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Treatment of Severe Osteogenesis Imperfecta by Allogeneic Bone Marrow Transplantation

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ClinicalTrials.gov Identifier: NCT00705120
Recruitment Status : Completed
First Posted : June 25, 2008
Last Update Posted : June 25, 2008
Sponsor:
Information provided by:
St. Jude Children's Research Hospital

Brief Summary:
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.

Condition or disease Intervention/treatment Phase
Osteogenesis Imperfecta Other: Bone Marrow Cell Transplantation Radiation: Irradiation, Total Body Drug: Cyclophosphamide Drug: Cyclosporin Procedure: Mesenchymal Stem Cell Transplantation Drug: Busulfan Phase 1

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  (Clinical Trial)
Actual Enrollment : 9 participants
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Treatment of Severe (Types II and III) Osteogenesis Imperfecta by Allogeneic Bone Marrow Transplantation
Study Start Date : November 1995
Actual Primary Completion Date : July 2000
Actual Study Completion Date : October 2007


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



Primary Outcome Measures :
  1. To investigate the safety and toxicity of allogeneic bone marrow transplantation (BMT) in children with severe Osteogenesis Imperfecta (OI) [ Time Frame: 1 year ]


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Ages Eligible for Study:   3 Years and older   (Child, Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT00705120


Locations
United States, Tennessee
St. Jude Children's Research Hospital
Memphis, Tennessee, United States, 38105
Sponsors and Collaborators
St. Jude Children's Research Hospital
Investigators
Principal Investigator: Kimberly Kasow, DO St. Jude Children's Research Hospital

Additional Information:
Responsible Party: Edwin M Horwitz, MD, PhD, St. Jude Children's Research Hospital
ClinicalTrials.gov Identifier: NCT00705120     History of Changes
Other Study ID Numbers: TOIT
First Posted: June 25, 2008    Key Record Dates
Last Update Posted: June 25, 2008
Last Verified: June 2008

Keywords provided by St. Jude Children's Research Hospital:
Osteogenesis Imperfecta
Bone Marrow Cell Transplantation
Mesenchymal Stem Cells
Stem Cell Transplantation, Mesenchymal

Additional relevant MeSH terms:
Osteogenesis Imperfecta
Osteochondrodysplasias
Bone Diseases, Developmental
Bone Diseases
Musculoskeletal Diseases
Genetic Diseases, Inborn
Collagen Diseases
Connective Tissue Diseases
Cyclophosphamide
Cyclosporins
Cyclosporine
Busulfan
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Antirheumatic Agents
Antineoplastic Agents, Alkylating
Alkylating Agents
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Myeloablative Agonists
Enzyme Inhibitors
Antifungal Agents
Anti-Infective Agents
Dermatologic Agents
Calcineurin Inhibitors