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

Primary Purpose

Type1 Diabetes Mellitus, Autoimmune Diabetes

Status
Recruiting
Phase
Phase 1
Locations
China
Study Type
Interventional
Intervention
Liraglutide
UCB-Treg
Insulin
Sponsored by
Second Xiangya Hospital of Central South University
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Type1 Diabetes Mellitus focused on measuring Autoimmune Diabetes, Umbilical Cord Blood Regulatory T Lymphocyte, Liraglutide

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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.

Sites / Locations

  • Institute of Metabolism and Endocrinology, Second Xiangya Hospital, Central South UniversityRecruiting

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm Type

Experimental

Active Comparator

Active Comparator

Active Comparator

Arm Label

UCB-Treg plus Liraglutide

UCB-Treg

Liraglutide

Insulin

Arm Description

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.

Subjects will receive a single infusion of ex vivo expanded Treg product (2 x 10^6). Insulin will be continued as a routine therapy.

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.

Patients will receive insulin injection as a routine therapy.

Outcomes

Primary Outcome Measures

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.

Secondary Outcome Measures

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

Full Information

First Posted
January 2, 2017
Last Updated
March 13, 2023
Sponsor
Second Xiangya Hospital of Central South University
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1. Study Identification

Unique Protocol Identification Number
NCT03011021
Brief Title
Safety and Efficacy of Umbilical Cord Blood Regulatory T Cells Plus Liraglutide on Autoimmune Diabetes
Official Title
Phase 1/ Phase 2 Study of the Therapeutic Effect of Ex-vivo Expanded Umbilical Cord Blood Regulatory T Cells With Liraglutide on Autoimmune Diabetes
Study Type
Interventional

2. Study Status

Record Verification Date
March 2023
Overall Recruitment Status
Recruiting
Study Start Date
January 2017 (undefined)
Primary Completion Date
June 2025 (Anticipated)
Study Completion Date
June 2025 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
Second Xiangya Hospital of Central South University

4. Oversight

Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No

5. Study Description

Brief Summary
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
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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Type1 Diabetes Mellitus, Autoimmune Diabetes
Keywords
Autoimmune Diabetes, Umbilical Cord Blood Regulatory T Lymphocyte, Liraglutide

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 1, Phase 2
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Randomized
Enrollment
40 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
UCB-Treg plus Liraglutide
Arm Type
Experimental
Arm Description
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.
Arm Title
UCB-Treg
Arm Type
Active Comparator
Arm Description
Subjects will receive a single infusion of ex vivo expanded Treg product (2 x 10^6). Insulin will be continued as a routine therapy.
Arm Title
Liraglutide
Arm Type
Active Comparator
Arm Description
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.
Arm Title
Insulin
Arm Type
Active Comparator
Arm Description
Patients will receive insulin injection as a routine therapy.
Intervention Type
Drug
Intervention Name(s)
Liraglutide
Intervention Description
Dose escalation of Liraglutide starts from 0.6 mg up to 1.2 mg per day.
Intervention Type
Biological
Intervention Name(s)
UCB-Treg
Intervention Description
Receive Treg infusion: 1~5*10^6/kg b.w. in 100ml normal saline
Intervention Type
Drug
Intervention Name(s)
Insulin
Intervention Description
Receive insulin following clinician's instruction.
Primary Outcome Measure Information:
Title
Adverse effects
Description
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.
Time Frame
2 years
Secondary Outcome Measure Information:
Title
Change in HbA1C
Description
Measure the HbA1C level after treatment
Time Frame
2 years
Title
Change in C-peptide
Description
Measure the C-peptide level after treatment
Time Frame
2 years
Title
Change in insulin dose
Description
Measure insulin dose patient used after treatment
Time Frame
2 years
Title
Hypoglycaemic events
Description
Measure the number of participants with Hypoglycaemic events
Time Frame
2 years
Title
Change in titer of autoantibodies
Description
Measure the titer of antoantibodies of participant after treatment
Time Frame
2 years
Title
Change in immune cells diversities and quantities.
Description
Measure the immune cells diversities and quantities after treatment
Time Frame
2 years
Title
Change in autoimmune-related cytokines
Description
Measure the change of autoimmune- related cytokines after treatment
Time Frame
2 years
Title
Life quality evaluation
Description
Number of participants with disturbance of emotion, sleep, resting or energy.
Time Frame
2 years

