An Open-label, Non-randomized Extension Study to Evaluate the Long Term Safety, Tolerability, Efficacy and Pharmacokinetics of CDZ173 in Patients With APDS/PASLI (Activated Phosphoinositide 3-kinase Delta Syndrome/p110δ-activating Mutation Causing Senescent T Cells, Lymphadenopathy and Immunodeficiency)
Phase: PHASE2
Conditions: Activated PI3Kdelta Syndrome (APDS); PASLI Disease
Sponsor: Pharming Technologies B.V.

CCDZ173X2201E1 
NCT Nr. 02859727 
Clinical Trial Protocol dated 13DEC2022 
 
 

 
 
  
 
 
 
Pharming Technologies B.V. 
 
 
CDZ173 (Leniolisib)  
 
Clinical Trial Protocol CCDZ173X2201E1 
 
 
An open-label, non-randomized extension study to evaluate 
the long term safety, tolerability, efficacy and 
pharmacokinetics 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: 
2016-000468-41 
Version number: 
v11 (Clean) 
 
Clinical Trial Phase: 
II/III 
 
Release date: 
13 Dec 2022 
 
 
Property of Pharming 
Confidential 
May not be used, divulged, published or otherwise disclosed 
without the consent of Pharming 

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            Protocol No. CCDZ173X2201E1 
 
 
 
 
Site Operations Manual (SOM) 
A Site Operations Manual (SOM) accompanies this protocol, providing the operational details 
for study conduct. Note: The SOM will not form part of the Clinical Study Report. 
 
 
Notification of serious adverse events and special situations 
Dear Investigator, 
You must report SAE and Special Situation (SS) (initial or follow-up) to Pharming as 
summarized below. Refer to Section 9.2 of the protocol for SAE criteria and additional 
requirements. See also page 2 of the SOM for further details on the method of reporting a SAE 
and SS. 
• Complete SAE reporting form 
• Submit SAE reporting form to Pharming Pharmacovigilance Department  (PHV) 
within 24 hours after awareness of the SAE or SS to e-mail address or fax 
number on the SAE reporting form 
• Notify the Pharming Medical Monitor 
• The fax number(s) and email addresses are located in the SOM. 

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Table of contents 
 
 
Site Operations Manual (SOM) .............................................................................................. 2 
Notification of serious adverse events and special situations ................................................. 2 
List of tables ........................................................................................................................... 9 
List of figures.......................................................................................................................... 9 
List of abbreviations ............................................................................................................. 10 
Pharmacokinetic definitions and symbols ............................................................................ 15 
Glossary of terms .................................................................................................................. 17 
Amendment 11 (December 2022) ........................................................................................ 19 
Amendment rationale ................................................................................................ 19 
Changes to the protocol ............................................................................................ 19 
IRB’s/IEC’s .............................................................................................................. 19 
Amendment 10 (December 2021) ........................................................................................ 19 
Amendment rationale ................................................................................................ 19 
Changes to the protocol ............................................................................................ 19 
IRBs/IECs ................................................................................................................. 20 
Amendment 9 (August 2021) ............................................................................................... 20 
Amendment rationale ................................................................................................ 20 
Changes to the protocol ............................................................................................ 20 
IRBs/IECs ................................................................................................................. 20 
Amendment 8 (June 2021) .................................................................................................... 20 
Amendment rationale ................................................................................................ 20 
Changes to the protocol ............................................................................................ 21 
IRBs/IECs ................................................................................................................. 21 
Amendment 7 (October 2020) .............................................................................................. 22 
Amendment rationale ................................................................................................ 22 
Changes to the protocol ............................................................................................ 22 
IRBs/IECs ................................................................................................................. 22 
Amendment 6 (June 2020) ................................................................................................... 22 
Amendment rationale ................................................................................................ 22 
Changes to the protocol ............................................................................................ 22 
Amendment 5 (March 2019) ................................................................................................ 24 
Amendment rationale ................................................................................................ 24 
Changes to the protocol ............................................................................................ 24 

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Amendment 4 (June 2018) .................................................................................................... 26 
Amendment rationale ................................................................................................ 26 
Changes to the protocol ............................................................................................ 26 
Amendment 3 (March 2018) ................................................................................................ 28 
Amendment rationale ................................................................................................ 28 
Changes to the protocol ............................................................................................ 28 
Amendment 2 (October 2017) .............................................................................................. 30 
Amendment rationale ................................................................................................ 30 
Changes to the protocol ............................................................................................ 30 
Amendment 1 (March 2017) ................................................................................................ 32 
Amendment rationale ................................................................................................ 32 
Changes to the protocol ............................................................................................ 33 
Protocol synopsis .................................................................................................................. 36 
1 
Introduction .......................................................................................................................... 40 
1.1 
Background ............................................................................................................... 40 
1.2 
Nonclinical data ........................................................................................................ 41 
1.2.1 
Pharmaceutical Properties ........................................................................ 41 
1.2.2 
Pharmacology ........................................................................................... 41 
1.2.3 
Toxicology ............................................................................................... 41 
1.2.4 
Non-clinical pharmacokinetics and metabolism ...................................... 43 
1.2.5 
Teratogenicity and reproductive toxicity data .......................................... 43 
1.3 
Clinical data .............................................................................................................. 44 
1.3.1 
Human safety and tolerability data ........................................................... 44 
1.3.2 
Human pharmacokinetic data ................................................................... 46 
1.3.3 
Human pharmacodynamic data ................................................................ 47 
1.4 
Study purpose ........................................................................................................... 49 
2 
Study objectives and endpoints............................................................................................. 50 
2.1 
Primary objective ...................................................................................................... 50 
Objective Endpoint ................................................................................................... 50 
2.2 
Secondary objectives ................................................................................................ 50 
Objective Endpoint ................................................................................................... 50 
2.3 
Exploratory objective(s) ............................................................................................ 51 
Objective Endpoint ................................................................................................... 51 
3 
Investigational plan ............................................................................................................... 51 
3.1 
Study design .............................................................................................................. 51 
3.1.1 
Treatment switch from HGC to FCT formulation and serial PK sampling
 .................................................................................................................. 53 

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3.2 
Rationale for study design ........................................................................................ 53 
3.3 
Rationale for dose/regimen, route of administration and duration of treatment ........ 54 
3.4 
Rationale for choice of comparator........................................................................... 55 
3.5 
Purpose and timing of interim analyses/design adaptations ..................................... 56 
3.6 
Risks and benefits ..................................................................................................... 56 
3.6.1 
Blood sample volumes ............................................................................. 59 
4 
Population ............................................................................................................................. 59 
4.1 
Inclusion criteria ....................................................................................................... 60 
4.2 
Exclusion criteria ...................................................................................................... 60 
5 
Restrictions for Study Patients .............................................................................................. 63 
5.1 
Contraception requirements ...................................................................................... 63 
5.2 
Prohibited treatment .................................................................................................. 64 
5.2.1 
Drugs that are prohibited Other investigational therapies ......................... 64 
5.2.2 
Drug to be used with caution ................................................................... 65 
5.3 
Smoking .................................................................................................................... 66 
6 
Treatment .............................................................................................................................. 67 
6.1 
Study treatment ......................................................................................................... 67 
6.1.1 
Investigational and control drugs ............................................................. 67 
6.1.2 
Additional study treatment ....................................................................... 67 
6.2 
Treatment assignment ............................................................................................... 67 
6.3 
Treatment blinding .................................................................................................... 67 
6.4 
Treating the patient ................................................................................................... 68 
6.5 
Permitted dose adjustments and interruptions of study treatment ............................. 68 
6.6 
Emergency breaking of assigned treatment code ...................................................... 68 
6.7 
Treatment exposure / compliance and assessment of relative bioavailability of the 
two formulations ....................................................................................................... 68 
6.8 
Recommended treatment of adverse events .............................................................. 69 
6.9 
Concomitant treatment .............................................................................................. 70 
7 
Study Completion and Discontinuation ................................................................................ 70 
7.1 
Study completion and post-study treatment .............................................................. 70 
7.2 
Discontinuation of study treatment ........................................................................... 70 
7.3 
Withdrawal of informed consent .............................................................................. 71 
7.4 
Lost to follow-up ...................................................................................................... 72 
7.5 
Study stopping rules .................................................................................................. 72 
7.6 
Early study termination by the sponsor ..................................................................... 72 
8 
Procedures and assessments ................................................................................................. 73 
8.1 
Assessment schedule................................................................................................. 73 

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8.2 
Informed consent procedures .................................................................................... 78 
8.3 
Patient screening ....................................................................................................... 78 
8.4 
Patient demographics/other baseline characteristics ................................................. 79 
8.4.1 
Hepatitis/HIV screening ........................................................................... 79 
8.4.2 
Tuberculosis testing ................................................................................. 79 
8.5 
Efficacy / Pharmacodynamics .................................................................................. 79 
8.5.1 
Efficacy .................................................................................................... 79 
8.5.1.1 
High Sensitivity C-reactive protein (hsCRP)/Lactate dehydrogenase 
(LDH) ....................................................................................................... 79 
8.5.1.2 
EBV and CMV assessments ..................................................................... 80 
8.5.1.3 
Serum Immunoglobulins .......................................................................... 80 
8.5.2 
Patient Report Outcomes (PRO) .............................................................. 80 
8.5.2.2 
Work Productivity and Activity Impairment (WPAI) plus Classroom 
Impairment (CIQ) Questionnaire ............................................................. 80 
8.5.2.3 
Patient Global assessment Questionnaire ................................................. 81 
8.5.2.4 
Physician’s Global assessment Questionnaire ......................................... 81 
8.5.2.5 
Patient narratives ...................................................................................... 81 
8.6 
Safety ........................................................................................................................ 81 
8.6.1 
Physical examination ............................................................................... 81 
8.6.2 
Vital signs ................................................................................................. 81 
8.6.3 
Height and weight .................................................................................... 82 
8.6.4 
Tanner Staging ......................................................................................... 82 
8.6.5 
Laboratory evaluations ............................................................................. 82 
Hematology ............................................................................................................... 82 
Clinical chemistry ..................................................................................................... 82 
Urinalysis   ................................................................................................................ 83 
8.6.6 
Electrocardiogram (ECG) ........................................................................ 83 
8.6.7 
Pregnancy test .......................................................................................... 83 
8.7 
Pharmacokinetics ...................................................................................................... 84 
8.8 
Other assessments ..................................................................................................... 84 
8.8.1 
Exploratory Biomarker assessments ........................................................ 84 
Soluble Biomarkers .................................................................................................. 84 
Cellular Biomarkers .................................................................................................. 85 
Exploratory Imaging ................................................................................................. 85 
9 
Safety monitoring ................................................................................................................. 85 
9.1 
Adverse events .......................................................................................................... 85 
9.2 
Serious adverse event and special situation reporting ............................................... 87 

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9.2.1 
Definitions ................................................................................................ 87 
9.2.2 
SAE and SS reporting ............................................................................... 88 
9.3 
Infection monitoring ................................................................................................. 90 
9.4 
Liver safety monitoring ............................................................................................ 90 
For the liver laboratory trigger: ................................................................................ 90 
For the liver events: .................................................................................................. 91 
9.5 
Renal safety monitoring ............................................................................................ 93 
9.6 
Reporting Medication errors including misuse/abuse ............................................... 94 
9.7 
Pregnancy reporting .................................................................................................. 95 
9.8 
Early phase safety monitoring .................................................................................. 95 
10 Data review and database management ................................................................................ 96 
10.1 
Site monitoring ......................................................................................................... 96 
10.2 
Data collection .......................................................................................................... 96 
10.3 
Database management and quality control ............................................................... 97 
10.4 
Data Monitoring Committee ..................................................................................... 97 
10.5 
Adjudication Committee ........................................................................................... 97 
11 Data analysis ......................................................................................................................... 97 
11.1 
Analysis sets ............................................................................................................. 97 
11.2 
Patient demographics and other baseline characteristics .......................................... 98 
11.3 
Treatments ................................................................................................................ 98 
11.4 
Analysis of the primary variable(s) ........................................................................... 98 
11.4.1 
Variable(s) ................................................................................................ 98 
11.4.2 
Statistical model, hypothesis, and method of analysis ............................. 98 
11.4.3 
Handling of missing values/censoring/discontinuations .......................... 98 
11.4.4 
Summary statistics of safety ..................................................................... 98 
11.4.5 
Sensitivity analyses .................................................................................. 99 
11.5 
Analysis of secondary variable(s) ............................................................................. 99 
11.5.1 
Efficacy / Pharmacodynamics .................................................................. 99 
11.5.2 
Pharmacokinetics ..................................................................................... 99 
11.5.3 
Pharmacokinetic / pharmacodynamic interactions ................................... 99 
11.5.4 
Other assessments .................................................................................... 99 
11.6 
Analysis of exploratory variables ........................................................................... 100 
11.6.1 
Exploratory biomarkers .......................................................................... 100 
11.7 
Sample size calculation ........................................................................................... 100 
11.8 
Power for analysis of key secondary variables ....................................................... 100 
Relative bioavailability of FCT vs HGC formulation ............................................. 100 
11.9 
Interim analyses ...................................................................................................... 100 

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12 Ethical considerations ......................................................................................................... 101 
12.1 
Regulatory and ethical compliance ......................................................................... 101 
12.2 
Responsibilities of the Investigator and IRB/IEC ................................................... 101 
12.3 
Publication of study protocol and results ................................................................ 101 
13 Protocol adherence ............................................................................................................. 101 
13.1 
Protocol Amendments ............................................................................................. 102 
14 References .......................................................................................................................... 103 
15 Appendix 1: List of prohibited CYP-interacting co- medications ....................................... 105 
 

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List of tables 
Table 5-1 
Prohibited immunosuppressive co-medication (examples) ................... 61 
Table 8-1 
Assessment schedule ............................................................................. 74 
Table 9-1 
Liver Event and Laboratory Trigger Definitions .................................. 91 
Table 9-2 
Follow Up Requirements for Liver Events and Laboratory Triggers ... 92 
Table 9-3 
Specific Renal Alert Criteria and Actions ............................................. 94 
Table 9-4 
Summary of reporting requirements for medication errors ................... 95 
Table 11-1 
Estimated tolerance limits for 90 percent confidence intervals with 
different CVs and sample sizes………………………………………100 
Table 15-1 
List of prohibited co-medications……………………………………105 
Table 15-2 
List of selected OATP substrates to be used with caution…………...106 
 
List of figures 
Figure 1-1 
Population PK-PD prediction for average pAkt inhibition (percent) ...... 47 
Figure 1-2 
Arithmetic mean (SD) CDZ173 plasma concentration-time profiles on  
 
Day 1 ....................................................................................................... 48 
Figure 1-3 
Arithmetic mean (SD) trough CDZ173 plasma concentration time     
profiles) ................................................................................................... 49 
Figure 3-1 
Study schema ........................................................................................... 53 

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List of abbreviations 
ACR 
Albumin-creatinine ratio 
AE 
Adverse event 
AIHA 
Autoimmune hemolytic anemia 
ALP 
Alkaline phosphatase 
ALT 
Alanine aminotransferase 
APC 
Antigen presenting cell 
APDS 
Activated phosphoinositide 3-kinase (PI3K)-delta syndrome 
aPTT 
Activated partial thromboplastin time 
AST 
Aspartate aminotransferase 
AV 
Atrioventricular 
BCRP 
Breast cancer resistance protein 
β-hCG 
Beta subunit of human chorionic gonadotropin 
b.i.d. 
bis in die (twice a day) 
BMI 
Body Mass Index 
BP 
Blood pressure 
BSA 
Body surface area 
BUN 
blood urea nitrogen 
CFR 
Code of Federal Regulations 
CIA 
Collagen-induced arthritis 
CK 
Creatine kinase 
CMO&PS 
Chief Medical Office and Patient Safety 
CMV 
Cytomegalovirus 
COAR 
Clinical Operations analytics and regions 
COVID-19 
Coronavirus disease 
CPK 
Creatine phosphokinase 
CRF 
Case Report/Record Form (paper or electronic) 
CRO 
Contract Research Organization 
CRP 
C- reactive protein 
CSF 
Clinical Service Form 
CT scan 
Computed Tomography with X rays 
CTC 
Common Toxicity Criteria 

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CV 
Coefficient of variation 
CYP 
Cytochrome P450 
DAR 
Dose administration record 
DDI 
Drug-drug interaction 
DMC 
Data Monitoring Committee 
DS&E 
Drug safety and Epidemiology 
DSMB 
Data safety monitoring board 
EBV 
Epstein-Barr virus 
EC 
Ethics committee 
ECG 
Electrocardiogram 
EDC 
Electronic Data Capture 
EE 
Ethinyl estradiol 
EOS 
End of study 
EOT 
End of Treatment 
ESR 
Erythrocyte sedimentation rate 
FCT 
Film-coated tablet 
FDA 
Food and Drug Administration 
FIH 
First in Human 
FMI 
Final market image 
GCP 
Good Clinical Practice 
GGT 
Gamma-glutamyl transpeptidase 
GI 
Gastro Intestinal 
GLP 
Good Laboratory Practice 
γ-GT 
Gamma-glutamyl transferase 
h 
Hour 
HGC 
Hard-gelatin capsule 
hsCRP 
High sensitivity C-reactive protein 
HV 
Healthy Volunteer 
IB 
Investigator Brochure 
ICH 
International Conference on Harmonization of Technical Requirements for 
Registration of Pharmaceuticals for Human Use 
IEC 
Independent Ethics Committee 

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IN 
Investigator Notification 
IRB 
Institutional Review Board 
ITP 
Idiopathic Thrombocytopenic purpura 
IUD 
Intrauterine device 
IUS 
Intrauterine system 
i.v. 
Intravenous 
kD 
Kilo Dalton 
LDH 
Lactate dehydrogenase 
LFT 
Liver function test 
LLOQ 
Lower limit of quantification 
LPLV 
Last patient last visit 
LVG 
Levonorgestrel 
MAD 
Multiple ascending dose 
MedDRA 
Medical dictionary for regulatory activities 
mg 
Milligram(s) 
mL 
Milliliter(s) 
msec 
Millisecond 
MRI 
Magnetic Resonance Imaging 
MTD 
Maximum tolerable dose 
mTOR 
Mammalian target of rapamycin 
NCA 
Non-compartmental analysis 
NOAEL 
No observed adverse effect level 
NTI 
Narrow therapeutic index 
OC/RDC 
Oracle Clinical/Remote Data Capture 
o.d. 
Once a day 
OGTT 
Oral glucose tolerance test 
PA 
Posteroanterior 
P-gp 
P-glycoprotein 
pAkt 
Phosphorylated Akt 
PASLI 
p110δ-activating mutation causing senescent T cells, lymphadenopathy and 
immunodeficiency 

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PBPK 
Physiology based pharmacokinetics 
PCR 
Polymerase chain reaction 
PD 
Pharmacodynamic(s) 
PDK1 
Phosphoinositide-dependent protein kinase 
PGA 
Physician’s Global Assessment 
PHV 
Pharming Pharmacovigilance Department 
PI 
Principal Investigator 
PI3K 
Phosphoinositide 3-kinases 
PI3Kδ 
Phosphoinositide 3-kinase delta 
PIP3 
Phosphatidylinositol-3,4,5-trisphosphate 
PK 
Pharmacokinetic(s) 
p.o. 
Oral(ly) 
popPK 
Population pharmacokinetics 
PRO 
Patient report outcome 
PT/INR 
Prothrombin time/international normalized ratio 
pSS 
Primary Sjögren’s syndrome 
PtGA 
Patient’s Global Assessment 
OATP 
Organic Anion-Transporting Polypeptide 
q.d. 
quaque die (once a day) 
QTcB 
Corrected QT interval by Bazett’s formula 
QTcF 
Corrected QT interval by Fridericia’s formula 
RBC 
Red blood cell(s) 
RoW 
Rest of World 
SAD 
Single ascending dose 
SAE 
Serious adverse event 
sCR 
Serum creatinine 
SD 
Standard deviation 
SF-36 
Short Form 36 
SOM 
Site operational manual 
SS 
Special Situation 
SVT 
Supraventricular tachycardia 
SUSAR 
Suspected Unexpected Serious Adverse Reactions 
TA 
Therapeutic area 
TBL 
Total bilirubin 

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TSH 
Thyroid stimulating hormone 
μL 
microliter 
ULN 
Upper limit of normal 
ULQ 
Upper limit of quantification 
US scan 
Ultrasound scan 
VAS 
Visual analogue scale 
WBC 
White blood cell(s) 
WHO 
World Health Organization 
WoC 
Withdrawal of consent 
WoCBP 
Woman of child bearing potential 
WPAI-CIQ 
Work Productivity Activity Impairment and Classroom Impairment 
Questionnaire 

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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 blood) 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. 
MRT 
Mean residence time determined as AUMCinf/AUCinf following intravenous 
administration [time]. 
Racc 
The accumulation ratio 
T1/2 
The terminal elimination half-life [time] 

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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] 
Vc/F 
The apparent initial volume of distribution of the central compartment 
following extravascular administration 
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 
administration [volume] 
Vss/F 
The apparent volume of distribution at steady state following extravascular 
administration [time]. 

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Glossary of terms 
Assessment 
A procedure used to generate data required by the study 
Dosage 
Dose of the study treatment given to the patient in a time unit 
(e.g. 100 mg once a day, 75 mg twice a day) 
Enrollment 
Point/time of patient entry into the study at which informed 
consent must be obtained (i.e. prior to starting any of the 
procedures described in the protocol) 
Epoch 
Interval of time in the planned conduct of a study. An epoch is 
associated with a purpose (e.g. screening, randomization, 
treatment, follow-up), which applies across all arms of a study 
Investigational drug 
The study drug whose properties are being tested in the study; 
this definition is consistent with US CFR 21 Section 312.3 and 
Directive 2001/20/EC and is synonymous with “investigational 
new drug” or “test substance” 
Patient 
An individual with the condition of interest 
Personal data 
Subject information collected by the Investigator that is 
transferred to Pharming 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 
discontinued and no further assessments are planned 
Screen failure 
A patient who is screened but is not treated or randomized 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) 
Subject 
A trial participant 
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. 
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 patient permanently stops taking study treatment prior 
to the defined study treatment completion date 

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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 study 
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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Amendment 11 (December 2022) 
 
Amendment rationale 
 
The purpose of this amendment is to notify all stakeholders of the results of an interim analysis 
of the CCDZX2210E1 and the update of the Investigators Brochure,  
 
Changes to the protocol 
 
Section 1.3 Clinical data has been updated with recent data. 
Section 3.6 Risks and benefits updated with recent data. 
Section 7.1 Study completion updated, EoT visit to be last study visit if patient transfers to 
compassionate use program. 
Table 8.1 updated, EoT visit to be last study visit if patient transfers to compassionate use 
program. 
 
IRB’s/IEC’s 
The changes herein affect the Informed Consent. Sites are required to update and submit for 
approval a revised Informed Consent that takes into account the changes described in this 
protocol amendment. 
A copy of this amended protocol will be sent to the Institutional Review Board 
(IRBs)/Independent Ethics Committee (IECs) and Health Authorities. 
The changes described in this amended protocol require IRB/IEC and Health Authority approval 
according to local regulations prior to implementation. 
 
