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Boost Brittle Bones Before Birth (BOOSTB4)

Primary Purpose

Osteogenesis Imperfecta

Status
Active
Phase
Phase 1
Locations
Sweden
Study Type
Interventional
Intervention
BOOST cells
Sponsored by
Karolinska Institutet
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Osteogenesis Imperfecta

Eligibility Criteria

undefined - 18 Months (Child)All SexesDoes not accept healthy volunteers

Inclusion Criteria Postnatal 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 less than 18 months (calculated from gestational week 40+0, i.e. the corrected age)
  5. Parent/legal guardian over 18 years of age

Inclusion Criteria Prenatal Group:

  1. Woman has signed the informed-consent form
  2. 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
  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

Inclusion Criteria 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. Data on fractures and growth is available
  4. 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:

  1. 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.
  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 example 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

Exclusion Criteria Prenatal Group:

  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 example 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

Exclusion Criteria Historical Control Group:

  1. Existence of other disorder that might interfere with the trial
  2. Abnormal karyotype

Exclusion Criteria Prospective Untreated Control Group:

  • Postnatal inclusion: The exclusion criteria, except exclusion criterium 2, 3, 4 and 5 for the postnatal group apply.
  • Prenatal inclusion: The exclusion criteria, except exclusion criterium 1, 4, 5, 6 and 7 for the prenatal group apply.

Sites / Locations

  • Karolinska University Hospital

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm Type

Experimental

Experimental

No Intervention

No Intervention

Arm Label

Postnatal

Prenatal

Prospective control (untreated)

Historic control

Arm Description

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.

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.

1-30 participants. Subjects eligible for the trial but not willing/able to participate in any of the experimental arms.

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).

Outcomes

Primary Outcome Measures

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

Secondary Outcome Measures

Number of fractures.
Number of fractures.
Time (days) to first fracture after each stem cell administration.
Time (days) to first fracture after each stem cell administration.
Numbers of fractures at birth.
Numbers of fractures at birth.
Change in bone-marrow density (g/cm2).
Change in bone-marrow density (g/cm2).
Growth (cm).
Growth (cm) as assessed by clinician.
Growth (kg).
Growth (kg) as assessed by clinician.
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.
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.

Full Information

First Posted
October 5, 2018
Last Updated
October 17, 2023
Sponsor
Karolinska Institutet
Collaborators
Karolinska University Hospital, Great Ormond Street Hospital for Children NHS Foundation Trust, University College, London, Universitätsklinikum Köln, UMC Utrecht, Leiden University Medical Center, Lund University
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1. Study Identification

Unique Protocol Identification Number
NCT03706482
Brief Title
Boost Brittle Bones Before Birth
Acronym
BOOSTB4
Official Title
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
Study Type
Interventional

2. Study Status

Record Verification Date
October 2023
Overall Recruitment Status
Active, not recruiting
Study Start Date
August 12, 2019 (Actual)
Primary Completion Date
April 2030 (Anticipated)
Study Completion Date
April 2030 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
Karolinska Institutet
Collaborators
Karolinska University Hospital, Great Ormond Street Hospital for Children NHS Foundation Trust, University College, London, Universitätsklinikum Köln, UMC Utrecht, Leiden University Medical Center, Lund University

4. Oversight

Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes

5. Study Description

Brief Summary
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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Osteogenesis Imperfecta

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 1, Phase 2
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Non-Randomized
Enrollment
18 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Postnatal
Arm Type
Experimental
Arm Description
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.
Arm Title
Prenatal
Arm Type
Experimental
Arm Description
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.
Arm Title
Prospective control (untreated)
Arm Type
No Intervention
Arm Description
1-30 participants. Subjects eligible for the trial but not willing/able to participate in any of the experimental arms.
Arm Title
Historic control
Arm Type
No Intervention
Arm Description
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).
Intervention Type
Biological
Intervention Name(s)
BOOST cells
Intervention Description
Four doses of expanded human 1st trimester fetal liver-derived mesenchymal stem cells.
Primary Outcome Measure Information:
Title
Safety and tolerability measured as seriousness, severity and frequency of treatment related adverse events.
Description
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
Time Frame
From baseline to the long-time follow-up (10 years after the first dose).
Secondary Outcome Measure Information:
Title
Number of fractures.
Description
Number of fractures.
Time Frame
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).
Title
Time (days) to first fracture after each stem cell administration.
Description
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. Assessed up to 10 years after the first stem cell dose.
Title
Numbers of fractures at birth.
Description
Numbers of fractures at birth.
Time Frame
Evaluated at birth.
Title
Change in bone-marrow density (g/cm2).
Description
Change in bone-marrow density (g/cm2).
Time Frame
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).
Title
Growth (cm).
Description
Growth (cm) as assessed by clinician.
Time Frame
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).
Title
Growth (kg).
Description
Growth (kg) as assessed by clinician.
Time Frame
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).
Title
Change in clinical status of OI.
Description
Change in clinical status of OI based on parameters defined under efficacy assessments described in protocol, as assessed by OI clinician.
Time Frame
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).
Title
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.
Description
Assessment of biochemical bone turnover.
Time Frame
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).
Other Pre-specified Outcome Measures:
Title
Impact on the subjects Quality of Life: Infant Toddler Quality of Life Questionnaire™ (ITQOL)
Description
Quality of life assessed using the Infant Toddler Quality of Life Questionnaire™ (ITQOL).
Time Frame
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).
Title
Incidence of donor cells engrafted into patient tissue samples assessed by histology.
Description
Donor cell engraftment.
Time Frame
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).
Title
Analysis of an array of cytokines and micro vesicles to evaluate paracrine effects.
Description
Paracrine effects will be analysed from plasma isolated from peripheral blood.
Time Frame
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).
Title
Assess the potential of non-invasive methods of prenatal diagnosis for OI by genetic analysis of parent DNA.
Description
Non-invasive prenatal diagnosis will be studied during the trial.
Time Frame
From baseline to birth for prenatal group.

10. Eligibility

Sex
All
Maximum Age & Unit of Time
18 Months
Accepts Healthy Volunteers
No
Eligibility Criteria
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.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Eva Åström, MD PhD
Organizational Affiliation
Karolinska University Hospital
Official's Role
Principal Investigator
Facility Information:
Facility Name
Karolinska University Hospital
City
Stockholm
ZIP/Postal Code
171 76
Country
Sweden

12. IPD Sharing Statement

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