Rituximab in patients with ST-elevation myocardial infarction. A phase 2 placebo controlled randomized clinical trial. RITA-MI 2
- Trial ID
- 2022-501893-21-00
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to evaluate the effect of a single injection of two doses of **rituximab** compared to placebo on left ventricular systolic function at 6 months, as assessed by cardiac magnetic resonance (CMR), in patients who have experienced an acute anterior ST-segment elevation myocardial infarction (STEMI). This is clinically relevant as improving left ventricular function post-STEMI can significantly impact patient outcomes, reducing the risk of heart failure and improving survival rates.
Secondary objectives include assessing the effects of rituximab versus placebo on several parameters:
- Infarct size by CMR using T1-weighted late gadolinium enhancement (LGE) between day 3 and day 7, and at 6 months.
- Oedema extension by CMR using T2-weighted imaging between day 3 and day 7.
- T2 relaxation time at the ischemic region by CMR using T2 mapping between day 3 and day 7.
- Microvascular obstruction by CMR, identified as hypointense areas within LGE, between day 3 and day 7.
- Levels of NT-pro-BNP at 6 months.
- Any adverse events related to the treatment.
Participants
The clinical trial involves participants who have experienced an **acute myocardial infarction**, specifically an ST segment elevation myocardial infarction (STEMI). The study population includes both male and female subjects aged over 18 years, with no upper age limit specified. Participants are required to have clinical evidence of anterior STEMI, characterized by symptoms indicative of acute myocardial ischemia and specific electrocardiogram findings. The trial does not include a vulnerable population. The sponsor has not provided information regarding the total number of participants. Selection criteria emphasize the necessity for participants to have experienced the onset of symptoms within 48 hours prior to primary percutaneous coronary intervention (PCI) and the ability to commence rituximab infusion within 3 hours post-PCI. Lifestyle factors such as diet and physical activity are not specified in the available data.
Plans and Procedures
The clinical trial is designed as a **randomized**, **double-blind**, **placebo-controlled** study to evaluate the efficacy of **rituximab** in patients with **acute myocardial infarction**, specifically ST-segment elevation myocardial infarction (STEMI). The trial aims to assess the impact of a single dose of rituximab (200 mg or 1000 mg) versus placebo on left ventricular function, using cardiac magnetic resonance imaging (CMR), over a period of six months. The study is expected to commence recruitment on June 1, 2022, and conclude by April 1, 2027.
Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age, clinical evidence of anterior STEMI, and the ability to start rituximab infusion within three hours of primary percutaneous coronary intervention (PPCI). Following the initial visit, participants will receive the investigational product or placebo via **intravenous infusion**. Subsequent follow-up visits will occur between days 3 and 7, and at six months, to evaluate primary and secondary endpoints, including left ventricular ejection fraction and infarct size by CMR.
The expected duration of participant involvement is approximately six months, with conditions for early termination including withdrawal of consent or any adverse event related to treatment. The primary endpoint is the left ventricular ejection fraction by CMR at six months, while secondary endpoints include infarct size, edema extension, T2 relaxation time, microvascular obstruction, and NT-pro-BNP levels. The trial's methodology ensures rigorous assessment of rituximab's efficacy in improving cardiac outcomes post-STEMI.
Treatment
The clinical trial involves the administration of **MabThera**, a **rituximab**-based medication, which is provided in two formulations: 500 mg and 100 mg concentrates for solution for infusion. Both formulations are intended for **intravenous infusion**. The maximum daily and total dose for each formulation is 1000 mg, administered over a treatment period of one day. Rituximab is a protein-based therapeutic agent, and its administration is monitored to ensure compliance with the dosing schedule.
**Paracetamol** is used as an auxiliary treatment in the trial. It is available in a pharmaceutical form denoted as PHF00245MIG and is administered orally. The active substances include **Paracetamol DC** and **Paracetamol Ph. Eur.** The maximum daily and total dose is 1 gram, with a treatment period of one day. Paracetamol serves as an analgesic to manage pain associated with the trial procedures.