 
Amendment 10 (December 2021)  
 
Amendment rationale 
 
The purpose of this amendment is to notify all stakeholders of a change in Sponsor for this 
study. After finalization of the Clinical Study Report of the randomized clinical trial, Study 
CCDZ173X2201, Pharming Technologies BV will take over Sponsorship of Clinical Study 
CCDZ173X2201E1 from Novartis. Pharming has acquired the exclusive license to leniolisib in 
2019 and is currently taking over the leniolisib clinical development program CDZ173/ 
leniolisib. Pharming will be the supplier of CDZ173 (leniolisib) following the transition of the 
Sponsorship. 
 
Changes to the protocol 
 
Changed Sponsor name from Novartis to Pharming throughout the document. 
Added IMP name ‘leniolisib’ as per Pharming IMP label. 
List of abbreviations was updated. 

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Section 9.2 ‘Serious adverse events and special situations reporting’ reporting of special 
situations added and updated reporting details from Novartis to Pharming PHV.    
 
IRBs/IECs 
The changes herein will not affect the Informed Consent. Patients will receive written 
notification of the change in Sponsor. 
A copy of this amended protocol and the patient notification letter will be sent to the 
Institutional Review Board (IRBs)/Independent Ethics Committee (IECs) and (National) Health 
Authorities. 
The changes described in this amended protocol require IRB/IEC and (National) Health 
Authority approval according to local regulations prior to implementation. 
 
 
Amendment 9 (August 2021) 
Amendment rationale 
The purpose of this amendment is to update the assessment schedule to correctly reflect the 
extended study duration (from 5 to 6 years) by adding End of Treatment (EoT) visit (V517) that 
was inadvertently omitted in the Protocol version 08. Also a typographical error in the List of 
abbreviations, for CK (creatine kinase), was corrected. 
 
Changes to the protocol 
• List of abbreviations CK abbreviation was corrected to creatine kinase. 
• Table 8-1 Assessment schedule was updated to correct the extended study duration by 
adding the previously omitted EoT visit – Visit 517. End of Study (EOS) visit was 
accordingly adjusted. 
 
Changes to specific sections of the protocol are shown in the track changes version of the 
protocol using strike through red font for deletions and red underlined for insertions. 
 
IRBs/IECs 
The changes herein affect the Informed Consent. Sites are required to update and submit for 
approval a revised Informed Consent that takes into account the changes described in this 
protocol amendment. 
A copy of this amended protocol will be sent to the Institutional Review Board 
(IRBs)/Independent Ethics Committee (IECs) and Health Authorities. 
The changes described in this amended protocol require IRB/IEC and Health Authority approval 
according to local regulations prior to implementation. 
 
 
Amendment 8 (June 2021) 
Amendment rationale 
The purpose of this amendment is to extend the individual treatment period to 6 years duration. 

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The study is an extension to the core CCDZ173X2201 study, for which recruitment has been 
delayed due to the global COVID-19 pandemic. Extended duration will also allow continued 
treatment of the patients who are benefitting from leniolisib treatment and who are approaching 
the end of the currently allowed 5 years treatment. The long-term safety data collected so far 
supports the extension to 6 years treatment duration. 
 
Changes to the protocol 
• Protocol Synopsis was updated to reflect the below changes as appropriate. 
• Section 1.3.1 was updated with the current number of patients treated with CDZ173, for 
whom no occurrence of skin rash was reported. 
• Section 3.1 was updated to reflect the extension of the treatment period to 6 years 
• Figure 3-1 was updated with the extended study treatment. 
• Section 3.2 and Section 3.3 were updated with the extended treatment period. 
• Section 3.6 was updated with the current number of patients treated with CDZ173, with 
no relevant AE reported. 
• Table 8-1 Assessment schedule was updated with the extended study period and 
accordingly with an additional study visit – Visit 516. 
Changes to specific sections of the protocol are shown in the track changes version of the 
protocol using strike through red font for deletions and red underlined for insertions. 
 
IRBs/IECs 
The changes herein affect the Informed Consent. Sites are required to update and submit for 
approval a revised Informed Consent that takes into account the changes described in this 
protocol amendment. 
A copy of this amended protocol will be sent to the Institutional Review Board 
(IRBs)/Independent Ethics Committee (IECs) and Health Authorities. 
The changes described in this amended protocol require IRB/IEC and Health Authority approval 
according to local regulations prior to implementation. 
 
 

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Amendment 7 (October 2020) 
Amendment rationale 
The purpose of this amendment is to align CCDZ173X2201E1 (extension study) with changes 
that were made to CCDZ173X2201 (core study) to address questions and comments raised by 
the Health Authority in Germany (BfArM). 
 
Changes to the protocol 
Section 3.6 has been expanded to include a sub-section on the risks and benefits for the 
adolescent population. Also, the number of patients enrolled into this study has been updated. 
Section 4.2, in the exclusion criteria vital signs and QTcF ranges have been updated to align 
with CCDZ173X2201 (core study) 
Section 5.1 was updated to include additional information for the adolescent population 
Section 11.4.3 was updated to specify that no methods for imputation of missing date (including 
those due to COVID-19) are planned 
Changes to specific sections of the protocol are shown in the track changes version of the 
protocol using strike through red font for deletions and red underlined for insertions. 
 
IRBs/IECs 
The changes described in this amended protocol require IRB/IEC and Health Authority 
approval according to local regulations prior to implementation. 
The changes herein do NOT affect the trial specific model ICF. 
 
Amendment 6 (June 2020) 
Amendment rationale 
The purpose of this amendment is to address changes to trial conduct in the case of an epidemic 
or pandemic that limits or prevents on-site visits (eg COVID-19 pandemic). The protocol is 
adapted to allow delivery of IMP directly to a participant’s home. Alternative methods of 
providing continuing care may be implemented, as well as remote collection of efficacy 
endpoints, where possible. Informed consent discussion can be done remotely. 
 
Changes to the protocol 
Changes to specific sections of the protocol are shown in the track changes version of the 
protocol using strike through red for deletions and red underlined for insertions. 
The major changes to the protocol are as follows: 
• List of abbreviations was updated. 
• Section 1.1 was updated with more recent information 
• Section 3.6 was updated to clarify risks related to the COVID-19 pandemic. 

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• Section 6.1.1 was updated to include the option of IMP home delivery, in cases when an 
epidemic or pandemic (e.g. COVID-19 pandemic) limits or prevents on-site study visits. 
• Section 8.1 was updated to allow alternative methods of replacing study visits, such as 
phone calls, virtual contacts (e.g. teleconsult) or visits by site staff/home nursing service to 
the participant´s home in cases when an epidemic or pandemic (e.g. COVID-19 pandemic) 
limits or prevents on-site study visits. 
• Section 8.2 was updated to allow the Investigator to conduct the informed consent 
discussion remotely due to limits that prevent an on-site visit during an epidemic or 
pandemic (e.g. COVID-19 pandemic). The potential for home nursing has been added as  
an option for providing continuing care during an epidemic or pandemic (e.g. COVID-19 
pandemic). Requirement for an additional informed consent for such case was added. 
• Section 8.5.1 Remote collection of efficacy endpoints, is allowed, where possible, if an 
epidemic or pandemic (e.g. COVID-19 pandemic) limits or prevents on-site study visits. 
• Section 8.6 was updated to allow safety monitoring and discussion of the participant´s 
health status to be conducted with regular phone or virtual calls during an epidemic or 
pandemic (e.g. COVID-19 pandemic), until the participant can again visit the site. 
• Section 8.7 was updated to allow a change in sample collection schedule if an epidemic or 
pandemic (e.g. COVID-19 pandemic) limits or prevents on-site study visits. 
• Section 8.8 was updated to allow modification of the sample collection for other 
assessments in case an epidemic or pandemic (e.g. COVID-19 pandemic) limits or 
prevents on-site study visits, or if visits by site staff to a participant’s home are not 
feasible. 
The changes herein affect the Informed Consent. Sites are required to update and submit for 
approval a revised Informed Consent that takes into account the changes described in this 
protocol amendment. 
A copy of this amended protocol will be sent to the Institutional Review Board 
(IRBs)/Independent Ethics Committee (IECs) and Health Authorities. 
The changes described in this amended protocol require IRB/IEC and Health Authority approval 
according to local regulations prior to implementation.” 

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Amendment 5 (March 2019) 
Amendment rationale 
The main purpose of this global amendment is to align this protocol with the CCDZ173X2201 
study protocol in relation to: eligibility criteria; prohibited medication and the option to use a 
low dose CT scan in adolescents between 12-15 years of age (inclusive) in sites, where local 
practice and local authorities/ECs/IRBs approve such CT scans in adolescents for research 
purposes. Additionally, the individual treatment period is extended to 5 years duration to allow 
continued treatment of the patients who are benefitting from leniolisib treatment and who are 
approaching the end of the currently allowed 3 years treatment. The long-term safety data 
collected so far supports the extension to 5 years treatment duration. 
The exploratory objective of the treatment effect on patients’ physical activity level by tri-axial 
accelerometer (exploratory endpoint) was removed, based on experience from the 
CCDZ173X2201 study and due to operational feasibility. 
Based on the feedback from Russian Health Authority, the protocol is also updated to allow for 
patients enrolled in Russia to keep using the hard-gelatin capsules (HGC) and thus to not 
participate in the cross-over assessment of the pharmacokinetics and bioavailability of the new 
film-coated tablets (FCT) formulation relative to the HGC. 
Furthermore, changes are made in the Introduction to reflect the updates in the latest 
Investigator’s Brochure. 
 
Changes to the protocol 
Changes to specific sections of the protocol are shown in the track changes version of the 
protocol using strike through red for deletions and red underlined for insertions. Editorial 
changes have been made throughout the protocol for improved clarity. 
 
• Front page: the INN name has been added to the protocol title. 
• Glossary of terms was updated with several definitions. 
• Protocol Synopsis was updated to reflect the below changes as appropriate. 
• Section 1.1 was updated with new CCDZ173X2201 study information. 
• Section 1.3.1 was updated with information from completed study CCDZ173X2203 and the 
Interim Analysis of this extension study CCDZ173X2201E1. 
• Section 2.3 the exploratory objective with physical activity assessment by a tri-axial 
accelerometers is no longer included. 
• Section 3.1 was updated to reflect the extension of the treatment period to 5 years. 
• Section 3.1.1 was updated with requirement of a phone contact 2 weeks after the switch to 
the FCT formulation. Additionally, patients enrolled in Russia are allowed to stay on the 
HGC and not to take part in the pharmacokinetics and relative bioavailability assessment of 
the FCT formulation. 

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• Section 3.2 and Section 3.3 were updated with the extended treatment period. 
• Section 3.6 Risks and benefits were updated with current information and with the option 
to use a CT scan of adolescents between 12-15 years of age (inclusive) in sites where local 
practice and local authorities/ECs/IRBs approve CT scans for research purposes using a low 
dose CT scan protocol. 
• Section 4.1 Inclusion criteria were updated to align with the Protocol Amendment v08 for 
CCDZ173X2201 study. 
• Section 4.2 Exclusion criteria were updated to align with the Protocol Amendment v08 for 
the CCDZ173X2201 study. 
• Section 5.2.1 The Table 5-1 with prohibited medication was updated to allow the use of 
max 25 mg per day of prednisone or equivalent. 
• Section 6.8 Clarification was added for management of Grade 2 or 3 rash. 
• Table 8-1 Assessment schedule was updated with clarifications regarding the imaging 
procedures and regarding assessments that do not need to be repeated for patients rolling 
over directly at their EoT/EoS of the CCDZ173X2201 study and/or having the visit 501/502 
done on the same day. Also the tri-axial accelerometer assessments have been removed and 
the treatment period was extended to 5 years. 
• Section 8.5.1.2 was updated for clarity. 
• Section 8.8 The patient’s physical activity assessment by the tri-axial accelerometer has 
been removed. 
• Section 8.8.1 was updated to allow CT scans in adolescents between 12-15 years of age 
(inclusive) in sites where local practice and local authorities/ECs/IRBs approve CT scans in 
adolescents for research purposes using a low dose CT scan protocol. 
• References were updated. 
The changes herein affect the Informed Consent. Sites are required to update and submit for 
approval a revised Informed Consent that takes into account the changes described in this 
protocol amendment. 
A copy of this amended protocol will be sent to the Institutional Review Board 
(IRBs)/Independent Ethics Committee (IECs) and Health Authorities. 
The changes described in this amended protocol require IRB/IEC and Health Authority approval 
according to local regulations prior to implementation. 

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Amendment 4 (June 2018) 
Amendment rationale 
The protocol was amended to incorporate health authority recommendations for: 1) the 
management of potentially occurring skin rashes, 2) pregnancy monitoring, and 3) additional 
screening assessments and eligibility criteria for patients who did not participate in the core 
study CCDZ173X2201. 
 
Changes to the protocol 
Changes to specific sections of the protocol are shown in the track changes version of the 
protocol using strike through red for deletions and red underlined for insertions. Editorial 
changes have been made throughout the protocol for improved clarity. 
• Glossary of terms was updated for Personal Data and Withdrawal of study consent. 
• Protocol Synopsis Key   inclusion criteria were updated to require documented 
APDS/PASLI-associated genetic PI3K delta mutation. 
• Section 1.1 was updated with CCDZ173X2201 study information. 
• Section 1.2.5 Teratogenicity and reproductive toxicity data was updated. 
• Section 1.3.1 was updated with latest results from study CCDZ173X2203. 
• Section 3.1.1 Text related to switch in formulation and related serial PK sampling was 
grouped in separate section for clarity. 
• Section 3.2 Rationale for study design was updated. 
• Section 3.6 Risks and benefits were updated with information from the current study. 
• Section 4 Population was updated to include patients 12 to 75 years of age, to be consistent 
with study CCDZ173X2201. 
• Section 4.1 Inclusion criteria were updated with the requirements of documented 
APDS/PASLI-associated genetic PI3K delta mutation which is consistent with core study 
CCDZ173X2201. 
• Section 4.2 Exclusion criteria were updated to be consistent with core study 
CCDZ173X2201. Additional exclusion criteria for patients who did not participate in the 
CCDZ173X2201 study were added. 
• Section 6.8 was updated to include instruction on handling of skin rashes. 
• Section 7.2 Discontinuation of study treatment criteria were amended with Grade 4 rashes. 
• Section 7.3 Withdrawal of informed consent was updated with the new required language. 
• Table 8-1 Assessment schedule was updated to include screen tests for HIV, Hepatitis and 
tuberculosis for patients who did not participate in the core study CCDZ173X2201. 
Additional pregnancy self-tests were amended as well. 

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• Section 8.2 Informed consent procedures were updated to clarify that written assent from 
the patient and consent from his/her parent/guardian are required for patients of 12 – 17 
years old. 
• Section 8.4.1 was added to include screening tests for hepatitis and HIV. 
• Section 8.4.2 was added to include screening test for tuberculosis. 
• Section 8.6.7 Pregnancy test was amended to include monthly self-tests. 
• Section 9.3 Infection monitoring was updated to suggest more frequent assessment of WBC 
if deemed necessary by the Investigator if the patient presents with any signs of an infection. 
• Section 10.4 Data Monitoring Committee was updated to indicate that the data monitoring 
committee is independent. 
The changes herein affect the Informed Consent. Sites are required to update and submit for 
approval a revised Informed Consent that takes into account the changes described in this 
protocol amendment. 
A copy of this amended protocol will be sent to the Institutional Review Board 
(IRBs)/Independent Ethics Committee (IECs) and Health Authorities. 
The changes described in this amended protocol require IRB/IEC and Health Authority approval 
according to local regulations prior to implementation. 

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Amendment 3 (March 2018) 
Amendment rationale 
The protocol was amended to introduce a film-coated tablets (FCT) formulation of CDZ173 
and to allow for a single sequence cross-over assessment of the pharmacokinetics and 
bioavailability of this new formulation relative to the CDZ173 hard-gelatin capsules (HGC). 
In addition to investigating Epstein-Barr Virus (EBV) and Cytomegalovirus (CMV) viremia, 
this amendment introduces measures of lytic and latent burden with these two viruses by 
exploratory DNA and RNA assessments. Also the viral load of EBV in saliva will be quantified. 
 
Changes to the protocol 
Changes to specific sections of the protocol are shown in the track changes version of the 
protocol using strike through red for deletions and red underlined for insertions. Editorial 
changes have been made throughout the protocol for improved clarity. 
• List of abbreviations were updated. 
• Pharmacokinetic definitions and symbols were updated 
• Synopsis was updated to reflect the changes as appropriate. 
• Section 1.2.1 was updated to include CDZ173 film-coated tablet (FCT). 
• Section 1.4 Study purpose was updated. 
• Section 2.2 Secondary objectives were updated to include evaluation of pharmacokinetics 
and relative bioavailability of CDZ173 FCT relative to CDZ173 HGC. 
• Section 2.3 Exploratory objectives were updated to include endpoint of EBV and CMV lytic 
and latent in blood, and EBV DNA in saliva. 
• Section 3.1 Study design was updated to include the investigation of pharmacokinetics and 
bioavailability of the CDZ173 FCT relative to the CDZ173 HGC by a single sequence cross- 
over design. 
• Section 3.2 Rationale for study design was updated. 
• Section 3.6.1 Blood sample volumes was updated. 
• Section 6.1.1 Investigational drug was updated to include both CDZ173 FCT and CDZ173 
HGC. 
• Section 6.2 Treatment assignment was updated. 
• Section 6.4 was updated with instructions on taking the study treatment. 
• Section 6.6 was revised for better clarity. 
• Section 6.7 was updated to include assessing the relative bioavailability of the two CDZ173 
formulations. 

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• Table 8-1 Assessment schedule was updated to include serial PK assessments, saliva EBV 
assessment and clarify the vital signs and body measurements. Clinical status evaluation is 
renamed as Patient Narratives to be consistent with that in the core study. 
• Section 8.5.1.2 was updated to include assessments of latent/lytic burden for EBV and CMV, 
as well as the viral load of EBV in saliva 
• Section 8.5.2.5 Clinical Status Evaluation was re-named as Patient Narratives, to be 
consistent with that in core study CCDZ173X2201. 
• Section 8.6.4 was revised to enhance clarity. 
• Section 8.7 pharmacokinetics assessments were updated. 
• Section 8.8.1 Analysis on tri-axial accelerometer monitoring was updated. 
• Section 11.5.2 Analysis of pharmacokinetics variables was updated. 
• Section 11.8 Power for analysis of key secondary variables was updated. 
• Section 14 References were updated. 
The changes described in this amended protocol require IRB/IEC approval prior to 
implementation. 
The changes herein affect the Informed Consent. Sites are required to update and submit for 
approval a revised Informed Consent that takes into account the changes described in this 
protocol amendment. 

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Amendment 2 (October 2017) 
Amendment rationale 
Two main reasons are behind this protocol amendment. One is the decision to offer treatment 
not only to patients who participated in study CCDZ173X2201 but also to patients who 
participated in other trials with other PI3Kδ inhibitors and to whom no extended treatment was 
offered. The second is the decision to add a visit at day 14, to ensure closer monitoring for 
safety. This addresses the fact that CDZ173-naïve patients could be now enrolled either from 
the CCDZ173X2201 study placebo arm or from trials with other PI3Kδ inhibitors. 
Moreover additional changes were implemented due to: 
• aligning protocol with protocol amendment version 07 of the CCDZ173X2201 study. 
• aligning protocol with IB edition 7. 
• re-introducing the WPAI-CIQ and the SF-36 questionnaires and the physician’s global 
assessment scale, per Health Authority requirement. 
 
Changes to the protocol 
Changes to specific sections of the protocol are shown in the track changes version of the 
protocol using strike through red for deletions and red underlined for insertions: 
• Cover page: title changed to underline that this is a non-randomized study. 
• Notification of serious adverse events: Drug Safety and Epidemiology (DS&E) is re-named 
as Chief Medical Office and Patient Safety (CMO & PS). 
• List of abbreviations is updated. 
• The synopsis was updated to reflect the changes as appropriate. 
• Section 1.2.3: Updated according to new IB edition 7. 
• Section 1.3.1: Updated according to new IB edition 7. 
• Section 1.3.2: Language modifications to enhance clarity. 
• Section 1.3.3: Updated according to new IB edition 7. 
• Section 1.4: Change of study purpose to provide access to the extension study not only for 
patients who participated in study CCDZ173X2201 but also for patients previously treated 
with PI3Kδ inhibitors other than CDZ173. 
• Section 2.1: Changed to recognize the new access granted to patients who were previously 
treated with PI3Kδ inhibitors other than CDZ173. 
• Section 2.2: Changed to recognize the new access granted to patients who were previously 
treated with PI3Kδ inhibitors other than CDZ173. 
• Section 2.3: Changed to align with protocol amendment version 07 of the 
CCDZ173X2201 study and to recognize the new access granted to patients who were 
previously treated with PI3Kδ inhibitors other than CDZ173. 

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• Section 3.1: Changed to recognize the new access granted to patients who were previously 
treated with PI3Kδ inhibitors other than CDZ173. 
• Section 3.2: Changed to recognize the new access granted to patients who were previously 
treated with PI3Kδ inhibitors other than CDZ173 and to add a new visit at day 14. 
• Section 3.3: Updated according new IB edition 7. 
• Section 3.6: Updated according new IB edition 7. 
• Section 3.6.1: Updated to include the blood sample volume for the amended visit and to 
enhance clarity in the text. 
• Section 4: Changed to recognize the new access granted to patients who were previously 
treated with PI3Kδ inhibitors other than CDZ173. 
• Section 4.1: Changed to recognize the new access granted to patients who were previously 
treated with PI3Kδ inhibitors other than CDZ173. 
• Section 4.2: Changed to align with protocol amendment version 07 of the 
CCDZ173X2201 study. 
• Table 8-1: Assessment schedule is updated to introduce an additional visit at day 14 for 
closer safety monitoring; WPAI-CIQ questionnaire is re-introduced; SF-36 questionnaire 
and physician’s global assessment scale are amended; The time interval for using the triaxial 
accelerometer is shortened. 
• Section 8.3: Changed to recognize the new access granted to patients who were previously 
treated with PI3Kδ inhibitors other than CDZ173. 
• Section 8.5.2: Updated in order to reintroduce the WPAI-CIQ questionnaire; to introduce 
the SF-36 questionnaire and physician’s global assessment scale. 
• Section 8.6.4: Updated to specify that only patients who are below 18 years of age at the 
time of enrollment will have the Tanner Staging performed. 
• Section 8.8.1: Updated to shorten the time interval for using the triaxial accelerometer to 
align with protocol amendment version 07 of the CCDZ173X2201 study. 
• Section 8.8.1: Updated to clarify the imaging details. 
• Section 8.9: Updated to specify additional research and state that the ICF for additional 
research is required. 
• Section 11.5.1: Updated in order to reintroduce the WPAI-CIQ questionnaire and to 
introduce the SF-36 questionnaire and physician’s global assessment scale. 
• Section 11.6.1: Language modifications to enhance clarity. 
• Section 14: A new reference is added. 

