AZD1656 in Transplantation With Diabetes tO PromoTe Immune TOleraNce
Phase: PHASE2
Conditions: Type 2 Diabetes, Diabetes Mellitus, Type 2, Renal Transplant, Kidney Transplant; Complications, End Stage Renal Disease
Sponsor: Queen Mary University of London

 
ADOPTION Study V1.8 07.07.21 
 
Page 1 of 78 
 
1.0 Title Page 
 
Full Title 
 
AZD1656 in Transplantation with Diabetes tO PromoTe Immune TOleraNce 
 
Short Title  
 
The ADOPTION Study 
 
Sponsor 
 
Queen Mary University of London 
 
Representative of the Sponsor: 
 
Dr Mays Jawad 
Research Governance Operations Manager 
Joint Research Management Office 
QM Innovation Building 
 
 
5 Walden Street 
 
 
London 
 
 
E1 2EF 
 
 
Phone: 020 7882 7260 
 
 
Email: research.governance@qmul.ac.uk 
 
 
 
REC Number  
 
19/EE/0209 
 
 
 
Sponsor Reference  
012657 
 
 

 
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2.0 Research Reference Numbers 
 
IRAS Number: 
252155 
 
EudraCT Number: 
 
2019-001587-30 
 
ISRCTN Number / Clinical 
trials.gov Number: 
 
TBC 
 
 

 
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3.0 Signature Pages 
 
Chief Investigator Declaration 
I confirm that the following protocol (Version 1.8, dated 07th July 2021), has been 
written by me and I, as the Chief Investigator, agree to conduct the trial in 
compliance with this version of the protocol. 
 
I will adhere to the principles outlined in the Medicines for Human Use (Clinical 
Trials) Regulations 2004 (SI 2004/1031), and all subsequent amendments of the 
clinical trial regulations; current UK Policy Framework for Health and Social Care 
Research; the World Medical Association Declaration of Helsinki (1996); GCP 
guidelines; the Sponsor’s SOPs; and other regulatory requirements as amended. 
 
I agree to ensure that the confidential information contained in this document will not 
be used for any other purpose other than the evaluation or conduct of the clinical 
investigation without the prior written consent of the sponsor. 
 
I also confirm that I will make the findings of the study publicly available through 
publication and/or other dissemination tools without any unnecessary delay and that 
an honest, accurate and transparent account of the study will be given; and that any 
discrepancies from the study as planned in this protocol will be explained. 
 
 
Chief Investigator:  
Kieran McCafferty 
Chief Investigator Site:  
Barts Health NHS Trust 
Signature:  
 
Date:   
 
 
07.07.21 
Name:  
 
 
Dr Kieran McCafferty 
 
 

 
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Statistician Declaration 
The clinical study as detailed within this research protocol (Version 1.8, dated 07th 
July 2021), involves the use of an investigational medicinal product and will be 
conducted in accordance with the current UK Policy Framework for Health & Social 
Care Research; the World Medical Association Declaration of Helsinki (1996); 
Principles of ICH E6-GCP; ICH E9 - Statistical principles for Clinical Trials; ICH E10 - 
Choice of Control Groups; and the current regulatory requirements, as detailed in the 
Medicines for Human Use (Clinical Trials) Regulations 2004 (UK S.I. 2004/1031) and 
any subsequent amendments of the clinical trial regulations. 
 
Statistician:  
 
 
Dr Stan Fan  
Job title: 
 
 
 
Consultant Nephrologist 
Statistician Site/Organisation: 
Barts Health NHS Trust 
Signature: 
 
 
 
  
 
Date:   
 
 
 
07.07.21 
Name:  
 
 
 
Dr Stan Fan 
 
 

 
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4.0 Key Trial Contacts 
 
Chief Investigator 
Kieran McCafferty 
Phone: 07980620627 
Email: kieran.mccafferty4@nhs.net 
Trial Co-ordinator/Manager 
Senior Renal Research Nurse 
Department of Nephrology  
Royal London Hospital 
Tel: 0203 5941706 
Fax: 0203 5943246 
Sponsor 
 
Sponsor Representative 
Queen Mary University of London 
 
Dr Mays Jawad 
Research Governance Operations Manager 
Joint Research Management Office 
QM Innovation Building 
5 Walden Street 
London 
E1 2EF 
Phone: 020 7882 7260 
Email: research.governance@qmul.ac.uk 
Laboratories  
Royal London Hospital Pathology department 
Whitechapel 
E1 1BB 
Funder(s) 
Diabetic Kidney Disease Centre with Astra Zeneca 
Statistician 
Dr Stan Fan 
Consultant Nephrologist 
Barts Health NHS Trust 
Trials pharmacist 
Rahi Shah 
Senior Research Pharmacist 
Barts Health NHS trust 
Phone: 02035946680 
Email: rlhpharmacyct.bartshealth@nhs.net 
Committees  
 
For membership and contract details please see 
TSC/DMC document 
 
 

 
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5.0 Trial Summary 
 
Full title 
AZD1656 in Transplantation with Diabetes tO PromoTe 
Immune TOleraNce  
Short title and/or Acronym 
 
The ADOPTION Study  
Trial Design 
Methodology 
Single site, placebo controlled, double blind randomised 
clinical trial. 
Phase of the Trial 
 
II 
Study Duration 
 
27 months 
Study setting 
 
 
Single NHS site 
Investigational Medicinal 
Product(s) 
AZD1656 
Medical condition or disease 
under investigation 
Post-renal transplant diabetes and graft rejection 
Planned Sample Size 
 
50 
(Maximum) Treatment 
duration 
3 months 
Follow up duration 
 
9 months 
End of Trial definition 
The last patient has completed their last follow up point 
at 1 year post-transplant (data review visit). 
 
 

 
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6.0 Protocol Contributors 
 
Key Protocol Contributors 
Full contact details including phone, email and fax 
numbers 
Prof Magdi Yaqoob 
 
 
 
 
 
 
 
Prof Federica Marelli-Berg 
Department of Nephrology 
Royal London Hospital  
Whitechapel 
E1 1BB 
Phone: +44(0) 20 3594 2658 
Email: m.m.yaqoob@qmul.ac.uk 
 
 
William Harvey Research Institute 
Queen Mary University London 
Phone: +44(0) 20 7882 3443 
Email: f.marelli-berg@qmul.ac.uk 
 
 

 
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7.0 List of Contents 
 
1.0 Title Page ............................................................................................................. 1 
2.0 Research Reference Numbers ............................................................................. 2 
3.0 Signature Pages ................................................................................................... 3 
4.0 Key Trial Contacts ................................................................................................ 5 
5.0 Trial Summary ...................................................................................................... 6 
6.0 Protocol Contributors ............................................................................................ 7 
7.0 List of Contents .................................................................................................... 8 
8.0 List of Abbreviations / Glossary of Terms ........................................................... 12 
9.0 Introduction ........................................................................................................ 14 
9.1 Background ..................................................................................................... 14 
9.2 Assessment and management of risk ............................................................. 16 
9.3 Rationale for study design ............................................................................... 20 
10.0 Trial Flowchart .................................................................................................. 21 
11.0 Trial Objectives and Design ............................................................................. 22 
11.1 Primary Objective/s ....................................................................................... 22 
11.2 Secondary Objective/s .................................................................................. 22 
11.3 Endpoints ...................................................................................................... 22 
11.3.1 Primary Endpoint .................................................................................... 22 
11.3.2 Secondary Endpoint ............................................................................... 22 
11.4 Exploratory or Tertiary Endpoints/outcomes ................................................. 22 
11.5 Objectives and End Points Summary ............................................................ 23 
11.6 Trial Design ................................................................................................... 24 
11.7 Study Setting ................................................................................................. 24 
12.1 Inclusion Criteria ........................................................................................... 25 
12.2 Exclusion Criteria .......................................................................................... 25 
13.0 Trial Procedures ............................................................................................... 27 
13.1 Participant identification ................................................................................ 27 
13.2 Informed Consent Procedures ...................................................................... 27 
13.2.1 Responsibility for obtaining consent ....................................................... 27 
13.2.2 Consent Considerations.......................................................................... 28 
13.2.3 Population ............................................................................................... 28 
13.2.4 Vulnerable participants’ considerations .................................................. 28 
13.2.5 Written/ reading / translation considerations ........................................... 28 
13.2.6 Participants lacking capacity ................................................................... 28 
13.2.7 Minors ..................................................................................................... 29 
13.2.8 Consenting process ................................................................................ 29 
13.2.9 Additional consent provisions for collection and use of participant data 
and biological specimens in ancillary studies .................................................... 29 
13.3 Screening Procedures................................................................................... 29 

 
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13.4 Treatment Allocation ..................................................................................... 30 
13.4.1 Randomisation Method ........................................................................... 30 
13.4.2 Randomisation Procedure ...................................................................... 30 
13.5 Blinding ......................................................................................................... 31 
13.6 Unblinding ..................................................................................................... 31 
13.7 Trial Schedule ............................................................................................... 32 
13.7.1 Schedule of Assessment (in Diagrammatic Format) ............................... 32 
13.7.2 Trial assessments ................................................................................... 34 
13.7.3 Follow up Procedures ............................................................................. 35 
13.8 Withdrawal criteria ........................................................................................ 36 
13.9 Early withdrawal ............................................................................................ 37 
13.10 End of trial (EOT) ........................................................................................ 37 
14.0 Laboratories and samples ................................................................................ 38 
14.1 Local Laboratories ........................................................................................ 38 
14.2 Sample Collection/Labelling/Logging ............................................................ 38 
14.3 Sample Receipt/Chain of Custody/Accountability ......................................... 39 
14.4 Sample Analysis Procedures ........................................................................ 39 
14.5 Sample and Data Recording/Reporting......................................................... 39 
14.6 End of study .................................................................................................. 39 
15.0 Trial Medication ................................................................................................ 41 
15.1 Name and description of investigational medicinal product(s) ...................... 41 
15.2 Legal status of the drug................................................................................. 41 
15.3 Summary of Product Characteristics (SmPC) or IB ...................................... 41 
15.4 Drug storage and supply ............................................................................... 41 
15.5 Supplier ......................................................................................................... 41 
15.6 Manufacturer ................................................................................................. 41 
15.7 IMP Storage .................................................................................................. 42 
15.8 Details of accountability ................................................................................ 42 
15.9 Medication destruction/return and recall ....................................................... 42 
15.10 Prescription of IMP / Placebo/ NIMP ........................................................... 42 
15.11 Preparation and labelling of IMP ................................................................. 42 
15.12 Preparation and Administration of IMP........................................................ 43 
15.13 Dosage schedules ...................................................................................... 43 
15.14 Dispensing of IMP ....................................................................................... 43 
15.15 Dosage modifications .................................................................................. 43 
15.16 Known drug reactions and interaction with other therapies ......................... 44 
15.17 Prior and Concomitant medication .............................................................. 44 
15.18 Assessment of compliance ......................................................................... 44 
15.19 Arrangements for post-trial access to IMP and care ................................... 44 
16 Equipment and Devices ...................................................................................... 45 
17 Pharmacovigilance .............................................................................................. 46 

 
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17.1 General Definitions ....................................................................................... 46 
17.2 Site Investigators’ Assessment ..................................................................... 47 
17.3 Reference Safety Information ....................................................................... 47 
17.4 Notification and Reporting Adverse Events or Reactions .............................. 49 
17.5 Notification of AEs of special interest ............................................................ 49 
17.6 Adverse events that do not require reporting ................................................ 50 
17.7 Notification and Reporting of Serious Adverse Events & SUSARs ............... 50 
17.8 Sponsor Medical Assessment ....................................................................... 50 
17.9 Urgent Safety Measures ............................................................................... 50 
17.10 Procedures for reporting blinded SUSARs .................................................. 51 
17.11 Pregnancy ................................................................................................... 51 
18.0 Annual reporting ............................................................................................... 52 
19.0 Statistical and Data Analysis ............................................................................ 53 
19.1 Sample size calculation................................................................................. 53 
19.2 Planned recruitment rate ............................................................................... 53 
19.3 Statistical analysis plan (SAP) ...................................................................... 53 
19.4 Summary of baseline data and flow of patients ............................................. 55 
19.5 Primary outcome analysis ............................................................................. 55 
19.6 Secondary outcome analysis ........................................................................ 56 
19.7 Interim analysis and criteria for the premature termination of the trial ........... 56 
19.8 Subject population ........................................................................................ 56 
19.9 Procedure(s) to account for missing or spurious data ................................... 56 
20.0 Data Handling & Record Keeping ..................................................................... 57 
20.1 Confidentiality ............................................................................................... 57 
20.2 Data Custodian Details ................................................................................. 57 
20.3 Pseudononymisation ..................................................................................... 57 
20.4 Transferring/Transporting Data ..................................................................... 57 
20.5 Data collection tools and source document identification .............................. 58 
20.6 Source Data .................................................................................................. 58 
20.7 Case Report Form ........................................................................................ 58 
20.8 Data handling and record keeping ................................................................ 58 
20.9 Access to Data, Source Data and Documents .............................................. 58 
21.0 Archiving .......................................................................................................... 59 
22.0 Monitoring, Audit and Inspection ................................................................... 60 
22.1 Monitoring ..................................................................................................... 60 
22.2 Auditing ......................................................................................................... 60 
22.3 Notification of Serious Breaches to GCP and/or the protocol ........................ 60 
22.4 Compliance ................................................................................................... 60 
22.5 Non-Compliance ........................................................................................... 60 
22.6 Regulatory Compliance ................................................................................. 61 

 
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23.0 Financial and other competing interests for the chief investigator, PIs at each 
site and committee members for the overall trial management ................................ 62 
24.0 Ethical and Regulatory Considerations ............................................................ 63 
25.0 Peer review ...................................................................................................... 64 
26.0 Public and Participant Involvement .................................................................. 65 
27.0 Indemnity .......................................................................................................... 66 
27.1 Amendments ................................................................................................. 66 
27.2 Access to the final trial dataset ..................................................................... 66 
28.0 Trial Committees .............................................................................................. 67 
29.0 Publication and Dissemination Policy ............................................................... 68 
29.1 Publication .................................................................................................... 68 
29.2 Dissemination policy ..................................................................................... 68 
30.0 References ....................................................................................................... 69 
 
