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

Acute ST Segment Elevation Myocardial Infarction Clinical Trial

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT04463251
• Other study ID #: CL04018075
• Status: Completed
• Phase: Phase 2
• Start date: December 7, 2020
• Est. completion date: October 10, 2022

Study information

• Verified date: December 2023
• Source: R-Pharm
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

The goal of the study was 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)

Description:

After signing the informed consent form, the investigator assessed the subject's eligibility for the study. The following procedures were 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 were 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 were 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 were performed.

The end of clinical part of the study was the date of the last visit of the last subject within additional 12-month clinical follow-up.

The maximum number of screened patients was planned to be 146 subjects, 102 subjects were randomized, 34 subjects per group.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 102
• Est. completion date: October 10, 2022
• Est. primary completion date: November 3, 2021
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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):

1. 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;

2. intrauterine device or contraceptive system;

3. 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 (TNFa) 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.

Related Conditions & MeSH terms

• Acute ST Segment Elevation Myocardial Infarction
• Infarction
• Inflammation
• Myocardial Infarction
• ST Elevation Myocardial Infarction

Intervention

Biological:
• RPH-104 80 mg
solution for subcutaneous administration 40 mg/mL, 2 mL in the 4-mL transparent glass vial

Drug:
• Placebo
Normal Saline (0.9% Sodium Chloride solution for Injection), 2 mL in the 4-mL transparent glass vial

Locations

Country	Name	City	State
Russian Federation	Federal State Budgetary Institution "National Medical Research Center for Cardiology" of the Ministry of Healthcare of the Russian Federation	Moscow
Russian Federation	State Budgetary Healthcare Institution of Moscow "City Clinical Hospital named after V.V. Veresaev of Moscow Healthcare Department"	Moscow
Russian Federation	State Budgetary Healthcare Institution of Moscow "City Clinical Hospital named after V.V. Vinogradov of Moscow Healthcare Department"	Moscow
Russian Federation	State Institution of Healthcare in Moscow "City Clinical Hospital ? 51 Moscow Health Department"	Moscow
Russian Federation	State Autonomous Healthcare Institution of the Perm Territory "City Clinical Hospital No. 4"	Perm
Russian Federation	Ryazan State Medical University n.a. academician I.P. Pavlov on the basis of Regional Clinical cardiology Dispensary	Ryazan
Russian Federation	St. Petersburg State Budgetary Healthcare Institution "Saint Martyr Elizabeth City Hospital"	St Petersburg
Russian Federation	The State Budgetary Health Care Institution of the Yaroslavl Region "Regional Clinical Hospital"	Yaroslavl
United States	University of Virginia Health System	Charlottesville	Virginia
United States	Cleveland Clinic	Cleveland	Ohio
United States	VCU Health-Virginia Commonwealth University Health	Richmond	Virginia

Sponsors (6)

Lead Sponsor	Collaborator
R-Pharm Overseas, Inc.	Cromos Pharma LLC, Data Management 365, K-Research, Keystat, LLC, R-Pharm

