if a p arti al st art or st o p d at e o c c ur s, 
t h e f oll o wi n g i m p ut ati o n pr o c e s s will b e i m pl e m e nt e d: 
P arti al Mi s si n g 
St art or St o p D at e  
I m p ut ati o n f or St art D at e 
I m p ut ati o n f or St o p 
D at e  
D a y mi s si n g, m o nt h 
a n d y e ar pr e s e nt 
  
M o nt h a n d/ or y e ar diff er e nt t o m o nt h a n d y e ar of 
fir st st u d y dr u g d o s e: I m p ut e d a y wit h “ 0 1”. 
  
M o nt h a n d/ or y e ar s a m e a s m o nt h a n d y e ar of fir st 
st u d y dr u g d o s e: I m p ut e d a y wit h s a m e d a y a s fir st 
d o s e of st u d y dr u g. 
I m p ut e d a y wit h l a st 
d a y of t h e m o nt h 
D a y a n d m o nt h 
mi s si n g, y e ar 
pr e s e nt 
  
Y e ar diff er e nt t o y e ar of fir st st u d y dr u g d o s e: 
I m p ut e d a y a n d m o nt h wit h “ 0 1 J A N”. 
  
Y e ar s a m e a s y e ar of fir st st u d y dr u g d o s e: I m p ut e 
m o nt h a n d d a y wit h s a m e m o nt h a n d d a y a s fir st 
d o s e of st u d y dr u g.  
I m p ut e d a y a n d 
m o nt h wit h “ 3 1 D E C” 
M o nt h mi s si n g, d a y 
a n d y e ar pr e s e nt 
  
Y e ar diff er e nt t o y e ar of fir st st u d y dr u g d o s e: 
I m p ut e m o nt h wit h “ J A N”. 
  
Y e ar s a m e a s y e ar of fir st st u d y dr u g d o s e: I m p ut e 
m o nt h wit h s a m e m o nt h a s fir st d o s e of st u d y dr u g. 
I m p ut e wit h “ D E C” 
C a v e at s 
  
If a n y i m p ut e d st art d at e l e a d s t o a st art d at e t h at i s aft er t h e st o p d at e, t h e n 
t h e st art d at e will b e i m p ut e d wit h t h e d at e of t h e st o p of A E. 
 
7. 3. 1. 
7. 3. 2. 
C CI


St ati sti c al A n al y si s Pl a n f or I nt er v e nti o n al St u di e s  
S p o n s or: A L MI R A L L, S. A.; Pr ot o c ol N o.: M- 1 7 9 2 3- 3 0 
 
 
T hi s d o c u m e nt i s c o nfi d e nti al. 
S A P t e xt V er si o n: S A P t e xt v 2. 0 2 2 M A R 2 0 2 3 
C o ntr oll e d D o c u m e nt I D:  
, Eff e cti v e D at e 3 1- A u g- 2 0 2 0 
Fili n g r e q uir e m e nt s: T M F  
 
P a g e 3 0  of 7 3  
I N T E R N AL U S E 
If t h e st art d at e of a n y T E A E  i s i n c o m pl et e or mi s si n g, t h e e v e nt will b e a s s u m e d t o b e i n t h e I n d u cti o n 
P eri o d, u nl e s s t h e i n c o m pl et e st art d at e ( m o nt h a n d/ or y e ar) cl e arl y i n di c at e s t h at t h e e v e nt st art e d o n or 
aft er t h e fir st d o si n g i n M ai nt e n a n c e P eri o d. 
 
Pri or/ C o n c o mit a nt M e di c ati o n s 
F or t h e p ur p o s e of a s s e s si n g w h et h er a m e di c ati o n i s pri or or c o n c o mit a nt, if a m e di c ati o n h a s a c o m pl et el y 
mi s si n g st art d at e it will b e c o n si d er e d a pri or m e di c ati o n, a n d if a m e di c ati o n h a s a c o m pl et el y mi s si n g 
st o p d at e it will b e c o n si d er e d a c o n c o mit a nt m e di c ati o n. If a p arti al st art or st o p d at e o c c ur s, t h e f oll o wi n g 
i m p ut ati o n pr o c e s s will b e i m pl e m e nt e d:  
P arti al Mi s si n g 
St art or St o p D at e  
I m p ut ati o n f or St art D at e 
I m p ut ati o n f or 
St o p D at e  
D a y mi s si n g, m o nt h 
a n d y e ar pr e s e nt 
  
M o nt h a n d/ or y e ar diff er e nt t o m o nt h a n d y e ar of fir st 
st u d y dr u g d o s e: I m p ut e d a y wit h “ 0 1” 
  
M o nt h a n d/ or y e ar s a m e a s m o nt h a n d y e ar of fir st 
st u d y dr u g d o s e: I m p ut e d a y wit h s a m e d a y a s fir st 
d o s e of st u d y dr u g. 
I m p ut e d a y wit h l a st 
d a y of t h e m o nt h 
D a y a n d m o nt h 
mi s si n g, y e ar 
pr e s e nt 
  
Y e ar diff er e nt t o y e ar of fir st st u d y dr u g d o s e: I m p ut e 
d a y a n d m o nt h wit h “ 0 1 J A N” 
  
Y e ar s a m e a s y e ar of fir st st u d y dr u g d o s e: I m p ut e 
m o nt h a n d d a y wit h s a m e m o nt h a n d d a y a s fir st d o s e 
of st u d y dr u g. 
I m p ut e d a y a n d 
m o nt h wit h 
“ 3 1 D E C” 
M o nt h mi s si n g, d a y 
a n d y e ar pr e s e nt 
  
Y e ar diff er e nt t o y e ar of fir st st u d y dr u g d o s e: I m p ut e 
m o nt h wit h “ J A N” 
  
Y e ar s a m e a s y e ar of fir st st u d y dr u g d o s e: I m p ut e 
m o nt h wit h s a m e m o nt h a s fir st d o s e of st u d y dr u g. 
I m p ut e wit h “ D E C” 
C a v e at s 
  
If a n y i m p ut e d st art d at e l e a d s t o a st art d at e t h at i s aft er t h e st o p d at e, t h e n 
t h e st art d at e will b e i m p ut e d wit h t h e d at e of t h e st o p of m e di c ati o n. 
 
N o st o p d at e will b e i m p ut e d if t h e tr e at m e nt i s o n g oi n g.  
 
If  t h e  st art  d at e  of  a n y  m e di c ati o n/ pr o c e d ur e  i s  i n c o m pl et e  or  mi s si n g,  a n d  it  i s  u n cl e ar  w h e n  i m p ut e d 
w h et h er t h e m e di c ati o n/ pr o c e d ur e st art e d i n I n d u cti o n or M ai nt e n a n c e P eri o d, t h e m e di c ati o n/ pr o c e d ur e 
will b e a s s u m e d t o b e c o n c o mit a nt wit h b ot h I n d u cti o n a n d M ai nt e n a n c e P eri o d, u nl e s s t h e i n c o m pl et e st art 
d at e ( m o nt h a n d/ or y e ar) cl e arl y i n di c at e s t h at t h e m e di c ati o n/ pr o c e d ur e st art e d o n or aft er t h e fir st d o si n g 
i n M ai nt e n a n c e P eri o d. 
 
7. 4.  
Vi sit Wi n d o w s 
I n g e n er al, all d at a fr o m t h e e C R F will b e or g a ni z e d a n d a n al y z e d a c c or di n g t o t h e s c h e d ul e d ti m e p oi nt s. 
If t h e s c h e d ul e d a s s e s s m e nt i s a v ail a bl e, a n y a d diti o n al or u n s c h e d ul e d a s s e s s m e nt s will n ot b e u s e d i n 
t h e  s u m m ar y  st ati sti c s  p er  ti m e  p oi nt  ( u nl e s s  ot h er wi s e  di s c u s s e d  i n  t h e  r el e v a nt  s e cti o n),  b ut  will  b e 
i n cl u d e d i n t h e d at a li sti n g s a c c or di n g t o t h e d at e/ti m e of a s s e s s m e nt.  
If t h e s c h e d ul e d a s s e s s m e nt  i s n ot a v ail a bl e,  t h e  u n s c h e d ul e d a s s e s s m e nt  will  b e  u s e d  if  it  i s c oll e ct e d 
wit hi n  fr o m  - 6  t o  + 7  d a y s    of  t h e  t ar g et  d a y/ti m e p oi nt  f or  t h e  s c h e d ul e d  a s s e s s m e nt.  If  t h er e  ar e  s o m e 
u n s c h e d ul e d a s s e s s m e nt s a v ail a bl e, t h e cl o s e st d at a t o t h e D a y will b e u s e d. If t h er e ar e pri or a n d p o st-
D a y d at a wit hi n s a m e d a y s fr o m t h e D a y, t h e l at er p o st- D a y d at a will b e u s e d. 
T h e u n s c h e d ul e d a s s e s s m e nt c o ul d b e a v ail a bl e b a s e d o n t h e f oll o wi n g vi sit wi n d o w s. 
7. 3. 3. 
C CI


St ati sti c al A n al y si s Pl a n f or I nt er v e nti o n al St u di e s  
S p o n s or: A L MI R A L L, S. A.; Pr ot o c ol N o.: M- 1 7 9 2 3- 3 0 
 
 
T hi s d o c u m e nt i s c o nfi d e nti al. 
S A P t e xt V er si o n: S A P t e xt v 2. 0 2 2 M A R 2 0 2 3 
C o ntr oll e d D o c u m e nt I D:  
 Eff e cti v e D at e 3 1- A u g- 2 0 2 0 
Fili n g r e q uir e m e nt s: T M F  
 
P a g e 3 1  of 7 3  
I N T E R N AL U S E 
S c h e d ul e d a s s e s s m e nt  
Vi sit - W e e k 
L o w er all o w a n c e  
T ar g et d a y 
U p p er all o w a n c e 
Vi sit 3 - W e e k 2 
8 
1 4 
2 1 
Vi sit 4 - W e e k 4 
2 2 
2 8 
3 5 
Vi sit 5 - W e e k 6 
3 6 
4 2 
4 9 
Vi sit 6 - W e e k 8 
5 0 
5 6 
6 3 
Vi sit 7 - W e e k 1 0 
6 4 
7 0 
7 7 
Vi sit 8 - W e e k 1 2 
7 8 
8 4 
9 1 
Vi sit 9 - W e e k 1 4 
9 2 
9 8 
1 0 5 
 
7. 5.  
A dj u st m e nt s f or C o v ari at e s 
U nl e s s  ot h er wi s e  s p e cifi e d,  t h e  st ati sti c al  a n al y si s  m o d el s  f or  t h e  I n d u cti o n  P eri o d  effi c a c y  a n d  h e alt h 
o ut c o m e a n al y si s will i n cl u d e t h e f oll o wi n g str atifi c ati o n f a ct or s f or B a s eli n e r a n d o mi z ati o n: a g e ( a d ol e s c e nt 
p ati e nt s  1 2  t o  < 1 8  v er s u s  a d ult s  ≥1 8  y e ar s)  a n d  b a s eli n e  di s e a s e  s e v erit y  (I G A = 3  v er s u s  I G A = 4). 
A d diti o n all y, t h e f oll o wi n g f a ct or s will b e i n cl u d e d i n t h e m o d el s: 
  
C o u ntr y of p ati e nt a s r e c or d e d at s cr e e ni n g 
  
F or a n al y s e s of t h e f ull p o p ul ati o n (i. e. n ot t h e s u b gr o u p s of d u pil u m a b n aï v e or pr e vi o u sl y e x p o s e d 
p ati e nt s), t h e str atifi c ati o n f a ct or of pri or u s e of d u pil u m a b ( y e s/ n o) will b e i n cl u d e d. 
If t h e m o d el d o e s n ot c o n v er g e, c o u ntr y will b e r e m o v e d a s a f a ct or fr o m t h e s p e cifi c m o d el. 
7. 6.  
S u b gr o u p s 
All e n d p oi nt s will b e a n al y s e d b y pr e vi o u s e x p o s ur e t o d u pil u m a b ( Y e s/ N o) a s  
. 
F or t h e m ai nt e n a n c e p h a s e, t h e a n al y si s will b e p erf or m e d f or b ot h ar m s s e p ar at el y: 
-  
L e bri ki z u m a b ( p ati e nt s pr e vi o u sl y t o o k l e bri ki z u m a b) 
-  
L e bri ki z u m a b ( p ati e nt s pr e vi o u sl y t o o k pl a c e b o) 
7. 7.  
G e n er al C o n si d er ati o n s f or Effi c a c y d uri n g I n d u cti o n P eri o d 
T h e I n d u cti o n P eri o d st art s aft er t h e fir st i nj e cti o n of st u d y tr e at m e nt at B a s eli n e Vi sit ( D a y 1) a n d e n d s 
pri or t o t h e fir st i nj e cti o n of st u d y tr e at m e nt at W e e k 1 6 or t h e e arl y t er mi n ati o n vi sit ( E T V) ( b et w e e n D a y 
1 a n d W e e k 1 6). F or p ati e nt s w h o ar e r a n d o mi z e d b ut n ot d o s e d, t h e I n d u cti o n P eri o d st art s o n t h e d at e 
of r a n d o mi z ati o n.  
F or Pr urit u s N u m eri c R ati n g S c al e ( N R S) a n d Sl e e p- L o s s d u e t o Pr urit u s c oll e ct e d vi a e Di ar y, t h e 
b a s eli n e p eri o d i s t h e 7- d a y wi n d o w pri or t o t h e fir st i nj e cti o n. A p ati e nt m u st h a v e r e s p o n s e s o n at l e a st 4 
of 7 d a y s t o c al c ul at e a b a s eli n e w e e kl y m e a n. If a p ati e nt h a s 3 or f e w er r e s p o n s e s, t h e b a s eli n e m e a n 
v al u e will b e c o n si d er e d mi s si n g.  
7. 8.  
G e n er al C o n si d er ati o n s f or Effi c a c y d uri n g M ai nt e n a n c e P eri o d 
T h e M ai nt e n a n c e P eri o d st art s aft er t h e fir st i nj e cti o n of st u d y tr e at m e nt at W e e k 1 6 a n d e n d s aft er l a st 
i nj e cti o n of st u d y tr e at m e nt at W e e k 5 2. 
B a s eli n e f or t h e M ai nt e n a n c e P eri o d a n al y s e s will b e t h e s a m e a s t h at f or t h e I n d u cti o n P eri o d. S e e 
S e cti o n 7. 2. 4 f or di s c u s si o n o n d eri v ati o n of b a s eli n e. 
C CI
C CI


St ati sti c al A n al y si s Pl a n f or I nt er v e nti o n al St u di e s  
S p o n s or: A L MI R A L L, S. A.; Pr ot o c ol N o.: M- 1 7 9 2 3- 3 0 
 
 
T hi s d o c u m e nt i s c o nfi d e nti al. 
S A P t e xt V er si o n: S A P t e xt v 2. 0 2 2 M A R 2 0 2 3 
C o ntr oll e d D o c u m e nt I D:  
, Eff e cti v e D at e 3 1- A u g- 2 0 2 0 
Fili n g r e q uir e m e nt s: T M F  
 
P a g e 3 2  of 7 3  
I N T E R N AL U S E 
All effi c a c y a n d Q o L v ari a bl e s f or t h e M ai nt e n a n c e P eri o d will b e a n al y s e d b y m e a n s of d e s cri pti v e 
st ati sti c s pr e s e nt e d b y tr e at m e nt gr o u p a s r a n d o mi s e d d uri n g t h e I n d u cti o n P eri o d. 
7. 9.  
C o ntr ol f or m ulti pli cit y 
I n t h e st u d y t h er e i s n o c o ntr ol f or t h e o v er all t y p e o n e err or, o nl y t h e pri m ar y e n d p oi nt n e e d s t o b e 
st ati sti c all y si g nifi c a nt i n or d er t h e st u d y t o b e a s u c c e s s. T h u s, n o c o ntr ol f or m ulti pli cit y a p pr o a c h i s 
d efi n e d. 
C CI


St ati sti c al A n al y si s Pl a n f or I nt er v e nti o n al St u di e s  
S p o n s or: A L MI R A L L, S. A.; Pr ot o c ol N o.: M- 1 7 9 2 3- 3 0 
 
 
T hi s d o c u m e nt i s c o nfi d e nti al. 
S A P t e xt V er si o n: S A P t e xt v 2. 0 2 2 M A R 2 0 2 3 
C o ntr oll e d D o c u m e nt I D:  
 Eff e cti v e D at e 3 1- A u g- 2 0 2 0 
Fili n g r e q uir e m e nt s: T M F  
 
P a g e 3 3  of 7 3  
I N T E R N AL U S E 
  
D e m o gr a p hi c, Ot h er B a s eli n e C h ar a ct eri sti c s a n d M e di c ati o n 
8. 1.  
P ati e nt Di s p o siti o n a n d Wit h dr a w al s 
T h e n u m b er of p ati e nt s i n cl u d e d i n e a c h a n al y si s s et will b e s u m m ari s e d u si n g d e s cri pti v e st ati sti c s b y 
st u d y p eri o d a n d tr e at m e nt gr o u p b a s e d o n t h e E nr oll e d S u bj e ct s. T h e r e a s o n s f or e x cl u si o n will b e 
pr e s e nt e d i n t h e li sti n g s of pr ot o c ol d e vi ati o n s, a n d i n t h e Bli n d D at a R e vi e w M e eti n g r e p ort I n a d diti o n, 
p ati e nt s c o m pl et e d tr e at m e nt a n d di s c o nti n u e d, t o g et h er wit h t h e r e a s o n s f or di s c o nti n u ati o n wit hi n e a c h 
st u d y p eri o d a n d f oll o w- u p will al s o b e s u m m ari s e d b y st u d y p eri o d a n d tr e at m e nt gr o u p b a s e d o n F A S. 
Si mil arl y, p ati e nt s c o m pl et e d st u d y a n d di s c o nti n u e d, t o g et h er wit h t h e r e a s o n s f or di s c o nti n u ati o n will b e 
s u m m ari z e d.  
8. 2.  
Pr ot o c ol D e vi ati o n s 
Pr ot o c ol d e vi ati o n s will b e s u m m ari z e d d e s cri pti v el y f or p ati e nt s wit h at l e a st 1 i m p ort a nt pr ot o c ol d e vi ati o n 
a n d p ati e nt s wit h at l e a st 1 n o n-i m p ort a nt pr ot o c ol d e vi ati o n f or e a c h tr e at m e nt gr o u p a n d o v er all. E a c h 
pr ot o c ol  d e vi ati o n  will  al s o  b e  s u m m ari z e d  d e s cri pti v el y  wit hi n  i m p ort a nt  a n d  n o n-i m p ort a nt  pr ot o c ol 
d e vi ati o n s f or e a c h tr e at m e nt gr o u p a n d o v er all of t h e F A S. A p ati e nt c a n h a v e m ulti pl e i m p ort a nt a n d/ or 
n o n-i m p ort a nt  d e vi ati o n s  a n d  c o u nt e d  o n c e  p er  i m p ort a nt  a n d/ or  n o n-i m p ort a nt  d e vi ati o n.  C O VI D- 1 9-
r el at e d  pr ot o c ol  d e vi ati o n s  will b e  s u m m ari z e d d e s cri pti v el y  f or  e a c h  tr e at m e nt  gr o u p a n d  o v er all of t h e 
F A S. 
A li sti n g of pr ot o c ol d e vi ati o n s, i n cl u di n g C O VI D- 1 9-r el at e d pr ot o c ol d e vi ati o n s, will b e pr o vi d e d. 
8. 3.  
D e m o gr a p hi c a n d B a s eli n e C h ar a ct eri sti c s 
T h e f oll o wi n g d e m o gr a p hi c a n d b a s eli n e c h ar a ct eri sti c s will b e a n al y s e d b y tr e at m e nt gr o u p b a s e d o n t h e 
F A S: 
-  
A g e (i n y e ar s) 
-  
A g e gr o u p ( A d ol e s c e nt s < = 1 2 t o < 1 8 Y e ar s ; A d ult s > = 1 8 Y e ar s) 
-  
S e x ( M al e; F e m al e) 
-  
Et h ni cit y ( Hi s p a ni c or L ati n o; N ot Hi s p a ni c or L ati n o; N ot R e p ort e d; U n k n o w n) 
-  
R a c e ( W hit e; Bl a c k or Afri c a n A m eri c a n; A m eri c a n I n di a n or Al a s k a N ati v e; A si a n; N ati v e 
H a w aii a n or Ot h er P a cifi c I sl a n d er; Ot h er; N ot R e p ort e d) 
-  
Fit z p atri c k S ki n T y p e (I; II; III; I V; V; VI) 
-  
H ei g ht (i n c m) 
-  
W ei g ht (i n k g) 
-  
B o d y M a s s I n d e x ( B MI ( k g/ m2 ) = W ei g ht( k g)/[ H ei g ht( m)2 ] 
-  
B o d y M a s s I n d e x ( B MI) c at e g ori e s ( U n d er w ei g ht / n or m al w ei g ht/ o v er w ei g ht/ o b e sit y) 
-  
Pri or u s e of d u pil u m a b ( Y e s/ N o) 
-  
 B a s eli n e di s e a s e s e v erit y: (I G A = 3 / I G A = 4) 
8. 
C CI


St ati sti c al A n al y si s Pl a n f or I nt er v e nti o n al St u di e s  
S p o n s or: A L MI R A L L, S. A.; Pr ot o c ol N o.: M- 1 7 9 2 3- 3 0 
 
 
T hi s d o c u m e nt i s c o nfi d e nti al. 
S A P t e xt V er si o n: S A P t e xt v 2. 0 2 2 M A R 2 0 2 3 
C o ntr oll e d D o c u m e nt I D:  
, Eff e cti v e D at e 3 1- A u g- 2 0 2 0 
Fili n g r e q uir e m e nt s: T M F  
 
P a g e 3 4  of 7 3  
I N T E R N AL U S E 
-  
A D d ur ati o n ( b a s e d o n A D o n s et, y e ar s) 
8. 4.  
M e di c al Hi st or y a n d C o n c o mit a nt Di s e a s e s 
M e di c al hi st or y i nf or m ati o n, a s r e c or d e d i n e C R F, will b e li st e d o n t h e S A F. 
M e di c al hi st ori e s ar e d efi n e d a s t h e c o n diti o n s/ e v e nt s r e c or d e d o n t h e M e di c al Hi st or y  el e ctr o ni c c a s e 
r e p ort f or m ( e C R F) wit h a st art d at e pri or t o t h e fir st st u d y dr u g i nj e cti o n. 
T h e n u m b er a n d p er c e nt a g e of p ati e nt s wit h m e di c al hi st ori e s will b e s u m m ari z e d f or t h e S A F P o p ul ati o n 
b y tr e at m e nt gr o u p u si n g t h e M e d D R A Pr ef err e d T er m ( P T) n e st e d wit hi n S y st e m Or g a n Cl a s s ( S O C), 
M e d D R A v er si o n 2 4. 1 or hi g h er. 
8. 5.  
Ot h er B a s eli n e C h ar a ct eri sti c s 
At o pi c D er m atiti s Hi st or y, S er ol o g y, C o a g ul ati o n, a n d W O C B P a s r e c or d e d o n t h e e C R F will o nl y b e 
pr e s e nt e d i n d at a li sti n g s o n t h e S A F. 
8. 6.  
M e di c ati o n 
M e di c ati o n s/ pr o c e d ur e s will b e c o d e d u si n g t h e l at e st v er si o n of t h e W H O Dr u g di cti o n ar y. T h e di cti o n ar y 
v er si o n u s e d will b e s p e cifi e d i n t h e d at a di s pl a y f o ot n ot e. I m p ut ati o n of mi s si n g a n d p arti al d at e s, f or t h e 
p ur p o s e of a s si g ni n g pri or/ c o n c o mit a nt st at u s i s d e s cri b e d i n  S e cti o n 7. 3. 3. 
 
