Acute ST Segment Elevation Myocardial Infarction
Conditions
Keywords
STEMI, Myocardial infarction, Cardiovascular diseases, CVD, Coronary heart disease, CHD
Brief 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)
Detailed 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.
Interventions
BIOLOGICALRPH-104 80 mg
solution for subcutaneous administration 40 mg/mL, 2 mL in the 4-mL transparent glass vial
DRUGPlacebo
Normal Saline (0.9% Sodium Chloride solution for Injection), 2 mL in the 4-mL transparent glass vial
Sponsors
Cromos Pharma LLC
Data Management 365
Keystat, LLC
R-Pharm
K-Research, LLC
R-Pharm Overseas, Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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 (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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| High-sensitive С-reactive Protein (hsCRP) Area Under Curve (AUC) From Baseline Until Day 14 (Multiple Imputation Procedure) | Day 1 until Day 14 | hsCRP area under curve (AUC) from baseline (Day 1) until Day 14 |
| High-sensitive С-reactive Protein (hsCRP) Area Under Curve (AUC) From Baseline Until Day 14 (сomplete Cases) | Day 1 until Day 14 | hsCRP area under curve (AUC) from baseline (Day 1) until Day 14 |
| High-sensitive С-reactive Protein (hsCRP) Area Under Curve (AUC) From Baseline Until Day 14 (Sensitivity Analysis, Multiple Imputation Procedure) | Day 1 until Day 14 | hsCRP area under curve (AUC) from baseline (Day 1) until Day 14 (sensitivity analysis) |
| High-sensitive С-reactive Protein (hsCRP) Area Under Curve (AUC) From Baseline Until Day 14 (Sensitivity Analysis, Complete Cases) | Day 1 until Day 14 | hsCRP area under curve (AUC) from baseline (Day 1) until Day 14 (sensitivity analysis) |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Patients With New Cases of HF During 12-month Follow-up Period | up to Day 365 | New cases of HF are defined as hospitalization due to HF or an emergency outpatient visit due to heart failure. ISOAC assessment |
| Changes in Levels of Brain Natriuretic Peptide (BNP) During 12-month Follow-up Period Compared to Baseline | From Day 1 until Day 365 | 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. |
| Changes in End-diastolic (EDV) Volume After 12 Months Compared to Baseline | From Day 1 Until Day 365 | 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. |
| 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 | — |
| 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 | up to Day 365 | ISOAC assessment |
| Number of Patients With Fatal Outcomes (Due to Any Reason) or Hospitalizations Due to HF During 12-month Follow-up Period | up to Day 365 | ISOAC assessment |
| Changes in Levels of Brain Natriuretic Peptide (NT-proBNP) During 12-month Follow-up Period Compared to Baseline | From Day 1 until Day 365 | 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. |
| Changes in End-systolic (ESV) Volume After 12 Months Compared to Baseline | From Day 1 Until Day 365 | 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. |
| Changes in Ejection Fraction (EF) After 12 Months Compared to Baseline | From Day 1 Until Day 365 | 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. |
| hsCRP AUC From Baseline Until Day 28 (Multiple Imputation Procedure) | up to Day 28 | hsCRP AUC from baseline (Day 1) until Day 28 |
| Changes in Stroke Volume (SV) Compared to Baseline | From Day 1 Until Day 365 | 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. |
| Changes in Global Longitudinal Strain (GLS) Compared to Baseline | From Day 1 Until Day 365 | 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. |
| Changes of Fractional Area Change (FAC) Compared to Baseline | From Day 1 Until Day 365 | 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. |
| Changes in Tricuspid Annular Plane Systolic Excursion (TAPSE) Parameter Compared to Baseline | From Day 1 Until Day 365 | 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. |
| Changes in Early Diastolic Transmitral Flow Velocity (E Velocity) Compared to Baseline | From Day 1 Until Day 365 | 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. |
| Changes in Mitral Valve (MV) e'Sept Compared to Baseline | From Day 1 Until Day 365 | 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. |
| Changes in Mitral Valve e'Lat Compared to Baseline | From Day 1 Until Day 365 | 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. |
| Changes in Left Ventricular Stroke Volume (LV SV) Compared to Baseline | From Day 1 Until Day 365 | 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. |
| Changes in hsCRP Levels During the Study Compared to Baseline | From Day 1 until Day 28 | 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. |
| Changes in Regional LV Function After 12 Months Compared to Baseline | From Day 1 Until Day 365 | 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. |
| hsCRP AUC From Baseline Until Day 28 (Complete Cases) | up to Day 28 | hsCRP AUC from baseline (Day 1) until Day 28 |
| Number of Patients With Fatal Outcomes (Cardiac and Non-cardiac) During 12-month Follow-up Period | up to Day 365 | 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. |
| 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 | up to Day 365 | Number of patients with hospitalizations for any reason during 12-month follow-up period, assessed by ISOAC. |
Countries
Russia, United States
Participant flow
Recruitment details
Patients were enrolled at 11 sites (Russia - 8, USA - 3). A total of 102 patients were randomized. The safety set included all randomized patients.The full analysis set for efficacy analysis (FAS) included 101 patients (who received the study products and underwent at least one hsCRP measurement after administration of the study products. The Per Protocol Set (PPS) included 92 subjects from the FAS without significant protocol deviations affecting assessment of the primary efficacy parameter.
Participants by arm
| Arm | Count |
|---|---|
| RPH-104 80 mg subjects received subcutaneous single injection of 2 mL (80 mg) of RPH-104 and 2 mL of placebo on different administration sites
RPH-104 80 mg: solution for subcutaneous administration 40 mg/mL, 2 mL in the 4-mL transparent glass vial
Placebo: Normal Saline (0.9% Sodium Chloride solution for Injection), 2 mL in the 4-mL transparent glass vial | 34 |
| RPH-104 160 mg subjects received subcutaneous single injection of 2 mL (80 mg) of RPH-104 and 2 mL of (80 mg) of RPH-104 on different administration sites
RPH-104 80 mg: solution for subcutaneous administration 40 mg/mL, 2 mL in the 4-mL transparent glass vial | 34 |
| Placebo subjects received subcutaneous single injection of 2 mL of placebo and 2 mL of placebo on different administration sites
Placebo: Normal Saline (0.9% Sodium Chloride solution for Injection), 2 mL in the 4-mL transparent glass vial | 33 |
| Total | 101 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Adverse Event | 0 | 1 | 0 |
| Overall Study | Death | 1 | 0 | 1 |
| Overall Study | Lost to Follow-up | 0 | 1 | 0 |
| Overall Study | Withdrawal by Subject | 0 | 2 | 2 |
Baseline characteristics
| Characteristic | RPH-104 80 mg | RPH-104 160 mg | Placebo | Total |
|---|---|---|---|---|
| Age, Continuous | 58.9 years | 58.7 years | 59.3 years | 59 years |
| Body Mass Index (BMI) | 28.7 kg/m^2 | 29.4 kg/m^2 | 30.3 kg/m^2 | 29.5 kg/m^2 |
| Race/Ethnicity, Customized Race Asian | 1 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized Race Black or African American | 3 Participants | 0 Participants | 0 Participants | 3 Participants |
| Race/Ethnicity, Customized Race Hispanic | 1 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized Race White | 29 Participants | 34 Participants | 33 Participants | 96 Participants |
| Sex: Female, Male Female | 11 Participants | 5 Participants | 12 Participants | 28 Participants |
| Sex: Female, Male Male | 23 Participants | 29 Participants | 21 Participants | 73 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk |
|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 1 / 34 | 0 / 34 | 1 / 34 | 0 / 34 | 0 / 34 | 0 / 34 |
| other Total, other adverse events | 21 / 34 | 20 / 34 | 14 / 34 | 3 / 34 | 3 / 34 | 2 / 34 |
| serious Total, serious adverse events | 7 / 34 | 1 / 34 | 4 / 34 | 0 / 34 | 0 / 34 | 0 / 34 |
Outcome results
Primary
High-sensitive С-reactive Protein (hsCRP) Area Under Curve (AUC) From Baseline Until Day 14 (Multiple Imputation Procedure)
hsCRP area under curve (AUC) from baseline (Day 1) until Day 14
Time frame: Day 1 until Day 14
Population: Full analysis set for efficacy analysis included all randomized subjects who received the study products (RPH-104 or placebo), and underwent at least one hsCRP measurement after administration of the study products. The FAS was the main population for efficacy assessment.~Multiple imputation procedure was performed for hsCRP values which were missed on Day 14.
| Arm | Measure | Value (GEOMETRIC_LEAST_SQUARES_MEAN) |
|---|---|---|
| RPH-104 80 mg | High-sensitive С-reactive Protein (hsCRP) Area Under Curve (AUC) From Baseline Until Day 14 (Multiple Imputation Procedure) | 106.84 mg*day/L |
| RPH-104 160 mg | High-sensitive С-reactive Protein (hsCRP) Area Under Curve (AUC) From Baseline Until Day 14 (Multiple Imputation Procedure) | 107.65 mg*day/L |
| Placebo | High-sensitive С-reactive Protein (hsCRP) Area Under Curve (AUC) From Baseline Until Day 14 (Multiple Imputation Procedure) | 184.30 mg*day/L |
Comparison: The following (two-sided) hypotheses were tested:~* Null hypothesis H0: the ratio of the geometric mean of hsCRP-AUC(days 1-14) in RPH-104 group to the geometric mean of hsCRP-AUC(days 1-14) in the placebo group is equal to 1.~* Alternative hypothesis H1: the ratio of the geometric mean of hsCRP-AUC(days 1-14) in RPH-104 group to the geometric mean of hsCRP-AUC(days 1-14) in the placebo group is different from 1.95% CI: [0.37, 0.91]
Comparison: The following (two-sided) hypotheses were tested:~* Null hypothesis H0: the ratio of the geometric mean of hsCRP-AUC(days 1-14) in RPH-104 group to the geometric mean of hsCRP-AUC(days 1-14) in the placebo group is equal to 1.~* Alternative hypothesis H1: the ratio of the geometric mean of hsCRP-AUC(days 1-14) in RPH-104 group to the geometric mean of hsCRP-AUC(days 1-14) in the placebo group is different from 1.95% CI: [0.37, 0.91]
Primary
High-sensitive С-reactive Protein (hsCRP) Area Under Curve (AUC) From Baseline Until Day 14 (Sensitivity Analysis, Complete Cases)
hsCRP area under curve (AUC) from baseline (Day 1) until Day 14 (sensitivity analysis)
Time frame: Day 1 until Day 14
Population: At the stage of final analysis, sensitivity analysis was performed for the per protocol population (PPS).~The model included patients with complete data (complete cases) in the PPS population. No data imputations were performed.
| Arm | Measure | Value (GEOMETRIC_LEAST_SQUARES_MEAN) |
|---|---|---|
| RPH-104 80 mg | High-sensitive С-reactive Protein (hsCRP) Area Under Curve (AUC) From Baseline Until Day 14 (Sensitivity Analysis, Complete Cases) | 95.35 mg*day/L |
| RPH-104 160 mg | High-sensitive С-reactive Protein (hsCRP) Area Under Curve (AUC) From Baseline Until Day 14 (Sensitivity Analysis, Complete Cases) | 104.26 mg*day/L |
| Placebo | High-sensitive С-reactive Protein (hsCRP) Area Under Curve (AUC) From Baseline Until Day 14 (Sensitivity Analysis, Complete Cases) | 171.69 mg*day/L |
Comparison: The following (two-sided) hypotheses were tested:~* Null hypothesis H0: the ratio of the geometric mean of hsCRP-AUC(days 1-14) in RPH-104 group to the geometric mean of hsCRP-AUC(days 1-14) in the placebo group is equal to 1.~* Alternative hypothesis H1: the ratio of the geometric mean of hsCRP-AUC(days 1-14) in RPH-104 group to the geometric mean of hsCRP-AUC(days 1-14) in the placebo group is different from 1.95% CI: [0.34, 0.91]
Comparison: The following (two-sided) hypotheses were tested:~* Null hypothesis H0: the ratio of the geometric mean of hsCRP-AUC(days 1-14) in RPH-104 group to the geometric mean of hsCRP-AUC(days 1-14) in the placebo group is equal to 1.~* Alternative hypothesis H1: the ratio of the geometric mean of hsCRP-AUC(days 1-14) in RPH-104 group to the geometric mean of hsCRP-AUC(days 1-14) in the placebo group is different from 1.95% CI: [0.38, 0.98]
Primary
High-sensitive С-reactive Protein (hsCRP) Area Under Curve (AUC) From Baseline Until Day 14 (Sensitivity Analysis, Multiple Imputation Procedure)
hsCRP area under curve (AUC) from baseline (Day 1) until Day 14 (sensitivity analysis)
Time frame: Day 1 until Day 14
Population: At the stage of final analysis, sensitivity analysis was performed for the per protocol population (PPS).~Multiple imputation procedure was performed for hsCRP values which were missed on Day 14.
| Arm | Measure | Value (GEOMETRIC_LEAST_SQUARES_MEAN) |
|---|---|---|
| RPH-104 80 mg | High-sensitive С-reactive Protein (hsCRP) Area Under Curve (AUC) From Baseline Until Day 14 (Sensitivity Analysis, Multiple Imputation Procedure) | 96.57 mg*day/L |
| RPH-104 160 mg | High-sensitive С-reactive Protein (hsCRP) Area Under Curve (AUC) From Baseline Until Day 14 (Sensitivity Analysis, Multiple Imputation Procedure) | 105.30 mg*day/L |
| Placebo | High-sensitive С-reactive Protein (hsCRP) Area Under Curve (AUC) From Baseline Until Day 14 (Sensitivity Analysis, Multiple Imputation Procedure) | 173.48 mg*day/L |
Comparison: The following (two-sided) hypotheses were tested:~* Null hypothesis H0: the ratio of the geometric mean of hsCRP-AUC(days 1-14) in RPH-104 group to the geometric mean of hsCRP-AUC(days 1-14) in the placebo group is equal to 1.~* Alternative hypothesis H1: the ratio of the geometric mean of hsCRP-AUC(days 1-14) in RPH-104 group to the geometric mean of hsCRP-AUC(days 1-14) in the placebo group is different from 1.95% CI: [0.34, 0.91]
Comparison: The following (two-sided) hypotheses were tested:~* Null hypothesis H0: the ratio of the geometric mean of hsCRP-AUC(days 1-14) in RPH-104 group to the geometric mean of hsCRP-AUC(days 1-14) in the placebo group is equal to 1.~* Alternative hypothesis H1: the ratio of the geometric mean of hsCRP-AUC(days 1-14) in RPH-104 group to the geometric mean of hsCRP-AUC(days 1-14) in the placebo group is different from 1.95% CI: [0.38, 0.98]
Primary
High-sensitive С-reactive Protein (hsCRP) Area Under Curve (AUC) From Baseline Until Day 14 (сomplete Cases)
hsCRP area under curve (AUC) from baseline (Day 1) until Day 14
Time frame: Day 1 until Day 14
Population: Full analysis set for efficacy analysis included all randomized subjects who received the study products (RPH-104 or placebo), and underwent at least one hsCRP measurement after administration of the study products. The FAS was the main population for efficacy assessment.~The model included patients with complete data (complete cases) in the FAS population. No data imputations were performed.
| Arm | Measure | Value (GEOMETRIC_LEAST_SQUARES_MEAN) |
|---|---|---|
| RPH-104 80 mg | High-sensitive С-reactive Protein (hsCRP) Area Under Curve (AUC) From Baseline Until Day 14 (сomplete Cases) | 96.72 mg*day/L |
| RPH-104 160 mg | High-sensitive С-reactive Protein (hsCRP) Area Under Curve (AUC) From Baseline Until Day 14 (сomplete Cases) | 106.71 mg*day/L |
| Placebo | High-sensitive С-reactive Protein (hsCRP) Area Under Curve (AUC) From Baseline Until Day 14 (сomplete Cases) | 178.59 mg*day/L |
Comparison: The following (two-sided) hypotheses were tested:~* Null hypothesis H0: the ratio of the geometric mean of hsCRP-AUC(days 1-14) in RPH-104 group to the geometric mean of hsCRP-AUC(days 1-14) in the placebo group is equal to 1.~* Alternative hypothesis H1: the ratio of the geometric mean of hsCRP-AUC(days 1-14) in RPH-104 group to the geometric mean of hsCRP-AUC(days 1-14) in the placebo group is different from 1.95% CI: [0.34, 0.87]
Comparison: The following (two-sided) hypotheses were tested:~* Null hypothesis H0: the ratio of the geometric mean of hsCRP-AUC(days 1-14) in RPH-104 group to the geometric mean of hsCRP-AUC(days 1-14) in the placebo group is equal to 1.~* Alternative hypothesis H1: the ratio of the geometric mean of hsCRP-AUC(days 1-14) in RPH-104 group to the geometric mean of hsCRP-AUC(days 1-14) in the placebo group is different from 1.95% CI: [0.37, 0.95]
Secondary
BNP AUC From Day 1 (Baseline) Until Day 28
Time frame: up to Day 28
Population: Full analysis set for efficacy analysis included all randomized subjects who received the study products (RPH-104 or placebo), and underwent at least one hsCRP measurement after administration of the study products. The FAS was the main population for efficacy assessment.~The model included patients with complete data (complete cases).
| Arm | Measure | Value (GEOMETRIC_LEAST_SQUARES_MEAN) |
|---|---|---|
| RPH-104 80 mg | BNP AUC From Day 1 (Baseline) Until Day 28 | 923.04 pmol*day/L |
| RPH-104 160 mg | BNP AUC From Day 1 (Baseline) Until Day 28 | 833.55 pmol*day/L |
| Placebo | BNP AUC From Day 1 (Baseline) Until Day 28 | 954.22 pmol*day/L |
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.
