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    Summary
    EudraCT Number:2017-004564-35
    Sponsor's Protocol Code Number:205739
    National Competent Authority:Sweden - MPA
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2018-05-09
    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 ConcernedSweden - MPA
    A.2EudraCT number2017-004564-35
    A.3Full title of the trial
    A Phase IIa Randomized, Placebo-Controlled, Double-Blind (Sponsor Open) Study to Investigate the Clinical Efficacy, Safety, and Tolerability of Nemiralisib (GSK2269557) in Symptomatic COPD Participants with a History of Exacerbations
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A 12 Month Proof of Concept Phase IIa Study of Nemiralisib
    (GSK2269557) in Symptomatic COPD Participants with a History of Exacerbations
    A.3.2Name or abbreviated title of the trial where available
    PH2a, efficacy and safety study of GSK2269557 Vs PBO in pts with COPD having history of exacerbation
    A.4.1Sponsor's protocol code number205739
    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 and 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 pointClinical Trials Helpdesk
    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 0208 990 44 66
    B.5.5Fax numberNot Applicable
    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 succinate
    D.3.9.1CAS number 1364799-98-3
    D.3.9.3Other descriptive nameGSK2269557
    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
    D.8 Placebo: 1
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboInhalation powder
    D.8.4Route of administration of the placeboInhalation use
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Chronic Obstructive Pulmonary Disease (COPD)/chronic bronchitis and emphysema
    E.1.1.1Medical condition in easily understood language
    Chronic Obstructive Pulmonary Disease (COPD)/chronic bronchitis and emphysema
    E.1.1.2Therapeutic area Diseases [C] - Respiratory Tract Diseases [C08]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level LLT
    E.1.2Classification code 10010953
    E.1.2Term COPD exacerbation
    E.1.2System Organ Class 100000004855
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    To evaluate the clinical efficacy of nemiralisib compared with placebo to reduce the annual rate of moderate and
    severe exacerbations in participants with COPD.
    E.2.2Secondary objectives of the trial
    -To evaluate the effect of nemiralisib compared to placebo on further efficacy parameters pertaining to exacerbations
    and aligned with the primary objective
    -To evaluate the effect of nemiralisib
    compared with placebo on respiratory symptoms and Health related quality of life (HRQoL) using Patient Reported Outcomes (PROs)
    -To evaluate the effect of nemiralisib compared to placebo on lung function
    - To evaluate the effect of nemiralisib compared to placebo on rescue medication use
    -To evaluate the population pharmacokinetics of nemiralisib
    -To evaluate the safety and tolerability of nemiralisib compared with placebo
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    Participants are eligible to be included in the study only if all the following criteria apply:
    Age
    1. ≥40 and ≤ 80 years of age inclusive, at the time of signing the informed consent.
    Type of Participant and Disease Characteristics
    2. Diagnosis: An established clinical history of COPD in accordance with the definition
    by the American Thoracic Society/European Respiratory Society [GOLD, 2017] as follows:
    “Chronic obstructive pulmonary disease is common, preventable, and treatable disease that is characterized by persistent respiratory symptoms and airflowlimitation that is due to airway and/or alveolar abnormalities usually caused by significant exposure to noxious particles or gases.”
    3. Documented history of COPD exacerbation (s): ≥ 2 moderate exacerbations (prescription for antibiotics and/or oral corticosteroids) or ≥ 1 severe exacerbation
    (hospitalisation or visit to the emergency room) in the 12 months prior to study participation Screening (Visit 1)
    4. Smoking History: Current or former cigarette smoker with a history of cigarette smoking of ≥ 10 pack-years. Former smokers are defined as those who have stopped
    smoking for at least 6 months prior to Screening (Visit 1).
    Number of pack years = (number of cigarettes per day/20) x number of years smoked) (e.g. 20 cigarettes per day for 10 years, or 10 cigarettes per day for 20 years
    both equal 10 pack-years
    5. Symptomatic COPD: A score of ≥ 10 on the COPD Assessment Test (CAT) at Screening (Visit 1).
    Existing prescribed inhaled COPD maintenance therapy: Must be receiving a stable daily inhaled COPD maintenance therapy for their COPD for at least 3 months prior to Screening (Visit 1). Participants may continue their prescribed inhaled maintenance COPD therapy throughout the study (Run-in and Treatment Periods).
    Note: Participants receiving only PRN COPD medications are not eligible.
    6. Must have a post-bronchodilator (albuterol/salbutamol) FEV1/ (forced vital capacity)
    (FVC) ratio ≤ 0.70 and post-bronchodilator FEV1 ≤ 80% of predicted [Quanjer, 2012] documented in the last 5 years.
    7. Must not be taking antibiotics and/or oral corticosteroids for a COPD exacerbation
    within 6 weeks prior to Screening (Visit 1).
