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    Summary
    EudraCT Number:2018-001514-15
    Sponsor's Protocol Code Number:EARLY_KUM_PSY
    National Competent Authority:Germany - BfArM
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2018-09-03
    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 number2018-001514-15
    A.3Full title of the trial
    Effects of early clozapine treatment on remission rates in acute schizophrenia (EARLY)
    Effekte der frühzeitigen Applikation von Clozapin auf die Remissionsrate bei akuter Schizophrenie
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Effects of early clozapine treatment on remission rates in acute schizophrenia (EARLY)
    Effekte der frühzeitigen Applikation von Clozapin auf die Remissionsrate bei akuter Schizophrenie
    A.3.2Name or abbreviated title of the trial where available
    EARLY
    EARLY
    A.4.1Sponsor's protocol code numberEARLY_KUM_PSY
    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 SponsorKlinikum der Universität München - AöR verteten duch den Vorstand des Bereiches Humanmedizin
    B.1.3.4CountryGermany
    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 supportDFG Grant Number HA 6091/4-1, project number: 316096538
    B.4.2CountryGermany
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationTechnische Universität München Fakultät für Medizin Muenchner Studienzentrum
    B.5.2Functional name of contact pointDr. med. Christiane Blankenstein
    B.5.3 Address:
    B.5.3.1Street AddressIsmaningerstr. 22
    B.5.3.2Town/ cityMünchen
    B.5.3.3Post code81675
    B.5.3.4CountryGermany
    B.5.4Telephone number00498941406321
    B.5.5Fax number00498941406322
    B.5.6E-mailchristiane.blankenstein@mri.tum.de
    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 nameClozapin HEXAL
    D.3.4Pharmaceutical form Capsule, hard
    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 INNClozapin
    D.3.9.1CAS number 5786-21-0
    D.3.9.2Current sponsor codeEARLY_KUM_PSY
    D.3.9.3Other descriptive nameCLOZAPINE
    D.3.9.4EV Substance CodeSUB06787MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number25
    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 No
    D.2.1.2Country which granted the Marketing AuthorisationGermany
    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 nameClozapin HEXAL
    D.3.4Pharmaceutical form Capsule, hard
    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 INNClozapin
    D.3.9.1CAS number 5786-21-0
    D.3.9.2Current sponsor codeEARLY_KUM_PSY
    D.3.9.3Other descriptive nameCLOZAPINE
    D.3.9.4EV Substance CodeSUB06787MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number75
    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: 3
    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.2.1.2Country which granted the Marketing AuthorisationGermany
    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 nameClozapin HEXAL
    D.3.4Pharmaceutical form Capsule, hard
    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 INNClozapin
    D.3.9.1CAS number 5786-21-0
    D.3.9.2Current sponsor codeEARLY_KUM_PSY
    D.3.9.3Other descriptive nameCLOZAPINE
    D.3.9.4EV Substance CodeSUB06787MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number12,5
    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: 4
    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.2.1.2Country which granted the Marketing AuthorisationGermany
    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 nameClozapin HEXAL
    D.3.4Pharmaceutical form Capsule, hard
    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 INNClozapin
    D.3.9.1CAS number 5786-21-0
    D.3.9.2Current sponsor codeEARLY_KUM_PSY
    D.3.9.3Other descriptive nameCLOZAPINE
    D.3.9.4EV Substance CodeSUB06787MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number150
    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: 5
    D.1.2 and D.1.3IMP RoleComparator
    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.2.1.2Country which granted the Marketing AuthorisationGermany
    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 nameZyprexa Lilly
    D.3.4Pharmaceutical form Capsule, hard
    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 INNZyprexa
    D.3.9.1CAS number 132539-06-1
    D.3.9.2Current sponsor codeEARLY_KUM_PSY
    D.3.9.4EV Substance CodeSUB09426MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number2,5
    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: 6
    D.1.2 and D.1.3IMP RoleComparator
    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.2.1.2Country which granted the Marketing AuthorisationGermany
    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 nameZyprexa Lilly
    D.3.4Pharmaceutical form Capsule, hard
    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 INNZyprexa
    D.3.9.1CAS number 132539-06-1
    D.3.9.2Current sponsor codeEARLY_KUM_PSY
    D.3.9.4EV Substance CodeSUB09426MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number5
    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 placeboCapsule, hard
    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
    Schizophrenia
    Schizophrenie
    E.1.1.1Medical condition in easily understood language
    Schizophrenia
    Schizophrenie
    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 10039626
    E.1.2Term Schizophrenia
    E.1.2System Organ Class 10037175 - Psychiatric 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 is to investigate the symptomatic remission rates in non-treatment-refractory patients with schizophrenia randomized to either early clozapine or olanzapine over an 8-week period.
    Der primäre Endpunkt ist die symptomatische Remissionsrate von nicht-therapierefraktären Patienten mit einer Schizophrenie, die nach Randomisierung entweder Clozapin oder Olanzapin über einen Zeitraum von 8 Wochen erhalten haben.
    E.2.2Secondary objectives of the trial
    Secondary objectives include differences in side effects, symptom severity, safety measures and cognitive functions as detailed below.
    Sekundäre Endpunkte beinhalten Unterschiede in den Nebenwirkungen, in der Symptomschwere, in der Sicherheit der Anwendung und in kognitiven Funktionen in den beiden Gruppen.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Age 18 to 65 years
    2. Signed informed consent
    3. DSM-V diagnosis of schizophrenia confirmed by the Mini international Neuropsychiatric Interview
    4. At least one documented prior hospitalization due to the illness in the medical history (the current hospitalization can be considered as “prior” hospitalization if its ≥ 4 weeks) at screening
    5. For treatment-naïve patients (defined as no previous antipsychotic treatment or a maximum of 30 days of treatment), an antipsychotic treatment attempt of at least 30 days with an antipsychotic in a therapeutic dose according to local guidelines other than clozapine and olanzapine before the screening phase is needed. For non-treatment-naïve patients (defined as having been treated for more than 30 days with an antipsychotic), a discontinuation of a foregoing antipsychotic treatment prior to the screening phase within a maximum of six months (=180 days) is possible (corresponding to the estimated average time for an antipsychotic washout phase and the expected time to develop a relapse of the disease). For patients being treated with a long-acting antipsychotic (other than PP3M), an inclusion is possible if inclusion date corresponds to the planned date of the next injection plus five to seven days
    6. Clinical need for a medication switch because of clinical inefficacy or side-effects or clinical need for a reintroduction of an antipsychotic treatment after treatment discontinuation prior to the screening phase (see 5.)
    7. Moderate symptomatology on the PANSS, defined as a score ≥ 4 for two or more symptoms from P1-P7 or a score of ≥ 6 for one symptom from P1-P7 (minimum threshold definition) at screening
    8. Male participants and female participants who are not capable of bearing children or who use a method of contraception that is medically approved by the health authority of the respective country at screening
    This includes:
    • A woman who is not capable of bearing a child is defined as follows: post-menopausal (12 months natural (spontaneous) amenorrhea or 6 months spontaneous amenorrhea with serum-FSH-values (follicle-stimulating hormone) of >40 mIU/mL); 6 weeks after a bilateral ovariectomy with or without hysterectomy or sterilization by means of tubal ligation
    • A woman capable of bearing child is defined as follows: a woman who is physiologically capable of becoming pregnant, including women whose occupation, lifestyle or sexual orientation exclude sexual intercourse with a male partner and women whose partners have been sterilized by vasectomy or other measures.
    • Medically-approved methods of contraception can include the following: hormonal contraceptives, intrauterine device and double barrier method. Acceptable preventive measures can include total abstinence at the discretion of the investigator, in cases where compliance is ensured because of the study participant’s age, occupation, lifestyle or sexual orientation. Periodical abstinence (e.g. calendar, ovulation, symptothermal methods or abstinence until the 4th day after the ovulation) as well as coitus interruptus are not acceptable methods of contraception.
    • A reliable method of contraception (CTFG guideline) must be used for the entire duration of the study.
    1. Alter 18 bis 65 Jahre
    2. Gültige Einwilligungserklärung
    3. DSM-V Diagnose einer Schizophrenie bestätigt durch das das Mini international Neuropsychiatric Interview (MINI)
    4. Mindestens eine dokumentierte Hospitalisierung in der medizinischen Vorgeschichte des Patienten aufgrund der Erkrankung (die aktuelle Hospitalisierung gilt als äquivalent, falls die Dauer ≥ 4 Wochen beträgt zum Zeitpunkt des Screenings
    5. Antipsychotischer Behandlungsversuch von mind. 4 Wochen mit einem Antipsychotikum (außer Clozapin und Olanzapin) in einer therapeutischen Dosierung gemäß nationalen Leitlinien vor der Screening-Phase. Falls eine vorhergehende antipsychotische Behandlung vom Patienten vor der Screening-Phase beendet wurde, muss dies vor max. 2 Wochen geschehen sein (entsprechend einer Auswasch-Phase des Antipsychotikums). Patienten, die ein Depotpräparat erhalten (ausgenommen PP3M), können eingeschlossen werden, wenn das Datum des Studieneinschlusses der geplanten nächsten Depotgabe plus 7 weitere Tage entspricht.
    6. Klinische Notwendigkeit einer medikamentösen Umstellung aufgrund von klinischer Wirkungslosigkeit oder Nebenwirkungen oder klinische Notwendigkeit für die erneute Einleitung einer antipsychotischen Behandlung nach Therapieabbruch vor der Screening-Phase (siehe 5.)
    7. Moderate Symptomschwere im PANSS-Score, definiert al sein Score ≥ 4 in zwei oder mehreren Items von P1-P7 oder ein Score ≥ 6 in den Items P1-P7 (minimum-threshold Definition) zum Zeitpunkt des Screenings
    8. Männliche oder weibliche Teilnehmer, die nicht gebährfähig sind bzw., die eine Verhütungsmethode verwenden, welche von der Gesundheitsautorität des jeweiligen Landes medizinisch anerkannt wird zum Zeitpunkt des Screenings
    Dies beinhaltet:
    • Eine Frau, die nicht gebärfähig ist, wird wie folgt definiert: post-menopausal (12 Monate andauernde natürliche (spontane) Amenorrhoe oder 6 Monate spontane Amenorrhoe mit Serum-FSH- (Follikel-stimulierendes Hormon) Werten von >40 mIU/mL); 6 Wochen nach bilateraler Ovarektomie mit oder ohne Hysterektomie oder Sterilisation durch Tubenligatur
    • Eine gebärfähige Frau wird wie folgt definiert: eine Frau, die physiologisch in der Lage ist schwanger zu werden, eingeschlossen Frauen, dessen Beruf, Lebenswandel oder sexuelle Orientierung Geschlechtsverkehr mit einem männlichen Partner ausschließen und Frauen, dessen Partner durch Vasektomie oder andere Verfahren sterilisiert worden sind. Medizinisch anerkannte Verhütungsmethoden können wie folgt sein: - hormonelle Kontrazeptiva, intrauterine Empfängnisverhütung und double barrier Methode. Anerkannte präventive Maßnahmen inkludieren vollständige Abstinenz im Ermessen des Prüfers in Fällen, in denen die Compliance gesichert ist aufgrund des Alters, des Berufes, des Lebenswandels oder der sexuellen Orientierung des Teilnehmers. Periodische Abstinenz (z.B. Kalendermethode, Ovulation, symptothermale Methoden oder Abstinenz bis zum 4. Tag nach der Ovulation) sowie Coitus interruptus sind nicht anerkannte Verhütungsmethoden.
    • Eine verlässliche Verhütungsmethode (CTFG Richtlinie) muss für den ganzen Zeitraum der Studie angewendet werden.
    E.4Principal exclusion criteria
    1. Patients who are not suitable for the study in the opinion of the investigator
    2. Patients who are unable to give informed consent
    3. Coercive treatment at the time of study inclusion
    4. White blood cell count (WBC) at inclusion not meeting the requirements for clozapine use in Germany. Patients must have normal leukocyte findings (white blood cell count ≥ 3500/mm3 (≥ 3.5x109/l), and Absolute Neutrophil Count (ANC) ≥ 2000/mm3 (≥ 2.0x109/l) at the screening visit
    5. The presence of one or more of the contraindications against any of the study drugs as mentioned in the SPC
    6. Treatment-naïve or treatment-resistant schizophrenia. Treatment-naïve will be defined as no previous antipsychotic treatment or a maximum of 30 days of treatment. Treatment resistance is defined as 2 antipsychotic trials (with antipsychotics from two different chemical classes) for a period of ≥ 6 weeks with CPZ equivalent doses ≥ 600 mg/day, both of which took place immediately before the screening phase
    7. Diagnosis of primary substance dependency other than nicotine
    8. Documented previous non-response to an 8-week drug trial with olanzapine or previous treatment with clozapine
    9. Intolerance to one of the study drugs
    10. Pregnancy (incl. positive urine pregnancy test) / lactation (female patients)
    1. Patienten, die nach Einschätzung des Prüfers nicht geeignet sind an der klinischen Studie teilzunehmen
    2. Nicht-einwilligungsfähige Patienten
    3. Zwangsbehandlung oder Unterbringung gegen den Willen zum Zeitpunkt des Studieneinschlusses
    4. Leukozytenzahl (WBC), die zum Zeitpunkt des Studieneinschlusses gegen eine Anwendung von Clozapin in Deutschland spricht. Patienten müssen zum Zeitpunkt des Screenings eine normwertige Leukozytenzahl ≥ 3500/mm3 (≥ 3.5x109/l), sowie eine absolute Anzahl neutrophiler Granulozyten ≥ 2000/mm3 (≥ 2.0x109/l) haben
    5. Das Vorhandensein von einer oder mehreren Kontraindikationen gegen die Anwendung einer der beiden Studienpräparate (siehe Fachinformationen)
    6. Therapie-naive oder therapie-resistente Schizophrenie. Therapie-naiv ist wie folgt definiert: keine vorherige antipsychotische Behandlung oder ein Zeitraum antipsychotischer Behandlung von max. 30 Tagen. Therapie-resistent ist wie folgt definiert: 2 antipsychotische Behandlungsversuche (mit Antipsychotika von zwei chemisch verschiedenen Substanzklassen) über einen Zeitraum von ≥ 6 Wochen mit CPZ Äquivalenzdosierungen ≥ 600 mg/Tag, wovon beide unmittelbar vor der Screeningphase stattgefunden haben.
    7. Diagnose einer primären Substanzabhängigkeit (außer Tabak)
    8. Dokumentierte vorherige Non-Response auf eine 8-wöchige Behandlungsphase mit Olanzapin oder Behandlung mit Clozapin in der Vorgeschichte
    9. Unverträglichkeit gegenüber eines der Studienpräparate
    10. Schwangerschaft (inkl. positiver Schwangerschaftstest im Urin/Laktation (weibliche Patienten)
    E.5 End points
    E.5.1Primary end point(s)
    Relative frequency of patients in the clozapine group in remission (Remission in Schizophrenia Working Group [RSWG] consensus criteria) at week 8 compared to the olanzapine group.
    Der primäre Endpunkt ist die symptomatische Remissionsrate von nicht-therapierefraktären Patienten mit einer Schizophrenie, die nach Randomisierung entweder Clozapin oder Olanzapin über einen Zeitraum von 8 Wochen erhalten haben.
    E.5.1.1Timepoint(s) of evaluation of this end point
    Screening, Baseline vist 5, visit 9
    Screening, Baseline vist 5, visit 9
    E.5.2Secondary end point(s)
    Secondary Endpoints:
    1. Relative frequency of patients in remission after four weeks (V5) according to the RSWG criteria (Andreasen, Carpenter et al. 2005).
    2. Change in Positive and Negative Syndrome Scale (PANSS) (Kay, Fiszbein et al. 1987) total and in the three PANSS subscales (positive, negative, general) from baseline (V1) to week four (V5) and week eight (V9).
    3. Frequency of patients in remission according to the RSWG criteria without the negative symptom Items (N1, N4 and N6) after four (V5), six (V7) and eight weeks (V9)
    4. Frequency of patients with a clinical response according to PANSS (≥ 20% change from baseline, corrected PANSS formula) (Leucht 2014) after four (V5) and eight weeks (V9).

    Secondary Endpoints: Side-effects and safety
    1. Change in white/complete blood count (WBC/CBC), creatinine kinase (CK) blood levels from screening (V0) to every visit during the study period (V13) (see Study Laboratory under 8.5.4).
    2. Relative change in Troponine, frequency of 2-fold elevated Troponine, and absolute change in C-reactive protein (CRP) (values) from screening to every visit during the first four weeks of the intervention period (V1-V5) and at week 6 (V7) and week eight (V9).
    3. Changes in standard parameters of Electrocardiography (ECG) (QT interval-value, heart rate value from screening/baseline (V1) to week 2 (V3), week 4 (V5), week 6 (V7) and week eight (V9).
    Sekundäre Endpunkte:
    Sekundäre Endpunkte beinhalten Unterschiede in den Nebenwirkungen, in der Symptomschwere, in der Sicherheit der Anwendung und in kognitiven Funktionen in den beiden Gruppen (Details siehe English Version)
    E.5.2.1Timepoint(s) of evaluation of this end point
    Screening, Baseline vist 5, visit 9
    Screening, Baseline vist 5, visit 9
    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 No
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic No
    E.6.7Pharmacodynamic No
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others Yes
    E.6.13.1Other scope of the trial description
    Pharmacoepigenomics
    Pharmacoepigenomics
    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) 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 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) Yes
    E.8.2.2Placebo No
    E.8.2.3Other Yes
    E.8.2.3.1Comparator description
    Olanzapin
    Olanzapin
    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 concerned10
    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 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
    LPLS
    LPLS
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years4
    E.8.9.1In the Member State concerned months
    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: 200
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 20
    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 state220
    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)
    See CSP part 6.4
    According to CSP, it is planned that patients who fulfill the remission rate at week 8 should continue to be treated with clozapine (open label extension study). Depending on the remission, olanzapine is treated further or switched to clozapine.
    siehe CSP part 6.4
    Es ist laut CSP geplant, dass Patienten die die Remmissionsrate in Woche 8 erfüllen mit Clozapin weiter behandelt werden sollen (open label extension study). Bei Olanzapin wird je nach Remission weiterbehandelt oder auf Clozapin umgestellt.
    G. Investigator Networks to be involved in the Trial
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2018-12-10
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2018-12-07
    P. End of Trial
    P.End of Trial StatusOngoing
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