EZETIMIBE, OBICETRAPIB for Atherosclerotic Cardiovascular Disease

Inclusion criteria

• {"criterion_text":"- 1. 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\n- 2. Participant must have body mass index within the range 18 to 40 kg/m2, inclusive at Screening (Visit 1)\n- 3. 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\n- 4. 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\n- 5. 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\n- 6. 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\n- 7. 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\n- 8. Have fasting triglycerides (TG) <400 mg/dL (<4.52 mmol/L) at Screening (Visit 1); and\n- 9. 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

• {"criterion_text":"- 1. Have current or any previous history of New York Heart Association class III or IV heart failure or left ventricular ejection fraction <30%\n- 10. 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)\n- 11. Have a known history of alcohol and/or drug abuse within 5 years prior to Randomization (Visit 2)\n- 12. 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.\n- 13. Are taking gemfibrozil or have taken gemfibrozil within 30 days of Screening (Visit 1)\n- 14. Are taking ezetimibe or have taken ezetimibe within 30 days of Screening (Visit 1)\n- 15. Have planned use of other IPs or investigational devices during the study\n- 16. Have participated in any clinical study evaluating obicetrapib\n- 17. 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\n- 18. 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\n- 19. 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.\n- 2. Have had any of the following clinical events within 3 months prior to Screening (Visit 1): • MI • Stroke • Non-elective coronary revascularization\n- 3. 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\n- 4. Have a formal diagnosis of homozygous familial hypercholesterolemia\n- 5. 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\n- 6. 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\n- 7. 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)\n- 8. Have a thyroid-stimulating hormone >1.5 × ULN at Screening (Visit 1)\n- 9. Have a creatine kinase >3 × ULN at Screening (Visit 1)"}

Primary endpoints

• {"endpoint_text":"- Percent change from baseline to 18 months in total NCPV in all major epicardial coronary arteries, as measured by CCTA, in participants treated with obicetrapib 10 mg + ezetimibe 10 mg FDC therapy compared with placebo.","definition_or_measurement_approach":"Total non-calcified coronary atherosclerotic plaque volume (NCPV) measured by coronary CT angiography (CCTA); percent change from baseline to 18 months."}

Secondary endpoints

• {"endpoint_text":"- Absolute change from baseline to 18 months in total NCPV in all major epicardial coronary arteries, as measured by CCTA, in participants treated with obicetrapib 10 mg + ezetimibe 10 mg FDC therapy compared with placebo","definition_or_measurement_approach":"Absolute change in total NCPV measured by CCTA from baseline to 18 months."}
• {"endpoint_text":"- Percent change from baseline to 18 months in LDL-C in participants treated with obicetrapib 10 mg + ezetimibe 10 mg FDC therapy compared to placebo.","definition_or_measurement_approach":"Percent change in fasting LDL-C from baseline to 18 months (LDL-C calculated using Martin/Hopkins equation at screening)."}
• {"endpoint_text":"- Percent change from baseline to 18 months in non-calcified coronary atherosclerotic plaque volume in the most diseased coronary segment (NCPVMD), as measured by CCTA, in participants treated with obicetrapib 10 mg + ezetimibe 10 mg FDC therapy compared with placebo.","definition_or_measurement_approach":"Percent change in NCPV in the most diseased coronary segment (NCPVMD) measured by CCTA from baseline to 18 months."}
• {"endpoint_text":"- Absolute change from baseline to 18 months in NCPVMD, as measured by CCTA, in participants treated with obicetrapib 10 mg + ezetimibe 10 mg FDC therapy compared with placebo.","definition_or_measurement_approach":"Absolute change in NCPVMD measured by CCTA from baseline to 18 months."}
• {"endpoint_text":"- Change from baseline to 18 months in perivascular fat attenuation index (FAI), FAI score and its age- and gender-specific centile in the principal epicardial coronary arteries (left anterior descending [LAD], left circumflex [LCx], right coronary artery [RCA]) as measured by CCTA in participants treated with obicetrapib 10 mg + ezetimibe 10 mg FDC therapy compared with placebo.","definition_or_measurement_approach":"Perivascular fat attenuation index (FAI) and derived scores/centiles measured by CCTA in LAD, LCx, RCA from baseline to 18 months."}

