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Clinical Trial Results:
An open-label, non-randomized, within-patient dose-finding study followed by a randomized, subject, investigator and sponsor-blinded placebo controlled study to assess the efficacy and safety of CDZ173 (leniolisib) in patients with APDS/PASLI (Activated phosphoinositide 3-kinase delta syndrome/ p110δ-activating mutation causing senescent T cells, lymphadenopathy and immunodeficiency).

Summary
EudraCT number	2014-003876-22
Trial protocol	GB CZ NL IE FR IT
Global end of trial date	16 Aug 2021

Results information
Results version number	v1(current)
This version publication date	08 Mar 2022
First version publication date	08 Mar 2022
Other versions

Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information

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Trial information

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Sponsor protocol code

CCDZ173X2201

ISRCTN number

US NCT number

NCT02435173

WHO universal trial number (UTN)

Sponsor organisation name

Novartis Pharmaceuticals

Sponsor organisation address

Novartis Campus, Basel, Switzerland,

Public contact

Study Director, Novartis Pharmaceuticals, 41 + 1 862 778 8300, Novartis.email@Novartis.com

Scientific contact

Study Director, Novartis Pharmaceuticals, 41 + 1 862 778 8300, Novartis.email@Novartis.com

Is trial part of an agreed paediatric investigation plan (PIP)

Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?

Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?

Yes

Analysis stage

Final

Date of interim/final analysis

16 Aug 2021

Is this the analysis of the primary completion data?

Global end of trial reached?

Yes

Global end of trial date

16 Aug 2021

Was the trial ended prematurely?

Main objective of the trial

This study is designed to evaluate CDZ173, a selective PI3Kδ inhibitor, in patients with genetically activated PI3Kδ, i.e. patients with APDS/PASLI. The study consists of two parts. Part I of the present protocol is now complete and was the open label part designed to establish the safety and pharmacokinetics of CDZ173 in the target population, as well as to select the optimal dose to be tested in Part II. Part II is the subject, investigator and sponsor-blinded, randomized part designed to assess efficacy and safety of CDZ173 in this population.

Protection of trial subjects

The study was in compliance with the ethical principles derived from the Declaration of Helsinki and the International Conference on Harmonization (ICH) Good Clinical Practice (GCP) guidelines. All the local regulatory requirements pertinent to safety of trial subjects were also followed during the conduct of the trial.

Background therapy

Evidence for comparator

Actual start date of recruitment

24 Aug 2015

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Yes

Number of subjects enrolled per country

Country: Number of subjects enrolled

Belarus: 1

Country: Number of subjects enrolled

Czechia: 4

Country: Number of subjects enrolled

Germany: 2

Country: Number of subjects enrolled

Ireland: 1

Country: Number of subjects enrolled

Italy: 4

Country: Number of subjects enrolled

Netherlands: 2

Country: Number of subjects enrolled

Russian Federation: 2

Country: Number of subjects enrolled

United Kingdom: 1

Country: Number of subjects enrolled

United States: 20

Worldwide total number of subjects

EEA total number of subjects

Number of subjects enrolled per age group

In utero

Preterm newborn - gestational age < 37 wk

Newborns (0-27 days)

Infants and toddlers (28 days-23 months)

Children (2-11 years)

Adolescents (12-17 years)

Adults (18-64 years)

From 65 to 84 years

85 years and over

Subject disposition

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Recruitment details

Participants took part in 10 investigative sites in 9 countries.

Screening details

The participants were screened within 50 days prior to enrollment. After screening and baseline assessments, the treatment period started on Day 1.

Period 1 title

Overall Study (overall period)

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

Investigator, Carer, Subject

Are arms mutually exclusive

Yes

Part I: CDZ173

Arm description

Participants consecutively received CDZ173 10 mg b.i.d. from Day 1 to Day 28, CDZ173 30 mg b.i.d. from Day 29 to Day 56 and CDZ173 70 mg b.i.d. from Day 57 to Day 84.

Arm type

Experimental

Investigational medicinal product name

Leniolisib

Investigational medicinal product code

CDZ173

Other name

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

Participants consecutively received CDZ173 10 mg b.i.d. from Day 1 to Day 28, CDZ173 30 mg b.i.d. from Day 29 to Day 56 and CDZ173 70 mg b.i.d. from Day 57 to Day 84.

Part II: CDZ173 70 mg

Arm description

Participants received CDZ173 70 mg b.i.d. from Day 1 to Day 85.

Arm type

Experimental

Investigational medicinal product name

Leniolisib

Investigational medicinal product code

Other name

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

Participants received CDZ173 70 mg b.i.d. from Day 1 to Day 85.

Part II: Placebo

Arm description

Participants received Placebo b.i.d. from Day 1 to Day 85.

Arm type

Placebo

Investigational medicinal product name

Placebo

Investigational medicinal product code

Other name

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

Participants received Placebo b.i.d. from Day 1 to Day 85.

Number of subjects in period 1	Part I: CDZ173	Part II: CDZ173 70 mg	Part II: Placebo
Started	6	21	10
Pharmacokinetics (PK) Analysis Set	6	19 ^[1]	0 ^[2]
Pharmacodynamic (PD) analysis set	6	19 ^[3]	8 ^[4]
Completed	6	21	10

Notes
[1] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
Justification: Pharmacokinetics (PK) Analysis Set and Pharmacodynamic (PD) analysis set SUBSETS
[2] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
Justification: Pharmacokinetics (PK) Analysis Set and Pharmacodynamic (PD) analysis set SUBSETS
[3] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
Justification: Pharmacokinetics (PK) Analysis Set and Pharmacodynamic (PD) analysis set SUBSETS
[4] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
Justification: Pharmacokinetics (PK) Analysis Set and Pharmacodynamic (PD) analysis set SUBSETS

Baseline characteristics

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Reporting group title

Part I: CDZ173

Reporting group description

Participants consecutively received CDZ173 10 mg b.i.d. from Day 1 to Day 28, CDZ173 30 mg b.i.d. from Day 29 to Day 56 and CDZ173 70 mg b.i.d. from Day 57 to Day 84.

Reporting group title

Part II: CDZ173 70 mg

Reporting group description

Participants received CDZ173 70 mg b.i.d. from Day 1 to Day 85.

Reporting group title

Part II: Placebo

Reporting group description

Participants received Placebo b.i.d. from Day 1 to Day 85.

Reporting group values	Part I: CDZ173	Part II: CDZ173 70 mg	Part II: Placebo	Total
Number of subjects	6	21	10	37
Age Categorical
Units: Participants
<=18 years	2	9	5	16
Between 18 and 65 years	4	12	5	21
>=65 years	0	0	0	0
Age Continuous
Units: Years
arithmetic mean (standard deviation)	22.2 ( 5.64 )	22.2 ( 10.00 )	26.7 ( 13.43 )	-
Sex: Female, Male
Units: Participants
Female	2	10	6	18
Male	4	11	4	19
Race (NIH/OMB)
Units: Subjects
American Indian or Alaska Native	0	0	0	0
Asian	0	1	1	2
Native Hawaiian or Other Pacific Islander	0	0	0	0
Black or African American	0	1	1	2
White	6	18	7	31
More than one race	0	1	1	2
Unknown or Not Reported	0	0	0	0

End points

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Reporting group title

Part I: CDZ173

Reporting group description

Participants consecutively received CDZ173 10 mg b.i.d. from Day 1 to Day 28, CDZ173 30 mg b.i.d. from Day 29 to Day 56 and CDZ173 70 mg b.i.d. from Day 57 to Day 84.

Reporting group title

Part II: CDZ173 70 mg

Reporting group description

Participants received CDZ173 70 mg b.i.d. from Day 1 to Day 85.

Reporting group title

Part II: Placebo

Reporting group description

Participants received Placebo b.i.d. from Day 1 to Day 85.

Subject analysis set title

Part I: CDZ173 10 mg

Subject analysis set type

Sub-group analysis

Subject analysis set description

Participants consecutively received CDZ173 10 mg b.i.d. from Day 1 to Day 28, CDZ173 30 mg b.i.d. from Day 29 to Day 56 and CDZ173 70 mg b.i.d. from Day 57 to Day 84.

Subject analysis set title

Part II: CDZ173

Subject analysis set type

Sub-group analysis

Subject analysis set description

Participants received CDZ173 70 mg b.i.d. from Day 1 to Day 85.

