Familial Hypercholesterolemia, Hypercholesterolemia
Conditions
Brief summary
The purpose of this study is to evaluate the efficacy and safety of enclitide chloride, an oral PCSK9 inhibitor, in lowering low-density lipoprotein cholesterol (LDL-C) in participants with hypercholesterolemia. The primary hypothesis is that at least one of the four doses of enclitide chloride tested in this study is superior to placebo on percent change from baseline in LDL-C at Week 8.
Interventions
DRUGEnclitide Chloride
Enclitide Chloride administered orally
DRUGPlacebo
Placebo matching enclitide chloride administered orally
Sponsors
Merck Sharp & Dohme LLC
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 80 Years
Healthy volunteers
No
Inclusion criteria
* History of clinical atherosclerotic cardiovascular disease (ASCVD), or has an ASCVD risk equivalent and/or a 10-year risk of having an ASCVD event ≥5.0%, AND has a corresponding LDL-C that falls within the protocol-specified range at screening. * Treatment with a stable dose of one or more lipid-lowering therapies for ≥30 days before screening, or has not received treatment with any lipid-lowering therapy for ≥30 days before screening. * A female participant is not pregnant or breastfeeding, not a woman of child-bearing potential (WOCBP) or is a WOCBP and agrees to follow contraceptive guidance during the intervention period and for at least 8 weeks after the last dose of study intervention.
Exclusion criteria
* History of homozygous familial hypercholesterolemia (FH) based on genetic or clinical criteria. * History of nephrotic syndrome. * History of unstable angina, a myocardial infarction, percutaneous transluminal coronary angioplasty, transient ischemic attack, or stroke within 3 months before Screening. * Has poorly controlled diabetes mellitus, defined as hemoglobin A1C (A1C) ≥9.0% at Screening. * History of malignancy ≤3 years before screening, except for adequately treated basal cell or squamous cell skin cancer or in situ cervical cancer, which have no timeframe limitations relative to screening. * Currently participating in or has previously participated in an interventional clinical study within 3 months before Screening. * Has moderate or greater renal insufficiency.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percent Change From Baseline in Low-density Lipoprotein Cholesterol (LDL-C) at Week 8 | Baseline and up to Week 8 | Blood samples were collected at baseline and after 8 weeks of treatment to assess mean percent change in LDL-C. Based on a constrained longitudinal analysis (cLDA) model including terms for treatment, time, baseline statin intensity, baseline renal function, and the interaction of treatment by time. The percent change from baseline in LDL-C at week 8 was reported. |
| Percentage of Participants Who Experienced One or More Adverse Events (AEs) | Up to approximately 17 Weeks | An AE was any untoward medical occurrence in a clinical study participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention. An AE could therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a study intervention. The percentage of participants who experienced at least one AE was reported. |
| Percentage of Participants Who Discontinued Study Intervention Due to AEs | Up to approximately 9 Weeks | An AE was any untoward medical occurrence in a clinical study participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention. An AE could therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a study intervention. The percentage of participants who discontinued study intervention due to AEs was reported. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percent Change From Baseline in Apolipoprotein B (ApoB) at Week 8 | Baseline and up to Week 8 | Blood samples were collected at baseline and after 8 weeks of treatment to assess mean percent change in ApoB. The least square mean and 95% CI were obtained from fitting a cLDA model including terms for treatment, time, baseline statin intensity, baseline renal function, and the interaction of treatment by time. The percent change from baseline in ApoB at week 8 was reported. |
| Percent Change From Baseline in Non-High-density Lipoprotein Cholesterol (Non-HDL-C) at Week 8 | Baseline and up to Week 8 | Blood samples were collected at baseline and after 8 weeks of treatment to assess mean percent change in non-HDL-C. The least square mean and 95% CI were obtained from fitting a cLDA model including terms for treatment, time, baseline statin intensity, baseline renal function, and the interaction of treatment by time. The percent change from baseline in non-HDL-C at week 8 was reported. |
| Percentage of Participants With LDL-C Value at Goal at Week 8 | Week 8 | LDL-C goal was defined as: LDL-C \<70 mg/dL (\<1.81 mmol/L) in participants with clinical atherosclerotic cardiovascular disease (ASCVD), LDL-C \<100 mg/dL (\<2.59 mmol/L) in participants with an ASCVD risk-equivalent and/or a 10-year risk of having an ASCVD event that is ≥7.5%, OR LDL-C \<130 mg/dL (\<3.37mmol/L) in participants with a 10-year risk of having an ASCVD event that is ≥5.0% and \<7.5%. The percentage of participants with LDL-C value at goal at week 8 were reported. |
Countries
Germany, Japan, Mexico, Norway, South Korea, Turkey (Türkiye), United Kingdom, United States
Participant flow
Recruitment details
Of 668 participants screened for inclusion, 381 were randomized 1:1:1:1:1 to receive MK-0616 6 mg, 12 mg, 18 mg, 30 mg, or placebo. Of the 381 randomized participants, one participant did not receive at least one dose of study intervention.
