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Trial registered on ANZCTR


Registration number
ACTRN12619000268145
Ethics application status
Approved
Date submitted
8/02/2019
Date registered
21/02/2019
Date last updated
21/02/2019
Date data sharing statement initially provided
21/02/2019
Type of registration
Prospectively registered

Titles & IDs
Public title
A multi-centre trial of a new immunosuppression regime for pancreatic islet transplant recipients
Scientific title
A phase II, single arm multi-centre trial of thymoglobulin, belatacept and sirolimus for the prevention of hypoglycaemia in pancreatic islet transplant recipientspancreatic islet transplant recipients.
Secondary ID [1] 295844 0
Nil
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Hypoglycaemia Unawareness 309422 0
Type 1 Diabetes 309423 0
Islet graft survival 309699 0
Condition category
Condition code
Metabolic and Endocrine 308578 308578 0 0
Diabetes

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
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.
Intervention code [1] 312495 0
Treatment: Drugs
Comparator / control treatment
To be compared with historical CNI-based immunosuppressive regimen collected between 2006 - 2018.
The patients received:
* Etanercept (Enbrel® )50 mg subcutaneously on Day 0,1 hour pre transplantation
Tacrolimus 0.05 mg / kg per dose Post Operatively bi-daily (Target levels:10 to 12 ng / mL)
* Mycophenolate MOFETIL (Sandoz®) – 1 g Post Operatively bi-daily
* 1st transplant –Thymoglobuline® 1.5 mg / kg per dose IV for 3 days (total 4.5 mg / kg)
* 2nd transplant – Thymoglobuline® 1.5 mg / kg per dose IV for 2 days (total 3 mg / kg)
* Etanercept (Enbrel®) 25 mg subcutaneously on Day 3, Day 7 and Day 10 after transplantation
* Subsequent transplant – Basiliximab 20 mg IV pre-op only

Control group
Historical

Outcomes
Primary outcome [1] 307539 0
Freedom from hypoglycaemia – as calculated by the Edmonton hypoglycaemia score. Percentage of patients’ c-peptide positive with an HbA1c less than 7.0% 12 months after transplant.
Timepoint [1] 307539 0
12 months after first transplant, and 12 months after each subsequent transplant.
Secondary outcome [1] 352256 0
The proportion of recipients that are insulin free. “Insulin Free” is reported as the patient being insulin independent. This means the patient insulin requirements are less than 5 units of insulin per day for over 1-2 week time period.
Timepoint [1] 352256 0
6 months, 12 months and 24 months after first transplant, and 6 months, 12 months and 24 months after each subsequent transplant.
Secondary outcome [2] 352257 0
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.

This is a procedure performed on the patient as an initial assessment tool to assess insulin resistance and to determine the Diagnosis of Type 1 diabetes. The test is considered to be “gold standard” in the evaluation of outcomes in clinical trials. Patients fast before the test and blood (serum) glucose, insulin and c-peptide levels are measured at designated time points (0 mins, 15 mins and 30 mins).
Venous sampling of blood is performed throughout the test.
If the venous sample reaches a blood glucose level of 15 mmol /L the glucose infusion is stopped and Arginine infusion commenced. This means not all stages of the Dextrose infusion are performed and provides an indication to the functioning of the islet cells or absence of function.
Intravenous 5% Dextrose infusion is commenced at a dosage of 2mg/kg /hour. The rate is calculated according to the weight of the patient.
This rate is increased to 4mg/kg/hour. The blood glucose is measured through venous sampling at regular time points 10mins 20mins, 30 mins, 36 mins, 38 mins and 40 mins.
This rate is increased to 6mg/kg/hour The blood glucose is measured through venous sampling at regular time points 10mins 20mins, 30 mins , 36 mins,38 mins and 40 mins.
This rate is increased to 8mg/kg/hour The blood glucose is measured through venous sampling at regular time points 10mins 20mins, 30 mins , 36 mins,38 mins and 40 mins.
Commencement of Arginine infusion ( 30 grams for baseline assessment and 5 grams for patients who have received and islet cell transplant.
Following the infusion of the Arginine further blood serum sampling is performed blood (serum) glucose, insulin and c-peptide levels.
Timepoint [2] 352257 0
Composite secondary outcome, 6 months, 12 months and 24 months after first transplant, and 6 months, 12 months and 24 months after each subsequent transplant. This continues until there is evidence to indicate graft failure. It is then no longer required.
Secondary outcome [3] 352258 0
Composite secondary outcome. The proportion of patients with a fasting BSL < 6 mmol/l and a 2 h our post glucose challenge of < 8.5 mmol/l and the proportion of patients with a HbA1c <6.5%