Subject analysis set title

Part II: CDZ173

Subject analysis set type

Sub-group analysis

Subject analysis set description

Participants received CDZ173 70 mg b.i.d. from Day 1 to Day 85.

Subject analysis set title

Part II: CDZ173

Subject analysis set type

Sub-group analysis

Subject analysis set description

Participants received CDZ173 70 mg b.i.d. from Day 1 to Day 85.

Subject analysis set title

Part II: CDZ173

Subject analysis set type

Sub-group analysis

Subject analysis set description

Participants received CDZ173 70 mg b.i.d. from Day 1 to Day 85.

Subject analysis set title

Part II: CDZ173

Subject analysis set type

Sub-group analysis

Subject analysis set description

Participants received CDZ173 70 mg b.i.d. from Day 1 to Day 85.

Primary: Part I: Number of participants with Adverse Events (AEs) and Serious Adverse Events (SAEs)

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End point title

Part I: Number of participants with Adverse Events (AEs) and Serious Adverse Events (SAEs) ^[1]

End point description

Number of participants with AEs and SAEs, including significant changes from baseline in physical findings, vital signs, electrocardiograms and laboratory values qualifying and reported as AEs. The number of participants in each category (AEs and SAEs) is reported per dose level: CDZ173 10 mg from Day 1 to Day 28, CDZ173 30 mg from day 29 to day 56 and CDZ173 70 mg from day 57 to day 84.

End point type

Primary

End point timeframe

From the start of treatment to 30 days after end of treatment, assessed up to maximum duration of 114 days

Notes
[1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: No statistical analysis was planned for this primary outcome

End point values	Part I: CDZ173 10 mg
Number of subjects analysed	6
Units: Participants
CDZ173 10 mg AEs	2
CDZ173 10 mg SAEs	0
CDZ173 30 mg AEs	2
CDZ173 30 mg SAEs	0
CDZ173 70 mg AEs	4
CDZ173 70 mg SAEs	0

No statistical analyses for this end point

Primary: Part I: CDZ173 dose concentration

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End point title

Part I: CDZ173 dose concentration ^[2] ^[3]

End point description

Venous whole blood samples were collected for the assessment of the dose-PD and the PK/PD relationship of CDZ173 in participants with APDS/PASLI for dose selection in Part II. CDZ173 was determined by a validated Liquid chromatography - Mass spectometry (LC-MS) method; anticipated Lower Limit of Quantification (LLOQ) was 3 ng/mL. Concentrations below the LLOQ were reported as “zero” and no methods for imputation of missing data were used.

End point type

Primary

End point timeframe

Days 1, 29 and 57 (0.25 and 3 h post morning dose) and Day 84

Notes
[2] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: No statistical analysis was planned for this primary outcome
[3] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: No statistical analysis was planned for this primary outcome

End point values	Part I: CDZ173
Number of subjects analysed	6
Units: Nanogram / millilitre
arithmetic mean (standard deviation)
Day 1: 0.25 h post-dose	10.10 ( 1.10 )
Day 1: 3 h post-dose	321.00 ( 115.00 )
Day 29: 0.25 h post-dose	249.00 ( 540.00 )
Day 29: 3 h post-dose	916.00 ( 185.00 )
Day 57: 0.25 h post-dose	150.00 ( 143.00 )
Day 57: 3 h post-dose	1710.00 ( 782.00 )
Day 84	998.00 ( 455.00 )

No statistical analyses for this end point

Primary: Part I: Percentage of inhibition of unstimulated and stimulated pAkt levels in B cells

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End point title

Part I: Percentage of inhibition of unstimulated and stimulated pAkt levels in B cells ^[4] ^[5]

End point description

Phosphorylation of Akt in ex vivo stimulated and unstimulated B cells was quantified at baseline and at the end of the 4-week treatment period for each of the three dose levels. Determination of the percentage (%) of CD20B+ phospho-Akt positive cells after ex vivo stimulation of whole blood was performed by flow cytometry analysis. The percentage of inhibition of pAkt was defined as (-1) * percent change from baseline pAkt value. Unstimulated cells served as controls at each time point. Baseline was defined as the mean of the day -1 value and the pre-dose value on Day 1 when both were available (if one was missing, then baseline was defined as the existing value). A higher percentage of inhibition of stimulated B cells indicates improvement. No methods for imputation of missing data were used.

End point type

Primary

End point timeframe

Baseline, days 29 and 57 (3 and 12 h post-dose) and day 84

Notes
[4] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: No statistical analysis was planned for this secondary outcome
[5] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: No statistical analysis was planned for this primary outcome

End point values	Part I: CDZ173
Number of subjects analysed	6
Units: Percentage
arithmetic mean (standard deviation)
CD20B Unstimulated: Day 29 - 3 h post-dose (n=6)	82.07 ( 7.25 )
CD20B Stimulated: Day 29 - 3 h post-dose (n=5)	78.00 ( 7.25 )
CD20B Unstimulated: Day 29 - 12 h post-dose (n=6)	50.58 ( 18.73 )
CD20B Stimulated: Day 29 - 12 h post-dose (n=6)	47.14 ( 7.83 )
CD20B Unstimulated: Day 57 - 3 h post-dose (n=2)	86.61 ( 5.26 )
CD20B Stimulated: Day 57 - 3 h post-dose (n=3)	60.98 ( 54.05 )
CD20B Unstimulated: Day 57 - 12 h post-dose (n=5)	53.18 ( 16.59 )
CD20B Stimulated: Day 57 - 12 h post-dose (n=3)	63.65 ( 21.03 )
CD20B Unstimulated: Day 84 (n=5)	74.35 ( 11.03 )
CD20B Stimulated: Day 84 (n=4)	78.65 ( 12.00 )

No statistical analyses for this end point

Primary: Part II: Change from baseline in the log10 transformed sum of product of diameters (SPD) in the index lesions

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End point title

Part II: Change from baseline in the log10 transformed sum of product of diameters (SPD) in the index lesions ^[6]

End point description

For the assessment of the impact of CDZ173 on lymphadenopathy, participants were scanned in a magnetic resonance imaging (MRI) or a computed tomography (CT) scanner as based on clinical practice and local regulation. MRI or CT imaging of the neck, chest, abdomen and pelvis was performed. Index lesions were selected from measurable nodal and extranodal lesions as per the Cheson methodology. A maximum of six of the largest dominant lesions were selected and documented at baseline and assessed again at the end of treatment. The change in lymph node size was measured using the log10 transformed sum of product of diameters (SPD), the sum of the longest lesion diameter (mm)” and “longest perpendicular diameter (mm)”. A lower score indicates index lesions SPD reduction. A negative change from baseline indicates improvement.

End point type

Primary

End point timeframe

Baseline and Day 85

Notes
[6] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: No statistical analysis was planned for this primary outcome

End point values	Part II: Placebo	Part II: CDZ173
Number of subjects analysed	8	18
Units: Millimeter on Log10 scale
least squares mean (standard error)	-0.06 ( 0.06 )	-0.30 ( 0.04 )

SPD in the index lesions

Comparison groups

Part II: Placebo v Part II: CDZ173

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

P-value

= 0.0012

Method

ANCOVA

Parameter type

Adjusted means difference

Point estimate

-0.24

Confidence interval

level

95%

sides

2-sided

lower limit

-0.37

upper limit

-0.11

Variability estimate

Standard error of the mean

Dispersion value

0.06

Primary: Part II: Change from baseline in percentage of naïve B cells out of total B cells

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End point title

Part II: Change from baseline in percentage of naïve B cells out of total B cells ^[7]

End point description

APDS/PASLI patients suffer from dysregulation in B cell function and differentiation with low numbers of naive B cells. Change from baseline in percentage of naïve B cells out of total B cells at the end of treatment was assessed by flow cytometry to evaluate the pharmacodynamic effect of CDZ173 on B cell immunophenotyping. A higher percentage in naïve B out of total B cells is a positive outcome. A positive change from baseline indicates improvement.

