Boost Brittle Bones Before Birth

Osteogenesis Imperfecta Clinical Trial

— 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

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT03706482
• Other study ID #: KIBB01
• Secondary ID: 2015-003699-60
• Status: Active, not recruiting
• Phase: Phase 1/Phase 2
• Start date: August 12, 2019
• Est. completion date: April 2030

Study information

• Verified date: March 2024
• Source: Karolinska Institutet
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 18
• Est. completion date: April 2030
• Est. primary completion date: April 2030
• Accepts healthy volunteers: No
• Gender: All
• Age group: N/A to 18 Months

Eligibility

Inclusion Criteria Postnatal Group:

1. Parent's/legal guardian's signed informed-consent form

2. Clinical diagnosis of OI type III or severe type 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 severe type 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. No lung hypoplasia (type II OI).

2. Abnormal karyotype

Exclusion Criteria Prospective Untreated Control Group:

• Postnatal inclusion: The exclusion criteria, except exclusion criterium 2, 3, 4 and 5 (Contraindication for invasive procedure, Known risk factor for clotting, Positive Donor Specific Antibody-test and Known allergy/hypersensitivity to Fungizone and/or Gensumycin) for the postnatal group apply.
• Prenatal inclusion: The exclusion criteria, except exclusion criterium 1, 4, 5, 6 and 7 (Multiple pregnancy, Contraindication for invasive procedure, Known risk factor for clotting, Positive Donor Specific Antibody-test and Known allergy/hypersensitivity to Fungizone and/or Gensumycin) for the prenatal group apply.

Related Conditions & MeSH terms

• Osteogenesis Imperfecta

Intervention

Biological:
• BOOST cells
Four doses of expanded human 1st trimester fetal liver-derived mesenchymal stem cells.

Locations

Country	Name	City	State
Sweden	Karolinska University Hospital	Stockholm

Sponsors (8)

Lead Sponsor	Collaborator
Karolinska Institutet	Great Ormond Street Hospital for Children NHS Foundation Trust, Karolinska University Hospital, Leiden University Medical Center, Lund University, UMC Utrecht, Universitätsklinikum Köln, University College, London

Country where clinical trial is conducted

Sweden, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Impact on the subjects Quality of Life: Infant Toddler Quality of Life Questionnaire™ (ITQOL)	Quality of life assessed using the Infant Toddler Quality of Life Questionnaire™ (ITQOL).	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	Incidence of donor cells engrafted into patient tissue samples assessed by histology.	Donor cell engraftment.	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	Analysis of an array of cytokines and micro vesicles to evaluate paracrine effects.	Paracrine effects will be analysed from plasma isolated from peripheral blood.	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	Assess the potential of non-invasive methods of prenatal diagnosis for OI by genetic analysis of parent DNA.	Non-invasive prenatal diagnosis will be studied during the trial.	From baseline to birth for prenatal group.
Primary	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	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).
Secondary	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.
Secondary	Numbers of fractures at birth.	Numbers of fractures at birth.	Evaluated at birth.
Secondary	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).
Secondary	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).
Secondary	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).
Secondary	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).
Secondary	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).

External Links

•   BOOSTB4 consortium web site