MK-0616 (Oral PCSK9 Inhibitor) Renal Impairment Study 2 (MK-0616-020)

Study Overview
=================
Brief Summary
-----------------
The primary objective of the study is to compare the plasma pharmacokinetics (PK) of MK-0616 following a single 20 mg dose in participants on a background of statin therapy with varying degrees of renal impairment (moderate, severe, end stage renal disease [ESRD]) to those of healthy mean matched control participants on a background of statin therapy. There is no formal hypothesis.

Official Title
-----------------
An Open-Label, Single-Dose Clinical Study to Evaluate the Pharmacokinetics of MK-0616 in Participants With Varying Degrees of Renal Impairment

Conditions
-----------------
Hypercholesterolaemia

Intervention / Treatment
-----------------
* Drug: MK-0616


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Be in good health with the exception of renal impairment (RI) and hypercholesterolemia for participants in Panels A, B, and C. Participants with RI that have stable, chronic medical or psychiatric conditions, including but not limited to hypertension, hypercholesterolemia, diabetes mellitus, hyper- or hypothyroidism, gout, and chronic anxiety or depression may be included at the discretion of the investigator. Body Mass Index (BMI) ≥ 18 kg/m2 and ≤ 40 kg/m2, inclusive Be on a stable dose of any statin therapy defined as: no changes to dose or type of statin therapy for at least 2 months prior to Screening and participant anticipates no changes to statin therapy throughout the study until the poststudy visit Exclusion Criteria: History or presence of renal artery stenosis. Had a functioning renal transplant in the past 5 years and is taking transplant medication. Participants in panels A, B and D: Has rapidly fluctuating renal function as determined by historical measurements Has a history gastrointestinal disease which might affect food and drug absorption, as determined by the investigator, or has had gastric bypass or similar surgery History of cancer (malignancy) History of significant multiple and/or severe allergies, or has had an anaphylactic reaction or significant intolerability to prescription or nonprescription drugs or food Has received an anti-proprotein convertase subtilisin/kexin type 9 (PCSK9) small molecule treatment, monoclonal antibody, or short interfering RNA (siRNA) or RNA interference (ie, Inclisiran) within 12 months prior to Screening Participants with RI (Panels A, B, and C): Taking medications to treat chronic medical conditions and/or conditions associated with renal disease, if participant has not been on a stable regimen for at least 1 month (other than statins, which require a stable dose for at least 2 months) prior to administration of the initial dose of study intervention, and/or is unable to withhold the use of the medication(s) within 4 hours prior to and 4 hours after administration of study intervention Participated in another investigational study within 4 weeks prior to the prestudy (screening) visit Consumes greater than 3 servings of alcoholic beverages per day Consumes excessive amounts, defined as greater than 6 servings of caffeinated beverages per day

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 85 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
Accepts Healthy Volunteers

