20th September 2023 RAMPART SUBSTANTIAL AMENDMENT 26 (Protocol v7.0)We have now received approval from the MHRA, HRA and REC for an amendment to the RAMPART Protocol (v7.0, Jun-23). The main reason for amending the RAMPART Protocol is modifications to the statistical analysis plan. In 2021, KEYNOTE-564 (NCT03142334) was the first trial to report results for an immune checkpoint inhibitor (ICI) as an adjuvant therapy for participants with renal cell cancer (RCC) at high risk of disease recurrence after its first planned interim analysis. Pembrolizumab after surgery resulted in a significant improvement in disease free survival (DFS) compared with placebo; a hazard ratio for DFS of 0.63 (95% CI 0.50–0.80) was observed with 30.1 months follow-up in updated results published in Sept 2022 (57). Based on these results, pembrolizumab was approved by the European Medicines Agency (EMA) and US Food and Drug Administration (FDA) for the treatment of RCC in the post-nephrectomy adjuvant setting. Recommendations for reimbursement from the National Institute for Health and Care Excellence (NICE) and the Scottish Medicines Consortium (SMC) meant pembrolizumab became available in the UK in October 2022 as a treatment option for many of the patients who would be eligible for RAMPART. Pembrolizumab was subsequently approved for reimbursement in Spain in December 2022. Pembrolizumab is not yet reimbursed in the other countries around the world where RAMPART is being conducted (France and Australia).Based on the KEYNOTE-564 trial results our pharmaceutical partner has requested that we stop recruitment. The decision to end recruitment to the current three arms RAMPART has not been made because of any safety concerns relating to either durvalumab or tremelimumab. The RAMPART trial has an adaptive platform design. We are closing recruitment to the original three arms of RAMPART. In the future we may use the platform design to investigate new research questions. We have taken this opportunity to make a number of smaller additional changes to the RAMPART Protocol. All amendments are listed in full in the supporting document Summary of Changes from RAMPART Protocol v6.0 to v7.0. Alongside the updated Protocol, we are also submitting some new and amended documents for review. The Durvalumab Investigator Brochure has recently been updated by AstraZeneca and there are new expected toxicities listed for durvalumab in combination with tremelimumab. It is our intention to use this new version of the IB (v18.0, Feb-2023) as our Reference Safety Information (RSI), specifically tables 30 and 32, once approval is granted by the MHRA. In response to the updated safety information, we have made the appropriate changes to our Participant Information Sheet (v8.0) to ensure are patients are adequately informed. LINKS: SA26 zip folder
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30th June 2023 RAMPART IS NOW CLOSED TO RECRUITMENT At 5pm (BST) on Friday 30th June 2023 RAMPART, in its current form, closed to recruitment. We will not be randomising any more patients to the trial from now. Nothing will change for current participants. All patients currently enrolled on the trial will continue their treatment and follow-up as per protocol. A protocol amendment reflecting the changes to the trial is currently with the regulators, awaiting their review. We wish to thank all out sites for their hard work recruiting patients to RAMPART and for your continued participation and support. |
3rd May 2023 RAMPART CLOSURE TO RECRUITMENTFollowing discussions between the TMG and our pharmaceutical partners, AstraZeneca, we are writing to notify you that RAMPART will be closing to recruitment on Friday 30th June 2023. Patients already participating in RAMPART and those who are randomised between now and the end of June will continue their allocated treatment/Follow-up as per the protocol. There are two documents linked below that provide details about this decision and what this means for your sites moving forward. These documents are:
The RAMPART Trial Management team wish to thank you all for your continued work and support on RAMPART and we look forward to continuing to work with you in the coming years. Links: RAMPART Closure letter, FAQs |
29th March 2023 RAMPART SUBSTANTIAL AMENDMENT 22 (Protocol v6.0)We have now received approval from the MHRA, HRA and REC for an amendment to the RAMPART Protocol (v6.0, Aug-22). Changes to the protocol There are two main reasons for amending the trial Protocol. Firstly, we are introducing a new patient population into the RAMPART trial. Patients that develop a single fully resected soft tissue metastasis at any organ site between 6-24 months after nephrectomy will now be considered eligible. These patients are considered to have a similar risk to those in the high risk group in RAMPART, and are currently treated in the same manner as adjuvant patients. They are an understudied group of patients with a substantial risk of relapse that the RAMPART Trial Management Group believe would benefit from adjuvant therapy after their metastectomy. This change will more closely align the RAMPART patient population with that of the KEYNOTE-564 and IMMOTION-010 studies. As part of this amendment, we have also made changes to the list of mandatory