None listed
Conditions
Brief summary
A phase II multicentre single arm study of patients with type I diabetes who receive a pancreatic islet transplant for hypoglycaemia unawareness. Patients will receive Thymoglobulin induction with belatacept and sirolimus without corticosteroids. Outcomes will be compared to historical controls receiving our standard immunosuppressive protocol of, ATG induction, tacrolimus and mycophenolate mofetil. In addition patient outcomes will be compared to data with islet registry outcome data from the Collaborative Islet Transplant Registry (CITR).
Interventions
Patients will be given:
Thymoglobulin 6mg/kg in two divided doses (i.e. 3mg/kg per dose), dose 1 on day 1(day of transplant) and dose 2 on day 3 post-transplant will be administered by intravenous infusion.
Belatacept will be administered IV at a dose of 10mg/kg on day 1 (day of transplant), day 5, weeks 2, 4, 8, 12 post-transplant followed by 5mg/kg every 4 weeks thereafter until 24 months.
At the time of transplant patients will receive oral Sirolimus 5 mg daily for 3 days then 3mg daily targe
Patients will be given: Thymoglobulin 6mg/kg in two divided doses (i.e. 3mg/kg per dose), dose 1 on day 1(day of transplant) and dose 2 on day 3 post-transplant will be administered by intravenous infusion. Belatacept will be administered IV at a dose of 10mg/kg on day 1 (day of transplant), day 5, weeks 2, 4, 8, 12 post-transplant followed by 5mg/kg every 4 weeks thereafter until 24 months. At the time of transplant patients will receive oral Sirolimus 5 mg daily for 3 days then 3mg daily targeting a level of 3 to 7 ng/ml for 24 months. If patients are unable to tolerate sirolimus or everolimus they will receive oral mycophenolate mofetil at a dose of 1 gram bi-daily to maintain adequate immunosuppression for 24 months. With the 2nd islet transplant patients receive Thymoglobulin 6 mg/kg in two divided doses. At the time of the 3rd islet transplant will receive basiliximab 20mg IV at the time of transplant. Fidelity will be assessed at the scheduled belatacept infusion study visits and participants will be asked about their compliance.
Sponsors
The University of Sydney
Study design
Allocation
Non-randomised trial
Intervention model
Other
Primary purpose
Prevention
Masking
Open (masking not used)
Eligibility
Sex/Gender
All
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Subjects must be diagnosed with type 1 diabetes for more than 5 years. 2. Subjects must, in the opinion of an endocrinologist, have severe recurrent episodes of hypoglycaemia not responsive to standard therapy. 3. Subjects must have a calculated GFR greater than or equal to 75 mL/min/1.73 m2 (MDRD formula) at the time of enrolment (based on screening/baseline central laboratory results). They must have a serum creatinine greater than or equal to 130 µmol/L and a 24 hour urine protein estimation < 300 mg/day. 4. Subjects must weigh less than 85 Kg 5. Subjects must be EBV IgG positive 6. Men and women, ages 18 years and older, inclusive 7. WOCBP must be using an adequate method of contraception to avoid pregnancy throughout the study and for up to 8 weeks after the last dose of study drug in such a manner that the risk of pregnancy is minimized. 8. For WOCBP using MMF and MPA, two reliable forms of contraception must be used simultaneously unless abstinence is the chosen method.
