Study Plan

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Groups

This will be a multi-centre, open label, multiple-dose, phase I/II trial of allogeneic expanded human first trimester fetal MSC administration for the treatment of Osteogenesis Imperfecta (OI) type III or severe type IV compared with historical and untreated prospective controls.

 

The trial is divided into 2 parts where Part 1 includes administration of 4 postnatal doses per subject and Part 2 includes administration of one prenatal and 3 postnatal doses per subject:

 

Part 1: Postnatal administration (n=15 in total)

  • Administration of four postnatal doses of MSC to 15 subjects

  • A safety assessment is performed by the Data Safety Monitoring Board (DSMB) of the first MSC administration to the first 5 subjects in any member state treated postnatally to open the prenatal group (Part 2)

 

Part 2: Prenatal administration (n=15 in total)

  • One prenatal MSC dose to 5 subjects in any member state. The 3 postnatal doses to these 5 subjects will proceed as planned.

  • A safety assessment is performed by the DSMB to continue prenatal inclusion of 10 additional subjects

 

Timings

The trial is divided into two periods, where Period 1 includes the administration of MSC and immediate and primary follow-up, and Period 2 includes the long-term follow-up:

 

Period 1: Four doses of MSC every 4 months with immediate follow-up after each MSC dose, and primary follow-up at 6 and 12 months after the fourth and last MSC dose.

 

Period 2: Yearly long-term follow-up until 10 years after the first MSC dose. The long-term follow-up will be done at the routine OI appointments.

Subjects in the postnatal group will be included, receive the first dose and evaluated as soon as possible after birth up to 12 months of corrected age. They will receive 3 additional doses at +4, +8 and +12 months (±1 month) after the 1st dose.

Subjects in the prenatal group will be included in the trial and receive the 1st dose prenatally (between 16+0 – 35+6 weeks+days of gestation) and receive 3 additional postnatal doses at +4 (or as soon as possible after birth), +8 and +12 months (±1 month) after the 1st dose.

Subjects can be enrolled during the initial 3 years of the trial. The expected duration of treatment is 12 months, the minimum treatment time is 9 months and the maximum treatment time is 15 months.

 

Objectives

Primary objectives:

To assess safety and tolerability in the child, fetus and woman after postnatal or prenatal and postnatal intravenous administration of 4 doses of BOOST cells every 4 months in subjects with OI type III or severe type IV.

 

Secondary objectives:

To assess the effect of intravenous administration of 4 doses of BOOST cells every 4 months in subjects with OI type III or severe type IV on:

  1. Number of fractures from baseline to primary and long-time follow-up

  2. Time (days) to first fracture after administration

  3. Number of fractures at birth (prenatal treatment group only, and postnatal treatment group when available)

  4. Bone mineral density (BMD)

  5. Growth

  6. Clinical status of OI

  7. Biochemical bone turnover

 

Exploratory objectives

  1. To study the impact of 4 doses of fetal MSC on Quality of Life (QoL)

  2. To study the extent of donor cell engraftment in tissue samples

  3. To study paracrine effects of 4 doses of fetal MSC

  4. To study the effect of 4 doses of fetal MSC on endogenous immune cells

  5. To study non-invasive prenatal diagnosis of OI (will not be used in the diagnostic procedure in the trial)

 

Endpoints

Primary Endpoints: 

The primary endpoint is safety and tolerability measured as seriousness, severity and frequency of MSC administration related adverse events (AEs), with specific focus on the following:

 

  1. Vital signs in conjunction with the MSC administration

  2. Transfusion reactions (administration toxicity, allergy, embolism)

  3. 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

  4. Prenatal complications (miscarriage/intrauterine fetal death, premature birth, infection in utero or persistent [>1 min] fetal bradycardia) in the prenatal group

  5. Adverse effects of feto-maternal transmission of donor cells in the prenatal group

  6. Tumourigenicity

  7. Mortality/morbidity

 

Key Secondary Endpoint:

  1. Number of fractures from baseline to primary and long-time follow-up 

 

Secondary Endpoints:

  1. Time (days) to first fracture after each MSC administration

  2. Number of fractures at birth (prenatal group, and postnatal group when available)

  3. Change in BMD (g/cm2) 

  4. Growth (cm and kg) 

  5. Change in clinical status of OI based on parameters defined under efficacy assessments described below

  6. Change in biochemical bone turnover

 

Exploratory endpoints:

  1. The QoL will be assessed through the Infant Toddler Quality of Life Questionnaire™ (ITQOL)

  2. Tissue samples (bone, bone marrow, muscle and skin, placenta, amniotic fluid, umbilical cord, umbilical cord blood, peripheral blood) will be collected in conjunction with clinically indicated surgery and at birth (prenatal group only) and analysed for donor cell engraftment

  3. Paracrine effects will be analysed from plasma isolated from peripheral blood

  4. Effect on immune cells will be analysed from peripheral blood

  5. Non-invasive prenatal diagnosis will be studied during the trial

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This project has received funding from the European Union's Horizon 2020 research and innovation programme under grant agreement 681045

© 2019 BOOSTB4 Consortium