    8. Able to perform lung function tests reliably.9. Must have the ability to use an electronic diary on a daily basis.
    Weight
    10. Body weight ≥ 45 kg and body mass index (BMI) within the range of 16-35 kg/m2 (inclusive).
    Sex
    11. Male and female participants are eligible to participate in the study:
    a. Female participants:
    A female participant is eligible to participate if she is not pregnant (see Appendix 5 of protocol), not breastfeeding, and at least one of the following conditions applies:
    (i) Not a woman of childbearing potential (WOCBP) as defined in Appendix 5 of protocol OR
    (ii) A WOCBP who agrees to follow the contraceptive guidance inAppendix 5 of protocol during the 12-Month Double-Blind Treatment Period and for at least 5 half- lives (10 days) after the last dose of double-blind study
    treatment. Contraceptive use by men or women should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies.
    Informed Consent
    12. Capable of giving signed informed consent as described in Appendix 3 of protocol, which
    includes compliance with the requirements and restrictions listed in the informed
    consent form (ICF) and in this protocol
    E.4Principal exclusion criteria
    Participants are excluded from the study if any of the following criteria apply:
    Medical Conditions
    1. Current diagnosis of asthma, according to the Global Initiative for Asthma [GINA, 2017].
    2. Less than 6 weeks elapsed from completion of a course of antibiotics or oral corticosteroids for a recent COPD exacerbation.
    3. Chest X-ray (or CT scan) that reveals evidence of clinically significant abnormalities not believed to be due to the presence of COPD. A chest X-ray (or CT scan) must be taken at Screening (Visit 1) (or historic radiograph or CT scan obtained within 3 months prior to screening). For sites in Germany: if a chest X-ray (or CT scan)
    within 1 year of Screening (Visit 1) is not available, approval to conduct a diagnostic chest X-ray (CT scan) will need to be obtained from the Federal Office for Radiation
    Protection (BfS).
    4. Diagnosis of Pneumonia (chest X-ray or CT confirmed) within the last 3 months prior to Screening (Visit 1).
    5. Other respiratory disorders: A diagnosis of α1-antitrypsin deficiency as the underlying cause of COPD, active tuberculosis, lung cancer, bronchiectasis (Note:
    focal bronchiectasis is not exclusionary), sarcoidosis, active tuberculosis, lung cancer, clinically overt bronchiectasis (Note: focal bronchiectasis is not
    exclusionary), pulmonary fibrosis (Note: focal fibrotic pulmonary lesions are not exclusionary), primary pulmonary hypertension, interstitial lung diseases, or any
    other respiratory condition that might, in the opinion of the investigator, compromise the safety of the subject or affect the interpretation of the results.
    6. Other diseases/abnormalities: A history or current evidence of clinically significant and unstabledisease such as cardiovascular (e.g., patients requiring implanted
    cardioverter defibrillator [ICD], pacemaker requiring a rate set>60bpm, uncontrolled hypertension, New Your Heart Association Class IV [NYHA, 1994], known left
    ventricular ejection fraction <30%) neurological, psychiatric, renal, hepatic, immunological, endocrine (including uncontrolled diabetes or thyroid disease),
    peptic ulcer disease, or hematological abnormalities. Significant is defined as anydisease that, in the opinion of the investigator, would put the safety of the subject at
    risk through participation, or which would affect the efficacy or safety analysis if the disease/condition exacerbated during the study. (Note: Participants with adequately treated and well controlled concurrent medical conditions (e.g. hypertension or
    noninsulin-dependent diabetes mellitus[NIDDM]) are permitted to be entered into the study).
    7. Lung resection: Having undergone lung volume reduction surgery or lung resection for any other reason (e.g. lung carcinoma)
    8. Liver disease
    a. ALT > 2xULN
    b. Total Bilirubin > 1.5xULN
    i. Isolated bilirubin >1.5xULN is acceptable if bilirubin is
    fractionated and direct bilirubin <35%
    c. Current or chronic history of liver disease or known hepatic or biliary abnormalities (with the exception of Gilbert’s syndrome or asymptomatic gallstones
    d. Presence of hepatitis B surface antigen (HBsAg) at Screening or within 3 months prior to first dose of study treatment
    e. Positive hepatitis C antibody test result at Screening orwithin 3 months prior to first dose of study treatment
    f. Participants with positive Hepatitis C antibody due to prior resolved disease can be enrolled, only if a confirmatory negative Hepatitis C RNA test is obtained.
    9. Positive hepatitis C RNA test result at Screening or within 3 months prior to first dose of study treatment. NOTE: Test is optional and participants with negative
    Hepatitis C antibody test are not required to also undergo Hepatitis C RNA testing
    10. Cancer: Carcinoma that has not been in complete remission for at least 5 years.
    Carcinoma in situ of the cervix, squamous cell carcinoma and basal cell carcinoma of the skin are not excluded if the participant has been considered cured within 5 years since diagnosis.
