Boost Brittle Bones Before Birth (BOOSTB4)

Karolinska Institute

Status and phase: Active, not recruiting; Phase 2; Phase 1

Conditions: Osteogenesis Imperfecta

Treatments: Biological: BOOST cells

Study type: Interventional

Funder types: Other

Identifiers

NCT03706482

2015-003699-60 (EudraCT Number)

KIBB01

Details and patient eligibility

About

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.

Enrollment: 18 patients

Sex: All

Ages: Under 18 months old

Volunteers: No Healthy Volunteers

Inclusion and exclusion criteria

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.

Trial design

Primary purpose: Treatment

Allocation: Non-Randomized

Interventional model: Parallel Assignment

Masking: None (Open label)

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18 participants in 4 patient groups

Postnatal

Experimental group

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.

Treatment:

Biological: BOOST cells

Prenatal

Experimental group

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.

Treatment:

Biological: BOOST cells

Prospective control (untreated)

No Intervention group

Description:

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

Historic control

No Intervention group

Description:

18-90 participants (1-5 per included and treated subject). 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).