Ignite Creation Date:
2024-05-06 @ 10:10 AM
Last Modification Date:
2024-10-26 @ 12:26 PM
Study NCT ID:
NCT03182426
Status:
COMPLETED
Last Update Posted:
2023-07-25
First Post:
2017-06-05
Brief Title:
Stem Cell Mobilization Plerixafor and Immunologic Reset in Type 1 Diabetes T1DM
Sponsor:
University of Alberta
Organization:
University of Alberta
Study Overview
Official Title:
Autologous Hematopoietic Stem Cell Mobilization Plerixafor and Immunologic Reset in New Onset Type 1 Diabetes Mellitus
Status:
COMPLETED
Status Verified Date:
2024-07
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
None
Brief Summary:
Type 1 diabetes is an autoimmune disease characterized by destruction of pancreatic beta-cells resulting in absolute deficiency of insulin Presently there is no known cure
Our proposed interventional trial is based on immunological reset approach T-depletion therapy and anti-inflammatory treatment will restore self-tolerance in T1DM Autologous peripheral-blood mobilized hematopoietic CD34-enriched stem cells and a long-acting GLP-1 analogue will promote pancreatic islet regeneration and repair
The short-term goals of this protocol is to demonstrate that subjects with new-onset T1DM undergoing autologous hematopoietic stem cell mobilization and immunologic reset will have greater preservation of endogenous insulin secretion compared to controls and foremost that this nonmyeloablative treatment is safe without the need for chronic immune suppression
Our proposed interventional trial is based on immunological reset approach T-depletion therapy and anti-inflammatory treatment will restore self-tolerance in T1DM Autologous peripheral-blood mobilized hematopoietic CD34-enriched stem cells and a long-acting GLP-1 analogue will promote pancreatic islet regeneration and repair
The short-term goals of this protocol is to demonstrate that subjects with new-onset T1DM undergoing autologous hematopoietic stem cell mobilization and immunologic reset will have greater preservation of endogenous insulin secretion compared to controls and foremost that this nonmyeloablative treatment is safe without the need for chronic immune suppression
Detailed Description:
Previous efforts to prevent or reverse new-onset T1DM have been fraught with disappointment despite considerable promise The non-obese diabetic NOD mouse is a poor surrogate of human T1DM Over 463 different treatments have been shown to prevent or reverse autoimmune diabetes in these mice Efforts focused on clinical translation of the most promising strategies have led to negative findings despite enormous investment and large-scale clinical trials Encouraging preliminary clinical pilot data suggested that a non-Fc binding CD3 antibody mycophenolate mofetil MMF daclizumab rituximab B-lymphocyte depletion a soluble NBI-6024 altered insulin peptide ligand vitamin D3 nicotinamide parenteral insulin oral insulin nasal insulin and elimination of cows milk from infant feeding could each potentially mitigate diabetes onset or at least prolong endogenous C-peptide and sustain honeymoon To date none of these approaches have demonstrated robust benefit when subjected to adequately powered randomized clinical trials Basing further clinical trials solely on responses in NOD mice would seem ill-advised
One of the most promising approaches to date has been use of intravenous non-myeloablative autologous hematopoietic stem cell transplantation after mobilization with granulocyte colony-stimulating factor G-CSF thymoglobulin and cyclophosphamide as first described by Voltarelli et al in 2007 in Brazil Voltarelli et al demonstrated that a potentially toxic cyclophosphamide-based depletional therapy and autologous bone marrow transplant rescue restores self-tolerance prolongs honeymoon and remarkably secures insulin independence This immunological reset approach was designed to eliminate autoreactive lymphocyte clones with subsequent immune reconstitution Remarkably 2023 children and adolescents with new-onset T1DM were rendered insulin independent for periods of 6-35 months In longer follow-up 1223 maintained this state for a mean of 31 months There were no deaths but nosocomial pneumonia occurred in 2 and oligospermia in 9 The underpinning mechanism appears to be restoration of apoptosis-related gene deregulation that contributed to breakdown of immune tolerance in T1DM
