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    EudraCT Number:2014-003876-22
    Sponsor's Protocol Code Number:CCDZ173X2201
    National Competent Authority:Ireland - HPRA
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2017-11-29
    Trial results View results
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    A. Protocol Information
    A.1Member State ConcernedIreland - HPRA
    A.2EudraCT number2014-003876-22
    A.3Full title of the trial
    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)
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Study to assess the safety and efficacy of CDZ173 in patients with APDS/PASLI
    A.3.2Name or abbreviated title of the trial where available
    Study of efficacy of CDZ173 in patients with APDS/PASLI
    A.4.1Sponsor's protocol code numberCCDZ173X2201
    A.7Trial is part of a Paediatric Investigation Plan No
    A.8EMA Decision number of Paediatric Investigation Plan
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorNovartis Pharma Services AG
    B.3.1 and B.3.2Status of the sponsorCommercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportNovartis Pharma Services AG
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationNovartis Ireland Limited
    B.5.2Functional name of contact pointMedical Information Department
    B.5.3 Address:
    B.5.3.1Street AddressBeech House Beech Hill Office Campus
    B.5.3.2Town/ cityClonskeagh, Dublin
    B.5.3.3Post code4
    B.5.4Telephone number +353 1 2601255
    B.5.5Fax number +353 1 2601263
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation No
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.2Product code CDZ173
    D.3.4Pharmaceutical form Capsule, hard
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNleniolisib
    D.3.9.2Current sponsor codeCDZ173
    D.3.9.4EV Substance CodeSUB168935
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number70
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D. cell therapy medicinal product No
    D. therapy medical product No
    D. Engineered Product No
    D. ATIMP (i.e. one involving a medical device) No
    D. on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.8 Information on Placebo
    D.8 Placebo: 1
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboCapsule, hard
    D.8.4Route of administration of the placeboOral use
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    APDS/PASLI (Activated phosphoinositide 3-kinase delta syndrome/ p110δ-activating mutation causing senescent T cells, lymphadenopathy and immunodeficiency)
    E.1.1.1Medical condition in easily understood language
    Gain of function genetic mutation in the PI3Kdelta gene causing immunodeficiency
    E.1.1.2Therapeutic area Diseases [C] - Immune System Diseases [C20]
    MedDRA Classification
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    • Part I: To assess the safety and tolerability as well as the dose-PD and PK/PD relationship of CDZ173 in patients with APDS/PASLI enabling dose selection for Part II
    • Part II: To assess the clinical efficacy of CDZ173 in patients with APDS/PASLI
    E.2.2Secondary objectives of the trial
    • Part II: To assess the effect of CDZ173 on lymphadenopathy (non-index lesions and spleen).
    • Part I and II: To assess the pharmacokinetics of CDZ173 in patients with APDS/PASLI
    • Part I and II: To assess the efficacy of CDZ173 to modify health-related quality of life in patients with APDS/PASLI
    • Part I and II: To assess the efficacy of CDZ173 by the Physician’s Global Assessment and the Patient’s Global Assessment
    • Part I and II: To assess biomarkers reflecting the efficacy of CDZ173 to reduce systemic inflammatory components of the disease
    • Part I and II: To assess the treatment benefit to individual patients
    • Part II: To assess the safety and tolerability of CDZ173 in patients with APDS/PASLI
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    • Male and female patients 12 to 75 years of age (inclusive), who have a documented APDS/PASLI-associated genetic PI3K delta mutation
    Patients with mutations in either PIK3CD or PIK3R1 can be included.
    • 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.
    • At screening, vital signs (systolic and diastolic blood pressure and pulse rate) will be assessed in the sitting position after the patient has rested for at least three minutes. Sitting vital signs should be within the following ranges:
    • Systolic blood pressure, 90-139 mm Hg
    • Diastolic blood pressure, 50-89 mm Hg
    • Pulse rate, 50 - 100 bpm; up to 110 bpm in adolescents
    E.4Principal exclusion criteria
    • Use of unstable i.v. Ig / s.c. Ig in the last 6 months before screening. Stable maintenance immunoglobulin regimen, as per local practice, such as regular injections with a consistent dosing interval (e.g., monthly) injections is acceptable
    • Previous or concurrent use of immunosuppressive medication such as:
    • use of an mTOR inhibitor (e.g., sirolimus, rapamycin, everolimus) or a PI3Kδ inhibitor (selective or non-selective PI3K inhibitors) within 6 weeks prior to first dosing, however short-term use for up to a total of 5 days is allowed but only up to 1 month prior to enrollment in the study.
    • B cell depleters (e.g., rituximab) within 6 months prior to first dosing of study medication; if patients have received prior treatment with a B cell depleter, absolute B lymphocyte counts in the blood must have regained normal values.
    • Belimumab or cyclophosphamide within 6 months prior to first dosing of study medication.
     Cyclosporine A, mycophenolate, 6-mercaptopurine, azathioprine or methotrexate within 3 months prior to first dosing of study medication.
    • Glucocorticoids above 25 mg prednisone or equivalent per day within 2 weeks prior to first dosing of study medication.
    • Other immunosuppressive medication where effects are expected to persist at start of dosing of study 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 exposure-response 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.
    E.5 End points
    E.5.1Primary end point(s)
    • Part I: All safety parameters (including AEs, physical exam, vital signs, ECG, safety laboratory (hematology, blood chemistry, urinalysis))
    • Part I: Single and multiple dose concentrations of CDZ173 and pAkt inhibition in unstimulated and stimulated whole blood
    • Part II: Co-primary endpoint;
    o 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.
    o Change from baseline in percentage of naïve B cells out of total B cells
    E.5.1.1Timepoint(s) of evaluation of this end point
    From beginning to end of study
    E.5.2Secondary end point(s)
    • Part II: 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
    • Part I and II: Single dose CDZ173 PK parameters (including but not limited to Cmax and AUC) and trough evaluations after multiple dose
    • Part I and II: SF-36 (Short Form 36) Survey and WPAI-CIQ (Work Productivity Activity Impairment plus Classroom Impairment Questionnaire)
    • Part I and II: Visual analogue scales for PGA and PtGA (for Part II the PGA is a key secondary endpoint)
    • Part I and II:
    o C reactive protein (CRP), Lactate dehydrogenase (LDH)
    o For Part II additional: beta2 microglobulin, ferritin, fibrinogen and erythrocyte sedimentation rate (ESR)
    • Part I and II: Narratives
    • Part II: All safety parameters, including AEs, physical exam, vital signs, ECG, safety laboratory (hematology, blood chemistry, urinalysis)
    E.5.2.1Timepoint(s) of evaluation of this end point
    From beginning to end of study
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy Yes
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic Yes
    E.6.7Pharmacodynamic Yes
    E.6.8Bioequivalence No
    E.6.9Dose response Yes
    E.6.10Pharmacogenetic Yes
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others No
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E. trial type description
    E.7.2Therapeutic exploratory (Phase II) Yes
    E.7.3Therapeutic confirmatory (Phase III) Yes
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled Yes
    E.8.1.1Randomised Yes
    E.8.1.2Open No
    E.8.1.3Single blind No
    E.8.1.4Double blind Yes
    E.8.1.5Parallel group Yes
    E.8.1.6Cross over No
    E.8.1.7Other Yes
    E. trial design description
    Part I : Open label, non-randomized; Part-II : subject, investigator and sponsor-blinded, Randomized
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo Yes
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial2
    E.8.3 The trial involves single site in the Member State concerned Yes
    E.8.4 The trial involves multiple sites in the Member State concerned No
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA10
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA Yes
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.6.3If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
    Russian Federation
    United States
    United Kingdom
    E.8.7Trial has a data monitoring committee Yes
    E.8.8 Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years3
    E.8.9.1In the Member State concerned months5
    E.8.9.1In the Member State concerned days7
    E.8.9.2In all countries concerned by the trial years6
    E.8.9.2In all countries concerned by the trial days7
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 Yes
    F.1.1Number of subjects for this age range: 11
    F.1.1.1In Utero No
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.3Newborns (0-27 days) No
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.5Children (2-11years) No
    F.1.1.6Adolescents (12-17 years) Yes
    F. of subjects for this age range: 11
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 24
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 1
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male Yes
    F.3 Group of trial subjects
    F.3.1Healthy volunteers No
    F.3.2Patients Yes
    F.3.3Specific vulnerable populations Yes
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception Yes
    F.3.3.3Pregnant women No
    F.3.3.4Nursing women No
    F.3.3.5Emergency situation No
    F.3.3.6Subjects incapable of giving consent personally Yes
    F. of subjects incapable of giving consent
    adolescents in presence of a guardian/parent
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state1
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 30
    F.4.2.2In the whole clinical trial 36
    F.5 Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)
    All patients completing the study will be offered continuous treatment in the extension study CCDZ173X2201E1. At a minimum, patients will be contacted for safety evaluations during the 30 days following the Study Completion visit, including a final post-study safety contact at the 30-day point. If the patients directly continue treatment in the extension study (CDZ173X2201E1), the safety follow up is not needed as they will be followed up during the Visit s in the extension study.
    G. Investigator Networks to be involved in the Trial
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2018-01-26
    N.Ethics Committee Opinion of the trial application
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2021-08-16
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