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    Summary
    EudraCT Number:2015-003699-60
    Sponsor's Protocol Code Number:KIBB01
    National Competent Authority:Sweden - MPA
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2018-07-23
    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 ConcernedSweden - MPA
    A.2EudraCT number2015-003699-60
    A.3Full title of the trial
    An exploratory, open label, multiple dose, multicentre phase I/II trial evaluating safety and efficacy of postnatal or prenatal and postnatal intravenous administration of allogeneic expanded fetal mesenchymal stem cells for the treatment of severe Osteogenesis Imperfecta compared with a combination of historical and untreated prospective controls.
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Treatment of severe congenital Brittle bone disease after or before and after birth.
    A.4.1Sponsor's protocol code numberKIBB01
    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 SponsorKarolinska Institutet
    B.1.3.4CountrySweden
    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 supportSwedish Research Council
    B.4.2CountrySweden
    B.4.1Name of organisation providing supportEuropean Commission
    B.4.2CountryEuropean Union
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationKarolinska Institutet
    B.5.2Functional name of contact pointCecilia Götherström
    B.5.3 Address:
    B.5.3.1Street AddressKarolinska Institutet, ANA Futura, CLINTEC, Alfred Nobels Alle 8, fl 8
    B.5.3.2Town/ cityHuddinge
    B.5.3.3Post code14152
    B.5.3.4CountrySweden
    B.5.4Telephone number460704712300
    B.5.6E-mailcecilia.gotherstrom@ki.se
    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 nameExpanded human first trimester fetal liver-derived mesenchymal stem cells
    D.3.2Product code BOOST cells
    D.3.4Pharmaceutical form Infusion
    D.3.4.1Specific paediatric formulation Yes
    D.3.7Routes of administration for this IMPIntrauterine use
    Intravenous use
    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 Osteogenesis Imperfecta (OI) type III and severe type IV.
    E.1.1.1Medical condition in easily understood language
    Treatment of severe type of congenital Brittle bone disease.
    E.1.1.2Therapeutic area Diseases [C] - Congenital, Hereditary, and Neonatal Diseases and Abnormalities [C16]
    MedDRA Classification
    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 assess safety and tolerability in the child, fetus and woman after postnatal or prenatal and postnatal intravenous administration of four doses of BOOST cells in individuals with OI type III or severe type IV. Evaluation is performed before and after all doses and primary follow-up is performed at 6 and 12 months after the last dose (Period 1). Thereafter the subjects are followed yearly until 10 years after the 1st dose (Period 2).
    E.2.2Secondary objectives of the trial
    The secondary objective is to assess the effect of four doses of BOOST cells in individuals with OI type III or severe type IV. Evaluation is performed before and after all administrations and primary follow-up is performed at 6 and 12 months after the last dose (Period 1) with regard to:
    1. Fracture frequency
    2. Time (days) to first fracture after last dose
    3. Number of fractures at birth (prenatal treatment group only)
    4. Bone mineral density
    5. Growth (cm and kg)
    6. Clinical status of OI
    7. Biochemical bone turnover
    Thereafter the subject is followed long-time until 10 years after the 1st dose (Period 2).
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    Postnatal group
    Infants diagnosed with OI type III or severe OI type IV postnatally and prenatally diagnosed cases who did not consent to prenatal treatment.
    1. Parent’s/legal guardian’s signed informed-consent form
    2. Clinical diagnosis of OI type III or IV AND
    3. Molecular diagnosis of OI (Glycine substitution in the collagen triple-helix encoding region of either the COL1A1 or COL1A2 gene)
    4. Age less than 12 months (calculated from gestational week 40+0, i.e. the corrected age)
    5. Parent/legal guardian over 18 years of age

    Prenatal group
    Pregnant women whose fetus has been diagnosed with OI type III or severe OI type IV prenatally and who consent to MSC administration in utero.
    1. Woman has signed the informed-consent form
    2. Only women where termination of the pregnancy is no longer possible or women that are committed to continue the pregnancy
    3. Suspicion of OI type III or IV in the fetus on ultrasound findings AND
    4. Molecular diagnosis of OI in the fetus (Glycine substitution in the collagen triple-helix encoding region of either the COL1A1 or COL1A2 gene)
    5. Gestation age between 16+0 and 35+6 weeks+days
    6. Pregnant woman over 18 years of age

    After birth and before the 2nd dose, subjects in the prenatal group will be assessed for the inclusion criteria described for the Postnatal group.

