A Study of MK-7145 in Participants With Renal Insufficiency (Part I) and Heart Failure With Renal Insufficiency (Part II) (MK-7145-011)

Study Overview
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Brief Summary
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Part I is a 3-period, active comparator-controlled, fixed sequence study to evaluate the safety, tolerability, pharmacokinetics and pharmacodynamics of MK-7145 compared to furosemide in participants with moderate-to-severe renal insufficiency (RI) without heart failure (HF). Primary hypothesis for Part I is that at least one well-tolerated dose of MK-7145 will produce a greater 24hr urinary excretion of sodium (UNa) on the 1st day of MK-7145 dosing than 80 mg furosemide (on the 1st day of furosemide dosing) in participants with moderate-to-severe RI. If MK-7145 is safe at natriuretic doses in RI in Part I of this study, MK-7145 will be investigated in participants with heart failure (HF) and RI (Part II). Part II is 4 period, fixed sequence, active comparator controlled (in Period 1), titration (in Periods 2, 3 and 4) study to evaluate the safety, tolerability, pharmacokinetics and pharmacodynamics of a titration regimen of MK-7145 compared to an optimized stable maintenance regimen of furosemide or torsemide in participants with New York Heart Association (NYHA) Class II and III heart failure and moderate or severe renal insufficiency. The primary hypothesis for Part II is that at least one dose of MK-7145, titrated according to a fixed dose titration regimen, will be associated with a reduction in N-terminal pro-brain natriuretic peptide (NT-proBNP) compared to furosemide or torsemide (at 24 hours post morning dose on the last dosing day of each period) in participants with NYHA class II/III HF with moderate or severe RI.

Official Title
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A Two Part, Open-label, Phase I Study to Evaluate the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of MK-7145 in Patients With Renal Insufficiency (Part I) and Heart Failure With Renal Insufficiency (Part II)

Conditions
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Renal Impairment, Heart Failure

Intervention / Treatment
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* Drug: MK-7145
* Drug: Furosemide
* Drug: Torsemide


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Parts I and II If female, must be of non-child bearing potential or, if of child-bearing potential agrees to use at least 2 acceptable contraceptive measures Body Mass Index (BMI) >=17.5 and <=38 kg/m^2 No present history of clinically significant uncontrolled arrhythmias on electrocardiogram (ECG) Nonsmoker or a light smoker consuming up to an average of 20 cigarettes (or equivalent tobacco product) per day. Part I Only - Estimated creatinine clearance of ≤45 mL/min. Part II Only Class II or III heart failure as specified by the New York Heart Association (NYHA) functional classification for heart failure with NT-proBNP >=1000 pg/mL on clinically optimized therapy with a stable dose (for at least 2 weeks) of furosemide or torsemide Estimated creatinine clearance of ≤45 mL/min Exclusion Criteria: Parts I and II Mentally or legally institutionalized and/or incapacitated, has significant emotional problems or has a history of a clinically significant psychiatric disorder over the last 5 years. This includes any mood disorder requiring concomitant use of lithium Diagnosed with acute coronary syndrome or acute cardiovascular (CV) event, or has been hospitalized for HF exacerbation within less than 3 months of study entry Unstable angina pectoris Diabetes requiring high dose peroxisome proliferator-activated receptor (PPAR) antagonist (e.g. >30 mg of pioglitazone) or unstable insulin use Infectious disease requiring concomitant use of aminoglycosides Low plasma potassium (hypokalemia) Recent (within 6 months) history of stroke, uncontrolled seizures, or uncontrolled major neurological disorder Urinary retention, hydronephrosis or hydroureter Active nephrocalcinosis, nephrolithiasis, or hypercalciuria Functional disability that can interfere with rising from a semi-recumbent position to the standing position History of malignant neoplastic disease Unable to refrain from the use of medication, including prescription and non-prescription drugs such as high-dose aspirin (≥325 mg/day), non-steroidal anti-inflammatory drugs (NSAIDs), human immunodeficiency virus (HIV) protease inhibitors (ritonavir, indinavir, nelfinavir), macrolide antibiotics (erythromycin, telithromycin, clarithromycin), chloramphenicol, azole antifungals (fluconazole, ketoconazole, itraconazole, nefazodone, aprepitant, verapamil, diltiazem, etc.), anticonvulsants and mood stabilizers (e.g., phenytoin, carbamazepine, oxcarbazepine), barbiturates (phenobarbital), HIV non-nucleoside reverse transcriptase inhibitors (efavirenz, nevirapine, etravirine), rifampicin, modafinil, St John's wort, cyproterone (antiandrogen, progestin), etc. beginning approximately 2 weeks (or 5 half-lives), prior to administration of the initial dose of study drug, throughout the study (including washout intervals between treatment periods) until the poststudy visit Consumes excessive amounts of alcohol, defined as greater than 5 glasses of alcoholic beverages (1 glass is approximately equivalent to: beer [284 mL/10 ounces], wine [125 mL/4 ounces], or distilled spirits [25 mL/1 ounce]) per day Consumes excessive amounts, defined as greater than 6 servings (1 serving is approximately equivalent to 120 mg of caffeine) of coffee, tea, cola, or other caffeinated beverages per day Had major surgery, donated or lost 1 unit of blood (approximately 500 mL) or participated in another investigational study within 4 weeks Regular user of any illicit drugs or has a history of drug (including alcohol) abuse within approximately 6 months

