The 3C Study (Campath, Calcineurin inhibitor reduction and Chronic allograft nephropathy)

The University of Oxford requires HES APC, mortality and cancer registration data for the purpose of the Campath, Calcineurin Inhibitor Reduction and Chronic Allograft Nephropathy (3C) study. Recruitment into 3C was completed in 2013 and the 6-month and 2-year outcomes have now been published. All participants are therefore in the long-term follow-up period. This will provide key information on the effects of the study treatments on patient-important outcomes including patient survival and transplant survival, as well as information on complications of transplantation including infections and cancer.

Despite improvements in short-term outcomes in kidney transplantation (e.g. acute rejection rates) there has been no improvement in long-term outcomes (e.g. transplant survival at 5-20 years after transplantation). One reason for this is that drugs (in particular, calcineurin inhibitors or “CNIs” used to prevent rejection in fact damage the transplant in the long-term and are major reasons for its ultimate failure. The 3C Study has been created as a result of this finding and therefore is a randomized trial investigating two strategies that may allow the use of CNIs to be minimised or removed completely. Nearly all kidney transplant trials to date have been both too small and in particular too short-term to detect any clinically meaningful treatment effects in outcomes that matter to patients i.e. long-term function and survival of the transplant. The 3C study therefore aims to study a large enough group of patients for long enough to detect such treatment effects. The 3C Study began in 2010 and will continue follow-up until 2025 at the earliest.

The research team have taken the opinion of the NRES Committee East Midlands – Nottingham 2, who have granted approval to the study in its current form.

Participants gave consent for their personal data to be collected via linkage with NHS registries (including NHS Digital, or the Health and Social Care Information Centre as it was at the time of consent) which addresses the common law duty of confidentiality.

The legal basis for processing and storing data under this Agreement is Article 6(1)e (UK GDPR). This research is in the public interest as it will lead to improved understanding of treatments used in kidney transplantation which could lead to improvements in care for the public.

In addition, processing and storage of special category (sensitive) personal data is being done under Article 9(2)(j) (UK GDPR) exemption, i.e. that the processing of the data is necessary for archiving purposes in the public interest, scientific or historical research purposes or statistical purposes.

There is minimal risk to the public in processing personal data for this purpose. All data will be processed in secure environments and the use of identifying data items will be kept to a minimum (only used to ensure that the linkage between individuals and their data is correct).

In order to detect the long-term effects of the study treatments cost-effectively, the Clinical Trial Service Unit (CTSU) at University of Oxford prospectively planned to flag all participants with available NHS registries (specifically NHS Digital, the UK Transplant Registry and the UK Renal Registry) to capture information on relevant outcomes. The outcomes that are covered by the registries include cause-specific mortality and site-specific cancer and data on hospitalisation (which includes infections which are a particularly important outcome for kidney transplant recipients).

The research objectives of 3C are:

• To determine the safety and efficacy of alemtuzumab- versus basiliximab-based induction therapy in kidney transplantation

• To determine the safety and efficacy of sirolimus- versus tacrolimus-based maintenance therapy in kidney transplantation

Data from NHS Digital will be combined with data from other sources (directly from participants via postal questionnaires; and from the UK Transplant Registry and UK Renal Registry) to provide a comprehensive assessment of relevant outcomes of kidney transplantation (e.g. transplant and patient survival). These data will be updated annually.

The 3C Study recruited 852 patients scheduled to undergo kidney transplantation between 2010 and 2013. They were randomized between different treatments at the time of transplantation and then again 6 months later.

The CTSU requires information from NHS Digital on:

(i) cause-specific mortality;

(ii) site-specific cancer; and

(iii) hospital episodes.

These outcomes are key outcomes after kidney transplantation and it would not be possible to properly assess the effects of treatment without such information.

As participants were randomized at an individual level, individual patient level data is required.

To address the GDPR principle of data minimisation the University of Oxford only request fields that are deemed necessary for the purpose of this research, and only receive data that relates to a specific cohort of 782 individuals (the number of people currently in the NHS Digital cohort).