Participants by arm
| Arm | Count |
|---|---|
| MK-0616 6 mg Participants received 6 mg of MK-0616 orally QD for 8 weeks | 77 |
| MK-0616 12 mg Participants received 12 mg of MK-0616 orally QD for 8 weeks | 76 |
| MK-0616 18 mg Participants received 18 mg of MK-0616 orally QD for 8 weeks | 76 |
| MK-0616 30 mg Participants received 30 mg of MK-0616 orally QD for 8 weeks | 76 |
| Placebo Participants received MK-0616-matching placebo orally QD for 8 weeks | 76 |
| Total | 381 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 |
|---|---|---|---|---|---|---|
| Overall Study | Death | 0 | 0 | 1 | 0 | 0 |
| Overall Study | Lost to Follow-up | 0 | 0 | 0 | 0 | 1 |
| Overall Study | Not Recorded | 0 | 0 | 0 | 1 | 0 |
| Overall Study | Physician Decision | 1 | 0 | 0 | 0 | 0 |
| Overall Study | Screen Failure | 0 | 0 | 0 | 0 | 1 |
| Overall Study | Withdrawal by Subject | 1 | 0 | 1 | 1 | 0 |
Baseline characteristics
| Characteristic | MK-0616 6 mg | MK-0616 12 mg | MK-0616 18 mg | MK-0616 30 mg | Placebo | Total |
|---|---|---|---|---|---|---|
| Age, Continuous | 61.7 Years STANDARD_DEVIATION 10.3 | 62.0 Years STANDARD_DEVIATION 9.4 | 62.0 Years STANDARD_DEVIATION 9.2 | 60.9 Years STANDARD_DEVIATION 10.2 | 60.6 Years STANDARD_DEVIATION 9.3 | 61.5 Years STANDARD_DEVIATION 9.7 |
| Baseline Low-density Lipoprotein Cholesterol (LDL-C) | 116.5 mg/dL STANDARD_DEVIATION 37 | 117.3 mg/dL STANDARD_DEVIATION 36.4 | 123.7 mg/dL STANDARD_DEVIATION 35.1 | 119.4 mg/dL STANDARD_DEVIATION 36.7 | 120.7 mg/dL STANDARD_DEVIATION 28.3 | 119.5 mg/dL STANDARD_DEVIATION 34.8 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 26 Participants | 29 Participants | 31 Participants | 31 Participants | 37 Participants | 154 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 51 Participants | 46 Participants | 45 Participants | 45 Participants | 38 Participants | 225 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 1 Participants | 2 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 4 Participants | 5 Participants | 5 Participants | 2 Participants | 5 Participants | 21 Participants |
| Race (NIH/OMB) Asian | 18 Participants | 13 Participants | 11 Participants | 13 Participants | 8 Participants | 63 Participants |
| Race (NIH/OMB) Black or African American | 4 Participants | 5 Participants | 2 Participants | 9 Participants | 4 Participants | 24 Participants |
| Race (NIH/OMB) More than one race | 2 Participants | 5 Participants | 3 Participants | 8 Participants | 5 Participants | 23 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 49 Participants | 48 Participants | 55 Participants | 44 Participants | 54 Participants | 250 Participants |
| Randomization Strata: Background Statin Dose High-intensity Statin Therapy | 20 Participants | 20 Participants | 19 Participants | 20 Participants | 20 Participants | 99 Participants |
| Randomization Strata: Background Statin Dose Low- to Moderate-intensity Statin Therapy | 27 Participants | 27 Participants | 26 Participants | 26 Participants | 26 Participants | 132 Participants |
| Randomization Strata: Background Statin Dose No Statin Therapy | 30 Participants | 29 Participants | 31 Participants | 30 Participants | 30 Participants | 150 Participants |
| Randomization Strata: Renal Function eGFR <60 ml/min/1.73 m^2 | 6 Participants | 4 Participants | 4 Participants | 5 Participants | 5 Participants | 24 Participants |
| Randomization Strata: Renal Function eGFR ≥60 ml/min/1.73 m^2 | 71 Participants | 72 Participants | 72 Participants | 71 Participants | 71 Participants | 357 Participants |
| Sex: Female, Male Female | 38 Participants | 35 Participants | 39 Participants | 38 Participants | 38 Participants | 188 Participants |
| Sex: Female, Male Male | 39 Participants | 41 Participants | 37 Participants | 38 Participants | 38 Participants | 193 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk |
|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 77 | 0 / 76 | 1 / 76 | 0 / 76 | 0 / 76 |
| other Total, other adverse events | 11 / 77 | 13 / 76 | 15 / 76 | 8 / 76 | 15 / 75 |
| serious Total, serious adverse events | 1 / 77 | 3 / 76 | 2 / 76 | 2 / 76 | 0 / 75 |
Outcome results
Primary
Percentage of Participants Who Discontinued Study Intervention Due to AEs
An AE was any untoward medical occurrence in a clinical study participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention. An AE could therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a study intervention. The percentage of participants who discontinued study intervention due to AEs was reported.
