Conditions: Common Variable Immunodeficiency (CVID), APDS / PASLI
Keywords: APDS PASLI PI3Kdelta
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 37
Healthy volunteers: no

Brief summary:
This study was designed to explore CDZ173, a selective PI3Kδ inhibitor, in patients with genetically activated PI3Kδ, i.e., patients with Activated phosphoinositide 3-kinase delta syndrome/ p110δ-activating mutation causing senescent T cells, lymphadenopathy and immunodeficiency (APDS/PASLI).

The study consisted of two parts: Part I was the open label part designed to establish the safety and pharmacokinetics of CDZ173 in the target population, as well as to select the optimal dose to be tested in Part II. Part II was designed to assess efficacy and safety of CDZ173 in the target population.

Detailed description:
This was a 2-part (Part I and Part II), Phase 2/3, multi-center study in subjects with APDS/PASLI.

Part I of the study was a non-randomized, open-label, within-patient up-titration dose-finding part in 6 participants with APDS/PASLI. The starting dose was 10 mg followed by 30 mg and 70 mg b.i.d. for 4 weeks at each dose level respectively. Part I consisted of three distinct study periods:

Screening / Baseline visit (Day -50 to Day-1): This period was used to confirm that the study inclusion and exclusion criteria were met. Participants who were deemed eligible for enrollment into the study attended the clinic on Day -1 for baseline assessments prior to randomization.

Treatment period (Day 1 to Day 84): Participants started treatment on Day 1 receiving 10 mg of CDZ173 twice daily (b.i.d.) until Day 28. After a continuous safety review and a review of PK and PD data, participants assessed as satisfactory proceeded to the next dose levels: from Day 29 to Day 56 participants received 30 mg CDZ173 b.i.d. and from Day 57 to Day 84, if assessed as satisfactory, participants received 70 mg CDZ173 b.i.d.

Follow-up (Day 85-114): After completion of the treatment period, participants were followed-up for safety for four weeks until Day 114.

Part II was a randomized, subject, investigator and sponsor-blinded, placebo-controlled, fixed dose part investigating 31 participants with APDS/PASLI. The CDZ173 dose used in this Part was selected based on safety, tolerability, PK and PD data from Part I. Part II consisted of three distinct study periods:

Screening / Baseline visit (Day -50 to Day-1): This period was used to confirm that the study inclusion and exclusion criteria were met. Participants who were deemed eligible for enrollment into the study attended the clinic on Day -1 for baseline assessments prior to randomization.

Treatment period (Day 1 to Day 85): On Day 1, Participants were randomized to one of the two treatment groups in a 2:1 ratio to receive either 70 mg CDZ173 b.i.d. or matching placebo until Day 85.

Follow-up (Day 86-115): On Day 86, a subset of participants rolled over to CCDZ173X2201E1 extension study and were not followed up for safety after end of treatment in CCDZ173X2201. Participants, who did not directly roll over to the extension study, after last treatment dose were followed-up for safety for four weeks until Day 115.

Arms:
arm 1: Participants consecutively received CDZ173 10 mg twice a day (b.i.d.) from Day 1 to Day 28, CDZ173 30 mg b.i.d. from Day 29 to Day 56 and CDZ173 70 mg b.i.d. from Day 57 to Day 84. arm 2: Participants received CDZ173 70 mg b.i.d. from Day 1 to Day 85. arm 3: Participants received Placebo b.i.d. from Day 1 to Day 85.

Interventions: intervention 1: CDZ173 intervention 2: Placebo
Intervention descriptions: intervention 1: CDZ173 10 and 70 mg capsules for oral administration. intervention 2: Placebo capsules for oral administration

Protocol document:
Prot_000.pdf: 
Novartis Institutes for BioMedical Research
CDZ173
Clinical Trial Protocol CCDZ173X2201 / NCT02435173
An open-label, non-randomized, within-patient dose-finding 
study followed by a randomized, subject, investigator and 
sponsor-blinded placebo controlled study to assess the 
efficacy and safety of CDZ173 (Leniolisib) in patients with 
APDS/PASLI (Activated phosphoinositide 3-kinase delta 
syndrome/ p110δ-activating mutation causing senescent T 
cells, lymphadenopathy and immunodeficiency)
Document type:
Amended Protocol Version
EUDRACT number:
2014-003876-22
Version number:
v10 (Clean)
Development phase:
II/III
Release date:
13-Oct-2020
Property of Novartis
Confidential
May not be used, divulged, published or otherwise disclosed
without the consent of Novartis


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Site Operations Manual (SOM)
A Site Operations Manual (SOM) accompanies this protocol, providing the operational details 
for study conduct.
Notification of serious adverse events
Refer to Section 9.2 of the protocol for definitions and reporting requirements for Serious 
Adverse Events (within 24 hours after awareness of the SAE to the local Novartis Chief Medical 
Office and Patient Safety Department and notify the Clinical Trial Leader).
Contact information is listed in the SOM.


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Table of contents
Site Operations Manual (SOM)...........................................................................................2
Notification of serious adverse events.................................................................................2
Table of contents .................................................................................................................3
List of tables ........................................................................................................................7
List of figures ......................................................................................................................7
List of abbreviations............................................................................................................8
Pharmacokinetic definitions and symbols.........................................................................12
Glossary of terms...............................................................................................................14
Protocol synopsis...............................................................................................................33
1
Introduction .......................................................................................................................37
1.1
Background............................................................................................................37
1.1.1
Relevant data summary.........................................................................38
1.2
Data from Study Part I...........................................................................................44
1.3
Study purpose ........................................................................................................45
2
Study objectives.................................................................................................................45
2.1
Primary objective(s)...............................................................................................45
2.2
Secondary objective(s)...........................................................................................46
2.3
Exploratory objective(s) ........................................................................................47
3
Investigational plan ...........................................................................................................48
3.1
Study design...........................................................................................................48
3.1.1
Part I......................................................................................................48
3.1.2
Part II.....................................................................................................49
3.2
Rationale of dose/regimen, duration of treatment .................................................52
3.2.1
Part I......................................................................................................52
3.2.2
Part II.....................................................................................................54
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3.3
Rationale for choice of comparator .......................................................................54
3.4
Purpose and timing of interim analyses/design adaptations..................................55
3.5
Risks and benefits..................................................................................................55
4
Population..........................................................................................................................58
4.1
Inclusion criteria ....................................................................................................59
4.2
Exclusion criteria...................................................................................................59
5
Restrictions for Study Subjects .........................................................................................62
5.2
Prohibited treatment...............................................................................................62
5.2.1
Drugs that are prohibited.......................................................................62
6
Treatment...........................................................................................................................66
6.1
Study treatment......................................................................................................66
6.1.1
Investigational treatment.......................................................................66
6.2
Treatment arms......................................................................................................66
6.3
Permitted dose adjustments and interruptions of study treatment.........................67
6.4
Treatment assignment............................................................................................67
6.5
Treatment blinding.................................................................................................67
6.6
Emergency breaking of assigned treatment code ..................................................68
6.7
Treatment exposure and compliance .....................................................................68
6.8
Recommended treatment of adverse events ..........................................................68
6.9
Concomitant treatment...........................................................................................70
7
Discontinuation and study completion ..............................................................................70
7.1
Discontinuation of study treatment........................................................................70
7.2
Study completion and post-study treatment ..........................................................71
7.2.1
Lost to follow-up...................................................................................71
7.3
Withdrawal of consent...........................................................................................71
7.4
Study stopping rules ..............................................................................................72
7.5
Early study termination..........................................................................................72
8
Procedures and assessments ..............................................................................................73
8.1
Informed consent procedures.................................................................................78
8.2
Subject demographics/other baseline characteristics.............................................78
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8.3
Efficacy / Pharmacodynamics ...............................................................................79
8.3.1
Efficacy .................................................................................................79
8.3.2
Pharmacodynamic assessments.............................................................80
8.3.3
Patient-Reported Outcome....................................................................81
8.4
Safety.....................................................................................................................82
8.4.1
Physical examination ............................................................................82
8.4.2
Vital signs..............................................................................................83
8.4.3
Height and weight .................................................................................83
8.4.5
Laboratory evaluations..........................................................................83
8.4.6
Electrocardiogram (ECG) .....................................................................84
8.5
Pharmacokinetics...................................................................................................85
8.6
Other assessments..................................................................................................85
8.6.2
Exploratory Biomarker assessments .....................................................86
8.7
Use of residual biological samples ........................................................................88
9
Safety monitoring..............................................................................................................88
9.1
Adverse events.......................................................................................................88
9.2
Serious adverse event reporting.............................................................................90
9.2.1
Definition of SAE .................................................................................90
9.2.2
SAE reporting........................................................................................91
9.3
Infection Monitoring..............................................................................................92
9.4
Liver safety monitoring .........................................................................................92
9.5
Renal safety monitoring.........................................................................................95
9.6
Pregnancy reporting...............................................................................................96
9.7
Early phase safety monitoring ...............................................................................97
10 Data review and database management.............................................................................97
10.1
Site monitoring ......................................................................................................97
10.2
Data collection.......................................................................................................98
10.3
Data Monitoring Committee..................................................................................99
10.4
Adjudication Committee........................................................................................99
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11 Data analysis......................................................................................................................99
11.1
Analysis sets ..........................................................................................................99
11.2
Subject demographics and other baseline characteristics......................................99
11.3
Treatments (study drug, rescue medication, other concomitant therapies, 
compliance)............................................................................................................99
11.4
Analysis of the primary variable(s) .....................................................................100
11.4.1
Variable(s)...........................................................................................100
11.4.2
Statistical model, hypothesis, and method of analysis........................100
11.4.3
Handling of missing values/censoring/discontinuations.....................102
11.4.4
Supportive analyses.............................................................................102
11.5
Analysis of secondary and exploratory variables ................................................103
11.5.1
Efficacy / Pharmacodynamics.............................................................103
11.5.2
Safety...................................................................................................104
11.5.3
Pharmacokinetics ................................................................................105
11.5.4
Pharmacokinetic / pharmacodynamic interactions..............................105
11.5.5
Other assessments ...............................................................................105
11.6
Sample size calculation........................................................................................106
11.7
Power for analysis of key secondary variables....................................................107
11.8
Interim analyses...................................................................................................107
12 Ethical considerations......................................................................................................107
12.1
Regulatory and ethical compliance......................................................................107
12.2
Responsibilities of the investigator and IRB/IEC................................................107
12.3
Publication of study protocol and results.............................................................108
13 Protocol adherence ..........................................................................................................108
13.1
Protocol Amendments .........................................................................................108
14 References .......................................................................................................................109
15 Appendix 1 ......................................................................................................................111


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List of tables
Table 8-1
Assessment schedule Part I...................................................................73
Table 8-2
Assessment Schedule Part II.................................................................75
Table 9-1
Liver Event and Laboratory Trigger Definitions ..................................93
Table 9-2
Follow Up Requirements for Liver Events and Laboratory Triggers...94
Table 9-3
Specific Renal Alert Criteria and Actions.............................................96
List of figures
Figure 3-1
Study Design Part I ...............................................................................48
Figure 3-2
Study Design Part II..............................................................................50
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List of abbreviations
AE 
adverse event
AIHA 
Autoimmune hemolytic anemia
ALT 
alanine aminotransferase
ALP 
alkaline phosphatase
APC
Antigen presenting cell
APDS 
Activated Phosphoinositide 3-kinase-Delta Syndrome
AST 
aspartate aminotransferase
AV
Atrioventricular
BCRP
Breast cancer resistance protein
b.i.d.
bis in die (twice a day)
BMI
Body Mass Index
BSA
Body Surface Area
BUN
blood urea nitrogen
CD-ROM
compact disc – read only memory
CDS
Core Data Sheet (for marketed drugs)
CFR
Code of Federal Regulation
CIA
Collagen-induced arthritis
CK
creatinine kinase
CMO&PS
Chief Medical Office and Patient Safety
CPAP 
Continuous positive airway pressure
CRF 
Case Report/Record Form (paper or electronic)
CO2 
carbon dioxide
COVID-19
Coronavirus disease 
CRO 
Contract Research Organization
CRP
C- reactive protein
CSF
Clinical Service Form
CT 
Computed Tomography with X rays
CTC 
Common Toxicity Criteria
CTRD 
Clinical Trial Results Database
CV
coefficient of variation
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CYP
Cytochrome
DDI 
Drug-drug interaction
DS&E
Drug safety and Epidemiology
DSMB
Data safety monitoring board
EC 
Ethics committee
ECG 
Electrocardiogram
EDC 
Electronic Data Capture
ELISA 
Enzyme-linked immunosorbent assay
ESR
Erythrocyte sedimentation rate
DMC 
Data Monitoring Committee
FIH
First in Human
FDA 
Food and Drug Administration
GCP 
Good Clinical Practice
γ-GT 
Gamma-glutamyl transferase
h 
hour
HV
Healthy Volunteer
IA
Interim analysis 
IB
Investigator’s Brochure
ICH 
International Conference on Harmonization of Technical Requirements for
Registration of Pharmaceuticals for Human Use
IEC 
Independent Ethics Committee
IN
Investigator Notification
IRB 
Institutional Review Board
IRT 
Interactive Response Technology
ITP 
Idiopathic Thrombocytopenic purpura
i.v.
Intravenous
kD
kilo Dalton
LFT
Liver function testLDH 
lactate dehydrogenase
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MAD
Multiple ascending dose
MAR
Missing at random
MedDRA 
Medical dictionary for regulatory activities
MRI
Magnetic Resonance Imaging
mTOR 
Mammalian target of rapamycin
mg 
milligram(s)
ml 
milliliter(s)
NCDS 
Novartis Clinical Data Standards
NOAEL
No observed adverse effect level
NOVDD 
Novartis Data Dictionary
NTI
Narrow therapeutic index
OC/RDC 
Oracle Clinical/Remote Data Capture
OGTT
Oral glucose tolerance test
P-gp
P-glycoprotein
PA
posteroanterior
pAkt
phosphorylated Akt
PASLI
p110δ-activating mutation causing senescent T cells, lymphadenopathy and
immunodeficiency
PBPK
physiology based pharmacokinetics
PD 
pharmacodynamic(s)
PDK1 
Phosphoinositide-dependent protein kinase
PGA
Physician Global Assessment
PI3K 
Phosphoinositide 3-kinases
PI3Kδ 
Phosphoinositide 3-kinase delta
PIP3 
Phosphatidylinositol-3,4,5-trisphosphate
PK 
pharmacokinetic(s)
p.o.
per os (oral(ly))
pSS
primary Sjögren’s syndrome
PtGA
Patient’s Global Assessment
q.d.
quaque die (once a day)
RBC
red blood cell(s)
RoW
Rest of World


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SAD
Single ascending dose
SAE 
serious adverse event
s.c.
subcutaneous
SGOT
serum glutamic oxaloacetic transaminase
SGPT
serum glutamic pyruvic transaminase
SD
standard deviation
SF-36
Short Form 36
SOM
Site operational manual
SPD
Sum of product of diameters
SUSAR
Suspected Unexpected Serious Adverse Reactions
TBL
total bilirubin
ULN
upper limit of normal
ULQ
upper limit of quantification
WBC
white blood cell(s)
WHO
World Health Organization
WPAI-CIQ
Work Productivity Activity Impairment and Classroom Impairment 
Questionnaire
Pharmacokinetic definitions and symbols
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Pharmacokinetic definitions and symbols
Ae0-t 
Amount of drug (or defined metabolite) excreted into the urine from time zero 
to time ‘t’ where t is a defined time point after administration [mass units or % 
of dose]
AUC0-t 
The area under the plasma (or serum or blood) concentration-time curve from 
time zero to time‘t’ where t is a defined time point after administration [mass 
x time / volume]
AUCinf 
The area under the plasma (or serum or blood) concentration-time curve from 
time zero to infinity [mass x time / volume]
AUClast The area under the plasma (or serum or blood) concentration-time 
curve from time zero to the time of the last quantifiable concentration [mass 
x time/volume]
AUCtau 
The area under the plasma (or serum or blood) concentration-time curve from 
time zero to the end of the dosing interval tau [mass x time / volume]
AUCtau,ss 
The area under the plasma (or serum or blood) concentration-time curve from 
time zero to the end of the dosing interval tau at steady state [mass x
time/volume]
Cav,ss 
The average steady state plasma (or serum or s) concentration during multiple 
dosing
Cmax 
The observed maximum plasma (or serum or blood) concentration following
drug administration [mass/volume]
Cmax,ss 
The observed maximum plasma (or serum or blood) concentration following
drug administration at steady state [mass/volume]
Cmin,ss 
The lowest plasma (or serum or blood) concentration observed during a
dosing interval at steady state [mass/volume]
CL 
The systemic (or total body) clearance from plasma (or serum or blood)
following intravenous administration [volume/time]
CL/F 
The apparent systemic (or total body) clearance from plasma (or serum or
blood) following extravascular administration [volume / time]
CLr 
The renal clearance from plasma (or serum or blood) [volume / time]
F 
Bioavailability of a compound. Fabs is the absolute bioavailability, i.e. the
fraction (or percentage) of the administered extravascular dose systemically
available. Frel is the relative bioavailability, i.e. the bioavailability relative to 
a reference.
Racc 
The accumulation ratio
T1/2 
The terminal elimination half-life [time]
T1/2,acc
The effective half-life based on drug accumulation at steady state [time]
Tmax 
The time to reach the maximum concentration after drug administration [time]


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Vz 
The volume of distribution during the terminal elimination phase following
intravenous administration [volume]
Vz/F 
The apparent volume of distribution during the terminal elimination phase
following extravascular administration [volume]
Vss 
The volume of distribution at steady state following intravenous 
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Glossary of terms
Assessment
A procedure used to generate data required by the study
Cohort
A specific group of subjects fulfilling certain criteria
Control drug
Any drug (an active drug or an inactive drug, such as a placebo) 
which is used as a comparator to the investigational drug being 
tested in the trial
Dosage
Dose of the study treatment given to the subject in a time unit (e.g. 
100 mg once a day, 75 mg twice a day)
Enrollment
Point/time of subject entry into the study at which informed consent 
must be obtained (i.e. prior to starting any of the procedures 
described in the protocol)
Healthy volunteer
A person with no known significant health problems who 
volunteers to be a study participant 
Investigational drug
The study drug whose properties are being tested in the study; this 
definition is consistent with USA CFR 21 Section 312.3 and 
Directive 2001/20/EC and is synonymous with “investigational 
new drug” or “test substance”
Investigational 
treatment
All investigational drug(s) whose properties are being tested in the 
study as well as their associated treatment controls. This includes 
any placebos, any active controls, as well as approved drugs used 
outside of their indication/approved dosage or tested in a fixed 
combination. Investigational treatment generally does not include 
other treatments administered as concomitant background therapy 
required or allowed by the protocol when used within approved 
indication/dosage.
Patient
An individual with the condition of interest
Period
A minor subdivision of the study timeline; divides phases into 
smaller functional segments such as screening, baseline, titration, 
washout, etc.
Personal Data:
Subject information collected by the Investigator that is 
transferred to Novartis for the purpose of the clinical trial. This 
data includes subject identifier information, study information and 
biological samples.
Premature subject 
withdrawal
Point/time when the subject exits from the study prior to the 
planned completion of all study drug administration and 
assessments; at this time all study drug administration is 
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Randomization 
number
A unique identifier assigned to each randomized subject, 
corresponding to a specific treatment arm assignment
Screen Failure
A subject who is screened but is not treated or randomized
Stage
A major subdivision of the study timeline; begins and ends with 
major study milestones such as enrollment, randomization, 
completion of treatment, etc.
Study completion
Point/time at which the subject came in for a final evaluation visit 
or when study drug was discontinued whichever is later.
Study drug 
discontinuation
Point/time when subject permanently stops taking study drug for 
any reason; may or may not also be the point/time of premature 
subject withdrawal.
Study treatment
Any drug administered to the study participants as part of the 
required study procedures; includes investigational drug (s), 
control(s) or non-investigational medicinal product(s)
Study treatment 
discontinuation
When the subject permanently stops taking study treatment prior to 
the defined study treatment completion date
Subject
A trial participant (can be a healthy volunteer or a patient)
Subject number
A unique number assigned to each subject upon signing the 
informed consent. This number is the definitive, unique identifier 
for the subject and should be used to identify the subject throughout 
the study for all data collected, sample labels, etc.
Treatment number
A unique identifier assigned in non-randomized studies to each 
dosed subject, corresponding to a specific treatment arm 
Variable
A measured value or assessed response that is determined in 
specific assessments and used in data analysis to evaluate the drug 
being tested in the study
Withdrawal of consent 
(WoC)
Withdrawal of consent from the study occurs only when a subject 
does not want to participate in the study any longer, and does not 
allow any further collection of personal data