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The changes described in this amended protocol require IRB/IEC approval prior to 
implementation. 
The changes herein affect the Informed Consent. Sites are required to update and submit for 
approval a revised Informed Consent that takes into account the changes described in this 
protocol amendment. 
 
Amendment 1 (March 2017) 
Amendment rationale 
This protocol amendment for study CCDZ173X2201E1 is being written to introduce the 
following changes: 
• to lower the minimum age for inclusion from 16 to 12 years of age equivalent to the core 
study CCDZ173X2201; 
• to reflect the updates in the latest Investigator’s Brochure (edition 6) and contraception 
requirements that have been changed to include hormonal contraceptives, based on results 
from a DDI study with a monophasic oral hormonal contraceptive (CCDZ173X2104); 
• to adjust the design based on the results obtained from study CCDZ173X2201 Part I; 
• to prolong the treatment period of patients beyond 9 months (up to 3 years) based on the 
successful completion of the 26 week oral (gavage) administration toxicity study in rats 
and the 39 week oral (gavage) administration toxicity study in monkeys (relevant reports 
completed). 
APDS/PASLI is a disease more common in pediatric patients than in adults. In a cohort of 
33 patients with APDS/PASLI at the National Institutes of Health, USA, 14 patients are adults 
and 19 patients are pediatric (APDS/PASLI Patients - NIH Cohort Overview). 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 onset of treatment is predicted to be advantageous. Further, 
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. The juvenile toxicity study in rats as formal requirement prior to treating younger 
adolescents has been completed. The juvenile toxicity study has been performed in rats as the 
rat is an accepted model for investigation in young animals. In addition, the rat has been shown to 
be a relevant species for PI3K inhibitors; the cross-reactivity has been evaluated both in vitro and 
in vivo. Based on this the rat is a suitable model to investigate potential effects of PI3K inhibitors 
in juveniles. The findings in that study were limited to reversible, minimal effects on the testes 
of animals from the high dose group. These results were included in the Investigator’s Brochure 
in December 2015. The dosage form currently used for adult study patients, i.e., capsules, is 
also a dosage form of choice for adolescents of 12 years of age and above (EMA “Reflection 
Paper: Formulations of Choice for the Paediatric 

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Population” 2006). In summary, the preclinical safety studies do not preclude inclusion of 
adolescents, and it may be expected that a long term treatment of adolescent patients might 
provide additional benefits compared to treating adult patients. Thus, it is proposed to extend 
the age range to patients with APDS/PASLI above 12 years of age equivalent to the core study 
CCDZ173X2201. 
In the narratives of study CCDZ173X2201 Part I increased levels of energy and/or decreased 
levels of fatigue were reported for all 6 patients. In an attempt to better objectify a patient’s 
activity this will be tracked using a tri-axial accelerometer both in study CCDZ173X2201 Part II 
and in this extension study. The Patient report outcome (PRO) questionnaires (SF-36 and Work 
Productivity Activity Impairment and Classroom Impairment Questionnaire (WPAI-CIQ)) did 
not provide conclusive outcomes in CCDZ173X2201 Part I and these are no longer considered 
adequate assessments for an open-label design study enrolling also adolescent patients at a 
minimum age of 12 years. Hence, these questionnaires have been removed from study 
CCDZ173X2201 Part II and consequently the WPAI-CIQ questionnaire has been removed also 
from this extension study. 
The reports of the 26 week toxicity study in rats and the 39 week toxicity study in monkeys were 
finalized recently. Rats received oral (gavage) doses of 15, 40 and 120 mg/kg/day CDZ173. In 
view of treatment-related skin lesions and associated mortality among animals treated at 40 or 
120 mg/kg/day, the No observed adverse effect level (NOAEL) was considered to be 15 
mg/kg/day (corresponding to Cmax values of 4560 and 6760 ng/mL and AUC values of 13600 
and 25900 ng*h/mL in males and females, respectively). Cynomolgus monkeys received doses 
of 20, 40 and 60 mg/kg/day CDZ173 orally by gavage. Mucosal erosion and ulceration of the 
large intestine in one male at 60 mg/kg/day and increased QT and QTcB intervals during 
electrocardiography evaluations at 40 and 60 mg/kg/day were considered adverse. The dose of 
20 mg/kg/day was therefore identified as the NOAEL which corresponded with a mean Cmax 
of 6570 ng/mL and an AUC of 25900 ng*h/mL in males and a mean Cmax of 6980 ng/mL and 
an AUC of 14700 ng*h/mL in females during Week 39. The results of these 26 week rodent and 
39 week non-rodent studies support prolonging the treatment period of patients beyond 9 months 
in this current study. 
 
Changes to the protocol 
Changes to specific sections of the protocol are shown in the track changes version of the 
protocol using strike through red font for deletions and red underlined for insertions: 
• The synopsis was updated to reflect the changes as appropriate. 
• Section 1.1: Updated with data from the studies completed and on-going till December 
2016. 
• Section 1.2.3: Updated with long term toxicology studies’ reports. 
• Section 1.2.4: Improvement of text. 
• Section 1.3: Updated with the studies completed and on-going till January 2017, including 
CCDZ173X2201 Part I. 
• Section 2.2: Deletion of WPAI-CIQ from secondary objectives. 
• Section 2.3: Update of the objective on lymphoproliferation and addition of the tri-axial 
accelerometer monitoring according CCDZ173X2201 study Part II. 

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• Section 3.1: Update of the study design to extend the study up to three years of treatment. 
• Section 3.2: Update of the study design to extend the study up to three years of treatment. 
• Section 3.3: Addition of information regarding age reduction and update to extend the 
study up to three years of treatment. 
• Section 3.6: Updated with the results of CCDZ173X2201 study Part I and on-going 
studies till December 2016. 
• Section 3.6.1: Updated to extend the study up to three years of treatment. 
• Section 4: Updated with the age reduction, contraception new information and rolling- 
over occurring also at CCDZ173X2201 End of Treatment. 
• Section 5.2.1: Sirolimus added to the table. 
• Section 5.2.2: Hormonal contraception has been removed from prohibited medication 
section based on the DDI study CCDZ173X2204 and concomitant medications that are 
metabolized by CYP3A is changed. 
• Section 5.3: Smoking habits will be checked through the whole study in order to capture 
any change during the long treatment period 
• Section 6.5: Addition of the possibility for dose interruption. 
• Section 7.2: Improvement of the text. 
• Section 8-Table 8-1: Prolongation of the study, addition of the tri-axial accelerometer for 
physical monitoring and Tanner staging, deletion of WPAI-CIQ questionnaire. 
• Section 8.2: Reminding for re-consent in case of changes added to the text. 
• Section 8.3: Improvement of the text. 
• Section 8.5.1.1: Improvement of the text. 
• Section 8.5.2.3: Deletion of the WPAI-CIQ questionnaire and number correction of 
following sections. 
• Section 8.6.3: Additional height measurement during the study has been added for the 
adolescent patients. 
• Section 8.6.4: Addition of Tanner staging for adolescent patients and number correction of 
following sections. 
• Section 8.6.5: Addition of erythrocyte sedimentation rate and removal of hsCRP and LDH 
in clinical chemistry, since these are already listed in Section 8.5.1.1 describing 
biomarkers which may reflect the impact of CDZ173 on the inflammatory components of 
APDS/PASLI. Moving of PT/INR and aPTT from clinical chemistry to hematology. 
• Section 8.8.1: A new section is inserted on tri-axial accelerometer monitoring. This new 
assessment is included in Part II with the aim to better objectify the assessment of changes 
in the patients’ activity level. It replaces the PRO questionnaires. 
• Section 9.3: Safety monitoring guidelines added for neutropenia. 
• Section 10.4: Addition of a Data Monitoring Committee. 
• Section 11.5.1: Analyses of WPAI-CIQ scores was removed. 
• Section 11.6.1: Description of handling of biomarker values which fall below the lower 
limit of quantification and above upper limit of quantification is changed. 

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• Section 14: Three new references have been added to the List of References. 
Minor editorial changes have been made throughout the protocol for improved clarity. 
Changes to specific sections of the protocol are shown in the track changes version of the 
protocol using strike through red font for deletions and red underlined for insertions. 
The changes described in this amended protocol require IRB/IEC approval prior to 
implementation. 
The changes herein affect the Informed Consent. Sites are required to update and submit for 
approval a revised Informed Consent that takes into account the changes described in this 
protocol amendment. 

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Protocol synopsis 
Protocol number 
CCDZ173X2201E1 
Title 
An open-label, non-randomized extension study to evaluate the long term 
safety, tolerability, efficacy and pharmacokinetics 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 
to 
evaluate 
pharmacokinetics 
of 
immunodeficiency 
long-term 
CDZ173 
safety, 
tolerability, 
in 
patients 
with 
efficacy 
and 
APDS/PASLI 
Sponsor and 
Clinical Trial Phase 
 
Pharming Technologies BV Phase II/III 
Intervention type 
Drug 
Study type 
Interventional 
Purpose and 
rationale 
This   study   is   an   open-label,   non-randomized   extension   to   study 
CCDZ173X2201. It aims to provide treatment with CDZ173 to patients with 
APDS/PASLI who participated in study CCDZ173X2201 or who were treated 
previously with PI3Kδ inhibitors other than CDZ173, and to obtain long term 
safety, tolerability, efficacy and pharmacokinetic data of CDZ173 in this 
patient population. 
Primary 
Objective(s) 
• 
To evaluate the long term safety and tolerability of CDZ173 in 
patients with APDS/PASLI. 
Secondary 
Objectives 
• 
To evaluate the long term efficacy of CDZ173 to modify health- 
related quality of life in patients with APDS/PASLI. 
• 
To evaluate the long term efficacy of CDZ173 by means of 
biomarkers reflecting the efficacy of CDZ173 to reduce systemic 
inflammatory components of the disease in patients with 
APDS/PASLI. 
• 
To characterize the pharmacokinetics (trough concentrations) of 
CDZ173 in patients with APDS/PASLI. 
• 
To evaluate the pharmacokinetics and relative bioavailability of 
CDZ173 film-coated tablets compared to CDZ173 hard-gelatin 
capsules 
Study design 
This is a multicenter, multinational, open-label, non-randomized trial to 
extend active treatment with oral CDZ173 70 mg b.i.d. to those patients with 
APDS/PASLI who participated in study CCDZ173X2201 or who were treated 
previously with PI3Kδ inhibitors other than CDZ173, in order to collect long 
term safety, tolerability, efficacy and pharmacokinetic data. 
Patients can be enrolled in this extension study either directly at the EOT or 
EOS visit of the study CCDZ173X2201 or later in time. Patients who were 
treated previously with PI3Kδ inhibitors other than CDZ173 can be enrolled 
if they meet the eligibility criteria at the screening visit. 
The study consists of a screening visit (if the patient rolls-over directly from 
the CCDZ173X2201 EOT/EOS visit, the screening visit is coincident with the 
CCDZ173X2201 EOT or EOS visit), a treatment period with CDZ173 oral 70 
mg b.i.d., an end of treatment visit and approximately 12 weeks of 

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follow-up, including the EOS visit. Treatment with CDZ173 in study 
CCDZ173X2201E1 will last at maximum 6 years for an individual patient. 
In case a patient will roll-over directly at the CCDZ173X2201 EOT/EOS visit, 
the results of the physical examination, pregnancy tests, vital signs and body 
measurements, ECG evaluation, hematology, blood chemistry and urinalysis 
of the CCDZ173X2201 EOT or EOS visit will be used as the screening visit 
assessments for the extension study and will be reported as such in the 
electronic case report form (CRF) of the extension study. Patients who do 
not directly roll-over will need to undergo the screening visit assessments at 
the time of enrollment in this extension study. 
Moreover the screening visit and the start of treatment (Day 1) can be 
performed on the same day, if this is needed to enable immediate access to 
CDZ173 for any patient who participated in the CCDZ173X2201 study. All 
the inclusion and exclusion criteria should be verified within that day 
(including laboratory results) and if the patient is enrolled in the afternoon, 
only one dose will be administered. Then from the next morning the patient 
will start taking CDZ173 as an oral 70 mg b.i.d. regimen. 
All patients will receive oral 70 mg b.i.d. CDZ173 hard gelatin capsules (HGC) 
from Visit 502 until the Investigator site is set up to administer CDZ173 film-
coated tablets (FCT). When the Investigator site is ready, at the patient’s next 
visit, the patient will have a last dose of CDZ173 HGC and have serial PK 
samples before switching to CDZ173 FCT. The day before this visit, the 
patient should record the time of his/her evening dose of CDZ173 HGC and 
provide the information to the Investigator. Next morning on the visit day, 
after an overnight fasting, the patient will have oral administration of CDZ173 
HGC 70 mg administered at the site either under fasting condition, or half an 
hour after a light breakfast. The dosing time should be 12 hours from that of 
previous evening, or as close as possible. PK blood samples will be taken 
before and after dosing until 8 hours post-dose. Safety, biomarker samples 
and other assessments will be taken as well. The patient will be dispensed 
CDZ173 FCT and discharged from the site on the same day after completion 
of all assessments, and will start to take CDZ173 FCT from that evening until 
next visit. 
On the day before next visit, the patient will again record the time of his/her 
evening dose. In the morning of the visit, after an overnight fasting, the 
patient will be administered oral CDZ173 FCT 70 mg at the site under fasting 
condition, or 30 minutes after light breakfast, which should be consistent with 
the previous visit. The dosing time should be 12 hours from that of previous 
evening, or as close as possible. PK blood samples will be taken before and 
after dosing until 8 hours post-dose. Safety, biomarker samples and other 
assessments will be taken as well before the patient is discharged from the 
site. 
The patient will continue to take CDZ173 FCT 70 mg b.i.d. until the end of 
treatment period. 
Immune dysfunction and lymphoproliferation are the two hallmarks of 
APDS/PASLI. Measurement of systemic biomarkers (immunophenotyping 
and chemokines) will allow the assessment of the long-term effect of CDZ173 on 
the immune system; Computer Tomography or Magnetic Resonance 
Imaging or Ultra Sound imaging will allow a long term estimation of the effect 
on the size of lymph nodes and other lymphatic organs. This assessment will 
be performed only by patients that participated in the CCDZ173X2201 study. 

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Population 
The study population will consist of male and female patients 12 to 75 years 
of age (inclusive), who participated in study CCDZ173X2201 or who were 
treated previously with PI3Kδ inhibitors other than CDZ173 and are deemed 
by the Investigator to benefit from PI3Kδ inhibitor therapy. 
A maximum of 42 patients are expected to be enrolled in this extension study. 
Patients who did not complete the planned 12 week treatment period in the 
CCDZ173X2201 study, can only be enrolled after the unblinding of the study 
CCDZ173X2201 and confirmation that the patients had deteriorated on 
placebo treatment. Patients who deteriorated on treatment with CDZ173 in 
the CCDZ173X2201 study should not be re-exposed to CDZ173. 
Key Inclusion 
criteria 
Patients must have completed the study CCDZ173X2201 EOT/EOS visit, or 
were treated previously with PI3Kδ inhibitors other than CDZ173. 
Patients who are deemed by the Investigator to benefit from PI3Kδ inhibitor 
therapy. 
Patients or their legal representatives (for patients under the age of 18 years) 
must be able to communicate well with the Investigator, to understand and 
comply with the requirements of the study. 
Documented APDS/PASLI-associated genetic PI3K delta mutation. Patients 
with mutations in either PIK3CD or PIK3R1 can be included. 
Key Exclusion 
criteria 
Patients who withdrew consent from the study CCDZ173X2201. 
Use of other investigational drugs, except CDZ173, within 5 half-lives of 
enrollment, or within 30 days, whichever is longer. 
Concurrent use of immunosuppressive medication 
Administration of any 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. 
Pregnant or nursing (lactating) women, where pregnancy is defined as the 
state of a female after conception and until the termination of gestation. 
Women of child-bearing potential, defined as all women physiologically 
capable of becoming pregnant, unless they are using highly effective 
methods of contraception during dosing and for 2 days after last dose of 
study medication. 
Uncontrolled chronic or recurrent infectious disease (with the exception of 
those that are considered to be characteristic of APDS/PASLI). 
Study treatment 
CDZ173 (leniolisib) 
Efficacy/PD 
assessments 
High sensitivity C reactive protein (hsCRP), lactate dehydrogenase (LDH), 
frequencies of infections and other disease complications, Short Form 36 
(SF-36) Survey and Work Productivity Activity Impairment plus Classroom 
Impairment Questionnaire (WPAI-CIQ), visual analogue scale for patient’s 
and physician’s global assessments, patient narratives by Investigator 

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Key safety 
assessments 
Adverse events 
Physical examination 
Vital signs 
Safety laboratory (hematology, blood chemistry, urinalysis) 
Other assessments 
PK assessments of relative bioavailability of the two CDZ173 formulations 
(HGC versus FCT), steady-state trough concentration of CDZ173 
Data analysis 
All data for vital signs, ECG evaluations and clinical laboratory evaluations 
will be listed by patient and summarized by descriptive statistics. 
All information obtained on adverse events will be displayed by patient. 
The number and percentage of patients with adverse events will be tabulated by 
body system and preferred term. A patient with multiple adverse events 
within a body system is only counted once towards the total of this body 
system. 
Log-transformed PK parameters Cmax,ss and AUC0-12,ss from the serial 
PK sampling visits will be analyzed by a fixed effects model, with formulation 
and subject as fixed factors. The estimated mean and 90% confidence 
interval of difference between formulations will be back transformed to obtain the 
geometric mean ratio (FCT vs. HGC) and corresponding 90% confidence 
interval. 
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 (Jamee, 2019). 
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 been investigated for safety and 
tolerability in a first in human study (CCDZ173X2101) and 2 drug-drug interaction (DDI) 
studies (CCDZ173X2102 and CCDZ173X2104). Healthy volunteers have been exposed to 
single ascending doses up to 400 mg and multiple doses up to 140 mg b.i.d. for two weeks. 
CDZ173 hasalso 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 expect 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. Part I data from the ongoing Phase 2/3 study CCDZ173X2201 in APDS/PASLI 
support a beneficial effect of CDZ173 in this disease. 

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1.2 
Nonclinical data 
The most relevant data for the present study are summarized in the sections below. For detailed 
information, please refer to the Investigator's Brochure (IB). 
 
1.2.1 
Pharmaceutical Properties 
CDZ173 phosphate shows good solubility over a broad pH range (> 10 g/L at pH 6.8) 
CDZ173 is provided in two formulations: a conventional capsule of granulated phosphate salt 
of CDZ173 constituting the primary clinical service form (CSF), also called hard gelatin 
capsules (HGC), and a film-coated tablet (FCT) that is expected to become the final market 
image (FMI). Patients will be switched from the CSF to the FCT formulation. 
 
1.2.2 
Pharmacology 
CDZ173 potently inhibits PI3Kδ with a good selectivity over other class I PI3 lipid kinases and 
related PI3 kinases which results in a low potential to inhibit the PI3Kα-dependent insulin 
pathway. CDZ173 has an excellent selectivity window to target-unrelated protein kinases, 
proteases, receptors and ion channels which suggests a favorable in vitro safety profile. On the 
cellular level, CDZ173 potently inhibits multiple PI3Kδ-dependent B cell activities such as 
proliferation, cytokine production, antigen presenting cell (APC) function and antibody 
production. In addition, CDZ173 affects the activation and/or function of cells of the innate 
(mast cells, neutrophils, basophils) and of the adaptive (T cells) immune system. In vivo, 
CDZ173 shows a PK-dependent reduction of ex vivo stimulated B cell activation (rat, monkey). 
This correlates with inhibition of antibody formation in immunized rats and efficacy in rat 
collagen-induced arthritis. CDZ173 was efficacious in rats in the prophylactic model of 
collagen-induced arthritis (CIA) at 3 mg/kg. 
CDZ173 inhibits, in in vitro studies, wild-type PI3Kδ and PI3Kδ carrying one of the published 
mutations of APDS/PASLI patients, with similar potency and efficacy. 
 
1.2.3 
Toxicology 
CDZ173 has been tested in rats and monkeys for up to 2 weeks at dose levels up to 300 
mg/kg/day. Mortality in rats and morbidity in monkeys were seen at the highest dose (300 
mg/kg/day) only, and was accompanied by severe diarrhea and body weight loss. Target 
organs could be identified in both species as the gastrointestinal (GI) tract 
(degenerative/regenerative changes, inflammation) and the hemolymphopoietic system 
(atrophic changes). In rats, effects (mainly at 300 mg/kg/day) in the heart (degenerative changes, 
necrosis), liver and kidneys (inflammation), thyroid (follicular cell hypertrophy/hyperplasia) and 
adrenal glands (cortical vacuolation, hypertrophy), mammary gland (activation), and female 
reproductive system (atrophic changes, inflammation) were recorded. Full or partial reversibility 
was indicated at the end of a 4-week recovery period. 
In addition, in 4 and/or 13-week toxicity studies in rats and monkeys, CDZ173 was tolerated up 
to the highest tested doses of 120 and 80 mg/kg/day, respectively. Diarrhea and emesis in the 
monkey limited potentially higher dosing. No test item related mortality was evident in these 
studies. In rats, the lymphatic tissues, the bone marrow of the sternum and the liver could be 
identified as target organs mainly in the high dose (120 mg/kg/day) animals. In monkeys, 

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histopathological findings were restricted to inflammatory effects in the gastrointestinal tract. 
All effects were generally observed at high dose levels and were fully or partially reversible 
within a 4 week recovery period. Based on these data, the no observed adverse effect level 
(NOAEL) in rats and monkeys after 13 weeks of treatment could be established at 30 and 20 
mg/kg/day, respectively. 
In a 39-week chronic toxicity study in monkeys at doses of 20, 40 and 60 mg/kg/day, 
4 unscheduled deaths occurred in study weeks 11 to 16. In these animals (three low-dose and 
one mid–dose animal), inflammatory effects on the GI tract accompanied by diarrhea and 
dehydration were considered to be the cause of the moribund condition. While diarrhea has also 
been observed in the vehicle control group, the incidence and clinical consequence have been 
greater in animals receiving CDZ173, although there was no dose-response relationship 
observed. Evaluation of the clinical findings and bacteriology culture results provide strong 
evidence of a role for Campylobacter infection in these events. In conclusion, based on the 
available data, mortality was a result of an underlying enteric infection (Campylobacter and 
possibly enteropathogenic Escherichia coli) that may have been exacerbated by CDZ173. 
It is possible that the immunomodulatory properties of CDZ173 could have contributed to the 
incidence and severity of the observed bacterial enterocolitis in monkeys. According to the final 
report mucosal erosion and ulceration of the large intestine in one male at 60 mg/kg/day and 
increased QT   and QTcB   intervals   during electrocardiography evaluations at   40   and 60 
mg/kg/day were considered adverse. The dose of 20 mg/kg/day was therefore identified as the 
NOAEL. 
The NOAEL of 10 mg/kg/day in male juvenile rats in a 10-week rat juvenile study has been 
established based on slight delays in sexual maturation, reduced sperm counts, decreased 
testicular weight, alteration in testicular tubular cellularity and minimal inflammatory changes 
in the epididymides at 30 mg/kg/day and higher dose levels. All these changes showed a clear 
tendency to recover and did not influence the male fertility even at high dose levels up to 
90 mg/kg/day. In chronic toxicity studies in rats, these effects have been observed at the same 
exposures with similar incidence and severity even after 26 weeks of treatment. There was no 
progression observed by increasing the treatment period. The described histological changes 
were restricted to studies in rats and have not been observed in any study in monkeys, even after 
39 weeks. 
According to the final report on the 26-week rat toxicity study treatment-related skin lesions 
and associated mortality among animals treated at 40 or 120 mg/kg/day were observed. 
Consequently, the dose of 15 mg/kg/day was identified as the NOAEL. 
Additionally, slight insulin insensitivity/resistance potential was observed following an oral 
glucose tolerance test (OGTT) study in mice at 100 mg/kg/day. No pancreatic histological 
effects have been observed in the repeat dose toxicity studies at doses below the maximal 
tolerated dose. 
There was no evidence for a genotoxic or mutagenic potential of CDZ173 in vitro or in vivo. 
The phototoxic effect observed in vitro was considered to be very weak (photo irritation factor 
of 5.3). 

