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    EudraCT Number:2012-002764-27
    Sponsor's Protocol Code Number:NILVAD2012
    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:2012-11-20
    Trial results View results
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    A. Protocol Information
    A.1Member State ConcernedSweden - MPA
    A.2EudraCT number2012-002764-27
    A.3Full title of the trial
    A European multicenre double-blind placebo controlled phase III trial of nilvadipine in mild to moderate Alzheimer's disease.
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A clinical trial to investigate the effectiveness of the drug Nilvadipine to treat mild to moderate Alzheimer's disease.
    A.3.2Name or abbreviated title of the trial where available
    A.4.1Sponsor's protocol code numberNILVAD2012
    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 SponsorSt James's Hospital
    B.3.1 and B.3.2Status of the sponsorNon-Commercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportEuropean Commission - Framework 7 Programme
    B.4.2CountryEuropean Union
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationSt James's Hospital
    B.5.2Functional name of contact pointFiona Cregg
    B.5.3 Address:
    B.5.3.1Street AddressDublin 8
    B.5.3.2Town/ cityDublin
    B.5.3.3Post coden/a
    B.5.4Telephone number35314162082
    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 Yes
    D. name Nilvadil 8mg Prolonged Release Capsule
    D. of the Marketing Authorisation holderAstellas
    D.2.1.2Country which granted the Marketing AuthorisationIreland
    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 nameNilvadil 8mg Prolonged release capsules
    D.3.2Product code not applicable
    D.3.4Pharmaceutical form Capsule
    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 INNNILVADIPINE
    D.3.9.1CAS number 75530-68-6
    D.3.9.4EV Substance CodeSUB09292MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number8
    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
    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
    Mild to Moderate Alzheimer's Disease
    E.1.1.1Medical condition in easily understood language
    Mild to Moderate Alzheimer's Disease
    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 16.1
    E.1.2Level LLT
    E.1.2Classification code 10001896
    E.1.2Term Alzheimer's disease
    E.1.2System Organ Class 100000004852
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    To investigate the efficacy of Nilvadipine as a disease course modifying treatment for mild to moderate AD in a phase III double-blind placebo-controlled study.
    E.2.2Secondary objectives of the trial
    Not applicable
    E.2.3Trial contains a sub-study Yes
    E.2.3.1Full title, date and version of each sub-study and their related objectives
    There are four sub studies associated with the NILVAD study. Sweden will take part in three of them.

    1. Blood and Genetic Biomarker Sub study (Protocol v1 051112)

    The objectives of the sub study are to:
    a- Determine whether there are genetic influences over the effect of Nilvadipine in AD
    b-To better understand the biological effects of nilvadipine in humans by measuring changes in amyloid, t tau and p tau and inflammatory markers in the peripheral blood from baseline to study endpoint.

    2. CSF Sub study (Protocol v1 051112)

    The objectives of thee sub study are:
    a - Subgroup analysis of the treatment effect in patients with neurochemical AD (at least deviations of two of the following biomarkers: Abeta42, T-tau, P-tau) at baseline vs those with non-neurochemical AD (less than two deviations).

    b -Subgroup analysis of the treatment effect in patients with subcortical (increased levels of NFL and/or MBP) vs cortical brain dysfunction (increased levels of T-tau) at baseline.
    [note: previous studies have found a positive treatment effect of nimodipine in patients with subcortical
    vascular dementia .
    c Exploration of the amyloid-related biomarker status at baseline for the outcome.
    d. Exploration of white matter biomarker status at baseline for the outcome.

    e. Exploration of the importance of inflammatory parameters and the pattern of matrix metallo proteinases at baseline for the outcome.

    f. Additional follow-up sampling of CSF after 78 weeks will allow us to investigate biomarker changes over time and possibly obtaining knowledge about the in vivo effect of the drug

    3. Fraility Sub study (Protocol v1 051112)

    The objectives of the fraility study are to:
    a - measure the fraility of all subjects that consent to participate cia fraility assessment schedule.
    b- To determine if fraility measures at baseline influence treatment response to Nilvadipine
    c- To determine if treatment with Nilvadipine alters the trajectory towards increased fraility over time

    E.3Principal inclusion criteria
    1. Age range: Adult subjects, males and females over age 50 years.
    2.Subjects with a diagnosis of probable Alzheimer’s disease based on the National Institute of Neurological and Communicative Disorders and Stroke/Alzheimer’s disease and Related Disorders Association, Inc (NINCDS-ADRDA) criteria (McKhann et al, 1984)
    3. Subjects with a Standardised Mini-Mental State Examination (SMMSE) (Standish & Molloy, 1991) score of greater than or equal to 12 and less than 27.
    4.Subjects on a stable dose (>3 months) of cholinesterase inhibitor or memantine. The dose must be stabilised prior to randomisation. Patients due to begin these medications must not be enrolled until the dose is stabilised. Subjects who are not on cholinesterase inhibitors or memantine due to poor tolerability and/or who will not require treatment with these medications during the course of the study can be included .
    5. Subjects who retain capacity will provide written informed consent for participation. The procedure for obtaining informed consent when the subject has reduced decision making capacity will follow national law and will be assessed by the relevant bodies in each of the participating countries.
    6.Fluency in relevant language sufficient to reliably complete all study assessments.
    7. Subjects with blood pressure values greater than 100/65 mmHg but less than 159/99 mmHg (Grade 1 hypertension, ECS guidelines 2007; escardio.org/guidelines) using an office based BP measurement will be included.
    Subjects with blood pressure values greater than 105/70mmHg but less than 140/90 mmHg using an Ambulatory BP measurement will be included.
    E.4Principal exclusion criteria
    1. Subjects with co-morbid dementia due to other neurological disorders such as Parkinson's disease, vascular dementia, Huntington's disease, Pick's disease, Creutzfeldt-Jakob disease, normal pressure hydrocephalus, brain tumour, progressive supranuclear palsy, seizure disorder, subdural hematoma, or multiple sclerosis, as well as subjects with HIV disease, neurosyphilis, history of significant head trauma with loss of consciousness followed by persistent neurological deficits, known structural brain abnormalities, or any other condition known to interfere with cognitive function.
    2. Subjects currently taking any calcium channel blocker or -blocker.
    3. Subjects who in the opinion of the investigator, have a medical condition that would preclude them from participating in the study (e.g.hemodynamically significant coronary artery disease., chronic heart failure, syncope within the past year, significant valvular heart disease i.e. severe aortic and mitral stenosis symptomatic orthostatic hypotension within the last year, or subjects who in the opinion of the investigator are unlikely to complete per protocol due to care issues etc.
    4.Current Axis I diagnosis of schizophrenia, bipolar disorder, major depression. Subjects who are currently or who have within the past year met criteria for drug or alcohol abuse or dependence.
    5.Pregnant women or women who may possibly become pregnant.
    6.Female subjects who are breastfeeding will be excluded from the study
    7.Subjects with a history of hypersensitivity to nilvadipine (Nivadil).
    8.Subjects who have taken an investigational or other unapproved drug during the 30 days or five half-lives, whichever is longer, prior to baseline.
    9. Subjects who are taking any medication listed in the list of exclusion medication for the study.
    10. Subjects with abnormal ECG results which prevent participation in the study.
    11. Standardised Mini-Mental State Examination (SMMSE) score of less than 12 or greater than 26.
    12. Subjects who are participating in other clinical research studies.
    13.Subjects with any clinically significant laboratory blood test abnormality on his/her screening test.
    14.Subjects with blood pressure values less than 100/65 mmHg but greater than 159/99 mmHg (Grade 1 hypertension, ECS guidelines 2007; escardio.org/guidelines) using an office based BP measurement will be excluded. Subjects with blood pressure values less than 105/70mmHg but greater than 140/90 mmHg using an Ambulatory BP measurement will be excluded.
    15.Subjects with clinically significant abnormalities in their CT/MRI results which would prevent inclusion in the study.
    16. Patients with sigificant renal insuffiency (estimated glomerular filtration rate : eGFR <30ml/min) will be excluded .
    17.Subjects with severly impaired hepatic function (liver cirrhosis)will be excluded.
    18.The medical food stuff SouvenaidR is under exclusion from the study.
    E.5 End points
    E.5.1Primary end point(s)
    The Alzheimer's Disease Assessment Scale (Cognitive) (ADAS-Cog) is the primary efficacy end point and includes 12 items of cognitive evaluation, namely immediate word recall, naming objects and fingers, commands, constructional praxis, ideational praxis, orientation, word recognition, remembering test instructions, spoken lanuage ability, word finding difficulty in spontaneous speech, comprehension and delayed recall. A higher ADAS-cog score indicates poorer cognitive function.
    E.5.1.1Timepoint(s) of evaluation of this end point
    The primary end point (ADAS-Cog) will be evaluated at Week 0, Week 13, Week 52 and Week 78.
    E.5.2Secondary end point(s)
    The Clinical Dementia rating sum of boxes (CDR-sb) and the Disability Assessment for Dementia (DAD) are the secondary end points for the study.
    The CDR-sb is a semi-structured interview with the caregiver and the patient. The patient’s performance in the domains of memory, orientation, judgment, problem solving, community affairs, home and hobbies and personal care are assessed. The CDR-sb is scored from 0-18, with the higher score indicated greater impairment.
    The DAD is a key secondary efficacy outcome measure and evaluates the basic and instrumental activities in daily activities of elderly people with dementia. This 40-item scale addresses a range of functional domains: eating, meal preparation, telephoning, hygienic, dressing, medication, corresponding, finance, leisure, and housework.
    E.5.2.1Timepoint(s) of evaluation of this end point
    The secondary end points (CDR-sb and DAD) will be evaluated at Week 0, Week 13, Week 52 and Week 78.
    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 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) No
    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 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 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 EEA23
    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 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
    When the last patient completes the last follow up visit which is scheduled to take place four weeks after the patient stops taking the study medication.
    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 months
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial years3
    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: 200
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 300
    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 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 Yes
    F. of subjects incapable of giving consent
    Subjects who retain capacity will provide written informed consent for participation. The procedure for obtaining informed consent when the subject has reduced decision making capacity will follow national law.
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state15
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 500
    F.4.2.2In the whole clinical trial 500
    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)
    There will be a follow up visit 4 weeks after the subject has stopped taking the study medication.
    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 Decision2012-11-23
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2013-01-16
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2016-11-01
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