This procedure may be used in sites where the Arginine Stimulation Test is not performed.
It may be seen as an alternate measuring tool, it is performed to assess islet cell graft function.
Timepoint [3] 352258 0
6 months, 12 months and 24 months after first transplant, and 6 months, 12 months and 24 months after each subsequent transplant.
Secondary outcome [4] 352259 0
The percentage of recipient’s insulin independent after 1 & 2 islet infusions.
The islet cell transplant recipient being assessed as being insulin independent. This means the patient insulin requirements are less than 5 units of insulin per day for over 1-2 week time period.
The patient will be assessed as being “Insulin independent “by using a combination of results:
1. Assessment Arginine Stimulation test or Glucose Tolerance test
2. Serum assessment of c- peptide ( level >0.03 nmol/l)
3. HYPO SCORE – performed at the time of islet assessment, 6 monthly intervals.
4. Clinical assessment and management of Diabetes Management
5. Continuous glucose monitoring to assess blood glucose response over 7 days’ time interval.
Timepoint [4] 352259 0
6 months, 12 months and 24 months after first transplant, and 6 months, 12 months and 24 months after each subsequent transplant.
Secondary outcome [5] 352260 0
The proportion of patient that have developed donor-specific antibodies (DSA) as assessed by luminex screen
Timepoint [5] 352260 0
6 months and 12 months after first transplant, and 6 months and 12 months after each subsequent transplant.
Secondary outcome [6] 352261 0
The proportion of patients with a >20% deterioration in eGFR at 12 months compared to baseline
Timepoint [6] 352261 0
12 months after first transplant, and 12 months after each subsequent transplant.
Secondary outcome [7] 352262 0
The impact of IBMIR after islet infusion as assessed by c-peptide levels one hour after islet infusion.
Timepoint [7] 352262 0
one hour after first islet infusion, and after each subsequent infusion.
Secondary outcome [8] 352263 0
Estimate of islet mass by maximal stimulated C-peptide using a stepped glucose infusion.
This is performed using the serum measurements of blood glucose, c-peptide and insulin.
The values are compared at the time points collected as per the secondary outcome 2.
Peak values are compared and calculated to assess the outcome.
Timepoint [8] 352263 0
6 and 12 months after islet first infusion, and 6 months and 12 months after each subsequent transplant.
Secondary outcome [9] 352264 0
Patient survival
Post Islet cell transplant patients are reviewed on a daily basis by Consultant and Diabetes management, and then patients attend outpatient clinic daily for blood pathology and clinical assessment. Outpatient visits will be adjusted according to clinical and pathology results and directed by Consultant and Medical staff.
Timepoint [9] 352264 0
6 months, 12 months and 24 months after first transplant, and 6 months, 12 months and 24 months after each subsequent transplant.
Secondary outcome [10] 352265 0
Assess QoL at baseline and at 6 and 12 months
Quality of Life is assessed using a Questionnaire designed by The Australian Centre for Behavioural Research in Diabetes Deakin University.
The questionnaire is given to patients to complete at time of assessment for islet cell transplantation. The Pre Transplant Questionnaire. Analysis of the data will be performed using the statistical package SPPS.

The Pre Transplant Questionnaire includes Subheadings:
1. Your expectations and experiences
2. Perceptions of Transplant Questionnaire
3. Your Quality of life ( Based on DQOL Quality of Life Questionnaire)
4. Fear Hypoglycaemia Survey

The Post Transplant Questionnaire includes Subheadings
1. Your experiences
2. Perceptions of Transplant Questionnaire
3. Your satisfaction with your transplant
4. Your Quality of life ( Based on DQOL Quality of Life Questionnaire)
5. Fear Hypoglycaemia Survey
6. Interview conducted at least 24 months after their first transplant
Timepoint [10] 352265 0
baseline, 6 months and 12 months after first transplant, and 6 months and 12 months after each subsequent transplant.
Secondary outcome [11] 366989 0
Graft Survival
Patients are assessed prior to transplantation and current c –peptide and function assessed
Post Islet cell transplant patients are reviewed on a daily basis by Consultant and Diabetes management.
Patients attend outpatient daily for at least clinic for blood pathology and clinical assessment.

Outpatient visits will be adjusted according to clinical and pathology results and directed by Consultant and Medical staff
Assessment Arginine Stimulation test or Glucose Tolerance test
Serum assessment of c- peptide (level >0.03 nmol/l)
HYPO SCORE – performed at the time of islet assessment, 6 monthly intervals.
Clinical assessment and management of Diabetes Management
Continuous glucose monitoring to assess blood glucose response over 7 days’ time interval. Performed at 6 monthly intervals.
Timepoint [11] 366989 0
6 months, 12 months and 24 months after first transplant., and 6 months, 12 months and 24 months after each subsequent transplant.