End point type

Primary

End point timeframe

Baseline and Day 85

Notes
[7] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: No statistical analysis was planned for this secondary outcome

End point values	Part II: Placebo	Part II: CDZ173
Number of subjects analysed	5	8
Units: Percentage change from baseline
least squares mean (standard error)	-5.37 ( 3.95 )	34.76 ( 3.08 )

Naïve B cells out of total B cells

Comparison groups

Part II: Placebo v Part II: CDZ173

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

P-value

< 0.0001

Method

ANCOVA

Parameter type

Adjusted means difference

Point estimate

40.13

Confidence interval

level

95%

sides

2-sided

lower limit

28.51

upper limit

51.75

Variability estimate

Standard error of the mean

Dispersion value

5.04

Secondary: Part I & II: Area Under the Plasma Concentration-time Curve From Time Zero to the Last Quantifiable Concentration (AUClast) for CDZ173

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End point title

Part I & II: Area Under the Plasma Concentration-time Curve From Time Zero to the Last Quantifiable Concentration (AUClast) for CDZ173 ^[8]

End point description

Venous whole blood samples were collected for activity-based pharmacokinetics characterization. AUClast was calculated from plasma concentration-time data using non-compartmental methods. AUClast was calculated at the first day of every CDZ173 dose level (10, 30 and 70 mg) for Part I and (70 mg) for Part II. No methods for imputation of missing data were used.

End point type

Secondary

End point timeframe

Part I: Days 1, 29 and 57 / Part II: Day 1

Notes
[8] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: No statistical analysis was planned for this secondary outcome

End point values	Part I: CDZ173	Part II: CDZ173
Number of subjects analysed	6	19
Units: Hour * nanogram / millilitre
arithmetic mean (standard deviation)
Day 1	1760.0 ( 441.0 )	10400.0 ( 2800.0 )
Day 29	4760.0 ( 816.0 )	0 ( 0 )
Day 57	10800.0 ( 3310.0 )	0 ( 0 )

No statistical analyses for this end point

Secondary: Part I & II: Maximum Observed Plasma Concentration (Cmax) for CDZ173

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End point title

Part I & II: Maximum Observed Plasma Concentration (Cmax) for CDZ173 ^[9]

End point description

Venous whole blood samples were collected for activity-based pharmacokinetics characterization. Cmax was calculated from plasma concentration-time data using non-compartmental methods. Cmax was calculated at the first day of every CDZ173 dose level (10, 30 and 70 mg) for Part I and (70 mg) for Part II. No methods for imputation of missing data were used.

End point type

Secondary

End point timeframe

Part I: Days 1, 29 and 57 / Part II: Day 1

Notes
[9] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: No statistical analysis was planned for this secondary outcome

End point values	Part I: CDZ173	Part II: CDZ173
Number of subjects analysed	6	19
Units: Nanogram / millilitre
arithmetic mean (standard deviation)
Day 1	393.0 ( 137.0 )	2150.0 ( 576.0 )
Day 29	1060.0 ( 222.0 )	0 ( 0 )
Day 57	2540.0 ( 747.0 )	0 ( 0 )

No statistical analyses for this end point

Secondary: Part I & II: Mental component summary (MCS) and Physical component summary (PCS) from Short Form 36 (SF-36) Survey

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End point title

Part I & II: Mental component summary (MCS) and Physical component summary (PCS) from Short Form 36 (SF-36) Survey ^[10]

End point description

The SF-36 is a widely used and extensively studied instrument to measure health-related quality of life (HRQoL) among healthy subjects and patients with acute and chronic conditions. It consists of eight subscales that can be scored individually: Physical Functioning, Role-Physical, Bodily Pain, General Health, Vitality, Social Functioning, Role-Emotional, and Mental Health. The subscales are aggregated to derive two overall summary scores: the Physical Component Summary (PCS) and the Mental Component Summary (MCS) scores. PCS and MCS scores range from 0 to 100 with a higher score indicating a more favorable health state (range = 0 "worst" - 100 "best"). No methods for imputation of missing data were used.

End point type

Secondary

End point timeframe

Part I: Baseline and Days 29, 57 and 84 / Part II: Baseline and Days 29, 57 and 85

Notes
[10] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: No statistical analysis was planned for this secondary outcome

End point values	Part I: CDZ173	Part II: Placebo	Part II: CDZ173
Number of subjects analysed	6	8	19
Units: Score on a scale
arithmetic mean (standard deviation)
Day -1: MCS	47.94 ( 8.22 )	45.94 ( 8.14 )	47.36 ( 7.98 )
Day -1: PCS	47.54 ( 9.24 )	44.06 ( 8.59 )	44.49 ( 7.08 )
Day 29: MCS	47.94 ( 8.22 )	49.52 ( 6.70 )	49.98 ( 8.06 )
Day 29: PCS	47.54 ( 9.24 )	44.62 ( 7.57 )	47.87 ( 7.66 )
Day 57: MCS	47.94 ( 8.22 )	45.92 ( 7.31 )	49.12 ( 8.17 )
Day 57: PCS	47.54 ( 9.24 )	47.20 ( 9.75 )	47.04 ( 7.30 )
Day 84 (Part I) / Day 85 (Part II): MCS	47.94 ( 8.22 )	47.32 ( 8.73 )	49.22 ( 8.17 )
Day 84 (Part I) / Day 85 (Part II): PCS	47.54 ( 9.24 )	47.48 ( 8.48 )	47.59 ( 6.22 )

No statistical analyses for this end point

Secondary: Part I & II: Physician’s Global Assessment (PGA)

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End point title

Part I & II: Physician’s Global Assessment (PGA) ^[11]

End point description

In the physician’s global assessment questionnaire the Investigator rated the disease activity of their patient using 100 mm Visual analogue Scale (VAS) ranging from “no disease activity” (0) to “maximal disease activity” (100). To enhance objectivity, the physician was not aware of the specific patient’s global assessment, when performing his own assessment on that patient. No methods for imputation of missing data were used.

End point type

Secondary

End point timeframe

Part I: Baseline and Days 29, 57 and 84 / Part II: Baseline and Days 29, 57 and 85

Notes
[11] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: No statistical analysis was planned for this secondary outcome

End point values	Part I: CDZ173	Part II: Placebo	Part II: CDZ173
Number of subjects analysed	6	8	19
Units: Score on a scale
arithmetic mean (standard deviation)
Baseline (n=6, 19, 8)	34.7 ( 17.07 )	41.38 ( 17.78 )	47.10 ( 17.65 )
Day 29 (n=6, 18, 8)	21.8 ( 9.70 )	29.75 ( 9.99 )	38.81 ( 23.73 )
Day 57 (n=6, 19, 8)	22.5 ( 13.55 )	24.13 ( 18.34 )	34.02 ( 18.89 )
Day 84 (Part I) / Day 85 (Part II) (n=6, 19, 8)	8.8 ( 4.12 )	25.88 ( 16.15 )	26.70 ( 22.82 )

No statistical analyses for this end point

Secondary: Part I & II: Patient’s Global Assessment (PtGA)

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End point title

Part I & II: Patient’s Global Assessment (PtGA) ^[12]

End point description

In the patient’s global assessment questionnaire patients are asked about their APDS/PASLI related well-being using 100 mm visual analogue scale (VAS) ranging from “very poor” (0) to “very good” (100). No methods for imputation of missing data were used.

End point type

Secondary

End point timeframe

Part I: Baseline and Days 29, 57 and 84 / Part II: Baseline and Days 29, 57 and 85

Notes
[12] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: No statistical analysis was planned for this secondary outcome

End point values	Part I: CDZ173	Part II: Placebo	Part II: CDZ173
Number of subjects analysed	6	8	19
Units: Score on a Scale
arithmetic mean (standard deviation)
Baseline	62.0 ( 21.90 )	62.50 ( 26.56 )	54.53 ( 21.47 )
Day 29	65.0 ( 22.21 )	57.75 ( 24.03 )	68.37 ( 19.31 )
Day 57	67.5 ( 21.83 )	69.50 ( 21.93 )	64.79 ( 19.61 )
Day 84 (Part I) / Day 85 (Part II)	72.5 ( 13.37 )	60.25 ( 23.66 )	67.58 ( 16.57 )

No statistical analyses for this end point

Secondary: Part I & II: High Sensivity C reactive protein (hsCRP) as biomarker for systemic inflammation

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End point title

Part I & II: High Sensivity C reactive protein (hsCRP) as biomarker for systemic inflammation ^[13]

End point description

High Sensitivity C reactive protein is a blood test biomarker for inflammation in the body. Sequential blood samples were collected in all participants. HsCRP was measured in serum using a latex immunochemilunminometric assay (ICMA). No methods for imputation of missing data were used.