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1.2.4 
Non-clinical pharmacokinetics and metabolism 
CDZ173 showed favorable pharmacokinetics (PK) in all   animal   species   tested. Oral 
bioavailability was medium to high (59-86%) and the exposures were roughly dose-
proportional, with no relevant drug accumulation upon multiple dosing. The steady state plasma 
volume of distribution (Vss) was low-to moderate in all species (0.6 – 3.1 L/kg). CDZ173 was not 
found to cross the blood brain barrier in rats. The in vitro binding of CDZ173 to human plasma 
proteins was 94.5% and similar to the other tested species (87.7 to 96.2%). 
In vivo (rat), [14C]CDZ173 was eliminated in nearly completely by metabolism (less than 10% 
intact parent). Urinary excretion of total radiolabeled dose represented only about 10% of the 
dose after intravenous (i.v.) and oral (p.o.) administration. Extensive oxidative metabolism was 
also seen in human hepatocytes in vitro. Human oxidative metabolism of CDZ173 was found 
to be predominantly mediated by cytochrome P450 (CYP) isoenzyme 3A (CYP3A). CYP1A1 
also has the capacity to metabolize CDZ173, suggesting a possible role for extra-hepatic 
metabolism. CDZ173 has low potential for covalent binding to protein. 
Based on in vitro results and lack of auto-induction in vivo, CDZ173 is not expected to affect 
PK of co-medications by reversible CYP inhibition or induction. CDZ173 showed time- 
dependent inhibition of CYP1A2 and weak inhibition potential on several hepatic and renal 
uptake and efflux transporters but not P-glycoprotein (P-gp, for details refer to the IB). CDZ173 
was found in vitro to be a substrate for P-gp and breast cancer resistance protein (BCRP), see 
also data in humans in Section 1.3.2). 
 
1.2.5 
Teratogenicity and reproductive toxicity data 
Potential effects on male fertility have been assessed by careful histopathologic examination of 
the testes and the accessory organs in the rodent and non-rodent 2-, 13- and 26/39-week toxicity 
studies. Minimal and reversible effects on the testes (lack of round spermatids in single tubuli) 
could be observed in rats at doses of 120 mg/kg/d. These effects were not present in monkeys. 
In a juvenile toxicity study in rats, animals were treated with CDZ173 for 10 weeks at dose 
levels up to 90 mg/kg/d. At the end of the study, male and female fertility has been assessed. At 
the highest dose of 90 mg/kg/d (AUC: 90900 ng*h/mL) a slight decrease of round spermatids and/ 
or spermatocytes was observed, as it has been reported from previous toxicity studies at this 
dose level. However, there was no impact on pregnancy parameters. Total sperm head count was 
reduced, but within the historical background data, recorded for animals of this strain and age. 
Relationship to CDZ173 is therefore considered to be unlikely. 
GLP embryo fetal development studies in rats and rabbits have been performed. In rats at doses 
of 120 mg/kg/d, microphthalmia/ anophthalmia was evident and considered to be related to 
CDZ173. In rabbit studies (dose-range finding study and main study) there was no biologically 
relevant increase in the incidence of embryo-fetal variations and malformations or any sign for 
a teratogenic effect of CDZ173 up to 30 mg/kg/d. At higher doses maternal toxicity (body weight 
loss) was evident and in one litter two fetuses showed microphthalmia. Considering the 
microphthalmia in rats, a test item relationship in rabbits cannot be excluded. Based on these 
data, it can be concluded that CDZ173 is teratogenic in rats at doses of 120 mg/kg/d. The 
NOAEL for maternal toxicity and embryo-fetal development could be established at 30 mg/kg/d. 

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Due to these findings women of child bearing potential (WoCBP) are required to use highly 
effective contraception methods. 
The exposure of female partners through semen of male study participants was estimated. 
Assuming a semen volume of 5 mL, a worst-case scenario of a maximal semen/plasma ratio of 
10, 100% bioavailability in the female partner and a volume of distribution of 23.4 L, the 
maximal exposure of female partners is 7.8 ng/mL. This constitutes a 990-fold safety factor 
compared to the Cmax at the embryofetal NOAEL in rats. The estimated volume used for these 
calculations was taken as the central volume (Vc/F) parameter of the current population PK 
model, which is in close agreement to the lower range value of Vz/F (Section 1.2.4). 
Preclinical data with CDZ173 did not show mutagenic, clastogenic or aneugenic potential in 
the GLP in vitro Ames test, chromosomal aberration test in human lymphocytes or in vivo 
micronucleus test in the rat. 
 
1.3 
Clinical data 
1.3.1 
Human safety and tolerability data 
CDZ173 has been investigated for safety, tolerability and pharmacokinetics in a first-in-human 
(FIH) trial (CCDZ173X2101), and in 2 DDI studies (CCDZ173X2102 and CCDZ173X2104). 
Single doses of CDZ173 up to 400 mg and multiple doses up to 140 mg b.i.d. for 14 days have 
been administered to 168 healthy volunteers. In study CCDZ173X2203 a total of 30 patients 
with pSS were enrolled. These were randomized in a ratio of 2:1 with 20 patients included in 
the CDZ173 group and 10 patients in the placebo group. 
Six (6) APDS patients have completed Part I of the CCDZ173X2201 study, and the report of 
these results is published (Rao et al 2017). All 6 patients entered this extension study 
(CCDZ173X2201E1) and results from an Interim Analysis with long-term safety and efficacy 
data were presented at the European Society for Immunodeficiencies (ESID) conference in 2018 
(Rao et al 2018). 
Thirty one (31) APDS patients have completed Part 2 of the CCDZ173X2201 study, and the 
report of these results is published (Rao et al 2022).  29 of the 31 patients entered this extension 
study (CCDZX2201E1). 
The IB provides a summary of safety, tolerability and pharmacokinetic data derived from the 
studies in healthy volunteers and patients. Overall, these studies demonstrated a favorable safety 
profile of CDZ173. 
In the FIH study (CCDZ173X2101) a serious adverse event (SAE) in the initial 70 mg b.i.d. 
cohort occurred: one subject experienced on day 3 an SAE of atrioventricular reentrant 
tachycardia (supraventricular tachycardia, SVT). The symptoms occurred after dosing with 
CDZ173 and were concurrent with the onset of a minor febrile (viral) illness. The diagnosis of 
atrio-ventricular re-entrant tachycardia and a concealed lateral bypass tract were confirmed on 
electrophysiological testing. A successful radiofrequency ablation of the bypass tract was 
performed and the event resolved. The lateral bypass tract identified during the 
electrophysiology study and now recognized as a pre-existing condition was considered to be 
the probable source of the subject’s SVT. In accordance with the protocol’s stopping rules, the 
cohort was discontinued on day 4 for all subjects and the Data Safety Monitoring Board (DSMB) 
was notified. No other abnormalities or SAEs were reported in other subjects for this cohort. A 
complete safety review was conducted by Novartis, the principal investigator (PI) and the 
DSMB for the SAE. Since the causative factor of the SAE was likely a congenital condition 

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and no other subjects had experienced any adverse events (AE) in this cohort, it was agreed to 
repeat the 70 mg twice daily (b.i.d.) cohort. 
An additional extended repeat 70 mg b.i.d. dose cohort and the 140 mg b.i.d. cohort showed no 
increase of QTcF for subjects administered CDZ173 compared to placebo. The 90% confidence 
intervals around the placebo-corrected QTcF change from baseline in this cohort exclude 5 msec 
at nearly all time points. 
In the highest dose group (140 mg b.i.d.) of this multiple dose part skin rash emerged as a 
limiting factor for dose escalation. Three of the 8 subjects in the 140 mg b.i.d. cohort 
experienced an event of rash. Two subjects reported maculo-papular rash; one was of moderate 
severity and necessitated discontinuation from the study, the other was of mild severity. A third 
subject experienced a mild follicular rash. All three events were suspected by the investigator 
to be related to study medication. Consequently a dose of 70 mg b.i.d. was determined as MTD 
for multiple dose treatment with CDZ173. 
A subject in the 70 mg b.i.d. cohort had an absolute neutrophil count of 900 cells/μL on Day 15 
and the repeat assessment was 1000 cells/μL (the baseline value was 1800 cells/μL). At the next 
assessment (3 days after stopping CDZ173 treatment) the neutrophil levels returned within the 
range seen at baseline (1900 cells/μL). 
In the drug-drug interaction study CCDZ173X2102 one male healthy subject experienced chest 
discomfort of moderate intensity after a single dose of 10 mg CDZ173 and a single dose of 300 
mg quinidine. He was discontinued from the study and hospitalized overnight; accordingly this 
event was rated as an SAE. The event was not considered related to the administration of 
CDZ173. 
Three healthy female subjects who participated in a second drug-drug interaction study 
evaluating the effects of multiple oral doses of CDZ173 on the pharmacokinetics of a 
monophasic oral contraceptive (CCDZ173X2104) and who were dosed with 70 mg b.i.d. 
CDZ173 experienced neutropenia of 700 - 900 cells/μL after 1–2 weeks of dosing; this 
laboratory finding was not associated with clinical symptoms and resolved in all subjects after 
stopping CDZ173 dosing: one subject with pre-existing neutropenia at baseline (1200 cells/μL) 
remained with neutrophil counts between 1000–1500 cells/μL, the other two subjects 
normalized to levels above 1500 cells/μL within 24 h post discontinuation of treatment with 
CDZ173. 
Two out of 30 healthy subjects reported occurrence of skin rash, starting after approximately 
12 days of treatment with CDZ173. In both subjects treatment with 70 mg b.i.d. CDZ173 was 
completed according to protocol (until Day 17) and skin rash did not increase in intensity. Skin 
rashes resolved approximately 10 days after treatment completion with CDZ173. 
In study CCDZ173X2203, 30 patients with pSS were investigated (20 patients received 70 mg 
b.i.d. CDZ173, 10 patients received placebo). Skin rashes were reported by 11 out of 20 patients 
(55%) dosed with 70 mg b.i.d. CDZ173 and by one patient (10%) in the placebo group. Three 
of the 11 patients with rash under treatment with CDZ173 discontinued treatment prematurely. 
One of these patients was hospitalized and accordingly this AE was reported as an SAE. Skin 
rash is a known AE with other PI3K inhibitors (Flinn et al 2014).  In the APDS population 
studied to date, skin rash was reported in 5 patients. This included 2 patients with an AEs of 
rash and 1 patient each with rash erythematous, rash maculo-papular, rash macular, and 
urticaria. All of the AEs of rash were mild (Grade 1). There were no SAEs of rash and no patient 
discontinued the study due to rash in patients with APDS. 
Six APDS/PASLI patients have completed Part I of the CCDZ173X2201 study. CDZ173 was 

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found safe and well tolerated at all three dose levels (10, 30 and 70 mg b.i.d.). There were no 
SAEs and no premature treatment discontinuations due to AEs. Twelve weeks 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 CD8+ T cells, reduction 
of elevated serum chemokines and suppression of the PI3K/Akt pathway activity. For further 
details of the results please refer to the Interim Clinical Study Report (Part I) of study 
CCDZ173X2201. 
 
A total of 31 patients in study CCDZ173X2201 Part 2 were given leniolisib 70 mg (21 patients) 
or placebo (10 patients) twice daily for 12 weeks. No deaths were reported during the study. 
Five patients (16.1%) reported 11 SAEs. The incidence of SAEs was lower in the CDZ173 70 
mg bid group than the placebo group. None of the SAEs were suspected related to study 
treatment. The results of Part 2 demonstrate clinical efficacy of CDZ173 70 mg bid over placebo 
in reduction of lymphoproliferation and immunophenotype normalization. The drug was safe 
and well tolerated in APDS patients aged <18 years and ≥18 years. For details of the results 
please refer to the   Clinical Study Report (Part II) of study CCDZ173X2201. 
  
An interim analysis was reported in 2022 for the CCDZ173X2201E1 (extension study) 
A total of 37 patients were enrolled in the extension study. Of these, 26 patients received 
leniolisib in study CCDZ173X2201 and 11 patients had no prior exposure to leniolisib. A total 
of 36/37 patients (97.3%) were ongoing in the study as of December 13, 2021. One patient with 
prior exposure to leniolisib experienced an SAE of cardiac arrest that resulted in discontinuation 
of study treatment, withdrawal from study, and death. This event was not related to the study 
drug. The results of the interim analysis of the long-term extension study demonstrate leniolisib 
is safe and well tolerated in APDS patients as chronic long-term therapy both with and without 
previous leniolisib treatment with continued improvement in measures of lymphoproliferation 
and immunophenotype reflecting immune parameters spanning beyond 5 years indicative of 
continued immune system reconstitution. Infection rates decreased with continued therapy 
despite decreased antibiotic and Ig support requirements over time. 
 
1.3.2 
Human pharmacokinetic data 
In the CCDZ173X2101 study, CDZ173 showed favorable pharmacokinetics in humans. No 
relevant time-dependencies or deviations from dose-proportionality in either oral AUC or Cmax 
were seen over the entire dose range investigated. The drug was rapidly absorbed, with Tmax 
being attained at approximately one hour post drug administration (fasted state). 
Modest drug accumulation was observed with twice daily dosing (about 1.4 fold), 
corresponding to an accumulation-derived effective half-life of ~7 hours. Steady-state plasma 
concentrations are reached in most subjects within 2 days of starting therapy. Inter-subject 
variability in steady-state AUC and Cmax was low with a maximum of 46% and 27% 
respectively. 
Oral plasma drug clearance at steady state was ~4 L/h, indicating CDZ173 is a low clearance 
drug. Accordingly, first pass metabolic extraction is not expected to restrict absolute oral bio-
availability in a relevant way (<10% of oral dose). Renal clearance was determined to be about 
0.2 L/h, approximating to less than 5% of oral dose. 
Single dose oral PK of CDZ173 under fed and fasted conditions showed that a high fat meal 
may affect the rate (~40% decrease in Cmax) but not the extent (AUCinf) of oral absorption of 
CDZ173. The effect of food intake on pAkt inhibition is expected to be minor and not leading 
to lower average or trough inhibition. 

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APDS patients 
Mean oral plasma clearance at steady-state in APDS patients (N=6, CCDZ173X2201 Part 1) 
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. 
 
Drug-drug interactions 
In the clinical study (CCDZ173X2102) investigating the pharmacokinetic interaction between 
CDZ173 and a strong dual inhibitor of CYP3A and P-gp (itraconazole) or a strong dual inhibitor 
of P-gp and CYP2D6 (quinidine), it was demonstrated that CDZ173 is neither a sensitive  
substrate of CYP3A (increase in oral exposure of CDZ173 by about 2-fold) nor a relevant in 
vivo substrate for P-gp or CYP2D6. 
Another clinical DDI study assessed the pharmacokinetic effect of CDZ173 on hormonal 
contraceptives and indicated that CDZ173 did not affect the levonorgestrel (LVG) exposure, 
while a modest increase of about 1.3-fold in the ethinyl estradiol (EE) exposure was seen 
(CCDZ173X2104). Consequently, the efficacy of an oral contraceptive of combined EE and 
LVG is not expected to be compromised by concomitant use of CDZ173. 
 
1.3.3 
Human pharmacodynamic data 
A population PK/PD model describing the relationship between drug exposure and inhibition 
of pAkt in ex-vivo stimulated B cells is being developed based on the emerging biomarker and 
PK data of the completed FIH study. CDZ173 potently inhibited pAkt (IC50 approx. 255 ng/mL) 
with a clear dose response in the dose range investigated, and the drug effect was sustained 
upon multiple dosing. Population median pAkt pathway inhibition was found to be about 50% 
at 10 mg b.i.d., and about 90% at 70 mg b.i.d. (see Figure 1-1). 
 
Figure 1-1 
Population PK-PD prediction for average pAkt inhibition (percent) 
 
Lower and upper dashed line correspond to the predicted 10th and 90th percentile, respectively, of the 
population. 
Six patients with APDS/PASLI were treated with CDZ173 in doses up to 70 mg b.i.d. in Part 1 
of the study CCDZ173X2201. Results confirmed the in vitro finding that not only wild-type 
PI3Kδ but also the mutated PI3Kδ – that characterizes APDS/PASLI – is inhibited by CDZ173 
and other finding include regression of lymph nodes and spleen size, reduction of senescent 
CD4+ and CD8+ T cells, reduction of elevated serum chemokines and suppression of the 
PI3K/Akt pathway activity. 

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In 2201 Part 2, systemic drug exposure was characterized by sequential sampling after the 
first dose administration until 8 hours post-dose and by predose sampling on Day 29, Day 57, 
and Day 85 after multiple dosing.  Arithmetic mean (±SD) CDZ173 plasma concentration-
time profiles are presented in figure x-x.  
 Figure 1-2:  Arithmetic mean (SD) CDZ173 plasma concentration-time profiles on Day 1 - 
Part II (PK analysis set)   
  
  
 Concentrations 
below 
the 
LLOQ 
are 
reported 
as 
zero.  
PK profile is derived from the first dose of 70mg CDZ173 on Day 1   
  
In 2201 Part2, multiple dose PK was characterized by means of steady-state predose plasma 
concentrations (Ctrough) on Days 29, 57, and 85 post onset of treatment.   Arithmetic mean 
(±SD) CDZ173 plasma concentration-time profiles are presented in figure x-y.  
  
 
 

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Figure 1-3:  Arithmetic mean (SD) trough CDZ173 plasma concentration time profiles- Part II 
(PK analysis set)  
  
  
  
Concentrations below the LLOQ are reported as zero  
 
 
1.4 
Study purpose 
This study is an open-label, non-randomized extension to study CCDZ173X2201. It aims to 
provide treatment with CDZ173 to patients with APDS/PASLI who have participated in study 
CCDZ173X2201 or who were treated previously with PI3Kδ inhibitors other than CDZ173 and 
to obtain long term safety, tolerability, efficacy and pharmacokinetic data of CDZ173 in this 
patient population. Obtaining pharmacokinetic and bioavailability data of the film-coated 
tablets (FCT) relative to the hard-gelatin capsules (HGC) will support use and dose justification 
of the FCT in APDS/PASLI patients. 
 
 

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2 
Study objectives and endpoints 
2.1 
Primary objective 
 
Objective 
Endpoint 
 
• To evaluate the long term safety and 
tolerability of CDZ173 in patients with 
APDS/PASLI 
 
2.2 
Secondary objectives 
• All safety parameters (including AEs, 
physical exam, vital signs, ECG, safety 
laboratory (hematology, blood chemistry, 
urinalysis)) 
 
Objective 
Endpoint 
 
• To evaluate the long term efficacy of 
CDZ173 to modify health-related quality 
of life in patients with APDS/PASLI 
 
 
 
 
• To evaluate the long term efficacy of 
CDZ173 by means of biomarkers 
reflecting the efficacy of CDZ173 to 
reduce systemic inflammatory 
components of the disease in patients 
with APDS/PASLI 
• To characterize the pharmacokinetics 
(trough concentrations) of CDZ173 in 
patients with APDS/PASLI. 
• To evaluate the pharmacokinetics and 
relative bioavailability of CDZ173 film- 
coated tablets compared to CDZ173 
hard-gelatin capsules 
• SF-36 (Short Form 36) Survey and 
WPAI-CIQ (Work Productivity Activity 
Impairment plus Classroom Impairment 
Questionnaire), Visual analogue scales 
for 
Physician’s 
Global 
Assessment 
(PGA) and Patient’s Global Assessment 
(PtGA), patient narratives by Investigator 
• High 
sensitivity 
C-reactive 
protein 
(CRP), lactate dehydrogenase (LDH), 
frequencies of infections and other 
disease complications 
 
 
• Steady-state trough concentration of 
CDZ173 
 
• PK parameters (including but not limited 
to AUC0-12,ss and Cmax,ss) 
 

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2.3 
Exploratory objective(s) 
 
Objective 
Endpoint 
 
• To explore biomarkers that may provide 
additional measures of efficacy. 
 
 
 
 
 
 
 
• To assess impact on lymphoadenopathy 
(non-index lesions and spleen) on 
patients who participated in 
CCDZ173X2201 study (refer to 
Section 8.8.1) 
May include but not limited to: 
• Soluble 
biomarkers 
(cytokine 
and 
chemokine panels); 
• EBV and CMV viremia; 
• EBV and CMV lytic and latent in blood; 
• EBV DNA in saliva; 
• IgM, IgG (total and subclasses), IgA; 
• T and B cell immunophenotyping. 
• Reduction 
of 
lymphoproliferation 
measured using MRI/CT imaging or US – 
e.g. 3D volume of index and measurable 
non-index lesions selected as per the 
Cheson methodology, 3D volume and bi- 
dimensional sizes of spleen and liver, 
where appropriate. 
 
 
3 
Investigational plan 
3.1 
Study design 
This is a multicenter, multinational open-label, non-randomized trial to extend active oral 
treatment with CDZ173 70 mg b.i.d. to those patients with APDS/PASLI who participated in 
study CCDZ173X2201 or who were previously treated with PI3Kδ inhibitors other than 
CDZ173, in order to collect long term safety, tolerability, efficacy and pharmacokinetic data. 
The study also investigates the pharmacokinetics and relative bioavailability of the CDZ173 
FCT compared to the CDZ173 HGC by a single sequence cross-over assessment. 
Patients can be enrolled in this extension study either directly at the end-of-treatment (EOT) or 
end-of-study (EOS) visit of the study CCDZ173X2201 or later in time. Patients who were 
treated previously with PI3Kδ inhibitors other than CDZ173 can be enrolled if they meet the 
eligibility criteria at the screening visit. The study consists of a screening visit (if the patient 
rolls-over directly from the CCDZ173X2201 EOT/EOS visit, the screening visit is coincident 
with the CCDZ173X2201 EOT or EOS visit), a treatment period with CDZ173 oral 70 mg b.i.d., 
an end of treatment visit and approximately 12 weeks of follow-up, including the EOS visit (see 
Figure 3-1 and Assessment schedule for more details). Treatment with CDZ173 in study 
CCDZ173X2201E1 will last up to 6 years for an individual patient. 

