Clinical Trial: Treatment of Atrophic Nonunion Fractures by Autologous Mesenchymal Stem Cell Percutaneous Grafting

Study Status: Not yet recruiting
Recruit Status: Not yet recruiting
Study Type: Interventional

Official Title: Treatment of Atrophic Nonunion Fractures by Autologous Mesenchymal Stem Cell Percutaneous Grafting. A Randomized, Double-blind, Controlled Study

Brief Summary:

Bone fractures heal most of the time particularly well and without complications. The solidification takes rarely more than two to three months. The wound healing depends greatly on a good blood supply and needs several steps. These processes culminate in a new mass of heterogeneous tissue which is known as the fracture callus. Unfortunately, 2%-5% bone fractures cannot achieve a proper solidification and between the ununited fragments a scar tissue appears. This incorrect healing induces pain and even infections. When this situation persists more than 6 months, it is referred to as nonunion fracture, which will require some form of intervention to stimulate the natural healing process of the body. First of all, good surgical techniques with stable immobilization should be applied and local infection should be excluded. Then stimulation of the callus is required. Cell therapy with bone marrow cells has emerged as a promising new approach for bone regeneration. Animal studies as well as preliminary human studies have shown that Mesenchymal Stem Cells, a particular kind of stem cells isolated from the bone marrow, could induce callus formation when injected in the nonunion site of a broken bone.

In this study the investigators aim at determining whether Mesenchymal Stem Cells (MSC) isolated from the patient's bone marrow and injected in the nonunion site could be a safe and effective treatment for nonunion fractures. Patients will be randomized in two groups; one injected with Mesenchymal Stem Cell and the other injected with placebo. The investigators seek also to know how long it takes to develop the callus formation and whether there is a partial or a complete callus formation.

Detailed Summary:
Sponsor: University Hospital of Liege

Current Primary Outcome:

• Safety of Mesenchymal Stem Cells injection in nonunion fractures. [ Time Frame: 12 months ]
  Follow-up for revealing any significant immediate or late adverse effects.
• Proportion of patients receiving Mesenchymal Stem Cells that develop a partial or complete callus at 6 and 12 months, compared to patients receiving placebo. [ Time Frame: 6 and 12 months ]
  Radiological evaluation of the callus by standard X-rays and computed tomography (CT).

Original Primary Outcome:

• Safety of Mensechymal Stem Cells injection in nonunion fractures. [ Time Frame: 12 months ]
  Follow-up for revealing any significant immediate or late adverse effects.
• Proportion of patients receiving Mensechymal Stem Cells that develop a partial or complete callus at 6 and 12 months compared to patients receiving placebo. [ Time Frame: 6 and 12 months ]

  -Radiological evaluation of the callus by standard X-rays. This evaluation will be stopped as soon as a score 3 is achieved. Four-point scale will be used for the evaluation.

  • 0 = no bone formation
  • 1 = at least bone spot
  • 2 = partial callus
  • 3 = complete callus

  CT in coronal and sagital planes at baseline and when standard X-rays will be evaluated at score 3. Further follow up will be done by CT only:

  • in case of score 0: every 3 months.
  • in case of score 2: every 6 weeks.
  • CT will be performed until a score 3 is confirmed or until month 12, whichever comes first.

Current Secondary Outcome:

• Proportion of patients receiving Mensechymal Stem Cells that develop a partial or complete callus at 2, 3, 4, 8 and 10 months, compared to patients receiving placebo [ Time Frame: 2, 3, 4, 8 and 10 months ]
  Radiological evaluation of the callus by standard X-rays and computed tomography (CT).
• Timing of development of a partial or complete callus in the 2 groups. [ Time Frame: 12 months for one injection or 18 months when a second injection is needed ]
  Time necessary for a partial or a complete callus formation. Radiological evaluation of the callus by standard X-rays and computed tomography (CT).
• Patient evaluation of pain and global satisfaction. [ Time Frame: 12 months ]
  This evaluation will be measured through a 100-mm Visual Analogue Scale at 2, 3, 4, 6, 8, 10 and 12 months in the 2 groups.
• Proportion of patients achieving different degrees of functional success. [ Time Frame: 2, 3, 4, 6, 8, 10 and 12 months ]

  The functional assessment will be evaluated in Mesenchymal Stem Cells treated and untreated patients by an orthopaedic surgeon and will include a 4-points scale:

