Condition category
Injury, Occupational Diseases, Poisoning
Date applied
12/11/2018
Date assigned
11/03/2019
Last edited
15/03/2019
Prospective/Retrospective
Retrospectively registered
Overall trial status
Ongoing
Recruitment status
Recruiting

Plain English Summary

Background and study aims
Antibody-mediated rejection (AMR) is when the immune system of the person who has received a transplanted organ, known as the recipient, produces antibodies against the organ. This can lead to damage to the organ so that it does not function well. AMR is the leading cause of kidney transplant failure. How to best treat AMR is not known. Different treatment combinations are used across the world. This study aims to investigate whether a drug called rituximab, when added to the usual treatment for AMR, can improves transplant survival. Rituximab works by reducing the numbers of B cells, the white blood cells that produce antibodies. This drug is widely used in transplantation and in other diseases involving B cells.

Who can participate?
Patients aged 5 years or older with AMR of their kidney transplant

What does the study involve?
All patients will receive treatment accepted as standard of care for AMR. This involves the use of plasma exchange (a process that removes antibodies from a patient’s body), together with steroids (to suppress immune system activity) and immunoglobulins (which inactivate antibodies). This treatment is given over approximately 2-3 weeks. One half of the patients will be allocated at random to receive rituximab. Rituximab is given through a patient’s vein, and is administered in 2 separate doses, 2 weeks apart. After treatment, all patients will be followed up for a period of 4 years and have their transplant function monitored. Study visits will coincide with the usual hospital appointments.

What are the possible benefits and risks of participating?
There are no guaranteed benefits of taking part in the study. Use of immunosuppressants (drugs that reduce the activity of the immune system) leads to an increased risk of infection and cancer compared with the general population. All patients, regardless of whether they participate in the trial or not, will require immunosuppression to treat AMR. The side effects of rituximab include that in patients who have previously had hepatitis B, the infection might be reactivated. Patients with active hepatitis will be excluded and patients who have previously had hepatitis B will be included or excluded from the trial on the decision of the researchers. There is also a very small chance of the brain condition progressive multifocal leukoencephalopathy (PML) with rituximab, but research suggests that this occurs in less than one in 25,000 people taking rituximab.

Where is the study run from?
The study is planned to take place across approximately 24 different hospitals, with Imperial College Healthcare NHS Trust being the lead centre.

When is the study starting and how long is it expected to run for?
November 2018 to February 2026

Who is funding the study?
The study is funded jointly by Kidney Research UK and the National Institute for Health Research.

Who is the main contact?
The chief investigator is Dr Michelle Willicombe and the trial contact is Dr Ashley Foster, ashley.foster@addenbrookes.nhs.uk.

Trial website

Contact information

Type

Public

Primary contact

Dr Ashley Foster

ORCID ID

Contact details

Cambridge Clinical Trials Unit
Coton House
Level 6
Box 401
Cambridge University Hospitals NHS Foundation Trust
Addenbrooke’s Hospital
Hill’s Road
Cambridge
Cambridge
CB2 0QQ
United Kingdom
01223 216809
ashley.foster@addenbrookes.nhs.uk

Additional identifiers

EudraCT number

2018-002882-20

ClinicalTrials.gov number

Nil known

Protocol/serial number

1.0; CPMS 40785

Study information

Scientific title

Transplant Antibody Mediated Rejection: Guiding Effective Treatments (TAR:GET-1): A multicentre randomised controlled trial to assess the safety and efficacy of rituximab compared with control in treating acute antibody-mediated rejection in kidney transplantation

Acronym

TAR:GET-1

Study hypothesis

The study aims to test the hypothesis of whether rituximab in addition to standard of care treatment (plasma exchange, IVIG and corticosteroids) is more effective than standard of care alone in treating antibody-mediated rejection of kidney transplants.

Ethics approval

Ethics submission is planned for November 2018

Study design

Multicentre phase 3 open-label randomised controlled trial

Primary study design

Interventional

Secondary study design

Randomised controlled trial

Trial setting

Hospitals

Trial type

Treatment

Patient information sheet

Not available in web format at this time.

Condition

Antibody-mediated kidney transplant rejection

Intervention

Patients will be stratified by age and kidney transplant function and randomised at a 1:1 ratio to receive standard of care treatment alone or standard of care plus rituximab. All patients will receive standard of care treatment, which involves 7 plasma exchanges, intravenous immunoglobulins and corticosteroids (3 doses intravenous methylprednisolone followed by oral corticosteroids). This treatment will occur over a 2- to 3-week period. Those in the rituximab group will also receive rituximab dosed at 2 x 375 mg/m2, given 2 weeks apart. Each patient will be followed up for a period of 48 months following randomisation.

Intervention type

Drug

Phase

Phase III

Drug names

Rituximab

Primary outcome measure

Allograft survival, defined as the duration from the date of randomisation to the date of starting dialysis dependency or date of eGFR <15 mL/min/1.73 m2, with follow-up of 48 months.

Secondary outcome measures

1. Serum creatinine ) at 1, 3, 6, and 12 months post-randomisation and then annually until 4 years
2. Estimated GFR (CKD-EPI) ) at 1, 3, 6, and 12 months post-randomisation and then annually until 4 years
3. Proteinuria (urinary protein:creatinine ratio) ) at 1, 3, 6, and 12 months post-randomisation and then annually until 4 years
4. Donor-specific antibody (DSA) positivity at 3 and 12 months
5. Number of different DSA at at 3 and 12 months
6. Level of the immunodominant DSA assessed using mean fluorescence index at 3 and 12 months
7. Adverse event rate assessed by reviewing patient medical records
8. Patient-reported health-related quality of life , assessed using EQ-5D-5L/EQ-5D-Y questionnaires at baseline, 3 months, and 1, 2, 3 and 4 years following transplantation
9. Economic analysis of cost per quality-adjusted life year (QALY) gained from the perspective of the NHS

Overall trial start date

01/11/2018

Overall trial end date

01/02/2026

Reason abandoned (if study stopped)

Eligibility

Participant inclusion criteria

1. Informed consent provided by patient or by a parent or legal guardian for patients aged <16 years
2. Aged 5 years or older
3. Diagnosis of acute antibody-mediated rejection (AMR) as defined by:
3.1. The presence of ≥1 donor-specific antibodies (DSA)
3.2. An adequate transplant biopsy (≥7 glomeruli and ≥1 artery) with histological features consistent with active AMR with no evidence of chronicity as defined by the Banff histological classification of allograft pathology:
3.2.1. If C4d positive (2 or 3): v score (for arteritis) ≥1 and/or thrombotic microangiopathy and/or g score (for glomerulitis) ≥1 and/or ptc score (for peritubular capillaritis) ≥1, or if co-existing cellular rejection, a g score ≥1
3.2.2. If C4d negative (0 or 1): microcirculation inflammatory score (g + ptc) ≥2, or if co-existing cellular rejection, a g score ≥1 and (g + ptc) ≥2 plus chronic glomerulopathy (cg) score 0 or 1a, or tubulo-interstitial fibrosis <50% and glomerular obsolescence <50%

Participant type

Patient

Age group

Mixed

Gender

Both

Target number of participants

170

Participant exclusion criteria

1. ABO-incompatible transplant
2. Received rituximab as part of induction or post-transplant for any other indications within the preceding 12 months (eg. recurrent focal and segmental glomerular sclerosis)
3. Received complete plasma exchange (PEX) treatment prior to the index biopsy on the suspicion of acute AMR in the absence of histology
4. Active infection including bacterial, viral (including CMV and EBV) or fungal infection or tuberculosis, which in the investigator’s opinion could affect the conduct of the study
5. Co-existing BK nephropathy
6. Active hepatitis B or hepatitis C (patients with prior exposure to hepatitis B may be enrolled at the discretion of the PI; patients may be included if a negative hepatitis C recombinant immunoblot assay is confirmed or have a negative hepatitis C virus RNA [qualitative] test), or subjects with suspected human immunodeficiency virus (HIV) infection
7. Active malignancy
8. Known allergy, intolerance or contraindication to the treatments in the standard of care arm or rituximab as outlined in the Summaries of Product Characteristics (SmPCs)
9. Clinically significant comorbidity
10. Females must be either post-menopausal for at least 1 year, surgically sterile or, if of child-bearing potential, must not be pregnant or lactating. If sexually active, must agree to use an acceptable method of birth control for the first year post-randomisation.

Recruitment start date

01/02/2019

Recruitment end date

01/08/2022

Locations

Countries of recruitment

United Kingdom

Trial participating centre

Imperial College Healthcare NHS Trust
Hammersmith Hospital, Du Cane Road, Acton. W12 0HS
London
W12 0HS
United Kingdom

Trial participating centre

Cambridge University Hosptials NHS Foundation Trust
Addenbrookes Hospital, Hills Road,
Cambridge
CB2 0QQ
United Kingdom

Trial participating centre

OXFORD UNIVERSITY HOSPITALS NHS FOUNDATION TRUST
JOHN RADCLIFFE HOSPITAL HEADLEY WAY HEADINGTON OXFORD OXFORDSHIRE
Oxford
OX3 9DU
United Kingdom

Trial participating centre

Leeds Teaching Hospitals NHS Trust
ST. JAMES'S UNIVERSITY HOSPITAL BECKETT STREET LEEDS WEST YORKSHIRE
Leeds
LS9 7TF
United Kingdom

