Rituximab in patients with ST-elevation myocardial infarction. A phase 2 placebo-controlled randomized clinical trial.

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Assistance Publique Hopitaux De Paris

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Cardiovascular Diseases [C14]

Trial duration

3 May 2022 → ongoing

Decision date (initial)

2023-03-06

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

No

External identifiers

EU CT number

2022-501893-21-00

EudraCT number

2021-003340-24

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Therapy

The primary 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.

Secondary objectives 6

1. The secondary endpoints will be assessed by comparing the effects of rituximab versus placebo on: • Infarct size by CMRI (using T1-weighted late gadolinium enhancement, LGE) between day 3 and day 7 (5+/-2) and at 6 months.
2. 2) Oedema extension by CMR (using T2W) between day 3 and day 7 (5±2)
3. 3) T2 relaxation time at ischemic region by CMR (using T2 mapping) between day 3 and day 7 (5±2)
4. 4) Microvascular obstruction by CMR (hypointense areas within LGE) between day 3 and day 7 (5±2)
5. 5) NT-pro-BNP at 6 months
6. 6) Any adverse event related to treatment

Conditions and MedDRA coding

Acute myocardial infarction

Study design 1 period

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 9

1. 1) 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) ;
2. 2) 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;
3. 3) 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);
4. 4) Onset of worse symptoms within 48 hours before primary PCI;
5. 5) Patients with neutrophils >1.5 x 109/L at the moment of admission
6. 6) Patients with platelet counts >75 x 109/L at the moment of admission
7. 7) Plan to provide primary percutaneous angioplasty (PPCI) for the patient within 2 hours of ECG diagnosis ;
8. 8) Ability to start infusion of rituximab within 3 hours of PPCI ;
9. 9) Written informed consent.

Exclusion criteria 26

1. 1) History of previous MI
2. 2) Presentation with cardiac arrest
3. 3) Cardiogenic shock (defined as systolic blood pressure <90 mmHg for >30minutes, or necessitating vasopressors to achieve a blood pressure ≥90 mmHg)
4. 4) Cardiac electrical instability (defined as complete heart block needing temporary pacing or any tachyarrhythmia needing cardioversion)
5. 5) Patients with Killip class III heart failure
6. 6) History of severe chronic renal failure (defined as stage 4 (GFR = 15-29 mL/min) or worse)
7. 7) History of hepatitis B, HIV or tuberculosis
8. 8) Patient positive for point of care bedside test of Ag HBs
9. 9) Severe, progressive infections documented
10. 10) Active COVID-19 infection or COVID-19 infection within 3 months
11. 11) Patient with documented severe immune deficiency
12. 12) Presence, or history in ≤ five years, of an ongoing cancer, (except in situ cancer of the cervix or basal cell carcinoma)
13. 13) QTcF> 450 msecs in males, > 470msecs in females
14. 14) Any oral or intravenous immunosuppressive treatment, immune modulatory monoclonal antibodies or immunodepleting therapy at any time (inhalers and topical creams with corticosteroids are permitted)
15. 15) Previous history of major organ transplant including renal transplant
16. 16) Known hypersensitivity to the active substance of rituximab or to proteins of murine origin, or to any of the other excipients
17. 17) Any contraindications to any of the rituximab premedication drugs
18. 18) Contraindications to injectable Polaramine: o Risk of closed-angle glaucoma, o Risk of urinary retention linked to urethro-prostatic disorders
19. 19) 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)
20. 20) 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
21. 21) 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)
22. 22) Known hepatic failure
23. 23) Previous history of progressive multifocal leukoencephalopathy
24. 24) Inclusion in other interventional drug study within the previous 3 months
25. 25) Inability to comply with study procedures
26. 26) Patients under guardianship or curatorship

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. The primary endpoint is the left ventricular ejection fraction (LVEF) by CMR at 6 months.

Secondary endpoints 6

1. • Infarct size by CMRI (using T1-weighted late gadolinium enhancement, LGE) between day 3 and day 7 (52) and at 6 months.
2. Oedema extension by CMRI (using T2W) between day 3 and day 7 (5±2)
3. T2 relaxation time at ischemic region by CMRI (using T2 mapping) between day 3 and day 7 (5±2)
4. Microvascular obstruction by CMRI (hypointense areas within LGE) between day 3 and day 7 (5±2)
5. NT-pro-BNP at 6 months
6. Any adverse event related to treatment

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 1

Placebo 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Assistance Publique Hopitaux De Paris

Sponsor organisation

Assistance Publique Hopitaux De Paris

Address

Porte 23, 1 Avenue Claude Vellefaux 1 Avenue Claude Vellefaux

City

Paris Cedex 10

Postcode

75475

Country

France

Scientific contact point

Organisation

Assistance Publique Hopitaux De Paris

Contact name

Pr Gabriel STEG

Public contact point

Organisation

Assistance Publique Hopitaux De Paris

Contact name

Sophie Courtial-Destembert

Locations

5 EU/EEA countries · 25 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 66 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

22 submissions — initial application plus substantial / non-substantial modifications