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

• Sponsor: Merck Sharp & Dohme LLC (Industry)
• Overall Status: Terminated
• CT.gov ID: NCT01558674
• Collaborator: (none)
• Enrollment: 11
• Arms: 7
• Actual Duration (Months): 6.8

Study Details

Study Description

Brief Summary

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.

Condition or Disease	Intervention/Treatment	Phase
Renal Impairment; Heart Failure	Drug: MK-7145; Drug: Furosemide; Drug: Torsemide	Phase 1

Study Design

• Study Type: Interventional
• Actual Enrollment: 11 participants
• Allocation: Non-Randomized
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: 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)
• Actual Study Start Date: May 23, 2014
• Actual Primary Completion Date: Dec 17, 2014
• Actual Study Completion Date: Dec 17, 2014

Arms and Interventions

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

Outcome Measures

Primary Outcome Measures

1. Change From Baseline in First 24hr Urinary Sodium (UNa) (Part 1) [Baseline (Day -1) and 0-24 hours postdose on Treatment Day 1 of each treatment period]

   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.

2. N-terminal Pro B-type Natriuretic Peptide (NT-proBNP) Values at 24 Hours Post Last Morning Dose of Each Period (Part 2) [Day 15 for Periods 1, 2, and 3; Day 29 for Period 4]

   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.

Secondary Outcome Measures

1. Fold Change From Baseline for Serum Creatinine at 24-hours Post Treatment Day 5 Morning Dose (Part 1) [Baseline (predose Treatment Day 1) and 24 hours post morning dose on Treatment Day 5 of each treatment period (Part I)]

   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.

2. 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) [up to 24 hours post-dose on Treatment Day 1 and Treatment Day 5]

   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

3. Maximum Plasma Concentration (Cmax) of MK-7145 (Treatment Days 1 and 5: Part 1) [Treatment Day 1 and Treatment Day 5]

   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.

4. Trough Plasma Concentration (Ctrough) of MK-7145 (Treatment Days 1 and 5: Part 1) [Treatment Day 1 and Treatment Day 5]

   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

5. Time to Cmax (Tmax) of MK-7145(Treatment Days 1 and 5: Part 1) [Treatment Day 1 and Treatment Day 5]

   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

6. Apparent Terminal Half-life (t1/2) of MK-7145 (Part 1) [Treatment Day 1 and Treatment Day 5]

   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.

7. Serum Creatinine Measured at 24 Hours Post Last Morning Dose of Each Period (Part 2) [Day 15 for Periods 1, 2, and 3; Day 29 for Period 4]

   Blood samples were collected at 24 hours post last morning dose of each period to determine serum creatinine levels

8. Area Under the Concentration-time Curve From Time Zero to 24 Hours After Dosing (AUC0-24hr) of MK-7145 (Part 2) [up to 24 hours post morning dose on Days 1 and 14 of Period 2 and Day 14 of Periods 3 and 4]

   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

9. Maximum Plasma Concentration (Cmax) of MK-7145 (Part 2) [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]

   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.

10. Trough Plasma Concentration (Ctrough) of MK-7145 (Part 2) [up to 24 hours post morning dose on Days 1 and 14 of Period 2 and Day 14 of Periods 3 and 4]

    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.

11. Time to Cmax (Tmax) of MK-7145(Part 2) [up to 24 hours post morning dose on Days 1 and 14 of Period 2 and Day 14 of Periods 3 and 4]

    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.

12. Apparent Terminal Half-life (t1/2) of MK-7145 (Part 2) [up to 24 hours post morning dose on Days 1 and 14 of Period 2 and Day 14 of Periods 3 and 4]

    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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 75 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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

Contacts and Locations

Locations

No locations specified.