End point type

Secondary

End point timeframe

Part I: Baseline and Days 1, 15, 29, 57, 84 / Part II: Baseline and Days 1, 15, 29, 57, 85

Notes
[13] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: No statistical analysis was planned for this secondary outcome

End point values	Part I: CDZ173	Part II: Placebo	Part II: CDZ173
Number of subjects analysed	6	8	19
Units: Milligram / liter
arithmetic mean (standard deviation)
Baseline (n=6, 4, 2)	2.49 ( 1.29 )	5.70 ( 2.19 )	10.58 ( 17.84 )
Day 1 (n=6, 4, 2)	2.43 ( 1.43 )	7.85 ( 4.88 )	8.95 ( 14.56 )
Day 15 (n=6, 18, 7)	0.93 ( 0.70 )	2.06 ( 1.02 )	9.19 ( 23.12 )
Day 29 (n=6, 18, 8)	0.77 ( 0.36 )	2.40 ( 1.75 )	5.55 ( 11.21 )
Day 57 (n=6, 18, 8)	1.20 ( 0.71 )	8.90 ( 16.66 )	6.57 ( 9.18 )
Day 84 (Part I) / Day 85 (Part II) (n=5, 18, 8)	2.82 ( 4.11 )	2.65 ( 1.79 )	7.54 ( 18.37 )

No statistical analyses for this end point

Secondary: Part I & II: Lactate dehydrogenase (LDH) as biomarker for systemic inflammation

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End point title

Part I & II: Lactate dehydrogenase (LDH) as biomarker for systemic inflammation ^[14]

End point description

Lactate dehydrogenase is a blood test biomarker for inflammation in the body. Sequential blood samples were collected in all participants. LDH was measured in serum using a latex immunochemilunminometric assay (ICMA). No methods for imputation of missing data were used.

End point type

Secondary

End point timeframe

Part I: Baseline and Days 1, 15, 29, 57, 84 / Part II: Baseline and Days 1, 15, 29, 57, 85

Notes
[14] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: No statistical analysis was planned for this secondary outcome

End point values	Part I: CDZ173	Part II: Placebo	Part II: CDZ173
Number of subjects analysed	6	8	19
Units: Units / liter
arithmetic mean (standard deviation)
Baseline (n=6, 19, 8)	130.42 ( 18.28 )	169.38 ( 41.95 )	172.92 ( 72.25 )
Day 1 (n=6, 17, 7)	132.17 ( 23.10 )	175.71 ( 53.72 )	170.88 ( 72.28 )
Day 15 (n=6, 18, 7)	132.17 ( 11.44 )	155.14 ( 48.09 )	190.94 ( 71.54 )
Day 29 (n=6, 18, 8)	125.17 ( 9.85 )	185.25 ( 51.62 )	227.17 ( 163.41 )
Day 57 (n=6, 19, 7)	135.50 ( 17.66 )	167.14 ( 40.45 )	193.11 ( 64.75 )
Day 84 (Part I) / Day 85 (Part II) (n=5, 19, 8)	142.60 ( 18.53 )	179.13 ( 73.96 )	190.63 ( 57.62 )

No statistical analyses for this end point

Secondary: Part II: Beta2 microglobulin as biomarker for systemic inflammation

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End point title

Part II: Beta2 microglobulin as biomarker for systemic inflammation ^[15]

End point description

Beta2 microglobulin is a blood test biomarker for inflammation in the body. Sequential blood samples were collected in all participants. Beta2 microglobulin was measured in serum using a latex immunochemilunminometric assay (ICMA). No methods for imputation of missing data were used.

End point type

Secondary

End point timeframe

Baseline and Days 1, 15, 29, 57, 85

Notes
[15] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: No statistical analysis was planned for this secondary outcome

End point values	Part II: Placebo	Part II: CDZ173
Number of subjects analysed	8	19
Units: Milligram / liter
arithmetic mean (standard deviation)
Baseline (n=19, 8)	2.32 ( 0.96 )	2.46 ( 0.87 )
Day 1 (n=19, 8)	2.31 ( 0.95 )	2.43 ( 0.88 )
Day 15 (n=18, 7)	2.31 ( 1.09 )	2.10 ( 1.03 )
Day 29 (n=18, 8)	3.21 ( 1.61 )	2.02 ( 1.17 )
Day 57 (n=19, 8)	2.42 ( 1.17 )	1.90 ( 0.72 )
Day 85 (n=19, 8)	2.57 ( 1.19 )	2.01 ( 1.04 )

No statistical analyses for this end point

Secondary: Part II: Ferritin as biomarker for systemic inflammation

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End point title

Part II: Ferritin as biomarker for systemic inflammation ^[16]

End point description

Ferritin is a blood test biomarker for inflammation in the body. Sequential blood samples were collected in all participants. Ferritin was measured in serum using a Electrochemiluminescence immunoassay (ECLIA). No methods for imputation of missing data were used.

End point type

Secondary

End point timeframe

Baseline and Days 1, 15, 29, 57, 85

Notes
[16] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: No statistical analysis was planned for this secondary outcome

End point values	Part II: Placebo	Part II: CDZ173
Number of subjects analysed	8	19
Units: Microgram / liter
arithmetic mean (standard deviation)
Baseline (n=18, 8)	62.05 ( 81.65 )	139.16 ( 399.73 )
Day 1 (n=18, 8)	61.34 ( 82.04 )	142.67 ( 411.57 )
Day 15 (n=17, 7)	24.61 ( 17.41 )	146.99 ( 494.88 )
Day 29 (n=16, 8)	48.43 ( 61.83 )	187.65 ( 641.16 )
Day 57 (n=18, 8)	51.40 ( 64.95 )	199.97 ( 657.31 )
Day 85 (n=18, 8)	63.16 ( 56.64 )	139.42 ( 368.68 )

No statistical analyses for this end point

Secondary: Part II: Fibrinogen as biomarker for systemic inflammation

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End point title

Part II: Fibrinogen as biomarker for systemic inflammation ^[17]

End point description

Fibrinogen is a blood test biomarker for inflammation in the body. Sequential blood samples were collected in all participants. Fibrinogen was measured in serum using an Electrochemiluminescence immunoassay (ECLIA). No methods for imputation of missing data were used.

End point type

Secondary

End point timeframe

Baseline and Days 1, 15, 29, 57, 85

Notes
[17] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: No statistical analysis was planned for this secondary outcome

End point values	Part II: Placebo	Part II: CDZ173
Number of subjects analysed	8	19
Units: Gram / liter
arithmetic mean (standard deviation)
Baseline (n=19, 8)	2.68 ( 0.44 )	2.66 ( 0.76 )
Day 1 (n=19, 8)	2.65 ( 0.42 )	2.61 ( 0.81 )
Day 15 (n=17, 7)	2.67 ( 0.42 )	2.65 ( 0.62 )
Day 29 (n=18, 8)	2.66 ( 0.58 )	2.53 ( 0.54 )
Day 57 (n=19, 8)	2.83 ( 1.13 )	3.01 ( 0.68 )
Day 85 (n=19, 8)	2.61 ( 0.57 )	2.81 ( 0.57 )

No statistical analyses for this end point

Secondary: Part II: Erythrocyte sedimentation rate (ESR) as biomarker for systemic inflammation

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End point title

Part II: Erythrocyte sedimentation rate (ESR) as biomarker for systemic inflammation ^[18]

End point description

Erythrocyte sedimentation rate (ESR) is a blood test biomarker for inflammation in the body. Sequential blood samples were collected in all participants. ESR was measured in whole blood using the Westergren method. No methods for imputation of missing data were used.

End point type

Secondary

End point timeframe

Baseline and Days 1, 15, 29, 57, 85

Notes
[18] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: No statistical analysis was planned for this secondary outcome

End point values	Part II: Placebo	Part II: CDZ173
Number of subjects analysed	8	19
Units: Millimeter / hour
arithmetic mean (standard deviation)
Baseline (n=16, 8)	25.44 ( 24.88 )	28.09 ( 19.79 )
Day 1 (n=16, 8)	25.13 ( 24.51 )	26.88 ( 19.33 )
Day 15 (n=14, 7)	16.00 ( 12.21 )	19.50 ( 13.52 )
Day 29 (n=15, 8)	26.00 ( 25.26 )	18.33 ( 13.80 )
Day 57 (n=17, 8)	27.88 ( 23.04 )	18.06 ( 15.36 )
Day 85 (n=17, 8)	19.63 ( 18.03 )	16.35 ( 15.99 )

No statistical analyses for this end point

Secondary: Part II: 3D volume of index lesions

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End point title

Part II: 3D volume of index lesions ^[19]

End point description

Participants were scanned in a magnetic resonance imaging (MRI) or a computed tomography (CT) scanner as based on clinical practice and local regulation. MRI or CT imaging of the neck, chest, abdomen and pelvis was performed. The 3D volume of index lesions was identified as per the Cheson criteria. A reduction of the 3D volume of the index lesions indicated a positive outcome.