Pri or M e di c ati o n 
M e di c ati o n s/ pr o c e d ur e s t h at st art pri or t o t h e d at e of fir st d o s e a n d st o p pri or t o or o n t h e d at e of fir st 
d o s e of st u d y dr u g ar e c o n si d er e d pri or m e di c ati o n s/ pr o c e d ur e s. Pri or m e di c ati o n s will b e s u m m ari z e d b y 
tr e at m e nt gr o u p a n d al s o pr e s e nt e d i n d at a li sti n g s o n t h e S A F.  
 
C o n c o mit a nt M e di c ati o n 
C o n c o mit a nt m e di c ati o n s/ pr o c e d ur e s ar e t h o s e m e di c ati o n s t h at st art b ef or e, o n, or aft er t h e fir st d a y of 
st u d y tr e at m e nt of t h e d efi n e d tr e at m e nt p eri o d a n d c o nti n u e i nt o t h e tr e at m e nt p eri o d. C o n c o mit a nt 
m e di c ati o n s ar e a s si g n e d t o t h e tr e at m e nt p eri o d i n w hi c h t h e y ar e a ct u all y o n g oi n g. F or e x a m pl e, if a 
p ati e nt i s r e c ei vi n g a c o n c o mit a nt m e di c ati o n d uri n g t h e I n d u cti o n P eri o d b ut h a s a st o p d at e d uri n g t h e 
I n d u cti o n P eri o d, t h e s a m e m e di c ati o n w o ul d n ot b e li st e d a s a c o n c o mit a nt m e di c ati o n d uri n g t h e 
M ai nt e n a n c e P eri o d u nl e s s p ati e nt h a s a n e w st art d at e. 
P ati e nt i n ci d e n c e will b e t a b ul at e d f or t h e c o n c o mit a nt m e di c ati o n s/ pr o c e d ur e s b y A n at o mi c T h er a p e uti c 
Cl a s s ( A T C) a n d pr ef err e d t er m f or all p ati e nt s i n t h e F A S, b y tr e at m e nt gr o u p a n d o v er all. T a bl e s will b e 
s ort e d b y d e s c e n di n g fr e q u e n c y of A T C l e v el 2 a n d d e s c e n di n g fr e q u e n c y of pr ef err e d t er m wit hi n t h e 
A T C l e v el. P ati e nt s will b e c o u nt e d o nl y o n c e f or e a c h A T C a n d e a c h pr ef err e d t er m i n t h e e v e nt t h at t h e y 
h a v e m ulti pl e r e c or d s of t h e s a m e A T C or pr ef err e d t er m i n t h e d at a b a s e. All c o n c o mit a nt 
m e di c ati o n s/ pr o c e d ur e s will b e pr e s e nt e d i n d at a li sti n g s.  
 
P o st M e di c ati o n 
O n c e t h e l a st d o s e of st u d y dr u g i s t a k e n (i. e., t h e l a st vi sit at w hi c h t h e p ati e nt t a k e s st u d y dr u g) a n d 
r el at e d tri al m e a s ur e m e nt s ar e c o m pl et e d, p ati e nt s s h o ul d c o nti n u e t o t a k e t h eir u s u al m e di c ati o n s, al s o 
all o w e d d uri n g t h e tri al, a n d m a y r e s u m e ot h er m e di c ati o n s t h at w er e i nt err u pt e d b ef or e tri al e nr ol m e nt a s 
d e e m e d a p pr o pri at e b y t h e I n v e sti g at or. T h e st u d y dr u g i s f or e x p eri m e nt al u s e o nl y, a n d t h er e ar e ot h er 
t h er a pi e s a v ail a bl e t o tr e at t h e di s e a s e.  
8. 6. 1. 
8. 6. 2. 
8. 6. 3. 
C CI


St ati sti c al A n al y si s Pl a n f or I nt er v e nti o n al St u di e s  
S p o n s or: A L MI R A L L, S. A.; Pr ot o c ol N o.: M- 1 7 9 2 3- 3 0 
 
 
T hi s d o c u m e nt i s c o nfi d e nti al. 
S A P t e xt V er si o n: S A P t e xt v 2. 0 2 2 M A R 2 0 2 3 
C o ntr oll e d D o c u m e nt I D:  
 Eff e cti v e D at e 3 1- A u g- 2 0 2 0 
Fili n g r e q uir e m e nt s: T M F  
 
P a g e 3 5  of 7 3  
I N T E R N AL U S E 
O nl y c o n c o mit a nt m e di c ati o n a s s o ci at e d wit h a d v er s e e v e nt s will b e c a pt ur e d b et w e e n t h e l a st st u d y dr u g 
a d mi ni str ati o n a n d l a st p h o n e c o nt a ct/ vi sit (i. e., s af et y f oll o w- u p).  
P o st m e di c ati o n s will b e fl a g g e d i n c o n c o mit a nt m e di c ati o n li sti n g s. 
 
R e s c u e M e di c ati o n 
R e s c u e m e di c ati o n s d uri n g t h e I n d u cti o n P eri o d a n d M ai nt e n a n c e Bli n d e d P eri o d will b e pr e s e nt e d b y 
tr e at m e nt gr o u p f or t h e F A S P o p ul ati o n. T h e u s e of s y st e mi c c orti c o st er oi d s f or t h e tr e at m e nt of A D i s 
pr o hi bit e d a n d r e q uir e s p er m a n e nt di s c o nti n u ati o n of t h e I n v e sti g ati o n al Pr o d u ct. If a s y st e mi c 
c orti c o st er oi d i s u s e d f or t h e tr e at m e nt of A E s ( e g, w or s e ni n g of e xi sti n g c o n diti o n, s u c h a s a st h m a 
e x a c er b ati o n), it will b e tr e at e d a s r e s c u e m e di c ati o n. 
T h e u s e of r e s c u e m e di c ati o n s i d e ntifi e d a s a n I C E will b e s u m m ari z e d u n d er t h e effi c a c y a n al y s e s of 
S e cti o n 9. 3 .  
8. 7.  
E xt e nt of E x p o s ur e 
T ot al dr u g e x p o s ur e (i n m g) i s d efi n e d a s t h e t ot al i n v e sti g ati o n al pr o d u ct i n m g t h at w a s t a k e n d uri n g t h e 
st u d y. 
T ot al e x p o s ur e d ur ati o n t o i n v e sti g ati o n al pr o d u ct (i n d a y s) i s d efi n e d a s: D at e of l a st d o s e – d at e of fir st 
d o s e + 1. N ot e t h at t hi s d o e s n ot e x cl u d e d a y s w h e n t h e d o s e h a s b e e n mi s s e d. 
P er c e nt of t h e pl a n n e d e x p o s ur e r e c ei v e d i s d efi n e d a s t h e t ot al dr u g e x p o s ur e, di vi d e d b y pl a n n e d 
e x p o s ur e, ti m e s 1 0 0.  
F or p ati e nt s i n t h e l e bri ki z u m a b ar m, 
-  
P ati e nt s w h o c o m pl et e t h e I n d u cti o n P eri o d, pl a n n e d e x p o s ur e i s 1 6 w e e k s of tr e at m e nt 
pl a n n e d, wit h a t ot al d o s e e q u al t o 2* 5 0 0 m g + 7* 2 5 0 m g = 2 7 5 0 m g 
-  
P ati e nt s w h o c o m pl et e t h e M ai nt e n a n c e P eri o d, pl a n n e d e x p o s ur e i s 3 5 w e e k s of tr e at m e nt 
pl a n n e d, wit h a t ot al d o s e e q u al t o 2 5 0 m g * 1 7 = 4 2 5 0 m g 
-  
G er m a n e xt e n si o n: t ot al d o s e (i n m g) i s c al c ul at e d b y t h e n u m b er of a cti v e i nj e cti o n s t a k e n 
d uri n g t h e tr e at m e nt p eri o d m ulti pli e d b y d o s e. 
F or p ati e nt s i n t h e pl a c e b o ar m, 
-  
P ati e nt s w h o c o m pl et e t h e I n d u cti o n P eri o d, pl a n n e d e x p o s ur e i s t h e l o a di n g d o s e at w e e k 
1 6, wit h a t ot al d o s e e q u al t o 2* 2 5 0 m g = 5 0 0 m g 
-  
P ati e nt s w h o c o m pl et e t h e M ai nt e n a n c e P eri o d, pl a n n e d e x p o s ur e i s 3 5 w e e k s of tr e at m e nt 
pl a n n e d, wit h a t ot al d o s e e q u al t o 2* 2 5 0 m g + 2 5 0 m g * 1 6 = 4 5 0 0 m g 
-  
G er m a n e xt e n si o n: t ot al d o s e (i n m g) i s c al c ul at e d b y t h e n u m b er of a cti v e i nj e cti o n s t a k e n 
d uri n g t h e tr e at m e nt p eri o d m ulti pli e d b y d o s e. 
Fi n all y, t h e t ot al e x p o s ur e i n p ati e nt y e ar s will b e c al c ul at e d a s: 
𝑇𝑜𝑡𝑎𝑙 𝑒𝑥𝑝𝑜𝑠𝑢𝑟𝑒 𝑖𝑛 𝑝𝑎𝑡𝑖𝑒𝑛𝑡 𝑦𝑒𝑎𝑟𝑠
= 𝑆𝑢𝑚 𝑜𝑓 𝑑𝑢𝑟𝑎𝑡𝑖𝑜𝑛 𝑜𝑓 𝑒𝑥𝑝𝑜𝑠𝑢𝑟𝑒𝑠 𝑓𝑜𝑟 𝑎𝑙𝑙 𝑝𝑎𝑡𝑖𝑒𝑛𝑡𝑠 𝑖𝑛 𝑡𝑟𝑒𝑎𝑡𝑚𝑒𝑛𝑡 𝑔𝑟𝑜𝑢𝑝
3 6 5. 2 5
 
8. 6. 4. 
C CI


St ati sti c al A n al y si s Pl a n f or I nt er v e nti o n al St u di e s  
S p o n s or: A L MI R A L L, S. A.; Pr ot o c ol N o.: M- 1 7 9 2 3- 3 0 
 
 
T hi s d o c u m e nt i s c o nfi d e nti al. 
S A P t e xt V er si o n: S A P t e xt v 2. 0 2 2 M A R 2 0 2 3 
C o ntr oll e d D o c u m e nt I D:  
, Eff e cti v e D at e 3 1- A u g- 2 0 2 0 
Fili n g r e q uir e m e nt s: T M F  
 
P a g e 3 6  of 7 3  
I N T E R N AL U S E 
 
T ot al dr u g e x p o s ur e, t ot al e x p o s ur e d ur ati o n, t ot al e x p o s ur e i n p ati e nt y e ar s, a n d p er c e nt of t h e pl a n n e d 
e x p o s ur e r e c ei v e d will b e s u m m ari z e d u si n g t h e S A F a n d a ct u al tr e at m e nt gr o u p f or e a c h p eri o d. 
8. 8.  
Tr e at m e nt C o m pli a n c e  
St u d y dr u g c o m pli a n c e will b e a s s e s s e d b y c o u nti n g r et ur n e d u s e d or u n u s e d pr efill e d s yri n g e s. A p ati e nt 
will b e c o n si d er e d c o m pli a nt wit h t h e d o si n g r e gi m e n if t h e p ati e nt r e c ei v e d ≥7 5 % of t h e e x p e ct e d n u m b er 
of i nj e cti o n s w hil e e nr oll e d i n t h e st u d y.  
T h e f or m ul a t o c al c ul at e t h e tr e at m e nt c o m pli a n c e i s t h e f oll o wi n g: 
 
W h er e a c c or di n g t o t h e e C R F e ntr y i n str u cti o n, t h e “ T ot al n ot r et ur n e d kit s” i s e q ui v al e nt t o t h e “t ot al u s e d 
kit s”. 
Tr e at m e nt c o m pli a n c e will b e li st e d f or e a c h p eri o d.  
T ot al n ot r et u r n e d kit 
Tr e at m e nt c o m pli a n c e( %) = 1 0 0 X T ot al n u m b er of i nj e cti o ns e x p e ct e d 
C CI


St ati sti c al A n al y si s Pl a n f or I nt er v e nti o n al St u di e s  
S p o n s or: A L MI R A L L, S. A.; Pr ot o c ol N o.: M- 1 7 9 2 3- 3 0 
 
 
T hi s d o c u m e nt i s c o nfi d e nti al. 
S A P t e xt V er si o n: S A P t e xt v 2. 0 2 2 M A R 2 0 2 3 
C o ntr oll e d D o c u m e nt I D:  
, Eff e cti v e D at e 3 1- A u g- 2 0 2 0 
Fili n g r e q uir e m e nt s: T M F  
 
P a g e 3 7  of 7 3  
I N T E R N AL U S E 
  
Effi c a c y 
9. 1.  
St ati sti c al H y p ot h e s e s 
T h e st ati sti c al h y p ot h e si s t o b e t e st e d f or t h e m ai n e sti m a n d of t h e pri m ar y effi c a c y e n d p oi nt ( P er c e nt a g e 
of p ati e nt s a c hi e vi n g E A SI 7 5 at W e e k 1 6) ar e:  
-  
H0 : PL e bri ki z u m a b  – Ppl a c e b o  = 0  
-  
H1 : PL e bri ki z u m a b  – Ppl a c e b o  ≠ 0, 
w h er e P L e bri ki z u m a b  r ef er s t o t h e tr u e pr o p orti o n of p ati e nt s r e c ei vi n g l e bri ki z u m a b, a n d Ppl a c e b o  r ef er s t o t h e 
tr u e pr o p orti o n of p ati e nt s r e c ei vi n g pl a c e b o t h at a c hi e v e E A SI 7 5 at W e e k 1 6. T h e t e sti n g pr o c e d ur e will 
t h u s b e 2- si d e d. C o nfir m at or y t e sti n g i s c o n d u ct e d u si n g t h e m ai n e sti m a n d of t h e pri m ar y effi c a c y 
e n d p oi nt.  
F or a n al y s e s r el at e d t o t h e M ai nt e n a n c e P eri o d, o nl y d e s cri pti v e a n al y s e s will b e pr e s e nt e d. N o s p e cifi c 
st ati sti c al h y p ot h e s e s t h u s a p pl y f or t h e M ai nt e n a n c e P eri o d. 
9. 2.  
D efi niti o n s f or Effi c a c y E n d p oi nt s 
F or all effi c a c y e n d p oi nt s w h er e a d eri v e d c at e g ori s ati o n i s d efi n e d i n t hi s s e cti o n, if t h e c at e g or y i s 
c oll e ct e d o n t h e e C R F t h e n it will b e u s e d i n t h e a n al y si s a n d will n ot b e d eri v e d. Ot h er wi s e, t h e c at e g or y 
will b e d eri v e d b a s e d o n t h e r e c or d e d ( or i m p ut e d) m e a s ur e.  
 
  
 
 
9. 
C CI


St ati sti c al A n al y si s Pl a n f or I nt er v e nti o n al St u di e s  
S p o n s or: A L MI R A L L, S. A.; Pr ot o c ol N o.: M- 1 7 9 2 3- 3 0 
 
 
T hi s d o c u m e nt i s c o nfi d e nti al. 
S A P t e xt V er si o n: S A P t e xt v 2. 0 2 2 M A R 2 0 2 3 
C o ntr oll e d D o c u m e nt I D:  
, Eff e cti v e D at e 3 1- A u g- 2 0 2 0 
Fili n g r e q uir e m e nt s: T M F  
 
P a g e 3 8  of 7 3  
I N T E R N AL U S E 
M e a s ur e  
D e s cri pti o n  
V ari a bl e  
D eri v ati o n / 
C o m m e nt  
I m p ut ati o n 
A p pr o a c h if 
Mi s si n g 
C o m p o n e nt s  
E c z e m a Ar e a a n d 
S e v erit y I n d e x 
( E A SI) 
T h e E A SI s c ori n g s y st e m 
u s e s a d efi n e d pr o c e s s ( St e p s 
1- 5 b el o w) t o gr a d e t h e 
s e v erit y of t h e si g n s of 
e c z e m a a n d t h e e xt e nt 
aff e ct e d.  
T h e e xt e nt of di s e a s e 
( p er c e nt a g e of s ki n aff e ct e d: 0 
= 0 %; 1 = 1- 9 %; 2 = 1 0- 2 9 %; 
3 = 3 0- 4 9 %; 4 = 5 0- 6 9 %; 5 = 
7 0- 8 9 %; 6 = 9 0- 1 0 0 %) a n d  
t h e s e v erit y of 4 cli ni c al si g n s 
( er yt h e m a, e d e m a/ p a p ul ati o n, 
e x c ori ati o n, a n d 
li c h e nifi c ati o n) e a c h o n a 
s c al e of 0 t o 3 ( 0 = n o n e, 
a b s e nt; 1 = mil d; 
2 = m o d er at e; 3 = s e v er e) at 
4 b o d y sit e s ( h e a d a n d n e c k, 
tr u n k, u p p er li m b s, a n d l o w er 
li m b s).  H alf s c or e s ar e 
all o w e d b et w e e n s e v eriti e s 1, 
2 a n d 3.  E a c h b o d y sit e will 
h a v e a s c or e t h at r a n g e s fr o m 
0 t o 7 2, a n d t h e fi n al E A SI 
s c or e will b e o bt ai n e d b y 
w ei g ht- a v er a gi n g t h e s e 4 
s c or e s.  H e n c e, t h e fi n al E A SI 
s c or e will r a n g e fr o m 0 t o 7 2 
f or e a c h ti m e p oi nt. 
E A SI s c or e 
D eri v e E A SI r e gi o n 
s c or e f or e a c h of 
h e a d a n d n e c k, 
tr u n k, u p p er li m b s, 
a n d l o w er li m b s a s 
f oll o w s: 
E A SI r e gi o n = 
( Er yt h e m a + 
e d e m a/ p a p ul ati o n + 
E x c ori ati o n + 
Li c h e nifi c ati o n) 
*( v al u e fr o m 
p er c e nt a g e 
i n v ol v e m e nt), w h er e 
er yt h e m a, 
e d e m a/ p a p ul ati o n, 
e x c ori ati o n, a n d 
li c h e nifi c ati o n ar e 
e v al u at e d o n a s c al e 
of 0 t o 3 a n d v al u e 
fr o m p er c e nt a g e 
i n v ol v e m e nt i s o n a 
s c al e of 0 t o 6.  
T h e n t ot al E A SI 
s c or e i s a s f oll o w s: 
E A SI = 
0. 1* E A SI h e a d a n d 
n e c k  + 
0. 3* E A SI tr u n k + 
0. 2* E A SI u p p er li m b s  
+ 0. 4* E A SI l o w er 
li m b s 
If v al u e of 
p er c e nt a g e 
i n v ol v e m e nt i s 0 
f or a n y r e gi o n, 
t h e n s e v erit y 
s c or e s of t h at 
r e gi o n c o ul d b e 
mi s si n g. 
Ot h er wi s e 
mi s si n g if a n y 
c o m p o n e nt i s 
mi s si n g.    
E A SI 5 0 
% I m pr o v e m e nt i n 
E A SI s c or e fr o m 
b a s eli n e ≥ 5 0 %: 
% c h a n g e fr o m 
b a s eli n e ≤- 5 0 
Mi s si n g if 
b a s eli n e or 
o b s er v e d v al u e 
i s mi s si n g. 
E A SI 7 5 
% I m pr o v e m e nt i n 
E A SI s c or e fr o m 
b a s eli n e ≥7 5 %: 
% c h a n g e fr o m 
b a s eli n e ≤- 7 5 
Mi s si n g if 
b a s eli n e or 
o b s er v e d v al u e 
i s mi s si n g. 
C CI


St ati sti c al A n al y si s Pl a n f or I nt er v e nti o n al St u di e s  
S p o n s or: A L MI R A L L, S. A.; Pr ot o c ol N o.: M- 1 7 9 2 3- 3 0 
 
 
T hi s d o c u m e nt i s c o nfi d e nti al. 
S A P t e xt V er si o n: S A P t e xt v 2. 0 2 2 M A R 2 0 2 3 
C o ntr oll e d D o c u m e nt I D:  
, Eff e cti v e D at e 3 1- A u g- 2 0 2 0 
Fili n g r e q uir e m e nt s: T M F  
 
P a g e 3 9  of 7 3  
I N T E R N AL U S E 
M e a s ur e  
D e s cri pti o n  
V ari a bl e  
D eri v ati o n / 
C o m m e nt  
I m p ut ati o n 
A p pr o a c h if 
Mi s si n g 
C o m p o n e nt s  
E A SI 9 0 
% I m pr o v e m e nt i n 
E A SI s c or e fr o m 
b a s eli n e ≥9 0 %: 
% c h a n g e fr o m 
b a s eli n e ≤- 9 0 
Mi s si n g if 
b a s eli n e or 
o b s er v e d v al u e 
i s mi s si n g. 
Ti m e (i n d a y s) t o E A SI 5 0 
( 7 5) ( 9 0) u p t o w e e k 1 6 
D at e of fir st ti m e % 
c h a n g e fr o m 
b a s eli n e i n E A SI 
s c or e ≥- 5 0 ( 7 5) ( 9 0) 
- d at e of W 1 6 vi sit 
+ 1 
If a p ati e nt h a s 
n ot e x p eri e n c e d 
a c hi e v e m e nt of 
E A SI 5 0 ( 7 5) 
( 9 0) b y 
c o m pl eti o n or 
e arl y 
di s c o nti n u ati o n 
of I n d u cti o n 
P eri o d, t h e 
p ati e nt will b e 
c e n s or e d at t h e 
d at e of t h eir l a st 
vi sit d uri n g 
I n d u cti o n P eri o d.  
 
