| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
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| E.1.1.1 | Medical condition in easily understood language |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Nutritional and Metabolic Diseases [C18] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10020604 |
| E.1.2 | Term | Hypercholesterolemia |
| E.1.2 | System Organ Class | 100000004861 |
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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 |
1. To compare the effect of MK-0616 with the effect of placebo on percent change from baseline in LDL-C at Week 8.
2. To evaluate the safety and tolerability of each dose of MK-0616.
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| E.2.2 | Secondary objectives of the trial |
1. To compare the effect of MK-0616 with the effect of placebo on percent change from baseline in ApoB and non-HDL-C at Week 8.
2. To compare the effect of MK-0616 with the effect of placebo on the proportion of participants with LDL-C value at goal at Week 8. |
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Meets 1 of the following ASCVD status/risk categories AND has a fasted LDL-C value in the corresponding LDL-C range at Visit 1 (Screening)
• Has clinical ASCVD
• Has an ASCVD risk equivalent and/or a 10-year risk of having an ASCVD event that is ≥7.5%
• Has a 10-year risk of having an ASCVD event that is ≥5.0% and <7.5%
2. Is either on a stable dose of 1 or more lipid-lowering therapies for ≥30 days before Visit 1 (Screening) or has not received treatment with any lipid-lowering therapy for ≥30 days before Visit 1 (Screening). Those who are not on a lipid-lowering therapy at Visit 1 (Screening) can either have been previously treated or be treatment naive.
3. Is male or a female, ≥18 years and ≤80 years of age, at the time of providing documented informed consent.
4. A female participant is eligible to participate if she is not pregnant or breastfeeding, and at least one of the following conditions applies:
• Not a WOCBP
OR
• A WOCBP and:
- Uses an acceptable contraceptive method, or be abstinent from heterosexual intercourse as their preferred and usual lifestyle (abstinent on a long-term and persistent basis), as described in Appendix 5 of the study protocol during the intervention period and for at least 8 weeks 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 women should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies
- Has a negative highly sensitive pregnancy test (urine or serum as required by local regulations) within 72 hours 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 8.3.7 of the study protocol.
- Medical history, menstrual history, and recent sexual activity has been reviewed by the investigator to decrease the risk for inclusion of a woman with an early undetected pregnancy.
5. The participant (or legally acceptable representative) provides documented informed consent for the study. The participant may also provide consent for FBR. However, the participant may participate in the study without participating in FBR.
6. Is willing and considered able by the investigator to comply with study procedures, including adherence with study intervention, fasting guidelines (Section 5.3.1 of the study protocol), and visit schedule.
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| E.4 | Principal exclusion criteria |
1. Has a history of homozygous FH based on genetic or clinical criteria [Cuchel, M., et al 2014].
2. Has a history of nephrotic syndrome.
3. Has any clinically significant malabsorption condition.
4. Had unstable angina, a myocardial infarction, percutaneous transluminal coronary angioplasty, transient ischemic attack, or stroke within 3 months before Visit 1 (Screening).
5. Has a planned coronary revascularization procedure within the next 3 months after Visit 1 (Screening).
6. Has poorly controlled diabetes mellitus, defined as A1C ≥9.0%, at Visit 1 (Screening).
7. Has a known allergy or intolerance to any ofthe ingredients in the study intervention.
8. 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).
9. Has a severe, acute or chronic medical or psychiatric condition or laboratory abnormality that may increase the risk associated with study participation or administration of study intervention or may interfere with the interpretation of study results and, in the opinion of the investigator, would make the participant inappropriate for entry into this study.
10. Is undergoing or previously underwent an LDL-C apheresis program within 3 months before Visit 1 (Screening).
11. Is receiving treatment with oral semaglutide at Visit 1 (Screening).
12. Meets 1 or more of the following criteria:
• Is on treatment with a PCSK9 inhibitor (siRNA or mAb), an ANGPTL3 inhibitor, or an MTP inhibitor (eg, lomitapide) at Visit 1 (Screening).
• Was previously treated with an siRNA PCSK9 inhibitor within 1 year before Visit 1 (Screening).
• Was previously treated with a mAb PCSK9 inhibitor within 6 months before Visit 1 (Screening).
• Was previously treated with an ANGPTL3 inhibitorwithin 6 months before Visit 1 (Screening).
• Was previously treated with an MTP inhibitor (eg, lomitapide) within 1 month before Visit 1 (Screening).
13. 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).
14. Has moderate or greater renal insufficiency defined as eGFR <45 mL/min/1.73 m2 at Visit 1 (Screening); eGFR will be calculated according to Appendix 2 of the study protocol.
15. Has laboratory or clinical evidence of clinically significant hepatic conditions, including 1 or more of the following:
• ALT or AST >2X 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.
16. Has elevated CK >3X ULN at Visit 1 (Screening).
17. Has a fasting triglyceride value ≥400 mg/dL (≥4.52 mmol/L) at Visit 1 (Screening).
18. Has an abnormal TSH value at Visit 1 (Screening) without a history of hypothyroidism.
Participants with a history of hypothyroidism are eligible if their treatment for this condition is stable for ≥3 months before Visit 1 (Screening) and their FT4 value at Visit 1 (Screening) is normal.
19. Routinely consumes >3 alcoholic drinks per day. One standard drink is defined as any beverage containing 14 g of pure alcohol (ie, 12 oz of beer, 8 to 9 oz of malt liquor, 5 oz of wine, 1.5 oz of distilled spirits).
20. Has a recent history of drug abuse (within the last year) or is a current user of recreational or illicit drugs at the time of Visit 1 (Screening).
21. 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.
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| E.5 End points |
| E.5.1 | Primary end point(s) |
1. Percent Change from Baseline in Low-density Lipoprotein Cholesterol (LDL-C) at Week 8
2. Proportion of Participants Who Experience One or More Adverse Events (AEs)
3.Proportion of Participants Who Discontinue Study Intervention Due to AEs |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
1. Baseline and Week 8
2. Up to approximately 16 Weeks
3. Up to approximately 8 Weeks |
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| E.5.2 | Secondary end point(s) |
1.Percent Change from Baseline in Apolipoprotein B (ApoB) at Week 8
2. Percent Change from Baseline in Non-High-density Lipoprotein Cholesterol (HDL-C) at Week 8
3. Proportion of Participants with LDL-C Value at Goal at Week 8
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
1. Baseline and Week 8
2. Baseline and Week 8
3. Up to 8 Weeks |
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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 | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | Yes |
| E.6.10 | Pharmacogenetic | Yes |
| 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) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| 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 | Yes |
| 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 | 5 |
| 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 | 5 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 14 |
| 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 |
| Japan |
| Korea, Republic of |
| Mexico |
| United States |
| Germany |
| Norway |
| Russian Federation |
| Turkey |
| United Kingdom |
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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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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 1 |
| E.8.9.1 | In the Member State concerned months | 1 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 1 |
| E.8.9.2 | In all countries concerned by the trial months | 1 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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