Safety and Efficacy of Umbilical Cord Blood Regulatory T Cells Plus Liraglutide on Autoimmune Diabetes

Study Overview
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Brief Summary
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The purpose of this study is to investigate the safety and therapeutic effect of ex-vivo expanded umbilical cord blood regulatory T cells adjunct with Liraglutide on autoimmune diabetes.

Detailed Description
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Autoimmune Diabetes Mellitus (AIDM) is a subtype of diabetes mellitus caused by autoimmune destruction of beta cells in the islet, including Type 1 diabetes and Latent Autoimmune Diabetes in Adults (LADA). Insulin has been used as a routine therapy for AIDM to alleviate the hyperglycemic status, yet cannot effectively prevent the progressing destruction of beta cells or preserve its function. Regulatory T cells expanded from umbilical cord blood (UCB-Treg) ex-vivo have shown strong capacity to control immune responses in autoimmune diseases, offering a hopeful therapeutic way for AIDM. Glucagon-like peptide (GLP-1) analog Liraglutide has been tested in large-scale clinical trial to prove its various benefits for beta cells and glucolipid metabolism in Type 2 diabetes and obesity patients. However, its clinical application in AIDM is not well-defined so far. The aim of this study is to investigate the potential use of Liraglutide with UCB-Treg infusion in AIDM and examine the safety and efficacy of this new therapy.

Official Title
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Phase 1/ Phase 2 Study of the Therapeutic Effect of Ex-vivo Expanded Umbilical Cord Blood Regulatory T Cells With Liraglutide on Autoimmune Diabetes

Conditions
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Type1 Diabetes Mellitus, Autoimmune Diabetes

Intervention / Treatment
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* Drug: Liraglutide
* Biological: UCB-Treg
* Drug: Insulin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Type 1 diabetes according to ADA criteria <3 years. Age≥ 18 years. Positive for at least one of the anti-islet autoantibodies: GADA, IA2A, ZnT8A Fasting or postprandial plasma C-peptide more than 100 pmol/L Written informed consent from the patient or family representative. Exclusion Criteria: History or family history of medullary thyroid carcinoma or MEN 2 syndrome; History of chronic or acute pancreatitis; Allergic to liraglutide or any components in Victoza®; Hepatic abnormalities (transaminase > 2 times normal); Renal impairments (serum creatinine >133 umol/L); Cardiovascular diseases (hypertension, coronary heart disease, etc.); Presence of anemia (Hb ≤100g/L), leukopenia (<3.5×109/L); Presence of disorder in coagulation or anticoagulation, or thrombocytopenia (platelets <100×109/L); Presence of acute metabolic disorders; In the case of acute ketone acidosis, with blood ketone over 0.3mmol/L and pH lower than 7.30; Presence of any kind of chronic infection or immune deficiency, including hepatitis B, hepatitis C, HIV, syphilis or tuberculosis, etc.; Chronic use of systemic glucocorticoids or other immunosuppressive agents for over 3 months; Any history of malignancy; Female patients who are pregnant or breastfeeding; any female who is unwilling to use a reliable and effective form of contraception for 2 years after recruitment; Presence of any infectious diseases, including active skin infections, flu, fever, upper or lower respiratory tract infections; those who wish to participate in the study should keep the infection under control for at least 1 week before receiving Treg product infusion; Any medical condition that, in the opinion of the investigator, will interfere with safe participation in the trial.

Ages Eligible for Study
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Minimum Age: 18 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: UCB-Treg plus Liraglutide<br>Subjects will receive a single infusion of ex vivo expanded umbilical cord blood derived Treg product (2 x 10^6). Dose escalation of liraglutide up to 1.2 mg will be started 3 days after Treg infusion only if no severe side effects showed. Subjects continue to receive the reached liraglutide dose once daily for 6 months thereafter. Insulin will be continued as a routine therapy. | Drug: Liraglutide<br>* Dose escalation of Liraglutide starts from 0.6 mg up to 1.2 mg per day.<br>Biological: UCB-Treg<br>* Receive Treg infusion: 1 5*10^6/kg b.w. in 100ml normal saline<br>Drug: Insulin<br>* Receive insulin following clinician's instruction.<br>|
| Active Comparator: UCB-Treg<br>Subjects will receive a single infusion of ex vivo expanded Treg product (2 x 10^6). Insulin will be continued as a routine therapy. | Biological: UCB-Treg<br>* Receive Treg infusion: 1 5*10^6/kg b.w. in 100ml normal saline<br>Drug: Insulin<br>* Receive insulin following clinician's instruction.<br>|
| Active Comparator: Liraglutide<br>Patients will be subjected to a dose escalation of liraglutide up to 1.2 mg, then continue to receive the reached liraglutide dose once daily for 6 months thereafter. Insulin will be continued as routine therapy. | Drug: Liraglutide<br>* Dose escalation of Liraglutide starts from 0.6 mg up to 1.2 mg per day.<br>Drug: Insulin<br>* Receive insulin following clinician's instruction.<br>|
| Active Comparator: Insulin<br>Patients will receive insulin injection as a routine therapy. | Drug: Insulin<br>* Receive insulin following clinician's instruction.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Adverse effects | Primary outcome measures will be the number of participants with adverse events, laboratory abnormalities and other signs of toxicity. Particular focus will be on the number and severity of infusion reactions, complications related to infection, and any potential negative impact on the course of diabetes. | 2 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in HbA1C | Measure the HbA1C level after treatment | 2 years | 
| Change in C-peptide | Measure the C-peptide level after treatment | 2 years | 
| Change in insulin dose | Measure insulin dose patient used after treatment | 2 years | 
| Hypoglycaemic events | Measure the number of participants with Hypoglycaemic events | 2 years | 
| Change in titer of autoantibodies | Measure the titer of antoantibodies of participant after treatment | 2 years | 
| Change in immune cells diversities and quantities. | Measure the immune cells diversities and quantities after treatment | 2 years | 
| Change in autoimmune-related cytokines | Measure the change of autoimmune- related cytokines after treatment | 2 years | 
| Life quality evaluation | Number of participants with disturbance of emotion, sleep, resting or energy. | 2 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Autoimmune Diabetes, Umbilical Cord Blood Regulatory T Lymphocyte, Liraglutide