Clinical trial NCT05559801: Mesenchymal Cell Therapy in Osteogenesis Imperfecta (OI)
Official title: A Phase 1/2 Study to Examine the Safety and Preliminary Efficacy of Mesenchymal Stromal Cells on Linear Growth and Bone Health Parameters in Children With Type 3 Osteogenesis Imperfecta (OI)
Study type: INTERVENTIONAL
Overall status: NOT_YET_RECRUITING
Phase: PHASE1
PHASE2
Conditions: Osteogenesis Imperfecta
Osteogenesis Imperfecta Type III
Lead sponsor: Emory University
Sponsor class: OTHER
First posted: 2022-09-29
Enrollment: 12
Sex: ALL
Minimum age (years): 3
Maximum age (years): 10
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: This is a Phase 1/2 study to determine the safety and efficacy of allogeneic (third party), bone-marrow derived mesenchymal stromal cells (MSCs) for the treatment of Osteogenesis Imperfecta (OI) Type 3. It will evaluate this by looking at whether there are treatment related infusion reactions, and assessing linear growth rates and bone health, both of which are impaired in patients ages 3-10 with Osteogenesis Imperfecta Type 3. This is a single-site non-randomized clinical trial, that will take place at Children's Healthcare of Atlanta (CHOA) at Egleston and Emory Children's Center.

Detailed description: This is a Phase 1/2 study to determine the safety and efficacy of allogeneic (third party), bone-marrow derived mesenchymal stromal cells (MSCs) for the treatment of Osteogenesis Imperfecta (OI) Type 3. It will evaluate this by looking at whether there are treatment related infusion reactions, and assessing linear growth rates and bone health, both of which are impaired in patients ages 3-10 with Osteogenesis Imperfecta Type 3. This is a single-site non-randomized clinical trial, that will take place at Children's Healthcare of Atlanta (CHOA) at Egleston and Emory Children's Center.

MSCs will be infused through IV every 4 months for 6 total infusions. There will be a baseline visit before MSC therapy is initiated, and there will be a follow up visits every 4 months for 1 year after the final MSC infusion. These infusions will take place in between pamidronate infusions (i.e. 2 months after the last pamidronate infusion, and 2 months before the next one). Pamidronate aids in treatment of bone pain and bone mineral density but does not correct the underlying defect nor does it show substantial improvements in linear growth.

After the MSC infusions, patients will be provided an overnight at Ronald McDonald House, or a hospital affiliated hotel so they can be near to the hospital in case of any unanticipated effects, and for a follow up visit the next morning.

Labs will be collected during every visit to look at bone metabolism. Limb and bone age x-rays, pQCT scans, and dual-energy x-ray absorptiometry (DXA) scans will be completed annually, while spine films will be completed every 18 months. These images will directly examine bone health. Body measurements will be taken every visit as well to assess linear growth. The patients' parents will complete events diaries and submit them each infusion day to evaluate fractures that occurred between visits. Patients and their parents will also complete quality of life surveys once a year.

There will be financial compensation for each study visit. Subjects will also be provided a free lunch on days when radiology visits occur and will be reimbursed for parking.

Subjects will be identified and recruited mainly through Children's endocrinology clinic. There will also be advertisements to the OI foundation, and neighboring pediatric hospitals with OI programs such as University of Alabama at Birmingham, and Vanderbilt. If identified as eligible to participate, the study team will seek approval by the subjects' primary endocrinologist. The consent process will then take place in person during a baseline visit.

There is an optional part of the study that involves donation of a bone fragment that is taken out during a routine surgical rodding procedure. This piece of bone is removed and discarded, if it is not donated, making it minimal risk. Bone sample donation will be available to OI Type 3 subjects receiving MSCs, and to OI Type 3 subjects who are not receiving MSCs but want to participate in research.

Leftover blood samples, and bone fragments may be stored for future research by the sponsor of this study.

The purpose of this study is to help doctors and scientists learn if serial MSC infusions will safely and effectively aid in growth, bone health, and ultimately improve motoric function and quality of life in this population.

Eligibility criteria: Inclusion Criteria:

* 1. Parent/legal guardian must be willing to sign consent forms to participate in this trial 2. Participants must be \>3 years of age and \<10 years of age at time of enrollment 3. Must carry mutation in either COL1A1 or COL1A2 genes and based on clinical assessment have severe Type 3 OI\* 4. Must be pre-pubertal to minimize potential influence of hormonal effects on growth velocity and BMD; for children who may be entering puberty at or near upper end of this age bracket, puberty assessment will be based on clinical and laboratory findings 5. Must have received IV pamidronate therapy for at least one year prior to study initiation.