 

 
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8.0 List of Abbreviations / Glossary of Terms 
 
AE 
 
 
 
Adverse event 
APR  
 
 
Annual Progress Report 
AR 
 
 
 
Adverse reaction 
AUC  
 
 
Area under curve 
BMI 
 
 
 
Body mass index 
BP 
 
 
 
Blood pressure 
CI 
 
 
 
Chief investigator 
CKD  
 
 
Chronic kidney disease 
Cmax  
 
 
Maximum concentration 
CTA   
 
 
Clinical Trial Authorisation 
CMV  
 
 
Cytomegalovirus 
CRF  
 
 
Case report form 
DSM  
 
 
Drug safety monitoring 
DSUR  
 
 
Development Annual Safety Update 
ECD  
 
 
Extended Criteria Donor 
ECG    
 
 
Electrocardiogram 
eCRF  
 
 
Electronic case report form 
eGFR  
 
 
Estimated Glomerular Filtration Rate 
EOT   
 
 
End of trial 
FACS  
 
 
Fluorescent-activated cell sorting 
GCP  
 
 
Good Clinical Practice 
HbA1c 
 
 
Haemoglobin A1c 
HDL   
 
 
High-density lipoprotein 
HLA  
 
 
Human leukocyte antigen 
HOMA 
 
 
Homeostatic model assessment 
HOMA IR 
 
 
Homeostatic model assessment of insulin resistance  
HRA  
 
 
Health Research Authority 
IB 
 
 
 
Investigator brochure 
ID 
 
 
 
Identifier 
IMP 
 
 
 
Investigational medical product 
IRAS  
 
 
Integrated Research Approval System 
ISF 
 
 
 
Investigator site file 
ITT 
 
 
 
Intention to treat 
JRMO  
 
 
Joint research management office (Sponsor) 
LDL 
 
 
 
Low-density lipoprotein 
 
MHRA   
 
 
Medicines and Healthcare products Regulatory Agency 
mTORC2 
 
 
Mammalian target of rapamycin complex 2 
NHS  
 
 
National Health Service 
NICE  
 
 
The National Institute for Health and Care Excellence 
ONS  
 
 
Office for National Statistics 

 
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PD 
 
 
 
Pharmacodynamics 
PI 
 
 
 
Primary investigator 
PI3K-Akt 
 
 
Phosphoinositide 3-kinase – Protein kinase B 
PIS 
 
 
 
Patient information sheet 
PK 
 
 
 
Pharmacokinetics 
QMUL  
 
 
Queen Mary University of London 
R&D  
 
 
Research and Development 
 
REC  
 
 
Research Ethics Committee 
RLH   
 
 
Royal London Hospital 
SAE  
 
 
Serious adverse event 
SAP  
 
 
Statistical analysis plan 
SAR  
 
 
Serious adverse reaction 
SOP  
 
  
Standard operating procedure 
SUB-I  
 
 
Sub investigator 
SUSAR 
 
 
Serious unexpected serious adverse reaction 
T1/2 
 
 
 
Half-life 
Treg  
 
 
Thymic regulatory T cells 
TSC  
 
 
Trial steering committee 
ULN  
 
 
Upper limit of normal 
UKAS  
 
 
United Kingdom Accreditation Service 
 
 
 

 
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9.0 Introduction 
 
9.1 Background  
 
Renal Transplantation and glucose control 
Type 2 diabetes is the most common cause of end-stage renal failure in the UK.  
Kidney transplantation is widely held to be the optimal form of renal replacement 
therapy for patients with end-stage renal disease, leading to a longer survival and 
improved quality of life in patients receiving a renal transplant compared to those that 
remain on dialysis (Reese et al, 2015). 
 
However transplantation leads to a higher glucose burden in patients. This has been 
associated with acute rejection, sepsis and worse outcomes, and patients frequently 
have to increase their anti-diabetic medication in the early post-transplant period. 
 
One reason for this is that immunosuppressive medications (glucocorticoids and 
calcineurin inhibitors) can lead directly to hyperglycaemia. In addition, as renal 
function improves, there is greater renal clearance of anti-diabetic agents and 
endogenous insulin leading to a reduced potency of these medications. These 
effects are most pronounced within the early post-transplant period, as this is the 
period when the immunosuppressive burden is the strongest and the changes in 
renal function most marked.  
 
The role of Glucokinase in glucose control 
Glucokinase is an enzyme which has two effects to lower glucose. In the pancreas, 
beta cells control insulin secretion. In pancreatic beta cells glucokinase converts 
glucose to glucose-6-phosphate, which is a rate-limiting step in the secretion of 
insulin; as such, increased glucokinase activity leads to more insulin secretion. 
Secondly, in the liver, glucokinase increases hepatic uptake of glucose (Scheen, 
2018). Defective glucose-induced insulin secretion and increased hepatic glucose 
output are of the hallmarks of type 2 diabetes. Because of these effects, glucokinase 
activators have been promising therapeutics for type 2 diabetes for almost two 
decades.  
 
One agent studied is AZD1656: a potent, selective activator of human 
glucokinase. Twenty-five clinical studies have been completed to evaluate the 
safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD) and drug 
interactions with AZD1656. Approximately 960 subjects have been exposed to 
AZD1656 in 25 clinical studies covering phase I to phase IIb as part of a global 
development program by AstraZeneca. Single oral doses of AZD1656 up to 180 mg 
have been given to healthy volunteers during euglycaemic clamp conditions 
(Ericsson et al, 2012). Patients with type 2 diabetes have been administered single 
oral doses up to 450 mg; and also daily doses of 10 to 200 mg have been given to 

 
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patients with type 2 diabetes for up to 6 months’ duration. AZD1656 has been shown 
to be a, well-tolerated medication in patients with type 2 diabetes and no safety 
concerns were raised in studies up to 6 months. Unfortunately, the anti-diabetic 
effect of AZD1656 has been found to wear off after several months, thus limiting its 
long-term use for patients with diabetes (Kiyosue et al, 2013; Wilding et al, 2013).  
 
A shorter course of AZD1656 may be of benefit in controlling the glucose levels of 
patients with diabetes during the time shortly after renal transplantation when the 
immunosuppressive burden, and hence gluconeogenesis, is greatest. In addition, 
AZD1656 may have other benefits post-renal transplantation in an unrelated action 
to its anti-diabetic action, which involve its effects on immune function. 
 
Treg cells in renal transplantation and tissue injury 
Thymic regulatory T (Treg) cells are a subpopulation of T cells that modulate the 
immune system. These cells have immunosuppressive functions and downregulate 
other effector T cell populations. As such, they are instrumental for the maintenance 
of tolerance to self-antigens.  A crucial step in their immuno-modulatory function is 
the ability of active Treg cells to migrate in the body and, during inflammation, to 
home on inflamed tissue (Tang et al, 2004; Kishore et al, 2017).  
 
In transplantation a major unmet need is to develop management strategies to 
prevent both acute and chronic rejection which are associated with poorer graft 
survival. Current therapies to minimise rejection rates have their own side effects 
including direct renal and pancreatic toxicity and the progression of cardiovascular 
disease. Treg cells are an attractive potential therapy for transplantation to reduce 
the immunosuppressive burden (Zwang et al, 2017). Evidence for the role of Treg 
cells’ beneficial effects in transplantation is suggested by data which demonstrates 
that Treg cells directly reduce inflammation and reperfusion injury in kidneys (Kinsey 
et al, 2009; Hu et al, 2016). 
 
Furthermore Treg cells suppress immune function in vitro, and are associated with 
transplant acceptance in kidney transplant patients (Daniel et al, 2012).  High levels 
of Treg cells positively correlate with renal allograft survival and function (Schaier et 
al, 2012). In addition, in renal biopsies, Treg infiltration is associated with better graft 
function (Bestard et al, 2008). Finally, there is evidence of tissue protection in 
transplantation mouse models following transfer of humanised Treg cells (Yi et al, 
2012). Therefore, Treg cell proliferation and activation may hold the keys to unlock 
the future promise of immune tolerance which is the ‘Holy Grail’ of transplant 
immunology: the potential to be able to perform solid organ transplants without the 
need for long term immunosuppression with all the advantages that this would bring.  
 
Role of glucokinase in Treg biology 
Recent data combines the two streams of research involving glucokinase biology, in 
the fields of immunosuppression and glucose lowering effects. As well as being 

 
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involved in glucose homeostasis, glucokinase has been shown to increase Treg 
migration and trafficking. Treg migration has been shown to be dependent on 
glycolysis which is mediated via the PI3K-Akt pathway and activation of mTORC2. 
mTORC2 in turn induces glucokinase expression which appears to be necessary for 
Treg migration. AZD1656 has been demonstrated to increase glucokinase activity, 
thus leading to reduced numbers of circulating Treg cells, with the hypothesis that 
they have been activated and migrated into the inflamed tissues (Kishore et al, 
2017). Further evidence for the role of glucokinase comes from data demonstrating 
that inhibition of glucokinase resulted in less Treg motility, leading to increased 
rejection in a skin transplant animal model. In addition, humans who have reduced 
inhibition of glucokinase due to a mutation in a glucokinase regulatory protein have 
been shown to have increased motility and decreased circulating numbers (Kishore 
et al, 2017). 
 
9.2 Assessment and management of risk 
 
Standard of care  
Renal transplantation is not without risk; however, overall the benefit of a functioning 
renal transplant outweighs the risks of remaining on dialysis. 
 
Patients in this study will have all their pre- and post-transplant care as per usual 
clinical care, with the exception of the following intervention: treatment with AZD1656 
or placebo for 3 months post-renal transplant. 
 
The standard of care follow up is that patients attend clinic twice a week for the first 6 
weeks post-transplant, then weekly for another 6 weeks, they remain on weekly or 
fortnightly clinic visits for a further 12 weeks, after which point depending on the 
stability of the patients graft function they reduce clinic visits to every 2-4 weeks up 
to one year. 
 
As with all patients with diabetes who have had a renal transplant, there is the risk of 
both hypoglycaemia and hyperglycaemia due to changing renal function and new 
medications which may alter glucose levels. Because of this, we measure patient’s 
glucose levels and diabetic control routinely when they are seen frequently in clinic 
and enquire as to any episodes of hypo or hyperglycaemia. The transplant clinician 
may alter patient’s anti-diabetic medications to maintain optimal glycaemic control as 
part of routine care. 
 
Risks associated with AZD1656 
The known risks to human subjects. 
 
Justification for the choice of route of administration, dosage, dosage regimen, and 
treatment period(s) 
 

 
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We are using a dose within the higher range that has shown to be safe and 
efficacious in clinical studies. We do not have human T reg efficacy data: therefore 
as this is an exploratory study, this is scientifically a good dose to use. We would 
therefore not up-titrate from this dose. We are working on the hypothesis that the 
pharmacodynamic effect of AZD1656 on Treg migration activity is the same as for 
glucose lowering (we have no evidence to suggest this is not correct), and we 
proposed using what we know is an effective and safe dose in order to adequately 
test the hypothesis. We have chosen not to start at and lower dose and 
subsequently up-titrate the dose: given the proposed mechanism of action of 
AZD1656, early mobilisation of regulatory T cells with subsequent amelioration of 
renal ischaemia-reperfusion injury is required in order to benefit the new transplant. 
We are measuring delayed graft function as one of the secondary clinical endpoints 
as a surrogate for improved renal outcome within the first 7 days. 
 
 
From a safety perspective, all of the patients will be diabetic and induction therapy 
given for renal transplantation is associated with hyperglycaemia; in addition as the 
patients are inpatients for the first 5-7 days post transplant (and during initiation of 
study drug) they are closely monitored for hypoglycaemia. The risk of hypoglycaemia 
after this period is low based on the data from the previous Phase 2 diabetes studies 
with AZD1656. If recurrent hypoglycaemia occurs despite removal of other anti-
diabetic medications, then the study medication will be withdrawn as per withdrawal 
criteria. 
 
 
Preclinical & Clinical Data  
Investigator’s Brochure AZD1656, Edition 9, September 2020 
Twenty-five clinical studies have been completed to evaluate the safety, tolerability, 
PK, PD and drug interactions with AZD1656. Approximately 960 subjects have been 
exposed to AZD1656 for up to 6 months’ duration. In patients with type 2 diabetes 
and renal impairment, the PK and PD effects after single doses of AZD1656 were 
comparable to diabetic patients with normal renal function. 
 
Across clinical studies, AZD1656 has been well tolerated and no safety concerns 
have been raised. No safety signals have been identified regarding vital signs, ECG, 
weight, BMI and physical findings.  
 
There have been no treatment related changes in safety laboratory variables 
including muscle biomarkers and liver function tests in Phase I to IIa. From the few 
cases with increased liver enzymes in Phase IIb, a minor increase from AZD1656 
treatments could not be excluded.  
 

 
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AZD1656 is mainly metabolised via CYP2C8, therefore potent inhibitors of CYP2C8 
(e.g. gemfibrozil) may increase exposure to this drug (AUC). 
 
Other than inhibitors of CYP2C8, no significant drug-drug interactions have been 
reported in phase I/II clinical trials; however there may be drug-drug interactions that 
are as yet unknown. 
 
Reproductive restrictions 
 
No data is available on the effects of AZD1656 on pregnancy and lactation in 
humans. Preclinical studies have shown that AZD1656 is not genotoxic. There was 
no effect on male fertility in rat. Overall, the effects of AZD1656 on embryofoetal 
development seen in pre-clinical studies were considered to be secondary to 
maternal hypoglycaemia. Results from the preclinical repro-toxicity studies support 
inclusion of women of childbearing potential in clinical studies, provided that 
pregnancy is prevented using a highly effective form of contraception. In case of 
pregnancy during the study, treatment should be stopped. 
 
