Mechanistic Evaluation of Treatments for Acute Antibody-Mediated Rejection of the Kidney Transplant
Conditions: Transplant; Complication, Rejection
Sponsor: Imperial College London

Mechanistic Evaluation of Treatments for Acute Antibody-Mediated Rejection of the Kidney 
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M.O.T. AMR 
 
 
 
 
Mechanistic Evaluation of Treatments for Acute Antibody-Mediated 
Rejection of the Kidney Transplant 
 
 
 
Version 1.4 27/05/2020 
 
 
 
 
MAIN SPONSOR: Imperial College London 
FUNDERS:  
Imperial College BRC, Immunology theme will fund transplant biopsy analysis 
Cambridge University BRC will fund blood collection and storage for peripheral blood transcriptomics 
NIHR EME 129029 will fund transplant biopsy analysis, protocol biopsy procedure cost, and extra DSA testing 
Funding for peripheral blood transcriptomics and peripheral blood B cell assays: pending 
 
STUDY COORDINATION CENTRE: Imperial College JRCO number: 19HH5204 
NRES reference: 19/SW/0240 
IRAS Project ID: 264179 
 
 
 
Protocol authorised by: 
 
Name & Role 
Date 
Signature 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

Mechanistic Evaluation of Treatments for Acute Antibody-Mediated Rejection of the Kidney 
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Study Management Group 
 
Chief Investigator: Dr Candice Roufosse 
 
Co-investigators: Dr Michelle Willicombe, Dr Olivia Shaw, Dr Thomas Hiemstra, James 
Hutchinson (lay representative) 
 
Statistician: Dr Simon Bond 
 
Study Management: Dr Candice Roufosse 
 
 
Study Coordination Centre 
 
For general queries, supply of study documentation, and collection of data, please contact: 
 
Study Coordinator: Dr Candice Roufosse 
Address: Centre for Inflammatory Diseases, Imperial College, Hammersmith Campus, 
Commonwealth Building 9th floor, DuCane Road, London W12 0NN 
 
 
 
Tel: 020 3313 8252 
 
 
 
 
 
 
E-mail:  c.roufosse@imperial.ac.uk  
 
 
 
 
 
Clinical Queries 
 
Clinical queries should be directed to Dr Candice Roufosse who will direct the query to the 
appropriate person. 
 
 
Sponsor 
 
Imperial College London is the main research Sponsor for this study.  For further information 
regarding the sponsorship conditions, please contact the Head of Regulatory Compliance at: 
 
 
 
Joint Research Compliance Office 
Imperial College London and Imperial College Healthcare NHS Trust 
Room 215, Level 2, Medical School Building 
Norfolk Place 
London, W2 1PG 
Tel: 0207 594 1862 
 
 
Funder 
 
Imperial College BRC, Immunology theme will fund transplant biopsy analysis. 
Cambridge University BRC will fund blood collection and storage for peripheral blood 
transcriptomics. 
NIHR EME 129029 will fund transplant biopsy analysis, protocol biopsy procedure cost, and 
extra DSA testing 

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Funding for peripheral blood transcriptomics and peripheral blood B cell assays: pending 
 
Samples will be analysed in 4 centres: 
- 
Imperial College will co-ordinate sample collection; and store and carry out analyses 
on biopsy samples and serum samples 
- 
Cambridge University will store and carry out analyses on peripheral blood 
transcriptomic and genomic samples 
- 
Guys’ and St Thomas’ NHS Trust will store and carry out analyses on serum samples 
(DSA testing) 
- 
Birmingham University will store and carry out analyses on serum samples (BAFF 
testing) and peripheral blood B cell analyses 
 
This protocol describes the MOT-AMR study and provides information about procedures for 
entering participants.  Every care was taken in its drafting, but corrections or amendments may 
be necessary. These will be circulated to investigators in the study.  Problems relating to this 
study should be referred, in the first instance, to the Chief Investigator.  
 
This study will adhere to the principles outlined in the UK Policy Frame Work for Health and 
Social Care Research It will be conducted in compliance with the protocol, the Data Protection 
Act and other regulatory requirements as appropriate.  
 
 

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Table of Contents 
1. 
INTRODUCTION 
9 
1.1 BACKGROUND 
9 
2.  STUDY OBJECTIVES 
11 
3.  STUDY DESIGN 
12 
3.1 STUDY OUTCOME MEASURES 
14 
4. 
PARTICIPANT ENTRY 
15 
4.1 PRE-REGISTRATION EVALUATIONS 
15 
4.2 INCLUSION CRITERIA 
15 
4.3 EXCLUSION CRITERIA 
15 
4.4 WITHDRAWAL CRITERIA 
15 
5. 
ADVERSE EVENTS 
15 
5.1 DEFINITIONS 
15 
5.3 REPORTING PROCEDURES 
15 
6. 
ASSESSMENT AND FOLLOW-UP 
16 
7. 
STATISTICS AND DATA ANALYSIS 
16 
8. 
REGULATORY ISSUES 
17 
8.1 ETHICS APPROVAL 
17 
8.2 CONSENT 
17 
8.3 CONFIDENTIALITY 
18 
8.4 INDEMNITY 
18 
8.5 SPONSOR 
18 
8.6 FUNDING 
18 
8.7 AUDITS AND INSPECTIONS 
18 
9. 
STUDY MANAGEMENT 
18 
11. 
PUBLICATION POLICY 
19 
12. 
REFERENCES 
19 
EXAMPLE APPENDICES 
ERROR! BOOKMARK NOT DEFINED. 
APPENDIX 1. 
SUMMARY OF INVESTIGATIONS, TREATMENT AND ASSESSMENTSERROR! 
BOOKMARK NOT DEFINED. 
 
 
 

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GLOSSARY OF ABBREVIATIONS 
(A)(C)AMR 
(Acute)(Chronic) Antibody-Mediated Rejection 
BAFF 
B-cell activating factor 
C1q 
Complement factor 1q 
C3 
Complement factor 3 
C4d 
Complement factor 4d 
Cg 
Banff lesion score chronic glomerular 
Ci 
Banff lesion score chronic interstitial  
Ct 
Banff lesion score chronic tubular 
Cv 
Banff lesion score chronic vascular 
CTU 
Clinical Trials Unit 
DMEC 
Data Monitoring and Ethics Committee 
(dn)DSA 
(de novo) Donor specific antibodies 
(e)GFR 
(Estimated) Glomerular Filtration Rate 
EM 
Electron microscopy 
ENDAT 
Endothelial cell associated transcripts 
ESKD 
End stage kidney disease 
FPFV 
First patient first visit 
g score 
Banff Lesion score Glomerulitis 
GCP 
Good Clinical Practice 
GFR 
Glomerular Filtration Rate 
HLA 
Human Leucocyte Antigen 
ICF  
Informed Consent Form 
IFN 
interferon 
IFTA 
Interstitial fibrosis/tubular atrophy 
iIFTA 
Banff lesion score interstitial inflammation in areas of Interstitial 
fibrosis/tubular atrophy 
IMP 
Investigational Medicinal Product 
IVIg 
Intravenous immunoglobulins 
KRUK 
Kidney Research UK 
MFI 
Mean Fluorescence Index 
MVI 
Microcirculation inflammation 
MHRA 
Medicines and Healthcare products Regulatory Agency 
NK 
Natural killer 
NHSBT 
NHS Blood and Transplant registry 

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PEX 
Plasma exchange 
PIS 
Participant Information Sheet 
ptc score 
Banff Lesion score Peritubular capillaritis 
R&D 
Research and Development 
REC 
Research Ethics Committee 
RCT 
Randomised controlled trial 
RRT 
Renal Replacement Therapy 
SOC 
Standard of Care 
SOCR 
Standard of Care plus Rituximab 
t 
Banff lesion score interstitial inflammation in non-scarred areas 
TAR:GET-1 
Transplant Antibody Mediated Rejection: Guiding Effective Treatments 
clinical trial 
TCMR 
T-cell mediated rejection 
ti 
Banff lesion score interstitial inflammation in total cortex 
TMG 
Trial Management Group 
TSC 
Trial Steering Committee 
UPCR 
Urinary protein:creatinine ratio 
v score 
Banff lesion score Arterial inflammation 
 
 
KEYWORDS 
 
Kidney transplant, antibody-mediated rejection, transplant biopsy, gene expression analysis, 
donor-specific antibody, B cells 
 
 

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STUDY SUMMARY 
 
 
Title of Study: Mechanistic Evaluation of Treatments for Acute Antibody-Mediated 
Rejection of the Kidney Transplant 
Design: Prospective observational study of patients enrolled in TAR:GET-1 
Objectives: 
TAR-GET-1 (starting in 2019) is a multi-centre UK clinical trial that will compare 
standard of care (SOC) treatment of Acute Antibody-Mediated Rejection of the 
Kidney Transplant (AAMR) to standard of care plus rituximab (SOCR). This trial 
presents a rare opportunity to investigate the mechanisms of action of treatments 
(including rituximab) in AAMR. The rationale for using rituximab is the depletion of 
CD20-positive precursors to antibody-producing cells. However, rituximab has 
effects on other B cell subtypes and not all studies have shown antibody level 
reductions. Furthermore, AAMR is a heterogeneous disease, as defined by 
variability in mechanistic markers of AAMR in blood (B cell and antibody 
characteristics) and in transplant biopsies (histological features and gene 
expression).   
The objectives of this study are: 
 To investigate how treatment with rituximab affects these mechanistic 
markers, by comparing SOC to SOCR  
 To predict treatment benefit early, by analysing the effect of treatment on the 
mechanistic markers     
Methodology: 
In patients enrolled in TAR:GET-1 (n=170), we will analyse mechanistic markers 
with established proof of concept (B cell and antibody characteristics, histological 
and transcriptional markers in the biopsy) at baseline and on follow-up, making 
use of clinical data, surplus diagnostic material from TAR:GET-1, and material 
from  optional extra blood samples for research taken as part of TAR:GET-1, at 3,6 
and 12 months. We will also offer an optional protocol biopsy at 6 months post 
treatment. Differences pre- and post-treatment will be analysed comparing SOC 
and SOCR. We will use mediation analysis models to decompose total effect of 
treatment effect on graft loss at 4 years (primary end point) into an indirect effect, 
which measures how much of the effect acts through the intermediate variable(s), 
and a residual direct effect.    
Number of Subjects and Study populations: 170 subjects enrolled in TAR:GET-
1 
 
Outcome measures: same as primary outcome of TAR:GET-1 (graft loss at 4 years 
after initiation of treatment) 
 
Inclusion Criteria: 
All patients enrolled in TAR:GET-1 
Signed informed consent prior to any study specific procedures. 
 

