Boost Brittle Bones Before Birth

Study Overview
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Brief Summary
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An exploratory, open label, multiple dose, multicentre phase I/II trial evaluating safety and efficacy of postnatal or prenatal and postnatal 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.

Official Title
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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

Conditions
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Osteogenesis Imperfecta

Intervention / Treatment
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* Biological: BOOST cells


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria Postnatal Group: Parent's/legal guardian's signed informed-consent form Clinical diagnosis of OI type III or IV AND Molecular diagnosis of OI (Glycine substitution in the collagen triple-helix encoding region of either the COL1A1 or COL1A2 gene) Age less than 18 months (calculated from gestational week 40+0, i.e. the corrected age) Parent/legal guardian over 18 years of age Inclusion Criteria Prenatal Group: Woman has signed the informed-consent form Only women where termination of the pregnancy is no longer possible or where the women are committed to continue the pregnancy may be included in the trial Suspicion of OI type III or IV in the fetus on ultrasound findings AND Molecular diagnosis of OI in the fetus (Glycine substitution in the collagen triple-helix encoding region of either the COL1A1 or COL1A2 gene) Gestation age between 16+0 and 35+6 weeks+days Pregnant woman over 18 years of age Inclusion Criteria Historical Control Group: Parent's/legal guardian's signed informed-consent form Clinical and molecular diagnosis of OI (Glycine substitution in the collagen triple-helix encoding region of either the COL1A1 or COL1A2 gene) Data on fractures and growth is available Parent/legal guardian over 18 years of age Inclusion Criteria Prospective Untreated Control Group: Postnatal inclusion: The inclusion criteria for the postnatal group apply. Prenatal inclusion: The inclusion criteria for the prenatal group apply, except inclusion criteria 2. Exclusion Criteria Postnatal Group: Existence of other known disorder that might interfere with the treatment, such as, but not limited to organ dysfunction (for example 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. Any contraindication for invasive procedures such as a moderate/severe bleeding tendency 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 example lupus, rheumatoid arthritis, inflammatory bowel disease) Positive Donor Specific Antibody-test Known allergy/hypersensitivity to Fungizone and/or Gensumycin Abnormal karyotype or other confirmed genetic syndromes Oncologic disease (previous or current malignancy) Inability to comply with the trial protocol and follow-up schedule Inability to understand the information and to provide informed consent Exclusion Criteria Prenatal Group: Multiple pregnancy Co-existence of other disorder that might interfere with the treatment, as judged by the Investigator or the patient's obstetrician Abnormal fetal karyotype or other confirmed genetic syndrome 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 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 example lupus, rheumatoid arthritis, inflammatory bowel disease) Positive Donor Specific Antibody-test Known allergy/hypersensitivity to Fungizone and/or Gensumycin Oncologic disease in woman or fetus (previous or current malignancy) Unwilling to or cannot undergo delivery by elective Caesarean section Inability to comply with the trial protocol and follow-up schedule Inability to understand the information and to provide informed consent Exclusion Criteria Historical Control Group: Existence of other disorder that might interfere with the trial. No lung hypoplasia (type II OI). Abnormal karyotype Exclusion Criteria Prospective Untreated Control Group: Postnatal inclusion: The exclusion criteria, except exclusion criterium 4, 5, 6 and 7 for the postnatal group apply. Prenatal inclusion: The exclusion criteria, except exclusion criterium 1, 4, 5, 6 and 7 for the prenatal group apply.

Ages Eligible for Study
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Maximum Age: 18 Months

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Postnatal<br>15 participants. Administration of four postnatal doses of BOOST cells with the first dose as soon as possible after birth and the three additional doses at +4, +8 and +12 months after the first dose. Each dose is 3x10^6 MSC/kg body weight. | Biological: BOOST cells<br>* Four doses of expanded human 1st trimester fetal liver-derived mesenchymal stem cells.<br>|
| Experimental: Prenatal<br>3 participants. Administration of one prenatal dose of BOOST cells followed by three postnatal doses at +4, +8 and +12 months after the first dose. Each dose is 3x10^6 MSC/kg body weight. | Biological: BOOST cells<br>* Four doses of expanded human 1st trimester fetal liver-derived mesenchymal stem cells.<br>|
| No Intervention: Prospective control (untreated)<br>1-30 participants. Subjects eligible for the trial but not willing/able to participate in any of the experimental arms. | |
| No Intervention: Historic control<br>30-150 participants. Matched historical controls. Subjects will be identified in historical registries and data will be retrieved from national OI registers and the OI Variant Database (Dalgleish 2018). | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety and tolerability measured as seriousness, severity and frequency of treatment related adverse events. | The primary endpoint is safety and tolerability measured as seriousness, severity and frequency of treatment related adverse events (AEs), with specific focus on the following: Vital signs in conjunction with the MSC administration Transfusion 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: Allergy or Hypersensitivity responses to antibiotics or antimycotics Development of Fetal Bovine Serum-specific antibodies Hypersensitivity responses to Human Serum Albumin Hypersensitivity to impurities in the IMP Prenatal complications (miscarriage/intrauterine fetal death, premature birth, infection in utero or persistent [>1 min] fetal bradycardia) in the prenatal group Adverse effects of feto-maternal transmission of donor cells in the prenatal group Tumourigenicity Mortality/morbidity | From baseline to the long-time follow-up (10 years after the first dose). | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of fractures. | Number of fractures. | From baseline to the primary follow-up (6 and 12 months after the last dose) and therafter assessed annually to the end of the long-time follow-up (10 years after the first dose). | 
| Time (days) to first fracture after each stem cell administration. | Time (days) to first fracture after each stem cell administration. | From each dose of stem cells to the time point of the first fracture. Assessed up to 10 years after the first stem cell dose. | 
| Numbers of fractures at birth. | Numbers of fractures at birth. | Evaluated at birth. | 
| Change in bone-marrow density (g/cm2). | Change in bone-marrow density (g/cm2). | From baseline to the primary follow-up (6 and 12 months after the last dose) and thereafter assessed annually to the end of the long-time follow-up (10 years after the first dose). | 
| Growth (cm). | Growth (cm) as assessed by clinician. | From baseline to the primary follow-up (6 and 12 months after the last dose) and thereafter assessed annually to the end of the long-time follow-up (10 years after the first dose). | 
| Growth (kg). | Growth (kg) as assessed by clinician. | From baseline to the primary follow-up (6 and 12 months after the last dose) and thereafter assessed annually to the end of the long-time follow-up (10 years after the first dose). | 
| Change in clinical status of OI. | Change in clinical status of OI based on parameters defined under efficacy assessments described in protocol, as assessed by OI clinician. | From baseline to the primary follow-up (6 and 12 months after the last dose) and thereafter assessed annually to the end of the long-time follow-up (10 years after the first dose). | 
| Assessment of biochemical bone turnover by analysis of the markers P-Calcium, P-Phosphate, P-Albumin, S-ALP, fP-PTH, S-25-OH Vitamin D, Bone specific S-ALP, S-CTx, S-Osteocalcin and U-DPD/Krea and U-NTx/Krea in blood and urine samples. | Assessment of biochemical bone turnover. | From baseline to the primary follow-up (6 and 12 months after the last dose) and thereafter assessed annually to the end of the long-time follow-up (10 years after the first dose). |