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Protocol synopsis
Protocol number
[CCDZ173X2201]
Title
An open-label, non-randomized, within-patient dose-finding study followed 
by a randomized subject, investigator and sponsor-blinded,
placebo 
controlled study to assess the efficacy and safety of CDZ173 (Leniolisib) in 
patients with APDS/PASLI (Activated phosphoinositide 3-kinase delta 
syndrome/ 
p110δ-activating 
mutation 
causing 
senescent 
T 
cells, 
lymphadenopathy and immunodeficiency)
Brief title
Study of efficacy of CDZ173 in patients with APDS/PASLI
Sponsor and 
Clinical Phase
Novartis 
Phase II/III
Intervention type
Drug
Study type
Interventional
Purpose and 
rationale
This study is designed to explore CDZ173, a selective PI3Kδ inhibitor, in 
patients with genetically activated PI3Kδ, i.e. patients with APDS/PASLI. The 
study consists of two parts. Part I was the open label part designed to 
establish the safety and pharmacokinetics of CDZ173 in the target 
population, as well as to select the optimal dose to be tested in Part II. Part 
II is designed to assess efficacy and safety of CDZ173 in this population.
Primary 
Objective(s)
Part I: To assess the safety and tolerability as well as the dose-PD and 
PK/PD relationship of CDZ173 in patients with APDS/PASLI enabling dose 
selection for Part II
Part II: To assess the clinical efficacy of CDZ173 in patients with 
APDS/PASLI
Secondary 
Objectives
Part II: To assess the effect of CDZ173 on lymphadenopathy (non-index 
lesions and spleen).
Part I and II: To assess the pharmacokinetics of CDZ173 in patients with 
APDS/PASLI 
Part I and II: To assess the efficacy of CDZ173 to modify health-related 
quality of life in patients with APDS/PASLI
Part I and II: To assess the efficacy of CDZ173 by the Physician’s Global 
Assessment and the Patient’s Global Assessment
Part I and II: To assess biomarkers reflecting the efficacy of CDZ173 to 
reduce systemic inflammatory components of the disease 
Part II: To assess the safety and tolerability of CDZ173 in patients with 
APDS/PASLI
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Study design
Part I of the study was the non-randomized, open-label, within-patient 
up-titration dose-finding part in 6 patients with APDS/PASLI. Safety, 
tolerability, pharmacokinetics (PK) and in vivo pharmacodynamics (PD pAkt) 
were assessed at three different dose levels of CDZ173. The starting dose 
was 10 mg followed by 30 mg and 70 mg b.i.d. for 4 weeks at each dose 
level respectively.
Part II is the randomized, subject, investigator and sponsor-blinded, placebo-
controlled, fixed dose part investigating approximately 30 patients with 
APDS/PASLI. Efficacy with respect to reduction of lymphadenopathy 
measured by sum of product diameters (SPD) in the index lesions selected 
as per the Cheson methodology from MRI or CT imaging as well as with 
respect to immunophenotype as assessed by change from baseline in 
percentage of naïve B cells out of total B cells will be investigated. Safety, 
tolerability, PK, and PD of CDZ173 will also be assessed.
Population
A total of 6 patients with APDS/PASLI were enrolled in the study in Part I. In 
Part II of the study approximately 30 patients will be randomized. 
Male and female patients age 12 to 75 years of age (inclusive), who have a 
documented APDS/PASLI-associated genetic PI3K delta mutation.
Inclusion criteria

Male and female patients  12 to 75 years of age (inclusive), who have 
a documented APDS/PASLI-associated genetic PI3K delta mutation. 
Patients with mutations in either PIK3CD or PIK3R1 can be included. 

In Part I and Part II, patients must have nodal and/or extranodal 
lymphoproliferation, and clinical findings and manifestations compatible 
with APDS/PASLI such as a history of repeated oto-sino-pulmonary 
infections and/or organ dysfunction (e.g., lung, liver). Additionally, in 
part II, patients must have at least one measurable nodal lesion on a
CT or MRI scan.

At screening, vital signs (systolic and diastolic blood pressure and 
pulse rate) will be assessed in the sitting position after the patient has 
rested for at least three minutes. Sitting vital signs should be within the 
following ranges:

Systolic blood pressure, 90-139 mm Hg

Diastolic blood pressure, 50-89 mm Hg

Pulse rate, 50 - 100 bpm; up to 110 bpm in adolescents
Exclusion criteria

Previous or concurrent use of immunosuppressive medication such as:

use of an mTOR inhibitor (e.g., sirolimus, rapamycin, everolimus) 
or a PI3Kδ inhibitor (selective or non-selective PI3K inhibitors) 
within 6 weeks prior to first dosing, however short-term use for up 
to a total of 5 days is allowed but only up to 1 month prior to 
enrollment in the study.

B cell depleters (e.g., rituximab) within 6 months prior to first 
dosing of study medication; if patients have received prior 
treatment with a B cell depleter, absolute B lymphocyte counts in 
the blood must have regained normal values.

Belimumab or cyclophosphamide within 6 months prior to first 
dosing of study medication.

Cyclosporine A, mycophenolate, 6-mercaptopurine, azathioprine or
methotrexate within 3 months prior to first dosing of study medication.

Glucocorticoids above 25 mg prednisone or equivalent per day
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
Other immunosuppressive medication where effects are expected
to persist at start of dosing of study medication.

Administration of live vaccines (this includes any attenuated live
vaccines) starting from 6 weeks before study entry, during the study
and up to 7 days after the last dose of CDZ173

Pregnant or nursing (lactating) women, where pregnancy is defined as
the state of a female after conception and until the termination of
gestation, confirmed by a positive hCG laboratory test.
Investigational and 
reference therapy
Part 1 : CDZ173
Part 2 : CDZ173 and placebo
Efficacy/PD 
assessments

pAkt inhibition in unstimulated and stimulated whole blood (only in
Part I)

Reduction of lymphadenopathy based on CT or MRI

Immunophenotype as assessed by changes from baseline in
percentage of naïve B cells out of total B cells

SF-36 Survey and WPAI-CIQ

Visual analogue scales for Patient and Physician Global assessment
Safety assessments

Adverse events

Physical exam

Vital signs

ECG

Safety laboratory (hematology, blood chemistry, urinalysis)
Other assessments

In Part I: Single and multiple dose PK parameters (including but not
limited to Cmax and AUC)

In Part II: Single dose (Day 1) CDZ173 PK parameters (including but
not limited to Cmax and AUC) and trough evaluations after multiple
dose
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Data analysis
The primary aim of Part I, along with assessing safety and tolerability, was 
to determine a dose to be used in the confirmatory Part II. The primary aim 
of Part II is to assess efficacy of CDZ173 at the selected dose (70 mg b.i.d.) 
after 12 weeks of treatment.
In Part II, lymphadenopathy will be measured by the SPD of index lesions
selected as per the Cheson methodology from MRI/CT imaging and 
immunodeficiency will be measured by percentage of naïve B cells out of 
total B cells. The co-primary endpoints are the change from baseline in the
log10 transformed SPD of index lesions and the change from baseline in the 
percentage of naïve B cells at the end of treatment.
Key words
APDS/PASLI
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1
Introduction
1.1
Background
Phosphoinositide 3-kinases (PI3K) are lipid kinases that are crucial for intracellular signal 
transduction. Activated through tyrosine kinase coupled receptors and recruited to the plasma 
membrane, their principal function is the generation of phosphatidylinositol-3,4,5-trisphosphate 
(PIP3). PIP3 serves as an important cellular second messenger specifically activating Akt 
(via Phosphoinositide-dependent protein kinase [PDK1]) and regulating a multitude of cellular 
processes (Kandel and Hay 1999). PI3K are classified according to their structural and 
functional properties into three classes (IA & B, II and III). All class IA PI3K are heterodimeric 
molecules composed of an 85 kilo Dalton (kD) regulatory subunit (p85) and one of three 
different 110 kD catalytic subunits (p110α, p110β and p110δ). PI3Kδ is expressed primarily in 
hematopoietic cells and functionally relevant in the activation of leukocytes of the adaptive as 
well as the innate immune system.
Mutations in the p110δ subunit that recruit the kinase to the plasma membrane independent of 
exogenous activation have been recently described, hence resulting in a gain-of-function of 
PI3Kδ (Lucas et al 2014; Angulo et al 2013; Crank et al 2014). This rare disease has been 
named “Activated PI3Kδ Syndrome” (APDS) or “p110δ-activating mutation causing senescent 
T cells, lymphadenopathy and immunodeficiency” (PASLI). More than 200 APDS patients 
have been identified (Michalovich and Nejentsev 2018).
The clinical phenotype frequently includes massive lymphoproliferation (lymphadenopathy, 
e.g., affecting breathing by mediastinal obstruction or leading to intestinal obstruction;
splenomegaly; hepatomegaly), recurrent oto-sino-pulmonary infections leading to lung
destruction, chronic viremia (e.g., Epstein-Barr Virus (EBV), Cytomegalovirus (CMV)),
increased risk for autoimmune diseases (e.g., Idiopathic Thrombocytopenic Purpura (ITP) - or
Autoimmune Hemolytic Anemia (AIHA) -like diseases), inability of successful vaccination
(notably with carbohydrate antigens), and risk of lymphomas. Current treatment options are
only symptomatic.
CDZ173 is a small molecule inhibitor of p110δ that inhibits the production of 
phosphatidylinositol-3,4,5-trisphosphate (PIP3). 
 CDZ173 has also been 
investigated in a study (CCDZ173X2203) in patients with primary Sjögren’s syndrome (pSS).
Given the specificity of CDZ173 to selectively inhibit the p110δ subunit of PI3K class IA, 
which harbors the gain-of-function mutation driving APDS/PASLI, we hypothesize that 
CDZ173 will specifically target the causative factor resulting in the pathogenesis of 
APDS/PASLI, and thereby provides effective treatment for this newly described disease with a 
significant unmet medical need.
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1.1.1
Relevant data summary
The most relevant data for the present study are summarized in the sections below. For detailed 
information, please refer to the Investigators Brochure (IB).
1.1.1.1
Preclinical data
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1.1.1.3
Human safety and tolerability data
Furthermore, a study in primary Sjögren’s Syndrome
(CCDZ173X2203) enrolled 20patients, receiving 70 mg bid, and 10 patients, receiving
matching placebo.
Six (6) APDS patients have completed the study Part I of the present protocol, and the results 
can be found in the interim analysis (IA) clinical study report and are also published (Rao et al 2017).
All six patients from the Part I study are currently on treatment in the extension study 
(CCDZ173X2201E1) and results from a recent IA with long-term safety and efficacy data were
presented at the European Society for Immunodeficiencies (ESID) conference 2018 (Rao et al 2018).
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1.2
Data from Study Part I
Six APDS/PASLI patients completed study Part I of the present protocol (amendment #8). 
CDZ173 was found safe and well tolerated at all three dose levels. There were no SAEs and no 
premature treatment discontinuations due to AEs. In summary, 12 week treatment with CDZ173 
led to significant improvements in the clinical presentation of the patients, including regression 
of lymph nodes and decrease in spleen size, naïve B cell numbers normalization, decrease of 
elevated transitional B cell numbers, reduction of senescent CD4+ and CD8+ T cells, reduction 
of elevated serum chemokines and suppression of the PI3K/Akt pathway activity. Mean oral 
plasma clearance at steady-state in the APDS patients was found to be 3.8 L/h, a value in close 
agreement to that seen in healthy volunteers. Also, no relevant time-dependencies or deviations 
from dose-proportionality were evident.
For further details of results please refer to the Clinical Study Report.
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1.3
Study purpose
This study is designed to evaluate CDZ173, a selective PI3Kδ inhibitor, in patients with 
genetically activated PI3Kδ, i.e. patients with APDS/PASLI. The study consists of two parts. 
Part I of the present protocol is now complete and was the open label part designed to establish 
the safety and pharmacokinetics of CDZ173 in the target population, as well as to select the 
optimal dose to be tested in Part II. Part II is the subject, investigator and sponsor-blinded, 
randomized part designed to assess efficacy and safety of CDZ173 in this population.
2
Study objectives
2.1
Primary objective(s)
Objective
Endpoint

Part I: To assess the safety and 
tolerability of CDZ173 in patients with 
APDS/PASLI

All safety parameters (including AEs, 
physical exam, vital signs, ECG, safety 
laboratory (hematology, blood chemistry, 
urinalysis))

Part I: To assess the dose-PD and PK/PD 
relationship of CDZ173 in patients with 
APDS/PASLI for dose selection in Part 
II
Single and multiple dose concentrations
of CDZ173 and pAkt inhibition in 
unstimulated and stimulated whole 
blood 

Part II: To assess the clinical efficacy 
(lymphadenopathy and 
immunophenotype normalization) of 
CDZ173 in patients with APDS/PASLI
Co-primary endpoint;

Change from baseline in the log10 
transformed sum of product of diameters 
(SPD) in the index lesions selected as per 
the Cheson methodology from MRI/CT 
imaging.

Change from baseline in percentage of 
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2.2
Secondary objective(s)
Objective
Endpoint

Part II: To assess the effect of CDZ173 
on lymphadenopathy (non-index lesions 
and spleen)

MRI/CT imaging – e.g. 3D volume of 
index and measurable non-index lesions
selected as per the Cheson methodology, 
and 3D volume and bi-dimensional size
of the spleen

Part I and II: To assess the 
pharmacokinetics of CDZ173 in patients 
with APDS/PASLI

Single dose CDZ173 PK parameters 
(including but not limited to Cmax and 
AUC) and trough evaluations after 
multiple dose

Part I and II: To assess the efficacy of 
CDZ173 to modify health-related quality 
of life in patients with APDS/PASLI

SF-36 (Short Form 36) Survey and 
WPAI-CIQ (Work Productivity Activity 
Impairment plus Classroom Impairment 
Questionnaire)

Part I and II: To assess the efficacy of 
CDZ173 by the Physician’s Global 
Assessment (PGA) and the Patient’s 
Global Assessment (PtGA)

Visual analogue scales for PGA and 
PtGA (for Part II the PGA is a key 
secondary endpoint)

Part I and II: To assess biomarkers 
reflecting the efficacy of CDZ173 to 
reduce systemic inflammatory 
components of the disease 

C reactive protein
(CRP), Lactate 
dehydrogenase (LDH)

For 
Part 
II 
additional: 
beta2 
microglobulin, ferritin, fibrinogen and 
erythrocyte sedimentation rate (ESR)

Part I and II: To assess the treatment 
benefit to individual patients

Narratives

Part II: To assess the safety and 
tolerability of CDZ173 in patients with 
APDS/PASLI

