Study to Evaluate the Effect on Parameters of Systemic Inflammation and Disease Outcomes and Safety of RPH-104 in Subjects With Acute ST-elevation Myocardial Infarction

Study Overview
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Brief Summary
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The goal of the study is to evaluate the effect of single administration of RPH-104 at 80 mg and 160 mg on parameters of systemic inflammation and outcomes of the disease in subjects with ST-segment elevation myocardial infarction (STEMI)

Detailed Description
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After signing informed consent, the investigator will assess the subject's eligibility for the study. After signing the informed consent form, the investigator will assess the subject's eligibility for the study. The following procedures will be performed during the screening: collection of medical history, recording previous and concomitant therapy, demographic data, recording 12-lead ECG findings on which STEMI diagnosis was based, recording date and time of STEMI symptom development, recording date, time and results of coronary angiography (CAG) at admission to the study site, measurement of blood neutrophil count, vital signs, physical examination including measurement of body weight (if hospital bed is available), blood sampling for hematology, biochemistry, determination of concentration of hsCRP and brain natriuretic peptide (BNP; N-terminal (NT)-pro hormone brain natriuretic peptide (NT-pro-BNP)), for females with retained reproductive potential - pregnancy test (test strips). The subjects meeting selection criteria will be randomized to one of the three groups (in 1:1:1 ratio) for single subcutaneous administration of RPH-104 80 mg, RPH-104 160 mg or placebo. Screening, randomization and administration of the study products will be made on the same (first) study day. Further 4-week (28-day) clinical follow-up and additional 6- and 12-month clinical follow-up period will be performed. The end of clinical part of the study will be the date of the last visit of the last subject within additional 12-month clinical follow-up. The maximum number of screened patients will be 146 subjects, 102 subjects will be randomized, 34 subjects per group.

Official Title
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International, Double Blind, Randomized, Placebo-controlled Study to Evaluate the Effect on Parameters of Systemic Inflammation and Disease Outcomes and Safety of RPH-104 in Subjects With Acute ST-elevation Myocardial Infarction

Conditions
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Acute ST Segment Elevation Myocardial Infarction

Intervention / Treatment
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* Biological: RPH-104 80 mg
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Subjects who gave voluntary written Informed consent to participate in the study and to follow all Protocol procedures. STEMI diagnosis defined as chest pain or its equivalent with ECG findings evidencing ST elevation (>1 mm) in two or more consecutive leads or acute left bunch branch block according the investigator's judgement. Percutaneous coronary intervention (PCI) with stenting was performed within no more than 12 hours after onset of chest pain or its equivalent and randomization was performed in no more than 12 hours after PCI (overall within 24 hours of onset of chest pain or equivalent). Consent of female subjects with childbearing potential defined as all female subjects with physiological potential to conceive, to use highly effective contraceptive methods throughout the study starting from screening (signing Informed Consent Form) and negative pregnancy test. Highly effective contraceptive methods include combination of two of the following methods (a+b or a+c or b+c): oral, injection or implanted hormonal contraceptives; in case of oral contraceptives, the female subjects should administer the same product for at least 3 months prior to the study therapy; intrauterine device or contraceptive system; barrier methods: condom or occlusive cap (diaphragm or cervical cap / vaginal fornix cap) with spermicidal foam/gel/film/cream/vaginal suppository Ability and willingness of the subject, according to the reasonable investigator's judgment, to attend the study site at all scheduled visits, undergo the study procedures and follow the Protocol requirements including subcutaneous injections by qualified site personnel. Exclusion Criteria: Hypersensitivity to test product (RPH-104) and/or its ingredients/excipients. Pregnancy and breastfeeding. Verified chronic heart failure (The American Heart Association / The American College of Cardiology (AHA/ACC) C-D class, New York Heart Association (NYHA) Functional class (FC) III-IV) Pre-existing severe valvular heart disease according to the investigator's assessment. Pre-existing left ventricular (LV) dysfunction (ejection fraction (EF)<40%) History of STEMI Complications of acute myocardial infarction (MI) in the form of acute left ventricular failure and cardiogenic shock defined as stable blood pressure decrease (SBP<90 mm Hg) associated with signs of hypoperfusion as well as cases when inotropic and/or mechanical support is required to maintain SBP; and / or unstable hemodynamics. Active infections (acute or chronic); active tuberculosis. Recent (less than 5 half-life periods) or current administration of colchicine, as well as agents with an immunosuppressant mechanism of action, including, but not limited to: glucocorticoids at doses of > 1 mg/kg of methylprednisolone equivalent, tumor necrosis factor-alfa (TNFα) blockers, Interleukin-1 (IL-1) and other biological drugs, cyclosporine and other immunosuppressants. Non-steroidal anti-inflammatory drugs (NSAIDs) are allowed. Immunization with live vaccines within 90 days prior to the study product administration. Chronic systemic autoimmune or autoinflammatory diseases Suspected necessity in cardiosurgery. Oncology (or diagnosis of oncology within the last 5 years). History of organ transplantation or necessity in transplantation at the screening initiation or scheduled transplantation during the study. Neutropenia (absolute neutrophil count <1800/mm^3). Participation in another clinical study within the previous 3 months prior to Screening visit. Other medical (including mental) conditions or abnormal laboratory findings which may increase the risk for the subject associated with the study participation or administration of the study products or which may affect interpretation of the study results and, according to the investigator, render the subject ineligible for the study.* *If, in the Investigator's opinion, administration of a non-live COVID-19 (SARS-CoV-2) vaccine increases the risk for the patient related to his/her participation in the study, the Investigator can make a decision not to include this patient into the study. The subjects working at the study site or subjects working for Sponsor directly involved in this clinical study.