Eligibility
Key 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.
Minimum age
18 Years
Maximum age
No limit
Gender
Both males and females
Can healthy volunteers participate?
No
Key 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

Study design
Purpose of the study
Prevention
Allocation to intervention
Non-randomised trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Other
Other design features
This is a single intervention study group with a historical control group.
Phase
Phase 2
Type of endpoint(s)
Statistical methods / analysis
Results before and after transplantation will be compared using analysis of variance. Patient and graft survival will be assessed by Kaplan-Meier. Patient follow up will be for 2 years.

Recruitment
Recruitment status
Not yet recruiting
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
ACT,NSW,NT,QLD,SA,TAS,WA,VIC
Recruitment hospital [1] 11993 0
Westmead Hospital - Westmead
Recruitment hospital [2] 11994 0
The Royal Adelaide Hospital - Adelaide
Recruitment hospital [3] 11995 0
St Vincent's Hospital (Melbourne) Ltd - Fitzroy
Recruitment postcode(s) [1] 24149 0
2145 - Westmead
Recruitment postcode(s) [2] 24150 0
5000 - Adelaide
Recruitment postcode(s) [3] 24151 0
3065 - Fitzroy

Funding & Sponsors
Funding source category [1] 300439 0
Charities/Societies/Foundations
Name [1] 300439 0
JDRF Australia
Address [1] 300439 0
Level 4
80 Chandos Street
St Leonards
NSW 2065
Country [1] 300439 0
Australia
Primary sponsor type
University
Name
The University of Sydney
Address
City Road
Camperdown/Darlington
NSW 2006
Country
Australia
Secondary sponsor category [1] 299901 0
None
Name [1] 299901 0
Address [1] 299901 0
Country [1] 299901 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 301241 0
Western Sydney Local Health District Human Research Ethics Committee
Ethics committee address [1] 301241 0
Research Office,
Level 2
REN Building
Westmead Hospital
Cnr Hawkesbury & Darcy Roads
Westmead
NSW 2145
Ethics committee country [1] 301241 0
Australia
Date submitted for ethics approval [1] 301241 0
17/01/2018
Approval date [1] 301241 0
31/08/2018
Ethics approval number [1] 301241 0
HREC/18/WMEAD/3

Summary
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).
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 86350 0
Prof Philip O'Connell
Address 86350 0
Renal Unit
Westmead Hospital
Cnr Hawkesbury Road and Darcy Road
Westmead, NSW 2145
Country 86350 0
Australia
Phone 86350 0
+61 2 88906962
Fax 86350 0
Email 86350 0
philip.oconnell@health.nsw.gov.au
Contact person for public queries
Name 86351 0
Ms Nicole WIlletts
Address 86351 0
Centre for Transplant and Renal Research
Westmead Institute of Medical Research
PO Box 412
Westmead, NSW, 2145
Country 86351 0
Australia
Phone 86351 0
+61 2 86276689
Fax 86351 0
Email 86351 0
nicole.willetts@sydney.edu.au
Contact person for scientific queries
Name 86352 0
Prof Philip O'Connell
Address 86352 0
Renal Unit
Westmead Hospital
Cnr Hawkesbury Road and Darcy Road
Westmead, NSW 2145
Country 86352 0
Australia
Phone 86352 0
+61 2 88906962
Fax 86352 0
Email 86352 0
philip.oconnell@health.nsw.gov.au

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
Yes
What data in particular will be shared?
The Trial outline with all methods will be published prior to commencement of the trial. All genomics data will be deposited on the NIH repository after publication. Requests for raw data for analysis will be evaluated by the Publication and Data committee for relevance, feasibility and to avoid duplication.
When will data be available (start and end dates)?
The description of the clinical trial including the methods will be deposited in a public data base or published at the beginning of patient recruitment.
Genomics Data will be placed in a public repository after publication.
Raw clinical data will available to appropriate researchers after evaluation of application 2 years after the completion of the study as suggested in the JDRF guidelines. : if we have not published using our own data, then the requestors will not be given data which may preclude our own publication(s) until a reasonable time frame such as that suggested in JDRF’s own document
Available to whom?
Data access will be available to appropriate researchers and will require a written request and proof of ethics approval to obtain / use the data. Because it is de-identified, we would envisage that this would usually take the form of a minimal impact ethics application for the person intending to do a study, thus lowering their workload.
Available for what types of analyses?
Metanalyses and substudies that require collaboration with other clinical trials of islet transplantation
How or where can data be obtained?
No identifiable data will be shared under any circumstances. Shared data will be given using only identifier codes.
Access will be subject to approvals by the Principal Investigator.
What supporting documents are/will be available?
Study protocol
Ethical approval
How or where can supporting documents be obtained?
Type [1] 1325 0
Ethical approval
Citation [1] 1325 0
Link [1] 1325 0
Email [1] 1325 0
Other [1] 1325 0
Summary results
No Results