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Exclusion Criteria: 
None 
 
Investigational Product:  N/A 
 
Duration of study: 8 years (duration is dictated by the need for primary outcome 
of TAR-GET-1 to be reached) 
 
Statistical Methods: 
 
Data from this research project will be merged and linked with data from the 
TAR:GET-1 clinical trial by the statistician team.  
 
Descriptive data  
 
This will include description of all the biological characteristics analysed in 2 
populations (rituximab + SOC and SOC) at baseline and at all follow-up time points. 
Summary statistics (mean, median, SD, range for continuous variables, and 
frequency tables for categorical variables) will be reported broken down by 
treatment, with exploratory figures (box-and-whisker plots for continuous, and 
stacked bar-charts for categorical).   
 
Outcome analysis   
 
Appropriate measures of differences between treatment groups will be estimated 
with point estimates, 95% confidence intervals, and p-values. Depending on the type 
of variable (continuous, categorical, time-to-event), regression techniques (linear, 
logistic, cox) and transformation of the endpoints will be considered.   
 
Differences in characteristics comparing pre- to post-treatment samples at 
sequential time points will be analysed comparing the 2 groups of patients (SOCR 
versus SOC) using r mixed effect models repeat measurement techniques.   
 
Mediation analysis, a special case of regression analysis, will be used to document 
that the treatment effects a change in the biomarker. We will use mediation analysis 
models to decompose total effect of treatment effect on graft loss into an indirect 
effect, which measures how much of the effect acts through the intermediate 
variable(s), and a residual direct effect. All the mediation analyses will be based on 
the Intention-to-Treat principle. We will fit the same form of outcome models as for 
the efficacy analyses, including the mediator as a covariate. We will use the 
mediation package within R which was developed specifically to make valid causal 
inference in explanatory analyses of the mechanisms of treatment-induced change 
in clinical outcomes in randomised clinical trials. All estimates of treatment 
differences will be summarised using effect size estimates and 95% confidence 
intervals (Dunn 2013). Collaborator for mediation analysis: Prof Ian White, Professor 
of Statistical Methods for Medicine, UCL.  
 
 
 

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1. 
INTRODUCTION  
 
1.1 
BACKGROUND 
 
Impact of Antibody-mediated rejection (AMR) on kidney allograft survival   
Kidney transplantation is the treatment of choice for patients with end stage kidney disease 
resulting in improved health, patient survival and quality of life (Gibbons 2016), as well as 
health economic benefit in comparison to remaining on dialysis (Baboolal 2008). The UK 
adult prevalence of renal replacement therapy (RRT) is 962 per million population 
(pmp)(Renal Registry Report 2017). The UK prevalent transplant population in 2016 was 
34,286 (Pyart 2018).  
The use of current immunosuppression regimens, along with careful immunological selection 
of transplant recipients, has improved short term renal allograft survival. However long term 
allograft survival remains unchanged, with the average lifespan of a kidney transplant up to 
15 years at most (Meier-Kriesche 2004). Rejection is an important cause of transplant 
failure, mostly due to chronic AMR (Loupy 2018).  
  
TAR:GET-1 : a clinical trial for the treatment of AAMR  
There is currently no high quality evidence from randomised trials to guide treatment of 
acute AMR (Velidedeoglu 2018). Clinical trials of existing and new drugs for AMR are a 
recognised priority for patients and researchers in the transplant community, as noted in the 
NIHR James Lind Alliance priority setting partnership 2016 (www.transplantpsp.org). The 
recently published UK Renal Research Strategy document (drafted following extensive 
patient and public consultation) similarly highlights the complete lack of evidence in treating 
AAMR and identifies this as a key research priority 
(www.kidneyresearchuk.org/research/ukkrc). This need for trials in acute AMR is recognised 
globally; the US FDA convened workshops aimed at assessing AMR treatments during 2010 
and 2017 (Velidedeoglu 2018).   
The TAR:GET-1 trial is due to start in early 2019. This trial provides a time-limited 
opportunity to carry out research into the mechanisms of action of rituximab in acute AMR 
(AAMR), which are poorly understood, using samples accrued in a randomised controlled 
trial, with uniform treatment and follow-up. 
 
MOT-AMR : a time-limited opportunity to advance our understanding of the mechanisms 
under-pinning AMR and how treatments affect them 
Kidney transplantation occurs most frequently across a degree of HLA incompatibility. 
Despite immunosuppression, this HLA disparity frequently leads to B cell activation and 
production of donor-specific antibodies (DSA), some of which cause antibody-mediated 
injury to the graft. In addition, depending on local protocols, some recipients already have 
antibodies against the HLA epitopes of the graft before transplantation (sensitised patients 
with pre-formed antibodies and positive cross match transplantation) (Lefaucheur 2008).   
 
