Condition médicale (spécialité visée)
Choix aire thérapeutique
Cardiologie et maladies vasculaires
Profil des participants
Sexe(s) des participants
Hommes
Femmes
Aptitude des participants
Majeurs aptes
Critères de sélection
Critères d'inclusion
Type of Participant and Disease Characteristics
1. Has either:
a. history of a major ASCVD event
Note: history of a major ASCVD event is defined as having a history of 1 or more of the following: acute coronary syndrome, myocardial infarction, coronary revascularization, cerebrovascular arterial revascularization, ischemic stroke, or peripheral arterial disease with a history of acute limb ischemia, peripheral arterial revascularization, or major amputation.
OR
b. If no history of a major ASCVD event, has intermediate to high risk for development of a first major ASCVD event.
Note: Intermediate to high risk for ASCVD event is defined as history of one or more of the following:
◦ Possible or definite diagnosis of heterozygous FH based on a locally accepted diagnostic algorithm (eg, AHA algorithm, US MEDPED, Simon Broome, Dutch Lipid Network, or Japanese Atherosclerosis Society Guidelines) {04ML6M, 06FZVF, 06FZVG}.
◦ Diabetes mellitus
◦ Stable angina pectoris
◦ Transient ischemic attack
◦ Symptomatic peripheral arterial disease without a history of acute limb ischemia, peripheral arterial revascularization, or major amputation.
◦ Age ≥40 years with ASCVD risk score ≥7.5% based on the Pooled Cohort Equation or equivalent
◦ Coronary artery calcium score ≥100 Agatston units (performed within 3 year of Visit 1)
2. Has fasted lipid values (evaluated by the central laboratory) at Visit 1 (Screening) as follows:
a. History of a major ASCVD event, has LDL-C ≥55 mg/dL (≥1.42 mmol/L).
OR
a. No history of a major ASCVD event, has LDL-C ≥70 mg/dL (≥1.81 mmol/L).
3. At Visit 1 (Screening) is either treated with a low, moderate, or high intensity statin (± non-statin LLT). (See Appendix 8).
4. LLTs (including statin [Table 2]) should be on a stable dose for ≥30 days before screening with no planned medication or dose change during the participation in the study.
5. Is an individual of any sex/gender, from 18 years of age inclusive, at the time of providing the informed consent.
6. A participant assigned female sex at birth is eligible to participate if not pregnant or breastfeeding, and at least one of the following conditions applies:
• Is not a POCBP
OR
• Is a POCBP and:
- Uses an acceptable contraceptive method, or is abstinent from penile-vaginal intercourse as their preferred and usual lifestyle (abstinent on a long-term and persistent basis), as described in Appendix 5 during the intervention period and for at least 56 days after the last dose of study intervention. The investigator should evaluate the potential for contraceptive method failure (ie, noncompliance, recently initiated) in relationship to the first dose of study intervention. Contraceptive use by POCBPs should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies.
If the contraception requirements in the local label for any of the study interventions are more stringent than the requirements above, the local label requirements are to be followed.
- Has a negative highly sensitive pregnancy test (urine or serum) as required by local regulations within 24 hours (for a urine test) or 72 hours (for a serum test) before the first dose of study intervention. If a urine test cannot be confirmed as negative (eg, an ambiguous result), a serum pregnancy test is required. In such cases, the participant must be excluded from participation if the serum pregnancy result is positive. Additional requirements for pregnancy testing during and after study intervention are in Section 8.3.6.
- Medical history, menstrual history, and recent sexual activity has been reviewed by the investigator to decrease the risk for inclusion of a POCBP with an early undetected pregnancy.
Informed Consent
7. The participant (or legally acceptable representative) has provided documented informed consent for the study. The participant may also provide consent/assent for FBR. However, the participant may participate in the study without participating in FBR.
Additional Categories
8. Is willing and considered able by the investigator to comply with study procedures, including adherence with study intervention, fasting guidelines (Section 5.3.1), and visit schedule.
Critères d'exclusion
Medical Conditions
1. Has a history of homozygous FH based on genetic or clinical criteria{04ML66), compound heterozygous FH, or double heterozygous FH.
Cardiac Conditions
2. Has New York Heart Association class IV heart failure, or last known left ventricular ejection fraction ≤ 25% by any imaging method, or had a heart failure hospitalization within 3 months before Visit 1 (Screening).
3. Has recurrent ventricular tachycardia within 3 months prior to randomization that is not controlled by medication or ablation.
4. Has QTc ≥500 ms (in the absence of intraventricular conduction delay and/or a bundle branch block) based on an ECG performed within 6 months before or at Visit 1 (Screening).