Long-term outcomes are the particular interest of the 3C Study (unlike other trials which often focus on short-term outcomes).

The geographical spread is determined by the location of the participants in the trial who were recruited from 18 of the 23 adult kidney transplant centres in the UK (including Scotland, Wales and England). There is no alternative method to collect these data which will be as comprehensive (and therefore minimise bias in the randomized comparisons). Similar data is being requested from Scottish and Welsh registries for participants recruited in those devolved nations.

The sole Data Controller and Data Processor is the University of Oxford. As stated above, participants were recruited at 18 UK NHS trusts (transplant centres), but those trusts are not involved in any way with the processing of these data.

Funding for this study has been provided by NHS Blood and Transplant Research and Development, Pfizer, and Novartis.

Funders/commissioners of kidney transplantation in the UK are not involved in the processing of these data (although they will be interested in the outputs).

The CTSU also intends to compare the data received from NHS Digital with that collected from other sources of more traditional follow-up (e.g., participant questionnaires). This will provide useful information on how such registry-based follow-up could be used in future trials in transplantation and kidney disease more generally. This may provide a significant opportunity to streamline such trials.

The results of the 3C Study have been published in general and renal/transplant journals. The early results were published in The Lancet July 2014 and the first results using these data were also published in a high-impact medical journal, including American Journal of Transplantation. In addition, they have been presented at national and international meetings such as the British Transplantation Society, the Renal Association. Also in the European Society of Transplantation in September 2017, the American Transplant Congress and the Transplantation Society in July 2014.

All outputs will contain only data that is aggregated with small numbers supressed in line with the HES Analysis Guide. The study team will present actual and modelled data in graphical and tabular format. No individuals will be identified in any study reports.

The outputs will also be shared with all appropriate bodies such as NICE and the Cochrane Centre who will inform policy.

The University of Oxford will send a plain English summary of the results to all surviving participants (and publish the same on the University website) at the time of any publication of the relevant output. The University of Oxford will ensure the results are available in open-access format so anyone with an interest can access the outputs.

The commercial sponsors provided funding for the trial and will receive copies of any outputs prior to their public dissemination. They have the right to comment on these outputs, but they cannot require or mandate any changes. For the avoidance of doubt, the principal investigators (all employed by the university) have the final decision regarding any outputs. Record level information will not be released to any third party.

The study team will also share outputs via all of the listed channels:

- Study website

- Open lectures and talks

- Exhibition at public events

- Posters

- Press/media engagement and other public promotion of the research

The NDPH contributes widely to health policy. It contributes to debate with academic papers, conference participation, lectures to the public and advice to government (including NHS Digital). Examples of the impact of the work performed by NDPH up to 2014 is available from: https://results.ref.ac.uk/(S(ep5gbndxsprqnc0kork3mjyu))/Submissions/Impact/728

The 3C Study has already published two major papers using previous data from NHS Digital and other registries. The results from the next period of the DSA would lead to a further presentation and publication. Publications have been delayed in the term of the last DSA because of COVID-19, but it planned that the protocol-defined 5 year analyses will be conducted within the next 12-18 months.

3C Publications:

The 3C Study Collaborative Group

Alemtuzumab-based induction treatment versus basiliximab-based induction treatment in kidney transplantation (the 3C Study): a randomised trial

Lancet 2014 Nov 8; 384(9955):1684-1690

https://doi.org/10.1016/S0140-6736(14)61095-3

Main point: Compared with standard basiliximab-based treatment, alemtuzumab-based induction therapy followed by reduced CNI and mycophenolate exposure and steroid avoidance reduced the risk of biopsy-proven acute rejection in a broad range of patients receiving a kidney transplant. Long-term follow-up of this trial will assess whether these effects translate into differences in long-term transplant function and survival.