A diagnosis of AAMR rests on the identification of serum DSA plus the presence in the graft 
biopsy of specific histological and/or transcriptional features related to the effect of antibody 
on the graft endothelium (Haas 2018a). The biopsy is necessary to prove that graft 
dysfunction is being caused by the antibody, as not all DSA cause injury. These diagnostic 
features are predictive of outcome and are used to enrol patients in clinical trials of AAMR.  
However, AAMR is a heterogeneous disease, as defined by variability in mechanistic 
markers of AAMR in blood (B cell and antibody characteristics) and in transplant biopsies 
(histological features and gene expression).  In addition, individual variations in genes 

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involved in co-ordinating the patient’s immune response (e.g. Fc gamma receptors) may 
influence B cell activation (Steri 2017; Andres Floto 2005).  
 
Rituximab is a chimeric murine-human monoclonal antibody directed against the B-cell 
surface molecule CD20, which depletes B cells with CD20 on their surface. Use of Rituximab 
in AMR has been developed on the basis that, following a primary challenge, in the presence 
of rituximab, B cells would be prevented from undergoing proliferation and would undergo 
apoptosis via complement-mediated and complement independent mechanisms. This may 
lead to reduction in antibody titre, and reduced antibody-mediated graft injury (Fehr 2009; Vo 
2010). However, on the one hand, the effects of rituximab on the immune system are wider 
ranging, and on the other hand, the limited studies that have investigated response to 
rituximab have not consistently demonstrated the expected effect (Gudbrandsdottir 2018, 
Cornec 2016, Ehrenstein 2016, Ikemiyagi 2017, Pallier 2010). Investigations of the 
transcriptional profile of peripheral blood B cells and B cell regulatory potential show promise 
in elucidating the link between B cell phenotype and AMR (Clatworthy 2009 and 2014, 
Banham 2018). 
This research will investigate the effect of rituximab along the pathophysiological pathway of 
development of AMR: changes in B cell characteristics; changes in anti-donor antibody titres 
and characteristics; and changes in histological and transcriptional evidence of AMR in the 
graft tissue. A better understanding of the mechanisms of rituximab in comparison to 
standard of care will provide evidence for its use in AAMR, and may provide information on 
the characteristics of patients with AAMR that are likely to respond to the drug, and 
information on how to measure response to the drug. These are vital to improving an 
effective and efficient use of drugs in treating AAMR.  
 
 
 
1.2 
RATIONALE FOR CURRENT STUDY 
 
This research proposal is a bolt-on mechanistic study, affiliated to an NIHR HTA/Kidney 
Research UK-funded UK multicentre randomised controlled trial to assess the safety and 
efficacy of rituximab + standard of care (SOCR) compared with SOC in treating acute 
antibody-mediated rejection (AAMR) in kidney transplantation (TAR:GET-1)(Transplant 
Antibody Mediated Rejection: Guiding Effective Treatments; ISRCTN pending, EudraCT ref 
2018-002882-20). This phase 3, 2-arm, open-label randomised controlled trial will enrol 
patients with biopsy-proven AAMR and randomise them to SOCR versus SOC (85 patients in 
each arm). The trial is scheduled to start in Spring 2019, and patients will be recruited over 40 
months, then followed up for 4 years post treatment (follow up complete late 2026). The 
primary objective is efficacy, with graft survival at 4 years the primary end point.  
 
Analysis of B cell, antibody and biopsy characteristics of patients enrolled in TAR:GET-1 will 
address several questions:  
 
1) Which patients with a diagnosis of AMR require additional immunosuppression?  
 
It is recognised that AAMR is a heterogeneous disease, and there is evidence that severity 
of the individual diagnostic features at presentation (HLA antibody strength, biopsy Banff 
scores) is associated with outcome. Novel parameters not yet used in routine diagnosis also 
hold promise in increasing diagnostic accuracy and directing treatment; these include 
complement-activating ability of DSA (Viglietti 2017, Sicard 2015, Bouquegneau 2018), the 
AAMR-related gene expression signature level (Loupy 2014, Halloran 2016), and B cell 
characteristics (genomic, transcriptional and functional). The data from past investigations is 
contradictory, most often derived from retrospective observational studies without uniform 

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follow-up and treatment, and often lacks robust multivariate analyses. There is insufficiently 
robust evidence to promote risk stratification and selection of patients for additional 
treatment.  
 
2) How can we tell if treatment is working?  
 
Serial measurements of the strength of DSA and severity of biopsy features have been used 
to describe the natural history of AAMR and to determine response to treatments, including 
rituximab. There is evidence in the literature that treatment of AAMR may reduce antibody 
strength and/or affect complement-activating ability (Cioni 2018, Viglietti 2018b, Bailly 2018, 
Lefaucheur 2018) and may have a positive effect on biopsy scores (Viglietti 2018a, 
Sautenet 2016, Eskandary 2018, Choi 2017) or transcript levels (Eskandary 2018, 
Lefaucheur 2018). Immunosuppression can induce changes in B cell gene expression and 
functional profile (Banham 2018). However, the evidence is inconclusive and in places 
contradictory, and has not been validated in the context of randomised controlled trials. 
Therefore, serial measurements are not yet used to guide treatment decisions.   
 