 
Ti m e (i n d a y s) t o E A SI 5 0 
( 7 5) ( 9 0) b et w e e n w e e k 
1 6 a n d w e e k 5 2 
D at e of fir st ti m e % 
c h a n g e fr o m W 1 6 
vi sit  i n E A SI s c or e 
≥- 5 0 ( 7 5) ( 9 0) - d at e 
of W 5 2 vi sit + 1 
If a p ati e nt h a s 
n ot e x p eri e n c e d 
a c hi e v e m e nt of 
E A SI 5 0 ( 7 5) 
( 9 0) b y 
c o m pl eti o n or 
e arl y 
di s c o nti n u ati o n 
of M ai nt e n a n c e 
P eri o d, t h e 
p ati e nt will b e 
c e n s or e d at t h e 
d at e of t h eir l a st 
vi sit d uri n g 
M ai nt e n a n c e 
P eri o d.  
I n v e sti g at or’ s Gl o b al 
A s s e s s m e nt (I G A) 
T h e I G A i s a st ati c 
a s s e s s m e nt a n d r at e s t h e 
s e v erit y of t h e p ati e nt’ s A D. 
T h e I G A i s c o m pri s e d of a 5-
p oi nt s c al e r a n gi n g fr o m 0 
( cl e ar) t o 4 ( s e v er e) a n d a 
I G A s c or e 
Si n gl e it e m.  R a n g e: 
0 t o 4 
0 r e pr e s e nt s “ cl e ar” 
4 r e pr e s e nt s 
“ s e v er e” 
Si n gl e it e m, 
mi s si n g if 
mi s si n g. 
C CI


St ati sti c al A n al y si s Pl a n f or I nt er v e nti o n al St u di e s  
S p o n s or: A L MI R A L L, S. A.; Pr ot o c ol N o.: M- 1 7 9 2 3- 3 0 
 
 
T hi s d o c u m e nt i s c o nfi d e nti al. 
S A P t e xt V er si o n: S A P t e xt v 2. 0 2 2 M A R 2 0 2 3 
C o ntr oll e d D o c u m e nt I D:  
, Eff e cti v e D at e 3 1- A u g- 2 0 2 0 
Fili n g r e q uir e m e nt s: T M F  
 
P a g e 4 0  of 7 3  
I N T E R N AL U S E 
M e a s ur e  
D e s cri pti o n  
V ari a bl e  
D eri v ati o n / 
C o m m e nt  
I m p ut ati o n 
A p pr o a c h if 
Mi s si n g 
C o m p o n e nt s  
s c or e i s s el e ct e d u si n g 
d e s cri pt or s t h at b e st d e s cri b e 
t h e o v er all a p p e ar a n c e of t h e 
l e si o n s at a gi v e n ti m e p oi nt. 
I G A 0/ 1 wit h 2- p oi nt 
i m pr o v e m e nt 
 
 
O b s er v e d s c or e of 0 
or 1 a n d c h a n g e 
fr o m b a s eli n e = - 2 
 
 
Mi s si n g if 
b a s eli n e or 
o b s er v e d v al u e 
i s mi s si n g. 
Si n gl e it e m, 
mi s si n g if 
mi s si n g. 
B o d y S urf a c e Ar e a 
( B S A)  
T h e B S A a s s e s s m e nt 
e sti m at e s t h e e xt e nt of 
di s e a s e or s ki n i n v ol v e m e nt 
wit h r e s p e ct t o A D a n d i s 
e x pr e s s e d a s a p er c e nt a g e of 
t ot al b o d y s urf a c e. B S A will 
b e d et er mi n e d b y t h e 
I n v e sti g at or or d e si g n e e u si n g 
t h e p ati e nt p al m = 1 % r ul e 
B S A s c or e 
B S A T ot al = 
B S A h e a d a n d n e c k  + 
B S A tr u n k + 
B S A u p p er 
e xtr e miti e s  + 
B S A l o w er 
e xtr e miti e s  
N/ A – p arti al 
a s s e s s m e nt s 
c a n n ot b e s a v e d.   
C h a n g e fr o m b a s eli n e i n 
B S A s c or e 
C h a n g e fr o m 
b a s eli n e: o b s er v e d 
B S A s c or e – 
b a s eli n e B S A s c or e 
Mi s si n g if 
b a s eli n e or 
o b s er v e d v al u e 
i s mi s si n g. 
S C O Ri n g At o pi c 
D er m atiti s 
( S C O R A D) 
S C O R A D s c or e 
S C O R A D = A/ 5 + 
7 B/ 2 + C, w h er e  
A i s e xt e nt of 
di s e a s e, r a n g e 0-
1 0 0 
B i s di s e a s e 
s e v erit y, r a n g e 0- 1 8 
C i s s u bj e cti v e 
s y m pt o m s, r a n g e 0-
2 0 
Mi s si n g if 
c o m p o n e nt A or 
B or C i s 
mi s si n g.   
C CI


St ati sti c al A n al y si s Pl a n f or I nt er v e nti o n al St u di e s  
S p o n s or: A L MI R A L L, S. A.; Pr ot o c ol N o.: M- 1 7 9 2 3- 3 0 
 
 
T hi s d o c u m e nt i s c o nfi d e nti al. 
S A P t e xt V er si o n: S A P t e xt v 2. 0 2 2 M A R 2 0 2 3 
C o ntr oll e d D o c u m e nt I D:  
, Eff e cti v e D at e 3 1- A u g- 2 0 2 0 
Fili n g r e q uir e m e nt s: T M F  
 
P a g e 4 1  of 7 3  
I N T E R N AL U S E 
M e a s ur e  
D e s cri pti o n  
V ari a bl e  
D eri v ati o n / 
C o m m e nt  
I m p ut ati o n 
A p pr o a c h if 
Mi s si n g 
C o m p o n e nt s  
S C O R A D i s a v ali d at e d 
cli ni c al t o ol f or a s s e s si n g t h e 
e xt e nt a n d i nt e n sit y of at o pi c 
d er m atiti s.  T h er e ar e 3 
c o m p o n e nt s t o t h e 
a s s e s s m e nt:  
  
T h e e xt e nt of A D i s 
a s s e s s e d a s a 
p er c e nt a g e of e a c h 
d efi n e d b o d y ar e a a n d 
r e p ort e d a s t h e s u m of 
all ar e a s, wit h a 
m a xi m u m s c or e of 1 0 0 % 
( a s si g n e d a s “ A” i n t h e 
o v er all S C O R A D 
c al c ul ati o n).  
  
T h e s e v erit y of 6 s p e cifi c 
s y m pt o m s of A D 
(r e d n e s s, s w elli n g, 
o o zi n g/ cr u sti n g, 
e x c ori ati o n, s ki n 
t hi c k e ni n g/li c h e nifi c ati o n, 
dr y n e s s) i s a s s e s s e d 
u si n g t h e f oll o wi n g 
s c al e: n o n e ( 0), mil d ( 1), 
m o d er at e ( 2), or s e v er e 
( 3) (f or a m a xi m u m of 1 8 
t ot al p oi nt s, a s si g n e d a s 
“ B” i n t h e o v er all 
S C O R A D c al c ul ati o n).  
S u bj e cti v e a s s e s s m e nt of it c h 
a n d of sl e e pl e s s n e s s i s 
r e c or d e d f or e a c h s y m pt o m 
b y t h e p ati e nt or r el ati v e o n a 
V A S, w h er e 0 i s n o it c h ( or 
sl e e pl e s s n e s s) a n d 1 0 i s t h e 
w or st i m a gi n a bl e it c h ( or 
sl e e pl e s s n e s s), wit h a 
m a xi m u m p o s si bl e s c or e of 
2 0 ( a s si g n e d a s “ C” i n t h e 
o v er all S C O R A D c al c ul ati o n. 
C h a n g e fr o m b a s eli n e i n 
S C O R A D s c or e 
 
 
C h a n g e fr o m 
b a s eli n e: o b s er v e d 
S C O R A D s c or e – 
b a s eli n e S C O R A D 
s c or e 
 
Mi s si n g if 
b a s eli n e or 
o b s er v e d v al u e 
i s mi s si n g. 
C CI


St ati sti c al A n al y si s Pl a n f or I nt er v e nti o n al St u di e s  
S p o n s or: A L MI R A L L, S. A.; Pr ot o c ol N o.: M- 1 7 9 2 3- 3 0 
 
 
T hi s d o c u m e nt i s c o nfi d e nti al. 
S A P t e xt V er si o n: S A P t e xt v 2. 0 2 2 M A R 2 0 2 3 
C o ntr oll e d D o c u m e nt I D:  
, Eff e cti v e D at e 3 1- A u g- 2 0 2 0 
Fili n g r e q uir e m e nt s: T M F  
 
P a g e 4 2  of 7 3  
I N T E R N AL U S E 
M e a s ur e  
D e s cri pti o n  
V ari a bl e  
D eri v ati o n / 
C o m m e nt  
I m p ut ati o n 
A p pr o a c h if 
Mi s si n g 
C o m p o n e nt s  
Pr urit u s N u m eri c 
R ati n g S c al e ( N R S)  
T h e Pr urit u s N u m eri c R ati n g 
S c al e ( N R S) i s a n 1 1- p oi nt 
s c al e u s e d b y p ati e nt s t o r at e 
t h eir w or st it c h s e v erit y o v er 
t h e p a st 2 4 h o ur s wit h 0 
i n di c ati n g “ N o it c h” a n d 1 0 
i n di c ati n g “ W or st it c h 
i m a gi n a bl e.” A s s e s s m e nt s will 
b e r e c or d e d d ail y b y t h e 
p ati e nt u si n g a n el e ctr o ni c 
di ar y.   
Pr urit u s N R S pr or at e d 
w e e kl y m e a n s c or e 
T h e pr or at e d w e e kl y 
m e a n i s b a s e d o n 
pr e vi o u s 7 d a y s. If 
t h e p ati e nt h a s at 
l e a st o n e d ail y 
s c or e, t h e w e e kl y 
m e a n i s t h e pr or at e d 
a v er a g e of d ail y 
s c or e s wit hi n t h e 
gi v e n w e e k. Si n gl e 
it e m; r a n g e 0- 1 0.   
W e e kl y m e a n 
s c or e mi s si n g if 
t h e p ati e nt h a s 
n o Pr urit u s- N R S 
r e s p o n s e s wit hi n 
t h e w e e k.  
4- p oi nt Pr urit u s 
i m pr o v e m e nt i n Pr urit u s 
N R S pr or at e d w e e kl y 
m e a n s c or e 
C h a n g e fr o m 
b a s eli n e i n Pr urit u s 
N R S pr or at e d 
w e e kl y m e a n s c or e 
≤- 4  
Mi s si n g if 
b a s eli n e i s 
mi s si n g or 
o b s er v e d v al u e 
i s mi s si n g. 
Sl e e p-l o s s  
Sl e e p-l o s s d u e t o pr urit u s will 
b e a s s e s s e d b y t h e p ati e nt. 
P ati e nt s r at e t h eir sl e e p 
b a s e d o n a 5- p oi nt Li k ert 
s c al e [ 0 ( n ot at all) t o 4 
( u n a bl e t o sl e e p at all)].  
A s s e s s m e nt s will b e r e c or d e d 
d ail y b y t h e p ati e nt u si n g a n 
el e ctr o ni c di ar y. 
Sl e e p-l o s s pr or at e d 
w e e kl y m e a n s c or e  
T h e pr or at e d w e e kl y 
m e a n i s b a s e d o n 
pr e vi o u s 7 d a y s.  If 
t h e p ati e nt h a s at 
l e a st o n e d ail y s c or e 
wit hi n t h e w e e k, t h e 
w e e kl y m e a n i s t h e 
pr or at e d a v er a g e of 
d ail y s c or e s wit hi n 
t h e gi v e n w e e k. 
Si n gl e it e m; r a n g e 0 
t o 4.   
 
W e e kl y m e a n 
s c or e mi s si n g if 
t h e p ati e nt h a s 
n o Sl e e p-l o s s 
r e s p o n s e s wit hi n 
t h e w e e k.  
C h a n g e fr o m b a s eli n e i n 
Sl e e p-l o s s pr or at e d 
w e e kl y m e a n s c or e 
 
C h a n g e fr o m 
b a s eli n e: o b s er v e d 
sl e e p l o s s pr or at e d 
w e e kl y m e a n s c or e 
– b a s eli n e sl e e p l o s s 
s c or e 
 
Mi s si n g if 
b a s eli n e or 
o b s er v e d v al u e 
i s mi s si n g. 
S ki n P ai n N R S  
T h e S ki n P ai n N R S i s a n 1 1-
p oi nt s c al e u s e d b y p ati e nt s t o 
r at e t h eir w or st p ai n o v er t h e 
p a st 2 4 h o ur s wit h 0 i n di c ati n g 
“ N o p ai n” a n d 1 0 i n di c ati n g 
“ W or st p ai n i m a gi n a bl e.” 
A s s e s s m e nt s will b e r e c or d e d 
d ail y b y t h e p ati e nt u si n g a n 
el e ctr o ni c di ar y.   
S ki n P ai n N R S pr or at e d 
w e e kl y m e a n s c or e 
T h e pr or at e d w e e kl y 
m e a n i s b a s e d o n 
pr e vi o u s 7 d a y s. If 
t h e p ati e nt h a s at 
l e a st o n e d ail y 
s c or e, t h e w e e kl y 
m e a n i s t h e pr or at e d 
a v er a g e of d ail y 
s c or e s wit hi n t h e 
gi v e n w e e k. Si n gl e 
it e m; r a n g e 0- 1 0.   
W e e kl y m e a n 
s c or e mi s si n g if 
t h e p ati e nt h a s 
n o S ki n P ai n 
N R S r e s p o n s e s 
wit hi n t h e w e e k 
C CI


St ati sti c al A n al y si s Pl a n f or I nt er v e nti o n al St u di e s  
S p o n s or: A L MI R A L L, S. A.; Pr ot o c ol N o.: M- 1 7 9 2 3- 3 0 
 
 
T hi s d o c u m e nt i s c o nfi d e nti al. 
S A P t e xt V er si o n: S A P t e xt v 2. 0 2 2 M A R 2 0 2 3 
C o ntr oll e d D o c u m e nt I D:  
 Eff e cti v e D at e 3 1- A u g- 2 0 2 0 
Fili n g r e q uir e m e nt s: T M F  
 
P a g e 4 3  of 7 3  
I N T E R N AL U S E 
M e a s ur e  
D e s cri pti o n  
V ari a bl e  
D eri v ati o n / 
C o m m e nt  
I m p ut ati o n 
A p pr o a c h if 
Mi s si n g 
C o m p o n e nt s  
C h a n g e fr o m b a s eli n e  
C h a n g e fr o m 
b a s eli n e: o b s er v e d 
S ki n P ai n N R S 
pr or at e d w e e kl y 
m e a n s c or e – 
b a s eli n e S ki n P ai n 
N R S s c or e 
 
Mi s si n g if 
b a s eli n e or 
o b s er v e d v al u e 
i s mi s si n g. 
4- p oi nt S ki n P ai n N R S 
i m pr o v e m e nt 
C h a n g e fr o m 
b a s eli n e i n S ki n P ai n 
N R S pr or at e d 
w e e kl y m e a n s c or e 
≤- 4 
Mi s si n g if 
b a s eli n e or 
o b s er v e d v al u e 
i s mi s si n g. 
P ati e nt- 
Ori e nt e d E c z e m a 
M e a s ur e ( P O E M) 
T h e P O E M i s a 7-it e m, 
v ali d at e d, q u e sti o n n air e u s e d 
b y t h e p ati e nt t o a s s e s s 
di s e a s e s y m pt o m s o v er t h e 
l a st w e e k. T h e p ati e nt i s 
a s k e d t o r e s p o n d t o 7 
q u e sti o n s o n s ki n dr y n e s s, 
it c hi n g, fl a ki n g, cr a c ki n g, 
sl e e p l o s s, bl e e di n g a n d 
w e e pi n g. All 7 a n s w er s c arr y 
e q u al w ei g ht wit h a t ot al 
p o s si bl e s c or e fr o m 0 t o 2 8 
( a n s w er s s c or e d a s: N o 
d a y s = 0; 1 ‒ 2 d a y s = 1; 3- 4 
d a y s = 2; 5 ‒ 6 d a y s = 3; 
e v er y d a y = 4). A hi g h s c or e i s 
i n di c ati v e of a p o or q u alit y of 
lif e. P O E M r e s p o n s e s will b e 
c a pt ur e d u si n g a n el e ctr o ni c 
di ar y a n d tr a n sf err e d i nt o t h e 
cli ni c al d at a b a s e.  
P O E M s c or e 
P O E M t ot al s c or e: 
s u m of q u e sti o n s 1 
t o 7, R a n g e 0 t o 2 8.  
If a si n gl e 
q u e sti o n i s l eft 
u n a n s w er e d, 
t h e n t h at 
q u e sti o n i s 
s c or e d a s 0.  If 
m or e t h a n o n e 
q u e sti o n i s 
u n a n s w er e d, 
t h e n t h e t o ol i s 
n ot s c or e d.  If 
m or e t h a n o n e 
r e s p o n s e i s 
s el e ct e d, t h e n 
t h e r e s p o n s e 
wit h t h e hi g h e st 
s c or e i s u s e d. 
C h a n g e fr o m b a s eli n e i n 
P O E M s c or e 
C h a n g e fr o m 
b a s eli n e: o b s er v e d 
P O E M s c or e – 
b a s eli n e P O E M 
s c or e 
Mi s si n g if 
b a s eli n e or 
o b s er v e d v al u e 
i s mi s si n g. 
C CI


St ati sti c al A n al y si s Pl a n f or I nt er v e nti o n al St u di e s  
S p o n s or: A L MI R A L L, S. A.; Pr ot o c ol N o.: M- 1 7 9 2 3- 3 0 
 
 
T hi s d o c u m e nt i s c o nfi d e nti al. 
S A P t e xt V er si o n: S A P t e xt v 2. 0 2 2 M A R 2 0 2 3 
C o ntr oll e d D o c u m e nt I D:  
, Eff e cti v e D at e 3 1- A u g- 2 0 2 0 
Fili n g r e q uir e m e nt s: T M F  
 
P a g e 4 4  of 7 3  
I N T E R N AL U S E 
M e a s ur e  
D e s cri pti o n  
V ari a bl e  
D eri v ati o n / 
C o m m e nt  
I m p ut ati o n 
A p pr o a c h if 
Mi s si n g 
C o m p o n e nt s  
D er m at ol o g y Lif e 
Q u alit y I n d e x ( D L QI)  
D L QI i s a v ali d at e d, 
d er m at ol o g y- s p e cifi c, p ati e nt-
r e p ort e d m e a s ur e t h at 
e v al u at e s p ati e nt’ s h e alt h-
r el at e d Q o L.  T hi s 
q u e sti o n n air e h a s 1 0 it e m s 
t h at ar e gr o u p e d i n 6 
d o m ai n s, i n cl u di n g s y m pt o m s 
a n d f e eli n g s, d ail y a cti viti e s, 
l ei s ur e, w or k a n d s c h o ol, 
p er s o n al r el ati o n s hi p s, a n d 
tr e at m e nt.  T h e r e c all p eri o d 
of t hi s s c al e i s o v er t h e “l a st 
w e e k”.  R e s p o n s e c at e g ori e s 
a n d c orr e s p o n di n g s c or e s 
ar e: 
V er y m u c h = 3 
A l ot = 2 
A littl e = 1 
N ot at all = 0 
N ot r el e v a nt = 0 
 
S c or e s r a n g e fr o m 0- 3 0 wit h 
hi g h er s c or e s i n di c ati n g 
gr e at er i m p air m e nt of q u alit y 
of lif e. A D L QI t ot al s c or e of 0 
t o 1 i s c o n si d er e d a s h a vi n g 
n o eff e ct o n a p ati e nt’ s h e alt h-
r el at e d Q o L ( H o n g b o et al. 
2 0 0 5), a n d a 4- p oi nt c h a n g e 
fr o m b a s eli n e i s c o n si d er e d 
a s t h e mi ni m al cli ni c all y 
i m p ort a nt diff er e n c e t hr e s h ol d 
( K hilji et al. 2 0 0 2; B a sr a et al. 
2 0 0 8) 
D L QI t ot al s c or e 
A D L QI t ot al s c or e i s 
c al c ul at e d b y 
s u m mi n g all 1 0 
q u e sti o n r e s p o n s e s 
a n d h a s a r a n g e of 
0- 3 0 (l e s s t o m or e 
i m p air m e nt)  
S c or e of 1 
u n a n s w er e d 
q u e sti o n = 0; If 2 
or m or e 
q u e sti o n s ar e 
mi s si n g, t h e t ot al 
s c or e i s mi s si n g.  
N ot e:  # 7 B c o ul d 
b e a v ali d 
mi s si n g w hil e 
# 7 A i s n ot “ N o.”  
T h at i s, # 7 
s h o ul d b e 
c o n si d er e d a s 1 
q u e sti o n. 
4- p oi nt i m pr o v e m e nt  
C h a n g e fr o m 
b a s eli n e ≤- 4  
Mi s si n g if 
b a s eli n e i s 
mi s si n g or 
o b s er v e d v al u e 
i s mi s si n g. 
D L QI t ot al s c or e a n d 
d o m ai n s c or e s c h a n g e 
fr o m b a s eli n e 
 
C al c ul at e d f or e a c h 
p o st- b a s eli n e 
a s s e s s m e nt a s:  
o b s er v e d D L QI (t ot al 
s c or e or d o m ai n 
s c or e s) – b a s eli n e 
D L QI (t ot al s c or e or 
d o m ai n s c or e s) 
Mi s si n g if 
b a s eli n e or 
o b s er v e d v al u e 
i s mi s si n g 
C hil dr e n’ s 
D er m at ol o g y Lif e 
Q u alit y I n d e x 
( C D L QI)  
T h e C D L QI i s d e si g n e d t o 
m e a s ur e t h e i m p a ct of a n y 
s ki n di s e a s e o n t h e li v e s of 
c hil dr e n. P ati e nt s ≤1 6 y e ar s 
will c o m pl et e t h e C D L QI a n d 
s h o ul d c o nti n u e t o c o m pl et e 
t h e C D L QI f or t h e d ur ati o n of 
t h e st u d y. 
 
T h e s c ori n g of e a c h q u e sti o n 
i s: 
C D L QI t ot al s c or e  
A C D L QI t ot al s c or e 
i s c al c ul at e d b y 
s u m mi n g all 1 0 
q u e sti o n r e s p o n s e s 
a n d h a s a r a n g e of 
0- 3 0   
S c or e of 1 
u n a n s w er e d 
q u e sti o n = 0; If 2 
or m or e 
q u e sti o n s ar e 
mi s si n g, t h e t ot al 
s c or e i s mi s si n g.   
4- p oi nt i m pr o v e m e nt   
C h a n g e fr o m 
b a s eli n e ≤- 4  
Mi s si n g if 
b a s eli n e i s 
mi s si n g or 
o b s er v e d v al u e 
i s mi s si n g. 
C CI


St ati sti c al A n al y si s Pl a n f or I nt er v e nti o n al St u di e s  
S p o n s or: A L MI R A L L, S. A.; Pr ot o c ol N o.: M- 1 7 9 2 3- 3 0 
 
 
T hi s d o c u m e nt i s c o nfi d e nti al. 
S A P t e xt V er si o n: S A P t e xt v 2. 0 2 2 M A R 2 0 2 3 
C o ntr oll e d D o c u m e nt I D:  
, Eff e cti v e D at e 3 1- A u g- 2 0 2 0 
Fili n g r e q uir e m e nt s: T M F  
 
P a g e 4 5  of 7 3  
I N T E R N AL U S E 
M e a s ur e  
D e s cri pti o n  
V ari a bl e  
D eri v ati o n / 
C o m m e nt  
I m p ut ati o n 
A p pr o a c h if 
Mi s si n g 
C o m p o n e nt s  
 
V er y m u c h = 3 
 
Q uit e a l ot = 2 
 
O nl y a littl e = 1 
 
N ot at all = 0 
 
Q u e sti o n u n a n s w er e d = 
0 
 
Q u e sti o n 7: ' Pr e v e nt e d 
s c h o ol' (t e xt- o nl y 
q u e sti o n n air e) = 3  
C D L QI t ot al s c or e a n d 
d o m ai n s c or e s c h a n g e 
fr o m b a s eli n e 
C al c ul at e d f or e a c h 
p o st- b a s eli n e 
a s s e s s m e nt a s:  
o b s er v e d C D L QI 
(t ot al s c or e or 
d o m ai n s c or e s) – 
b a s eli n e C D L QI 
(t ot al s c or e or 
d o m ai n s c or e s) 
Mi s si n g if 
b a s eli n e or 
o b s er v e d v al u e 
i s mi s si n g 
D er m at ol o g y Lif e 
Q u alit y I n d e x-
R el e v a nt ( D L QI- R) 
T h e D L QI- R el e v a nt ( D L QI- R) 
i s a r e c e ntl y d e v el o p e d 
s c ori n g t h at a dj u st s t h e t ot al 
s c or e of t h e q u e sti o n n air e f or 
t h e n u m b er of ‘ n ot r el e v a nt’ 
r e s p o n s e s ( N R R s) i n di c at e d 
b y a p ati e nt. 
C h a n g e fr o m B a s eli n e i n 
D L QI- R t ot al s c or e b y 
w e e k u p t o W e e k 1 6  
 
T h e D L QI- R t ot al 
s c or e i s c al c ul at e d 
b y s u m mi n g t h e 
s c or e of t h e 1 0 
it e m s. Fr o m h er e, 
t h e D L QI- R t ot al 
s c or e i s c al c ul at e d 
f or e a c h p ati e nt at 
e a c h vi sit a s t h e t ot al 
D L QI s c or e 
m ulti pli e d b y 1 0/( 1 0-
N R R), w h er e N R R i s 
t h e n u m b er of n ot 
r el e v a nt r e s p o n s e s 
f or q u e sti o n s 3- 1 0.  
 