Time frame: From Day 1 Until Day 365
Population: FAS population. No data imputations were performed. Here, Number Analyzed indicates patients with assessable date each corresponding time point. Change from baseline was calculated for patients who had data at baseline and corresponding time point.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) |
|---|---|---|---|
| RPH-104 80 mg | Changes in Early Diastolic Transmitral Flow Velocity (E Velocity) Compared to Baseline | Month 12 | 0.67 m/s |
| RPH-104 80 mg | Changes in Early Diastolic Transmitral Flow Velocity (E Velocity) Compared to Baseline | Change from baseline (Day 28 / Early withdrawal) | -0.00 m/s |
| RPH-104 80 mg | Changes in Early Diastolic Transmitral Flow Velocity (E Velocity) Compared to Baseline | Day 1 (Baseline) | 0.72 m/s |
| RPH-104 80 mg | Changes in Early Diastolic Transmitral Flow Velocity (E Velocity) Compared to Baseline | Day 28 / Early withdrawal | 0.72 m/s |
| RPH-104 80 mg | Changes in Early Diastolic Transmitral Flow Velocity (E Velocity) Compared to Baseline | Change from baseline (Month 12) | -0.05 m/s |
| RPH-104 160 mg | Changes in Early Diastolic Transmitral Flow Velocity (E Velocity) Compared to Baseline | Change from baseline (Day 28 / Early withdrawal) | -0.01 m/s |
| RPH-104 160 mg | Changes in Early Diastolic Transmitral Flow Velocity (E Velocity) Compared to Baseline | Day 1 (Baseline) | 0.70 m/s |
| RPH-104 160 mg | Changes in Early Diastolic Transmitral Flow Velocity (E Velocity) Compared to Baseline | Day 28 / Early withdrawal | 0.69 m/s |
| RPH-104 160 mg | Changes in Early Diastolic Transmitral Flow Velocity (E Velocity) Compared to Baseline | Month 12 | 0.70 m/s |
| RPH-104 160 mg | Changes in Early Diastolic Transmitral Flow Velocity (E Velocity) Compared to Baseline | Change from baseline (Month 12) | -0.00 m/s |
| Placebo | Changes in Early Diastolic Transmitral Flow Velocity (E Velocity) Compared to Baseline | Change from baseline (Month 12) | 0.06 m/s |
| Placebo | Changes in Early Diastolic Transmitral Flow Velocity (E Velocity) Compared to Baseline | Month 12 | 0.76 m/s |
| Placebo | Changes in Early Diastolic Transmitral Flow Velocity (E Velocity) Compared to Baseline | Day 1 (Baseline) | 0.70 m/s |
| Placebo | Changes in Early Diastolic Transmitral Flow Velocity (E Velocity) Compared to Baseline | Change from baseline (Day 28 / Early withdrawal) | 0.09 m/s |
| Placebo | Changes in Early Diastolic Transmitral Flow Velocity (E Velocity) Compared to Baseline | Day 28 / Early withdrawal | 0.79 m/s |
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.
Time frame: From Day 1 Until Day 365
Population: FAS population. No data imputations were performed. Here, Number Analyzed indicates patients with assessable date each corresponding time point. Change from baseline was calculated for patients who had data at baseline and corresponding time point.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) |
|---|---|---|---|
| RPH-104 80 mg | Changes in Ejection Fraction (EF) After 12 Months Compared to Baseline | Change from baseline (Month 12) | 3.94 percentage of blood |
| RPH-104 80 mg | Changes in Ejection Fraction (EF) After 12 Months Compared to Baseline | Change from baseline (Day 28 / Early withdrawal) | 2.05 percentage of blood |
| RPH-104 80 mg | Changes in Ejection Fraction (EF) After 12 Months Compared to Baseline | Day 1 (Baseline) | 56.93 percentage of blood |
| RPH-104 80 mg | Changes in Ejection Fraction (EF) After 12 Months Compared to Baseline | Day 28 / Early withdrawal | 58.98 percentage of blood |
| RPH-104 80 mg | Changes in Ejection Fraction (EF) After 12 Months Compared to Baseline | Month 12 | 60.87 percentage of blood |
| RPH-104 160 mg | Changes in Ejection Fraction (EF) After 12 Months Compared to Baseline | Day 28 / Early withdrawal | 58.35 percentage of blood |
| RPH-104 160 mg | Changes in Ejection Fraction (EF) After 12 Months Compared to Baseline | Change from baseline (Month 12) | 3.80 percentage of blood |
| RPH-104 160 mg | Changes in Ejection Fraction (EF) After 12 Months Compared to Baseline | Month 12 | 60.31 percentage of blood |
| RPH-104 160 mg | Changes in Ejection Fraction (EF) After 12 Months Compared to Baseline | Change from baseline (Day 28 / Early withdrawal) | 1.84 percentage of blood |
| RPH-104 160 mg | Changes in Ejection Fraction (EF) After 12 Months Compared to Baseline | Day 1 (Baseline) | 56.51 percentage of blood |
| Placebo | Changes in Ejection Fraction (EF) After 12 Months Compared to Baseline | Change from baseline (Month 12) | 4.55 percentage of blood |
| Placebo | Changes in Ejection Fraction (EF) After 12 Months Compared to Baseline | Day 1 (Baseline) | 56.62 percentage of blood |
| Placebo | Changes in Ejection Fraction (EF) After 12 Months Compared to Baseline | Change from baseline (Day 28 / Early withdrawal) | 4.64 percentage of blood |
| Placebo | Changes in Ejection Fraction (EF) After 12 Months Compared to Baseline | Month 12 | 61.17 percentage of blood |
| Placebo | Changes in Ejection Fraction (EF) After 12 Months Compared to Baseline | Day 28 / Early withdrawal | 61.26 percentage of blood |
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.
Time frame: From Day 1 Until Day 365
Population: FAS population. No data imputations were performed. Here, Number Analyzed indicates patients with assessable date each corresponding time point. Change from baseline was calculated for patients who had data at baseline and corresponding time point.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) |
|---|---|---|---|
| RPH-104 80 mg | Changes in End-diastolic (EDV) Volume After 12 Months Compared to Baseline | Month 12 | 112.80 ml |
| RPH-104 80 mg | Changes in End-diastolic (EDV) Volume After 12 Months Compared to Baseline | Change from baseline (Day 28 / Early withdrawal) | -0.60 ml |
| RPH-104 80 mg | Changes in End-diastolic (EDV) Volume After 12 Months Compared to Baseline | Day 1 (Baseline) | 123.92 ml |
| RPH-104 80 mg | Changes in End-diastolic (EDV) Volume After 12 Months Compared to Baseline | Day 28 / Early withdrawal | 123.32 ml |
| RPH-104 80 mg | Changes in End-diastolic (EDV) Volume After 12 Months Compared to Baseline | Change from baseline (Month 12) | -11.12 ml |
| RPH-104 160 mg | Changes in End-diastolic (EDV) Volume After 12 Months Compared to Baseline | Change from baseline (Day 28 / Early withdrawal) | 3.40 ml |
| RPH-104 160 mg | Changes in End-diastolic (EDV) Volume After 12 Months Compared to Baseline | Day 1 (Baseline) | 123.10 ml |
| RPH-104 160 mg | Changes in End-diastolic (EDV) Volume After 12 Months Compared to Baseline | Day 28 / Early withdrawal | 126.49 ml |
| RPH-104 160 mg | Changes in End-diastolic (EDV) Volume After 12 Months Compared to Baseline | Month 12 | 116.88 ml |
| RPH-104 160 mg | Changes in End-diastolic (EDV) Volume After 12 Months Compared to Baseline | Change from baseline (Month 12) | -6.22 ml |
| Placebo | Changes in End-diastolic (EDV) Volume After 12 Months Compared to Baseline | Change from baseline (Month 12) | -2.66 ml |
| Placebo | Changes in End-diastolic (EDV) Volume After 12 Months Compared to Baseline | Month 12 | 119.98 ml |
| Placebo | Changes in End-diastolic (EDV) Volume After 12 Months Compared to Baseline | Day 1 (Baseline) | 122.64 ml |
| Placebo | Changes in End-diastolic (EDV) Volume After 12 Months Compared to Baseline | Change from baseline (Day 28 / Early withdrawal) | 9.70 ml |
| Placebo | Changes in End-diastolic (EDV) Volume After 12 Months Compared to Baseline | Day 28 / Early withdrawal | 132.34 ml |
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.
