Does rituximab added to usual treatment reduce kidney transplant failure following rejection?
| ISRCTN | ISRCTN18179652 |
|---|---|
| DOI | https://doi.org/10.1186/ISRCTN18179652 |
| EudraCT/CTIS number | 2018-002882-20 |
| ClinicalTrials.gov number | NCT03994783 |
| Secondary identifying numbers | 1.0; CPMS 40785 |
- Submission date
- 12/11/2018
- Registration date
- 11/03/2019
- Last edited
- 12/09/2023
- Recruitment status
- Stopped
- Overall study status
- Stopped
- Condition category
- Injury, Occupational Diseases, Poisoning
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
The trial contact is Dr Graham Armstrong, graham.armstrong@addenbrookes.nhs.uk
Contact information
Public
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
| Phone | +44 01223 254918 |
|---|---|
| graham.armstrong@addenbrookes.nhs.uk |
Study information
| Study design | Multicentre phase 3 open-label randomised controlled trial |
|---|---|
| Primary study design | Interventional |
| Secondary study design | Randomised controlled trial |
| Study setting(s) | Hospital |
| Study type | Treatment |
| Participant information sheet | Not available in web format at this time. |
| 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 |
| Study 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(s) |
Approved 17/04/2019, London – West London & GTAC REC (The Old Chapel, Royal Standard Place, Nottingham, NG1 6FS, United Kingdom; +44 (0)2071048007; NRESCommitte.London-WestLondon@nhs.net), ref: 19/LO/0180 |
| 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 |
| Pharmaceutical study type(s) | |
| Phase | Phase III |
| Drug / device / biological / vaccine name(s) | 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 study start date | 01/11/2018 |
| Overall study end date | 01/02/2026 |
| Reason abandoned (if study stopped) | Objectives no longer viable |
Eligibility
| Participant type(s) | Patient |
|---|---|
| Age group | Mixed |
| Sex | Both |
| Target number of participants | 170 |
| 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 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
- England
- Northern Ireland
- Scotland
- United Kingdom
- Wales
Study participating centres
London
W12 0HS
United Kingdom
Cambridge
CB2 0QQ
United Kingdom
HEADLEY WAY
HEADINGTON OXFORD OXFORDSHIRE
Oxford
OX3 9DU
United Kingdom
BECKETT STREET
LEEDS WEST YORKSHIRE
Leeds
LS9 7TF
United Kingdom
London
WC1N 3JH
United Kingdom
GREAT MAZE POND LONDON GREATER LONDON
London
SE1 9RT
United Kingdom
Edinburgh
Edinburgh
EH16 4SA
United Kingdom
Heath Park Way
Cardiff
CF14 4XW
United Kingdom
Bristol
BS10 5NB
United Kingdom
Coventry
CV2 2DX
United Kingdom
Glasgow
G51 4TF
United Kingdom
Leicester
LE1 5WW
United Kingdom
Liverpool
L7 8XP
United Kingdom
London
SW17 0QT
United Kingdom
London
NW3 2QG
United Kingdom
London
E1 1BB
United Kingdom
Manchester
M13 9WL
United Kingdom
Freeman Road
Newcastle
NE7 7DN
United Kingdom
Hucknall Road
Nottingham
NG5 1PB
United Kingdom
Plymouth
PL6 8DH
United Kingdom
Portsmouth
PO6 3LY
United Kingdom
Sheffield
S5 7AU
United Kingdom
N Ireland
Belfast
BT9 7AB
United Kingdom
Sponsor information
University/education
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
England
United Kingdom
| Phone | +44 20 7594 9480 |
|---|---|
| jrco.ctimp.team@imperial.ac.uk | |
"ROR" |
https://ror.org/041kmwe10 |
Funders
Funder type
Charity
Private sector organisation / Other non-profit organizations
- Location
- United Kingdom
Government organisation / National government
- Alternative name(s)
- National Institute for Health Research, NIHR Research, NIHRresearch, NIHR - National Institute for Health Research, NIHR (The National Institute for Health and Care Research), NIHR
- Location
- United Kingdom
Results and Publications
| Intention to publish date | 01/02/2027 |
|---|---|
| Individual participant data (IPD) Intention to share | No |
| IPD sharing plan summary | Data sharing statement to be made available at a later date |
| 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 plan | The data sharing plans for the current study are unknown and will be made available at a later date. |
Editorial Notes
12/09/2023: The following changes were made:
1. The study was stopped because the objectives were no longer viable due to a change in clinical practice/policy and the increased risk from COVID for this trial population.
2. The ethics approval was updated.
20/09/2021: Internal review.
29/04/2020: Due to current public health guidance, recruitment for this study has been paused. The public contact has been updated and the plain English summary has been updated accordingly.
10/01/2020: ClinicalTrials.gov number added.
15/03/2019: Internal review.
13/03/2019: Internal review.
