Human islet transplantation provides a virtual cure for people with type 1 diabetes, but the major obstacles preventing its widespread use are the shortage of donor islets and the need for powerful, lifelong immunosuppressive drugs to prevent islet rejection. 

Professor Philip O’Connell and collaborators from across Australia aim to make islet transplantation a viable option for more people living with type 1 diabetes. Their T1DCRN funded research program is focussed on developing a new islet transplantation protocol with drug-free strategies to prevent islet rejection.

The multi-layered strategy begins before transplantation even begins. Human donor islets will be treated with anti-inflammatory agents prior to transplantation to reduce their ability to stimulate the immune system. At the time of transplantation, the patient’s immune system will be targeted with specific compounds that will shift the balance of immune cells to favour beneficial regulatory T cells over killer T cells. These short-term interventions will hopefully have a long-term impact by training the immune system to tolerate the transplanted islets and allow them to survive permanently.

Once the protocol has been optimised, it will be tested in a clinical trial of up to 20 participants with type 1 diabetes and hypoglycaemia unawareness. Success of the protocol will be measured by assessing the proportion of patients who remain hypoglycaemia and insulin-free with an HbA1c of less than 7% at 6, 12 and 24 months.  The safety of the procedure will be measured by keeping a careful watch on the immune system, kidney function and markers of cardiovascular risk.

If this study can successfully program the immune system to tolerate transplanted human islets, the same procedure could likely be applied to islet transplantation using islets from renewable sources such as pigs or stem cells. This would solve the problem of donor islet shortage as well as eliminating the need for lifelong immnosuppressants. By overcoming current barriers to islet transplantation, this project has the potential to provide a viable cure for most people living with type 1 diabetes.

More information about the project will be released when available.

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Full Detail About This Clinical Trial

Technical Summary

The overarching objective of this program is to develop islet replacement therapy into an attractive, clinically realistic therapeutic option for most people with type 1 diabetes.

The program aims to discover a means for reliable islet transplantation that eliminates the need for chronic immunosuppression, and to develop a renewable source of beta cells. This will be achieved by defining the clinical criteria for recommending islet allotransplantation based on best available evidence, trialling novel tolerance inducing reagents and drugs, and optimizing the graft micro-environment for immunological non-responsiveness.

The research has been divided into two themes:

THEME 1 - Novel immune strategies to allow islet graft tolerance without immunosuppression

Project 1: Modify host immune responses to favour Treg, eliminate effector T cells, and establish permanent immunological tolerance

Project 2: Optimisation of the graft microenvironment for immunological non-responsiveness through A20 expression

THEME 2 - Development of a clinical trial of tolerance in islet transplantation

Project 3: Define the clinical criteria for islet allotransplantation as the gold standard for comparison of all future focused initiatives

Project 4: Design of a clinical trial to test the best available pro-tolerogenic protocol.

Trial Design

Project 1 (Preclinical): This project will develop novel combination immunotherapy treatments in a pre-clinical mouse model to achieve 100% long-term graft survival.

Project 2 (Preclinical): Clinical grade vectors and peptide mimics will be used to up-regulate endogenous A20 expression in human isolated islets in order to achieve tolerance in humanized mouse models of human islet allotransplantation and optimize protocols to mobilize and allow homing of Treg cells to the islet grafts.

Project 3: Understanding both the immunological phenotype as well as the clinical and metabolic outcomes of islet transplant recipient on standard immunosuppression is an essential first step before the initiation of a clinical tolerance protocol.

Thirty-two adults with type I diabetes with severe recurrent asymptomatic hypoglycaemia without renal impairment and who are suitable for islet cell transplantation will be followed for 3 – 5 years both pre-and post-transplantation.

This study is a single-arm sequential clinical trial. Minimum 6 month CSII using Medtronic Veo pump in conjunction with RT-GMS using the Guardian™ real time system with minilink transmitter. Evaluation studies performed at baseline at 6 and 12 months following combined continuous subcutaneous insulin infusion (CSII) and real-time glucose monitoring (RT-GMS) and again at 6 and 12 months post islet cell transplant (with baseline performed within 6 months of islet transplantation).

Evaluation using:

    1. Edmonton hyposcore
    2. 72 hour CGMS mean glucose and sd (measurement of glycaemic variability)
    3. CONGA score calculated from CGMS
    4. Assessment of beta cell function by a) Maximal stimulated C-peptide b) Beta score c) HOMA-Beta
    5. Serum 1’5 anhydroglucitol levels

Project 4: Based on findings obtained in Projects 2 and 3 a tolerance protocol will be submitted for clinical trial in 5 -10 patients. The exact therapeutic protocol for tolerance will be formulated in the first 3 years of the project and is not yet defined.