 
How the risk will be minimised/managed 
 
Hypoglycaemia: 
As with most anti-diabetic medications there is a risk of hypoglycaemia. However, 
following a renal transplant, given the increased glucose production from the steroid 
medications along with increased insulin metabolism, hyperglycaemia rather than 
hypoglycaemia is more of an issue. For AZD1656, in phase I to IIa, few 
hypoglycaemic events have been reported and only rarely with a plasma glucose 
level below 3 mmol/L (54 mg/dL). In phase IIb, the proportion of patients reporting 
hypoglycaemic events was overall small. Fewer patients in the AZD1656 treatment 
groups reported hypoglycaemic events compared to the glipizide group. Low glucose 
levels were either asymptomatic (detected in scheduled measurement) or associated 
with mild symptoms, and in all cases manageable by the patients. All events with low 
plasma glucose have responded rapidly to carbohydrate intake.  
 
All patients will be seen frequently in a specialist post-transplant clinic where, as part 
of their standard of care, they will have their blood glucose measured regularly along 
with makers of diabetic control including HbA1c. The patient will be given instructions 
to measure blood glucose if they get symptoms of hyperglycaemia (e.g. thirst, 
polyuria) or hypoglycaemia (cold sweat, dizziness). If a major hypoglycaemic event 
occurs, or more than one minor event since last visit, the patient will be told to 
contact the investigator before the next visit. 
 
As with all patients with diabetes post-transplant, if a patient’s blood glucose control 
is considered by their clinical team to be too high or low, then their regular anti-
diabetic medications will be altered to achieve diabetic control targets as per our 

 
ADOPTION Study V1.8 07.07.21 
 
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standard of clinical care. National guidelines in the management of CKD patients 
with diabetes suggest controlling the HbA1c to between 6.5% (48mmol/mol) to 8.5% 
(68mmol/mol). Within this range there are suggestions to aim for tighter control 
(towards 6.5%) or less tight control (towards 8.5%) on an individualised patient basis 
(Renal Association 2018). 
 
Reproductive restrictions 
 
Female study participants 
 
Women of child-bearing potential are permitted to participate in this study provided 
that they agree to avoid pregnancy through the use of a highly effective form of 
contraception starting from the time of study enrolment until the final safety follow-up 
visit has been completed (2 weeks after cessation of study medication). AZD1656 
has low potential for drug-drug interaction through induction of any of the CYP 
enzymes so an interaction with hormonal contraception is not anticipated. Methods 
of highly effective contraception are outlined in section 12.2 (Exclusion criteria). If a 
female participant should become pregnant, then the study medication will be 
stopped. She will be asked to consent to the collection of data about her pregnancy, 
and the birth and health of her baby. 
 
 
Male study participants 
 
It is important that women of childbearing potential, who are the partners of male 
patients, do not become pregnant during the study and until the participant has 
completed the safety follow up visit.  
 
All male study participants should avoid fathering a child by using an effective 
method of contraception together with their female partner/spouse, starting from the 
time of study enrolment until the final safety follow-up visit has been completed. In 
this scenario, we have advised the use of a condom and female partners to use a 
method of highly effective contraception. If a female partner of a male patient should 
become pregnant, then she will also be asked to consent to the collection of data 
about her pregnancy, and the birth and health of her baby.  
 
For male patients whose partner is pregnant, the man should use a condom for the 
duration of the study and until the final safety follow-up visit has been completed.  
 
Sperm Donation 
 
Male patients should not donate sperm for the duration of their participation in the 
study and until they have completed the study follow-up visit. 
 
This trial is categorised as: Type C 
 

 
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9.3 Rationale for study design 
 
Our hypothesis is that treatment with AZD1656 may lead to increased Treg 
localisation to the transplant kidney in the early post-operative course. This may lead 
to reduced ischaemia reperfusion injury through the immunosuppressive effects of 
Tregs, measurable by a change in the incidence of delayed grant function. At 3 
months we hypothesize that AZD1656 may lead to increased Treg cell localisation in 
the transplanted kidney, as a marker for improved graft survival. We will measure 
peripheral Treg population as a marker for Treg trafficking to the kidney as this can 
be measured serially with minimal risk to the patient. We will include histological 
parameters from the standard of care 3 month protocol biopsy as a key secondary 
endpoint. Finally, we hypothesize that AZD1656 may be an effective and safe 
adjunct for the early management of diabetes post-renal transplant. 
 
We propose an exploratory phase 2 study, examining the efficacy and safety of 3 
months’ treatment with AZD1656 100mg twice daily in patients with diabetes 
undergoing renal transplantation in a tertiary renal unit.  
 
 
 

 
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10.0 Trial Flowchart 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
Diabetic Patients soon to undergo renal 
transplant at RLH 
Pre or Post op: approached by clinical team 
Patient screened+ consented by study team 
3 month treatment 
with placebo 
Randomised within 24h of 
3 month treatment 
with AZD1656 
ADOPTIO 
End of active study 
 Patients return to standard care including biopsy 
2 weeks post end of treatment safety visit 
1 year post randomisation: patient renal function 
and diabetes control recorded 

 
ADOPTION Study V1.8 07.07.21 
 
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11.0 Trial Objectives and Design 
11.1 Primary Objective/s 
 
To determine whether treating post-transplant patients with AZD1656 compared to 
placebo for 3 months leads to altered Treg migration. 
11.2 Secondary Objective/s 
 
To determine the safety and efficacy of AZD1656 to control diabetes post-transplant. 
To investigate the effect of AZD1656 on Treg cell infiltration in renal transplant 
tissue. 
 
11.3 Endpoints 
11.3.1 Primary Endpoint 
 
The primary endpoint is the change in mean peripheral Treg cell number between 
baseline and 3 months measured using flow cytometry analysis (FACS) between 
AZD1656 and placebo.  
 
11.3.2 Secondary Endpoints 
1) Histological staining for Treg cells in renal biopsy tissue between baseline 
and 3 month protocol biopsy  
2) Incidence of delayed graft function, defined as the need for dialysis within 
1 week post-transplant 
3) Diabetic control between baseline and month 3 using change in HbA1c 
measurement 
4) Dose of other anti-diabetic medication between baseline and month 3 
(descriptive) 
5) Safety endpoints: i.e. number of hypoglycaemic episodes (descriptive) 
6) Insulin resistance: HOMA IR measurement at month 3 
7) Graft function: (eGFR) at month 3  
8) Episodes of acute rejection (defined as biopsy proven acute rejection) 
9) Episodes of opportunistic infections: bacterial and viral (descriptive) 
 
11.4 Exploratory or Tertiary Endpoints/outcomes 
1) 12-month graft function (eGFR) and diabetic control (HbA1c; medication 
review) to assess legacy effect (potential follow up publication) 
2) Differences in other peripheral T cell populations, measured by FACS 
analysis 
3) Histological staining for Treg cells in any renal biopsy taken for clinical 
indications between baseline and month 3 protocol biopsy 
4) Differences in the functional phenotype of the Treg cells  
 

 
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11.5 Objectives and Endpoints Summary 
Objective
How objective measured
Outcome
Examine the effect of 
AZD1656  on Treg 
cell migration
Change in peripheral Treg population 
between randomisation and month 3 
measured by mean change in Treg 
cell number between baseline and 3 
months using FACS analysis.
Does  AZD1656 lead to 
enhanced migration as 
demonstrated by a fall in 
peripheral Treg population over 
time compared to placebo?
Examine the 
effectiveness of 
AZD1656 on diabetic 
control
Change in HbA1c between baseline 
and month 3 visit, HOMA-IR at 
month 3, descriptive change in anti 
diabetic medication dose/need for 
additional anti-diabetic therapy.
Is there a difference between 
placebo and IMP on diabetic 
control/insulin resistance?
To investigate the 
effect of AZD1656 on 
renal transplant 
function
Renal function (eGFR CKD EPI) 
measured at 3 months and 12 
months. 
Is there a difference between 
AZD1656 and placebo treated 
patients' renal function at 3 and 
12 months?
To determine the 
safety of AZD1656 to 
control diabetes post-
transplant.
Patient and graft survival, number 
and type of AE (hypoglycaemic 
episodes, infective episodes), 
number and type of SAE, rejection 
rates (defined as incidence of biopsy 
proven acute rejection)
Is there a difference between 
placebo and AZD1656 treated 
groups in terms of number of 
AE, SAE, renal function and 
rejection rates?
Effect of AZD156 on 
Treg cell infiltration in 
renal transplant 
tissue
Change in Treg staining on renal 
biopsies collected as standard of 
care at implantation and 3 months 
post transplant.
Is there a difference between 
placebo and AZD1656 treated 
groups in terms of change in 
Treg cell infiltration between 
baseline and 3 month 
transplant biopsy?
 
 
 
 
 
 
 
 

 
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11.6 Trial Design 
 
A single site, prospective, double blind randomised controlled pilot study 
investigating the safety and efficacy of 3 months’ treatment with AZD1656 100mg 
twice daily or placebo in 50 patients who have undergone a renal transplant at the 
Royal London Hospital. 
 
11.7 Study Setting 
 
This is a single centre study with no other patient identification centres or sites. 
 
The study will take place in an NHS setting (Barts Health NHS Trust), specifically in 
the Renal Department at the Royal London Hospital. 
 
Patients will be recruited exclusively from a cohort of patients undergoing renal 
transplantation at the Royal London Hospital. 
 

 
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12.0 Eligibility Criteria 
 
In order to be eligible for the trial, participants must meet all of the below inclusion 
criteria and none of the below exclusion criteria. 
 
12.1 Inclusion Criteria 
 
a) Females or males aged 18 years and above 
b) Having undergone renal transplantation at the Royal London Hospital within 
the previous 24 hours 
c) A pre-transplant diagnosis of Type 2 diabetes  
d) Provision of written, informed consent prior to any study specific procedures 
e) In women of childbearing potential* documentation of a negative pregnancy 
test during admission for renal transplant. 
 
*Women of childbearing potential are defined as women following menarche until 
becoming post-menopausal, unless permanently sterile. Permanent sterilisation 
methods include hysterectomy, bilateral salpingectomy and bilateral oophorectomy. 
A post-menopausal state is defined as the absence of menses for 12 months without 
an alternative medical cause. 
 
12.2 Exclusion Criteria 
 
a) Unable to consent  
b) Known allergy/intolerance to AZD1656 
c) Pregnant or breastfeeding women 
d) Planning 
on 
becoming 
pregnant/unwilling 
to 
use 
highly 
effective 
contraception* during the 3 month treatment period and for 2 weeks 
afterwards 
a. In the case of men with sexual partners who are women of childbearing 
potential: refusal to wear a condom and female partner planning on 
becoming pregnant/unwilling to use highly effective contraception* 
during the 3 month treatment period and for 2 weeks afterwards 
e) Clinically significant history of abnormal physical and/or mental health as 
judged by the investigator other than conditions related to chronic kidney 
disease  
f) Current or planned use of strong inhibitors of CYP2C8 
g) Participation in an investigational drug trial in the 3 months prior to 
administration of the initial dose of study drug  
 
*Highly effective contraception methods are defined as those that can achieve a 
failure rate of <1% per year when used correctly and consistently. These include: 

 
ADOPTION Study V1.8 07.07.21 
 
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 
Combined (oestrogen and progestogen containing) hormonal contraception 
associated with inhibition of ovulation – either oral, transvaginal or transdermal 
 
Progestogen-only hormonal contraception associated with inhibition of ovulation – 
either oral, injectable or implantable 
 
Intrauterine device (IUD) or intrauterine hormone-releasing system (IUS) 
 
Bilateral tubal occlusion 
 
Vasectomised partner – provided that the partner is the sole sexual partner of the 
participant and that the vasectomised partner has received medical assessment of 
surgical success 
 
 
 

 
ADOPTION Study V1.8 07.07.21 
 
Page 27 of 78 
 
13.0 Trial Procedures 
 
13.1 Participant identification 
 
Participants will be identified by their regular clinical team from those patients 
admitted or soon to be admitted for a renal transplant. Eligibility decision will be 
made by the Chief Investigator (CI) or Sub Investigator (Sub-I). 
 
13.2 Informed Consent Procedures 
 
Informed consent will be obtained either pre-transplantation or within 24 hours post-
transplantation, but prior to the participant undergoing procedures that are specific to 
the trial, and are outside standard routine care at the participating site (including the 
collection of identifiable participant data).  
 
In the case of deceased donor transplantation, patients do not know when they will 
receive a transplant, and it is therefore impossible to approach patients in the days 
and weeks before their transplant. Patients will have already given consent to 
undergo their renal transplant at short notice, however some patients may be unable 
to give fully informed consent in the time immediately before or within 24 hours after 
transplant for this research study. If the PI or patient feels they are unable to give 
fully informed consent within the first 24 hours after the operation, then they will not 
be consented.  
 
Patients who are planned to undergo live-donor transplantation will be given 
information about the study pre-transplantation during the assessment process, but 
will not be consented until they proceed with the transplant. 
 
We hold regular pre-transplant open days to which all patients on the transplant 
waiting list are invited. At these open days we will inform patients of the current study 
opportunities. We will use the PIS as the text for these discussions and will be free to 
verbally discuss the study with patients on the day. 
 
13.2.1 Responsibility for obtaining consent 
 
The CI retains overall responsibility for the informed consent of participants at their 
site and must ensure that any person delegated responsibility to participate in the 
informed consent process is duly authorised, trained and competent to participate 
according to the ethically approved protocol, principles of Good Clinical Practice 
(GCP) and the Declaration of Helsinki. If delegation of consent occurs then details 
must be provided in the Site Delegation Log. 
 

 
ADOPTION Study V1.8 07.07.21 
 
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Consent can only be taken by the CI or a medical practitioner trained in the study 
and delegated on the study log. 
 
13.2.2 Consent Considerations 
 
The right of a patient to refuse participation without giving reasons will be respected. 
 
The participant must remain free to withdraw from the trial at any time without giving 
reasons and without this compromising his/her further treatment and must be 
provided with a contact point where he/she may obtain further information about the 
trial. Where a participant is required to re-consent, for example if during the trial new 
Research Safety Information becomes available, or following an amendment that 
affects the patient, or new information needs to be provided to a participant, it is the 
responsibility of the CI to ensure this is done in a timely manner. 
 
