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 (part of Novartis) · Phase 2/3, Interventional, and Treatment
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.
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.
54 studies on the registry are indexed under Common Variable Immunodeficiency; 13 are open to participants now.
This study's enrollment of 37 is close to the median of 40 across 39 interventional studies indexed under Common Variable Immunodeficiency.
Browse Common Variable Immunodeficiency studies →Novartis Pharmaceuticals is the lead sponsor of 2,718 studies on the registry; 221 are open to participants now.
Of its 585 completed or terminated interventional studies of FDA-regulated products, 438 (75%) have results posted.
Counted across the registry records on this site, refreshed daily.
Key Inclusion Criteria:
Key Exclusion Criteria:
Underlined terms in the criteria open these too. Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
A weakened immune system. It can come from an illness, such as HIV or some blood cancers, or from medicines that turn the immune system down, for example after an organ transplant or for an autoimmune disease; steroids at higher doses count.
Read whether the line is about a condition or about medicines, and which medicines and doses it means.
CYP3A is a group of enzymes, mainly CYP3A4, in the liver and gut that break down many medicines. Some medicines, supplements and foods (grapefruit, St John’s wort) slow them down or speed them up, which changes how much of a study drug stays in the body.
Studies list them so they can be avoided or switched; bring a list of everything you take, including supplements.
Vaccines made with a weakened form of the germ, such as measles–mumps–rubella (MMR), chickenpox and yellow fever. They can be risky when the immune system is weakened. Flu injections are not live; the nasal flu spray is.
Able to become pregnant: from the first period until menopause, unless permanently unable to through surgery (removal of the womb, or of both ovaries or both fallopian tubes).
Criteria for people of childbearing potential usually ask for a negative pregnancy test and for contraception during the study and for a time after it.
Ways of preventing pregnancy. “Highly effective” methods fail less than 1% of the time a year when used correctly — for example an IUD or an implant.
Criteria usually say which methods count and how long to keep using them after the last dose, sometimes for male participants too. Some studies accept a partner’s vasectomy if it was confirmed successful and that person is the participant’s only sexual partner.
Immunosuppression
A weakened immune system. It can come from an illness, such as HIV or some blood cancers, or from medicines that turn the immune system down, for example after an organ transplant or for an autoimmune disease; steroids at higher doses count.
Read whether the line is about a condition or about medicines, and which medicines and doses it means.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
CYP3A (CYP3A4) inhibitors and inducers
CYP3A is a group of enzymes, mainly CYP3A4, in the liver and gut that break down many medicines. Some medicines, supplements and foods (grapefruit, St John’s wort) slow them down or speed them up, which changes how much of a study drug stays in the body.
Studies list them so they can be avoided or switched; bring a list of everything you take, including supplements.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Live vaccines
Vaccines made with a weakened form of the germ, such as measles–mumps–rubella (MMR), chickenpox and yellow fever. They can be risky when the immune system is weakened. Flu injections are not live; the nasal flu spray is.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Childbearing potential
Able to become pregnant: from the first period until menopause, unless permanently unable to through surgery (removal of the womb, or of both ovaries or both fallopian tubes).
Criteria for people of childbearing potential usually ask for a negative pregnancy test and for contraception during the study and for a time after it.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Contraception
Ways of preventing pregnancy. “Highly effective” methods fail less than 1% of the time a year when used correctly — for example an IUD or an implant.
Criteria usually say which methods count and how long to keep using them after the last dose, sometimes for male participants too. Some studies accept a partner’s vasectomy if it was confirmed successful and that person is the participant’s only sexual partner.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
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
Participants received CDZ173 70 mg b.i.d. from Day 1 to Day 85.
Drug: CDZ173
Participants received Placebo b.i.d. from Day 1 to Day 85.
Other: Placebo
CDZ173 10 and 70 mg capsules for oral administration.