All safety parameters, including AEs, 
physical exam, vital signs, ECG, safety 
laboratory (hematology, blood chemistry, 
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2.3
Exploratory objective(s)
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3
Investigational plan
3.1
Study design
3.1.1
Part I
Part I of the study was the non-randomized, open-label, within-patient up-titration dose-finding 
part performed in 6 patients with APDS/PASLI. Safety, tolerability, pharmacokinetics (PK) and 
in vivo pharmacodynamics (PD pAkt) were assessed at three different dose levels of CDZ173. 
The starting dose was 10 mg followed by 30 mg and 70 mg b.i.d. for 4 weeks at each dose level 
respectively.
Figure 3-1 illustrates the study design of part I.
Figure 3-1
Study Design Part I
Screening Period/Baseline Visit
During the Screening Visit (Day -50 to Day -2) patients’ eligibility was assessed and then 
reviewed during the Baseline Visit. During this phase patients were assessed for the following: 
Safety assessments which will include physical examinations, vital signs, standard clinical 
laboratory evaluations (hematology, blood chemistry, and urinalysis), adverse event and serious
adverse event monitoring and cardiac safety which were monitored by means of triplicate
12-lead electrocardiograms (ECG).
Further assessments included
SF-36 and WPAI
questionnaires and patient global assessment.
CDZ173 (up-titration)
12 weeks
screening
follow-up
1
2
3
4
5
6
7
8
9
10
11
12
weeks
10 mg
30 mg
70 mg
bid dose
MRI/CT
PD, PK
PD, PK
PD, PK
PD, PK
PD, PK
PD, PK
PD, PK
PD, PK
PD, PK
MRI/CT
PD, PK
Dosing and Key Assessments
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Patients who were
deemed eligible for enrollment into the study based on the 
inclusion/exclusion criteria attended the clinic on Day -1 for baseline assessments which 
include vital signs, ECG and PD blood collection.
An MRI or CT scan (for further information see Section 8.3.1.1) was performed prior to Day 1 
– this could be carried out during screening or baseline periods, depending on the logistical
requirements of both the site and patient.
Treatment Period (Day 1 to Day 84)
The first day of dosing was started on Day 1 with patients receiving 10 mg of CDZ173 b.i.d. 
Prior to escalation of a patient to the next dose level a continuous safety review and review of 
PK and key PD data up to 7 days after the first dose (Day 8) was performed and had to be
assessed as satisfactory to proceed with next dose level.
The final dose strength that patients received was 70 mg CDZ173 b.i.d 
.
Assessments done on Day 84 included the end of treatment MRI or CT scan.
Follow-Up/End of study visit
During the four weeks after the last day of dosing the patients were followed-up for safety. 
On Day 112 patients underwent the end of study visit. 
3.1.2
Part II
Part II is the randomized, subject, investigator and sponsor-blinded, placebo-controlled, fixed 
dose part investigating approximately 30 patients with APDS/PASLI (Figure 3-2). 
Efficacy with respect to reduction of lymphadenopathy measured by SPD in the index lesions 
selected as per the Cheson methodology from MRI or CT imaging as well as with respect to 
immunophenotype as assessed by change from baseline in percentage of naïve B cells out of 
total B cells will be investigated. For imaging, sites may choose either of the two imaging 
modalities (MRI or CT) as per clinical practice and local regulations (see Imaging Review 
Charter). Baseline and end of treatment assessments must be done using the same modality. 
Safety, tolerability, PK, and patient reported outcomes of CDZ173 will also be assessed.
The CDZ173 dose to be used in this part is selected based on safety, tolerability, PK and PD 
data from Part I. See Section 3.2 for more details.
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The study design is illustrated in Figure 3-2.
Figure 3-2
Study Design Part II
Screening Period/Baseline Visit
During the Screening Visit (Day -50 to Day -2) patients’ eligibility will be assessed and then 
reviewed during the Baseline Visit. 
During this phase patients will be assessed for the following: Safety assessments which will 
include physical examinations, vital signs, standard clinical laboratory evaluations (hematology, 
blood chemistry, and urinalysis), adverse event and serious adverse event monitoring and 
cardiac safety which will be monitored by means of triplicate 12-lead electrocardiograms 
(ECG). Further assessments will include an MRI or CT scan (for further information see 
Section 8.3.1.1). 
Patients who are deemed eligible for enrollment into the study based on the inclusion/exclusion 
criteria will attend the clinic on Day -1 for baseline assessments which include physical exam, 
vital signs, ECG, blood collection and PRO questionnaires.
Treatment Period (12 weeks)
On Day 1 patients will be randomly allocated to one of the two treatment groups in a 2:1 ratio 
to receive either 70 mg CDZ173 b.i.d. or matching placebo for a twelve week period in a patient, 
investigator and sponsor blind fashion. 
Efficacy, safety and PK assessments will be performed at scheduled times. Safety assessment 
will include physical examination, ECGs, vital signs, standard clinical laboratory evaluations 
(hematology, blood chemistry, urinalysis), adverse event and serious adverse event monitoring.
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Follow-Up/End of study visit
For the patients who do not directly roll over from Part II to treatment in the extension study 
(CCDZ173X2201E1) at the Part II End of treatment visit, the following applies: 
During the four weeks after the last day of dosing the patients will be followed-up for safety. 
On Day 112 patients will undergo the end of study visit. 
Premature discontinuation of study treatment
Patients who discontinue study treatment prematurely will perform an early treatment 
discontinuation visit (named V104.1) with the assessments marked with a * in the assessment 
schedule (including imaging), as soon as possible after their treatment discontinuation. 
If the premature discontinuation from study treatment happens before the scheduled V104, the
patients will be asked to also return at Day 85, and complete the Visit 105 (without further 
imaging assessments to avoid additional radiation). This will be considered their last Visit.
If on the other hand the premature discontinuation from study treatment happens at or after the
scheduled V104, the patients will in addition to the early treatment discontinuation visit be 
asked to perform the EOS visit 4 weeks after the treatment discontinuation visit. This will be 
considered their last Visit.
Rationale of study design
The design of this study addresses the primary objective of decreasing lymphoproliferation and 
its sequelae in patients with APDS/PASLI and takes into account the rarity of this disease. 
 After completion of Part I, the 
dose selection for Part II was based on the safety and tolerability profile observed during up-
titration in Part I (and also in the FIH study), and on a combined assessment of all available 
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PK/PD and biomarker data. This included PD biomarkers immediately downstream of PI3Kδ 
(notably ex vivo stimulated and non-stimulated cellular pAkt levels) as well as biomarkers 
further downstream (such as cytokine serum levels) to ensure that the selected dose for Part II 
adequately suppresses the genetically activated pathway.
CT or MRI imaging in Part I allowed assessment of feasibility with these imaging modalities 
in APDS/PASLI patients and a first estimation of the effect size.
Part II aims to demonstrate evidence of efficacy and further information on safety and 
tolerability. Lymphoproliferation, including lymphadenopathy, hepatomegaly, splenomegaly
and lymphocytic aggregates in intestinal and bronchial mucosa, is a hallmark of the disease and 
considered responsible for sequelae such as infections (such as pneumonia), bronchiectasis and 
obstructions.
The second major phenotype of patients
with APDS/PASLI is an 
immunodeficiency leading to frequent bacterial, fungal and viral infections, including 
opportunistic infections; these infections further contribute to the tissue destruction in the 
pulmonary tract. Thus, measures for lymphoproliferation and immunodeficiency have been 
selected as co-primary endpoints in Part II.
3.2
Rationale of dose/regimen, duration of treatment
3.2.1
Part I
The same maximum dose of 70 mg CDZ173 b.i.d. is proposed for both adults and adolescents 
(12 years of age and older). 
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3.2.2
Part II
Lymphoma showed a time to response - assessed by Cheson criteria - of 1-2 months 
(Gopal et al 2014, Brown et al 2014). Therefore, Novartis considers reduction of 
lymphadenopathy a clinically relevant endpoint in a 12-week efficacy study.
Based on the results from the Part I study, Part II will be performed with 70 mg b.i.d. CDZ173.
All 6 patients enrolled in Part I completed the 12 week treatment period as planned, with no 
significant safety or tolerability issues. CDZ173 treatment reduced PI3Kδ-pAkt pathway 
activity as measured by the phosphorylation of Akt (pAkt) in B cells and results from the 
3 different dose levels indicate that 70 mg b.i.d. is needed for adequate suppression of the 
pathway
3.3
Rationale for choice of comparator
There is no approved treatment for APDS/PASLI and standard of care is primarily symptomatic 
treatment including intravenous (i.v.) or subcutaneous (s.c.) immunoglobulin replacement and 
antibiotic therapy for infections, and steroids or other immunosuppressants to control 
lymphoproliferation. In the absence of disease-modifying approved treatment, this study does 
not use an active comparator but explores CDZ173 on top of pre-established symptomatic 
treatment.
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The conclusions from Part I for dose selection in Part II are based on objective laboratory 
biomarkers and no relevant subjective influence is expected; further, comparisons will be done 
between dose-levels (during up-titration) within subjects. Thus, no critical information would 
be obtained from including placebo patients and Part I was designed uncontrolled which also 
accounts for the rarity of patients with the studied disease.
Part II includes both objective and subjective assessments necessitating the use of placebo to 
introduce a subject, investigator and sponsor-blinded design. Furthermore, APDS has been 
described only recently and the natural history of the disease is not well-characterized. In this 
situation subject, investigator and sponsor-blinded, placebo-controlled design is needed to 
determine if potential changes from baseline are due to the effects of CDZ173 or to natural 
changes in disease characteristics over time. To account for the rarity of patients with the studied 
disease, patients will be randomized 2:1 as described in Section 3.1.2.
3.4
Purpose and timing of interim analyses/design adaptations
3.5
Risks and benefits
APDS/PASLI patients have a mutation in the gene encoding the PI3Kδ, leading to a constitutive 
activation of the PI3Kδ – pAkt pathway, which is considered to be the etiopathology of the 
disease manifestations (see Section 1.1). CDZ173 inhibits the PI3Kδ – pAkt pathway 
(see Section 1.1.1.5), thus, CDZ173 may be effective in counter-regulating the constitutive 
activation of this pathway. Although, 12 weeks treatment with CDZ173 in the open-label Part I 
of the study led to significant improvements in the clinical presentation of the patients, it is still 
unknown whether this can solely be attributed to the treatment with CDZ173 and whether such 
beneficial effects can be confirmed in a larger group of patients in Part II of this study. 
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Currently only a limited number of APDS/PASLI patients have been exposed to CDZ173 and 
this patient group could show additional adverse events and/or a different PK profile than 
healthy volunteers. The study design applying within-patient up-titration in Part I minimized
the risk associated with unexpected adverse events in this population.
Risks and benefits evaluation for the adolescent population (12 – 15 years of 
age)
APDS/PASLI is a disease more common in pediatric patients than in adults. Infections and 
obstructions caused by the immunodeficiency and the lymphoproliferation associated with 
APDS/PASLI lead to permanent tissue destructions such as bronchiectasis (Lucas et al 2014; 
Angulo et al 2013). Thus, early treatment is predicted to be advantageous. Furthermore, 
senescent T cells are a hallmark of APDS/PASLI (Lucas et al 2014). The thymus, the major site 
of T cell production and thus the source of T cell replenishment, undergoes in childhood and 
notably under the influence of sex hormones during puberty, an involution characterized by a 
decrease in size, weight and activity (Appay et al 2010). It may be expected that an early 
treatment of patients with APDS/PASLI, prior to near-complete involution of the thymus, might 
be beneficial.
Due to the seriousness of the disease and its early onset, adolescent APDS patients already have 
a long history of hospital visits, including those with invasive measures (e.g. IVIG). Although 
the additional burden of this clinical trial is relatively modest, procedures, pain and burden will
be minimized in adolescents. In particular there will be pain prevention (e.g. by local anesthesia
if wished by the participant) and timing coordinated with daily activities as far as possible and 
defined in the protocol.
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MRI or CT scans have associated risks related to the contrast media such as nausea, 
hypersensitivity reactions, accumulation and functional impact of contrast agents in several 
organs. In case of known hypersensitivity, no contrast media will be used. Burdens may include 
discomfort, claustrophobia, fear, pain from venipuncture and heat sensation in case of contrast 
agent injection and need for specialist setting. Patients will be fully informed about all details 
of the procedure. During the procedure patients carry an emergency button with them, allowing 
premature termination of the procedure at any time. 
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4
Population
A total of 6 patients with APDS/PASLI were enrolled in the study in Part I. In Part II of the 
study approximately 30 patients will be randomized. Patients enrolled in Part I of the study will 
not participate in Part II, i.e. new patients will be recruited.
The Investigator must ensure that all patients being considered for the study meet the following 
eligibility criteria.
Patient selection is to be established by checking through all eligibility criteria at screening. 
A relevant record (e.g. checklist) of the eligibility criteria must be stored with the source 
documentation at the study site.
Deviation from any entry criterion excludes a patient from enrollment into the study.
The inclusion and exclusion criteria listed in Section 4.1 and Section 4.2 are valid for the 
population to be included in Part I and Part II of the study, no additional differentiation should 
be made between patients selected for Part I or II.
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4.1
Inclusion criteria
Patients eligible for inclusion in this study have to fulfill all of the following criteria:
1. Written informed consent must be obtained before any assessment is performed.
2. Male and female patients age 12 to 75 years of age (inclusive), who have a documented
APDS/PASLI-associated genetic PI3K delta mutation.
3. In Part I and II of the study patients must have nodal and/or extranodal
lymphoproliferation and clinical findings and manifestations compatible with
APDS/PASLI such as a history of repeated oto-sino-pulmonary infections and/or organ
dysfunction (e.g., lung, liver). Additionally in Part II, patients must have at least one
measurable nodal lesion on a CT or MRI scan.
4. At screening, vital signs (systolic and diastolic blood pressure and pulse rate) will be
assessed in the sitting position after the patient has rested for at least three minutes.
Sitting vital signs should be within the following ranges:

Systolic blood pressure, 90-139 mm Hg

Diastolic blood pressure, 50-89 mm Hg

Pulse rate, 50 - 100 bpm; up to 110 bpm in adolescents
5.
6.
4.2
Exclusion criteria
Patients fulfilling any of the following criteria are not eligible for inclusion in this study. 
No additional exclusions may be applied by the Investigator, in order to ensure that the study 
population will be representative of all eligible patients.
1.
2.
3. Previous or concurrent use of immunosuppressive medication such as:

mTOR inhibitor (e.g. sirolimus, rapamycin, everolimus) or a PI3Kδ inhibitor
(selective or non-selective PI3K inhibitors) within 6 weeks prior to first dosing,
however short-term use for up to a total of 5 days is allowed but only up to 1 month
prior to enrollment in the study.

B cell depleters (e.g., rituximab) within 6 months prior to first dosing of study
medication; if patients have received prior treatment with a B cell depleter, absolute
B lymphocyte counts in the blood must have regained normal values.
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
Belimumab or cyclophosphamide within 6 months prior to first dosing of study
medication.

Cyclosporine A, mycophenolate, 6-mercaptopurine, azathioprine or methotrexate
within 3 months prior to first dosing of study medication.

Glucocorticoids above 25 mg prednisone or equivalent per day within 2 weeks prior
to first dosing of study medication.

Other immunosuppressive medication where effects are expected to persist at start of
dosing of study medication.
4.
5.
6.
7.
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8.
9.
10.
11.
12.
13. Administration of live vaccines (including any attenuated live vaccines) starting from
6 weeks before study entry, during  the study and up to 7 days after the last dose of
CDZ173 should be excluded.
14. Pregnant or nursing (lactating) women, where pregnancy is defined as the state of a female
after conception and until the termination of gestation, confirmed by a positive hCG
laboratory test.
15.
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5
Restrictions for Study Subjects
During recruitment, screening/informed consent review and baseline visit the subjects must be 
informed and reminded of the following restrictions:
5.2
Prohibited treatment
It is recommended that a pharmacist should review a patient’s concomitant medication in 
relation to the potential drug interactions described below.
5.2.1
Drugs that are prohibited
Other investigational therapies
Other investigational therapies must not be used while the patient is on the study. If such agents 
are required for a patient then the patient must be permanently discontinued from the treatment 
portion of the study.
Vaccination
Live/Attenuated Vaccination: The study drug is considered to decrease activities of cells of the 
immune system, thus from 6 weeks prior to start of treatment, until 7 days after end of study 
treatment, live vaccines (incl. attenuated viruses) are not permitted.
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Dead vaccines: Due to the decreased activities of the immune cells, use of dead vaccines is 
expected to be less effective or ineffective. Patients should be advised that their vaccination 
may be ineffective if administered within the timeframe specified above. However, patients will 
not be discouraged from receiving dead vaccines, including the seasonal influenza vaccination.
Patients and physicians are encouraged to plan required vaccinations outside this window.
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6
Treatment
6.1
Study treatment
Details on the storage and management of study medication, randomization and instructions for 
prescribing and taking study treatment are outlined in the Site Operations Manual. The subject 
number assigned to a patient at screening remains the unique identifier for the subject 
throughout the study.  For information on subject numbering, please see ‘Subject numbering’ 
section in the SOM.
6.1.1
Investigational treatment
The investigational drug, CDZ173 10 and 70 mg capsules and matching placebo capsules will 
be prepared by Novartis and supplied to the investigator site as open label patient-specific packs 
for Part I and blinded patient specific packs for Part II.
6.2
Treatment arms
CDZ173 capsules or matching placebo capsules will be administered orally as follows:
Part I of the study was open-label; all patients sequentially received 10 mg, 30 mg and 70 mg 
CDZ173 b.i.d. for 4 weeks duration.
Part II
Study treatments are defined as:
a: 70 mg oral dose of CDZ173 b.i.d. for 12 weeks
b: matching placebo b.i.d. for 12 weeks
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6.3
Permitted dose adjustments and interruptions of study treatment
6.4
Treatment assignment
Treatment numbers for Part I of the study and randomization numbers for part II of the study
will be assigned in ascending, sequential order to eligible subjects (see Site Operations Manual
for details). The Investigator will enter the randomization/treatment number on the CRF.
The randomization numbers for part II of the study will be generated using the following 
procedure to ensure that treatment assignment is unbiased and concealed from patients and 
investigator staff. A randomization list will be produced by or under the responsibility of 
Novartis Drug Supply Management using a validated system that automates the randomization
assignment of treatment arms to randomization numbers in the specified ratio. 
The randomization scheme for subjects will be reviewed and approved by a member of the 
Novartis IIS Randomization Group.
6.5
Treatment blinding
Part II of the study is subject, investigator and sponsor-blinded: patients, investigator staff, and 
sponsor persons performing the assessments, and data analysts will remain blind to the identity 
of study treatments. An independent data monitoring committee (DMC) will evaluate unblinded 
data for safety purposes (See Section 10.3)
The identity of the treatments will be concealed by the use of study drugs that are all identical 
in packaging, labeling, schedule of administration, appearance and odor. 
Randomization data are kept strictly confidential until the time of unblinding, and will not be 
accessible by anyone else involved in the study with the following exceptions: DMC members, 
unblinded pharmacist or authorized designee at site, unblinded monitor (where used) and the 
PK bioanalyst. 
Unblinding will only occur in the case of patient emergencies (see Section 6.6) and at the 
conclusion of the study.
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6.6
Emergency breaking of assigned treatment code
Emergency unblinding should only be undertaken when it is essential to treat the subject safely 
and efficaciously. Most often, study treatment discontinuation and knowledge of the possible 
treatment assignments are sufficient to treat a study subject who presents with an emergency 
condition. A complete set of emergency code break cards will be provided to the investigator 
site(s) and a complete set will be available at Novartis. All code break cards must be retained 
until the end of the study and returned to Novartis. They must be stored in a secure place but be 
accessible in case of emergency. The investigator will receive a blinded code break card for 
each subject, with the details of drug treatment covered by a removable, scratch-off cover. In an 
emergency, the scratch-off cover can be removed to determine the treatment. The scratch-off 
covers are not to be removed for any reason other than an emergency. When the investigator 
removes the scratch-off cover he/she must note the date, time, and reason for removing it and 
retain this information with the case report form documentation. The unblinded treatment 
code should not be recorded on the CRF. The investigator must also immediately inform the 
Novartis local monitor that the code has been broken.
It is the investigator’s responsibility to ensure that there is a procedure in place to allow access 
to the code break cards in case of emergency. If appropriate, the investigator will inform the 
patient how to contact his/her backup in cases of emergency when he/she is unavailable.
6.7
Treatment exposure and compliance
Sequential blood samples will be collected in all patients up to 8 hours post after the first dose 
administration (Day 1).
  In addition, trough samples 
to assess PK steady-state will be taken at weekly or two-weekly intervals in Part I and Part II
of the study, respectively.
Pharmacokinetic parameters (measures of treatment exposure) will be determined in all subjects 
treated with CDZ173, as detailed in Section 8.5.
Patients will complete a patient diary to ensure compliance in taking study medication and study 
drug accountability will be performed by study personnel.
6.8
Recommended treatment of adverse events
Medication used to treat AEs must be recorded on the Concomitant medications/Significant 
non-drug therapies CRF.
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6.9
Concomitant treatment
All prescription medications, over-the-counter drugs and significant non-drug therapies
(including physical therapy and blood transfusions) administered or taken within the timeframe 
defined in the entry criteria prior to the start of the study and during the study, must be recorded 
on the Concomitant medications/ Significant non-drug therapies section of the CRF.
Medication entries should be specific to trade name, the single dose and unit, the frequency and 
route of administration, the start and discontinuation date and the reason for therapy.
7
Discontinuation and study completion
7.1
Discontinuation of study treatment
Patients may voluntarily discontinue study treatment for any reason at any time. 
The Investigator should discontinue study treatment for a given patient if, on balance, they 
believe that continuation would be detrimental to the patient’s well-being.
Study treatment must be discontinued under any of the following circumstances:

Patient withdraws consent

Pregnancy

The patient experiences a drug-related serious adverse event

Diarrhea of CTCAE Grade 2 or higher on 3 consecutive days

Diarrhea of CTCAE Grade 3 or higher

Diarrhea or abdominal pain with accompanying fever assessed to be related to a
gastrointestinal infection

More than 10 missed doses in Part I of the study and more than 28 missed doses
of study treatment in Part II (cumulative; whether consecutive or otherwise).
Discontinuation of study treatment will be at the discretion of the investigator, under the 
following circumstances: 

Any protocol deviation or adverse event that results in a significant risk to the
patient’s safety

Use of prohibited treatment, see Section 5.2
The appropriate personnel from the site and Novartis will assess whether study treatment should 
be discontinued for any patient whose treatment code has been broken inadvertently for any 
reason.
Patients who discontinued study treatment prematurely will perform an early treatment 
discontinuation visit (named V104.1) with the assessments marked with a * in the assessment 
schedule (including imaging), as soon as possible after their treatment discontinuation. 
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If the premature discontinuation from study treatment happens before the scheduled V104, the 
patients will be asked to also return at Day 85, and complete the Visit 105 (without further 
imaging assessments to avoid additional radiation). This will be considered their last Visit.
If on the other hand the premature discontinuation from study treatment happens at or after the
scheduled V104, the patients will in addition to the early treatment discontinuation visit be 
asked to perform the EOS visit 4 weeks after the treatment discontinuation visit. This will be 
considered their last Visit.
Subjects who discontinue study treatment or who decide they do not wish to participate in the study 
further should NOT be considered withdrawn from the study UNLESS they withdraw their consent
(see Section 7.3). If they fail to return for these assessments for unknown reasons, every effort 
(e.g. telephone, e-mail, and letter) should be made to contact them as specified in Section 7.2.1. 
7.2
Study completion and post-study treatment
Each patient will be required to complete the study in its entirety, unless consent is withdrawn. 
All patients completing the study will be offered continuous treatment in the extension study 
CCDZ173X2201E1. Study completion is defined as when the last patient completes their End 
of Study visit, or in the event of an early study termination decision, the date of that decision.
Study completion is defined as when the last patient completes 12 weeks treatment and his/her
End of Study visit, or the Visit 105 in the case where the patient rolls over to continuous 
treatment in the CCDZ173X2201E1 study.
At a minimum, patients will be contacted for safety evaluations during the 30 days 
followingcompletion of treatment, either via the scheduled EOS visit or via the first visits in the 
CCDZ173X2201E1 study in the cases where patient rolls over directly to this study for 
continued treatment .
If the patients directly continue treatment in the extension study (CDZ173X2201E1), the safety 
follow up is not needed as they will be followed up during the Visits in the extension study. 
Documentation of attempts to contact the patient should be recorded in the source 
documentation.
7.2.1
Lost to follow-up
For patients whose status is unclear because they fail to appear for study visits without stating 
an intention to discontinue or withdraw, the Investigator should show "due diligence" by 
documenting in the source documents steps taken to contact the patient, e.g. dates of telephone 
calls, registered letters, etc. A patient should not be formally considered lost to follow-up until 
his/her scheduled end of study visit would have occurred.
7.3
Withdrawal of consent
Subjects may voluntarily withdraw consent to participate in the study for any reason at any time. 
Withdrawal of consent occurs only when a subject: 

Does not want to participate in the study anymore, and

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In this situation, the investigator should make a reasonable effort (e.g. telephone, e-mail, letter) 
to understand the primary reason for the subject’s decision to withdraw his/her consent and 
record this information.
Study treatment must be discontinued and no further assessments conducted, and the data that 
would have been collected at subsequent visits will be considered missing.
Further attempts to contact the subject are not allowed unless safety findings require 
communicating or follow-up. 
All efforts should be made to complete the assessments prior to study withdrawal. A final 
evaluation at the time of the subject’s study withdrawal should be made as detailed in the 
assessment table.
7.4
Study stopping rules
The study will be put on temporary hold and safety data will be reviewed if any of the following 
criteria are met and no further enrollment will take place pending a full safety review conducted 
by the sponsor

Two or more patients experience a drug-related serious adverse event

More than two patients in Part I or more than three patients in Part II report CTCAE
(current version) Grade 3 or higher adverse events within the same organ class that are
considered to be related to study drug

The sponsor considers that the number and/or severity of adverse events justify
discontinuation of the study

