MSC and MC in Type 2 Diabetes Mellitus

Study Overview
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Brief Summary
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Cell injury in human islets induced by non-immune mediated inflammation occur in vitro upon hyperglycemia in type 2 diabetes mellitus. Infusion of autologous bone marrow mononuclear cells (MCs) is an emerging therapeutic approach for DM, which showed promising outcomes with mild side effects. Infusion of MCs and autologous bone marrow mesenchymal stem cells in combination might exert enhanced repairing effects. We hypothesized that infusion of these two classes of cells might provide multiple signals for regeneration and improve recovery from inflammation-induced lesion. The effects might be maximized by intra-arterial pancreatic infusion.

Official Title
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Autologous Bone Marrow Mesenchymal Stem Cell and Bone Marrow Mononuclear Cell Infusion in Type 2 Diabetes Mellitus

Conditions
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Diabetes Mellitus, Type 2

Intervention / Treatment
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* Drug: infusion of MSCs
* Drug: infusion MCs
* Drug: insulin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Ability to provide written informed consent. Mentally stable and able to comply with the procedures of the study protocol. Clinical history compatible with type 2 diabetes (T2DM) as defined by the Expert Committee on the Diagnosis and classification of Diabetes Mellitus Onset of T2DM disease at ≥ 35 years of age. T2DM duration ≥ 3 and ≤ 20 years at the time of enrollment. Basal C-peptide 0.3-2.0 ng/mL HbA1c ≥ 7.5 and ≤ 12% before standard medical therapy (SMT). Patients must have been treated with SMT for minimum of 4 months prior to randomization. Insulin dose and metformin doses should be stable over the 3 months prior to randomization. HbA1c ≥ 7.5 and ≤ 9.5% at time of randomization. Total insulin daily dose (TDD) at time of randomization should not exceed 1.0 units/day/kg Exclusion Criteria: BMI >35 kg/m2. Insulin requirements of > 100 U/day. HbA1c >9.5%. (at the time of randomization) C-reactive protein (hs-CRP) >3.00 Uncontrolled blood Pressure: SBP >160 mmHg or DBP >100 mmHg at the time of randomization. Evidence of renal dysfunction, serum creatinine > 1.5 mg/dl (males) and 1.4 mg/dl (females). Proteinuria > 300 mg/day Evidence of cardiovascular disease, existing congestive cardiac failure on physical exam and/or acute coronary syndrome in past 6 months. For female participants: Positive pregnancy test, presently breast-feeding, or unwillingness to use effective contraceptive measures for the duration of the study.For male participants: intent to procreate 3 months before or after the intervention or unwillingness to use effective measures of contraception. Oral contraceptives,Norplant®, Depo-Provera®, and barrier devices with spermicide are acceptable contraceptive methods; condoms used alone are not acceptable Active infection including hepatitis C, HIV, or TB as determined by a positive skin test or clinical presentation, or under treatment for suspected TB. Positive tests are acceptable only if associated with a history of previous vaccination in the absence of any sign of active infection. Positive tests are otherwise not acceptable, even in the absence of any active infection at the time of evaluation Known active alcohol or substance abuse including cigarette/cigar smoking Baseline Hgb below the lower limits of normal at the local laboratory; lymphopenia (<1,000/L), neutropenia (<1,500/L), or thrombocytopenia (platelets <100,000/L). A history of Factor V deficiency or other coagulopathy defined by INR >1.5, PTT>40, PT >15. Any coagulopathy or medical condition requiring long-term anticoagulant therapy(e.g., warfarin) after transplantation (low-dose aspirin treatment is allowed) or patients with an INR >1.5. Acute or chronic pancreatitis. Symptomatic peptic ulcer disease. Hyperlipidemia despite medical therapy (fasting LDL cholesterol >130 mg/dl, treated or untreated; and/or fasting triglycerides > 200 mg/dl). Receiving treatment for a medical condition requiring chronic use of systemic steroids. Symptomatic cholecystolithiasis. Use of any investigational agents within 4 weeks of enrollment. Admission to hospital for any reason in the 14 days prior to enrollment (signing consent). Presence of active proliferative diabetic retinopathy or macular edema Any malignancy Abnormal liver function >1.5 x ULN Abdominal aortic aneurysm History of cerebro-vascular accident Any patient with acute or subacute decompensation from diabetes Any acute or chronic infectious condition that in the criteria of the investigator would be a risk for the patient. Subjects with hypoproteinemia, cachexia or terminal states Subjects with history of anorexia/bulimia Subjects with respiratory insufficiency Subjects that are being treated with any medication that could interfere with the outcome of the study such as: Sulfonylureas, Thiazolidinediones and glucagon like peptide 1 (GLP-1) analogues (Exenatide, Byetta), Pramlintide (Amylin), Dipeptidylpeptidase IV (DPP-IV) inhibitors (i.e. Sitagliptin, Januvia) Any medical condition that, in the opinion of the investigator, will interfere with thesafe completion of the trial.

Ages Eligible for Study
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Minimum Age: 40 Years
Maximum Age: 65 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: MSC+MC<br>infusion of BMMSC+BMMNC and insulin injection | Drug: infusion of MSCs<br>* infusion of MSCs<br>Drug: infusion MCs<br>* infusion of MCs<br>Drug: insulin<br>* intensive insulin care<br>|
| Active Comparator: MC<br>infusion of BMMNC and insulin injection | Drug: infusion MCs<br>* infusion of MCs<br>Drug: insulin<br>* intensive insulin care<br>|
| Active Comparator: Insulin<br>insulin injection | Drug: insulin<br>* intensive insulin care<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| macrovascular complications |  | 8 years | 
| microvascular complications |  | 8 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| DPN | diabetes peripheral neuropathy | 8 years | 
| MI | myocardial infarction | 8 years | 
| angina | angina | 8 years | 
| stroke | stroke | 8 years | 
| amputation | amputation | 8 years | 
| DN | diabetes nephropathy | 8 years | 
| DRP | diabetes retinopathy | 8 years | 
| pro-DRP | proliferative diabetes retinopathy | 8 years | 
| C-peptide AUC | C-peptide area under the curve | 1y | 
| insulin AUC | insulin area under the curve | 1y | 
| HbA1c | glycated hemoglobin | 1y | 
| FBG | fasting hemoglucose | 1y | 
| insuline dose | exogenous insulin requirements | 1y | 
| fasting C-p | fasting c-peptide | 1y | 
| The incidence and severity of adverse events related to the stem cell infusion procedure |  | 8y | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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mesenchymal stem cells, bone marrow mononeclear cells, type 2 diabetes mellitus