Countries where clinical trial is conducted

United States,  Russian Federation, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	High-sensitive ?-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
Primary	High-sensitive ?-reactive Protein (hsCRP) Area Under Curve (AUC) From Baseline Until Day 14 (Sensitivity Analysis)	hsCRP area under curve (AUC) from baseline (Day 1) until Day 14 (sensitivity analysis)	Day 1 until Day 14
Secondary	hsCRP AUC From Baseline Until Day 28	hsCRP AUC from baseline (Day 1) until Day 28	up to Day 28
Secondary	Number of Patients With Fatal Outcomes (Cardiac and Non-cardiac) During 12-month Follow-up Period	Any fatal outcomes were evaluated by the investigators and Independent study outcome assessment committee (ISOAC). ISOAC assessments were considered as the main data for conclusions, the investigator's assessments were presented for informational purposes only.	up to Day 365
Secondary	Number of Patients With 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	Number of patients with hospitalizations for any reason during 12-month follow-up period, assessed by ISOAC.	up to Day 365
Secondary	Number of Patients With New Cases of HF During 12-month Follow-up Period	New cases of HF are defined as hospitalization due to HF or an emergency outpatient visit due to heart failure.; ISOAC assessment	up to Day 365
Secondary	Changes in Levels of Brain Natriuretic Peptide (BNP) During 12-month Follow-up Period Compared to Baseline	Change in levels of BNP during 12-month follow-up period compared to baseline. (Brain Natriuretic Peptide (BNP) was measured in pmol/L.) Increased levels of BNP can be considered as marker of hemodynamic stress and surrogate marker of Heart Failure.; The reported Least square means and confidence interval were from a repeated measures model on log transformed BNP data containing treatment, visit as factors, log baseline BNP as a continuous covariate and treatment by visit as interaction terms. Due to log-transformed data, change from baseline was defined as division value at corresponding time point and baseline value, thus the smallest value of the change from baseline indicates a better outcome or improvement.	From Day 1 until Day 365
Secondary	Changes in End-diastolic (EDV) Volume After 12 Months Compared to Baseline	Apical 4-, 2-, and 3-chamber view in B-mode: End-diastolic (EDV) volumes. Measured by echocardiography (Echo-CG) (in mL). The reported Least square means and confidence interval were from a repeated measures model on EDV data containing treatment, visit as factors, baseline EDV as a continuous covariate and treatment by visit as interaction terms.	From Day 1 Until Day 365
Secondary	BNP AUC From Day 1 (Baseline) Until Day 28		up to Day 28
Secondary	NT-pro-BNP AUC From Day 1 (Baseline) Until Day 28		up to Day 28
Secondary	Number of Patients With Fatal Outcomes (Due to Any Reason) or Hospitalizations Due to HF or Emergency Outpatient Visits Due to HF During 12-month Follow-up Period	ISOAC assessment	up to Day 365
Secondary	Number of Patients With Fatal Outcomes (Due to Any Reason) or Hospitalizations Due to HF During 12-month Follow-up Period	ISOAC assessment	up to Day 365
Secondary	Changes in Levels of Brain Natriuretic Peptide (NT-proBNP) During 12-month Follow-up Period Compared to Baseline	Change in levels of NT-proBNP during 12-month follow-up period compared to baseline.; The reported Least square means and confidence interval were from a repeated measures model on log transformed NT-proBNP data containing treatment, visit as factors, log transformed baseline NT-proBNP as a continuous covariate and treatment by visit as interaction terms.; For log-transformed data change was defined as division value at corresponding time point and baseline value.	From Day 1 until Day 365
Secondary	Changes in End-systolic (ESV) Volume After 12 Months Compared to Baseline	Apical 4-, 2-, and 3-chamber view in B-mode: End-systolic (ESV) volumes. Measured by echocardiography (Echo-CG) (in mL). The reported Least square means and confidence interval were from a repeated measures model on ESV data containing treatment, visit as factors, baseline ESV as a continuous covariate and treatment by visit as interaction terms.	From Day 1 Until Day 365
Secondary	Changes in Ejection Fraction (EF) After 12 Months Compared to Baseline	Apical 4-, 2-, and 3-chamber view in B-mode: Ejection fraction (EF) (Simpson method).; Measured by echocardiography (Echo-CG) (in percentage). The reported Least square means and confidence interval were from a repeated measures model on EF data containing treatment, visit as factors, baseline EF as a continuous covariate and treatment by visit as interaction terms.	From Day 1 Until Day 365
Secondary	Changes in Regional LV Function After 12 Months Compared to Baseline	Apical 4-, 2-, and 3-chamber view in B-mode: assessment of regional LV function using the wall motion score index (WMSI), measured by Echo-CG.; The wall motion score index was calculated by assigning each segment a score based on its systolic function (normal = 1 (the best), hypokinesis = 2, akinesis = 3, dyskinesis = 4 (the worst)). The WMSI is the sum of all segmental scores divided by the number of segments analyzed (scale 1 - 4). A wall motion score index of 1 is normal (the best outcome). The higher the wall motion score index the worse is the outcome.; The reported Least square means and confidence interval were from a repeated measures model on Regional LV Function data containing treatment, visit as factors, baseline Regional LV Function data as a continuous covariate and treatment by visit as interaction terms.	From Day 1 Until Day 365
