Common Variable Immunodeficiency (CVID), APDS / PASLIPhase 2/3NCT02435173
Study of Efficacy of CDZ173 in Patients With APDS/PASLI
A Phase 2/3 study testing CDZ173 in people with Common Variable Immunodeficiency (CVID), APDS / PASLI, run by Novartis Pharmaceuticals at 10 sites in 9 countries.
Trial 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). Read more about this study
- Who is it for?
- Ages 12 to 75 years
- Conditions the study is for
- Common Variable Immunodeficiency (CVID), APDS / PASLI
- What is being tested?
- CDZ173
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 37 participants
- Where
- 10 sitesin 9 countries
- Study dates
- 24 Aug 2015to 16 Aug 2021
- Phase
- Phase 2/3
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 12 to 75 years
- All sexes
- No healthy volunteers
- Child, Adult, Older adult
Who may be able to join
- 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.
Who cannot join
- 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.
Trial locations and contacts
10 sites in 9 countries.
10 sites in 9 countries
Italy2 sites
Novartis Investigative Site
Brescia, 25123
Novartis Investigative Site
Palermo, PA, 90127
United States1 site
National Institute of Health NIH
Bethesda, Maryland, 20814
About this study
Official title: An Open-label, Non-randomized, Within-patient Dose-finding Study Followed by a Randomized, Subject, Investigator and Sponsor Blinded Placebo Controlled Study to Assess the Efficacy and Safety of CDZ173 (Leniolisib) in Patients With APDS/PASLI (Activated Phosphoinositide 3-kinase Delta Syndrome/ p110δ-activating Mutation Causing Senescent T Cells, Lymphadenopathy and Immunodeficiency)
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.
- Being tested
- CDZ173, Placebo
- Keywords
- APDS, PASLI, PI3Kdelta
- Medical subject headings
- Common Variable Immunodeficiency, Activated PI3K-delta Syndrome
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
CDZ173Drug
Also called Leniolisib
CDZ173 10 and 70 mg capsules for oral administration.
PlaceboOther
Placebo capsules for oral administration
| Study group | Role | What they receive |
|---|---|---|
| Part I: CDZ173 | Experimental | 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. Receives: Drug: CDZ173 |
| Part II: CDZ173 | Experimental | Participants received CDZ173 70 mg b.i.d. from Day 1 to Day 85. Receives: Drug: CDZ173 |
| Part II: Placebo | Placebo comparator | Participants received Placebo b.i.d. from Day 1 to Day 85. Receives: Other: Placebo |
What is being measured
The primary outcome is the main question the study is designed to answer.
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.
Measured: From the start of treatment to 30 days after end of treatment, assessed up to maximum duration of 114 days
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.
Measured: Days 1, 29 and 57 (0.25 and 3 h post morning dose) and Day 84
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.
Measured: Baseline, days 29 and 57 (3 and 12 h post-dose) and day 84
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.
Measured: Baseline and Day 85
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.
Measured: Baseline and Day 85
Secondary outcomes (15)
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.
Measured: Part I: Days 1, 29 and 57 / Part II: Day 1
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.
Measured: Part I: Days 1, 29 and 57 / Part II: Day 1
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.
Measured: Part I: Baseline and Days 29, 57 and 84 / Part II: Baseline and Days 29, 57 and 85
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.
Measured: Part I: Baseline and Days 29, 57 and 84 / Part II: Baseline and Days 29, 57 and 85
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.
Measured: Part I: Baseline and Days 29, 57 and 84 / Part II: Baseline and Days 29, 57 and 85
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.
Measured: Part I: Baseline and Days 29, 57 and 84 / Part II: Baseline and Days 29, 57 and 85
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.
Measured: Part I: Baseline and Days 29, 57 and 84 / Part II: Baseline and Days 29, 57 and 85
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.
Measured: Part I: Baseline and Days 1, 15, 29, 57, 84 / Part II: Baseline and Days 1, 15, 29, 57, 85
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.
Measured: Part I: Baseline and Days 1, 15, 29, 57, 84 / Part II: Baseline and Days 1, 15, 29, 57, 85
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.
Measured: Baseline and Days 1, 15, 29, 57, 85
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.