blood tests that must be performed and checked as part of screening and prior to each treatment administration (see tables 3, 4, 13 and 14 in the RAMPART Protocol). After review by the clinical members of the Trial Management Group, we have removed the blood tests that were both considered to have lower clinical importance in this setting, and which have very low numbers of associated adverse events reported within the trial to date. All participants will still be required to have the reduced list of blood tests checked prior to randomisation and treatment to ensure that it is safe to proceed, and sites are advised to continue to undertake any additional investigations as clinically indicated. We have taken this opportunity to make a number of smaller additional changes to the RAMPART Protocol. All amendments are listed in full in the supporting document Summary of Changes from RAMPART Protocol v5.0 to v6.0. Updated supporting documents Alongside the updated Protocol, we are also introducing some new and updated supporting documents. The Durvalumab Investigator Brochure (IB) has recently been updated by AstraZeneca and there are new expected toxicities listed for both durvalumab monotherapy and the combination with tremelimumab. It is our intention to use this new version of the IB (v17.0, Oct-2021) as our Reference Safety Information (RSI) moving forward. In response to the updated safety information, we have made some changes to our Participant Information Sheet (PIS) to ensure that our patients are adequately informed. The PIS has also been updated to reflect changes to the standard of care in the UK. These updates to the PIS have been approved by the TMG, CI (Dr James Larkin) and Patient and Public Involvement (PPI) representative. The new version of the PIS (v7.0, 17-Oct-2022) should be given to all prospective patients once local approval has been granted. It is not necessary to re-consent existing participants as the TMG do not feel these updates change the risk/benefit assessment. Please note that we have also made some changes to existing CRFs to accommodate the protocol amendments. New versions of the Randomisation CRF (Form01), Eligibility CRF (Form02), Surgery CRF (Form03), Treatment CRF (Form05A) and Additional Lab (Form19A). These forms were not part of the substantial amendment submissions and do not require approval for use Training We have prepared a brief set of slides to provide some additional details and guidance about the changes to the RAMPART Protocol and trial practice. These slides should be forwarded to all members of the local research team who are working on the study. Please ensure that the RAMPART Training Log is updated following review of the slides and a copy sent to the RAMPART team (mrcctu.rampart@ucl.ac.uk). Links: SA 22 zip folder, Updated CRFs |
2nd July 2020
RAMPART Re-Opens
The RAMPART trial has now officially re-opened in the UK. All participating sites will need to complete the re-activation process before they are ready to start recruiting new patients and treating existing patients again. Please contact the RAMPART team if you have not received an email outlining this process. We have made amendments to the trial protocol in response to the Covid-19 pandemic. The study will now allow extended treatment breaks for the management of patients during the Covid-19 pandemic. There are also new inclusion/exclusion criteria relating to Covid-19. All trial participants will be offered the opportunity to resume their trial treatment, provided this does not extend beyond one year after their first dose. The local study team will be in contact with all patients to discuss their options.
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19th March 2020
COVID-19 Update
In the light of the rapidly evolving situation with COVID-19 in the UK, we are implementing a number of amendments to the RAMPART trial with immediate effect. This builds on initial, more general COVID-19 correspondence that was sent on behalf of our unit director on 13th March 2020. Recruitment
Treatment
Follow-up
Communication with Patients
Reporting SAEs and Data Collection
Reason for this Amendment
Review of this Amendment
Practicalities
Contacting Us
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16th September 2021 New Publications
We're pleased to announce that we have recently published two RAMPART articles in the journal of Contemporary Clinical Trials. The first is focussed on the RAMPART Protocol and describes some of the unique and interesting approaches we are taking to trial conduct. The second paper explores adaptive trial designs, regulatory futureproofing and our experiences in RAMPART. Links: Protocol Paper, Design Rationale Paper
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15th September 2021 New Patient Population Goes Live
We’re pleased to confirm that we are now in a position to start recruiting patients with synchronous ipsilateral adrenal metastases into the RAMPART trial. Thank you for your patience while we made the necessary changes to our trial database. Sites can start screening these patients with immediate effect once RAMPART Protocol v5.0 has received local approval.
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22nd July 2021 Recruitment Milestone - 300 Participants!
