Clinical trial NCT03873038: Safety and Pharmacokinetics of MK-2060 in Older Participants With End-Stage Renal Disease on Hemodialysis (MK-2060-004)
Official title: Single and Multiple Dose Clinical Trial to Study the Safety and Pharmacokinetics of MK-2060 in Older Participants With End-Stage Renal Disease on Hemodialysis
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Renal Dialysis
Kidney Failure, Chronic
Lead sponsor: Merck Sharp & Dohme LLC
Sponsor class: INDUSTRY
First posted: 2019-03-13
Enrollment: 38
Sex: ALL
Minimum age (years): 18
Maximum age (years): 80
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: SEQUENTIAL
Primary purpose: TREATMENT

Brief summary: The purpose of this study is to evaluate the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of MK-2060 after intravenous (IV) administration of single and multiple doses in older adult participants with end-stage renal disease (ESRD) on hemodialysis (HD).


Eligibility criteria: Inclusion Criteria:

* Male or female, of non-child bearing potential (WONCBP) age ≥40 and ≤80 years for Part 1 and ≥18 and ≤80 years for Part 2.
* End-stage renal disease (ESRD) maintained on stable outpatient hemodialysis (HD) regimen, using an established (\> 3 months) and normally functioning, regular flow, uninfected mature arteriovenous (AV) fistula or AV graft and skin consistent with standard chronic HD access injuries, and HD stability defined as (\[K, dialyzer clearance, multiplied by t, time, divided by V, patient's total body water\] Kt/V) ≥ 1.2 within 3 months prior to dosing at a healthcare center for \> 3 months from dosing.
* On HD regimen at least 3 times per week for a minimum of 3 hours per dialysis session, using a complication-free well-maintained AV fistula or AV graft, expected and plan to continue this throughout and for at least 3 months beyond the study.
* Has a Body Mass Index (BMI) ≥ 18 and ≤ 45 kg/m\^2, BMI = weight (kg)/height (m)\^2.
* Baseline health is judged to be stable based on medical history, physical examination, vital sign measurements and electrocardiogram (ECG) performed prior to randomization.
* Liver function test (serum alanine aminotransferase \[ALT\] and aspartate aminotransferase \[AST\]) must be equal to or below 1.5X upper limit of normal (ULN) and deemed not clinically significant by both the investigator and the Sponsor.
* Contraceptive use by men should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies by agreeing to use a male condom plus partner use of an additional contraceptive method when having penile-vaginal intercourse with a woman of childbearing potential (WOCBP) who is not currently pregnant. Also, men with a pregnant or breastfeeding partner must agree to remain abstinent from penile-vaginal intercourse or use a male condom during each episode of penile-vaginal penetration.
* Contraceptive use by women should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies in that a female participant is eligible to participate if she is not pregnant or breastfeeding and she is not a WOCBP in that she is a postmenopausal female without menses for at least 1 year OR is a surgically sterile female, post hysterectomy, bilateral salpingectomy, oophorectomy or tubal ligation.

Exclusion Criteria:

