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    Summary
    EudraCT Number:2015-004876-31
    Sponsor's Protocol Code Number:204745
    National Competent Authority:UK - MHRA
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2015-11-30
    Trial results View results
    Index
    A. PROTOCOL INFORMATION
    B. SPONSOR INFORMATION
    C. APPLICANT IDENTIFICATION
    D. IMP IDENTIFICATION
    D.8 INFORMATION ON PLACEBO
    E. GENERAL INFORMATION ON THE TRIAL
    F. POPULATION OF TRIAL SUBJECTS
    G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
    N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
    P. END OF TRIAL
    Expand All   Collapse All
    A. Protocol Information
    A.1Member State ConcernedUK - MHRA
    A.2EudraCT number2015-004876-31
    A.3Full title of the trial
    An open-label, single arm study to investigate the safety, pharmacokinetics and pharmacodynamics of repeat doses of inhaled nemiralisib in patients with APDS/PASLI
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A study to understand disease biology and to test the effect and safety of inhaled nemiralisib in adult patients with APDS
    A.4.1Sponsor's protocol code number204745
    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 SponsorGlaxoSmithKline Research & Development Ltd
    B.1.3.4CountryUnited Kingdom
    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 supportGlaxoSmithKline Research & Development Ltd
    B.4.2CountryUnited Kingdom
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationGlaxoSmithKline Research & Development Ltd
    B.5.2Functional name of contact pointGSK Clinical Support Help Desk
    B.5.3 Address:
    B.5.3.1Street AddressIron Bridge Road, Stockley Park West
    B.5.3.2Town/ cityUxbridge, Middlesex
    B.5.3.3Post codeUB11 1BT
    B.5.3.4CountryUnited Kingdom
    B.5.4Telephone number+44 0800 783 9733
    B.5.6E-mailGSKClinicalSupportHD@gsk.com
    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.3.1Product nameNemiralisib
    D.3.2Product code GSK2269557
    D.3.4Pharmaceutical form Inhalation powder
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPInhalation use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNNemiralisib
    D.3.9.1CAS number 1364799-98-3
    D.3.9.2Current sponsor codeGSK2269557
    D.3.9.4EV Substance CodeSUB73036
    D.3.10 Strength
    D.3.10.1Concentration unit µg microgram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number500
    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.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee 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
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    patients with APDS/PASLI
    E.1.1.1Medical condition in easily understood language
    Activated PI3K Delta Syndrome, a disease which predisposes affected patients to an increased frequency of infections especially of the lungs and ears
    E.1.1.2Therapeutic area Diseases [C] - Immune System Diseases [C20]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level HLGT
    E.1.2Classification code 10024970
    E.1.2Term Respiratory tract infections
    E.1.2System Organ Class 10038738 - Respiratory, thoracic and mediastinal disorders
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    Safety
    To assess the safety and tolerability of 84 days repeat dosing of inhaled nemiralisib in patients with APDS
    E.2.2Secondary objectives of the trial
    Pharmacokinetics
    To define the plasma pharmacokinetics (PK) of inhaled nemiralisib following repeat dosing in patients with APDS.
    E.2.3Trial contains a sub-study Yes
    E.2.3.1Full title, date and version of each sub-study and their related objectives
    Title: Bronchoalveolar lavage (BAL) Sub-Study

    Objectives: Pharmacokinetics: To define the lung trough concentration of nemiralisib after repeat dosing
    •Trough nemiralisib concentration in lung epithelial lining fluid (ELF) and Bronchoalveolar lavage (BAL) cell pellet at Day 84 visit.

    Pharmacodynamics: To understand lung disease biology in patients with APDS and to explore the pharmacodynamic effects of inhaled nemiralisib.
    •In BAL cell pellet/ELF when available analysis of:
    o Lymphocyte cell subsets
    o Exploratory phospho-protein biomarkers (e.g. pAKT)
    o Soluble proinflammatory mediators (including IL-8, IL-6, TNFα & MMP9)
    o Exploratory mRNA biomarkers
    o Proteomic markers
    o Antibody levels
    E.3Principal inclusion criteria
    A subject will be eligible for inclusion in this study only if all of the following criteria apply:
    AGE
    1. Male and female subjects aged 18 or older at the time of signing the informed consent.