Measured: Baseline and Days 1, 15, 29, 57, 85
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.
Measured: Baseline and Days 1, 15, 29, 57, 85
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.
Measured: Baseline and Days 1, 15, 29, 57, 85
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.
Measured: Baseline and Day 85
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.
Measured: Baseline and Day 85
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted6 May 2015 (estimated)
- Study start24 Aug 2015
- Primary completion16 Aug 2021
- Study completion16 Aug 2021
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Publications (3)Papers the sponsor has linked to this study.
- Other trials for Common Variable Immunodeficiency (CVID), APDS / PASLIStudies of the same condition, open and under way.
- More trials run by Novartis PharmaceuticalsThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 2/3
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Model description
- Part I of the study was a non-randomized, open-label, within-patient up-titration dose-finding part in 6 participants with APDS/PASLI. Part II was a randomized, subject, investigator and sponsor-blinded, placebo-controlled, fixed dose part investigating 31 participants with APDS/PASLI.
- Masking
- Triple blind
- Who is masked
- Participant, Care provider, Investigator
- Enrolment
- 37 participants (actual)
Sponsor and investigators
- Lead sponsor
- Novartis Pharmaceuticals
- Sponsor type
- Industry (pharma, biotech, devices)
- Responsible party
- Sponsor
- Investigators
- Koneti V Rao, MD, Principal investigator, National Institutes of Health (NIH)Virgil Dalm, MD, Principal investigator, Erasmus Medical CenterAnna Šedivá, MD, Principal investigator, Motol University
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT02435173
- Sponsor's protocol ID
- CCDZ173X2201
- Other IDs
- 2014-003876-22, 2014
- Status last verified
- Aug 2022
- First submitted
- 24 Feb 2015
- Last updated
- 10 Aug 2022
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- Yes
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
- Individual data sharing
- 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
Publications
Upton JEM, Williams KW, Cant A, Santos A, Bana E Costa J, Bradt J, Harrington A, Gwaltney C. Key outcomes in treatment of activated phosphoinositide 3-kinase delta syndrome: An e-Delphi panel study and responder threshold application. PLoS One. 2025 Oct 15;20(10):e0333341. doi: 10.1371/journal.pone.0333341. eCollection 2025.
PubMed 41091701Rao 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 36399712Rao 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 at a glance
From the registry record, last updated by the sponsor on 10 Aug 2022. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- An Open-label, Non-randomized, Within-patient Dose-finding Study Followed by a Randomized, Subject, Investigator and Sponsor Blinded Placebo Controlled Study to Assess the Efficacy and Safety of CDZ173 (Leniolisib) in Patients With APDS/PASLI (Activated Phosphoinositide 3-kinase Delta Syndrome/ p110δ-activating Mutation Causing Senescent T Cells, Lymphadenopathy and Immunodeficiency)
- ClinicalTrials.gov ID
- NCT02435173
- Acronym / sponsor ID
- CCDZ173X2201
- Keywords
- APDS, PASLI, PI3Kdelta
- Phase
- Phase 2/3
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 37 participants (actual)
- Lead sponsor
- Novartis PharmaceuticalsIndustry (pharma, biotech, devices)
- Study start
- 24 Aug 2015 (actual)
- Primary completion
- 16 Aug 2021 (actual)
- Study completion
- 16 Aug 2021 (actual)
- First posted
- 6 May 2015 (estimated)
- Results
- Posted 11 Mar 2022
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
This study was designed to explore CDZ173, a selective PI3Kδ inhibitor, in patients with genetically activated PI3Kδ, i.e., patients with Activated phosphoinositide 3-kinase delta syndrome/ p110δ-activating mutation causing senescent T cells, lymphadenopathy and immunodeficiency (APDS/PASLI).
The study consisted of two parts: Part I was the open label part designed to establish the safety and pharmacokinetics of CDZ173 in the target population, as well as to select the optimal dose to be tested in Part II. Part II was designed to assess efficacy and safety of CDZ173 in the target population.
Detailed description
This was a 2-part (Part I and Part II), Phase 2/3, multi-center study in subjects with APDS/PASLI.