Time frame: From Day 1 Until Day 365
Population: FAS population. No data imputations were performed. Here, Number Analyzed indicates patients with assessable date each corresponding time point. Change from baseline was calculated for patients who had data at baseline and corresponding time point.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) |
|---|---|---|---|
| RPH-104 80 mg | Changes in End-systolic (ESV) Volume After 12 Months Compared to Baseline | Month 12 | 45.88 ml |
| RPH-104 80 mg | Changes in End-systolic (ESV) Volume After 12 Months Compared to Baseline | Change from baseline (Day 28 / Early withdrawal) | -1.90 ml |
| RPH-104 80 mg | Changes in End-systolic (ESV) Volume After 12 Months Compared to Baseline | Day 1 (Baseline) | 54.20 ml |
| RPH-104 80 mg | Changes in End-systolic (ESV) Volume After 12 Months Compared to Baseline | Day 28 / Early withdrawal | 52.30 ml |
| RPH-104 80 mg | Changes in End-systolic (ESV) Volume After 12 Months Compared to Baseline | Change from baseline (Month 12) | -8.33 ml |
| RPH-104 160 mg | Changes in End-systolic (ESV) Volume After 12 Months Compared to Baseline | Change from baseline (Day 28 / Early withdrawal) | -0.30 ml |
| RPH-104 160 mg | Changes in End-systolic (ESV) Volume After 12 Months Compared to Baseline | Day 1 (Baseline) | 54.60 ml |
| RPH-104 160 mg | Changes in End-systolic (ESV) Volume After 12 Months Compared to Baseline | Day 28 / Early withdrawal | 54.31 ml |
| RPH-104 160 mg | Changes in End-systolic (ESV) Volume After 12 Months Compared to Baseline | Month 12 | 48.67 ml |
| RPH-104 160 mg | Changes in End-systolic (ESV) Volume After 12 Months Compared to Baseline | Change from baseline (Month 12) | -5.94 ml |
| Placebo | Changes in End-systolic (ESV) Volume After 12 Months Compared to Baseline | Change from baseline (Month 12) | -5.88 ml |
| Placebo | Changes in End-systolic (ESV) Volume After 12 Months Compared to Baseline | Month 12 | 48.67 ml |
| Placebo | Changes in End-systolic (ESV) Volume After 12 Months Compared to Baseline | Day 1 (Baseline) | 54.55 ml |
| Placebo | Changes in End-systolic (ESV) Volume After 12 Months Compared to Baseline | Change from baseline (Day 28 / Early withdrawal) | -2.47 ml |
| Placebo | Changes in End-systolic (ESV) Volume After 12 Months Compared to Baseline | Day 28 / Early withdrawal | 52.07 ml |
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.
Time frame: From Day 1 Until Day 365
Population: FAS population. No data imputations were performed. Here, Number Analyzed indicates patients with assessable date each corresponding time point. Change from baseline was calculated for patients who had data at baseline and corresponding time point.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) |
|---|---|---|---|
| RPH-104 80 mg | Changes in Global Longitudinal Strain (GLS) Compared to Baseline | Month 12 | -17.80 percentage of myocardial shortening |
| RPH-104 80 mg | Changes in Global Longitudinal Strain (GLS) Compared to Baseline | Change from baseline (Day 28 / Early withdrawal) | -1.30 percentage of myocardial shortening |
| RPH-104 80 mg | Changes in Global Longitudinal Strain (GLS) Compared to Baseline | Day 1 (Baseline) | -15.39 percentage of myocardial shortening |
| RPH-104 80 mg | Changes in Global Longitudinal Strain (GLS) Compared to Baseline | Day 28 / Early withdrawal | -16.69 percentage of myocardial shortening |
| RPH-104 80 mg | Changes in Global Longitudinal Strain (GLS) Compared to Baseline | Change from baseline (Month 12) | -2.41 percentage of myocardial shortening |
| RPH-104 160 mg | Changes in Global Longitudinal Strain (GLS) Compared to Baseline | Change from baseline (Day 28 / Early withdrawal) | -0.96 percentage of myocardial shortening |
| RPH-104 160 mg | Changes in Global Longitudinal Strain (GLS) Compared to Baseline | Day 1 (Baseline) | -15.24 percentage of myocardial shortening |
| RPH-104 160 mg | Changes in Global Longitudinal Strain (GLS) Compared to Baseline | Day 28 / Early withdrawal | -16.20 percentage of myocardial shortening |
| RPH-104 160 mg | Changes in Global Longitudinal Strain (GLS) Compared to Baseline | Month 12 | -18.16 percentage of myocardial shortening |
| RPH-104 160 mg | Changes in Global Longitudinal Strain (GLS) Compared to Baseline | Change from baseline (Month 12) | -2.91 percentage of myocardial shortening |
| Placebo | Changes in Global Longitudinal Strain (GLS) Compared to Baseline | Change from baseline (Month 12) | -4.87 percentage of myocardial shortening |
| Placebo | Changes in Global Longitudinal Strain (GLS) Compared to Baseline | Month 12 | -19.47 percentage of myocardial shortening |
| Placebo | Changes in Global Longitudinal Strain (GLS) Compared to Baseline | Day 1 (Baseline) | -14.60 percentage of myocardial shortening |
| Placebo | Changes in Global Longitudinal Strain (GLS) Compared to Baseline | Change from baseline (Day 28 / Early withdrawal) | -3.62 percentage of myocardial shortening |
| Placebo | Changes in Global Longitudinal Strain (GLS) Compared to Baseline | Day 28 / Early withdrawal | -18.22 percentage of myocardial shortening |
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.
Time frame: From Day 1 until Day 28
Population: Analysis was performed at the stage of final analysis for the FAS population. No data imputations were performed.~Here, Number Analyzed indicates patients with assessable date each corresponding time point. Change from baseline was calculated for patients who had data at baseline and corresponding time point.
| Arm | Measure | Group | Value (GEOMETRIC_LEAST_SQUARES_MEAN) |
|---|---|---|---|
| RPH-104 80 mg | Changes in hsCRP Levels During the Study Compared to Baseline | Change from baseline (Day 14) | 0.31 ratio |
| RPH-104 80 mg | Changes in hsCRP Levels During the Study Compared to Baseline | Change from baseline (Day 3) | 2.54 ratio |
| RPH-104 80 mg | Changes in hsCRP Levels During the Study Compared to Baseline | Change from baseline (Day 28 / Early withdrawal) | 0.34 ratio |
| RPH-104 160 mg | Changes in hsCRP Levels During the Study Compared to Baseline | Change from baseline (Day 14) | 0.22 ratio |
| RPH-104 160 mg | Changes in hsCRP Levels During the Study Compared to Baseline | Change from baseline (Day 3) | 2.81 ratio |
| RPH-104 160 mg | Changes in hsCRP Levels During the Study Compared to Baseline | Change from baseline (Day 28 / Early withdrawal) | 0.23 ratio |
| Placebo | Changes in hsCRP Levels During the Study Compared to Baseline | Change from baseline (Day 3) | 3.75 ratio |
| Placebo | Changes in hsCRP Levels During the Study Compared to Baseline | Change from baseline (Day 28 / Early withdrawal) | 0.56 ratio |
| Placebo | Changes in hsCRP Levels During the Study Compared to Baseline | Change from baseline (Day 14) | 1.54 ratio |
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.