Sponsors and Collaborators

• Merck Sharp & Dohme LLC

Investigators

• Study Director: Medical Director, Merck Sharp & Dohme LLC

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Merck Sharp & Dohme LLC
• ClinicalTrials.gov Identifier: NCT01558674
• Other Study ID Numbers: 7145-011
• First Posted: Mar 20, 2012
• Last Update Posted: Sep 21, 2018
• Last Verified: Aug 1, 2018

• Individual Participant Data (IPD) Sharing Statement: Yes
• Plan to Share IPD: Yes
• Additional relevant MeSH terms: Renal Insufficiency; Heart Failure; Torsemide; Furosemide

Study Results

Participant Flow

Pre-assignment Detail	Study was terminated early due to lack of efficacy of MK-7145. Only 11 participants were enrolled and dosed in Part 1. Period 3 of Part 1 was not conducted. No participants were enrolled in the planned Part 2 of the study.

Arm/Group Title	MK-7145 8 mg→Furosemide 40 mg 2 x Day (BID)→ MK-7145 16 mg	Furosemide/Torsemide→MK-7145 10 mg→MK-7145 16 mg→MK-7145 24 mg
Arm/Group Description	Part 1: Participants receive 8 mg MK-7145 once daily (QD) for 5 days, then furosemide 40 mg BID for 5 days and then 16 mg MK-7145 QD for 5 days. Each treatment period was separated by a 3-day wash-out.	Part 2: Participants receive Furosemide/Torsemide for 2 weeks , then 10 mg MK-7145 for 14 days, then MK-7145 16 mg for 14 days and then MK-7145 24 mg for 28 days. Each treatment period was separated by a 3-day wash-out.
Period Title: Part 1
STARTED	11	0
COMPLETED	0	0
NOT COMPLETED	11	0
Period Title: Part 1
STARTED	0	0
COMPLETED	0	0
NOT COMPLETED	0	0

Baseline Characteristics

Arm/Group Title	MK-7145 8 mg→Furosemide 40 mg 2 x Day (BID)→ MK-7145 16 mg	Furosemide/Torsemide→MK-7145 10 mg→MK-7145 16 mg→MK-7145 24 mg	Total
Arm/Group Description	Part 1: Participants receive 8 mg MK-7145 once daily (QD) for 5 days, then furosemide 40 mg BID for 5 days and then 16 mg MK-7145 QD for 5 days. Each treatment period was separated by a 3-day wash-out.	Part 2: Participants receive Furosemide/Torsemide for 2 weeks , then 10 mg MK-7145 for 14 days, then MK-7145 16 mg for 14 days and then MK-7145 24 mg for 28 days. Each treatment period was separated by a 3-day wash-out.	Total of all reporting groups
Overall Participants	11	0	11
Age (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]	61.4 (16.0)	61.4 (16.0)
Sex: Female, Male (Count of Participants)
Female	3 27.3%	3 Infinity
Male	8 72.7%	8 Infinity

Outcome Measures

1. Primary Outcome

Title	Change From Baseline in First 24hr Urinary Sodium (UNa) (Part 1)
Description	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.
Time Frame	Baseline (Day -1) and 0-24 hours postdose on Treatment Day 1 of each treatment period

Outcome Measure Data

Analysis Population Description

All participants who received at least 1 dose of study drug and who complied with the protocol sufficiently. One participant did not participate for several time intervals on Period 2: Day 8 due to being unwell, and data from this day of this participant were excluded from the analysis. Part 1: Period 3 was not conducted.

Arm/Group Title	MK-7145 8 mg (Part 1: Period 1)	Furosemide 40 mg BID (Part 1: Period 2)	MK-7145 16 mg (Part 1: Period 3)
Arm/Group Description	8 mg MK-7145 QD for 5 days, capsules, orally administered in a fasted state	40 mg Furosemide tablet BID for 5 days administered in a fasted state	16 mg MK-7145 QD for 5 days, capsules, orally administered in a fasted state
Measure Participants	11	10	0
Least Squares Mean (95% Confidence Interval) [mEq]	11.0	109.5

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	MK-7145 8 mg (Part 1: Period 1), Furosemide 40 mg BID (Part 1: Period 2)
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Difference in Least Squares (LS) Means
	Estimated Value	-98.5
	Confidence Interval	(2-Sided) 95%; -138.0 to -59.1
	Parameter Dispersion	Type: Value:
	Estimation Comments	8-mg MK-7145 LS Mean minus Furosemide LS Mean

2. Primary Outcome

Title	N-terminal Pro B-type Natriuretic Peptide (NT-proBNP) Values at 24 Hours Post Last Morning Dose of Each Period (Part 2)
Description	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.
Time Frame	Day 15 for Periods 1, 2, and 3; Day 29 for Period 4

Outcome Measure Data

Analysis Population Description

Part 2 of the study was not conducted. No participants were enrolled.

Arm/Group Title	Furosemide/Torsemide (Part 2; Period 1)	MK-7145 10 mg (Part 2: Period 2)	MK-7145 16 mg (Part 2: Period 3)	MK-7145 24 mg (Part 2: Period 4)
Arm/Group Description	Stable, clinically optimized maintenance dose regimen of furosemide or torsemide for at least 2 weeks.	10 mg of MK-7145 once daily for 14 days	14 mg of MK-7145 once daily for 14 days	24 mg of MK-7145 once daily for 28 days
Measure Participants	0	0	0	0

3. Secondary Outcome

Title	Fold Change From Baseline for Serum Creatinine at 24-hours Post Treatment Day 5 Morning Dose (Part 1)
Description	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.
Time Frame	Baseline (predose Treatment Day 1) and 24 hours post morning dose on Treatment Day 5 of each treatment period (Part I)

Outcome Measure Data

Analysis Population Description

All participants who received at least 1 dose of study drug , who complied with the protocol sufficiently and had data available for endpoint. Part 1: Period 3 was not conducted.

Arm/Group Title	MK-7145 8 mg (Part 1: Period 1)	Furosemide 40 mg BID (Part 1: Period 2)	MK-7145 16 mg (Part I:Period 3)
Arm/Group Description	8 mg MK-7145 QD for 5 days, capsules, orally administered in a fasted state	40 mg Furosemide tablet BID for 5 days administered in a fasted state	16 mg MK-7145 QD for 5 days, capsules, orally administered in a fasted state
Measure Participants	11	10	0
Geometric Mean (95% Confidence Interval) [mg/dL]	1.30	1.18

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	MK-7145 8 mg (Part 1: Period 1), Furosemide 40 mg BID (Part 1: Period 2)
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Geometric Mean Ratio (GMR)
	Estimated Value	1.10
	Confidence Interval	(2-Sided) 90%; 0.99 to 1.22
	Parameter Dispersion	Type: Value:
	Estimation Comments	GMR = Geometric mean (GM) MK-7145 8 mg divided by GM Furosemide

4. Secondary Outcome

Title	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)
Description	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
Time Frame	up to 24 hours post-dose on Treatment Day 1 and Treatment Day 5

Outcome Measure Data

Analysis Population Description

All participants who received at least 1 dose of MK-7145, who complied with the protocol sufficiently and had data available for endpoint. Part 1: Period 3 was not conducted

Arm/Group Title	MK-7145 8 mg (Part 1: Period 1)	MK-7145 16 mg (Part I:Period 3)
Arm/Group Description	8 mg MK-7145 QD for 5 days, capsules, orally administered in a fasted state	16 mg MK-7145 QD for 5 days, capsules, orally administered in a fasted state
Measure Participants	11	0
Treatment Day 1	158 (49.2)
Treatment Day 5	485 (50.4)

5. Secondary Outcome

Title	Maximum Plasma Concentration (Cmax) of MK-7145 (Treatment Days 1 and 5: Part 1)
Description	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.
Time Frame	Treatment Day 1 and Treatment Day 5

Outcome Measure Data

Analysis Population Description

All participants who received at least 1 dose of MK-7145, who complied with the protocol sufficiently and had data available for endpoint. Part 1: Period 3 was not conducted

Arm/Group Title	MK-7145 8 mg (Part 1: Period 1)	MK-7145 16 mg (Part I:Period 3)
Arm/Group Description	8 mg MK-7145 QD for 5 days, capsules, orally administered in a fasted state	16 mg MK-7145 QD for 5 days, capsules, orally administered in a fasted state
Measure Participants	11	0
Treatment Day 1	10.2 (57.9)
Treatment Day 5	26.0 (50.3)

6. Secondary Outcome

Title	Trough Plasma Concentration (Ctrough) of MK-7145 (Treatment Days 1 and 5: Part 1)
Description	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
Time Frame	Treatment Day 1 and Treatment Day 5

Outcome Measure Data

Analysis Population Description

All participants who received at least 1 dose of MK-7145, who complied with the protocol sufficiently and had data available for endpoint. Ctrough for MK-7145 8 mg arm could not be estimated due to insufficient terminal phase sample. Part 1: Period 3 was not conducted.

Arm/Group Title	MK-7145 8 mg (Part 1: Period 1)	MK-7145 16 mg (Part I:Period 3)
Arm/Group Description	8 mg MK-7145 QD for 5 days, capsules, orally administered in a fasted state	16 mg MK-7145 QD for 5 days, capsules, orally administered in a fasted state
Measure Participants	11	0
Treatment Day 1	NA (NA)
Treatment Day 5	NA (NA)

7. Secondary Outcome

Title	Time to Cmax (Tmax) of MK-7145(Treatment Days 1 and 5: Part 1)
Description	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
Time Frame	Treatment Day 1 and Treatment Day 5

Outcome Measure Data

Analysis Population Description

All participants who received at least 1 dose of MK-7145 who complied with the protocol sufficiently and had data available for endpoint. Part 1: Period 3 was not conducted.

Arm/Group Title	MK-7145 8 mg (Part 1: Period 1)	MK-7145 16 mg (Part I:Period 3)
Arm/Group Description	8 mg MK-7145 QD for 5 days, capsules, orally administered in a fasted state	16 mg MK-7145 QD for 5 days, capsules, orally administered in a fasted state
Measure Participants	11	0
Treatment Day 1	10.0
Treatment Day 5	5.0

8. Secondary Outcome

Title	Apparent Terminal Half-life (t1/2) of MK-7145 (Part 1)
Description	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.
Time Frame	Treatment Day 1 and Treatment Day 5

Outcome Measure Data

Analysis Population Description

All participants who received at least 1 dose of MK-7145 and who complied with the protocol sufficiently and had data available for endpoint. t1/2 could not be estimated due to insufficient terminal phase sample. Part 1: Period 3 was not conducted.

Arm/Group Title	MK-7145 8 mg (Part 1: Period 1)	MK-7145 16 mg (Part I:Period 3)
Arm/Group Description	8 mg MK-7145 QD for 5 days, capsules, orally administered in a fasted state	16 mg MK-7145 QD for 5 days, capsules, orally administered in a fasted state
Measure Participants	11	0
Treatment Day 1	NA
Treatment Day 5	NA

9. Secondary Outcome

Title	Serum Creatinine Measured at 24 Hours Post Last Morning Dose of Each Period (Part 2)
Description	Blood samples were collected at 24 hours post last morning dose of each period to determine serum creatinine levels
Time Frame	Day 15 for Periods 1, 2, and 3; Day 29 for Period 4

Outcome Measure Data

Analysis Population Description

No participants were enrolled in Part 2 of the study.

Arm/Group Title	Furosemide/Torsemide (Part 2; Period 1)	MK-7145 10 mg (Part 2:Period 2)	MK-7145 16 mg (Part 2: Period 3)	MK-7145 24 mg (Part 2: Period 4)
Arm/Group Description	Stable, clinically optimized maintenance dose regimen of furosemide or torsemide for at least 2 weeks.	10 mg of MK-7145 once daily for 14 days	14 mg of MK-7145 once daily for 14 days	24 mg of MK-7145 once daily for 28 days
Measure Participants	0	0	0	0

10. Secondary Outcome

Title	Area Under the Concentration-time Curve From Time Zero to 24 Hours After Dosing (AUC0-24hr) of MK-7145 (Part 2)
Description	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
Time Frame	up to 24 hours post morning dose on Days 1 and 14 of Period 2 and Day 14 of Periods 3 and 4

Outcome Measure Data

Analysis Population Description

No participants were enrolled in Part 2 of the study.

