Periodic Reporting for period 1 - RITA-MI 2 (Rituximab in patients with acute myocardial infarction: a phase 2 placebo-controlled randomised clinical trial)
Reporting period: 2021-06-01 to 2022-11-30
Despite major progress in the management of acute myocardial infarction, it remains the leading cause of death across Europe and worldwide. In addition to the existing therapies, basic and clinical results support a new concept: interfering with selected white blood cells with rituximab, a drug commonly used clinically in other disease settings, may limit the size of myocardial infarction (MI) and improve the recovery of heart function. The RITA-MI2 project investigators have successfully completed a phase 1/2a clinical trial, which established the safety of rituximab treatment at the acute phase of MI. The project includes a phase 2b randomised double-blind placebo-controlled clinical trial to assess the impact of B cell depletion using the CD20 mAb rituximab on the recovery of heart function after acute MI. A sub-study will assess the impact of rituximab on the progression of vascular inflammation after acute MI.
The project has made good progress towards its objectives during its first 18 months.
WP1 aims at ensuring the RITA-MI2 project achieves its objectives and outcomes. To this end, the RITA-MI2 consortium management framework was set up, several consortium meetings organised and the private project management platform activated. The External Advisory Board has been established and met at the 1st Annual Meeting.
WP2 aims to coordinate the conduct of the RITA-MI2 trial, and monitor its progress by providing operational support in all countries. During this reporting period, the study has been approved and authorized by the French national competent authority and the French ethics committee. Regulatory authorization for all other participating countries has been submitted (via the CTIS for all but the UK, and to MHRA for the UK). At the end of the reporting period, authorization from the national competent authorities and the ethics committees was still pending, but in progress. The trial specific documentation has been prepared, recruitment monitored, and meetings organized. A CRO was nominated, and the DSMB met. Quality Management procedures have been prepared ensuring the trial safety.
WP3 is related to the operational organisation and conduct of the RITA-MI 2 trial, in accordance with Good Clinical Practice (GCP). During this reporting period, the trial has been set-up in 14 sites in France. The first patient has been included in June 2022 and monitoring visits have begun. The Statistical Analysis Plan has been validated and approved. The eCRF has been made available for use, and access enabled for Cardiac Magnetic Resonance Imaging reading and analyses. A first version of the Data Management Plan, covering all data to be generated during the project, has been elaborated.
WP4 objective is to assess the effect of a single dose of rituximab in patients with a first acute STEMI by cardiovascular magnetic resonance (CMR). Vascular inflammation will also be assessed using PET/CT. A protocol for the acquisition and analysis of the CMR has been prepared, in accordance with the objectives of the RITA-MI2 trial, and has been distributed to the participating centers, as well as a manual for sending images to the CMR Core Lab. The latter has started validating recruiting centers via test studies. Feedback has been sent to most centers to optimize and standardize CMR acquisition. Most of the CMRs of the recruited patients have been successfully received, and the analysis and uploading of data in the eCRF has begun. The CMR analysis has been performed keeping the blind and analyzing the objectives set out in the project.
A protocol for the acquisition and analysis of the PET-CT data has also been prepared, in accordance with the objectives of the trial, and has been distributed to participating centers. The protocol was designed by the PET-CT Core Lab team and approved by all centers participating in the PET-CT substudy. PET-CT variables have been included in the eCRF, which has been tested. As part of the protocol, a phantom study has been designed to standardize PET-CT reconstructions across scanners from different partner sites. The validation process of the PET-CT imaging tests of the centers that will participate in this substudy has been initiated.
WP5 objective is to assess the biological efficacy of rituximab in depleting circulating B cells. Work related to this WP is currently on hold, as patients’ recruitment is delayed. However, as similar blood sample types are used in other ongoing clinical trials, we are confident that the blood samples to be collected in RITA-MI2 will be of high quality for CyTOF and single-cell transcriptomic analyses.
WP6 objective is to ensure international visibility of the RITA-MI 2 project, as well as the optimal exploitation of the project’s results. Communication tools have been developed to inform on the project and its findings, of which the RITA-MI2 logo and graphical chart, and the RITA-MI2 website. A poster and a flyer have also been issued. The project’s Communications Plan has been prepared.
WP7 ethics requirements due during the period have been complied with.
WP1 aims at ensuring the RITA-MI2 project achieves its objectives and outcomes. To this end, the RITA-MI2 consortium management framework was set up, several consortium meetings organised and the private project management platform activated. The External Advisory Board has been established and met at the 1st Annual Meeting.
WP2 aims to coordinate the conduct of the RITA-MI2 trial, and monitor its progress by providing operational support in all countries. During this reporting period, the study has been approved and authorized by the French national competent authority and the French ethics committee. Regulatory authorization for all other participating countries has been submitted (via the CTIS for all but the UK, and to MHRA for the UK). At the end of the reporting period, authorization from the national competent authorities and the ethics committees was still pending, but in progress. The trial specific documentation has been prepared, recruitment monitored, and meetings organized. A CRO was nominated, and the DSMB met. Quality Management procedures have been prepared ensuring the trial safety.