Time frame: From Day 1 Until Day 365
Population: FAS population. No data imputations were performed. Here, Number Analyzed indicates patients with assessable date each corresponding time point. Change from baseline was calculated for patients who had data at baseline and corresponding time point.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) |
|---|---|---|---|
| RPH-104 80 mg | Changes in Left Ventricular Stroke Volume (LV SV) Compared to Baseline | Month 12 | 74.14 ml |
| RPH-104 80 mg | Changes in Left Ventricular Stroke Volume (LV SV) Compared to Baseline | Change from baseline (Day 28 / Early withdrawal) | 1.79 ml |
| RPH-104 80 mg | Changes in Left Ventricular Stroke Volume (LV SV) Compared to Baseline | Day 1 (Baseline) | 66.18 ml |
| RPH-104 80 mg | Changes in Left Ventricular Stroke Volume (LV SV) Compared to Baseline | Day 28 / Early withdrawal | 67.97 ml |
| RPH-104 80 mg | Changes in Left Ventricular Stroke Volume (LV SV) Compared to Baseline | Change from baseline (Month 12) | 7.95 ml |
| RPH-104 160 mg | Changes in Left Ventricular Stroke Volume (LV SV) Compared to Baseline | Change from baseline (Day 28 / Early withdrawal) | 4.08 ml |
| RPH-104 160 mg | Changes in Left Ventricular Stroke Volume (LV SV) Compared to Baseline | Day 1 (Baseline) | 67.25 ml |
| RPH-104 160 mg | Changes in Left Ventricular Stroke Volume (LV SV) Compared to Baseline | Day 28 / Early withdrawal | 71.33 ml |
| RPH-104 160 mg | Changes in Left Ventricular Stroke Volume (LV SV) Compared to Baseline | Month 12 | 71.11 ml |
| RPH-104 160 mg | Changes in Left Ventricular Stroke Volume (LV SV) Compared to Baseline | Change from baseline (Month 12) | 3.86 ml |
| Placebo | Changes in Left Ventricular Stroke Volume (LV SV) Compared to Baseline | Change from baseline (Month 12) | 8.02 ml |
| Placebo | Changes in Left Ventricular Stroke Volume (LV SV) Compared to Baseline | Month 12 | 73.12 ml |
| Placebo | Changes in Left Ventricular Stroke Volume (LV SV) Compared to Baseline | Day 1 (Baseline) | 65.09 ml |
| Placebo | Changes in Left Ventricular Stroke Volume (LV SV) Compared to Baseline | Change from baseline (Day 28 / Early withdrawal) | 11.45 ml |
| Placebo | Changes in Left Ventricular Stroke Volume (LV SV) Compared to Baseline | Day 28 / Early withdrawal | 76.55 ml |
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.
Time frame: From Day 1 until Day 365
Population: Analysis was performed at the stage of final analysis for the FAS population. No data imputations were performed.~Here, Number Analyzed indicates patients with assessable date each corresponding time point. Change from baseline was calculated for patients who had data at baseline and corresponding time point.
| Arm | Measure | Group | Value (GEOMETRIC_LEAST_SQUARES_MEAN) |
|---|---|---|---|
| RPH-104 80 mg | Changes in Levels of Brain Natriuretic Peptide (BNP) During 12-month Follow-up Period Compared to Baseline | Change from baseline (Day 14) | 2.04 ratio |
| RPH-104 80 mg | Changes in Levels of Brain Natriuretic Peptide (BNP) During 12-month Follow-up Period Compared to Baseline | Change from baseline (Day 3) | 1.74 ratio |
| RPH-104 80 mg | Changes in Levels of Brain Natriuretic Peptide (BNP) During 12-month Follow-up Period Compared to Baseline | Change from baseline (Day 28 / Early withdrawal) | 1.50 ratio |
| RPH-104 80 mg | Changes in Levels of Brain Natriuretic Peptide (BNP) During 12-month Follow-up Period Compared to Baseline | Change from baseline (Month 12) | 0.64 ratio |
| RPH-104 160 mg | Changes in Levels of Brain Natriuretic Peptide (BNP) During 12-month Follow-up Period Compared to Baseline | Change from baseline (Day 14) | 1.27 ratio |
| RPH-104 160 mg | Changes in Levels of Brain Natriuretic Peptide (BNP) During 12-month Follow-up Period Compared to Baseline | Change from baseline (Day 28 / Early withdrawal) | 1.05 ratio |
| RPH-104 160 mg | Changes in Levels of Brain Natriuretic Peptide (BNP) During 12-month Follow-up Period Compared to Baseline | Change from baseline (Month 12) | 0.44 ratio |
| RPH-104 160 mg | Changes in Levels of Brain Natriuretic Peptide (BNP) During 12-month Follow-up Period Compared to Baseline | Change from baseline (Day 3) | 1.23 ratio |
| Placebo | Changes in Levels of Brain Natriuretic Peptide (BNP) During 12-month Follow-up Period Compared to Baseline | Change from baseline (Month 12) | 0.67 ratio |
| Placebo | Changes in Levels of Brain Natriuretic Peptide (BNP) During 12-month Follow-up Period Compared to Baseline | Change from baseline (Day 28 / Early withdrawal) | 1.14 ratio |
| Placebo | Changes in Levels of Brain Natriuretic Peptide (BNP) During 12-month Follow-up Period Compared to Baseline | Change from baseline (Day 14) | 1.52 ratio |
| Placebo | Changes in Levels of Brain Natriuretic Peptide (BNP) During 12-month Follow-up Period Compared to Baseline | Change from baseline (Day 3) | 1.62 ratio |
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.
Time frame: From Day 1 until Day 365
Population: Analysis was performed at the stage of final analysis for the FAS population. No data imputations were performed.~Here, Number Analyzed indicates patients with assessable date each corresponding time point. Change from baseline was calculated for patients who had data at baseline and corresponding time point.
| Arm | Measure | Group | Value (GEOMETRIC_LEAST_SQUARES_MEAN) |
|---|---|---|---|
| RPH-104 80 mg | Changes in Levels of Brain Natriuretic Peptide (NT-proBNP) During 12-month Follow-up Period Compared to Baseline | Change from baseline (Day 3) | 2.24 ratio |
| RPH-104 80 mg | Changes in Levels of Brain Natriuretic Peptide (NT-proBNP) During 12-month Follow-up Period Compared to Baseline | Change from baseline (Day 14) | 1.70 ratio |
| RPH-104 80 mg | Changes in Levels of Brain Natriuretic Peptide (NT-proBNP) During 12-month Follow-up Period Compared to Baseline | Change from baseline (Day 28 / Early withdrawal) | 1.46 ratio |
| RPH-104 80 mg | Changes in Levels of Brain Natriuretic Peptide (NT-proBNP) During 12-month Follow-up Period Compared to Baseline | Change from baseline (Month 12) | 0.38 ratio |
| RPH-104 160 mg | Changes in Levels of Brain Natriuretic Peptide (NT-proBNP) During 12-month Follow-up Period Compared to Baseline | Change from baseline (Month 12) | 0.37 ratio |
| RPH-104 160 mg | Changes in Levels of Brain Natriuretic Peptide (NT-proBNP) During 12-month Follow-up Period Compared to Baseline | Change from baseline (Day 3) | 1.85 ratio |
| RPH-104 160 mg | Changes in Levels of Brain Natriuretic Peptide (NT-proBNP) During 12-month Follow-up Period Compared to Baseline | Change from baseline (Day 28 / Early withdrawal) | 1.28 ratio |
| RPH-104 160 mg | Changes in Levels of Brain Natriuretic Peptide (NT-proBNP) During 12-month Follow-up Period Compared to Baseline | Change from baseline (Day 14) | 1.28 ratio |
| Placebo | Changes in Levels of Brain Natriuretic Peptide (NT-proBNP) During 12-month Follow-up Period Compared to Baseline | Change from baseline (Month 12) | 0.46 ratio |
| Placebo | Changes in Levels of Brain Natriuretic Peptide (NT-proBNP) During 12-month Follow-up Period Compared to Baseline | Change from baseline (Day 14) | 1.59 ratio |
| Placebo | Changes in Levels of Brain Natriuretic Peptide (NT-proBNP) During 12-month Follow-up Period Compared to Baseline | Change from baseline (Day 28 / Early withdrawal) | 1.45 ratio |
| Placebo | Changes in Levels of Brain Natriuretic Peptide (NT-proBNP) During 12-month Follow-up Period Compared to Baseline | Change from baseline (Day 3) | 2.32 ratio |
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.
