| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Renal Transplant antibody-mediated rejection |
|
| E.1.1.1 | Medical condition in easily understood language |
| Rejection of a transplanted kidney |
|
| E.1.1.2 | Therapeutic area | Body processes [G] - Immune system processes [G12] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10023439 |
| E.1.2 | Term | Kidney transplant rejection |
| E.1.2 | System Organ Class | 10021428 - Immune system disorders |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| The trial will test two different treatment options currently used to treat acute antibody-mediated rejection (aAMR) in kidney transplant patients in the UK. Trial participants will be allocated randomly (decided by chance using a computer) to receive one of the two treatments. To find out how the trial treatments compare, we will measure kidney transplant function over time. Each participant will be followed up for a minimum of 4 years. The time from the date of randomisation to the date of transplant failure (measured as return to dialysis treatment or function test failure) will be measured in both groups. |
|
| E.2.2 | Secondary objectives of the trial |
• As well as determining how many transplants are still working in each of the treatment arms, we will also determine how well the remaining transplants are functioning. This will be analysed by assessing the level of function using a blood test and testing for protein leak in the urine over time.
• The effect the two different treatments has on the level of detectable antibody against in the transplant (donor specific antibody) will also be measured.
• It is also important to know how safe these treatments are. Therefore, we need to compare how common and frequent certain side effects occur with each treatment.
• Because these treatments are expensive, we next need to analyse whether they provide value for money for the NHS (and the taxpayer). The way in which we measure value for money includes how well people feel and how active they are.
|
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. 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
2. Aged 5 years old or older, at the time of consent
3. A diagnosis of acute AMR as defined by:
a. The presence of ≥1 donor specific antibodies (DSA)
b. 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:
i. 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
ii. 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%
|
|
| E.4 | Principal exclusion criteria |
1. Patients who have received an ABO incompatible transplant
2. Patients who have received rituximab as part of induction or post-transplant for any other indications (eg. recurrent focal and segmental glomerular sclerosis)
3. Patients who have received complete PEX treatment prior to the index biopsy on the suspicion of acute AMR in the absence of histology
4. Have active infection including bacterial, viral (including CMV and EBV), fungal or tuberculosis, which in the investigator’s opinion could affect the conduct of the study
5. Co-existing BK nephropathy
6. Patients with hepatitis B (patients with prior exposure to hepatitis B may be enrolled at the discretion of the PI)
7. 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)
8. Active malignancy
9. 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)
10. Clinically significant comorbidity
11. 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 rituximab treatment. Female participants must also agree not to breastfeed for 12 months post rituximab treatment. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Allograft survival, defined as the duration from the date of randomisation to the date of starting dialysis dependency or date of eGFR (estimated Glomerular Filtration Rate) <15 mL/min/1.73 m2, whichever occurs first. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
Allograft survival will be determined at 4 years.
Interim analyses will also be made for DMEC review.
|
|
| E.5.2 | Secondary end point(s) |
1. Allograft function measured by serum creatinine, estimated glomerular filtration rate (CKD-EPI) and proteinuria (urinary ptotein:creatinine ratio) at 1, 3, 6, and 12 months post-randomisation and then annually until 4 years
2. Donor specific antibody (DSA) positivity, number of DSA and mean fluorescence index (immunodominant)
3. Safety, determined by adverse event reporting
4. Health-related quality of life, assessed by EQ-5D-5L/EQ-5D-Y questionnaire
5. Economic analysis of cost per quality-adjusted life year gained from the perspective of the NHS
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
These will be determined at 4 years.
Interim analyses will also be made for DMEC review. |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | Yes |
| E.8.2.3.1 | Comparator description |
|
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 24 |
| E.8.5 | The trial involves multiple Member States | No |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.7 | Trial has a data monitoring committee | No |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 7 |
| E.8.9.1 | In the Member State concerned months | 10 |
| E.8.9.1 | In the Member State concerned days | 1 |
| E.8.9.2 | In all countries concerned by the trial years | 7 |
| E.8.9.2 | In all countries concerned by the trial months | 10 |
| E.8.9.2 | In all countries concerned by the trial days | 1 |
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