The 3C Study Collaborative Group

Campath, calcineurin inhibitor reduction, and chronic allograft nephropathy (the 3C Study) - results of a randomized controlled clinical trial

Am J Transplant 2018 Jun;18(6):1424-1434

https://doi.org/10.1111/ajt.14619

Main point: The findings suggest that compared with continuation of a tacrolimus‐based regimen, elective conversion to sirolimus‐based maintenance therapy does not improve transplant function 18 months later (regardless of induction therapy) and is associated with significant hazards of rejection and infection.

Two major publications have informed practice nationally and internationally. In particular, the first Lancet publication has increased the use of alemtuzumab (one of the tested interventions) nationally.

The published outputs have indicated that alemtuzumab-based induction therapy reduces the risk of rejection compared to current standard treatment with no early complications. This has led some kidney transplant units to adopt alemtuzumab as their standard of care , whereas others are waiting for the longer-term results (and NICE appraisal) to decide whether to change. The avoidance of rejection is of benefit to patients as rejection may reduce the longevity of the transplant. It is also costly so strategies to reduce rejection can save money.

There have been no further yielded benefits realised due to the current constraints of work involving the COVID 19 pandemic. Some of the planned analyses were diverted onto the RECOVERY trial and other Covid-related work, therefore the 3C study was put on hold.

The University of Oxford requires HES, mortality and cancer registration data for the purpose of the 3C study.

Despite improvements in short-term outcomes in kidney transplantation (e.g. acute rejection rates) there has been no improvement in long-term outcomes (e.g. transplant survival at 5 – 20 years after transplantation). One reason for this is that drugs (in particular, calcineurin inhibitors or “CNIs”) used to prevent rejection in fact damage the transplant in the long-term and are major reasons for its ultimate failure. The 3C Study is a randomized trial investigating two strategies that may allow the use of CNIs to be minimised or removed completely. Nearly all kidney transplant trials to date have been both too small and in particular too short-term to detect any clinically meaningful treatment effects in outcomes that matter to patients i.e. long-term function and survival of the transplant. The 3C study therefore aims to study a large enough group of patients for long enough to detect such treatment effects. The 3C Study began in 2010 and will continue follow-up until 2025 at the earliest.

The University of Oxford has determined that there are no moral or ethical issues from dissemination of data for this purpose and the legal basis for processing personal data from NHS Digital is the performance of research in the public interest. Participants also gave consent for their personal data to be collected via linkage with NHS registries (including NHS Digital, or the Health and Social Care Information Centre as it was at the time of consent) which addresses the duty of confidence.

There is minimal risk to the public in processing these data for this purpose. All data will be processed in secure environments and the use of identifying data items will be kept to a minimum (only used to ensure that the linkage between individuals and their data is correct). This research is in the public interest as it will lead to improved understanding of treatments used in kidney transplantation which could lead to improvements in care for the public.

In order to detect the long-term effects of the study treatments cost-effectively, the Clinical Trial Service Unit (CTSU) at University of Oxford prospectively planned to flag all participants with available NHS registries (specifically NHS Digital, the UK Transplant Registry and the UK Renal Registry) to capture information on relevant outcomes. The outcomes that are covered by the registries include cause-specific mortality and site-specific cancer and data on hospitalisation (which includes infections which are a particularly important outcome for kidney transplant recipients).

Data from NHS Digital will be combined with data from other sources (directly from participants via postal questionnaires; and from the UK Transplant Registry and UK Renal Registry) to provide a comprehensive assessment of relevant outcomes of kidney transplantation (e.g. transplant and patient survival). These data will be updated annually.

The 3C Study recruited 852 patients scheduled to undergo kidney transplantation between 2010 and 2013. They were randomized between different treatments at the time of transplantation and then again 6 months later.

The CTSU requires information from NHS Digital on:

(i) cause-specific mortality;

(ii) site-specific cancer; and

(iii) hospital episodes.

These outcomes are key outcomes after kidney transplantation and it would not be possible to properly assess the effects of treatment without such information.