    11. Contraindications: History of allergy or hypersensitivity to any of the studymedications (e.g. beta-agonists, PI3Kd inhibitors). In addition, participants with a
    history of severe milk protein allergy (e.g lactose) that, in the opinion of the investigator, contraindicates the participant’s participation are excluded.Prior/Concomitant Therapy
    12. Use of the following medications:
    - Strong inhibitors of cytochrome P450 3A4: Currently, only 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 metabolized by CYP3A4 enzymes with minor contributions from CYP1A1,CYP1A2, CYP2C8, CYP2C9, CYP2C19, CYP2D6 and CYP2J2.
    Refer Protocol for other exclusions points
    E.5 End points
    E.5.1Primary end point(s)
    Annualised rate of on-treatment moderate and severe exacerbations as defined by Health Care Resources Utilization (HCRU)
    E.5.1.1Timepoint(s) of evaluation of this end point
    Evaluated at 8 clinic visits over a 52-week treatment period
    E.5.2Secondary end point(s)
    Annualised rate of on-treatment HCRU/EXACT defined mile, moderate, and severe exacerbations
    Time to first on treatment HCRU/EXACT defined moderate/severe exacerbation
    Time to first on treatment HCRU/EXACT defined mild/moderate/severe exacerbation
    Evaluating Respiratory Symptoms (E-RS) in COPD (E-RS: COPD)
    Change from baseline in monthly weighted mean of E-RS: COPD (Total score and sub domains)
    - Proportion of responders according to ERS:
    COPD (Total score and sub domains)
    COPD Assessment Test (CAT)
    - Proportion of responders according to CAT
    at Weeks 4, 12, 28, 52
    - Change from baseline in CAT total score at
    Weeks 4, 12, 28, 52
    St. George’s Respiratory Questionnaire total score (measuring using SGRQ for COPD Patients (SGRQ-C))
    - Proportion of responders SGRQ-C total score at Weeks 4, 12, 28, 52
    - Change from baseline SGRQ-C total score at Weeks 4, 12, 28, 52
    Exacerbations of Chronic Pulmonary Disease Tool (EXACT)
    - Annualised rate of HCRU/EXACT events
    - Time to first HCRU/EXACT event
    - Severity and duration of each
    HCRU/EXACT event
    - Change from baseline in clinic visit trough pre-and post-bronchodilator Inspiratory
    Capacity (IC), FEV1, and FVC, at Weeks, 4, 12, 28, 52
    Rescue Medication Use (occasions/day)
    - The percentage of rescue-free days (24- hour periods) during each month of treatment and over the 12 Month Treatment Period
    PK concentrations and parameters
    - Incidence of Adverse Events (AEs; including serious AEs and AE of Special Interest (AESI))
    - Vital Signs (pulse rate, systolic and diastolic blood pressure) measured at each clinic visit up through Week 52 or Early Withdrawal Visit
    - 12-Lead ECG performed at Screening, Weeks 4, 12, 28, 52 or Early Withdrawal Visit
    - Clinical laboratory evaluations
    (haematology, clinical chemistry, urinalysis) performed at each clinic visit up through
    Week 52 or Early Withdrawal
    - Incidence of COPD exacerbations
    E.5.2.1Timepoint(s) of evaluation of this end point
    Evaluated at 8 clinic visits over a 52-week treatment period
    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 No
    E.6.7Pharmacodynamic No
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others Yes
    E.6.13.1Other scope of the trial description
    Tolerability
    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 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 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 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 No
    E.8.4 The trial involves multiple sites in the Member State concerned Yes
    E.8.4.1Number of sites anticipated in Member State concerned8
    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 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
    Argentina
    Germany
    Mexico
    Poland
    Spain
    Sweden
    United States
    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
    LVLS
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years1
    E.8.9.1In the Member State concerned months9
    E.8.9.1In the Member State concerned days24
    E.8.9.2In all countries concerned by the trial years1
    E.8.9.2In all countries concerned by the trial months9
    E.8.9.2In all countries concerned by the trial days24
    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: 300
    F.1.3Elderly (>=65 years) No
    F.1.3.1Number of subjects for this age range: 100
    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 Yes
    F.3.3.2Women of child-bearing potential using contraception No
    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 state35
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 200
    F.4.2.2In the whole clinical trial 400
    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)
    Participants will not receive any additional treatment from GSK after completion of the
    study as other treatment options are available.
    The investigator is responsible for ensuring that consideration has been given to the poststudy
    care of the participant’s medical condition. At the end of the treatment period
    (Visit 9 or Early Withdrawal), participants should continue their COPD therapy as
    prescribed by their health care provider.
    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 Decision2018-06-19
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2018-08-14
    P. End of Trial
    P.End of Trial StatusCompleted
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