C h a n g e c al c ul at e d 
f or e a c h p o st-
b a s eli n e a s s e s s m e nt 
a s:  o b s er v e d D L QI-
R t ot al s c or e – 
b a s eli n e D L QI- R 
t ot al s c or e 
Mi s si n g if 
b a s eli n e i s 
mi s si n g or 
o b s er v e d v al u e 
i s mi s si n g. 
T o pi c al 
C orti c o st er oi d s 
( T C S) 
T o pi c al C orti c o st er oi d s ( T C S) 
Di ar y r e c or d s p ati e nt’ s 
tr e at m e nt of At o pi c 
D er mit atiti s wit h a T C S a n d 
t h e ar e a s of a p pli c ati o n.   
A s s e s s m e nt s will b e r e c or d e d 
d ail y u p t o W 2, w e e kl y fr o m 
W 2 t o W 1 6, a n d e v er y 4 
w e e k s fr o m W 1 6 o n w ar d b y 
t h e p ati e nt u si n g a n el e ctr o ni c 
di ar y. 
Pr o p orti o n of fr e e d a y s 
fr o m b a s eli n e t o w e e k 1 6 
Pr o p orti o n of T C S-
fr e e d a y s i s 
c al c ul at e d a s t h e 
t ot al n u m b er of d a y s 
i n st u d y fr o m 
b a s eli n e t o W e e k 1 6 
w h er e T C S w er e n ot 
u s e d, di vi d e d b y t h e 
t ot al n u m b er of d a y s 
i n st u d y fr o m 
b a s eli n e t o W e e k 1 6.  
If p ati e nt d o e s 
n ot c o m pl et e 
st u d y u ntil W e e k 
1 6 t h e n t ot al 
n u m b er of d a y s 
will b e c a p p e d at 
t h e d at e of t h e 
l a st a s s e s s m e nt 
i n st u d y 
C CI


St ati sti c al A n al y si s Pl a n f or I nt er v e nti o n al St u di e s  
S p o n s or: A L MI R A L L, S. A.; Pr ot o c ol N o.: M- 1 7 9 2 3- 3 0 
 
 
T hi s d o c u m e nt i s c o nfi d e nti al. 
S A P t e xt V er si o n: S A P t e xt v 2. 0 2 2 M A R 2 0 2 3 
C o ntr oll e d D o c u m e nt I D:  
 Eff e cti v e D at e 3 1- A u g- 2 0 2 0 
Fili n g r e q uir e m e nt s: T M F  
 
P a g e 4 6  of 7 3  
I N T E R N AL U S E 
M e a s ur e  
D e s cri pti o n  
V ari a bl e  
D eri v ati o n / 
C o m m e nt  
I m p ut ati o n 
A p pr o a c h if 
Mi s si n g 
C o m p o n e nt s  
Ti m e t o T C S-fr e e d a y s 
fr o m b a s eli n e t o w e e k 1 6 
Ti m e t o T C S-fr e e d a ys 
is c alc ul at e d as t h e 
ti m e fr o m b as eli n e t o 
first p oi nt w h er e T C S 
ar e n ot us e d or W e e k 
1 6 + 1, w hic h e v er is 
t h e e arli er.  
If p ati e nt d o e s 
n ot c o m pl et e 
st u d y t o W e e k 
1 6 t h e n c e n s or 
at t h e d at e of t h e 
l a st a s s e s s m e nt 
i n st u d y 
R E C A P 
R E C A P i s a s e v e n-it e m 
q u e sti o n n air e d e si g n e d t o 
c a pt ur e t h e e x p eri e n c e of 
e c z e m a c o ntr ol i n all a g e s 
a n d e c z e m a s e v eriti e s. 
 
E a c h of t h e s e v e n q u e sti o n s 
i n R E C A P c arri e s e q u al 
w ei g ht a n d i s s c or e d fr o m 0 t o 
4 (t ot al s c or e of 0- 2 8).  
 
 
C h a n g e fr o m B a s eli n e i n 
R E C A P b y w e e k u p t o 
W e e k 1 6 
 
T h e t ot al R E C A P 
s c or e i s c al c ul at e d 
a s t h e s u m of all 
q u e sti o n s c or e s.  
 
C h a n g e c al c ul at e d 
f or e a c h p o st-
b a s eli n e a s s e s s m e nt 
a s:  
 o b s er v e d R E C A P 
t ot al s c or e – 
b a s eli n e R E C A P 
t ot al s c or e 
If o n e q u e sti o n i s 
l eft u n a n s w er e d 
t hi s i s s c or e d 0 
a n d t h e s c or e s 
ar e s u m m e d a n d 
e x pr e s s e d a s 
u s u al o ut of a 
m a xi m u m of 2 8. 
 
If t w o or m or e 
q u e sti o n s ar e l eft 
u n a n s w er e d t h e 
q u e sti o n n air e i s 
n ot s c or e d. 
 
If t w o or m or e 
r e s p o n s e o pti o n s 
ar e s el e ct e d, t h e 
r e s p o n s e o pti o n 
wit h t h e hi g h e st 
s c or e s h o ul d b e 
r e c or d e d 
W orl d H e alt h 
Or g a ni s ati o n – Fi v e 
W ell- B ei n g I n d e x 
( W H O- 5) 
T h e W H O- 5 i s a s h ort, s elf-
a d mi ni st er e d m e a s ur e of w ell-
b ei n g o v er t h e l a st t w o w e e k s. 
It c o n si st s of fi v e p o siti v el y 
w or d e d it e m s t h at ar e r at e d 
o n 6- p oi nt Li k ert s c al e, 
r a n gi n g fr o m 0 ( at n o t h e ti m e) 
t o 5 ( all of t h e ti m e). T h e r a w 
s c or e s ar e tr a n sf or m e d t o a 
s c or e fr o m 0 t o 1 0 0, wit h 
l o w er s c or e s i n di c ati n g w or s e 
w ell- b ei n g. A s c or e of ≤5 0 
i n di c at e s p o or w ell b ei n g a n d 
s u g g e st s f urt h er i n v e sti g ati o n 
i nt o p o s si bl e s y m pt o m s of 
d e pr e s si o n. A s c or e of 2 8 or 
b el o w i s i n di c ati v e of 
d e pr e s si o n. 
C h a n g e fr o m B a s eli n e 
W H O- 5 b y w e e k u p t o 
W e e k 1 6  
 
T ot al r a w s c or e 
c al c ul at e d a s t h e 
s u m of all r a w 
s c or e s. T h e t ot al r a w 
s c or e (r a n gi n g fr o m 
0 t o 2 5) i s t h e n 
m ulti pli e d b y 4 t o g et 
t h e tr a n sf or m e d t ot al 
s c or e b et w e e n 0 a n d 
1 0 0. 
 
C h a n g e c al c ul at e d 
f or e a c h p o st-
b a s eli n e a s s e s s m e nt 
a s:  
 o b s er v e d W H O- 5 
tr a n sf or m e d t ot al 
s c or e – b a s eli n e 
W H O- 5 tr a n sf or m e d 
t ot al s c or e 
N o n e 
C CI


St ati sti c al A n al y si s Pl a n f or I nt er v e nti o n al St u di e s  
S p o n s or: A L MI R A L L, S. A.; Pr ot o c ol N o.: M- 1 7 9 2 3- 3 0 
 
 
T hi s d o c u m e nt i s c o nfi d e nti al. 
S A P t e xt V er si o n: S A P t e xt v 2. 0 2 2 M A R 2 0 2 3 
C o ntr oll e d D o c u m e nt I D:  
, Eff e cti v e D at e 3 1- A u g- 2 0 2 0 
Fili n g r e q uir e m e nt s: T M F  
 
P a g e 4 7  of 7 3  
I N T E R N AL U S E 
M e a s ur e  
D e s cri pti o n  
V ari a bl e  
D eri v ati o n / 
C o m m e nt  
I m p ut ati o n 
A p pr o a c h if 
Mi s si n g 
C o m p o n e nt s  
Tr e at m e nt 
S ati sf a cti o n 
Q u e sti o n n air e f or 
M e di c ati o n- 9 it e m s 
( T S Q M- 9) 
V er si o n 9 of t h e T S Q M 
c o n si st s of 9 it e m s t h at r e s ult s 
i n t hr e e s p e cifi c d o m ai n s: 
Eff e cti v e n e s s, C o n v e ni e n c e, 
a n d o n e gl o b al s c al e it e m, 
Gl o b al S ati sf a cti o n. S c or e s f or 
e a c h d o m ai n ar e c o m p ut e d b y 
a d di n g t h e T S Q M it e m s i n 
e a c h d o m ai n a n d t h e n 
tr a n sf or mi n g t h e c o m p o sit e 
s c or e i nt o a v al u e r a n gi n g 
fr o m 0 t o 1 0 0.  
E F F E C TI V E N E S S  
([(It e m 1 + It e m 2 + 
It e m 3) – 3] di vi d e d 
b y 1 8) * 1 0 0 
If o n e it e m i s 
mi s si n g 
([( S u m(It e m 1 ? + 
It e m 2 ? + It e m 
3 ?)) – 2] di vi d e d 
b y 1 2) * 1 0 0  
 
C O N V E NI E N C E 
([ S u m(It e m 9 t o It e m 
1 1) – 3] di vi d e d b y 
1 8) * 1 0 0 
If o n e it e m i s 
mi s si n g 
([( S u m(It e m 9 ? t o 
It e m 1 1 ?)) – 2] 
di vi d e d b y 1 2) * 
1 0 0  
 
G L O B A L 
S A TI S F A C TI O N 
([ S u m(It e m 1 2 t o 
It e m 1 4) – 3] di vi d e d 
b y 1 4) * 1 0 0 
If eit h er It e m 1 2 
or 1 3 i s mi s si n g 
([( S u m(It e m 1 2 ? 
t o It e m 1 4 ?)) – 2] 
di vi d e d b y 1 0) * 
1 0 0  
If It e m 1 4 i s 
mi s si n g 
([( S u m(It e m 1 2 
a n d It e m 1 3)) – 2] 
di vi d e d b y 8) * 
1 0 0 
 
 A b br e vi ati o n s:  e C O A = el e ctr o ni c cli ni c al o ut c o m e a s s e s s m e nt 
9. 3.  
A n al y si s of t h e Pri m ar y a n d K e y S e c o n d ar y Effi c a c y E n d p oi nt s  
T h e pri m ar y a n d k e y s e c o n d ar y effi c a c y e n d p oi nt s (f or t h e m ai n a n d s e c o n d e sti m a n d s) will b e a n al y s e d 
b y m e a n s of a C o c hr a n- M a nt el- H a e n s z el ( C M H) m o d el a dj u st e d b y c o u ntr y, a g e ( a d ol e s c e nt s/ a d ult s), 
pri or u s e of d u pil u m a b ( y e s/ n o), a n d B a s eli n e s e v erit y of di s e a s e (I G A = 3/I G A = 4). If t h e m o d el d o e s n ot 
c o n v er g e, c o u ntr y will b e r e m o v e d a s a n a dj u sti n g f a ct or. T h e e sti m at e of t h e a dj u st e d c o m m o n ri s k 
diff er e n c e, wit h c orr e s p o n di n g M a nt el- H a e n s z el- S at o ( S at o 1 9 8 9) a dj u st e d 2- si d e d 9 5 % CI a n d p- v al u e 
will b e pr e s e nt e d. A d diti o n all y, t h e C M H a dj u st e d o d d s r ati o al o n g wit h t h e 9 5 % t w o- si d e d a s y m pt oti c CI 
will b e pr e s e nt e d. T h e pri m ar y a n al y si s will b e b a s e d o n t h e F A S w hi c h w a s d efi n e d a s all r a n d o mi z e d 
p ati e nt s. W h e n a n al y si n g t h e d u pil u m a b n aï v e a n d pr e vi o u sl y e x p o s e d p o p ul ati o n s, t h e f a ct or f or pri or 
u s e of d u pil u m a b will b e r e m o v e d fr o m t h e C M H a dj u st m e nt. 
D et ail s ar e d e s cri b e d i n A p p e n di x 2 . D et ail s of C o m bi ni n g E sti m at e s a n d T e st St ati sti c s f or C at e g ori c al 
E n d p oi nt s wit h M ulti pl e I m p ut ati o n 
E x a m pl e c o d e f or C M H t e st: 
C CI
C CI


St ati sti c al A n al y si s Pl a n f or I nt er v e nti o n al St u di e s  
S p o n s or: A L MI R A L L, S. A.; Pr ot o c ol N o.: M- 1 7 9 2 3- 3 0 
 
 
T hi s d o c u m e nt i s c o nfi d e nti al. 
S A P t e xt V er si o n: S A P t e xt v 2. 0 2 2 M A R 2 0 2 3 
C o ntr oll e d D o c u m e nt I D:  
, Eff e cti v e D at e 3 1- A u g- 2 0 2 0 
Fili n g r e q uir e m e nt s: T M F  
 
P a g e 4 8  of 7 3  
I N T E R N AL U S E 
F or a n al y s e s u si n g m ulti pl e i m p ut ati o n, t h e a n al y si s will b e c o n d u ct e d o n t h e c o m pl et e d at a s et, f or e a c h 
i m p ut ati o n s e p ar at el y. M o d ell e d r e s ult s will b e c o m bi n e d u si n g R u bi n’ s r ul e ( P R O C MI A N A L Y Z E). 
S A S Pr o c MI A N A L Y Z E will b e u s e d t o c o m bi n e t h e 1 0 0 p oi nt e sti m at e s ( m ai n e sti m a n d) f or t h e diff er e n c e 
i n p er c e nt a g e of p ati e nt s a c hi e vi n g E A SI 7 5 r e s p o n s e at W e e k 1 6 b et w e e n tr e at m e nt s a n d st a n d ar d 
err or s, all o wi n g a p pr o pri at e st ati sti c al i nf er e n c e a s d e s cri b e d b el o w: 
T h e f oll o wi n g s e n siti vit y a n al y si s will al s o b e c o n d u ct e d f or t h e m ai n a n d s e c o n d e sti m a n d s of t h e pri m ar y 
a n d k e y s e c o n d ar y effi c a c y e n d p oi nt s, o n t h e o v er all p o p ul ati o n: 
A n al y si s S et  
M o d elli n g M et h o d  
E sti m a n d a n d D at a H a n dli n g  
S e n siti vit y A n al y si s C o n d u ct e d o n M ai n a n d S e c o n d E sti m a n d s 
P P S 
C M H m o d el a dj u st e d b y 
c o u ntr y, a n d str atifi c ati o n 
f a ct or s u s e d i n t h e 
r a n d o mi s ati o n ( a g e, pr e vi o u s 
u s e of d u pil u m a b, a n d 
B a s eli n e s e v erit y of di s e a s e, 
a s p er pri m ar y a n al y si s). 
A s p er m ai n a n d s e c o n d 
e sti m a n d s 
A b br e vi ati o n s: C M H = C o c hr a n- M a nt el- H a e n s z el; P P S = P er Pr ot o c ol S et. 
All i nf er e nti al a n al y s e s of t h e pri m ar y a n d k e y s e c o n d ar y effi c a c y e n d p oi nt s, i n cl u di n g m ulti pl e i m p ut ati o n 
a p pr o a c h e s will b e c o n d u ct e d d uri n g t h e I n d u cti o n P eri o d o nl y ( e g, u p t o a n d i n cl u di n g W e e k 1 6). D uri n g 
t h e M ai nt e n a n c e P eri o d, o nl y d e s cri pti v e a n al y s e s will b e p erf or m e d f or effi c a c y. T h e h a n dli n g of 
e sti m a n d s a s d et ail e d a b o v e will al s o o nl y a p pl y u p t o a n d i n cl u di n g W e e k 1 6. Aft er t hi s p oi nt, d at a will 
o nl y b e a n al y s e d a s o b s er v e d. 
I n a d diti o n, t o s u p p ort effi c a c y a n al y s e s, a s u m m ar y of t h e i n ci d e n c e of t h e I C E s at e a c h vi sit u p t o W e e k 
1 6 will b e pr e s e nt e d. 
9. 4.  
A n al y si s of all Ot h er S e c o n d ar y a n d Ot h er Effi c a c y E n d p oi nt  
T h e m ai n a n d s e c o n d e sti m a n d s a s d e s cri b e d i n S e cti o n 6. 1. 2 will b e a n al y s e d b y m e a n s of a mi x e d 
eff e ct m o d el f or r e p e at e d m e a s ur e s ( M M R M), i n cl u di n g t h e B a s eli n e v al u e a s a c o v ari at e, a n d a dj u sti n g 
b y t h e f a ct or s of c o u ntr y, a g e ( a d ol e s c e nt s/ a d ult s), B a s eli n e s e v erit y of di s e a s e (I G A = 3/I G A = 4), pr e vi o u s 
e x p o s ur e t o d u pil u m a b ( y e s/ n o, w h e n t h e o v er all p o p ul ati o n i s a n al y s e d) a n d vi sit a n d tr e at m e nt- vi sit 
i nt er a cti o n. A r e stri ct e d m a xi m u m li k eli h o o d m et h o d will b e s p e cifi e d, al o n g wit h a n u n str u ct ur e d 
c o v ari a n c e m atri x. E sti m at e s of t h e L S M e a n s f or e a c h of t h e 2 tr e at m e nt gr o u p s at e a c h vi sit u p t o a n d 
i n cl u di n g W e e k 1 6, al o n g wit h t h e diff er e n c e b et w e e n tr e at m e nt s i n L S M e a n s, 2- si d e d 9 5 % CI a n d p-
v al u e f or t h e diff er e n c e will b e pr e s e nt e d. 
E x a m pl e S A S s y nt a x i s a s f oll o w s: 
C CI
C CI
C CI


St ati sti c al A n al y si s Pl a n f or I nt er v e nti o n al St u di e s  
S p o n s or: A L MI R A L L, S. A.; Pr ot o c ol N o.: M- 1 7 9 2 3- 3 0 
 
T hi s d o c u m e nt i s c o nfi d e nti al. 
S A P t e xt V er si o n: S A P t e xt v 2. 0 2 2 M A R 2 0 2 3 
C o ntr oll e d D o c u m e nt I D:  
 Eff e cti v e D at e 3 1- A u g- 2 0 2 0 
Fili n g r e q uir e m e nt s: T M F  
 
P a g e 4 9  of 7 3  
I N T E R N AL U S E 
F or all c o nti n u o u s s e c o n d ar y effi c a c y e n d p oi nt s, i n c a s e of n o n- c o n v er g e n c e, t h e c o u ntr y f a ct or will b e 
r e m o v e d fr o m t h e m o d el.  
Ti m e-t o- e v e nt ( T T E) e n d p oi nt s will b e a n al y s e d o n t h e s e c o n d e sti m a n d f or c o nti n u o u s e n d p oi nt s u si n g 
K a pl a n- M ei er s ur vi v al a n al y si s m et h o d s. If a v ail a bl e, f or d e s cri pti v e p ur p o s e s, t h e e sti m at e of t h e m e di a n 
ti m e-t o- e v e nt (i n w e e k s) a n d t h e 2- si d e d 9 5 % CI will b e pr e s e nt e d. A c o m p ari s o n of t h e s ur vi v al 
di stri b uti o n c ur v e s f or t h e 2 tr e at m e nt gr o u p s will b e m a d e b y m e a n s of t h e l o g-r a n k t e st. T h e C o x 
pr o p orti o n al h a z ar d s m o d el will b e u s e d t o e sti m at e t h e h a z ar d r ati o a n d it s 9 5 % CI of l e bri ki z u m a b 
c o m p ar e d wit h pl a c e b o  at t h e r e s p e cti v e ti m e p oi nt. T h e m ai n C o x pr o p orti o n al h a z ar d s m o d el will i n cl u d e 
tr e at m e nt gr o u p, wit h c o u ntr y, a g e, B a s eli n e di s e a s e s e v erit y a n d pr e vi o u s e x p o s ur e t o d u pil u m a b ( w h e n 
t h e o v er all p o p ul ati o n i s a n al y s e d) a s f a ct or s. T h e pr o p orti o n al h a z ar d a s s u m pti o n will b e e v al u at e d o n all 
f a ct or s (i e, tr e at m e nt a n d str atifi c ati o n f a ct or s) b y gr a p hi c al i n s p e cti o n of t h e S c h o e nf el d r e si d u al s a n d b y 
Gr a m b s c h a n d T h er n e a u t e st a s w ell.  C o u ntr y m a y b e r e m o v e d fr o m t h e m o d el a s a p pr o pri at e, si mil ar t o 
t h e ot h er a n al y s e s of effi c a c y. B e c a u s e of t h e f a ct t h at t h e I n d u cti o n a n d M ai nt e n a n c e P eri o d s will b e 
r e p ort e d s e p ar at el y, T T E e n d p oi nt s will b e a n al y s e d at 2 s e p ar at e ti m e p oi nt s: i niti all y u p t o a n d i n cl u di n g 
W e e k 1 6, a n d t h e n s e p ar at el y f or t h e w h ol e st u d y, i n c or p or ati n g b ot h t h e I n d u cti o n a n d M ai nt e n a n c e 
P eri o d s. 
All bi n ar y ot h er s e c o n d ar y a n d ot h er effi c a c y e n d p oi nt s will b e a n al y s e d u si n g t h e s a m e m et h o d ol o g y a s 
d e s cri b e d f or t h e pri m ar y effi c a c y e n d p oi nt u si n g o nl y t h e m ai n e sti m a n d. S e n siti vit y a n al y s e s b a s e d o n 
t h e P P S p o p ul ati o n will n ot b e c o n d u ct e d f or t h e s e e n d p oi nt s.  
All effi c a c y v ari a bl e s f or t h e M ai nt e n a n c e/ E xt e n si o n P eri o d will b e a n al y s e d b y m e a n s of d e s cri pti v e 
st ati sti c s pr e s e nt e d b y tr e at m e nt gr o u p a s r a n d o mi s e d d uri n g t h e I n d u cti o n P eri o d. 
A d diti o n all y, all s e c o n d ar y a n d 
effi c a c y e n d p oi nt s f or t h e s e c o n d ar y o bj e cti v e will b e 
pr e s e nt e d i n b y- p ati e nt li sti n g s. 
9. 5.  
S u b gr o u p Effi c a c y A n al y s e s ( D u pil u m a b N aï v e a n d P ati e nt s Pr e vi o u sl y E x p o s e d t o 
D u pil u m a b) 
T h e s a m e a n al y s e s d e s cri b e d f or t h e Pri m ar y effi c a c y a n al y s e s ( S e cti o n 9. 3 ) will b e p erf or m e d b y 
pr e vi o u s e x p o s ur e t o d u pil u m a b ( Y e s/ N o), f or
 p ur p o s e s. 
All effi c a c y v ari a bl e s f or t h e M ai nt e n a n c e P eri o d f or s u b gr o u p a n al y s e s will b e a n al y s e d b y m e a n s of 
d e s cri pti v e st ati sti c s pr e s e nt e d b y tr e at m e nt gr o u p a s r a n d o mi s e d d uri n g t h e I n d u cti o n P eri o d, i n t h e 
s a m e w a y a s f or t h e pri m ar y a n d s e c o n d ar y effi c a c y a n al y s e s o n t h e o v er all p o p ul ati o n. 
9. 6.  
S u m m ar y of t h e St ati sti c al Effi c a c y A n al y si s t o b e p erf or m e d wit h I n d u cti o n p eri o d 
d at a  
 
C CI
C CI
C CI
C CI


St ati sti c al A n al y si s Pl a n f or I nt er v e nti o n al St u di e s  
S p o n s or: A L MI R A L L, S. A.; Pr ot o c ol N o.: M- 1 7 9 2 3- 3 0 
 
