Rituximab in Patients With ST-elevation Myocardial Infarction

Study Overview
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Brief Summary
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The main objective is to compare the effect of a single injection of two doses of rituximab versus placebo on 6 months left ventricular systolic function, using CMR, in patients who have had an acute anterior STEMI. The primary endpoint is the left ventricular ejection fraction (LVEF) by CMR at 6 months.

Detailed Description
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RITA-MI 2 is an european phase IIb, multi-center, randomized, parallel, double-blind, placebo-controlled, clinical trial to assess the impact of B cell depletion with the CD20 mAb rituximab (200mg, and 1000mg) on left ventricular dysfunction and cardiac remodelling after acute MI. Sample size : 558 patients, 1:1:1 ratio Assessement: Patients will be recruited immediately after admission for MI. The aim is to start the infusion of IMP within 3 hours of PPCI (defined as first balloon inflation). Eligible patients will be offered to enter the study. In France, Spain and Czech Republic: If they accept, the investigator will collect informed written consent from the patient or from a person of trust/next of kin if the patient is unable to consent. While In Germany, UK and Netherlands, only the patient will be informed and will be able to give consent and no next-of-kin will be informed and have the possibility to give consent. Once the inclusion is confirmed, a specific study blood sample will be taken for later assessment of cytokines and biomarkers related to immune responses, inflammation and cardiac remodelling. It will also be done at discharge and at 6 months. According to usual practice the following blood exams will be done: Kidney function parameters (including serum creatinine, BUN, electrolytes, calcium and eGFR). It will also be done at day 5 (+ 2 days) and at 6 months. NT-pro-BNP will be performed at admission and at 6 months. Blood leukocytes, platelets and hematologic/haemostatic parameters will also be measured at admission and at 6 months. The randomization will be performed and the pharmacy will extemporaneously prepare (aseptically) 2 infusion bags per patient (cf. treatments below). During the infusion, the patient will be carefully monitored with continuous cardiac telemetry: 12 lead ECG with QTc measurement will be performed pre-dosing and post-dosing at admission, discharge and at 6 months. Kidney functions. The patients will be carefully monitored by their treating physicians, as done in usual care, with a special attention to the occurrence of any adverse event related to treatment. CMR will be done at 5 days (+ 2 days) to assess the left ventricular (LV) function, the infarct size and microvascular obstruction and at 6 months. Study staff at the clinical sites will contact each patient at 30 days, 3 months and 12 months following randomization, by phone or during a hospital visit. The patient participation will last after the 12-month visit.

Official Title
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Rituximab in Patients With ST-elevation Myocardial Infarction: A Phase 2 Placebo-controlled Randomized Clinical Trial: RITA-MI 2

Conditions
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ST Elevated Myocardial Infarction

Intervention / Treatment
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* Drug: Active arm 200 mg
* Drug: Active arm 1000 mg
* Drug: Placebo arm


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age 18-75 (women must be either postmenopausal defined as being amenorrhoeic for greater than 2 years with an appropriate clinical profile, e.g. age appropriate (>55 years old), history of vasomotor symptoms) or having documented hysterectomy and/or bilateral oophorectomy) ; Clinical evidence at presentation of anterior ST-elevation myocardial infarction (STEMI) defined as symptoms suggestive of acute myocardial ischemia, an electrocardiogram showing ST-segment elevation ≥2 mm in ≥2 contiguous leads in V1 to V4; Complete occlusion (i.e. TIMI flow 0-1) of proximal or mid left anterior descending (LAD) coronary artery on urgent angiography interpreted as the infarct-related artery (IRA); Onset of worse symptoms within 24 hours before admission; Patients with neutrophils >1.5 x 109/L at the moment of admission Patients with platelet counts >75 x 109 /L at the moment of admission Plan to provide primary percutaneous angioplasty (PPCI) for the patient within 2 hours of ECG diagnosis; Ability to start infusion of rituximab within 3 hours of PPCI ; Written informed consent. Exclusion Criteria: Exclusion Criteria : History of previous MI; Presentation with cardiac arrest; Cardiogenic shock (defined as systolic blood pressure <90 mmHg for >30minutes, or necessitating vasopressors to achieve a blood pressure ≥90 mmHg); Cardiac electrical instability (defined as complete heart block needing temporary pacing or any tachyarrhythmia needing cardioversion); Patients with Killip class III heart failure; History of severe chronic renal failure (define as stage 4 (GFR = 15-29 mL/min) or worse); History of hepatitis B, HIV or tuberculosis; Patient positive for point of care bedside test of Ag HBs; Severe, progressive infections documented; Active COVID-19 infection or COVID-19 infection within 3 months; Patient with documented severe immune deficiency; Presence, or history in ≤ five years, of an ongoing cancer, (except in situ cancer of the cervix or basal cell carcinoma); QTcF> 450 msecs in males, > 470msecs in females; Any oral or intravenous immunosuppressive treatment, immune modulatory monoclonal antibodies or immunodepleting therapy at any time (inhalers and topical creams with corticosteroids are permitted); Previous history of major organ transplant including renal transplant; Known hypersensitivity to the active substance of rituximab or to proteins of murine origin, or to any of the other excipients; Any contraindications to any of the rituximab premedication drugs; Contraindications to injectable Polaramine: Risk of closed-angle glaucoma, Risk of urinary retention linked to urethro-prostatic disorders; Expected need for vaccination with a live attenuated vaccine during the study, including incomplete vaccination courses (in case, life, attenuated vaccine must be administered at least 30 days before inclusion in study); Absence of a complete COVID-19 vaccination scheme (including recovery from documented COVID infection) as approved at the time of enrollment in the country where the patient is recruited; Any obvious contraindications for MRI or conditions which will impede image acquisition for example: Severe claustrophobia Non-MRI compatible permanent pacemaker Patients who have a metallic foreign body (metal silver) in their eye, or who have an aneurysm clip in their brain Patients who have had metallic devices placed in their back Known hypersensitivity to imaging products (gadoteric acid, meglumin or any drug containing gadolinium) Known hepatic failure; Previous history of progressive multifocal leukoencephalopathy; Inclusion in other interventional drug study within the previous 3 months; Inability to comply with study procedures; Patients under guardianship or curatorship.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Active arm 200 mg<br>Active arm 200 mg: 1 bag containing 200 mg of rituximab (MabThera® or biosimilar ) in 100ml of NaCl 0.9%; 1 bag of 400 ml of NaCl 0.9%. | Drug: Active arm 200 mg<br>* Active arm 200 mg: 1 bag containing 200 mg of rituximab (MabThera® or biosimilar ) in 100ml of NaCl 0.9%; 1 bag of 400 ml of NaCl 0.9%.<br>|
| Experimental: Active arm 1000 mg<br>Active arm 1000 mg: 1 bag containing 200 mg of rituximab (MabThera® or biosimilar ) in 100ml of NaCl 0.9%; 1 bag containing 800 mg rituximab (MabThera® or biosimilar ) in 400 ml of NaCl 0.9%. | Drug: Active arm 1000 mg<br>* Active arm 1000 mg: 1 bag containing 200 mg of rituximab (MabThera® or biosimilar ) in 100ml of NaCl 0.9%; 1 bag containing 800 mg rituximab (MabThera® or biosimilar ) in 400 ml of NaCl 0.9%.<br>|
| Placebo Comparator: Placebo arm<br>1 bag of 100 ml of NaCl 0.9%; 1 bag of 400 ml of NaCl 0.9%. | Drug: Placebo arm<br>* Placebo arm: 1 bag of 100 ml of NaCl 0.9%; 1 bag of 400 ml of NaCl 0.9%.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Left ventricular ejection fraction (LVEF) by CMR at 6 months. | To compare the effect of a single injection of two doses of rituximab versus placebo on 6 months left ventricular systolic function, using CMR, in patients who have had an acute anterior STEMI. | 6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Infarct size by CMR | To compare the effects of rituximab versus placebo on infarct size by CMR at day 5 (+/-2) and at 6 months. | At day 5 (+/-2) and at 6 months | 
| Oedema extension by CMR | To compare the effects of rituximab versus placebo on oedema extension by CMR at day 5 (+/-2) . | At day 5 (+/-2) | 
| T2 relaxation time at ischemic region by CMR | To compare the effects of rituximab versus placebo on T2 relaxation time at ischemic region by CMR (using T2 mapping) at day 5 (+/-2). | At day 5 (+/-2) | 
| Microvascular obstruction by CMR | To compare the effects of rituximab versus placebo on microvascular obstruction by CMR (hypointense areas within LGE) at day 5 (+2/-) . | At day 5 (+/-2) | 
| NT-pro-BNP | To compare the effects of rituximab versus placebo on NT-pro-BNP at 6 months. | At 6 months | 
| Adverse event related to treatment | To compare the effects of rituximab versus placebo on any adverse event related to treatment . | Until 12 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Acute Myocardial Infarction, Anterior STEMI, Rituximab, Left ventricular systolic function, Cardiac remodelling, CMR