Boost to Brittle Bones - Stem Cell Transplantation for Treatment of Brittle Bones (BOOST2B)

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

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.

Study Overview

• Status: Unknown
• Conditions: Osteogenesis Imperfecta
• Intervention / Treatment: Biological: BOOST cells

• Study Type: Interventional
• Enrollment (Anticipated): 15
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• India
  • Tamil Nadu
    • Vellore, Tamil Nadu, India, 632004
      • Recruiting
      • Christian Medical College
      • Contact: Suhasini Ganesh, M.Pharm; Phone Number: 91-416-2285117; Email: brittlebonekids@cmcvellore.ac.in
      • Contact: Suhasini Ganesh, M Pharm; Phone Number: 91-416-2285117; Email: brittlebonekids@cmcvellore.ac.in

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 1 year to 8 years (Child)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

(i)Inclusion Criteria Treatment group

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 between 1 to 4 years
5. BP treatment initiated before inclusion
6. Parent/legal guardian over 18 years of age

(ii)Inclusion Criteria Prospective Untreated Control Group and Historical Control Group:

1. Parent's/legal guardian's signed informed-consent form
2. Clinical and molecular diagnosis of OI (Glycine substitution in the collagen triple-helix encoding region of either the COL1A1 or COL1A2 gene)
3. Age between 4 to 8 years
4. Parent/legal guardian over 18 years of age

(iii)Exclusion Criteria Treatment group Prospective and historical control group:

1. 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
2. Any contraindication for invasive procedures such as a moderate/severe bleeding tendency or contagious infections
3. Abnormal karyotype or other confirmed genetic syndromes
4. Oncologic disease
5. Inability to comply with the trial protocol and evaluation and follow-up schedule
6. Inability to understand the information and to provide informed consent

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
No Intervention: Prospective Control (Untreated) and historical controls; 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; 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; Four doses of expanded human 1st trimester fetal liver-derived mesenchymal stem cells.

What is the study measuring?

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

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Impact on the subjects Quality of Life: Pediatric Quality of Life Questionnaire™ (PedsQOL) [ Time Frame: From baseline to the 16 month follow-up	Quality of life assessed using the Infant Pediatric Quality of Life Questionnaire™ (PedsQOL).	From baseline to 16 months follow up
Incidence of donor cells engrafted into patient tissue samples assessed by histology. [ Time Frame: From baseline to the 16 month follow up	Donor cell engraftment.	From baseline to 16 months follow up
Analysis of an array of cytokines and micro vesicles to evaluate paracrine effects. [ Time Frame: From baseline to the 16 month follow up	Paracrine effects will be analysed from plasma isolated from peripheral blood.	From baseline to 16 months follow up

Collaborators and Investigators

• Sponsor: Christian Medical College, Vellore, India
• Collaborators: Karolinska Institutet; Vinnova; Ministry of Science and Technology, India
• Investigators: Principal Investigator: Vrisha Madhuri, MS Orth, Christian Medical College, Vellore, India

Publications and helpful links

Helpful Links

• Boost to Brittle Bones

Study record dates

Study Major Dates

• Study Start (Actual): May 20, 2019
• Primary Completion (Anticipated): November 1, 2021
• Study Completion (Anticipated): December 1, 2021

Study Registration Dates

• First Submitted: September 18, 2020
• First Submitted That Met QC Criteria: November 6, 2020
• First Posted (Actual): November 10, 2020

Study Record Updates

• Last Update Posted (Actual): November 10, 2020
• Last Update Submitted That Met QC Criteria: November 6, 2020
• Last Verified: November 1, 2020

More Information

Terms related to this study

• Keywords: OI, Brittle bone disease; Hereditary bone fragility
• Additional Relevant MeSH Terms: Genetic Diseases, Inborn; Musculoskeletal Diseases; Connective Tissue Diseases; Bone Diseases; Bone Diseases, Developmental; Osteochondrodysplasias; Collagen Diseases; Osteogenesis Imperfecta
• Other Study ID Numbers: CMCB2B0X

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No