**Clemastine** is another auxiliary treatment, provided in a form identified as PHF00244MIG, and administered via **intravenous administration**. The maximum daily dose is 1 mg/l, with a total dose of 10 mg/l over a 15-day treatment period. Clemastine is classified as an antihistaminic, used to manage allergic reactions during the trial.
**Dexchlorpheniramine**, also in the PHF00244MIG form, is administered intravenously. The maximum daily and total dose is 10 mg, with a treatment period of one day. It is categorized under substituted alkylamines and serves to mitigate allergic responses.
**Sodium Chloride** is utilized as a placebo in the trial. It is provided as a solution for injection and administered via **intravenous infusion**. The dosing is not specified in terms of milligrams, as it functions primarily as a control substance in the study.
**Methylprednisolone** is included as an auxiliary treatment, available in the PHF00230MIG form, and administered intravenously. The maximum daily and total dose is 100 mg, with a treatment period of one day. Methylprednisolone is a glucocorticoid used to manage inflammation and immune responses during the trial.
Efficacy
Efficacy in this clinical trial will be assessed primarily by evaluating the left ventricular ejection fraction (LVEF) using cardiac magnetic resonance imaging (CMR) at 6 months. This serves as the primary endpoint to determine the effect of a single injection of two doses of **rituximab** versus placebo in patients who have experienced an acute anterior ST-elevation myocardial infarction (STEMI). Secondary endpoints include the assessment of infarct size by CMR imaging using T1-weighted late gadolinium enhancement (LGE) between days 3 and 7 and at 6 months, as well as the evaluation of edema extension using T2-weighted imaging (T2W) within the same timeframe. Additionally, T2 relaxation time at the ischemic region will be measured using T2 mapping, and microvascular obstruction will be assessed by identifying hypointense areas within LGE between days 3 and 7. The level of NT-pro-BNP at 6 months will also be measured, alongside monitoring for any adverse events related to the treatment.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Age>18 years with no upper limit (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; or a large inferior MI with evidence of low-ejection fraction (LVEF<45%)
- 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 48 hours before primary PCI;
- 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 confirmed before enrollment ;;
- Ability to start infusion of rituximab within 3 hours of PPCI ;confirmed before enrollment ;
- Written informed consent.
Exclusion Criteria
- History of previous myocardial infarction without documented preserved left ventricular ejection fraction (LVEF >50%) prior to the current admission will be an exclusion criterion
- Contraindications to injectable Polaramine: o Risk of closed-angle glaucoma, o 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)
- Presentation with cardiac arrest
- Absence of a complete COVID-19 vaccination scheme (including recovery from documented COVID infection) as approved at the time of enrolment in the country where the patient is recruited
- Any obvious contraindications for MRI or conditions which will impede image acquisition for example: o Severe claustrophobia o Non-MRI compatible permanent pacemaker o Patients who have a metallic foreign body (metal silver) in their eye, or who have an aneurysm clip in their brain o Patients who have had metallic devices placed in their back o 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
- Active COVID-19 infection or COVID-19 infection within 3 months
- 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)
- History of severe chronic renal failure (defined 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
- 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
- Patients with Killip class III heart failure
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Czechia | Recruiting | 01 Jun 2022 | 100 |
 France | Recruiting | 01 Jun 2022 | 130 |
 Germany | Recruiting | 01 Jun 2022 | 50 |
 The Netherlands | Not Yet Recruiting | 01 Jun 2022 | — |
 Spain | Recruiting | 01 Jun 2022 | 36 |
| Netherlands | — | — | 100 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
SODIUM CHLORIDE | Placebo | — | INTRAVENIOUS INFUSION | 0 | 1 | SUB12581MIG |
MabThera 500 mg concentrate for solution for infusion | Test | CONCENTRATE FOR SOLUTION FOR INFUSION | INTRAVENIOUS INFUSION | 1000 | 1 | PRD2154043 |