Treatment of severe congenital Brittle bone disease after or before and after birth.

• Register: EUCTR
• Last refreshed on: 30 June 2019
• Main ID: EUCTR2015-003699-60-SE
• Date of registration: 23/07/2018
• Prospective Registration: Yes
• Primary sponsor: Karolinska Institutet
• Public title: Treatment of severe congenital Brittle bone disease after or before and after birth.
• Scientific 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.
• Date of first enrolment: 28/09/2018
• Target sample size: 210
• Recruitment status: Authorised-recruitment may be ongoing or finished
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2015-003699-60
• Study type: Interventional clinical trial of medicinal product
• Study design: Controlled: yes; Randomised: no; Open: yes; Single blind: no; Double blind: no; Parallel group: no; Cross over: no; Other: no; If controlled, specify comparator, Other Medicinial Product: no; Placebo: no; Other: yes; Other specify the comparator: Historical and untreated prospective controls; Number of treatment arms in the trial: 1
• Phase: Human pharmacology (Phase I): yes Therapeutic exploratory (Phase II): yes Therapeutic confirmatory - (Phase III): no Therapeutic use (Phase IV): no

Countries of recruitment

Sweden

Contacts

• Name: Cecilia Götherström
• Affiliation: Karolinska Institutet

• Name: Cecilia Götherström
• Affiliation: Karolinska Institutet

Key inclusion & exclusion criteria

Inclusion criteria:
Postnatal group
Infants diagnosed with OI type III or severe OI type IV postnatally and prenatally diagnosed cases who did not consent to prenatal treatment.
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 12 months (calculated from gestational week 40+0, i.e. the corrected age)
5. Parent/legal guardian over 18 years of age

Prenatal group
Pregnant women whose fetus has been diagnosed with OI type III or severe OI type IV prenatally and who consent to MSC administration in utero.
1. Woman has signed the informed-consent form
2. Only women where termination of the pregnancy is no longer possible or women that are committed to continue the pregnancy
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

After birth and before the 2nd dose, subjects in the prenatal group will be assessed for the inclusion criteria described for the Postnatal group.

Matched historical controls
Subjects will be identified in historical registries and data will be retrieved from national OI registers and the OI Variant Database.
1. Parent’s/legal guardian’s signed informed-consent form (according to decision from national Ethical review board)
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

Prospective untreated controls
Subjects eligible for the trial but not willing/able to participate will be asked for consent to be included as prospective controls.
- Postnatal participation: For postnatally included prospective untreated controls the inclusion for the postnatal group apply.
- Prenatal participation: For prenatally included prospective untreated controls the inclusion criteria for the prenatal group apply, except inclusion criteria 2.
Are the trial subjects under 18? yes
Number of subjects for this age range: 210
F.1.2 Adults (18-64 years) no
F.1.2.1 Number of subjects for this age range
F.1.3 Elderly (>=65 years) no
F.1.3.1 Number of subjects for this age range

Exclusion criteria:
Postnatal group
Infants diagnosed with OI type III or severe OI type IV postnatally and prenatally diagnosed cases who did not consent to prenatal treatment.
1. Existence of other known disorder that might interfere with the treatment, such as, but not limited to organ dysfunction (for e.g. 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 e.g. 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

Prenatal group
Pregnant women whose fetus has been diagnosed with OI type III or severe OI type IV prenatally and who consent to prenatal MSC administration.
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 e.g. 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

After birth and before the 2nd dose, subjects in the prenatal group will be assessed for the exclusion criteria described for the postnatal group.

Matched historical controls
Subjects will be identified in historical registries and data will be retrieved from national OI registers and the OI Variant Database.
1. Existence of other disorder that might interfere with the trial
2. Abnormal karyotype

Prospective untreated controls
Subjects eligible for the trial but not willing/able

Age minimum:
Age maximum:
Gender:
Female: yes
Male: yes

Health Condition(s) or Problem(s) studied

Treatment of Osteogenesis Imperfecta (OI) type III and severe type IV.

Therapeutic area: Diseases [C] - Congenital, Hereditary, and Neonatal Diseases and Abnormalities [C16]

Intervention(s)

Product Name: Expanded human first trimester fetal liver-derived mesenchymal stem cells
Product Code: BOOST cells
Pharmaceutical Form: Infusion

Primary Outcome(s)

Primary end point(s): The primary endpoints are seriousness, severity and frequency of treatment-related AEs, with specific focus on the following:
• Vital signs in conjunction with the MSC administration
• Administration 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:
a) Allergy or Hypersensitivity responses to antibiotics or antimycotics
b) Development of Fetal Bovine Serum-specific antibodies
c) Hypersensitivity responses to Human Serum Albumin
d) Hypersensitivity to impurities in the IMP
• Prenatal complications (miscarriage, preterm rupture of membranes, spontaneous preterm birth, fetal bleeding) in prenatal group only
• Adverse effects of feto-maternal transmission of donor cells (prenatal group only)
• Tumourigenicity
• Mortality/morbidity

Timepoint(s) of evaluation of this end point: Child
Immediate follow-up: Before, 1 and until 45±3 h after dose 1 and 2, and before, 1 and until 21±3 h after dose 3 and 4
Primary follow-up: 6 and 12 months after the last dose
Long-time follow-up: Minimum once per year for at least 10 years after the first dose

Fetus
Immediate follow-up: Before, 1, 21±3 h and until 45±3h after administration, thereafter every 2 weeks
Primary follow-up: To birth and then according to the description for child

Women
Immediate follow-up: Before, 1, 21±3 h and until 45±3 h after administration, thereafter every 2 weeks until birth
Primary follow-up: To her child's next dose (+4 months)
Long-time follow-up: Minimum once per year for at least 10 years after the first dose

Secondary Objective: The secondary objective is to assess the effect of four doses of BOOST cells in individuals with OI type III or severe type IV. Evaluation is performed before and after all administrations and primary follow-up is performed at 6 and 12 months after the last dose (Period 1) with regard to:
1. Fracture frequency
2. Time (days) to first fracture after last dose
3. Number of fractures at birth (prenatal treatment group only)
4. Bone mineral density
5. Growth (cm and kg)
6. Clinical status of OI
7. Biochemical bone turnover
Thereafter the subject is followed long-time until 10 years after the 1st dose (Period 2).

Main Objective: The primary objective is to assess safety and tolerability in the child, fetus and woman after postnatal or prenatal and postnatal intravenous administration of four doses of BOOST cells in individuals with OI type III or severe type IV. Evaluation is performed before and after all doses and primary follow-up is performed at 6 and 12 months after the last dose (Period 1). Thereafter the subjects are followed yearly until 10 years after the 1st dose (Period 2).

Secondary Outcome(s)

Secondary end point(s): The secondary endpoints are:
• Number of fractures from baseline to primary and long-time follow-up (key secondary endpoint)
• Time (days) to first fracture after last dose
• Number of fractures at birth (prenatal treatment group, and postnatal treatment group when available)
• Change in Bone mineral density (g/cm2) (supportive for the endpoint fracture frequency)
• Growth (cm and kg)
• Change in clinical status of OI based on parameters defined under efficacy assessments
• Change in biochemical bone turnover

Timepoint(s) of evaluation of this end point: Child
Primary: 6 and 12 months after the last dose
Long-time: Minimum once per year for at least 10 years after the first dose

Fetus
Primary: Every 2 weeks until birth and then according to the description for child

Not applicable for the woman.

Secondary ID(s)

KIBB01

Source(s) of Monetary Support

Swedish Research Council

European Commission

Ethics review

Status: Approved
Approval date:
Contact: