Evaluation of Obicetrapib and Ezetimibe Fixed Dose Combination on Coronary Plaque in Atherosclerotic Cardiovascular Disease: A Phase 3 Randomized Study
- Trial ID
- 2023-508475-36-00
- Protocol
- OBEZ-302
- Sponsor
- NewAmsterdam Pharma B.V.
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to evaluate the effect of **obicetrapib** 10 mg combined with **ezetimibe** 10 mg fixed dose combination (FDC) therapy on total non-calcified coronary atherosclerotic plaque volume (NCPV) at 18 months in participants with **atherosclerotic cardiovascular disease**. This is clinically relevant as reducing NCPV may decrease the risk of cardiovascular events, providing a potential therapeutic benefit for patients with this condition.
Secondary objectives include: - Evaluating the effect of the FDC therapy on other parameters of total coronary atherosclerotic plaque burden, coronary plaque characteristics, coronary inflammation metrics, and lipoproteins at 18 months. - Assessing the safety and tolerability profile of the therapy. - Exploratory evaluations include the effect on additional coronary inflammation and radiotranscriptomic biomarker metrics, lipoprotein particle numbers and size, the proportion of participants achieving predefined low-density lipoprotein cholesterol (LDL-C) targets, biomarkers of glycemic control, lipid-laden circulating monocytes, and trough levels of obicetrapib.
Participants
The clinical trial involves a total of **112 participants** diagnosed with **Atherosclerotic Cardiovascular Disease**. The study population includes both male and female subjects aged **45 years and older**. Participants were selected based on specific inclusion criteria, including a body mass index within the range of 18 to 40 kg/m² and evidence of atherosclerotic cardiovascular disease. The trial does not involve a vulnerable population. Participants are required to be on lipid-modifying therapy as an adjunct to a lipid-lowering diet and other lifestyle modifications. This includes the use of statins, bempedoic acid, or proprotein convertase subtilisin kexin type 9-targeted therapy. Additionally, participants must have a fasting serum LDL-C of at least 70 mg/dL and fasting triglycerides less than 400 mg/dL. The study ensures that participants are not pregnant or breastfeeding and have no plans to become pregnant during the trial. The selection process ensures a diverse representation of individuals with established cardiovascular conditions, adhering to strict health and lifestyle criteria to maintain the integrity of the study outcomes.
Plans and Procedures
The clinical trial is designed to evaluate the effect of a **fixed dose combination** of **obicetrapib** 10 mg and **ezetimibe** 10 mg on coronary plaque characteristics in participants with **atherosclerotic cardiovascular disease**. This is a **randomized**, **double-blind**, **placebo-controlled**, **Phase 3** study. The primary objective is to assess the impact on total non-calcified coronary atherosclerotic plaque volume over an 18-month period. The trial is expected to commence recruitment in August 2024 and conclude by November 2026, with a total duration of approximately 27 months.
Participants will undergo a series of study visits, beginning with a screening visit to confirm eligibility based on specific inclusion criteria, such as age, body mass index, and evidence of atherosclerotic cardiovascular disease. The screening visit will also include a fasting serum LDL-C test and a comprehensive review of the participant's medical history and current lipid-modifying therapy. Following successful screening, participants will be randomized to receive either the active treatment or placebo.
Subsequent follow-up visits will occur at regular intervals to monitor the participants' health status, adherence to the study protocol, and any adverse events. These visits will include assessments such as coronary CT angiography to measure changes in plaque volume and laboratory tests to evaluate lipid levels and other relevant biomarkers. The end-of-study visit will mark the completion of the 18-month treatment period, where final assessments will be conducted to determine the primary and secondary endpoints.
Participant involvement is expected to last for the entire 18-month treatment period, with additional time allocated for initial screening and final assessments. Conditions that may lead to early termination from the study include non-compliance with study procedures, withdrawal of consent, or the occurrence of significant adverse events that compromise participant safety. The study aims to provide valuable insights into the efficacy of the obicetrapib and ezetimibe combination in managing coronary plaque characteristics in individuals with atherosclerotic cardiovascular disease.
