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    Summary
    EudraCT Number:2010-020993-41
    Sponsor's Protocol Code Number:LPZ114458
    National Competent Authority:Italy - Italian Medicines Agency
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2012-03-20
    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 ConcernedItaly - Italian Medicines Agency
    A.2EudraCT number2010-020993-41
    A.3Full title of the trial
    A phase IIa study to evaluate the effect of rilapladib (SB-659032) on biomarkers related to the pathogenesis and progression of Alzheimer's disease.
    Studio di fase IIa per valutare l’effetto di rilapladib (SB-659032) sugli indicatori biologici correlati alla patogenesi e alla progressione della malattia di Alzheimer.
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A study to assess the effect of rilapladib (SB 659032) on Alzheimer’s disease
    Studio per valutare l'effetto di rilapladib(SB-659032)nella malattia di Alzheimer.
    A.4.1Sponsor's protocol code numberLPZ114458
    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 SponsorGLAXO SMITH KLINE 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 R&D
    B.4.2CountryUnited Kingdom
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationGLAXOSMITHKLINE R&D
    B.5.2Functional name of contact pointCLINICAL TRIALS HELPDESK di GSK R&D
    B.5.3 Address:
    B.5.3.1Street Address1-3 Iron Bridge Road
    B.5.3.2Town/ cityStockley Park, Uxbridge
    B.5.3.3Post codeUB11 1BU
    B.5.3.4CountryItaly
    B.5.4Telephone number800786766 o +44 20 8990 4466
    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 nameRilapladib
    D.3.2Product code SB-659032
    D.3.4Pharmaceutical form Tablet
    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.3.9.2Current sponsor codeSB-659032
    D.3.9.3Other descriptive nameRILAPLADIB
    D.3.9.4EV Substance CodeNA
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number250
    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 placeboTablet
    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
    Alzheimer's Disease
    Malattia di Alzheimer
    E.1.1.1Medical condition in easily understood language
    Alzheimer's Disease is a brain disease that causes problems with memory, thinking and behavior.
    La Malattia di Alzheimer è una malattia del cervello che causa problemi con la memoria, il pensiero e comportamento.
    E.1.1.2Therapeutic area Diseases [C] - Nervous System Diseases [C10]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 14.1
    E.1.2Level LLT
    E.1.2Classification code 10001896
    E.1.2Term Alzheimer's disease
    E.1.2System Organ Class 10029205 - Nervous system disorders
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    To examine in an exploratory manner whether rilapladib produces changes in CSF biomarkers that are consistent with effects on increased CNS Aβ clearance in AD patients and whether these findings are associated with changes in CSF neurodegenerative markers and selected cognitive endpoints
    Esaminare in modo esplorativo se rilapladib produce delle variazioni negli indicatori biologici del CSF che siano coerenti con gli effetti sull’aumento della clearance di Aβ nel CNS in pazienti con AD e se questi esiti sono associati a variazioni negli indicatori biologici neurodegenerativi del CSF e in endpoint cognitivi selezionati
    E.2.2Secondary objectives of the trial
    To examine the effects of rilapladib on BBB permeability (CSF albumin quotient), peripheral Aβ levels (Aβ42 and Aβ40) and plasma Lp-PLA2 activity. - To further evaluate the effects of rilapladib on cognition. - To assess the safety and tolerability of rilapladib over a 24 week treatment period.
    •Esaminare gli effetti di rilapladib sulla permeabilità della BBB (quoziente dell’albumina nel CSF), sui livelli periferici di Aβ (Aβ42 e Aβ40) e sull’attività plasmatica di Lp-PLA2. •Valutare ulteriormente gli effetti di rilapladib sulle capacità cognitive. •Valutare la sicurezza e la tollerabilità di rilapladib in un periodo di trattamento di 24 settimane.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1)diagnosi clinica di possibile malattia di Alzheimer secondo i criteri del National Institute of Neurological and Communicative Diseases e della Stroke/Alzheimer’s Disease and Related Disorders Association (NINCDS-ADRDA), con evidenza radiologica (risonanza magnetica nucleare - RMN, o tomografia computerizzata – TAC) di significativa CVD, valutata nei 12 mesi precedenti 2)soggetti di sesso maschile o femminile di età compresa tra i 50 e gli 80 anni, estremi inclusi, al momento della firma del consenso informato. 3)soggetti con anamnesi documentata di almeno 6 mesi di terapia in corso per la malattia di Alzheimer (AChEI  memantina) con dosaggio stabile almeno per i 2 mesi precedenti (e senza intenzione di variare il dosaggio per tutta la durata dello studio). 4)punteggio Mini-Mental Status Examination (MMSE) tra 20 e 26 allo screening. 5)punteggio Clinical Dementia Rating Scale (CDR) di 0.5 o 1.0 allo screening. 6)le donne possono partecipare allo studio se: a)non potenzialmente fertili, b)potenzialmente fertili che acconsentono ad utilizzare uno dei metodi contraccettivi elencati nella Sezione 8.1 del protocollo 7)soggetti che hanno fornito il proprio consenso informato scritto 8)soggetti che hanno una persona dedicata che li assiste (caregiver).
