Mesenchymal Stem Cells Transplantation in Newly Diagnosed Type-1 Diabetes Patients

Study Overview
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Brief Summary
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Study Objects: Diabetes is an autoimmune disease which is mainly caused an immune reaction to beta cells in the pancreas. In this study, mesenchymal stem cells will be used for immune response modulation and improving regeneration. Study design and method: In a Triple blinded randomized placebo-controlled phase I/II clinical trial, 20 patients with newly diagnosed type-1 diabetes who would be visited in Children's Growth and Development Research Center of Tehran University of Medical Sciences and Royan Institute Cell Therapy Center, would be assessed through two groups including the case group and the placebo group. Participants: Patients of both sexes in a range of 8 to 40 years old who have been diagnosed to have type-1 diabetes in no more than 6 weeks, antibody against beta cells diagnosed in their blood, fasting c-peptide more than or equal to 0.3 ng/ml, and are not suffered from other acute or chronic diseases and cancers, would be studied. Interventions: Intravascular transplantation of autologous mesenchymal stem cells in the case group; placebo injection in the control group. Outcome variables: safety and efficacy.

Detailed Description
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Diabetes is an autoimmune disease which is mainly caused by an immune reaction to beta cells in the pancreas. Today, insulin injection is a routine treatment for diabetes. Although injected insulin maintains blood glucose, this method cannot result in physiologic reaction to blood glucose changes. Moreover, patients are encountered with diabetes complications like neuropathy, nephropathy, visual and cardiovascular problems, and hypoglycemic unawareness. Therefore, based on previous studies, a treatment option that leads to pancreatic beta cell restoration and inhibits the immune response to these cells could be a hopeful clinical choice. In this clinical trial, autologous bone marrow-derived mesenchymal stem cells will be used for immune response modulation and improving regeneration. Hence, based on inclusion and exclusion criteria, 20 patients with type-1 diabetes will be selected and after clarifying the procedure and fulfilling the agreement to participate in this trial, they will be sorted in two groups. Bone marrow is aspirated from patients bone and after isolation of Mesenchymal stem cells and characterization of these cells, patients in case group will be intravenously injected by 1 million autologous mesenchymal stem cells per kg of patient's body weight in each dose in week 0 and 3, whereas the control group receives a placebo. Then patients will be followed up for 1 year. During this time, different parameters would be evaluated in weeks 1, 2,4, and Months 2,3,6,9 and 12. Laboratory screenings will be done during this period to evaluate the safety and efficacy of this treatment.

Official Title
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Phase I/II Clinical Trial to Examine the Safety and Efficacy of Transplantation of Mesenchymal Stem Cells in New-onset Type 1 Diabetes Patients

Conditions
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Diabetes Mellitus, Diabetes Mellitus, Type 1, Diabetes Mellitus, Insulin-Dependent

Intervention / Treatment
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* Biological: Intravenous Injection of autologous mesenchymal stem cells
* Other: Intravenous injection of placebo


Participation Criteria
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Eligibility Criteria
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Inclusion criteria: Type 1 diabetes detection in less than 6 weeks Diabetes diagnosis according to American Diabetes Association (ADA) Presence of Antibodies against pancreatic beta cells Fasting C-peptide ≥ 0.3 ng/ml Exclusion Criteria Pregnancy or breastfeeding Cancer Any acute or severe disease (According to physicians' diagnosis: such as cardiac, pulmonary, hepatic, kidney, mental, … diseases) Positive results for: Human Immunodeficiency Virus (HIV), Human T-Lymphotropic Virus (HTLV), Hepatitis B Virus (HBV), Hepatitis C Virus (HCV), Cytomegalovirus (CMV) Immune deficient or hyper aesthesia History of severe ketoacidosis

