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    Summary
    EudraCT Number:2012-001725-26
    Sponsor's Protocol Code Number:X-CGD-Version2
    National Competent Authority:Germany - PEI
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2012-12-18
    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 ConcernedGermany - PEI
    A.2EudraCT number2012-001725-26
    A.3Full title of the trial
    A Phase I/II Gene Therapy trial for X-CGD with a SIN gamma retroviral vector
    Phase I/II somatische Gentherapiestudie zur Behandlung der X-chromosomalen septischen Granulomatose
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A Phase I/II Gene Therapy trial for X-CGD with a SIN gamma retroviral vector
    Phase I/II somatische Gentherapiestudie zur Behandlung der X-chromosomalen septischen Granulomatose
    A.3.2Name or abbreviated title of the trial where available
    gene therapy for X-CGD
    Gentherapie für X-CGD
    A.4.1Sponsor's protocol code numberX-CGD-Version2
    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 SponsorJohann Wolfgang Goethe-University
    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 supportLOEWE
    B.4.2CountryGermany
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationStudy Center
    B.5.2Functional name of contact pointStudy Center
    B.5.3 Address:
    B.5.3.1Street AddressTheodor-Stern-Kai 7
    B.5.3.2Town/ cityFrankfurt am Main
    B.5.3.3Post code60590
    B.5.3.4CountryGermany
    B.5.4Telephone number00496963016366
    B.5.5Fax number00496963017463
    B.5.6E-mailgmall@em.uni-frankfurt.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 namegenetically modified autologous blood stem cells
    D.3.2Product code somatic gene-therapy by X-CGD
    D.3.4Pharmaceutical form Suspension for infusion
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNG1XCG
    D.3.9.3Other descriptive nameGenetically modified autologous blood stem cells
    D.3.10 Strength
    D.3.10.1Concentration unit Other
    D.3.10.2Concentration typerange
    D.3.10.3Concentration number100 to 500
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin No
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) Yes
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) Yes
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product Yes
    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 Yes
    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
    Chronic granulomatous disease (CGD) is a congenital immunodeficiency, in which neutrophil granulocytes and monocytes are not capable of producing reactive oxygen species and therefore are unable to kill phagocytized bacteria or fungi.
    Die septische Granulomatose (CGD) ist ein angeborener Immundefekt, bei dem neutrophile Granulozyten und Monozyten keine Sauerstoffradikale produzieren können, und somit nicht in der Lage sind, phagozytierte Bakterien oder Pilze abzutöten.
    E.1.1.1Medical condition in easily understood language
    Chronic granulomatous disease (CGD)
    Septische Granulomatose (CGD)
    E.1.1.2Therapeutic area Diseases [C] - Blood and lymphatic diseases [C15]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 14.1
    E.1.2Level PT
    E.1.2Classification code 10008906
    E.1.2Term Chronic granulomatous disease
    E.1.2System Organ Class 10010331 - Congenital, familial and genetic disorders
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    1. Investigation of the clinical feasibility of a therapy with genetically modified autologous peripheral CD34+ cells for genetic correction of the NADPH oxidase in CGD patients with gp91phox defect.
    2. Investigation of the efficacy of the somatic gene-therapy by monitoring oxidase function in circulating granulocytes in long-term course.
    1. Untersuchung der klinischen Durchführbarkeit einer Therapie mit genmodifizierten, autologen peripheren mobilisierten CD34+ Zellen zur genetischen Korrektur der NADPH-Oxidase bei CGD Patienten mit gp91phox Defekt
    2. Untersuchung der Wirksamkeit der somatischen Gentherapie mittels Untersuchung der Oxidase-Funktion in zirkulierenden Granulozyten im langfristigen Verlauf
    E.2.2Secondary objectives of the trial
    Only main objectives were defined.
    Es wurden ausschließlich Hauptziele formuliert.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Verified diagnosis of the X-linked form of chronic granulomatous disease, with loss of gp91phox expression (Western Blot). Evidence of less than 5% of normal oxidase production in circulating neutrophil granulocytes as measured by DHR- and NBT-assay.
    2. History of severe chronic infections with life-threatening course or severe steroid- sensitive or steroid insensitive granulomatous disease, with necessity of inpatient treatment, without sustained improvement even under maximum conservative treatment measures.
    3. 18 years old or older
    4. No HLA identical (10/10 match) sibling- or unrelated donor, or contraindications for allogenic stem cell transplantation in presence of a suitable donor. The lack of an HLA-identical (10/10 match) sibling- or unrelated donor has to be confirmed by an unsuccessful search in national and international donor registers for at leat 3 months.
    5. Normal organ-function: GFR ≥ 60ml/min., Bilirubin ≤ 1,5-fold upper reference-level, normal parameters for liver enzymes and clotting (TPZ 75-100%, PTT 30-38sec, Fibrinogen 200-400mg/dl), Leukocytes > 3 x 109/l, Granulocytes > 1.5 x 109/l, Thrombocytes >100 x 109/l

    6. Contraception from start of G-CF application until 1 year after retransfusion of the gene-corrected cells.
    Women with childbearing potential or partners with childebearing potential of male patients with have to apply safe contraceptive measures (Pearlindex <1%), as sexual abstinence, combination of an oral contraceptive, IUS, vaginal ring with drug delivery, contraceptive pad, implanted contraceptive, injected depot-contraceptive; in combination with a second contraceptive method, in terms os a barrier-method, such as condom, diaphragm /cervical cap with spermicide or sterilization in male patients or partners.
    a. A woman of childbearing potential is defined, as sexually mature woman without hysterectomy or surgical sterilization, who has not been postmenopausal for at least 12 months (no menstruation within the last 12 months).
    7. No interferon-gamma injection within two weeks prior to hematopoietic stem cell mobilization
    8. Karnofsky-Index > 70%
    9. Signed informed consent
    1. Gesicherte Diagnose einer X-chromosomalen Form der septischen Granulomatose mit einem Verlust der gp91phox Expression (Western Blot). Nachweis von weniger als 5% der normalen Oxidaseproduktion in zirkulierenden neutrophilen Granulozyten im NBT und DHR Assay
    2. Anamnese von schweren chronischen Infektionen, mit lebensbedrohlichem Verlauf oder schweren steroid-abhängigen oder steroid-resistenten granulomatösen Erkrankungen, mit der Notwendigkeit einer stationären Behandlung, trotz konservativer Therapie
    3. 18 Jahre und älter
    4. kein HLA identer (10 aus 10 HLA-Merkmale) Familien- oder Fremdspender vorhanden, oder Kontra-indikationen bezügl. allogenen Stammzelltransplantation bei vorhandenem Spender. Das Fehlen eines HLA-identen (10/10 Match) Familien- oder Fremdspenders muss durch eine mindestens 3 monatige erfolglose Suche in nationalen und internationalen Spenderregistern nachgewiesen werden.
    5. Normale Organfunktionen: GFR ≥ 60ml/min., Bilirubin ≤ 1,5-facher oberer Normwert, normale Laborwerte für Transaminasen, alkalische Phosphatase und Gerinnungsparameter (TPZ 75-100%, PTT 30-38sec, Fibrinogen 200-400mg/dl), Leukozyten > 3 x 109/l, Granulozyten > 1.5 x 109/l, Thrombozyten >100 x 109/l
    6. Kontrazeption ab der G-CSF Applikation und bis zu 1 Jahr nach der Retransfusion der transduzierten CD34+ Zellen
    Frauen im gebärfähigen Alter oder Partnerinnen im gebärfähigen Alter von männlichen Studienteilnehmern müssen sichere Methoden der Verhütung (Pearlindex <1%) verwenden, wie komplette sexuelle Abstinenz, Kombinationen von einem oralen Kontrazeptivum, Hormonspirale, hormoneller Vaginalring, Hormonpflaster, Implantierten Kontrazeptivum oder injizierte Depot-Kontrazeptiva; in Kombination mit einer zweiten Verhütungsmethode, im Sinne einer Barrierenmethode, wie einem Kondom oder Portiokappe/Diaphragma mit Spermiziden oder Sterilisation bei männlichen Patienten oder Partnerinnen.
    a. Eine Frau im gebärfähigen Alter ist als sexuell reife Frau definiert, die sich keiner Hysterektomie (Entfernung der Gebärmutter) oder einer chirurgischen Sterilisation unterzogen hat und die sich nicht im natürlichen postmenopausalen Zustand für mindestens 12 aufeinanderfolgende Monate befindet (d.h. in den vorangegangenen 12 Monaten keine Monatsblutungen hatte).
    7. Keine Interferon-gamma Injektion innerhalb von 2 Wochen vor Beginn der Stammzellmobilisierung
    8. Karnofsky-Index > 70%
    9. Unterschriebene Einverständniserklärung
    E.4Principal exclusion criteria
    1. Patients with non-controlled acute infections
    2. Severe cardiac or pulmonary malfuctions: ejection fraction < 60%, valvular heart disease > II°, arrhythmia requiring therapy, FEV1/VC < 75% , DLCO <60%
    3. Bilirubin > 1,5-fold upper reference-level
    4. Creatinine-clearance <60ml/min

    5. HIV-, Hepatitis B- or C - infection

    6. Contraindications for G-CSF administration, as autoimmune vasculitis.
    7. Contraindications for stem cell apheresis, as low hemoglobin <8g/dl, cardiovascular instability or severe coagulapathy
    8. Pregnacy or breast-feeding
    9. Drug- or alcohol-abuse
    10. Lack of search for an unrelated donor
    11. Patients with an available HLA 9/10 MMUD will be excluded from the study if SCT is considered to be beneficial according to thorough risk-benefit-assessment
    1. Patienten mit unkontrollierten akuten Infektionen
    2. Schwere kardiale oder pulmonale Dysfunktionen: Ejektionsfraktion < 60%, Klappenfehlbildungen > II°, therapiebedürftige Herzrhythmusstörungen, FEV1/VC < 75% , DLCO <60%
    3. Bilirubin > 1.5-facher oberer Normwert
    4. Kreatininclearance von <60ml/min
    5. HIV-, Hepatitis B- oder C-Infektion
    6. Kontraindikationen für eine G-CSF Administration, wie eine autoimmune Vaskulitis
    7. Kontraindikationen für eine Stammzellapherese, wie ein erniedrigter HB <8g/dl, kardiovaskuläre Instabilität oder eine schwere Koagulopathie
    8. Schwangerschaft oder Stillzeit
    9. Drogen-und Alkoholmissbrauch
    10. Fehlende Fremdspendersuche
    11. Patienten mit einem verfügbaren HLA 9/10 MMUD werden ausgeschlossen, wenn eine sorgfältige Nutzen Risiko Abwägung zugunsten einer Stammzelltransplantation ausgeht
    E.5 End points
    E.5.1Primary end point(s)
    1. The transduction rate of G-CSF mobilized periperal CD34+ cells from CGD patients with a SIN-gammaretroviral vector.
    2. Engraftment rate of the transduced CD34+ cells in the patients.
    3 Long-term expression of the transgene (gp91phox) and functional reconstitution of the NADPH oxidase in circulating cells of the peripheral blood.
    4. Frequency and severity of unexpected toxic adverse events during and after infusion of the genetically modified CD34+ cells.
    1. Rate der Transduktion peripherer G-CSF - mobilisierter CD34+ Zellen von CGD Patienten mit einem SIN-gammaretroviralen Vektor.
    2. Rate des Engraftments der transduzierten CD34+ Zellen in den Patienten.
    3. Langzeitexpression des Transgens (gp91phox) und der funktionellen Rekonstitution der NADPH-Oxidase in zirkulierenden Zellen des peripheren Blutes.
    4. Auftreten und Schweregrad von unerwarteten toxischen Nebenwirkungen bei und nach der Infusion der genetisch modifizierten CD34+ Zellen.
    E.5.1.1Timepoint(s) of evaluation of this end point
    Monthly for the first 6 month after treatment, thereafter quarterly for 5 years.
    Completion of follow-up: 01.04.2020
    Final report: 01.11.2020
    Während der ersten sechs Monate nach Behandlung monatlich, danach vierteljährlich für fünf Jahre.
    Abschluss der Nachbeobachtung: 01.04.2020
    Abschlussbericht 01.11.2020
    E.5.2Secondary end point(s)
    1. Frequency of infections as indicator for clinical benefit for CGD patients
    2. Proliferation, differentiation and transduction-efficiency of CD34+ cells in ex-vivo culture under serum-free conditions.
    1. Häufigkeit der auftretenden Infektionen als Indikator für den klinischer Nutzen für den CGD Patienten
    2. Proliferation, Differenzierung und Transduktionseffizienz von CD34+ Zellen in einer ex-vivo Kultur unter serumfreien Bedingungen.
    E.5.2.1Timepoint(s) of evaluation of this end point
    Monthly for the first 6 month after treatment, thereafter quarterly for 5 years.
    Completion of follow-up: 01.04.2020
    Final report: 01.11.2020
    Während der ersten sechs Monate nach Behandlung monatlich, danach vierteljährlich für fünf Jahre.
    Abschluss der Nachbeobachtung: 01.04.2020
    Abschlussbericht 01.11.2020
    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 No
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) Yes
    E.7.1.1First administration to humans Yes
    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 No
    E.8.1.1Randomised No
    E.8.1.2Open No
    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 No
    E.8.2.4Number of treatment arms in the trial1
    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 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
    01.12.2014
    01.12.2014
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years8
    E.8.9.1In the Member State concerned months0
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years0
    E.8.9.2In all countries concerned by the trial months0
    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: 5
    F.1.3Elderly (>=65 years) No
    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 state5
    F.4.2 For a multinational trial
    F.4.2.2In the whole clinical trial 5
    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)
    After 5 years, a detailed final examination will be performed. Thereafter the patients will be followed-up within our routine program for patients after autologous hematopoietic stem cell transplantation. The intervals of examination will be 6 months or longer, according to the judgment of the treating physician.
    Nach fünf Jahren findet eine ausführliche Abschlussuntersuchung statt.
    Die weitere Nachsorge findet im Rahmen der Routine-Nachsorge für autolog transplantierte Patienten statt. Die Abstände der weiteren Untersuchungen betragen sechs Monate oder je nach Ermessen des behandelnden Arztes auch länger.
    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 Decision2013-01-15
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2013-03-12
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2019-09-11
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