The sponsor requests it (e.g. in the case of pre-clinical safety findings, or issues with the
study drug)
7.5
Early study termination
The study can be terminated at any time for any reason by Novartis. Should this be necessary, 
patients should be seen as soon as possible and treated as a prematurely withdrawn subject. 
The Investigator may be informed of additional procedures to be followed in order to ensure 
that adequate consideration is given to the protection of the subject’s interests.
The Investigator will be responsible for informing IRBs/IECs of the early termination of the 
trial.
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8
Procedures and assessments
Table 8-1
Assessment schedule Part I
Patients should be seen for all visits on the designated day, with the assessments performed as per schedule, within the allowed 
“visit/assessment.
SCR
BSL
EOS
1 Visit Numbers
1
2
101
102
103
199
201
202
203
299
301
302
303
304
499
Days
-50 to -2
-1
1
8
15
28
29
36
43
56
57
64
71
84
112
Visit Window s
-3 days*
+/- 1 day
+/- 1 day
+/- 1 day +/- 1 day
+/- 1 day
+/- 1 day +/- 1 day
+/- 1 day
+3 days
+/- 2 days
Written Informed Consent
X
Inclusion /Exclusion criteria
X
X2
Relevant medical  History / Current medical 
conditions
X
X2
Demography 
X
Physical examination
X
X
X
X
X
X
X
X3
X
X
X
X
X
Vital signs and body measurements
Body height
X
Body w eight
X
X
X
Body temperature
X
X
X
X
X
X
X
X
X
X
X
X
X
Blood pressure / Pulse rate4
X
X
X5
X
X
X5
X
X
X5
X
X
X
X
ECG evaluation (triplicates)
X
X
X5
X
X
X5
X
X
X5
X
X
X
X
Hematology, Blood chemistry, Urinalysis
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
PK blood collection
X7
X
X
X7
X
X
X7
X
X
X
PD blood collection
X
X8
X
X
X8
X
X
X8
X
X
X
X
X
X
X
X
X
X
X
X
X
PBMC for functional T cell assay
X
X
X
X
Drug administration record9
X
X
X
X
X
X
X
X
X
X
X
X
MRI or CT scan
X12
SF-36/WPAI-CIQ Questionnaires
X
X
X
X
Physican/Patients Global assessment
X
X
X
X
Patient Narratives
X
Phase/Study completion
X
X
X
X14
X
Comments
Adverse Events (comment)
Concomitant meds/Therapies
Study phase
As required
As required
Dose 1 (10 mg)
Dose 2 (30 mg)
Dose 3 (70mg)
As required
X6
X11
CCI
CCI
CCI
CCI
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Table 8-2
Assessment Schedule Part II
Epoch
Follow-up
Visit name
SCR
BSL
EOT
EOS
1 Visit Numbers, Core Period
1
2
101
102
103
104
105
199
1  Visit structure given for internal programming purpose only
Days
-50 to -7
-1
1
15
29
57
85
112
Visit windows
+/- 3 day
+/- 3 day
+/- 3 day
+/- 3 day
+/- 5 day
Written Informed Consent
X
Inclusion /Exclusion criteria
X
X2
Relevant medical  History / Current medical 
conditions
X
X2
Demography 
X
Physical examination*
X
X
X16
X
X
X
X
X
X
X
S
X4
X
X
X
X
X
S
Randomisation 
X
Vital signs and body measurements
          Body height*
X
X
          Body weight*
X
X
X
X
X
X
          Body temperature*
X
X
X
X
X
X
X
X
          Blood pressure / Pulse rate5*
X
X
X6
X
X
X
X
X
ECG evaluation* 
X
X
X6
X
X
X
X
X
Hematology, Blood chemistry, Urinalysis7*
X
X
X
X
X
X
X
X
S
X
X
X
X
X
Screening
Treatment
Notes
Treatment
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Epoch
Follow-up
Visit name
SCR
BSL
EOT
EOS
1 Visit Numbers, Core Period
1
2
101
102
103
104
105
199
1  Visit structure given for internal programming purpose only
Days
-50 to -7
-1
1
15
29
57
85
112
Visit windows
+/- 3 day
+/- 3 day
+/- 3 day
+/- 3 day
+/- 5 day
X
X
X
X
X
PK blood collection*
X10
X
X
X
X
X
X
X
X
X
X
X
X
X
PBMC for functional T cell assay*
X
X
X
X
Drug administration record12*
X
X
X
X
X17
MRI or CT scan*
X13
X13
SF-36/WPAI-CIQ Questionnaires*
X
X
X
X
X
X
X
X
Patient/Physician global assessment*
X
X
X
X
Patient Narratives
X
Study/Epoque completion information
X
X15
Comments
Adverse Events (comment)
Concomitant meds/Therapies
Screening
Treatment
Notes
Treatment
X9
X
As required
As required
As required
CCI
CCI
CCI
CCI
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Footnotes Assessment Schedule Part II
BSL: Baseline, SCR: Screening, EOT: End of treatment, EOS: End of Study, ICF: Informed Consent Form, S: source data only (not to be captures in the 
eCRF), X for any blood collection unless otherwise mentioned pre-dose is meant.
Patients can roll over for continuous treatment in the open-label CCDZ173X2201E1 extension study, after their EOT visit. For the patients who do not 
directly roll over to treatment in the extension study (CCDZ173X2201E1) at the EOT visit, the following applies: During the four weeks after the last day 
of dosing the patients will be followed-up for safety. On Day 112 patients will undergo the EOS visit.
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8.1
Informed consent procedures
Eligible patients may only be included in the study after providing written (witnessed, where 
required by law or regulation), IRB/IEC-approved informed consent. 
If incapable of doing so, in cases where the patient’s representative gives consent, the patient
should be informed about the study to the extent possible given his/her understanding. If the 
patient is capable of doing so, he/she should indicate assent by personally signing and dating 
the written informed consent document or a separate assent form.
Informed consent must be obtained before conducting any study-specific procedures (i.e. all of 
the procedures described in the protocol). The process of obtaining informed consent should be 
documented in the subject source documents.
The date of signing of informed consent (and withdrawal, if later withdrawn) should be 
documented in the CRF.
Novartis will provide to Investigators a proposed informed consent form that complies with the 
ICH GCP guideline and regulatory requirements and is considered appropriate for this study. 
Any changes to the proposed consent form suggested by the Investigator must be agreed to by 
Novartis before submission to the IRB/IEC.
In the event that Novartis wants to perform testing on the samples that are not described in this 
protocol, additional Institutional Review Board and/or Ethics Committee approval will be 
obtained.
A copy of the approved version of all consent forms must be provided to the Novartis monitor 
after IRB/IEC approval.
8.2
Subject demographics/other baseline characteristics
Patient demographics: year of birth, sex, race, predominant ethnicity and relevant medical 
history/current medical conditions (until date of signature of informed consent) will be recorded 
in the CRF. Where possible, the diagnoses and not symptoms should be recorded.
All prescription medications, over-the-counter drugs and significant non-drug therapies 
(including physical therapy and blood transfusions) administered or taken within the timeframe 
defined in the entry criteria prior to the start of the study must be recorded on the Concomitant 
medications/ Significant non-drug therapies section of the CRF.
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Medication entries should be specific to trade name, the single dose and unit, the frequency and 
route of administration, the start and discontinuation date and the reason for therapy.
Investigators have the discretion to record abnormal test findings on the medical history CRF 
whenever in their judgment, the test abnormality occurred prior to the informed consent 
signature.
8.3
Efficacy / Pharmacodynamics
8.3.1
Efficacy
8.3.1.1
Imaging with MRI/CT
For the assessment of the impact of CDZ173 on lymphadenopathy, patients will be scanned in 
an MRI or a CT scanner as based on clinical practice and local regulation. The same imaging 
modality will be used throughout the study for the same patient.
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In Part I of the study MRI or CT imaging modalities was used in APDS/PASLI patients for a 
first estimation of the effect size. In Part II clinical efficacy will be assessed. The SPD approach 
will be used for primary endpoint while more experimental yet accurate 3D measures will be 
used for secondary endpoint.
For further details on image acquisition and image analysis, see site operations manual/MRI/CT 
subject scanning guide and imaging review charter, respectively. 
8.3.1.2
High Sensitivity C-reactive protein (hsCRP), Lactate dehydrogenase 
(LDH), beta2 microglobulin, ferritin, fibrinogen and analysis of 
erythrocyte sedimentation rate
The following parameters will be measured to assess biomarkers reflecting the efficacy of 
CDZ173 to reduce systemic inflammatory components of APDS/PASLI: High Sensitivity C-
reactive protein (hsCRP), Lactate dehydrogenase (LDH) and for Part II additional: beta2 
microglobulin, ferritin, fibrinogen and analysis of erythrocyte sedimentation rate.
8.3.2
Pharmacodynamic assessments
Pharmacodynamic assessments are specified below, with the methods for assessment and 
recording specified in the Study Operations Manual. Assessments will be performed/samples 
collected at the timepoint(s) defined in the Assessment schedule.
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8.3.2.1
Ex vivo stimulated phosphorylation of Akt in B cells from whole blood
The pharmacodynamic effect of CDZ173 is assessed using ex vivo stimulated and unstimulated 
phosphorylation of Akt in B cells in the Part I of the study. Akt is a direct downstream target of 
activated PI3Kdelta. Determination of the percentage (%) of CD20+ phospho-Akt positive cells 
after ex vivo stimulation of whole blood is performed by flow cytometry analysis. Unstimulated 
cells will serve as controls. The stimulation of fresh samples and freezing of stimulated and 
unstimulated samples are to be performed at the clinical sites.
8.3.3
Patient-Reported Outcome
8.3.3.1
Short form 36 Survey (SF-36)
The purpose of SF-36 in this study is to assess the physical and mental functioning of patients.
The SF-36 is a widely used instrument to measure generic health status. It is a 36-item 
questionnaire that has proven useful in monitoring generic and specific populations, comparing 
the relative burden of different diseases, differentiating the health benefits produced by different 
treatments, and in screening individual patients.
The SF-36 measures the impact of disease on overall quality of life and consists of eight 
subscales (physical function, pain, general and mental health, vitality, social function, physical 
and emotional health) which can be aggregated to derive a physical-component summary score 
and a mental-component summary score
All patient-reported measures should be completed at the center by the latest 3 hours post dose.
Completed questionnaires will be reviewed and examined by the Investigator. The Investigator 
should review not only the responses to the questions in the questionnaires but also for any 
unsolicited comments written by the patient.
If AEs or SAEs are confirmed then the physician must record the events as per instructions 
given in Section 9 of the protocol. Investigators should not encourage the patients to change the 
responses reported in the completed questionnaires.
8.3.3.2
Work Productivity and Activity Impairment (WPAI) plus Classroom 
Impairment (CIQ) Questionnaire
The WPAI in this study measures the amount of absence or presence and daily activity 
impairment attributable to APDS/PASLI. As younger patients (age 12 and above) may also be 
enrolled in the study the WPAI-CIQ version of the questionnaire will be used for all patients as 
it also measures the amount of absence or presence for school attendance and daily classroom 
activity impairment attributable to APDS/PASLI.
8.3.3.3
Patient Global assessment Questionnaire
The patient’s global assessment questionnaire asks patients about their APDS related well-being 
using 100 mm visual analogue scale (VAS) ranging from “very poor” (0) to “very good” (100).


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8.3.3.4
Physician’s Global assessment Questionnaire
In the physician’s global assessment questionnaire the Investigator rates the disease activity of 
their patient using 100 mm VAS ranging from “no disease activity” (0) to “maximal disease 
activity” (100).
To enhance objectivity, the physician must not be aware of the specific patient’s global 
assessment, when performing his own assessment on that patient.
8.3.3.5
Narratives
Narratives on each individual patient will be collected in order to assess the treatment benefit.
Investigators will be asked for a description of the patient’s disease manifestations at the end of 
treatment, and to provide details on the areas where the patient improved or worsened during 
the treatment phase.
8.4
Safety
Safety assessments are specified below; methods for assessment and recording are specified in 
the Site Operations Manual, with the Assessment Schedule detailing when each assessment is 
to be performed.
During an epidemic or pandemic (e.g. COVID-19 pandemic) that limits or prevents on-site 
study visits regular phone or virtual calls will occur (as per the assessment schedule or more
frequently if needed) for safety monitoring and discussion of the participant´s health status until 
the participant can again visit the site.
8.4.1
Physical examination
A complete physical examination will include the examination of general appearance, skin, 
neck (including thyroid), eyes, ears, nose, throat, lungs, heart, abdomen, back, lymph nodes, 
extremities, vascular and neurological. If indicated based on medical history and/or symptoms, 
rectal, external genitalia, breast, and/or pelvic exams may be performed.
Information for all physical examinations must be included in the source documentation at the 
study site and will not be recorded the CRF. Significant findings that are present prior to 
informed consent are included in the Relevant Medical History CRF. Significant findings 
observed after informed consent signature which meet the definition of an Adverse Event must 
be appropriately recorded on the Adverse Event CRF.
If assessment of the patient's general clinical status shows no significant change between 
baseline (visit 2) and the first treatment visit (visit 101), the results of the physical examination 
at baseline (visit 2) can be used for first treatment visit (visit 101) data entry as well, and the 
actual physical exam does not need to be repeated.


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8.4.2
Vital signs
Vital signs will include the collection of body temperature (recorded in °C), blood pressure (BP) 
and pulse measurements. 
After the patient has been sitting for 3 minutes, with back supported and both feet placed on the 
floor, systolic and diastolic BP will be measured using an automated validated device, with an 
appropriately sized cuff. In case the cuff sizes available are not large enough for the patient's 
arm circumference, a sphygmomanometer with an appropriately sized cuff may be used.
If vital signs are out-of-range at screening and/or baseline, two additional readings can be 
obtained, so that a total of up to three consecutive assessments are made, with the patient seated 
quietly for approximately five minutes preceding each repeat assessment. The last reading must 
be within the ranges provided in the eligibility criteria in order for the subject to qualify.
8.4.3
Height and weight
Height in centimeters (cm) and body weight (to the nearest 0.1 kilogram [kg] in indoor clothing, 
but without shoes) will be measured.
8.4.5
Laboratory evaluations
Clinically relevant deviations of laboratory test results occurring during or at completion of the 
study must be reported and discussed with Novartis personnel. The results should be evaluated 
for criteria defining an adverse event and reported as such if the criteria are met. 
Repeated evaluations are mandatory until normalization of the result(s) or until the change is 
no longer clinically relevant. In case of doubt, Novartis personnel should again be contacted.
Hematology
Hemoglobin, hematocrit, red blood cell count, white blood cell count with differential and 
platelet count, aPTT and PT/INR will be measured.
Clinical chemistry
Sodium, potassium, creatinine, urea, uric acid, chloride, albumin, calcium, alkaline phosphatase, 
total bilirubin, GGT, AST, ALT, amylase, lipase, CK, glucose, insulin, total cholesterol and 
triglycerides. If the total bilirubin concentration is increased above 1.5 times the upper limit of 
normal, direct and indirect reacting bilirubin should be differentiated.
Thyroid stimulating hormone (TSH), T3 and T4 will also be measured as part of the clinical 
chemistry safety laboratory panel.
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Urinalysis
Urine test by dipstick e.g. Combur9: leucocytes, nitrite, pH, protein, glucose, ketones, 
urobilinogen, bilirubin, blood/ hemoglobin
If the dipstick result is positive for protein, nitrite, leucocytes and/or blood, the sample will be 
sent for microscopic analysis of WBC, RBC and casts.
8.4.6
Electrocardiogram (ECG)
A standard 12 lead ECG will be performed in triplicate (mean value recorded in the CRF) with 
the patient in the supine position as indicated in the Assessment Schedule. Interpretation of the 
tracing must be made by a qualified physician and documented on the ECG printout. Each ECG 
tracing should be labeled with the

study number

patient initials

patient number

date and signature of ECG interpreter
and kept in the source documents at the study site. 
Clinically significant abnormalities detected during the Screening visit exam should be recorded 
on the relevant Medical history CRF page, and on the Adverse Events page if detected during 
other visits. Clinically significant findings must be discussed with the sponsor.
The CRF will contain:

date and time of ECGs

statement of clinically significant findings

PR interval, QRS duration, heart rate, RR, QT, QTcF (Fridericia QT correction formula to
be used).
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8.5
Pharmacokinetics
Pharmacokinetic (PK) samples will be collected at the time points defined in the 
Assessment schedule.
Further details on sample collection, numbering, processing and shipment can be found in the 
Site Operations Manual.
PK samples will be obtained and evaluated in all subjects at all dose levels.
Untreated samples (placebo) will not be analyzed.
Concentrations will be expressed in mass per volume units and will refer to the free base.  
For standard pharmacokinetic abbreviations and definitions see the list provided at the 
beginning of this protocol.
The following plasma pharmacokinetic parameters will be determined using the actual recorded 
sampling times and non-compartmental method(s) with Phoenix WinNonlin (Version 6.2 or 
higher): Cmax, Tmax and AUClast. Other PK parameters, including but not limited to AUCinf, 
CL(ss)/F and Cmax may be added as appropriate.
The linear trapezoidal rule will be used for AUC calculation. Regression analysis of the terminal 
plasma elimination phase for the determination of T1/2 will include at least 3 data points after 
Cmax. If the adjusted R2 value of the regression analysis of the terminal phase will be less than 
0.75, no values will be reported for T1/2, AUCinf and CL/F.
In addition to non-compartmental methods, 
individual compartmental modelling 
(Phoenix WinNonlin, version 6.2 or higher) may be used to derive individual estimates of oral 
drug clearance (CLss/F) as well other model-derived parameters such as absorption rate 
constant and volume of distribution.  
8.6
Other assessments
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8.6.2
Exploratory Biomarker assessments
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8.7
Use of residual biological samples
9
Safety monitoring
9.1
Adverse events
An adverse event (AE) is any untoward medical occurrence (i.e. any unfavorable and 
unintended sign [including abnormal laboratory findings], symptom or disease) in a subject or 
clinical investigation subject after providing written informed consent for participation in the 
study. Therefore, an AE may or may not be temporally or causally associated with the use of a 
medicinal (investigational) product.
The occurrence of adverse events should be sought by non-directive questioning of the patient
at each visit during the study. Adverse events also may be detected when they are volunteered 
by the patient during or between visits or through physical examination, laboratory test, or other 
assessments.
Abnormal laboratory values or test results constitute adverse events only if they fulfill at least 
one of the following criteria:

they induce clinical signs or symptoms,

they are considered clinically significant,

they require therapy.
Clinically significant abnormal laboratory values or test results should be identified through a 
review of values outside of normal ranges/clinically notable ranges, significant changes from 
baseline or the previous visit, or values which are considered to be non-typical in patients with 
underlying disease. Investigators have the responsibility for managing the safety of individual 
patients and identifying adverse events. Alert ranges for liver related events are included in
Section 9.4.
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Adverse events must be recorded on the Adverse Events CRF for patients that pass screening 
and enter into the study. The adverse events should be reported according to the signs, 
symptoms or diagnosis associated with them, and accompanied by the following information:
1. the Common Toxicity Criteria (CTC) AE grade (current)
If CTC-AE grading does not exist for an adverse event, use:

1=mild, 

2=moderate, 

3=severe 

4=life threatening. 
CTC-AE grade 5 (death) is not used, but is collected in other CRFs (e.g. Study Completion, 
Death/Survival).
2. its relationship to the study treatment (no/yes)
3. its duration (start and end dates) or if the event is ongoing an outcome of not 
recovered/not resolved should be reported.
4. whether it constitutes a serious adverse event (SAE) See Section 9.2 for definition of SAE
5. action taken regarding [study/investigational] treatment(select as appropriate). 
All adverse events should be treated appropriately. Treatment may include one or more of 
the following: 

no action taken (i.e. further observation only) 

study treatment dosage adjusted/temporarily interrupted 

study treatment permanently discontinued due to this adverse event 

concomitant medication given 

non-drug therapy given 

subject hospitalized/subject’s hospitalization prolonged 
6. its outcome (not recovered/not resolved; recovered/resolved; recovering/resolving, 
recovered/resolved with sequelae; fatal; or unknown)
Once an adverse event is detected, it should be followed until its resolution or until it is judged 
to be permanent, and assessment should be made at each visit (or more frequently, if necessary) 
of any changes in severity, the suspected relationship to the study drug, the interventions 
required to treat it, and the outcome.
Information about common side effects already known about the investigational drug can be 
found in the Investigator Brochure (IB) or Core Data Sheet (for marketed drugs) or will be 
communicated between IB updates in the form of Investigator Notifications. This information 
will be included in the patient informed consent and should be discussed with the patient during 
the study as needed.
The Investigator should also instruct each patient to report any new adverse event (beyond the 
protocol observation period) that the patient, or the patients’s personal physician, believes might 
reasonably be related to study treatment. This information should be recorded in the 
Investigator’s source documents; however, if the AE meets the criteria of an SAE, it must be 
reported to Novartis.


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9.2
Serious adverse event reporting
9.2.1
Definition of SAE
An SAE is defined as any adverse event (appearance of (or worsening of any pre-existing) 
undesirable sign(s), symptom(s) or medical conditions(s) which meets any one of the following 
criteria:

is fatal or life-threatening 

results in persistent or significant disability/incapacity

constitutes a congenital anomaly/birth defect

requires inpatient hospitalization or prolongation of existing hospitalization, unless 
hospitalization is for:

routine treatment or monitoring of the studied indication, not associated with any 
deterioration in condition 

elective or pre-planned treatment for a pre-existing condition that is unrelated to the 
indication under and has not worsened since the start of study drug

treatment on an emergency outpatient basis for an event not fulfilling any of the 
definitions of a SAE given above and not resulting in hospital admission 

social reasons and respite care in the absence of any deterioration in the patient’s 
general condition

is medically significant, i.e. defined as an event that jeopardizes the subject or may require 
medical or surgical intervention.
Life-threatening in the context of a SAE refers to a reaction in which the subject was at risk of 
death at the time of the reaction; it does not refer to a reaction that hypothetically might have 
caused death if more severe.
All malignant neoplasms will be assessed as serious under “medically significant” if other 
seriousness criteria are not met.
Any suspected transmission via a medicinal product of an infectious agent is also considered a 
serious adverse reaction.
Medical and scientific judgment should be exercised in deciding whether other situations should 
be considered serious reactions, such as important medical events that might not be immediately 
life threatening or result in death or hospitalization but might jeopardize the patient or might 
require intervention to prevent one of the other outcomes listed above. Examples of such events 
are intensive treatment in an emergency room or at home for allergic bronchospasm, blood 
dyscrasias or convulsions that do not result in hospitalization or development of dependency or 
abuse.
All AEs (serious and non-serious) are captured on the CRF, SAEs also require individual 
reporting to Drug Safety and Epidemiology (DS&E) as per Section 9.2.2.