As participants were randomized at an individual level, individual patient level data is required. Linkage between the 3C Study dataset and NHS Digital has already been completed under a previous iteration of this Agreement and, therefore, no further identifying data items are requested from NHS Digital as data can be re-identified and linked using the participant ID.

Long-term outcomes are the particular interest of the 3C Study (unlike other trials which often focus on short-term outcomes).

The geographical spread is determined by the location of the participants in the trial who were recruited from 18 of the 23 adult kidney transplant centres in the UK (including Scotland, Wales and England). There is no alternative method to collect these data which will be as comprehensive (and therefore minimise bias in the randomized comparisons). Similar data is being requested from Scottish and Welsh registries for participants recruited in those devolved nations.

The sole Data Controller and Data Processor is the University of Oxford. As stated above, participants were recruited at 18 NHS trusts (transplant centres), but those trusts are not involved in any way with the processing of these data.

Funders/commissioners of kidney transplantation in the UK are not involved in the processing of these data (although they will be interested in the outputs).

The CTSU also intends to compare the data received from NHS Digital with that collected from other sources of more traditional follow-up (e.g., participant questionnaires). This will provide useful information on how such registry-based follow-up could be used in future trials in transplantation and kidney disease more generally. This may provide a significant opportunity to streamline such trials.

The results of the 3C Study have been published in general and renal/transplant journals. The early results were published in The Lancet July 2014 and the first results using these data were also published in a high-impact medical journal, including American Journal of Transplantation. In addition, they have been presented at national and international meetings such as the British Transplantation Society, the Renal Association. Also in the European Society of Transplantation in September 2017, the American Transplant Congress and the Transplantation Society in July 2014. All outputs will contain only data that is aggregated with small numbers supressed in line with the HES Analysis Guide.

The outputs will also be shared with all appropriate bodies such as NICE and the Cochrane Centre who will inform policy.

The University of Oxford will send a plain English summary of the results to all surviving participants (and publish the same on the University website) at the time of any publication of the relevant output. The University of Oxford will ensure the results are available in open-access format so anyone with an interest can access the outputs.

The commercial sponsors provided funding for the trial and will receive copies of any outputs prior to their public dissemination. They have the right to comment on these outputs, but they cannot require or mandate any changes. For the avoidance of doubt, the principal investigators (all employed by the university) have the final decision regarding any outputs.

The 3C Study has already published two major papers using previous data from NHS Digital and other registries. The results from the next period of the DSA would lead to a further presentation and publication in 2019.

Two major publications have informed practice nationally and internationally. In particular, the first Lancet publication has increased the use of alemtuzumab (one of the tested interventions) nationally.

The University of Oxford requires HES, mortality and cancer registration data for the purpose of the 3C study.

Despite improvements in short-term outcomes in kidney transplantation (e.g. acute rejection rates) there has been no improvement in long-term outcomes (e.g. transplant survival at 5 – 20 years after transplantation). One reason for this is that drugs (in particular, calcineurin inhibitors or “CNIs”) used to prevent rejection in fact damage the transplant in the long-term and are major reasons for its ultimate failure. The 3C Study is a randomized trial investigating two strategies that may allow the use of CNIs to be minimised or removed completely. Nearly all kidney transplant trials to date have been both too small and in particular too short-term to detect any clinically meaningful treatment effects in outcomes that matter to patients i.e. long-term function and survival of the transplant. The 3C study therefore aims to study a large enough group of patients for long enough to detect such treatment effects. The 3C Study began in 2010 and will continue follow-up until 2025 at the earliest.

The University of Oxford has determined that there are no moral or ethical issues from dissemination of data for this purpose and the legal basis for processing personal data from NHS Digital is the performance of research in the public interest. Participants also gave consent for their personal data to be collected via linkage with NHS registries (including NHS Digital, or the Health and Social Care Information Centre as it was at the time of consent) which addresses the duty of confidence.

