Stem Cell Mobilization (Plerixafor) and Immunologic Reset in Type 1 Diabetes (T1DM)

Diabetes Mellitus, Type 1 Clinical Trial

Official title: Autologous Hematopoietic Stem Cell Mobilization (Plerixafor) and Immunologic Reset in New Onset Type 1 Diabetes Mellitus

Status Active, not recruiting

Clinical Trial 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.

Clinical Trial 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 cow's 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, 20/23 children and adolescents with new-onset T1DM were rendered insulin independent for periods of 6-35 months. In longer follow-up, 12/23 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 Voltarelli's 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 B(10-18), prepro-insulin (PPI)(15-24), islet antigen (IA)-2(797-805), GAD65(114-123), islet-specific glucose-6-phosphatase catalytic subunit-related protein (IGRP)(265-273), and prepro islet amyloid polypeptide (ppIAPP)(5-13)-specific CD8(+) T-cells

3. Participants will be randomly assigned to treated arm or control arm in a 2:1 allocation, resulting N=40 for treated arm and N=20 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 (Lemtrada®),(30mg iv single dose); Anakinra (100 mg sc.); Etanercept (50 mg sc.) and Liraglutide (0.6 mg sc.) at University of Alberta Hospital.

2. Day 1: Subjects will receive Plerixafor (0.24 mg/kg/day) 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 0.6 mg sc. daily for 7 days, then 1.2 mg sc. daily (or up to 1.8mg 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 (0.6 mg sc.) at University of Alberta Hospital.

2. Month 12 + 1 day: Subjects will receive Plerixafor (0.24 mg/kg/day) 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 0.6 mg sc. daily for 7 days, then 1.2 mg sc. daily (or up to 1.8mg 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. ;

Related Conditions & MeSH terms

• Diabetes Mellitus
• Diabetes Mellitus, Type 1

• NCT number: NCT03182426
• Study type: Interventional
• Source: University of Alberta
• Status: Active, not recruiting
• Phase: Phase 1/Phase 2
• Start date: August 15, 2017
• Completion date: December 31, 2025