PolyTreg Immunotherapy in Islet Transplantation

NCT03444064 | Completed Phase 1 DMC FDA Drug

• 1 other identifier: Pro00071320
• Study Type: interventional
• Target: 11
• Locations: 1 country
• Sites: 1

Brief Summary

Islet transplantation is a relatively new procedure used in people with difficult to control Type 1 diabetes. Patients who receive an islet transplant take medication that suppresses their immune system and prevent rejection of the islet tissue. In spite of the strengths of the current immunosuppression regimen, it has failed to enhance single-donor success rates, and the majority of patients require 2 or more islet transplants to achieve insulin independence. The need for life-long, high-dose immunosuppression is also associated with substantial side effects, and continues to limit application of islet transplantation earlier in the course of the disease. The investigators have learned that Regulatory T cells (Tregs), a small subset of cluster of differentiation 4+ (CD4+) T cells, have emerged as the major contributor to self-tolerance through suppression of activation and effector function of other immune cells. Tregs function by preventing the initiation of unwanted immune activation and by suppressing ongoing immune response to limit bystander tissue destruction. It has been suggested that infusion of Tregs before extensive graft damage may improve long-term graft outcomes. This study is an open label, controlled, dose finding pilot study. Up to 18 participants will be recruited including 12 participants receiving the investigational treatment and 6 participants being assigned to control group. All participants will undergo the routine Standard of Care islet transplant procedure, and will be maintained on lower dose tacrolimus and sirolimus immunosuppression. The primary goal is to assess the safety and feasibility of intravenous infusion of ex vivo-selected and ex vivo-expanded autologous PolyTregs in islet transplant patients. The other goal is to assess the effect of Tregs on beta cell function in islet transplant patients. The control group (6) will receive the current Edmonton islet transplant induction therapy (Alemtuzumab with Etanercept and Anakinra). The intervention group (up to 12) will receive islet transplant with same induction therapy as control group and PolyTregs (400-1600 million) six weeks post- transplant and will be followed for 1 year to assess safety and preliminary efficacy of Treg therapy. The Treg product will be administered via a peripheral intravenous (IV) line primed with saline per established standard operating procedures in approximately 20 to 30 minutes. The intravenous line will be maintained after the infusion and the participant will be asked to remain in the hospital for 24 hours. All participants will be maintained on low dose tacrolimus and sirolimus immunosuppression. The investigators will also use retrospective data from the islet transplant cohort receiving Tac/mycophenolate mofetil(MMF) with alemtuzumab (\>100 patients). All study participants will be followed up for 58 weeks. Tests and assessments will be performed at each key study visit and will be allowed for +/- 2 weeks to accommodate scheduling. The following measurements will be recorded at each key study visit : Blood work, including the following: Complete blood count (CBC) and differential Creatinine and electrolytes Fasting glucose and c-peptide Any adverse events Physical examination Body weight (kg) Vital signs (BP, HR) Glucose records for self-monitoring. Hemoglobin A1c Insulin use (total daily dose) Autoantibodies and autoreactive T cell MMTT Immune profile

Conditions

Diabetes; Diabetes Mellitus, Type 1

Keywords

Islet transplantation; Diabetes treatment; PolyTregs; Immunotherapy

Outcome Measures

Primary Outcomes (1)

• Adverse Events

  Any adverse event that occurs during the study

  58 weeks

Secondary Outcomes (4)

• Stimulated C-peptide level

  Baseline

• Stimulated C-peptide level

  Day 30 post islet transplant

• Stimulated C-peptide level

  Day 90 post islet transplant

• Stimulated C-peptide level

  Week 58 post islet transplant

Study Arms (2)

Control

NO INTERVENTION

Participants in this arm receive islet transplant only, and no PolyTregs.

Treatment

EXPERIMENTAL

Participants in this arm receive PolyTregs infusion at week 6 post islet transplant.