Also known as: Leniolisib
Placebo capsules for oral administration
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
Participants took part in 10 investigative sites in 9 countries.
| Milestone | Part I: CDZ173 | Part II: CDZ173 70 mg | Part II: Placebo |
|---|---|---|---|
| Started | 6 | 21 | 10 |
| Pharmacokinetics (pk) analysis set | 6 | 19 | 0 |
| Pharmacodynamic (pd) analysis set | 6 | 19 | 8 |
| Completed | 6 | 21 | 10 |
| Not completed | 0 | 0 | 0 |
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.
| Participants | Part I: CDZ173 10 mg |
|---|---|
| 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 |
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.
| Nanogram / millilitre | Part I: CDZ173 |
|---|---|
| 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 |
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.
| Percentage | Part I: CDZ173 |
|---|---|
| CD20B Unstimulated: Day 29 - 3 h post-dose | 82.07 ± 7.25 |
| CD20B Stimulated: Day 29 - 3 h post-dose | 78.00 ± 7.25 |
| CD20B Unstimulated: Day 29 - 12 h post-dose | 50.58 ± 18.73 |
| CD20B Stimulated: Day 29 - 12 h post-dose | 47.14 ± 7.83 |
| CD20B Unstimulated: Day 57 - 3 h post-dose | 86.61 ± 5.26 |
| CD20B Stimulated: Day 57 - 3 h post-dose | 60.98 ± 54.05 |
| CD20B Unstimulated: Day 57 - 12 h post-dose | 53.18 ± 16.59 |
| CD20B Stimulated: Day 57 - 12 h post-dose | 63.65 ± 21.03 |
| CD20B Unstimulated: Day 84 | 74.35 ± 11.03 |
| CD20B Stimulated: Day 84 | 78.65 ± 12.00 |
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.
| Millimeter on Log10 scale | Part II: CDZ173 | Part 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 |
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.
| Percentage change from baseline | Part II: CDZ173 | Part II: Placebo |
|---|---|---|
| Part II: Change From Baseline in Percentage of naïve B Cells Out of Total B Cells | 34.76 ± 3.08 | -5.37 ± 3.95 |
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.
| Hour * nanogram / millilitre | Part I: CDZ173 | Part II: CDZ173 |
|---|---|---|
| Day 1 | 1760.0 ± 441.0 | 10400.0 ± 2800.0 |
| Day 29 | 4760.0 ± 816.0 | — |
| Day 57 | 10800.0 ± 3310.0 | — |
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.
| Nanogram / millilitre | Part I: CDZ173 | Part II: CDZ173 |
|---|---|---|
| Day 1 | 393.0 ± 137.0 | 2150.0 ± 576.0 |
| Day 29 | 1060.0 ± 222.0 | — |
| Day 57 | 2540.0 ± 747.0 | — |
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.
| Score on a scale | Part I: CDZ173 | Part II: CDZ173 | Part II: Placebo |
|---|---|---|---|
| Day -1: Mental Component Summary | 47.94 ± 8.22 | 47.36 ± 7.98 | 45.94 ± 8.14 |
| Day -1: Physical Component Summary | 47.54 ± 9.24 | 44.49 ± 7.08 | 44.06 ± 8.59 |
| Day 29: Mental Component Summary | 47.94 ± 8.22 | 49.98 ± 8.06 | 49.52 ± 6.70 |
| Day 29: Physical Component Summary | 47.54 ± 9.24 | 47.87 ± 7.66 | 44.62 ± 7.57 |
| Day 57: Mental Component Summary | 47.94 ± 8.22 | 49.12 ± 8.17 | 45.92 ± 7.31 |
| Day 57: Physical Component Summary | 47.54 ± 9.24 | 47.04 ± 7.30 | 47.20 ± 9.75 |
| Day 84 (Part I) / Day 85 (Part II): Mental Component Summary | 47.94 ± 8.22 | 49.22 ± 8.17 | 47.32 ± 8.73 |
| Day 84 (Part I) / Day 85 (Part II): Physical Component Summary | 47.54 ± 9.24 | 47.59 ± 6.22 | 47.48 ± 8.48 |
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.
| Percentage | Part I: CDZ173 | Part II: CDZ173 | Part II: Placebo |
|---|---|---|---|
| Baseline | 25.00 ± 35.36 | 51.25 ± 37.23 | 5.00 ± 7.07 |
| Day 29 | 44.00 ± 0 | 35.31 ± 23.12 | 5.00 ± 7.07 |
| Day 57 | 62.31 ± 0 | 35.49 ± 24.70 | 10.00 ± 14.14 |
| Day 84 (Part I) / Day 85 (Part II) | 44.41 ± 7.90 | 35.59 ± 31.85 | 25.00 ± 7.07 |
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.
