Periodic Reporting for period 2 - RITA-MI 2 (Rituximab in patients with acute myocardial infarction: a phase 2 placebo-controlled randomised clinical trial)
Periodo di rendicontazione: 2022-12-01 al 2024-05-31
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 RITA-MI2 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 the second reporting period.
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 project’s progress is regularly monitored, during monthly Project Management Team meetings, and bi-annual EX-COM meetings. The External Advisory Board has been established, met at the 1st and 2nd Annual Meeting, and issued reports correspondingly. Continuous support on all administrative, financial, and legal issues is provided to the project partners.
WP2 aims to coordinate the conduct of the RITA-MI2 trial, and monitor its progress by providing operational support in all countries. The study has been approved and authorized by the French national competent authority and the French ethics committee. During this second reporting period, regulatory authorization for all other participating countries has been obtained (via the CTIS for all, and MHRA for the UK). The trial specific documentation has been prepared, recruitment monitored, and meetings organized.
WP3 is related to the operational organisation and conduct of the RITA-MI 2 trial, in accordance with Good Clinical Practice (GCP). During this second reporting period, a centre was added for France, bringing the total number of centres in France to 15. 5 sites were opened to recruitment in the UK, Spain, Germany and Czech Republic (Papworth, Charité, IIS-FJD, TUM-MED and FNKV) between September 2023 and May 2024. 55 patients were included during the reporting period, bringing the total number of patients included since the start of the study to 67. 10 monitoring visits were carried out in operating centres in France, one monitoring in the UK (at Papworth) and one in Spain (IIS-FJD).
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.
During this second reporting period, the protocol for CMR acquisition and analysis, in accordance with the objectives of the RITA-MI2 trial, as well as a manual for uploading images to P5 CMR Core Lab server has been distributed to the newly included sites. All documents are also available on the RITA-MI2 extranet. A meeting with Centres’ CMR Managers has been held to review the main imaging objectives of the trial. The CMR images from enrolled patients have been received and properly stored on the CMR Core Lab server. Centres are contacted by the CMR Core Lab if help is needed to upload the CMR images, as well as to give feedback in case acquisitions can be further optimized. CMR analyses are carried out in accordance with current standards and the main objectives of the trial, and in a centralized unit (Core Lab) which offers impartial and reliable assessments, thus reducing variability.
PET/CT imaging validations have been initiated. The protocol for the acquisition and analysis of the PET-CT data has been prepared and distributed to participating centers. Clinical variables and imaging-related parameters have been added to the online CRF. REC and ARSAC applications have been submitted. An online DICOM transfer system has been arranged.
WP5 objective is to assess the biological efficacy of rituximab in depleting circulating B cells, and to determine the levels of several circulating cytokines and cardiobiomarkers. Analysis of RITA-MI2 samples is currently on hold, as patients’ recruitment is delayed. Meanwhile, feasibility studies using similar blood sample types from other ongoing clinical trials (RITA-MI and LILACS) have been performed. These feasibility studies have enabled us to validate our methodologies for multiplex biomarker measurements on plasma using the O’LINK platform, as well as single-cell RNA sequencing and single-cell BCR sequencing on blood immune cells. This ensures our readiness to conduct optimal analysis on the RITA-MI2 samples upon their availability.
WP6 objective is to ensure international visibility of the RITA-MI2 project, as well as the optimal exploitation of the project’s results. Communication tools have been developed to communicate 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 project’s progress is regularly monitored, during monthly Project Management Team meetings, and bi-annual EX-COM meetings. The External Advisory Board has been established, met at the 1st and 2nd Annual Meeting, and issued reports correspondingly. Continuous support on all administrative, financial, and legal issues is provided to the project partners.
WP2 aims to coordinate the conduct of the RITA-MI2 trial, and monitor its progress by providing operational support in all countries. The study has been approved and authorized by the French national competent authority and the French ethics committee. During this second reporting period, regulatory authorization for all other participating countries has been obtained (via the CTIS for all, and MHRA for the UK). The trial specific documentation has been prepared, recruitment monitored, and meetings organized.
WP3 is related to the operational organisation and conduct of the RITA-MI 2 trial, in accordance with Good Clinical Practice (GCP). During this second reporting period, a centre was added for France, bringing the total number of centres in France to 15. 5 sites were opened to recruitment in the UK, Spain, Germany and Czech Republic (Papworth, Charité, IIS-FJD, TUM-MED and FNKV) between September 2023 and May 2024. 55 patients were included during the reporting period, bringing the total number of patients included since the start of the study to 67. 10 monitoring visits were carried out in operating centres in France, one monitoring in the UK (at Papworth) and one in Spain (IIS-FJD).
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.
During this second reporting period, the protocol for CMR acquisition and analysis, in accordance with the objectives of the RITA-MI2 trial, as well as a manual for uploading images to P5 CMR Core Lab server has been distributed to the newly included sites. All documents are also available on the RITA-MI2 extranet. A meeting with Centres’ CMR Managers has been held to review the main imaging objectives of the trial. The CMR images from enrolled patients have been received and properly stored on the CMR Core Lab server. Centres are contacted by the CMR Core Lab if help is needed to upload the CMR images, as well as to give feedback in case acquisitions can be further optimized. CMR analyses are carried out in accordance with current standards and the main objectives of the trial, and in a centralized unit (Core Lab) which offers impartial and reliable assessments, thus reducing variability.
PET/CT imaging validations have been initiated. The protocol for the acquisition and analysis of the PET-CT data has been prepared and distributed to participating centers. Clinical variables and imaging-related parameters have been added to the online CRF. REC and ARSAC applications have been submitted. An online DICOM transfer system has been arranged.
WP5 objective is to assess the biological efficacy of rituximab in depleting circulating B cells, and to determine the levels of several circulating cytokines and cardiobiomarkers. Analysis of RITA-MI2 samples is currently on hold, as patients’ recruitment is delayed. Meanwhile, feasibility studies using similar blood sample types from other ongoing clinical trials (RITA-MI and LILACS) have been performed. These feasibility studies have enabled us to validate our methodologies for multiplex biomarker measurements on plasma using the O’LINK platform, as well as single-cell RNA sequencing and single-cell BCR sequencing on blood immune cells. This ensures our readiness to conduct optimal analysis on the RITA-MI2 samples upon their availability.
WP6 objective is to ensure international visibility of the RITA-MI2 project, as well as the optimal exploitation of the project’s results. Communication tools have been developed to communicate 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.