End point type

Secondary

End point timeframe

Baseline and Day 85

Notes
[19] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: No statistical analysis was planned for this secondary outcome

End point values	Part II: Placebo	Part II: CDZ173
Number of subjects analysed	8	19
Units: Millimeter^3
arithmetic mean (standard deviation)
Baseline	37123.69 ( 67325.94 )	20142.12 ( 15617.13 )
Day 85	40169.28 ( 81844.45 )	7858.08 ( 6290.98 )

No statistical analyses for this end point

Secondary: Part II: 3D volume of the spleen

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End point title

Part II: 3D volume of the spleen ^[20]

End point description

Participants were scanned in a magnetic resonance imaging (MRI) or a computed tomography (CT) scanner as based on clinical practice and local regulation. MRI or CT imaging of the spleen was performed and its 3D volume was identified as per the Cheson criteria. A reduction of the spleen volume indicated a positive outcome.

End point type

Secondary

End point timeframe

Baseline and Day 85

Notes
[20] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: No statistical analysis was planned for this secondary outcome

End point values	Part II: Placebo	Part II: CDZ173
Number of subjects analysed	8	19
Units: Millimeter^3
arithmetic mean (standard deviation)
Baseline	448456.15 ( 328641.78 )	586448.74 ( 311482.61 )
Day 85	480333.09 ( 445371.99 )	411130.98 ( 193977.46 )

No statistical analyses for this end point

Secondary: Part I & II: Overall work impairment due to health score from Work Productivity Activity Impairment and Classroom Impairment Questionnaire (WPAI-CIQ)

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End point title

Part I & II: Overall work impairment due to health score from Work Productivity Activity Impairment and Classroom Impairment Questionnaire (WPAI-CIQ) ^[21]

End point description

The Work Productivity Activity Impairment (WPAI) questionnaire measures the amount of absence or presence for work attendance and daily work activity impairment attributable to APDS/PASLI. As younger participants (age 12 and above) were enrolled in the study the WPAI-CIQ was used for all participants as it also measures the amount of absence or presence for school attendance and daily classroom activity impairment. Participants answered for classroom or work-related questions depending on their situation. WPAI-CIQ consists of 10 questions that yield 4 types of scores: absenteeism, presenteeism, work/classroom productivity loss and activity impairment. The Overall work impairment due to health (%) score ranges from 0 to 100% with 100% indicating total work impairment and 0% no impairment at all. No methods for imputation of missing data were used.

End point type

Secondary

End point timeframe

Part I: Baseline and Days 29, 57 and 84 / Part II: Baseline and Days 29, 57 and 85

Notes
[21] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: No statistical analysis was planned for this secondary outcome

End point values	Part I: CDZ173	Part II: Placebo	Part II: CDZ173
Number of subjects analysed	2	2	9
Units: Percentage
arithmetic mean (standard deviation)
Baseline (n=2, 9, 2)	25.00 ( 35.36 )	5.00 ( 7.07 )	51.25 ( 37.23 )
Day 29 (n=1, 9, 2)	44.00 ( 0 )	5.00 ( 7.07 )	35.31 ( 23.12 )
Day 57 (n=1, 8, 2)	62.31 ( 0 )	10.00 ( 14.14 )	35.49 ( 24.70 )
Day 84 (Part I) / Day 85 (Part II) (n=2, 9, 2)	44.41 ( 7.90 )	25.00 ( 7.07 )	35.59 ( 31.85 )

No statistical analyses for this end point

Secondary: Part I & II: Overall classroom impairment due to health score from the Work Productivity Activity Impairment and Classroom Impairment Questionnaire (WPAI-CIQ)

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End point title

Part I & II: Overall classroom impairment due to health score from the Work Productivity Activity Impairment and Classroom Impairment Questionnaire (WPAI-CIQ) ^[22]

End point description

The Work Productivity Activity Impairment (WPAI) questionnaire measures the amount of absence or presence for work attendance and daily work activity impairment attributable to APDS/PASLI. As younger participants (age 12 and above) were enrolled in the study the WPAI-CIQ was used for all participants as it also measures the amount of absence or presence for school attendance and daily classroom activity impairment. Participants answered for classroom or work-related questions depending on their situation. WPAI-CIQ consists of 10 questions that yield 4 types of scores: absenteeism, presenteeism, work/classroom productivity loss and activity impairment. The Overall classroom impairment due to health (%) score ranges from 0 to 100% with 100% indicating total classroom impairment and 0% no impairment at all. A higher percentage indicates a negative outcome. No methods for imputation of missing data were used.

End point type

Secondary

End point timeframe

Part I: Baseline and Days 29, 57 and 84 / Part II: Baseline and Days 29, 57 and 85

Notes
[22] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: No statistical analysis was planned for this secondary outcome

End point values	Part I: CDZ173	Part II: Placebo	Part II: CDZ173
Number of subjects analysed	3	4	5
Units: Percentage
arithmetic mean (standard deviation)
Baseline (n=3, 5, 4)	65.68 ( 33.49 )	23.75 ( 30.92 )	47.33 ( 44.75 )
Day 29 (n=3, 2, 4)	57.30 ( 18.09 )	22.65 ( 24.37 )	0.00 ( 0 )
Day 57 (n=2, 2, 4)	70.13 ( 18.68 )	22.40 ( 26.16 )	12.14 ( 3.03 )
Day 84 (Part I) / Day 85 (Part II) (n=3, 1, 2)	68.52 ( 18.74 )	5.00 ( 7.07 )	51.00 ( 0.00 )

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

Part I and Part II: Adverse events (AEs) were reported from the start of treatment to 30 days after end of treatment, assessed up to maximum duration of 114 days for Part I and 115 days for Part II.

Adverse event reporting additional description

Any sign or symptom that occurs during the study treatment plus 30 days post treatment. For Part I AEs are reported based on the CDZ173 dose level received when AE started. So the 30 days post treatment are only applicable for the CDZ173 70 mg arm.

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

24.0

Reporting group title

Part I: CDZ173 10 mg

Reporting group description

Participants received CDZ173 10 mg b.i.d. from Day 1 to Day 28.

Reporting group title

Part II: Placebo

Reporting group description

Participants received Placebo b.i.d. from Day 1 to Day 85.

Reporting group title

Part I: Total

Reporting group description

Participants consecutively received CDZ173 10 mg b.i.d. from Day 1 to Day 28, CDZ173 30 mg b.i.d. from Day 29 to Day 56 and CDZ173 70 mg b.i.d. from Day 57 to Day 84.

Reporting group title

Part II: CDZ173 70 mg

Reporting group description

Participants received CDZ173 70 mg b.i.d. from Day 1 to Day 85.

Reporting group title

Part I: CDZ173 30 mg

Reporting group description

Participants received CDZ173 30 mg b.i.d. from Day 29 to Day 56.

Reporting group title

Part I: CDZ173 70 mg

Reporting group description

Participants received CDZ173 70 mg b.i.d. from Day 57 to Day 84.