    Matched historical controls
    Subjects will be identified in historical registries and data will be retrieved from national OI registers and the OI Variant Database.
    1. Parent’s/legal guardian’s signed informed-consent form (according to decision from national Ethical review board)
    2. Clinical and molecular diagnosis of OI (Glycine substitution in the collagen triple-helix encoding region of either the COL1A1 or COL1A2 gene)
    3. Data on fractures and growth is available
    4. Parent/legal guardian over 18 years of age

    Prospective untreated controls
    Subjects eligible for the trial but not willing/able to participate will be asked for consent to be included as prospective controls.
    - Postnatal participation: For postnatally included prospective untreated controls the inclusion for the postnatal group apply.
    - Prenatal participation: For prenatally included prospective untreated controls the inclusion criteria for the prenatal group apply, except inclusion criteria 2.
    E.4Principal exclusion criteria
    Postnatal group
    Infants diagnosed with OI type III or severe OI type IV postnatally and prenatally diagnosed cases who did not consent to prenatal treatment.
    1. Existence of other known disorder that might interfere with the treatment, such as, but not limited to organ dysfunction (for e.g. liver or renal failure or bronchopulmonary dysplasia), congenital heart defect, hypoxic encephalopathy l-lll, severe neurological problems, immune deficiencies, muscle diseases, severe malformations or syndromes diagnosed by clinical examination
    2. Any contraindication for invasive procedures such as a moderate/severe bleeding tendency
    3. Known risk factors for clotting, such as, but not limited to previous blood clot, family history of clots, clotting disorder (inherited or acquired), heart failure, inflammatory disorders (for e.g. lupus, rheumatoid arthritis, inflammatory bowel disease)
    4. Positive Donor Specific Antibody-test
    5. Known allergy/hypersensitivity to Fungizone and/or Gensumycin
    6. Abnormal karyotype or other confirmed genetic syndromes
    7. Oncologic disease (previous or current malignancy)
    8. Inability to comply with the trial protocol and follow-up schedule
    9. Inability to understand the information and to provide informed consent

    Prenatal group
    Pregnant women whose fetus has been diagnosed with OI type III or severe OI type IV prenatally and who consent to prenatal MSC administration.
    1. Multiple pregnancy
    2. Co-existence of other disorder that might interfere with the treatment, as judged by the Investigator or the patient’s obstetrician
    3. Abnormal fetal karyotype or other confirmed genetic syndrome
    4. Any contraindication for invasive procedures such as a bleeding tendency or contagious infections, such as, but not limited to HIV, Syphilis, Hepatitis B, Hepatitis C or other known infectious diseases that can harm the fetus
    5. Known risk factors for clotting, such as, but not limited to previous blood clot, family history of clots, clotting disorder (inherited or acquired), heart failure, inflammatory disorders (for e.g. lupus, rheumatoid arthritis, inflammatory bowel disease)
    6. Positive Donor Specific Antibody-test
    7. Known allergy/hypersensitivity to Fungizone and/or Gensumycin
    8. Oncologic disease in woman or fetus (previous or current malignancy)
    9. Unwilling to or cannot undergo delivery by elective Caesarean section
    10. Inability to comply with the trial protocol and follow-up schedule
    11. Inability to understand the information and to provide informed consent

    After birth and before the 2nd dose, subjects in the prenatal group will be assessed for the exclusion criteria described for the postnatal group.