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9.2.2
SAE reporting
To ensure subject safety, every SAE, regardless of causality, occurring after the patient has 
provided informed consent and until 30 days after the last study visit must be reported to 
Novartis within 24 hours of learning of its occurrence as described below. Any SAEs 
experienced after this should only be reported to Novartis if the Investigator suspects a causal 
relationship to study treatment. 
Recurrent episodes, complications, or progression of the initial SAE must be reported as follow-
up to the original episode, regardless of when the event occurs. This report must be submitted 
within 24 hours of the Investigator receiving the follow-up information. An SAE that is 
considered completely unrelated to a previously reported one should be reported separately as 
a new event.
Information about all SAEs (either initial or follow up information) is collected and recorded 
on the paper Serious Adverse Event Report Form. The Investigator must assess the relationship 
to each specific component of study treatment (if study treatment consists of several drugs)
complete the SAE Report Form in English, and send the completed, signed form by fax within 
24 hours after awareness of the SAE to the local Novartis DS&E Department, notifying the 
Clinical Trial Leader. Contact information is listed in the Site Operations Manual. 
The original copy of the SAE Report Form and the fax confirmation sheet must be kept with 
the source documentation at the study site. Follow-up information should be provided using a 
new paper SAE Report Form stating that this is a follow-up to a previously reported SAE.
SAEs (initial and follow-up) that are recorded electronically in the Electronic Data Capture 
system should be entered, saved and e-signed within 24 hours of awareness of the SAE or 
changes to an existing SAE. These data will automatically be submitted to Novartis Drug Safety 
& Epidemiology immediately after Investigator signature or 24 hours after entry, whichever 
occurs first. Study site personnel must also inform the Clinical Trial Leader.
Follow- up information provided should describe whether the event has resolved or continues, 
if and how it was treated, whether the treatment code was broken or not and whether the subject
continued or withdrew from study participation. Each re-occurrence, complication, or 
progression of the original event should be reported as a follow-up to that event regardless of 
when it occurs.
If the SAE is not previously documented in the Investigator’s Brochure or Package Insert (new 
occurrence) and is thought to be related to the investigational treatment a DS&E Department 
associate may urgently require further information from the Investigator for Health Authority 
reporting. Novartis may need to issue an Investigator Notification (IN) to inform all 
Investigators involved in any study with the same investigational treatment that this SAE has 
been reported. Suspected Unexpected Serious Adverse Reactions (SUSARs) will be collected 
and reported to the competent authorities and relevant ethics committees in accordance with EU 
Guidance 2011/C 172/01 or as per national regulatory requirements in participating countries.


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9.3
Infection Monitoring
All infections that develop during the study will be reported as AEs. Investigators are requested 
to specifically enquire about signs and symptoms of infections at each visit, in particular 
bacterial enterocolitis. Treatment and additional evaluations will be performed at the discretion 
of the Investigator. WBC count (including differential count) is assessed at every visit. If the 
neutrophil count falls below 1000 per μL, then weekly assessments of WBC are recommended
until recovery to within 80% of baseline.
The Investigator should consider early treatment with specific antimicrobial therapy on the 
basis of clinical diagnosis or suspicion thereof, in consultation with infectious disease experts, 
as appropriate.
The Investigator should remind the patient of the risk of infections and to instruct them to 
promptly report any symptoms of infections to the Investigator. The patients must also be 
reminded to always carry their Patient Information Card (with site contact information and 
which identifies them as participants in a clinical study with an agent with potential 
immunosuppressive effects) and to show this to any local healthcare provider they may consult 
and ask that the Investigator be contacted.
9.4
Liver safety monitoring
To ensure patient safety and enhance reliability in determining the hepatotoxic potential of an 
investigational drug, a standardized process for identification, monitoring and evaluation of 
liver events has to be followed. 
The following two categories of abnormalities / adverse events have to be considered during 
the course of the study:

Liver laboratory triggers, which will require repeated assessments of the abnormal 
laboratory parameter

Liver events, which will require close observation, follow-up monitoring and completion 
of the standard base liver CRF pages
Please refer to Table 9-1 and Table 9-2 for complete definitions of liver laboratory triggers and 
liver events. 
Every liver laboratory trigger or liver event should be followed up by the Investigator or 
designated personal at the trial site, as summarized below and detailed in in Table 9-2.
For the liver laboratory trigger:

Repeating the liver function test (LFT) within the next week to confirm elevation.
These LFT repeats should be performed using the central laboratory if possible. If this is not 
possible, then the repeats can be performed at a local laboratory to monitor the safety of the 
patient. Repeats laboratory should then be performed at central laboratory as soon as possible. 
If a liver event is subsequently reported, any local LFTs previously conducted that are 
associated with this event should be reported on the Liver CRF pages.


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For the liver events:

Repeating the LFT to confirm elevation as appropriate

Discontinuation of the investigational drug (refer to Section 7.1, if appropriate)

Hospitalization of the patient if appropriate

A causality assessment of the liver event via exclusion of alternative causes (e.g. disease, 
co-medications)

An investigation of the liver event which needs to be followed until resolution. 
These investigations can include serology tests, imaging and pathology assessments, 
hepatologist’s consultancy, based on Investigator’s discretion. All follow-up information, and 
the procedures performed should be recorded as appropriate in the CRF, including the liver 
event overview CRF pages.
Table 9-1
Liver Event and Laboratory Trigger Definitions
Definition/ threshold
Liver laboratory triggers
3 x ULN < ALT / AST 5 x ULN
1.5 x ULN < TBL 2 x ULN
Liver events
ALT or AST > 5 × ULN
ALP > 2 × ULN (in the absence of known bone pathology)
TBL > 2 × ULN (in the absence of known Gilbert syndrome)
ALT or AST > 3 × ULN and INR > 1.5 
Potential Hy’s Law cases (defined as ALT or AST > 3 × ULN and 
TBL > 2 × ULN [mainly conjugated fraction] without notable 
increase in ALP to > 2 × ULN)
Any clinical event of jaundice (or equivalent term)
ALT or AST > 3 × ULN accompanied by (general) malaise, fatigue, 
abdominal pain, nausea, or vomiting, or rash with eosinophilia
Any adverse event potentially indicative of a liver toxicity * 


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Table 9-2
Follow Up Requirements for Liver Events and Laboratory Triggers
Criteria
Actions required
Follow-up monitoring
Potential Hy’s Law casea

Discontinue the study drug 
immediately

Hospitalize, if clinically 
appropriate

Establish causality

Complete liver CRF
ALT, AST, TBL, Alb, PT/INR, 
ALP and γGT until resolutionc
(frequency at Investigator 
discretion)
ALT or AST
> 8 × ULN

Discontinue the study drug 
immediately

Hospitalize if clinically appropriate

Establish causality

Complete liver CRF
ALT, AST, TBL, Alb, PT/INR, 
ALP and γGT until resolutionc
(frequency at Investigator 
discretion)
> 3 × ULN and INR > 1.5

Discontinue the study drug 
immediately

Hospitalize, if clinically 
appropriate

Establish causality

Complete liver CRF
ALT, AST, TBL, Alb, PT/INR, 
ALP and γGT until resolutionc
(frequency at Investigator 
discretion)
> 5 to ≤ 8 × ULN

Repeat LFT within 48 hours

If elevation persists, continue 
follow-up monitoring

If elevation persists for more than 
2 weeks, discontinue the study 
drug

Establish causality

Complete liver CRF
ALT, AST, TBL, Alb, PT/INR, 
ALP and γGT until resolutionc
(frequency at Investigator 
discretion)
> 3 × ULN accompanied 
by symptomsb

Discontinue the study drug 
immediately

Hospitalize if clinically appropriate

Establish causality

Complete liver CRF
ALT, AST, TBL, Alb, PT/INR, 
ALP and γGT until resolutionc
(frequency at Investigator 
discretion)
> 3 to ≤ 5 × ULN 
(patient is asymptomatic)

Repeat LFT within the next week

If elevation is confirmed, initiate 
close observation of the patient
Investigator discretion
Monitor LFT within 1 to 4 weeks 
ALP (isolated)
> 2 × ULN (in the 
absence of known bone 
pathology)

Repeat LFT within 48 hours

If elevation persists, establish 
causality

Complete liver CRF
Investigator discretion
Monitor LFT within 1 to 4 weeks 
or at next visit


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Criteria
Actions required
Follow-up monitoring
TBL (isolated)
> 2 × ULN (in the 
absence of known Gilbert 
syndrome)

Repeat LFT within 48 hours

If elevation persists, discontinue 
the study drug immediately

Hospitalize if clinically appropriate

Establish causality

Complete liver CRF
ALT, AST, TBL, Alb, PT/INR, 
ALP and γGT until resolutionc
(frequency at Investigator 
discretion)
Test for hemolysis (e.g. 
reticulocytes, haptoglobin, 
unconjugated [indirect] bilirubin)
> 1.5 to ≤ 2 × ULN
(patient is asymptomatic)

Repeat LFT within the next week

If elevation is confirmed, initiate 
close observation of the patient
Investigator discretion
Monitor LFT within 1 to 4 weeks 
or at next visit
Jaundice

Discontinue the study drug 
immediately

Hospitalize the patient

Establish causality

Complete liver CRF
ALT, AST, TBL, Alb, PT/INR, 
ALP and γGT until resolutionc
(frequency at Investigator 
discretion)
Any AE potentially 
indicative of a liver 
toxicity*

Consider study drug interruption 
or discontinuation 

Hospitalization if clinically 
appropriate

Establish causality

Complete liver CRF
Investigator discretion
*These events cover the following: hepatic failure, fibrosis and cirrhosis, and other liver damage-
related conditions; the non-infectious hepatitis; the benign, malignant and unspecified liver 
neoplasms
aElevated ALT/AST > 3 × ULN and TBL > 2 × ULN but without notable increase in ALP to > 2 × ULN
b(General) malaise, fatigue, abdominal pain, nausea, or vomiting, or rash with eosinophilia 
c Resolution is defined as an outcome of one of the following: (1) return to baseline values, (2) stable 
values at three subsequent monitoring visits at least 2 weeks apart, (3) remain at elevated level 
after a maximum of 6 months, (4) liver transplantation, and (5) death.
9.5
Renal safety monitoring
Renal events are defined as one of the following:

confirmed (after ≥ 24h) increase in serum creatinine of ≥ 25% compared to baseline 
during normal hydration status

new onset (≥1+) proteinuria, hematuria or glucosuria; or as a

doubling in the urinary albumin-creatinine ratio (ACR) or urinary protein-creatinine ratio 
(PCR) (if applicable).


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The following two categories of abnormalities/adverse events have to be considered during the 
course of the study:

Serum creatinine triggers that will require follow up and repeat assessments of the 
abnormal laboratory parameter 

Urine dipstick triggers that will require follow up and repeat assessments of the abnormal 
laboratory parameter
Baseline serum creatinine is determined as the mean of the serum creatinine measurements at 
screening and pretreatment on Day 1. 
Table 9-3
Specific Renal Alert Criteria and Actions
Renal Event
Actions
Serum creatinine increase
25 – 49% compared to baseline
Confirm 25% increase after 24-48h 
Follow up within 2-5 days
Serum creatinine increase  50 % 
compared to baseline
Follow up within 24-48h if possible
Consider drug interruption 
Consider patient hospitalization /specialized treatment
Albumin- or Protein-creatinine ratio 
increase ≥ 2-fold
Albumin-creatinine ratio (ACR) ≥ 30 
mg/g or ≥ 3 mg/mmol;
New dipstick proteinuria ≥ 1+
Protein-creatinine ratio (PCR )≥ 150 
mg/g or >15 mg/mmol
Confirm value after 24-48h
Perform urine microscopy
Consider drug interruption / discontinuation 
New dipstick glucosuria ≥ 1+ not due to 
diabetes
Blood glucose (fasting)
Perform serum creatinine, ACR 
New dipstick hematuria not due to 
trauma
Urine sediment microscopy
Perform serum creatinine, ACR 
Document contributing factors: co-medication, other co-morbid conditions, and additional diagnostic 
procedures performed in the CRF
Monitor patient regularly (frequency at investigator’s discretion) until one of the following:
Event resolution: (sCr within 10% of baseline or protein-creatinine ratio within 50% of baseline) 
Event stabilization: sCr level with ±10% variability over last 6 months or protein-creatinine ratio 
stabilization at a new level with ±50% variability over last 6 months.
9.6
Pregnancy reporting
To ensure patient safety, each pregnancy in a patient on study drug must be reported to Novartis 
within 24 hours of learning of its occurrence. The pregnancy should be followed up to determine 
outcome, including spontaneous or voluntary termination, details of the birth, and the presence 
or absence of any birth defects, congenital abnormalities, or maternal and/or newborn 
complications. The study drug must be discontinued, though the patient may stay in the study, 
if she wishes to do so. All assessments that are considered as a risk during pregnancy must not 
be performed. The patient may continue all other protocol assessments. Pregnancy must be 
recorded on a Pharmacovigilance Pregnancy Form and reported by the Investigator to the local 


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Novartis DS&E Department. Pregnancy follow-up should be recorded on the same form and 
should include an assessment of the possible relationship to the Novartis study drug of any 
pregnancy outcome. Any SAE experienced during pregnancy must be reported on an SAE 
Report Form.
9.7
Early phase safety monitoring
The Investigator will monitor adverse events in an ongoing manner and inform the Sponsor of 
any clinically relevant observations. Any required safety reviews will be made jointly between 
medically qualified personnel representing the Sponsor and Investigator. Such evaluations may 
occur verbally, but the outcome and key discussion points will be summarized in writing 
(e-mail) and made available to both Sponsor and all Investigator(s). Criteria pertaining to 
stopping the study/treatment or adapting the study design are presented above.
When two or more clinical site(s) are participating in the clinical study, the Sponsor will advise 
the Investigator(s) at all sites in writing (e-mail) (and by telephone if possible) of any new, 
clinically relevant safety information reported from another site during the conduct of the study 
in a timely manner.
10
Data review and database management
10.1
Site monitoring
Before study initiation, at a site initiation visit or at an Investigator’s meeting, a Novartis
representative will review the protocol and CRFs with the Investigators and their staff. 
During the study Novartis employs several methods of ensuring protocol and GCP compliance 
and the quality/integrity of the sites’ data. The monitor will visit the site to check the 
completeness of patient records, the accuracy of entries on the CRFs, the adherence to the 
protocol and to Good Clinical Practice, the progress of enrollment, and to ensure that study drug 
is being stored, dispensed, and accounted for according to specifications. Key study personnel 
must be available to assist the monitor during these visits.
The Investigator must maintain source documents for each patient in the study, consisting of 
case and visit notes (hospital or clinic medical records) containing demographic and medical 
information, laboratory data, electrocardiograms, and the results of any other tests or 
assessments. All information on CRFs must be traceable to these source documents in the 
patient's file. The Investigator must also keep the original informed consent form signed by the 
patient (a signed copy is given to the patient).
The Investigator must give the monitor access to all relevant source documents to confirm their 
consistency with the CRF entries. Novartis monitoring standards require full verification for the 
presence of informed consent, adherence to the eligibility criteria, documentation of SAEs, and 
the recording of data that will be used for all primary and safety variables. Additional checks 
of the consistency of the source data with the CRFs are performed according to the study-
specific monitoring plan. No information in source documents about the identity of the patients
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10.2
Data collection
Designated Investigator staff will enter the data required by the protocol into the Electronic 
Case Report Forms (eCRFs) using fully validated software that conforms to 21 CFR Part 11 
requirements. Designated Investigator site staff will not be given access to the Electronic Data 
Capture (EDC) system until they have been trained. Automatic validation programs check for 
data discrepancies and, by generating appropriate error messages, allow the data to be 
confirmed or corrected before transfer of the data to the CRO working on behalf of Novartis. 
The Investigator must certify that the data entered into the eCRF are complete and accurate. 
After database lock, the Investigator will receive a CD-ROM or paper copies of the patient data 
for archiving at the investigational site.
All data should be recorded, handled and stored in a way that allows its accurate reporting, 
interpretation and verification.
The CRO working on behalf of Novartis review the data entered into the eCRF by 
investigational staff for completeness and accuracy and instructs the site personnel to make any 
required corrections or additions. Queries are sent to the investigational site using an electronic 
data query. Designated Investigator site staff is required to respond to the query and confirm or 
correct the data. If the electronic query system is not used, a paper Data Query Form will be 
faxed to the site. Site personnel will complete and sign the faxed copy and fax it back to the
CRO working on behalf of Novartis who will make the correction to the database.
Concomitant medications entered into the database will be coded using the WHO Drug 
Reference List, which employs the Anatomical Therapeutic Chemical classification system. 
Medical history/current medical conditions and adverse events will be coded using the Medical 
dictionary for regulatory activities (MedDRA) terminology.
Laboratory samples will be processed centrally and the results will be sent electronically to 
Novartis (or a designated CRO).
At the conclusion of a non-IRT study, the occurrence of any emergency code breaks will be 
determined after return of all code break reports and unused drug supplies to Novartis. 
The occurrence of any protocol deviations will be determined. After these actions have been 
completed and the database has been declared to be complete and accurate, it will be locked 
and the treatment codes will be unblinded and made available for data analysis. Any changes 
to the database after that time can only be made by joint written agreement between the 
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10.3
Data Monitoring Committee
The DMC will be established (according to Novartis Standard Operating Procedures) for part 
II of the study. The DMC is an unblinded independent board comprised of specialists with 
specific knowledge related to conducting clinical studies. Specific details on the composition 
and the scope of its mandate will be presented in a DMC charter document.
10.4
Adjudication Committee
Not required.
11
Data analysis
11.1
Analysis sets
For all analysis sets, patients will be analyzed according to the study treatment(s) received.
The full analysis set will include all patients that received any study drug.
The safety analysis set will include all patients that received any study drug.
The PK analysis set will include all patients with available PK data and no protocol deviations 
with relevant impact on PK data.
The PD analysis set will include all patients who received any study drug and with no protocol 
deviations with relevant impact on PD data.
In Part II, the key safety and efficacy endpoints will also be reported by age group (>=18 years 
old and < 18 years old).
11.2
Subject demographics and other baseline characteristics
In Part I
All data for background and demographic variables will be listed by patient. Summary statistics 
will be provided for all patients.
Relevant medical history, current medical conditions, results of laboratory screens, drug tests 
and any other relevant information will be listed by patient.
In Part II
All data for background and demographic variables will be listed by treatment and patient. 
Summary statistics will be provided by treatment.
Relevant medical history, current medical conditions, results of laboratory screens, drug tests 
and any other relevant information will be listed by treatment and patient.
11.3
Treatments (study drug, rescue medication, other concomitant 
therapies, compliance)
Data for study drug administration (rescue medication) and concomitant therapies will be listed 
by patient in Part I, and by treatment and patient in Part II.