Anticipated Outcomes

The anticipated outcomes for this project are:

    1. Development of clinical standards for islet transplantation and development of better guidelines for the management of severe hypoglycaemia.
    2. Reduce requirements for immunosuppression for beta cell replacement therapy and the development of islet cell transplantation tolerance.Novel therapeutic reagents will be developed into a clinical therapy to reduce or eliminate the requirement of chronic immunosuppression.

If successful this strategy will have implications for endeavours to prevent the onset of type 1 diabetes as well as for those who aim to treat beta-cell autoimmunity and preserve residual islet tissue.

Principal Investigator

Professor Philip O’Connell

Funder

The Australian Type 1 Diabetes Clinical Research Network

Locations
  • Westmead Hospital, NSW
  • St Vincent’s Hospital Melbourne, Victoria
  • Royal Adelaide Hospital, South Australia
Primary Endpoints

Project 1 and 2: N/A

Project 3:

    1. Proportion achieving >50% change in Edmonton hypo score. Patients on CSII with RT-CGMS who achieve a >50% reduction in Edmonton hypo score and achieves a hypo score of <500 will not proceed to islet transplantation unless they subsequently fail CSII with RT-CGMS treatment.
    2. Change in CONGA score as measured by 72 hour CGMS.
    3. Change in 72 hour CGMS sd of mean glucose (change >0.55 mmol/L indicating clinical significance)

Project 4:

    1. Freedom from hypoglycemia – as calculated by the Edmonton hypoglycaemia score.
    2. Percentage of patients c-peptide positive with a HbA1c less than 7.0% 12 months after transplant.
Secondary Endpoints

Project 1 – 3: N/A

Project 4:

    1. The proportion of recipients that are insulin free at 6 months, 12 months and 24 months post-transplant.
    2. The proportion of patients with an arginine stimulated c-peptide of > 0.17 nmol/l and an oral glucose stimulated c-peptide of >0.30 nmol/l at 6 months, 12 months and 24 months post-transplant.
    3. The proportion of patients with a fasting BSL < 6 mmol/l and a 2 hour post glucose challenge of < 8.5 mmol/l and the proportion of patients with a HbA1c <6.5% at 6 months, 12 months and 24 months post-transplant.
    4. The percentage of recipients insulin independent after 1 & 2 islet infusions. The impact of IBMIR after islet infusion as assessed by c-peptide levels one hour after islet infusion.
    5. Assessment of insulin resistance and beta cell function as described in project 3.Estimate of islet mass by maximal stimulated C-peptide using a stepped glucose infusion six and 12 months after islet infusion.
Inclusion/Exclusion

Inclusion Criteria:

    1. Adults with type 1 diabetes for 5 yrs. or more, aged 18-65, weight < 80kg
    2. Severe hypoglycaemic unawareness that has not responded to optimal conventional insulin therapy, as assessed by an endocrinologist.
    3. Creatinine clearance > 75/ml/min/1.73m2, serum creatinine < 130 μmol/l
    4. 24 hr urine protein estimation < 300mg/day
    5. Absence of donor reactive antibodies by Luminex and cytotoxic crossmatch
    6. Willingness to use effective contraception measures

Exclusion Criteria:

    1. Creatine clearance < 75 mL/min/1.73 m2, serum creatinine > 130 μmol/l
    2. 24 hr Urine Protein estimation >300 mg/day
    3. Hb < 12 gm/dL in women, or < 13 gm/dL in men
    4. Baseline LFT's outside of normal range
    5. Insulin requirement > 0.7 IU/kg/day
    6. HbA1c > 12%
    7. Serum Cholesterol > 10 mmol/l
    8. Systemic Corticosteroid usage
    9. Treatment with terfenadine, cisapride, astemizole, pimozide, or ketoconazole (that is not discontinued prior to sirolimus administration).
    10. A positive pregnancy test or desire to fall pregnant within the timeframe of the trial.
    11. Malignant disease other than localized and excised skin Squamous Cell or Basal Cell Carcinoma
    12. Hepatic disease, including any form of active viral hepatitis, portal venous abnormality or cirrhosis
    13. Chronic Pancreatitis
    14. Significant cardiac disease including ischaemic and valvular heart disease
    15. Respiratory disease including clinically significant asthma, bronchiectasis or obstructive airways disease.
    16. Any form of chronic or current acute mental or psychiatric illness
    17. Any form of chronic infection that could in the view of the investigator pose a risk after transplantation
    18. Major abdominal surgery
    19. Allergy to intravenous contrast agents, sirolimus, tofacitinib or anti-thymocyte globulin
    20. Anaemia, Thrombocytopenia, Leucopoenia, clotting abnormality or other clinically significant haematological disorder
    21. Any other disease which in the opinion of the investigator may represent a significant risk after transplantation and immunosuppression
Start/End Date

2016 - 2019