Boost to Brittle Bones - Stem Cell Transplantation for Treatment of Brittle Bones

Study Overview
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Brief Summary
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An exploratory, open label, multiple dose, phase I/II trial (n=15) evaluating safety and efficacy of intravenous and intraosseous infusion of allogeneic expanded fetal mesenchymal stem cells (MSC) for the treatment of severe Osteogenesis Imperfecta (OI) compared with historical and untreated prospective controls.

Official Title
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Exploratory, Open Label, Multiple Dose, Phase I/II Trial Evaluating Safety, Efficacy of Intravenous and Intraosseous Infusion of Allogeneic Fetal Mesenchymal Stem In Treatment of Severe Osteogenesis Imperfecta Compared With 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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(i)Inclusion Criteria Treatment 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 between 1 to 4 years BP treatment initiated before inclusion Parent/legal guardian over 18 years of age (ii)Inclusion Criteria Prospective Untreated Control Group and 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) Age between 4 to 8 years Parent/legal guardian over 18 years of age (iii)Exclusion Criteria Treatment group Prospective and historical control group: Existence of other known disorder that might interfere with the treatment (such as severe malformations, congenital heart defect, hypoxic encephalopathy (l-lll), neurological problems, immune deficiencies, muscle diseases, syndromes) diagnosed by clinical examination Any contraindication for invasive procedures such as a moderate/severe bleeding tendency or contagious infections Abnormal karyotype or other confirmed genetic syndromes Oncologic disease Inability to comply with the trial protocol and evaluation and follow-up schedule Inability to understand the information and to provide informed consent

Ages Eligible for Study
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Minimum Age: 1 Year
Maximum Age: 8 Years

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
Interventional Model Description: Historical and Untreated prospective control and Treatment group
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| No Intervention: Prospective Control (Untreated) and historical controls<br>Subjects eligible for the trial but not willing/able to participate in any of the experimental arms Matched historical controls. Subjects will be identified in historical registries and data will be retrieved from OI database | |
| Experimental: Treatment<br>Administration of four doses of BOOST cells with the first dose between 1-4 years of age 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>|

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 (AEs) | The primary endpoint is safety and tolerability measured as seriousness, severity and frequency of treatment related adverse events (AEs)/Serious AE (SAE)/Suspected Unexpected Serious Adverse Reaction (SUSAR)with specific focus on the following: Vital signs in conjunction with the MSC infusion Transfusion reactions (infusion toxicity, embolism, allergy, infections) Immune reaction towards the cells, donor-specific antibodies, graft rejection, Graft versus Host Disease, autoimmunity) Tumourigenicity Mortality/morbidity | From baseline to 16 months follow up | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of fractures [ Time Frame: From baseline to 16 months follow-up ] | Number of fractures. | From baseline to 16 months follow up | 
| Time (days) to first fracture after each stem cell administration. [ Time Frame: From each dose of stem cells to the time point of the first fracture. | Time (days) to first fracture after each stem cell administration. Number of fractures | From baseline to 16 months follow up | 
| Change in bone-marrow density (g/cm2). [ Time Frame: From baseline to the primary follow-up (From baseline to 16 months follow up) | Change in bone-marrow density (g/cm2). | From baseline to 16 months follow up | 
| Growth (cm). [ Time Frame: From baseline to16 months follow up] | Growth (cm) as assessed by clinician | From baseline to 16 months follow up | 
| Weight (kg). [ Time Frame: From baseline to 16 months follow up] | Growth (kg) as assessed by clinician. | From baseline to 16 months follow up | 
| Change in clinical status of OI. [ Time Frame: From baseline to 16 months follow up] | Change in clinical status of OI based on parameters defined under efficacy assessments described in protocol, as assessed by OI clinician. | From baseline to 16 months follow up | 
| Assessment of biochemical bone turnover by analysis of the markers P-Calcium (mg %) in blood samples. | Assessment of biochemical bone turnover marker P-Calcium (mg %) | From at baseline to 16 months follow up | 
| Assessment of biochemical bone turnover by analysis of the markers P-Phosphate (mg %) in blood samples. | Assessment of biochemical bone turnover marker P-Phosphate (mg %) | From baseline to 16 months follow up | 
| Assessment of biochemical bone turnover by analysis of the markers P-Albumin (g/dL) | Assessment of biochemical bone turnover marker P-Albumin (g/dL) | From baseline to 16 months follow up | 
| Assessment of biochemical bone turnover by analysis of the markers S-ALP (IU/L) in blood samples. | Assessment of biochemical bone turnover marker S-ALP (IU/L) | From baseline to 16 months follow up | 
| Assessment of biochemical bone turnover by analysis of the markers S-CTx (mg %) in blood samples. | Assessment of biochemical bone turnover marker S-CTx (mg %) | From baseline to 16 months follow up | 
| Assessment of biochemical bone turnover by analysis of the markers fP-PTH (pg/mL)in blood samples. | Assessment of biochemical bone turnover marker fP-PTH (pg/mL) | From baseline to 16 months follow up | 
| Assessment of biochemical bone turnover by analysis of the markers Vitamin D (nmol/L) in blood samples. | Assessment of biochemical bone turnover marker Vitamin D (nmol/L) | From baseline to 16 months follow up | 
| Assessment of biochemical bone turnover by analysis of the markers Bone specific S-ALP (μg/L) in blood samples. | Assessment of biochemical bone turnover marker Bone specific S-ALP (μg/L) | From baseline to 16 months follow up | 
| Assessment of biochemical bone turnover by analysis of the markers S-Osteocalcin (ng/mL) in blood samples. | Assessment of biochemical bone turnover marker S-Osteocalcin (ng/mL) | From baseline to 16 months follow up | 
| Assessment of biochemical bone turnover by analysis of the markers U-DPD/Krea and U-NTx/Krea (mg %) in blood samples. | Assessment of biochemical bone turnover marker U-DPD/Krea and U-NTx/Krea (mg %) | From baseline to 16 months follow up | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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OI, Brittle bone disease, Hereditary bone fragility