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CompletedNCT02435173Updated Aug 10, 2022Results posted

Study of Efficacy of CDZ173 in Patients With APDS/PASLI

A Phase 2/3 interventional study of CDZ173 and Placebo in Common Variable Immunodeficiency (CVID), APDS / PASLI, sponsored by Novartis Pharmaceuticals. Completed at 10 sites in 9 countries. Open to participants aged 12 Years to 75 Years. Per ClinicalTrials.gov, last updated 2022-08-10.

Sponsored by Novartis Pharmaceuticals · Phase 2/3, Interventional, and Treatment

Phase
Phase 2/3
Study type
Interventional
Enrollment
37
Allocation
Randomized
Ages
12 Years to 75 Years
Sex
All
01

Study summary

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

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

Read the detailed description

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

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

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

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

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

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

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

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

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

02

Conditions studied

  • Common Variable Immunodeficiency (CVID), APDS / PASLI

Keywords

  • APDS
  • PASLI
  • PI3Kdelta
03

Who can participate

Ages eligible
12 Years to 75 Years
Sexes eligible
All
Accepts healthy volunteers
No

Eligibility criteria

Key Inclusion Criteria:

  • Male and female patients 12 to 75 years of age (inclusive), who had a documented APDS/PASLI-associated genetic PI3K delta mutation.
  • In Part I and Part II, patients must had nodal and/or extranodal lymphoproliferation, and clinical findings and manifestations compatible with APDS/PASLI such as a history of repeated oto-sino-pulmonary infections and/or organ dysfunction (e.g., lung, liver). Additionally, in part II, patients must had at least one measurable nodal lesion on a CT or MRI scan.
  • At screening, vital signs (systolic and diastolic blood pressure and pulse rate) were assessed in the sitting position after the patient rested for at least three minutes.

Key Exclusion Criteria:

  • Previous or concurrent use of immunosuppressive medication.
  • Current use of medication known to be strong inhibitor or moderate or strong inducers of isoenzyme CYP3A, if treatment cannot be discontinued or switched to a different medication prior to starting study treatment.
  • Current use of medications that are metabolized by isoenzyme CYP1A2 and have a narrow therapeutic index (drugs whose exposureresponse 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)).
  • Administration of live vaccines (this includes any attenuated live vaccines) starting from 6 weeks before study entry, during the study and up to 7 days after the last dose of CDZ173.
  • Pregnant or nursing (lactating) women, where pregnancy is defined as the state of a female after conception and until the termination of gestation, confirmed by a positive hCG laboratory test.
  • 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 of study medication and for 2 days after stopping study treatment.
04

Study design

Phase
Phase 2 / Phase 3
Primary purpose
Treatment
Allocation
Randomized
Intervention model
Parallel assignment
Masking
Triple (Participant, Care provider, Investigator)
Enrollment
37 participants (actual)

Study arms

  • Experimental
    Part I: CDZ173

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

    Drug: CDZ173

  • Experimental
    Part II: CDZ173

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

    Drug: CDZ173

  • Placebo comparator
    Part II: Placebo

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

    Other: Placebo

Interventions

  • DrugCDZ173

    CDZ173 10 and 70 mg capsules for oral administration.

    Also known as: Leniolisib

  • OtherPlacebo

    Placebo capsules for oral administration

05

What researchers measure

Primary outcomes

  1. Part I: Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs)

    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.

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

  2. Part I: CDZ173 Dose Concentration

    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.

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

  3. Part I: Percentage of Inhibition of Unstimulated and Stimulated pAkt Levels in B Cells

    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.

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

  4. Part II: Change From Baseline in the log10 Transformed Sum of Product of Diameters (SPD) in the Index Lesions

    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.

    Time frame: Baseline and Day 85

  5. Part II: Change From Baseline in Percentage of naïve B Cells Out of Total B Cells

    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.

    Time frame: Baseline and Day 85

Secondary outcomes

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

    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.

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

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

    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.

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

  3. Part I & II: Mental Component Summary (MCS) and Physical Component Summary (PCS) From Short Form 36 (SF-36) Survey

    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.

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

  4. Part I & II: Overall Work Impairment Due to Health Score From Work Productivity Activity Impairment and Classroom Impairment Questionnaire (WPAI-CIQ)

    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 responded 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.

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

  5. Part I & II: Overall Classroom Impairment Due to Health Score From the Work Productivity Activity Impairment and Classroom Impairment Questionnaire (WPAI-CIQ)

    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 responded 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.

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

  6. Part I & II: Physician's Global Assessment (PGA)

    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.

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

  7. Part I & II: Patient's Global Assessment (PtGA)

    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.

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

  8. Part I & II: High Sensivity C Reactive Protein (hsCRP) as Biomarker for Systemic Inflammation

    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.

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

  9. Part I & II: Lactate Dehydrogenase (LDH) as Biomarker for Systemic Inflammation

    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.

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

  10. Part II: Beta2 Microglobulin as Biomarker for Systemic Inflammation

    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.

    Time frame: Baseline and Days 1, 15, 29, 57, 85

  11. Part II: Ferritin as Biomarker for Systemic Inflammation

    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.

    Time frame: Baseline and Days 1, 15, 29, 57, 85

  12. Part II: Fibrinogen as Biomarker for Systemic Inflammation

    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.

    Time frame: Baseline and Days 1, 15, 29, 57, 85

  13. Part II: Erythrocyte Sedimentation Rate (ESR) as Biomarker for Systemic Inflammation

    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.

    Time frame: Baseline and Days 1, 15, 29, 57, 85

  14. Part II: 3D Volume of Index Lesions

    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.

    Time frame: Baseline and Day 85

  15. Part II: 3D Volume of the Spleen

    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.

    Time frame: Baseline and Day 85

06

Results

Posted Mar 11, 2022

Participant flow

Participants took part in 10 investigative sites in 9 countries.

Participant flow — Overall Study
MilestonePart I: CDZ173Part II: CDZ173 70 mgPart II: Placebo
Started62110
Pharmacokinetics (pk) analysis set6190
Pharmacodynamic (pd) analysis set6198
Completed62110
Not completed000

Outcome measures

PrimaryPart I: Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs)

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.

Time frame:
From the start of treatment to 30 days after end of treatment, assessed up to maximum duration of 114 days
Reported as:
Count of participants · Participants
Part I: Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs)
ParticipantsPart I: CDZ173 10 mg
CDZ173 10 mg AEs2
CDZ173 10 mg SAEs0
CDZ173 30 mg AEs2
CDZ173 30 mg SAEs0
CDZ173 70 mg AEs4
CDZ173 70 mg SAEs0
PrimaryPart I: CDZ173 Dose Concentration

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.

Time frame:
Days 1, 29 and 57 (0.25 and 3 h post morning dose) and Day 84
Reported as:
Mean · Nanogram / millilitre
Part I: CDZ173 Dose Concentration
Nanogram / millilitrePart I: CDZ173
Day 1: 0.25 h post-dose10.10 ± 1.10
Day 1: 3 h post-dose321.00 ± 115.00
Day 29: 0.25 h post-dose249.00 ± 540.00
Day 29: 3 h post-dose916.00 ± 185.00
Day 57: 0.25 h post-dose150.00 ± 143.00
Day 57: 3 h post-dose1710.00 ± 782.00
Day 84998.00 ± 455.00
PrimaryPart I: Percentage of Inhibition of Unstimulated and Stimulated pAkt Levels in B Cells

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.

Time frame:
Baseline, days 29 and 57 (3 and 12 h post-dose) and day 84
Reported as:
Mean · Percentage
Part I: Percentage of Inhibition of Unstimulated and Stimulated pAkt Levels in B Cells
PercentagePart I: CDZ173
CD20B Unstimulated: Day 29 - 3 h post-dose82.07 ± 7.25
CD20B Stimulated: Day 29 - 3 h post-dose78.00 ± 7.25
CD20B Unstimulated: Day 29 - 12 h post-dose50.58 ± 18.73
CD20B Stimulated: Day 29 - 12 h post-dose47.14 ± 7.83
CD20B Unstimulated: Day 57 - 3 h post-dose86.61 ± 5.26
CD20B Stimulated: Day 57 - 3 h post-dose60.98 ± 54.05
CD20B Unstimulated: Day 57 - 12 h post-dose53.18 ± 16.59
CD20B Stimulated: Day 57 - 12 h post-dose63.65 ± 21.03
CD20B Unstimulated: Day 8474.35 ± 11.03
CD20B Stimulated: Day 8478.65 ± 12.00
PrimaryPart II: Change From Baseline in the log10 Transformed Sum of Product of Diameters (SPD) in the Index Lesions

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.