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11.4
Analysis of the primary variable(s)
The primary aim of Part I, along with assessing safety and tolerability, was to determine a dose 
to be used in the confirmatory Part II. The primary aim of Part II is to assess efficacy of CDZ173
at the selected dose (70 mg b.i.d.) after 12 weeks of treatment. 
In Part I, phosphorylated Akt from unstimulated B cells was quantified at baseline and at the 
end of the 4-week treatment period with each of the three dose levels. The lowest dose level (up 
to 70 mg b.i.d.) leading to normalization of the unstimulated pAkt in B cells to healthy volunteer 
levels should be carried into Part II for generation of confirmatory data, but ex vivo stimulated 
pAkt in B cells and other variables may also be taken into account for the selection of the dose. 
In Part II, lymphadenopathy will be measured by the SPD of index lesions (selected as per the 
Cheson methodology (Cheson et al 1999) from MRI/CT imaging) and immunodeficiency will 
be measured by percentage of naïve B cells out of total B cells. The co-primary endpoints are 
the change from baseline in the log10 transformed SPD of index lesions and the change from 
baseline in the percentage of naïve B cells out of total B cells at the end of treatment.
11.4.1
Variable(s)
The selection of the dose from Part I to be carried into Part II was based on inhibition of 
unstimulated or stimulated pAkt levels in B cells and other variables, including but not 
necessarily limited to, safety and PK data and biomarkers. Average pAkt inhibition over the 
dosing interval is defined as the AUC of the inhibition from baseline over 12 hours normalized 
by the length of the dosing interval (12 hours). Baseline is defined as the arithmetic mean of the 
Day -1 sample and the Dose 1 Day 1 pre-dose sample. 
In Part II, index lesions will be selected from measurable nodal and extranodal lesions as per 
the Cheson methodology (Cheson et al 1999, see the imaging review charter for details). 
A maximum of six of the largest dominant lesions should be selected and documented at 
baseline and assessed again at the end of treatment (i.e. the Day 85 assessment for patients who 
complete the 12 week treatment period or the treatment discontinuation visit for patients who 
discontinue treatment prematurely prior to Day 85 visit). The percentage of naïve B cells is 
assessed at baseline, Day 1, Day 29, Day 57 and Day 85, and at the discontinuation visit for 
patients who discontinue treatment prematurely prior to Day 85 visit. The co-primary variables
to assess efficacy in Part II will be the change from baseline in the log10-transformed sum of 
the products of diameters (SPD) of the index lesions and the change from baseline in the
percentage of naïve B cells out of total B cells.
In Part I, the variables to assess safety consist of AEs, physical exam, vital signs, ECGs, and 
safety laboratory parameters.
11.4.2
Statistical model, hypothesis, and method of analysis
In Part I, a repeated measure concentration-response model will be fitted to link systemic drug 
concentration and (un)stimulated pAkt inhibition at each measured time point (including the 
trough samples taken at later visits). An Emax model will be considered, where the inhibition 
at dose 0 is fixed at 0. The ED50, the Emax and the hill parameter will be estimated from the 
data, and a random effect for ED50 and Emax will be estimated for each patient to account for 
the within-subject correlation between timepoints. Population model parameters will be 


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converted into their dose equivalents based on desired time-averaged pathway inhibition and 
estimated oral drug clearance of CDZ173 in the target population.  
The average unstimulated pAkt inhibition over the dosing interval (12 h) at each dose level will
also be estimated from an Emax dose-response model accounting for intra-individual 
correlation for the measurements at different doses. The average pAkt inhibition over the dosing 
interval of 12 h will be calculated based on the measured pre-dose and the 1 h, 3 h, 8 h post-
dose samples for each dose level with a trapezoidal rule as the AUC over 12 hours normalized 
by the length of the dosing interval (12 h). Baseline will be defined as the arithmetic mean of 
the Day -1 sample and the Dose 1 Day 1 pre-dose sample. The 12h time point will be estimated
as an arithmetic mean of the Day 8 and Day 15 pre-dose.
In the Emax dose-response model, the inhibition at doses 0 will be fixed to zero. The hill parameter 
will be fixed to 1 and the Emax (inhibition at dose of infinity) and ED50 (dose leading to 50% 
inhibition of unstimulated pAkt) will be estimated from the data. A random effect for ED50 will be 
estimated for each patient to account for within-patient correlation.
Depending on the average baseline unstimulated pAkt levels, the average level of inhibition 
needed to reach healthy volunteer levels will be determined. If the dose achieving this level of 
inhibition cannot be estimated reliably, other parameters such as ED50, either from 
unstimulated or simulated cells (see below) may be used for the selection of the dose to be 
carried into Part II. This may be a different dose (up to 70 mg b.i.d) than the 3 doses studied in Part I. 
All available data will be included in the model. In case it is not possible to measure or model the 
unstimulated pAkt levels accurately, decision may be based on modeling of the stimulated pAkt levels. 
Other variables may also be taken into account for the selection of the dose. 
In Part II, the SPD of index lesions will be log10 transformed and the change from baseline of 
the log10 transformed SPD at the end of treatment (i.e. the Day 85 assessment for patients who 
complete the 12 week treatment period or the treatment discontinuation visit for patients who 
discontinue treatment prematurely prior to Day 85 visit) will be calculated for patients with
baseline and end of treatment SPD measurements. An analysis of covariance will be done to 
compare the change of the log10 transformed SPD from baseline with treatment as fixed and log10 
transformed baseline SPD as a covariate. The baseline intake of glucocorticoids as well as the 
information about being treated with intravenous immunoglobulin G (IgG) will both be included as 
categorical (Yes/No) covariates. Comparison of the two treatment groups will be two-sided, with a 
5% type I error. Patients with zero lesions at baseline will be excluded from the analysis.
The change from baseline in naïve B cells out of total B cells at the end of treatment (i.e. the 
Day 85 assessment for patients who complete the 12 week treatment period or the treatment 
discontinuation visit for patients who discontinue treatment prematurely prior to Day 85 visit) 
will be calculated for patients with baseline and end of treatment measurements. Baseline will 
be defined as the arithmetic mean of the baseline and Day 1 values. An analysis of covariance 
will be done to compare the change from baseline in the naïve B cells between the two treatment 
groups, adjusted for baseline naïve B cells count. The use of glucocorticoids and intravenous 
IgG at baseline will both be included as categorical (Yes/No) fixed effects. Comparison of the 
two treatment groups will be two-sided, with a 5% type I error. Only patients with a reduced 
percentage of naïve B cells at baseline (defined as below 48 % van Gent et al 2009) will be 
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In Part I, all vital signs, ECG, and laboratory data were listed by patient and visit/time and if 
ranges are available abnormalities (and relevant orthostatic changes) were flagged. Summary 
statistics were provided by visit/time. All information obtained on adverse events was displayed 
by treatment and patient. The number and percentage of subjects with adverse events were
tabulated by body system and preferred term with a breakdown by treatment. An adverse event 
starting in one period and continuing into the next period was counted only in the onset period. 
A patient with multiple adverse events within a body system and treatment period was only 
counted once towards the total of this body system and treatment.
11.4.3
Handling of missing values/censoring/discontinuations
In Part I, the primary analysis model included all available data, which were considered valid 
under the missing at random (MAR) assumption.
In Part II, the primary analysis of the lymphadenopathy will include only patients with baseline 
and end of treatment lymphadenopathy measurements. Also patients with zero lesions at 
baseline will be excluded from the lymphadenopathy analysis. The primary analysis of the naïve 
B cells will include only patients who have baseline and end of treatment naïve B cells 
measurements and who also have a reduced percentage of naïve B cells at baseline (defined as 
below 48 % van Gent et al 2009). Data collected after the treatment discontinuation visit will 
not be used in the primary analysis. No methods for imputation of missing data (including those 
due to COVID-19) are planned.
11.4.4
Supportive analyses
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11.5
Analysis of secondary and exploratory variables
11.5.1
Efficacy / Pharmacodynamics
In Part I
The changes from baseline of SF-36 and WPAI-CIQ summary scores, and of visual analogue 
scale scores for PGA and PtGA, were calculated and summary statistics were provided by visit.
Summary statistics by treatment and visit were provided for the change from baseline in High 
Sensitivity C-reactive protein (hsCRP) and Lactate dehydrogenase (LDH). 
The SPD of index lesions will be log10 transformed and the change from baseline of the log 
transformed SPD at the end of treatment were calculated for all patients. Summary statistics for 
the change from baseline of the log10 transformed SDP were provided.
The non-index lesions were analyzed as per the Cheson criteria (Cheson et al 1999) described 
in the imaging manual.
In Part II
The change from baseline of SF-36 and WPAI-CIQ scores, and of visual analogue scale scores 
for PGA and PtGA, will be calculated and summary statistics will be provided by treatment and 
visit. An analysis of covariance will be done to compare the change from baseline at the end of 
treatment (i.e. the Day 85 assessment for patients who complete the 12 week treatment period 
or the treatment discontinuation visit for patients who discontinue treatment prematurely prior 
to Day 85 visit) between the two treatment groups, adjusted for baseline value. Comparison of
the two treatment groups will be two-sided, with a 5% type I error.  The change from baseline 
will also be analyzed using a longitudinal mixed model, with treatment, time, treatment by time, 
baseline and baseline by time interaction as fixed effects. For patients who complete the 
treatment period, this repeated measures analysis will include all measurements in the treatment 
period (Baseline, Day 29, Day 57 and Day 85). For patients who discontinue treatment 
prematurely only data up to and including the last planned visit prior to discontinuation will be 
included in the analysis. Data collected at the treatment discontinuation visit and thereafter will 
be excluded. An unstructured covariance matrix will be fitted to adjust for correlations among 
the measurements made on the same patient. The difference between the treatment groups in 
the change from baseline after 12 weeks of treatment will be assessed at two-sided 5% 
significance level.
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Summary statistics by visit will be provided for the change from baseline hsCRP, LDH, beta2
macroglobulin, ferritin, fibrinogen and ESR.
Summary statistics for the 3D volume of index and measureable non-index lesions and 3D 
volume and bi-dimensional size of spleen will be provided. An analysis of covariance will be 
done to compare the change of the log10 transformed value from baseline between the two 
treatment groups, adjusted for baseline value. Comparison of the two treatment groups will be 
two-sided, with a 5% type I error.
In Part I and II the non-index lesions will be analyzed as per the Cheson criteria (Cheson et al 1999) 
described in the imaging manual.
In Part II, summary statistics for the activity parameters (e.g. mean daily number of steps, real 
world gait speed, overall distance of walking) will be provided by treatment and period (one 
week at baseline before first treatment and one week as close as possible to Day 85 visit). 
11.5.2
Safety
Vital signs
In Part II, all vital signs data will be listed by treatment, patient and visit/time, and if ranges are 
available abnormalities (and relevant orthostatic changes) will be flagged. Summary statistics 
will be provided by treatment group and visit/time.
ECG evaluations
In Part II, all ECG data will be listed by treatment, patient and visit/time, abnormalities will be 
flagged. Summary statistics will be provided by visit/time.
Clinical laboratory evaluations
In Part II, all laboratory data will be listed by treatment, patient and visit/time, and if normal 
ranges are available abnormalities will be flagged. Summary statistics will be provided by 
treatment and visit/time.
Adverse events
In Part II, all information obtained on adverse events will be displayed by treatment and patient. 
The number and percentage of patients with adverse events will be tabulated by body system 
and preferred term with a breakdown by treatment. A subject with multiple adverse events 
within a body system is only counted once towards the total of this body system.


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11.5.3
Pharmacokinetics
CDZ173 plasma concentration data will be listed by treatment, patient, and visit/sampling time 
point. Descriptive summary statistics will be provided by treatment and visit/sampling time 
point. 
. Summary statistics will include 
mean (arithmetic and geometric), SD, CV (arithmetic and geometric), median, minimum and 
maximum. 
A geometric mean will not be reported if the dataset includes zero values.
Pharmacokinetic parameters will be calculated as described in Section 8.5 and will be listed by 
treatment and subject. Summary statistics will include mean (arithmetic and geometric), SD, 
CV (arithmetic and geometric), median, minimum and maximum. An exception to this is Tmax 
where median, minimum and maximum will be presented.
11.5.4
Pharmacokinetic / pharmacodynamic interactions
Relationships between exposure and selected PD or biomarker variables will be explored by a 
graphical approach and descriptive statistics of exposure and PD or biomarker variables will be 
provided. Additional analysis such as exposure-response models will be performed, if warranted.
11.5.5
Other assessments
11.5.5.1 Exploratory biomarkers
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11.6
Sample size calculation
In Part I
The sample size for Part I (6 patients) was mainly based on feasibility, while still providing 
adequate precision to identify an appropriate dose for Part II. 
In Part II
For Part II, the sample size (20 patients in active and 10 patients in placebo for a total of 
30 patients) is mostly driven by the analysis of one of the two co-primary efficacy variables, 
the change from baseline in the log10-transformed SPD of index lesions. 
Assuming that 10% of patients are excluded from the analysis of the other co-primary variable, 
the change from baseline in the percentage of naïve B cells out of total B cells, due to no reduced 
percentage of naïve B cells at baseline, it is anticipated that 27 patients will provide data for the
analysis. Assuming an increase of 25% points and comparable variability as in Part I for the 
change from baseline to 12 weeks in the percentage of naïve B cells (standard deviation of 14), 
with 27 patients this part of the study will have 98% power to detect a statistically significant 
p-value at the 5% level.
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With the above assumptions, the power to achieve a statistical significance in both endpoints is 
at least 78%.
11.7
Power for analysis of key secondary variables
Not applicable.
11.8
Interim analyses
12
Ethical considerations
12.1
Regulatory and ethical compliance
This clinical study was designed and shall be implemented and reported in accordance with the 
ICH Harmonized Tripartite Guidelines for Good Clinical Practice, with applicable local 
regulations (including European Directive 2001/20/EC, US Code of Federal Regulations Title 
21, and Japanese Ministry of Health, Labor, and Welfare), and with the ethical principles laid 
down in the Declaration of Helsinki.
12.2
Responsibilities of the investigator and IRB/IEC
Before initiating a trial, the Investigator/institution should obtain approval/favorable opinion 
from the Institutional Review Board/Independent Ethics Committee (IRB/IEC) for the trial 
protocol, written informed consent form, consent form updates, patient recruitment procedures 
(e.g. advertisements) and any other written information to be provided to patients. Prior to study 
start, the Investigator is required to sign a protocol signature page confirming his/her agreement 
to conduct the study in accordance with these documents and all of the instructions and 
procedures found in this protocol and to give access to all relevant data and records to Novartis 
monitors, auditors, Novartis Quality Assurance representatives, designated agents of Novartis, 
IRBs/IECs, and regulatory authorities as required. If an inspection of the clinical site is 
requested by a regulatory authority, the Investigator must inform Novartis immediately that this 
request has been made.
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For multi-center trials, a Coordinating Investigator will be selected by Novartis around the time 
of Last Patient Last Visit to be a reviewer and signatory for the clinical study report.
12.3
Publication of study protocol and results
Novartis assures that the key design elements of this protocol will be posted in a publicly 
accessible database such as clinicaltrials.gov. In addition, upon study completion and 
finalization of the study report the results of this trial will be either submitted for publication 
and/or posted in a publicly accessible database of clinical trial results.
13
Protocol adherence
This protocol defines the study objectives, the study procedures and the data to be collected on 
study participants. Additional assessments required to ensure safety of subjects should be 
administered as deemed necessary on a case by case basis. Under no circumstances should an 
Investigator collect additional data or conduct any additional procedures for any research related 
purpose involving any investigational drugs.
Investigators must apply due diligence to avoid protocol deviations. If the Investigator feels a 
protocol deviation would improve the conduct of the study this must be considered a protocol 
amendment, and unless such an amendment is agreed upon by Novartis and approved by the 
IRB/IEC/REB it cannot be implemented. All significant protocol deviations will be recorded 
and reported in the CSR.
13.1
Protocol Amendments
Any change or addition to the protocol can only be made in a written protocol amendment that 
must be approved by Novartis, Health Authorities where required, and the IRB/IEC prior to 
implementation. 
Only amendments that are intended to eliminate an apparent immediate hazard to subjects may 
be implemented, provided the Health Authorities and the reviewing IRB/IEC are subsequently
notified by protocol amendment.
Notwithstanding the need for approval of formal protocol amendments, the Investigator is 
expected to take any immediate action required for the safety of any subject included in this 
study, even if this action represents a deviation from the protocol. In such cases, the CTL should 
be informed and (serious) adverse event reporting requirements (Section 9) followed as 
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14
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standardization in children and adolescents with cystic fibrosis: the way forward. Eur Respir J 
47:1706-1717.
Lucas C, Kuehn HS, Zhao F, et al (2014) Dominant-activating germline mutations in the gene 
encoding the PI(3)K catalytic subunit p110δ result in T cell senescence and human 
immunodeficiency. Nat Immunol 15: 88-97.
Michalovich D and Nejentsev S (2018) Activated PI3 Kinase Delta Syndrome: From Genetics 
to Therapy. Front Immunol 9: 369.


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Nagayama Y, Oda S, Nakaura T, et al (2018) Radiation dose reduction at pediatric CT: use of 
low tube voltage and iterative reconstruction. Radiographics 38:1421-1440.
Rao VK, Webster S, Dalm VASH, et al (2017) Effective “activated PI3Kd syndrome”–
targeted therapy with the PI3Kd inhibitor leniolisib. Blood 130(21): 2307-2316
Rao VK, Webster S, Dalm VASH, et al (2018) Safety and efficacy of long term suppression
of PI3kinase pathway by small molecule PI3Kδ inhibitor leniolisib in APDS 
(ActivatedPI3KδSyndrome). Poster presentation ESID, Lisbon, Portugal Oct 2018.
van Gent R, van Tilburg CM, Nibbelke EE, et al (2009) Refined characterization and 
reference values of the pediatric T- and B-cell compartments. Clin Immunol 133: 95–107.
Wang M, Popplewell LL, Collins RH, et al (2014) Everolimus for patients with mantle cell 
lymphoma refractory to or intolerant of bortezomib: multicentre, single-arm, phase 2 study. 
British Journal of Haematology, 165: 510–518
Wang Y, Moss J, Thisted R (1992) Predictors of body surface area. J Clin Anesth. 4:4-10


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Appendix 1
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SAP_001.pdf: 
Clinical Development
CDZ173
CCDZ173X2201 / NCT02435173
An open-label, non-randomized, within-patient dose-finding 
study followed by a randomized, double-blind placebo 
controlled study with extension to assess the safety and 
efficacy of CDZ173 in patients with APDS/PASLI (Activated 
phosphoinositide 3-kinase delta syndrome/ p110δ-
activating mutation causing senescent T cells, 
lymphadenopathy and immunodeficiency)
RAP Module 3: Detailed Statistical Methodology-Part I
Author(s):
Document type:
Document status:
Release date:
Property of Novartis
Confidential
May not be used, divulged, published or otherwise disclosed
without the consent of Novartis
Personal Protected Data
RAP Module 3: Detailed Statistical Methodology
Final V3
8-NOV-2016
`


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Table of contents
Table of contents.............................................................................................................................................2
List of tables....................................................................................................................................................3
1
Introduction to RAP documentation ...............................................................................................................4
1.1
Scope.................................................................................................................................................4
1.2
Changes to RAP documentation (M3) ..............................................................................................4
2
Study objectives and design............................................................................................................................5
2.1
Study objectives................................................................................................................................5
2.1.1
Part I..............................................................................................................................5
2.2
Study design and treatment...............................................................................................................6
2.2.1
Part I..............................................................................................................................6
3
First interpretable results (FIR).......................................................................................................................7
4
Interim analyses ..............................................................................................................................................7
5
Statistical methods: Analysis sets ...................................................................................................................7
6
Statistical methods for Pharmacokinetic (PK) parameters..............................................................................8
6.1
Pharmacokinetic parameters .............................................................................................................8
6.2
Statistical methods for pharmacokinetic parameters.........................................................................8
6.3
Pharmacokinetic / pharmacodynamic interactions............................................................................8
7
Statistical methods for Pharmacodynamic (PD) parameters...........................................................................9
7.1
Primary Objective .............................................................................................................................9
7.1.1
PD Variable(s)...............................................................................................................9
7.1.2
Statistical analysis of PD parameter(s)........................................................................10
7.1.3
Handling of missing values/censoring/discontinuations .............................................12
7.2
Analysis of secondary and exploratory variables............................................................................12
7.2.1
Efficacy / Pharmacodynamic.......................................................................................12
7.2.2
Efficacy: Imaging........................................................................................................12
8
Statistical methods for safety and tolerability data .......................................................................................13
8.1
Patient demographics and other baseline characteristics.................................................................13
8.2
Treatments (study drug, rescue medication, other concomitant therapies, compliance).................13
8.3
Vital signs .......................................................................................................................................13
8.4
ECG evaluations .............................................................................................................................13
8.5
Clinical laboratory evaluations .......................................................................................................13
8.6
Adverse Effect................................................................................................................................. 13
8.8
Pregnancy test .................................................................................................................................13
9
Statistical methods for Biomarker data.........................................................................................................14
9.1
Efficacy and mechanistic markers ..................................................................................................14
9.1.1
Immuno-phenotyping..................................................................................................14
9.1.2
Functional immune cell assays....................................................................................16
9.1.3
Soluble protein markers ..............................................................................................16
9.1.4
Viremia markers..........................................................................................................16
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9.1.5
Exploratory genetic markers and miRNA ...................................................................16
List of tables
Table 5-1
Protocol deviation severity codes and analysis sets ......................................................7


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1
Introduction to RAP documentation
1.1
Scope
The RAP documents contain detailed information to aid the production of Statistics & Programming input into 
the Clinical Study Report (CSR) of trial “CCDZ173X2201”. This document describes the analyses for Part I. 
Module 3 (M3) provides the description of the statistical methodology used to analyze the data, Module 7
(M7) details the presentation of the data, including shells of summary tables, figures and listings, and Module 8 
(M8) contains programming specifications e.g. for derived variables and derived datasets, to support the creation 
of CSR outputs.
1.2
Changes to RAP documentation (M3)
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2
Study objectives and design 
This study is designed to explore CDZ173, a selective PI3Kδ inhibitor, in patients with genetically activated 
PI3Kδ, i.e., patients with APDS/PASLI. The study consists of two parts. Part I is the open label part designed to 
establish the safety and pharmacokinetics of CDZ173 in the target population, as well as to select the optimal 
dose to be tested in Part II. Part II is designed to assess efficacy and safety of CDZ173 in this population.
This RAP focuses on Part I only.
2.1
Study objectives
2.1.1
Part I 
2.1.1.1
Primary Objectives

