Treatment of Severe Osteogenesis Imperfecta by Allogeneic Bone Marrow Transplantation

Treatment of Severe (Types II and III) Osteogenesis Imperfecta by Allogeneic Bone Marrow Transplantation

This protocol was a prospective, Phase I study of allogeneic bone marrow transplantation (BMT) as the primary therapy for Osteogenesis Imperfecta Types II and III. Compatible sibling donors and unrelated donors were stratified and analyzed according to the type of donor. All patients with a sibling donor will received a chemotherapy conditioning regimen; a non-T cell depleted allogeneic marrow, and GVHD prophylaxis. All patients with an unrelated donor will receive a chemoradiotherapy conditioning regimen, a T-cell depleted allogeneic marrow, and GVHD prophylaxis. The primary objective of this study was to investigate the safety and toxicity of these BMT procedures in this particular population.

Study Overview

• Status: Completed
• Conditions: Osteogenesis Imperfecta
• Intervention / Treatment: Drug: Cyclophosphamide; Drug: Busulfan; Other: Bone Marrow Cell Transplantation; Drug: Cyclosporin; Procedure: Mesenchymal Stem Cell Transplantation; Radiation: Irradiation, Total Body

Detailed Description

The secondary objective of the protocol assessed the engraftment of donor mesenchymal cells and their ability to increase the synthesis of normal type I procollagen relative to the synthesis of mutated type I procollagen and to assess whether BMT improves the bone structure and the clinical condition of these patients with OI.

• Study Type: Interventional
• Enrollment (Actual): 9
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • Tennessee
    • Memphis, Tennessee, United States, 38105
      • St. Jude Children's Research Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 3 years and older (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Patient has diagnosis of OI Type II or III. Because there are no specific, defined clinical criteria consistently used to make this diagnosis, we provide the following clinical guidelines to assist in diagnosis. Any appropriate combinations of the following clinical findings will be acceptable.

Diagnosis of OI Type II

• Antenatal ultrasonography (if performed for other indications) by established obstetric impressions including short femurs, a small thoracic cage and poorly mineralized bones. Analysis of collagen synthesized from cultured cells obtained from chorionic villus sampling (CVS) may establish the diagnosis; however, no CVS will be performed specifically for enrollment into this study.
• Clinical examination including prematurity, low birth weight, characteristic facies (blue sclera, beaked nose, extremely soft calvarium), "frog-leg" hips, small thoracic cavity, fractures at birth or shortly thereafter, loose skin or lax joints that cannot be readily explained by other factors.
• Radiographic evaluation demonstrating various aspects of the characteristic picture of telescoped femur, bowed tibias, beaded ribs, flattened vertebral bodies and virtual absence of calvarial mineralization.

Diagnosis of OI Type III

• Antenatal ultrasonography (performed for other indications) by established obstetric impressions for this more moderate form of OI. Chorionic villus sampling will be accepted as above.
• Clinical examination including short stature, bony deformities, many fractures at birth or shortly thereafter. Blue scleras and dental abnormalities are also common.
• Radiographic abnormalities including thin, osteopenic bones of the limbs with evidence of fractures, growth plate abnormalities, and an undermineralized calvarium.
• Diagnosis of other diseases with possibly similar presentation to OI (e.g. hypophosphatasia and rickets) should be excluded by obtaining a serum calcium, phosphate and alkaline phosphatase. These parameters can be expected to be within normal limits (alkaline phosphatase may be somewhat elevated) in patients with OI.
• Age less than 3 years at time of transplant.
• Parents or legal guardians must sign an informed consent indicating that they are aware this is a research study and have been told of its possible benefits and toxic side effects, including treatment related mortality. Patients or their guardians will be given a copy of the consent form.
• Identification of a suitable bone marrow donor.
• Any donor must be of sufficient size so that adequate bone marrow may be harvested.
• HLA mismatched sibling or unrelated donor. DNA typing will be per- formed on unrelated donors. Donors must be a 6/6 match or a 5/6 match (with serologic mismatch at a single Class I allele or mismatch at a single DR1 allele).

Exclusion Criteria:

• Patients who are ventilatory dependent due to primary lung parenchymal disease prior to BMT.
• Patients with evidence of basilar invagination/compression.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Other: 1	Drug: Cyclophosphamide; Drug: Busulfan; Other: Bone Marrow Cell Transplantation; Drug: Cyclosporin; Procedure: Mesenchymal Stem Cell Transplantation
Other: 2	Drug: Cyclophosphamide; Drug: Busulfan; Other: Bone Marrow Cell Transplantation; Procedure: Mesenchymal Stem Cell Transplantation; Radiation: Irradiation, Total Body

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
To investigate the safety and toxicity of allogeneic bone marrow transplantation (BMT) in children with severe Osteogenesis Imperfecta (OI)	1 year

Collaborators and Investigators

• Sponsor: St. Jude Children's Research Hospital

Publications and helpful links

Helpful Links

• Related Info

Study record dates

Study Major Dates

• Study Start: November 1, 1995
• Primary Completion (Actual): July 1, 2000
• Study Completion (Actual): October 1, 2007

Study Registration Dates

• First Submitted: June 23, 2008
• First Submitted That Met QC Criteria: June 23, 2008
• First Posted (Estimate): June 25, 2008

Study Record Updates

• Last Update Posted (Estimate): June 25, 2008
• Last Update Submitted That Met QC Criteria: June 23, 2008
• Last Verified: June 1, 2008

More Information

Terms related to this study

• Keywords: Mesenchymal Stem Cells; Osteogenesis Imperfecta; Bone Marrow Cell Transplantation; Stem Cell Transplantation, Mesenchymal
• Additional Relevant MeSH Terms: Genetic Diseases, Inborn; Musculoskeletal Diseases; Connective Tissue Diseases; Bone Diseases; Bone Diseases, Developmental; Osteochondrodysplasias; Collagen Diseases; Osteogenesis Imperfecta; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Enzyme Inhibitors; Antirheumatic Agents; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Antineoplastic Agents, Alkylating; Alkylating Agents; Myeloablative Agonists; Dermatologic Agents; Antifungal Agents; Calcineurin Inhibitors; Cyclophosphamide; Busulfan; Cyclosporine; Cyclosporins
• Other Study ID Numbers: TOIT