Time frame:
Baseline and Day 85
Reported as:
Least squares mean · Millimeter on Log10 scale
Part II: Change From Baseline in the log10 Transformed Sum of Product of Diameters (SPD) in the Index Lesions
Millimeter on Log10 scalePart II: CDZ173Part II: Placebo
Part II: Change From Baseline in the log10 Transformed Sum of Product of Diameters (SPD) in the Index Lesions-0.30 ± 0.04-0.06 ± 0.06
Statistical analysis
  • Part II: CDZ173 vs Part II: Placebo · ANCOVA · p = 0.0012 · Adjusted means difference: -0.24 · 95% CI -0.37 to -0.11Treatment as a fixed effect and log10 transformed baseline SPD as a covariate.
PrimaryPart II: Change From Baseline in Percentage of naïve B Cells Out of Total B Cells

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.

Time frame:
Baseline and Day 85
Reported as:
Least squares mean · Percentage change from baseline
Part II: Change From Baseline in Percentage of naïve B Cells Out of Total B Cells
Percentage change from baselinePart II: CDZ173Part II: Placebo
Part II: Change From Baseline in Percentage of naïve B Cells Out of Total B Cells34.76 ± 3.08-5.37 ± 3.95
Statistical analysis
  • Part II: CDZ173 vs Part II: Placebo · ANCOVA · p = <0.0001 · Adjusted means difference: 40.13 · 95% CI 28.51 to 51.75Treatment as a fixed effect and baseline as a covariate.
SecondaryPart I & II: Area Under the Plasma Concentration-time Curve From Time Zero to the Last Quantifiable Concentration (AUClast) for CDZ173

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.

Time frame:
Part I: Days 1, 29 and 57 / Part II: Day 1
Reported as:
Mean · Hour * nanogram / millilitre
Part I & II: Area Under the Plasma Concentration-time Curve From Time Zero to the Last Quantifiable Concentration (AUClast) for CDZ173
Hour * nanogram / millilitrePart I: CDZ173Part II: CDZ173
Day 11760.0 ± 441.010400.0 ± 2800.0
Day 294760.0 ± 816.0—
Day 5710800.0 ± 3310.0—
SecondaryPart I & II: Maximum Observed Plasma Concentration (Cmax) for CDZ173

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.

Time frame:
Part I: Days 1, 29 and 57 / Part II: Day 1
Reported as:
Mean · Nanogram / millilitre
Part I & II: Maximum Observed Plasma Concentration (Cmax) for CDZ173
Nanogram / millilitrePart I: CDZ173Part II: CDZ173
Day 1393.0 ± 137.02150.0 ± 576.0
Day 291060.0 ± 222.0—
Day 572540.0 ± 747.0—
SecondaryPart I & II: Mental Component Summary (MCS) and Physical Component Summary (PCS) From Short Form 36 (SF-36) Survey

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.

Time frame:
Part I: Baseline and Days 29, 57 and 84 / Part II: Baseline and Days 29, 57 and 85
Reported as:
Mean · Score on a scale
Part I & II: Mental Component Summary (MCS) and Physical Component Summary (PCS) From Short Form 36 (SF-36) Survey
Score on a scalePart I: CDZ173Part II: CDZ173Part II: Placebo
Day -1: Mental Component Summary47.94 ± 8.2247.36 ± 7.9845.94 ± 8.14
Day -1: Physical Component Summary47.54 ± 9.2444.49 ± 7.0844.06 ± 8.59
Day 29: Mental Component Summary47.94 ± 8.2249.98 ± 8.0649.52 ± 6.70
Day 29: Physical Component Summary47.54 ± 9.2447.87 ± 7.6644.62 ± 7.57
Day 57: Mental Component Summary47.94 ± 8.2249.12 ± 8.1745.92 ± 7.31
Day 57: Physical Component Summary47.54 ± 9.2447.04 ± 7.3047.20 ± 9.75
Day 84 (Part I) / Day 85 (Part II): Mental Component Summary47.94 ± 8.2249.22 ± 8.1747.32 ± 8.73
Day 84 (Part I) / Day 85 (Part II): Physical Component Summary47.54 ± 9.2447.59 ± 6.2247.48 ± 8.48
SecondaryPart I & II: Overall Work Impairment Due to Health Score From Work Productivity Activity Impairment and Classroom Impairment Questionnaire (WPAI-CIQ)

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 responded 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.

Time frame:
Part I: Baseline and Days 29, 57 and 84 / Part II: Baseline and Days 29, 57 and 85
Reported as:
Mean · Percentage
Part I & II: Overall Work Impairment Due to Health Score From Work Productivity Activity Impairment and Classroom Impairment Questionnaire (WPAI-CIQ)
PercentagePart I: CDZ173Part II: CDZ173Part II: Placebo
Baseline25.00 ± 35.3651.25 ± 37.235.00 ± 7.07
Day 2944.00 ± 035.31 ± 23.125.00 ± 7.07
Day 5762.31 ± 035.49 ± 24.7010.00 ± 14.14
Day 84 (Part I) / Day 85 (Part II)44.41 ± 7.9035.59 ± 31.8525.00 ± 7.07
SecondaryPart I & II: Overall Classroom Impairment Due to Health Score From the Work Productivity Activity Impairment and Classroom Impairment Questionnaire (WPAI-CIQ)

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 responded 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.

Time frame:
Part I: Baseline and Days 29, 57 and 84 / Part II: Baseline and Days 29, 57 and 85
Reported as:
Mean · Percentage
Part I & II: Overall Classroom Impairment Due to Health Score From the Work Productivity Activity Impairment and Classroom Impairment Questionnaire (WPAI-CIQ)
PercentagePart I: CDZ173Part II: CDZ173Part II: Placebo
Baseline65.68 ± 33.4947.33 ± 44.7523.75 ± 30.92
Day 2957.30 ± 18.090.00 ± 022.65 ± 24.37
Day 5770.13 ± 18.6812.14 ± 3.0322.40 ± 26.16
Day 84 (Part I) / Day 85 (Part II)68.52 ± 18.7451.00 ± 0.005.00 ± 7.07
SecondaryPart I & II: Physician's Global Assessment (PGA)

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.

Time frame:
Part I: Baseline and Days 29, 57 and 84 / Part II: Baseline and Days 29, 57 and 85
Reported as:
Mean · Score on a scale
Part I & II: Physician's Global Assessment (PGA)
Score on a scalePart I: CDZ173Part II: CDZ173Part II: Placebo
Baseline34.7 ± 17.0747.10 ± 17.6541.38 ± 17.78
Day 2921.8 ± 9.7038.81 ± 23.7329.75 ± 9.99
Day 5722.5 ± 13.5534.02 ± 18.8924.13 ± 18.34
Day 84 (Part I) / Day 85 (Part II)8.8 ± 4.1226.70 ± 22.8225.88 ± 16.15
SecondaryPart I & II: Patient's Global Assessment (PtGA)

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.

Time frame:
Part I: Baseline and Days 29, 57 and 84 / Part II: Baseline and Days 29, 57 and 85
Reported as:
Mean · Score on a Scale
Part I & II: Patient's Global Assessment (PtGA)
Score on a ScalePart I: CDZ173Part II: CDZ173Part II: Placebo
Baseline62.0 ± 21.9054.53 ± 21.4762.50 ± 26.56
Day 2965.0 ± 22.2168.37 ± 19.3157.75 ± 24.03
Day 5767.5 ± 21.8364.79 ± 19.6169.50 ± 21.93
Day 84 (Part I) / Day 85 (Part II)72.5 ± 13.3767.58 ± 16.5760.25 ± 23.66
SecondaryPart I & II: High Sensivity C Reactive Protein (hsCRP) as Biomarker for Systemic Inflammation

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.