Ages Eligible for Study
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Minimum Age: 8 Years
Maximum Age: 40 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: Crossover Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Mesenchymal Stem Cells Transplantation<br>The patients with Type 1 Diabetes, who will receive Intravenous injection of autologous bone-marrow derived mesenchymal stem cells | Biological: Intravenous Injection of autologous mesenchymal stem cells<br>* Intravenous injection 1 millions of bone-marrow derived autologous Mesenchymal Stem Cells (MSCs) per kg of patient's body weight in each dose, weeks 0 & 3<br>|
| Placebo Comparator: Placebo<br>The patients with Type 1 Diabetes, who will receive intravenous injection of normal saline (sodium chloride 0.9%) | Other: Intravenous injection of placebo<br>* Intravenous injection of normal saline (sodium chloride 0.9%)<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of participants with treatment-related adverse events as assessed by CTCAE v5.0 | Safety will be assessed by evaluating patients based on CTCAE (v.5) to assess treatment-related adverse events after intravenous transplantation of autologous bone marrow derived Mesenchymal Stem Cells | 12 months after the first infusion | 
| Change from baseline number of hypoglycemic Unawareness episodes at 12 months after intravenous transplantation of autologous bone marrow derived Mesenchymal Stem Cells | Number of hypoglycemic unawareness episodes will be assessed by evaluating patients' blood glucose monitoring sheets | 12 months after the first infusion | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change from Baseline Fasting Blood Sugar (FBS) at 12 months after intravenous transplantation of autologous bone marrow derived Mesenchymal Stem Cells | Assessing Fasting Blood Sugar (FBS) at 12 months after intravenous transplantation of autologous bone marrow derived Mesenchymal Stem Cells and compare the results with baseline Fasting Blood Sugar (FBS) | 12 months after the first infusion | 
| Change from Baseline C-peptide at 12 months after intravenous transplantation of autologous bone marrow derived Mesenchymal Stem Cells | Assessing serum C-peptide at 12 months after intravenous transplantation of autologous bone marrow derived Mesenchymal Stem Cells and compare the results with baseline serum C-peptide level | 12 months after the first infusion | 
| Change from Baseline HbA1C at 12 months after intravenous transplantation of autologous bone marrow derived Mesenchymal Stem Cells | Assessing HbA1C at 12 months after intravenous transplantation of autologous bone marrow derived Mesenchymal Stem Cells and compare the results with baseline HbA1C | 12 months after the first infusion | 
| Change from Baseline 2-hour postprandial blood glucose at 12 months after intravenous transplantation of autologous bone marrow derived Mesenchymal Stem Cells | Assessing 2-hour postprandial blood glucose at 12 months after intravenous transplantation of autologous bone marrow derived Mesenchymal Stem Cells and compare the results with baseline 2-hour postprandial blood glucose | 12 months after the first infusion | 
| Change from Baseline daily dose of exogenous insulin injected by patients (IU/kg/day) at 12 Months after intravenous transplantation of autologous bone marrow derived Mesenchymal Stem Cells | Exogenous Insulin requirement of patients will be measured based on their daily insulin injection report sheets, total injected insulin units per day will be divided by patient's weight in order to be comparable between different patients. | 12 months after the first infusion | 
| Change from baseline Lability Index (LI) at 12 Months after intravenous transplantation of autologous bone marrow derived Mesenchymal Stem Cells | Assessing 2 weeks of blood glucose report sheets, calculation is based on the changes in blood glucose levels over time | 12 months after the first infusion | 
| Change from Baseline SF-36 Quality of life (QOL) questionnaire score at 12 months after intravenous transplantation of autologous bone marrow derived Mesenchymal Stem Cells | Assessing change in patients' Quality of life by answering SF-36 questionnaire before transplantation and 12 months after intravenous transplantation of autologous bone marrow derived Mesenchymal Stem Cells; This questionnaire asks about general aspects of patients' life. The results would be reported as the total score and the scale range is from 0% to 100%. 0% is considered as worse condition and 100% is considered as the best condition. | 12 months after the first infusion | 
| Change from Baseline Diabetes Specific Quality of life (DQOL) questionnaire score at 12 months after intravenous transplantation of autologous bone marrow derived Mesenchymal Stem Cells | Assessing change in patients' Quality of life by answering Diabetes Specific Quality of Life (DQOL) questionnaire before transplantation and 12 months after intravenous transplantation of autologous bone marrow derived Mesenchymal Stem Cells; This questionnaire asks about different aspects of patients' life in relation to diabetes. The results would be reported as the total score and the scale range is from 0% to 100%. 0% is considered as worse condition and 100% is considered as the best condition. | 12 months after the first infusion | 
| Changes from baseline Autoantibodies levels in patients' blood at 12 months after intravenous transplantation of autologous bone marrow derived Mesenchymal Stem Cells | Assessing patients Islet Cell Antibodies (ICA), Glutamic Acid Decarboxylase Antibodies (GADA), Insulinoma-Associated protein-2 Antibodies (IA-2A) levels after intravenous transplantation of autologous bone marrow derived Mesenchymal Stem Cells | 12 months after the first infusion | 
| Changes from baseline serum cytokines levels in patients' blood at 12 months after intravenous transplantation of autologous bone marrow derived Mesenchymal Stem Cells | Assessing serum cytokines levels of patients after intravenous transplantation of autologous bone marrow derived Mesenchymal Stem Cells | 12 months after the first infusion | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Diabetes Mellitus, Diabetes Mellitus, Type 1, Cell Transplantation, Autologous Transplantation, Mesenchymal Stem Cell