Treatment
The clinical trial involves the administration of an **experimental medication** known as Obicetrapib 10 mg + Ezetimibe 10 mg fixed dose combination (FDC). This medication is provided in the form of a **tablet** and is intended for **oral use**. The active substances in this combination are **Ezetimibe** and **Obicetrapib**, both of which are of chemical origin. The dosage for this experimental treatment is 10 mg of Obicetrapib combined with 10 mg of Ezetimibe, administered once daily. The maximum treatment period is 545 days, with a total maximum dose of 5450 mg. The medication is manufactured by NewAmsterdam Pharma B.V. and is identified by the product number PRD11167913.
In addition to the experimental medication, the study includes a **placebo** as a non-experimental treatment. The placebo is used to maintain the double-blind nature of the trial, ensuring that neither the participants nor the investigators know which treatment is being administered. The placebo is also provided in a form suitable for oral administration, although specific details regarding its pharmaceutical form are not available. The use of a placebo allows for a controlled comparison to evaluate the efficacy of the experimental medication.
Participant compliance with the dosing schedule will be monitored throughout the study to ensure adherence to the treatment regimen. This monitoring is crucial for maintaining the integrity of the trial results and ensuring that the data collected accurately reflects the effects of the experimental medication. The primary objective of the study is to assess the impact of the Obicetrapib/Ezetimibe FDC on total non-calcified coronary atherosclerotic plaque volume over an 18-month period in participants with atherosclerotic cardiovascular disease.
Efficacy
The efficacy of the investigational therapy, a fixed-dose combination of obicetrapib 10 mg and ezetimibe 10 mg, will be assessed in a placebo-controlled, double-blind, randomized, Phase 3 clinical trial. The primary endpoint for evaluating efficacy is the percent change from baseline to 18 months in total non-calcified coronary atherosclerotic plaque volume (**NCPV**) in all major epicardial coronary arteries, as measured by coronary computed tomography angiography (CCTA). Secondary endpoints include the absolute change in total NCPV, percent change in low-density lipoprotein cholesterol (LDL-C), and changes in non-calcified plaque volume in the most diseased coronary segment, all measured from baseline to 18 months using CCTA.
Additional exploratory efficacy endpoints will assess changes in various biomarkers and laboratory parameters, such as low attenuation plaque volume, calcified plaque volume, and radiotranscriptomic biomarkers of coronary inflammation. These will also be measured by CCTA. Changes in lipoprotein metabolism parameters, including non-high-density lipoprotein cholesterol, apolipoprotein B, and very-low-density lipoprotein cholesterol, will be evaluated at Day 84 (Month 3) and 18 months. The study will also explore the effect on LDL-C, HDL-C, and VLDL-C particle numbers and size using NMR analysis at 3 months. Furthermore, the trial will assess changes in biomarkers of glycemic control and lipid accumulation in circulating monocytes at 18 months.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Are willing and able to give written informed consent before initiation of any study-related procedures and willing to comply with all required study procedures
- Participant must have body mass index within the range 18 to 40 kg/m2, inclusive at Screening (Visit 1)
- Are male or female and ≥45 years of age at Screening (Visit 1) A. Females may be enrolled if all 3 of the following criteria are met: i. They are not pregnant ii. They are not breastfeeding; and iii. They do not plan on becoming pregnant during the study B. Females of childbearing potential must have a negative urine pregnancy test at Screening (Visit 1) Note: Females are not considered to be of childbearing potential if they meet 1 of the following criteria, as documented by the investigator: i. They have had a hysterectomy or tubal ligation at a minimum of 1 cycle prior to signing the ICF; or ii. They are postmenopausal, defined as ≥1 year since their last menstrual period for females ≥55 years of age or ≥1 year since their last menstrual period and have a follicle-stimulating hormone level in the postmenopausal range at Screening (Visit 1) for females <55 years of age C. Females