Serious adverse events	Part I: CDZ173 10 mg	Part II: Placebo	Part I: Total	Part II: CDZ173 70 mg	Part I: CDZ173 30 mg	Part I: CDZ173 70 mg
Total subjects affected by serious adverse events
subjects affected / exposed	0 / 6 (0.00%)	2 / 10 (20.00%)	0 / 6 (0.00%)	3 / 21 (14.29%)	0 / 6 (0.00%)	0 / 6 (0.00%)
number of deaths (all causes)	0	0	0	0	0	0
number of deaths resulting from adverse events	0	0	0	0	0	0
Investigations
Lipase increased
subjects affected / exposed	0 / 6 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	1 / 21 (4.76%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Injury, poisoning and procedural complications
Alcohol poisoning
subjects affected / exposed	0 / 6 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	1 / 21 (4.76%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Nervous system disorders
Coma
subjects affected / exposed	0 / 6 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	1 / 21 (4.76%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Blood and lymphatic system disorders
Lymphadenopathy
subjects affected / exposed	0 / 6 (0.00%)	1 / 10 (10.00%)	0 / 6 (0.00%)	0 / 21 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Social circumstances
Dependence on oxygen therapy
subjects affected / exposed	0 / 6 (0.00%)	1 / 10 (10.00%)	0 / 6 (0.00%)	0 / 21 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
Respiratory, thoracic and mediastinal disorders
Pulmonary hypertension
subjects affected / exposed	0 / 6 (0.00%)	1 / 10 (10.00%)	0 / 6 (0.00%)	0 / 21 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
Dyspnoea
subjects affected / exposed	0 / 6 (0.00%)	1 / 10 (10.00%)	0 / 6 (0.00%)	0 / 21 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Infections and infestations
Infective exacerbation of bronchiectasis
subjects affected / exposed	0 / 6 (0.00%)	1 / 10 (10.00%)	0 / 6 (0.00%)	0 / 21 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Mastoiditis
subjects affected / exposed	0 / 6 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	1 / 21 (4.76%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Urinary tract infection
subjects affected / exposed	0 / 6 (0.00%)	1 / 10 (10.00%)	0 / 6 (0.00%)	0 / 21 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Metabolism and nutrition disorders
Failure to thrive
subjects affected / exposed	0 / 6 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	1 / 21 (4.76%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0

