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PolyTreg Immunotherapy in Islet Transplantation

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details. Identifier: NCT03444064
Recruitment Status : Recruiting
First Posted : February 23, 2018
Last Update Posted : April 17, 2019
Information provided by (Responsible Party):
University of Alberta

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


Immune profile

Condition or disease Intervention/treatment Phase
Diabetes Diabetes Mellitus, Type 1 Biological: PolyTregs Phase 1

  Show Detailed Description

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 18 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Polyclonal Regulatory T Cell (PolyTreg) Immunotherapy in Islet Transplantation
Actual Study Start Date : February 1, 2018
Estimated Primary Completion Date : March 2020
Estimated Study Completion Date : March 2021

Resource links provided by the National Library of Medicine

Arm Intervention/treatment
No Intervention: Control
Participants in this arm receive islet transplant only, and no PolyTregs.
Experimental: Treatment
Participants in this arm receive PolyTregs infusion at week 6 post islet transplant.
Biological: PolyTregs
Treatment group receive PolyTregs 6 weeks after islet transplantation as immunotherapy to improve islet survival and reduce the need for immunosuppression drugs.
Other Name: Ex vivo Expanded Autologous CD4+CD127lo/-CD25+ Polyclonal Regulatory T cells

Primary Outcome Measures :
  1. Adverse Events [ Time Frame: 58 weeks ]
    Any adverse event that occurs during the study

Secondary Outcome Measures :
  1. Stimulated C-peptide level [ Time Frame: Baseline ]
    Stimulated C-peptide response during Mixed Meal Tolerance Test (MMTT)

  2. Stimulated C-peptide level [ Time Frame: Day 30 post islet transplant ]
    Stimulated C-peptide response during Mixed Meal Tolerance Test (MMTT)

  3. Stimulated C-peptide level [ Time Frame: Day 90 post islet transplant ]
    Stimulated C-peptide response during Mixed Meal Tolerance Test (MMTT)

  4. Stimulated C-peptide level [ Time Frame: Week 58 post islet transplant ]
    Stimulated C-peptide response during Mixed Meal Tolerance Test (MMTT)

Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.

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Ages Eligible for Study:   18 Years to 68 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

Inclusion Criteria:

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:

  1. 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.
  2. 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.

Exclusion Criteria:

Patients will be excluded if they meet any one or more of the following criteria:

  1. 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
  2. Active alcohol or substance abuse (must be abstinent for 6 months prior to transplant)
  3. Clinical history of T1DM diagnosed >age 40, insulin dependent <5 years
  4. 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)
  5. Measured glomerular filtration rate (GFR) < 60mL/min/1.73 m2
  6. Presence or history of macroalbuminuria (>300 mg/g creatinine)
  7. 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)
  8. Baseline Hb < 105g/L (<10.5 g/dL) in women, or < 120 g/L (<12 g/dL) in men
  9. Untreated proliferative retinopathy
  10. Positive pregnancy test, intent for future pregnancy, failure to follow effective contraceptive measures, or presently breast‑feeding
  11. Previous transplant or evidence of significant sensitization on panel reactive antibody (PRA) (at the discretion of the investigator).
  12. Insulin requirement >1.0 U/kg/day
  13. HbA1C >12%
  14. 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)]
  15. Under treatment for a medical condition requiring chronic use of steroids
  16. Use of coumadin or other anticoagulant therapy (except aspirin) or subject with PT‑INR > 1.5
  17. Untreated Celiac disease
  18. Patients with a Graves disease will be excluded unless previously adequately treated with radioiodine ablative therapy

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT03444064

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Contact: Andrew Malcolm, PhD 780-407-6952
Contact: Parastoo Dinyari, BSc 780-407-3904

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Canada, Alberta
University of Alberta Recruiting
Edmonton, Alberta, Canada, T6G 2C8
Contact: Andrew Malcolm, PhD    (780) 407-6952   
Contact: Parastoo Dinyari, BSc    (780) 407-3904   
Principal Investigator: James Shapiro, MD PhD         
Sponsors and Collaborators
University of Alberta
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Principal Investigator: James Shapiro, MD, PhD University of Alberta

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Responsible Party: University of Alberta Identifier: NCT03444064     History of Changes
Other Study ID Numbers: Pro00071320
First Posted: February 23, 2018    Key Record Dates
Last Update Posted: April 17, 2019
Last Verified: April 2019

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: Yes

Keywords provided by University of Alberta:
Islet transplantation
Diabetes treatment

Additional relevant MeSH terms:
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Diabetes Mellitus
Diabetes Mellitus, Type 1
Glucose Metabolism Disorders
Metabolic Diseases
Endocrine System Diseases
Autoimmune Diseases
Immune System Diseases
Immunologic Factors
Physiological Effects of Drugs