Arm/Group Title	MK-7145 10 mg (Part 2: Period 2)	MK-7145 16 mg (Part 2: Period 3)	MK-7145 24 mg (Part 2: Period 4)
Arm/Group Description	10 mg of MK-7145 once daily for 14 days	14 mg of MK-7145 once daily for 14 days	24 mg of MK-7145 once daily for 28 days
Measure Participants	0	0	0

11. Secondary Outcome

Title	Maximum Plasma Concentration (Cmax) of MK-7145 (Part 2)
Description	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.
Time Frame	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

Outcome Measure Data

Analysis Population Description

No participants were enrolled in Part 2 of the study.

Arm/Group Title	MK-7145 10 mg (Part 2: Period 2)	MK-7145 16 mg (Part 2: Period 3)	MK-7145 24 mg (Part 2: Period 4)
Arm/Group Description	10 mg of MK-7145 once daily for 14 days	14 mg of MK-7145 once daily for 14 days	24 mg of MK-7145 once daily for 28 days
Measure Participants	0	0	0

12. Secondary Outcome

Title	Trough Plasma Concentration (Ctrough) of MK-7145 (Part 2)
Description	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.
Time Frame	up to 24 hours post morning dose on Days 1 and 14 of Period 2 and Day 14 of Periods 3 and 4

Outcome Measure Data

Analysis Population Description

No participants were enrolled in Part 2 of the study.

Arm/Group Title	MK-7145 10 mg (Part 2: Period 2)	MK-7145 16 mg	MK-7145 24 mg (Part 2: Period 4)
Arm/Group Description	10 mg of MK-7145 once daily for 14 days	14 mg of MK-7145 once daily for 14 days	24 mg of MK-7145 once daily for 28 days
Measure Participants	0	0	0

13. Secondary Outcome

Title	Time to Cmax (Tmax) of MK-7145(Part 2)
Description	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.
Time Frame	up to 24 hours post morning dose on Days 1 and 14 of Period 2 and Day 14 of Periods 3 and 4

Outcome Measure Data

Analysis Population Description

No participants were enrolled in Part 2 of the study.

Arm/Group Title	MK-7145 10 mg (Part 2: Period 2)	MK-7145 16 mg	MK-7145 24 mg (Part 2: Period 4)
Arm/Group Description	10 mg of MK-7145 once daily for 14 days	14 mg of MK-7145 once daily for 14 days	24 mg of MK-7145 once daily for 28 days
Measure Participants	0	0	0

14. Secondary Outcome

Title	Apparent Terminal Half-life (t1/2) of MK-7145 (Part 2)
Description	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.
Time Frame	up to 24 hours post morning dose on Days 1 and 14 of Period 2 and Day 14 of Periods 3 and 4

Outcome Measure Data

Analysis Population Description

No participants were enrolled in Part 2 of the study.

Arm/Group Title	MK-7145 10 mg (Part 2: Period 2)	MK-7145 16 mg (Part 2: Period 3)	MK-7145 24 mg (Part 2: Period 4)
Arm/Group Description	10 mg of MK-7145 once daily for 14 days	14 mg of MK-7145 once daily for 14 days	24 mg of MK-7145 once daily for 28 days
Measure Participants	0	0	0

Adverse Events

Time Frame	Up to 33 days for each treatment period (Period 1includes a break of up to 25 days between Periods 1 and 2; Period 2 includes 14 days post last dose in Period 2). Post-trial period includes time from 14 days post last dose to last reported AE (~ 90 days)
Adverse Event Reporting Description	Population includes all participants who received at least one dose of the study drug. Adverse events (AEs) for the treatment period are reported by study drug taken during the active treatment periods. AEs for the post trial period are reported as one group. Part 1: Period 3 and Part 2: All periods were not conducted.
Arm/Group Title	MK-7145 8 mg (Part 1:Period 1)		Furosemide 40 mg (Part 1:Period 2)		Post Trial
Arm/Group Description	Single daily dose of 8 mg MK-7145 for 5 days, capsules, orally administered in a fasted state		Two daily doses of one 40 mg Furosemide tablet for 5 days administered in a fasted state		Participants who received at least one dose of study drug during Period 1 or 2 of Part 1 of the study
All Cause Mortality
	MK-7145 8 mg (Part 1:Period 1)		Furosemide 40 mg (Part 1:Period 2)		Post Trial
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	MK-7145 8 mg (Part 1:Period 1)		Furosemide 40 mg (Part 1:Period 2)		Post Trial
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/11 (0%)		0/10 (0%)		1/11 (9.1%)
Infections and infestations
Septic shock	0/11 (0%)	0	0/10 (0%)	0	1/11 (9.1%)	1
Renal and urinary disorders
Nephrolithiasis	0/11 (0%)	0	0/10 (0%)	0	1/11 (9.1%)	1
Other (Not Including Serious) Adverse Events
	MK-7145 8 mg (Part 1:Period 1)		Furosemide 40 mg (Part 1:Period 2)		Post Trial
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	10/11 (90.9%)		5/10 (50%)		3/11 (27.3%)
Gastrointestinal disorders
Nausea	0/11 (0%)	0	2/10 (20%)	2	0/11 (0%)	0
Rectal haemorrhage	0/11 (0%)	0	1/10 (10%)	1	0/11 (0%)	0
Vomiting	1/11 (9.1%)	1	0/10 (0%)	0	0/11 (0%)	0
General disorders
Application site inflammation	0/11 (0%)	0	1/10 (10%)	1	0/11 (0%)	0
Catheter site bruise	1/11 (9.1%)	1	0/10 (0%)	0	0/11 (0%)	0
Catheter site swelling	2/11 (18.2%)	2	0/10 (0%)	0	0/11 (0%)	0
Chest pain	1/11 (9.1%)	1	0/10 (0%)	0	0/11 (0%)	0
Fatigue	1/11 (9.1%)	1	0/10 (0%)	0	0/11 (0%)	0
Infections and infestations
Upper respiratory tract infection	1/11 (9.1%)	1	0/10 (0%)	0	0/11 (0%)	0
Injury, poisoning and procedural complications
Contusion	1/11 (9.1%)	1	0/10 (0%)	0	0/11 (0%)	0
Ligament sprain	0/11 (0%)	0	0/10 (0%)	0	1/11 (9.1%)	1
Metabolism and nutrition disorders
Gout	2/11 (18.2%)	2	0/10 (0%)	0	0/11 (0%)	0
Hyponatraemia	1/11 (9.1%)	1	0/10 (0%)	0	0/11 (0%)	0
Musculoskeletal and connective tissue disorders
Back pain	0/11 (0%)	0	1/10 (10%)	1	1/11 (9.1%)	1
Muscle spasms	1/11 (9.1%)	1	0/10 (0%)	0	0/11 (0%)	0
Neck pain	0/11 (0%)	0	0/10 (0%)	0	1/11 (9.1%)	1
Nervous system disorders
Dizziness	0/11 (0%)	0	1/10 (10%)	1	0/11 (0%)	0
Dizziness postural	2/11 (18.2%)	2	0/10 (0%)	0	0/11 (0%)	0
Headache	4/11 (36.4%)	4	1/10 (10%)	1	0/11 (0%)	0
Lethargy	0/11 (0%)	0	1/10 (10%)	1	0/11 (0%)	0
Paraesthesia	1/11 (9.1%)	1	0/10 (0%)	0	0/11 (0%)	0
Psychiatric disorders
Abnormal dreams	1/11 (9.1%)	1	1/10 (10%)	1	0/11 (0%)	0
Renal and urinary disorders
Renal failure acute	3/11 (27.3%)	3	0/10 (0%)	0	0/11 (0%)	0
Respiratory, thoracic and mediastinal disorders
Cough	1/11 (9.1%)	1	0/10 (0%)	0	0/11 (0%)	0
Epistaxis	0/11 (0%)	0	1/10 (10%)	1	0/11 (0%)	0
Skin and subcutaneous tissue disorders
Xeroderma	1/11 (9.1%)	1	0/10 (0%)	0	0/11 (0%)	0
Vascular disorders
Orthostatic hypotension	1/11 (9.1%)	2	1/10 (10%)	1	0/11 (0%)	0

Limitations/Caveats

Study terminated early due to lack of efficacy.

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The Sponsor must have the opportunity to review all proposed abstracts, manuscripts, or presentations regarding this study 60 days prior to submission for publication/presentation. Any information identified by the Sponsor as confidential must be deleted prior to submission. Sponsor review can be expedited to meet publication timelines.