Frequency threshold for reporting non-serious adverse events: 5%

Non-serious adverse events	Part I: CDZ173 10 mg	Part II: Placebo	Part I: Total	Part II: CDZ173 70 mg	Part I: CDZ173 30 mg	Part I: CDZ173 70 mg
Total subjects affected by non serious adverse events
subjects affected / exposed	2 / 6 (33.33%)	9 / 10 (90.00%)	4 / 6 (66.67%)	18 / 21 (85.71%)	2 / 6 (33.33%)	4 / 6 (66.67%)
Vascular disorders
Hypotension
subjects affected / exposed	0 / 6 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	1 / 21 (4.76%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences all number	0	0	0	1	0	0
Vasculitis
subjects affected / exposed	0 / 6 (0.00%)	1 / 10 (10.00%)	0 / 6 (0.00%)	0 / 21 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences all number	0	2	0	0	0	0
General disorders and administration site conditions
Asthenia
subjects affected / exposed	0 / 6 (0.00%)	2 / 10 (20.00%)	0 / 6 (0.00%)	1 / 21 (4.76%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences all number	0	2	0	1	0	0
Pyrexia
subjects affected / exposed	0 / 6 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	2 / 21 (9.52%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences all number	0	0	0	2	0	0
Fatigue
subjects affected / exposed	0 / 6 (0.00%)	1 / 10 (10.00%)	0 / 6 (0.00%)	2 / 21 (9.52%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences all number	0	2	0	2	0	0
Vascular device occlusion
subjects affected / exposed	0 / 6 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	1 / 21 (4.76%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences all number	0	0	0	1	0	0
Reproductive system and breast disorders
Adnexa uteri cyst
subjects affected / exposed	0 / 6 (0.00%)	1 / 10 (10.00%)	0 / 6 (0.00%)	0 / 21 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences all number	0	1	0	0	0	0
Menstrual disorder
subjects affected / exposed	0 / 6 (0.00%)	1 / 10 (10.00%)	0 / 6 (0.00%)	0 / 21 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences all number	0	1	0	0	0	0
Respiratory, thoracic and mediastinal disorders
Asthma
subjects affected / exposed	0 / 6 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	1 / 21 (4.76%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences all number	0	0	0	1	0	0
Cough
subjects affected / exposed	1 / 6 (16.67%)	1 / 10 (10.00%)	1 / 6 (16.67%)	0 / 21 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences all number	1	1	1	0	0	0
Dyspnoea
subjects affected / exposed	0 / 6 (0.00%)	1 / 10 (10.00%)	0 / 6 (0.00%)	0 / 21 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences all number	0	3	0	0	0	0
Epistaxis
subjects affected / exposed	0 / 6 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	1 / 21 (4.76%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences all number	0	0	0	1	0	0
Oropharyngeal pain
subjects affected / exposed	0 / 6 (0.00%)	0 / 10 (0.00%)	1 / 6 (16.67%)	0 / 21 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)
occurrences all number	0	0	1	0	0	1
Psychiatric disorders
Depressed mood
subjects affected / exposed	0 / 6 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	1 / 21 (4.76%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences all number	0	0	0	1	0	0
Investigations
Amylase increased
subjects affected / exposed	1 / 6 (16.67%)	0 / 10 (0.00%)	1 / 6 (16.67%)	1 / 21 (4.76%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences all number	1	0	1	1	0	0
Aspartate aminotransferase increased
subjects affected / exposed	0 / 6 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	1 / 21 (4.76%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences all number	0	0	0	1	0	0
Lipase increased
subjects affected / exposed	1 / 6 (16.67%)	0 / 10 (0.00%)	1 / 6 (16.67%)	0 / 21 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences all number	1	0	1	0	0	0
Body temperature increased
subjects affected / exposed	0 / 6 (0.00%)	1 / 10 (10.00%)	0 / 6 (0.00%)	0 / 21 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences all number	0	1	0	0	0	0
Blood creatine phosphokinase increased
subjects affected / exposed	1 / 6 (16.67%)	0 / 10 (0.00%)	1 / 6 (16.67%)	0 / 21 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences all number	1	0	1	0	0	0
Pancreatic enzymes increased
subjects affected / exposed	0 / 6 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	1 / 21 (4.76%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences all number	0	0	0	1	0	0
Protein urine present
subjects affected / exposed	0 / 6 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	1 / 21 (4.76%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences all number	0	0	0	1	0	0
SARS-CoV-2 test positive
subjects affected / exposed	0 / 6 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	1 / 21 (4.76%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences all number	0	0	0	1	0	0
Weight increased
subjects affected / exposed	0 / 6 (0.00%)	1 / 10 (10.00%)	0 / 6 (0.00%)	1 / 21 (4.76%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences all number	0	1	0	1	0	0
Injury, poisoning and procedural complications
Contusion
subjects affected / exposed	0 / 6 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	1 / 21 (4.76%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences all number	0	0	0	2	0	0
Iliotibial band syndrome
subjects affected / exposed	0 / 6 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	1 / 21 (4.76%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences all number	0	0	0	1	0	0
Road traffic accident
subjects affected / exposed	0 / 6 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	1 / 21 (4.76%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences all number	0	0	0	1	0	0
Joint injury
subjects affected / exposed	0 / 6 (0.00%)	1 / 10 (10.00%)	0 / 6 (0.00%)	0 / 21 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences all number	0	1	0	0	0	0
Musculoskeletal injury
subjects affected / exposed	0 / 6 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	1 / 21 (4.76%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences all number	0	0	0	1	0	0
Sunburn
subjects affected / exposed	0 / 6 (0.00%)	0 / 10 (0.00%)	1 / 6 (16.67%)	0 / 21 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)
occurrences all number	0	0	1	0	0	1
Congenital, familial and genetic disorders
Methylenetetrahydrofolate reductase gene mutation
subjects affected / exposed	0 / 6 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	1 / 21 (4.76%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences all number	0	0	0	1	0	0
Cardiac disorders
Sinus tachycardia
subjects affected / exposed	0 / 6 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	1 / 21 (4.76%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences all number	0	0	0	1	0	0
Tachycardia
subjects affected / exposed	0 / 6 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	1 / 21 (4.76%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences all number	0	0	0	1	0	0
Nervous system disorders
Headache
subjects affected / exposed	0 / 6 (0.00%)	2 / 10 (20.00%)	1 / 6 (16.67%)	5 / 21 (23.81%)	1 / 6 (16.67%)	0 / 6 (0.00%)
occurrences all number	0	3	1	6	1	0
Dizziness
subjects affected / exposed	0 / 6 (0.00%)	1 / 10 (10.00%)	0 / 6 (0.00%)	1 / 21 (4.76%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences all number	0	1	0	1	0	0
Paraesthesia
subjects affected / exposed	0 / 6 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	1 / 21 (4.76%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences all number	0	0	0	1	0	0
Somnolence
subjects affected / exposed	0 / 6 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	1 / 21 (4.76%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences all number	0	0	0	1	0	0
Syncope
subjects affected / exposed	0 / 6 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	1 / 21 (4.76%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences all number	0	0	0	1	0	0
Taste disorder
subjects affected / exposed	0 / 6 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	1 / 21 (4.76%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences all number	0	0	0	1	0	0
Ear and labyrinth disorders
Deafness
subjects affected / exposed	0 / 6 (0.00%)	0 / 10 (0.00%)	1 / 6 (16.67%)	0 / 21 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)
occurrences all number	0	0	1	0	0	1
External ear pain
subjects affected / exposed	0 / 6 (0.00%)	1 / 10 (10.00%)	0 / 6 (0.00%)	0 / 21 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences all number	0	1	0	0	0	0
Hypoacusis
subjects affected / exposed	0 / 6 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	1 / 21 (4.76%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences all number	0	0	0	2	0	0
Vertigo
subjects affected / exposed	0 / 6 (0.00%)	1 / 10 (10.00%)	0 / 6 (0.00%)	0 / 21 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences all number	0	1	0	0	0	0
Eye disorders
Conjunctivitis allergic
subjects affected / exposed	0 / 6 (0.00%)	1 / 10 (10.00%)	0 / 6 (0.00%)	0 / 21 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences all number	0	1	0	0	0	0
Episcleritis
subjects affected / exposed	0 / 6 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	1 / 21 (4.76%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences all number	0	0	0	1	0	0
Gastrointestinal disorders
Abdominal discomfort
subjects affected / exposed	0 / 6 (0.00%)	1 / 10 (10.00%)	0 / 6 (0.00%)	1 / 21 (4.76%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences all number	0	1	0	1	0	0
Abdominal pain
subjects affected / exposed	0 / 6 (0.00%)	1 / 10 (10.00%)	0 / 6 (0.00%)	0 / 21 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences all number	0	2	0	0	0	0
Abdominal pain upper
subjects affected / exposed	0 / 6 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	1 / 21 (4.76%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences all number	0	0	0	1	0	0
Aphthous ulcer
subjects affected / exposed	0 / 6 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	1 / 21 (4.76%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences all number	0	0	0	2	0	0
Constipation
subjects affected / exposed	0 / 6 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	1 / 21 (4.76%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences all number	0	0	0	1	0	0
Dental caries
subjects affected / exposed	0 / 6 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	1 / 21 (4.76%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences all number	0	0	0	3	0	0
Diarrhoea
subjects affected / exposed	0 / 6 (0.00%)	0 / 10 (0.00%)	1 / 6 (16.67%)	2 / 21 (9.52%)	0 / 6 (0.00%)	1 / 6 (16.67%)
occurrences all number	0	0	1	2	0	1
Dyspepsia
subjects affected / exposed	0 / 6 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	1 / 21 (4.76%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences all number	0	0	0	1	0	0
Gastrooesophageal reflux disease
subjects affected / exposed	0 / 6 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	1 / 21 (4.76%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences all number	0	0	0	1	0	0
Haematochezia
subjects affected / exposed	0 / 6 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	1 / 21 (4.76%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences all number	0	0	0	1	0	0
Nausea
subjects affected / exposed	0 / 6 (0.00%)	3 / 10 (30.00%)	0 / 6 (0.00%)	1 / 21 (4.76%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences all number	0	3	0	1	0	0
Toothache
subjects affected / exposed	0 / 6 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	1 / 21 (4.76%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences all number	0	0	0	1	0	0
Vomiting
subjects affected / exposed	0 / 6 (0.00%)	1 / 10 (10.00%)	0 / 6 (0.00%)	1 / 21 (4.76%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences all number	0	1	0	2	0	0
Skin and subcutaneous tissue disorders
Alopecia
subjects affected / exposed	0 / 6 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	2 / 21 (9.52%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences all number	0	0	0	2	0	0
Dermatitis
subjects affected / exposed	0 / 6 (0.00%)	1 / 10 (10.00%)	0 / 6 (0.00%)	0 / 21 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences all number	0	1	0	0	0	0
Dermatitis atopic
subjects affected / exposed	0 / 6 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	1 / 21 (4.76%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences all number	0	0	0	1	0	0
Eczema
subjects affected / exposed	0 / 6 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	2 / 21 (9.52%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences all number	0	0	0	2	0	0
Hyperhidrosis
subjects affected / exposed	0 / 6 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	1 / 21 (4.76%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences all number	0	0	0	1	0	0
Pruritus
subjects affected / exposed	0 / 6 (0.00%)	0 / 10 (0.00%)	1 / 6 (16.67%)	1 / 21 (4.76%)	0 / 6 (0.00%)	1 / 6 (16.67%)
occurrences all number	0	0	1	1	0	1
Seborrhoeic dermatitis
subjects affected / exposed	0 / 6 (0.00%)	0 / 10 (0.00%)	1 / 6 (16.67%)	0 / 21 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)
occurrences all number	0	0	1	0	0	1
Rash maculo-papular
subjects affected / exposed	0 / 6 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	1 / 21 (4.76%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences all number	0	0	0	1	0	0
Renal and urinary disorders
Anuria
subjects affected / exposed	0 / 6 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	1 / 21 (4.76%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences all number	0	0	0	1	0	0
Pollakiuria
subjects affected / exposed	0 / 6 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	1 / 21 (4.76%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences all number	0	0	0	1	0	0
Musculoskeletal and connective tissue disorders
Bursitis
subjects affected / exposed	0 / 6 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	1 / 21 (4.76%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences all number	0	0	0	1	0	0
Back pain
subjects affected / exposed	0 / 6 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	2 / 21 (9.52%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences all number	0	0	0	2	0	0
Musculoskeletal chest pain
subjects affected / exposed	0 / 6 (0.00%)	1 / 10 (10.00%)	0 / 6 (0.00%)	0 / 21 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences all number	0	1	0	0	0	0
Flank pain
subjects affected / exposed	0 / 6 (0.00%)	1 / 10 (10.00%)	0 / 6 (0.00%)	0 / 21 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences all number	0	1	0	0	0	0
Neck pain
subjects affected / exposed	0 / 6 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	2 / 21 (9.52%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences all number	0	0	0	2	0	0
Infections and infestations
Acute sinusitis
subjects affected / exposed	0 / 6 (0.00%)	0 / 10 (0.00%)	1 / 6 (16.67%)	0 / 21 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)
occurrences all number	0	0	1	0	0	1
Clostridium difficile colitis
subjects affected / exposed	0 / 6 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	1 / 21 (4.76%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences all number	0	0	0	1	0	0
Conjunctivitis
subjects affected / exposed	0 / 6 (0.00%)	1 / 10 (10.00%)	0 / 6 (0.00%)	0 / 21 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences all number	0	1	0	0	0	0
Fungal skin infection
subjects affected / exposed	0 / 6 (0.00%)	0 / 10 (0.00%)	1 / 6 (16.67%)	0 / 21 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)
occurrences all number	0	0	1	0	0	1
Gastroenteritis
subjects affected / exposed	0 / 6 (0.00%)	0 / 10 (0.00%)	1 / 6 (16.67%)	1 / 21 (4.76%)	0 / 6 (0.00%)	1 / 6 (16.67%)
occurrences all number	0	0	1	1	0	1
Gastrointestinal infection
subjects affected / exposed	0 / 6 (0.00%)	0 / 10 (0.00%)	1 / 6 (16.67%)	0 / 21 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)
occurrences all number	0	0	1	0	0	1
Lower respiratory tract infection
subjects affected / exposed	0 / 6 (0.00%)	1 / 10 (10.00%)	0 / 6 (0.00%)	0 / 21 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences all number	0	1	0	0	0	0
Groin infection
subjects affected / exposed	0 / 6 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	1 / 21 (4.76%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences all number	0	0	0	1	0	0
Nasal herpes
subjects affected / exposed	0 / 6 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	1 / 21 (4.76%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences all number	0	0	0	1	0	0
Nasopharyngitis
subjects affected / exposed	0 / 6 (0.00%)	1 / 10 (10.00%)	1 / 6 (16.67%)	0 / 21 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)
occurrences all number	0	1	1	0	0	1
Oral candidiasis
subjects affected / exposed	0 / 6 (0.00%)	1 / 10 (10.00%)	0 / 6 (0.00%)	0 / 21 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences all number	0	1	0	0	0	0
Oral herpes
subjects affected / exposed	0 / 6 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	1 / 21 (4.76%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences all number	0	0	0	1	0	0
Otitis externa
subjects affected / exposed	0 / 6 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	1 / 21 (4.76%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences all number	0	0	0	1	0	0
Pneumonia
subjects affected / exposed	0 / 6 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	1 / 21 (4.76%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences all number	0	0	0	1	0	0
Rhinitis
subjects affected / exposed	0 / 6 (0.00%)	0 / 10 (0.00%)	1 / 6 (16.67%)	0 / 21 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)
occurrences all number	0	0	1	0	1	0
Respiratory tract infection
subjects affected / exposed	0 / 6 (0.00%)	1 / 10 (10.00%)	0 / 6 (0.00%)	0 / 21 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences all number	0	1	0	0	0	0
Sinusitis
subjects affected / exposed	0 / 6 (0.00%)	0 / 10 (0.00%)	1 / 6 (16.67%)	4 / 21 (19.05%)	1 / 6 (16.67%)	0 / 6 (0.00%)
occurrences all number	0	0	1	4	1	0
Upper respiratory tract infection
subjects affected / exposed	0 / 6 (0.00%)	2 / 10 (20.00%)	0 / 6 (0.00%)	2 / 21 (9.52%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences all number	0	2	0	2	0	0
Urinary tract infection
subjects affected / exposed	0 / 6 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	1 / 21 (4.76%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences all number	0	0	0	1	0	0
Vulvovaginal candidiasis
subjects affected / exposed	0 / 6 (0.00%)	1 / 10 (10.00%)	0 / 6 (0.00%)	0 / 21 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences all number	0	1	0	0	0	0
Vulvovaginal mycotic infection
subjects affected / exposed	0 / 6 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	1 / 21 (4.76%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences all number	0	0	0	1	0	0
Metabolism and nutrition disorders
Decreased appetite
subjects affected / exposed	0 / 6 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	1 / 21 (4.76%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences all number	0	0	0	1	0	0
Hypokalaemia
subjects affected / exposed	0 / 6 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	1 / 21 (4.76%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences all number	0	0	0	1	0	0