3) The need for surrogate endpoints for clinical trials in AMR  
 
Given that the end point for trials in AAMR (graft loss) is remote, development of surrogate 
end points for AAMR trials is a priority (Velidedeoglu 2018). Longitudinal assessment of 
biomarkers in patients with AAMR has been shown to assist in outcome prediction, but here 
again data is limited (Viglietti 2018a). This project provides an opportunity to investigate 
potential surrogate markers of outcome.   
 
 
This MOT-AMR research proposal has 2 hypotheses:  
 
Hypothesis 1: AMR is a heterogeneous disease, with outcome and response to treatment 
accurately predicted by mechanistic biomarkers (B cell, DSA and biopsy features) at baseline, 
including more recently characterised complement-activating ability of DSA and AAMR gene 
expression biopsy signature.   
 
Hypothesis 2: Although the clinical endpoint of TAR:GET-1 is graft loss, effective AAMR 
therapy will be reflected in changes in mechanistic features in serum and in biopsies. In the 
case of treatment with rituximab, this is achieved through favourable changes in B cell 
characteristics.   
 
2.  STUDY OBJECTIVES 
 
 
The primary objective is to investigate the mechanisms of treatments including rituximab in 
AAMR, by measuring the effect of SOCR versus SOC on mechanistic markers of AMR (B cell 
characteristics, antibody characteristics, end organ damage assessed by histology and 
transcript analysis)  
 
The secondary objective is to predict treatment benefit early, by decomposing the effect of 
treatment on graft loss at 4 years (primary end point) into an indirect effect, which measures 
how much of the effect acts through the changes in mechanistic markers, and a residual direct 
effect.     
 

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3.  STUDY DESIGN 
 
 
Patient Cohort  
This is a prospective cohort study using samples from all patients enrolled in the TAR:GET-1 
(170 patients, 85 in each arm). The TAR:GET-1 trial will recruit patients starting in June 
2019, over a period of 4 years, and patient will be followed up with further biological samples 
taken over a further period of 4 years. This will need to be analysed for which we estimate a 
further 2 years. The total duration of the study is therefore 10 years starting June 2019. 
 
We aim to collect all samples from each patient to maximise the information obtained, whilst 
incurring negligible extra risk to the study participants.  
Some of the samples are already obtained as part of the TAR:GET-1 protocol and we will 
use left over material to carry out analyses.  
Some of the samples are not routinely obtained for TAR:GET-1 enrolment, but the 
TAR:GET-1 protocol and consent process covers their (optional) collection.  
The only extra samples that requires a new consent process as part of M.O.T.-AMR is an 
optional post-treatment protocol biopsy. 
 
The study aim is to be a comprehensive assessment of antibody-mediated rejection 
biomarkers pre- and post-treatment, but has below been artificially divided into Parts 1 and 
2, Part 1 being funded by Imperial BRC, Cambridge BRC and NIHR EME (funding secured) 
whereas applications for funding for Part 2 are in process. A funding approval letter will be 
provided to the Sponsor and REC committee prior to commencing any element of part 2 of 
the study, and will specify which further specific elements of the study have received funding 
approval. 
 
Samples taken as part of TAR:GET-1: 
Patients enrolled in TAR:GET-1 will have a number of samples taken, and consent for 
enrolment in TAR:GET-1 includes agreement to the use of extra material left after diagnosis 
for research. We will therefore be able to access in 100% of patients enrolled in TAR:GET-1: 
- 
Enrolment biopsy material 
- 
Serum samples taken for DSA measurements 
- 
Post-treatment indication biopsies taken as part of routine clinical care.  
TAR:GET-1 is already assessing DSA MFI, DSA target and B lymphocyte numbers at 
baseline and 3 months post-treatment. In addition to these,M.O.T.-AMR will analyse in left 
over material from these routine samples: 
 
1) Serum DSA characteristics at an extra timepoint (costs not covered in TAR:GET-1; 1 
year), plus more detailed DSA analyses at all 3 timepoints including not only anti-HLA 
antibodies (IgG subtype, complement-activating ability) but also non-HLA antibodies;   
 
2) Biopsy Banff histological scores (Roufosse 2018); The following data will be obtained for 
each biopsy: 
• 
Total number of glomeruli 
• 
Number of glomeruli with global sclerosis 
• 
Number of glomeruli with segmental sclerosis 
• 
Number of scorable glomeruli (excluding those with global/segmental 
sclerosis and ischaemic changes) 
• 
Percentage of cortical scarring [tubular atrophy, interstitial fibrosis] 