Our proposed new-onset intervention trial is based on Voltarellis concept but we have eliminated cyclophosphamide replaced GCSF with plerixafor substituted thymoglobulin for a single dose of alemtuzumab and added anti-inflammatory treatments derived from the Clinical Islet Program in Edmonton with excellent safety profiles to date Cellular and immunologic data from our Clinical Islet Transplant program indicates that T-depletion with alemtuzumab and anti-inflammatory treatment with etanercept and anakinra markedly suppress autoimmunity a much safer and better tolerated combination than cyclophosphamide The addition of a long-acting glucagon-like peptide-1 GLP-1 analogue liraglutide is based on its known positive trophic and metabolic protective effects
Study Procedures
1 Patient selection New onset of T1DM diagnosed 180 days positive anti-GAD antibodies Informed consent will be obtained from adult patients aged 18 and older
2 Participants will go through screening evaluation which will include C-peptide levels during mixed-meal tolerance test MMTT HbA1c exogenous insulin infectious and malignancy screening pregnancy test for women assessment of cardiac renal hepatic pulmonary and hematologic function assessment of T cells autoreactivity measurement of autoantibodies for GAD ICA512 IA2A ZnT8 and mIAA monitoring of HLA-A2 restricted insulin B10-18 prepro-insulin PPI15-24 islet antigen IA-2797-805 GAD65114-123 islet-specific glucose-6-phosphatase catalytic subunit-related protein IGRP265-273 and prepro islet amyloid polypeptide ppIAPP5-13-specific CD8 T-cells
3 Participants will be randomly assigned to treated arm or control arm in a 21 allocation resulting N40 for treated arm and N20 for control arm
4 For participants assigned to the treated arm Intervention treatment will last from Day 0 up to Month 24
1 Day 0 Subjects will receive Alemtuzumab Lemtrada30mg iv single dose Anakinra 100 mg sc Etanercept 50 mg sc and Liraglutide 06 mg sc at University of Alberta Hospital
2 Day 1 Subjects will receive Plerixafor 024 mgkgday sc at University Hospital to mobilize CD34 stem cells to peripheral blood
3 Day 1 Continuing with Anakinra 100mg sc daily for 12 month Etanercept 50mg sc twice weekly for first 3 months and 50mg sc weekly for another 9 months Liraglutide 06 mg sc daily for 7 days then 12 mg sc daily or up to 18mg daily as tolerated for 24 months
5 For participant assigned to the control arm they will be monitored and tested for the first 12 months and receive intervention treatment from Month 12 up to Month 24
1 Month 12 Subjects will receive Alemtuzumab Lemtrada 30mg iv single dose Anakinra 100 mg sc Atanercept 50 mg sc and Liraglutide 06 mg sc at University of Alberta Hospital
2 Month 12 1 day Subjects will receive Plerixafor 024 mgkgday sc at University Hospital to mobilize CD34 stem cells to peripheral blood
3 Month 12 1 day Continuing with Anakinra 100mg sc daily for 12 month Etanercept 50mg sc twice weekly for first 3 months and 50mg sc weekly for another 9 months Liraglutide 06 mg sc daily for 7 days then 12 mg sc daily or up to 18mg daily as tolerated for 12 months
6 Follow-up All study participants will be followed for 24 months Study visits will take place at Month 3 6 9 12 18 and 24 Unscheduled visits will occur as medically necessary