 
T hi s d o c u m e nt i s c o nfi d e nti al. 
S A P t e xt V er si o n: S A P t e xt v 2. 0 2 2 M A R 2 0 2 3 
C o ntr oll e d D o c u m e nt I D:  
, Eff e cti v e D at e 3 1- A u g- 2 0 2 0 
Fili n g r e q uir e m e nt s: T M F  
 
P a g e 5 0  of 7 3  
I N T E R N AL U S E 
T h e t a bl e b el o w pr o vi d e s t h e d et ail e d a n al y s e s r el ati v e t o e sti m a n d s i n cl u di n g a n al y si s t y p e, m et h o d a n d 
i m p ut ati o n, p o p ul ati o n, ti m e p oi nt, a n d tr e at m e nt c o m p ari s o n s f or effi c a c y/ h e alt h o ut c o m e s a n al y s e s. 
M e a s ur e  
V ari a bl e  
E sti m a n d  
(S e cti o n  6 ) 
A n al y si s 
M et h o d 
(S e cti o n  6. 3 ) 
P o p ul ati o n 
(S e cti o n 5 ) 
A n al y si s 
T y p e  
E c z e m a Ar e a 
a n d S e v erit y 
I n d e x ( E A SI) 
Pr o p orti o n of 
p ati e nt s 
a c hi e vi n g 
E A SI 7 5 at 
W 1 6 
 
 
Pri m ar y 
E sti m a n d 
( H y bri d) 
 
C M H a n al y si s 
wit h M C M C-
MI 
F A S 
P P S 
Pri m ar y 
a n al y si s: E A SI 
7 5 at W 1 6 
 
K e y 
s e c o n d ar y 
a n al y si s: E A SI 
9 0 at W 1 6 
E A SI 7 5; 9 0 
a n d 5 0 u p t o 
W 1 6 
 
S u p p orti v e 
E sti m a n d 
( H y p ot h eti c al) 
N RI 
F A S 
 
Pri m ar y 
a n al y si s: E A SI 
7 5 at W 1 6 
 
K e y 
s e c o n d ar y 
a n al y si s: E A SI 
9 0 at W 1 6 
E A SI 7 5; 9 0 
a n d 5 0 u p t o 
W 1 6 
 
Ti m e t o E A SI 
7 5 
N A 
N A 
F A S 
 
a n al y si s: ti m e 
t o E A SI 5 0- 7 5-
9 0 u p t o W 1 6 
 
I n v e sti g at or’ s 
Gl o b al 
A s s e s s m e nt 
(I G A) 
Pr o p orti o n of 
p ati e nt s 
a c hi e vi n g I G A 
[ 0, 1] wit h a 
≥2- p oi nt 
i m pr o v e m e nt 
at W 1 6 
Pri m ar y 
E sti m a n d 
( H y bri d)  
M C M C- MI 
 
F A S 
P P S 
K e y 
s e c o n d ar y 
a n al y si s: 
a c hi e vi n g I G A 
[ 0, 1] wit h a 
≥2- p oi nt 
i m pr o v e m e nt 
at W 1 6 
 
C CI
C CI


St ati sti c al A n al y si s Pl a n f or I nt er v e nti o n al St u di e s  
S p o n s or: A L MI R A L L, S. A.; Pr ot o c ol N o.: M- 1 7 9 2 3- 3 0 
 
 
T hi s d o c u m e nt i s c o nfi d e nti al. 
S A P t e xt V er si o n: S A P t e xt v 2. 0 2 2 M A R 2 0 2 3 
C o ntr oll e d D o c u m e nt I D:  
, Eff e cti v e D at e 3 1- A u g- 2 0 2 0 
Fili n g r e q uir e m e nt s: T M F  
 
P a g e 5 1  of 7 3  
I N T E R N AL U S E 
M e a s ur e  
V ari a bl e  
E sti m a n d  
(S e cti o n  6 ) 
A n al y si s 
M et h o d 
(S e cti o n  6. 3 ) 
P o p ul ati o n 
(S e cti o n 5 ) 
A n al y si s 
T y p e  
S u p p orti v e 
E sti m a n d 
( H y p ot h eti c al) 
N RI 
F A S 
 
K e y 
s e c o n d ar y 
a n al y si s: 
a c hi e vi n g I G A 
[ 0, 1] wit h a 
≥2- p oi nt 
i m pr o v e m e nt 
at W 1 6 
 
Pr urit u s N R S  
Pr o p orti o n of 
p ati e nt s 
a c hi e vi n g at 
l e a st 4- p oi nt 
i m pr o v e m e nt 
i n pr urit u s 
N R S at W 1 6 
Pri m ar y 
E sti m a n d 
( H y bri d)  
M C M C- MI 
 
F A S* 
P P S* 
K e y 
s e c o n d ar y 
a n al y si s: 
a c hi e vi n g at 
l e a st 4- p oi nt 
i m pr o v e m e nt 
i n pr urit u s 
N R S at W 1 6 
 
S u p p orti v e 
E sti m a n d 
( H y p ot h eti c al) 
N RI 
F A S* 
 
K e y 
s e c o n d ar y 
a n al y si s: 
a c hi e vi n g at 
l e a st 4- p oi nt 
i m pr o v e m e nt 
i n pr urit u s 
N R S at W 1 6 
 
C h a n g e fr o m 
b a s eli n e i n 
Pr urit u s N R S 
u p t o W 1 6 
 
Pri m ar y 
E sti m a n d 
( H y bri d) 
M M R M a n d 
B O C F 
F A S 
K e y 
s e c o n d ar y 
a n al y si s: 
C h a n g e fr o m 
b a s eli n e i n 
Pr urit u s N R S 
u p t o W 1 6 
 
 
B o d y S urf a c e 
Ar e a ( B S A) 
C h a n g e fr o m 
b a s eli n e i n 
B S A s c or e u p 
t o W 1 6 
Pri m ar y 
E sti m a n d 
( H y bri d) 
M M R M a n d 
B O C F 
F A S 
K e y 
s e c o n d ar y 
a n al y si s: 
C h a n g e fr o m 
b a s eli n e i n 
B S A s c or e u p 
t o W 1 6 
 
C CI


St ati sti c al A n al y si s Pl a n f or I nt er v e nti o n al St u di e s  
S p o n s or: A L MI R A L L, S. A.; Pr ot o c ol N o.: M- 1 7 9 2 3- 3 0 
 
 
T hi s d o c u m e nt i s c o nfi d e nti al. 
S A P t e xt V er si o n: S A P t e xt v 2. 0 2 2 M A R 2 0 2 3 
C o ntr oll e d D o c u m e nt I D:  
, Eff e cti v e D at e 3 1- A u g- 2 0 2 0 
Fili n g r e q uir e m e nt s: T M F  
 
P a g e 5 2  of 7 3  
I N T E R N AL U S E 
M e a s ur e  
V ari a bl e  
E sti m a n d  
(S e cti o n  6 ) 
A n al y si s 
M et h o d 
(S e cti o n  6. 3 ) 
P o p ul ati o n 
(S e cti o n 5 ) 
A n al y si s 
T y p e  
S C O Ri n g At o pi c 
D er m atiti s 
( S C O R A D) 
C h a n g e fr o m 
b a s eli n e i n 
S C O R A D 
s c or e u p t o 
W 1 6 
 
Pri m ar y 
E sti m a n d 
( H y bri d) 
M M R M a n d 
B O C F 
F A S 
K e y 
s e c o n d ar y 
a n al y si s: 
C h a n g e fr o m 
b a s eli n e i n 
S C O R A D 
s c or e u p t o 
W 1 6 
 
Sl e e p-l o s s 
S c or e 
C h a n g e fr o m 
b a s eli n e sl e e p 
l o s s u p t o 
W 1 6 
Pri m ar y 
E sti m a n d 
( H y bri d) 
M M R M a n d 
B O C F 
F A S 
K e y 
s e c o n d ar y 
a n al y si s: 
C h a n g e fr o m 
b a s eli n e sl e e p 
l o s s u p t o 
W 1 6 
 
P ati e nt- Ori e nt e d 
E c z e m a 
M e a s ur e 
( P O E M) 
C h a n g e fr o m 
b a s eli n e i n 
P O E M s c or e 
Pri m ar y 
E sti m a n d 
( H y bri d) 
M M R M a n d 
B O C F 
F A S 
K e y 
s e c o n d ar y 
a n al y si s: 
C h a n g e fr o m 
b a s eli n e 
P O E M u p t o 
W 1 6 
 
( C hil dr e n) 
D er m at ol o g y 
Lif e Q u alit y 
I n d e x ( D L QI/ 
C D L QI) 
C h a n g e fr o m 
b a s eli n e i n 
D L QI t ot al 
s c or e u p t o 
W 1 6 
 
C h a n g e fr o m 
b a s eli n e i n 
C D L QI t ot al 
s c or e u p t o 
W 1 6 
Pri m ar y 
E sti m a n d 
( H y bri d) 
M M R M a n d 
B O C F 
F A S 
K e y 
s e c o n d ar y 
a n al y si s: 
C h a n g e fr o m 
b a s eli n e 
D L QI/ 
C D L QI u p t o 
W 1 6 
Pr o p orti o n of 
p ati e nt s 
a c hi e vi n g at 
l e a st 4- p oi nt 
i m pr o v e m e nt 
i n D L QI u p t o 
W 1 6 
Pri m ar y 
E sti m a n d 
( H y bri d) 
M M R M a n d 
B O C F 
F A S* 
K e y 
s e c o n d ar y 
a n al y si s: 
a c hi e vi n g at 
l e a st 4- p oi nt 
i m pr o v e m e nt 
i n D L QI u p t o 
W 1 6 
 
C CI


St ati sti c al A n al y si s Pl a n f or I nt er v e nti o n al St u di e s  
S p o n s or: A L MI R A L L, S. A.; Pr ot o c ol N o.: M- 1 7 9 2 3- 3 0 
 
 
T hi s d o c u m e nt i s c o nfi d e nti al. 
S A P t e xt V er si o n: S A P t e xt v 2. 0 2 2 M A R 2 0 2 3 
C o ntr oll e d D o c u m e nt I D:  
, Eff e cti v e D at e 3 1- A u g- 2 0 2 0 
Fili n g r e q uir e m e nt s: T M F  
 
P a g e 5 3  of 7 3  
I N T E R N AL U S E 
M e a s ur e  
V ari a bl e  
E sti m a n d  
(S e cti o n  6 ) 
A n al y si s 
M et h o d 
(S e cti o n  6. 3 ) 
P o p ul ati o n 
(S e cti o n 5 ) 
A n al y si s 
T y p e  
T o pi c al 
c orti c o st er oi d s 
( T C S)-fr e e 
T C S d at a 
c oll e ct e d i n 
C R F a n d n ot 
fr o m e Di ar y. 
 
Pr o p orti o n of 
T C S-fr e e d a y s 
u p t o W 1 6 
Pri m ar y 
E sti m a n d 
( H y bri d) 
M M R M a n d 
B O C F 
F A S 
K e y 
s e c o n d ar y 
a n al y si s: 
Pr o p orti o n of 
T C S-fr e e d a y s 
u p t o W 1 6 
 
Ti m e t o T C S-
fr e e d a y s u p 
t o W 1 6 
Pri m ar y 
E sti m a n d 
( H y bri d) 
K a pl a n- M ei er  
F A S 
K e y 
s e c o n d ar y 
a n al y si s: Ti m e 
t o T C S-fr e e 
d a y s u p t o 
W 1 6 
 
Ti m e t o T C S-
fr e e d a y s u p 
t o W 1 6 
S e c o n d ar y 
E sti m a n d 
( C o m p o sit e) 
K a pl a n- M ei er  
F A S 
K e y 
s e c o n d ar y 
a n al y si s: Ti m e 
t o T C S-fr e e 
d a y s u p t o 
W 1 6 
 
S ki n P ai n N R S  
C h a n g e fr o m 
b a s eli n e S ki n 
P ai n N R S u p 
t o W 1 6 
Pri m ar y 
E sti m a n d 
( H y bri d) 
M M R M a n d 
B O C F 
F A S 
K e y 
s e c o n d ar y 
a n al y si s: 
C h a n g e fr o m 
b a s eli n e S ki n 
P ai n N R S u p 
t o W 1 6 
 
P er c e nt a g e of 
p ati e nt s 
a c hi e vi n g a 4-
p oi nt 
i m pr o v e m e nt 
S ki n P ai n 
N R S at W 1 6 
Pri m ar y 
E sti m a n d 
( H y bri d) 
M M R M a n d 
B O C F 
F A S* 
K e y 
s e c o n d ar y 
a n al y si s: 
P er c e nt a g e of 
p ati e nt s 
a c hi e vi n g a 4-
p oi nt 
i m pr o v e m e nt 
S ki n P ai n 
N R S at W 1 6 
 
R e c a p of at o pi c 
e c z e m a 
( R E C A P) 
C h a n g e fr o m 
B a s eli n e 
R E C A P u p t o 
W 1 6 
Pri m ar y 
E sti m a n d 
( H y bri d) 
M M R M a n d 
B O C F 
F A S 
 
a n al y si s: 
C h a n g e fr o m 
B a s eli n e 
R E C A P u p t o 
W 1 6 
 
C CI
C CI


St ati sti c al A n al y si s Pl a n f or I nt er v e nti o n al St u di e s  
S p o n s or: A L MI R A L L, S. A.; Pr ot o c ol N o.: M- 1 7 9 2 3- 3 0 
 
 
T hi s d o c u m e nt i s c o nfi d e nti al. 
S A P t e xt V er si o n: S A P t e xt v 2. 0 2 2 M A R 2 0 2 3 
C o ntr oll e d D o c u m e nt I D:  
, Eff e cti v e D at e 3 1- A u g- 2 0 2 0 
Fili n g r e q uir e m e nt s: T M F  
 
P a g e 5 4  of 7 3  
I N T E R N AL U S E 
M e a s ur e  
V ari a bl e  
E sti m a n d  
(S e cti o n  6 ) 
A n al y si s 
M et h o d 
(S e cti o n  6. 3 ) 
P o p ul ati o n 
(S e cti o n 5 ) 
A n al y si s 
T y p e  
W orl d H e alt h 
Or g a ni s ati o n – 
Fi v e W ell- B ei n g 
I n d e x ( W H O- 5) 
C h a n g e fr o m 
B a s eli n e 
W H O- 5 u p t o 
W 1 6 
Pri m ar y 
E sti m a n d 
( H y bri d) 
M M R M a n d 
B O C F 
F A S 
 
a n al y si s: 
C h a n g e fr o m 
B a s eli n e 
W H O- 5 u p t o 
W 1 6 
 
Tr e at m e nt 
S ati sf a cti o n 
Q u e sti o n n air e 
f or M e di c ati o n- 9 
it e m s ( T S Q M- 9) 
T S Q M- 9 u p t o 
W 1 6 
Pri m ar y 
E sti m a n d 
( H y bri d) 
M M R M a n d 
B O C F 
F A S 
 
a n al y si s: 
T S Q M- 9 u p t o 
W 1 6 
 
D L QI- R el e v a nt 
( D L QI- R) 
C h a n g e fr o m 
B a s eli n e 
D L QI- R u p t o 
W 1 6 
Pri m ar y 
E sti m a n d 
( H y bri d) 
M M R M a n d 
B O C F 
F A S 
 
a n al y si s: 
C h a n g e fr o m 
B a s eli n e 
D L QI- R u p t o 
W 1 6 
 
* T h e a n alys es of 4 p oi nt N R S pr urit us i m pr ov e m e nt will b e b as e d o n t h os e p ati e nts t h at h a d a b as eli n e N R S pr urit us sc or e ≥ 4 p oi nts 
T h e a n alys es of 4 p oi nt DL QI i m pr ov e m e nt will b e b as e d o n t h os e p ati e nts t h at h a d a b as eli n e DL QI sc or e ≥ 4 p oi nts 
T h e a n alys es of 4 p oi nt N R S S KI N P ai n i m pr ov e m e nt will b e b as e d o n t h os e p ati e nts t h at h a d a b as eli n e N R S S KI N P ai n sc or e ≥ 4 p oi nts.  
9. 7.  
M ai nt e n a n c e P eri o d ( a n d E xt e n si o n P eri o d f or P ati e nt s fr o m G er m a n y) A n al y s e s 
T h e I n d u cti o n a n d M ai nt e n a n c e/ E xt e n si o n P eri o d s will b e r e p ort e d s e p ar at el y. F or t h e 
M ai nt e n a n c e/ E xt e n si o n P eri o d, t h e s a m e a n al y s e s a s f or I n d u cti o n P eri o d, a s d e s cri b e d i n s e cti o n エラ
ー
エラ
ー! 参照元が見つかりません。
参照元が見つかりません。, will b e p erf or m e d d e s cri pti v el y o n t h e F A S. 
C CI
C CI
C CI
C CI


St ati sti c al A n al y si s Pl a n f or I nt er v e nti o n al St u di e s  
S p o n s or: A L MI R A L L, S. A.; Pr ot o c ol N o.: M- 1 7 9 2 3- 3 0 
 
 
T hi s d o c u m e nt i s c o nfi d e nti al. 
S A P t e xt V er si o n: S A P t e xt v 2. 0 2 2 M A R 2 0 2 3 
C o ntr oll e d D o c u m e nt I D:  
, Eff e cti v e D at e 3 1- A u g- 2 0 2 0 
Fili n g r e q uir e m e nt s: T M F  
 
P a g e 5 5  of 7 3  
I N T E R N AL U S E 
  
S af et y 
T h e p o p ul ati o n u s e d f or s af et y a n al y s e s will b e t h e S af et y A n al y si s S et ( S A F). S af et y will b e a s s e s s e d 
b a s e d o n a d v er s e e v e nt ( A E), tr e at m e nt e m er g e nt a d v er s e e v e nt ( T E A E), vit al si g n s, l a b or at or y r e s ult s, 
a n d p h y si c al e x a mi n ati o n s. 
S af et y will b e d e s cri b e d b y tr e at m e nt gr o u p s:  
  
U p t o W e e k 1 6: L e bri / Pl a c e b o 
  
U p t o W e e k 5 2/ 6 8/ E xt e n si o n p eri o d: L e bri- L e bri / Pl a c e b o- L e bri 
All s af et y a n al y si s e x c e pt f or l a b or at or y e v al u ati o n s/ vit al si g n s/ p h y si c al e x a mi n ati o n s will b e s u m m ari z e d 
f or t h e t hr e e st u d y p eri o d s d e s cri b e d b el o w: 
  
I n d u cti o n P eri o d ( u p t o W e e k 1 6), 
  
M ai nt e n a n c e P eri o d a n d S af et y F oll o w- u p: 
o   
F or all p ati e nt s: fr o m W e e k 1 6 t o W e e k 5 2 
o   
F or all p ati e nt s e x c e pt G er m a n p ati e nt s i n t h e e xt e n si o n: fr o m W e e k 1 6 t o 6 8 
o   
F or G er m a n p ati e nt s i n t h e e xt e n si o n: fr o m W e e k 1 6 t o l a st vi sit i n t h e G er m a n e xt e n si o n 
  
C o m bi n e d I n d u cti o n a n d M ai nt e n a n c e/ E xt e n si o n P eri o d s ( u p t o W e e k 5 2 or l at er f or t h e 
E xt e n si o n a s d e s cri b e d a b o v e – s e e m ai nt e n a n c e p eri o d), a n d C o m bi n e d I n d u cti o n a n d 
M ai nt e n a n c e/ E xt e n si o n P eri o d s pl u s F oll o w -U p P eri o d [ s el e cti v e a n al y si s] ( U p t o W e e k 6 8 or 
l at er f or t h e E xt e n si o n a s d e s cri b e d a b o v e – s e e m ai nt e n a n c e p eri o d). 
 
1 0. 1.  
A d v er s e E v e nt s  
A d v er s e e v e nt s ( A E s) will b e c o d e d u si n g M e d D R A V er si o n 2 4. 1 or hi g h er. I n t h e e v e nt of a 
mi s si n g/i n c o m pl et e st art or st o p d at e a s s o ci at e d wit h a n a d v er s e e v e nt, o nl y t h e tr e at m e nt- e m er g e n c e 
will b e i m p ut e d u si n g t h e al g orit h m d e s cri b e d i n エラー
エラー! 参照元が見つかりません。
参照元が見つかりません。s e cti o n 7. 3. 2 . D at e s 
will n ot b e i m p ut e d.  
A T E A E i s a n y A E t h at n e wl y a p p e ar e d, or w or s e n e d i n s e v erit y f oll o wi n g i niti ati o n of st u d y m e di c ati o n 
u ntil l a st f oll o w- u p vi sit. O nl y T E A E will b e i n cl u d e d i n t h e s u m m ar y t a bl e s, b ut all A E will b e i n cl u d e d i n 
t h e li sti n g s. 
F oll o wi n g t a bl e s will b e pr o d u c e d: 
- 
A n o v er all s u m m ar y of t h e n u m b er a n d p er c e nt a g e of p ati e nt s r e p orti n g T E A E s, A d v er s e 
E v e nt s of S p e ci al I nt er e st ( A E SI), s eri o u s T E A E s, S u s p e ct e d U n e x p e ct e d S eri o u s A d v er s e 
R e a cti o n s ( S U S A R s), T E A E s l e a di n g t o st u d y dr u g di s c o nti n u ati o n, r el at e d T E A E s, r el at e d 
S A E s a n d D e at h s.  
- 
I n ci d e n c e of A E s ( A E s i n cl u di n g T E A E s, S A E s, r el at e d T E A E s, r el at e d S A E s, T E A E s l e a di n g 
t o st u d y tr e at m e nt di s c o nti n u ati o n, A E SI s a n d d e at h s) 
-  
T E A E s o v er all a n d b y s y st e m or g a n cl a s s a n d pr ef err e d t er m 
1 0. 
C CI


St ati sti c al A n al y si s Pl a n f or I nt er v e nti o n al St u di e s  
S p o n s or: A L MI R A L L, S. A.; Pr ot o c ol N o.: M- 1 7 9 2 3- 3 0 
 
 
T hi s d o c u m e nt i s c o nfi d e nti al. 
S A P t e xt V er si o n: S A P t e xt v 2. 0 2 2 M A R 2 0 2 3 
C o ntr oll e d D o c u m e nt I D:  
, Eff e cti v e D at e 3 1- A u g- 2 0 2 0 
Fili n g r e q uir e m e nt s: T M F  
 
P a g e 5 6  of 7 3  
I N T E R N AL U S E 
-  
T E A E s b y s e v erit y ( Mil d, M o d er at e, S e v er e), o v er all a n d b y s y st e m or g a n cl a s s a n d pr ef err e d 
t er m 
-  
T E A E s b y r el ati o n s hi p t o st u d y tr e at m e nt ( u nr el at e d v s. r el at e d), o v er all a n d b y s y st e m or g a n 
cl a s s a n d pr ef err e d t er m 
-  
T E A E s l e a di n g t o st u d y dr u g di s c o nti n u ati o n, o v er all a n d b y s y st e m or g a n cl a s s a n d 
pr ef err e d t er m 
-  
T E A E s l e a di n g t o d e at h, o v er all a n d b y s y st e m or g a n cl a s s a n d pr ef err e d t er m 
-  
S eri o u s A d v er s e E v e nt s, o v er all a n d b y s y st e m or g a n cl a s s a n d pr ef err e d t er m 
-  
A E SI s b y s e v erit y ( Mil d, M o d er at e, S e v er e), o v er all a n d b y pr ef err e d t er m  
-  
A E SI s b y r el ati o n s hi p t o st u d y tr e at m e nt ( u nr el at e d v s. r el at e d), o v er all a n d b y pr ef err e d t er m  
-  
S U S A R s, o v er all a n d b y s y st e m or g a n cl a s s a n d pr ef err e d t er m 
 
A E s p o s si bl y r el at e d a n d r el at e d t o st u d y m e di c ati o n will b e c o m bi n e d f or t h e “r el at e d” 
s u m m ari e s.  
If a p ati e nt m et t h e s a m e A E m or e t h a n o n e ti m e, A E will b e c o u nt e d o nl y o n c e wit h t h e m a xi m u m 
of s e v erit y.   
 
