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出境医 / 临床实验 / Transplant Antibody-Mediated Rejection: Guiding Effective Treatments (TAR:GET-1)
Transplant Antibody-Mediated Rejection: Guiding Effective Treatments (TAR:GET-1)
Study Description
Brief Summary:
This trial evaluates the addition of rituximab to standard of care in the treatment of antibody-mediated rejection in kidney transplant patients. The trial will involve adults and children. Half of participants will receive standard of care (methylprednisolone, intravenous immunoglobulin and plasma exchange), while the other half will receive standard of care and rituximab.
| Condition or disease | Intervention/treatment | Phase |
|---|---|---|
| Kidney Transplant Rejection Antibody-mediated Rejection | Drug: Rituximab Drug: Methylprednisolone Drug: Intravenous Immunoglobulin Procedure: Plasma Exchange | Phase 3 |
Detailed Description:
Chronic antibody-mediated rejection (cAMR) is the leading cause of kidney transplant failure. Fifty percent of kidney transplant patients who develop acute antibody-mediated rejection (aAMR) will develop evidence of cAMR within 1 year of the acute rejection episode. There is currently no evidence on how to treat aAMR.
The planned research is a randomised controlled trial, which compares an acceptable and commonly used therapy, which will be referred to as "standard of care", with an additional agent, rituximab, added to the "standard of care" treatment. The participants with be randomised in a 1:1 ratio.
"Standard of care" will include optimisation of the participant's baseline anti-rejection medications and therapy to remove the antibodies which have developed against the kidney transplant, which are causing the damage. This is called plasma exchange. The participants will also receive therapy to reduce inflammation and reduce their immune response to their kidney transplant. This will be achieved using corticosteroids and intravenous immunoglobulins, respectively. These therapies have been used to treat aAMR for many decades.
The intervention arm will consist of the "standard of care" treatment, with the addition of a drug called rituximab, which will be administered in 2 separate doses. Rituximab is itself an antibody, which binds to certain cells in the body involved in antibody production, called B cells. Following the administration of rituximab, the number of B cells is reduced, which affects antibody production. Rituximab is commonly used in transplantation for this indication, as well as for other conditions.
Participants in both arms will be followed up to determine if there is a difference in the time to transplant failure and/or transplant function.
Study Design
| Study Type : | Interventional (Clinical Trial) |
| Actual Enrollment : | 3 participants |
| Allocation: | Randomized |
| Intervention Model: | Parallel Assignment |
| Masking: | None (Open Label) |
| Primary Purpose: | Treatment |
| Official Title: | A Multicentre Randomised Controlled Trial to Assess the Efficacy of Adding Rituximab to Standard of Care in Treating Acute Antibody-mediated Rejection in Kidney Transplantation |
| Actual Study Start Date : | July 17, 2019 |
| Estimated Primary Completion Date : | July 2027 |
| Estimated Study Completion Date : | July 2027 |
Arms and Interventions
| Arm | Intervention/treatment |
|---|---|
|
Active Comparator: Standard of Care (SOC)
Intravenous Methylprednisolone (500 mg (600 mg/m2 for paediatric participants), n=3) Plasma Exchange (PEX) (60 ml/kg max 4 l (1 - 1.5 plasma volumes for paediatric participants), n=7) Intravenous Immunoglobulin (high dose: 2 g/kg total, or low dose: 100 mg/kg n=7 after each PEX, no dose adjustment for paediatric participants)
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Drug: Methylprednisolone
Intravenous infusion of methylprednisolone
Drug: Intravenous Immunoglobulin High dose (2 g/kg total) or Low dose (100 mg/kg, n=7)
Procedure: Plasma Exchange Blood is removed from the patient and filtered to remove the plasma. Red and white blood cells and platelets are returned to the patient with replacement fluid.
