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

This study is currently recruiting participants. (see Contacts and Locations)
Verified November 2014 by Merck Sharp & Dohme Corp.
Sponsor:
Information provided by (Responsible Party):
Merck Sharp & Dohme Corp.
ClinicalTrials.gov Identifier:
NCT01558674
First received: March 16, 2012
Last updated: November 5, 2014
Last verified: November 2014
  Purpose

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 postdose on the last dosing day of each period) in participants with NYHA class II/III HF with moderate or severe RI.


Condition Intervention Phase
Renal Impairment
Heart Failure
Drug: MK-7145 2 mg
Drug: MK-7145 8 mg
Drug: Furosemide
Drug: Torsemide
Phase 1

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Endpoint Classification: Pharmacokinetics/Dynamics Study
Intervention Model: Single Group Assignment
Masking: 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)

Resource links provided by NLM:


Further study details as provided by Merck Sharp & Dohme Corp.:

Primary Outcome Measures:
  • Change from baseline in first 24hr UNa (Part I) [ Time Frame: Baseline (Day 3 predose) and 0-24 hours postdose on Day 4 (first day of active treatment) of each treatment period (Treatments A,B and C) ] [ Designated as safety issue: No ]
  • NT-proBNP values at 24 hours post last dose (Part II) [ Time Frame: Day 14 for Periods 1-3 (Treatments D, E, and F); Day 28 of Period 4 (Treatment G) ] [ Designated as safety issue: No ]

Secondary Outcome Measures:
  • Fold change from baseline for serum creatinine (Part I) [ Time Frame: Baseline (predose Day 4; first day of active treatment) and Day 8 of each treatment period (Part I-Treatments A,B and C) ] [ Designated as safety issue: No ]
  • Area under the concentration-time curve from time zero to 24 hours after dosing (AUC0-24hr) for MK-7145 (Part I) [ Time Frame: Day 4 (first day of active treatment) and Day 8 of Part I:Periods 1 and 3 (Treatments A, and C) ] [ Designated as safety issue: No ]
  • Maximum plasma concentration (Cmax) for MK-7145 (Part I) [ Time Frame: Day 4 (first day of active treatment) and Day 8 of Part I:Periods 1 and 3 (Treatments A, and C) ] [ Designated as safety issue: No ]
  • Trough plasma concentration (Ctrough) for MK-7145 (Part I) [ Time Frame: Day 4 (first day of active treatment) and Day 8 of Part I:Periods 1 and 3 (Treatments A, and C) ] [ Designated as safety issue: No ]
  • Time to Cmax (Tmax) for MK-7145 (Part I) [ Time Frame: Day 4 (first day of active treatment) and Day 8 of Part I:Periods 1 and 3 (Treatments A, and C) ] [ Designated as safety issue: No ]
  • Apparent terminal half-life (t1/2) for MK-7145 (Part I) [ Time Frame: Day 4 (first day of active treatment) and Day 8 of Part I:Periods 1 and 3 (Treatments A, and C) ] [ Designated as safety issue: No ]
  • Serum creatinine measured at 24 hours post last dose (Part II) [ Time Frame: Day 14 for Periods 1-3 (Treatments D, E, and F) and Day 28 of Period 4 (Treatment G) ] [ Designated as safety issue: No ]
  • Area under the concentration-time curve from time zero to 24 hours after dosing (AUC0-24hr) for MK-7145 (Part II) [ Time Frame: Day 1 of Period 2 (Treatment E) and Day 14 of Periods 2-4 (Treatments E, F, and G) ] [ Designated as safety issue: No ]
  • Maximum plasma concentration (Cmax) for MK-7145 (Part II) [ Time Frame: Day 1 of Period 2 (Treatment E) and Day 14 of Periods 2-4 (Treatments E, F, and G) ] [ Designated as safety issue: No ]
  • Trough plasma concentration (Ctrough) for MK-7145 (Part II) [ Time Frame: Day 1 of Period 2 (Treatment E) and Day 14 of Periods 2-4 (Treatments E, F, and G) ] [ Designated as safety issue: No ]
  • Time to Cmax (Tmax) for MK-7145 (Part II) [ Time Frame: Day 1 of Period 2 (Treatment E) and Day 14 of Periods 2-4 (Treatments E, F, and G) ] [ Designated as safety issue: No ]
  • Apparent terminal half-life (t1/2) for MK-7145 (Part II) [ Time Frame: Day 1 of Period 2 (Treatment E) and Day 14 of Periods 2-4 (Treatments E, F, and G) ] [ Designated as safety issue: No ]

Estimated Enrollment: 26
Study Start Date: May 2014
Estimated Study Completion Date: May 2015
Estimated Primary Completion Date: May 2015 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Treatment A (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 2 mg
Active Comparator: Treatment B (Part I:Period 2)
Two daily doses of one 40 mg Furosemide tablet for 5 days administered in a fasted state
Drug: Furosemide
Other Name: Lasix
Experimental: Treatment C (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 2 mg Drug: MK-7145 8 mg
Active Comparator: Treatment D (Part II:Period1)
Run-in of stable, clinically optimized maintenance dose regimen of furosemide or torsemide for at least 2 weeks
Drug: Furosemide
Other Name: Lasix
Drug: Torsemide
Experimental: Treatment E (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 2 mg Drug: MK-7145 8 mg
Experimental: Treatment F (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 2 mg Drug: MK-7145 8 mg
Experimental: Treatment G (Part II:Period 4)
Single dose of 24 mg MK-7145 for 28 days, capsules, orally administered in a fasted state
Drug: MK-7145 2 mg Drug: MK-7145 8 mg

  Eligibility

Ages Eligible for Study:   18 Years to 75 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

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
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01558674

Contacts
Contact: Toll Free Number 1-888-577-8839

Locations
Australia
Merck Sharp & Dohme Recruiting
North Ryde, Australia
Contact: Gary Jankelowitz    61 2 8988 8246      
New Zealand
Merck Sharp & Dohme (New Zealand) Ltd., Recruiting
Wellington, New Zealand
Contact: Gary Jankelowitz    61 2 8988 8246      
Sponsors and Collaborators
Merck Sharp & Dohme Corp.
Investigators
Study Director: Medical Director Merck Sharp & Dohme Corp.
  More Information

No publications provided

Responsible Party: Merck Sharp & Dohme Corp.
ClinicalTrials.gov Identifier: NCT01558674     History of Changes
Other Study ID Numbers: 7145-011
Study First Received: March 16, 2012
Last Updated: November 5, 2014
Health Authority: Australia: Department of Health and Ageing Therapeutic Goods Administration

Additional relevant MeSH terms:
Heart Failure
Renal Insufficiency
Cardiovascular Diseases
Heart Diseases
Kidney Diseases
Urologic Diseases
Furosemide
Torsemide
Antihypertensive Agents
Cardiovascular Agents
Diuretics
Membrane Transport Modulators
Molecular Mechanisms of Pharmacological Action
Natriuretic Agents
Pharmacologic Actions
Physiological Effects of Drugs
Sodium Potassium Chloride Symporter Inhibitors
Therapeutic Uses

ClinicalTrials.gov processed this record on November 25, 2014