Time frame: Up to approximately 9 Weeks
Population: All randomized participants who received at least one dose of study intervention were analyzed.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| MK-0616 6 mg | Percentage of Participants Who Discontinued Study Intervention Due to AEs | 2.6 Percentage of Participants |
| MK-0616 12 mg | Percentage of Participants Who Discontinued Study Intervention Due to AEs | 0.0 Percentage of Participants |
| MK-0616 18 mg | Percentage of Participants Who Discontinued Study Intervention Due to AEs | 2.6 Percentage of Participants |
| MK-0616 30 mg | Percentage of Participants Who Discontinued Study Intervention Due to AEs | 2.6 Percentage of Participants |
| Placebo | Percentage of Participants Who Discontinued Study Intervention Due to AEs | 1.3 Percentage of Participants |
Primary
Percentage of Participants Who Experienced One or More Adverse Events (AEs)
An AE was any untoward medical occurrence in a clinical study participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention. An AE could therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a study intervention. The percentage of participants who experienced at least one AE was reported.
Time frame: Up to approximately 17 Weeks
Population: All randomized participants who received at least one dose of study intervention were analyzed.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| MK-0616 6 mg | Percentage of Participants Who Experienced One or More Adverse Events (AEs) | 44.2 Percentage of Participants |
| MK-0616 12 mg | Percentage of Participants Who Experienced One or More Adverse Events (AEs) | 39.5 Percentage of Participants |
| MK-0616 18 mg | Percentage of Participants Who Experienced One or More Adverse Events (AEs) | 43.4 Percentage of Participants |
| MK-0616 30 mg | Percentage of Participants Who Experienced One or More Adverse Events (AEs) | 42.1 Percentage of Participants |
| Placebo | Percentage of Participants Who Experienced One or More Adverse Events (AEs) | 44.0 Percentage of Participants |
95% CI: [-15.5, 15.8]
95% CI: [-20, 11.2]
95% CI: [-16.3, 15.1]
95% CI: [-17.5, 13.8]
Primary
Percent Change From Baseline in Low-density Lipoprotein Cholesterol (LDL-C) at Week 8
Blood samples were collected at baseline and after 8 weeks of treatment to assess mean percent change in LDL-C. Based on a constrained longitudinal analysis (cLDA) model including terms for treatment, time, baseline statin intensity, baseline renal function, and the interaction of treatment by time. The percent change from baseline in LDL-C at week 8 was reported.
Time frame: Baseline and up to Week 8
Population: All randomized participants who received at least one dose of study intervention, had at least one observation for the analysis endpoint, and had baseline data were analyzed.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| MK-0616 6 mg | Percent Change From Baseline in Low-density Lipoprotein Cholesterol (LDL-C) at Week 8 | -40.0 Percentage Change |
| MK-0616 12 mg | Percent Change From Baseline in Low-density Lipoprotein Cholesterol (LDL-C) at Week 8 | -54.5 Percentage Change |
| MK-0616 18 mg | Percent Change From Baseline in Low-density Lipoprotein Cholesterol (LDL-C) at Week 8 | -57.9 Percentage Change |
| MK-0616 30 mg | Percent Change From Baseline in Low-density Lipoprotein Cholesterol (LDL-C) at Week 8 | -59.7 Percentage Change |
| Placebo | Percent Change From Baseline in Low-density Lipoprotein Cholesterol (LDL-C) at Week 8 | 1.2 Percentage Change |
p-value: <0.00195% CI: [-47.8, -34.7]cLDA
p-value: <0.00195% CI: [-62.3, -49.1]cLDA
p-value: <0.00195% CI: [-65.7, -52.5]cLDA
p-value: <0.00195% CI: [-67.6, -54.3]cLDA
Secondary
Percentage of Participants With LDL-C Value at Goal at Week 8
LDL-C goal was defined as: LDL-C \<70 mg/dL (\<1.81 mmol/L) in participants with clinical atherosclerotic cardiovascular disease (ASCVD), LDL-C \<100 mg/dL (\<2.59 mmol/L) in participants with an ASCVD risk-equivalent and/or a 10-year risk of having an ASCVD event that is ≥7.5%, OR LDL-C \<130 mg/dL (\<3.37mmol/L) in participants with a 10-year risk of having an ASCVD event that is ≥5.0% and \<7.5%. The percentage of participants with LDL-C value at goal at week 8 were reported.