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Experimental: Standard of Care plus Rituximab (SOCR)
Intravenous Methylprednisolone (500 mg (600 mg/m2 for paediatric participants), n=3) Plasma Exchange (PEX) (60 ml/kg max 4 l (1 - 1.5 plasma volumes for paediatric participants), n=7) Intravenous Immunoglobulin (high dose: 2 g/kg total, or low dose: 100 mg/kg n=7 after each PEX, no dose adjustment for paediatric participants) Rituximab (375 mg/m2 max 1 g (no dose adjustment for paediatric participants), n=2 14 days +/- 2 days apart)
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Drug: Rituximab
2 intravenous infusions of rituximab or approved biosimilar given 14 days +/- 2 days apart.
Other Names:
Drug: Methylprednisolone Intravenous infusion of methylprednisolone
Drug: Intravenous Immunoglobulin High dose (2 g/kg total) or Low dose (100 mg/kg, n=7)
Procedure: Plasma Exchange Blood is removed from the patient and filtered to remove the plasma. Red and white blood cells and platelets are returned to the patient with replacement fluid.
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Outcome Measures
Primary Outcome Measures :
- Allograft Survival as assessed by statistical model [ Time Frame: 4 years ]Statistical model measuring allograft survival as defined as duration from the date of randomisation to the date of eGFR ≤15 mL/min/1.72 m2 (where the eGFR measurement is not due to an acute reversible cause, as determined by the PI, or a follow-up consecutive eGFR measurement of ≤15 mL/min/1.72 m2 is recorded (where the first date is recorded as the date of failure)), or the date of renal replacement therapy (date of starting maintenance dialysis dependency, retransplantation etc), whichever occurs first.
Secondary Outcome Measures :
- Serum creatinine as assessed by blood test [ Time Frame: 1, 3, 6 and 12 months, 2, 3 and 4 years ]Serum creatinine is an allograft function. Change in serum creatinine from baseline at 1, 3, 6 and 12 months post-randomisation and then annually until 4 years
- Estimated glomerular filtration rate (eGFR) as assessed by blood test [ Time Frame: 1, 3, 6 and 12 months, 2, 3 and 4 years ]eGFR is an allograft function. Change in eGFR from baseline at 1, 3, 6 and 12 months post-randomisation and then annually until 4 years
- Proteinuria as assessed by urine test [ Time Frame: 1, 3, 6 and 12 months, 2, 3 and 4 years ]Proteinuria is an allograft function. Change in proteinuria from baseline at 1, 3, 6 and 12 months post-randomisation and then annually until 4 years. Proteinuria is a ratio between urinary protein and creatinine.
- Change in donor specific antibodies as assessed by blood test [ Time Frame: 3 and 12 months ]Change in number of donor specific antibodies from baseline
- Change in positivity of donor specific antibodies as assessed by blood test [ Time Frame: 3 and 12 months ]Change in positivity of donor specific antibodies from baseline
- Change in mean fluorescence index of donor specific antibodies as assessed by blood test [ Time Frame: 3 and 12 months ]Change in mean fluorescence index of donor specific antibodies from baseline
- Incidence rate of adverse event as assessed by questionnaire [ Time Frame: 4 years ]Summary tables of incidence rates for adverse event reporting of participants receiving rituximab in addition to standard of care compared to participants receiving standard of care alone
- Health-related quality of life (QoL) as assessed by EuroQoL EQ-5D-5L/EQ-5D-Y questionnaire [ Time Frame: 3 months, 1, 2, 3 and 4 years ]A QoL score is obtained according to the answers to the EQ-5D-5L/EQ-5D-Y questionnaires. The QoL score comprises of 2 numbers. The first is a 5-digit number for the EQ-5D-5L descriptive system describing the 5 dimensions asked in the questionnaire. For example 11111 indicates no problems on any of the 5 dimensions whilst 55555 indicates extreme problems on all of the 5 dimensions. The second number is the EQ-VAS (EuroQoL-Visual Analogue Scale) score. This is a value between 0 and 100 where 0 is the worst health the respondent can imagine and 100 is the best health.