| Percentage | Part I: CDZ173 | Part II: CDZ173 | Part II: Placebo |
|---|---|---|---|
| Baseline | 65.68 ± 33.49 | 47.33 ± 44.75 | 23.75 ± 30.92 |
| Day 29 | 57.30 ± 18.09 | 0.00 ± 0 | 22.65 ± 24.37 |
| Day 57 | 70.13 ± 18.68 | 12.14 ± 3.03 | 22.40 ± 26.16 |
| Day 84 (Part I) / Day 85 (Part II) | 68.52 ± 18.74 | 51.00 ± 0.00 | 5.00 ± 7.07 |
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.
| Score on a scale | Part I: CDZ173 | Part II: CDZ173 | Part II: Placebo |
|---|---|---|---|
| Baseline | 34.7 ± 17.07 | 47.10 ± 17.65 | 41.38 ± 17.78 |
| Day 29 | 21.8 ± 9.70 | 38.81 ± 23.73 | 29.75 ± 9.99 |
| Day 57 | 22.5 ± 13.55 | 34.02 ± 18.89 | 24.13 ± 18.34 |
| Day 84 (Part I) / Day 85 (Part II) | 8.8 ± 4.12 | 26.70 ± 22.82 | 25.88 ± 16.15 |
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.
| Score on a Scale | Part I: CDZ173 | Part II: CDZ173 | Part II: Placebo |
|---|---|---|---|
| Baseline | 62.0 ± 21.90 | 54.53 ± 21.47 | 62.50 ± 26.56 |
| Day 29 | 65.0 ± 22.21 | 68.37 ± 19.31 | 57.75 ± 24.03 |
| Day 57 | 67.5 ± 21.83 | 64.79 ± 19.61 | 69.50 ± 21.93 |
| Day 84 (Part I) / Day 85 (Part II) | 72.5 ± 13.37 | 67.58 ± 16.57 | 60.25 ± 23.66 |
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.
| Milligram / liter | Part I: CDZ173 | Part II: CDZ173 | Part II: Placebo |
|---|---|---|---|
| Baseline | 2.49 ± 1.29 | 10.58 ± 17.84 | 5.70 ± 2.19 |
| Day 1 | 2.43 ± 1.43 | 8.95 ± 14.56 | 7.85 ± 4.88 |
| Day 15 | 0.93 ± 0.70 | 9.19 ± 23.12 | 2.06 ± 1.02 |
| Day 29 | 0.77 ± 0.36 | 5.55 ± 11.21 | 2.40 ± 1.75 |
| Day 57 | 1.20 ± 0.71 | 6.57 ± 9.18 | 8.90 ± 16.66 |
| Day 84 (Part I) / Day 85 (Part II) | 2.82 ± 4.11 | 7.54 ± 18.37 | 2.65 ± 1.79 |
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.
| Units / liter | Part I: CDZ173 | Part II: CDZ173 | Part II: Placebo |
|---|---|---|---|
| Baseline | 130.42 ± 18.28 | 172.92 ± 72.25 | 169.38 ± 41.95 |
| Day 1 | 132.17 ± 23.10 | 170.88 ± 72.28 | 175.71 ± 53.72 |
| Day 15 | 132.17 ± 11.44 | 190.94 ± 71.54 | 155.14 ± 48.09 |
| Day 29 | 125.17 ± 9.85 | 227.17 ± 163.41 | 185.25 ± 51.62 |
| Day 57 | 135.50 ± 17.66 | 193.11 ± 64.75 | 167.14 ± 40.45 |
| Day 84 (Part I) / Day 85 (Part II) | 142.60 ± 18.53 | 190.63 ± 57.62 | 179.13 ± 73.96 |
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.