Trial participating centre

Great Ormond Street Hospital for Children NHS Foundation Trust
Great Ormond Street,
London
WC1N 3JH
United Kingdom

Trial participating centre

GUY'S AND ST THOMAS' NHS FOUNDATION TRUST
GUY'S HOSPITAL GREAT MAZE POND LONDON GREATER LONDON
London
SE1 9RT
United Kingdom

Trial participating centre

Royal Infirmary of Edinburgh
51 Little France Crescent, Edinburgh
Edinburgh
EH16 4SA
United Kingdom

Trial participating centre

University Hospital of Wales
Cardiff & Vale University Health Board Heath Park Way
Cardiff
CF14 4XW
United Kingdom

Trial participating centre

NORTH BRISTOL NHS TRUST
SOUTHMEAD HOSPITAL, SOUTHMEAD ROAD
Bristol
BS10 5NB
United Kingdom

Trial participating centre

UNIVERSITY HOSPITALS COVENTRY AND WARWICKSHIRE NHS TRUST
CLIFFORD BRIDGE ROAD
Coventry
CV2 2DX
United Kingdom

Trial participating centre

NHS Greater Glasgow and Clyde
Queen Elizabeth University Hospital 1345 Govan Road
Glasgow
G51 4TF
United Kingdom

Trial participating centre

UNIVERSITY HOSPITALS OF LEICESTER NHS TRUST
LEICESTER ROYAL INFIRMARY, INFIRMARY SQUARE
Leicester
LE1 5WW
United Kingdom

Trial participating centre

ROYAL LIVERPOOL AND BROADGREEN UNIVERSITY HOSPITALS NHS TRUST
ROYAL LIVERPOOL UNIVERSITY HOSPITAL, PRESCOT STREET
Liverpool
L7 8XP
United Kingdom

Trial participating centre

ST GEORGE'S UNIVERSITY HOSPITALS NHS FOUNDATION TRUST
St George's Hospital, Blackshaw Road,
London
SW17 0QT
United Kingdom

Trial participating centre

ROYAL FREE LONDON NHS FOUNDATION TRUST
ROYAL FREE HOSPITAL, POND STREET
London
NW3 2QG
United Kingdom

Trial participating centre

BARTS HEALTH NHS TRUST
THE ROYAL LONDON HOSPITAL, WHITECHAPEL
London
E1 1BB
United Kingdom

Trial participating centre

MANCHESTER UNIVERSITY NHS FOUNDATION TRUST
Manchester Royal Infirmary, Oxford Road
Manchester
M13 9WL
United Kingdom

Trial participating centre

The Newcastle Upon Tyne Hospitals NHS Foundation Trust
Freeman Hospital Freeman Road
Newcastle
NE7 7DN
United Kingdom

Trial participating centre

NOTTINGHAM UNIVERSITY HOSPITALS NHS TRUST
City Hospital Hucknall Road
Nottingham
NG5 1PB
United Kingdom

Trial participating centre

PLYMOUTH HOSPITALS NHS TRUST
DERRIFORD HOSPITAL, DERRIFORD ROAD
Plymouth
PL6 8DH
United Kingdom

Trial participating centre

Portsmouth Hospitals NHS Trust
Queen Alexandra Hospital
Portsmouth
PO6 3LY
United Kingdom

Trial participating centre

SHEFFIELD TEACHING HOSPITALS NHS FOUNDATION TRUST
NORTHERN GENERAL HOSPITAL, HERRIES ROAD
Sheffield
S5 7AU
United Kingdom

Trial participating centre

Belfast City Hospital
Belfast N Ireland
Belfast
BT9 7AB
United Kingdom

Sponsor information

Organisation

Imperial College London

Sponsor details

Joint Research Compliance Office
Imperial College London and Imperial College Healthcare NHS Trust
Room 215
Level 2
Medical School Building
Norfolk Place
London
London
W2 1PG
United Kingdom
+44 20 7594 9480
jrco.ctimp.team@imperial.ac.uk

Sponsor type

Hospital/treatment centre

Website

Funders

Funder type

Charity

Funder name

Kidney Research UK

Alternative name(s)

Funding Body Type

private sector organisation

Funding Body Subtype

other non-profit

Location

United Kingdom

Funder name

National Institute for Health Research

Alternative name(s)

NIHR

Funding Body Type

government organisation

Funding Body Subtype

Federal/National Government

Location

United Kingdom

Results and Publications

Publication and dissemination plan

Study results will be presented at national and international transplant conferences and published in a high-impact peer reviewed journal.

IPD sharing statement:
The data sharing plans for the current study are unknown and will be made available at a later date.

Intention to publish date

01/02/2027

Participant level data

To be made available at a later date

Basic results (scientific)

Publication list

Publication citations

Additional files

Editorial Notes

15/03/2019: Internal review. 13/03/2019: Internal review.