Exclusion criteria
1) WOCBP who are unwilling or unable to use an acceptable method of contraception to avoid pregnancy for the entire study period and for up to 8 weeks after the last dose of study medication. It should be noted that according to the US product information for mycophenolate mofetil (CellCept©) and mycophenolic acid (Myfortic©), “two reliable forms of contraception be used simultaneously unless abstinence is the chosen method” 2) WOCBP using a prohibited contraceptive method 3) Women who are pregnant or breastfeeding 4) Women with a positive pregnancy test on enrolment or prior to study drug administration 5) Subjects who had a positive T-cell or B-cell crossmatch 6) Subjects with a prior solid organ (kidney, heart, liver, pancreas) or cell ( bone marrow, stem cell) transplants 7) Subjects who are known hepatitis C antibody-positive or PCR-positive for hepatitisC (neither hepatitis C antibody or PCR for hepatitis C testing is required for entry into the study) 8) Subjects who are known hepatitis B surface antigen-positive or PCR-positive for hepatitis B (neither hepatitis B surface antigen or PCR for hepatitis B testing is required for entry into the study) 9) Subjects with known human immunodeficiency virus (HIV) infection. HIV testing is not required for entry into the study 10) Subjects with a chest radiograph (posterior-anterior and lateral views) consistent with an acute lung parenchymal process, malignancy, or active tuberculosis. Subjects must have a chest radiograph within 2 months prior to transplantation 11) Subjects with any significant infection 12) Baseline LFT's outside of normal range 13) Insulin requirement > 0.7 IU/kg/day or a HbA1c > 12% 14) Serum Cholesterol > 10 mmol/l 15) Requirement for systemic corticosteroid usage 16) Treatment with terfenadine, cisapride, astemizole, pimozide, or ketoconazole (that is not discontinued prior to sirolimus administration). 17) Malignant disease other than localized and excised skin Squamous Cell or Basal Cell Carcinoma 18) Hepatic disease, including any form of active viral hepatitis, portal venous abnormality or cirrhosis 19) Chronic Pancreatitis 20) Significant cardiac disease including ischaemic and valvular heart disease 21) Respiratory disease including clinically significant asthma, bronchiectasis or obstructive airways disease. 22) Any form of chronic or current acute mental or psychiatric illness that in the opinion of the investigator would prevent them from adhering to the trial protocol 23) Any form of chronic infection that could in the view of the investigator pose a risk after transplantation 24) Allergy to intravenous contrast agents, sirolimus, belatacept or anti-thymocyte globulin 25) Subjects whose life expectancy is severely limited by disease state or other underlying medical condition 26) Subjects with a history of cancer (other than non-melanoma skin cell cancers cured by local resection) within the last 5 years 27) Subjects with a history of substance abuse (drug or alcohol) within the past 5 years, or psychotic disorders that are not compatible with adequate study follow-up 28) Any other disease which in the opinion of the investigator may represent a significant risk after transplantation and immunosuppression 29) Subjects with laboratory values that meet the following criteria are to be excluded from the study: 30) Urine Assay: a) Proteinuria > 300 mg/day or b) Urine protein : creatinine ratio > 1 31) Hematology: a) Hemoglobin < 7 g/dL b) Platelets < 80,000/mm3 c) White blood cell count < 3000/mm3 (3 x 109/L) 32) Chemistry: a) Bilirubin >1.5 x upper limit of normal range (ULN); Subjects who have Gilbert’s syndrome and have a normal direct bilirubin are permitted b) Aspartate aminotransferase (AST) greater than or equal to 2 x ULN c) Alanine aminotransferase (ALT) greater than or equal to 2 x ULN 33) All women 50 years or older must have a screening mammogram or provide results of a mammogram performed within 6 months of enrolment. Subjects with a mammogram that is suspicious for malignancy and in whom the possibility of malignancy cannot be reasonably excluded following additional clinical or diagnostic evaluations will be excluded. Women of any age who have a first degree relative with a history of breast cancer or who have other risk factors for breast cancer must undergo increased surveillance for breast cancer according to local practice. 34) Subjects who have difficult i.v. access 35) Subjects who have used any investigational drug within 30 days prior to the Day 1 visit 36) Subjects previously treated with belatacept 37) Prisoners or subjects who are compulsorily detained (involuntarily incarcerated) for treatment of either a psychiatric or physical (e.g., infectious disease) illness must not be enrolled into this study. 38) Subjects previously treated with belatacept or previously enrolled in a belatacept trial with their present allograft
Outcome results
None listed