A Pilot Study of MSCs Iufusion and Etanercept to Treat Ankylosing Spondylitis

Study Overview
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Brief Summary
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The purpose of this study is to evaluate the safety and clinical effect of mesenchymal stem cells (MSCs) derived from human bone marrow at a dose of 1.0E+6 MSC/kg in subject for the therapy of Ankylosing spondylitis (AS) and to compare the efficacy of MSCs and Etanercept to treat this disease.

Detailed Description
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Ankylosing spondylitis (AS) is a chronic, progressive inflammatory rheumatic disease involving primarily the sacroiliac joints and the axial skeleton. The main clinical features are back pain and progressive stiffness of the spine. Oligoarthritis of the hips and shoulders, enthesopathy, and anterior uveitis are common, and involvement of the heart and lungs is rare. The current understanding of the pathogenesis of this disorder is limited.It mainly about to hereditary susceptibility (eg HLA-B27),infection and autoimmunity. Although traditional drugs, such as Nonsteroidal antiinflammatory drugs (NSAIDs) disease-modifying antirheumatic drugs (DMARDs such as methotrexate, salicylazosulfapyridine OR thalidomide) and steroids have been used in the treatment of AS, however, many studies have indicated that the overall response to these drugs is not satisfied. Addition, the severe side effects of these drugs have also been observed. The management of AS patients therefore remains unsatisfactory and targeted therapies are needed. Although the application of TNF alpha receptor inhibitor (such as Etanercept) has got the success in the early treatment of ankylosing spondylitis, the tolerance to this biological agent make the therapy to this disease rather difficult. Recently, owning to its immunoregulatory, immunosuppressive, stimulating hematopoiesis and tissue repairing properties, the infusion of human MSCs isolated from human bone marrow have been a promising and effective treatment to AS patients. This study will evaluate the safety and effectiveness of MSC transplantation in the AS patients and compare the efficiency with the Etanercept to treat AS patients. This study will last 2 to 3 years. Participants will be randomly assigned to receive either MSC transplant therapy (experimental group) or Etanercept therapy (control group). Patients will undergo MSC transplant at the start of the study on Day 0. The experimental group will receive infusion per week in the first 4 weeks and every two weeks in the second 8 weeks, totally for 12 weeks. After 3 months, patients will receive the second MSC transplantation. After 12 weeks (Phase I) and 48 weeks (Phase II) from the first transplantation, patients will be evaluated.

Official Title
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Phase III Study of Human Bone Marrow-Derived Mesenchymal Stem Cells to Treat AS

Conditions
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Spondylitis, Spondylitis, Ankylosing, Ankylosis, Arthritis, Spondylarthritis, Spondylarthropathies, Spinal Diseases, Musculoskeletal Diseases, Bone Diseases

Intervention / Treatment
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* Biological: Intravenous infusion of MSCs
* Drug: Etanercept


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: The male or female patient aged 18 to 45 years; Fulfill 1984 modified NewYork classification criteria for AS; The score of the Bath AS Disease Activity Index (BASDAI)≥40 on (0-100) despite optimal non-steroidal anti-inflammatory drug (NSAID) treatment. Before each experiment, patients subscribe voluntarily to the agreement approved by Ethics Committees and sign the date. Exclusion Criteria: The patient diagnosed in doubt; Completely stiff spine Received spinal or joint surgery within 2 months Received anti-TNF therapy within 3 months pregnant or suckling period female patients; Patients with the Medical or mentally imbalance charged by researchers. patients associated cardiovascular, cerebrovascular, liver,renal and hematological system diseases or mental disease; Patients could not accept the research or could not cooperate well. Patients with other sever diseases at the same time, such as abnormality of joints, other seronegative spondyloarthropathy, or other Rheumatic Diseases.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 45 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Intravenous infusion of MSCs<br>Human bone marrow-derived MSCs at a dose of 1.0E+6 MSC/kg, receive infusion per week in the first 4 weeks and every two weeks in the second 8 weeks. total for 12 weeks. | Biological: Intravenous infusion of MSCs<br>* Intravenous infusion of MSCs:Human bone marrow-derived MSCs 1.0E+6 MSC/kg, IV drop<br>|
| Active Comparator: Etanercept<br>50mg,hypodermic injection,once per week, for 12 weeks | Drug: Etanercept<br>* 50mg,hypodermic injection,once per week, for 12 weeks<br>* Other names: TNF alpha receptor inhibitor;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The Assessment of Spondyloarthritis International Society (ASAS)20 response | ASAS measures symptomatic improvement in AS patients.ASAS=4 domains:patient global assessment of disease activity,pain,function,inflammation.ASAS 20=20% improvement(vs.baseline)and an absolute change≥1 units on a 0-10 scale(0=no disease activity;10=high disease activity)for ≥3 domains,and no worsening in remaining domain. | 48 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| BASDAI score comparing to baseline |  | 48 weeks | 
| BASFI score comparing to baseline | the Bath Ankylosing Spondylitis Functional Index | 48 weeks | 
| Imageology | The bone marrow of the whole spine (from C2 to S1) can be detected by Magnetic resonance imaging (MRI) scan. The MRI sequence included a T1-weighted turbo spin-echo (TSE) sequence and a fat-saturated short tau inversion recovery (STIR) sequence. MR images were first analyzed using the ASspiMRI-a scoring system , which is based on grading disease activity on a scale of 0 to 6. In addition to the ASspiMRI-a scoring system, the inflammation area and average intensityof each inflammatory site were calculated. The background value (BV) was obtained by taking 10 normal sites of the vertebral body of 1 layer and calculating the average. The inflammation extent of each inflammatory site was calculated by the formula: value of inflammation area (VIA) × [value of average intensity (VAI) - BV]. The summation of the inflammation extent of all inflammatory sites in all scanning layers was defined as the total inflammation extent (TIE) of each patient. | 48 weeks | 
| C-reactive protein (CRP) |  | 12 weeks | 
| Erythrocyte sedimentation rate (ESR) |  | 12 weeks | 
| Tumor necrosis factor alpha (TNF-α) |  | 12 weeks | 
| Interleukin 6 (IL-6) |  | 12 weeks | 
| Interleukin 17 (IL-17) |  | 12 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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ankylosing spondylitis, mesenchymal stem cell, etanercept