13.2.3 Population 
 
The patient population will be patients aged 18 or over undergoing renal 
transplantation at the Royal London Hospital. 
 
13.2.4 Vulnerable participants’ considerations 
 
The CI takes responsibility for ensuring that all vulnerable subjects are protected and 
participate voluntarily in an environment free from coercion or undue influence.  
 
13.2.5 Written/ reading / translation considerations 
 
Patients will not have cognitive impairment as this is a standard contraindication to 
undergoing renal transplantation. In the case of patients who speak no English, we 
will use independent advocates or standard clinical translation support services 
which are readily available during the consent process for the operation itself. Once 
consented verbally, patients will be provided with a translation of the patient 
information sheet and consent form. 
 
In addition, we recognise that there are a significant number of patients who speak 
Bengali in our local population. We will consent these patients with a Bengali-
translated PIS and consent form.  
 
13.2.6 Participants lacking capacity 
 
The clinical team will not approach any patient who is felt not to have capacity to 
take part in the study.  
 

 
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13.2.7 Minors 
 
Patients under 18 are not eligible to participate in the study. 
13.2.8 Consenting process 
 
Patients will be approached by a member of the clinical team and asked if they 
would like to know more about the study. If the patient is interested, the research 
team will contact the patient to discuss the trial. They will inform the potential 
participant or his/her legal representative about the nature and objectives of the trial 
and possible risks associated with their participation. 
 
They will receive the PIS and have as long as they need to read it and have all their 
queries satisfactorily answered. However if they are unable to come to a decision 24 
hours after their transplant the consent process will be abandoned and they will not 
take part in the trial. 
 
The consent process will be documented in the source documents.  
 
13.2.9 Additional consent provisions for collection and use of participant data and 
biological specimens in ancillary studies 
 
Patient samples will be stored as per standard practice. These samples may only be 
used in future research following a substantial amendment to the protocol and ethical 
approval. Patients would be re-consented in such a scenario. 
 
13.3 Screening Procedures  
 
All participants that undergo screening will be logged into a study specific screening 
log. 
 
Following informed consent being signed, and before randomisation takes place, the 
following information will be collected: 
 
Inclusion/exclusion criteria 
Demographic data 
Transplant data (if appropriate) 
Concomitant medication  
Medical history 
 
 
 
 

 
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13.4 Treatment Allocation 
 
13.4.1 Randomisation Method 
 
The method of randomisation will be a simple randomisation using pre-filled 
envelopes with study numbers 1 - 50 printed on them.  The envelopes will be pre-
filled by a doctor who is independent to the study and quality control checks will be 
performed and documented by an independent member of the clinical team. Inside 
the envelope there will be a treatment code, which will be sent to pharmacy along 
with the patient’s study number. If a patient is randomised but does not receive any 
IMP/placebo they will not be included in the study and will not be replaced. 
 
Both the patient’s study number and the treatment code will be documented in the 
trial master file. 
 
13.4.2 Randomisation Procedure 
 
A spreadsheet of treatment codes (linked to either IMP or placebo) will be created 
using an online generator using a block randomisation sequence (Sealed Envelope 
Ltd. 2016. Create a blocked randomisation list. [Online] Available from: 
https://www.sealedenvelope.com/simple-randomiser/v1/lists 
[Accessed 
31 
Jul 
2017].) 
This spread sheet will be stored in the pharmacy dispensary.  
 
Each treatment code (for example A1, A2,…A50) will be written on a card and 
sealed in an envelope. 
 
At randomisation, one of these envelopes will be chosen at random to associate the 
patient’s study ID (e.g. patient 01 or 13) to the treatment code, which will be 
recorded in the CRF. This linked study code and patient identification will be sent to 
pharmacy for dispensing. The pharmacist will use their spread sheet, which links the 
treatment code with the allocation of IMP or placebo. 
 
Finally, each study participant will have their Study ID linked to their treatment 
allocation written on a card, which will be sealed in an envelope with their study ID 
on the front of the envelope (this will be created by an independent doctor). This 
means that breaking the study allocation will only compromise that individual 
patient’s allocation.  
 
The people who will have access to the envelope section are the CI and Sub-I only. 
The people who will have access to the treatment code (without the treatment 
allocation) are the study team. The people who will have access to the treatment 
code matched to the treatment allocation are the pharmacy team and sponsor office 
only. Should there be the need to break the treatment allocation, the CI or Sub 

 
ADOPTION Study V1.8 07.07.21 
 
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investigator will open the locked container which is stored on the renal unit to allow 
out of hours access, and pick out the relevant patient’s ID number and open only this 
envelope. 
 
13.5 Blinding 
 
This is a double blind placebo study: both the patient and the study team will be 
blinded to the treatment intervention. 
Pharmacy staff who dispense the study medication will not be blinded, nor will 
Sponsor Office staff responsible for reporting unblinded SUSAR reports to the 
MHRA.  
 
13.6 Unblinding 
 
The code breaks for the trial will be held in the research office of the renal 
department and are the responsibility of the CI Kieran McCafferty. 
 
If a patient has a significant adverse reaction or a SUSAR then they should stop the 
study medication and be managed by their clinical team as if the patient was on the 
active drug. Further advice should be sought from the CI as necessary.  
 
In the event a code is required to be broken a request for unblinding will be made by 
the Investigator or treating health care professional. 
 
If the person requiring the unblinding is not the CI or their team then the healthcare 
professional will notify the Investigator team that an unblinding is required for a trial 
subject which will then occur. 
 
In emergency situations, the responsibility to break the unblinding treatment code 
resides solely with the CI and will not be delayed in any way. The CI may delegate 
this duty to the sub-I or senior renal research nurse if there would otherwise be 
unreasonable delay in unblinding. 
 
On receipt of the treatment allocation details the CI or treating health care 
professional will continue to deal with the participant’s medical emergency as 
appropriate. 
 
The CI must document the breaking of the code and the reasons for doing so on the 
CRF/data collection tool, in the site file and medical notes. The CI will ensure it is 
also documented in the final study report and/or statistical report at the end of the 
study. 
  
The written information will be disseminated to the Trial Steering Committee. 
 
 

 
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13.7 Trial Schedule 
 
13.7.1 Schedule of Assessment (in Diagrammatic Format) 
 
Schedule of 
visits 
Screening 
Visit 1 
Visit 2 
Visit 3 
Visit 4 
Visit 5 
Visit 6 
Visit 7 
Data 
review 
Day/Month 
Before or 
within 24h 
post 
transplant 
Randomisati
on up to 24h 
post 
transplant 
week 1 
post 
randomisat
ion (+/- 3 
days) 
week 2 
post 
randomisat
ion (+/- 3 
days) 
week 4 
post 
randomisat
ion (+/- 3 
days) 
week 8 
post 
randomisat
ion (+/- 1 
week) 
week 12 
post 
randomisat
ion (+/- 1 
week) 
2 weeks after 
stopping 
study 
medication 
(+/- 1 week) 
1 yr post 
transplant 
+/- 2 
weeks 
Informed 
Consent 
X 
Inclusion/ 
exclusion 
criteria 
X 
X 
Negative 
pregnancy test 
X 
X 
X 
X 
X 
X 
X 
X 
Demographics 
X 
Transplant 
data 
X 
Medical 
history 
X 
X* 
Randomisation 
X 
Study drug 
dispense 
X 
Drug 
accountability 
X 
X 
X 
X 
X 
Physical 
examination 
X 
X 
X 
X 
X 
X 
X 
Weight 
X 
X 
X 
X 
X 
X 
X 
X* 
Vital signs 
X 
X 
X 
X 
X 
X 
X 
X* 
Concomitant 
medication 
X 
X 
X 
X 
X 
X 
X 
X 
X* 
Laboratory 
bloods** 
X 
X 
X 
X 
X 
X 
X 
X* 
Blood for Treg 
quantification  
X 
X 
X 
X 
AE assessment 
X 
X 
X 
X 
X 
X 
X 
X* 
End-point 
assessment 
X 
 

 
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*At this review, the patient’s medical records will be reviewed and their clinical data 
extracted to include: 
Graft function as measured by eGFR and serum creatinine 
Episodes of rejection 
Episodes of infection 
Diabetic control measured by HbA1c 
Vital signs 
Weight 
Current medication and anti-diabetic medication regimen 
 
**Laboratory bloods: including fasting c-peptide, cholesterol and serum glucose; 
serum urea and electrolytes (including creatinine), albumin, alkaline 
phosphatase (ALP), bilirubin, alanine aminotransferase (ALT), bone profile and 
C-reactive protein; haemoglobin and HbA1c; and serum save +/- blood for 
peripheral Tregs as per protocol. The serum save will be taken and processed 
in keeping with normal protocols but will be used for functional assays to 
measure the activity of the Tregs at different time points. 
 
 
 
 

 
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13.7.2 Trial assessments 
 
Screening visit 
Informed consent 
Inclusion/exclusion criteria 
Documentation of a negative pregnancy test from pre-transplant care  
In women of childbearing potential: defined as women following menarche until 
becoming post-menopausal, unless permanently sterile. Permanent sterilisation 
methods include hysterectomy, bilateral salpingectomy and bilateral oophorectomy. 
A postmenopausal state is defined as the absence of menses for 12 months without 
an alternative medical cause. 
Medical history  
Demographic data 
Concomitant medication  
 
Visit 1 - to occur within 24 hours post-transplant 
Inclusion/exclusion criteria 
Transplant data  
Documentation of a negative pregnancy test 
Concomitant medication  
Targeted physical examination 
Adverse event reporting 
Laboratory bloods: including fasting c-peptide, cholesterol and serum glucose; serum 
urea and electrolytes (including creatinine), albumin, alkaline phosphatase (ALP), 
bilirubin, alanine aminotransferase (ALT), bone profile and C-reactive protein; 
haemoglobin and HbA1c; and serum save. Results from bloods that have been 
taken as part of routine care may also be included on the case record forms. 
20ml of blood will also be taken for peripheral Treg quantification. 
Vital signs recording 
Weight 
Randomisation 
Study drug dispense 
 
In addition, the renal biopsy specimen collected as per clinical care at time of biopsy 
will be stained for Treg cell markers. 
 
Visit 2 (1 week post randomisation +/- 3 days)) 
Check drug adherence  
Concomitant medication   
Documentation of a negative pregnancy test 
Targeted physical examination 
Weight 
Vital signs recording 

 
ADOPTION Study V1.8 07.07.21 
 
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Fasting blood tests: including fasting c-peptide, cholesterol and serum glucose; 
serum urea and electrolytes (including creatinine), albumin, alkaline phosphatase 
(ALP), bilirubin, alanine aminotransferase (ALT), bone profile and C-reactive protein; 
haemoglobin and HbA1c and serum save. Results from bloods that have been taken 
as part of routine care may also be included on the case record forms. 
20ml of blood will also be taken for peripheral Treg quantification. 
Adverse event reporting 
 
Visit 3 (2 weeks post randomisation +/- 3 days) 
Activities as per visit 2 with exception of blood collection for Treg quantification 
 
Visit 4 (4 weeks post randomisation +/- 3 days) 
Activities as per visit 3 
 
Visit 5 (8 weeks post randomisation +/- 1 week) 
Activities as per visit 3 
 
Visit 6 (12 week post randomisation +/- 1 week) 
Activities as per visit 2 (i.e. additional blood taken for Treg quantification).  
In addition, patient will stop study medication and then revert back to usual care. 
Drug accountability (formal) 
Endpoint assessment  
 
As part of their usual care, and like all patients who undergo a renal transplant, 
patients have a transplant biopsy at 3 months. This histology specimen will be 
examined for Treg cell infiltration in addition to standard of care review. 
 
Visit 7 (2 weeks after stopping study medication +/- 1 week) 
Patients will have their vital signs and weight recorded, a targeted physical 
examination, an AE assessment, their laboratory bloods done (as above), blood 
taken for Treg quantification, and their concomitant medication checked. Female 
patients will have a pregnancy test. 
 
13.7.3 Follow-up Procedures 
 
After the last patient has completed visit 7, there will be an interim deadlock, at which 
point we will analyse the primary endpoint data.  
 
At 1 year post-transplant the patient’s medical records will be reviewed for the 
following data which will be extracted: 
Graft function as measured by eGFR and serum creatinine 
Episodes of rejection 
Episodes of infection 
Diabetic control measured by HbA1c 

 
ADOPTION Study V1.8 07.07.21 
 
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Current anti-diabetic medication regimen 
 
We will then perform a secondary data analysis.  
 
13.8 Withdrawal criteria 
 
Study medication will be stopped in the following situations: 
1. Hypoglycaemia despite removal of other glucose-lowering drugs: e.g. 
repeated events of minor hypoglycaemia defined as: 
− An episode with symptoms and confirmed low glucose (<3.9 mmol/L). 
− An episode with low glucose (<3.9 mmol/L). 
− An episode with symptoms suggestive of hypoglycaemia when glucose was 
not measured. 
If a patient has episodes of hypoglycaemia, their anti-diabetic medications will 
be altered as per standard of clinical care. 
2. One event of major hypoglycaemia regardless of any other diabetes drugs, as 
defined by the American Diabetes Association (ADA): 
- Requires assistance of another person to actively administer carbohydrates, 
glucagon, or take other corrective actions. 
Plasma glucose concentrations may not be available during an event, but 
neurological recovery following the return of plasma glucose to normal is 
considered sufficient evidence that the event was induced by a low plasma 
glucose level 
 
3. Impaired hepatic function (AST/ALT >x3 ULN,) due to the hepatic metabolism 
of AZD1656 
4. The patient’s target HbA1c is less than 6.5% and their other anti-diabetic 
medications have been withdrawn. 
 
If any of these situations occur, the subject will be withdrawn from the study 
medication, but will continue in the study with other study related activities.  
 
If the patient’s clinical care team feel that the patient requires treatment with 
gemfibrozil, then the patient will be withdrawn from the study medication, but 
continue other study related activities. This is not expected to happen in practice as 
gemfibrozil interacts with other immunosuppression medication the patient takes as 
part of their standard transplant regime, so gemfibrozil is avoided in transplantation 
medicine. 
 
Patients may be withdrawn from the study if the investigator feels that individual 
adverse events or new information gained mean that it is not safe to continue the 
study, or if it is felt to be in the participant’s best interest to stop the study.  

 
ADOPTION Study V1.8 07.07.21 
 
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Should a participant wish to withdraw from the study treatment, the patient will stop 
the study medication. Patients would be encouraged to continue with the study visits 
for safety, however should they not want to take part in any further study visits, they 
will continue to be followed up by their clinical care team as standard. It should be 
noted that routine clinical visits are very frequent for patients in their first year post-
transplant so it is unlikely that any patients will get lost to follow-up, or be put at risk 
should they withdraw from the study. 
 
Participants will continue to receive follow up procedures unless they specifically opt 
out. 
 
Routine clinical data collection will continue for patients who have withdrawn from 
the study unless they specifically opt out of using routine clinical data collection. 
Should a patient withdraw from the study this will be documented on the CRF using 
a study termination form, which includes recording reasons for withdrawal and 
consent for any follow-up information being collected. This would include a scenario 
in which a female participant had a positive pregnancy test. We would consent her 
for monitoring her during her pregnancy. 
 
 
13.9 Early withdrawal 
 
If a patient is withdrawn from the study early they will continue with their standard 
care at the unit. 
 
It will be documented in the CRF and medical notes if the patient is happy to 
continue on with study visits (without the study medication), or continue to have their 
clinical data collected, or no further data collected. 
 
13.10 End of trial (EOT) 
 
It is the CI’s responsibility to submit the EOT notification to REC and MHRA once 
obtaining sponsor approval. The EOT notification must be received by REC and MHRA 
within 90 days of the end of the trial. 
 
If the study is ended prematurely, the Chief Investigator will notify the Sponsor, REC 
& MHRA including the reasons for the premature termination (within 15 days). 
 
End of Trial definition: is after the last patient has completed their last follow up 
point at 1 year post-transplant (data review visit). 
 
 
 
 

 
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14.0 Laboratories and samples 
 
14.1 Local Laboratories  
 
Standard biochemistry samples will be sent to the Royal London Hospital 
Laboratory. All the tests that will be performed are part of the standard diagnostic set 
of tests commonly used to test for diabetes. 
 
Research blood samples will be taken at the same time, labelled with the patient’s 
study number and date of sampling. They will be taken to the Immunology 
laboratories at the Royal London Hospital in order to isolate and store the patient’s 
peripheral blood cells. Flow cytometry analysis of peripheral T cell populations will 
take place in the Immunology laboratories. Stored peripheral blood cells may also be 
taken to the William Harvey Research Institute by members of the study team, for 
functional analysis of peripheral Treg populations and analysis of inflammatory 
signalling markers. The serum save will be taken and processed in keeping with 
normal protocols in the Royal London Hospital Laboratory but will be taken to either 
the Royal London Immunology laboratories or the William Harvey Research Institute 
to be used in functional assays to measure the activity of the Tregs at different time 
points. 
 
 
In addition, renal biopsy tissue collected as part of standard of care at the time of 
transplant and at month 3 will be examined for Treg cell infiltration. If any renal 
biopsies are carried out for a clinical indication in the interim period, then these will 
also be examined for Treg cell infiltration.  
 
14.2 Sample Collection/Labelling/Logging 
 
Samples will be collected by the research nurse or trained phlebotomist as per 
standard of care. 
 
Samples will be labelled with patient identification and sent to the local labs as per 
routine care and the results logged on the pathology system and transcribed to the 
CRF. 
 
The only samples that will be sent to the local lab, which are not part of routine care, 
are for serum C-peptide. 
 
Volume of samples to be collected: 
The total volume of blood which will be taken on top of routine care is: 
1 table-spoon (approximately 20ml) of blood per clinic visit (4x 6ml samples of blood) 
in lithium heparin tubes provided locally. 

 
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In addition, 20ml of blood will be taken at visit 1, 2, 6 and 7 for Treg quantification via 
FACS. This sample will be taken to the Royal London Immunology laboratories by 
members of the study team for processing. 
 
Any biopsy material will be processed and stored as part of routine clinical care.  
 
14.3 Sample Receipt/Chain of Custody/Accountability 
 
Samples will be sent to the lab by the research nurse, where they will be processed 
as per the lab’s standard SOPs under their UKAS accreditation. The research team 
will have responsibility for the custody of the samples until they are handed over the 
lab technicians at the sample collection point. Research blood samples will remain 
within the custody of the research team. 
 
14.4 Sample Analysis Procedures 
 
All standard (biochemistry, haematology) samples will be taken to the local lab by 
the research nurse/team after being taken. All samples will be processed in 
accordance with local procedures. 
 
In addition, research blood samples will be taken at the same time, labelled with the 
patient’s study number. The isolation and FACS analysis of peripheral blood cells will 
be performed by members of the study team as per the Immunology lab’s standard 
SOPs. 
  
Peripheral blood cell samples and stored serum may also be taken to the William 
Harvey Research Institute by members of the study team, for functional analysis of 
peripheral T cell populations and analysis of inflammatory signalling markers. After 
sample processing is completed the samples will be destroyed and not stored 
further. 
 
14.5 Sample and Data Recording/Reporting  
 
Data will be recorded on the CRF/eCRF. 
 
The CRF will be completed by the CI, SUB-I or research nurse. The CI will counter-
sign completed CRFs and these will be stored securely in the study file in the 
research office.  
 
14.6 End of study 
 
No biological material will be kept in the department. All biological samples will have 
been sent to the lab and disposed of as per their routine SOP. No biological samples 

 
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will be retained at William Harvey Research Institute: they will be destroyed after 
sample processing. 
 
 
 

 
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15.0 Trial Medication 
 
15.1 Name and description of investigational medicinal product(s) 
 
AZD1656 is a potent and selective glucokinase activator that is administered orally 
as a tablet formulation. The matching placebo tablets have the same appearance as 
the tablets containing AZD1656.  
 
15.2 Legal status of the drug 
 
Not licenced 
 
15.3 Summary of Product Characteristics (SmPC) or IB 
 
See IB Edition 9, Sept 15th 2020 
 
15.4 Drug storage and supply 
 
The IMP/placebo will be shipped securely to the clinical trials pharmacy unit from the 
pharmacy manufacturing unit, where it will be stored until needed. The research 
nurse will collect the IMP/placebo from the clinical trials pharmacy and give this to 
the study patients. All medicinal products left over after study completion will be 
destroyed. 
 
15.5 Supplier 
 
The IMP and placebo will be packed and labelled by Fisher Clinical Services and 
sent to the clinical trials pharmacy at the Royal London Hospital. 
  
Fisher Clinical Services U.K. Limited 
Langhurstwood Road 
Horsham 
RH12 4QD 
United Kingdom 
 
The supply is being made specifically for use in the trial, and will not be used for any 
other purpose then as stated in the trial. 
 
15.6 Manufacturer 
 
The tablets were manufactured by Patheon. 
  
Patheon UK Limited 

 
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151 Brook Drive 
Milton Park 
Abingdon 
OX14 4SD 
United Kingdom 
 
15.7 IMP Storage 
 
The drug should not be stored above 25°C or stored anywhere other than in the 
original package. The containers should be kept tightly closed.  
 
The shelf life of the drug will be updated based on read-outs from an on ongoing 
stability study.  The initial shelf life will be at least 12 months. 
 
There are no special arrangements needed for the storage of the medication (it can 
be stored at room temperature). 
 
15.8 Details of accountability 
 
The study medication will be dispensed from pharmacy and given to the patient by a 
member of the research team on the delegation log. An accountability log will be 
used to record the details of each batch of study medication dispensed to a patient, 
including subject identification code, drug batch number, date of dispensing and 
quantity dispenses, date returned and quantity returned, and date destroyed. 
Accountability logs will be maintained by the clinical trial pharmacist. 
 
15.9 Medication destruction/return and recall 
 
At month 3 any unused study medication will be returned, counted and then 
destroyed as per local policy. 
 
15.10 Prescription of IMP / Placebo/ NIMP 
 
The ADOPTION prescription form will be used to prescribe IMP or placebo. 
 
15.11 Preparation and labelling of IMP and Placebo 
 
The active treatment is AZD1656 50mg tablets. The placebo tablet contains no 
active ingredient and is a visual match to the active.  
 
The IMP and placebo will be packed and labelled by Fisher Clinical Services and 
sent to the clinical trials pharmacy at the Royal London Hospital. 
  

 
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Fisher Clinical Services U.K. Limited 
Langhurstwood Road 
Horsham 
RH12 4QD 
United Kingdom 
 
15.12 Preparation and Administration of IMP 
 
The IMP will be dispensed as 50mg tablets with two to be taken twice a day. Patients 
will be counselled on their dose during visit 1. 
 
15.13 Dosage schedules 
 
The patient will be dispensed either placebo or AZD1656 tablets for a 3 month 
supply. 
 
These are two 50mg oral tablets to be taken twice a day with or after meals. 
 
Missed doses will be permitted: if a patient misses a dose they should take their next 
dose at the usual time. Drug adherence will be encouraged at each visit. Drug 
accountability will be assessed at each study visit where patients will bring back their 
unused supply with non-adherence defined as less than 80% or more than 120% of 
medications taken.  
 
15.14 Dispensing of IMP 
 
There will be a dispensing guideline in place within pharmacy. Each member of staff 
who dispenses the IMP will sign the local/pharmacy dispensing log to document 
appropriate IMP tracking. All members of the trial team should ensure that they have 
had study specific training and their involvement should be demonstrated by the 
study specific trial delegation log.  
 
15.15 Dosage modifications 
 
No dosage modifications will be allowed. 
 
However the study medication may be stopped if the investigator feels it is not safe 
for the patient to continue treatment with the study medication. At this point the 
patient will be withdrawn from the treatment with study medication for the rest of the 
trial but will continue in all other study related activities. 
 

 
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15.16 Known drug reactions and interaction with other therapies 
 
Gemfibrozil is a potent inhibitor of the isoenzyme CYP2C8. When AZD1656 was 
administered as a single dose together with gemfibrozil, a 2.7-fold increase in AUC 
of AZD1656 was observed compared to single dose administration of AZD1656 
alone. The t1/2 of AZD1656 increased, suggesting that AZD1656 will accumulate by 
approximately 50% following repeated twice daily dosing of AZD1656 to steady state 
during concomitant gemfibrozil administration. However, the levels of the active 
metabolite, AZD5658, were reduced during co-administration with gemfibrozil. No 
statistically significant increase was observed for Cmax when dosed together with 
gemfibrozil (D1020C00030).  
 
15.17 Prior and Concomitant medication 
 
Given the theoretical increase in AUC (but not Cmax) with gemfibrozil. Any patient 
who is currently taking this agent will be excluded from the study.  
 
Prior and Concomitant medication lists will be recorded in the case record forms 
 
15.18 Assessment of compliance 
 
Compliance will be assessed at study visits, when the research team will count the 
number of tablets returned and consider less than 80% or more than 120% 
adherence to be non-compliant. 
 
15.19 Arrangements for post-trial access to IMP and care 
 
This agent will not be available for long-term use as published studies have shown 
that its biological effect wears off after 3-4 months.  
 
 
 

 
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16 Equipment and Devices 
 
No equipment or devices will be used outside of standard care. 
 
 

 
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17 Pharmacovigilance 
 
17.1 General Definitions 
Term 
Definition 
Adverse Event (AE) 
Any untoward medical occurrence in a participant to whom a 
medicinal product has been administered, including occurrences 
which are not necessarily caused by, or related to, that product. 
Adverse Reaction (AR) 
 
An untoward and unintended response in a participant to an 
investigational medicinal product which is related to any dose 
administered to that participant. 
 
The phrase "response to an investigational medicinal product" means 
that a causal relationship between a trial medication and an AE is at 
least a reasonable possibility: i.e. the relationship cannot be ruled out. 
 
All cases judged by either the reporting medically qualified 
professional or the Sponsor as having a reasonable suspected causal 
relationship to the trial medication qualify as adverse reactions. 
Serious Adverse Event 
(SAE) 
A serious adverse event is any untoward medical occurrence that: 
 Results in death. 
 Is life-threatening. 
 Requires 
inpatient 
hospitalisation 
or 
prolongation 
of 
existing 
hospitalisation. 
 Results in persistent or significant disability/incapacity. 
 Consists of a congenital anomaly or birth defect. 
Other ‘important medical events’ may also be considered serious if 
they jeopardise the participant or require an intervention to prevent 
one of the above consequences. 
 
NOTE: The term "life-threatening" in the definition of "serious" refers 
to an event in which the participant was at risk of death at the time of 
the event; it does not refer to an event which hypothetically might 
have caused death if it were more severe. 
Serious Adverse 
Reaction (SAR) 
An adverse event that is both serious and, in the opinion of the 
reporting Investigator, believed with reasonable probability to be due 
to one of the trial treatments, based on the information provided. 
Suspected Unexpected 
Serious Adverse 
Reaction (SUSAR) 
A serious adverse reaction, the nature and severity of which is not 
consistent with the information about the medicinal product in 
question set out in the Reference Safety Information (RSI): 
 In the case of a product with a marketing authorisation, in the summary 
of product characteristics (SmPC) for that product. 
 In the case of any other investigational medicinal product, in the 
investigator’s brochure (IB) relating to the trial in question. 
 
 

 
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17.2 Site Investigators’ Assessment 
 
The Chief Investigator is responsible for the care of the participant, or in his/her 
absence a delegated medical practitioner and is responsible for assessment of any 
event for: 
 
 Seriousness 
Assessing whether the event is serious according to the definitions given in 
section 17.1. 
 
 Causality 
Assessing the causality of all serious adverse events/reactions in relation to 
the trial treatment according to the definition given. If the SAE is assessed as 
having a reasonable causal relationship, then it is defined as a SAR. 
 
 Expectedness 
Assessing the expectedness of all SAEs according to the definition given.  If 
the SAE is unexpected, then it is a SUSAR. 
 
 Severity 
Assessing the severity of the event according to the following terms and 
assessments. The intensity of an event should not be confused with the term 
“serious” which is a regulatory definition based on patient/event outcome 
criteria. 
 
o Mild: Some discomfort noted but without disruption of daily life 
o Moderate: Discomfort enough to affect/reduce normal activity 
o Severe: Complete inability to perform daily activities and lead a normal 
life 
 
17.3 Reference Safety Information 
 
Reference Safety Information is the information used for assessing whether an 
adverse reaction is expected. See IB Edition 9, September 15th 2020 for further 
details. 
 
Undesirable effects 
Across clinical studies, AZD1656 has been well tolerated and no safety concerns 
have been raised. No safety signals have been identified regarding vital signs, ECG, 
weight, BMI and physical findings.  
 
There have been no treatment related changes in safety laboratory variables 
including muscle biomarkers and liver function tests in Phase I to IIa.  From the few 

 
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cases with increased liver enzymes in Phase IIb, a minor increase from AZD1656 
treatments could not be excluded.  
 
From the phase IIb published studies the following side effects occur more frequently 
than placebo. 
 
See below for tables 3 and 4 taken from AZD1656 IB version 9 2020. 
 
 
 
 
 

 
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Special warnings and precautions for use 
 
Nil 
 
17.4 Notification and Reporting Adverse Events or Reactions 
 
If the AE is not defined as SERIOUS, the AE is recorded in the CRF and the 
participant is followed up by the research team. The AE is documented in the 
participant’s medical notes (where appropriate) and the CRF. 
 
If, as part of the routine care of patients post-renal transplant, the clinical care team 
withhold the study medication, they must inform the CI/research team. Members of 
the transplant team will be educated on the protocol and study requirements. 
  
In addition to ensure that all AEs are gathered by the research team during the 3-
month treatment period in a timely manner, the research team will review the source 
documents (clinic letters and or clinical entries on electronic patient record) on a 
regular basis (maximum every month). 
 
17.5 Notification of AEs of special interest 
 
There are no Adverse Events of Special Interest for this trial. 
 

 
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17.6 Adverse events that do not require reporting 
 
It is standard protocol to stop CMV prophylaxis within the first-year post transplant. It 
is also standard practice to wean some patients off prednisolone medication in the 
first year. 
 
Therefore we do not consider these changes an adverse event and they will not be 
formally reported. 
 
17.7 Notification and Reporting of Serious Adverse Events & SUSARs  
 
All Serious Adverse Events (SAEs) will be recorded in the participants’ notes, the 
CRF, the sponsor SAE form, and reported to the sponsor (Joint Research 
Management Office) within 24 hours of the CI or co-investigators becoming aware of 
the event. Nominated co-investigators (as listed in the delegation log) will sign the 
SAE forms in the absence of the CI.  
 
Reporting of SUSARs 
Suspected Unexpected Serious Adverse Reactions (SUSARs) that occur during the 
trial will be reported to the sponsor (joint management research office) within 24 
hours of the CI or co-investigator becoming aware of the event. The sponsor will 
then report this to the MHRA. 
 
Reporting of SAE/SUSAR to Astra Zeneca (see appendix 1: Safety Reporting 
Responsibilities) 
Report unblinded Suspected Unexpected Serious Adverse Reactions (SUSARs) to 
AstraZeneca (via Kinapse) as individual case reports as they occur.  
 
17.8 Sponsor Medical Assessment 
 
The CI retains overall responsibility for oversight of IMP safety profile and medical 
assessment of SAEs and SUSARs. The CI must review all SAEs within 48 hours of 
receipt. This review should encompass seriousness, relatedness and expectedness. 
Day 0 for all SUSARs is when the SAE/SUSAR is received by the CI and/or 
coordinating team and/or sponsor whichever is first. 
 
It is expected that the CI will achieve oversight of IMP safety profile through 
trial committees as per section 28.0. 
 
17.9 Urgent Safety Measures 
 
The CI may take urgent safety measures to ensure the safety and protection of the 
clinical trial subjects from any immediate hazard to their health and safety. The 
measures should be taken immediately. In this instance, approval from the 

 
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Competent Authority prior to implementing these safety measures is not required. 
However, it is the responsibility of the CI to attempt, where possible, to discuss the 
proposed measures with the Sponsor and Medical Advisor at the MHRA (via 
telephone) prior to implementing them if possible. 
 
The CI has an obligation to inform both the MHRA and Research Ethics Committee 
in writing within 3 days, in the form of a substantial amendment. The sponsor 
(JRMO) must be sent a copy of the correspondence with regards to this matter as 
soon as it is sent. 
 
17.10 Procedures for reporting blinded SUSARs 
 
The CI as sponsor medical assessor will assess the event blinded, and will assess 
for active IMP and Placebo. For SUSARS the CI will remain blinded, however the 
sponsor will be unblinded for reporting to the MHRA. 
 
17.11 Pregnancy 
 
If a patient becomes pregnant whilst enrolled in the study, the study medication will 
be withdrawn but the patient will continue on in the study. No data is available on the 
effects of AZD1656 on pregnancy and lactation in humans. Results from the repro-
toxicity studies in animals (fertility and embryo-foetal development) support inclusion 
of women of childbearing potential in clinical studies, provided that pregnancy is 
prevented using a reliable form of contraception. The results from the animal studies 
suggest that any adverse effect observed was as a result of maternal 
hypoglycaemia.  
 
If a patient on the study medication becomes pregnant the CI has the responsibility 
to ensure that the pregnancy form is completed and sent to the sponsor within the 
agreed timelines.  The initial report should be sent within 24 hours and follow up 
information submitted as and when it becomes available up to agreed follow up time 
after birth. 
 
If a female patient on the study medication, or the female partner of a patient on the 
study medication, becomes pregnant, she will be asked to sign an additional consent 
form to allow data collection and monitoring during her pregnancy. 
 
 

 
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18.0 Annual reporting 
 
Development Annual Safety Update (DSUR) 
The DSUR will be written by the CI (using the Sponsor’s template) and submitted to 
the sponsor for review prior to submission to the MHRA. The DSUR is due for 
submission within 60 days of the end of the reporting period. The reporting period is 
annually from the date on the “notice of acceptance letter” from the MHRA. As 
delegated Sponsor Medical Assessor the CI will carry out a risk benefit analysis of 
the IMPs encompassing all events having arisen on the trial. REC will be sent a copy 
of the DSUR. Any findings in the DSUR that are inconsistent with the Investigator 
Brochure should be communicated to AZ during DSUR production but at the latest in 
parallel to the DSUR being sent to the RA/Ethics committee. 
 
 
Annual Progress Report (APR) 
The APR will be written by the CI (using HRA template) and submitted to the 
sponsor for review prior to submission to the REC. The APR is due within 30 days of 
the anniversary date of the “favourable opinion” letter from the REC. 
 
 

 
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19.0 Statistical and Data Analysis 
19.1 Sample size calculation 
 
n=25 in each arm. This is a pilot/exploratory study: the numbers were chosen as this 
was felt to be feasible given the resources of the site, and will enable generation of 
data for a larger scale trial should the results of this pilot be encouraging. 
 
19.2 Planned recruitment rate 
 
Based on analysis from the renal unit at the Royal London Hospital (where the study 
will be based), around 140 transplants are performed per year, of which 30% have 
type 2 diabetes. We expect up to 20% of patients to decline to take part. Therefore, it 
is expected that the recruitment will be complete within 16-20 months.   
 
19.3 Statistical analysis plan (SAP) 
Please refer to SAP for full details 
Primary Endpoint 
 
The primary endpoint is the change in mean peripheral Treg cell number between 
baseline and 3 months measured using FACS analysis between AZD1656 and 
placebo. 
 
This will be analysed at the first data analysis. 
Secondary Endpoints: 
1) Histological staining for Treg cells in renal biopsy tissue between baseline 
and 3 month protocol biopsy  
2) Incidence of delayed graft function, defined as the need for dialysis within 
1 week post-transplant 
3) Diabetic control between baseline and month 3 using change in HbA1c 
measurement 
4) Dose of other anti-diabetic medication between baseline and month 3 
(descriptive) 
5) Safety endpoints i.e. number of hypoglycaemic episodes (descriptive) 
6) Insulin resistance: HOMA IR measurement at month 3 
7) Graft function: (eGFR) at month 3  
8) Episodes of acute rejection (defined as biopsy proven acute rejection) 
9) Episodes of opportunistic infections: bacterial and viral (descriptive) 
 
All of these endpoints will be analysed at the first data analysis; endpoints 8 and 9 
will also be re-examined at the second data analysis. 

 
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 Exploratory or Tertiary Endpoints/outcomes 
 
1) 12-month graft function (eGFR) and diabetic control (HbA1c; medication 
review) to assess legacy effect (potential follow up publication) 
2) Differences in other peripheral T cell populations, measured by FACS 
analysis 
3) Histological staining for Treg cells in any renal biopsy taken for clinical 
indications between baseline and month 3 protocol biopsy 
4) Differences in the functional phenotype of the Treg cells  
 
 
Endpoints 2 and 3-4 will be analysed at the first data analysis; endpoint 1 will be 
analysed at the second data analysis. 
 
Baseline Demographics and Biochemical parameters 
Demographics and Clinical Characteristics 
 Age at recruitment (derived from date of birth; continuous)  
 Sex (categorical) 
 Self-reported ethnicity (using ONS categories; categorical) 
 Weight (continuous) 
 Systolic BP (continuous) 
 Diastolic BP (continuous) 
 
Medical History 
 Cause of end stage renal failure (categorical) 
 Dialysis modality (categorical) 
 Dialysis vintage (continuous) 
 Diabetes duration (continuous) 
 Retinopathy (yes/no, categorical) 
 Neuropathy (yes/no, categorical) 
 Coronary artery disease (yes/no, categorical) 
 Peripheral artery disease (yes/no, categorical) 
 Cerebrovascular disease (yes/no, categorical) 
 Hypertension (yes/no, categorical) 
 Heart failure (yes/no, categorical) 
 
Pregnancy test 
 
Pregnancy test negative (either serum or urine) (yes/no, categorical) 
 
Transplant details 

 
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 Cold ischaemia time in hours (continuous) 
 Warm ischaemic rime minutes (continuous) 
 Donor age (continuous) 
 ECD (yes/no, categorical) 
 CMV mismatch (yes/no, categorical) 
 HLA mismatch (categorical) 
 
Medication 
 
Each medication will be recorded as name/dose/start date (categorical) 
 
Biochemical Parameters 
 Fasting c-peptide (continuous) 
 Fasting cholesterol (continuous) 
 Haemoglobin (continuous) 
 Serum sodium (continuous) 
 Serum potassium (continuous) 
 Serum urea (continuous) 
 Serum creatinine (continuous) 
 eGFR (CKD-EPI formula, continuous) 
 Serum albumin (continuous) 
 Serum alkaline phosphatase (continuous) 
 Serum bilirubin (continuous) 
 Serum alanine aminotransferase (continuous) 
 Serum calcium (continuous) 
 Serum phosphate (continuous) 
 C-reactive protein (continuous) 
 Glucose (continuous) 
 Haemoglobin A1C (DCCT aligned; continuous) 
 Peripheral Treg Cell number (interval) 
 HOMA IR  (continuous) 
 
19.4 Summary of baseline data and flow of patients 
 
The IMP versus placebo groups will be compared using standard statistical methods. 
 
19.5 Primary outcome analysis 
 
The endpoint data will be analysed on an ITT basis, with no subgroup analysis using 
unpaired parametric and non-parametric analysis as necessary, comparing the 

 
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change in mean Treg cell number between baseline and month 3 between the 2 
groups. 
 
Continuous variables will be tested for normality using D'Agostino-Pearson normality 
test. Mean (standard deviation), median (interquartile ranges) will be displayed along 
with max-min point estimate and confidence intervals. Statistical analysis will be by 
student t-test (unpaired) or Mann-Whitney U test.  
 
Categorical data will be analysed by Chi Square test.  
 
Statistical significance considered if P-value <0.05. 
 
19.6 Secondary outcome analysis 
 
Each of the secondary endpoints will be analysed with the null hypothesis that the 
IMP and placebo are similar for the primary endpoint.  
 
19.7 Interim analysis and criteria for the premature termination of the trial 
 
There will be an interim datalock after the last patient has completed visit 7, at which 
point we will analyse the primary endpoint data and the relevant secondary and 
tertiary endpoints. There will be a secondary analysis after the final data collection 
review one year after transplant.  
 
19.8 Subject population 
 
The study population will be those patients undergoing a renal transplant at the RLH 
renal unit who satisfy the inclusion criteria and do not meet any of the exclusion 
criteria. 
 
19.9 Procedure(s) to account for missing or spurious data  
 
As this group of patients attend standard of care clinic visits very frequently post 
transplantation, it is not expected that they will be lost to follow up. The research 
team will make every effort to rectify any missing or spurious data. 
 
 
 
 

 
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20.0 Data Handling & Record Keeping 
 
20.1 Confidentiality 
 
The Chief Investigator has the responsibility to ensure that participant anonymity is 
protected and maintained. They must also ensure that their identities are protected 
from any unauthorised parties. Information with regards to study participants will be 
kept confidential and managed in accordance with the Data Protection Act; NHS 
Caldicott Guardian; the UK Policy Framework of Health and Social Care Research; 
and Ethics Committee Approval. All trial data will be stored in line with the Medicines 
for Human Use (Clinical Trials) Amended Regulations 2006 and the Data Protection 
Act 2018, and archived in line with the Medicines for Human Use (Clinical Trials) and 
all subsequent amendments as defined in the JRMO SOP 20 Archiving. 
 
The Chief Investigator and the study team will adhere to these regulations to ensure 
that the participants’ identities are protected at every stage of their participation in 
the study. To ensure this is done accordingly, at time of consent each participant will 
be allocated a unique screening number by either the CI or a member of the study 
team before undergoing any screening procedures. 
 