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Panel A: Moderate Renal Impairment (RI)<br>Period 1 Day 1: Participants receive MK-0616 20 mg tablet single dose orally (Period 1 = 15 days) | Drug: MK-0616<br>* Single oral dose<br>|
| Experimental: Panel B: Severe RI<br>Period 1 Day 1: Participants receive MK-0616 20 mg tablet single dose orally (Period 1 = 15 days) | Drug: MK-0616<br>* Single oral dose<br>|
| Experimental: Panel C: End-Stage Renal Disease (ESRD) on Hemodialysis (HD)<br>Period 1 Day 1: Participants receive MK-0616 20 mg tablet single dose orally (Period 1 = 15 days). Period 2 Day 1: Participants receive MK-0616 20 mg tablet single dose orally (Period 2 = 15 days). A washout period of 14 days will separate Period 1 and Period 2. | Drug: MK-0616<br>* Single oral dose<br>|
| Experimental: Panel D: Healthy<br>Period 1 Day 1: Participants receive MK-0616 20 mg tablet single dose orally (Period 1 = 15 days) | Drug: MK-0616<br>* Single oral dose<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Panels A, B, and D: Area Under the Concentration-Time Curve from Time 0 to Infinity (AUC0-Inf) of MK-0616: Period 1 | Blood for plasma samples will be collected at pre-specified timepoints to determine the AUC0-inf of MK-0616 | Period 1: Predose and 0.5, 1.5, 2, 4, 8, 12, 24, 36, 48, 72, 120, 168, and 240 hours postdose (Period 1 = 15 days) | 
| Panel C: AUC0-inf of MK-0616: Periods 1 and 2 | Blood for plasma samples will be collected at pre-specified timepoints to determine the AUC0-inf of MK-0616 | Periods 1 and 2: Predose and 0.5, 1.5, 2, 4, 8, 12, 24, 36, 48, 72, 120, 168, and 240 hours postdose (each period = 15 days) | 
| Panels A, B and D: AUC from Time 0 to Last Measurable Concentration (AUClast) of MK-0616: Period 1 | Blood for plasma samples will be collected at pre-specified timepoints to determine the AUClast of MK-0616 | Period 1: Predose and 0.5, 1.5, 2, 4, 8, 12, 24, 36, 48, 72, 120, 168, and 240 hours postdose (Period 1 = 15 days) | 
| Panel C: AUClast of MK-0616: Periods 1 and 2 | Blood for plasma samples will be collected at pre-specified timepoints to determine the AUClast of MK-0616 | Periods 1 and 2: Predose and 0.5, 1.5, 2, 4, 8, 12, 24, 36, 48, 72, 120, 168, and 240 hours postdose (each period = 15 days | 
| Panels A, B and D: Maximum Plasma Concentration (Cmax) of MK-0616: Period 1 | Blood for plasma samples will be collected at pre-specified time points to determine the Cmax of MK-0616 | Period 1: Predose and 0.5, 1.5, 2, 4, 8, 12, 24, 36, 48, 72, 120, 168, and 240 postdose (Period 1 = 15 days) | 
| Panel C: Maximum Plasma Concentration (Cmax) of MK-0616: Periods 1 and 2 | Blood for plasma samples will be collected at pre-specified time points to determine the Cmax of MK-0616 | Periods 1 and 2: Predose and 0.5, 1.5, 2, 4, 8, 12, 24, 36, 48, 72, 120, 168 and 240 hours postdose (each period = 15 days | 
| Panel A, B, and D: Time to Maximum Plasma Concentration (Tmax) of MK-0616: Period 1 | Blood for plasma samples will be collected at pre-specified time points to determine the Tmax of MK-0616 | Period 1: Predose and 0.5, 1, 1.5, 2, 4, 8, 12, 24, 36, 48, 72, 120, 168 and 240 hours postdose | 
| Panel C: Time to Maximum Plasma Concentration (Tmax) of MK-0616: Periods 1 and 2 | Blood for plasma samples will be collected at pre-specified time points to determine the Tmax of MK-0616 | Periods 1 and 2: Predose and 0.5, 1, 1.5, 2, 4, 8, 12, 24, 36, 48, 72, 120, 168 and 240 hours postdose | 
| Panels A, B and D: Apparent Terminal Half-life (t1/2) of MK-0616: Period 1 | Blood for plasma samples will be collected at pre-specified time points to determine the t1/2 of MK-0616 | Period 1: Predose and 0.5, 1, 1.5, 2, 4, 8, 12, 24, 36, 48, 72, 120, 168 and 240 hours postdose | 
| Panel C: t1/2 of MK-0616: Periods 1 and 2 | Blood for plasma samples will be collected at pre-specified time points to determine the t1/2 of MK-0616 | Periods 1 and 2: Predose and 0.5, 1, 1.5, 2, 4, 8, 12, 24, 36, 48, 72, 120, 168 and 240 hours postdose | 
| Panel A, B and D: Apparent Clearance (CL/F) of MK-0616: Period 1 | Blood for plasma samples will be collected at pre-specified time points to determine the CL/F of MK-0616 | Period 1: Predose and 0.5, 1.5, 2, 4, 8, 12, 24, 36, 48, 72, 120, 168 and 240 hours postdose (Period 1 = 15 days) | 
| Panel C: Apparent Clearance (CL/F) of MK-0616: Periods 1 and 2 | Blood for plasma samples will be collected at pre-specified time points to determine the CL/F of MK-0616 | Periods 1 and 2: Predose and 0.5, 1, 1.5, 2, 4, 8, 12, 24, 36, 48, 72, 120, 168 and 240 hours postdose | 
| Panels A, B and D: Apparent Volume of Distribution (Vz/F) of MK-0616 | Blood for plasma samples will be collected at pre-specified time points to determine the Vz/F of MK-0616 | Period 1: Predose and 0.5, 1, 1.5, 2, 4, 8, 12, 24, 36, 48, 72, 120, 168 and 240 hours postdose | 
| Panel C: Apparent Volume of Distribution (Vz/F) of MK-0616 | Blood for plasma samples will be collected at pre-specified time points to determine the Vz/F of MK-0616 | Periods 1 and 2: Predose and 0.5, 1, 1.5, 2, 4, 8, 12, 24, 36, 48, 72, 120, 168 and 240 hours postdose | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Dialysate Clearance (CLd) of MK-0616 | CLd is the amount of MK-0616 cleared from plasma via dialysis. | Predose and up to 8 hours postdose- Panel C (Period 2) | 
| Dialysate Concentration of MK-0616 | Cd is the concentration of MK-0616 in dialysate. | Predose and up to 8 hours postdose- Panel C (Period 2) | 
| Amount of MK-0616 Excreted (AEd) in Dialysate | The amount of MK-0616 excreted in the dialysate will be assessed. | Predose and up to 8 hours postdose- Panel C (Period 2) | 
| Percentage of Dose (%Dose) of MK-0616 Excreted in Dialysate | The percentage of the dose of MK-0616 in the dialysate will be assessed. | Predose and up to 8 hours postdose- Panel C (Period 2) | 
| Amount of MK-0616 Excreted in Urine from 0 to 24 hours (AE0-24) | The amount of MK-0616 excreted in urine in first 24 hours after dosing will be reported. | Predose and up to 24 hours postdose (All Panels: Period 1; Panel C: Period 2) | 
| Fraction of Unchanged MK-0616 Excreted in Urine (Fe) | The fraction of unchanged MK-0616 excreted in urine will be reported | Predose and up to 24 hours postdose (All Panels: Period 1; Panel C: Period 2) | 
| Renal Clearance (CLr) of MK-0616 | The CLr of MK-0616 will be reported | Predose and up to 24 hours postdose (All Panels: Period 1; Panel C: Period 2) | 
| Percentage of Participants Who Experience at Least 1 Adverse Event (AE) | An AE is 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 can 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 | Up to approximately 30 days | 
| Percentage of Participants Who Discontinue From the Study due to an AE | An AE is 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 can 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 | Up to approximately 30 days |