Treatment of Osteogenesis Imperfecta (OI) type III and severe type IV.
Conditions
Interventions
Product Name: Expanded human first trimester fetal liver-derived mesenchymal stem cells
Product Code: BOOST cells
Pharmaceutical Form: Infusion
Sponsors
Karolinska Institutet
Eligibility
Sex/Gender
All
Inclusion criteria
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. Are the trial subjects under 18? yes Number of subjects for this age range: 138 F.1.2 Adults (18-64 years) no F.1.2.1 Number of subjects for this age range F.1.3 Elderly (>=65 years) no F.1.3.1 Number of subjects for this age range
Exclusion criteria
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. No lung hypoplasia (type II OI). 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 criteriu
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: 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). ;Secondary Objective: 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).;Primary 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) • T | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary 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 ;Timepoint(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. | — |
Countries
Sweden
Contacts
Public ContactCecilia Götherström
Karolinska Institutet
Outcome results
None listed