Our 300th RAMPART participant was recruited this afternoon at Charing Cross Hospital. A massive thank you to all our RAMPART teams for their ongoing support of this important study. Please check out our recruitment table if you'd like to see how you compare to other sites. There has been a notable increase in recruitment over recent months and we hope to reach the next milestone in record time! Links: Recruitment Table
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22nd July 2021 First French Site
The RAMPART trial has now officially opened in France. The first site open to recruitment is Institut Paoli-Calmettes in Marseille. We plan to open a further 24 sites before the end of the year, please refer to the site map for details. Links: Site Map
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29th June 2021 Protocol Amendment (v5.0 March 2021)
We have now received approval from the MHRA, HRA and REC for an amendment to the RAMPART Protocol (v5.0, Mar-2021) Changes to the Protocol There are two main reasons for amending the trial Protocol. Firstly, we are introducing a new patient population into the RAMPART trial. Patients who present with synchronous ipsilateral adrenal metastases, which can be completely resected (adrenal metastasectomy) at the time of nephrectomy, will now be considered eligible for the RAMPART trial. These patients are considered to have a similar risk to those in the high risk group in RAMPART, and are currently treated in the same manner as adjuvant patients. They are an understudied group of patients with a substantial risk of relapse that the RAMPART Trial Management Group (TMG) believe will benefit from adjuvant therapy after surgery. We need to make some minor changes to our trial database to allow these patients to be randomised. We ask that you hold-off screening these patients until you receive further notification from the RAMPART team. The other main reason for this amendment is a series of changes that aim to reduce the burden on our sites and participants. To achieve this we are implementing remote practices across the study. It is now acceptable to conduct remote pre-treatment assessments, where deemed appropriate by the Investigator. We have also introduced new guidance on the remote consent of potential participants. There are also some substantial changes to the trial assessments. We have removed (ECGs) or reduced the frequency (physical exams, vital signs) of our trial assessments where the TMG felt it was safe to do so. Updated Supporting Documents Alongside the updated Protocol, we are also introducing some new and updated supporting documents. The Durvalumab Investigator Brochure (IB) has recently been updated by AstraZeneca and there are new expected toxicities listed for both durvalumab monotherapy and the combination with tremelimumab. It is our intention to use this new version of the IB (v16.0, Oct-2021) as our Reference Safety Information (RSI) moving forward. In response to the updated safety information we have made some changes to our Participant Information Sheet (PIS) to ensure that our patients are adequately informed. The new version of the PIS (v5.0, Mar-2021) should be given to all prospective patients once local approval has been granted. It is not necessary to re-consent existing participants as the TMG do not feel these updates change the risk/benefit assessment. We also have a new participation questionnaire, Preferences for Adjuvant Immunotherapy in RAMPART (PAIR), which aims to establish the benefit our participants judge sufficient to make their treatment worthwhile. These questionnaires are optional for RAMPART participants. Those who agree to participate in the Participant Reported Outcome sub-study on the RAMPART Consent Form (optional consent A) should be asked to complete the questionnaire at the relevant visits. Please note that we have also made some changes to existing CRFs to accommodate the protocol amendments. New versions of the Randomisation CRF (Form01), Eligibility CRF (Form02) and Treatment CRF (Form05) have been attached and should be used with immediate effect. These forms were not part of the substantial amendment submissions and do not require approval for use. Training We have prepared a brief set of slides to provide some additional details and guidance about the changes to the RAMPART Protocol and trial practice. These slides should be forwarded to all members of the local research team who are working on the study. Please ensure that the RAMPART Training Log is updated following review of the slides and a copy sent to the RAMPART team mrcctu.rampart@ucl.ac.uk. Links: Amendment Documents, Randomisation CRF, Eligibility CRF, Treatment CRF, Training Slides
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4th February 2021 New Covid-19 CRF and Analysis
There are currently no published prospective data on the safety of Covid-19 vaccines for patients receiving immune checkpoint inhibitor (ICPI) therapy. Thus, there is a need to capture data and understand the impact of ICPIs in modulating the response to the vaccine. Three Covid-19 vaccines have been approved for use in the UK to date: the Pfizer BioNTec, Oxford University/AstraZeneca and Moderna vaccines. The vaccines are not live vaccines and are therefore acceptable for patients with immunosuppression undergoing cancer treatment. RAMPART trial participants are eligible to receive a Covid-19 vaccine via their registered GPs and we recently contacted sites to provide recommendations for patients about the Covid-19 vaccine. We expect that most RAMPART participants will be vaccinated. In RAMPART, RCC patients are randomised to receive either active monitoring (no treatment, but observation by clinical and radiological means), durvalumab monotherapy (an anti-PDL-1 therapy), or a combination of durvalumab and tremelimumab (an anti-CTLA-4 therapy). We collect comprehensive data on patient safety. We are therefore in a privileged position where we can prospectively evaluate the safety (and efficacy) of Covid-19 vaccination in patients who are randomised to ICPI therapy or no treatment. We are therefore introducing a new CRF and asking for your help to collect this important data on as many RAMPART patients as possible. The data generated will be relevant to the many patients around the world receiving ICPI therapy and to all patients who will get Covid-19 vaccines in due course. The new Covid-19 CRF (Form22) has been designed to capture specific information about the vaccinations patients receive and information on subsequent infection. The CRF should be completed once per participant and updated as appropriate. We are very interested to know about any adverse events that are experienced following administration of the vaccines and would ask that you continue to document these on the Adverse Events Log (Form06). Links: Covid-19 CRF
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7th January 2021 First TransRAMPART Site and Participant
Congratulations to the team at Warwick Hospital, who are the first TransRAMPART site to open to recruitment. The team have subsequently also enrolled the first TransRAMPART participant into the study. |
14th July 2022
The latest RAMPART Newsletter was sent out today. It contains some important updates including; information about the latest protocol amendments for RAMPART and TransRAMPART, CRF updates, Image Repository and the future of RAMPART moving forward.
Links: July Newsletter