    TYPE OF SUBJECT AND DIAGNOSIS INCLUDING DISEASE SEVERITY
    2. Patients with a clinical phenotype consistent with APDS, including a history of recurrent (frequency greater than would be expected in an immunocompetent individual) ear, sinus or pulmonary infections, and who have a known type 1 APDS associated genetic PI3Kdelta mutation (e.g. E1021K, N334K, E525K and C416R) or type 2 APDS-associated mutation

    WEIGHT
    3. Body weight ≥40 kg and body mass index (BMI) ≥17kg/m2 (inclusive)

    SEX
    4. Female subject. A female subject is eligible to participate if she is not pregnant (as confirmed by a negative urine human chorionic gonadotrophin (hCG) test), not lactating, and at least one of the following conditions applies:
    - Non-reproductive potential defined as:
    o Pre-menopausal females with one of the following:
    – Documented tubal ligation
    – Documented hysteroscopic tubal occlusion procedure with followup confirmation of bilateral tubal occlusion
    – Hysterectomy
    – Documented Bilateral Oophorectomy
    o Postmenopausal defined as 12 months of spontaneous amenorrhea [in questionable cases a blood sample with simultaneous follicle stimulating hormone (FSH) and estradiol levels consistent with menopause (refer to laboratory reference ranges for confirmatory levels)]. Females on hormone replacement therapy (HRT) and whose menopausal status is in doubt will be required to use one of the highly effective contraception methods if they wish to continue their HRT during the study. Otherwise, they must discontinue HRT to allow confirmation of post-menopausal status prior to study enrolment.
    - Reproductive potential and agrees to follow one of the options listed in the Modified List of Highly Effective Methods for Avoiding Pregnancy in Females of Reproductive Potential (FRP) (see Appendix 5 of the study protocol) from 30 days prior to the first dose of study medication and until completion of the follow-up telephone call at 1-2 weeks from last dose.
    The investigator is responsible for ensuring that subjects understand how to properly use these methods of contraception.

    INFORMED CONSENT
    5. Capable of giving signed informed consent as described in Section 10.2 of the study protocol which includes compliance with the requirements and restrictions listed in the consent form and in this protocol’.
    E.4Principal exclusion criteria
    A subject will not be eligible for inclusion in this study if any of the following criteria apply:
    CONCURRENT CONDITIONS/MEDICAL HISTORY (INCLUDES LIVER
    FUNCTION AND QTc INTERVAL)
    1. Alanine aminotransferase (ALT) >2xULN and bilirubin >1.5xULN (isolated bilirubin >1.5xULN is acceptable if bilirubin is fractionated and direct bilirubin <35%).
    2. Current or chronic history of liver disease except where hepatomegaly is identified by their clinician to be secondary to APDS, or known hepatic or biliary abnormalities (with the exception of Gilbert's syndrome or asymptomatic gallstones).
    3. QTc > 450 millisecond (msec) or QTc > 480 msec in subjects with Bundle Branch Block
    NOTES: The QTc is the QT interval corrected for heart rate (HR) according to Bazett’s formula (QTcB), Fridericia’s formula (QTcF), and/or another method, machineread or manually over-read.

    The specific formula that will be used to determine eligibility and discontinuation for an individual subject should be determined prior to initiation of the study. In other words, several different formulae cannot be used to calculate the QTc for an individual subject and then the lowest QTc value used to include or discontinue the subject from the trial.
    For purposes of data analysis, QTcB, QTcF, another QT correction formula, or a composite of available values of QTc will be used as specified in the Reporting and Analysis Plan (RAP).
    4. A subject with a clinical abnormality or laboratory parameter(s) which is/are not specifically listed in the inclusion or exclusion criteria, outside the reference range for the population being studied may be included only if the investigator, in consultation with the Medical Monitor if required, agree and document that the finding is unlikely to introduce additional risk factors and will not interfere with the study procedures.

    CONCOMITANT MEDICATIONS
    5. CYTOCHROME P450 3A4:
    Strong CYP3A4 substrates:
    Strong inhibitors of cytochrome P450 3A4: Currently, only limited in vivo information is available on the in vivo metabolism of nemiralisib; and, the role of
    cytochrome P450s (CYPs) in the elimination of nemiralisib is based upon in vitro data. In vitro studies indicate that nemiralisib is predominantly metabolised by CYP3A4 enzymes with minor contributions from CYP1A1, CYP1A2, CYP2C8, CYP2C9, CYP2C19, CYP2D6 and CYP2J2. Co-administration of nemiralisib with
    CYP3A4 inhibitors may result in increased systemic exposure to nemiralisib.
    Regular or chronic treatment with medications that are considered strong inhibitors
    of CYP3A4 are not permitted:
    • Antiretrovirals including protease inhibitors (e.g., indinavir, nelfinavir,ritonavir, saquinavir, atazanavir)
    • Oral antifungal treatments such as ketoconazole and itraconazole. Short courses of up to 14 days are allowed for fluconazole and voriconazole,but chronic
    administrations are not permitted. It is recommended that amphotericin or posaconazole are used as oral antifungal treatment of choice.
    • Antibiotics such as telithromycin and troleandomycin (macrolide). Short courses up to 14 days are allowed for mibefradil (calcium channel blocker), erythromycin
    and clarithromycin (including intravenous clarithromycin) but chronic administrations are not permitted. Azithromycin may be used chronically and is
    recommended as the macrolide antibiotic of choice.
    • Anti-epileptic treatments; and anti-tuberculous therapy.
    These medications must all have been stopped at least 14 days prior to first dose of study treatment.
    Sensitive narrow therapeutic index CYP3A4 substrates:
    Nemiralisib is a time-dependent inhibitor of CYP3A4 and co-administration of CYP3A4 substrates with nemiralisib may result in increased systemic exposure to the CYP3A4 substrate. Regular or chronic treatment with medications that are considered sensitive narrow therapeutic index substrates of CYP3A4 are, therefore,
    not permitted:
    • Alfentanil, cyclosporine, dihydroergotamine, ergotamine, fentanyl, pimozide, quinidine and tacrolimus.
    These medications must all have been stopped at least 14 days prior to first dose of study treatment.
    - Intravenous and oral theophylline will be allowed according to the approved label/Prescribing Information, since a specific mechanistic model constructed for nemiralisib co-administered with theophylline, suggests a negligible effect of
    nemiralisib on theophylline exposure. Monitoring of patients receiving IV theophylline will be required in line with normal practice.
    • Use of unstable dosing regimen with 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) is acceptable.
    • Previous use of an mTOR antagonist (e.g. rapamycin, everolimus) or PI3K delta inhibitor (selective or non-selective PI3K inhibitors) within 6 weeks prior to first dosing.
    Refer remaining Exclusion criteria from points 6 to 15 in the protocol.
    E.5 End points
    E.5.1Primary end point(s)
    –Adverse Events (AE)
    –Vital signs
    –12-lead electrocardiogram (ECG)
    –Clinical laboratory parameters (Haematology, clinical chemistry, urinalysis)
    –Spirometry (forced expiratory volume in 1 second (FEV1)1 hr post-dose)
    E.5.1.1Timepoint(s) of evaluation of this end point
    –Adverse events (AEs): From start of study treatment until 3 month follow-up visit
    –Hematology, clinical chemistry, urinalysis: Screening, clinic visit #1, Day -1, Day 14, Day 28, Day 56, Day 83, 3 month follow-up visit
    –Vital signs, 12-lead ECG: Screening, clinic visit #1, Day -1, Day 1, Day 14, Day 28, Day 56, Day 83, Day 84, 3 month follow-up visit
    –FEV1: Screening, clinic visit #1, Day 1, Day 2, Day 14.
    E.5.2Secondary end point(s)
    –nemiralisib trough plasma concentration following single and repeated treatment
    E.5.2.1Timepoint(s) of evaluation of this end point
    –Day 1: pre-dose then 5 min, 3 h and 24h post-dose
    –Trough concentration Day 2, Day 14, Day 83
    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 No
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic Yes
    E.6.7Pharmacodynamic Yes
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    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.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) Yes
    E.7.3Therapeutic confirmatory (Phase III) No
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled No
    E.8.1.1Randomised No
    E.8.1.2Open Yes
    E.8.1.3Single blind No
    E.8.1.4Double blind No
    E.8.1.5Parallel group No
    E.8.1.6Cross over No
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo No
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial1
    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.8.4.1Number of sites anticipated in Member State concerned1
    E.8.5The trial involves multiple Member States No
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA No
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.7Trial has a data monitoring committee No
    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
    LSLV
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years2
    E.8.9.1In the Member State concerned months0
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years2
    E.8.9.2In all countries concerned by the trial months0
    E.8.9.2In all countries concerned by the trial days0
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 No
    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) No
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 19
    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 No
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state20
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 20
    F.4.2.2In the whole clinical trial 20
    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)
    Subjects will not receive any additional treatment from GSK after completion of the study because the safety and efficacy of nemiralisib has not yet been defined in APDS patients. Treatment after the end of the study will continue as per the standard of care for APDS at the site.

    The investigator is responsible for ensuring that consideration has been given to the poststudy care of the patient’s medical condition, whether or not GSK is providing specific post-study treatment.
    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 Decision2016-01-22
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2016-03-28
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2020-06-04
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