Time frame:
Part I: Baseline and Days 1, 15, 29, 57, 84 / Part II: Baseline and Days 1, 15, 29, 57, 85
Reported as:
Mean · Milligram / liter
Part I & II: High Sensivity C Reactive Protein (hsCRP) as Biomarker for Systemic Inflammation
Milligram / literPart I: CDZ173Part II: CDZ173Part II: Placebo
Baseline2.49 ± 1.2910.58 ± 17.845.70 ± 2.19
Day 12.43 ± 1.438.95 ± 14.567.85 ± 4.88
Day 150.93 ± 0.709.19 ± 23.122.06 ± 1.02
Day 290.77 ± 0.365.55 ± 11.212.40 ± 1.75
Day 571.20 ± 0.716.57 ± 9.188.90 ± 16.66
Day 84 (Part I) / Day 85 (Part II)2.82 ± 4.117.54 ± 18.372.65 ± 1.79
SecondaryPart I & II: Lactate Dehydrogenase (LDH) as Biomarker for Systemic Inflammation

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.

Time frame:
Part I: Baseline and Days 1, 15, 29, 57, 84 / Part II: Baseline and Days 1, 15, 29, 57, 85
Reported as:
Mean · Units / liter
Part I & II: Lactate Dehydrogenase (LDH) as Biomarker for Systemic Inflammation
Units / literPart I: CDZ173Part II: CDZ173Part II: Placebo
Baseline130.42 ± 18.28172.92 ± 72.25169.38 ± 41.95
Day 1132.17 ± 23.10170.88 ± 72.28175.71 ± 53.72
Day 15132.17 ± 11.44190.94 ± 71.54155.14 ± 48.09
Day 29125.17 ± 9.85227.17 ± 163.41185.25 ± 51.62
Day 57135.50 ± 17.66193.11 ± 64.75167.14 ± 40.45
Day 84 (Part I) / Day 85 (Part II)142.60 ± 18.53190.63 ± 57.62179.13 ± 73.96
SecondaryPart II: Beta2 Microglobulin as Biomarker for Systemic Inflammation

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.

Time frame:
Baseline and Days 1, 15, 29, 57, 85
Reported as:
Mean · Milligram / liter
Part II: Beta2 Microglobulin as Biomarker for Systemic Inflammation
Milligram / literPart II: CDZ173Part II: Placebo
Baseline2.46 ± 0.872.32 ± 0.96
Day 12.43 ± 0.882.31 ± 0.95
Day 152.10 ± 1.032.31 ± 1.09
Day 292.02 ± 1.173.21 ± 1.61
Day 571.90 ± 0.722.42 ± 1.17
Day 852.01 ± 1.042.57 ± 1.19
SecondaryPart II: Ferritin as Biomarker for Systemic Inflammation

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.

Time frame:
Baseline and Days 1, 15, 29, 57, 85
Reported as:
Mean · Microgram / liter
Part II: Ferritin as Biomarker for Systemic Inflammation
Microgram / literPart II: CDZ173Part II: Placebo
Baseline139.16 ± 399.7362.05 ± 81.65
Day 1142.67 ± 411.5761.34 ± 82.04
Day 15146.99 ± 494.8824.61 ± 17.41
Day 29187.65 ± 641.1648.43 ± 61.83
Day 57199.97 ± 657.3151.40 ± 64.95
Day 85139.42 ± 368.6863.16 ± 56.64
SecondaryPart II: Fibrinogen as Biomarker for Systemic Inflammation

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.

Time frame:
Baseline and Days 1, 15, 29, 57, 85
Reported as:
Mean · Gram / liter
Part II: Fibrinogen as Biomarker for Systemic Inflammation
Gram / literPart II: CDZ173Part II: Placebo
Baseline2.66 ± 0.762.68 ± 0.44
Day 12.61 ± 0.812.65 ± 0.42
Day 152.65 ± 0.622.67 ± 0.42
Day 292.53 ± 0.542.66 ± 0.58
Day 573.01 ± 0.682.83 ± 1.13
Day 852.81 ± 0.572.61 ± 0.57
SecondaryPart II: Erythrocyte Sedimentation Rate (ESR) as Biomarker for Systemic Inflammation

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.

Time frame:
Baseline and Days 1, 15, 29, 57, 85
Reported as:
Mean · Millimeter / hour
Part II: Erythrocyte Sedimentation Rate (ESR) as Biomarker for Systemic Inflammation
Millimeter / hourPart II: CDZ173Part II: Placebo
Baseline28.09 ± 19.7925.44 ± 24.88
Day 126.88 ± 19.3325.13 ± 24.51
Day 1519.50 ± 13.5216.00 ± 12.21
Day 2918.33 ± 13.8026.00 ± 25.26
Day 5718.06 ± 15.3627.88 ± 23.04
Day 8516.35 ± 15.9919.63 ± 18.03
SecondaryPart II: 3D Volume of Index Lesions

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.