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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.
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Zhiguang Zhou, MD/PhD
Phone
86-731-85292154
Email
zhouzg@hotmail.com
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Zhiguang Zhou, MD/PhD
Organizational Affiliation
Second Xiangya Hospital
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Haibo Yu, MD/PhD
Organizational Affiliation
Second Xiangya Hospital
Official's Role
Principal Investigator
Facility Information:
Facility Name
Institute of Metabolism and Endocrinology, Second Xiangya Hospital, Central South University
City
Changsha
State/Province
Hunan
ZIP/Postal Code
410011
Country
China
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Zhiguang Zhou, MD/PhD
Phone
86-731-85292154
Email
zhouzg@hotmail.com

12. IPD Sharing Statement

Citations:
PubMed Identifier
23263503
Citation
Milward K, Issa F, Hester J, Figueroa-Tentori D, Madrigal A, Wood KJ. Multiple unit pooled umbilical cord blood is a viable source of therapeutic regulatory T cells. Transplantation. 2013 Jan 15;95(1):85-93. doi: 10.1097/TP.0b013e31827722ed.
Results Reference
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PubMed Identifier
22348606
Citation
Fan H, Yang J, Hao J, Ren Y, Chen L, Li G, Xie R, Yang Y, Gao F, Liu M. Comparative study of regulatory T cells expanded ex vivo from cord blood and adult peripheral blood. Immunology. 2012 Jun;136(2):218-30. doi: 10.1111/j.1365-2567.2012.03573.x.
Results Reference
background
PubMed Identifier
20952687
Citation
Brunstein CG, Miller JS, Cao Q, McKenna DH, Hippen KL, Curtsinger J, Defor T, Levine BL, June CH, Rubinstein P, McGlave PB, Blazar BR, Wagner JE. Infusion of ex vivo expanded T regulatory cells in adults transplanted with umbilical cord blood: safety profile and detection kinetics. Blood. 2011 Jan 20;117(3):1061-70. doi: 10.1182/blood-2010-07-293795. Epub 2010 Oct 15.
Results Reference
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PubMed Identifier
24003936
Citation
Rondas D, D'Hertog W, Overbergh L, Mathieu C. Glucagon-like peptide-1: modulator of beta-cell dysfunction and death. Diabetes Obes Metab. 2013 Sep;15 Suppl 3:185-92. doi: 10.1111/dom.12165.
Results Reference
background
PubMed Identifier
26997114
Citation
Chang TJ, Tseng HC, Liu MW, Chang YC, Hsieh ML, Chuang LM. Glucagon-like peptide-1 prevents methylglyoxal-induced apoptosis of beta cells through improving mitochondrial function and suppressing prolonged AMPK activation. Sci Rep. 2016 Mar 21;6:23403. doi: 10.1038/srep23403. Erratum In: Sci Rep. 2016 May 31;6:26917.
Results Reference
background
PubMed Identifier
27285580
Citation
Zoso A, Serafini P, Lanzoni G, Peixoto E, Messinger S, Mantero A, Padilla-Tellez ND, Baidal DA, Alejandro R, Ricordi C, Inverardi L. G-CSF and Exenatide Might Be Associated with Increased Long-Term Survival of Allogeneic Pancreatic Islet Grafts. PLoS One. 2016 Jun 10;11(6):e0157245. doi: 10.1371/journal.pone.0157245. eCollection 2016.
Results Reference
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Safety and Efficacy of Umbilical Cord Blood Regulatory T Cells Plus Liraglutide on Autoimmune Diabetes

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