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Study of Efficacy of CDZ173 in Patients With APDS/PASLI

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ClinicalTrials.gov Identifier: NCT02435173
Recruitment Status : Completed
First Posted : May 6, 2015
Last Update Posted : September 20, 2021
Sponsor:
Information provided by (Responsible Party):
Novartis ( Novartis Pharmaceuticals )

Brief Summary:
This study is 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 consists of two parts: Part I is the open label part designed to establish the safety and pharmacokinetics of CDZ173 in the target population, as well as to select the optimal dose to be tested in part II. Part II is designed to assess efficacy and safety of CDZ173 in this population.

Condition or disease Intervention/treatment Phase
Common Variable Immunodeficiency (CVID), APDS / PASLI Drug: CDZ173 Other: Placebo Phase 2 Phase 3

Detailed Description:
This study is 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 consists of two parts: Part I is the open label part designed to establish the safety and pharmacokinetics of CDZ173 in the target population, as well as to select the optimal dose to be tested in part II. Part II is designed to assess efficacy and safety of CDZ173 in this population.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 37 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description:

Part I of the study was a non-randomized, open-label, within-patient up-titration study.

Part II is a randomized, subject, investigator and sponsor-blinded, placebo-controlled, fixed dose study

Masking: Triple (Participant, Care Provider, Investigator)
Masking Description: Part I was a non-randomized, open-label study Part II is a randomized subject, investigator and sponsor-blinded, placebo controlled study
Primary Purpose: Treatment
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 in Patients With APDS/PASLI
Actual Study Start Date : August 24, 2015
Actual Primary Completion Date : August 16, 2021
Actual Study Completion Date : August 16, 2021


Arm Intervention/treatment
Experimental: Part I: CDZ173
Part I was with-in patient dose escalation with CDZ173 10, 30 and 70 mg bid
Drug: CDZ173
Part I: 10, 30 and 70 mg bid Part II: 70 mg bid
Other Name: Leniolisib

Placebo Comparator: Part II: Placebo
Part II is randomized placebo-controlled with CDZ173 70 mg bid and matching placebo
Other: Placebo
Placebo 70 mg bid

Experimental: Part II: CDZ173
Part II is randomized placebo-controlled with CDZ173 70 mg bid and matching placebo
Drug: CDZ173
Part I: 10, 30 and 70 mg bid Part II: 70 mg bid
Other Name: Leniolisib




Primary Outcome Measures :
  1. 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 16 weeks ]
    Part I: 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 is reported in the table.

  2. Part I: Single and multiple dose concentrations of CDZ173 [ Time Frame: 12 weeks ]
    Part I: To assess the dose-PD and PK/PD relationship of CDZ173 in patients with APDS/PASLI for dose selection in Part II

  3. Part I: pAkt inhibition in unstimulated and stimulated whole blood [ Time Frame: 12 weeks ]
    Part I: To assess the dose-PD and PK/PD relationship of CDZ173 in patients with APDS/PASLI for dose selection in Part II

  4. Part II: Change from baseline in the log10 transformed sum of product of diameters (SPD) in the index lesions selected as per the Cheson methodology from MRI/CT imaging [ Time Frame: 12 weeks ]
    Part II: To assess the clinical efficacy of CDZ173 in patients with APDS/PASLI

  5. Part II: Change from baseline in percentage of naïve B cells out of total B cells [ Time Frame: 12 weeks ]
    Part II: To assess the clinical efficacy of CDZ173 in patients with APDS/PASLI


Secondary Outcome Measures :
  1. Part I & II: AUClast [ Time Frame: 12 weeks ]
    Part I & II: To assess the pharmacokinetics of CDZ173 in patients with APDS/PASLI

  2. Part I & II: Cmax [ Time Frame: 12 weeks ]
    Part I & II: To assess the pharmacokinetics of CDZ173 in patients with APDS/PASLI

  3. Part I & II: To assess the efficacy of CDZ173 to modify health-related quality of life in patients with APDS/PASLI [ Time Frame: 12 weeks ]
    Part I & II: SF-36 (Short Form 36) Survey and WPAI-CIQ (Work Productivity Activity Impairment plus Classroom Impairment Questionnaire)

  4. Part I & II: SF-36 (Short Form 36) Survey [ Time Frame: 12 weeks ]
    Part I & II: To assess the efficacy of CDZ173 to modify health-related quality of life in patients with APDS/PASLI

