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    Summary
    EudraCT Number:2014-000870-20
    Sponsor's Protocol Code Number:IMU-AD-001
    National Competent Authority:Germany - BfArM
    Clinical Trial Type:EEA CTA
    Trial Status:Prematurely Ended
    Date on which this record was first entered in the EudraCT database:2014-09-15
    Trial 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 ConcernedGermany - BfArM
    A.2EudraCT number2014-000870-20
    A.3Full title of the trial
    An open-label, multicenter, controlled pharmaco-dynamic clinical trial to explore the Amyloid beta draining effect of Thiethylperazine (TEP) in subjects with early-to-mild dementia due to Alzheimer’s Disease in comparison to healthy volunteers
    Eine offene, multizentrische, kontrollierte pharmakodynamische klinische Prüfung, um die Drainagewirkung von Thiethylperazin (TEP) auf Amyloid beta bei Patienten mit beginnender bis leichter Alzheimer-Demenz, im Vergleich zu gesunden Probanden zu untersuchen.
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Study to assess the Amyloid beta draining effect of Thiethylperazine (TEP) in subjects with newly diagnosed early-to-mild dementia due to Alzheimer’s Disease in comparison to healthy volunteers
    Studie zur Untersuchung der Drainagewirkung von Thiethylperazin (TEP) auf Amyloid beta bei Patienten mit neu diagnostizierter, beginnender bis leichter Alzheimer-Demenz, im Vergleich zu gesunden Probanden
    A.3.2Name or abbreviated title of the trial where available
    drainAD
    drainAD
    A.4.1Sponsor's protocol code numberIMU-AD-001
    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 SponsorImmungenetics 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 supportImmungenetics AG
    B.4.2CountryGermany
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationImmungenetics AG
    B.5.2Functional name of contact pointChairman
    B.5.3 Address:
    B.5.3.1Street AddressEifflerstr. 43
    B.5.3.2Town/ cityHamburg
    B.5.3.3Post code22769
    B.5.3.4CountryGermany
    B.5.4Telephone number00491725455943
    B.5.6E-maildrainad@immungenetics.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 Yes
    D.2.1.1.1Trade name Torecan
    D.2.1.1.2Name of the Marketing Authorisation holderKRKA, d.d., Novo mesto, Slovenia
    D.2.1.2Country which granted the Marketing AuthorisationSlovenia
    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 nameThiethlyperazine
    D.3.4Pharmaceutical form Coated 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 INNTHIETHYLPERAZINE
    D.3.9.1CAS number 1420-55-9
    D.3.9.4EV Substance CodeSUB10973MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number26
    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.IMP: 2
    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.2.1.1.1Trade name Torecan
    D.2.1.1.2Name of the Marketing Authorisation holderKRKA, d.d., Novo mesto, Slovenia
    D.2.1.2Country which granted the Marketing AuthorisationSlovenia
    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 nameThiethlyperazine
    D.3.4Pharmaceutical form Coated 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 INNTHIETHYLPERAZINE
    D.3.9.1CAS number 1420-55-9
    D.3.9.4EV Substance CodeSUB10973MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number52
    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
    Newly diagnosed early-to-mild dementia due to Alzheimer's Disease
    Neu diagnostizierte, beginnende bis leichte Alzheimer-Demenz
    E.1.1.1Medical condition in easily understood language
    Newly diagnosed early-to-mild dementia due to Alzheimer's Disease
    Neu diagnostizierte, beginnende bis leichte Alzheimer-Demenz
    E.1.1.2Therapeutic area Psychiatry and Psychology [F] - Mental Disorders [F03]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level PT
    E.1.2Classification code 10012271
    E.1.2Term Dementia Alzheimer's type
    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 demonstrate a significantly increased efflux of Amyloid beta peptides from the brain into the bloodstream in subjects with newly diagnosed (within last 12 months) early-to-mild dementia due to Alzheimer’s Disease vs. healthy volunteers that is expected to be caused by the ABCC1 transporter-stimulating effect of thiethylperazine.
    Nachweis eines signifikant vermehrten Ausstroms von Amyloid-beta-Peptiden aus dem Gehirn in die Blutbahn bei Patienten mit neu diagnostizierter (innerhalb der letzten 12 Monate), beginnender bis leichter Alzheimer-Demenz im Vergleich zu gesunden Probanden; mit diesem Effekt wird als Folge der ABCC1-Transporter-stimulierenden Wirkung von Thiethylperazin gerechnet.
    E.2.2Secondary objectives of the trial
    1.To assess the thiethylperazine dependent changes in cognition.
    2.To determine plasma concentrations of thiethylperazine during therapy
    3.To assess the safety and tolerability of thiethylperazine in newly diagnosed (within last 12 months) subjects with early-to-mild dementia due to AD and to compare this profile with the outcome of a control group of healthy volunteers
    4.To investigate the effect of thiethylperazine on CSF levels of phosphoTau181 and total Tau in subjects with newly diagnosed (within last 12 months) early-to-mild dementia due to AD
    1.Beurteilung der Thiethylperazin-abhängigen Veränderungen der kognitiven Leistungsfähigkeit.
    2.Bestimmung der Plasma-konzentrationen von Thiethylperazin während der Behandlung.
    3.Beurteilung der Sicherheit und Verträglichkeit von Thiethylperazin bei Patienten mit neu diagnostizierter (innerhalb der letzten 12 Monate), beginnender bis leichter Alzheimer-Demenz und Vergleich dieses Profils mit demjenigen einer Kontrollgruppe, die aus gesunden Probanden besteht.
    4.Untersuchung des Einflusses von Thiethylperazin auf die Plasma-spiegel von Phospho-Tau-181 und Gesamt-Tau bei Patienten mit neu diagnostizierter (innerhalb der letzten 12 Monate), beginnender bis leichter Alzheimer-Demenz.
    E.2.3Trial contains a sub-study Yes
    E.2.3.1Full title, date and version of each sub-study and their related objectives
    Blood-based Biomarker Assay Substudy:
    To develop and establish the first internationally recognized blood-based biomarker assay for the detection and diagnosis of Early Alzheimer’s Disease
    E.3Principal inclusion criteria
    For AD subject only:
    1.Newly diagnosed (≤ 12 months) early-to-mild Alzheimer’s disease as classified by a Mini-Mental State Examination (MMSE) Score of 25-18 reconfirmed at screening
    2.AD diagnosis confirmed by recommended examinations in accordance with German DGN/DGPPN S3 Guideline “Dementia” and to standard at the clinical unit by:
    -psychometric and cognitive tests
    -lumbar puncture in subjects with uncertain AD diagnosis following CNS imaging
    -Clinical Dementia Rating (global CDR) is 0.5 or 1. Memory box score must be at least 0.5. Isolated or predominant episodic memory deficit, manifested as memory performance in the Logical Memory subscale (Delayed Paragraph Recall) from the Wechsler Memory Scale-III 1 SD below age adjusted norms, according to hospital standard)
    3.AD subject has full legal competence according to investigator opinion
    4.Ability to comply with requirements or cognitive and other testing for the entire length of the trial available

    For healthy volunteer:
    5.Subject is a non-demented volunteer, based on the assessment of medical history, physical examination and clinically laboratory data at screening as determined by the Investigator

    For AD subject and healthy volunteer:
    6.Age ≥ 55 - ≤ 75 years
    7.Written informed consent to participate within this trial
    8.Subject is on stable dose for at least 3 month prior to screening when receiving protocol-allowed concomitant medications at screening (e.g. acetylcholinesterase inhibitors, NMDA receptor antagonists)
    9.For subject receiving anticholinergic agents, oral corticosteroids, propranolol, clonidine, antihistamines other than cetirizin and EBSTEL® a washout period of 4 weeks prior to screening must be completed. Concerning anticholinergic agents in Group 1a: only for high- to medium-potency anticholinergic agents a washout period of 4 weeks prior to screening must be completed.
    10.Post-menopausal females (post menopausal amenorrhea for at least 2 years or surgically sterilized (hysterectomy), tubal ligation is not acceptable)
    11.Male subjects with reproductive potential, and have not been surgically sterilized, that have been informed and agreed to that he and his partner must use a highly effective method of contraception (Pearl Index <1%) such as implants, injectables, combined oral contraceptives, or hormonal IUDs (intrauterine devices), or refrain from sexual intercourse during the trial and until 3 months after completion of the trial
    12.Good general health with no additional disease states that could interfere with the trial due to the investigator’s assessment
    Nur beim Alzheimer-Patienten:
    1.Neu (≤ 12 Monate) diagnostizierte, beginnende bis leichte Alzheimer-Demenz (AD), eingestuft anhand eines MMST (Mini-Mental State Test)-Scores von 25–18 und beim Screening erneut bestätigt.
    2.Bestätigung der Diagnose AD anhand der in der S3-Leitlinie „Demenzen“ der DGN/DGPPN empfohlenen Untersuchungen und nach Maßgabe des kliniküblichen Standards im jeweiligen Prüfzentrum, nämlich:
    -psychometrische und kognitive Tests
    -Lumbalpunktion bei Patienten mit unsicherer AD-Diagnose nach ZNS-Bildgebung
    -„Clinical Dementia Rating“ (globaler CDR-Score) von 0,5 oder 1. Der „Memory Box Score“ muss mindestens 0,5 betragen. Isoliertes oder vorwiegend episodisches Gedächtnisdefizit, welches sich manifestiert als eine um 1 Standardabweichung (SD) unter der altersangepassten Norm liegende Gedächtnisleistung im Untertest „Logisches Gedächtnis“ (verzögerter Abruf eines Abschnitts) der „Wechsler Memory Scale-III“, nach kliniküblichem Standard.
    3.Der AD-Patient ist nach Meinung des Prüfers voll geschäftsfähig.
    4.Der Patient ist während der gesamten Studiendauer dazu in der Lage, den Studienanforderungen zu entsprechen und die kognitiven Test und anderen Untersuchungendurchführen zu lassen.

    Beim gesunden Probanden:
    5.Nach Beurteilung der Anamnese, der körperlichen Untersuchungsbefunde und der klinischen Laborwerte bei der Screening-Untersuchung handelt es sich nach Einschätzung des Prüfers um einen nicht dementen Probanden.

    Beim AD-Patienten und beim gesunden Probanden:
    6.Alter ≥ 55 bis ≤ 75 Jahre.
    7.Nach erfolgter Aufklärung schriftliche Einwilligung in die Teilnahme an der Studie.
    8.Wenn der Studienteilnehmer zum Zeitpunkt der Screening-Untersuchung laut Prüfplan erlaubte Begleitmedikationen (z. B. Acetylcholinesterasehemmer, NMDA-Rezeptor-Antagonisten) erhält, so müssen diese seit mindestens 3 Monaten vor dem Screening-Termin stabil dosiert gewesen sein.
    9.Bei Studienteilnehmern, die Anticholinergika, orale Kortikosteroide, Propranolol, Clonidin, Antihistaminika mit Ausnahme von Cetirizin und EBSTEL® erhalten, muss vor dem Screening eine 4-wöchige Auswaschphase eingehalten werden. Bezüglich Anticholinergika in Gruppe 1a: Nur bei hoch- bis mittelstarken Anticholinergika muss vor dem Screening eine 4-wöchige Auswaschphase eingehalten werden.
    10.Postmenopausale Frauen (postmenopausale Amenorrhoe seit mindestens 2 Jahren oder chirurgische Sterilisation (Hysterektomie) – Tubenligatur ist nicht akzeptabel).
    11.Zeugungsfähige männliche Studienteilnehmer, die nicht chirurgisch sterilisiert wurden und die darüber aufgeklärt wurden und sich dazu verpflichten, zusammen mit ihrer Partnerin während der Studie und bis 3 Monate nach Abschluss der Studie eine hochwirksame Verhütungsmethode (Pearl-Index < 1 %), wie z. B. implantierbare oder injizierbare Kontrazeptiva, kombinierte orale Kontrazeptiva oder hormonelle Intrauterinpessare (IUP), anzuwenden oder auf Geschlechtsverkehr zu verzichten.
    12.Guter Allgemeinzustand ohne weitere Erkrankungen, die nach Einschätzung des Prüfers die Studiendurchführung beeinträchtigen könnten.
    E.4Principal exclusion criteria
    1.CSF cut-off values identified during routine Neurochemical Dementia Diagnostics
    2.History or evidence of other significant neurological disease of the Central Nervous System (such as Parkinson's disease, multi-infarct dementia, fronto-temporal dementia, Huntington's disease, normal pressure hydrocephalus, brain tumor, pro-gressive supra nuclear palsy, epilepsy, myasthenia gravis, subdural hematoma or multiple sclerosis)
    3.History of significant head trauma followed by persistent neurologic defaults or known structural brain abnormalities
    4.Significant neuroimaging abnormalities, previously known or discovered on the MRI scan, including evidence of infection, infarction (> 3 mm in size), brain tumors (other than small meningiomas), or other focal lesions, multiple lacunas or lacunas in a critical memory structure or severe confluent microvascular disease (but not mild white matter changes, which are frequent with aging)
    5.History or evidence of moderate congestive heart failure defined by the New York Heart Association criteria (class I-IV)
    6.Clinical relevant ECG findings, abnormalities, e.g. pro-arrhythmic potential/effects on QT interval (QTc >450 msec for males, >470 msec for females, confirmed by manual assessment of ECG parameters)
    7.History of new cardiovascular event within the last 6 months
    8.Resting sitting vital signs: Systolic blood pressure ≤ 100 mmHg or ≥ 165 mmHg, Diastolic blood pressure ≤ 60 mmHg or ≥ 100 mmHg, heart rate ≤ 50 beats/min or ≥ 90 beats/min
    9. Clinically significant renal disease or insufficiency, including but not limited to creatinine value of >1.5 mg/dl
    10.ALT, AST, total bilirubin, or alkaline phosphatase >2.5 times the upper limit of normal laboratory range, or history of severe hepa-tobiliary disease (e.g. hepatitis B or C, or cirrhosis) without enzyme elevation
    11.Positive tested for hepatitis B surface antigen (HBsAG) or hepatitis C virus/antibodies (anti-HCV) for the first time within the last 6 months prior to the Screening Visit
    12.Positive tested for human immunodeficiency virus (HIV) at Screening Visit
    13.Fasting triglycerides >2.5 times of the upper limit of normal
    14.Uncontrolled diabetes (FBG > 150 mg/dl)
    15.Coagulopathy or any kind of anti-coagulant therapy
    16.Extrapyramidal syndrome
    17.Elevation of prolactin, e.g. subject with prolactin-dependent breast cancer or pituitary tumor
    18.History of severe psychiatric disease like psychotic disorder or current anxiolytic or neuroleptic therapy (for dementia-related or other psychiatric disorder) within the last 3 months of enrolment
    19.Chronic depression or bipolar disorder or history of major depression within the past 2 years or history of any episode of treatment-resistant depression (requiring > 1 antidepressants, ECT etc.)
    20.Significant history of alcohol abuse or drug abuse within the past 6 months (at the judgment of the investigator)
    21.Current treatment with TEP or treatment up to 24 month prior to screening
    22.Known incompatibility of TEP or phenothiazines
    23.Subject is receiving the following treatment that may interact with TEP, e.g. adrenaline, tricyclic antidepressants, narcotics, bromocriptine, MAO inhibitors, CYP2D6 inhibitors, tramadol, pentetrazol, levodopa, anticonvulsants, medication causing extrapyramidal symptoms increases the likelihood of central nervous system side effects
    24.Participation in a clinical trial involving another investigational drug within 4 weeks prior to screening visit
    25.Women of child bearing potential or women who are pregnant or nursing
    26.Male subjects with reproductive potential who refuse to use adequate means of contraception during and up to 3 months after stopping treatment with TEP
    1.Bei der neurochemischen Routine-Demenzdiagnostik Feststellung von Liquorwerten außerhalb der vorgegebenen Grenzwerte.
    2.Anamnestisch bekannte oder Hinweise auf andere erhebliche neurologische Erkrankungen des Zentralnervensystems (z. B. Morbus Parkinson, Multiinfarktdemenz, frontotemporale Demenz, Chorea Huntington, Normaldruckhydrozephalus, Hirntumor, progressive supranukleäre Blickparese, Epilepsie, Myasthenia gravis, Subduralhämatom oder Multiple Sklerose).
    3.Z. n. erheblichem Schädel-Hirn-Trauma mit nachfolgend persistierenden neurologischen Ausfällen oder bekannten hirnstrukturellen Auffälligkeiten.
    4.Zuvor bereits bekannte oder bei der MRT entdeckte erhebliche bildgebend nachweisbare neurologische Auffälligkeiten, z. B. Hinweise auf Infektionen, Infarkt (> 3 mm Größe), Hirntumoren (mit Ausnahme von kleinen Meningeomen) oder sonstige fokale Läsionen, multiple Lakunen oder Lakunen in einer kritischen Gedächtnisstruktur oder schwere konfluierende mikrovaskuläre Schädigungen (ausgenommen sind jedoch geringfügige Veränderungen der weißen Hirnsubstanz, die mit zunehmendem Alter häufig vorkommen).
    5.Anamnestische oder aktuelle Hinweise auf eine moderate dekompensierte Herzinsuffizienz, definiert nach den Kriterien der New York Heart Association (NYHA-Klasse I–IV).
    6.Klinisch relevante EKG-Befunde, Auffälligkeiten wie z. B. ein proarrhythmisches Potential/Auswirkungen auf das QT-Intervall
    7.Z. n. einem innerhalb der letzten 6 Monate neu aufgetretenen kardiovaskulären Ereignis.
    8.Vitalzeichen im Ruhezustand, sitzend: systolischer Blutdruck ≤ 100 mmHg oder ≥ 165 mmHg, diastolischer Blutdruck ≤ 60 mmHg oder ≥ 100 mmHg, Puls ≤ 50 Schläge/min oder ≥ 90 Schläge/min
    9.Klinisch relevante Nierenerkrankung bzw. -insuffizienz, unter anderem ein Kreatininwert > 1,5 mg/dl.
    10.ALT, AST, Gesamtbilirubin oder alkalische Phosphatase > das 2,5-Fache des oberen Normalwerts des Referenzbereichs des jeweiligen Labors oder anamnestisch bekanntes schweres Leber- oder Gallenleiden (z. B. Hepatitis B oder C oder Zirrhose) ohne erhöhte Enzymwerte.
    11.Innerhalb der letzten 6 Monate vor dem Screening-Termin erstmals positiv ausgefallener Test auf Hepatitis-B-Oberflächenantigen (HBsAg) oder Hepatitis-C-Virus/ Antikörper (anti-HCV).
    12.Beim Screening-Termin positiver Test auf humanes Immundefizienzvirus (HIV).
    13.Nüchtern-Triglyzeride > das 2,5-Fache des oberen Normalwerts.
    14.Nicht eingestellter Diabetes (Nüchtern-Blutglukose > 150 mg/dl).
    15.Gerinnungsstörung oder jede Form der Antikoagulation.
    16.Extrapyramidales Syndrom.
    17.Erhöhte Prolaktinwerte, z. B. Studienteilnehmer/in mit einem prolaktinabhängigen Mammakarzinom oder Hypophysentumor.
    18.Anamnestisch bekannte schwere psychiatrische Erkrankung wie eine psychotische Störung oder derzeitige Behandlung mit Anxiolytika oder Neuroleptika (wegen demenzbedingter oder anderer psychiatrischer Störungen) innerhalb der letzten 3 Monate vor Einschluss.
    19.Chronische Depression oder bipolare Störung oder innerhalb der letzten 2 Jahre bekannte Major Depression oder jegliche anamnestisch bekannte Episode einer therapieresistenten Depression (mit Bedarf an > 1 Antidepressivum, EKT etc.).
    20.Relevante anamnestische Hinweise auf Alkohol-, oder Medikamentenmissbrauch innerhalb der letzten 6 Monate (nach Einschätzung des Prüfers).
    21.Derzeitige Behandlung mit TEP oder Behandlung mit TEP bis zu 24 Monate vor dem Screening.
    22.Bekannte Inkompatibilität von TEP oder Phenothiazinen.
    23.Derzeitige Behandlung mit einer der folgenden Substanzen mit möglichen Wechselwirkungen mit TEP: Adrenalin, trizyklische Antidepressiva, Narkotika, Bromocriptin, MAO-Hemmer, CYP2D6-Inhibitoren, Tramadol, Pentetrazol, Levodopa, Antikonvulsiva; Arzneistoffe, die extrapyramidale Symptome hervorrufen können, erhöhen die Wahrscheinlichkeit zentralnervöser Nebenwirkungen.
    24.Teilnahme an einer klinischen Prüfung mit einem anderen noch in der Erprobung befindlichen Arzneimittel innerhalb von 4 Wochen vor dem Screening-Termin.
    25.Frauen im gebärfähigen Alter oder Frauen, die schwanger sind oder stillen.
    26.Zeugungsfähige männliche Studienteilnehmer, die es ablehnen, während und bis zu 3 Monate nach dem Ende der Behandlung mit TEP eine adäquate Kontrazeption anzuwenden.
    E.5 End points
    E.5.1Primary end point(s)
    Group mean changes from baseline day 2 to day 5 for Group 1a and 1b in plasma Aβ
    Group mean changes from baseline day 2 to day 55 for Group 2 in plasma Aβ

    Veränderung des Gruppenmittelwerts des Aβ-Plasmaspiegels von Baseline (Tag 2) bis Tag 5 in Gruppe 1a und 1b
    Veränderung des Gruppenmittelwerts des Aβ-Plasmaspiegels von Baseline (Tag 2) bis Tag 55 in Gruppe 2
    E.5.1.1Timepoint(s) of evaluation of this end point
    Aβ endpoints assessed at the following timepoints:
    Group 1a and 1b: Day 2, 3, 4, 5
    Group 2: Day 2, 3, 4, 5, 6, 7, 8, 9, 14, 21, 28, 35, 42, 49, 56
    Aβ Endpunkte werden untersucht zu folgenden Zeitpunkten:
    Gruppe 1a und 1b: Tag 2, 3, 4, 5
    Gruppe 2: Tag 2, 3, 4, 5, 6, 7, 8, 9, 14, 21, 28, 35, 42, 49, 56
    E.5.2Secondary end point(s)
    Pharmacokinetics (PK) and pharmacodynamics (PD) of TEP after 26 mg and 52 mg daily doses in AD subjects and healthy volunteers

    Treatment-emergent Adverse Events (AEs)
    Treatment-emergent Serious Adverse Events (SAEs)
    Adverse Events leading to premature discontinuation of trial medication
    Treatment-emergent clinically relevant laboratory abnormalities
    Vital signs (heart rate, blood pressure)
    12-lead ECG (overall rhythm analysis, heart rate, PQ, PR, QRS, QT, QTc, P wave)
    Pharmakokinetik (PK) und Pharmakodynamik (PD) von TEP nach Tagesdosen von 26 mg bzw. 52 mg bei AD-Patienten und bei gesunden Probanden

    Unter der Behandlung aufgetretene unerwünschte Ereignisse (UE)
    Unter der Behandlung aufgetretene schwerwiegende unerwünschte Ereignisse (SUE)
    Unerwünschte Ereignisse, die zum vorzeitigen Absetzen des Prüfpräparats führen
    Unter der Behandlung aufgetretene klinisch relevante Abweichungen bei Laborwerten
    Vitalparameter (Herzfrequenz, Blutdruck)
    12-Kanal-EKG (Rhythmusanalyse insgesamt, Herzfrequenz, PQ-Intervall, PR-Intervall, QRS-Komplex, QT-Intervall, QTc-Intervall, P-Welle)
    E.5.2.1Timepoint(s) of evaluation of this end point
    Pharmacokinetic and pharmacodynamic endpoints assessed at the following timepoints in Group 1a, Group 1b and Group 2, starting on day 2: Prior to TEP dosing and at 0,5, 1, 1,5, 2, 4, 6, 8, 12 and 24 hours following the first administration of TEP
    Pharmakokinetic und Pharmakodynamik werden zu folgenden Endpunkten in Gruppe 1a, Gruppe 1b und Gruppe 2 untersucht beginnend mit Tag 2: Vor TEP Dosierung und nach 0,5, 1, 1,5, 2, 4, 6, 8, 12 und 24 Stunden nach der ersten TEP Applikation.
    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 Yes
    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 Yes
    E.6.13.1Other scope of the trial description
    Proof-of-Concept
    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 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 Yes
    E.8.2.3.1Comparator description
    im Vergleich zu gesunden Probanden
    Comparison to healthy volunteers
    E.8.2.4Number of treatment arms in the trial3
    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 concerned4
    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
    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 months3
    E.8.9.1In the Member State concerned days
    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: 70
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 70
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male Yes
    F.3 Group of trial subjects
    F.3.1Healthy volunteers Yes
    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 state70
    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)
    Patients: Other choices:
    - other medical care
    - Volunteer for another clinical Trial

    Healty Volunteers:
    No further treatment after end of study.
    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 Decision2015-02-05
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2015-05-27
    P. End of Trial
    P.End of Trial StatusPrematurely Ended
    P.Date of the global end of the trial2021-10-05
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