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Figure 3-1 
Study schema 
 
 
 
In case a patient will roll-over directly at the CCDZ173X2201 EOT/EOS visit, the results of the 
physical examination, pregnancy tests, vital signs and body measurements, ECG evaluation, 
hematology, blood chemistry and urinalysis of the CCDZ173X2201 EOT or EOS visit will be 
used as the screening visit assessments for the extension study and will be reported also in the 
electronic case report form (e-CRF) of the extension study. Patients who do not directly roll- 
over will need to undergo the screening visit assessments at the time of enrollment in this 
extension study (see Assessment schedule, Section 8.1). 
Moreover, the screening visit and the start of treatment (Day 1) can be performed on the same 
day, if this is needed to enable immediate access to CDZ173 for any patient who participated in 
the CCDZ173X2201 study. All the inclusion and exclusion criteria should be verified within that 
day (including laboratory results) and if the patient is enrolled in the afternoon, only one dose 
will be administered. Then from the next morning the patient will start taking CDZ173 as a 70 
mg b.i.d. regimen. 
Immune dysfunction and lymphoproliferation are the two hallmarks of APDS/PASLI. 
Measurement of systemic biomarkers (immunophenotyping and chemokines) will allow to 
assess the long-term effect of CDZ173 on the immune system. Performance of CT or MRI or 
ultrasound (US) imaging will allow a long term estimation of the effect on the size of lymph 
nodes and other lymphatic organs (for methodology refer to SOM and Imaging Reviewing 
Charter). This assessment will be performed only by patients that participated in the 
CCDZ173X2201 study. 
Patients will be evaluated for any disease recurrence, worsening or improvement as well as for 
AEs, SAEs and for the criteria for discontinuation throughout the study (refer to Discontinuation 
of Study Treatment, Section 7.2). For this reason, patients will be encouraged to take notes on 
any AE and concomitant medication taken at home to be reported to the Investigator. 
Safety assessments will include physical examinations, electrocardiograms (ECGs), vital signs, 
standard clinical laboratory evaluations (hematology, blood chemistry, and urinalysis), AE and 
SAE monitoring. 

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3.1.1 
Treatment switch from HGC to FCT formulation and serial PK 
sampling 
This section is not applicable for patients participating in this study in Russia; these patients 
will be allowed to continue on the HGC formulation without switching to the FCT formulation 
and thus will not take part in the pharmacokinetics and relative bioavailability assessment of 
the FCT formulation. 
At all other sites, the treatment will be switched from the HGC formulation to FCT per the 
process described below: 
All patients will receive oral 70 mg b.i.d. CDZ173 HGC from Visit 502 until the Investigator 
site is set up to administer CDZ173 FCT. When the Investigator site is ready (upon FCT supply 
at the site), at the patient’s next visit, the patient will have a last dose of CDZ173 HGC and have 
serial PK samples before switching to CDZ173 FCT. The day before this visit (earliest possible 
visit is Visit 502.1), the patient should record the time of his/her evening dose of CDZ173 HGC 
and provide the information to the Investigator. Next morning on the visit day, after an overnight 
fasting, the patient will have oral administration of CDZ173 HGC 70 mg administered by the 
Investigator at the site either under fasting condition, or half an hour after a light breakfast. The 
dosing time should be 12 hours from that of previous evening, or as close as possible. Patients 
should refrain from eating and drinking for 2 hours post dose. PK blood samples will be taken 
before and after dosing until 8 hours post-dose. Safety, biomarker samples and other assessments 
will be taken as well. The patient will then be dispensed CDZ173 FCT and discharged from the 
site on the same day after completion of all assessments, provided there are no safety concerns. 
The patient will start to take CDZ173 FCT from that evening until next visit. Patients should be 
contacted by phone approximately 2 weeks after the start on the FCT formulation to assess for 
safety (any new adverse events). In case of any concerns, patients should be followed-up as 
deemed appropriate by the investigator; this may include an unscheduled on-site visit. 
On the day before next visit, the patient will again record the time of his/her evening dose. In the 
morning of the visit, after an overnight fasting, the patient will be administered oral CDZ173 
FCT 70 mg by the Investigator at the site under fasting condition, or 30 minutes after a light 
breakfast, which should be consistent with the previous visit. The dosing time should be 12 
hours from that of previous evening, or as close as possible. Food and drink should not be 
consumed within 2 hours post dose. PK blood samples will be taken before and after dosing 
until 8 hours post-dose. Safety, biomarker samples and other assessments will be taken as well 
before the patient is discharged from the site, if no safety concerns. 
The patient will continue to take CDZ173 FCT 70 mg b.i.d. until the end of treatment period. 
Please refer to Assessment schedule, Section 8.1 and Site Operational Manual for detailed PK 
sampling and other assessments. 
 
3.2 
Rationale for study design 
Currently no approved treatment exists for APDS/PASLI. Based on preclinical data (see IB for 
details) and early, preliminary data from the study CCDZ173X2201 Part I, CDZ173 may 
specifically target the causative factor of APDS/PASLI, and thereby provide effective treatment 
for this newly described disease with a significant unmet medical need. Thus, this extension 

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study will offer continuous CDZ173 therapy to patients who participated in study 
CCDZ173X2201 or who received previously treatment with PI3Kδ inhibitors other than 
CDZ173. 
Moreover, this study will provide long-term safety, tolerability, efficacy and pharmacokinetic 
data. Efficacy endpoints may include soluble markers (such as immunoglobulin fractions, 
cytokines and chemokines) and lymphocyte phenotyping. Increased transitional B lymphocytes 
and reduced naïve B lymphocytes, as well as senescent T lymphocytes are hallmarks of 
APDS/PASLI (Lucas et al 2014). Many patients have a class switch defect, and the majority of 
patients, >80%, have low IgG2 levels and high IgM level; this is expected to contribute to the 
greatly increased infection risk of APDS/PASLI patients (Angulo et al 2013). Thus, these 
biomarkers may be supportive data for long-term efficacy of CDZ173 in APDS/PASLI. 
However, as these markers have so far not been validated as surrogate disease markers for 
efficacy in APDS, these assessments are considered exploratory. Classic albeit less specific 
markers of inflammation (hsCRP) and of lymphoproliferation (LDH) will also be measured. 
In line with the primary purpose of the study, which is continued treatment availability for the 
patients that completed the study CCDZ173X2201, this extension is a single arm open-label 
study. This is a standard design for this type of extension studies. 
Safety assessments will be performed regularly: after 14 days of treatment, every 6 weeks for 
the first three months, then every 3 months until week 36, after one year of treatment and then 
every 26 weeks until 6 years of treatment for each individual patient. This will ensure that 
patients who are experiencing any safety issues, considered to be due to the study drug, will exit 
the study; patients may also exit from the study based on the advice of the Investigator or upon 
patient's wish. According to the clinical data obtained thus far the Day 14 safety assessment is 
of specific relevance since the onset of a decrease in absolute neutrophil count was mainly seen 
within the first two weeks of treatment with CDZ173. 
PK trough and PD assessments will be performed every 6 weeks for the first three months, then 
every 3 months until week 36. Based on the data generated in Part I of study CCDZ173X2201 
this schedule appears to be appropriate and it restricts the volume of blood to be collected from 
each patient to an acceptable level. 
A single sequence cross-over comparison of the pharmacokinetics and relative bioavailability 
of CDZ173 FCT and HGC will provide relevant data for qualification of the FCT as replacement 
of the HGC while minimizing impact on the overall study conduct and convenience to study 
participants. 
 
3.3 
Rationale for dose/regimen, route of administration and duration 
of treatment 
A CDZ173 dose of 70 mg b.i.d. was well tolerated in the completed FIH study. In this study, 
CDZ173 demonstrated a direct pharmacokinetic (PK)/pharmacodynamic (PD) relationship 
(as measured by pAkt inhibition) and the population median pAkt pathway inhibition at 70 mg 
b.i.d. was found to be about 90% (see Figure 1-1). Seventy mg b.i.d. is also the final dose given 
in the preceding study CCDZ173X2201. Thus, the proposed dose for this extension study is 70 
mg b.i.d. 

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The same maximum dose of 70 mg CDZ173 b.i.d. is proposed for both adults and adolescents 
(12 years of age and older). CDZ173 was found to be predominantly cleared via CYP-mediated 
oxidative clearance, and the relevant organ functions and metabolic clearance are expected to 
be mature in adolescents; for such drugs clearance is expected to be more consistent when 
normalized to the body surface area (BSA) than to the body weight (Bartelink et al 2006). Also 
the available preclinical and clinical interaction data (study CCDZ173X2102) suggests that the 
body weight-normalized clearance of CDZ173 is expected to be higher in adolescents relative 
to adults. As body weight is generally lower in adolescents, compared to adults, the proposed 
fixed dose regimen will institute a higher dose per kg in adolescents relative to adults, thus 
limiting the risk of relative under-dosing of adolescents. 
Nonetheless, as age and body weight are correlated, absolute values for oral drug clearance vary 
likely as a function of age, hence, the population median oral drug clearance (CL/F) of CDZ173 
is expected to be, on average, lower in adolescents compared to adults. In order to limit the 
extent of higher exposure in adolescents than in adults, a lower body weight limit of 45 kg is 
proposed: 
• For a 45 kg adolescent with normal body habitus, the DuBois formula (Wang et al 1992) 
calculates the median BSA to be 1.4 m2 (male and female), corresponding to a BSA-scaled 
CL/F of 3.1 L/h, which represents about 80% of the respective adult reference value (3.8 
L/h, 1.75 m2). 
• Assuming similar between-subject variability in CL/F in adolescents compared to adults 
(geomean CV 35 %), the probability is less than 1% that any adolescent with a body weight 
of 45 kg will experience a drug exposure exceeding the maximum exposure observed in 
adults so far (59900 ng.hr/mL) at 140 mg b.i.d. At this dose, adult AUC0-12h,ss ranged 
25400-59900 ng.hr/mL; in this dose cohort rashes occurred but CDZ173 was otherwise well 
tolerated with a promising safety profile. Also, no more than 9% of adolescents with a body 
weight of 45 kg are estimated to have a steady-state oral drug exposure that exceeds the 
adult 97.5th percentile (AUC0-12h,ss, 35500 ng.hr/mL). 
Based on the direct PK/PD relationship and the short residence time (see Section 1.3.2), the 
same total daily dose given b.i.d. may establish more sustained pathway inhibition with less 
fluctuation between two consecutive doses compared to once daily (q.d.) dosing. The dosing 
frequency in the preceding study CCDZ173X2201 was also b.i.d. In agreement with the short half- 
life of CDZ173, no relevant drug accumulation was seen with b.i.d. dosing (see Section 1.3.2). 
The duration of this extension study with maximum individual treatment duration of 6 years, 
offers to patients a longer treatment and allows for the assessment of safety, tolerability, efficacy 
and pharmacokinetics over a prolonged period. The available preclinical toxicology data 
package supports chronic treatment (see also Section 1.2.3). 
While the terminal half-life of CDZ173 – approximately 10 hours – ensures a drug wash-out 
within a few days, the time needed for pharmacodynamic markers to start returning to 
(pathological) pre-treatment values is expected to be longer than the wash-out of CDZ173. Thus, 
a follow-up period of 12 weeks has been chosen. 
 
3.4 
Rationale for choice of comparator 
Not applicable. 

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3.5 
Purpose and timing of interim analyses/design adaptations 
Interim analyses may be conducted to support decision making concerning the current clinical 
study, the Sponsor’s clinical development projects in general or in case of any safety concerns. 
 
3.6 
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 1.3.3), thus, CDZ173 may be effective in counter-regulating the constitutive activation 
of this pathway. Although 12 weeks’ treatment with CDZ173 in the open-label 
CCDZ173X2201 study Part I led to significant improvements in the clinical presentation of the 
patients, it is still unknown whether this can be solely attributed to the treatment with CDZ173 
and whether such beneficial effects can be confirmed in a larger group of patients. 
In this study, 37 APDS/PASLI patients have received treatment with 70 mgb.i.d. CDZ173 
between 50 and 1664 days without relevant CDZ173-related AEs (status of March 31, 2021). 
 
In a recently completed randomized, subject, investigator and sponsor-blinded, placebo-
controlled, fixed dose part investigating in 31 adolescent and adult patients with APDS 
(CCDZ2201 Part 2), 21 patients received CDZ173 70 mg bid and 10 patients received placebo 
for 12 weeks.  The primary objective was to assess the clinical efficacy (lymphadenopathy and 
immunophenotype normalization) of CDZ173 in patients with Activated Phosphoinositide 3-
kinase-Delta Syndrome (APDS).  The co-primary endpoints were improvement in 
lymphoproliferation as measured by 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 and improvement in immunophenotype as measured by change from baseline 
in percentage of naïve B cells out of total B cells.  The co-primary endpoints (change from 
baseline in the log10 transformed SPD in index lesions and change from baseline in percentage 
of naïve B cells) were met.    CDZ173 70 mg bid over three months was well tolerated by APDS 
patients.  No deaths were reported during the study.  Five patients (16.1%) reported 11 SAEs in 
the study. The incidence of SAEs was lower in the CDZ173 70 mg bid group than the placebo 
group. None of the SAEs were suspected related to study treatment.  The majority of AEs were 
of Grade 1 or Grade 2 severity.  Overall, 25.8% patients (23.8% in CDZ173 70 mg bid vs 30.0% 
in placebo) reported AEs suspected related to study treatment by the Investigator.  None of the 
AEs led to discontinuation of study treatment.  The results of this study demonstrated clinical 
efficacy of CDZ173 70 mg bid over placebo in reduction of lymphoproliferation and 
improvement in immunophenotype.  
 
 
 
In preclinical in vivo studies, adverse effects have been observed after administration of high 
doses of CDZ173, including diarrhea and vomiting, QTc prolongation, slight insulin 
insensitivity and thyroid adverse effects (see IB for details). Moderate to severe diarrhea and 
morbidity requiring euthanasia (individual animals) have been observed in monkeys with an 
underlying bacterial enterocolitis (see Section 1.3.2). These effects have not been observed in 
healthy volunteers with single doses of CDZ173 up to and including the highest dose of 400 mg 
and with multiple doses up to the highest dose of 140 mg b.i.d. Multiple doses of 140 and 70 
mg b.i.d. in healthy subjects caused a few events of skin rash and decreases of neutrophils (as 
described in Section 1.3.1). Skin rashes were also observed in patients with pSS receiving 

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treatment with 70 mg b.i.d. CDZ173 or placebo (data also described in Section 1.3.1). 
CCDZ173X2201 Part I PK data have confirmed an oral clearance of about 4 L/h, in full 
agreement to the value found in healthy volunteers. At 70 mg b.i.d., median steady-state 
exposure (AUC0-24h,ss) will be about 35000 ng.hr/mL, which therefore remains about 1.5-fold 
below the NOAEL observed in the 13-week toxicity study in rats and corresponds to a similar 
unbound NOAEL exposure observed in the 39-week toxicity study in monkeys (the longest 
duration toxicity studies available to date). Based on Cmax, even larger safety margins exist 
(details in IB Section 4.4). 
To date only a limited number of APDS/PASLI patients have been exposed to CDZ173 as 
described above. This sample size is not sufficiently large to exclude occurrence of adverse 
events in the APDS patient population which are different from those seen in healthy subjects. 
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, 

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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. 
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. 
No risks are expected to be associated with Tanner staging or with standard physical 
examination. However, burden (embarrassment, discomfort, distress) is usually associated with 
examinations that are particularly comprehensive or intrusive such as those related to sexual 
development. To minimize the burden the examiner will explain every step prior to execution 
and will adjust the examination time to the individual. 
Risks related to an infection with SARS-CoV-2 (all participants) 
It is not known whether CDZ173 can have a direct impact on an infection with Coronavirus 
SARS-CoV-2. However, in Part I of CCDZ173X2201 study CDZ173 improved immune 
dysregulation in APDS patients, e.g. normalization of circulating transitional and naïve B cells 
and reduction of senescent T cells was observed (Rao et al 2017), which is why no additional 
risk is expected for APDS patients treated with CDZ173 during the COVID-19 pandemic. 
The risk to subjects in this trial will be minimized by adherence to the eligibility criteria, close 
clinical monitoring, defined stopping rules and by prohibiting concomitant medication expected 
to possibly lead to significant DDI. 
WoCBP should be informed that taking the study drug may involve unknown risks to the fetus 
if pregnancy were to occur during the study and agree that in order to participate in the study 
they must adhere to the contraception requirement for the duration of the study. 

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No radiation dose is imparted to the patients receiving an MRI scan or an ultrasound 
examination. For patients receiving a CT scan, the radiation dose will be between 5 mSv to 
15 mSv. This is considered to be a moderate risk level corresponding to the benefit to the patient 
(category III based on ICR62) and is balanced against the substantial societal benefit gained 
from the trial. The radiation dose from CT scans will be in accordance with local clinical 
practice and local regulations. Imaging is an optional procedure in this study. Adolescents 
between 12-15 years of age will only be assessed by MRI, or using a low dose CT scan protocol 
at sites where local practice and local authorities/ECs/IRBs approve such CT scans in 
adolescents for research purposes. 
There may be unknown risks of CDZ173 which may be serious and unforeseen. 
 
3.6.1 
Blood sample volumes 
No more than 400 mL of blood will be collected over the entire study period. Additional blood 
samples for monitoring safety may be required during the study. The blood loss due to sampling 
is not considered a risk to this patient population (both adults and adolescents) since the 
maximum volume collected at each visit will not exceed 65 mL, and the accumulated volume 
collected in 12 weeks will not exceed 200 mL. 
Timings of blood sample collection are outlined in the Assessment schedule (see Section 8.1). 
A summary blood log is provided in the SOM, together with instructions for all sample 
collection, processing, storage and shipment information. 
See Section 8.9 regarding the potential use of residual samples. 
 
4 
Population 
The study population will consist of male and female APDS/PASLI patients 12 to 75 years of 
age (inclusive), who participated in study CCDZ173X2201 or who were treated previously with 
PI3Kδ inhibitors other than CDZ173 and are deemed by the Investigator to benefit from PI3Kδ 
inhibitor therapy. 
A maximum of 42 patients are expected to be enrolled in this extension study. The Investigator 
must ensure that all patients being considered for the study meet the following eligibility criteria. 
For patients who do not roll-over directly at the EOT or EOS visit of CCDZ173X2201 study or 
who were treated previously with PI3Kδ inhibitors, patient selection is to be established by 
checking through all eligibility criteria at the Screening visit. 
For patients who do roll-over directly from the CCDZ173X2201 study, patient selection is to be 
established by checking through all eligibility criteria at the CCDZ173X2201 EOT/EOS visit. 
Patients should not sign the informed consent before eligibility is confirmed at CCDZ173X2201 
EOT/EOS visit. A relevant record (e.g. checklist) of the eligibility criteria must be stored with 
the source documentation at the study site. 

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Patients who did not complete the planned 12 week treatment period in CCDZ173X2201 study 
can only be enrolled after the unblinding of the study CCDZ173X2201 and confirmation that 
the patients had deteriorated on placebo treatment. Patients who deteriorated on treatment with 
CDZ173 in the CCDZ173X2201 study should be not re-exposed to CDZ173. 
Deviation from any entry criterion excludes a patient from enrollment into the study. 
 
4.1 
Inclusion criteria 
Patients eligible for inclusion in this study must fulfill all of the following criteria: 
1. Written informed consent must be obtained before any assessment is performed. 
2. Patients must have participated in study CCDZ173X2201 or were treated previously 
with PI3Kδ inhibitors other than CDZ173. 
3. Patients who are deemed by the Investigator to benefit from PI3Kδ inhibitor therapy. 
4. Patients or their legal representatives (for patients under the age of 18 years) must be 
able to communicate well with the Investigator, to understand and comply with the 
requirements of the study. 
5. Documented APDS/PASLI-associated genetic PI3K delta mutation. Patients with 
mutations in either PIK3CD or PIK3R1 can be included. 
 
4.2 
Exclusion criteria 
Patients fulfilling any of the following criteria are not eligible for inclusion in this study. 
1. Patients who withdrew consent from the study CCDZ173X2201. 
2. Use of other investigational drugs, except CDZ173, within 5 half-lives of enrollment, 
or within 30 days, whichever is longer. 
3. History of hypersensitivity to any of the study treatments or excipients or to drugs of 
similar chemical classes. 
4. History or current diagnosis of ECG abnormalities indicating significant risk of safety 
for patients participating in the study such as: 
• History of familial long QT syndrome or known family history of Torsades de 
Pointes. 
• Concomitant clinically significant cardiac arrhythmias, e.g. sustained 
ventricular tachycardia, and clinically significant second or third degree 
atrioventricular (AV) block without a pacemaker. 
• Resting QTcF (Fridericia preferred, but Bazett acceptable) > 450 msec in male 
patients of the age group 16 – 75 years, > 460 msec in female patients of the 
age group 16 – 75 years and > 440 msec in patients of the age group 12 – 15 
years, if the measurement is confirmed with an additional ECG repeated as 
soon as possible. Concomitant use of agents known to prolong the QT interval 
unless it can be permanently discontinued for the duration of the study. 
5. Current use of medication known to be strong inhibitors, or moderate or strong inducers 
of isoenzyme CYP3A and the treatment cannot be discontinued or switched to a 
different medication prior to starting study treatment. 

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6. Current use of medications that are metabolized by isoenzyme CYP1A2 and have a 
narrow therapeutic index (drugs whose exposure-response indicates that increases in 
their exposure levels by the concomitant use of potent inhibitors may lead to serious 
safety concerns (e.g. Torsades de Pointes)). 
7. 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. 
• 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. 
8. Donation or loss of 400 mL or more of blood within 8 weeks before Day 1. 
9. 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. 
10. Pregnant or nursing (lactating) women, where pregnancy is defined as the state of a 
female after conception and until the termination of gestation. 
11. Women of childbearing potential, defined as all women physiologically capable of 
becoming pregnant, unless they are using highly effective methods of contraception 
during   dosing   and   for   2   days   after   last    dose    of    study    medication. Highly 
effective contraception methods include: 
• Total abstinence (when this is in line with the preferred and usual lifestyle of the 
patient. Periodic abstinence (e.g. calendar, ovulation, symptothermal, post-ovulation 
methods) and withdrawal are not acceptable methods of contraception. 
• Female sterilization (have had surgical bilateral oophorectomy with or without 
hysterectomy) or total hysterectomy or tubal ligation at least 6 weeks before taking 
study treatment. In case of oophorectomy alone, only when the reproductive status 
of the woman has been confirmed by follow up hormone level assessment. 
• Male sterilization (at least 6 months prior to screening). For female patients on the 
study, the vasectomized male partner should be the sole partner for that patient. 
• Use of oral, injected or implanted hormonal methods of contraception or 
placement of an intrauterine device (IUD) or intrauterine system (IUS) or other 
forms of hormonal contraception that have comparable efficacy (failure rate <1%), 
for example hormone vaginal ring or transdermal hormone contraception. 

