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Renal ImpairmentPhase 1NCT01558674

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

A Phase 1 study testing MK-7145, Furosemide and Torsemide in people with Renal Impairment and Heart Failure, run by Merck Sharp & Dohme LLC.

Terminated

Stopped early. The study ended before it was planned to and will not resume.

Official record
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Trial 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). Read more about this study

Who is it for?
Ages 18 to 75 years
Conditions the study is for
Renal Impairment, Heart Failure
What is being tested?
MK-7145, Furosemide and Torsemide
Type of treatment
Pill or oral medicine
Could I receive a placebo?
No, everyone receives an active treatment
How many people
11 participants
Where
No sites listed yet
Study dates
23 May 2014to 17 Dec 2014
Phase
Phase 1
Are there results?
Yes, posted in the registrySummary in the doctors' view

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 to 75 years
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • 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
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  • 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

Who cannot join

  • 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
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  • 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

About this study

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)

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.

Being tested
MK-7145, Furosemide, Torsemide
Medical subject headings
Renal Insufficiency, Heart Failure

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • MK-7145Drug

  • FurosemideDrug

    Also called Lasix

  • TorsemideDrug

Study groups in NCT01558674
Study groupRoleWhat they receive
MK-7145 8 mg (Part I:Period 1)ExperimentalSingle daily dose of 8 mg MK-7145 for 5 days, capsules, orally administered in a fasted state
Receives: Drug: MK-7145
Furosemide 40 mg (Part I:Period 2)Active comparatorTwo daily doses of one 40 mg Furosemide tablet for 5 days administered in a fasted state
Receives: Drug: Furosemide
MK-7145 16 mg (Part I:Period 3)ExperimentalSingle daily dose of 16 mg MK-7145 for 5 days, capsules, orally administered in a fasted state
Receives: Drug: MK-7145
Furosemide/Torsemide Run-in (Part II:Period1)Active comparatorRun-in of stable, clinically optimized maintenance dose regimen of furosemide or torsemide for at least 2 weeks
Receives: Drug: Furosemide; Drug: Torsemide
MK-7145 10 mg (Part II:Period 2)ExperimentalSingle daily dose of 10 mg MK-7145 for 14 days, capsules, orally administered in a fasted state
Receives: Drug: MK-7145
MK-7145 16 mg (Part II:Period 3)ExperimentalSingle daily dose of 16 mg MK-7145 for 14 days, capsules, orally administered in a fasted state
Receives: Drug: MK-7145
MK-7145 24 mg (Part II:Period 4)ExperimentalSingle dose of 24 mg MK-7145 for 28 days, capsules, orally administered in a fasted state
Receives: Drug: MK-7145

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. 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.

    Measured: Baseline (Day -1) and 0-24 hours postdose on Treatment Day 1 of each treatment period

  2. 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.

    Measured: Day 15 for Periods 1, 2, and 3; Day 29 for Period 4

Secondary outcomes (12)

  1. 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.

    Measured: Baseline (predose Treatment Day 1) and 24 hours post morning dose on Treatment Day 5 of each treatment period (Part I)

  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)

    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

    Measured: up to 24 hours post-dose on Treatment Day 1 and Treatment Day 5

  3. 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.

    Measured: Treatment Day 1 and Treatment Day 5

  4. 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

    Measured: Treatment Day 1 and Treatment Day 5

  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

    Measured: Treatment Day 1 and Treatment Day 5

  6. 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.

    Measured: Treatment Day 1 and Treatment Day 5

  7. 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

    Measured: Day 15 for Periods 1, 2, and 3; Day 29 for Period 4

  8. 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

    Measured: up to 24 hours post morning dose on Days 1 and 14 of Period 2 and Day 14 of Periods 3 and 4

  9. 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.

    Measured: 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

  10. 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.

    Measured: up to 24 hours post morning dose on Days 1 and 14 of Period 2 and Day 14 of Periods 3 and 4

  11. 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.

    Measured: up to 24 hours post morning dose on Days 1 and 14 of Period 2 and Day 14 of Periods 3 and 4

  12. 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.

    Measured: up to 24 hours post morning dose on Days 1 and 14 of Period 2 and Day 14 of Periods 3 and 4

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted20 Mar 2012 (estimated)
  2. Study start23 May 2014
  3. Primary completion17 Dec 2014
  4. Study completion17 Dec 2014

Why it stopped: Lack of efficacy

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 1
Primary purpose
Treatment
Allocation
Non-randomised
Intervention model
Single group
Masking
None (open label)
Enrolment
11 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT01558674
Sponsor's protocol ID
7145-011
Status last verified
Aug 2018
First submitted
16 Mar 2012
Last updated
21 Sep 2018
Data monitoring committee
Yes
Individual data sharing
Yes: https://www.merck.com/clinical-trials/pdf/ProcedureAccessClinicalTrialData.pdf

Questions about this trial

What is this clinical trial studying?

A Phase 1 study testing MK-7145, Furosemide and Torsemide in people with Renal Impairment and Heart Failure, run by Merck Sharp & Dohme LLC.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 10 inclusion and 17 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: stopped early, as of the sponsor's last update on 21 Sep 2018. Status can change between updates, so confirm with the study contact before making plans.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

Yes. Results are posted in the registry (first posted 3 Mar 2017). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Change From Baseline in First 24hr Urinary Sodium (UNa) (Part 1) (time frame: Baseline (Day -1) and 0-24 hours postdose on Treatment Day 1 of each treatment period). The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT01558674.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 21 Sep 2018.

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