* Has a history of any clinically significant concomitant disease or condition (including treatment for such conditions) or diseases whose current condition is considered clinically unstable that, in the opinion of the investigator, could either interfere with the study drug, compromise interpretation of study data, or pose an unacceptable risk. Participants with a remote history of uncomplicated medical events (e.g., uncomplicated kidney stones, as defined as spontaneous passage and no recurrence in the last 5 years, or childhood asthma) may be enrolled in the study at the discretion of the investigator.
* Is mentally or legally incapacitated, has significant emotional problems at the time of prestudy (screening) visit or expected during the conduct of the study or has a history of clinically significant psychiatric disorder of the last 5 years. Participants who have had situational depression may be enrolled in the study at the discretion of the investigator.
* Has a history of cancer (malignancy), including adenocarcinoma, with possible exceptions being participants with adequately treated non-melanomatous skin carcinoma; participants with other malignancies which have been successfully treated ≥10 years prior to the pretrial (screening) visit; or participants who, in the opinion of the trial investigator, are highly unlikely to sustain a recurrence for the duration of the trial.
* Has blood coagulation test (activated partial thromboplastin time \[aPTT\], prothrombin time \[PT\]) ≥ 20 % outside of normal range on pretrial (screening), which are considered clinically significant by both the investigator and the sponsor.
* Any other clinically significant abnormalities in laboratory test results at screening that would, in the opinion of the investigator, increase the participant's risk of participation, jeopardize complete participation in the study, or compromise interpretation of study data.
* Has a history of deep vein thrombosis or pulmonary embolism. Has a history of vascular access thrombosis within 1 month prior to enrollment. Has a personal or family history of bleeding disorder.
* Has a history of gastrointestinal (GI) bleeding, duodenal polyps or gastric ulcer in the last 5 years or severe hemorrhoidal bleed in last 3 months.
* Has a history of or current frequent epistaxis within the last 3 months or active gingivitis.
* Has ongoing anticoagulant therapy (warfarin, apixaban, dabigatran, rivaroxaban, edoxaban, betrixaban) or antiplatelet therapy (clopidogrel, prasugrel, ticagrelor, ticlopidine). Intradialytic heparin and aspirin are permitted.
* At the time of screening or pre-dose, has planned significant dental procedures (including planned dental surgery), or other planned surgical procedures within duration of participation in the trial.
* Is positive for hepatitis B surface antigen or human immunodeficiency viruses (HIV).
* Has had major surgery, donated or lost 1 unit of blood (approximately 500 mL) within 4 weeks prior to the pre-study (screening) visits.
* Has a history of significant multiple and/or severe allergies (e.g. food, drug, latex allergy), or has had an anaphylactic reaction or significant intolerability (i.e. systemic allergic reaction) to prescription or non-prescription drugs or food.
* Has a tattoo, scar, or other physical finding at the area of the infusion site that would interfere with infusion or a local tolerability assessment.
* Has a history of receiving any human immunoglobulin preparation such as intravenous immunoglobulin (IVIG) or RhoGAM within the last year.
* Has a history of receiving any biological therapy (including human blood products or monoclonal antibodies; excluding erythropoietin and insulin) within the last 3 months or 5 half-lives (whichever is longer), or vaccination within the last 1 month (exceptions include seasonal flu vaccine and pneumococcal vaccine within the last month; coronavirus disease 2019 \[COVID-19\] vaccine that is licensed and approved for emergency use and with the study intervention given 72 hours following vaccination or 48 hours prior to vaccination).
* The exclusion criteria for ECG is a heart rate \< 40 or \> 110 beats per minute (bpm); corrected Q-T (QTc) interval \> 500 minutes/second; any significant arrhythmia or conduction abnormality, (including but not specific to atrioventricular block \[2nd degree or higher\], Wolff Parkinson White syndrome \[unless curative radio ablation therapy\]), which, in the opinion of the investigator and sponsor, could interfere with the safety for the individual participant; and non-sustained or sustained ventricular tachycardia (\> 2 consecutive ventricular ectopic beats at a rate of \> 1.7/second).
* Is unable to refrain from or anticipates the use of medication, including prescription and nonprescription drugs or herbal remedies beginning approximately 2 weeks prior to administration of the initial dose of study drug, throughout the study until the poststudy visit. Specific allowed and prohibited medications are provided in the protocol.
* Has participated in another investigational study within 4 weeks prior to sponsor's investigational drug (MK-2060/placebo) administration.
* Has a blood pressure \>190 mmHg systolic or \>110 mmHg diastolic.
* Consumes greater than 3 glasses of alcoholic beverages (1 glass is approximately equivalent to: beer 354 mL/12 ounces, wine 118 mL/4 ounces, or distilled spirits 29.5 mL/1 ounce) per day. Participants who consume 4 glasses of alcoholic beverages per day may be enrolled at the discretion of the investigator.
* Consumes excessive amounts, defined as greater than 6 servings (1 serving is approximately equivalent to 120 mg of caffeine) of coffee, tea, cola, energy drinks, or other caffeinated beverages per day.
* Is a regular user of any illicit drugs or has a history of drug (including alcohol) abuse within approximately 2 years. Participants must have a negative serum or saliva drug screen prior to randomization. Participants with a positive drug screen due to the use of physician prescribed medications (e.g., opioids, benzodiazepines, antidepressants) may be enrolled at the discretion of the investigator. In addition, participants with a positive tetrahydrocannabinol (THC) may be enrolled at the discretion of the investigator if the participants' THC use is under 4 times/month and the participants agree to not use during their study participation. Participants with positive THC on screening may have rechecks performed at the discretion of the investigator to ensure compliance with abstinence from THC use during study participation.