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In case of use of oral contraception women should have been stable on the same pill 
for a minimum of 3 months before taking study treatment. 
Women are considered post-menopausal and not in of child bearing potential if they 
have had 12 months of natural (spontaneous) amenorrhea with an appropriate clinical 
profile (e.g. age appropriate, history of vasomotor symptoms) or have had surgical 
bilateral oophorectomy (with or without hysterectomy), total hysterectomy or tubal 
ligation at least six weeks ago. In the case of oophorectomy alone, only when the 
reproductive status of the woman has been confirmed by follow up hormone level 
assessment she is considered not of child bearing potential. 
12. Patients who were non-compliant or demonstrated a serious protocol deviation in the 
study CCDZ173X2201. 
13. History of malignancy of any organ system (other than localized basal cell carcinoma 
of the skin), treated or untreated, regardless of whether there is evidence of local 
recurrence or metastases. 
14. Any surgical or medical condition, which may jeopardize the patient in case of 
participation in the study or which might significantly alter the absorption, distribution, 
metabolism, or excretion of drugs. Conditions due to APDS/PASLI are permitted. The 
Investigator should make this determination in consideration of the patient’s medical 
history and/or clinical or laboratory evidence (e.g. assessed at the end of treatment or 
EOT/EOS visit of the study CCDZ173X2201): 
• Uncontrolled hypertension (≥140/90 mmHg). 
• Congestive heart failure (New York Heart Association status of class III or IV). 
• Chronic obstructive pulmonary disease (GOLD stage 3-4). 
• Inflammatory bowel disease, peptic ulcers, gastrointestinal including rectal bleeding. 
• Major gastrointestinal tract surgery such as gastrectomy, gastroenterostomy, or 
bowel resection. 
• Pancreatic injury or pancreatitis. 
• Liver disease or liver injury as indicated by clinically significant abnormal liver 
function tests. Alanine aminotransferase (ALT) and aspartate aminotransferase 
(AST) greater than 2.5 times upper limit of normal (ULN). 
• History of renal injury/renal disease (e.g. renal trauma, glomerulonephritis, or one 
kidney only) or presence of impaired renal function as indicated by a serum 
creatinine level exceeding 1.5 mg/dL (133 μmol/L). 
• Evidence of urinary obstruction or difficulty in voiding at screening. 
• Uncontrolled diabetes (insulin dependent or non-insulin dependent). 
15. Uncontrolled chronic or recurrent infectious disease (with the exception of those that 
are considered to be characteristic of APDS/PASLI) 
Note: In the case where a safety laboratory assessment at screening or at the CCDZ173X2201 
EOT/EOS visit is outside of the range specified above, the assessment may be repeated. Values 
should be within specified ranges prior to treatment. 
For patients who did not participate in study CCDZ173X2201 but were treated previously with 
PI3Kδ inhibitors other than CDZ173, the following additional exclusion criteria apply: 

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16. 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 for adolescents 
17. Patient must have a minimum body weight of 45 kg 
18. Evidence of tuberculosis infection as defined by a positive QuantiFERON TB test 
(or comparable test) at screening. If presence of latent tuberculosis is established then 
treatment according to local country guidelines must have been completed before 
patients can be considered for enrollment. 
19. Intentionally blank; exclusion criterion removed in this protocol amendment. 
20. History of acquired immunodeficiency diseases, or a positive HIV (ELISA and 
Western blot) test result at screening. 
21. A positive Hepatitis B surface antigen or Hepatitis C test (by PCR) result at screening. 
No additional exclusions may be applied by the Investigator, in order to ensure that the study 
population will be representative of all eligible patients. 
 
5 
Restrictions for Study Patients 
During recruitment, screening/informed consent review, the patients must be informed and 
reminded of the restrictions outlined in this section. 
 
5.1 
Contraception requirements 
WoCBP must be informed that taking the study treatment may involve unknown risks to the 
fetus if pregnancy were to occur during the study, and agree that in order to participate in the 
study they must adhere to the contraception requirement for the duration of the study. If there 
is any question that the patient will not reliably comply, they should not be entered or continue 
in the study. 
Please refer to exclusion criteria (see Section 4.2) for details of contraception requirements for 
the study. 
For the adolescent population (12 – 15 years of age) previously or temporary abstinent 
adolescent males and females of child bearing potential must implement effective methods of 
contraception when becoming sexually active. Female adolescents of child bearing potential as 
well as males are only to be included in the clinical study if adequately informed about the 
contraceptive requirements and the need for contraception understood by the study participants 
and their legal representatives. Consultation, monitoring and questioning regarding potential 
sexual contacts at each study visit are considered a pre-requisite for adequate contraception in 
the adolescent population. 

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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. 
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 physician are encouraged to plan required vaccinations outside this window. 
 
Immunosuppressive drugs 
Immunosuppressive co-medication could increase the susceptibility to infections. Such drugs 
are thus prohibited during study participation (see Table 5-1). 
 
Table 5-1 
Prohibited immunosuppressive co-medication (examples) 
 
mTOR inhibitors (e.g. sirolimus, rapamycin, everolimus) 
Selective or non-selective PI3K inhibitors 
B cell depleting medication (e.g. rituximab) 
Belimumab 
Cyclophosphamide 
Cyclosporine A 
Mycophenolate 
6-mercaptopurine, azathioprine 
Methotrexate 
Systemic glucocorticoids above 25 mg prednisone or equivalent per day 

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Strong CYP3A inhibitors, and moderate or strong CYP3A inducers. 
Concomitant use of CDZ173 with strong CYP3A inhibitors and moderate and strong inducers 
is prohibited. In addition, if a patient, after being enrolled, requires the concomitant use of a 
strong CYP3A inhibitor, then CDZ173 dosing must be interrupted. In this case, CDZ173 dosing 
may be interrupted for the duration of therapy and up to 1 week of an adequate washout of the 
inhibitor. CDZ173 dosing may then recommence following consultation with Pharming. 
Please refer to Appendix 1-Table 15-1 for a list of prohibited CYP-interacting drugs. Please 
note that this list may not be comprehensive. 
 
Drugs that are metabolized by CYP1A2 
Time-dependent (irreversible) inhibition by CDZ173 was observed for CYP1A2. Concomitant 
use of CDZ173 with drugs that are primarily metabolized by isoenzyme CYP1A2 and have a 
narrow therapeutic index (NTI) is prohibited. CDZ173 dosing may be interrupted (*) for 
clinically-required treatment with such co-medications for the duration of therapy and up to 1 
week of an adequate washout of the co-medication. CDZ173 dosing may then recommence 
following consultation with Pharming. 
(*) It is recommended to respect a CDZ173 washout of at least 3 days prior to initiating therapy 
with the NTI CYP1A2 substrate. 
Please refer to Appendix 1-Table 15-1 for a list of prohibited CYP-interacting drugs. Please 
note that this list may not be comprehensive 
 
5.2.2 
Drug to be used with caution 
 
Concomitant medications that are moderate inhibitors of CYP3A 
Concomitant treatment of CDZ173 with moderate inhibitors of CYP3A4 is permitted, however, 
alternatives with less CYP3A interaction potential should be considered first. Duration of 
concomitant treatment with moderate inhibitors of CYP3A should be kept as short as possible. 
Note that co-administration of CDZ173 with strong and moderate inducers and with strong 
inhibitors of CYP3A is prohibited. 
 
Drugs with a risk to induce Torsades de Pointes 
If a patient requires the concomitant use of any QT prolonging medication with a risk for 
Torsades de Pointes, then Investigators, at their discretion, may co-administer such medications. 
Patients receiving such medications must however be closely monitored due to pre-clinical 
cardiac observations which however have not been replicated in the completed FIH trial with 
CDZ173. Note that some drugs with risk for Torsades de Pointes are also strong inhibitors of 
CYP3A (see Section 5.2.1). 

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Concomitant medications that are metabolized by CYP3A 
CDZ173 was identified in vitro as a potential weak CYP3A inducer. Although the likelihood of 
an in vivo induction is low (as confirmed by dynamic PBPK modelling), a slight decrease in 
systemic exposure of concomitant medications that are sensitive substrates of CYP3A (sensitive 
substrates) cannot be entirely ruled out. Investigators, at their discretion, may administer 
concomitant medications metabolized by CYP3A but caution is advised when CDZ173 is co- 
administered with drugs that are sensitive substrates of CYP3A and have an NTI. Patients 
receiving such medications must be monitored for potentiation of toxicity/loss of efficacy due 
to any individual concomitant medications and may require reduction of the concomitant 
medication. 
 
Concomitant medications that are substrates or inhibitors/inducers of the 
efflux transporters BCRP 
CDZ173 was identified in vitro as a substrate and inhibitor for the efflux transporter BCRP. 
Although unlikely, an increase in systemic drug exposure and/or altered tissue uptake of oral 
CDZ173 when co-administered with BCRP inhibitors cannot be ruled out. Likewise, CDZ173 
may increase the drug disposition of BCRP substrates. Investigators at their discretion may co- 
administer known BCRP inhibitors/substrates, however their duration should be kept as short 
as possible and patients must be closely monitored. Note that some BCRP inhibitors/substrates 
may also be strong or moderate inducers, or strong inhibitors of CYP3A, which are prohibited 
(see Appendix 1-Table 15-1). 
 
Drugs that substrates of the hepatic uptake transporter OATP1B1/B3 
CDZ173 was identified in vitro as a weak potential inhibitor of the uptake transporter 
OATP1B1/B3. In vivo interaction with this transporter is considered remote, however an 
increase in systemic exposure of OATP1B1/B3 substrates when co-administered with CDZ173 
cannot be entirely ruled out. Investigators may co-administer OATP substrates at their 
discretion when clinically indicated, however, their duration should be kept as short as possible 
and/or patients must be closely monitored (see Appendix 1-Table 15-2). 
 
Herbal medications 
Interactions between herbal supplements/medications and drugs can be multiple and are in 
general not fully understood. Therefore, herbal supplements/medications should be avoided 
throughout the study and if taken it should be documented in the concomitant medication page 
in the CRF. Note that supplements with known CYP3A interaction potential such as St. John’s 
Wort are prohibited as per Appendix 1-Table 15-1. 
 
5.3 
Smoking 
It is recommended to reduce or completely refrain from smoking. Smoking status will be 
recorded in the case report form (CRF) at each visit starting from screening. CDZ173 was found 
to be metabolized by CYP1A1 and CYP1A2, which are inducible by polycyclic hydrocarbons 
which are formed and inhaled during tobacco smoking although the response varies greatly. 
This restriction does not apply to nicotine gum or electronic cigarettes. 

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6 
Treatment 
6.1 
Study treatment 
Details on the requirements for storage and management of study treatment, and instructions to 
be followed for patient numbering, prescribing/dispensing, and taking study treatment are 
outlined in the SOM. 
 
6.1.1 
Investigational and control drugs 
The investigational drug CDZ173 (leniolisib) 70 mg will be prepared by Pharming and supplied 
to the Investigator site as open-label patient-specific packs. 
Two formulations of CDZ173 as HGC and FCT will be supplied (except for Russia). 
During an epidemic or pandemic (e.g. COVID-19 pandemic) that limits or prevents on-site 
study visits, delivery of IMP directly to a participant’s home is generally permitted in the event 
the Investigator has decided that an on-site visit by the participant is no longer appropriate or 
possible, and that it is in the interest of the participant’s health to administer the study treatment 
even without performing an on-site visit. Implementation will need to be discussed with 
Pharming. The dispatch of IMP from the site to the participant’s home remains under the 
accountability of the Investigator. Each shipment/provisioning will be for a maximum of 3- 
months supply. In this case, regular phone calls or virtual contacts (as per the assessment 
schedule or more frequently if needed) will occur between the site and the participant for 
instructional purposes, safety monitoring, and discussion of the participant´s health status until 
the participants can again visit the site. 
 
6.1.2 
Additional study treatment 
No additional treatment beyond investigational drug is included in this trial. 
 
6.2 
Treatment assignment 
All patients will receive the same dose and dosing regimen of CDZ173. Patients who were 
rolled over from study CCDZ173X2201 will keep the patient number they were allocated in 
that study for the duration of this extension study. For information on patient numbering, please 
see ‘Patient numbering’ section in the SOM. 
 
6.3 
Treatment blinding 
It is an open-label treatment, so no blinding is applicable. 

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6.4 
Treating the patient 
CDZ173 will be administered to the patient as oral 70 mg b.i.d. treatment. 
• Patients should be instructed to take the dose of CDZ173 daily in the morning and in the 
evening, at approximately the same time each day. The recommendation is to take the 
morning dose at approximately 8 am. The evening dose should be taken approximately 
12 hours after the morning dose. CDZ173 should be taken with a glass of water and 
consumed over as short a time as possible. Patients should be instructed to swallow the 
capsule or tablet as a whole and not to chew it. 
• If vomiting occurs during the course of treatment, no re-dosing of the patient is allowed 
before the next scheduled dose. 
• Missed doses should not be made up for. 
• On clinic visit days, patients should NOT take their morning dose at home. Instead, the 
study medication will be administered by the study staff at the clinic. 
See the SOM for further details. 
Sponsor qualified medical personnel will be readily available to advise on trial related medical 
questions or problems. 
 
6.5 
Permitted dose adjustments and interruptions of study treatment 
Study treatment dose adjustments are not permitted (see Section 7.2). 
CDZ173 dosing may be interrupted for clinically required treatment with strong CYP3A 
inhibitors and/or narrow TI CYP1A2 substrates (see Section 5.2.1) or for tolerability or safety 
issues for a maximum of 28 days. If patients discontinue treatment with CDZ173 for a longer 
time period they are allowed to restart treatment following thorough evaluation by the 
Investigator. In such cases the Investigator should also discuss the case with the sponsor and 
should capture all relevant information in patient narratives. 
 
6.6 
Emergency breaking of assigned treatment code 
Not applicable since it is an open-label study. 
 
6.7 
Treatment exposure / compliance and assessment of relative 
bioavailability of the two formulations 
Pharmacokinetic parameters (measures of treatment exposure) will be determined in all subjects, 
as detailed in Section 8.7. 
PK sampling for assessing relative bioavailability of the two CDZ173 formulations (FCT versus 
HGC) will be done with more time points allowing the application of non-compartmental 
methods to derive pharmacokinetic parameters. Eight samples will be collected on two 
subsequent visits when steady state is reached with either HGC or FCT treatment, as detailed 
in Assessment schedule. 

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The Investigator must promote compliance by instructing the patient to take the study treatment 
exactly as prescribed and by stating that compliance is necessary for the patient’s safety and the 
validity of the study. The patient must also be instructed to contact the Investigator if he/she is 
unable for any reason to take the study treatment as prescribed. 
Compliance will be assessed by the Investigator and/or study personnel at each visit. This 
information should be captured in the source document at each visit. All study treatment 
dispensed and returned must be recorded in the Drug Accountability Log. 
 
6.8 
Recommended treatment of adverse events 
Medication used to treat AEs must be recorded on the Concomitant medications/Significant 
non-drug therapies CRF pages. 
 
Instruction on handling of skin rashes 
As outlined in the current protocol (CCDZ173X2201E1) as well as in the CDZ173 
Investigator’s Brochure, occurrence of skin rashes has been reported for PI3K inhibitor drugs. 
Treatment with CDZ173 at doses ≥ 70 mg bid caused skin rashes in a frequency < 10% in 
healthy subjects, while in patients with primary Sjogren’s Syndrome receiving a dose of 70 mg 
bid skin rash was observed in a frequency of 55% (CCDZ173X2203). Yet, as of 12-Apr-2018, 
no skin rash has been reported in APDS patients treated with CDZ173. 
The following instructions describe the recommended management of potential CDZ173-related 
skin rashes in the present study. 
Grade 1 skin rash (i.e. <10% body surface area (BSA) with active skin toxicity): 
• Continue CDZ173 dosing at the same dose level. 
• Initiate topical corticosteroids 3-4 times daily, for a maximum of 28 days. 
Preferred compounds to use are triamcinolone or betamethasone while skin toxicity is 
active. 
• For patients with symptoms like burning, stinging and/or pruritus, add non-sedating anti- 
histamine. 
• If active rash is not resolved within 28 days of appropriate treatment, CDZ173 should be 
suspended for a maximum duration of 28 days until rash/ skin toxicity is resolved. 
If longer interruption is needed, restarting CDZ173 treatment should only be initiated 
following thorough evaluation by the Investigator. Re-start CDZ173 at the same dose. 
Grade 2 (10-30% BSA with active skin toxicity) and Grade 3 skin rash (>30% BSA with 
active skin toxicity): 
• Suspend CDZ173 dosing until rash/skin toxicity is no longer active but fading (Grade 1), 
up to a maximum duration of 28 days. If CDZ173 treatment interruption is longer than 
28 days, restart should only be initiated following thorough evaluation by the Investigator. 
• Initiate topical corticosteroids 3-4 times daily, for a maximum of 28 days. Preferred 
compounds to use are triamcinolone or betamethasone while skin toxicity is active. 

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• In case of Grade 2, consider adding systemic corticosteroids 20-40mg/day. In case of 
Grade 3, add systemic corticosteroids. If rash resolves to ≤ Grade 1 within 10 days, 
systemic corticosteroids may be discontinued. Please note that any systemic 
glucocorticoids above 25 mg/day prednisone or equivalent per day will lead to patient 
having to discontinue CDZ173 treatment and only be followed-up for safety monitoring. 
• For patients with symptoms like burning, stinging and/ or pruritus, add non-sedating anti- 
histamine. 
• In case of first occurrence of skin rash, CDZ173 dosing can be re-started at the same dose 
once rash/ skin toxicity is no longer active but fading (Grade 1). In case of second 
occurrence, CDZ173 dosing can be re-started at the same dose once rash/ skin toxicity has 
resolved (this may require CDZ173 treatment interruption > 28 days, and further 
evaluation by the Investigator is needed). 
Grade 4 skin rash (any BSA associated with extensive superinfection, with i.v. antibiotics 
indicated, life-threatening consequences): 
• Permanently discontinue patient from CDZ173 treatment and consider dermatology 
consultation. 
• Treatment of rash should follow instructions for Grade 3 rash above with the exception of 
re-challenge and with any additional measures needed. 
 
6.9 
Concomitant treatment 
The Investigator must instruct the patient to notify the study site about any new medications 
he/she takes after the patient was enrolled into the study. 
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 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. 
Each concomitant drug must be individually assessed against all exclusion criteria/prohibited 
medication. If in doubt, the Investigator should contact Pharming before treating a patient or, if the 
patient is already enrolled, to determine if the patient should continue participation in the study. 
 
7 
Study Completion and Discontinuation 
7.1 
Study completion and post-study treatment 
Patients will continue in the study for 6 years. After completion of the study no further study 
treatment will be made available to patients unless a prolongation of this study or a 
compassionate use is provided. 
Study completion is defined as when the last patient completes his/her End of Study visit, and 
any repeat assessments associated with this visit have been documented and followed-up 
appropriately by the Investigator, or in the event of an early study termination decision, the date of 
that decision. In case compassionate use will be provided, the End of Treatment visit will be 
considered the final study visit.   
7.2 
Discontinuation of study treatment 
Discontinuation of study treatment for a patient occurs when study treatment is stopped earlier 

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than the protocol planned duration. Discontinuation of study treatment can be decided by either 
the patient or the Investigator. 
Study treatment must be discontinued under the following circumstances: 
• Patient decision - patients may choose to discontinue study treatment for any reason at any time. 
• The Investigator believes that continuation would negatively impact the safety of the 
patient or the risk/benefit ratio of trial participation. 
• Any protocol deviation that results in a significant risk to the patient’s safety. 
• Pregnancy (see Section 8.6 (Safety) and Section 9.7 (Pregnancy reporting)) 
• The patient experiences a drug-related SAE. 
• Diarrhea of CTC-AE Grade 2 or higher on 3 consecutive days. 
• Diarrhea of CTC-AE Grade 3 or higher. 
• Diarrhea or abdominal pain with accompanying fever assessed to be related to a GI 
infection. 
• Grade 4 skin rashes as per protocol Section 6.8. 
• Use of prohibited treatment as per protocol Section 5.2 
If discontinuation of study treatment occurs, Investigator must determine the primary reason for 
the patient’s premature discontinuation of study treatment and record this information on the 
Dosage Administration CRF. Resuming study treatment after a full safety review of the patient 
needs to be agreed with the investigator and with the Sponsor. 
Patients 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, Withdrawal of Informed Consent). Where possible, they should 
return for the assessments indicated by an asterisk (*) in the Assessment schedule. If they fail 
to return for these assessments for unknown reasons, every effort (e.g. telephone, e-mail, letter) 
should be made to contact the patient/pre-designated contact as specified in Section 7.4 (Lost 
to follow-up). 
 
7.3 
Withdrawal of informed consent 
Subjects may voluntarily withdraw consent to participate in the study for any reason at any time. 
Withdrawal of consent occurs only when a subject: 
• Does not want to participate in the study anymore, and 
• Does not allow further collection of personal data 
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. 

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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. 
Pharming will continue to keep and use collected study information (including any data resulting 
from the analysis of a subject’s samples until their time of withdrawal) according to applicable 
law. 
For US and Japan: All biological samples not yet analyzed at the time of withdrawal may still 
be used for further testing/analysis in accordance with the terms of this protocol and of the 
informed consent form. 
For EU and RoW: All biological samples not yet analyzed at the time of withdrawal will no 
longer be used, unless permitted by applicable law. They will be stored according to applicable 
legal requirements. 
 
7.4 
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.  
 
7.5 
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 Pharming: 
• Two or more patients experience a drug-related SAE. 
• More than three patients report CTC-AE (current version) Grade 3 or higher AEs within 
the same organ class that are considered to be related to study drug. 
• Pharming considers that the number and/or severity of AEs justify discontinuation of 
the study. 
• Pharming requests it (e.g. in the case of pre-clinical safety findings, or issues with the 
study drug). 
 
7.6 
Early study termination by the sponsor 
The study can be terminated by Pharming at any time for any reason. This may include reasons 
related to the benefit/ risk assessment of participating in the study, practical reasons (including 
slow enrollment), or for regulatory or medical reasons. Should this be necessary, patients must 
be seen as soon as possible and treated as a prematurely withdrawn patient. 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 patient’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 
8.1 
Assessment schedule 
Patients should be seen for all visits/assessments as outlined in the Assessment schedule or as 
close to the designated day/time as possible. 
If an epidemic or pandemic (e.g. COVID-19 pandemic) limits or prevents on-site study visits, 
alternative methods of providing continuing care may be implemented. Phone calls, virtual 
contacts (e.g. teleconsult) or visits by site staff/home nursing service to the participant´s home 
depending on local regulations and capabilities, can replace on-site study visits, for the 
duration of the pandemic until it is safe for the participant to visit the site again. 
Missed or rescheduled visits should not lead to automatic discontinuation. Patients who 
prematurely discontinue the study for any reason should be scheduled for a visit as soon as 
possible, at which time all of the assessments listed for the final visit will be performed. At this 
final visit, all dispensed investigational product should be reconciled, and the AEs and 
concomitant medications recorded in the CRF. 
In case that a patient rolls-over directly at the End of Treatment visit of the CCDZ173X2201 
study and the visits 501 & 502 are done on the same day, the extension study assessments that 
correspond to the CCDZ173X2201 assessments (including lab samples, PROs, vital signs, 
pregnancy test) will not be repeated. Please see the SOM for more guidance. 