  5. Part I & II: Work Productivity Activity Impairment and Classroom Impairment Questionnaire (WPAI-CQ) [ Time Frame: 12 weeks ]
    Part I & II: To assess the efficacy of CDZ173 to modify health-related quality of life in patients with APDS/PASLI

  6. Part I & II: Visual analogue scales for Physician's Global Assessment (PGA) [ Time Frame: 12 weeks ]
    Part I & II: To assess the efficacy of CDZ173 by the Physician's Global Assessment (PGA)

  7. Part I & II: Visual analogue scales for Patient's Global Assessment (PtGA) [ Time Frame: 12 weeks ]
    Part I & II: To assess the efficacy of CDZ173 by the Patient's Global Assessment (PtGA)

  8. Part I & II: C reactive protein (CRP) [ Time Frame: 12 weeks ]
    Part I & II: To assess biomarkers reflecting the efficacy of CDZ173 to reduce systemic inflammatory components of the disease

  9. Part I & II: Lactate dehydrogenase (LDH) [ Time Frame: 12 weeks ]
    Part I & II: To assess biomarkers reflecting the efficacy of CDZ173 to reduce systemic inflammatory components of the disease

  10. Part II: beta2 microglobulin [ Time Frame: 12 weeks ]
    Part II: To assess biomarkers reflecting the efficacy of CDZ173 to reduce systemic inflammatory components of the disease

  11. Part II: ferritin [ Time Frame: 12 weeks ]
    Part II: To assess biomarkers reflecting the efficacy of CDZ173 to reduce systemic inflammatory components of the disease

  12. Part II: fibrinogen [ Time Frame: 12 weeks ]
    Part II: To assess biomarkers reflecting the efficacy of CDZ173 to reduce systemic inflammatory components of the disease

  13. Part II: Erythrocyte sedimentation rate (ESR) [ Time Frame: 12 weeks ]
    Part II: To assess biomarkers reflecting the efficacy of CDZ173 to reduce systemic inflammatory components of the disease

  14. Part II: To assess the effect of CDZ173 on lymphadenopathy(non-index lesions and spleen) [ Time Frame: 12 weeks ]
    MRI/CT imaging - e.g. 3D volume of index and measurable non-index lesions selected as per the Cheson methodology, and 3D volume and bi-dimensional size of the spleen



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   12 Years to 75 Years   (Child, Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Key Inclusion Criteria:

  • Patients who have a documented APDS/PASLI-associated genetic PI3K delta mutation
  • In Part I and Part II, patients must have 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 have at least one measurable nodal lesion on a CT or MRI scan.

Key Exclusion Criteria:

  • Any medically significant disease or condition that is unrelated to APDS/PASLI

Other protocol-defined inclusion/exclusion criteria may apply.


Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02435173


Locations
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United States, Maryland
National Institute of Health NIH
Bethesda, Maryland, United States, 20814
Belarus
Novartis Investigative Site
Minsk, Belarus, 223053
Czechia
Novartis Investigative Site
Prague 5, Czechia, 150 00
Germany
Novartis Investigative Site
Dresden, Germany, 01307
Ireland
Novartis Investigative Site
Dublin, Ireland
Italy
Novartis Investigative Site
Palermo, PA, Italy, 90127
Novartis Investigative Site
Brescia, Italy, 25123
Netherlands
Novartis Investigative Site
Rotterdam, Netherlands, 3000 CA
Russian Federation
Novartis Investigative Site
Moscow, Russian Federation, 117198
United Kingdom
Novartis Investigative Site
Belfast, United Kingdom, BT9 7AB
Novartis Investigative Site
London, United Kingdom, NW3 2PF
Sponsors and Collaborators
Novartis Pharmaceuticals
Investigators
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Principal Investigator: Koneti V Rao, MD National Institutes of Health (NIH)
Principal Investigator: Virgil Dalm, MD Erasmus Medical Center
Principal Investigator: Anna Šedivá, MD Motol University
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
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Responsible Party: Novartis Pharmaceuticals
ClinicalTrials.gov Identifier: NCT02435173    
Other Study ID Numbers: CCDZ173X2201
2014-003876-22 ( EudraCT Number )
First Posted: May 6, 2015    Key Record Dates
Last Update Posted: September 20, 2021
Last Verified: September 2021
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description:

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 a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Novartis ( Novartis Pharmaceuticals ):
APDS
PASLI
PI3Kdelta
Additional relevant MeSH terms:
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Common Variable Immunodeficiency
Immunologic Deficiency Syndromes
Immune System Diseases