Secondary	Changes in Stroke Volume (SV) Compared to Baseline	Apical 4-, 2-, and 3-chamber view in B-mode: assessment of Stroke Volume (SV), measured by Echo-CG.; The reported Least square means and confidence interval were from a repeated measures model on SV data containing treatment, visit as factors, baseline SV data as a continuous covariate and treatment by visit as interaction terms.	From Day 1 Until Day 365
Secondary	Changes in Global Longitudinal Strain (GLS) Compared to Baseline	Apical 4-, 2-, and 3-chamber view in B-mode: assessment of Global Longitudinal Strain (GLS), measured by Echo-CG.; GLS is a measure of longitudinal shortening of the myocardium as a percentage (change in length as a proportion to baseline length), thus explaining the negative values.; The reported Least square means and confidence interval were from a repeated measures model on GLS data containing treatment, visit as factors, baseline GLS data as a continuous covariate and treatment by visit as interaction terms.	From Day 1 Until Day 365
Secondary	Changes of Fractional Area Change (FAC) Compared to Baseline	Right atrium and ventricle assessment from the apical 4-chamber right ventricular-focused view (with maximal right ventricular basal dimension) in B-mode and M-mode: Fractional Area Change (FAC).; The reported Least square means and confidence interval were from a repeated measures model on FAC data containing treatment, visit as factors, baseline FAC data as a continuous covariate and treatment by visit as interaction terms.	From Day 1 Until Day 365
Secondary	Changes in Tricuspid Annular Plane Systolic Excursion (TAPSE) Parameter Compared to Baseline	Right atrium and ventricle assessment from the apical 4-chamber right ventricular-focused view (with maximal right ventricular basal dimension) in B-mode and M-mode: tricuspid annular plane systolic excursion (TAPSE).; The reported Least square means and confidence interval were from a repeated measures model on TAPSE data containing treatment, visit as factors, baseline TAPSE data as a continuous covariate and treatment by visit as interaction terms.	From Day 1 Until Day 365
Secondary	Changes in Early Diastolic Transmitral Flow Velocity (E Velocity) Compared to Baseline	Assessment of diastolic and systolic function, apical 4-chamber view in pulse-wave Doppler mode, tissue Doppler mode: Transmitral flow, pulsed wave (PW) Doppler, E.; The reported Least square means and confidence interval were from a repeated measures model on E velocity data containing treatment, visit as factors, baseline E velocity data as a continuous covariate and treatment by visit as interaction terms.	From Day 1 Until Day 365
Secondary	Changes in Mitral Valve (MV) e'Sept Compared to Baseline	Assessment of diastolic and systolic function, apical 4-chamber view in pulse-wave Doppler mode, tissue Doppler mode: Tissue Doppler Imaging, MV e'sept. Unit of measure is centimeter/second (cm/s). This is one of the diastolic function parameters (septal velocity fibrous ring of the mitral valve (MV)).; The reported Least square means and confidence interval were from a repeated measures model on MV e'Sept data containing treatment, visit as factors, baseline MV e'Sept data as a continuous covariate and treatment by visit as interaction terms.	From Day 1 Until Day 365
Secondary	Changes in Mitral Valve e'Lat Compared to Baseline	Assessment of diastolic and systolic function, apical 4-chamber view in pulse-wave Doppler mode, tissue Doppler mode: Tissue Doppler Imaging, MV e'lat. Unit of measure is centimeter/second (cm/s). This is one of the diastolic function parameters (lateral velocity of fibrous ring of the mitral valve (MV)).; The reported Least square means and confidence interval were from a repeated measures model on MV e'Lat data containing treatment, visit as factors, baseline MV e'Lat data as a continuous covariate and treatment by visit as interaction terms.	From Day 1 Until Day 365
Secondary	Changes in Left Ventricular Stroke Volume (LV SV) Compared to Baseline	Assessment of diastolic and systolic function, apical 4-chamber view in pulse-wave Doppler mode, tissue Doppler mode: LV outflow tract velocity-time integral (VTI) + Diameter. Tissue Doppler Imaging, LV Stroke Volume (pulse-wave Doppler mode).; The reported Least square means and confidence interval were from a repeated measures model on LV SV data containing treatment, visit as factors, baseline LV SV data as a continuous covariate and treatment by visit as interaction terms.	From Day 1 Until Day 365
Secondary	Changes in hsCRP Levels During the Study Compared to Baseline	Change in levels of hsCRP during the study compared to baseline. The reported Least square means and confidence interval were from a repeated measures model on log transformed hsCRP data containing treatment, visit as factors, log transformed baseline hsCRP data as a continuous covariate and treatment by visit as interaction terms.; For log-transformed data change was defined as division value at corresponding time point and baseline value.	From Day 1 until Day 28