1 0. 2.  
L a b or at or y E v al u ati o n s 
All st ati sti c al a n al y s e s of l a b or at or y v al u e s will b e p erf or m e d u si n g SI u nit s.  
Cli ni c al l a b or at or y d at a a n d c h a n g e fr o m b a s eli n e will b e s u m m ari z e d b y t h e s c h e d ul e d ti m e p oi nt f or t h e 
s er u m c h e mi str y, h e m at ol o g y a n d uri n al y si s t o w e e k s 1 6, 3 2 a n d 5 2 pl u s G er m a n e xt e n si o n w e e k s.  
P ati e nt i n ci d e n c e s of c h a n g e i n cl a s sifi c ati o n wit h r e s p e ct t o t h e l a b or at or y n or m al r a n g e s will b e 
s u m m ari z e d a s s hift t a bl e s.  
S hift t a bl e s will s h o w t h e n u m b er of p ati e nt s w h o s hift fr o m e a c h c at e g or y of m a xi m u m ( mi ni m u m) 
b a s eli n e o b s er v ati o n t o e a c h c at e g or y of m a xi m u m ( mi ni m u m) p o st- b a s eli n e o b s er v ati o n. H er e 
c at e g ori e s m a y b e l o w, n or m al, or hi g h a c c or di n g t o t h e c e ntr al l a b d efi niti o n. 
B a s eli n e will b e t h e l a st v al u e o bt ai n e d b ef or e r a n d o mi z ati o n.  
C h e mi str y a n d h e m at ol o g y d at a will b e li st e d wit h t h e v al u e s o ut si d e t h e n or m al r a n g e s fl a g g e d. 
 
1 0. 3.  
Vit al Si g n s  
S u m m ar y st ati sti c s f or vit al si g n ( s y st oli c a n d di a st oli c bl o o d pr e s s ur e [ m m H g], b o d y t e m p er at ur e [° C], 
r e s pir at or y r at e [ br e at h s p er mi n ut e] a n d p ul s e [ b e at s p er mi n ut e or b p m]) will b e pr e s e nt e d f or e a c h 
s c h e d ul e d ti m e p oi nt m e a s ur e d a n d f or t h e c h a n g e fr o m b a s eli n e t o e a c h ti m e p oi nt. 
F or c o n v e ni e n c e, t h e c o n v er si o n f or t e m p er at ur e: 
T e m p er at ur e (i n ° C) = 5/ 9 ( T e m p er at ur e [i n ° F]- 3 2) 
O b s er v e d r e s ult s a n d c h a n g e s fr o m b a s eli n e t o w e e k s 2, 4, 8, 1 2 a n d 1 6 will b e s u m m ari z e d. 
C CI


St ati sti c al A n al y si s Pl a n f or I nt er v e nti o n al St u di e s  
S p o n s or: A L MI R A L L, S. A.; Pr ot o c ol N o.: M- 1 7 9 2 3- 3 0 
 
 
T hi s d o c u m e nt i s c o nfi d e nti al. 
S A P t e xt V er si o n: S A P t e xt v 2. 0 2 2 M A R 2 0 2 3 
C o ntr oll e d D o c u m e nt I D:  
, Eff e cti v e D at e 3 1- A u g- 2 0 2 0 
Fili n g r e q uir e m e nt s: T M F  
 
P a g e 5 7  of 7 3  
I N T E R N AL U S E 
O b s er v e d r e s ult s a n d c h a n g e s fr o m b a s eli n e t o w e e k s 2 0, 2 4, 2 8, 3 2, 3 6, 4 0, 4 4, 4 8 a n d 5 2  pl u s G er m a n 
e xt e n si o n w e e k s will b e s u m m ari z e d. 
N u m b er a n d p er c e nt a g e of p ati e nt s w h o s hift fr o m n or m al/ hi g h t o l o w (i e, tr e at m e nt- e m er g e nt l o w) a n d 
t h e n u m b er a n d p er c e nt a g e of p ati e nt s w h o s hift fr o m n or m al/l o w t o hi g h (i e, tr e at m e nt- e m er g e nt hi g h) 
will b e di s pl a y e d. 
 
T a bl e of C at e g ori c al Crit eri a f or A b n or m al Tr e at m e nt - E m er g e nt Bl o o d Pr e s s ur e a n d P ul s e m e a s ur e m e nt, 
a n d C at e g ori c al Crit eri a f or W ei g ht C h a n g e s f or A d ult 
P ar a m et er  
L o w  
Hi g h  
S y st oli c B P ( m m H G) 
 
≤9 0 a n d d e cr e a s e fr o m b a s eli n e ≥2 0 
≥1 4 0 a n d i n cr e a s e fr o m b a s eli n e ≥2 0 
Di a st oli c B P ( m m H G) 
 
≤5 0 a n d d e cr e a s e fr o m b a s eli n e ≥1 0 
≥9 0 a n d i n cr e a s e fr o m b a s eli n e ≥1 0 
P ul s e ( b p m) 
 
≤5 0 a n d d e cr e a s e fr o m b a s eli n e ≥1 5 
≥1 0 0 a n d i n cr e a s e fr o m b a s eli n e ≥1 5 
W ei g ht ( k g) 
 
( L o s s) d e cr e a s e ≥7 % 
( G ai n) i n cr e a s e ≥7 % 
 
1 0. 4.  
P h y si c al E x a mi n ati o n 
Cli ni c all y si g nifi c a nt p h y si c al e x a mi n ati o n a b n or m aliti e s will b e s u m m ari z e d at w e e k s 1 6, 3 2 a n d 5 2 pl u s 
G er m a n e xt e n si o n w e e k s.  
R e s ult s of p h y si c al e x a mi n ati o n will b e li st e d b y p ati e nt a n d vi sit. 
  
1 0. 5.  
S p e ci al S af et y T o pi c s i n cl u di n g A d v er s e E v e nt s of S p e ci al I nt er e st 
 
E o si n o p hili a a n d E o si n o p hil- R el at e d Di s or d er s 
I n a d diti o n t o t h e st a n d ar d l a b or at or y a n al y si s (S e cti o n 1 0. 2 ), e o si n o p hili a a n d e o si n o p hil-r el at e d A E s will 
b e s u m m ari z e d f or t h e S A F. D et ail s r e g ar di n g e o si n o p hil-r el at e d P T s ar e d e s cri b e d i n t h e s e p ar at e 
Al mir all S af et y T o pi c s of I nt er e st. 
A s hift t a bl e s u m m ari zi n g t h e n u m b er a n d p er c e nt a g e of p ati e nt s wit hi n e a c h m a xi m u m b a s eli n e c at e g or y 
v er s u s e a c h m a xi m u m p o st- b a s eli n e c at e g or y b y tr e at m e nt will b e di s pl a y e d f or t h e S A F. T h e f oll o wi n g 
E o si n o p hil c at e g ori e s will b e c o n si d er e d:  
E o si n o p hil c at e g ori e s: n or m al ( < 5 0 0 p er mi cr olit er), mil d ( 5 0 0 t o < 1 5 0 0 p er mi cr olit er), m o d er at e ( 1 5 0 0 t o 
< 5 0 0 0 p er mi cr olit er), s e v er e ( > = 5 0 0 0 p er mi cr olit er).  
  
 
I nf e cti o n s, I n cl u di n g H er p e s I nf e cti o n s a n d R el e v a nt P ar a siti c I nf e cti o n s 
I nf e cti o n s will b e d efi n e d u si n g t h e P T s fr o m t h e M e d D R A I nf e cti o n s a n d I nf e st ati o n s S O C. T h e M e d D R A 
t er m s u s e d t o i d e ntif y i nf e cti o n s c o n si d er e d t o b e o p p ort u ni sti c i nf e cti o n s ( OI) i n p ati e nt s wit h i m m u n e 
m e di at e d i nfl a m m at or y c o n diti o n s tr e at e d wit h i m m u n o m o d ul at or y dr u g s ar e b a s e d o n Wi nt hr o p et al. 
( 2 0 1 5) a n d ar e li st e d i n t h e Al mir all S af et y T o pi c s of I nt er e st. T h e li st c o nt ai n s n arr o w ( m or e s p e cifi c) a n d 
br o a d (l e s s s p e cifi c) P T s wit h r e s p e ct t o t h e s e pr o s p e cti v el y d efi n e d OI s. D efi niti o n s of h er p e s i nf e cti o n s, 
p ar a siti c i nf e cti o n s a n d s ki n i nf e cti o n s ar e li st e d i n t h e Al mir all S af et y T o pi c s of I nt er e st. 
1 0. 5. 1. 
1 0. 5. 2. 
C CI


St ati sti c al A n al y si s Pl a n f or I nt er v e nti o n al St u di e s  
S p o n s or: A L MI R A L L, S. A.; Pr ot o c ol N o.: M- 1 7 9 2 3- 3 0 
 
 
T hi s d o c u m e nt i s c o nfi d e nti al. 
S A P t e xt V er si o n: S A P t e xt v 2. 0 2 2 M A R 2 0 2 3 
C o ntr oll e d D o c u m e nt I D:  
, Eff e cti v e D at e 3 1- A u g- 2 0 2 0 
Fili n g r e q uir e m e nt s: T M F  
 
P a g e 5 8  of 7 3  
I N T E R N AL U S E 
T h e f oll o wi n g t a bl e s will b e pr o d u c e d f or t h e S A F: 
-  
S u m m ar y of tr e at m e nt- e m er g e nt i nf e cti o n s b y P T b y m a xi m u m s e v erit y 
-  
S u m m ar y of s eri o u s i nf e cti o n s b y P T 
-  
S u m m ar y of i nf e cti o n A E s r e s ulti n g i n p er m a n e nt st u d y dr u g di s c o nti n u ati o n 
-  
Tr e at m e nt- e m er g e nt p ot e nti al OI b y P T n e st e d wit h c at e g ori e s f or n arr o w t er m s a n d br o a d 
t er m s s e p ar at el y 
-  
Tr e at m e nt- e m er g e nt a d v er s e e v e nt s, h er p e s a n d p ar a siti c i nf e cti o n s 
-  
Tr e at m e nt- e m er g e nt a d v er s e e v e nt s, s ki n i nf e cti o n 
I n a d diti o n, a li sti n g of p ati e nt s wit h p ot e nti al OI, S eri o u s I nf e cti o n, h er p e s a n d p ar a siti c i nf e cti o n s will b e 
di s pl a y e d. 
 
C o nj u n cti viti s 
C o nj u n cti viti s ar e e v e nt s of s p e ci al i nt er e st a n d will b e i d e ntifi e d u si n g P T s n e st e d wit hi n t h e c at e g ori e s of 
c o nj u n cti viti s a n d K er atiti s a s d e s cri b e d i n t h e Al mir all S af et y T o pi c s of I nt er e st: 
T h e f oll o wi n g t a bl e s a n d li sti n g s will b e pr o d u c e d f or t h e S A F:  
-  
S u m m ar y of T E A E of c o nj u n cti viti s o v er all a n d b y c at e g ori e s, a n d al s o d e s cri bi n g s e v erit y, 
s eri o u s n e s s, o ut c o m e a n d a cti o n t a k e n.   
-  
S u m m ar y a n d/ or li sti n g of c o nj u n cti viti s a n d e y e i nfl a m m ati o n f oll o w- u p f or m 
-  
A li sti n g of p ati e nt s wit h c o nj u n cti viti s 
 
H y p er s e n siti vit y 
P ot e nti al h y p er s e n siti vit y r e a cti o n s will b e d et er mi n e d u si n g t h e f oll o wi n g St a n d ar di s e d M e d D R A Q u er y 
( S M Q s): a n a p h yl a cti c r e a cti o n, h y p er s e n siti vit y, a n d a n gi o e d e m a. P ot e nti al h y p er s e n siti vit y will b e 
c at e g ori z e d a s i m m e di at e (i. e., o c c urri n g t h e s a m e d a y a s dr u g a d mi ni str ati o n) a n d n o n-i m m e di at e (i. e., 
o c c urri n g aft er t h e d a y of st u d y dr u g a d mi ni str ati o n b ut pri or t o s u b s e q u e nt dr u g a d mi ni str ati o n). 
-  
f or i m m e di at e h y p er s e n siti vit y: ( 1) c o m bi n e d n arr o w/ al g orit h mi c s e ar c h (t h at i s, a n y n arr o w 
t er m fr o m a n y o n e of t h e S M Q s, or a n a p h yl a xi s al g orit h m); ( 2) n arr o w s e ar c h (t h at i s, a n y 
n arr o w t er m) b y S M Q; ( 3) T E A E s ( o c c urri n g o n t h e d a y of st u d y dr u g a d mi ni str ati o n) b y P T 
n ot i n a n y of t h e 3 S M Q s 
 
-  
f or n o ni m m e di at e h y p er s e n siti vit y: ( 1) c o m bi n e d n arr o w s e ar c h (t h at i s, a n y n arr o w t er m fr o m 
a n y o n e of t h e S M Q s); ( 2) n arr o w s e ar c h (t h at i s, a n y n arr o w t er m) b y S M Q; a n d ( 3) br o a d 
s e ar c h (t h at i s, a n y n arr o w or br o a d t er m) b y S M Q 
 
 
I nj e cti o n Sit e R e a cti o n s (I S R) 
I nj e cti o n sit e r e a cti o n s (I S R s) ar e A E s l o c ali z e d t o t h e i m m e di at e sit e of t h e a d mi ni str ati o n of a dr u g. T h e 
e v al u ati o n of st u d y dr u g r el at e d I S R s will b e t hr o u g h t h e u n s oli cit e d r e p orti n g of I S R T E A E s. I nj e cti o n sit e 
r e a cti o n s will b e d efi n e d u si n g t h e M e d D R A Hi g h L e v el T er m ( H L T) of I S R, e x cl u di n g c ert ai n P T s r el at e d 
t o j oi nt s a s d e s cri b e d i n t h e Al mir all S af et y T o pi c s of I nt er e st. 
A s u m m ar y t a bl e of T E A E of I S R o v er all a n d b y P T will b e di s pl a y e d. 
 
1 0. 5. 3. 
1 0. 5. 4. 
1 0. 5. 5. 
C CI


St ati sti c al A n al y si s Pl a n f or I nt er v e nti o n al St u di e s  
S p o n s or: A L MI R A L L, S. A.; Pr ot o c ol N o.: M- 1 7 9 2 3- 3 0 
 
 
T hi s d o c u m e nt i s c o nfi d e nti al. 
S A P t e xt V er si o n: S A P t e xt v 2. 0 2 2 M A R 2 0 2 3 
C o ntr oll e d D o c u m e nt I D:  
, Eff e cti v e D at e 3 1- A u g- 2 0 2 0 
Fili n g r e q uir e m e nt s: T M F  
 
P a g e 5 9  of 7 3  
I N T E R N AL U S E 
 
M ali g n a n ci e s 
M ali g n a n ci e s will b e d efi n e d u si n g P T s fr o m t h e M ali g n a nt t u m or s S M Q a n d s u m m ari z e d s e p ar at el y f or 
t h e 2 c at e g ori e s: N o n- m el a n o m a s ki n c a n c er ( N M S C) a n d M ali g n a n ci e s e x cl u di n g N M S C. 
 
 
At o pi c D er m atiti s E x a c er b ati o n 
A s u m m ar y t a bl e of T E A E of at o pi c d er m atiti s e x a c er b ati o n will b e di s pl a y e d. At o pi c d er m atiti s 
e x a c er b ati o n will b e d efi n e d u si n g t h e f oll o wi n g P T s: 
  
D er m atiti s at o pi c 
  
E c z e m a 
  
R e b o u n d at o pi c d er m atiti s 
  
R e b o u n d e c z e m a 
  
D er m atiti s all er gi c 
  
Er yt hr o d er mi c at o pi c d er m atiti s 
1 0. 5. 6. 
1 0. 5. 7. 
C CI


St ati sti c al A n al y si s Pl a n f or I nt er v e nti o n al St u di e s  
S p o n s or: A L MI R A L L, S. A.; Pr ot o c ol N o.: M- 1 7 9 2 3- 3 0 
 
 
T hi s d o c u m e nt i s c o nfi d e nti al. 
S A P t e xt V er si o n: S A P t e xt v 2. 0 2 2 M A R 2 0 2 3 
C o ntr oll e d D o c u m e nt I D:  
, Eff e cti v e D at e 3 1- A u g- 2 0 2 0 
Fili n g r e q uir e m e nt s: T M F  
 
P a g e 6 0  of 7 3  
I N T E R N AL U S E 
  
C h a n g e s fr o m A n al y si s Pl a n n e d i n Pr ot o c ol 
T h e r e a s o n s f or e x cl u si o n will b e pr e s e nt e d i n t h e li sti n g s of pr ot o c ol d e vi ati o n s i n st e a d of s u m m ari zi n g i n 
t a bl e.  
A n y a n al y si s d e s cri b e d a s ‘ b y vi sit’ i n t h e pr ot o c ol ar e d e s cri b e d a s ‘ b y w e e k’ i n t hi s S A P a n d i n t h e t a bl e s 
a n d fi g ur e s. 
F oll o wi n g 2 S e c o n d ar y E n d p oi nt s ar e a d d e d i n t hi s S A P. 
-  
P er c e nt a g e of p ati e nt s a c hi e vi n g I G A 0/ 1 a n d 2- p oi nt i m pr o v e m e nt b y w e e k u p t o W e e k 1 6. 
-  
P er c e nt a g e of p ati e nt s a c hi e vi n g a 4- p oi nt i m pr o v e m e nt Pr urit u s N R S b y w e e k u p t o W e e k 1 6. 
1 1. 
C CI


St ati sti c al A n al y si s Pl a n f or I nt er v e nti o n al St u di e s  
S p o n s or: A L MI R A L L, S. A.; Pr ot o c ol N o.: M- 1 7 9 2 3- 3 0 
 
 
T hi s d o c u m e nt i s c o nfi d e nti al. 
S A P t e xt V er si o n: S A P t e xt v 2. 0 2 2 M A R 2 0 2 3 
C o ntr oll e d D o c u m e nt I D:  
, Eff e cti v e D at e 3 1- A u g- 2 0 2 0 
Fili n g r e q uir e m e nt s: T M F  
 
P a g e 6 1  of 7 3  
I N T E R N AL U S E 
  
R ef er e n c e Li st 
[ 1]  H a nifi n  J M,  R aj k a  G.  Di a g n o sti c  f e at ur e s  of  at o pi c  d er m atiti s.  A ct a  D er m  V e n er e ol  ( St o c k h). 
1 9 8 0; 9 2( s u p pl): 4 4- 4 7 
[ 2]  S a m p s o n  H A,  M u ñ o z- F url o n g  A,  C a m p b ell  R L,  et  al.  S e c o n d  s y m p o si u m  o n  t h e  d efi niti o n  a n d 
m a n a g e m e nt  of  a n a p h yl a xi s:  s u m m ar y  r e p ort-- S e c o n d  N ati o n al  I n stit ut e  of  All er g y  a n d  I nf e cti o u s 
Di s e a s e/ F o o d All er g y a n d A n a p h yl a xi s N et w or k s y m p o si u m. J All er g y Cli n I m m u n ol. 2 0 0 6; 1 1 7( 2): 3 9 1- 3 9 7. 
d oi: 1 0. 1 0 1 6/j.j a ci. 2 0 0 5. 1 2. 1 3 0 3  
1 2. 
C CI


St ati sti c al A n al y si s Pl a n f or I nt er v e nti o n al St u di e s  
S p o n s or: A L MI R A L L, S. A.; Pr ot o c ol N o.: M- 1 7 9 2 3- 3 0 
 
 
T hi s d o c u m e nt i s c o nfi d e nti al. 
S A P t e xt V er si o n: S A P t e xt v 2. 0 2 2 M A R 2 0 2 3 
C o ntr oll e d D o c u m e nt I D:  
, Eff e cti v e D at e 3 1- A u g- 2 0 2 0 
Fili n g r e q uir e m e nt s: T M F  
 
P a g e 6 2  of 7 3  
I N T E R N AL U S E 
  
Pr o gr a m mi n g C o n si d er ati o n s 
All  t a bl e s,  fi g ur e s,  li sti n g s  ( T F L s),  a n d  st ati sti c al  a n al y s e s  will  b e  g e n er at e d  u si n g  S A S  f or  Wi n d o w s, 
R el e a s e  9. 4 or  hi g h er ( S A S  I n stit ut e  I n c.,  C ar y,  N C, U S A).  C o m p ut er- g e n er at e d t a bl e,  li sti n g  a n d fi g ur e 
o ut p ut will a d h er e t o t h e f oll o wi n g s p e cifi c ati o n s.  
1 3. 1.  
G e n er al C o n si d er ati o n s 
  
O n e S A S pr o gr a m c a n cr e at e s e v er al o ut p ut s, or a s e p ar at e S A S pr o gr a m will b e cr e at e d f or e a c h 
o ut p ut 
  
O n e o ut p ut fil e c a n c o nt ai n s e v er al o ut p ut s. or e a c h o ut p ut will b e st or e d i n a s e p ar at e fil e 
  
O ut p ut fil e s will b e d eli v er e d i n W or d f or m at or p ort a bl e d o c u m e nt f or m at p df 
  
N u m b eri n g of T F L s will f oll o w I C H E 3 g ui d a n c e  
 
1 3. 2.  
T a bl e, Fi g ur e, a n d Li sti n g F or m at 
 
G e n er al 
  
All T F L s will b e pr o d u c e d i n l a n d s c a p e f or m at o n A 4 p a p er si z e, u nl e s s ot h er wi s e s p e cifi e d.  
  
All T F L s will b e pr o d u c e d u si n g t h e C o uri er N e w f o nt, si z e 8 w hi c h i s t h e s m all e st a c c e pt a bl e p oi nt 
si z e f or t h e R e g ul at or y A ut h oriti e s. 
  
T h e d at a di s pl a y s f or T F L s will h a v e a mi ni m u m bl a n k 1-i n c h m ar gi n o n all 4 si d e s. 
  
H e a d er s a n d f o ot er s f or fi g ur e s will b e i n C o uri er N e w f o nt, si z e 8 w hi c h i s t h e s m all e st a c c e pt a bl e 
p oi nt si z e f or t h e R e g ul at or y A ut h oriti e s. 
  
L e g e n d s will b e u s e d f or all fi g ur e s wit h m or e t h a n o n e v ari a bl e, gr o u p, or it e m di s pl a y e d. 
  
T F L s will b e i n bl a c k a n d w hit e ( n o c ol or), u nl e s s ot h er wi s e s p e cifi e d. 
  
S p e ci ali z e d  t e xt  st yl e s,  s u c h  a s  b ol di n g,  it ali c s,  b or d er s,  s h a di n g,  a n d  s u p er s cri pt e d  a n d 
s u b s cri pt e d  t e xt,  will  n ot  b e  u s e d  i n  t h e  T F L s,  u nl e s s  ot h er wi s e  s p e cifi e d.  O n  s o m e  o c c a si o n s, 
s u p er s cri pt s 1, 2, or 3 m a y b e u s e d ( s e e b el o w). 
  
