Evaluation of Safety, Pharmacokinetics, and Pharmacodynamics of Subcutaneous RBD4059 in Stable Coronary Artery Disease Patients on Low-Dose Aspirin
- Trial ID
- 2023-510370-14-00
- Protocol
- RC03T001
- Sponsor
- Ribocure Pharmaceuticals AB
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to evaluate the **safety** of RBD4059 compared to placebo when administered subcutaneously as repeated doses in participants with stable **Coronary Artery Disease** (CAD) who are under treatment with low-dose aspirin (75 mg). This is clinically relevant as it aims to determine the tolerability and potential adverse effects of RBD4059, which could impact its future use in managing CAD.
Secondary objectives include:
- Assessing the plasma exposure of RBD4059 in participants with stable CAD.
- Evaluating the pharmacodynamic effect of RBD4059 on FXI activity in participants with stable CAD.
- Measuring anti-drug antibodies (ADA) to evaluate immunogenicity related to RBD4059.
- Evaluating the effect of RBD4059 on levels of biomarkers: activated partial thromboplastin time (APTT) and PK(INR).
- Evaluating the effect on platelet inhibition when RBD4059 is added to low-dose aspirin.
These secondary objectives are crucial for understanding the pharmacokinetics, pharmacodynamics, and potential immunogenicity of RBD4059, as well as its interaction with aspirin, which could inform its therapeutic application in CAD management.
Participants
The clinical trial involves participants diagnosed with **Stable Coronary Artery Disease** (CAD) who are currently undergoing treatment with low-dose aspirin (75 mg). The study population includes both male and female participants, specifically post-menopausal females, aged between 50 to 75 years. Participants are required to have stable CAD, defined as chronic coronary syndromes, and must be asymptomatic or symptomatic for more than one year following the initial diagnosis or revascularization. All participants are expected to have been on a stable prescription drug regimen for at least 30 days prior to randomization and to continue this regimen throughout the trial. The trial does not include a vulnerable population. The sponsor has not provided information regarding the total number of participants in the study.
Plans and Procedures
The clinical trial is designed as a **randomized, double-blind, placebo-controlled** Phase IIa study to evaluate the safety, pharmacokinetics, and pharmacodynamics of repeated subcutaneous administration of **RBD4059** in participants with stable **coronary artery disease** (CAD). The trial will involve participants who are currently under treatment with low-dose **aspirin** (75 mg). The study is expected to commence recruitment on August 1, 2024, and conclude by December 31, 2025, with an overall duration of approximately 17 months.
Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to assess eligibility based on criteria such as age (50-75 years), stable CAD diagnosis, and ongoing aspirin treatment. Following successful screening, participants will be randomized to receive either the investigational product, RBD4059, or a placebo, both administered via subcutaneous injection. The trial will include multiple follow-up visits to monitor safety and efficacy endpoints, including adverse events, laboratory parameters, and vital signs. The primary endpoint focuses on the frequency, intensity, and seriousness of adverse events, while secondary endpoints include plasma concentrations of RBD4059, changes in FXI activity, and immunogenicity assessments.
The expected length of participant involvement is up to 12 weeks, with conditions for early termination including significant adverse events or withdrawal of consent. The end-of-study visit will involve a comprehensive evaluation of the participant's health status and the collection of final data points. Throughout the trial, participants will continue their standard treatment with aspirin, and any changes in their prescription drugs will be documented. The trial aims to provide valuable insights into the safety profile and pharmacological effects of RBD4059 in a population with stable CAD.
Treatment
The clinical trial involves the administration of **RBD4059**, an experimental medication formulated as an **injection**. The active substance, RBD4059, is derived from nucleic acid and is provided by Ribocure Pharmaceuticals AB. The medication is administered via **subcutaneous injection**. The dosing schedule involves repeated administrations over a maximum treatment period of 12 weeks. The specific dosage and frequency of administration are not detailed in the provided data. Participant compliance with the dosing regimen will be monitored throughout the trial to ensure adherence to the protocol.
The trial also includes a **placebo** control, which consists of a 25 mM phosphate buffer solution with 2 µg of vitamin B2 added solely for coloring purposes. This placebo is administered in the same pharmaceutical form and route as the experimental medication, namely, as a subcutaneous injection. The placebo is used to maintain the double-blind nature of the study, ensuring that neither the participants nor the investigators are aware of the treatment assignments.
In addition to the experimental and placebo treatments, participants will continue their standard-of-care therapy with **Trombyl 75 mg tabletter**, which contains **acetylsalicylic acid** as the active substance. This medication is provided by Pfizer AB and is administered orally in tablet form. The maximum daily dose is 75 mg, with a treatment period extending up to 60 weeks. The inclusion of Trombyl ensures that participants maintain their existing treatment regimen for stable coronary artery disease, allowing for the evaluation of RBD4059's safety and efficacy in conjunction with standard therapy.
Efficacy
The efficacy of the investigational product, **RBD4059**, in the clinical trial will be assessed through a series of primary and secondary endpoints. The primary endpoint focuses on the safety profile, including the frequency, intensity, and seriousness of adverse events (AEs), as well as clinically significant changes in laboratory parameters, vital signs, physical examinations, and 12-lead ECGs from baseline to the end of the trial. These assessments will be conducted at each visit throughout the trial duration.
Secondary endpoints will provide additional insights into the pharmacokinetics and pharmacodynamics of **RBD4059**. Plasma concentrations of **RBD4059** will be summarized using descriptive statistics at each sampling collection time point. The trial will also evaluate the actual and percentage change from baseline in FXI activity, comparing these changes to placebo throughout the trial period. The proportion of participants with positive immunogenicity, measured as titers of anti-drug antibodies (ADAs), will be assessed at each evaluation time point. Furthermore, changes from baseline in activated partial thromboplastin time (APTT) and prothrombin time international normalized ratio (PK(INR)) levels, as well as platelet inhibition levels, will be compared to placebo throughout the trial period.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Willing and able to give written informed consent for participation in the trial
- Male or female (post-menopausal) participants ≥50-75 years.
- Patients with stable CAD defined as chronic coronary syndromes according to ESCs guideline on chronic coronary syndromes including the category asymptomatic or symptomatic patients >1 year after initial diagnosis or revascularization
- Ongoing standard treatment with aspirin 75 mg for at least 3 months
- Stable prescription drugs i.e., ongoing since at least 30 days prior to randomization, should continue during the trial.
Exclusion Criteria
- Presence of any significant arrythmia in opinion of the investigator
- Left ventricular ejection fraction (LVEF) < 30% at enrolment
- New York Heart Association (NYHA) class III-IV heart failure at entry, hospitalization for exacerbation of chronic heart failure within the previous 12 months or other indices of unstable heart failure
- Creatinine clearance calculated by Cockcroft Gault equation <60ml/min*m2 at the time of enrolment. Hemodynamically significant valvular disease or valvular disease likely to require surgery within 3 years
- Hemodynamically significant valvular disease or valvular disease likely to require surgery within 3 years.
- Expected survival time is less than one year for non-cardiac related disorders
- History or presence of: a. Bleeding disorder(s) and/or at risk of bleeding, including relevant familial history. b. Thromboembolic diseases
- An underlying known disease, or surgical or medical condition that, in the opinion of the Investigator, might interfere with the participants ability to comply with the protocol or the interpretation of the clinical trial results
- Alanine aminotransferase (ALT) and/or total bilirubin >1.5 the upper limit of normal (ULN) (as per the local laboratory reference range); No repeat assessments are allowed
- AST, ALP, or GGT > ULN (as per the local laboratory reference range), and considered clinically significant by the Investigator
- Positive hepatitis B surface antigen (HBsAg), hepatitis B core antibody (HBcAb), hepatitis C virus antibody (HCVAb), HIV antibody (HIVAb) at screening
- Any clinical suspicion on acute coronary syndrome or unstable angina at enrolment according to ESC criteria : (i) rest angina, i.e. pain of characteristic nature and location occurring at rest and for prolonged periods (>20 min); (ii) new-onset angina, i.e. recent (2 months) onset of moderate-to-severe angina (Canadian Cardiovascular Society grade II or III); or (iii) crescendo angina, i.e. previous angina, which progressively increases in severity and intensity, and at a lower threshold, over a short period of time.
- Clinically significant acute illness within 7 days before the first dose of trial drug
- Consume more than 8 (female) or 14 (male) units of alcohol per week (1 standard unit of alcohol contains 14 g of alcohol and corresponds to, e.g., 360 mL of beer, 150 mL of wine, or 45 mL of spirits at 40% alcohol content.) within 6 months before screening or positive screen for alcohol abuse or clinical evidence of other drug abuse within 12 months
- Donated more than 300 mL of blood within 56 days before the first dose of trial drug
- History of multiple drug allergies or history of allergic reaction to an oligonucleotide or N-acetylgalactosamine (GalNAc).
- Patients with other clinical scenarios qualifying in the ESC definition of chronic coronary syndromes: patients with suspected CAD and ‘stable’ anginal symptoms, and/or dyspnoea, with new onset of heart failure (HF) or left ventricular (LV) dysfunction and suspected CAD, with angina and suspected vasospastic or microvascular disease
- High bleeding risk defined as history of any significant bleeding (included but not limited to intracerebral haemorrhage and gastrointestinal), anaemia, liver failure, age >75 years or Clinical Frailty Score [2] > 5, or weight <60kg
- Major surgery during last 30 days or planned major surgery or intervention within trial period
- Capillary Hb <120 g/l for women and <130 g/L for men.
- Elective PCIor CABG within the previous 12 months
- Previously confirmed ischemic stroke
- Ongoing indication for chronic anti-coagulation therapy (incl. but not limited to patients with: atrial fibrillation, venous thrombo-embolism, mechanical cardiac valves) with NOACs, warfarin or other similar anticoagulants
- History of severe intolerance to subcutaneous (SC) injection (minor reactions are permitted, e.g. localised swelling or redness.).
- Received an investigational product within 30 days or 5 half-lives (whichever is longer) before the first dose of the study drug or are in the follow-up of another clinical study. If subjects used advanced therapy (ASO/siRNA/gene therapy/cell therapy), it should be judged by the investigator
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Sweden | Not Recruiting | 01 Aug 2024 | 30 |
Sites & Investigators
Research sites
Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
RBD4059 injection | Test | INJECTION | SUBCUTANEOUS INJECTION | 000 | 12 | PRD11068371 |
Trombyl 75 mg tabletter | Other | TABLETTER | ORAL | 75 | 60 | PRD411504 |
The corresponding placebo consist of the 25 mM phosphate buffer solution with 2 µg of vitamin b2 added for colouring purposes only | Placebo | N/A | SUBCUTANEOUS INJECTION | 000 | 12 | N/A |