Our trial is a multicenter, phase IIa, double-blind, randomized, placebo-controlled clinical study comparing single administration of RPH-104 80 mg, RPH-104 160 mg and placebo (1:1:1 randomization) in subjects with STEMI at the study sites in the Russian Federation and in the USA. Potential patients will be assessed for eligibility and sign and informed consent form prior to randomization and study drug administration. The following procedures will be performed during the screening: collection of medical history, recording previous and concomitant therapy, demographic data, recording a 12-lead ECG.
2.2 Overall Objective
2.3 Patient inclusion and Exclusion Criteria
Study Inclusion Criteria
The subjects eligible for the study should meet all of the following criteria:
1. Subjects of either gender aged from 18 years old inclusive.
2. Subjects who gave voluntary written Informed consent to participate in the study and to follow all Protocol procedures.
3. 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 (LBBB) according the investigator's judgement.
4. 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).
5. 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) and negative pregnancy test. Highly effective contraceptive methods include combination of two of the following methods (a+b or a+c or b+c):
a) 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;
b) intrauterine device or contraceptive system;
c) barrier methods: condom or occlusive cap (diaphragm or cervical cap / vaginal fornix cap) with spermicidal foam/gel/film/cream/vaginal suppository.
6. 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.
Study Exclusion Criteria
The subjects meeting any of exclusion criteria should not be enrolled:
1. Hypersensitivity to test product (RPH-104) and/or its ingredients/excipients.
2. Pregnancy and breastfeeding.
3. Chronic heart failure (AHA/ACC C-D class, NYHA FC III-IV).
4. Pre-existing severe valvular heart disease.
5. Pre-existing left ventricular dysfunction (EF<40%).
6. History of STEMI.
7. Complications of acute myocardial infarction 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.
8. Active infections (acute or chronic); active tuberculosis.
9. 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, TNFα blockers, IL-1 and other biological drugs, cyclosporine and other immunosuppressants. NSAIDs are allowed.
10. Immunization with live vaccines within 90 days prior to the study product administration.
11. Chronic systemic autoimmune or autoinflammatory diseases.
12. Suspected need for cardiosurgery.
13. Active oncologic disease (or diagnosis of cancer within the last 5 years).
14. History of organ transplantation or necessity in transplantation at the screening initiation or scheduled transplantation during the study.
15. Neutropenia (absolute neutrophil count <1800/mm3).
16. Participation in another clinical study within the previous 3 months prior to Screening visit.
17. Other medical or 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.
18. The subjects working at the study site or subjects working for Sponsor directly involved in this clinical study.
2.4 Patient Randomization and Treatment Allocation
Consented patients will be randomized in 1:1:1 ratio without stratification into one of treatment groups: RPH-104 80 mg, RPH-104 160 mg or placebo based on randomization scheme prepared using
the relevant software by the responsible study statistician. Distribution will be made using block, non-adaptive, centralized randomization using Interactive Web Response System (IWRS).
The study will be double-blinded. Detailed description of operational peculiarities will be presented in an individual guideline on medicinal product handling. Given that administration of RPH-104 at 160 mg is only possible by two 80 mg injections (2 mL) at different sites and appearance of the finished forms of test product and placebo may differ, the following dosing regimen will be used to assure double blind design:
- RPH-104 80 mg group: Subjects will receive 2 mL (80 mg) of RPH-104 and 2 mL of placebo at different administration sites.
- RPH-104 160 mg group: Subjects will receive 2 mL (80 mg) of RPH-104 and 2 mL of (80 mg) of RPH-104 at different administration sites.
- Placebo group: Subjects will receive 2 mL of placebo and 2 mL of placebo at different administration sites.
2.5.1 Efficacy Outcomes
The primary endpoint will include hsCRP area under curve (AUC) from Day 1 (baseline) until Day 14. The secondary endpoints will include hsCRP area under curve (AUC) from Day 1 (baseline) until Day 28, rate of fatal outcomes (cardiac and non-cardiac), hospitalizations (due to HF and other cardiac reasons not associated with HF or due to non-cardiac reasons), frequency of new cases of HF (defined as hospitalization due to HF or necessity in a loop diuretic administration intravenously or oral dose doubling in the relevant clinical facilities), changes in levels of brain natriuretic peptide (BNP, NT-pro-BNP) during 12-month follow-up period compared to baseline and changes in structural and functional echocardiographic parameters, including, but not limited to, left ventricular (LV) dimensions, LVMI, systolic and diastolic function after 12 months compared to baseline. An independent study outcome assessment committee (ISOAC) will be arranged to assure reliability and quality of data on assessment of cardiovascular and other protocol-defined outcomes as efficacy parameters. The committee will include three independent cardiologists with the relevant qualification for outcome classification according to terminology criteria 2017 Cardiovascular and Stroke Endpoint Definitions for Clinical Trials .
2.6 Statistical Analysis
2.6.1. Sample size justification
Rationale for sample size will be based on testing the hypothesis of statistical superiority to
compare hsCRP area under curve AUC between day 1 and day 14 (primary endpoint) between
each RPH-104 group and placebo. Given exploratory nature of the study, adjustment of α-level
due to multiple comparisons (two RPH-104 doses and placebo) will not be used.