Ages Eligible for Study
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Minimum Age: 18 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: RPH-104 80 mg<br>subjects will receive subcutaneous single injection of 2 mL (80 mg) of RPH-104 and 2 mL of placebo on different administration sites | Biological: RPH-104 80 mg<br>* solution for subcutaneous administration 40 mg/mL, 2 mL in the 4-mL transparent glass vial<br>Drug: Placebo<br>* Normal Saline (0.9% Sodium Chloride solution for Injection), 2 mL in the 4-mL transparent glass vial<br>|
| Experimental: RPH-104 160 mg<br>subjects will receive subcutaneous single injection of 2 mL (80 mg) of RPH-104 and 2 mL of (80 mg) of RPH-104 on different administration sites | Biological: RPH-104 80 mg<br>* solution for subcutaneous administration 40 mg/mL, 2 mL in the 4-mL transparent glass vial<br>|
| Placebo Comparator: Placebo<br>subjects will receive subcutaneous single injection of 2 mL of placebo and 2 mL of placebo on different administration sites | Drug: Placebo<br>* Normal Saline (0.9% Sodium Chloride solution for Injection), 2 mL in the 4-mL transparent glass vial<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| High-sensitive С-reactive protein (hsCRP) area under curve (AUC) from baseline until Day 14 | hsCRP area under curve (AUC) from baseline (Day 1) until Day 14 | Day 1 until Day 14 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| hsCRP AUC from baseline until Day 28 | hsCRP AUC from baseline (Day 1) until Day 28 | up to Day 28 | 
| Incidence of fatal outcomes (cardiac and non-cardiac) during 12-month follow-up period |  | up to Day 365 | 
| Incidence of hospitalizations due to heart failure (HF) or other cardiac reasons not associated with HF, or due to non-cardiac reasons during 12-month follow-up period |  | up to Day 365 | 
| Incidence of new cases of HF during 12-month follow-up period | New cases of HF are defined as hospitalization due to HF or new onset of HF. | up to Day 365 | 
| Changes in levels of brain natriuretic peptide (BNP, NT-proBNP) during 12-month follow-up period compared to baseline |  | From Day 1 until Day 365 | 
| Changes in End-diastolic (EDV) volume after 12 months compared to baseline | Measured by echocardiography (Echo-CG) (in mL). | From Day 1 Until Day 365 | 
| Changes in End-systolic (ESV) volume after 12 months compared to baseline | Measured by Echo-CG (in mL). | From Day 1 Until Day 365 | 
| Changes in EF (Simpson BP) after 12 months compared to baseline | Measured by Echo-CG (in percentage). | From Day 1 Until Day 365 | 
| Changes in regional LV function after 12 months compared to baseline | Assessment of regional LV function using the wall motion score index (WMSI), measured by Echo-CG. | From Day 1 Until Day 365 | 
| Changes in fractional area change (FAC) parameter after 12 months compared to baseline | Measured by Echo-CG (in percentage). | From Day 1 Until Day 365 | 
| Changes in Tricuspid Annular Plane Systolic Excursion (TAPSE) parameter after 12 months compared to baseline | Measured by Echo-CG (in mm). | From Day 1 Until Day 365 | 
| Changes in Transmitral flow rate | Changes in Transmitral flow rate after 12 months compared to baseline, measured by Echo-CG. | From Day 1 Until Day 365 | 
| Changes in mitral valve (MV) septal e' velocity (e'sept) after 12 months compared to baseline | Measured by Echo-CG (in cm/s). | From Day 1 Until Day 365 | 
| Changes in MV lateral e' velocity (e'lat) after 12 months compared to baseline | Measured by Echo-CG (in cm/s). | From Day 1 Until Day 365 | 
| BNP AUC from Day 1 (baseline) until Day 28 |  | up to Day 28 | 
| NT-pro-BNP AUC from Day 1 (baseline) until Day 28 |  | up to Day 28 | 
| Incidence of fatal outcome (due to any reason) or hospitalization due to HF or new onset of HF during 12-month follow-up period |  | up to Day 365 | 
| Incidence of fatal outcome (due to any reason) or hospitalization due to HF during 12-month follow-up period |  | up to Day 365 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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STEMI, Myocardial infarction, Cardiovascular diseases, CVD, Coronary heart disease, CHD