WP3 is related to the operational organisation and conduct of the RITA-MI 2 trial, in accordance with Good Clinical Practice (GCP). During this reporting period, the trial has been set-up in 14 sites in France. The first patient has been included in June 2022 and monitoring visits have begun. The Statistical Analysis Plan has been validated and approved. The eCRF has been made available for use, and access enabled for Cardiac Magnetic Resonance Imaging reading and analyses. A first version of the Data Management Plan, covering all data to be generated during the project, has been elaborated.
WP4 objective is to assess the effect of a single dose of rituximab in patients with a first acute STEMI by cardiovascular magnetic resonance (CMR). Vascular inflammation will also be assessed using PET/CT. A protocol for the acquisition and analysis of the CMR has been prepared, in accordance with the objectives of the RITA-MI2 trial, and has been distributed to the participating centers, as well as a manual for sending images to the CMR Core Lab. The latter has started validating recruiting centers via test studies. Feedback has been sent to most centers to optimize and standardize CMR acquisition. Most of the CMRs of the recruited patients have been successfully received, and the analysis and uploading of data in the eCRF has begun. The CMR analysis has been performed keeping the blind and analyzing the objectives set out in the project.
A protocol for the acquisition and analysis of the PET-CT data has also been prepared, in accordance with the objectives of the trial, and has been distributed to participating centers. The protocol was designed by the PET-CT Core Lab team and approved by all centers participating in the PET-CT substudy. PET-CT variables have been included in the eCRF, which has been tested. As part of the protocol, a phantom study has been designed to standardize PET-CT reconstructions across scanners from different partner sites. The validation process of the PET-CT imaging tests of the centers that will participate in this substudy has been initiated.
WP5 objective is to assess the biological efficacy of rituximab in depleting circulating B cells. Work related to this WP is currently on hold, as patients’ recruitment is delayed. However, as similar blood sample types are used in other ongoing clinical trials, we are confident that the blood samples to be collected in RITA-MI2 will be of high quality for CyTOF and single-cell transcriptomic analyses.
WP6 objective is to ensure international visibility of the RITA-MI 2 project, as well as the optimal exploitation of the project’s results. Communication tools have been developed to inform on the project and its findings, of which the RITA-MI2 logo and graphical chart, and the RITA-MI2 website. A poster and a flyer have also been issued. The project’s Communications Plan has been prepared.
WP7 ethics requirements due during the period have been complied with.
The RITA-MI2 project is unique for several reasons:
1. Despite the critical role of the immune system in ischaemic cardiovascular diseases, we lack effective and safe cardiovascular immunotherapies. The RITA-MI2 project is built on ground breaking scientific concepts and aims to interfere with the most critical pathways in the chain of events leading to cardiovascular complications after MI. We target previously unsuspected inflammatory and immune-related pathways (dependent on mature B lymphocytes) involved in the initiation and progression of atherosclerotic cardiovascular disease. Our strategy has the potential to radically change the management of patients with ischaemic heart disease.
2. The RITA-MI2 project is straightforward and the treatment strategy is easy to implement. It involves a ‘fire-and-forget’ approach with a single infusion of the CD20 antibody rituximab at the admission for acute MI, with the aim to deplete the harmful white blood cells transiently during the most critical first few weeks / months after MI, thereby improving efficacy while limiting any potential side effect.
3. The proposed therapeutic approach simultaneously targets critical pathways involved in comorbidities associated with ischaemic heart disease, including diabetes and rheumatoid arthritis. As such, RITA-MI 2 has the ambition to provide novel therapeutic solutions to patients with multi-morbidities who suffer the most from the complications of cardiovascular diseases.
1. Despite the critical role of the immune system in ischaemic cardiovascular diseases, we lack effective and safe cardiovascular immunotherapies. The RITA-MI2 project is built on ground breaking scientific concepts and aims to interfere with the most critical pathways in the chain of events leading to cardiovascular complications after MI. We target previously unsuspected inflammatory and immune-related pathways (dependent on mature B lymphocytes) involved in the initiation and progression of atherosclerotic cardiovascular disease. Our strategy has the potential to radically change the management of patients with ischaemic heart disease.
2. The RITA-MI2 project is straightforward and the treatment strategy is easy to implement. It involves a ‘fire-and-forget’ approach with a single infusion of the CD20 antibody rituximab at the admission for acute MI, with the aim to deplete the harmful white blood cells transiently during the most critical first few weeks / months after MI, thereby improving efficacy while limiting any potential side effect.
3. The proposed therapeutic approach simultaneously targets critical pathways involved in comorbidities associated with ischaemic heart disease, including diabetes and rheumatoid arthritis. As such, RITA-MI 2 has the ambition to provide novel therapeutic solutions to patients with multi-morbidities who suffer the most from the complications of cardiovascular diseases.