O nl y  st a n d ar d  k e y b o ar d  c h ar a ct er s  will  b e  u s e d  i n  t h e  T F L s.  S p e ci al  c h ar a ct er s,  s u c h  a s  n o n-
pri nt a bl e  c o ntr ol  c h ar a ct er s,  pri nt er- s p e cifi c,  or  f o nt- s p e cifi c  c h ar a ct er s,  will  n ot  b e  u s e d. 
H e x a d e ci m al- d eri v e d c h ar a ct er s will b e u s e d, w h er e p o s si bl e, if t h e y ar e a p pr o pri at e t o h el p di s pl a y 
m at h s y m b ol s ( e. g., μ). C ert ai n s u b s cri pt s a n d s u p er s cri pt s ( e. g., c m 2, C m a x) will b e e m pl o y e d o n 
a c a s e- b y- c a s e b a si s. 
  
Mi x e d c a s e will b e u s e d f or all titl e s, f o ot n ot e s, c ol u m n h e a d er s, a n d pr o gr a m m er- s u p pli e d f or m at s, 
a s a p pr o pri at e. 
 
H e a d er s 
  All o ut p ut will h a v e t h e f oll o wi n g h e a d er at t h e t o p l eft of e a c h p a g e:  
  A L MI R A L L S. A. Pr ot o c ol M- 1 7 9 2 3- 3 0 A D v a nt a g e  
 H e alt h st u d y n u m b er  
) 
1 3. 
1 3. 2. 1. 
1 3. 2. 2. 
C CI
P P D
C CI


St ati sti c al A n al y si s Pl a n f or I nt er v e nti o n al St u di e s  
S p o n s or: A L MI R A L L, S. A.; Pr ot o c ol N o.: M- 1 7 9 2 3- 3 0 
 
 
T hi s d o c u m e nt i s c o nfi d e nti al. 
S A P t e xt V er si o n: S A P t e xt v 2. 0 2 2 M A R 2 0 2 3 
C o ntr oll e d D o c u m e nt I D:  
, Eff e cti v e D at e 3 1- A u g- 2 0 2 0 
Fili n g r e q uir e m e nt s: T M F  
 
P a g e 6 3  of 7 3  
I N T E R N AL U S E 
  Dr aft/ Fi n al R u n 
  All o ut p ut will h a v e P a g e n of N at t h e t o p or b ott o m ri g ht c or n er of e a c h p a g e. T F L s ar e i nt er n all y 
p a gi n at e d i n r el ati o n t o t h e t ot al l e n gt h (i. e., t h e p a g e n u m b er will a p p e ar s e q u e nti all y a s p a g e n of 
N, w h er e N i s t h e t ot al n u m b er of p a g e s i n t h e t a bl e) 
  T h e d at e t h e o ut p ut w a s g e n er at e d will a p p e ar al o n g wit h t h e pr o gr a m n a m e a s a f o ot er o n e a c h 
p a g e 
 
Di s pl a y Titl e s 
  E a c h T F L will b e i d e ntifi e d b y t h e d e si g n ati o n a n d a n u m er al. (i. e., T a bl e 1 4. 1. 1). A d e ci m al s y st e m 
( x. y a n d x. y. z) ar e u s e d t o i d e ntif y T F L s wit h r el at e d c o nt e nt s. T h e titl e will b e c e nt er e d. T h e 
a n al y si s s et will b e i d e ntifi e d o n t h e li n e i m m e di at el y f oll o wi n g t h e titl e a n d will b e e n cl o s e d i n 
p ar e nt h e si s. T h e titl e a n d t a bl e d e si g n ati o n will b e si n gl e s p a c e d. A s oli d li n e s p a n ni n g t h e m ar gi n s 
will s e p ar at e t h e di s pl a y titl e s fr o m t h e C ol u m n h e a d er s. T h er e will b e o n e bl a n k li n e b et w e e n t h e 
l a st titl e a n d t h e s oli d li n e. 
T a bl e x. y. z 
Fir st Li n e of Titl e 
S e c o n d Li n e of Titl e if N e e d e d 
( F ull A n al y si s S et) 
 
 
C ol u m n H e a d er s 
  C ol u m n h e a di n g s will b e di s pl a y e d i m m e di at el y b el o w t h e s oli d li n e d e s cri b e d a b o v e i n i niti al 
u p p er- c a s e c h ar a ct er s.   
  I n t h e c a s e of effi c a c y t a bl e s, t h e v ari a bl e ( or c h ar a ct eri sti c) c ol u m n i s o n t h e f ar l eft f oll o w e d b y t h e 
tr e at m e nt gr o u p c ol u m n s a n d t ot al c ol u m n (if a p pli c a bl e). P- v al u e s m a y b e pr e s e nt e d u n d er t h e 
t ot al c ol u m n or i n s e p ar at e p- v al u e c ol u m n (if a p pli c a bl e). Wit hi n-tr e at m e nt c o m p ari s o n s m a y h a v e 
p- v al u e s pr e s e nt e d i n a r o w b e n e at h t h e s u m m ar y st ati sti c s f or t h at tr e at m e nt 
  F or n u m eri c v ari a bl e s, i n cl u d e ‘ u nit’ i n c ol u m n or r o w h e a di n g w h e n a p pr o pri at e 
  A n al y si s s et si z e s will b e pr e s e nt e d f or e a c h tr e at m e nt gr o u p i n t h e c ol u m n h e a di n g a s ( N = x x) ( or 
i n t h e r o w h e a di n g s, if a p pli c a bl e). T hi s i s di sti n ct fr o m t h e ‘ n’ u s e d f or t h e d e s cri pti v e st ati sti c s 
r e pr e s e nti n g t h e n u m b er of p ati e nt s i n t h e a n al y si s s et 
  T h e or d er of tr e at m e nt s i n t h e t a bl e s a n d li sti n g s will b e Pl a c e b o fir st i n t h e c a s e of pl a c e b o 
c o ntr oll e d st u di e s a n d A cti v e c o m p ar at or s fir st i n t h e c a s e of a cti v e c o m p ar at or tri al s, f oll o w e d b y a 
t ot al c ol u m n (if a p pli c a bl e) 
 
B o d y of t h e D at a Di s pl a y 
1 3. 2. 5. 1. 
G e n er al C o n v e nti o n s 
D at a i n c ol u m n s of a t a bl e or li sti n g ar e f or m att e d a s f oll o w s: 
  Al p h a n u m eri c v al u e s will b e l eft-j u stifi e d; 
1 3. 2. 3. 
1 3. 2. 4. 
1 3. 2. 5. 
C CI


St ati sti c al A n al y si s Pl a n f or I nt er v e nti o n al St u di e s  
S p o n s or: A L MI R A L L, S. A.; Pr ot o c ol N o.: M- 1 7 9 2 3- 3 0 
 
 
T hi s d o c u m e nt i s c o nfi d e nti al. 
S A P t e xt V er si o n: S A P t e xt v 2. 0 2 2 M A R 2 0 2 3 
C o ntr oll e d D o c u m e nt I D:  
 Eff e cti v e D at e 3 1- A u g- 2 0 2 0 
Fili n g r e q uir e m e nt s: T M F  
 
P a g e 6 4  of 7 3  
I N T E R N AL U S E 
  W h ol e n u m b er s ( e. g., c o u nt s) will b e ri g ht-j u stifi e d; a n d 
  N u m b er s c o nt ai ni n g fr a cti o n al p orti o n s will b e d e ci m al ali g n e d. 
1 3. 2. 5. 2. 
T a bl e C o n v e nti o n s 
  U nit s will b e i n cl u d e d w h er e a v ail a bl e 
  F or c at e g ori c al p ar a m et er s, all c at e g ori e s will b e pr e s e nt e d i n t h e t a bl e, e v e n if n = 0 f or all tr e at m e nt 
gr o u p s i n a gi v e n c at e g or y. F or e x a m pl e, t h e fr e q u e n c y di stri b uti o n f or s y m pt o m s e v erit y w o ul d 
a p p e ar a s: 
S e v erit y 
R ati n g 
N 
s e v er e  
0 
m o d er at e  
8 
mil d  
3 
 
W h er e p er c e nt a g e s ar e pr e s e nt e d i n t h e s e t a bl e s, z er o p er c e nt a g e s will n ot b e pr e s e nt e d a n d s o c o u nt s 
of 0 will b e pr e s e nt e d a s 0 a n d n ot a s 0 ( 0 %). 
  A n U n k n o w n or Mi s si n g c at e g or y will b e a d d e d t o e a c h p ar a m et er f or w hi c h i nf or m ati o n i s n ot 
a v ail a bl e f or 1 or m or e p ati e nt s 
  U nl e s s ot h er wi s e s p e cifi e d, t h e e sti m at e d m e a n a n d m e di a n f or a s et of v al u e s will b e pri nt e d o ut 
t o 1 m or e si g nifi c a nt di git t h a n t h e ori gi n al v al u e s, a n d st a n d ar d d e vi ati o n s will b e pri nt e d o ut t o 2 
m or e si g nifi c a nt di git s t h a n t h e ori gi n al v al u e s. T h e mi ni m u m a n d m a xi m u m will r e p ort t h e s a m e 
si g nifi c a nt di git s a s t h e ori gi n al v al u e s. F or e x a m pl e, s y st oli c bl o o d pr e s s ur e will b e pr e s e nt e d a s 
f oll o w s: 
N 
 X X 
M e a n 
X X X. X 
St d D e v 
   X. X X 
M e di a n 
X X X. X 
Mi ni m u m 
X X X 
M a xi m u m 
X X X 
 
  P- v al u e s will b e o ut p ut i n t h e f or m at: ‘ 0. x x x’, w h er e x x x i s t h e v al u e r o u n d e d t o 3 d e ci m al pl a c e s. 
E v er y p- v al u e l e s s t h a n 0. 0 0 1 will b e pr e s e nt e d a s < 0. 0 0 1. If t h e p- v al u e ar e l e s s t h a n 0. 0 0 0 1, t h e n 
pr e s e nt a s < 0. 0 0 0 1. If t h e p- v al u e i s r et ur n e d a s > 0. 9 9 9, t h e n pr e s e nt a s > 0. 9 9 9 
  P er c e nt a g e v al u e s will b e pri nt e d t o o n e d e ci m al pl a c e, i n p ar e nt h e s e s wit h n o s p a c e s, o n e s p a c e 
aft er t h e c o u nt ( e. g., 7 ( 1 2. 8 %), 1 3 ( 5. 4 %)). U nl e s s ot h er wi s e n ot e d, f or all p er c e nt a g e s, t h e 
n u m b er of p ati e nt s i n t h e a n al y si s s et f or t h e tr e at m e nt gr o u p w h o h a v e a n o b s er v ati o n will b e t h e 
d e n o mi n at or. P er c e nt a g e s aft er z er o c o u nt s will n ot b e di s pl a y e d a n d p er c e nt a g e s e q u ati n g t o 
1 0 0 % will b e pr e s e nt e d a s 1 0 0 %, wit h o ut d e ci m al pl a c e s  
  T a b ul ar di s pl a y of d at a f or m e di c al hi st or y, pri or/ c o n c o mit a nt m e di c ati o n s, a n d all t a b ul ar di s pl a y s 
of a d v er s e e v e nt d at a will b e pr e s e nt e d b y t h e b o d y s y st e m, tr e at m e nt cl a s s, or S O C wit h t h e 
C CI


St ati sti c al A n al y si s Pl a n f or I nt er v e nti o n al St u di e s  
S p o n s or: A L MI R A L L, S. A.; Pr ot o c ol N o.: M- 1 7 9 2 3- 3 0 
 
 
T hi s d o c u m e nt i s c o nfi d e nti al. 
S A P t e xt V er si o n: S A P t e xt v 2. 0 2 2 M A R 2 0 2 3 
C o ntr oll e d D o c u m e nt I D:  
, Eff e cti v e D at e 3 1- A u g- 2 0 2 0 
Fili n g r e q uir e m e nt s: T M F  
 
P a g e 6 5  of 7 3  
I N T E R N AL U S E 
hi g h e st o c c urr e n c e i n t h e a cti v e tr e at m e nt gr o u p i n d e cr e a si n g or d er, a s s u mi n g all t er m s ar e 
c o d e d. Wit hi n t h e b o d y s y st e m, dr u g cl a s s a n d S O C, m e di c al hi st or y ( b y pr ef err e d t er m), dr u g s ( b y 
A T C 1 c o d e), a n d a d v er s e e v e nt s ( b y pr ef err e d t er m) will b e di s pl a y e d i n d e cr e a si n g or d er. If 
i n ci d e n c e f or m or e t h a n 1 t er m i s i d e nti c al, t h e y will t h e n b e s ort e d al p h a b eti c all y. Mi s si n g 
d e s cri pti v e st ati sti c s or p- v al u e s w hi c h c a n n ot b e e sti m at e d will b e r e p ort e d a s ‘-’ 
  T h e p er c e nt a g e of p ati e nt s will n or m all y b e c al c ul at e d a s a pr o p orti o n of t h e n u m b er of p ati e nt s 
a s s e s s e d i n t h e r el e v a nt tr e at m e nt gr o u p ( or o v er all) f or t h e a n al y si s s et pr e s e nt e d. H o w e v er, 
c ar ef ul c o n si d er ati o n i s r e q uir e d i n m a n y i n st a n c e s d u e t o t h e c o m pli c at e d n at ur e of s el e cti n g t h e 
d e n o mi n at or, u s u all y t h e a p pr o pri at e n u m b er of p ati e nt s e x p o s e d. D et ail s will b e d e s cri b e d i n 
f o ot n ot e s or pr o gr a m mi n g n ot e s, a s n e c e s s ar y 
  F or c at e g ori c al s u m m ari e s ( n u m b er a n d p er c e nt a g e of p ati e nt s) w h er e a p ati e nt c a n b e i n cl u d e d i n 
m or e t h a n o n e c at e g or y, a f o ot n ot e or pr o gr a m mi n g n ot e will b e a d d e d d e s cri bi n g w h et h er t h e 
p ati e nt i s i n cl u d e d i n t h e s u m m ar y st ati sti c s f or all r el e v a nt c at e g ori e s or j u st 1 c at e g or y a s w ell a s 
t h e s el e cti o n crit eri a 
  W h er e a c at e g or y wit h a s u b h e a di n g ( s u c h a s s y st e m or g a n cl a s s) h a s t o b e s plit o v er m or e t h a n 
o n e p a g e, o ut p ut t h e s u b h e a di n g f oll o w e d b y ‘( c o nt)’ at t h e t o p of e a c h s u b s e q u e nt p a g e. T h e 
o v er all s u m m ar y st ati sti c s f or t h e s u b h e a di n g s h o ul d o nl y b e o ut p ut o n t h e fir st r el e v a nt p a g e 
1 3. 2. 5. 3. 
Li sti n g C o n v e nti o n s 
  Li sti n g s will b e s ort e d f or pr e s e nt ati o n i n or d er of tr e at m e nt gr o u p s a s a b o v e, p ati e nt n u m b er, 
vi sit/ c oll e cti o n d a y, a n d vi sit/ c oll e cti o n ti m e 
  Mi s si n g d at a will b e r e pr e s e nt e d o n p ati e nt li sti n g s a s eit h er a h y p h e n (‘-’) wit h a c orr e s p o n di n g 
f o ot n ot e (‘- = u n k n o w n or n ot e v al u at e d’), or a s ‘ N/ A’, wit h t h e f o ot n ot e ‘ N/ A = n ot a p pli c a bl e’, 
w hi c h e v er i s a p pr o pri at e 
  D at e s will b e pri nt e d i n S A S D A T E 9.f or m at (‘ D D _ M M M _ Y Y Y Y’: 0 1 J U L 2 0 0 0). Mi s si n g p orti o n s of 
d at e s will b e r e pr e s e nt e d o n p ati e nt li sti n g s a s d a s h e s (-- J U L 2 0 0 0). D at e s t h at ar e mi s si n g 
b e c a u s e t h e y ar e n ot a p pli c a bl e f or t h e p ati e nt will b e o ut p ut a s ‘ N/ A’, u nl e s s ot h er wi s e s p e cifi e d 
  All o b s er v e d ti m e v al u e s will b e pr e s e nt e d u si n g a 2 4- h o ur cl o c k H H: M M or H H: M M: S S f or m at 
( e. g., 1 1: 2 6: 4 5, or 1 1: 2 6). Ti m e will o nl y b e r e p ort e d if it w a s m e a s ur e d a s p art of t h e st u d y 
  U nit s will b e i n cl u d e d w h er e a v ail a bl e 
1 3. 2. 5. 4. 
Fi g ur e C o n v e nti o n s 
  U nl e s s ot h er wi s e s p e cifi e d, f or all fi g ur e s, st u d y vi sit s will b e di s pl a y e d o n t h e X- a xi s a n d e n d p oi nt 
( e. g., tr e at m e nt m e a n c h a n g e fr o m B a s eli n e) v al u e s will b e di s pl a y e d o n t h e Y- a xi s 
 
F o ot n ot e s 
  A s oli d li n e s p a n ni n g t h e m ar gi n s will s e p ar at e t h e b o d y of t h e d at a di s pl a y fr o m t h e f o ot n ot e s. 
  All f o ot n ot e s will b e l eft j u stifi e d wit h si n gl e-li n e s p a ci n g i m m e di at el y b el o w t h e s oli d li n e 
u n d er n e at h t h e d at a di s pl a y 
1 3. 2. 6. 
C CI


St ati sti c al A n al y si s Pl a n f or I nt er v e nti o n al St u di e s  
S p o n s or: A L MI R A L L, S. A.; Pr ot o c ol N o.: M- 1 7 9 2 3- 3 0 
 
 
T hi s d o c u m e nt i s c o nfi d e nti al. 
S A P t e xt V er si o n: S A P t e xt v 2. 0 2 2 M A R 2 0 2 3 
C o ntr oll e d D o c u m e nt I D:  
, Eff e cti v e D at e 3 1- A u g- 2 0 2 0 
Fili n g r e q uir e m e nt s: T M F  
 
P a g e 6 6  of 7 3  
I N T E R N AL U S E 
  F o ot n ot e s will al w a y s b e gi n wit h ‘ N ot e:’ if a n i nf or m ati o n al f o ot n ot e, or 1, 2, 3, et c. if a r ef er e n c e 
f o ot n ot e. E a c h n e w f o ot n ot e will st art o n a n e w li n e, w h er e p o s si bl e 
  P ati e nt s p e cifi c f o ot n ot e s ar e a v oi d e d, w h er e p o s si bl e 
  F o ot n ot e s will b e u s e d s p ari n gl y a n d a d d v al u e t o t h e T F L. If m or e t h a n si x li n e s of f o ot n ot e s ar e 
pl a n n e d, t h e n a c o v er p a g e i s str o n gl y r e c o m m e n d e d t o b e u s e d t o di s pl a y f o ot n ot e s, a n d o nl y 
t h o s e e s s e nti al t o c o m pr e h e n si o n of t h e d at a will b e r e p e at e d o n e a c h p a g e 
  T h e l a st li n e of t h e f o ot n ot e s e cti o n will b e a st a n d ar d s o ur c e li n e t h at i n di c at e s t h e n a m e of t h e 
pr o gr a m u s e d t o pr o d u c e t h e d at a di s pl a y, t h e d at e t h e pr o gr a m w a s r u n, a n d t h e li sti n g s o ur c e 
(i. e., ‘ Pr o gr a m : m y pr o gr a m. s a s  Li sti n g s o ur c e: 1 6. x. y. z’) 
  S o ur c e s a n d/ or cr o s s-r ef er e n c e s i n f o ot n ot e s will u s e t h e k e y w or d pr efi x (i n si n g ul ar f or m) f or e a c h 
r ef er e n c e a n d will b e s e p ar at e d b y a c o m m a w h e n m uti pl e cr o s s-r ef er e n c e s ar e di s pl a y e d 
E x a m pl e 
Li sti n g s o ur c e: Li sti n g 1 6. 2. 4. 1. 1, Li sti n g 1 6. 2. 4. 1. 2, Li sti n g 1 6. 2. 4. 2. 1 
C CI


St ati sti c al A n al y si s Pl a n f or I nt er v e nti o n al St u di e s  
S p o n s or: A L MI R A L L, S. A.; Pr ot o c ol N o.: M- 1 7 9 2 3- 3 0 
 
 
T hi s d o c u m e nt i s c o nfi d e nti al. 
S A P t e xt V er si o n: S A P t e xt v 2. 0 2 2 M A R 2 0 2 3 
C o ntr oll e d D o c u m e nt I D:  
, Eff e cti v e D at e 3 1- A u g- 2 0 2 0 
Fili n g r e q uir e m e nt s: T M F  
 
P a g e 6 7  of 7 3  
I N T E R N AL U S E 
  
Q u alit y C o ntr ol 
S A S pr o gr a m s ar e d e v el o p e d t o pr o d u c e o ut p ut s u c h a s a n al y si s d at a s et s, s u m m ar y t a bl e s, d at a 
li sti n g s, fi g ur e s or st ati sti c al a n al y s e s. A n o v er vi e w of t h e d e v el o p m e nt of pr o gr a m s i s d et ail e d i n  
 
 D e v el o pi n g St ati sti c al Pr o gr a m s S O P ( 3 9 0 7) . 
 D e v el o pi n g St ati sti c al Pr o gr a m s S O P ( 3 9 0 7), C o n d u cti n g t h e Tr a n sf er of Bi o st ati sti c al 
D eli v er a bl e s S O P ( 3 9 0 8) a n d t h e S A S Pr o gr a m mi n g a n d V ali d ati o n Pl a n d e s cri b e s t h e q u alit y c o ntr ol 
pr o c e d ur e s t h at ar e p erf or m e d f or all S A S pr o gr a m s a n d o ut p ut. Q u alit y c o ntr ol i s d efi n e d h er e a s t h e 
o p er ati o n al t e c h ni q u e s a n d a cti viti e s u n d ert a k e n t o v erif y t h at t h e S A S pr o gr a m s pr o d u c e t h e o ut p ut b y 
c h e c ki n g f or t h eir l o gi c, effi ci e n c y a n d c o m m e nti n g a n d b y r e vi e w of t h e pr o d u c e d o ut p ut.  
1 4. 
C CI
P P D
P P D


St ati sti c al A n al y si s Pl a n f or I nt er v e nti o n al St u di e s  
S p o n s or: A L MI R A L L, S. A.; Pr ot o c ol N o.: M- 1 7 9 2 3- 3 0 
 
 
T hi s d o c u m e nt i s c o nfi d e nti al. 
S A P t e xt V er si o n: S A P t e xt v 2. 0 2 2 M A R 2 0 2 3 
C o ntr oll e d D o c u m e nt I D:  
, Eff e cti v e D at e 3 1- A u g- 2 0 2 0 
Fili n g r e q uir e m e nt s: T M F  
 
P a g e 6 8  of 7 3  
I N T E R N AL U S E 
  
A p p e n di c e s 
A p p e n di x 1. St u d y Vi sit M a p pi n g f or Pr urit u s N R S a n d Sl e e p-l o s s Di ar y a n d P O E M 
 
Pr urit u s N R S a n d sl e e p l o s s ar e c oll e ct e d a s a d ail y di ar y; e ntri e s will b e m a p p e d t o st u d y w e e k b y t h e 
f oll o wi n g: 
W e e k 
St art D a y 
E n d D a y 
B a s eli n e 
D at e of Fir st I nj e cti o n a  - 7 
D at e of Fir st I nj e cti o n- 1 
W e e k 2 
W e e k 2 Vi sit D at e – 7 
W e e k 2 Vi sit D at e - 1  
W e e k 4 
W e e k 4 Vi sit D at e – 7 
W e e k 4 Vi sit D at e – 1 
W e e k 6 
W e e k 6 Vi sit D at e – 7 
W e e k 6 Vi sit D at e - 1  
W e e k 8 
W e e k 8 Vi sit D at e – 7 
W e e k 8 Vi sit D at e - 1  
W e e k 1 0 
W e e k 1 0 Vi sit D at e – 7 
W e e k 1 0 Vi sit D at e - 1  
W e e k 1 2 
W e e k 1 2 Vi sit D at e – 7 
W e e k 1 2 Vi sit D at e – 1 
W e e k 1 4 
W e e k 1 4 Vi sit D at e – 7 
W e e k 1 4 Vi sit D at e - 1  
W e e k 1 6 
W e e k 1 6 Vi sit D at e – 7 
W e e k 1 6 Vi sit D at e – 1 
W e e k 2 0 
W e e k 2 0 Vi sit D at e – 7 
W e e k 2 0 Vi sit D at e – 1 
W e e k 2 4 
W e e k 2 4 Vi sit D at e – 7 
W e e k 2 4 Vi sit D at e – 1 
W e e k 2 8 
W e e k 2 8 Vi sit D at e – 7 
W e e k 2 8 Vi sit D at e – 1 
W e e k 3 2 
W e e k 3 2 Vi sit D at e – 7 
W e e k 3 2 Vi sit D at e – 1 
W e e k 3 6 
W e e k 3 6 Vi sit D at e – 7 
W e e k 3 6 Vi sit D at e – 1 
W e e k 4 0 
W e e k 4 0 Vi sit D at e – 7 
W e e k 4 0 Vi sit D at e – 1 
W e e k 4 4 
W e e k 4 4 Vi sit D at e – 7 
W e e k 4 4 Vi sit D at e – 1 
W e e k 4 8 
W e e k 4 8 Vi sit D at e – 7 
W e e k 4 8 Vi sit D at e – 1 
W e e k 5 2 
W e e k 5 2 Vi sit D at e – 7 
W e e k 5 2 Vi sit D at e – 1 
a  If d at e of fir st i nj e cti o n i s mi s si n g, t h e r a n d o mi z ati o n d at e will b e u s e d. 
 