To assess the safety and tolerability of CDZ173 in patients with APDS/PASLI

To assess the dose-PD and PK/PD relationship of CDZ173 in patients with APDS/PASLI for dose
selection in Part II
2.1.1.2
Secondary Objectives 

To assess the pharmacokinetics of CDZ173 in patients with APDS/PASLI

To assess the efficacy of CDZ173 to modify health-related quality of life in patients with APDS/PASLI

To assess the efficacy of CDZ173 by the Physician’s Global Assessment (PGA) and the Patient’s
Global Assessment (PtGA)

To assess biomarkers reflecting the efficacy of CDZ173 to reduce systemic inflammatory components
of the disease

To assess the treatment benefit to individual patients
2.1.1.3
Exploratory Objectives
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2.2
Study design and treatment
2.2.1
Part I
The final dose strength that patients will be receiving is 70 mg CDZ173 b.i.d 
. 
Assessments done on Day 84 will include the end of treatment MRI or CT scan.
During the four weeks after the last day of dosing the patients will be followed-up for safety. On Day 112 
patients will undergo the end of study visit. Patients who are withdrawn from the study prematurely will still be 
required to complete the follow-up period including the Study Completion Visit.
Figure 2-1 illustrates the study design for Part I.
Figure 2-1
Study Design Part I
CDZ173 (up-titration)
12 weeks
screening
follow-up
1
2
3
4
5
6
7
8
9
10
11
12
weeks
10 mg
30 mg
70 mg
bid dose
MRI/CT
PD, PK
PD, PK
PD, PK
PD, PK
PD, PK
PD, PK
PD, PK
PD, PK
PD, PK
MRI/CT
PD, PK
Dosing and Key Assessments
Part 
I 
of 
the 
study 
will 
be 
the 
non-randomized, 
open-label, 
within-patient 
up-titration 
dose-finding part in approximately 6 patients with APDS/PASLI. Safety, tolerability, pharmacokinetics (PK) and 
in vivo pharmacodynamics (PD pAkt) will be assessed at three different dose levels of CDZ173. The starting 
dose is 10 mg followed by 30 mg and 70 mg b.i.d. for 4 weeks at each dose level respectively.
During the Screening Visit (Day -50 to Day -2) patients’ eligibility will be assessed and then reviewed during the 
Baseline Visit. During this phase patients will be assessed for the following: Safety assessments which will 
include physical examinations, vital signs, standard clinical laboratory evaluations (hematology, blood chemistry, 
and urinalysis), adverse event and serious adverse event monitoring and cardiac safety which will be monitored 
by means of triplicate 12-lead electrocardiograms (ECG). Further assessments will include an MRI or CT scan, 
SF-36 and WPAI questionnaires and patient global assessment.
Patients who are deemed eligible for enrollment into the study based on the inclusion/exclusion criteria will 
attend the clinic on Day -1 for baseline assessments which include vital signs, ECG and PD blood collection.
The first day of dosing will start on Day 1 with patients receiving 10 mg of CDZ173 b.i.d.     
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 Prior to escalation of a patient to the next dose level a continuous 
safety review and review of PK and key PD data up to 7 days after the first dose (Day 8) must be assessed as 
satisfactory to proceed with next dose level.
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3
First interpretable results (FIR)
4
Interim analyses 
5
Statistical methods: Analysis sets
For all analysis sets, patients will be analyzed according to the study treatment(s) received.
The safety analysis set will include all patients that received study drug and with no protocol deviations with 
relevant impact on safety.
The PK analysis set will include all patients with at least one available valid (i.e. not flagged for exclusion) PK 
concentration measurement, who received any study drug and experienced no protocol deviations with relevant 
impact on PK data.
The PD analysis set will include all patients with any available PD data, who received any study drug and 
experienced no protocol deviations with relevant impact on PD data.
Although the study includes both pediatric and adult patients, no separate analysis by age group (>18 years, ≤18 
years) will be provided due to the small sample size. Listings will be provided by age group.
The analysis sets and protocol deviation codes are related as follows:
Table 5-1
Protocol deviation codes and analysis sets
Category
Deviation code
Text description of deviation
Data exclusion
Subjects are excluded from all (safety) analysis in case of these 
PDs: 
Exclude subject completely 
from all (safety) analysis 
sets
INCL01
Written informed consent was not obtained 
before any study assessment was performed
Yes
Subjects are excluded from PK analysis in case of these PDs: 
Exclude subject from PK 
analysis set 
INCL01
Written informed consent was not obtained 
before any study assessment was performed
Yes
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Category
Deviation code
Text description of deviation
Data exclusion
Subjects are excluded from PD analysis in case of these PDs:
Exclude subject from PD 
analysis set
INCL01
Written informed consent was not obtained 
before any study assessment was performed
Yes
Subjects are excluded from PK and PD analysis in case of these 
PDs:
Exclude subject from PK and 
PD analysis sets
INCL01
Written informed consent was not obtained 
before any study assessment was performed
Yes
6
Statistical methods for Pharmacokinetic (PK) parameters
6.1
Pharmacokinetic parameters
The following plasma pharmacokinetic parameters will be determined using the actual recorded sampling times 
and non-compartmental method(s) with Phoenix WinNonlin (Version 6.2 or higher): Cmax, Tmax and AUClast. 
Other PK parameters, including but not limited to AUCinf, CL(ss)/F and Cmax may be added as appropriate.
The linear trapezoidal rule will be used for AUC calculation. Regression analysis of the terminal plasma 
elimination phase for the determination of T1/2 will include at least 3 data points after Cmax. If the adjusted R2
value of the regression analysis of the terminal phase will be less than 0.75, no values will be reported for T1/2, 
AUCinf and CL/F.
In addition to non-compartmental methods, individual compartmental modelling (Phoenix WinNonlin, version 
6.2 or higher) may be used to derive individual estimates of oral drug clearance (CLss/F) as well other model-
derived parameters such as absorption rate constant and volume of distribution.  
6.2
Statistical methods for pharmacokinetic parameters
 A geometric mean will not be reported 
if the dataset includes zero values.
Pharmacokinetic parameters will be calculated and will be listed by treatment and patient. Summary statistics 
will include mean (arithmetic and geometric), SD, CV (arithmetic and geometric), median, minimum and 
maximum. An exception to this is Tmax where median, minimum and maximum will be presented. 
6.3
Pharmacokinetic / pharmacodynamic interactions
Relationships between exposure (plasma concentration and PK parameters) and pAkt PD biomarkers in B and T 
cells (endogenous, stimulated and unstimulated), will be explored by a graphical approach and descriptive 
CDZ173 plasma concentration data will be listed by treatment, patient, and visit/sampling time point. 
Descriptive summary statistics will be provided by treatment and visit/sampling time point, 
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 Summary statistics will include mean (arithmetic and 
geometric), SD, CV (arithmetic and geometric), median, minimum and maximum. An exception to this is Tmax 
where median, minimum and maximum will be presented.
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statistics of exposure and PD or biomarker variables will be provided. 
7
Statistical methods for Pharmacodynamic (PD) parameters
7.1
Primary Objective 
The primary aim of Part I, along with assessing safety and tolerability, is to determine a dose to be used in the 
confirmatory Part II.
7.1.1
PD Variable(s)
The primary parameter in Part I will be % pAkt positive B cells (unstimulated and stimulated samples) and will 
be used as PD marker to select the dose for Part II.
In Part I, phosphorylated Akt in B cells will be quantified at baseline and at Day 1 (pre-dose, and 1h, 3h, 8h post 
dose), Day 8 (pre-dose) and Day 15 (pre-dose) of each of the three dose levels and at Day 28 (pre-dose) of the 
last dose level. The dose level (up to 70 mg b.i.d.) leading to normalization of pAkt in B cells similar to healthy 
volunteer levels should be carried into Part II for generation of confirmatory data. Typically, pAKT levels in 
endogenous B-cells of healthy volunteers are not measurable due to limitation in detecting low levels of pAkt in 
these cells. Therefore, an integrated pharmacology approach consisting of the concentration/dose-effect 
relationship in inhibition of pAkt (unstimulated and stimulated B cells), as well as an estimate of the endogenous 
pAkt levels in APDS patients (if measurable) will be used to inform the best estimate of the level of inhibition 
required for normalization. Other variables including but not necessarily limited to safety and biomarkers will be 
taken into account for the selection of the dose. 
Average pAkt inhibition (defined as (-1)*%change from baseline) over the dosing interval of 12h will be 
calculated for each patient at each dose level based on the measured pre-dose and the 1h, 3h, 8h post dose 
samples with a trapezoidal rule as AUC over 12 hours normalized by the length of the dosing interval (12h).
Baseline will be defined as the arithmetic mean of the Day -1 value and the first dose level Day 1 pre-dose value. 
The 12h time point will be estimated as an arithmetic mean of the Day 8 and Day 15 pre-dose values.
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7.1.2
Statistical analysis of PD parameter(s)
7.1.2.1
Concentration-response (Plasma concentration vs PD parameter)
In Part I, a concentration-response model will be fitted to link systemic drug concentration and pAkt inhibition at 
each measured time point (the 1h, 3h, 8h post dose samples on Day 1 and pre-dose samples on Days 8 and 15 of 
each dose level; pre-dose samples on Day 1 of dose levels 2 and 3; and pre-dose sample on Day 28 of dose level 
3). An Emax model will be considered, where the inhibition at concentration 0 is fixed at 0. The EC50, the Emax 
and the Hill parameter will be estimated from the data, and a random effect for EC50 and Emax will be estimated 
for each patient to account for the within-patient correlation between time points. Population model parameters 
will be converted into their dose equivalents based on desired time-averaged pathway inhibition and estimated 
oral drug clearance of CDZ173 in the target population. 
The systemic drug concentrations used within the model will be the raw plasma concentrations measured at the 
same time points that the PD parameters were measured.
For the assessment of concentration-response, the following Emax model will be used:
 = 
	
 . 

	
 + 
  + 
Yij : pAkt inhibition ((-1)*percent change from baseline) of the i-th patient at time point j=1,…,18
Cij : Concentration (ng/mL) of the i-th patient at time point j=1,….,18
Emax : Maximum effect, logit transformed (between 0 and 100) = 100 / (1+exp(-ϴ1))
EC50: Concentration (ng/nL) at which 50% of Emax is reached, log transformed exp(ϴ2)
h : Hill parameter, log transformed exp(ϴ3)
eij: residual error normally distributed
Random effects with multivariate normal distributions on transformed parameters (ϴ1,ϴ2,ϴ3) will be estimated 
for each patient to account for the within-subject correlation between time points using a full covariance matrix.
In case of estimation issues, a diagonal covariance matrix (i.e. off-diagonal elements are zero) will be used. In 
case there are still estimation issues, the below steps will be successively taken until there are no estimation 
issues. For each step, first a full covariance matrix will be used and in case of estimation issues, a diagonal 
covariance matrix will be used.
1.
The random effect from the Hill parameter will be removed
2.
The Hill parameter will be fixed to 1
3.
The random effect on Emax will be removed
4.
The random effect on EC50 will be removed
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The dose DXX (mg) that provides a given level (xx % of Emax) of time-averaged pathway inhibition over a dosing 
period (12h) is defined as follows:
 = 10−3 . 	 . ()

 . 12
CL(ss)/F : apparent Clearance (L/h)
ECXX : Concentration (ng/mL) at which XX % of Emax is reached i.e. "
##
100−##$
1/ℎ
× 	50 where h is the Hill
parameter and EC50 the concentration at which 50% of Emax is reached.
To estimate ECxx, the value CL(ss)/F estimated from the pharmacokinetics assessment (see section 6.1) will be 
used.
7.1.2.2
Dose-response (Dose vs PD AUC)
The average of pAkt inhibition over the dosing interval (12h) at each dose level will also be estimated from an 
Emax dose-response model accounting for intra-individual correlation for the measurements at different doses. 
In the Emax dose response model the Hill parameter is fixed to 1 and the inhibition at dose 0 is fixed to 0.  The 
following model will be used:
 =  	
. 
	 + 
 + 
Yij : average pAkt inhibition of the i-th patient on dose j=1,2,3
Dij : Dose (mg) of the i-th patient on dose j=1,2,3
Emax : Maximum effect, logit transformed (between 0 and 100) = 100 / (1+exp(-ϴ1))
ED50: Dose (mg) at which 50% of Emax is reached, log transformed exp(ϴ2)
eij: residual error normally distributed.
A random effect with normal distribution on transformed parameter ϴ2 will be estimated for each patient to 
account for the within-subject correlation between time points. 
The dose DXX (mg) that provides a given level (xx % of Emax) of time-averaged pathway inhibition over a dosing 
period (12h) is defined as 
)
##
100 −##* × 	
where ED50 the dose at which 50% of Emax is reached.
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In case the above model cannot be fitted, a slope model will be fitted:
Yij = Dij + i + eij
Yij : average pAkt inhibition of the i-th patient on dose j=1,2,3
Dij : Dose (mg) of the i-th patient on dose j=1,2,3
i: patient effect
eij: residual error normally distributed.
Depending on the feasibility to measure average baseline unstimulated pAkt levels, the minimum average level 
of inhibition needed for undetectable pAkt may be determined. If the dose achieving this level of inhibition 
cannot be estimated reliably from the unstimulated pAkt levels, then the stimulated pAkt levels may be used for 
the selection of the dose to be carried into Part II. The dose selected for Part II may be different (up to 70 mg bid) 
than the 3 doses studied in Part I. Other variables may also be taken into account for the selection of the dose.
7.1.3
Handling of missing values/censoring/discontinuations
In Part I, the primary analysis model will include all available data, there will be no imputation of missing data.
7.2
Analysis of secondary and exploratory variables
7.2.1
Efficacy / Pharmacodynamic 
The changes from baseline of SF-36 and WPAI-CIQ scores, and of Visual analogue scale scores for PGA and 
PtGA, will be calculated and summary statistics will be provided by treatment and visit. 
Summary statistics by treatment and visit will be provided for the change from baseline in High Sensitivity C-
reactive protein (hsCRP) and Lactate dehydrogenase (LDH).
7.2.2
Efficacy: Imaging
The MRI/CT images will be analyzed by VirtualScopics as described in the imaging charter. The following 
quantitative and qualitative measurements are to be summarized by Covance.

Sum of product of diameters of the index lesions and percent change in sum of product of diameters
relative to baseline

3D volume of index lesions.