of childbearing potential must agree to use an effective method of avoiding pregnancy from Screening (Visit 1) until 35 days after the last dose of study drug. Males whose partners are of childbearing potential must agree to use an effective method of avoiding pregnancy from Screening (Visit 1) until 35 days after the last dose of study drug. Effective methods of avoiding pregnancy are contraceptive methods used consistently and correctly (including implantable contraceptives, injectable contraceptives, oral contraceptives, transdermal contraceptives, intrauterine devices, and barrier methods) or a sterile sexual partner for at least 3 months prior to study drug administration
- Have ASCVD as evidenced by having AT LEAST ONE feature in Group A AND/OR Group B below: A. Imaging evidence of vascular disease This is defined as having one of the following on prior clinically indicated vascular imaging: i. Angiographic evidence of coronary artery disease (invasive or CCTA) with a visual diameter stenosis <50% in at least one major epicardial coronary artery ii. Angiographic evidence of coronary artery disease with a visual diameter stenosis >50% in at least one major epicardial coronary artery but fractional flow reserve >0.8 (invasive or CCTA derived) iii. Carotid artery stenosis >50% B. Having established clinically manifest ASCVD This is defined as having one of the following: i. History of myocardial infarction (MI) ii. History of ischemic stroke iii. Previous percutaneous coronary intervention (PCI) iv. Previous carotid artery revascularization v. Documentation of a resting ankle-brachial index ≤0.85 vi. Previous revascularization of an iliac, femoral, or popliteal artery or lower extremity amputation due to peripheral artery disease
- Has evidence by CCTA of evaluable non-calcified plaque (as determined by a central study core imaging laboratory) of at least 75 mm3 in the major epicardial coronary arteries
- Are on lipid-modifying therapy as an adjunct to a lipid-lowering diet and other lifestyle modifications, defined as ANY ONE of the below: A. A statin at a maximally tolerated stable dose i. A participant’s maximally tolerated stable statin dose will be determined by the investigator using his/her medical judgment and available sources, including the participant’s self-reported history of lipid-modifying therapy for at least 4 weeks prior to Screening (Visit 1); and ii. For any participant not taking statin therapy due to statin intolerance, including those participants taking bempedoic acid or fibrate monotherapy, written confirmation will be required of both the participant and the investigator stating that the participant was statin intolerant, aware of the benefit of statins to reduce the risk of a major adverse cardiovascular events, and aware that many other patients who are unable to tolerate a statin were actually able to tolerate a different statin or dose. Note: Statin intolerance will be defined as intolerance due to an adverse safety effect that started or increased during statin therapy and resolved or improved when statin therapy was discontinued, resulting in an inability to tolerate either 1) two or more statins at any dose, or 2) one statin at any dose and either an unwillingness to attempt a second statin or advice by a physician not to attempt a second statin B. Bempedoic acid for at least 4 weeks in combination with a maximally tolerated statin prior to Screening (Visit 1); and/or C. A proprotein convertase subtilisin kexin type 9-targeted therapy alone or in combination with other lipid-modifying therapy for at least 4 stable doses prior to Screening (Visit 1). Note: Participants taking inclisiran must have received at least 2 stable doses prior to Screening (Visit 1). Note: Approximately 50% of the participants enrolled into this study must be taking HIS. Documentation in the electronic case report form of the reason why a participant is unable to take HIS is required. HIS include the following: • Atorvastatin from 40 to 80 mg once a day; and • Rosuvastatin from 20 to 40 mg once a day
- Have a fasting serum LDL-C ≥70 mg/dL (≥1.81 mmol/L) at Screening (Visit 1) Note: LDL-C at Screening (Visit 1) will be calculated using the Martin/Hopkins equation
- Have fasting triglycerides (TG) <400 mg/dL (<4.52 mmol/L) at Screening (Visit 1); and
- Have an estimated glomerular filtration rate ≥40 mL/min/1.73 m2 calculated using the Chronic Kidney Disease Epidemiology Collaboration equation at Screening (Visit 1).
