E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
atherosclerotic cardiovascular disease (ASCVD) |
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E.1.1.1 | Medical condition in easily understood language |
atherosclerotic heart and blood vessel disease (the narrowing of arteries from a buildup of plaque) |
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E.1.1.2 | Therapeutic area | Diseases [C] - Cardiovascular Diseases [C14] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 26.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10051615 |
E.1.2 | Term | Atherosclerotic cardiovascular disease |
E.1.2 | System Organ Class | 100000004866 |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10076622 |
E.1.2 | Term | Atherosclerotic plaque |
E.1.2 | System Organ Class | 100000004866 |
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E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
To evaluate the effect of obicetrapib on the risk of major adverse cardiovascular events (MACE), including CV death, non-fatal MI, non-fatal stroke, or non-elective coronary revascularization. |
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E.2.2 | Secondary objectives of the trial |
• CV death, non-fatal MI, or non-fatal stroke; • All-cause mortality, non-fatal MI, non-fatal stroke, or non-elective coronary revascularization; • Any individual component of the primary composite endpoint; • Total CV events; • New-onset diabetes mellitus (NODM); • Percent change in low-density lipoprotein cholesterol (LDL-C); • Percent change in non-high-density lipoprotein cholesterol (non-HDL-C); • Percent change in apolipoprotein B (ApoB); and • Absolute change in glycosylated hemoglobin (HbA1c) in participants with diabetes mellitus and HbA1c ≥7% at Baseline. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
- Male or female and ≥18 years of age at Screening (Visit 1); - Have a history of ASCVD, defined by at least 1 of the following conditions: o Coronary artery disease o Cerebrovascular disease o Peripheral arterial disease - Are on maximally tolerated lipid-modifying therapy as an adjunct to a lipid-lowering diet and other lifestyle modifications, defined as follows: o A statin at a maximally tolerated stable dose; o Ezetimibe for at least 8 weeks with or without a maximally tolerated statin prior to Screening (Visit 1); o Bempedoic acid for at least 8 weeks in combination with a maximally tolerated statin prior to Screening (Visit 1); and/or o A PCSK9-targeted therapy alone or in combination with other lipid-modifying therapy for at least 4 stable doses prior to Screening (Visit 1); Note: At least 70% of the participants enrolled into this study must be taking HISs. Documentation in the eCRF of the reason why a participant is unable to take HISs is required. HISs include the following: - Atorvastatin 40 and 80 mg; and - Rosuvastatin 20 and 40 mg.
- Have a fasting serum LDL-C at Screening (Visit 1) as follows: o Have a fasting serum LDL-C ≥70 mg/dL (≥1.81 mmol/L) to <100 mg/dL (<2.59 mmol/L) with at least 1 of the following risk enhancers: - Recent MI (>3 and <12 months prior to Randomization); - Type 2 diabetes mellitus; - Fasting triglycerides (TG) >150 mg/dL (>1.7 mmol/L); and/or - Fasting HDL-C <40 mg/dL (<1.0 mmol/L). OR o Have a fasting serum LDL-C ≥100 mg/dL (≥2.59 mmol/L)
- Have fasting TG <400 mg/dL (<4.52 mmol/L) at Screening (Visit 1); and - Have an estimated glomerular filtration rate ≥30 mL/min/1.73 m2 calculated using the Chronic Kidney Disease Epidemiology Collaboration equation at Screening (Visit 1).
Other protocol-defined criteria apply. |
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E.4 | Principal exclusion criteria |
1. Have current or any previous history of New York Heart Association class III or IV HF or left ventricular ejection fraction <30%; 2. Have been hospitalized for HF within 5 years prior to Screening (Visit 1); 3. Have had any of the following clinical events within 3 months prior to Screening (Visit 1): o Non-fatal MI; o Non-fatal stroke; o Non-elective coronary revascularization; and/or o Hospitalization for unstable angina and/or chest pain; 4. 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 will be allowed during the same visit, at which point if the retest result is no longer exclusionary, the participant may be randomized; 5. Have a formal diagnosis of homozygous familial hypercholesterolemia; 6. Have active liver disease, defined as any known current infectious, neoplastic, or metabolic pathology of the liver; 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); 7. Have an HbA1c ≥10.0% (≥0.100 hemoglobin fraction) or a fasting glucose ≥270 mg/dL (≥15.0 mmol/L) at Screening (Visit 1); 8. Have a thyroid-stimulating hormone >1.5 × ULN at Screening (Visit 1); 9. Have a creatine kinase >3 × ULN at Screening (Visit 1);
Other protocol-defined criteria apply. |
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E.5 End points |
E.5.1 | Primary end point(s) |
EFFICACY
1) the time from Randomization to the first confirmed occurrence of any component of the composite endpoint, including the following: - CV death; - Non-fatal MI; - Non-fatal stroke; or - Non-elective coronary revascularization.
SAFETY
2) AEs and events of special interest (ESIs); 3) Vital signs (including blood pressure); 4) Electrocardiograms; and 5) Clinical laboratory assessment |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
1) Baseline to EOS 2) V1 to EOT and EOS 3) V1, V2, V4, V5, V6+Q6M, EOT 4) Visit 2, EOT 5) V1, V2, V4, V5, V6+Q6M, EOT |
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E.5.2 | Secondary end point(s) |
The secondary efficacy endpoints, in hierarchical order, include the following: 1) The time from Randomization until the first confirmed occurrence of a composite of CV death, non-fatal MI, or non-fatal stroke; 2) The time from Randomization until the first confirmed occurrence of a composite of all-cause mortality, non-fatal MI, non-fatal stroke, or nonelective coronary revascularization; 3)The time from Randomization until the first confirmed occurrence of non-elective coronary revascularization 4) A total event analysis, defined as the number of CV death events, and first and subsequent/recurrent events of non-fatal MIs, non-fatal strokes, and non-elective coronary revascularization from Randomization until the EOS Visit; 5) The time from Randomization until the first confirmed occurrence of non-fatal MI; 6) The time from Randomization until the confirmed occurrence of CV death; 7) The time from Randomization until the first confirmed occurrence of non-fatal stroke; 8) The time from Randomization until the confirmed occurrence of allcause mortality; 9) The time from Randomization until the first confirmed occurrence of NODM; 10) Percent change in LDL-C from Baseline to Day 365 and to the EOT Visit; 11) Percent change in non-HDL-C from Baseline to Day 365 and to the EOT Visit; 12) Percent change in ApoB from Baseline to Day 365; and 13) Percent change in HbA1c in participants with diabetes mellitus and HbA1c ≥7% at Baseline, from Baseline to Day 365 and to the EOT Visit.
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
1,2,3,4,5,6,8,9) Baseline through EOS 10,11,12,13) Baseline, Day 365/EOT
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | No |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 2 |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 30 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 200 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
European Union |
Australia |
Canada |
China |
Israel |
Japan |
United Kingdom |
United States |
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E.8.7 | Trial has a data monitoring committee | Yes |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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LSLV- After the last randomized participant has been followed for min. 2.5 years or after the number of primary endpoint events (i.e. 959 events) is reached, all participants return to the clinic within 30 days period for an End of Tretament (EOT) visit. An assessment of efficacy, safety and PK will be performed and all remaining study drug will be collected. Within 35-60 days after the EOT visit, an End-of-Study (EOS) visit will occur to assess for MACE and AEs and to review medication. |
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 2 |
E.8.9.1 | In the Member State concerned months | 8 |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 2 |
E.8.9.2 | In all countries concerned by the trial months | 8 |