Time frame: Week 8
Population: All randomized participants who received at least one dose of study intervention and had at least one observation for the analysis endpoint were analyzed.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| MK-0616 6 mg | Percentage of Participants With LDL-C Value at Goal at Week 8 | 80.5 Percentage of Participants |
| MK-0616 12 mg | Percentage of Participants With LDL-C Value at Goal at Week 8 | 85.5 Percentage of Participants |
| MK-0616 18 mg | Percentage of Participants With LDL-C Value at Goal at Week 8 | 90.8 Percentage of Participants |
| MK-0616 30 mg | Percentage of Participants With LDL-C Value at Goal at Week 8 | 90.8 Percentage of Participants |
| Placebo | Percentage of Participants With LDL-C Value at Goal at Week 8 | 9.3 Percentage of Participants |
p-value: <0.00195% CI: [56.2, 79]Miettinen & Nurminen
p-value: <0.00195% CI: [62.9, 84]Miettinen & Nurminen method
p-value: <0.00195% CI: [67.1, 87.1]Miettinen & Nurminen method
p-value: <0.00195% CI: [67.9, 87.4]Miettinen & Nurminen method
Secondary
Percent Change From Baseline in Apolipoprotein B (ApoB) at Week 8
Blood samples were collected at baseline and after 8 weeks of treatment to assess mean percent change in ApoB. The least square mean and 95% CI were obtained from fitting a cLDA model including terms for treatment, time, baseline statin intensity, baseline renal function, and the interaction of treatment by time. The percent change from baseline in ApoB at week 8 was reported.
Time frame: Baseline and up to Week 8
Population: All randomized participants who received at least one dose of study intervention, had at least one observation for the analysis endpoint, and had baseline data were analyzed.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| MK-0616 6 mg | Percent Change From Baseline in Apolipoprotein B (ApoB) at Week 8 | -32.8 Percentage Change |
| MK-0616 12 mg | Percent Change From Baseline in Apolipoprotein B (ApoB) at Week 8 | -45.8 Percentage Change |
| MK-0616 18 mg | Percent Change From Baseline in Apolipoprotein B (ApoB) at Week 8 | -48.7 Percentage Change |
| MK-0616 30 mg | Percent Change From Baseline in Apolipoprotein B (ApoB) at Week 8 | -51.8 Percentage Change |
| Placebo | Percent Change From Baseline in Apolipoprotein B (ApoB) at Week 8 | 0.0 Percentage Change |
p-value: <0.00195% CI: [-38.6, -26.9]cLDA
p-value: <0.00195% CI: [-51.7, -39.9]cLDA
p-value: <0.00195% CI: [-54.6, -42.8]cLDA
p-value: <0.00195% CI: [-57.7, -45.9]cLDA
Secondary
Percent Change From Baseline in Non-High-density Lipoprotein Cholesterol (Non-HDL-C) at Week 8
Blood samples were collected at baseline and after 8 weeks of treatment to assess mean percent change in non-HDL-C. The least square mean and 95% CI were obtained from fitting a cLDA model including terms for treatment, time, baseline statin intensity, baseline renal function, and the interaction of treatment by time. The percent change from baseline in non-HDL-C at week 8 was reported.
Time frame: Baseline and up to Week 8
Population: All randomized participants who received at least one dose of study intervention, had at least one observation for the analysis endpoint, and had baseline data were analyzed.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| MK-0616 6 mg | Percent Change From Baseline in Non-High-density Lipoprotein Cholesterol (Non-HDL-C) at Week 8 | -34.4 Percentage Change |
| MK-0616 12 mg | Percent Change From Baseline in Non-High-density Lipoprotein Cholesterol (Non-HDL-C) at Week 8 | -49.0 Percentage Change |
| MK-0616 18 mg | Percent Change From Baseline in Non-High-density Lipoprotein Cholesterol (Non-HDL-C) at Week 8 | -51.8 Percentage Change |
| MK-0616 30 mg | Percent Change From Baseline in Non-High-density Lipoprotein Cholesterol (Non-HDL-C) at Week 8 | -54.3 Percentage Change |
| Placebo | Percent Change From Baseline in Non-High-density Lipoprotein Cholesterol (Non-HDL-C) at Week 8 | 1.5 Percentage Change |
p-value: <0.00195% CI: [-42.4, -29.4]cLDA
p-value: <0.00195% CI: [-57, -44]cLDA
p-value: <0.00195% CI: [-59.7, -46.7]cLDA
p-value: <0.00195% CI: [-62.3, -49.3]cLDA