Part I of the study was a non-randomized, open-label, within-patient up-titration dose-finding part in 6 participants with APDS/PASLI. The starting dose was 10 mg followed by 30 mg and 70 mg b.i.d. for 4 weeks at each dose level respectively. Part I consisted of three distinct study periods:
Screening / Baseline visit (Day -50 to Day-1): This period was used to confirm that the study inclusion and exclusion criteria were met. Participants who were deemed eligible for enrollment into the study attended the clinic on Day -1 for baseline assessments prior to randomization.
Treatment period (Day 1 to Day 84): Participants started treatment on Day 1 receiving 10 mg of CDZ173 twice daily (b.i.d.) until Day 28. After a continuous safety review and a review of PK and PD data, participants assessed as satisfactory proceeded to the next dose levels: from Day 29 to Day 56 participants received 30 mg CDZ173 b.i.d. and from Day 57 to Day 84, if assessed as satisfactory, participants received 70 mg CDZ173 b.i.d.
Follow-up (Day 85-114): After completion of the treatment period, participants were followed-up for safety for four weeks until Day 114.
Part II was a randomized, subject, investigator and sponsor-blinded, placebo-controlled, fixed dose part investigating 31 participants with APDS/PASLI. The CDZ173 dose used in this Part was selected based on safety, tolerability, PK and PD data from Part I. Part II consisted of three distinct study periods:
Screening / Baseline visit (Day -50 to Day-1): This period was used to confirm that the study inclusion and exclusion criteria were met. Participants who were deemed eligible for enrollment into the study attended the clinic on Day -1 for baseline assessments prior to randomization.
Treatment period (Day 1 to Day 85): On Day 1, Participants were randomized to one of the two treatment groups in a 2:1 ratio to receive either 70 mg CDZ173 b.i.d. or matching placebo until Day 85.
Follow-up (Day 86-115): On Day 86, a subset of participants rolled over to CCDZ173X2201E1 extension study and were not followed up for safety after end of treatment in CCDZ173X2201. Participants, who did not directly roll over to the extension study, after last treatment dose were followed-up for safety for four weeks until Day 115.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Triple blind (participant, care provider, investigator)
- Number of arms
- 3
- Model description
- Part I of the study was a non-randomized, open-label, within-patient up-titration dose-finding part in 6 participants with APDS/PASLI. Part II was a randomized, subject, investigator and sponsor-blinded, placebo-controlled, fixed dose part investigating 31 participants with APDS/PASLI.
| Arm | Type | Receives |
|---|---|---|
| Part I: CDZ173 | Experimental | Drug: CDZ173Participants 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. |
| Part II: CDZ173 | Experimental | Drug: CDZ173Participants received CDZ173 70 mg b.i.d. from Day 1 to Day 85. |
| Part II: Placebo | Placebo comparator | Other: PlaceboParticipants received Placebo b.i.d. from Day 1 to Day 85. |
Who may qualify
- Ages
- 12 to 75 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Child, Adult, Older adult
Key inclusion criteria (3 listed)
- 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 (6 listed)
- 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.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| CDZ173Also: LeniolisibCDZ173 10 and 70 mg capsules for oral administration. | Drug | Part I: CDZ173, Part II: CDZ173 |
| PlaceboPlacebo capsules for oral administration | Other | Part II: Placebo |
Primary outcome
Part I: Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs)
Time frame: From the start of treatment to 30 days after end of treatment, assessed up to maximum duration of 114 days
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.
Part I: CDZ173 Dose Concentration
Time frame: Days 1, 29 and 57 (0.25 and 3 h post morning dose) and Day 84
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.
Part I: Percentage of Inhibition of Unstimulated and Stimulated pAkt Levels in B Cells
Time frame: Baseline, days 29 and 57 (3 and 12 h post-dose) and day 84
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.
Part II: Change From Baseline in the log10 Transformed Sum of Product of Diameters (SPD) in the Index Lesions
Time frame: Baseline and Day 85
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.
Part II: Change From Baseline in Percentage of naïve B Cells Out of Total B Cells
Time frame: Baseline and Day 85
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.