Time frame: From Day 1 Until Day 365
Population: FAS population. No data imputations were performed. Here, Number Analyzed indicates patients with assessable date each corresponding time point. Change from baseline was calculated for patients who had data at baseline and corresponding time point.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) |
|---|---|---|---|
| RPH-104 80 mg | Changes in Mitral Valve e'Lat Compared to Baseline | Month 12 | 9.24 cm/s |
| RPH-104 80 mg | Changes in Mitral Valve e'Lat Compared to Baseline | Change from baseline (Day 28 / Early withdrawal) | 0.51 cm/s |
| RPH-104 80 mg | Changes in Mitral Valve e'Lat Compared to Baseline | Day 1 (Baseline) | 9.04 cm/s |
| RPH-104 80 mg | Changes in Mitral Valve e'Lat Compared to Baseline | Day 28 / Early withdrawal | 9.55 cm/s |
| RPH-104 80 mg | Changes in Mitral Valve e'Lat Compared to Baseline | Change from baseline (Month 12) | 0.20 cm/s |
| RPH-104 160 mg | Changes in Mitral Valve e'Lat Compared to Baseline | Change from baseline (Day 28 / Early withdrawal) | -0.18 cm/s |
| RPH-104 160 mg | Changes in Mitral Valve e'Lat Compared to Baseline | Day 1 (Baseline) | 9.04 cm/s |
| RPH-104 160 mg | Changes in Mitral Valve e'Lat Compared to Baseline | Day 28 / Early withdrawal | 8.86 cm/s |
| RPH-104 160 mg | Changes in Mitral Valve e'Lat Compared to Baseline | Month 12 | 9.83 cm/s |
| RPH-104 160 mg | Changes in Mitral Valve e'Lat Compared to Baseline | Change from baseline (Month 12) | 0.79 cm/s |
| Placebo | Changes in Mitral Valve e'Lat Compared to Baseline | Change from baseline (Month 12) | 0.87 cm/s |
| Placebo | Changes in Mitral Valve e'Lat Compared to Baseline | Month 12 | 9.63 cm/s |
| Placebo | Changes in Mitral Valve e'Lat Compared to Baseline | Day 1 (Baseline) | 8.76 cm/s |
| Placebo | Changes in Mitral Valve e'Lat Compared to Baseline | Change from baseline (Day 28 / Early withdrawal) | 0.85 cm/s |
| Placebo | Changes in Mitral Valve e'Lat Compared to Baseline | Day 28 / Early withdrawal | 9.61 cm/s |
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.
Time frame: From Day 1 Until Day 365
Population: FAS population. No data imputations were performed. Here, Number Analyzed indicates patients with assessable date each corresponding time point. Change from baseline was calculated for patients who had data at baseline and corresponding time point.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) |
|---|---|---|---|
| RPH-104 80 mg | Changes in Mitral Valve (MV) e'Sept Compared to Baseline | Month 12 | 6.51 cm/s |
| RPH-104 80 mg | Changes in Mitral Valve (MV) e'Sept Compared to Baseline | Day 1 (Baseline) | 7.17 cm/s |
| RPH-104 80 mg | Changes in Mitral Valve (MV) e'Sept Compared to Baseline | Day 28 / Early withdrawal | 6.47 cm/s |
| RPH-104 80 mg | Changes in Mitral Valve (MV) e'Sept Compared to Baseline | Change from baseline (Day 28 / Early withdrawal) | -0.70 cm/s |
| RPH-104 80 mg | Changes in Mitral Valve (MV) e'Sept Compared to Baseline | Change from baseline (Month 12) | -0.66 cm/s |
| RPH-104 160 mg | Changes in Mitral Valve (MV) e'Sept Compared to Baseline | Day 28 / Early withdrawal | 7.03 cm/s |
| RPH-104 160 mg | Changes in Mitral Valve (MV) e'Sept Compared to Baseline | Change from baseline (Month 12) | -0.02 cm/s |
| RPH-104 160 mg | Changes in Mitral Valve (MV) e'Sept Compared to Baseline | Change from baseline (Day 28 / Early withdrawal) | -0.11 cm/s |
| RPH-104 160 mg | Changes in Mitral Valve (MV) e'Sept Compared to Baseline | Month 12 | 7.11 cm/s |
| RPH-104 160 mg | Changes in Mitral Valve (MV) e'Sept Compared to Baseline | Day 1 (Baseline) | 7.14 cm/s |
| Placebo | Changes in Mitral Valve (MV) e'Sept Compared to Baseline | Day 1 (Baseline) | 6.69 cm/s |
| Placebo | Changes in Mitral Valve (MV) e'Sept Compared to Baseline | Day 28 / Early withdrawal | 7.09 cm/s |
| Placebo | Changes in Mitral Valve (MV) e'Sept Compared to Baseline | Month 12 | 7.11 cm/s |
| Placebo | Changes in Mitral Valve (MV) e'Sept Compared to Baseline | Change from baseline (Month 12) | 0.42 cm/s |
| Placebo | Changes in Mitral Valve (MV) e'Sept Compared to Baseline | Change from baseline (Day 28 / Early withdrawal) | 0.40 cm/s |
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.
Time frame: From Day 1 Until Day 365
Population: FAS population. No data imputations were performed. Here, Number Analyzed indicates patients with assessable date each corresponding time point. Change from baseline was calculated for patients who had data at baseline and corresponding time point.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) |
|---|---|---|---|
| RPH-104 80 mg | Changes in Regional LV Function After 12 Months Compared to Baseline | Month 12 | 1.19 index units |
| RPH-104 80 mg | Changes in Regional LV Function After 12 Months Compared to Baseline | Change from baseline (Day 28 / Early withdrawal) | -0.17 index units |
| RPH-104 80 mg | Changes in Regional LV Function After 12 Months Compared to Baseline | Day 1 (Baseline) | 1.40 index units |
| RPH-104 80 mg | Changes in Regional LV Function After 12 Months Compared to Baseline | Day 28 / Early withdrawal | 1.23 index units |
| RPH-104 80 mg | Changes in Regional LV Function After 12 Months Compared to Baseline | Change from baseline (Month 12) | -0.21 index units |
| RPH-104 160 mg | Changes in Regional LV Function After 12 Months Compared to Baseline | Change from baseline (Day 28 / Early withdrawal) | -0.10 index units |
| RPH-104 160 mg | Changes in Regional LV Function After 12 Months Compared to Baseline | Day 1 (Baseline) | 1.39 index units |
| RPH-104 160 mg | Changes in Regional LV Function After 12 Months Compared to Baseline | Day 28 / Early withdrawal | 1.29 index units |
| RPH-104 160 mg | Changes in Regional LV Function After 12 Months Compared to Baseline | Month 12 | 1.26 index units |
| RPH-104 160 mg | Changes in Regional LV Function After 12 Months Compared to Baseline | Change from baseline (Month 12) | -0.13 index units |
| Placebo | Changes in Regional LV Function After 12 Months Compared to Baseline | Change from baseline (Month 12) | -0.23 index units |
| Placebo | Changes in Regional LV Function After 12 Months Compared to Baseline | Month 12 | 1.17 index units |
| Placebo | Changes in Regional LV Function After 12 Months Compared to Baseline | Day 1 (Baseline) | 1.40 index units |
| Placebo | Changes in Regional LV Function After 12 Months Compared to Baseline | Change from baseline (Day 28 / Early withdrawal) | -0.19 index units |
| Placebo | Changes in Regional LV Function After 12 Months Compared to Baseline | Day 28 / Early withdrawal | 1.21 index units |
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.
Time frame: From Day 1 Until Day 365
Population: FAS population. No data imputations were performed. Here, Number Analyzed indicates patients with assessable date each corresponding time point. Change from baseline was calculated for patients who had data at baseline and corresponding time point.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) |
|---|---|---|---|
| RPH-104 80 mg | Changes in Stroke Volume (SV) Compared to Baseline | Month 12 | 66.09 ml |
| RPH-104 80 mg | Changes in Stroke Volume (SV) Compared to Baseline | Change from baseline (Day 28 / Early withdrawal) | 0.96 ml |
| RPH-104 80 mg | Changes in Stroke Volume (SV) Compared to Baseline | Day 1 (Baseline) | 70.09 ml |
| RPH-104 80 mg | Changes in Stroke Volume (SV) Compared to Baseline | Day 28 / Early withdrawal | 71.05 ml |
| RPH-104 80 mg | Changes in Stroke Volume (SV) Compared to Baseline | Change from baseline (Month 12) | -4.00 ml |
| RPH-104 160 mg | Changes in Stroke Volume (SV) Compared to Baseline | Change from baseline (Day 28 / Early withdrawal) | 3.48 ml |
| RPH-104 160 mg | Changes in Stroke Volume (SV) Compared to Baseline | Day 1 (Baseline) | 68.15 ml |
| RPH-104 160 mg | Changes in Stroke Volume (SV) Compared to Baseline | Day 28 / Early withdrawal | 71.62 ml |
| RPH-104 160 mg | Changes in Stroke Volume (SV) Compared to Baseline | Month 12 | 67.61 ml |
| RPH-104 160 mg | Changes in Stroke Volume (SV) Compared to Baseline | Change from baseline (Month 12) | -0.54 ml |
| Placebo | Changes in Stroke Volume (SV) Compared to Baseline | Change from baseline (Month 12) | 3.02 ml |
| Placebo | Changes in Stroke Volume (SV) Compared to Baseline | Month 12 | 70.63 ml |
| Placebo | Changes in Stroke Volume (SV) Compared to Baseline | Day 1 (Baseline) | 67.61 ml |
| Placebo | Changes in Stroke Volume (SV) Compared to Baseline | Change from baseline (Day 28 / Early withdrawal) | 12.17 ml |
| Placebo | Changes in Stroke Volume (SV) Compared to Baseline | Day 28 / Early withdrawal | 79.79 ml |
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.
Time frame: From Day 1 Until Day 365
Population: FAS population. No data imputations were performed. Here, Number Analyzed indicates patients with assessable date each corresponding time point. Change from baseline was calculated for patients who had data at baseline and corresponding time point.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) |
|---|---|---|---|
| RPH-104 80 mg | Changes in Tricuspid Annular Plane Systolic Excursion (TAPSE) Parameter Compared to Baseline | Month 12 | 21.88 mm |
| RPH-104 80 mg | Changes in Tricuspid Annular Plane Systolic Excursion (TAPSE) Parameter Compared to Baseline | Change from baseline (Day 28 / Early withdrawal) | 0.21 mm |
| RPH-104 80 mg | Changes in Tricuspid Annular Plane Systolic Excursion (TAPSE) Parameter Compared to Baseline | Day 1 (Baseline) | 21.87 mm |
| RPH-104 80 mg | Changes in Tricuspid Annular Plane Systolic Excursion (TAPSE) Parameter Compared to Baseline | Day 28 / Early withdrawal | 22.09 mm |
| RPH-104 80 mg | Changes in Tricuspid Annular Plane Systolic Excursion (TAPSE) Parameter Compared to Baseline | Change from baseline (Month 12) | 0.00 mm |
| RPH-104 160 mg | Changes in Tricuspid Annular Plane Systolic Excursion (TAPSE) Parameter Compared to Baseline | Change from baseline (Day 28 / Early withdrawal) | 0.96 mm |
| RPH-104 160 mg | Changes in Tricuspid Annular Plane Systolic Excursion (TAPSE) Parameter Compared to Baseline | Day 1 (Baseline) | 21.76 mm |
| RPH-104 160 mg | Changes in Tricuspid Annular Plane Systolic Excursion (TAPSE) Parameter Compared to Baseline | Day 28 / Early withdrawal | 22.71 mm |
| RPH-104 160 mg | Changes in Tricuspid Annular Plane Systolic Excursion (TAPSE) Parameter Compared to Baseline | Month 12 | 21.05 mm |
| RPH-104 160 mg | Changes in Tricuspid Annular Plane Systolic Excursion (TAPSE) Parameter Compared to Baseline | Change from baseline (Month 12) | -0.70 mm |
| Placebo | Changes in Tricuspid Annular Plane Systolic Excursion (TAPSE) Parameter Compared to Baseline | Change from baseline (Month 12) | 1.52 mm |
| Placebo | Changes in Tricuspid Annular Plane Systolic Excursion (TAPSE) Parameter Compared to Baseline | Month 12 | 22.71 mm |
| Placebo | Changes in Tricuspid Annular Plane Systolic Excursion (TAPSE) Parameter Compared to Baseline | Day 1 (Baseline) | 21.19 mm |
| Placebo | Changes in Tricuspid Annular Plane Systolic Excursion (TAPSE) Parameter Compared to Baseline | Change from baseline (Day 28 / Early withdrawal) | 1.60 mm |
| Placebo | Changes in Tricuspid Annular Plane Systolic Excursion (TAPSE) Parameter Compared to Baseline | Day 28 / Early withdrawal | 22.79 mm |
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.
Time frame: From Day 1 Until Day 365
Population: FAS population. No data imputations were performed. Here, Number Analyzed indicates patients with assessable date each corresponding time point. Change from baseline was calculated for patients who had data at baseline and corresponding time point.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) |
|---|---|---|---|
| RPH-104 80 mg | Changes of Fractional Area Change (FAC) Compared to Baseline | Month 12 | 49.22 percentage of area |
| RPH-104 80 mg | Changes of Fractional Area Change (FAC) Compared to Baseline | Change from baseline (Day 28 / Early withdrawal) | 3.09 percentage of area |
| RPH-104 80 mg | Changes of Fractional Area Change (FAC) Compared to Baseline | Day 1 (Baseline) | 48.65 percentage of area |
| RPH-104 80 mg | Changes of Fractional Area Change (FAC) Compared to Baseline | Day 28 / Early withdrawal | 51.73 percentage of area |
| RPH-104 80 mg | Changes of Fractional Area Change (FAC) Compared to Baseline | Change from baseline (Month 12) | 0.57 percentage of area |
| RPH-104 160 mg | Changes of Fractional Area Change (FAC) Compared to Baseline | Change from baseline (Day 28 / Early withdrawal) | 2.33 percentage of area |
| RPH-104 160 mg | Changes of Fractional Area Change (FAC) Compared to Baseline | Day 1 (Baseline) | 48.45 percentage of area |
| RPH-104 160 mg | Changes of Fractional Area Change (FAC) Compared to Baseline | Day 28 / Early withdrawal | 50.78 percentage of area |
| RPH-104 160 mg | Changes of Fractional Area Change (FAC) Compared to Baseline | Month 12 | 51.32 percentage of area |
| RPH-104 160 mg | Changes of Fractional Area Change (FAC) Compared to Baseline | Change from baseline (Month 12) | 2.87 percentage of area |
| Placebo | Changes of Fractional Area Change (FAC) Compared to Baseline | Change from baseline (Month 12) | -0.78 percentage of area |
| Placebo | Changes of Fractional Area Change (FAC) Compared to Baseline | Month 12 | 48.15 percentage of area |
| Placebo | Changes of Fractional Area Change (FAC) Compared to Baseline | Day 1 (Baseline) | 48.93 percentage of area |
| Placebo | Changes of Fractional Area Change (FAC) Compared to Baseline | Change from baseline (Day 28 / Early withdrawal) | 1.34 percentage of area |
| Placebo | Changes of Fractional Area Change (FAC) Compared to Baseline | Day 28 / Early withdrawal | 50.27 percentage of area |
Secondary
hsCRP AUC From Baseline Until Day 28 (Complete Cases)
hsCRP AUC from baseline (Day 1) until Day 28
Time frame: up to Day 28
Population: Full analysis set for efficacy analysis included all randomized subjects who received the study products (RPH-104 or placebo), and underwent at least one hsCRP measurement after administration of the study products. The FAS was the main population for efficacy assessment.~The model included patients with complete data (complete cases) in the FAS population. No data imputations were performed.
