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    Summary
    EudraCT Number:2014-001967-11
    Sponsor's Protocol Code Number:PBD01071
    National Competent Authority:Netherlands - Competent Authority
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2014-08-20
    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 ConcernedNetherlands - Competent Authority
    A.2EudraCT number2014-001967-11
    A.3Full title of the trial
    A Phase 2A Multicenter, Randomized, Double Blind, Placebo-Controlled, Parallel-Group Safety and Tolerability Trial of PQ912 in Subjects with early Alzheimer's Disease
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A study of PQ912 in patients with Alzheimer's Disease.
    A.3.2Name or abbreviated title of the trial where available
    SAPHIR study
    A.4.1Sponsor's protocol code numberPBD01071
    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 SponsorProbiodrug AG
    B.1.3.4CountryGermany
    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 supportProbiodrug AG
    B.4.2CountryGermany
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationJulius Clinical
    B.5.2Functional name of contact pointSuzanne Bruins
    B.5.3 Address:
    B.5.3.1Street AddressBroederplein 41 - 43
    B.5.3.2Town/ cityZeist
    B.5.3.3Post code3703 CD
    B.5.3.4CountryNetherlands
    B.5.4Telephone number0031306569158
    B.5.5Fax number0031306569990
    B.5.6E-mailsuzanne.bruins@juliusclinical.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 namePQ912
    D.3.2Product code PQ912
    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.3.8INN - Proposed INNPQ912
    D.3.9.3Other descriptive namePQ912
    D.3.9.4EV Substance CodeSUB120856
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number200
    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
    Early Stage Alzheimer's Disease
    E.1.1.1Medical condition in easily understood language
    Early Stage 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 19.0
    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.1.2 Medical condition or disease under investigation
    E.1.2Version 19.0
    E.1.2Level PT
    E.1.2Classification code 10074616
    E.1.2Term Prodromal 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
    The primary objective of this study is to assess the safety and tolerability of multiple doses of PQ912 compared with placebo in subjects with early stage AD.
    E.2.2Secondary objectives of the trial
    • To explore the efficacy of PQ912 from baseline to week 12 on cognitive function, as measured by a neuropsychological test battery.
    • To assess the pharmacodynamics of PQ912 and to identify therapeutic markers as measured by a panel of concept- and AD-related biomarkers in CSF.
    • To investigate the effect of PQ912 on brain functional connectivity as assessed by RSfMRI.
    • To provide biological support for the hypothesized PQ912 efficacy in counter-acting disruption of the functional network organization in MCI due to AD or mild dementia due to AD, using functional connectivity and network analysis in EEG.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Signed and dated written informed consent obtained from the subject in accordance with local regulations.
    2. Male or surgically sterile or postmenopausal female, aged ≥50 to ≤89 years. Male subjects with childbearing potential partners are willing to and should use condoms during study medication treatment and until 28 days after the last dose of study medication.
    3. Diagnosis of MCI due to AD or mild dementia due to AD with amnestic presentation, according to Alzheimer Association – National Institute on Aging (AA-NIA) criteria [Albert et al 2011; McKhann et al 2011].
    4. MMSE score of 21 to 30 inclusive at screening.
    5. Screening visit brain MRI scan consistent with the diagnosis of MCI due to AD or mild dementia due to AD, as judged by central rater.
    6. A positive AD signature showing one of the following (either a, b, c, OR d):
    a. Screening CSF sample with an A-beta 42 concentration of less than 638 ng/L AND total tau >375 ng/L, as assessed by central laboratory.
    b. Screening CSF sample with an A-beta 42 concentration of less than 638 ng/L AND p-tau > 52 ng/L, as assessed by central laboratory.
    c. Tau/A-beta ratio > 0.52, as assessed by central laboratory.
    d. Positive amyloid PET if available prior to screening.
    7. Treatment naïve, this means not having received any prior established specific treatment for MCI due to AD or mild dementia due to AD including no (prior) use of an acetylcholinesterase inhibitor, or memantine. A maximum of two months of prior cumulative treatment with an acetylcholinesterase inhibitor or memantine is allowed if the acetylcholinesterase inhibitor or memantine was discontinued due to intolerance and if this was done at least two months prior to baseline. Use of Souvenaid will be allowed if Souvenaid was discontinued at least two months prior to baseline, or if the subject is on stable dose for at least six months prior to baseline and is willing to continue during the study on the same dose and frequency.
    8. Fluency in local language and evidence of adequate premorbid intellectual functioning in the opinion of the investigator.
    9. Adequate visual and auditory abilities to perform the cognitive and functional assessments in the opinion of the investigator.
    10. Outpatient with study partner (age 18 years or older) capable of accompanying the subject on all clinic visits. In accordance to Swedish regulations the availability of a study partner is not applicable for Sweden.
    11. The subject and study partner are likely to be able to participate in all scheduled evaluations. In accordance to Swedish regulations the availability of a study partner is not applicable for Sweden.
    12. In the opinion of the investigator, the subject and study partner can be compliant and have a high probability of completing the study. In accordance to Swedish regulations the availability of a study partner is not applicable for Sweden.
    E.4Principal exclusion criteria
    1. Significant neurologic disease, other than AD, that may affect cognition.
    2. Atypical clinical presentations of MCI due to AD or mild dementia due to AD, such as the visual variant of AD (including posterior cortical atrophy) or the language variant (including logopenic aphasia).

    Concomitant disorders:
    3. History of or screening visit brain MRI scan indicative of any other significant abnormality, including but not limited to multiple microhaemorrhages (4 or more, defined as 10 mm or less at the greatest diameter), severe white matter hyper intensities (Fazekas score 3), history or evidence of a single prior haemorrhage >1 cm3, multiple lacunar infarcts or evidence of a single prior infarct >1 cm3, evidence of a cerebral contusion, encephalomalacia, aneurysms, vascular malformations, subdural hematoma, or space-occupying lesions (e.g. brain tumours).
    4. Current presence of a clinically important major psychiatric disorder (e.g. major depressive disorder) as defined by DSM-5 criteria, or symptom(s) (e.g. hallucinations) that could affect the subject’s ability to complete the study.
    5. Current clinically important systemic illness that is likely to result in clinically relevant deterioration of the subject’s condition or might affect the subject’s safety during the study.
    6. History of clinically evident stroke or history of clinically important and symptomatic carotid or vertebrobasilar stenosis or plaque.
    7. History of seizures within the last two years prior to the screening visit.
    8. Weight > 120 kg (264 lb) at screening.
    9. Myocardial infarction within the last six months prior to screening.
    10. History of cancer within the last two years prior to screening, with the exception of any of the following conditions: non-metastatic basal cell carcinoma, and squamous cell carcinoma of the skin or any other cancer if evidence of no residual cancer has been clinically confirmed within the last six months before baseline.
    11. History of uncontrolled hypertension (in the opinion of the investigator) within six months prior to screening.
    12. Other clinically important diseases or conditions or abnormalities of vital signs, physical examination, neurologic examination, laboratory results, or ECG examination (e.g. atrial fibrillation) that could compromise the study or the safety of the subject.
    13. Haemoglobin level less than 11 g/dL (6.8 mmol/L) at screening.
    14. Clinically important infection within 30 days prior to screening (e.g. chronic persistent or acute infection, such as bronchitis or urinary tract infection.
    15. Any known hypersensitivity to any of the excipients contained in the test article formulation.
    16. Severe hepatic failure (Child-Pugh C) or kidney failure (creatinine clearance (eGFR) ≤ 30 ml/min/1.73m2) or serum creatinine above 1.5 fold of ULN or AST or ALT above 3 fold of ULN at screening.

    17. The following therapies are not permitted for the given intervals prior to baseline and until V5/EOT:
     Anticoagulants (e.g. heparin and vitamin K antagonists) within 30 days
     Use of experimental medications for AD or any other investigational medications or devices for treatment of indications other than AD within 60 days.
     Treatment with an acetylcholinesterase inhibitor or memantine or Souvenaid, except for an acetylcholinesterase inhibitor or memantine in case of clinically relevant worsening of cognitive performance during the double blind study period, and for Souvenaid if only on stable dose for at least six weeks prior to baseline.
     Treatment with immunosuppressive medications (e.g. systemic corticosteroids in a dose of more than 10 mg/day) within the last 90 days (topical and nasal corticosteroids and inhaled corticosteroids for asthma are permitted).
     Treatment with chemotherapeutic agents for malignancy within the last year.
     Concomitant treatment with strong inhibitors or moderate inducers of the metabolic enzyme CYP 2C19 or substrates with narrow therapeutic margin: fluconazole, fluvoxamin, ticlopidin, rifampicin, S-mephenytoin, repaglinide, phenytoin, phenobarbital and indometacin. A washout phase of at least two weeks before baseline is required for subjects having been treated with any of the above medicinal products.
    Concomitant treatment with St. John’s Wort (a wash out phase of at least two weeks prior to baseline is required).
    Any concomitant treatment which impairs cognitive function and cannot be washed out at least four weeks prior to baseline.

    Other
    18. Blood donation (routine blood donation) in the 90 days prior to screening.
    19. History of alcohol or drug dependence or abuse as defined by DSM-5 criteria within the last 2 years prior to screening.
    20. Presence of pacemakers, aneurysm clips, artificial heart valves, ear implants, CSF shunts, claustrophobia, or metal fragments or foreign objects in the eyes, skin, or body that would contraindicate a brain MRI scan.
    21. Inadequate venous access to allow multiple blood draws.
    E.5 End points
    E.5.1Primary end point(s)
    Three primary safety endpoints are defined: time to dose adjustment (as an indication of tolerability), number of (S)AEs (as an indication of safety) and compliance as measured by adherence to prescribed investigational product compared to placebo (as an indication of feasibility).

    E.5.1.1Timepoint(s) of evaluation of this end point
    V5/EOT
    E.5.2Secondary end point(s)
    Additionally the following safety endpoints will be assessed throughout the study: spontaneously reported adverse events (AEs), vital signs (heart rate, blood pressure), ECG measurements, clinical laboratory tests, changes on brain MRI scans as judged by central rating (ARIA-E, ARIA-H, infarcts etc.), physical and neurologic examinations.

    Secondary study endpoints are:

    Neuropsychological endpoints:
    An exploratory endpoint is efficacy of PQ912 versus placebo on cognitive function as measured by a neuropsychological test battery between baseline (V2) and End-of-treatment visit (V5/EOT).

    CSF endpoints:
    The levels of and correlation between at least a choice of the following biomarkers will be assessed in CSF at screening (V1) and End-of-treatment visit (V5/EOT):
    1. Individual tests for diagnosis:
     A-beta 1-42.
     Tau.
     P- tau.
    2. Exploratory biomarkers as clusters:
     QC enzyme.
     Panel of A-beta peptide versions of various length (X-40/42).
     Panel measuring pGluAbeta and its substrates A-beta 3-40/42 and 11-40/42.
     Panel of A-beta oligomer assays using different technologies, each likely detecting A-beta-Oligomers of different a length.
     Panel of inflammatory markers.

    Neuronal network endpoints:
    The functional connectivity of the neuronal network will be evaluated with EEG and resting-state fMRI.
    The following endpoints will be calculated from the EEG:
     Mean peak frequency in the parieto-occipital region.
     Mean global Phase Lag Index in the alpha band.
     Minimum Spanning Tree analyses:
    o Leaf fraction in the alpha band.
    o Tree hierarchy in the alpha band.

    The following endpoints will be calculated from the RSfMRI:
     Eigenvector centrality values.
     Average path length and clustering.
    E.5.2.1Timepoint(s) of evaluation of this end point
    V5/EOT
    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 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 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 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 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 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 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
    End of trial will be when last patient completed follow up phase. 28 days after End of treatment visit a Follow up visit will take place. No study drug will be given during this phase.
    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 months8
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years1
    E.8.9.2In all countries concerned by the trial months8
    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: 55
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 55
    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 No
    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 No
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state16
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 110
    F.4.2.2In the whole clinical trial 110
    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)
    None
    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 Decision2014-08-20
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2015-02-05
    P. End of Trial
    P.End of Trial StatusCompleted
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