All investigators and trial site staff will comply with the requirements of the Data 
Protection Act 2018 with regards to the collection, storage, processing and 
disclosure of personal information and will uphold the Act’s core principles. 
 
20.2 Data Custodian Details  
 
The Chief Investigator Kieran McCafferty, Royal London Hospital, E1 1BB is the 
‘Custodian’ of the research data. 
 
20.3 Pseudononymisation  
 
Data will be in the form of linked anonymised data. Unique study numbers will be 
used, which are linked to a treatment code. This will be contained in the ISF on the 
enrolment log. 
 
20.4 Transferring/Transporting Data 
 
All patient-identifiable information will be stored in a locked environment, or on 
password protected NHS computers on an electronic database. 
 
No data will be transferred out of this environment. 
 

 
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20.5 Data collection tools and source document identification 
 
The source document will be paper medical records and the electronic patient record 
CRS Millenium. Data from the source document will be added to a paper CRF. 
 
20.6 Source Data 
 
The source documents will comprise the site medical notes and health records 
(paper and electronic), including Barts Health laboratory and pharmacy records. 
 
20.7 Case Report Form 
 
Data will be transcribed from source documents to paper Case Report Forms. Paper 
CRFs will be kept in the investigator file and they will be reviewed as part of source 
data verification during site monitoring. Patients will be identified only by initials, trial 
number and day (dd) of birth. 
 
20.8 Data handling and record keeping 
 
Data will be recorded from study visits in the source data and transcribed to the 
CRF. All documents (CRF, signed consent forms etc.) will be kept according to the 
sponsor’s requirements. All research staff will be trained on the use of the database 
and CRF. 
 
20.9 Access to Data, Source Data and Documents 
 
Direct access will be granted to authorised representatives from the Sponsor or 
delegate, host institution and the regulatory authorities to permit trial-related 
monitoring, audits and inspections. 
 
 

 
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21.0 Archiving 
 
During the course of research and for the archiving period, all records are the 
responsibility of the Chief Investigator and must be kept in secure conditions. When 
the research trial is complete, it is a requirement of the Trust Policy that the records 
are kept for a further 25 years. 
 
Destruction of essential documents will require authorisation from the Sponsor. 
 
Archiving will be authorised by the sponsor following submission of the end of study 
report. 
 
 
 

 
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22.0 Monitoring, Audit and Inspection 
 
22.1 Monitoring 
 
A Trial Monitoring Plan will be developed and signed by the Sponsor and Chief 
investigator based on the sponsor’s trial risk assessment, this will include on site 
monitoring. Monitoring procedures are detailed in the Trial Monitoring Plan. 
 
A sponsor monitor will monitor the trial on a regular basis. 
 
22.2 Auditing 
 
The sponsor retains the right to audit the trial. In addition, any part of the trial may be 
inspected by the regulatory bodies and funders where applicable. 
 
22.3 Notification of Serious Breaches to GCP and/or the protocol 
 
The CI is responsible for reporting any serious breaches to the sponsor (JRMO) 
within 24 hours of becoming aware of the breach. 
 
The sponsor will work with the CI to investigate any potential breach. The sponsor 
will notify the MHRA, and the CI will notify the REC, within 7 working days of 
becoming aware of the serious breach. 
 
22.4 Compliance 
 
The CI will ensure that the trial is conducted in compliance with the principles 
outlined in the Medicines for Human Use (Clinical Trials) Regulations 2004 (SI 
2004/1031), and any subsequent amendments of the clinical trial regulations, current 
UK Policy Framework for Health and Social Care Research, GCP guidelines, the 
World Medical Association Declaration of Helsinki (1996), the Sponsor’s SOPs, and 
other regulatory requirements as amended. 
 
The trial will not commence until a Clinical Trial Authorisation (CTA) is obtained from 
the MHRA. 
 
22.5 Non-Compliance 
 
Planned deviations or waivers to the protocol and specifically the eligibility criteria 
are not allowed.  
 

 
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Accidental protocol deviations can happen at any time. They must be adequately 
documented on the relevant forms and reported to the Chief Investigator and 
Sponsor immediately. 
 
All deviations will be documented in the patient records, deviation log and CRF. 
 
The CI and the co-ordinating team should assess the non-compliances and agree on 
a timeframe in which they need to be dealt with. This assessment should include the 
need to escalate to the sponsor. Any event with the potential to affect participant 
safety or data integrity should be reported to the sponsor within 24 hours of the co-
ordinating team becoming aware. 
 
Where applicable, corrective and preventative actions should be taken. Each action 
will be given a different timeframe dependent on the severity. If the actions are not 
dealt with accordingly, the Sponsor will agree an appropriate action, which could 
include an on-site audit. 
 
22.6 Regulatory Compliance 
 
The trial will not commence until a Clinical Trial Authorisation (CTA) is obtained from 
the MHRA, favourable opinion has been obtained from an NHS REC, and HRA 
Approval has been granted. 
 
The protocol and trial conduct will comply with the Medicines for Human Use 
(Clinical Trials) Regulations 2004 and any relevant amendments. 
 
Before any site can enrol participants into the trial, the site will confirm to the CI that 
it has capacity and capability to run the trial, and the CI will activate the site. 
 
The Chief Investigator will obtain approval from the appropriate review bodies before 
implementing any amendments to the trial. 
 
This study does not involve ionising radiation. 
 
 
      
 
 

 
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23.0 Financial and other competing interests for the chief investigator, PIs at each 
site and committee members for the overall trial management 
 
The Chief Investigator has no financial or other competing interests.  
 
All members of committee will sign a competing interests form. 
 

 
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24.0 Ethical and Regulatory Considerations 
Before the start of the trial, approval will be sought from the Research Ethics 
Committee (REC) and MHRA for the trial protocol, informed consent forms and other 
relevant documents e.g. advertisements and GP information letters. 
 
The authority to make a decision whether an amendment constitutes a minor or 
substantial amendment lies with the sponsor. 
 
Substantial amendments that require review by the Sponsor and REC and MHRA 
(where relevant) will not be implemented until the REC and or MHRA grants a 
favourable opinion for the study and until capacity and capability has been confirmed 
by the site. 
 
All correspondence with the Sponsor, REC and MHRA will be retained in the Trial 
Master File at the lead site and Investigator Site File at each site. 
 
The Chief Investigator will notify the REC, MHRA and Sponsor of the end of the 
study. 
 
 

 
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25.0 Peer review 
 
The clinical trial protocol has been reviewed by an independent consultant 
nephrologist, by IMP supplier AstraZeneca and internally by consultants within the 
nephrology department at Barts Health NHS Trust. 
  
 

 
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26.0 Public and Participant Involvement 
 
Haemodialysis patients (who may be potential future recruits) and patients who 
currently have a renal transplant were involved in reviewing the patient documents to 
ensure ease of reading and clarity. We have engaged with our patient group to invite 
them to nominate one or more patients to sit on the Trial Study group. 
 
 

 
ADOPTION Study V1.8 07.07.21 
 
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27.0 Indemnity 
 
Queen Mary University of London’s research insurance will apply to the design and 
management of the trial. The NHS indemnity scheme will apply to site-level research 
activities taking place at Barts Health NHS Trust.  
 
27.1 Amendments 
 
Under the Medicines for Human Use (Clinical Trials) Regulations 2004, the sponsor 
may make a non-substantial amendment at any time during a trial. If the sponsor 
wishes to make a substantial amendment to the CTA or the documents that supported 
the original application for the CTA, the sponsor must submit a valid notice of 
amendment to the licencing authority (MHRA) and to the HRA and REC for 
consideration. The MHRA, REC and HRA will provide a response regarding the 
amendment within 35 days of receipt of the notice. It is the sponsor’s responsibility to 
decide whether an amendment is substantial or non-substantial for the purposes of 
submission to the MHRA, REC and HRA. 
 
If applicable, other specialist review bodies (e.g. Clinical Boards) need to be notified 
about substantial amendments in case the amendment affects their opinion of the 
study. 
 
Amendments will also be notified to NHS R&D departments of participating sites to 
assess whether the amendment affects the NHS capability and capacity for that site.  
 
The CI, along with the steering committee, will be responsible for making the decision 
to amend the protocol. Amendments will be submitted by the CI to the MHRA, HRA 
and REC and will inform the Trial registries and local R&D departments.  Any changes 
to study documents will be subject to version control and amendment history. 
 
27.2 Access to the final trial dataset 
 
The steering committee will have access to the final dataset along with the CI. 
 
 
 

 
ADOPTION Study V1.8 07.07.21 
 
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28.0 Trial Committees 
 
The trial steering committee/ drug safety monitoring committee will be made up of: 
 Independent Chair 
 Trials statistician 
 Director of the Diabetic Kidney Centre 
 Consultant Transplant Surgery 
 Consultant in Transplant surgery/renal medicine/diabetic medicine 
 Chief Investigator 
For the current names of the members please see TSC/DSM document. 
 
There will be regular documented management meetings and a trial steering 
committee with independent representation.  
 
This group will meet every 6 months to ensure all practical details of the trial are 
progressing and working well, and that everyone within the trial understands them. 
This group will review safety/operational concerns and will have the authority to 
terminate / prematurely discontinue the trial. They will not have access to unblinded 
data unless a specific unblinding request is made for an individual patient. 
 
 
 
 

 
ADOPTION Study V1.8 07.07.21 
 
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29.0 Publication and Dissemination Policy 
29.1 Publication 
 
The study will be registered on clinical trials.gov. 
 
Publications will occur at the end of the study. 
The sponsor retains the right to review all publications prior to submission or 
publication. 
Responsibility for ensuring accuracy of any publication from this study is delegated 
to the Chief Investigator. 
All publications should acknowledge the Sponsor.  
 
The full study report will be accessible via EudraCT. 
 
Should the results of the study suggest benefit, an application will be made to 
consider a further larger powered study. 
 
Publications will be in accordance with the external sponsored research clinical 
agreement with AZ: the sponsor/PI will provide Astra Zeneca with copies of any 
materials relating to the Study, the Study Data or the Developed Technologies that it 
either intends to publish or make any presentations relating to, at least thirty (30) 
days in advance of publication, submission or presentation. 
 
At the request of the Company, the Sponsor/PI will not include in or remove from any 
proposed publication any confidential information; and withhold publication, 
submission for publication or presentation for a period of ninety days from the date 
on which the Company receives the material to allow the Company to take such 
measures as the Company considers necessary to preserve its proprietary rights 
and/or protect its confidential information. 
 
29.2 Dissemination policy 
 
Data arising from the trial is owned by the sponsor. In all publications arising from 
this study, the Diabetic Kidney Disease Centre will be acknowledged in the final 
manuscript. 
 
Participants will be notified of the outcome of the trial in writing. Their non-blinded 
treatment allocation will be made available to patients on request following 
publication. 
The trial protocol and the full study report will be made publicly available via 
EudraCT. 
 
 
 

 
ADOPTION Study V1.8 07.07.21 
 
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30.0 References 
Aroda VR, Christophi CA, Edelstein SL, Zhang P, Herman WH, Barrett-Connor E, 
Delahanty LM, Montez MG, Ackermann RT, Zhuo X, Knowler WC, Ratner RE; 
Diabetes Prevention Program Research Group. The effect of lifestyle intervention 
and metformin on preventing or delaying diabetes among women with and without 
gestational diabetes: the Diabetes Prevention Program outcomes study 10-year 
follow-up. J Clin Endocrinol Metab. 2015 Apr;100(4):1646-53.  
 
Balla A, Chobanian M. New-onset diabetes after transplantation: a review of recent 
literature. Curr Opin Organ Transplant. 2009 Aug;14(4):375-379. 
 
Bestard O, Cruzado JM, Rama I, Torras J, Gomà M, Serón D, Moreso F, Gil-Vernet 
S, Grinyó JM. Presence of FoxP3+ regulatory T Cells predicts outcome of subclinical 
rejection of renal allografts. J Am Soc Nephrol. 2008 Oct;19(10):2020–2026. 
 
Chakkera HA, Weil EJ, Pham PT, Pomeroy J, Knowler WC. Can new-onset diabetes 
after kidney transplant be prevented? Diabetes care. May 2013;36(5):1406-1412. 
 
Chowdhury TA, Srirathan D, Abraham G, Oei EL, Fan SL, McCafferty K, Yaqoob 
MM. Could metformin be used in patients with diabetes and advanced chronic kidney 
disease? Diabetes Obes Metab. 2017 Feb;19(2):156-161.  
 
Daniel V, Sadeghi M, Wang H, Opelz G. CD4(+)CD25(+)Foxp3(+) IFNγ(+) Treg are 
immunosuppressive in vitro and increase with intensity of the alloresponse in 
pretransplant MLC. Transpl Immunol. 2012 Oct;27(2-3):114–121. 
 
Dissanayake AM, Wheldon MC, Jafar Ahmed, Hood CJ. Extending Metformin Use in 
Diabetic Kidney Disease: A Pharmacokinetic Study in Stage 4 Diabetic Nephropathy. 
Kidney Int Rep. 2017 Mar;2(4):705–712. 
 
Ericsson H, Röshammar D, Wollbratt M, Heijer M, Persson M, Ueda S, Leonsson-
Zachrisson M, Norjavaara E. Tolerability, pharmacokinetics, and pharmacodynamics 
of the glucokinase activator AZD1656, after single ascending doses in healthy 
subjects during euglycemic clamp. Int J Clin Pharmacol Ther. 2012 Nov;50(11):765-
77. 
 
 
Hecking M, Haidinger M, Doller D, Werzowa J, Tura A, Zhang J, Tekoglu H, Pleiner 
J, Wrba T, Rasoul-Rockenschaub S, Muhlbacher F, Schmaldienst S, Druml W, Horl 
WH, Krebs M, Wolzt M, Pacini G, Port FK, Saemann MD. Early basal insulin therapy 
decreases new-onset diabetes after renal transplantation. J Am Soc Nephrol. 2012 
Apr;23(4):739-749. 
 