There is minimal risk to the public in processing these data for this purpose. All data will be processed in secure environments and the use of identifying data items will be kept to a minimum (only used to ensure that the linkage between individuals and their data is correct). This research is in the public interest as it will lead to improved understanding of treatments used in kidney transplantation which could lead to improvements in care for the public.

In order to detect the long-term effects of the study treatments cost-effectively, the Clinical Trial Service Unit (CTSU) at University of Oxford prospectively planned to flag all participants with available NHS registries (specifically NHS Digital, the UK Transplant Registry and the UK Renal Registry) to capture information on relevant outcomes. The outcomes that are covered by the registries include cause-specific mortality and site-specific cancer and data on hospitalisation (which includes infections which are a particularly important outcome for kidney transplant recipients).

Data from NHS Digital will be combined with data from other sources (directly from participants via postal questionnaires; and from the UK Transplant Registry and UK Renal Registry) to provide a comprehensive assessment of relevant outcomes of kidney transplantation (e.g. transplant and patient survival). These data will be updated annually.

The 3C Study recruited 852 patients scheduled to undergo kidney transplantation between 2010 and 2013. They were randomized between different treatments at the time of transplantation and then again 6 months later.

The CTSU requires information from NHS Digital on:

(i) cause-specific mortality;

(ii) site-specific cancer; and

(iii) hospital episodes.

These outcomes are key outcomes after kidney transplantation and it would not be possible to properly assess the effects of treatment without such information.

As participants were randomized at an individual level, individual patient level data is required. Linkage between the 3C Study dataset and NHS Digital has already been completed under a previous iteration of this Agreement and, therefore, no further identifying data items are requested from NHS Digital as data can be re-identified and linked using the participant ID.

Long-term outcomes are the particular interest of the 3C Study (unlike other trials which often focus on short-term outcomes).

The geographical spread is determined by the location of the participants in the trial who were recruited from 18 of the 23 adult kidney transplant centres in the UK (including Scotland, Wales and England). There is no alternative method to collect these data which will be as comprehensive (and therefore minimise bias in the randomized comparisons). Similar data is being requested from Scottish and Welsh registries for participants recruited in those devolved nations.

The sole Data Controller and Data Processor is the University of Oxford. As stated above, participants were recruited at 18 NHS trusts (transplant centres), but those trusts are not involved in any way with the processing of these data.

Funders/commissioners of kidney transplantation in the UK are not involved in the processing of these data (although they will be interested in the outputs).

The CTSU also intends to compare the data received from NHS Digital with that collected from other sources of more traditional follow-up (e.g., participant questionnaires). This will provide useful information on how such registry-based follow-up could be used in future trials in transplantation and kidney disease more generally. This may provide a significant opportunity to streamline such trials.

The results of the 3C Study have been published in general and renal/transplant journals. The early results were published in The Lancet July 2014 and the first results using these data were also published in a high-impact medical journal, including American Journal of Transplantation. In addition, they have been presented at national and international meetings such as the British Transplantation Society, the Renal Association. Also in the European Society of Transplantation in September 2017, the American Transplant Congress and the Transplantation Society in July 2014. All outputs will contain only data that is aggregated with small numbers supressed in line with the HES Analysis Guide.

The outputs will also be shared with all appropriate bodies such as NICE and the Cochrane Centre who will inform policy.

The University of Oxford will send a plain English summary of the results to all surviving participants (and publish the same on the University website) at the time of any publication of the relevant output. The University of Oxford will ensure the results are available in open-access format so anyone with an interest can access the outputs.

The commercial sponsors provided funding for the trial and will receive copies of any outputs prior to their public dissemination. They have the right to comment on these outputs, but they cannot require or mandate any changes. For the avoidance of doubt, the principal investigators (all employed by the university) have the final decision regarding any outputs.

The 3C Study has already published two major papers using previous data from NHS Digital and other registries. The results from the next period of the DSA would lead to a further presentation and publication in 2019.

Two major publications have informed practice nationally and internationally. In particular, the first Lancet publication has increased the use of alemtuzumab (one of the tested interventions) nationally.