- Cost effectiveness economic analysis [ Time Frame: 4 years ]Statistical decision model built for economic analysis of cost per quality-adjusted life year gained from perspective of the National Health Service
Eligibility Criteria
| Ages Eligible for Study: | 5 Years and older (Child, Adult, Older Adult) |
| Sexes Eligible for Study: | All |
| Accepts Healthy Volunteers: | No |
Criteria
Inclusion Criteria:
- Willing and able to give written informed consent by patient aged 16 years and over; or by a parent or legal guardian for patients who are under 16 years old
- 5 years old or older
- A diagnosis of acute AMR as defined by:
- The presence of ≥1 donor specific antibodies (DSA)
- An adequate renal transplant biopsy with histological features consistent with active AMR with no evidence of chronicity as defined by the Banff histological classification of allograft pathology:
- If C4d positive (2 or 3):
- v score ≥1 and/or
- g score ≥1 and/or
- thrombotic microangiopathy and/or
- ptc score ≥1
- or if co-existent cellular rejection, a g score of ≥1 OR
- 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 AND
- Chronic glomerulopathy (cg) score 0 or 1a
- Tubulo-interstitial fibrosis <50% and glomerular obsolescence <50%
Exclusion Criteria:
- Patients who have received an ABO incompatible transplant
- Patients who have received rituximab as part of induction or post-transplant for any other indications (e.g. recurrent focal and segmental glomerular sclerosis)
- Patients who have completed PEX treatment prior to the index biopsy on the suspicion of acute AMR in the absence of histology
- Have active infection including bacterial, viral (including CMV (cytomegalovirus) and EBV (Epstein-Barr virus)), fungal or tuberculosis, which in the investigator's opinion could affect the conduct of the trial
- Co-existing BK (BK virus) nephropathy
- Patients with hepatitis B (patients with prior exposure to hepatitis B may be enrolled at the discretion of the PI)
- Have active hepatitis C (patients may be included if a negative hepatitis C recombinant immunoblot assay is confirmed or have a negative hepatitis C virus RNA [qualitative] test)
- Have human immunodeficiency virus (HIV)
- Active malignancy, which would pose a contraindication to any of the trial interventions
- Patients with known allergy, intolerance or contraindication to treatments in the standard of care arm or rituximab as outlined in the Summaries of Product Characteristics (SmPCs)
- Clinically significant comorbidity
- 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, female participants must agree to use an acceptable method of birth control for 12 months post treatment with rituximab. Female participants must also agree not to breastfeed for 12 months post treatment with rituximab.
Contacts and Locations
Locations
| United Kingdom | |
| Imperial College London | |
| London, United Kingdom | |
Sponsors and Collaborators
Imperial College London
Cambridge Clinical Trials Unit
National Institute for Health Research, United Kingdom
Kidney Cancer UK
Investigators
| Principal Investigator: | Michelle Willicombe, MA MRCP MD | Imperial College London |
| Tracking Information | |||||
|---|---|---|---|---|---|
| First Submitted Date ICMJE | June 17, 2019 | ||||
| First Posted Date ICMJE | June 21, 2019 | ||||
| Last Update Posted Date | April 1, 2021 | ||||
| Actual Study Start Date ICMJE | July 17, 2019 | ||||
| Estimated Primary Completion Date | July 2027 (Final data collection date for primary outcome measure) | ||||
| Current Primary Outcome Measures ICMJE |
Allograft Survival as assessed by statistical model [ Time Frame: 4 years ] Statistical model measuring allograft survival as defined as duration from the date of randomisation to the date of eGFR ≤15 mL/min/1.72 m2 (where the eGFR measurement is not due to an acute reversible cause, as determined by the PI, or a follow-up consecutive eGFR measurement of ≤15 mL/min/1.72 m2 is recorded (where the first date is recorded as the date of failure)), or the date of renal replacement therapy (date of starting maintenance dialysis dependency, retransplantation etc), whichever occurs first.
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| Original Primary Outcome Measures ICMJE |
Allograft Survival as assessed by statistical model [ Time Frame: 4 years ] Statistical model measuring allograft survival as defined as duration from the date of randomisation to the date of eGFR ≤15 mL/min/1.72 m2, or the date of renal replacement therapy (date of starting dialysis dependency, transplantation etc), whichever occurs first.