| Milligram / liter | Part II: CDZ173 | Part II: Placebo |
|---|---|---|
| Baseline | 2.46 ± 0.87 | 2.32 ± 0.96 |
| Day 1 | 2.43 ± 0.88 | 2.31 ± 0.95 |
| Day 15 | 2.10 ± 1.03 | 2.31 ± 1.09 |
| Day 29 | 2.02 ± 1.17 | 3.21 ± 1.61 |
| Day 57 | 1.90 ± 0.72 | 2.42 ± 1.17 |
| Day 85 | 2.01 ± 1.04 | 2.57 ± 1.19 |
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.
| Microgram / liter | Part II: CDZ173 | Part II: Placebo |
|---|---|---|
| Baseline | 139.16 ± 399.73 | 62.05 ± 81.65 |
| Day 1 | 142.67 ± 411.57 | 61.34 ± 82.04 |
| Day 15 | 146.99 ± 494.88 | 24.61 ± 17.41 |
| Day 29 | 187.65 ± 641.16 | 48.43 ± 61.83 |
| Day 57 | 199.97 ± 657.31 | 51.40 ± 64.95 |
| Day 85 | 139.42 ± 368.68 | 63.16 ± 56.64 |
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.
| Gram / liter | Part II: CDZ173 | Part II: Placebo |
|---|---|---|
| Baseline | 2.66 ± 0.76 | 2.68 ± 0.44 |
| Day 1 | 2.61 ± 0.81 | 2.65 ± 0.42 |
| Day 15 | 2.65 ± 0.62 | 2.67 ± 0.42 |
| Day 29 | 2.53 ± 0.54 | 2.66 ± 0.58 |
| Day 57 | 3.01 ± 0.68 | 2.83 ± 1.13 |
| Day 85 | 2.81 ± 0.57 | 2.61 ± 0.57 |
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.
| Millimeter / hour | Part II: CDZ173 | Part II: Placebo |
|---|---|---|
| Baseline | 28.09 ± 19.79 | 25.44 ± 24.88 |
| Day 1 | 26.88 ± 19.33 | 25.13 ± 24.51 |
| Day 15 | 19.50 ± 13.52 | 16.00 ± 12.21 |
| Day 29 | 18.33 ± 13.80 | 26.00 ± 25.26 |
| Day 57 | 18.06 ± 15.36 | 27.88 ± 23.04 |
| Day 85 | 16.35 ± 15.99 | 19.63 ± 18.03 |
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.
| Millimeter^3 | Part II: CDZ173 | Part II: Placebo |
|---|---|---|
| Baseline | 20142.12 ± 15617.13 | 37123.69 ± 67325.94 |
| Day 85 | 7858.08 ± 6290.98 | 40169.28 ± 81844.45 |
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.
| Millimeter^3 | Part II: CDZ173 | Part II: Placebo |
|---|---|---|
| Baseline | 586448.74 ± 311482.61 | 448456.15 ± 328641.78 |
| Day 85 | 411130.98 ± 193977.46 | 480333.09 ± 445371.99 |
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.
| Group | Deaths | Serious | Other |
|---|---|---|---|
| Part I: CDZ173 10 mg | 0/6 (0%) | 0/6 (0%) | 2/6 (33.3%) |
| Part I: CDZ173 30 mg | 0/6 (0%) | 0/6 (0%) | 2/6 (33.3%) |
| Part I: CDZ173 70 mg | 0/6 (0%) | 0/6 (0%) | 4/6 (66.7%) |
| Part I: Total | 0/6 (0%) | 0/6 (0%) | 4/6 (66.7%) |
| Part II: CDZ173 70 mg | 0/21 (0%) | 3/21 (14.3%) | 18/21 (85.7%) |
| Part II: Placebo | 0/10 (0%) | 2/10 (20%) | 9/10 (90%) |
| Event | Part I: CDZ173 10 mg | Part I: CDZ173 30 mg | Part I: CDZ173 70 mg | Part I: Total | Part II: CDZ173 70 mg | Part II: Placebo |
|---|---|---|---|---|---|---|
| LymphadenopathyBlood and lymphatic system disorders | 0/6 | 0/6 | 0/6 | 0/6 | 0/21 | 1/10 |
| Infective exacerbation of bronchiectasisInfections and infestations | 0/6 | 0/6 | 0/6 | 0/6 | 0/21 | 1/10 |