Exclusion Criteria
- Have current or any previous history of New York Heart Association class III or IV heart failure or left ventricular ejection fraction <30%
- Have had any of the following clinical events within 3 months prior to Screening (Visit 1): • MI • Stroke • Non-elective coronary revascularization
- Have uncontrolled severe hypertension, defined as either systolic blood pressure ≥160 mmHg or diastolic blood pressure ≥100 mmHg prior to randomization, taken as the average of triplicate measurements. One triplicate retest (repeat of all 3) will be allowed during the same visit, at which point if the retest result is no longer exclusionary, the participant may be randomized
- Have a formal diagnosis of homozygous familial hypercholesterolemia
- Have a history of coronary artery bypass graft surgery or a planned PCI, or coronary artery bypass graft, or valvular intervention. NOTE: Eligible participants who have a diagnostic coronary angiogram performed in the absence of undergoing a new PCI may continue screening after the diagnostic angiogram has been performed or may be rescreened
- Have active liver disease, defined as: • any known current infectious, neoplastic, or metabolic pathology of the liver • Child-Pugh score of 7 to 9 (Class B) or 10 to 15 (Class C) • unexplained elevations in alanine aminotransferase (ALT) or aspartate aminotransferase (AST) >3 × upper limit of normal (ULN); or • total bilirubin >2 × ULN at Screening (Visit 1) Note: An abnormal ALT, AST, or total bilirubin must be confirmed by a repeat abnormal measurement at least 1 week apart
- Have a glycosylated hemoglobin (HbA1c) ≥10.0% (≥0.100 hemoglobin fraction) or a fasting glucose ≥270 mg/dL (≥15.0 mmol/L) at Screening (Visit 1)
- Have a thyroid-stimulating hormone >1.5 × ULN at Screening (Visit 1)
- Have a creatine kinase >3 × ULN at Screening (Visit 1)
- Have a history of a malignancy that required surgery (excluding local and wide-local excision), radiation therapy, and/or systemic therapy during the 3 years prior to Randomization (Visit 2)
- Have a known history of alcohol and/or drug abuse within 5 years prior to Randomization (Visit 2)
- Have received treatment with other investigational products (IPs) or devices within 30 days of Screening (Visit 1) or 5 half-lives of the previous IP, whichever is longer. Note: Participants who have received treatment for coronavirus disease 2019 with standard of care and/or emergency use authorization medications, including vaccinations and boosters, within 30 days of Screening (Visit 1) or 5 half-lives of the previous IP will be permitted.
- Are taking gemfibrozil or have taken gemfibrozil within 30 days of Screening (Visit 1)
- Are taking ezetimibe or have taken ezetimibe within 30 days of Screening (Visit 1)
- Have planned use of other IPs or investigational devices during the study
- Have participated in any clinical study evaluating obicetrapib
- Have a known allergy or hypersensitivity to the ezetimibe or cholesteryl ester transfer protein inhibitors, or any of the excipients contained within the FDC of ezetimibe and obicetrapib (ie, the IP) or the placebo
- Have any participant condition that, according to the investigator, could interfere with the conduct of the study, such as, but not limited to, the following: • Are unable to communicate or to cooperate with the investigator • Are unable to understand the protocol requirements, instructions and study-related restrictions, and the nature, scope, and possible consequences of the study (including participants whose cooperation is doubtful due to drug abuse or alcohol dependency) • Are unlikely to comply with the protocol requirements, instructions, and study-related restrictions (eg, uncooperative attitude, inability to return for follow-up visits, and improbability of completing the study) • At the discretion of the clinician or the learned opinion of the trial participant, an inability of the participant to comfortably lie flat AND still for at least 15 minutes • Have any medical or surgical condition which, in the opinion of the investigator, would put the participant at increased risk from participating in the study; or • Are directly involved in the conduct of the study
- Participants with any of the following contraindications to CCTA: a. Are unable to communicate or to cooperate with the investigator b. History of contrast-induced nephropathy c. Allergy to iodinated contrast d. Contraindication to nitroglycerin e. Rapid heart rate that is uncontrolled by medical therapy f. Persistent or permanent atrial fibrillation g. Inability to hold breath for at least 6 seconds h. Any known contraindications to CCTA per local standards.
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Czechia | Recruiting | 01 Aug 2024 | 40 |
 Hungary | Recruiting | 01 Aug 2024 | 30 |
 Italy | Recruiting | 01 Aug 2024 | 25 |
 The Netherlands | Recruiting | 01 Aug 2024 | — |
 Poland | Recruiting | 01 Aug 2024 | 45 |
 Spain | Recruiting | 01 Aug 2024 | 25 |
| Netherlands | — | — | 85 |
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 |
|---|---|---|---|---|---|---|
Placebo | Placebo | N/A | — | — | — | N/A |
Obicetrapib 10 mg + ezetimibe 10 mg fixed dose combinationFDC | Test | TABLET | ORAL USE | 10 | 545 | PRD11167913 |