  * Type 3 OI will be confirmed with an Invitae Skeletal Dysplasia test, and clinical assessment including:

    * Blue/grey sclerae
    * Presence of prenatal fractures (on ultrasound when available)
    * Deformities present at birth (confirming prenatal fractures)
    * Severity of fractures and progressive deformities although no absolute 'number' of fractures is available

Exclusion Criteria:

1. Lacking confirmation of mutation in either COLA1A1 or COL1A2 genes
2. Other pathological types of OI
3. Any concurrent medical issue(s) known to decrease BMD (e.g., malabsorption conditions, glucocorticoid use)
4. Participation in other clinical trial
5. Vitamin D deficiency (\<20 ng/dL) despite treatment
6. Clinically significant thrombocytopenia as defined by a platelet count of \< 150,000x103/microliter ; anemia as defined by hemoglobin \< 5th percentile for age (\<11.5g/dL); neutropenia as defined by absolute neutrophil count \< 1.5 x103/microliter; or elevations in the white blood cell count as defined by 3-6 year old-WBC \> 15.5WBC x 103/microliter; 6-9 year old WBC \>13.5 x103/microliter (Flerlage 2015)

8. PRA screening positive for anti-HLA antibodies 9. Elevated LFT's greater than 2 times the upper limit of normal 10. Other genetic disorders 11. Other skeletal dysplasia disorders 12. Other primary or secondary bone disorders 13. History of acute or chronic infections 14. History of cancer 15. History of thrombosis or prothrombotic disorders 16. History of heart disease 17. History of diabetes 18. History of strokes 19. History of vascular conditions 20. History of lung disease

Primary outcomes:
measure: Recruitment rate of participants
timeFrame: Up to 24 months post-intervention
measure: Number of participants with correctly collected data for the study outcomes
timeFrame: Up to 24 months post-intervention
measure: Total number of visits with protocol deviation
timeFrame: Up to 24 months post-intervention
measure: Visit attendance by participants
timeFrame: Up to 1 year post last infusion intervention
measure: Patient retention rate
timeFrame: Up to 1 year post last infusion intervention
measure: Patient Primary Clinical Outcome Retention Rate
timeFrame: Up to 1 year post last infusion intervention
measure: Change in acceptability from baseline
timeFrame: Baseline, Up to 36 months post-intervention
measure: Number of unexpected adverse events
timeFrame: Up to 1 year post last infusion intervention
measure: Number of participants with change in vital signs from baseline
timeFrame: Baseline, 10 minutes pre-intervention, 15 minutes post-intervention, 30 minutes post-intervention, 1 hour post-intervention, 1 hour post completion of the infusion
measure: Number of participants with changes in laboratory panels from baseline (CBC, CMP)
timeFrame: Baseline, every 4 months post-intervention
measure: Change in number of participants with changes in radiological parameters
timeFrame: Baseline, 8, 20 and 32 months post-intervention
measure: Change in annualized linear growth velocity
timeFrame: Baseline, every 4 months until 1 year after last infusion intervention
measure: Change in fracture rate from baseline
timeFrame: Baseline, every 4 months post-intervention until 1 year after last infusion intervention
measure: Change in bone mineral density from baseline
timeFrame: Baseline, yearly until 1 year after last infusion intervention
measure: Change in bone age
timeFrame: Baseline, yearly until 1 year after last infusion intervention
measure: Change in Vertebral Compression Fractures (VCFs)
timeFrame: Baseline, every 18 months until one year after last infusion intervention
Secondary outcomes:
measure: Number of participants with changes in bone metabolism markers
timeFrame: Baseline, every 12 months post-intervention, and at the conclusion of the study (up to 36 months post-intervention)
measure: Change in Limb Deformity Modified EOS Questionnaire (LD-EOSQ-22) from baseline
timeFrame: Baseline, annually until 1 year after last infusion
measure: Change in BAMF (Brief Assessment of Motor Function) from baseline
timeFrame: Baseline, annually until 1 year after last infusion
measure: Change in Pediatric Orthopedic Data Collection Instrument (PODCI) from baseline
timeFrame: Baseline, annually until 1 year after last intervention
Other outcomes:
Locations:
Study officials:
affiliation: Emory University
name: Doris Fadoju, MD
role: PRINCIPAL_INVESTIGATOR
References: