Rituximab in Patients With Acute ST-elevation Myocardial Infarction Study

Study Overview
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Brief Summary
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RITA-MI aims to develop of a novel therapeutic concept to target the immune response in patients with acute myocardial infarction (MI) by depleting B-cells with a single injection of Rituximab which is approved for clinical use in cancer, autoimmune disease and inflammatory conditions. The goal is to re-purpose the drug, and translate the discovery into benefit for patients at high risk of cardiovascular events. Rituximab is expected to limit infarction size and improve the healing process, as complementary to other therapeutic strategies. The applicants intend to perform a clinical study in patients with acute myocardial infarction (MI). The objective is to find the optimal dose (lowest dose with highest biological efficacy and best safety profile) for peripheral blood B cell depletion during the first 6 days after injection, and selective molecular signatures associated with improved heart function through analysis of peripheral blood samples. The study rationale is to decrease the inflammatory reaction upon tissue necrosis following heart muscle ischemia.

Official Title
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Rituximab in Patients With Acute ST-elevation Myocardial Infarction Study

Conditions
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Ischemic Heart Disease, Myocardial Infarction, Inflammation

Intervention / Treatment
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* Drug: RiTUXimab Injection


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age 18-75 years old Acute anterior (left anterior descending artery) STEMI and successful primary percutaneous coronary intervention (PCI) with stent implantation in the culprit lesion during the first 24h after onset of symptoms Exclusion Criteria: A previous history of STEMI Cardiogenic shock (systolic blood pressure <80 mm Hg, unresponsive to fluids, or necessitating catecholamines), electrical instability or severe congestive heart failure Residual severe proximal bystander disease awaiting inpatient revascularisation Corrected QT interval (QTc) > 500 msecs using Bazett's formula Hematologic abnormalities (hemoglobin <10 g/dL or hematocrit <30%, platelet cell count of <100 x103/μL, white blood cell count <4 x103/μL) Hypogammaglobulinaemia (defined as <3g/L of IgG) Renal failure (estimated GFR by the MDRD formula < 45 ml/min/1.73m2); Known hepatic failure or abnormal liver function tests at baseline (ALT > 2 x ULN). Active or recurrent hepatitis (type B). Known HIV infection Current or previous tuberculosis (Chest X-Ray) Current infections Presence or history in the previous five years of an ongoing cancer, except in situ cancer of the cervix or basal cell carcinoma Any oral or intravenous immunosuppressive treatment (other than concomitant 100 mg methylprednisolone), disease modifying drugs, or other immune modulatory monoclonal antibodies or immunodepleting therapy at any time Allergy to rituximab or one of its excipients Expected need for vaccination with a live attenuated vaccine during the study including incomplete vaccination courses. Known or suspected pregnancy at screening or lactating woman Women of childbearing age unless confirmed by direct questioning that they are reproductively sterile or post-menopausal Participation in other clinical trials Inability to comply with study procedures

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
Intervention Model: Single Group Assignment
Interventional Model Description: Phase 1/2 unblinded interventional dose escalation study
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Rituximab<br> | Drug: RiTUXimab Injection<br>* Single dose of Rituximab given intravenously within 48hours of myocardial infarction<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety - Review of Adverse Events and Serious Adverse Events; | Adverse and serious adverse events will be reviewed by daily history taking and clinical examination of patients whilst they are an inpatient. Subsequently patients will be followed up on discharge daily until day 6 with telephone follow up. On days 6, 14 and 6month patients will be assess again in an outpatient setting where adverse events will be documented. There is additional follow telephone follow up at day 30. After each group of 6 patients are recruited and infused with rituximab, an independent Data and Safety Monitoring Board will review the clinical and biological data and their side effect profile, including adverse events. | 6month | 
| Safety - Clinically significant changes in biochemical and haematological markers | Biochemistry and haematology bloods will be taken daily after drug administration whilst an inpatient. Upon discharge bloods will be taken on days 6, 14 and 6month for further assessment. Any new abnormalities will be flagged. After each group of 6 patients are recruited and infused with rituximab, an independent Data and Safety Monitoring Board will review the clinical and biological data and their side effect profile, including adverse events. | 6month | 
| Safety - Clinically significant ECG changes | Arrhythmia will be assess as patients will have continued cardiac monitoring whilst an inpatient. ECGs will be performed daily whilst an inpatient and also during outpatient attendance. QTc will be assessed using the Bazett formula. After each group of 6 patients are recruited and infused with rituximab, an independent Data and Safety Monitoring Board will review the clinical and biological data and their side effect profile, including adverse events. | 6month | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| B cells | Circulating B cells count before, immediately after administration (30 mins and 6 hours), and extended follow up (6 days, 14 days and 6months) | Days 0, 6, 14 and 6months | 
| Cardiac biomarkers - Circulating inflammatory (hsCRP and IL6) and cardiovascular (BNP and Troponin) biomarkers. | These will be measure before the infusion and compared to after infusion on days 2, 6 and 6 months | Days 0, 2 and 6 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Rituximab, B cells