  • 0 = only passive motion allowed
  • 1 = only active mobilization without any opposition allowed
  • 2 = active mobilization with some opposition and partial weight-bearing allowed
  • 3 = weight-bearing and full active mobilization allowed
• Incidence of adverse events and severe adverse events in the 2 groups. [ Time Frame: 12 months for one injection and 18 months when a second injection is performed ]
  Adverse events and serious adverse events will be continuously monitored .
• Evaluation of early homing of Mesenchymal Stem Cells. [ Time Frame: 24 hours ]
  Indium radiolabeled Mesenchymal Stem Cells (MSC) will be visualized with a Siemens e-CAM dual head gamma camera: 10% of the total amount of MSC will be incubated with 200 µCi In-111-oxine. The radiolabelled cells will be mixed with the unlabelled ones. Twenty-four hours after injecting the cells into the target bone lesion, static images centered over the injection site and whole-body images will be acquired during 20 minutes. This will be performed with a Siemens e-CAM dual head gamma camera.
• Value of [18F]-NaF PET scans for early prediction of the onset of the bone healing process. [ Time Frame: 3 months ]
  PET Fluor kinetics could identify early and perhaps quantify the increase of bone forming in the treated area. Four [18F]-NaF PET scan studies will be performed: at baseline, as well as around days 7-9 (1 week), 27-33 (one month) and 83-97 (three months).

Original Secondary Outcome:

• Proportion of patients receiving Mensechymal Stem Cells that develop a partial or complete callus at 2, 3, 4, 8 and 10 months, compared to patients receiving placebo [ Time Frame: 2, 3, 4, 8 and 10 months ]

  -Radiological evaluation of the callus by standard X-rays. This evaluation will be stopped as soon as a score 3 is achieved. Four-point scale will be used for the evaluation.

  • 0 = no bone formation
  • 1 = at least bone spot
  • 2 = partial callus
  • 3 = complete callus

  CT in coronal and sagital planes at baseline and when standard X-rays will be evaluated at score 3. Further follow up will be done by CT only:

  • in case of score 0: every 3 months.
  • in case of score 2: every 6 weeks.
  • CT will be performed until a score 3 is confirmed or until month 12, whichever comes first.
• Timing of development of a partial or complete callus in the Mesenchymal Stem Cells treated and untreated patients. [ Time Frame: 12 months for one injection or 18 months when a second injection is needed ]

  Time necessary for a partial or a complete callus formation.

  -Radiological evaluation of the callus by standard X-rays. Four-point scale will be used for the evaluation. Patients with score 2 and 3 will be considered having a partial and complete callus, respectively.

• Patient evaluation of pain and global satisfaction. [ Time Frame: 12 months ]
  This evaluation will be measured through a 100-mm Visual Analogue Scale at 2, 3, 4, 6, 8, 10 and 12 months in Mesenchymal Stem Cells treated and untreated patients.
• Proportion of patients achieving different degrees of functional success. [ Time Frame: 12 months ]

  The functional assessment will be evaluated in Mesenchymal Stem Cells treated and untreated patients by an orthopaedic surgeon and will include a 4-points scale:

  • 0 = only passive motion allowed
  • 1 = only active mobilization without any opposition allowed
  • 2 = active mobilization with some opposition and partial weight-bearing allowed
  • 3 = weight-bearing and full active mobilization allowed
• Incidence of adverse events and severe adverse events. [ Time Frame: 12 months for one injection and 18 months when a second injection is performed ]
  Adverse events will be continuously monitored and serious adverse events will be reported to the LTCG (Laboratory of Cell and Gene Therapy) and the principal investigator, using the Serious Adverse Event form.
• Evaluation of early homing of Mesenchymal Stem Cells. [ Time Frame: 24 hours ]
  Indium radiolabeled Mesenchymal Stem Cells (MSC) will be visualized with a Siemens e-CAM dual head gamma camera: 10% of the total amount of MSC will be incubated with 200 µCi In-111-oxine. The radiolabelled cells will be mixed with the unlabelled ones. Twenty-four hours after injecting the cells into the target bone lesion, static images centered over the injection site and whole-body images will be acquired during 20 minutes. This will be performed with a Siemens e-CAM dual head gamma camera.
• Value of [18F]-NaF PET scans for early prediction of the onset of the bone healing process. [ Time Frame: 3 months ]
  PET Fluor kinetics could identify early and perhaps quantify the increase of bone forming in the treated area. Four [18F]-NaF PET scan studies will be performed: at baseline, as well as around days 7-9 (1 week), 27-33 (one month) and 83-97 (three months).

Dates:
Date Received: September 1, 2011
Date Started: October 2013
Date Completion: November 2017
Last Updated: January 17, 2013
Last Verified: January 2013