 
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Hu M, Wang YM, Wang Y, Zhang GY, Zheng G, Yi S, O'Connell PJ, Harris DC, 
Alexander SI. Regulatory T cells in kidney disease and transplantation. Kidney Int. 
2016 Sep;90(3):502-14. 
 
 
Kasiske BL, Snyder JJ, Gilbertson D, Matas AJ. Diabetes mellitus after kidney 
transplantation in the United States. Am J Transplant. 2003 Feb;3(2):178-185. 
 
Kinsey GR, Sharma R, Huang L, Li L, Vergis AL, Ye H, Ju ST, Okusa MD. 
Regulatory T cells suppress innate immunity in kidney ischemia-reperfusion injury. J 
Am Soc Nephrol. 2009 Aug;20(8):1744-53.  
 
Kishore M, Cheung KCP, Fu H, Bonacina F, Wang G, Coe D, Ward EJ, Colamatteo 
A, Jangani M, Baragetti A, Matarese G, Smith DM, Haas R, Mauro C, Wraith DC, 
Okkenhaug K, Catapano AL, De Rosa V, Norata GD, Marelli-Berg FM. Regulatory T 
Cell Migration Is Dependent on Glucokinase-Mediated Glycolysis. Immunity. 2017 
Nov;47(5):875-889. 
 
Kiyosue A, Hayashi N, Komori H, Leonsson-Zachrisson M, Johnsson E. 
Dose-ranging study with the glucokinase activator AZD1656 as monotherapy in 
Japanese patients with type 2 diabetes mellitus. Diabetes Obes Metab. 2013 
Oct;15(10):923-30.  
 
Knowler WC, Barrett-Connor E, Fowler SE, Hamman RF, Lachin JM, Walker EA, 
Nathan DM, Diabetes Prevention Program Research G. Reduction in the incidence 
of type 2 diabetes with lifestyle intervention or metformin. N Eng J Med. 2002 
Feb;346(6):393-403. 
 
Levy JC, Matthews DR, Hermans MP. Correct homeostasis model assessment 
(HOMA) 
evaluation 
uses 
the 
computer 
program. 
Diabetes 
Care. 
1998 
Dec;21(12):2191-2192. 
 
Margreiter 
R, 
European 
Tacrolimus 
vs 
Ciclosporin 
Microemulsion 
Renal 
Transplantation Study Group. Efficacy and safety of tacrolimus compared with 
ciclosporin microemulsion in renal transplantation: a randomised multicentre study. 
Lancet. 2002 Mar;359(9308):741-746. 
 
 
NICE. Type 2 diabetes: the management of type 2 diabetes. Accessed 25/7/15, 
2015. 
 
 
Palepu S, Prasad GV. New-onset diabetes mellitus after kidney transplantation: 
Current status and future directions. World J Diabetes. 2015 Apr;6(3):445-455. 
 
 
Pilmore HL. Review: metformin: potential benefits and use in chronic kidney disease. 
Nephrology (Carlton). 2010 Jun;15(4):412-418. 

 
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Reese PP, Shults J, Bloom RD, Mussell A, Harhay MN, Abt P, Levine M, Johansen 
KL, Karlawish JT, Feldman HI. Functional Status, Time to Transplantation, and 
Survival Benefit of Kidney Transplantation Among Wait-Listed Candidates. Am J 
Kidney Dis. 2015 Nov;66(5):837-845. 
 
Renal association 2018 guidelines.  
https://renal.org/wp-content/uploads/2017/07/ABCD–RA_Managing-glycaemia-
guideline_2018Publication.pdf accessed 28.7.18 
 
Salpeter S, Greyber E, Pasternak G, Salpeter E. Risk of fatal and nonfatal lactic 
acidosis with metformin use in type 2 diabetes mellitus. Cochrane Database Syst 
Rev. 2002(2):CD002967. 
 
Schaier M, Seissler N, Schmitt E, Hug F, Zeier M, Steinborn A. DR(high+)CD45RA(-) 
-Tregs potentially affect the suppressive activity of the total Treg pool in renal 
transplant patients. PLoS One. 2012;7(3):e34208. 
 
Scheen AJ. New hope for glucokinase activators in type 2 diabetes? Lancet 
Diabetes Endocrinol. 2018 Aug;6(8):591-593.  
 
Tang Q, Boden EK, Henriksen KJ, Bour-Jordan H, Bi M, Bluestone JA. Distinct roles 
of CTLA-4 and TGF-beta in CD4+CD25+ regulatory T cell function. Eur J Immunol. 
2004 Nov;34(11):2996-3005. 
 
Wilding JP, Leonsson-Zachrisson M, Wessman C, Johnsson E. Dose-ranging study 
with the glucokinase activator AZD1656 in patients with type 2 diabetes mellitus on 
metformin. Diabetes Obes Metab. 2013 Aug;15(8):750-9.  
 
Yi S, Ji M, Wu J, Ma X, Phillips P, Hawthorne WJ, O'Connell PJ. Adoptive transfer 
with in vitro expanded human regulatory T cells protects against porcine islet 
xenograft rejection via interleukin-10 in humanized mice. Diabetes. 2012 
May;61(5):1180–1191. 
 
Zwang NA, Leventhal JR. Cell Therapy in Kidney Transplantation: Focus on 
Regulatory T Cells. J Am Soc Nephrol. 2017 Jul;28(7):1960-1972.  
 
 
This protocol is based on JRMO CTIMP Protocol Template June 2015 version 
4.0. 
 
 
 
 

 
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APPENDIX 1: Safety Reporting Responsibilities 
 
Sponsor:  QMUL 
 
Trial: ADOPTION 
                        
 
 
 
 
 
 
AstraZeneca Reference number:  
                 
Sponsors and AstraZeneca will exchange safety information in accordance with the 
requirements set out in the summary table at the end of this document. 
 
The following information is required. 
 
 
Before the trial starts: 
 
 Sponsor will provide AstraZeneca with:  
 
A copy of the format of the SAE report form including the AZ Reference number. 
 
 
An example of the format by which SAEs (including SUSARS) will be reported from 
sponsor to AZ. This should include the format of any individual reports (this may be 
the same form used for reporting SAEs above) and/or the format of quarterly listings if 
appropriate. 
 
 
The format by which site and patient ID will be presented in safety reports so that they 
can be entered in a consistent way on the AZ safety database. 
 
AstraZeneca will provide the sponsor with: 
 
The current IB  
An adverse event should only be considered expected for an AstraZeneca 
Investigational Medicinal Product (IMP) if it is included in Section 5.4 of the IB.  
These will be available to access through ES2ROS – Externally Sponsored Scientific 
Research Operations System 
 
 
The contact information for our safety reporting: astrazeneca@kinapse.com. All 
information that needs to be shared with AstraZeneca should be sent to Kinapse at 
the email address provided according to the guidelines set out in subsequent sections 
of this document. 
 
 
 

 
ADOPTION Study V1.8 07.07.21 
 
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During the Trial 
            Sponsor will: 
 Report unblinded Suspected Unexpected Serious Adverse Reactions (SUSARs) to 
AstraZeneca (via Kinapse) as individual case reports as they occur  
 Report blinded listings of Serious Adverse Events (SAEs) and Suspected Serious 
Adverse Reactions (SSAR’s) to AstraZeneca on a quarterly basis.  
 Inform AstraZeneca within 24 hours of knowledge of the event of any emerging safety 
data or actions that the Sponsor is considering as a result of a safety signal with the IMP.  
This includes but is not limited to:  
o Urgent safety measures to be implemented in the study 
o Safety amendments to protocol/patient information & informed consent 
o Open reports from Independent Data Monitoring Committees (IDMCs) 
excluding confidential reports to IDMC and minutes of IDMC meetings 
o Interactions with Regulatory Authorities (RA’s)/ Ethics Committees (EC’s) 
o Inform AZ on an ongoing basis of any new safety trends or signals observed 
during routine safety  surveillance activities 
 
 Include the following essential information in SUSAR, SSAR and SAE reports provided to 
AstraZeneca (initial and follow-up) :  
 
o AstraZeneca Reference number  
o Sponsor trial number 
o Centre number 
o Patient trial number 
o Year of birth or age 
o Sex 
o IMP(s) dose, start & stop date 
o SAE onset & stop date 
o Event term as reported by the investigator (and/or the CTCAE V4 term and 
grade) 
o Investigator’s assessment of seriousness (ICH definitions) 
o Investigator’s assessment of causality  
o SAE Outcome 
During the Trial 
 
           AstraZeneca will:  
 
 Immediately inform the sponsor of any emerging safety data or actions that AstraZeneca 
is considering as a result of a safety signal with the IMP.  This includes but is not limited 
to: 
o New safety information which may alter the benefit risk assessment  
o Urgent safety measures to be implemented 
 
 Request follow-up information on an SAE that is of interest and is related to the 
IMP(s). 
 Provide the Sponsor with IB updates on an annual basis or as new safety information 
emerges.  

 
ADOPTION Study V1.8 07.07.21 
 
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 Consult with the sponsor in the unlikely circumstance that code break information is 
required for an individual patient, should AstraZeneca need to expedite an SAE that 
has not been reported to RAs by the sponsor. 
 Provide SAE Line Listings of the IMP if required 
 
 
 
 
At the end of the Trial 
Sponsor will: 
 
Provide safety listings (details are included in the summary table below) 
 

 
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Summary of Minimum Requirements for Exchange of Safety Data 
           Sponsors will submit safety information in compliance with clinical trial regulations and the Standard Operating Procedures of their 
organisation including to: 
 Regulatory authorities 
 Ethics committees 
 Site investigators 
 
In addition, Sponsors will submit the following safety information to AstraZeneca: 
 
 
Category of Adverse Event/ 
Report 
Report Type 
When to send report 
to AZ 
 
Method of Submission 
 
 
Additional Information 
 
SUSARs 
 
Individual unblinded case 
reports 
(Initial and follow-up reports) 
 
Within one (1) 
business day of the 
reports being sent to 
the Regulatory 
Authority 
Email to: 
astrazeneca@kinapse.com 
 
 
Sponsor responsible for: 
 
Expedited reporting of all SUSARs to the RA of 
participating countries in line with local 
requirements.  
 
Compliance with local regulations of participating 
countries for reporting of SUSARs to 
investigational sites and EC’s. 
 
 AstraZeneca responsible for: 
 
Reporting SUSARs to RA’s where AstraZeneca 
sponsored studies are being conducted with the 
IMP as appropriate. 
 
Reporting SUSARs to investigators participating 
in any AstraZeneca sponsored studies with the 
IMP as required by RA’s. 
 

 
ADOPTION Study V1.8 07.07.21 
 
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SAEs/ SSARs 
 
Summary Line Listings 
 
On a quarterly basis 
from the date of the 
first patient consent 
 
SAEs and SSARs should be provided as blinded 
line listings. 
 
Where possible the listing should include only 
events that are new or updated since the last 
report.  
 
Category of Adverse Event/ 
Report 
Report Type 
When to send report 
to AZ 
 
Method of Submission 
 
 
 
Additional Information 
 
 
 
 
Annual DSUR – (EU only) 
 
 
 
 
Periodic safety reports 
(produced for external 
purposes e.g. EC or RA of 
participating countries) 
Only required if the 
DSUR is inconsistent 
with the IB. 
Contact your AZ 
operational representative 
 
Ideally any findings in the DSUR that are 
inconsistent with the IB should be communicated 
to AZ during DSUR production but at the latest in 
parallel to the DSUR being sent to the RA/Ethics 
committee. If this situation arises contact your AZ 
operational representative. 
 
 
The production of any DSUR with no new safety 
concerns should be confirmed in writing to your 
AZ operational representative.  
 
End of Study 
 
 
SAEs, SSARs & SUSARs 
(for entry onto AZ Patient 
Safety database) 
 
 
 
A cumulative final listing of 
all unblinded SAEs, SSAR’s 
& SUSARs 
At ‘clean file’  (when all 
study queries have 
been answered and 
the database is 
locked) at the following 
time points: 
1. At primary analysis 
2. After last patient 
has completed 
study treatment 
 
Email to: 
astrazeneca@kinapse.com 
and to AZ operational 
representative 
 
 
 
 
For blinded studies AZ require an unblinded 
listing of SAEs and SSARs to enable unblinding 
of these events on the AZ safety database.  
 
 
For convenience and completeness SUSARs 
should also be included and easily identifiable. 
 
 
 
 

 
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AstraZeneca will submit the following safety information to trial Sponsors:  
 
Category of Adverse Event/ 
Report 
Report Type 
Frequency/ 
Timeframe 
Method of Submission 
 
Additional Information 
 
SUSARs 
 
Final CIOMS report of case 
(password protected) 
 
Within 15 days of 
initial receipt 
Email to Sponsor contact. 
 These may be provided whilst clinical studies 
(AZ-sponsored or externally-sponsored) are on-
going or until the IMP becomes marketed. 
 AstraZeneca will provide these over the time 
period stated in the bullet point above to 
investigators, EC’s and relevant RAs involved in 
AstraZeneca sponsored studies.  
 Sponsor will distribute these to investigators and 
ECs in line with local requirements.  

       
 
  
 
                       
ADOPTION Study V1.7 20.11.20 
 
Page 78 of 78  
Contact Details 
 
AstraZeneca: 
 
Emerging safety data or actions: 
 
Email to: 
astrazeneca@kinapse.com 
 
 
General enquiries to AZ: 
 
 
AZ Operational or Scientific 
Representative 
 
The AstraZeneca Reference number and IMP name(s) should be included in 
email headers and emails should be sent in an encrypted file e.g. WinZip  
 
 
Sponsor responsibility:  
 
Periodic line listings notification:  Name of Trial Coordinator of Study:  
 
 
Sindu Sivarajan 
 
Address:  Renal Research Department 
 
 
       Whitechapel E1 1BB  
  
 
SAE follow-up queries: 
Name: Kieran McCafferty 
 
Email: kieran.mccafferty4@nhs.net 
 
Telephone:     07980620627 
  
 
Unblinded Request:  
Name: Dr Conor Byrne 
 
Email: conor.byrne1@nhs.net 
 
Telephone:     02073777000 
 
  
 
Only organisational emails may be used