| Arm | Measure | Value (GEOMETRIC_LEAST_SQUARES_MEAN) |
|---|---|---|
| RPH-104 80 mg | hsCRP AUC From Baseline Until Day 28 (Complete Cases) | 130.07 mg*day/L |
| RPH-104 160 mg | hsCRP AUC From Baseline Until Day 28 (Complete Cases) | 131.27 mg*day/L |
| Placebo | hsCRP AUC From Baseline Until Day 28 (Complete Cases) | 277.13 mg*day/L |
Comparison: The following (two-sided) hypotheses were tested:~Null hypothesis H0: the ratio of the geometric mean of hsCRP-AUC(days 1-28) in RPH-104 group to the geometric mean of hsCRP-AUC(days 1-28) in the placebo group is equal to 1.~Alternative hypothesis H1: the ratio of the geometric mean of hsCRP-AUC(days 1-28) in RPH-104 group to the geometric mean of hsCRP-AUC(days 1-28) in the placebo group is different from 1.95% CI: [0.29, 0.75]
Comparison: The following (two-sided) hypotheses were tested:~Null hypothesis H0: the ratio of the geometric mean of hsCRP-AUC(days 1-28) in RPH-104 group to the geometric mean of hsCRP-AUC(days 1-28) in the placebo group is equal to 1.~Alternative hypothesis H1: the ratio of the geometric mean of hsCRP-AUC(days 1-28) in RPH-104 group to the geometric mean of hsCRP-AUC(days 1-28) in the placebo group is different from 1.95% CI: [0.3, 0.75]
Secondary
hsCRP AUC From Baseline Until Day 28 (Multiple Imputation Procedure)
hsCRP AUC from baseline (Day 1) until Day 28
Time frame: up to Day 28
Population: Full analysis set for efficacy analysis included all randomized subjects who received the study products (RPH-104 or placebo), and underwent at least one hsCRP measurement after administration of the study products. The FAS was the main population for efficacy assessment.~Multiple imputation procedure was performed for hsCRP values which were missed on Day 28.
| Arm | Measure | Value (GEOMETRIC_LEAST_SQUARES_MEAN) |
|---|---|---|
| RPH-104 80 mg | hsCRP AUC From Baseline Until Day 28 (Multiple Imputation Procedure) | 148.58 mg*day/L |
| RPH-104 160 mg | hsCRP AUC From Baseline Until Day 28 (Multiple Imputation Procedure) | 136.84 mg*day/L |
| Placebo | hsCRP AUC From Baseline Until Day 28 (Multiple Imputation Procedure) | 285.78 mg*day/L |
Comparison: The following (two-sided) hypotheses were tested:~Null hypothesis H0: the ratio of the geometric mean of hsCRP-AUC(days 1-28) in RPH-104 group to the geometric mean of hsCRP-AUC(days 1-28) in the placebo group is equal to 1.~Alternative hypothesis H1: the ratio of the geometric mean of hsCRP-AUC(days 1-28) in RPH-104 group to the geometric mean of hsCRP-AUC(days 1-28) in the placebo group is different from 1.95% CI: [0.34, 0.81]
Comparison: The following (two-sided) hypotheses were tested:~Null hypothesis H0: the ratio of the geometric mean of hsCRP-AUC(days 1-28) in RPH-104 group to the geometric mean of hsCRP-AUC(days 1-28) in the placebo group is equal to 1.~Alternative hypothesis H1: the ratio of the geometric mean of hsCRP-AUC(days 1-28) in RPH-104 group to the geometric mean of hsCRP-AUC(days 1-28) in the placebo group is different from 1.95% CI: [0.31, 0.74]
Secondary
NT-pro-BNP AUC From Day 1 (Baseline) Until Day 28
Time frame: up to Day 28
Population: Full analysis set for efficacy analysis included all randomized subjects who received the study products (RPH-104 or placebo), and underwent at least one hsCRP measurement after administration of the study products. The FAS was the main population for efficacy assessment.~The model included patients with complete data (complete cases).
| Arm | Measure | Value (GEOMETRIC_LEAST_SQUARES_MEAN) |
|---|---|---|
| RPH-104 80 mg | NT-pro-BNP AUC From Day 1 (Baseline) Until Day 28 | 2152.07 pmol*day/L |
| RPH-104 160 mg | NT-pro-BNP AUC From Day 1 (Baseline) Until Day 28 | 1940.71 pmol*day/L |
| Placebo | NT-pro-BNP AUC From Day 1 (Baseline) Until Day 28 | 2597.13 pmol*day/L |
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.
Time frame: up to Day 365
Population: Analysis was performed at the stage of final analysis for the FAS population. Data for fatal cases (deaths) were derived from CRF records. The CRF provided Yes, No and Unknown for patient's alive status. Unknown was naturally missing data.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| RPH-104 80 mg | Number of Patients With Fatal Outcomes (Cardiac and Non-cardiac) During 12-month Follow-up Period | Cardiovascular death | 1 Participants |
| RPH-104 80 mg | Number of Patients With Fatal Outcomes (Cardiac and Non-cardiac) During 12-month Follow-up Period | Non-cardiovascular death | 0 Participants |
| RPH-104 80 mg | Number of Patients With Fatal Outcomes (Cardiac and Non-cardiac) During 12-month Follow-up Period | Patient is alive | 33 Participants |
| RPH-104 80 mg | Number of Patients With Fatal Outcomes (Cardiac and Non-cardiac) During 12-month Follow-up Period | Unknown | 0 Participants |
| RPH-104 160 mg | Number of Patients With Fatal Outcomes (Cardiac and Non-cardiac) During 12-month Follow-up Period | Unknown | 3 Participants |
| RPH-104 160 mg | Number of Patients With Fatal Outcomes (Cardiac and Non-cardiac) During 12-month Follow-up Period | Cardiovascular death | 0 Participants |
| RPH-104 160 mg | Number of Patients With Fatal Outcomes (Cardiac and Non-cardiac) During 12-month Follow-up Period | Patient is alive | 31 Participants |
| RPH-104 160 mg | Number of Patients With Fatal Outcomes (Cardiac and Non-cardiac) During 12-month Follow-up Period | Non-cardiovascular death | 0 Participants |
| Placebo | Number of Patients With Fatal Outcomes (Cardiac and Non-cardiac) During 12-month Follow-up Period | Unknown | 2 Participants |
| Placebo | Number of Patients With Fatal Outcomes (Cardiac and Non-cardiac) During 12-month Follow-up Period | Non-cardiovascular death | 0 Participants |
| Placebo | Number of Patients With Fatal Outcomes (Cardiac and Non-cardiac) During 12-month Follow-up Period | Patient is alive | 30 Participants |
| Placebo | Number of Patients With Fatal Outcomes (Cardiac and Non-cardiac) During 12-month Follow-up Period | Cardiovascular death | 1 Participants |
Secondary
Number of Patients With Fatal Outcomes (Due to Any Reason) or Hospitalizations Due to HF During 12-month Follow-up Period
ISOAC assessment
Time frame: up to Day 365
Population: FAS population
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| RPH-104 80 mg | Number of Patients With Fatal Outcomes (Due to Any Reason) or Hospitalizations Due to HF During 12-month Follow-up Period | 1 Participants |
| RPH-104 160 mg | Number of Patients With Fatal Outcomes (Due to Any Reason) or Hospitalizations Due to HF During 12-month Follow-up Period | 0 Participants |
| Placebo | Number of Patients With Fatal Outcomes (Due to Any Reason) or Hospitalizations Due to HF During 12-month Follow-up Period | 1 Participants |
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
Time frame: up to Day 365
Population: FAS population
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| RPH-104 80 mg | 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 | 1 Participants |
| RPH-104 160 mg | 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 | 0 Participants |
| Placebo | 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 | 1 Participants |
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
Time frame: up to Day 365
Population: FAS population
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| RPH-104 80 mg | Number of Patients With New Cases of HF During 12-month Follow-up Period | 0 Participants |
| RPH-104 160 mg | Number of Patients With New Cases of HF During 12-month Follow-up Period | 0 Participants |
| Placebo | Number of Patients With New Cases of HF During 12-month Follow-up Period | 0 Participants |
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.
Time frame: up to Day 365
Population: Analysis was performed at the stage of final analysis for the FAS population.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| RPH-104 80 mg | 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 | Hospitalization for cardiovascular reasons (except Heart Failure) | 2 Participants |
| RPH-104 80 mg | 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 | Hospitalization for new HF onset | 0 Participants |
| RPH-104 80 mg | 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 | Hospitalization due to non-cardiac reasons | 2 Participants |
| RPH-104 80 mg | 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 | Unknown (premature discontinuation) | 0 Participants |
| RPH-104 160 mg | 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 | Unknown (premature discontinuation) | 3 Participants |
| RPH-104 160 mg | 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 | Hospitalization for cardiovascular reasons (except Heart Failure) | 0 Participants |
| RPH-104 160 mg | 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 | Hospitalization due to non-cardiac reasons | 1 Participants |
| RPH-104 160 mg | 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 | Hospitalization for new HF onset | 0 Participants |
| Placebo | 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 | Unknown (premature discontinuation) | 2 Participants |
| Placebo | 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 | Hospitalization for new HF onset | 0 Participants |
| Placebo | 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 | Hospitalization due to non-cardiac reasons | 1 Participants |
| Placebo | 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 | Hospitalization for cardiovascular reasons (except Heart Failure) | 3 Participants |