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• 
Full Banff lesion scores (t,i,ti,v,g,ptc,ct,ci,cg,cv,ah, C4d) and the  
microcirculation inflammation score (MI=g+ptc) 
• 
Extent of peritubular capillary inflammation (% of cortex) 
• 
Number of glomeruli with glomerulitis  
• 
Number of glomeruli with capillary wall double contours 
• 
Result of SV40 immunostain (positive/negative) 
• 
Banff Classification for Allograft Pathology diagnostic category(ies) and 
subcategory(ies) 
• 
Ultrastructural features: presence and distribution of electron dense deposits; 
extent of foot process effacement; extent of glomerular and peritubular 
capillary basement membrane mulitlayering; extent of ultrastructural 
endothelial activation; presence of tubuloreticular inclusions 
• 
If performed, immunofluorescence staining pattern for IgG, IgA, IgM, C3, C1q, 
kappa light chain and lambda light chain; 
 
3) Biopsy gene expression with be assessed using Nanostring nCounter technology (Adam 
2016; Dominy 2019); this will include the AMR-gene expression signature (Haas 2018), and 
a B cell signature. As literature is evolving and it is possible to test for hundreds of genes on 
the same sample, the list of genes to be studied may evolve. 
 
4) Serum BAFF (B cell activating factor) levels 
 
Funding: 
Part 1 (covered by Imperial BRC, Cambridge BRC and NIHR EME 129029): Shipping of the 
samples, 1), 2) and 3). 
Part 2: 1) and 4); we will be applying to other funding sources, including Kidney Research 
UK and local NHS Trust research charity funds.  
 
Optional samples covered by TAR:GET-1 consent process 
 
The additional samples are optional and M.O.T.-AMR is not dependent on them being 
obtained. As part of TAR:GET-1, patients will be offered the option of contributing extra 
tubes of blood at baseline, 3 months, 6 months and 1 year, and may decline any of them or 
all of them.  
The extra samples will be: 1) lithium heparin tubes for PBMC isolation in order to carry out B 
cell immunophenotyping (flow cytometry); peripheral blood B cell stimulation assay 
(stimulation assay utilising intracellular staining for IL10 and IL6 and deriving a ratio to study 
regulatory potential of peripheral blood B cells)(Banham 2018)(extra tube of blood at 3 time 
points, fresh sample needed); and DNA analysis; and 2) PAXgene tubes for peripheral blood 
transcriptomics (whole blood transcriptomic analysis)(extra tube of blood at 3 time points). 
 
Samples for 1) need to be shipped rapidly and we do not expect to take these samples until 
funding is secured, so estimate 50% of patients will contribute these, in the later stages of 
the trial. Samples for 2) can be frozen and batch-shipped so we expect them to be obtained 
in about 90% of patients. 
 
Funding: 
Part 1: Funding for taking and shipping of the PAXgene tubes will be covered by Cambridge 
BRC.  
Part 2: We are applying for funding for the lithium heparin tube samples, and their collection 
will not be started until funding is secured. We are also applying for funding for the transcript 
analysis and DNA analysis. 
 

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Optional post-treatment renal transplant protocol biopsy 
 
Specifically for M.O.T-AMR, patients enrolled in TAR:GET-1 will be offered an 
optional protocol biopsy at 6 months post-treatment. This additional sample is optional and 
M.O.T.-AMR is not dependent on it being obtained. This protocol biopsy will be carried out in 
the local centre, by the local clinical team. A post-treatment protocol biopsy is a biopsy taken 
in a patient with stable transplant function and no indication for a biopsy to be taken. The 
literature suggests that this a useful tool for monitoring response to treatment (Viglietti 
2018a), but strong evidence from randomised controlled trials such as TAR:GET-1 is lacking 
for its routine introduction into clinical care and therefore, in most centres a post-treatment 
protocol biopsy is not offered to patients. The protocol biopsy will be collected for research 
and costed as research. Biopsy results on these protocol biopsies will be made available to 
the clinicians if any unexpected findings that need to be acted upon for patient benefit are 
noted.  We will carry out the same histological and transcriptional investigations on these 
biopsies as for the enrolment and indication biopsies. A conservative estimate of protocol 
biopsy acceptance is 50%, based on our local experience (85 samples), and this is the 
number of samples we aim to achieve. 
 
Funding: 
Part 2: Funding for taking these biopsies is covered by NIHR EME 129029. Shipping and 
analysis will be partly covered by Imperial BRC. 
 
This table illustrates how visits and samples in TAR:GET-1 will be used for investigations in 
M.O.T.-AMR. The additional samples needed for M.O.T.-AMR are in italic. 
 
TAR:GET-1 trial 
visits  
Baseline  
Unscheduled 
Visit 3 ( month 
3)  
Visit 4 ( month 
6)   
Visit 5 
(month 12)  
Biopsy histology 
and gene 
expression 
analysis 
Use leftover 
sample  
Indication biopsy for 
graft dysfunction: 
Use leftover 
samples 
 
 
Optional 
protocol biopsy  
 
 
Serum DSA 
characteristics and 
BAFF  
Use leftover 
sample  
Use leftover 
sample  
 
Use leftover 
sample  
B cell 
characteristics and 
Peripheral blood 
transcriptomics 
2 extra blood 
tubes  
2 extra blood 
tubes  
2 extra blood 
tubes  
2 extra blood 
tubes  
 
 
Sample storage: 
Central storage will be at Imperial College. Samples will be dispatched to other centres for 
processing. Samples will be stored at Imperial College and Cambridge University, using -
80C freezers for frozen samples and room temperature storage for slides and paraffin 
blocks. For B cell immunophenotyping, we will have samples sent fresh to Birmingham 
University for PBMC preparation, immediate flow cytometry, and storage of left over frozen 
PBMC. Samples may also be stored at Viapath. 
 