Time frame:
Baseline and Day 85
Reported as:
Mean · Millimeter^3
Part II: 3D Volume of Index Lesions
Millimeter^3Part II: CDZ173Part II: Placebo
Baseline20142.12 ± 15617.1337123.69 ± 67325.94
Day 857858.08 ± 6290.9840169.28 ± 81844.45
SecondaryPart II: 3D Volume of the Spleen

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.

Time frame:
Baseline and Day 85
Reported as:
Mean · Millimeter^3
Part II: 3D Volume of the Spleen
Millimeter^3Part II: CDZ173Part II: Placebo
Baseline586448.74 ± 311482.61448456.15 ± 328641.78
Day 85411130.98 ± 193977.46480333.09 ± 445371.99

Adverse events

Collected over 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. For the subset of participants in Part II that rolled over to the extension study (CCDZ173X2201E1) directly after the last treatment dose in Part II, AEs were reported from the start of treatment to end of treatment, assessed up to maximum duration of 85 days.. Non-serious events are listed at a 0% frequency threshold.

Adverse event summary by group
GroupDeathsSeriousOther
Part I: CDZ173 10 mg0/6 (0%)0/6 (0%)2/6 (33.3%)
Part I: CDZ173 30 mg0/6 (0%)0/6 (0%)2/6 (33.3%)
Part I: CDZ173 70 mg0/6 (0%)0/6 (0%)4/6 (66.7%)
Part I: Total0/6 (0%)0/6 (0%)4/6 (66.7%)
Part II: CDZ173 70 mg0/21 (0%)3/21 (14.3%)18/21 (85.7%)
Part II: Placebo0/10 (0%)2/10 (20%)9/10 (90%)
Most frequent serious events
Showing 10 of 11
Most frequent serious events
EventPart I: CDZ173 10 mgPart I: CDZ173 30 mgPart I: CDZ173 70 mgPart I: TotalPart II: CDZ173 70 mgPart II: Placebo
LymphadenopathyBlood and lymphatic system disorders0/60/60/60/60/211/10
Infective exacerbation of bronchiectasisInfections and infestations0/60/60/60/60/211/10
Urinary tract infectionInfections and infestations0/60/60/60/60/211/10
DyspnoeaRespiratory, thoracic and mediastinal disorders0/60/60/60/60/211/10
Pulmonary hypertensionRespiratory, thoracic and mediastinal disorders0/60/60/60/60/211/10
Dependence on oxygen therapySocial circumstances0/60/60/60/60/211/10
MastoiditisInfections and infestations0/60/60/60/61/210/10
Alcohol poisoningInjury, poisoning and procedural complications0/60/60/60/61/210/10
Lipase increasedInvestigations0/60/60/60/61/210/10
Failure to thriveMetabolism and nutrition disorders0/60/60/60/61/210/10
Most frequent other events
Showing 10 of 95
Most frequent other events
EventPart I: CDZ173 10 mgPart I: CDZ173 30 mgPart I: CDZ173 70 mgPart I: TotalPart II: CDZ173 70 mgPart II: Placebo
NauseaGastrointestinal disorders0/60/60/60/61/213/10
HeadacheNervous system disorders0/61/60/61/65/212/10
AstheniaGeneral disorders0/60/60/60/61/212/10
Upper respiratory tract infectionInfections and infestations0/60/60/60/62/212/10
SinusitisInfections and infestations0/61/60/61/64/210/10
DeafnessEar and labyrinth disorders0/60/61/61/60/210/10
DiarrhoeaGastrointestinal disorders0/60/61/61/62/210/10
Acute sinusitisInfections and infestations0/60/61/61/60/210/10
Fungal skin infectionInfections and infestations0/60/61/61/60/210/10
GastroenteritisInfections and infestations0/60/61/61/61/210/10