One of the most promising approaches to date has been use of intravenous non-myeloablative autologous hematopoietic stem cell transplantation after mobilization with granulocyte colony-stimulating factor G-CSF thymoglobulin and cyclophosphamide as first described by Voltarelli et al in 2007 in Brazil Voltarelli et al demonstrated that a potentially toxic cyclophosphamide-based depletional therapy and autologous bone marrow transplant rescue restores self-tolerance prolongs honeymoon and remarkably secures insulin independence This immunological reset approach was designed to eliminate autoreactive lymphocyte clones with subsequent immune reconstitution Remarkably 2023 children and adolescents with new-onset T1DM were rendered insulin independent for periods of 6-35 months In longer follow-up 1223 maintained this state for a mean of 31 months There were no deaths but nosocomial pneumonia occurred in 2 and oligospermia in 9 The underpinning mechanism appears to be restoration of apoptosis-related gene deregulation that contributed to breakdown of immune tolerance in T1DM
Our proposed new-onset intervention trial is based on Voltarellis concept but we have eliminated cyclophosphamide replaced GCSF with plerixafor substituted thymoglobulin for a single dose of alemtuzumab and added anti-inflammatory treatments derived from the Clinical Islet Program in Edmonton with excellent safety profiles to date Cellular and immunologic data from our Clinical Islet Transplant program indicates that T-depletion with alemtuzumab and anti-inflammatory treatment with etanercept and anakinra markedly suppress autoimmunity a much safer and better tolerated combination than cyclophosphamide The addition of a long-acting glucagon-like peptide-1 GLP-1 analogue liraglutide is based on its known positive trophic and metabolic protective effects
Study Procedures
1 Patient selection New onset of T1DM diagnosed 180 days positive anti-GAD antibodies Informed consent will be obtained from adult patients aged 18 and older
2 Participants will go through screening evaluation which will include C-peptide levels during mixed-meal tolerance test MMTT HbA1c exogenous insulin infectious and malignancy screening pregnancy test for women assessment of cardiac renal hepatic pulmonary and hematologic function assessment of T cells autoreactivity measurement of autoantibodies for GAD ICA512 IA2A ZnT8 and mIAA monitoring of HLA-A2 restricted insulin B10-18 prepro-insulin PPI15-24 islet antigen IA-2797-805 GAD65114-123 islet-specific glucose-6-phosphatase catalytic subunit-related protein IGRP265-273 and prepro islet amyloid polypeptide ppIAPP5-13-specific CD8 T-cells
3 Participants will be randomly assigned to treated arm or control arm in a 21 allocation resulting N40 for treated arm and N20 for control arm
4 For participants assigned to the treated arm Intervention treatment will last from Day 0 up to Month 24
1 Day 0 Subjects will receive Alemtuzumab Lemtrada30mg iv single dose Anakinra 100 mg sc Etanercept 50 mg sc and Liraglutide 06 mg sc at University of Alberta Hospital
2 Day 1 Subjects will receive Plerixafor 024 mgkgday sc at University Hospital to mobilize CD34 stem cells to peripheral blood
3 Day 1 Continuing with Anakinra 100mg sc daily for 12 month Etanercept 50mg sc twice weekly for first 3 months and 50mg sc weekly for another 9 months Liraglutide 06 mg sc daily for 7 days then 12 mg sc daily or up to 18mg daily as tolerated for 24 months
5 For participant assigned to the control arm they will be monitored and tested for the first 12 months and receive intervention treatment from Month 12 up to Month 24
1 Month 12 Subjects will receive Alemtuzumab Lemtrada 30mg iv single dose Anakinra 100 mg sc Atanercept 50 mg sc and Liraglutide 06 mg sc at University of Alberta Hospital
2 Month 12 1 day Subjects will receive Plerixafor 024 mgkgday sc at University Hospital to mobilize CD34 stem cells to peripheral blood
3 Month 12 1 day Continuing with Anakinra 100mg sc daily for 12 month Etanercept 50mg sc twice weekly for first 3 months and 50mg sc weekly for another 9 months Liraglutide 06 mg sc daily for 7 days then 12 mg sc daily or up to 18mg daily as tolerated for 12 months
6 Follow-up All study participants will be followed for 24 months Study visits will take place at Month 3 6 9 12 18 and 24 Unscheduled visits will occur as medically necessary
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
False
Is a FDA Regulated Device?:
False
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
False
Is an FDA AA801 Violation?:
None