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Table 8-1 
Assessment schedule 
 
Epoch 
Extensi 
on- 
Screeni 
ng 
Extension-Treatment 
Visit Name Screeni 
ng 
Treatment 
EoT 
EOS19 
Visit Numbers1 
5012 
5023 
502.1 503 
504 
505 
506 
507 
508 
509 
510 
511 
512 
513 
514 
515 
516 
517 
599 
Study Day(s) 
-7 
-3 +7 
1 
14 
-3 +3 
42 
-7 +7 
84 
-10 
+10 
168 
-10 
+10 
252 
-10 
+10 
364 
-10 
+10 
546 
±2 
weeks 
728 
±2 
weeks 
910 
±2 
weeks 
1092 
±2 
weeks 
1274 
±2 
weeks 
1456 
±2 
weeks 
1638 
±2 
week 
s 
1820 
±2 
weeks 
2002 
±2 
weeks 
2184 
±2 
weeks 
2268 
±2 
weeks 
Written Informed 
Consent4 
X 
Inclusion / Exclusion 
criteria 
X 
Medical history/current 
medical conditions 
X 
Demography 
X 
Physical examination* 
X5 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Tanner Staging6 
X5 
X 
X 
X 
X 
X 
X 
Pregnancy test7 
X5 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Vital signs and body 
measurements 
Body height8* 
X5 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Body weight* 
X5 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Body temperature* 
X5 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Blood pressure/ 
pulse rate9* 
X5 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
ECG evaluation* 
X5 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Hematology* 
X5 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Blood chemistry10* 
X5 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 

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Epoch 
Extensi 
on- 
Screeni 
ng 
Extension-Treatment 
Visit Name Screeni 
ng 
Treatment 
EoT 
EOS19 
Visit Numbers1 
5012 
5023 
502.1 503 
504 
505 
506 
507 
508 
509 
510 
511 
512 
513 
514 
515 
516 
517 
599 
Study Day(s) 
-7 
-3 +7 
1 
14 
-3 +3 
42 
-7 +7 
84 
-10 
+10 
168 
-10 
+10 
252 
-10 
+10 
364 
-10 
+10 
546 
±2 
weeks 
728 
±2 
weeks 
910 
±2 
weeks 
1092 
±2 
weeks 
1274 
±2 
weeks 
1456 
±2 
weeks 
1638 
±2 
week 
s 
1820 
±2 
weeks 
2002 
±2 
weeks 
2184 
±2 
weeks 
2268 
±2 
weeks 
Urinalysis* 
X5 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
HIV/Hepatitis/QuantiFe 
ron test 
X11 
Trough PK blood 
collection12 
X 
X 
X 
X 
Serial PK blood 
collection13 
X13 
X13 
X13 
X13 
X13 
X13 
X13 
X13 
X13 
X13 
X13 
X13 
X13 
X13 
Phone contact to 
assess for safety14 
X14 
X14 
X14 
X14 
X14 
X14 
X14 
X14 
X14 
X14 
X14 
X14 
X14 
Soluble biomarkers 
X 
X 
X 
X 
T and B cell 
immunophenotyping 
X 
X 
X 
X 
Serum 
immunoglobulins 
X 
X 
X 
X 
EBV/CMV test17 
X 
X 
X 
X 
EBV test in saliva 
X 
X 
X 
X 
SF-36/WPAI-CIQ 
Questionnaires 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Physician’s/Patient’s 
global assessment 
scales 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
MRI or CT or US 
scan15 
X15 
X15 

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Epoch 
Extensi 
on- 
Screeni 
ng 
Extension-Treatment 
Visit Name Screeni 
ng 
Treatment 
EoT 
EOS19 
Visit Numbers1 
5012 
5023 
502.1 503 
504 
505 
506 
507 
508 
509 
510 
511 
512 
513 
514 
515 
516 
517 
599 
Study Day(s) 
-7 
-3 +7 
1 
14 
-3 +3 
42 
-7 +7 
84 
-10 
+10 
168 
-10 
+10 
252 
-10 
+10 
364 
-10 
+10 
546 
±2 
weeks 
728 
±2 
weeks 
910 
±2 
weeks 
1092 
±2 
weeks 
1274 
±2 
weeks 
1456 
±2 
weeks 
1638 
±2 
week 
s 
1820 
±2 
weeks 
2002 
±2 
weeks 
2184 
±2 
weeks 
2268 
±2 
weeks 
Patient Narratives* 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Study drug 
administration16 
X18 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Study/epoch 
completion information 
X 
X 
Concomitant 
medications* 
X 
Adverse events 
X 
Comments 
X 
 
 
Note: If several assessments are scheduled at the same time point, please see the SOM for guidance on recommended sequence of assessments 
Keys 
* These assessments are also to be conducted for patients who discontinue study treatment 
1 Visit structure given for internal programming purpose only. 
2 To be performed only if patient does not roll-over directly at CCDZ173X2201 EOT/EOS visit. 
3 Visit 502 can be performed on the same day of visit 501, if all the inclusion and exclusion criteria can be verified on that day. In that case the assessments of body 
weight, body temperature and blood pressure/pulse rate don’t have to be repeated. 
4 The extension study can be described and the ICF for the extension study can be provided to the patient already during the CCDZ173X2201 study, in order to let 
the patient having enough time to properly think about his/her participation. 
5 If patient roll-over at the CCDZ173X2201 EOT/EOS visit this assessment will correspond to the assessment performed at that visit and will not be re-done. 
6 Only assessed in patients who are younger than 18 years old at the time of assessment. 

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7 Serum pregnancy test is required at Screening if the patient is not roll-over directly from study CCDZ173X2201EOT/EOS visit. Urine pregnancy test for all other 
patients and time points. Patients will carry out self-pregnancy tests between visits after Visit 504, data will be kept as source document. 
8 Only assessed in patients who are younger than 18 years old at the time of assessment. Adult patients who did not participate in CCDZ173X2201 study will have 
one assessment at Visit 501 only. 
9 Sitting blood pressure and pulse rate will be measured after 3 minutes of sitting rest. 
10 Including hsCRP and LDH assessments. 
11 Only assessed in patients who did not participate in CCDZ173X2201 study. 
12 Not applicable for patients enrolled in Russia. Refer to SOM for timing of collections. Additional trough PK samples will not be taken if the visit has serial PK blood 
collection. 
13 Not applicable for patients enrolled in Russia. For all other patients, serial PK blood collection will occur in any two consecutive visits from Visit 502.1 to Visit 511. 
The first visit has PK blood sampling before and after the final dose of HGC, and then patient should be switched to FCT. The second visit is the next study visit 
following the switch to FCT. Each of these two visits will have PK samples collected at pre-dose, and post dose 0.25, 0.5. 1. 2. 4. 6 and 8 hours. 
14 A phone contact should be made approximately 2 weeks after the first dose of FCT to check for any potential safety issues. In case of any concerns, patients 
should be followed-up as deemed appropriate by the investigator; this may include an unscheduled on-site visit. 
15 Optional for patient: it can be performed at Visit 505 (Day 168), or at Visit 506 (Day 252) or between these two visits. Same modality as in the CCDZ173X2201 
should be used. Not to be performed by patients who did not participate in CCDZ173X2201 study. 
16 Morning dose after blood sample collections. Also refer to Footnote 13 and protocol Section 3.1 for dosing details. 
17 Samples for EBV/CMV test will be collected as EBV/CMV viremia (plasma) and as EBV/CMV latent (plasma). 
18  If patient rolls-over directly at the CCDZ173X2201 EoT visit and visits 501 and 502 are performed on the same day (see Footnote 3 above), the extension study  
medication will be given as the morning dose. 
     19 If patient rolls-over to compassionate use the EoS visit will not take place and EoT visit will be the last study visit. 

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8.2 
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, or parent/guardian if the 
patient is 12 – 17 years old, gives consent (if allowed according to local requirements) by 
providing written informed consent, the patient must be informed about the study to the extent 
possible given his/her understanding. If the patient is capable of doing so, he/she must indicate 
assent by personally signing and dating the written informed consent document or a separate 
assent form. 
Pharming will provide to Investigators a proposed informed consent form that complies with the 
ICHE6 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 
Pharming before submission to the IRB/IEC. 
Information about common side effects already known about the investigational drug can be 
found in the IB. This information will be included in the subject informed consent and should 
be discussed with the patient during the study as needed. Any new information regarding the 
safety profile of the investigational drug that is identified between IB updates will be 
communicated as appropriate, for example, via an Investigator Notification or an Aggregate 
Safety Finding. New information might require an update to the informed consent and then must 
be discussed with the patient and patients must re-consent. 
Ensure patients are informed of the contraception requirements outlined in the Section 4.2 
(Exclusion criteria) and in Section 5.1 (Contraception requirements). 
A copy of the approved version of all consent forms must be provided to the Pharming monitor 
after IRB/IEC approval. 
During an epidemic or pandemic (e.g. COVID-19 pandemic) that may challenge the ability to 
obtain a standard written informed consent due to limits that prevent an on-site visit, the 
Investigator may conduct the informed consent discussion remotely (e.g. telephone, 
videoconference). Guidance issued by local regulatory bodies on this aspect prevail and must 
be implemented and appropriately documented (e.g. the presence of an impartial witness, 
sign/dating separate ICFs by trial participant and person obtaining informed consent, etc). 
In case Home Nursing is implemented during an epidemic or pandemic (e.g. COVID-19 
pandemic), a separate Home Nursing consent document must be used in addition to the main 
ICF. 
 
8.3 
Patient screening 
In case a patient will roll-over directly at the CCDZ173X2201 EOT/EOS visit, the results of the 
physical examination, pregnancy tests, vital signs and body measurements, ECG evaluation, 
hematology, blood chemistry and urinalysis of the CCDZ173X2201 EOT/EOS visit will be 
used as the screening visit assessments for the extension study and will be reported also in the 
electronic case report form (e-CRF) of the extension study. 

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Patients who do not directly roll-over will need to undergo the screening visit at the time of 
enrollment in this extension study see Assessment schedule (Section 8.1). 
Patients that were treated previously with PI3Kδ inhibitors other than CDZ173 will perform the 
screening visit as per protocol. Information on what data should be collected for screening 
failures is outlined in the SOM. 
 
8.4 
Patient 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. 
Investigators have the discretion to record abnormal test findings on the medical history CRF, 
if in their judgment, the test abnormality occurred prior to the informed consent signature. 
 
8.4.1 
Hepatitis/HIV screening 
All patients who did not roll-over directly from core study CCDZ173X2201 EOT/EOS will be 
screened for hepatitis B surface antigen (HbsAg), hepatitis C and HIV. 
Screening for Hepatitis C will be based on HCV antibodies (by PCR). 
Evaluation for HIV seropositivity will be performed, and, if positive, confirmation by a second 
technique available at the laboratory site, e.g. Western blot. 
Appropriate counseling will be made available by the Investigator in the event of a positive 
finding. Notification of state and federal authorities, as required by law, will be the 
responsibility of the Investigator. 
Results will be available as source data and will not be recorded within the CRF. 
 
8.4.2 
Tuberculosis testing 
In order to evaluate an eventual infection with tuberculosis, a QuantiFeron test (or a comparable 
tuberculosis blood test) will be performed at screening for patients who did not roll-over directly 
from core study CCDZ173X2201. 
 
8.5 
Efficacy / Pharmacodynamics 
8.5.1 
Efficacy 
If an epidemic or pandemic (e.g. COVID-19 pandemic) limits or prevents on-site study visits, 
where possible efficacy endpoints could be collected remotely. For example, PRO data 
collection may be done by sending the patient questionnaires by post. 
 
8.5.1.1 
High Sensitivity C-reactive protein (hsCRP)/Lactate dehydrogenase 
(LDH) 
These parameters will be measured to assess biomarkers reflecting the efficacy of CDZ173 to 
reduce systemic inflammatory components of APDS/PASLI. 

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8.5.1.2 
EBV and CMV assessments 
Chronic or intermittent viremia of EBV and/or CMV has been observed in APDS/PASLI 
patients, consistent with the described T cell defect (Lucas et al 2014). Plasma samples will be 
used for investigation of EBV and CMV viremia. Depending on the results, PBMC and plasma 
fraction will be used for investigation of latent/lytic burden of EBV and CMV. In addition the 
viral load of EBV in saliva will also be quantified. 
 
8.5.1.3 
Serum Immunoglobulins 
Most patients with APDS/PASLI have a Hyper-IgM syndrome and/or a reduced number of class 
switched B memory cells (Angulo et al 2013, Lucas et al 2014, Crank et al 2014). Serum IgG 
(including subclasses), IgE, IgM and IgA will be quantified as measure of the B cell function and 
of class switching. 
 
8.5.2 
Patient Report Outcomes (PRO) 
 
8.5.2.1 
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. 
 
8.5.2.2 
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 below 18) 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. 

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8.5.2.3 
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). 
 
8.5.2.4 
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. 
 
8.5.2.5 
Patient 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 during the 
study, and to provide details on the areas where the patient improved or worsened during the 
treatment phase. 
 
8.6 
Safety 
Safety assessments are specified below; methods for assessment and recording are specified in 
the SOM, with the Assessment schedule (Section 8.1) 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. 
 
8.6.1 
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 AE must be 
appropriately recorded on the Adverse Event CRF. 
 
8.6.2 
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 

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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, 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 patient to qualify. 
 
8.6.3 
Height and weight 
Height in centimeters (cm) (to be measured only at screening visit for adult patients, and to be 
measured at each visit for adolescent patients as per Assessment schedule) and body weight (to 
the nearest 0.1 kilogram [kg] in indoor clothing, but without shoes) will be measured. 
 
8.6.4 
Tanner Staging 
Tanner Staging will be determined for patients below 18 years of age at the time of the 
assessment. The assessment includes external genitals development stage I-V for males, breast 
development stage I-V for females and pubic hair development stage I-V for both sexes. To be 
performed once per year. 
 
8.6.5 
Laboratory evaluations 
Clinically relevant deviations of laboratory test results occurring during or at completion of the 
study must be reported and discussed with Pharming personnel. The results should be evaluated 
for criteria defining an AE 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, Pharming personnel should be contacted. 
 
Hematology 
Hemoglobin, hematocrit, red blood cell (RBC) count, white blood cell (WBC) count with 
differentials and platelet count, PT/INR, aPTT 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, 
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. 
ESR, 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. 
 
8.6.6 
Electrocardiogram (ECG) 
A standard 12 lead ECG will be performed in single 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 AEs 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). 
 
8.6.7 
Pregnancy test 
All WoCBP will have pregnancy tests at visits shown in the Assessment schedule, Section 8.1. 
Between visits, monthly pregnancy tests are carried out by patients using the self-test kits after 
Visit 504. Additional pregnancy testing may be performed to meet local requirements. The test 
results outside of study visits will be reported to the Investigator and kept as source 
documentation. Results should be entered in eCRF Comments page. A positive urine pregnancy 
test requires immediate interruption of study treatment until serum β-hCG is performed and 
found to be negative. 
During an epidemic or pandemic (e.g. COVID-19 pandemic) that limits or prevents on-site 
study visits, relevant participants can perform the urine pregnancy test at home and report the 
result to the site. It is important that participants are instructed to perform the urine pregnancy 
test first and only if the test result is negative proceed with the administration of the study 
treatment. A communication process should be established with the participant so that the Site 
is informed of the pregnancy test results. 

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8.7 
Pharmacokinetics 
During an epidemic or pandemic (e.g. COVID-19 pandemic) that limits or prevents on-site 
study visits, or if visits by site staff to a participant’s home are not feasible the collection of 
samples may be modified by Pharming and will be communicated to the Investigator. 
PK samples will be collected at the time points defined in the Assessment schedule (see 
Section 8.1) and SOM. Follow instructions outlined in the SOM regarding sample collection, 
numbering, processing and shipment. See Section 8.9 regarding the potential use of  residual 
samples. 
PK samples will be obtained and evaluated in all patients (except for patients enrolled in Russia). 
CDZ173 will be determined by a validated LC-MS/MS method; the anticipated Lower Limit of 
Quantification (LLOQ) is approximately 3 ng/mL. 
Concentrations will be expressed in mass per volume units and will refer to the free base. 
Concentrations below the LLOQ will be reported as “zero” and missing data will be labeled as 
such in the Bioanalytical Data Report. 
The following pharmacokinetic parameters will be determined using the actual recorded 
sampling times and non-compartmental method(s) with Phoenix WinNonlin (Version 6.2 or 
higher): AUC0-12,ss and Cmax,ss. Other parameters may be added. For calculation of AUC0-
12,ss the pre-dose concentration will also be used as 12 h concentration. 
In addition steady-state drug exposure in this extension study will be summarized in terms of 
trough concentration (Ctrough). 
 
8.8 
Other assessments 
During an epidemic or pandemic (e.g. COVID-19 pandemic) that limits or prevents on-site study 
visits, or if visits by site staff to a participant’s home are not feasible the collection of samples may 
be modified by Pharming and will be communicated to the Investigator. 
 
8.8.1 
Exploratory Biomarker assessments 
Details on the assessed biomarkers are provided below. Samples will be collected at the time 
points defined in the Assessment schedule. Further details on sample collection, numbering, 
processing and shipment will be provided in the SOM. 
The following biomarkers may provide additional measures of efficacy, and may include, but 
are not be limited to: 
 
Soluble Biomarkers 
A panel of chemokines and/or cytokines selected based on Part 1 results of CCDZ173X2201 
study will be quantified in serum. Sample processing will be detailed in the SOM. 

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Cellular Biomarkers 
To demonstrate that CDZ173 improves the disturbed immune system in a long term manner, 
immunophenotyping of B and T cell subsets will be explored. 
Sample processing will be detailed in the SOM. 
The detailed method descriptions of the assays will be included in the bioanalytical data reports. 
 
Exploratory Imaging 
Lymphoproliferation is one of the hallmarks of APDS/PASLI. As optional for a patient, MRI 
or CT or ultrasound may be performed for long term estimation of the CDZ173 effect on lymph 
nodes sizes and on extranodal lymphoproliferation. The same imaging modality as in the 
CCDZ173X2201 study will be used for the same patient. Adolescents between 12-15 years of 
age (inclusive) will be assessed by MRI, or using a low dose CT scan protocol (Buty et al 2017; 
Nagayama et al 2018; Kuo et al 2016) at sites where local practice and local 
authorities/ECs/IRBs approve such type of CT scans in adolescents for research purposes. 
For further details on image acquisition and analysis, refer to SOM, MRI/CT subject scanning 
guide and imaging review charter. 
This assessment will be exclusively performed in patients that participated in study 
CCDZ173X2201 since only these patients provide baseline data. 
 
8.9 
Use of residual biological samples 
Any residual samples remaining after the protocol-defined analysis has been performed may be 
used for additional exploratory analysis. This may include, but is not limited to, using residual 
samples for protein binding, metabolite profiling, biomarkers of transporters or metabolic 
enzyme activity or other bioanalytical purposes (e.g. cross check between different sites and/or 
stability assessment). Given the exploratory nature of the work, the analytical method used for 
those assessments will not be validated. As such, the results from this exploratory analysis will 
not be included in the clinical study report. 
Use of samples for additional, non-protocol defined endpoints would only be allowed if the 
subject signed the “additional (future) research” section of the Informed Consent Form. 
 
9 
Safety monitoring 
9.1 
Adverse events 
An 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 patient after providing written informed consent for participation in the study until 
the end of study visit. Therefore, an AE may or may not be temporally or causally associated 
with the use of a medicinal (investigational) product. 

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In addition, all reports of Special Situations (SSs) are also considered an AE irrespective if a 
clinical event has occurred. See Section 9.2 for an overview of the reporting requirements. 
The occurrence of AEs must be sought by non-directive questioning of the patient at each visit 
during the study. AEs also may be detected when they are volunteered by the patient during or 
between visits or through physical examination finding, laboratory test finding, or other 
assessments. Study patients will be instructed to take notes of any AE and bring those notes to 
the study visits. 
Abnormal laboratory values or test results constitute AEs 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 
patient and identifying AEs. Alert ranges for liver and kidney related events are included in 
Table 9-1 and Table 9-3, respectively. AEs must be recorded on the Adverse Events CRF under  
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 AE, use: 
• 1=mild, 
• 2=moderate, 
• 3=severe 
• 4=life threatening* (see Section 9.2.1 for definition of a SAE) 
*Note: There may be cases where a CTC-AE with a grade of 4 (life-threatening) may 
not necessarily be an SAE (e.g. certain laboratory abnormalities in the absence of 
meeting other seriousness criteria). 
CTC-AE grade 5 (death) is not used, but is collected as a seriousness criteria and also 
collected in other CRFs (e.g. Study Completion, Death/Survival). 
2. Its relationship to the study treatment: 
• Yes or 
• No 
3. Its duration (start and end dates) or if the event is ongoing an outcome of 
not recovered/not resolved must be reported. 
4. Whether it constitutes a SAE(see Section 9.2.1 for definition of SAE) and 
which  seriousness criteria have been met 
5. Action taken regarding investigational treatment. 

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All AEs must be treated appropriately. Treatment may include one or more of the 
following: 
• no action taken (e.g. further observation only) 
• investigational treatment temporarily interrupted/withdrawn 
• concomitant medication or non-drug therapy given 
• hospitalization/prolonged hospitalization (see Section 9.2.1 for definition of SAE) 
6. Its outcome (not recovered/not resolved; recovered/resolved with sequelae; fatal 
or unknown). 
Information about common side effects already known about the investigational drug can be 
found in the IB. Once an AE is detected, it must 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 investigational drug, the 
interventions required to treat it, and the outcome. 
The Investigator must also instruct each patient to report any new AE (beyond the protocol 
observation period) that the patient, or the patient’s personal physician, believes might 
reasonably be related to study treatment. This information must be recorded in the Investigator’s 
source documents; however, if the AE meets the criteria of an SAE and SS, it must be reported 
to Pharming. 
 
9.2 
Serious adverse event and special situation reporting 
9.2.1 
Definitions  
A Serious Adverse Event (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 study 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, e.g. defined as an event that jeopardizes the patient or may 
require medical or surgical intervention. 

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All malignant neoplasms will be assessed as serious under “medically significant” if other 
seriousness criteria are not met. 
Life-threatening in the context of a SAE refers to a reaction in which the patient was at risk of 
death at the time of the reaction; it does not refer to a reaction that hypothetically might have 
caused death if it were more severe (see Annex IV, ICH-E2D Guideline). 
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 (see Annex IV, ICH-E2D Guideline). 
Any suspected transmission via a medicinal product of an infectious agent is also considered a 
serious adverse reaction. 
All AEs (serious and non-serious) are captured on the CRF; SAEs and SSs also require 
individual reporting to Pharming PHV as per Section 9.2.2. 
 
A Special Situation (SS) is defined as any report, whether or not associated with an AE, of: 
• Use of an (investigational) medicinal product during pregnancy;  
• Use of an (investigational) medicinal product during breastfeeding; 
• Overdose (accidental or intentional); 
• Abuse / Misuse; 
• Off-label use; 
• Medication error;  
• Occupational exposure; 
• Lack of therapeutic efficacy; 
• (Suspected) transmission of an infectious agent; 
• Drug-Drug or Drug-Food interactions; or 
• Unexpected therapeutic benefit. 
 
A Suspected Unexpected Serious Adverse Reaction (SUSAR) is defined as any adverse 
reaction, which is considered unexpected, serious and as having a reasonable possibility of a 
causal relationship with the medicinal product. 
 
9.2.2 
SAE and SS reporting 
To ensure patient safety, every SAE and SS, regardless of causality, occurring after the patient 
has provided informed consent and until 30 days after the last study visit must be reported by 
e-mail or facsimile noted below to Pharming PHV within 24 hours of learning of its occurrence 
using the SAE reporting form in accordance with the completion instructions. Any SAE and SS 
experienced after this period should only be reported to Pharming if the Investigator suspects a 

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causal relationship to study treatment. 
Pharming PHV Department Contact Information:  
• 
E-mail: safety@pharming.com 
• 
Fax: +31 (0)85 0643 382 
 
Note: SAEs and SSs reported by patients deemed to be screen failures must be reported to 
Pharming as outlined here with appropriate information also captured in the CRFs as specified 
in the Site Operations Manual. 
All follow-up information for the SAE and SSs including information on complications, 
progression of the initial SAE and SSs and recurrent episodes must be reported Pharming PHV 
as follow-up to the original episode using the SAE reporting form within 24 hours of the 
Investigator receiving the follow-up information. An SAE and SS occurring at a  different time 
interval or otherwise considered completely unrelated to a previously reported one must be 
reported separately as a new event. 
 
Follow- up information provided must describe whether the event has resolved or continues, if 
and how it was treated, whether the blind was broken or not (if applicable) and whether the 
patient continued or withdrew from study participation. Each re-occurrence, complication, or 
progression of the original event must be reported as a follow-up to that event regardless of 
when it occurs. 
If the SAE and SS is not previously documented in the IB or Package Insert (new occurrence) 
and is thought to be related to the study treatment a DS&E Department associate may urgently 
require further information from the Investigator for (National) Health Authority reporting. 
Pharming may need to  issue an Investigator Notification (IN) to inform all Investigators 
involved in any study with the  same study treatment that this SAE or SS 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. 
Follow the detailed instructions outlined in the SOM regarding the submission process for 
reporting SAEs and SSs to Pharming. Note: SAEs and SSs must be reported to Pharming within 
24 hours of the Investigator learning of its occurrence/receiving follow-up information. 

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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 (including differential count) is to be assessed at every visit; it can be 
more frequently assessed if deemed necessary by the Investigator, e.g. if a patient presents with 
any signs of an infection. 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. This measure ensures that WBC (including 
differential count) is being timely checked. 
 
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 Table 9-2. 
 
For the liver laboratory trigger: 
• Repeating the liver function test (LFT) within the next week to confirm elevation. 

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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. 
 
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 
> 3 × ULN and INR > 1.5 
• Discontinue the study drug 
immediately 
• Hospitalize, if clinically 
appropriate 
• Establish causality 
• Complete liver CRF 
> 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) 
 
 
 
ALT, AST, TBL, Alb, PT/INR, 
ALP and γGT until resolutionc 
(frequency at investigator 
discretion) 
 
 
 
ALT, AST, TBL, Alb, PT/INR, 
ALP and γGT until resolutionc 
(frequency at investigator 
discretion) 
> 3 × ULN accompanied 
by symptomsb 
 
 
 
 
 
> 3 to ≤ 5 × ULN 
(patient is asymptomatic) 
 
ALP (isolated) 
> 2 × ULN (in the 
absence of known bone 
pathology) 
• Discontinue the study drug 
immediately 
• Hospitalize if clinically 
appropriate 
• Establish causality 
• Complete liver CRF 
• Repeat LFT within the next week 
• If elevation is confirmed, initiate 
close observation of the patient 
 
• Repeat LFT within 48 hours 
• If elevation persists, establish 
causality 
• Complete liver CRF 
ALT, AST, TBL, Alb, PT/INR, 
ALP and γGT until resolutionc 
(frequency at investigator 
discretion) 
 
 
 
Investigator discretion 
Monitor LFT within 1 to 4 weeks 
 
 
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) 
 
 
 
 
 
> 1.5 to ≤ 2 × ULN 
(patient is asymptomatic) 
• Repeat LFT within 48 hours 
• If elevation persists, discontinue 
the study drug immediately 
• Hospitalize if clinically 
appropriate 
• Establish causality 
• Complete liver CRF 
• Repeat LFT within the next week 
• If elevation is confirmed, initiate 
close observation of the patient 
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) 
 
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 
• doubling in the urinary albumin-creatinine ratio (ACR) or urinary protein-creatinine ratio 
(PCR) (if applicable). 
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 

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• 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 
Serum creatinine increase ≥ 50 % 
compared to baseline 
 
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 
New dipstick glucosuria ≥ 1+ not due to 
diabetes 
New dipstick hematuria not due to 
trauma 
Confirm 25% increase after 24-48h 
Follow up within 2-5 days 
Follow up within 24-48h if possible 
Consider drug interruption 
Consider patient hospitalization /specialized treatment 
Confirm value after 24-48h 
Perform urine microscopy 
Consider drug interruption / discontinuation 
 
 
 
 
Blood glucose (fasting) 
Perform serum creatinine, ACR 
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 
Reporting Medication errors including misuse/abuse 
Medication errors are unintentional errors in the prescribing, dispensing, administration or 
monitoring of a medicine while under the control of a healthcare professional, patient/subject 
or consumer (EMA definition). 
Misuse refers to situations where the medicinal product is intentionally and inappropriately used 
not in accordance with the protocol. 
Abuse corresponds to the persistent or sporadic, intentional excessive use of a medicinal product, 
which is accompanied by harmful physical or psychological effects. 
All study treatment errors and uses outside of what is foreseen in the protocol will be collected 
in the dose administration record (DAR) CRF. Study treatment errors are only to be reported 
to Pharming PHV if the treatment error is associated with an SAE. 

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All instances of misuse or abuse must be documented in the AE CRF irrespective of the 
misuse/abuse being associated with an AE/SAE. In addition, all instances of misuse or abuse 
must be reported to Pharming PHV. As such, instances of misuse or abuse are also to be reported 
using the SAE form/CRF. Table 9-4 summarizes the reporting requirements. 
 
Table 9-4 
Summary of reporting requirements for medication errors 
Treatment error type 
Document in 
Dose 
Administration 
(DAR) CRF 
Document in AE 
CRF 
Complete SAE form/CRF 
Unintentional study 
treatment error 
Yes 
Only if associated 
with an AE 
Only if associated with an 
SAE 
 
Misuse/Abuse 
Yes 
Yes 
Yes, even if not associated 
with a SAE 
For more information on AE and SAE definition and reporting requirements, please see Section 
9.1 and Section 9.2, respectively. 
 
9.7 
Pregnancy reporting 
To ensure patient safety, each pregnancy occurring after signing the informed consent must be 
reported to Pharming within 24 hours of learning of its occurrence. The pregnancy should 
be followed up to determine outcome, including spontaneous or voluntary termination, details 
of the birth, and the presence or absence of any birth defects, congenital abnormalities, or 
maternal and/or newborn complications. 
Pregnancy must be recorded on the Pregnancy Form and reported by the Investigator to the 
Pharming PHV Department. Pregnancy follow-up should be recorded on the same form and 
should include an assessment of the possible relationship to the study treatment. 
Any SAE experienced during the pregnancy and unrelated to the pregnancy must be reported 
on a SAE form. 
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. 
 
9.8 
Early phase safety monitoring 
The Investigator will monitor AEs 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, 

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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 Pharming 
representative will review the protocol and CRFs with the Investigators and their staff. During 
the study Pharming 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 (GCP), the progress of enrollment, and 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. Pharming 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  will be 
disclosed. 
 
10.2 
Data collection 
Designated Investigator staff will enter the data required by the protocol into the Electronic 
CRFs using fully validated software that conforms to 21 CFR Part 11 requirements. Designated 
Investigator site staff will not be given access to the 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 Pharming. The Investigator must certify that the data entered into the 
Electronic CRFs are complete and accurate. After database lock, the Investigator will receive 
copies of the patient data for archiving at the investigational site. 
Data not requiring a separate written record will be defined in the SOM and Assessment 
schedule and can be recorded directly on the CRFs. All other data captured for this study will 
have an external originating source (either written or electronic) with the CRF not being 
considered as source. 
All data should be recorded, handled and stored in a way that allows its accurate reporting, 
interpretation and verification. 

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10.3 
Database management and quality control 
The CRO working on behalf of Pharming reviews the data entered into the CRFs by 
investigational staff for completeness and accuracy and instruct 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 Pharming who will make the correction to the database. The signed 
copy of the Data Query Form is kept at the Investigator site. 
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 AEs will be coded using the Medical dictionary 
for regulatory activities (MedDRA) terminology. 
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 COAR 
Analytics NIBR Franchise Head and the relevant NIBR TA Head. 
 
10.4 
Data Monitoring Committee 
The DMC will be established (according to Pharming Standard Operating Procedures). 
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. 
 
10.5 
Adjudication Committee 
Not required. 
 
11 
Data analysis 
The analysis will be conducted on all patient data at the time the trial ends. Any data analysis 
carried out independently by the Investigator should be submitted to Pharming before publication 
or presentation. 
 
11.1 
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 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 with no 
protocol deviations that 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. 

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11.2 
Patient demographics and other baseline characteristics 
All data for background and demographic variables will be listed by patient. Summary statistics 
will be provided for all patients in the safety analysis set. 
Relevant medical history, current medical conditions, results of laboratory screens, drug tests 
and any other relevant information will be listed by patient. 
 
11.3 
Treatments 
Data for study drug administration and concomitant therapies will be listed by patient. 
 
11.4 
Analysis of the primary variable(s) 
The primary objective of the study is to evaluate the long term safety and tolerability of CDZ173 
in APDS/PASLI patients. 
 
11.4.1 
Variable(s) 
Safety and tolerability assessments include vital signs, ECG evaluations, clinical laboratory 
evaluations and AEs. 
 
11.4.2 
Statistical model, hypothesis, and method of analysis 
All data for vital signs, ECG evaluations and clinical laboratory evaluations will be listed by 
patient and summarized by descriptive statistics. All information obtained on AEs will be 
displayed by patient. The number and percentage of patients with AEs will be tabulated by body 
system and preferred term. A patient with multiple AEs within a body system is only counted 
once towards the total of this body system. 
 
11.4.3 
Handling of missing values/censoring/discontinuations 
All patients who received study drug will be included in the safety and tolerability evaluation. 
No methods for imputation of missing data (including those due to COVID-19) are planned. 
 
11.4.4 
Summary statistics of safety 
Vital signs 
All vital signs data will be listed by 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. 
 
ECG evaluations 
All ECG data will be listed by patient and visit/time, abnormalities will be flagged. Summary 
statistics will be provided by visit/time. 

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Clinical laboratory evaluations 
All laboratory data will be listed by patient, and visit/time and if normal ranges are available 
abnormalities will be flagged. Summary statistics will be provided by visit/time. 
 
Adverse events 
All information obtained on AEs will be displayed by patient. 
The number and percentage of patients with AEs will be tabulated by body system and preferred 
term. A patient with multiple AEs within a body system is only counted once towards the total 
of this body system. 
 
11.4.5 
Sensitivity analyses 
Not applicable. 
 
11.5 
Analysis of secondary variable(s) 
11.5.1 
Efficacy / Pharmacodynamics 
The hsCRP, LDH, SF-36 and WPAI-CIQ scores, visual analogue scale scores for PGA and 
PtGA, will be listed by patient and visit and summary statistics will be provided by visit. 
Frequencies of infections and other disease complications data will be listed by patient and visit. 
 
11.5.2 
Pharmacokinetics 
CDZ173 plasma concentration data will be listed by patient, and visit/sampling time point. 
Descriptive summary statistics will be provided by visit/sampling time point, including the 
frequency (n, %) of concentrations below the LLOQ and reported as zero. 
PK parameters Cmax,ss and AUC0-12,ss for CDZ173 from the serial sampling visits will be 
the primary variables for the assessment of relative bioavailability of FCT vs HGC. 
Only subjects with evaluable PK parameter data for both FCT and HGC formulations will be 
included in this analysis. For FCT and HGC log-transformed PK parameters Cmax,ss and 
AUC0-12,ss will be analyzed by a fixed effects model with formulation and subject as fixed 
factors. 
The estimated mean and 90% confidence interval of difference in formulations between FCT 
vs HGC will be back transformed to obtain the geometric mean ratio and 90% confidence 
interval of the ratio. For each of the primary PK parameters AUC0-12,ss and Cmax,ss the 90% 
confidence interval for the PK parameter ratio of FCT vs HGC will be reported to represent 
bioavailability of FCT relative to HGC. 
 
11.5.3 
Pharmacokinetic / pharmacodynamic interactions 
Not applicable. 
 
11.5.4 
Other assessments 
Not applicable. 

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11.6 
Analysis of exploratory variables 
Statistical analysis for exploratory variables will be described in the SAP. 
 
11.6.1 
Exploratory biomarkers 
Selected biomarker data will be listed by patient, and visit/time. Summary statistics will be 
provided by visit/time. 
In the summary tables, the frequency (n, %) of values below the LLOQ and above the upper 
limit of quantification (ULOQ), respectively, will be included. 
For values which fall below the lower limit of quantification (LLOQ) or above the upper limit 
of quantification (ULOQ), the inequality sign with the limit value should be kept in the 
individual listing. To avoid being treated as missing values when calculating summary statistics 
or analyzing, a value below the LLOQ will be replaced by LLOQ/2 and a value above ULOQ 
will be replaced by ULOQ. 
 
11.7 
Sample size calculation 
Not applicable. 
 
11.8 
Power for analysis of key secondary variables 
Relative bioavailability of FCT vs HGC formulation 
For sample sizes up to the maximum planned enrollment of 42 patients tolerance limits for the 
90% confidence intervals were calculated. Estimation of the confidence interval width will be 
measured by the ratio of the geometric means of the PK parameters AUC0-12,ss and Cmax,ss 
for FCT versus HGC. With complete data from 30 patients there is a 90% probability that the 
90% confidence interval of PK parameter ratio is within 86% to 116% of the observed geometric 
mean. An intra-subject coefficient of variation of 30% was assumed in this calculation based 
on the results for AUC and Cmax of the study CCDZ173X2101. If the observed variability 
differs from the assumed 30% the calculated tolerance limits will change. Table 11-1 gives the 
estimated tolerance limits for the 90% confidence intervals (with 90% probability) for different 
CVs and different sample sizes. 
 
Table 11-1 
Estimated tolerance limits for 90 percent confidence intervals with 
different CVs and sample sizes 
 
CV (%) 
Sample Size 
20 
30 
40 
20 
[0.88, 1.14] 
[0.83, 1.21] 
[0.78, 1.29] 
30 
[0.90, 1.11] 
[0.86, 1.16] 
[0.82, 1.22] 
42 
[0.92, 1.09] 
[0.89, 1.13] 
[0.85, 1.17] 
 
11.9 
Interim analyses 
Interim analyses may be conducted to support decision making concerning the current clinical 
study, the Sponsor’s clinical development projects in general or in case of any safety concerns. 

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12 
Ethical considerations 
12.1 
Regulatory and ethical compliance 
This clinical study was designed and shall be implemented, executed and reported in accordance 
with the ICH Harmonized Tripartite Guidelines for Good Clinical Practice, with applicable local 
regulations (including European Directive 2001/20/EC, US 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 must obtain approval/favorable opinion from 
the Institutional Review Board/Independent Ethics Committee (IRB/IEC) for the trial protocol, 
written informed consent form, consent form updates, 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 Pharming monitors, 
auditors, Pharming Quality Assurance representatives, designated agents of Pharming, 
IRBs/IECs, and regulatory authorities as required. If an inspection of the clinical site is requested 
by a regulatory authority, the Investigator must inform Pharming immediately that this request 
has been made. 
For multi-center trials, a Coordinating Investigator will be selected by Pharming around the time 
of Last Patient Last Visit (LPLV) to be a reviewer and signatory for the clinical study report. 
 
12.3 
Publication of study protocol and results 
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 patients should be 
administered as deemed necessary on a case by case basis. Under no circumstances is an 
Investigator allowed to collect additional data or conduct any additional procedures for any 
research related purpose involving any investigational drugs under the protocol. 
Investigators ascertain they will apply due diligence to avoid protocol deviations. If an 
Investigator feels a protocol deviation would improve the conduct of the study this must be 
considered a protocol amendment, and unless such an amendment is agreed upon by Pharming 
and approved by the IRB/IEC and health authorities, where required, it cannot be implemented. 

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13.1 
Protocol Amendments 
Any change to the protocol can only be made in a written protocol amendment that must be 
approved by Pharming, Health Authorities where required, and the IRB/IEC prior to 
implementation. 
Amendments that are intended to eliminate an apparent immediate hazard to patients may be 
implemented immediately, provided the Health Authorities are subsequently notified by 
protocol amendment and the reviewing IRB/IEC is notified. 
Notwithstanding the need for approval of formal protocol amendments, the Investigator is 
expected to take any immediate action required for the safety of any patient included in this 
study, even if this action represents a deviation from the protocol. In such cases, the reporting 
requirements identified in Section 9 (Safety Monitoring) must be followed and the Study Lead 
informed. 

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14 
References 
References are available upon request. 
Angulo I, Vadas O, Garçon F, et al (2013) Phosphoinositide 3-kinase delta gene mutation 
predisposes to respiratory infection and airway damage. Science; 342: 866-871. 
Appay V, Sauce D and Prelog M (2010) The role of the thymus in immunosenescence: lessons 
from the study of thymectomized individuals. Aging; 2:78-81. 
Bartelink IH, Rademaker CM, Schobben AF, et al (2006) Guidelines on paediatric dosing on 
the basis of developmental physiology and pharmacokinetic considerations. Clin 
Pharmacokinet 45:1077-97. 
Buty M, Xu Ziyue, Gao M, et al (2017) Quantitative image quality comparison of reduced- and 
standard-dose   dual-energy   multiphase    chest,    abdomen,    and    pelvis    CT. Tomography 
3:114-122. 
Crank MC, Grossman JK, Moir S, et al (2014). Mutations in PIK3CD can cause hyper IgM 
syndrome (HIGM) associated with increased cancer susceptibility. J Clin Immunol 34: 272-276. 
EMA “Reflection Paper: Formulations of Choice for the Paediatric Population” (2006) 
http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/09/WC5 
00003782.pdf. 
Flinn IW, Kahl BS, Leonard JP, et al (2014) Idelalisib, a selective inhibitor of 
phosphatidylinositol 3-kinase-δ, as therapy for previously treated indolent non-Hodgkin 
lymphoma. Blood 123: 3406-13. 
Kandel ES and Hay N (1999). The Regulation and Activities of the Multifunctional 
Serine/Threonine Kinase Akt/PKB. Experimental Cell Research 253: 210–229. 
Kuo W, Corput M, Perez-Rovira A, et al (2016) Multicenter chest computed tomography 
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. 
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 KR, Webster S, Dalm VASH, et al (2017) Effective “Activated PI3Kδ Syndrome’-targeted 
therapy with the PI3Kδ inhibitor leniolisib. Blood 130(21):2307-2316. 
Rao K, Webster S, Šedivá A,  ; Randomized, Placebo-Controlled, Phase 3 Trial of PI3Kδ 
Inhibitor Leniolisib for Activated PI3Kδ Syndrome. Blood; blood.2022018546. doi: 
https://doi.org/10.1182/blood.2022018546  
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 (Activated 
PI3Kδ Syndrome). Poster presentation ESID, Lisbon, Portugal Oct 2018. 

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Wang Y, Moss J, Thisted R (1992) Predictors of body surface area. J Clin Anesth; 4:4-10. 

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15 
Appendix 1: List of prohibited CYP-interacting co- 
medications 
 
Table 15-1 
List of prohibited co-medications 
Compound 
CYP3A inhibitor1 
CYP3A Inducer1 
Narrow TI CYP1A2 
substrates 
Avasimibe 
Strong 
Boceprevir 
Strong 
Bosentan 
Moderate 
Carbamazepine 
Strong 
Clarithromycin 
Strong2 
Conivaptan 
Strong 
Efavirenz 
Moderate 
Elvitegravir 
Strong 
Etravirine 
Moderate 
Genistein 
Moderate 
Indinavir 
Strong 
Itraconazole 
Strong 
Ketoconazole 
Strong 
Lopinavir 
Strong2 
Mibefradil 
Strong 
Mitotane 
Strong 
Modafenil 
Moderate 
Nafcillin 
Moderate 
Nefazodone 
Strong 
Nelfinavir 
Strong 
Phenobarbital 
Strong 
Phenytoin 
Strong 
Posaconazole 
Strong 
Ramelteon 
yes 
Rifabutin 
Strong 
Rifampin 
Strong 
Ritonavir 
Strong2 
Moderate 
Saquinavir 
Strong2 
St John's Wort 
Strong 
Telaprevir 
Strong 
Weak 
Telithromycin 
Strong 
Theophylline 
yes 
Thioridazine 
Moderate 
Tipranavir 
Strong 
Moderate 

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Protocol No. CCDZ173X2201E1 
 
 
 
 
 
Compound 
CYP3A inhibitor1 
CYP3A Inducer1 
Narrow TI CYP1A2 
substrates 
Tizanidine 
yes 
Troleandomycin 
Strong 
Voriconazole 
Strong 
1. Refer to Section 5.2.1: CDZ173 dosing must be interrupted until the co-medication is considered 
washed out (5 terminal half-lives or at least 1 week washout for a time-dependent inhibitor or 
inducer). See also next footnote 
2. Time-dependent inhibitor of CYP3A 
 
Table 15-2 
List of selected OATP substrates to be used with caution 
 
Compound 
OATP1B3 substrate 
OATP1B1 substrate 
Atorvastatin 
yes 
yes 
Atrasentan 
yes 
Ezetimibe 
yes 
Fluvastatin 
yes 
Glyburide 
yes 
Olmesartan 
yes 
yes 
Pitavastatin 
yes 
yes 
Pravastatin 
yes 
Repaglinide 
yes 
Rosuvastatin 
yes 
yes 
Simvastatin acid 
yes 
SN-38 
yes 
Telmisartan 
yes 
Valsartan 
yes 
yes