Overall index lesion response

Overall non-index lesion response

Presence of newly appearing lesions,

Liver volume

Spleen volume

Qualitative assessment of splenomegaly and hepatomegaly

Overall patient response
The sum of the products of diameters (SPD) of index lesions will be log10 transformed and the change from 
baseline of the log transformed SPD after 12 weeks of treatment will be calculated for all patients with 
measureable lymph nodes at baseline. The sum of the 3D volumes of the index lesions will be log10 transformed 
and the change from baseline after 12 weeks of treatment will be calculated. Spaghetti plots and summary 
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statistics for the change from baseline of the log10 transformed SPD will be provided. Response (CR [complete 
response], PR [partial response], etc.) of index and non-index lesions will be analyzed qualitatively. Liver and 
spleen volumes will be visualized as spaghetti plots.
8
Statistical methods for safety and tolerability data
Boxplots to visualize trends in longitudinal safety data (vital signs, ECG, lab parameters) will be created.
8.1
Patient demographics and other baseline characteristics 
All data for background and demographic variables will be listed by age group and patient. Summary statistics 
will be provided for patients overall.
Relevant medical history, current medical conditions, results of laboratory screens, drug tests and any other 
relevant information will be listed by patient.
8.2
Treatments (study drug, rescue medication, other concomitant 
therapies, compliance)
Data for study drug administration (rescue medication) and concomitant therapies will be listed by age group and
patient.
8.3
Vital signs
All vital signs data will be listed by age group, patient and visit/time and if ranges are available abnormalities 
(and relevant orthostatic changes) will be flagged. Summary statistics will be provided by visit/time.
8.4
ECG evaluations 
All ECG data will be listed by age group, patient and visit/time, abnormalities will be flagged. Summary 
statistics will be provided by treatment and visit/time.
8.5
Clinical laboratory evaluations
All laboratory data will be listed by age group, patient and visit/time and if ranges are available abnormalities 
will be flagged. Summary statistics will be provided by visit/time.
8.6
Adverse events
All information obtained on adverse events will be displayed by treatment and patient. 
The number and percentage of patients with adverse events will be tabulated by body system and preferred term 
with a breakdown by treatment. An adverse event starting in one ‘period’ (i.e. under one dose level in Part 1) and 
continuing into the next period is counted only in the onset period. A patient with multiple adverse events within 
a body system and treatment period is only counted once towards the total of this body system.
8.8
Pregnancy test
All pregnancy test results for women will be listed by age group, patient and visit.
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9
Statistical methods for Biomarker data
9.1
Efficacy and mechanistic markers
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Biostatistics & Statistical Programming / 
Novartis Institutes for BioMedical Research
CDZ173
CCDZ173X2201 – Part II / NCT02435173
An open-label, non-randomized, within-patient dose-finding 
study followed by a randomized, subject, investigator and 
sponsor-blinded placebo controlled study to assess the 
efficacy and safety of CDZ173 in patients with APDS/PASLI 
(Activated phosphoinositide 3-kinase delta syndrome/ 
p110δ-activating mutation causing senescent T cells, 
lymphadenopathy and immunodeficiency)
Statistical Analysis Plan (SAP)
Author(s):
Document type:
SAP Documentation – NIBR 
Document status:
Addendum V01 - Final
Release date:
05-Jan-2022
Number of pages:
23
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For business use only
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CCDZ173X2201 – Part II
Table of contents
Table of contents .................................................................................................................3
List of tables ........................................................................................................................4
List of figures ......................................................................................................................4
1
Introduction .........................................................................................................................5
1.1
Scope of document ..................................................................................................5
1.2
Study reference documentation ...............................................................................5
1.3
Study objectives.......................................................................................................5
1.3.1
Part II.......................................................................................................5
1.4
Study design and treatment......................................................................................6
1.4.1
Part II.......................................................................................................6
2
First interpretable results (FIR) ...........................................................................................8
3
Interim analyses...................................................................................................................8
4
Statistical methods: Analysis sets........................................................................................8
5
Statistical methods for Pharmacokinetic (PK) parameters..................................................9
5.1
Variables..................................................................................................................9
5.2
Descriptive analyses ................................................................................................9
5.4
Pharmacokinetic / pharmacodynamic interactions ................................................10
6
Statistical methods for primary efficacy parameters.........................................................10
6.1
Primary objective...................................................................................................10
6.1.1
Estimands..............................................................................................11
6.1.2
Variables ...............................................................................................11
6.1.3
Descriptive analyses..............................................................................12
6.1.4
Statistical model, assumptions and hypotheses.....................................12
6.2
Secondary objectives .............................................................................................14
6.2.1
Estimands..............................................................................................14
6.2.2
Variables ...............................................................................................14
6.2.3
Descriptive analyses..............................................................................15
6.2.4
Statistical model, assumptions and hypotheses.....................................16
6.3
Exploratory objectives...........................................................................................16
6.3.1
Variables ...............................................................................................16
6.3.2
Descriptive analyses..............................................................................17
7
Statistical methods for safety and tolerability data............................................................17
7.1
Variables................................................................................................................17
7.1.1
Variables for gender split analysis ........................................................18
7.2
Descriptive analyses ..............................................................................................18
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7.3
Graphical presentation...........................................................................................19
8
Statistical methods for biomarker data..............................................................................19
9
References .........................................................................................................................23
List of tables
Table 4-1
Protocol deviation codes and analysis sets..............................................8
List of figures
Figure 1-1
Study Design Part II................................................................................7
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1
Introduction 
1.1
Scope of document
The RAP documents contain detailed information to aid the production of Statistics & 
Programming input into the Clinical Study Report (CSR) for trial “CCDZ173X2201-Part II”.
The Statistical analysis plan (SAP) describes the implementation of the statistical analysis 
planned in the protocol
1.2
Study reference documentation
This Statistical Analysis Plan is based on the amended protocol v10 dated 13th-Oct-2020.
1.3
Study objectives
This study is designed to evaluate CDZ173, a selective PI3Kδ inhibitor, in patients with 
genetically activated PI3Kδ, i.e., patients with APDS/PASLI. The study consists of two parts. 
Part I is now complete and was the open label part designed to establish the safety and 
pharmacokinetics of CDZ173 in the target population, as well as to select the optimal dose to 
be tested in Part II. Part II is the subject, investigator and sponsor-blinded, randomized part 
designed to assess efficacy and safety of CDZ173 in this population.
This SAP focuses on Part II only.
1.3.1
Part II
1.3.1.1
Primary Objective(s)
• To assess the clinical efficacy (lymphadenopathy and immunophenotype normalization)
of CDZ173 in patients with APDS/PASLI
1.3.1.2
Secondary Objective(s)
• To assess the effect of CDZ173 on lymphadenopathy (non-index lesions and spleen)
• To assess the pharmacokinetics of CDZ173 in patients with APDS/PASLI
• To assess the efficacy of CDZ173 to modify health-related quality of life in patients with
APDS/PASLI
• To assess the efficacy of CDZ173 by the Physician’s Global Assessment (PGA) and the
Patient’s Global Assessment (PtGA)
• To assess biomarkers reflecting the efficacy of CDZ173 to reduce systemic inflammatory
components of the disease
• To assess the treatment benefit to individual patients
• To assess the safety and tolerability of CDZ173 in patients with APDS/PASLI
1.3.1.3
Exploratory Objective(s)
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1.3.1.4
Objective for gender split analysis
• To assess whether there is comparable efficacy and tolerability/safety of CDZ173 (70 mg
b.i.d.) after 12 weeks of treatment for men and women.
1.4
Study design and treatment
1.4.1
Part II
Part II is the randomized, subject, investigator and sponsor-blinded, placebo-controlled, fixed 
dose part investigating approximately 30 patients with APDS/PASLI (Figure 1-1). Since the 
primary endpoint (SPD) requires imaging by either MRI or CT, which results in patients being 
exposed to radiation, the design is planned factoring these measurements in.
The CDZ173 dose to be used in this part is selected based on safety, tolerability, PK and PD 
data from Part I.
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Figure 1-1
Study Design Part II
During the Screening Visit (Day -50 to Day -2) patients’ eligibility will be assessed and then 
reviewed during the Baseline Visit. 
Patients who are deemed eligible for enrollment into the study based on the inclusion/exclusion 
criteria will attend the clinic on Day -1 for baseline assessments.
On Day 1 patients will be randomly allocated to one of the two treatment groups in a 2:1 ratio 
to receive either 70 mg CDZ173 b.i.d. or matching placebo for a twelve week period in a patient, 
investigator and sponsor blind fashion.
Patients enrolled in Part I of the study will not participate in Part II, i.e. new patients will be 
selected.
For the patients who do not directly roll over from Part II to treatment in the extension study 
[CCDZ173X2201E1], the following applies: 
During the four weeks after the last day of dosing the patients will be followed-up for safety. 
On Day 112 patients will undergo the end of study visit.
Patients who discontinued study treatment prematurely will perform an early treatment 
discontinuation visit (named V104.1) as soon as possible after their treatment discontinuation.
The assessments scheduled for this visit are the ones marked with a * in Table 8-2 of the study 
protocol.
If the premature discontinuation from study treatment happens before the scheduled V104, the 
patients will be asked to also return at Day 85, and complete the Visit 105 (without further 
imaging assessments to avoid additional radiation). This will be considered their last Visit.
If on the other hand the premature discontinuation from study treatment happens at or after the 
scheduled V104, the patients will in addition to the early treatment discontinuation visit be 
asked to perform the EOS visit 4 weeks after the treatment discontinuation visit. This will be 
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2
First interpretable results (FIR)
3
Interim analyses 
Not applicable.
4
Statistical methods: Analysis sets
For all analysis sets, patients will be analyzed according to the study treatment received.
The safety analysis set will include all patients that received any study drug.
The PK analysis set will include all patients with at least one available valid (i.e. not flagged 
for exclusion) PK concentration measurement, who received any study drug and experienced 
no protocol deviations with relevant impact on PK data.
The PD analysis set will include all patients who received any study drug and with no protocol 
deviations with relevant impact on PD data.
The key safety and efficacy endpoints will also be reported by age group determined at 
Screening visit (>=18 years old and < 18 years old).
The analysis sets and protocol deviation codes are related as follows:
Table 4-1
Protocol deviation codes and analysis sets
Category
Deviation code
Text description of deviation
Data exclusion
Subjects are excluded from PK analysis in case of these PDs: 
Exclude subject from 
PK analysis set 
INCL01
Written informed consent was not obtained
before any study assessment was performed
Yes
Subjects are excluded from PD analysis in case of these PDs:
Exclude subject from 
PD analysis set
INCL01
Written informed consent was not obtained
before any study assessment was performed
Yes
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Category
Deviation code
Text description of deviation
Data exclusion
Subjects are excluded from PK and PD analysis in case of these 
PDs:
Exclude subject from 
PK and PD analysis 
sets
INCL01
Written informed consent was not obtained
before any study assessment was performed
Yes
5
Statistical methods for Pharmacokinetic (PK) parameters
5.1
Variables 
The following plasma pharmacokinetic parameters will be determined using the actual recorded 
sampling times and non-compartmental method(s) with Phoenix WinNonlin (Version 6.2 or 
higher): Cmax, Tmax, AUC0-8h and AUClast. Other PK parameters may be added as 
appropriate. After multiple doses, PK will be summarized in terms of trough concentration 
(Ctrough). 
PK parameters will be calculated as per Novartis Guidance on Standardization of 
Pharmacokinetic Parameters. The linear trapezoidal rule will be used for AUC calculation. 
Regression analysis of the terminal plasma elimination phase for the determination of T1/2 will 
include at least 3 data points after Cmax. If the adjusted R2 value of the regression analysis of 
the terminal phase will be less than 0.75, no values will be reported for T1/2, AUCinf and CL/F.
In addition to non-compartmental methods, individual compartmental modelling (Phoenix 
WinNonlin, version 6.2 or higher) may be used to derive individual estimates of oral drug 
clearance (CLss/F) as well other model-derived parameters such as absorption rate constant and 
volume of distribution.  
5.2
Descriptive analyses
The pharmacokinetics of CDZ173 will be evaluated in patients in the PK analysis set. CDZ173 
plasma concentration data will be listed by treatment, patient, and visit/sampling time point. 
Descriptive summary statistics will be provided by treatment and visit/sampling time point. 
 Summary statistics will include mean 
(arithmetic and geometric), SD, CV (arithmetic and geometric), median, minimum and 
maximum. 
 A 
geometric mean will not be reported if the dataset includes zero values. 
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Pharmacokinetic parameters will be calculated and will be listed by treatment and patient. 
Summary statistics will include mean (arithmetic and geometric), SD, CV (arithmetic and 
geometric), median, minimum and maximum. An exception to this is Tmax where median, 
minimum and maximum will be presented. 
Arithmetic mean (SD) profiles and geometric mean (95% CI) for plasma concentration-time 
data (day 1) and Ctrough versus Visit (multiple dose) data will be plotted over time.
Overlaying individual plasma concentration-time profiles (day 1) as well as for Ctrough-visit 
(after multiple dose) will be generated along profiles for individual subjects.
5.4
Pharmacokinetic / pharmacodynamic interactions
Relationships between exposure and selected PD or biomarker variables will be explored by a 
graphical approach and descriptive statistics of exposure and PD or biomarker variables will be 
provided. Additional analysis such as exposure-response models will be performed, if 
warranted.
6
Statistical methods for primary efficacy parameters
6.1
Primary objective
The primary aim of Part II is to assess efficacy of CDZ173 at the selected dose (70 mg b.i.d.) 
after 12 weeks of treatment. 
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6.1.1
Estimands
6.1.2
Variables 
Index lesions will be selected from measurable nodal and extranodal lesions as per the Cheson 
methodology (Cheson et al 1999). A maximum of six of the largest dominant lesions should be 
selected and documented at baseline and assessed again at the end of treatment (i.e. the Day 85 
assessment for patients who complete the 12 week treatment period or the treatment 
discontinuation visit for patients who discontinue treatment prematurely prior to Day 85 visit). 
The percentage of naïve B cells is assessed at baseline, Day 1, Day 29, Day 57 and Day 85, and 
at the discontinuation visit for patients who discontinue treatment prematurely prior to Day 85 
visit. The co-primary variables to assess efficacy in Part II will be the change from baseline in 
the log10-transformed sum of the products of diameters (SPD) of the index lesions and the 
change from baseline in the percentage of naïve B cells out of total B cells, see Section 8.3 for 
details of the read-out names for all biomarkers.
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6.1.3
Descriptive analyses
The SPD of index lesions will be log10 transformed and the change from baseline of the log10 
transformed SPD at the end of treatment (i.e. the Day 85 assessment for patients who complete 
the 12 week treatment period or the treatment discontinuation visit for patients who discontinue 
treatment prematurely prior to Day 85 visit) will be calculated for patients with baseline and 
end of treatment SPD measurements. A second endpoint will be derived as the sum of the square 
root of the products of diameters along with the change from baseline.
The change from baseline in naïve B cells out of total B cells at Day 29, Day 57 and Day 85 
and the end of treatment (i.e. the Day 85 assessment for patients who complete the 12 week 
treatment period or the treatment discontinuation visit for patients who discontinue treatment 
prematurely prior to Day 85 visit) will be calculated for patients with baseline and the 
corresponding time-point measurements. Baseline will be defined as the arithmetic mean of the 
baseline and Day 1 values when both are available, and if either baseline or the Day 1 value is 
missing, the existing value will be used.
Descriptive summary statistics and individual patient profiles will be provided by age group, 
treatment and time point.
6.1.4
Statistical model, assumptions and hypotheses
An analysis of covariance will be performed to compare the change of the log10 transformed 
SPD from baseline between the two treatment groups, with treatment as a fixed effect and log10 
transformed baseline SPD as a covariate. The baseline intake of glucocorticoids as well as the 
information about being treated with intravenous immunoglobulin G (IgG) will both be 
included as categorical (Yes/No) covariates. The comparison of the two treatment groups will 
be two-sided, with a 5% type I error. Patients with zero lesions at baseline will be excluded 
from the analysis. 
An analysis of covariance will be performed to compare the change from baseline in the naïve 
B cells at the end of treatment (i.e. Day 85 assessment for patients who complete the 12 week 
treatment period or the treatment discontinuation visit for patients who discontinue treatment 
prematurely prior to Day 85 visit) between the two treatment groups, adjusted for baseline naïve 
B cells frequencies. The use of glucocorticoids and intravenous IgG at baseline will both be 
included as categorical (Yes/No) fixed effects. Comparison of the two treatment groups will be 
two-sided, with a 5% type I error. Only patients with a reduced percentage of naïve B cells at 
baseline (defined as below 48 % van Gent et al 2009) will be included to the analysis. Baseline 
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6.1.4.1
Model checking procedures
Residual plots will be inspected to assess the adequacy of the model.
6.1.4.2
Handling of missing values/censoring/discontinuations
The inferential analyses of the lymphadenopathy will include only patients with baseline and 
end of treatment lymphadenopathy measurements. Also patients with zero lesions at baseline 
will be excluded from the primary and sensitivity analysis for lymphadenopathy. 
The primary analysis of the naïve B cells will include only patients who have baseline and end 
of treatment naïve B cells measurements and who also have a reduced percentage of naïve B 
cells at baseline (defined as below 48 % van Gent et al 2009). 
6.1.4.3
Graphical presentation of results
Model estimated mean (SE) profiles and individual patient profiles will be provided by 
treatment and age group.
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For the individual patient profiles using the PD analysis set all data will be displayed but the 
lines will be solid up to the treatment discontinuation +14 days and for subsequent time points 
the line will be dotted.
6.2
Secondary objectives
All subjects within the secondary efficacy analysis (efficacy parameters other than those used 
for primary objectives) will be included in the secondary efficacy data analysis where not 
otherwise specified. The rules as detailed in Section 6.1.4.2 regarding discontinuation and 
treatment withdrawal will also be followed for the secondary efficacy parameters.
6.2.1
Estimands
6.2.2
Variables 
Short form 36 Survey (SF-36)
SF-36 in this study is to assess the physical and mental functioning of patients.
The SF-36 is a widely used instrument to measure generic health status. It is a 36-item 
questionnaire that has proven useful in monitoring generic and specific populations, comparing 
the relative burden of different diseases, differentiating the health benefits produced by different 
treatments, and in screening individual patients.
The SF-36 measures the impact of disease on overall quality of life and consists of eight 
subscales (physical function, pain, general and mental health, vitality, social function, physical 
and emotional health) which can be aggregated to derive a physical-component summary score 
and a mental-component summary score.
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Work Productivity and Activity Impairment (WPAI) plus Classroom Impairment (CIQ) 
Questionnaire
The WPAI in this study measures the amount of absence or presence and daily activity 
impairment attributable to APDS/PASLI. As younger patients (age 12 and above) may also be 
enrolled in the study the WPAI-CIQ version of the questionnaire will be used for all patients as 
it also measures the amount of absence or presence for school attendance and daily classroom 
activity impairment attributable to APDS/PASLI.
Patient Global assessment (PtGA) Questionnaire
The patient’s global assessment questionnaire asks patients about their APDS related well-being 
using 100 mm visual analogue scale (VAS) ranging from “very poor” (0) to “very good” (100).
Physician’s Global assessment (PGA) Questionnaire
In the physician’s global assessment questionnaire the Investigator rates the disease activity of 
their patient using 100 mm VAS ranging from “no disease activity” (0) to “maximal disease 
activity” (100).
To enhance objectivity, the physician must not be aware of the specific patient’s global 
assessment, when performing his own assessment on that patient.
Imaging Data
The MRI/CT images will be analyzed by VirtualScopics as described in the imaging charter. 
The following quantitative and qualitative measurements will be summarized.

Sum of product of diameters of the index lesions and percent change in sum of product
of diameters relative to baseline

3D volume of index and measureable non-index lesions

Presence of newly appearing lesions

Liver volume and bi-dimensional size

Spleen volume and bi-dimensional size

Qualitative assessment of splenomegaly and hepatomegaly
6.2.3
Descriptive analyses
The change from baseline of SF-36 and WPAI-CIQ summary scores, and of visual analogue 
scale scores for PGA and PtGA, will be calculated and summary statistics will be provided by 
age group, treatment and visit. Mean (SD) profiles and individual profile plots will be provided
by age group and treatment.
Summary statistics by age group, treatment and visit will be provided for the change from 
baseline in High Sensitivity C-reactive protein (hsCRP), Lactate dehydrogenase (LDH), beta2 
microglobulin, ferritin, fibrinogen and erythrocyte sedimentation rate (ESR). Treatment with 
glucocorticoid drugs (e.g., prednisolone) can have an effect on these parameters and product, 
dose and timing of such treatment will be captured. Appropriate information needed for 


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interpretation will be added to the outputs as footnotes as required. Mean (SD) and individual 
profile plots will be provided by age group and treatment.
The 3D volume of index lesions will be log10 transformed and the change from baseline of the 
log10 transformed 3D volume at the end of treatment (i.e. the Day 85 assessment for patients 
who complete the 12 week treatment period or the treatment discontinuation visit for patients 
who discontinue treatment prematurely prior to Day 85 visit) will be calculated for patients with 
baseline and end of treatment measurements. Individual profile plots and summary statistics 
will be provided by age group and treatment.
6.2.4
Statistical model, assumptions and hypotheses
An analysis of covariance will be performed for SF-36 and WPAI-CIQ scores, and of visual 
analogue scale scores for PGA and PtGA, to compare the change from baseline at the end of 
treatment (i.e. the Day 85 assessment for patients who complete the 12 week treatment period 
or the treatment discontinuation visit for patients who discontinue treatment prematurely prior 
to Day 85 visit) between the two treatment groups, with treatment as a fixed effect and baseline 
as a covariate. The use of glucocorticoids and intravenous IgG at baseline will both be included 
as categorical (Yes/No) fixed effects. Comparison of the two treatment groups will be two-
sided, with a 5% type I error.  
The change from baseline will also be analyzed using a longitudinal mixed model, with 
treatment, time (as categorical), treatment by time, baseline and baseline by time interaction as 
fixed effects. The use of glucocorticoids and intravenous IgG at baseline will both be included 
as categorical (Yes/No) fixed effects. For patients who complete the treatment period, this 
repeated measures analysis will include all measurements in the treatment period (Baseline, 
Day 29, Day 57 and Day 85). An unstructured covariance matrix will be fitted to adjust for 
correlations among the measurements made on the same patient. The difference between the 
treatment groups in the change from baseline after 12 weeks of treatment will be assessed at 
two-sided 5% significance level.
An analysis of covariance will be performed for the 3D volume of index and measureable non-
index lesions and 3D volume and bi-dimensional size of spleen to compare the change of the 
log10 transformed value from baseline between the two treatment groups, with treatment as a 
fixed effect and baseline as a covariate. The use of glucocorticoids and intravenous IgG at 
baseline will both be included as categorical (Yes/No) fixed effects. Comparison of the two 
treatment groups will be two-sided, with a 5% type I error. 
6.3
Exploratory objectives
6.3.1
Variables 
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6.3.2
Descriptive analyses
7
Statistical methods for safety and tolerability data
All patients within the safety analysis set will be included in the safety data analysis.
7.1
Variables
Adverse events, vital signs (blood pressure, pulse rate, body temperature), ECG intervals, 
laboratory measurements, as well as patient demographics, baseline characteristics, and 
treatment information.
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7.1.1
Variables for gender split analysis
Variables to be used in the gender split analysis for safety and tolerability are: adverse events, 
vital signs (blood pressure, pulse rate, body temperature), ECG intervals, laboratory 
measurements.
7.2
Descriptive analyses
Patient demographics and other baseline characteristics
All data for background and demographic variables will be listed by treatment and patient.
Summary statistics will be provided by age group and treatment and will also include PIK3CD 
mutation. Demographic summary will be provided by using the Safety set and all enrolled
patients.
Relevant medical history, current medical conditions, results of laboratory screens, drug tests 
and any other relevant information will be listed by age group, treatment and patient.
Treatment
Data for study drug administration (rescue medication) and concomitant therapies will be listed 
by age group, treatment and patient.
Vital signs
All vital signs data will be listed by age group, treatment, patient and visit/time, and if ranges 
are available abnormalities (and relevant orthostatic changes) will be flagged. Summary 
statistics will be provided by age group, treatment group and visit/time.
Summary statistics will also be provided by gender, treatment group and visit/time.
ECG evaluations
All ECG data will be listed by age group, treatment, patient and visit/time, abnormalities will 
be flagged. Summary statistics will be provided by age group, treatment group and visit/time.
Summary statistics will also be provided by gender, treatment group and visit/time.
Clinical laboratory evaluations
All laboratory data will be listed by age group, treatment, patient, and visit/time, and if normal 
ranges are available abnormalities will be flagged. Summary statistics will be provided by age 
group, treatment group and visit/time.
Summary statistics will also be provided by gender, treatment group and visit/time.
Adverse events
All information obtained on adverse events will be displayed by age group, treatment and
patient. The number and percentage of patients with adverse events will be tabulated by body 
system and preferred term with a breakdown by age group and treatment. A patient with 
multiple adverse events within a body system is only counted once towards the total of this 
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All information obtained on adverse events will also be displayed by gender, treatment and
patient.
For the legal requirements of ClinicalTrials.gov and EudraCT, two required tables on treatment 
emergent adverse events which are not serious adverse events with an incidence greater than 
0% and on treatment emergent serious adverse events and SAE suspected to be related to study 
treatment will be provided by system organ class and preferred term on the safety set population.
If for a same patient, several consecutive AEs (irrespective of study treatment causality, 
seriousness and severity) occurred with the same SOC and PT:

a single occurrence will be counted if there is ≤ 1 day gap between the end date of the
preceding AE and the start date of the consecutive AE

more than one occurrence will be counted if there is > 1 day gap between the end date
of the preceding AE and the start date of the consecutive AE.
For occurrence, the presence of at least one SAE / SAE suspected to be related to study 
treatment / non SAE has to be checked in a block e.g., among AE's in a ≤ 1 day gap block, if at 
least one SAE is occurring, then one occurrence is calculated for that SAE.
The number of deaths resulting from SAEs suspected to be related to study treatment and SAEs 
irrespective of study treatment relationship will be provided by SOC and PT. 
Pregnancy test
All pregnancy test results for pre-menopausal women who are not surgically sterile will be 
listed by age group, treatment, patient and visit/time.
7.3
Graphical presentation 
Boxplots to visualize trends in longitudinal safety data (vitals, ECG, lab parameter) will be 
created.
8
Statistical methods for biomarker data
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9
References
Cheson BD, Horning SJ, Coiffier B, et al (1999) "Report of an international workshop to 
standardize response criteria for non-Hodgkin's lymphomas. NCI Sponsored International 
Working Group." J Clin Oncol 17(4): 1244.
van Gent R, van Tilburg CM, Nibbelke EE, et al (2009) Refined characterization and reference 
values of the pediatric T- and B-cell compartments.  Clin Immunol 133: 95–107.
Belavý DL, Gast U, Daumer M, Fomina E, Rawer R, et al. (2013) Progressive Adaptation in 
Physical Activity and Neuromuscular Performance during 520d Confinement. PLOS ONE 8(3): 
e60090. https://doi.org/10.1371/journal.pone.0060090
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