Assuming that the expected mean hsCRP AUC at 14 days will be 350±250 mg/L for the subjects with STEMI
in placebo group and standardized effect size (d Cohan) 0.80 for the lowest dose (conservative estimate based on 34 randomized subjects in each treatment group (1:1:1) (102 randomized subjects in
total) will assure the study power >90% for comparison of lower dose with placebo and study power > 95% to detect the expected further hsCRP AUC 50% reduction by 50% and increased effect of the higher RPH-104 dose compared to placebo. Unadjusted P values will be reported throughout, with statistical significance set at the 2‐tailed 0.025 levels for the primary analysis, to adjust for multiplicity. Given proportion of withdrawals and/or 20% statistical analysis (conservative estimate), study power >80% will be maintained for all comparisons. Given potential screening failures of up to 30%, the study will enroll 146 subjects with the intent to randomize 102 subjects.
2.6.2. Primary Outcome Analysis
The following hypotheses will be tested for each RPH-104 dose level:
Null hypothesis H0: difference between mean AUC1-14 days CRP in RPH-104 group and mean AUC1-14 days CRP in placebo group is equal to 0.
Two-sided alternative hypothesis H1: difference between mean AUC1-14 days CRP in RPH- 104 group and mean AUC1-14 days CRP in placebo group is different from 0.
Individual AUC1-14 days CRP values will be calculated using trapezoidal method. Mean AUC1-14 days CRP value will be compared between RPH-104 and placebo groups using analysis of variance ANOVA. Mean AUC values for RPH-104 80 mg, RPH-104 160 mg and placebo groups, differences in mean values and relevant two-sided 95% confidence intervals and well as р-values will be presented.
2.6.3. Secondary Outcome Analysis
Analysis will be done similar to the analysis of the primary endpoint described above.
- Rate of fatal outcomes (cardiac and non-cardiac), hospitalizations (due to HF and other cardiac reasons not associated with HF or due to non-cardiac reasons) during 12-month follow-up period.
- Frequency of new cases of HF (defined as hospitalization due to HF or necessity in a loop diuretic administration intravenously or oral dose doubling in the relevant clinical facilities) during 12-month follow-up period.
Time to event parameters will be analyzed using survival analyses (including Kaplan-Meier estimate) and compared using log-rank test if applicable. The number and proportions of subjects (of the number of FAS subjects and valid %) with fatal outcomes, subjects with hospitalizations and subjects with new cases of HF will be presented by treatment groups. Intergroup comparisons will also be performed using exact Fisher's test.
- Changes in levels of brain natriuretic peptide (BNP, NT-pro-BNP) during 12-month follow-up period compared to baseline.
Changes in BNP, NT-pro-BNP levels will be presented by descriptive statistics by the study visits and treatment groups. Changes relative to baseline will be calculated for each visit. To test statistical significance of changes post baseline in the treatment groups, paired Student's test will be used (in case of major deviations from normal law of distribution ln-transformation or nonparametric methods will be used if applicable).
Intergroup comparisons of mean changes in BNP, NT-pro-BNP by visits will be made using analysis of covariance (ANCOVA) including baseline as a covariate and treatment group as a factor.
- Changes in structural and functional echocardiographic parameters including, but not limited, to, left ventricular (LV) dimensions, LVMMI, systolic and diastolic function after 12 months compared to baseline.
The parameters will be analyzed similar to the analysis of changes in brain natriuretic peptide level described above.
If the assumptions underlying analysis of variance (ANOVA) / analysis of covariance (ANCOVA), are violated, ln-transformation, rank ANOVA/ANCOVA or non-parametric methods will be used if applicable. Where ln-transformation is used, the relevant descriptive statistics will also include geometric mean value.
In addition, changes in marker and CRP values (based on the original scheme or after transformation) will be analyzed using mixed model repeated measures (MMRM), if applicable.
2.6.4. Safety analysis
Safety analysis will be carried out on safety set. Scope of application will be presented specifying the following variables: the number of subjects receiving RPH-104 80 mg, the number of subjects receiving RPH-104 160 mg and the number of subjects receiving placebo. Adverse events will be coded using Medical Dictionary for Regulatory Activities (MedDRA). The number and percentage of the subjects with AE/SAE, overall number and percentage of recorded AE/SAE, the number and percentage of AE/SAE resulting in early withdrawal will be presented by system organ class, preferred terms and treatment groups. The data will also be generalized by the number and percentage of AEs/SAEs with various categories of causality, expectedness and severity. All AEs will be additionally presented as lists. Quantitative safety laboratory parameters will be presented using descriptive statistics by visits and treatment groups. Changes relative to baseline and abnormal laboratory values will also be provided. The data on the number of subjects with abnormal laboratory values will be generalized for the whole study period, by visits and treatment groups. All laboratory findings will be presented as lists. Vital signs will be presented using descriptive statistics by visits and treatment groups. Changes relative to baseline will also be presented.