5. Has uncontrolled hypertension defined as sitting SBP >160 mm Hg or DBP >100 mm Hg at Visit 2 (Randomization) despite stable antihypertensive treatment.
6. Has unstable angina, a myocardial infarction, coronary artery bypass graft, percutaneous transluminal coronary angioplasty, transient ischemic attack, or stroke within 3 months before Visit 1 (Screening).
7. Has a planned arterial revascularization procedure within 8 weeks after randomization.
Non-Cardiac Conditions
8. Has a history of nephrotic syndrome.
9. Has any clinically significant malabsorption condition based on principal investigator assessment (eg, recurrent vomiting, inflammatory bowel disease with ongoing symptoms, chronic intestinal disease accompanied by a disturbance in digestion and absorption, or a history of extensive resection of the upper GI tract,)
10. Has poorly controlled diabetes mellitus, defined as A1C ≥9.0%, at Visit 1 (Screening).
11. Has laboratory or clinical evidence of clinically significant hepatic conditions, including 1 or more of the following:
• ALT or AST ≥3 x ULN at Visit 1 (Screening)
• Direct bilirubin >2 x ULN at Visit 1 (Screening),
• A history of hepatitis or liver disease that, in the opinion of the investigator, has been active within the 6 months before Visit 1 (Screening) and may increase the risk associated with study participation or administration of study intervention.
12. Participants with a history of tendon disorder or tendon rupture
13. Participants with a history of gout.
14. Has an abnormal TSH (defined as TSH < LLN or > 1.5 x ULN) at Visit 1 (Screening). Participants with a history of hypothyroidism must be on a stable treatment for this condition for ≥3 months before Visit 1 (Screening).
15. Has a known allergy or intolerance to any of the ingredients in the study intervention.
16. Is actively receiving chemotherapy for malignancy or has a history of malignancy ≤3 years before Visit 1 (Screening), except for adequately treated basal cell or squamous cell skin cancer or in situ cervical cancer, which have no timeframe limitations relative to Visit 1 (Screening).
17. Has a life expectancy of <2 years based on investigator judgement.
Prior/Concomitant Therapy
18. Is undergoing or previously underwent an LDL-C apheresis program within 3 months before Visit 1 (Screening) or plans to initiate an LDL-C apheresis program.
19. Meets 1 or more of the following criteria:
• Is on treatment with ezetimibe or bempedoic acid within 30 days before Visit 1 (Screening).
• Is on treatment with simvastatin >20 mg or pravastatin > 40 mg within 30 days before Visit 1 (Screening).
• Is on treatment with fibrates other than fenofibrates within 30 days before Visit 1 (Screening).
• Is on fenofibrates and have cholelithiasis.
• Is on cholestyramine.
• Is on treatment with a PCSK9i (siRNA or mAb), an ANGPTL3 inhibitor, or an MTP inhibitor (eg, lomitapide) at Visit 1 (Screening) or such treatment planned.
• Was previously treated with an siRNA PCSK9i within 18 months before Visit 1 (Screening).
• Was previously treated with a mAb PCSK9i within 3 months before Visit 1 (Screening).
• Was previously treated with an ANGPTL3 inhibitor within 6 months before Visit 1 (Screening).
Was previously treated with an MTP inhibitor (eg, lomitapide) within 1 month before Visit 1 (Screening).
Prior/Concurrent Clinical Study Experience
20. Is currently participating in or has previously participated in an interventional clinical study within 3 months (or 5 half-lives for agents in the previous study, whichever is longer) before Visit 1 (Screening).
Diagnostic Assessments
21. Has severe renal insufficiency defined as eGFR <30 mL/min/1.73 m2 at Visit 1 (Screening); or has ESRD on dialysis (eGFR will be calculated according to Appendix 2 For country specific requirements, see Appendix 7.
22. Has elevated CK >3 x ULN at Visit 1 (Screening).
23. Has a fasting triglyceride value ≥400 mg/dL (≥4.52 mmol/L) at Visit 1 (Screening).
Other Exclusions
24. Routinely consumes >3 alcoholic drinks per day. One standard drink is defined as any beverage containing 14 g of pure alcohol (ie, 12 oz [355 ml] of beer, 8 to 9 oz [237 to 266 ml] of malt liquor, 5 oz [148 ml] of wine, 1.5 oz [44 ml] of distilled spirits).
25. Has a recent history of drug abuse (within the last year) or is a current user of illicit drugs at the time of Visit 1 (Screening).
26. Has a medical disorder, condition, or history thereof that in the opinion of the investigator would impair the participant’s ability to participate in or complete the study.
27. Is or has an immediate family member (eg, spouse, parent/legal guardian, sibling, or child) who is investigational site or Sponsor staff directly involved with this study.