| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Highly Sensitised Patients(patients with high levels of human leucocyte antigen specific antibodies) awaiting renal transplantation.These patients are difficult to match to a compatible donor and thus rates of transplantation are low. |
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| E.1.1.1 | Medical condition in easily understood language |
| Highly sensitised patients are difficult to transplant due to the risk of rejection. They may not be able to receive a kidney directly from their living donor, and may wait a long time for transplant. |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Immune System Diseases [C20] |
| MedDRA Classification |
| 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 |
To assess the efficacy of a combination of B cell depletion and proteasome inhibition, together with antibody removal and steroids, to reduce HLA antibodies in Highly Sensitised Patients.
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| E.2.2 | Secondary objectives of the trial |
i. To confirm that the expected number of patients can be recruited in the time frame of the trial.
ii. To confirm that the intervention is sufficient to result in a durable fall in cRF.
iii. To confirm that B cell depletion persists at 12 weeks following intervention.
iii. To determine whether the intervention impacts on Quality of Life.
iv. To confirm whether any transplants arise as a consequence of the intervention.
v. To confirm incidence of peripheral neuropathy (any grade).
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| E.2.3 | Trial contains a sub-study | Yes |
| E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
Sample collections parallel to the main study.
A number of recent studies have demonstrated that the cytokine profile, immunophenotype or detailed antibody characteristics of an individual may be predictive of response to desensitisation and subsequent outcome (3-7). There will therefore be a parallel collection of clinical samples for mechanistic studies, at time points beginning prior to desensitisation treatment and continuing post-transplantation. These samples will be stored in the Wales Kidney Tissue Bank in the Institute of Nephrology, University Hospital of Wales, Cardiff. The necessary HTA approvals are in place for sample storage. Subsequent release of samples for scientific studies is approved by the Tissue Bank oversight committee. Any results from the parallel studies will be correlated with clinical outcomes, with the aim of will increasing understanding of the response of HLA sensitised patients to proteasome inhibition, enabling future risk stratification and prediction of those more likely to respond to this intervention. |
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| E.3 | Principal inclusion criteria |
1. Male or female, aged 18 years and older.
2. Able to give informed consent and willing to fulfil trial requirements.
3. Have completed the necessary assessments to receive a renal transplant.
4. In stable health as determined by the Investigator based on medical history and laboratory tests during the screening period. See Exclusion Criteria for specific exclusions.
5. Negative serological test for hepatitis B (surface antigen and core antibody) and hepatitis C within the last 6 months, and HIV within the last 12 months.
6. Documented immune status to varicella zoster virus (VZV) (at any time).
7. Female participant of childbearing potential must be willing to use a highly effective method of contraception for one year following rituximab (this period will also include the recommended three-month period for avoidance of pregnancy following bortezomib). Male participants must be willing to use a highly effective form of contraception for 3 months post last dose of bortezomib (effective forms of contraception are listed in section 8.10)
8. Persistent (for at least one year) and stable (tested on at least three occasions over the preceding 18 months) circulating HLA antibodies defined by Luminex Single Antigen Bead analysis at the time of recruitment.
9. Recipients awaiting deceased donor transplantation:
o cRF >85% and at least 3 years on the transplant waiting list as determined by the UK deceased donor organ allocation policy for kidney transplantation.
10. Recipients with an HLA incompatible living donor who have been considered for enrolment in the UK Living Kidney Sharing Scheme:
o cRF is >95% or,
o cRF is ≥85% and they have received no offers after three runs in the UKLKSS.
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| E.4 | Principal exclusion criteria |
1. Pregnancy, planned pregnancy during the trial period, or current breast feeding.
2. Active viral, bacterial or fungal infection precluding immunosuppression.
3. Active malignant disease.
4. Patients listed for transplantation of any organ other than kidney alone.
5. History of or active, clinically significant, respiratory, gastrointestinal (including pancreatitis), hepatic, cardiac, neurological, psychiatric, musculoskeletal, genitourinary, dermatological, or other disorder that, in the Investigator’s opinion, could affect the conduct of the trial.
6. Have a history of non-adherence, alcohol or substance abuse that, in the judgment of the Investigator, may impair or risk the subject’s full participation in the trial.
7. Positive serological test for hepatitis B, C or HIV.
8. Negative serological test for VZV.
9. Previous graft loss to recurrent primary disease within 2 years of transplantation.
10. Documented intolerance of bortezomib, rituximab or their exipients, or dexamethasone.
11. Persistent thrombocytopaenia, platelet count <100 X 109/L for the past three consecutive months.
12. Persistent neutropaenia, absolute neutrophil count < 2 X 109/L for the past three consecutive months.
13. Hypogammaglobulinaemia, serum IgG less than local laboratory lower limit of normal at screening.
14. Peripheral neuropathy of any grade (reported by symptoms or on clinical examination).
15. Currently involved in any other clinical trial of an investigational medicinal product (IMP) or have taken an IMP within 30 days prior to trial entry except the SIMPLIFIED trial. |
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| E.5 End points |
| E.5.1 | Primary end point(s) |
The proportion of patients achieving an absolute reduction in calculated reaction frequency (cRF) of at least 10% at 12 weeks following their last intervention, compared to control group who have received no intervention.
For the purposes of calculating reaction frequency in the ITOPS trial, all HLA A, B and DR antibodies with an MFI >2000 when tested in the local H&I laboratory will be classified as positive. HLA Cw, DP and DQ antibodies will be classified as positive according to local practice.
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| 12 weeks following last intervention or from enrolment on routine monitoring. |
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| E.5.2 | Secondary end point(s) |
1- The proportion of participants achieving an absolute reduction in calculated reaction frequency of at least 10%, as compared to cRF at enrolment.
2- Confirmation that at 12 weeks post-final intervention there has been an absolute fall in cRF of least 10% in at least 50% of the participants treated, compared to cRF at enrolment.
3- The proportion of participants achieving an absolute reduction in calculated reaction frequency of at least 10%, as compared to cRF at enrolment.
4- The percentage change in cRF, as compared to cRF at enrolment.
5- The proportion of participants in the intervention group with B cell depletion.
6- Completion of quality of life questionnaires (EQ-5D and KDQoL-SF) by participants.
7- The number of participants receiving a transplant from either a deceased or living donor (with confirmation that any increase in offer rate was as a results of change in cRF).
8- The number of participants developing any grade neuropathy, assessed by completion of the FACT/GOG-Ntx questionnaire. |
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
1- 12 months from trial initiation.
2- 12 weeks following last intervention.
3- 6 and 12 months following last intervention or on routine monitoring.
4- 12 weeks, 6 and 12 months following last intervention or on routine monitoring.
5- 12 weeks following intervention.
6- At enrolment and after 18 months after enrolment in both groups (or 90 days after transplantation, whichever is earlier).
7- All transplants in both groups will be included for 18 months from enrolment.
8- At baseline, the end of each cycle of treatment with bortezomib (in intervention group), and at 18 months post enrolment. |
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| 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 | Yes |
| 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 | Yes |
| 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 |
| No intervention as per standard of care |
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| E.8.2.4 | Number of treatment arms in the trial | 1 |
| 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 | 3 |
| 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 | Yes |
| 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
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| The trial will be closed 30 days after the date of the last visit of the last patient enrolled, to allow sufficient time for completion of HLA antibody testing and data entry. |
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 3 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | 1 |
| E.8.9.2 | In all countries concerned by the trial years | 3 |
| 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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