    1.A clinical diagnosis of possible Alzheimer’s disease in accordance with the National Institute of Neurological and Communicative Diseases and Stroke/Alzheimer’s Disease and Related Disorders Association (NINCDS-ADRDA) criteria, with radiological (Magnetic Resonance Imaging [MRI] or Computed Tomography [CT]) evidence of significant cerebrovascular disease (CVD), assessed within the last 12 months 2. Male or female between 50 and 80 years of age inclusive, at the time of signing the informed consent. 3. Subject has a documented history of at least 6 months of ongoing Alzheimer's disease therapy (AChEIs ± memantine) with stable dosing for at least the last 2 months (and with no intent to change for the duration of the study). 4. Mini-Mental Status Examination (MMSE) score between 20 and 26 at Screening. 5. Clinical Dementia Rating Scale (CDR) score of 0.5 or 1.0 at Screening. 6. A female subject is eligible to participate if she is of: a. Non-childbearing potential b. Child-bearing potential and agrees to use one of the contraception methods listed in the protocol for an appropriate period of time 7. Subject has provided full written informed consent prior to the performance of any protocol-specified procedure 8. The subject has a dedicated caregiver who is willing to supervise participation in the study (i.e. clinic visits, medication).
    E.4Principal exclusion criteria
    1) anamnesi e/o evidenza di qualsiasi altro disordine del CNS che potrebbe essere interpretato come causa di demenza 2) anamnesi di patologia psichiatrica significativa come la schizofrenia o il disturbo affettivo bipolare che, a giudizio dello sperimentatore, interferirebbe con la partecipazione allo studio; disturbo depressivo maggiore (secondo i criteri DSM-IV) nell’ultimo anno; depressione attiva in atto che richiede l’inizio di un trattamento (o che si ritiene giustifichi un grado sostanziale di deterioramento cognitivo). 3)presenza dei seguenti disordini: attuale carenza di vitamina B12, sierologia positiva per sifilide (a meno che non sia stata esclusa la neurosifilide) o disfunzione tiroidea attiva storia di abuso di alcol o di altre sostanze 4)anamnesi di emorragia intracerebrale. 5) evento cardiovascolare recente (cioe, entro 6 mesi dalla visita di screening) 6)ipertensione scarsamente controllata nonostante modifiche allo stile di vita e terapia farmacologica. 7) intervallo QTcB > 450 msec; oppure QTcB > 480 msec in soggetto con blocco di branca sulla base della valutazione dell’ECG alla visita di screening. 8)HbA1c > 12.0 allo screening, oppure diabete non controllato a giudizio dello sperimentatore. 9)anamnesi di glaucoma o qualsiasi altro esito dell’esame oculare basale che, a giudizio dello sperimentatore, possa escludere il soggetto dalla partecipazione allo studio. 10)anamnesi di asma da adulto (o patologia reattiva delle vie aeree), manifestata con broncospasmo nei 6 mesi precedenti, o trattamento corrente con farmaci anti-asma su base regolare. 11) precedente storia di anafilassi, reazione allergica severa o storia di ipersensibilità a qualsiasi componente della formulazione. 12)anomalie significative nella chimica clinica, nell’ematologia o nell’analisi delle urine allo screening, inclusa anemia clinicamente significativa. 13) anamnesi di epatite virale cronica (inclusa la presenza di antigene B di superficie o di anticorpo dell’epatite C) o altri disordini epatici cronici. 14) esami del sangue anormali allo screening 15) altre anomalie clinicamente significative all’esame fisico 16)uso di steroidi sistemici o altri agenti immunosoppressivi nei 30 giorni precedenti lo screening. 17) trattamento corrente con barbiturici, inibitori delle MAO, butirrofenoni, fenotiazina e altri antipsicotici “convenzionali” nei 30 giorni o 5 emivite precedenti lo screnning, a seconda di quale dei due periodi sia il più lungo. 18) trattamento con antidepressivi, (diversi dagli inibitori delle MAO), ormoni tiroidei, antipsicotici atipici (ad es. risperidone), benzodiazepine e altri sedativi/ipnotici, a meno che prescritti a dose stabile per almeno 2 mesi prima dello screening. 19) trattamento in atto con noti inibitori potenti di CYP3A4 (ad es. chetoconazolo, rifampicina, modafinil). 20)trattamento in atto con noti potenti inibitori di Pgp (itraconazolo, chetoconazolo, ciclosporina, loperamide, diltiazem, verapamil, spironolattone, chinidina, bepridil, chinina, carvediolo) 21) soggetti che, a giudizio dello sperimentatore, sono a rischio significativo di suicidio. 22) qualsiasi controindicazione alla puntura lombare o all’inserimento di un catetere per CSF
    1. History and/or evidence of any other CNS disorder that could be interpreted as a cause of dementia 2. History of significant psychiatric illness such as schizophrenia or bipolar affective disorder that would interfere with participation in the study; major depressive disorder in the past year; current active depression requiring initiation of treatment 3. Evidence of: current vitamin B12 deficiency, positive syphilis serology or active thyroid dysfunction. 4. History of alcohol or other substance abuse. 5. History of intra cerebral haemorrhage 6. Recent CV event 7. Poorly controlled hypertension despite lifestyle modifications and pharmacotherapy (either systolic blood pressure &gt;160mmHg or diastolic blood pressure &gt;110mmHg). 8. QTcB interval &gt;450 msec; or QTcB &gt; 480 msec in subjects with bundle branch block based on ECG assessment at the Screening. 9. HbA1c &gt;12.0 at Screening, or uncontrolled diabetes. 10. History of glaucoma or any other findings in the baseline eye exam. 11. History of adult asthma (or reactive airway disease). 12. Previous history of anaphylaxis, severe allergic reaction or history of hypersensitivity to any of the components of the formulation. 13. Significant abnormalities on clinical chemistry, haematology or urinalysis. 14. History of chronic viral hepatitis or other chronic hepatic disorders. 15. Abnormal Screening blood tests 16. Other clinically significant abnormality on physical (including neurological), laboratory or ECG examination that could be detrimental to the subject. 18. Use of systemic steroids or other immunosuppressants within the last 30 days. 19. Current treatment with barbiturates, MAO inhibitors, butyrophenones, phenothiazines and other “conventional” antipsychotic within 30 days or 5 half-lives prior to Screening, whichever is longer. 20. Treatment with antidepressants, (other than MAO inhibitors), thyroid hormones, atypical antipsychotics (e.g. risperidone), benzodiazepines and other sedatives / hypnotics unless prescribed at a stable dose for at least 2 months prior to Screening. 21. Current treatment with known potent inhibitors of CYP3A4. 22. Current treatment with known potent Pgp inhibitors. 23. Cognitive tasks prescribed for cognitive rehabilitation and performed under medical supervision in the 6 months prior to screening and/or during study 26. Subjects who pose a significant suicide risk. 28. Any contraindication to lumbar puncture or insertion of CSF catheter.
    E.5 End points
    E.5.1Primary end point(s)
    Change from baseline in CSF Aβ42, Aβ40 and Aβ42/ Aβ40 ratios at Week 24. • Change from baseline in CSF tau and P-tau measures at Week 24. • Change from baseline in the CogState battery working memory/executive function composite score at Week 24.
    •variazione rispetto al basale di Aβ42, Aβ40 e dei rapporti Aβ42/Aβ40 nel CSF alla Settimana 24. •variazione rispetto al basale nelle misure di tau e P-tau nel CSF alla Settimana 24. •variazione rispetto al basale nel punteggio composito memoria di lavoro/ funzione esecutiva della batteria di test CogState alla Settimana 24.
    E.5.1.1Timepoint(s) of evaluation of this end point
    24 weeks
    24 settimane
    E.5.2Secondary end point(s)
    Change from baseline in CSF albumin quotients at Week 24. • Change from baseline in plasma levels of Aβ42, Aβ40 and ratio Aβ42/Aβ40 at Week 24. • Change from baseline in plasma Lp-PLA2 activity at Week 24. • Change from baseline in CogState battery overall composite score. • Change from baseline in CogState battery attention composite score. • Change from baseline in CogState battery individual subtest scores and possibly, other composite scores. • Assessment of safety and tolerability by analysis of AE data and changes from baseline in vital signs, clinical laboratory values, neurological examination, EM of peripheral blood mononuclear cells and electrocardiograms (ECGs)
    •variazione rispetto al basale nei quozienti di albumina nel CSF alla Settimana 24. •variazione rispetto al basale nei livelli plasmatici di Aβ42, Aβ40 e del rapporto Aβ42/Aβ40 alla Settimana 24. •variazione rispetto al basale nell’attività di Lp-PLA2 plasmatica alla Settimana 24. •variazione rispetto al basale nel punteggio composito complessivo della batteria CogState. •variazione rispetto al basale nel punteggio composito dell’attenzione della batteria CogState. •variazione rispetto al basale nei punteggi dei sotto-test individuali della batteria CogState e, se possibile, in altri punteggi compositi. •valutazione della sicurezza e della tollerabilità attraverso l’analisi dei dati sugli eventi avversi e delle variazioni rispetto al basale nei segni vitali, nei valori clinici di laboratorio, nell’esame neurologico, nell’esame con microscopia elettronica delle cellule mononucleate del sangue periferico e nell’ECG.
    E.5.2.1Timepoint(s) of evaluation of this end point
    24 weeks.
    24 settimane.
    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 No
    E.6.6Pharmacokinetic Yes
    E.6.7Pharmacodynamic Yes
    E.6.8Bioequivalence No
    E.6.9Dose response No
    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.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 Yes
    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 concerned7
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA20
    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
    LVLS
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years0
    E.8.9.1In the Member State concerned months17
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years0
    E.8.9.2In all countries concerned by the trial months17
    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.1.1Number of subjects for this age range: 0
    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: 18
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 102
    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 state36
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 120
    F.4.2.2In the whole clinical trial 120
    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)
    Not applicable.
    Non applicabile.
    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 Decision2011-06-20
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2011-06-14
    P. End of Trial
    P.End of Trial StatusCompleted
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