Baseline characteristics

Age, Categorical
Age, Categorical(Participants)Part I: CDZ173Part II: CDZ173 70 mgPart II: PlaceboTotal
<=18 years29516
Between 18 and 65 years412521
>=65 years0000
Age, Continuous
Age, Continuous(Years)Part I: CDZ173Part II: CDZ173 70 mgPart II: PlaceboTotal
Mean22.2 ± 5.6422.2 ± 10.0026.7 ± 13.4323.43 ± 10.44
Sex: Female, Male
Sex: Female, Male(Participants)Part I: CDZ173Part II: CDZ173 70 mgPart II: PlaceboTotal
Female210618
Male411419
Race (NIH/OMB)
Race (NIH/OMB)(Participants)Part I: CDZ173Part II: CDZ173 70 mgPart II: PlaceboTotal
American Indian or Alaska Native0000
Asian0112
Native Hawaiian or Other Pacific Islander0000
Black or African American0112
White618731
More than one race0112
Unknown or Not Reported0000
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Study locations

10 sites
  • National Institute of Health NIH
    Bethesda, Maryland 20814, United States
  • Novartis Investigative Site
    Minsk, 223053, Belarus
  • Novartis Investigative Site
    Prague 5, 150 00, Czechia
  • Novartis Investigative Site
    Dresden, 01307, Germany
  • Novartis Investigative Site
    Dublin, Ireland
  • Novartis Investigative Site
    Palermo, PA 90127, Italy
  • Novartis Investigative Site
    Brescia, 25123, Italy
  • Novartis Investigative Site
    Rotterdam, 3000 CA, Netherlands
  • Novartis Investigative Site
    Moscow, 117198, Russian Federation
  • Novartis Investigative Site
    Belfast, BT9 7AB, United Kingdom
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References and documents

Publications

  • Rao VK, Webster S, Sediva A, Plebani A, Schuetz C, Shcherbina A, Conlon N, Coulter T, Dalm VA, Trizzino A, Zharankova Y, Kulm E, Korholz J, Lougaris V, Rodina Y, Radford K, Bradt J, Kucher K, Relan A, Holland SM, Lenardo MJ, Uzel G. A randomized, placebo-controlled phase 3 trial of the PI3Kdelta inhibitor leniolisib for activated PI3Kdelta syndrome. Blood. 2023 Mar 2;141(9):971-983. doi: 10.1182/blood.2022018546. PubMed 36399712 ↗
  • Rao VK, Webster S, Dalm VASH, Sediva A, van Hagen PM, Holland S, Rosenzweig SD, Christ AD, Sloth B, Cabanski M, Joshi AD, de Buck S, Doucet J, Guerini D, Kalis C, Pylvaenaeinen I, Soldermann N, Kashyap A, Uzel G, Lenardo MJ, Patel DD, Lucas CL, Burkhart C. Effective "activated PI3Kdelta syndrome"-targeted therapy with the PI3Kdelta inhibitor leniolisib. Blood. 2017 Nov 23;130(21):2307-2316. doi: 10.1182/blood-2017-08-801191. Epub 2017 Sep 29. PubMed 28972011 ↗

Study documents

  • Study protocol · Oct 13, 2020
  • Statistical analysis plan · Jan 5, 2022

Documents are hosted by the registry — open the source record to download them.

Individual participant data

Plan to share: Yes — Novartis is committed to sharing with qualified external researchers, access to patient-level data and supporting clinical documents from eligible studies. These requests are reviewed and approved by an independent review panel on the basis of scientific merit. All data provided is anonymized to respect the privacy of patients who have participated in the trial in line with applicable laws and regulations. This trial data availability is according to the criteria and process described on www.clinicalstudydatarequest.com

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Registry details

Key details

Study ID
NCT02435173
Lead sponsor
Novartis Pharmaceuticals
Responsible party
Sponsor
First posted
May 6, 2015
Start date
Aug 24, 2015
Primary completion
Aug 16, 2021
Completion
Aug 16, 2021
Results posted
Mar 11, 2022
Last update
Aug 10, 2022

Study contacts

Koneti V Rao, MD
principal investigator · National Institutes of Health (NIH)
Virgil Dalm, MD
principal investigator · Erasmus Medical Center
Anna Šedivá, MD
principal investigator · Motol University

Oversight

Data monitoring committee
Yes
FDA-regulated drug
Yes
FDA-regulated device
No
View the source record on ClinicalTrials.gov ↗

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