More information

Top of page

Were there any global substantial amendments to the protocol? Yes

01 Feb 2015

The purpose of this amendment is to address feedback received by the National Institute of Allergy and Infectious Diseases (NIAID) IRB, NIH, USA, the FDA and the MHRA in relation to the study protocol. Inclusion/exclusion criteria have been amended to remove inconsistencies.

01 Mar 2015

The purpose of this protocol amendment is to provide updated information related to safety findings observed in an ongoing 39-week toxicology study and related additional safety measures implemented in relation to the potential risk of infections and gastrointestinal infection, in particular.

01 Jun 2015

The purpose of this protocol amendment is to enable the use of the new 70 mg capsule of CDZ173 for the 70 mg b.i.d. dose level, rather than 7 capsules of 10 mg CDZ173 b.i.d.

01 Sep 2015

The purpose of this protocol amendment is to revise the requirements related to contraception in-line with the “recommendations related to contraception and pregnancy testing in clinical trials” issued by the European Heads of Medicine Agencies (HMA) clinical trial facilitation group (CTFG) in September 2014.

01 Dec 2015

The purpose of this protocol amendment is to revise the restrictions of concomitant medication use following the outcome of a preliminary data review of a drug-drug interaction study (CCDZ173X2102).

01 Apr 2016

One purpose of this amendment is to introduce a safety measure based on information emerging from another PI3Kδ inhibitor.

01 Jul 2017

The main purpose of this protocol amendment is to adjust the design, endpoints and biomarkers of the study Part II based on the results obtained from the study Part I.

01 Feb 2019

The main purpose of this amendment is to change eligibility criteria to allow for inclusion of APDS patients with more severe disease phenotype, who often do not have stable maintenance immunoglobulin replacement treatment, but receive varying doses according to their actual need. Eligibility criteria for vital signs of the pediatric patient population are slightly adapted. Furthermore, the restricted medication section is updated to allow for treatment with higher dose of corticosteroids, since patients could be in need of this rescue medication.

01 Feb 2020

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 (e.g. COVID-19 pandemic). The protocol is adapted to allow alternative methods of providing continuing care as well as remote collection of efficacy endpoints, where possible.

16 Oct 2020

The purpose of this amendment is to address questions and comments raised by the Health Authority in Germany (BfArM). The Risks and benefits section has been expanded to include a sub-section to show the specific benefit / risk profile of adolescents (12 – 15 years of age). In addition, in accordance with internal Novartis guidelines, a COVID-19 test prior to enrollment into the study has been included.

Were there any global interruptions to the trial? No

Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.

None reported

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Clinical trials

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Part I: Number of participants with Adverse Events (AEs) and Serious Adverse Events (SAEs)

Primary: Part I: Number of participants with Adverse Events (AEs) and Serious Adverse Events (SAEs)

Primary: Part I: CDZ173 dose concentration

Primary: Part I: CDZ173 dose concentration

Primary: Part I: Percentage of inhibition of unstimulated and stimulated pAkt levels in B cells

Primary: Part I: Percentage of inhibition of unstimulated and stimulated pAkt levels in B cells

Primary: Part II: Change from baseline in the log10 transformed sum of product of diameters (SPD) in the index lesions

Primary: Part II: Change from baseline in the log10 transformed sum of product of diameters (SPD) in the index lesions

Primary: Part II: Change from baseline in percentage of naïve B cells out of total B cells

Primary: Part II: Change from baseline in percentage of naïve B cells out of total B cells

Secondary: Part I & II: Area Under the Plasma Concentration-time Curve From Time Zero to the Last Quantifiable Concentration (AUClast) for CDZ173

Secondary: Part I & II: Area Under the Plasma Concentration-time Curve From Time Zero to the Last Quantifiable Concentration (AUClast) for CDZ173

Secondary: Part I & II: Maximum Observed Plasma Concentration (Cmax) for CDZ173

Secondary: Part I & II: Maximum Observed Plasma Concentration (Cmax) for CDZ173

Secondary: Part I & II: Mental component summary (MCS) and Physical component summary (PCS) from Short Form 36 (SF-36) Survey

Secondary: Part I & II: Mental component summary (MCS) and Physical component summary (PCS) from Short Form 36 (SF-36) Survey

Secondary: Part I & II: Physician’s Global Assessment (PGA)

Secondary: Part I & II: Physician’s Global Assessment (PGA)

Secondary: Part I & II: Patient’s Global Assessment (PtGA)

Secondary: Part I & II: Patient’s Global Assessment (PtGA)

Secondary: Part I & II: High Sensivity C reactive protein (hsCRP) as biomarker for systemic inflammation

Secondary: Part I & II: High Sensivity C reactive protein (hsCRP) as biomarker for systemic inflammation

Secondary: Part I & II: Lactate dehydrogenase (LDH) as biomarker for systemic inflammation

Secondary: Part I & II: Lactate dehydrogenase (LDH) as biomarker for systemic inflammation

Secondary: Part II: Beta2 microglobulin as biomarker for systemic inflammation

Secondary: Part II: Beta2 microglobulin as biomarker for systemic inflammation

Secondary: Part II: Ferritin as biomarker for systemic inflammation

Secondary: Part II: Ferritin as biomarker for systemic inflammation

Secondary: Part II: Fibrinogen as biomarker for systemic inflammation

Secondary: Part II: Fibrinogen as biomarker for systemic inflammation

Secondary: Part II: Erythrocyte sedimentation rate (ESR) as biomarker for systemic inflammation

Secondary: Part II: Erythrocyte sedimentation rate (ESR) as biomarker for systemic inflammation

Secondary: Part II: 3D volume of index lesions

Secondary: Part II: 3D volume of index lesions

Secondary: Part II: 3D volume of the spleen

Secondary: Part II: 3D volume of the spleen

Secondary: Part I & II: Overall work impairment due to health score from Work Productivity Activity Impairment and Classroom Impairment Questionnaire (WPAI-CIQ)

Secondary: Part I & II: Overall work impairment due to health score from Work Productivity Activity Impairment and Classroom Impairment Questionnaire (WPAI-CIQ)

Secondary: Part I & II: Overall classroom impairment due to health score from the Work Productivity Activity Impairment and Classroom Impairment Questionnaire (WPAI-CIQ)

Secondary: Part I & II: Overall classroom impairment due to health score from the Work Productivity Activity Impairment and Classroom Impairment Questionnaire (WPAI-CIQ)

Adverse events

Adverse events

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Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

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