Primary outcomes:
measure: Part 1: Percentage of Participants With Any Adverse Event (AE)
timeFrame: Up to 164 days
measure: Part 2: Percentage of Participants With Any AE
timeFrame: Up to 118 days
measure: Part 1: Percentage of Participants With Any Serious Adverse Event
timeFrame: Up to 164 days
measure: Part 2: Percentage of Participants With Any SAE
timeFrame: Up to 118 days
measure: Part 1: Percentage of Participants With a Systemic AE
timeFrame: Up to 164 days
measure: Part 2: Percentage of Participants With a Systemic AE
timeFrame: Up to 118 days
measure: Part 1: Percentage of Participants With an Injection-Site AE
timeFrame: Up to 164 days
measure: Part 2: Percentage of Participants With an Injection-Site AE
timeFrame: Up to 118 days
measure: Part 1: Percentage of Participants Discontinuing the Study Due to an AE
timeFrame: Up to 164 days
measure: Part 2: Percentage of Participants Discontinuing Study Drug Due to an AE
timeFrame: Up to 4 weeks
Secondary outcomes:
measure: Part 1: Area Under the Plasma Concentration-Time Curve of MK-2060 From 0 to Infinity (AUC0-inf)
timeFrame: Predose Day 1 and 1, 12, 24, 48, 52, 96, 168 hours postdose, then Days 12, 15, 22, 29, 60, 90, 120, 150
measure: Part 1: Area Under the Plasma Concentration-Time Curve of MK-2060 From Time 0 to 168 Hours (AUC0-168)
timeFrame: Predose Day 1 and 1, 12, 24, 48, 52, 96, 168 hours postdose
measure: Part 1: Maximum Observed Plasma Concentration (Cmax) of MK-2060
timeFrame: Predose Day 1 and 1, 12, 24, 48, 52, 96, 168 hours postdose, then Days 12, 15, 22, 29, 60, 90, 120, 150
measure: Part 1: Plasma Concentration of MK-2060 at 168 Hours (C168)
timeFrame: 168 hours post dose
measure: Part 1: Time to Maximum Observed Plasma Drug Concentration (Tmax) of MK-2060
timeFrame: Predose Day 1 and 1, 12, 24, 48, 52, 96, 168 hours postdose
measure: Part 1: Plasma Elimination Terminal Half-life (t ½) of MK-2060
timeFrame: Predose Day 1 and 1, 12, 24, 48, 52, 96, 168 hours postdose
measure: Part 1: Plasma Clearance (CL) of MK-2060
timeFrame: Predose Day 1 and 1, 12, 24, 48, 52, 96, 168 hours postdose
measure: Part 1: Plasma Volume of Distribution (Vz) of MK-2060
timeFrame: Predose Day 1 and 1, 12, 24, 48, 52, 96, 168 hours postdose
measure: Part 2: AUC0-168 of MK-2060
timeFrame: Up to 168 hours on Day 1 and Day 22
measure: Part 2: Cmax of MK-2060
timeFrame: Day 1 and Day 22
measure: Part 2: C168 of MK-2060
timeFrame: 168 hours post dose on Days 1 and 22
measure: Part 2: Tmax of MK-2060
timeFrame: Day 1 and Day 22
measure: Fold Change From Baseline in Activated Partial Thromboplastin Time (aPTT) of MK-2060: Part 1
timeFrame: Baseline and 168 hours post-dose (Day 8)
measure: Fold Change From Baseline in aPTT of MK-2060: Part 2
timeFrame: Baseline and Day 8
Other outcomes:
Locations:
city: Orlando
country: United States
facility: Orlando Clinical Research Center ( Site 0002)
state: Florida
city: Saint Paul
country: United States
facility: Prism Research ( Site 0003)
state: Minnesota
city: Knoxville
country: United States
facility: New Orleans Center for Clinical Research ( Site 0001)
state: Tennessee
Study officials:
affiliation: Merck Sharp & Dohme LLC
name: Medical Director
role: STUDY_DIRECTOR
References: