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    Summary
    EudraCT Number:2021-000608-39
    Sponsor's Protocol Code Number:21-ItolDC-028-01
    National Competent Authority:Norway - NOMA
    Clinical Trial Type:EEA CTA
    Trial Status:Trial now transitioned
    Date on which this record was first entered in the EudraCT database:2022-01-10
    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 ConcernedNorway - NOMA
    A.2EudraCT number2021-000608-39
    A.3Full title of the trial
    An open-label, multi-center, first in human, phase 1/2a trial to evaluate the safety and preliminary efficacy of autologous tolerogenic dendritic cells ex vivo loaded with recombinant Factor VIII (FVIII) in adults with congenital Hemophilia A (HA) with neutralizing antibodies to FVIII and having failed Immune Tolerance Induction (ITI)
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    This is a first in human study, in patients with severe bleeding disorder (hemophilia A), who has developed inhibitory antibodies against coagulation factor VIII.
    The aim is to study the safety and efficacy of dendritic cells, originating from the patient itself. The dendritic cells has been loaded with coagulation factor VIII for an improved immunological tolerance.
    A.4.1Sponsor's protocol code number21-ItolDC-028-01
    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 SponsorIdogen AB
    B.1.3.4CountrySweden
    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 supportIdogen AB
    B.4.2CountrySweden
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationIdogen
    B.5.2Functional name of contact pointChief Medical Officer
    B.5.3 Address:
    B.5.3.1Street AddressScheelevägen 2
    B.5.3.2Town/ cityLund
    B.5.3.3Post code223 81
    B.5.3.4CountrySweden
    B.5.4Telephone number+46 709 848094
    B.5.6E-mailchristina.brattstrom@idogen.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 Yes
    D.2.5.1Orphan drug designation numberEU/3/16/1813
    D.3 Description of the IMP
    D.3.1Product nameItolDC-028
    D.3.2Product code ItolDC-028
    D.3.4Pharmaceutical form Suspension for injection
    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.3.9.2Current sponsor codeItolDC-028
    D.3.9.3Other descriptive nameautologous tolerogenic dendritic cells loaded with Factor VIII
    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) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) Yes
    D.3.11.3.1Somatic cell therapy medicinal product Yes
    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
    Treatment of patients with Hemophilia A who have developed inhibitory antibodies to clotting Factor VIII and have failed Immune Tolerance Induction
    E.1.1.1Medical condition in easily understood language
    Patients with severe bleeding disorder (hemophilia A), who
    has developed inhibitory antibodies against coagulation factor VIII
    E.1.1.2Therapeutic area Body processes [G] - Immune system processes [G12]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level LLT
    E.1.2Classification code 10053751
    E.1.2Term Hemophilia A with anti factor VIII
    E.1.2System Organ Class 100000004850
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    The primary objective is to evaluate the safety and tolerability of ItolDC-028 administered in subjects with Hemophilia A having neutralizing antibodies towards FVIII and having failed ITI
    E.2.2Secondary objectives of the trial
    The secondary objective is to evaluate preliminary therapeutic efficacy of 3 therapeutic dose levels of ItolDC-028 through immune response evaluation, titer of Bethesda units (BU) and FVIII recovery and FVIII half-life as response to a FVIII challenge (Kovaltry®, octocog alfa)
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Men, 18‒60 years of age, diagnosed with congenital severe Hemophilia A (defined as <1% of normal activity of FVIII).
    2. Positive history of neutralizing anti-FVIII antibodies with a historic peak titer of BU>5, BU>1 at inclusion, confirmed loss of effect of FVIII and by the investigator judged not being able to be treated with FVIII to stop a bleed.
    3.Confirmed failure with conventional immune tolerance induction (ITI) protocols (i.e. regular, longtime, daily/several times weekly administration of FVIII at high or low dose with or without concomitant immunosuppression) such as the Malmö protocol (Freiburghaus 1999), the high-dose Bonn-protocol (Brackmann 1996) or the low-dose Dutch protocol (Mauser-Bunschoten 1995, Ter Avest 2010).
    a) Definition of ITI failure: Inhibitor titer decline less than 20% over any 6-month period after the first 3 months of ITI or failure to achieve success or partial response after 33 months of ITI (DiMichele 2007). The subject should have failed at least 1 ITI.
    4. By the investigator been judged not eligible for, or not possible to treat, with conventional immune tolerance induction (ITI) protocols (i.e. not available at site; patient fulfilling established “bad risk criteria” for ITI (Osooli & Berntorp, 2015) and thus assessed as not suitable for ITI; other non-immunological contraindications to ITI such as problematic venous access and/or not willing to undergo the burden of frequent injections)
    5. Peripheral venous access suitable for leukapheresis.
    6. Appropriate contraceptive measures for preventing pregnancy to occur during the trial in the subjects’ spouses (as per Clinical Trial facilitation Group [CTFG] guidance, 2014.) (Clinical Trial Facilitation Group (CTFG) 2014).
    7. Written informed consent is obtained. The subject signing the research consent form is, in the investigator's judgement, deemed to have adequate decision-making capacity to do so.
    8. Investigator’s judgement that the subject has the physical and mental capacity to participate and complete the trial.
    9. Vaccinated against Covid-19.
    E.4Principal exclusion criteria
    1. Treatment with Feiba throughout the trial. (Since Feiba contains small amount of FVIII, it will challenge the subject and interfere with the design of the trial, which includes a FVIII challenge with 50 IU/Kg Kovaltry, octocog alfa at Week 20.) However, if a serious bleed not responding to treatment with NovoSeven occurs, Feiba may be considered.
    2. Treatment with other experimental treatment within 6 months prior to trial start.
    3. Active infection requiring antibiotics or anti-viral treatment at screening.
    4. Laboratory test results that deviate more than ±3 standard deviations (SD) from the local site laboratory's normal reference range at screening
    5. History of clinically significant allergy (anaphylactic shock or anaphylactoid symptoms).
    6. Previous or concomitant autoimmunity.
    7. Previous or concomitant malignancy.
    8. All immunocompromised subjects as determined by the investigator including subjects on systemic immunosuppressant drugs within 12 weeks of enrolment, or planned use during the trial period.
    9. Any other disease, metabolic dysfunction, physical examination or laboratory finding giving reasonable suspicion that it may impact the safety or efficacy evaluation or render the subject at risk. The absence of such concomitant disease is ensured by a thorough history and physical examination prior to inclusion. If necessary, relevant medical records are requested.
    10. Systemic inflammation.
    11. Planned surgery including tooth extraction during the trial period.
    12. Vaccination within 4 weeks prior to enrollment or planning to be vaccinated during the trial period.
    13. Contraindications for undergoing leukapheresis:
    • Abnormal vital parameters, abnormal blood pressure or pulse
    • Fever
    • Infectious laboratory parameters (human immunodeficiency virus [HIV] and syphilis). Regarding hepatitis, patients with antibodies against HBs or HBc can be accepted if they are HBsAg negative, and patients with antibodies against HCV (Hepatitis C-Virus) can be accepted if they are HCV RNA negative. Regarding HIV, patients treated with anti-viral treatment with a PCR level of <50 HIV-1 RNA copies/mL and CD34+ >200 cells/µL (validated cell count method) can be accepted.
    • Angiotensin-Converting Enzyme (ACE) inhibitor
    E.5 End points
    E.5.1Primary end point(s)
    Primary safety endpoint:
    Number of adverse events (AEs)/serious AEs (SAEs) from the first administration of ItolDC-028 to the end of trial visit at Week 26
    E.5.1.1Timepoint(s) of evaluation of this end point
    End of trial, visit at week 26
    E.5.2Secondary end point(s)
    Secondary safety endpoints:
    - Changes in clinical safety assessments (coagulation, hematology, chemistry)
    - Changes in inhibitor titer of Bethesda units (BU)
    - Changes in urinalysis including glucose, protein and blood measurements
    - Changes in vital sign recordings
    - Changes in physical examination findings
    - Changes in ECG (electrocardiogram) recordings
    - Changes in chest X-ray recordings


    Secondary efficacy endpoints:
    - Proportion of subjects with no increase of inhibitor titer in BU 6 weeks after a FVIII challenge
    - Proportion of subjects having FVIII inhibitors <0.6 BU 6 weeks after a FVIII challenge
    - Proportion of subjects with eradication of inhibitors defined as a FVIII recovery of at least 66% of expected values in non-inhibitor subjects after an FVIII challenge.
    - Proportion of subjects with eradication of inhibitors defined as a FVIII half-life of at least 66% of expected values in non-inhibitor subjects after an FVIII challenge.
    - Changes in neutralizing antibodies (measured in functional assay as BU) between pre-treatment and the end of trial visit at Week 26
    - Changes in immunophenotyping measurements (regulatory T cells [Tregs]), regulatory B cells [Bregs]) and effector T cells [Teffs]) between pre-treatment and the end of trial visit at Week 26
    - Number of bleeding episodes from administration of ItolDC-028 to the end of trial visit at Week 26
    - Changes in quality of life (evaluated by Haem-A-QoL total score) from before administration of ItolDC-028 to the end of trial visit at Week 26
    E.5.2.1Timepoint(s) of evaluation of this end point
    Secondary safety endpoints:
    - End of trial, visit at week 26

    Secondary efficacy endpoints:
    - 6 weeks after FVIII challenge
    - End of trial, visit at week 26
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy No
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic No
    E.6.7Pharmacodynamic No
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others No
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) 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 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 No
    E.8.3 The trial involves single site in the Member State concerned Yes
    E.8.4 The trial involves multiple sites in the Member State concerned No
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA9
    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 months6
    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 months6
    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: 9
    F.1.3Elderly (>=65 years) No
    F.2 Gender
    F.2.1Female No
    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 state2
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 9
    F.4.2.2In the whole clinical trial 9
    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 Decision2022-04-08
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2022-09-20
    P. End of Trial
    P.End of Trial StatusTrial now transitioned
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