15 secondary outcomes
Part I & II: Area Under the Plasma Concentration-time Curve From Time Zero to the Last Quantifiable Concentration (AUClast) for CDZ173
Time frame: Part I: Days 1, 29 and 57 / Part II: Day 1
Part I & II: Maximum Observed Plasma Concentration (Cmax) for CDZ173
Time frame: Part I: Days 1, 29 and 57 / Part II: Day 1
Part I & II: Mental Component Summary (MCS) and Physical Component Summary (PCS) From Short Form 36 (SF-36) Survey
Time frame: Part I: Baseline and Days 29, 57 and 84 / Part II: Baseline and Days 29, 57 and 85
Part I & II: Overall Work Impairment Due to Health Score From Work Productivity Activity Impairment and Classroom Impairment Questionnaire (WPAI-CIQ)
Time frame: Part I: Baseline and Days 29, 57 and 84 / Part II: Baseline and Days 29, 57 and 85
Part I & II: Overall Classroom Impairment Due to Health Score From the Work Productivity Activity Impairment and Classroom Impairment Questionnaire (WPAI-CIQ)
Time frame: Part I: Baseline and Days 29, 57 and 84 / Part II: Baseline and Days 29, 57 and 85
Part I & II: Physician's Global Assessment (PGA)
Time frame: Part I: Baseline and Days 29, 57 and 84 / Part II: Baseline and Days 29, 57 and 85
Part I & II: Patient's Global Assessment (PtGA)
Time frame: Part I: Baseline and Days 29, 57 and 84 / Part II: Baseline and Days 29, 57 and 85
Part I & II: High Sensivity C Reactive Protein (hsCRP) as Biomarker for Systemic Inflammation
Time frame: Part I: Baseline and Days 1, 15, 29, 57, 84 / Part II: Baseline and Days 1, 15, 29, 57, 85
Part I & II: Lactate Dehydrogenase (LDH) as Biomarker for Systemic Inflammation
Time frame: Part I: Baseline and Days 1, 15, 29, 57, 84 / Part II: Baseline and Days 1, 15, 29, 57, 85
Part II: Beta2 Microglobulin as Biomarker for Systemic Inflammation
Time frame: Baseline and Days 1, 15, 29, 57, 85
Part II: Ferritin as Biomarker for Systemic Inflammation
Time frame: Baseline and Days 1, 15, 29, 57, 85
Part II: Fibrinogen as Biomarker for Systemic Inflammation
Time frame: Baseline and Days 1, 15, 29, 57, 85
Part II: Erythrocyte Sedimentation Rate (ESR) as Biomarker for Systemic Inflammation
Time frame: Baseline and Days 1, 15, 29, 57, 85
Part II: 3D Volume of Index Lesions
Time frame: Baseline and Day 85
Part II: 3D Volume of the Spleen
Time frame: Baseline and Day 85
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 10 Aug 2022.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Derived from this study: PubMed 41091701Upton JEM, Williams KW, Cant A, Santos A, Bana E Costa J, Bradt J, Harrington A, Gwaltney C. Key outcomes in treatment of activated phosphoinositide 3-kinase delta syndrome: An e-Delphi panel study and responder threshold application. PLoS One. 2025 Oct 15;20(10):e0333341. doi: 10.1371/journal.pone.0333341. eCollection 2025.
- Derived from this study: PubMed 36399712Rao 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.
- Derived from this study: PubMed 28972011Rao 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.
- A Plain Language Trial Summary is available on novctrd.comLink provided by the sponsor.
- A pediatric Plain Language Trial Summary is available on novctrd.comLink provided by the sponsor.
- Individual participant dataSharing planned: 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
Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
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
10 sites in 9 countries: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2/3 study testing CDZ173 in people with Common Variable Immunodeficiency (CVID), APDS / PASLI, run by Novartis Pharmaceuticals at 10 sites in 9 countries.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 3 inclusion and 6 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 10 Aug 2022. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 10 sites in Italy, United States, Belarus, Czechia, Germany and 4 more countries. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this combined phase mean?
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 11 Mar 2022). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Part I: Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) (time frame: From the start of treatment to 30 days after end of treatment, assessed up to maximum duration of 114 days). The study lists 5 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT02435173, which also lists 3 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 10 Aug 2022.