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: MK-7145 8 mg (Part I:Period 1)<br>Single daily dose of 8 mg MK-7145 for 5 days, capsules, orally administered in a fasted state | Drug: MK-7145<br> <br> |
| Active Comparator: Furosemide 40 mg (Part I:Period 2)<br>Two daily doses of one 40 mg Furosemide tablet for 5 days administered in a fasted state | Drug: Furosemide<br> <br> * Other names: Lasix;|
| Experimental: MK-7145 16 mg (Part I:Period 3)<br>Single daily dose of 16 mg MK-7145 for 5 days, capsules, orally administered in a fasted state | Drug: MK-7145<br> <br> |
| Active Comparator: Furosemide/Torsemide Run-in (Part II:Period1)<br>Run-in of stable, clinically optimized maintenance dose regimen of furosemide or torsemide for at least 2 weeks | Drug: Furosemide<br> <br> * Other names: Lasix;Drug: Torsemide<br> <br> |
| Experimental: MK-7145 10 mg (Part II:Period 2)<br>Single daily dose of 10 mg MK-7145 for 14 days, capsules, orally administered in a fasted state | Drug: MK-7145<br> <br> |
| Experimental: MK-7145 16 mg (Part II:Period 3)<br>Single daily dose of 16 mg MK-7145 for 14 days, capsules, orally administered in a fasted state | Drug: MK-7145<br> <br> |
| Experimental: MK-7145 24 mg (Part II:Period 4)<br>Single dose of 24 mg MK-7145 for 28 days, capsules, orally administered in a fasted state | Drug: MK-7145<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in First 24hr Urinary Sodium (UNa) (Part 1) | Urine was collected at Treatment Day -1 and Treatment Day 1 at 0-2, 2-4, 4-6, 6-8, 8-12, 12-24 hour. The 24-hour cumulative natriuresis will be estimated by the amount of sodium excreted into urine over 24 hour period postdose, where amount of sodium is the product of sodium concentration and the volume of urine. The change from baseline in UNa from baseline (Treatment Day -1) and 24 hours post-dose on Treatment Day 1 were calculated. | Baseline (Day -1) and 0-24 hours postdose on Treatment Day 1 of each treatment period | 
| N-terminal Pro B-type Natriuretic Peptide (NT-proBNP) Values at 24 Hours Post Last Morning Dose of Each Period (Part 2) | B-type natriuretic peptide (BNP) is a substance secreted from the ventricles or lower chambers of the heart in response to changes in pressure that occur when heart failure develops and worsens. The level of BNP in the blood increases when heart failure symptoms worsen, and decreases when the heart failure condition is stable. The BNP level in a person with heart failure is higher than in a person with normal heart function. Levels of BNP levels were assessed 24 hours post last morning dose of study drug for each treatment period. | Day 15 for Periods 1, 2, and 3; Day 29 for Period 4 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Fold Change From Baseline for Serum Creatinine at 24-hours Post Treatment Day 5 Morning Dose (Part 1) | Blood was collected predose on Treatment Day 1 and at 24 hours post morning dose on Treatment Day 5 to determine serum creatinine levels. Creatinine levels were log transformed and then fold change from baseline was calculated. | Baseline (predose Treatment Day 1) and 24 hours post morning dose on Treatment Day 5 of each treatment period (Part I) | 
| Area Under the Concentration-time Curve From Time Zero to 24 Hours After Dosing (AUC0-24hr) of MK-7145 (Treatment Days 1 and 5: Part 1) | Blood samples for pharmacokinetic analysis were collected on Day 4 (Treatment Day 1) through Day 8 (Treatment Day 5) at the following time points: Predose, 3, 5, 6, 8, 10, 12, 14, 18, 24 , 96, 101, 104, 106, 108, 110 and 120 hours (relative to Day 4 dosing). The AUC0-24 was calculated for Days 1 and 5 | up to 24 hours post-dose on Treatment Day 1 and Treatment Day 5 | 
| Maximum Plasma Concentration (Cmax) of MK-7145 (Treatment Days 1 and 5: Part 1) | Blood samples for pharmacokinetic analysis were collected on Treatment Day 1 through Treatment Day 5 at the following time points: Predose, 3, 5, 6, 8, 10, 12, 14, 18, 24, 96, 101, 104, 106, 108, 110 and 120 hours (relative to Treatment Day 1 dosing). The Cmax was calculated for Treatment Days 1 and 5. | Treatment Day 1 and Treatment Day 5 | 
| Trough Plasma Concentration (Ctrough) of MK-7145 (Treatment Days 1 and 5: Part 1) | Blood samples for pharmacokinetic analysis were collected on Treatment Day 1 through Treatment Day 5 at the following time points: Predose, 3, 5, 6, 8, 10, 12, 14, 18, 24 , 96 , 101, 104, 106, 108, 110 and 120 hours (relative to Treatment Day 1 dosing). The Ctrough for was calculated for Treatment Days 1 and 5 | Treatment Day 1 and Treatment Day 5 | 
| Time to Cmax (Tmax) of MK-7145(Treatment Days 1 and 5: Part 1) | Blood samples for pharmacokinetic analysis were collected on Treatment Day 1 through Treatment Day 5 at the following time points: Predose, 3, 5, 6, 8, 10, 12, 14, 18, 24, 96 , 101, 104, 106, 108, 110 and 120 hours (relative to Treatment Day 1 dosing). The time to Cmax (Tmax) calculated for Treatment Days 1 and 5 | Treatment Day 1 and Treatment Day 5 | 
| Apparent Terminal Half-life (t1/2) of MK-7145 (Part 1) | Blood samples for pharmacokinetic analysis were collected on Treatment Day 1 through Treatment Day 5 at the following time points: Predose, 3, 5, 6, 8, 10, 12, 14, 18, 24, 96, 101, 104, 106, 108, 110 and 120 hours (relative to Treatment Day 1 dosing). The t1/2 was calculated. | Treatment Day 1 and Treatment Day 5 | 
| Serum Creatinine Measured at 24 Hours Post Last Morning Dose of Each Period (Part 2) | Blood samples were collected at 24 hours post last morning dose of each period to determine serum creatinine levels | Day 15 for Periods 1, 2, and 3; Day 29 for Period 4 | 
| Area Under the Concentration-time Curve From Time Zero to 24 Hours After Dosing (AUC0-24hr) of MK-7145 (Part 2) | Blood samples taken at predose, 0.5, 1, 2, 5, 8, 12, 14 and 24 hours postdose on Days 1 and 14 of Period 2 and Day 14 of Periods 3-4 to determine the AUC0-24hr | up to 24 hours post morning dose on Days 1 and 14 of Period 2 and Day 14 of Periods 3 and 4 | 
| Maximum Plasma Concentration (Cmax) of MK-7145 (Part 2) | Blood samples taken at predose, 0.5, 1, 2, 5, 8, 12, 14 and 24 hours postdose on Days 1 and 14 of Period 2 and Day 14 of Periods 2-4 to determine the Cmax. | up to 24 hours post morning dose on up to 24 hours post morning dose on Days 1 and 14 of Period 2 and Day 14 of Periods 3 and 4 | 
| Trough Plasma Concentration (Ctrough) of MK-7145 (Part 2) | Blood samples taken at predose, 0.5, 1, 2, 5, 8, 12, 14 and 24 hours postdose on Days 1 and 14 of Period 2 and Day 14 of Periods 3 and 4 to determine the Ctrough. | up to 24 hours post morning dose on Days 1 and 14 of Period 2 and Day 14 of Periods 3 and 4 | 
| Time to Cmax (Tmax) of MK-7145(Part 2) | Blood samples taken at predose, 0.5, 1, 2, 5, 8, 12, 14 and 24 hours postdose on Days 1 and 14 of Period 2 and Day 14 of Periods 3 and 4 to determine the Tmax. | up to 24 hours post morning dose on Days 1 and 14 of Period 2 and Day 14 of Periods 3 and 4 | 
| Apparent Terminal Half-life (t1/2) of MK-7145 (Part 2) | Blood samples taken at predose, 0.5, 1, 2, 5, 8, 12, 14 and 24 hours postdose on Days 1 and 14 of Period 2 and Day 14 of Periods 3 and 4 to determine the t1/2. | up to 24 hours post morning dose on Days 1 and 14 of Period 2 and Day 14 of Periods 3 and 4 |