3.1 
STUDY OUTCOME MEASURES 
 

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Primary outcome is graft survival 4 years post-treatment. 
 
4. 
PARTICIPANT ENTRY  
 
4.1 
PRE-REGISTRATION EVALUATIONS  
 
None 
 
4.2 
INCLUSION CRITERIA 
 
All patients enrolled in TAR:GET-1 are eligible.  
 
4.3 
EXCLUSION CRITERIA 
 
None. If some patients decline extra samples to be taken for research, we can still analyse 
left over tissue from routine clinical samples for some aspects of the study. 
 
4.4 
WITHDRAWAL CRITERIA 
 
 
Subject decision. A subject is free to withdraw consent and discontinue participation in 
the study at any time 
 
Patients who withdraw from TAR:GET-1 will also be withdrawn from MOT-AMR and 
withdrawal criteria is the same as TAR:GET-1. 
 
5. 
ADVERSE EVENTS 
 
5.1 
DEFINITIONS   
Adverse Event (AE): any untoward medical occurrence in a patient or clinical study subject.   
 
Serious Adverse Event (SAE): any untoward and unexpected medical occurrence or effect 
that: 
 
Results in death 
 
Is life-threatening – refers to an event in which the subject 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 
 
 
Requires 
hospitalisation, 
or 
prolongation 
of 
existing 
inpatients’ 
hospitalisation 
 
Results in persistent or significant disability or incapacity 
 
Is a congenital anomaly or birth defect 
 
Medical judgement should be exercised in deciding whether an AE is serious in other 
situations.  Important AEs that are not immediately life-threatening or do not result in death or 
hospitalisation but may jeopardise the subject or may require intervention to prevent one of 
the other outcomes listed in the definition above, should also be considered serious. 
 
5.3 
REPORTING PROCEDURES 
All adverse events should be reported.  Depending on the nature of the event the reporting 
procedures below should be followed.  Any questions concerning adverse event reporting 
should be directed to the Chief Investigator in the first instance.   
 
5.3.1 Non serious AEs 
All such events, whether expected or not, should be recorded.   

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5.3.2 Serious AEs 
An SAE form should be completed and faxed to the Chief Investigator within 24 hours.  
However, relapse and death due to transplantation, and hospitalisations for elective treatment 
of a pre-existing condition do not need reporting as SAEs. 
 
All SAEs should be reported to the South West -Frenchay Research Ethics Committee where 
in the opinion of the Chief Investigator, the event was: 
 
‘related’, ie resulted from the administration of any of the research procedures; 
and 
 
‘unexpected’, ie an event that is not listed in the protocol as an expected 
occurrence 
 
Reports of related and unexpected SAEs should be submitted within 15 days of the Chief 
Investigator becoming aware of the event, using the NRES SAE form for non-IMP studies.  
The Chief Investigator must also notify the Sponsor of all SAEs. 
 
Local investigators should report any SAEs as required by their Local Research Ethics 
Committee, Sponsor and/or Research & Development Office. 
 
Contact details for reporting SAEs 
jrco@imperial.ac.uk 
 
 
 
6. 
ASSESSMENT AND FOLLOW-UP  
 
Assessment and follow-up of subjects is part of the TAR:GET-1 trial. 
 
 
7. 
STATISTICS AND DATA ANALYSIS 
 
 
The patient cohort size is dictated by TAR:GET-1: 170 patients, 85 in each arm. Under 
plausible modelling assumptions, for any biomarker that is on the mechanistic pathway 
between treatment and primary outcome, the power of the main study (90%) will be matched 
or exceeded when comparing the mean biomarker values between treatment groups. The 
mediation analysis will estimate for each biomarker the influence on allograft survival rate 
per unit change in biomarker, above and beyond, the direct effect of treatment. This will 
decompose the overall, marginal, treatment effect into a proportion attributable to a 
mechanism via the biomarker, and the compliment attributable to direct effects, or 
other mechanisms. A similar multivariable analysis will proceed to estimate the mediation 
effects of multiple biomarkers acting in parallel, as an exploratory analysis using variable 
selection methods to control for over-fitting.  
 
Data from this research project will be merged and linked with data from the TAR:GET-1 
clinical trial by the statistician team.  
 
Descriptive data  
 

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This will include description of all the biological characteristics analysed in 2 populations 
(rituximab + SOC and SOC) at baseline and at all follow-up time points. Summary statistics 
(mean, median, SD, range for continuous variables, and frequency tables for categorical 
variables) will be reported broken down by treatment, with exploratory figures (box-and-
whisker plots for continuous, and stacked bar-charts for categorical).   
 
Outcome analysis   
 
Appropriate measures of differences between treatment groups will be estimated with point 
estimates, 95% confidence intervals, and p-values. Depending on the type of variable 
(continuous, categorical, time-to-event), regression techniques (linear, logistic, cox) and 
transformation of the endpoints will be considered.   
 
Differences in characteristics comparing pre- to post-treatment samples at sequential time 
points will be analysed comparing the 2 groups of patients (SOCR versus SOC) using r 
mixed effect models repeat measurement techniques.   
 
Mediation analysis, a special case of regression analysis, will be used to document that the 
treatment effects a change in the biomarker. We will use mediation analysis models to 
decompose total effect of treatment effect on graft loss into an indirect effect, which 
measures how much of the effect acts through the intermediate variable(s), and a residual 
direct effect. All the mediation analyses will be based on the Intention-to-Treat principle. We 
will fit the same form of outcome models as for the efficacy analyses, including the mediator 
as a covariate. We will use the mediation package within R which was developed specifically 
to make valid causal inference in explanatory analyses of the mechanisms of treatment-
induced change in clinical outcomes in randomised clinical trials. All estimates of treatment 
differences will be summarised using effect size estimates and 95% confidence intervals 
(Dunn 2013). Collaborator for mediation analysis: Prof Ian White, Professor of Statistical 
Methods for Medicine, UCL 
 
Data and all appropriate documentation will be stored for a minimum of 10 years after the 
completion of the study, including the follow-up period.   
 
 
8. 
REGULATORY ISSUES 
 
8.1 
ETHICS APPROVAL 
The Chief Investigator has obtained approval from the Health Research Authority (HRA) and 
Research Ethics Committee.  The study must also receive confirmation of capacity and 
capability from each participating NHS Trust before accepting participants into the study. The 
study will be conducted in accordance with the recommendations for physicians involved in 
research on human subjects adopted by the 18th World Medical Assembly, Helsinki 1964 and 
later revisions. 
 
8.2 
CONSENT  
 
 
As part of the consent procedure for enrolment in TAR:GET-1 patients will: 
- 
Consent for use of left over material from samples taken as part of TAR:GET-1 to be 
used for research 
- 
Consent to be offered optional extra tubes of blood for research during the scheduled 
blood drawing events of TAR:GET-1 

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We will separately obtain consent for use of TAR:GET-1 samples for this specific project 
(M.O.T.-AMR), and for an optional post-treatment protocol biopsy at 6 months after initiation 
of treatment. 
 
The ICF and process for obtaining informed consent must comply with the applicable national 
and international laws, rules, and regulations. The ICF will document the study-specific 
information the Investigator or his/her designee provides to the subject and the subject’s 
agreement to participate in the study and to comply with the instructions of the Investigator 
and study staff. The Investigator/designee will fully explain, in terms understandable to the 
subject, the nature of the study, along with the aims, methods, anticipated benefits, potential 
risks, and any discomfort that participation in the study may entail. The ICF must be signed 
and dated by the subject before the subject participates in any study-related activities. The 
original and any amended signed and dated ICFs must be retained in the subject’s file at the 
study site, and a copy must be given to the subject at the time that it is signed by the subject. 
The Investigator must also maintain a log of all informed consents obtained. 
 
Consent to enter the study must be sought from each participant only after a full explanation 
has been given, an information leaflet offered and time allowed for consideration.  Signed 
participant consent should be obtained.  The right of the participant to refuse to participate 
without giving reasons must be respected.  After the participant has entered the study the 
clinician remains free to give alternative treatment to that specified in the protocol at any stage 
if he/she feels it is in the participant’s best interest, but the reasons for doing so should be 
recorded.  In these cases the participants remain within the study for the purposes of follow-
up and data analysis.  All participants are free to withdraw at any time from the protocol 
treatment without giving reasons and without prejudicing further treatment. 
 
8.3 
CONFIDENTIALITY 
The Chief Investigator will preserve the confidentiality of participants taking part in the study 
and is registered under the Data Protection Act. 
 
8.4 
INDEMNITY 
Imperial College London holds negligent harm and non-negligent harm insurance policies 
which apply to this study/ Imperial College Healthcare NHS Trust holds standard NHS Hospital 
Indemnity and insurance cover with NHS Resolution for NHS Trusts in England, which apply 
to this study (delete as applicable) 
 
8.5 
SPONSOR 
Imperial College London will act as the main Sponsor for this study.  Delegated responsibilities 
will be assigned to the NHS trusts taking part in this study.   
 
8.6 
FUNDING 
Funding for some aspects of the research will be provided by the Imperial Biomedical 
Research Centre (Immunology theme), the Cambridge BRC, and NIHR EME. 
Applications for funding of some aspects of the study are still on-going. 
  
 
8.7 
AUDITS  
The study is subject to inspection and audit by Imperial College London under their remit as 
sponsor, the Study Coordination Centre and other regulatory bodies to ensure adherence to 
GCP. 
 
9. 
STUDY MANAGEMENT 
 

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The day-to-day management of the study will be co-ordinated through Dr Candice Roufosse 
at Imperial College, Centre for Inflammatory Diseases. 
 
10. 
PUBLICATION POLICY 
 
After conclusion of the study, Investigators in this study may communicate, orally present, or 
publish in scientific journals or other scholarly media, the results of the study. 
 
10. 
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