Biological: PolyTregs

Interventions

PolyTregs BIOLOGICAL

Treatment group receive PolyTregs 6 weeks after islet transplantation as immunotherapy to improve islet survival and reduce the need for immunosuppression drugs.

Also known as: Ex vivo Expanded Autologous CD4+CD127lo/-CD25+ Polyclonal Regulatory T cells

Treatment

Eligibility Criteria

• Age: 18 Years - 68 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• To be eligible, subjects must be 18-68 years old, and have had T1DM for more than 5 years, complicated by at least 1 of the following situations that persist despite intensive insulin management efforts:
• Reduced awareness of hypoglycemia, as defined by the absence of adequate autonomic symptoms at plasma glucose levels \< 3.0 mmol/L, indicated by, 1 or more episodes of severe hypoglycemia requiring third party assistance within 12 months, or a Clarke score ≥4, or HYPO score ≥1000, or lability index (LI) ≥400 or combined HYPO/LI \>400/\>300.
• Metabolic instability, characterized by erratic blood glucose levels that interfere with daily activities and or 1 or more hospital visits for diabetic ketoacidosis over the last 12 months.
• In addition, participants must be capable of understanding the purpose and risks of the study and must sign a statement of informed consent.

You may not qualify if:

• Patients will be excluded if they meet any one or more of the following criteria:
• Severe co-existing cardiac disease, characterized by any one of these conditions: (a) recent myocardial infarction (within past 6 months); (b) left ventricular ejection fraction \<30%; or (c) evidence of ischemia on functional cardiac exam
• Active alcohol or substance abuse (must be abstinent for 6 months prior to transplant)
• Clinical history of T1DM diagnosed \>age 40, insulin dependent \<5 years
• Active infection including Hepatitis C, Hepatitis B, HIV, tuberculosis (TB) (subjects with a positive purified protein derivative (PPD) performed within one year of enrolment, and no history of adequate chemoprophylaxis)
• Measured glomerular filtration rate (GFR) \< 60mL/min/1.73 m2
• Presence or history of macroalbuminuria (\>300 mg/g creatinine)
• Clinical suspicion of nephritic (hematuria, active urinary sediment) or rapidly progressing renal impairment (e.g. Increase in serum creatinine of 25% within the last 3-6 months)
• Baseline Hb \< 105g/L (\<10.5 g/dL) in women, or \< 120 g/L (\<12 g/dL) in men
• Untreated proliferative retinopathy
• Positive pregnancy test, intent for future pregnancy, failure to follow effective contraceptive measures, or presently breast-feeding
• Previous transplant or evidence of significant sensitization on panel reactive antibody (PRA) (at the discretion of the investigator).
• Insulin requirement \>1.0 U/kg/day
• HbA1C \>12%
• Uncontrolled hyperlipidemia \[fasting LDL cholesterol \> 3.4 mmol/L (133 mg/dL), treated or untreated; and/or fasting triglycerides \> 2.3 mmol/L (90 mg/dL)\]

Sponsors & Collaborators

• University of Alberta: lead
• Diabetes Research Institute Foundation: collaborator
• Liana's Dream Foundation: collaborator
• Juvenile Diabetes Research Foundation: collaborator
• Alberta Diabetes Institute: collaborator

Study Sites (1)

University of Alberta

Edmonton, Alberta, T6G 2C8, Canada

Location

MeSH Terms

Conditions

Diabetes Mellitus; Diabetes Mellitus, Type 1

Condition Hierarchy (Ancestors)

Glucose Metabolism Disorders; Metabolic Diseases; Nutritional and Metabolic Diseases; Endocrine System Diseases; Autoimmune Diseases; Immune System Diseases

Study Officials

• James Shapiro, MD, PhD

  University of Alberta

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: February 16, 2018
• First Posted: February 23, 2018
• Study Start: February 1, 2018
• Primary Completion: August 12, 2024
• Study Completion: December 17, 2024
• Last Updated: December 27, 2024

Record last verified: 2024-12

Locations

CA (1)