Other endpoints

• {"endpoint_text":"- Exploratory: To evaluate the absolute and percent change from baseline to 18 months in low attenuation plaque volume, calcified plaque volume and other relevant metrics as measured by CCTA in participants treated with obicetrapib 10 mg + ezetimibe 10 mg FDC therapy compared to placebo","definition_or_measurement_approach":"Low attenuation plaque volume, calcified plaque volume and related metrics measured by CCTA; absolute and percent change from baseline to 18 months."}
• {"endpoint_text":"- Exploratory: To evaluate the change from baseline to 18 months in radiotranscriptomic biomarkers of coronary inflammation (eg, C19RS) as measured by CCTA in participants treated with obicetrapib 10 mg + ezetimibe 10 mg FDC therapy compared to placebo","definition_or_measurement_approach":"Radiotranscriptomic biomarkers of coronary inflammation (e.g., C19RS) measured via CCTA-derived methods; change from baseline to 18 months."}
• {"endpoint_text":"- Exploratory Efficacy: To evaluate the following changes in laboratory parameters of lipoprotein metabolism in participants treated with obicetrapib 10 mg + ezetimibe 10 mg FDC therapy compared with placebo): o Percent change from baseline to Day 84 (Month 3) and 18 months in non-high-density lipoprotein cholesterol, apolipoprotein B, very-low-density lipoprotein cholesterol (VLDL-C), high-density lipoprotein cholesterol (HDL-C), LDL-C, small doteinense LDL-C, TG, apolipoprotein E, [.","definition_or_measurement_approach":"Laboratory parameters of lipoprotein metabolism measured at Day 84 (~3 months) and 18 months; percent and absolute changes versus baseline."}
• {"endpoint_text":"- Exploratory Efficacy: To evaluate the effect from baseline of obicetrapib 10 mg + ezetimibe 10 mg FDC therapy on LDL-C, HDL-C, and VLDL-C particle numbers and size as measured by NMR analysis at 3 months (Day 84)","definition_or_measurement_approach":"NMR analysis of lipoprotein particle numbers and sizes for LDL-C, HDL-C, VLDL-C at Day 84 versus baseline."}
• {"endpoint_text":"- Exploratory Efficacy: To evaluate the percent change from baseline to 18 months in biomarkers of glycemic control, including HbA1c, homeostatic model assessment of insulin resistance, and blood glucose after 18 months","definition_or_measurement_approach":"Biomarkers of glycemic control (HbA1c, HOMA-IR, fasting glucose) percent change from baseline to 18 months."}
• {"endpoint_text":"- Exploratory Efficacy: To evaluate the effect from baseline of obicetrapib 10 mg + ezetimibe 10 mg FDC therapy on aortic valve indices evaluated on CCTA at 18 months","definition_or_measurement_approach":"Aortic valve indices measured by CCTA at baseline and 18 months."}
• {"endpoint_text":"- Exploratory Efficacy: To evaluate the effect from baseline of obicetrapib 10 mg + ezetimibe 10 mg FDC therapy on lipid accumulation in circulating monocytes at 18 months. Furthermore, association between change in lipid-laden circulating monocytes and change in atherosclerotic plaque parameters will be evaluated. Note: endpoint for lymphocyte lipid substudy for participants in the European Union only.","definition_or_measurement_approach":"Lipid accumulation in circulating monocytes measured at baseline and 18 months; correlation with plaque parameter changes. (Substudy limited to EU participants.)"}

Italy

Earliest CTIS Part Ii Submission Date

09-07-2024

Latest Decision Or Authorization Date

16-12-2024

Processing Time Days

160

Number Of Sites

2

Number Of Participants

25

Netherlands

Earliest CTIS Part Ii Submission Date

12-07-2024

Latest Decision Or Authorization Date

26-11-2024

Processing Time Days

137

Number Of Sites

5

Number Of Participants

85

Spain

Earliest CTIS Part Ii Submission Date

24-06-2024

Latest Decision Or Authorization Date

14-01-2025

Processing Time Days

204

Number Of Sites

3

Number Of Participants

25

Czechia

Earliest CTIS Part Ii Submission Date

24-06-2024

Latest Decision Or Authorization Date

11-12-2024

Processing Time Days

164

Number Of Sites

5

Number Of Participants

40

Hungary

Earliest CTIS Part Ii Submission Date

11-07-2024

Latest Decision Or Authorization Date

11-09-2025

Processing Time Days

427

Number Of Sites

5

Number Of Participants

30

Poland

Earliest CTIS Part Ii Submission Date

03-07-2024

Latest Decision Or Authorization Date

29-10-2025

Processing Time Days

483

Number Of Sites

8

Number Of Participants

45

Primary sponsor

Full Name

NewAmsterdam Pharma B.V.

Organisation Type

Pharmaceutical company

Country Of Registered Address

Netherlands

Contract research organisations

Name

Endpoint Clinical Inc.

Responsibilities

code: 3

Name

Medpace Inc.

Responsibilities

Central Lab

Name

Scarritt Group Inc.

Responsibilities

Patient Reimbursement; IM

Name

Medidata Solutions Inc.

Responsibilities

code: 7

Name

Fortrea Inc.

Responsibilities

codes: 1,10,11,12,2,5,6,9

Third parties

• {"country":"United States","full_name":"Welocalize Inc.","duties_or_roles":"Translation","organisation_type":"Pharmaceutical company"}
• {"country":"United States","full_name":"Fortrea Inc.","duties_or_roles":"codes: 1,10,11,12,2,5,6,9","organisation_type":"Pharmaceutical company"}
• {"country":"United Kingdom","full_name":"Caristo Diagnostics Limited","duties_or_roles":"Imaging","organisation_type":"Industry"}
• {"country":"United States","full_name":"Endpoint Clinical Inc.","duties_or_roles":"code: 3","organisation_type":"Pharmaceutical company"}
• {"country":"United States","full_name":"Medidata Solutions Inc.","duties_or_roles":"code: 7","organisation_type":"Non-Pharmaceutical company"}
• {"country":"United States","full_name":"Merge LLC","duties_or_roles":"Investigator Portal","organisation_type":"Industry"}
• {"country":"United Kingdom","full_name":"Greens","duties_or_roles":"Printing","organisation_type":"Industry"}
• {"country":"Finland","full_name":"Moncyte Ltd.","duties_or_roles":"code: 4","organisation_type":"Industry"}
• {"country":"United States","full_name":"Scarritt Group Inc.","duties_or_roles":"Patient Reimbursement; IM","organisation_type":"Non-Pharmaceutical company"}
• {"country":"United States","full_name":"Medpace Inc.","duties_or_roles":"Central Lab","organisation_type":"Pharmaceutical company"}