| Urinary tract infectionInfections and infestations | 0/6 | 0/6 | 0/6 | 0/6 | 0/21 | 1/10 |
| DyspnoeaRespiratory, thoracic and mediastinal disorders | 0/6 | 0/6 | 0/6 | 0/6 | 0/21 | 1/10 |
| Pulmonary hypertensionRespiratory, thoracic and mediastinal disorders | 0/6 | 0/6 | 0/6 | 0/6 | 0/21 | 1/10 |
| Dependence on oxygen therapySocial circumstances | 0/6 | 0/6 | 0/6 | 0/6 | 0/21 | 1/10 |
| MastoiditisInfections and infestations | 0/6 | 0/6 | 0/6 | 0/6 | 1/21 | 0/10 |
| Alcohol poisoningInjury, poisoning and procedural complications | 0/6 | 0/6 | 0/6 | 0/6 | 1/21 | 0/10 |
| Lipase increasedInvestigations | 0/6 | 0/6 | 0/6 | 0/6 | 1/21 | 0/10 |
| Failure to thriveMetabolism and nutrition disorders | 0/6 | 0/6 | 0/6 | 0/6 | 1/21 | 0/10 |
| Event | Part I: CDZ173 10 mg | Part I: CDZ173 30 mg | Part I: CDZ173 70 mg | Part I: Total | Part II: CDZ173 70 mg | Part II: Placebo |
|---|---|---|---|---|---|---|
| NauseaGastrointestinal disorders | 0/6 | 0/6 | 0/6 | 0/6 | 1/21 | 3/10 |
| HeadacheNervous system disorders | 0/6 | 1/6 | 0/6 | 1/6 | 5/21 | 2/10 |
| AstheniaGeneral disorders | 0/6 | 0/6 | 0/6 | 0/6 | 1/21 | 2/10 |
| Upper respiratory tract infectionInfections and infestations | 0/6 | 0/6 | 0/6 | 0/6 | 2/21 | 2/10 |
| SinusitisInfections and infestations | 0/6 | 1/6 | 0/6 | 1/6 | 4/21 | 0/10 |
| DeafnessEar and labyrinth disorders | 0/6 | 0/6 | 1/6 | 1/6 | 0/21 | 0/10 |
| DiarrhoeaGastrointestinal disorders | 0/6 | 0/6 | 1/6 | 1/6 | 2/21 | 0/10 |
| Acute sinusitisInfections and infestations | 0/6 | 0/6 | 1/6 | 1/6 | 0/21 | 0/10 |
| Fungal skin infectionInfections and infestations | 0/6 | 0/6 | 1/6 | 1/6 | 0/21 | 0/10 |
| GastroenteritisInfections and infestations | 0/6 | 0/6 | 1/6 | 1/6 | 1/21 | 0/10 |
| Age, Categorical(Participants) | Part I: CDZ173 | Part II: CDZ173 70 mg | Part II: Placebo | Total |
|---|---|---|---|---|
| <=18 years | 2 | 9 | 5 | 16 |
| Between 18 and 65 years | 4 | 12 | 5 | 21 |
| >=65 years | 0 | 0 | 0 | 0 |
| Age, Continuous(Years) | Part I: CDZ173 | Part II: CDZ173 70 mg | Part II: Placebo | Total |
|---|---|---|---|---|
| Mean | 22.2 ± 5.64 | 22.2 ± 10.00 | 26.7 ± 13.43 | 23.43 ± 10.44 |
| Sex: Female, Male(Participants) | Part I: CDZ173 | Part II: CDZ173 70 mg | Part II: Placebo | Total |
|---|---|---|---|---|
| Female | 2 | 10 | 6 | 18 |
| Male | 4 | 11 | 4 | 19 |
| Race (NIH/OMB)(Participants) | Part I: CDZ173 | Part II: CDZ173 70 mg | Part II: Placebo | Total |
|---|---|---|---|---|
| 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 |
PDFs hosted by the registry, ClinicalTrials.gov.
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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Studies of the drug tested here: Leniolisib
Common Variable Immunodeficiency →