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

NCT01558674 | Terminated Phase 1 Results DMC

• 1 other identifier: 7145-011
• Study Type: interventional
• Target: 11
• Locations: 0 countries
• Sites: N/A

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.

Conditions

Renal Impairment; Heart Failure

Outcome Measures

Primary Outcomes (2)

• 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 Outcomes (12)

• 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)

• 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

• Maximum Plasma Concentration (Cmax) of MK-7145 (Treatment Days 1 and 5: Part 1)

  Treatment Day 1 and Treatment Day 5

• Trough Plasma Concentration (Ctrough) of MK-7145 (Treatment Days 1 and 5: Part 1)

  Treatment Day 1 and Treatment Day 5

• Time to Cmax (Tmax) of MK-7145(Treatment Days 1 and 5: Part 1)

  Treatment Day 1 and Treatment Day 5

Study Arms (7)

MK-7145 8 mg (Part I:Period 1)

EXPERIMENTAL

Single daily dose of 8 mg MK-7145 for 5 days, capsules, orally administered in a fasted state

Drug: MK-7145

Furosemide 40 mg (Part I:Period 2)

ACTIVE COMPARATOR

Two daily doses of one 40 mg Furosemide tablet for 5 days administered in a fasted state

Drug: Furosemide

MK-7145 16 mg (Part I:Period 3)

EXPERIMENTAL

Single daily dose of 16 mg MK-7145 for 5 days, capsules, orally administered in a fasted state

Drug: MK-7145

Furosemide/Torsemide Run-in (Part II:Period1)

ACTIVE COMPARATOR

Run-in of stable, clinically optimized maintenance dose regimen of furosemide or torsemide for at least 2 weeks

Drug: Furosemide; Drug: Torsemide

MK-7145 10 mg (Part II:Period 2)

EXPERIMENTAL

Single daily dose of 10 mg MK-7145 for 14 days, capsules, orally administered in a fasted state

Drug: MK-7145

MK-7145 16 mg (Part II:Period 3)

EXPERIMENTAL

Single daily dose of 16 mg MK-7145 for 14 days, capsules, orally administered in a fasted state

Drug: MK-7145

MK-7145 24 mg (Part II:Period 4)

EXPERIMENTAL

Single dose of 24 mg MK-7145 for 28 days, capsules, orally administered in a fasted state

Drug: MK-7145

Interventions

MK-7145 DRUG

MK-7145 10 mg (Part II:Period 2); MK-7145 16 mg (Part I:Period 3); MK-7145 16 mg (Part II:Period 3); MK-7145 24 mg (Part II:Period 4); MK-7145 8 mg (Part I:Period 1)

Furosemide DRUG

Also known as: Lasix

Furosemide 40 mg (Part I:Period 2); Furosemide/Torsemide Run-in (Part II:Period1)

Torsemide DRUG

Furosemide/Torsemide Run-in (Part II:Period1)

Eligibility Criteria

• Age: 18 Years - 75 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• Merck Sharp & Dohme LLC: lead

MeSH Terms

Conditions

Renal Insufficiency; Heart Failure

Interventions

MK-7145; Furosemide; Torsemide

Condition Hierarchy (Ancestors)

Kidney Diseases; Urologic Diseases; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Male Urogenital Diseases; Heart Diseases; Cardiovascular Diseases

Intervention Hierarchy (Ancestors)

Sulfanilamides; Sulfonamides; Amides; Organic Chemicals; Aniline Compounds; Amines; Sulfones; Sulfur Compounds; Pyridines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds

Limitations and Caveats

Study terminated early due to lack of efficacy.

Results Point of Contact

• Title: Senior Vice President, Global Clinical Development
• Organization: Merck Sharp & Dohme Corp.

ClinicalTrialsDisclosure@merck.com

1-800-672-6372

Study Officials

• Medical Director

  Merck Sharp & Dohme LLC

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: March 16, 2012
• First Posted: March 20, 2012
• Study Start: May 23, 2014
• Primary Completion: December 17, 2014
• Study Completion: December 17, 2014
• Last Updated: September 21, 2018
• Results First Posted: March 3, 2017

Record last verified: 2018-08

Data Sharing

• IPD Sharing: Will share