    Matched historical controls
    Subjects will be identified in historical registries and data will be retrieved from national OI registers and the OI Variant Database.
    1. Existence of other disorder that might interfere with the trial
    2. Abnormal karyotype

    Prospective untreated controls
    Subjects eligible for the trial but not willing/able to participate will be asked for consent to be included as prospective controls.
    - Postnatal participation: The exclusion criteria, except exclusion criterium 4, 5, 6 and 7 (Contraindication for invasive procedure, Known risk factor for clotting, Positive Donor Specific Antibody-test and Known allergy/hypersensitivity to Fungizone and/or Gensumycin), for the postnatal group apply.
    - Prenatal participation: The exclusion criteria, except exclusion criterium 1, 4, 5, 6 and 7 (Multiple pregnancy, Contraindication for invasive procedure, Known risk factor for clotting, Positive Donor Specific Antibody-test and Known allergy/hypersensitivity to Fungizone and/or Gensumycin), for the prenatal group apply.
    E.5 End points
    E.5.1Primary end point(s)
    The primary endpoints are seriousness, severity and frequency of treatment-related AEs, with specific focus on the following:
    • Vital signs in conjunction with the MSC administration
    • Administration reactions (administration toxicity, allergy, embolism)
    • Immune reaction with or without symptoms of inflammation, potentially resulting in rejection of the cells or development of donor-specific antibodies:
    a) Allergy or Hypersensitivity responses to antibiotics or antimycotics
    b) Development of Fetal Bovine Serum-specific antibodies
    c) Hypersensitivity responses to Human Serum Albumin
    d) Hypersensitivity to impurities in the IMP
    • Prenatal complications (miscarriage, preterm rupture of membranes, spontaneous preterm birth, fetal bleeding) in prenatal group only
    • Adverse effects of feto-maternal transmission of donor cells (prenatal group only)
    • Tumourigenicity
    • Mortality/morbidity
    E.5.1.1Timepoint(s) of evaluation of this end point
    Child
    Immediate follow-up: Before, 1 and until 45±3 h after dose 1 and 2, and before, 1 and until 21±3 h after dose 3 and 4
    Primary follow-up: 6 and 12 months after the last dose
    Long-time follow-up: Minimum once per year for at least 10 years after the first dose

    Fetus
    Immediate follow-up: Before, 1, 21±3 h and until 45±3h after administration, thereafter every 2 weeks
    Primary follow-up: To birth and then according to the description for child

    Women
    Immediate follow-up: Before, 1, 21±3 h and until 45±3 h after administration, thereafter every 2 weeks until birth
    Primary follow-up: To her child's next dose (+4 months)
    Long-time follow-up: Minimum once per year for at least 10 years after the first dose
    E.5.2Secondary end point(s)
    The secondary endpoints are:
    • Number of fractures from baseline to primary and long-time follow-up (key secondary endpoint)
    • Time (days) to first fracture after last dose
    • Number of fractures at birth (prenatal treatment group, and postnatal treatment group when available)
    • Change in Bone mineral density (g/cm2) (supportive for the endpoint fracture frequency)
    • Growth (cm and kg)
    • Change in clinical status of OI based on parameters defined under efficacy assessments
    • Change in biochemical bone turnover
    E.5.2.1Timepoint(s) of evaluation of this end point
    Child
    Primary: 6 and 12 months after the last dose
    Long-time: Minimum once per year for at least 10 years after the first dose

    Fetus
    Primary: Every 2 weeks until birth and then according to the description for child

    Not applicable for the woman.
    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 No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other Yes
    E.7.1.3.1Other trial type description
    Exploratory phase I/II
    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
    Historical and untreated prospective controls
    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 Yes
    E.8.5.1Number of sites anticipated in the EEA6
    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
    The time from first treatment of last patient to last follow-up is 10 years.
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years13
    E.8.9.1In the Member State concerned months
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial years13
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 Yes
    F.1.1Number of subjects for this age range: 210
    F.1.1.1In Utero Yes
    F.1.1.1.1Number of subjects for this age range: 15
    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) Yes
    F.1.1.4.1Number of subjects for this age range: 15
    F.1.1.5Children (2-11years) Yes
    F.1.1.5.1Number of subjects for this age range: 180
    F.1.1.6Adolescents (12-17 years) No
    F.1.2Adults (18-64 years) No
    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 No
    F.3.3.3Pregnant women Yes
    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 state4
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 210
    F.4.2.2In the whole clinical trial 210
    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)
    Treatment will be carried out according to routine clinical care.
    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 Decision2018-09-28
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2018-09-26
    P. End of Trial
    P.End of Trial StatusOngoing
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