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| Change History | |||||
| Current Secondary Outcome Measures ICMJE |
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| Original Secondary Outcome Measures ICMJE |
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| Current Other Pre-specified Outcome Measures | Not Provided | ||||
| Original Other Pre-specified Outcome Measures | Not Provided | ||||
| Descriptive Information | |||||
| Brief Title ICMJE | Transplant Antibody-Mediated Rejection: Guiding Effective Treatments | ||||
| Official Title ICMJE | A Multicentre Randomised Controlled Trial to Assess the Efficacy of Adding Rituximab to Standard of Care in Treating Acute Antibody-mediated Rejection in Kidney Transplantation | ||||
| Brief Summary | This trial evaluates the addition of rituximab to standard of care in the treatment of antibody-mediated rejection in kidney transplant patients. The trial will involve adults and children. Half of participants will receive standard of care (methylprednisolone, intravenous immunoglobulin and plasma exchange), while the other half will receive standard of care and rituximab. | ||||
| Detailed Description |
Chronic antibody-mediated rejection (cAMR) is the leading cause of kidney transplant failure. Fifty percent of kidney transplant patients who develop acute antibody-mediated rejection (aAMR) will develop evidence of cAMR within 1 year of the acute rejection episode. There is currently no evidence on how to treat aAMR. The planned research is a randomised controlled trial, which compares an acceptable and commonly used therapy, which will be referred to as "standard of care", with an additional agent, rituximab, added to the "standard of care" treatment. The participants with be randomised in a 1:1 ratio. "Standard of care" will include optimisation of the participant's baseline anti-rejection medications and therapy to remove the antibodies which have developed against the kidney transplant, which are causing the damage. This is called plasma exchange. The participants will also receive therapy to reduce inflammation and reduce their immune response to their kidney transplant. This will be achieved using corticosteroids and intravenous immunoglobulins, respectively. These therapies have been used to treat aAMR for many decades. The intervention arm will consist of the "standard of care" treatment, with the addition of a drug called rituximab, which will be administered in 2 separate doses. Rituximab is itself an antibody, which binds to certain cells in the body involved in antibody production, called B cells. Following the administration of rituximab, the number of B cells is reduced, which affects antibody production. Rituximab is commonly used in transplantation for this indication, as well as for other conditions. Participants in both arms will be followed up to determine if there is a difference in the time to transplant failure and/or transplant function. |
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| Study Type ICMJE | Interventional | ||||
| Study Phase ICMJE | Phase 3 | ||||
| Study Design ICMJE | Allocation: Randomized Intervention Model: Parallel Assignment Masking: None (Open Label) Primary Purpose: Treatment |
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| Condition ICMJE |
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| Intervention ICMJE |
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| Study Arms ICMJE |
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| Publications * | Not Provided | ||||
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* Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline. |
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| Recruitment Information | |||||
| Recruitment Status ICMJE | Active, not recruiting | ||||
| Actual Enrollment ICMJE |
3 | ||||
| Original Estimated Enrollment ICMJE |
170 | ||||
| Estimated Study Completion Date ICMJE | July 2027 | ||||
| Estimated Primary Completion Date | July 2027 (Final data collection date for primary outcome measure) | ||||
| Eligibility Criteria ICMJE |
Inclusion Criteria:
Exclusion Criteria:
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| Sex/Gender ICMJE |
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| Ages ICMJE | 5 Years and older (Child, Adult, Older Adult) | ||||
| Accepts Healthy Volunteers ICMJE | No | ||||
| Contacts ICMJE | Contact information is only displayed when the study is recruiting subjects | ||||
| Listed Location Countries ICMJE | United Kingdom | ||||
| Removed Location Countries | |||||
| Administrative Information | |||||
| NCT Number ICMJE | NCT03994783 | ||||
| Other Study ID Numbers ICMJE | 2018-002882-20 | ||||
| Has Data Monitoring Committee | Yes | ||||
| U.S. FDA-regulated Product |
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| IPD Sharing Statement ICMJE |
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| Responsible Party | Imperial College London | ||||
| Study Sponsor ICMJE | Imperial College London | ||||
| Collaborators ICMJE |
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| Investigators ICMJE |
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| PRS Account | Imperial College London | ||||
| Verification Date | March 2021 | ||||
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ICMJE Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP |
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