If m ulti pl e a s s e s s m e nt s o n a si n gl e d a y ar e pr e s e nt, u s e t h e fir st a s s e s s m e nt. If a n a s s e s s m e nt c o ul d 
b e m a p p e d t o diff er e nt w e e k s, it will b e m a p p e d t o t h e e arli er w e e k. D eri v ati o n of t h e w e e kl y m e a n 
1 5. 
C CI


St ati sti c al A n al y si s Pl a n f or I nt er v e nti o n al St u di e s  
S p o n s or: A L MI R A L L, S. A.; Pr ot o c ol N o.: M- 1 7 9 2 3- 3 0 
 
 
T hi s d o c u m e nt i s c o nfi d e nti al. 
S A P t e xt V er si o n: S A P t e xt v 2. 0 2 2 M A R 2 0 2 3 
C o ntr oll e d D o c u m e nt I D:  
 Eff e cti v e D at e 3 1- A u g- 2 0 2 0 
Fili n g r e q uir e m e nt s: T M F  
 
P a g e 6 9  of 7 3  
I N T E R N AL U S E 
s c or e s f or Pr urit u s N R S a n d Sl e e p-l o s s c o ul d b e f o u n d i n t h e t a bl e i n t h e s e cti o n 9. 2.  D efi niti o n s f or 
Effi c a c y E n d p oi nt s. If at l e a st 1 of t h e 7 d a y s c o nt ai n s n o n- mi s si n g d ail y a s s e s s m e nt s, p o st- b a s eli n e 
w e e kl y s c or e will b e c al c ul at e d u si n g pr or at e d w e e kl y a v er a g e. If t h e r a n g e of 7 d a y s ar e all mi s si n g 
d ail y a s s e s s m e nt s, t h e n t h e w e e kl y s c or e i s mi s si n g. 
P O E M ar e c oll e ct e d e v er y w e e k vi a e Di ar y, t h e vi sit w e e k m a p pi n g will f oll o w t h e f oll o wi n g r ul e: t h e 
l a st c oll e ct e d P O E M d at a b ef or e t h e vi sit d at e w o ul d b e u s e d, t h e e v al u ati o n wi n d o w i s i nj e cti o n d at e - 
7 t o i nj e cti o n d at e – 1 f or b a s eli n e a n d a s s e s s m e nt d at e - 7 t o a s s e s s m e nt d at e – 1 f or p o st- b a s eli n e. 
F or e x a m pl e, if a p ati e nt g et s a n i nj e cti o n/ a s s e s s m e nt o n t h e 1 4 t h, w e w o ul d u s e t h e s c al e c o m pl et e d 
i n b et w e e n t h e 1 3t h a n d t h e 7t h. 
 
 
 
 
C CI


St ati sti c al A n al y si s Pl a n f or I nt er v e nti o n al St u di e s  
S p o n s or: A L MI R A L L, S. A.; Pr ot o c ol N o.: M- 1 7 9 2 3- 3 0 
 
 
T hi s d o c u m e nt i s c o nfi d e nti al. 
S A P t e xt V er si o n: S A P t e xt v 2. 0 2 2 M A R 2 0 2 3 
C o ntr oll e d D o c u m e nt I D:  
, Eff e cti v e D at e 3 1- A u g- 2 0 2 0 
Fili n g r e q uir e m e nt s: T M F  
 
P a g e 7 0  of 7 3  
I N T E R N AL U S E 
A p p e n di x 2. D et ail s of C o m bi ni n g E sti m at e s a n d T e st St ati sti c s f or C at e g ori c al E n d p oi nt s wit h M ulti pl e 
I m p ut ati o n 
F oll o wi n g t h e i m pl e m e nt ati o n of M C M C- MI i m p ut ati o n a s s p e cifi e d i n S e cti o n エラー
エラー! 参照元が見つか
りません。
参照元が見つか
りません。, t h e d at a s et s wit h i m p ut ati o n s s h o ul d b e s et t o g et h er a n d s ort e d b y i m p ut ati o n n u m b er. 
T h e f oll o wi n g s e cti o n s d e s cri b e t h e pr o c e s s e s f or c o m bi ni n g i nf er e n c e s f or t h e i n di vi d u al i m p ut e d d at a 
s et s i nt o o n e i nf er e n c e f or r e p orti n g. All c al c ul ati o n s ar e p erf or m e d i n S A S s oft w ar e v er si o n 9. 4 or 
hi g h er.  
S u m m ari z e U n a dj u st e d R e s p o n s e R at e 
T h e r e s p o n s e r at e s, o v er all a n d b y tr e at m e nt ar m, a n d t h eir a s s o ci at e d st a n d ar d err or s ( S E) ar e 
c o m p ut e d f or e a c h i m p ut e d d at a s et u si n g P R O C F R E Q wit h t h e ri s k diff o pti o n s p e cifi e d f or t h e 
a p pr o pri at e c ol u m n i n t h e T A B L E S st at e m e nt. T h e r e s p o n s e r at e s a n d S E s fr o m t h e r e s ulti n g o ut p ut 
ar e c o m bi n e d a cr o s s t h e i m p ut e d d at a s et s u si n g P R O C MI A N A L Y Z E, s e p ar at el y f or e a c h ar m a n d 
t h e o v er all gr o u p. 
N ot e t h at t h e e sti m at e a n d 9 5 % c o nfi d e n c e i nt er v al ( CI) b o u n d s o ut p ut b y P R O C MI A N A L Y Z E ar e 
p er c e nt s (i. e., t h e y ar e i n t er m s of t h e r e s p o n s e r at e). T o o bt ai n t h e n u m b er of r e s p o n d er s, t h e 
e sti m at e d p er c e nt a g e i s m ulti pli e d b y t h e n u m b er of i n di vi d u al s i n t h e a n al y si s p o p ul ati o n a n d r o u n d e d 
t o t h e n e ar e st i nt e g er. 
C o m p ut e Str atifi e d M e a s ur e s of A s s o ci ati o n 
T h e c o m m o n ri s k diff er e n c e, c o m m o n o d d s r ati o ( O R), a n d C o c hr a n- M a nt el- H a e n s z el ( C M H) t e st 
st ati sti c ar e c o m p ut e d f or e a c h i m p ut e d d at a s et u si n g P R O C F R E Q wit h t h e ri s k diff o pti o n f or t h e 
a p pr o pri at e c ol u m n (f or ri s k diff er e n c e) a n d t h e c m h  o pti o n (f or o d d s r ati o a n d C M H t e st st ati sti c) 
s p e cifi e d i n t h e T A B L E S st at e m e nt. E a c h of t h e s e a n al y s e s ar e str atifi e d b y g e o gr a p hi c r e gi o n, a g e 
gr o u p, a n d b a s eli n e di s e a s e s e v erit y vi a i n cl u si o n of t h e s e v ari a bl e s i n t h e T A B L E S st at e m e nt wit h t h e 
tr e at m e nt a n d o ut c o m e v ari a bl e s.  
N ot e t h at t h e P R O C F R E Q o ut p ut c orr e s p o n di n g t o t h e M a nt el- H a e n s z el m et h o d i s u s e d f or t h e ri s k 
diff er e n c e, a n d t h e o ut p ut c orr e s p o n di n g t o t h e G e n er al A s s o ci ati o n st ati sti c i s u s e d f or t h e C M H 
st ati sti c. P R O C MI A N A L Y Z E i s t h e n c all e d s e p ar at el y f or e a c h of t h e s e m e a s ur e s, wit h f urt h er d et ail s 
i n t h e s e cti o n s b el o w. 
C o m m o n Ri s k Diff er e n c e 
N o tr a n sf or m ati o n i s n e c e s s ar y b ef or e u si n g P R O C MI A N A L Y Z E t o c o m bi n e t h e ri s k diff er e n c e 
e sti m at e s a n d t h eir a s s o ci at e d S E s a cr o s s t h e i m p ut e d d at a s et s. T hi s pr o c e d ur e o ut p ut s a n e sti m at e 
of t h e c o m m o n ri s k diff er e n c e a n d t h e a s s o ci at e d 9 5 % CI b o u n d s. 
C o m m o n O d d s R ati o 
T h e O R fr o m e a c h i m p ut e d d at a s et i s fir st tr a n sf or m e d u si n g t h e n at ur al l o g arit h m. T h e S E f or e a c h 
l o g O R (𝑇𝑜
) i s d eri v e d fr o m t h e O R 9 5 % CI b o u n d s (𝑡𝑎
, 𝑙𝑒
) a c c or di n g t o t h e f oll o wi n g 
e q u ati o n: 𝑥𝑝
= (l n (𝑜𝑠
) −   l n (𝑢𝑟
)) /( 2 ∗ 1. 9 6). T h e l o g O R a n d d eri v e d S E ar e t h e n c o m bi n e d 
u si n g P R O C MI A N A L Y Z E, w hi c h o ut p ut s a c o m bi n e d e sti m at e of t h e l o g O R a n d t h e a s s o ci at e d 9 5 % 
CI. Fi n all y, t h e s e m e a s ur e s c a n b e e x p o n e nti at e d t o tr a n sf or m t h e m b a c k t o t h e O R s c al e. 
C CI


St ati sti c al A n al y si s Pl a n f or I nt er v e nti o n al St u di e s  
S p o n s or: A L MI R A L L, S. A.; Pr ot o c ol N o.: M- 1 7 9 2 3- 3 0 
 
 
T hi s d o c u m e nt i s c o nfi d e nti al. 
S A P t e xt V er si o n: S A P t e xt v 2. 0 2 2 M A R 2 0 2 3 
C o ntr oll e d D o c u m e nt I D:  
, Eff e cti v e D at e 3 1- A u g- 2 0 2 0 
Fili n g r e q uir e m e nt s: T M F  
 
P a g e 7 1  of 7 3  
I N T E R N AL U S E 
C o c hr a n- M a nt el- H a e n s z el T e st 
T h e C M H t e st st ati sti c ( 𝑇𝑜𝑡) fr o m e a c h i m p ut e d d at a s et i s tr a n sf or m e d u si n g t h e Wil s o n- Hilf ert y 
tr a n sf or m ati o n a n d st a n d ar di z e d s o t h at it h a s a p pr o xi m at el y a st a n d ar d N or m al di stri b uti o n ( R atit c h 
2 0 1 3). I n p arti c ul ar, t h e tr a n sf or m e d C M H st ati sti c i s c o m p ut e d a s f oll o w s: 𝑎𝑙𝑒
=
(
)
(
∗
)
∗
, 
w h er e 𝑥𝑝 i s t h e d e gr e e s of fr e e d o m of t h e C M H st ati sti c. T h e n t h e S E f or e a c h 𝑜𝑠𝑢
 i s 1, a n d 
P R O C MI A N A L Y Z E i s u s e d t o o ut p ut a c o m bi n e d e sti m at e of t h e tr a n sf or m e d C M H st ati sti c. N ot e t h at 
t h e t w o- si d e d p- v al u e o ut p ut b y P R O C MI A N A L Y Z E i s n ot u s e d dir e ctl y, b ut i n st e a d t h e o n e- si d e d p-
v al u e i s c o m p ut e d m a n u all y u si n g b ot h t h e t st ati sti c a n d t w o- si d e d p- v al u e o ut p ut b y P R O C 
MI A N A L Y Z E: if t st ati sti c i s gr e at er t h a n 0, t h e n o n e- si d e d p- v al u e i s c o m p ut e d a s h alf of t h e t w o- si d e d 
p- v al u e; ot h er wi s e, t h e o n e- si d e d p- v al u e i s c o m p ut e d a s 1 - h alf of t h e t w o- si d e d p- v al u e. T h e 
r e s ulti n g o n e- si d e p- v al u e i s r e p ort e d a s t h e p o ol e d p- v al u e f or t h e C M H t e st.  
 
 
 
C CI


St ati sti c al A n al y si s Pl a n f or I nt er v e nti o n al St u di e s  
S p o n s or: A L MI R A L L, S. A.; Pr ot o c ol N o.: M- 1 7 9 2 3- 3 0 
 
 
T hi s d o c u m e nt i s c o nfi d e nti al. 
S A P t e xt V er si o n: S A P t e xt v 2. 0 2 2 M A R 2 0 2 3 
C o ntr oll e d D o c u m e nt I D:  
, Eff e cti v e D at e 3 1- A u g- 2 0 2 0 
Fili n g r e q uir e m e nt s: T M F  
 
P a g e 7 2  of 7 3  
I N T E R N AL U S E 
 
A p p e n di x 3. D efi niti o n of R e s c u e M e di c ati o n s 
T hi s a p p e n di x pr o vi d e s t h e d efi niti o n of r e s c u e m e di c ati o n s f or t hi s st u d y, i n cl u di n g t o pi c al a n d s y st e mi c 
tr e at m e nt s d efi n e d a s f oll o w s: 
1.  T o pi c al At o pi c D er m atiti s Tr e at m e nt (i n cl u di n g t o pi c al c orti c o st er oi d s, T CI, a n d 
cri s a b or ol e) 
R o ut e of t o pi c al tr e at m e nt s i n cl u d e s: T o pi c al a n d Tr a n s d er m al. 
T o pi c al C orti c o st er oi d s ( T C S): A T C c o d e i s D 0 7 
Hi g h or Ultr a Hi g h P ot e n c y T C S: a s p er e C R F cl a s sifi c ati o n  
T o pi c al c al ci n e uri n i n hi bit or ( T CI): Pr ef err e d T er m i n cl u d e s: T A C R O LI M U S, PI M E C R O LI M U S 
Cri s a b or ol e: Pr ef err e d T er m i n cl u d e s: C RI S A B O R O L E 
 
2.  S y st e mi c At o pi c D er m atiti s Tr e at m e nt (i n cl u di n g s y st e mi c c orti c o st er oi d s, 
i m m u n o s u p pr e s s a nt, bi ol o gi c s a n d p h ot ot h er a p y/ p h ot o c h e m ot h er a p y) 
R o ut e of s y st e mi c tr e at m e nt s a d mi ni str ati o n i n cl u d e s: Or al, I ntr a- Art eri al, I ntr a m u s c ul ar, I ntr a p erit o n e al, 
I ntr a v e n o u s, S u b c ut a n e o u s, Tr a n s d er m al. ( T hi s c o n diti o n a p pli e s t o t h e f oll o wi n g c at e g ori e s e x c e pt f or 
p h ot ot h er a pi e s.) 
 
S y st e mi c C orti c o st er oi d s: A T C c o d e i s H 0 2 
I m m u n o s u p pr e s s a nt: D efi n e d a s: A T C 2 i s L 0 4 or Pr ef err e d t er m s of A br o citi ni b or R u x oliti ni b or 
U p a d a citi ni b or B ari citi ni b  
Bi ol o gi c s: D efi n e d a s f oll o wi n g Pr ef err e d t er m s:  
I nfli xi m a b, I nfli xi m a b u m, Et a n er c e pt, Et a n er c e pt u m, A d ali m u m a b, A d ali m u m a b u m, C ert oli z u m a b, 
C ert oli z u m a b u m, C ert oli z u m a b p e g ol, G oli m u m a b, G oli m u m a b u m, O z or ali z u m a b, Af eli m o m a b, 
Af eli m o m a b u m, T u m or N e cr o si s F a ct or Al p h a ( T N F-) I n hi bit or s, T a b al u m a b, Tr e g ali z u m a b, A n a ki nr a, 
B a sili xi m a b, B a sili xi m a b u m, D a cli z u m a b, D a cli z u m a b u m, T o cili z u m a b, T o cili z u m a b u m, M e p oli z u m a b, 
M e p oli z u m a b u m, Ril o n a c e pt, Ril o n a c e pt u m, U st e ki n u m a b, C a n a ki n u m a b, Bri a ki n u m a b, F e z a ki n u m a b, 
Sir u k u m a b, S aril u m a b, L e bri ki z u m a b, S e c u ki n u m a b, Ol o ki z u m a b, G e v o ki z u m a b, Br o d al u m a b, L a d ari xi n, 
I x e ki z u m a b, D u pil u m a b, Til dr a ki z u m a b, Til dr a ki z u m a b u m, R e sli z u m a b, R e sli z u m a b u m, G u s el k u m a b, 
G u s el k u m a b u m, Ol a m ki c e pt, Fl eti k u m a b, Bi m e ki z u m a b, Miri ki z u m a b, Ri s a n ki z u m a b, A b at a c e pt, 
Li g eli z u m a b, V e d oli z u m a b, B eli m u m a b, N e m oli z u m a b, Tr al o ki n u m a b, O m ali z u m a b, B e nr ali z u m a b 
P h ot ot h er a p y or P h ot o c h e m ot h er a p y: 
C CI


St ati sti c al A n al y si s Pl a n f or I nt er v e nti o n al St u di e s  
S p o n s or: A L MI R A L L, S. A.; Pr ot o c ol N o.: M- 1 7 9 2 3- 3 0 
 
 
T hi s d o c u m e nt i s c o nfi d e nti al. 
S A P t e xt V er si o n: S A P t e xt v 2. 0 2 2 M A R 2 0 2 3 
C o ntr oll e d D o c u m e nt I D:  
, Eff e cti v e D at e 3 1- A u g- 2 0 2 0 
Fili n g r e q uir e m e nt s: T M F  
 
P a g e 7 3  of 7 3  
I N T E R N AL U S E 
Pr o gr a m mi n g s e ar c h of m e di c ati o n n a m e ( a ct u al t er m or pr ef err e d t er m) c o nt ai n s ‘ p h ot o’ t h e n m e di c al s t o 
m a n u all y r e vi e w t o c o nfir m w h et h er t h e m e di c ati o n i n q u e sti o n i s i n d e e d ‘ P h ot ot h er a p y’ or 
‘ P h ot o c h e m ot h er a p y’ 
 
 
C CI


3 9 0 3 A. 0 2 _ St ati sti c al _ A n al y si s _ Pl a n _ M- 1 7 9 2 3- 3
0 _ v 2. 0 2 2 M ar 2 0 2 3
Fi n al A u dit R e p ort
2 0 2 3- 0 3- 2 3
Cr e at e d:
2 0 2 3- 0 3- 2 2
B y:
St at u s:
Si g n e d
Tr a n s a cti o n I D:
" 3 9 0 3 A. 0 2 _ St ati sti c al _ A n al y si s _ Pl a n _ M- 1 7 9 2 3- 3 0 _ v 2. 0 2 2 M ar 2 0
2 3" Hi st or y
D o c u m e nt cr e at e d b y 
2 0 2 3- 0 3- 2 2 - 1 0: 2 5: 4 3 P M G M T
Si g n er
 e nt er e d n a m e at si g ni n g a s 
2 0 2 3- 0 3- 2 2 - 1 0: 3 1: 3 0 P M G M T
 a ut h e nti c at e d wit h A d o b e A cr o b at Si g n.
2 0 2 3- 0 3- 2 2 - 1 0: 3 1: 3 2 P M G M T
D o c u m e nt e- si g n e d b y 
Si g ni n g r e a s o n: I a m t h e a ut h or
Si g n at ur e D at e: 2 0 2 3- 0 3- 2 2 - 1 0: 3 1: 3 2 P M G M T - Ti m e S o ur c e: s er v er
D o c u m e nt e m ail e d t o 
f or si g n at ur e
2 0 2 3- 0 3- 2 2 - 1 0: 3 1: 3 4 P M G M T
E m ail vi e w e d b y 
2 0 2 3- 0 3- 2 3 - 8: 2 1: 0 7 A M G M T
Si g n er 
e nt er e d n a m e at si g ni n g a s 
2 0 2 3- 0 3- 2 3 - 8: 2 1: 5 4 A M G M T
a ut h e nti c at e d wit h A d o b e A cr o b at Si g n.
2 0 2 3- 0 3- 2 3 - 8: 2 1: 5 6 A M G M T
D o c u m e nt e- si g n e d b y 
Si g ni n g r e a s o n: I a m t h e r e vi e w er
Si g n at ur e D at e: 2 0 2 3- 0 3- 2 3 - 8: 2 1: 5 6 A M G M T - Ti m e S o ur c e: s er v er
6e 
6e 
6e 
6e 
I 
P o w er e d b y 
A d o be 
A cr o b at Si g n 
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D


D o c u m e nt e m ail e d t o
 f or si g n at ur e
2 0 2 3- 0 3- 2 3 - 8: 2 2: 0 0 A M G M T
E m ail vi e w e d b y 
2 0 2 3- 0 3- 2 3 - 9: 2 2: 3 5 A M G M T
Si g n er 
 e nt er e d n a m e at si g ni n g a s 
2 0 2 3- 0 3- 2 3 - 9: 2 3: 0 9 A M G M T
 a ut h e nti c at e d wit h A d o b e A cr o b at Si g n.
2 0 2 3- 0 3- 2 3 - 9: 2 3: 1 1 A M G M T
D o c u m e nt e- si g n e d b y Ni c
Si g ni n g r e a s o n: I a m t h e r e vi e w er
Si g n at ur e D at e: 2 0 2 3- 0 3- 2 3 - 9: 2 3: 1 1 A M G M T - Ti m e S o ur c e: s er v er
D o c u m e nt e m ail e d t o 
 f or si g n at ur e
2 0 2 3- 0 3- 2 3 - 9: 2 3: 1 4 A M G M T
E m ail vi e w e d b y 
2 0 2 3- 0 3- 2 3 - 3: 4 9: 1 1 P M G M T
a ut h e nti c at e d wit h A d o b e A cr o b at Si g n.
2 0 2 3- 0 3- 2 3 - 3: 5 1: 1 1 P M G M T
D o c u m e nt e- si g n e d b y 
Si g ni n g r e a s o n: I a m t h e a p pr o v er
Si g n at ur e D at e: 2 0 2 3- 0 3- 2 3 - 3: 5 1: 1 1 P M G M T - Ti m e S o ur c e: s er v er
A gr e e m e nt c o m pl et e d.
2 0 2 3- 0 3- 2 3 - 3: 5 1: 1 1 P M G M T
N a m e s a n d e m ail a d dr e s s e s ar e e nt er e d i nt o t h e A cr o b at Si g n s er vi c e b y A cr o b at Si g n u s er s a n d ar e u n v erifi e d u nl e s s ot h er wi s e n ot e d.
6 e 
6 e 
6 e 
I 
P o w er e d b y 
A d o be 
A cr o b at Si g n 
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D