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
Overview
- Phase
- Phase 1
- Intervention
- MK-2060
- Conditions
- Renal Dialysis
- Sponsor
- Merck Sharp & Dohme LLC
- Enrollment
- 38
- Locations
- 3
- Primary Endpoint
- Part 2: Percentage of Participants With Any SAE
- Status
- Completed
- Last Updated
- last year
Overview
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).
Investigators
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
- •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)\^
- •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.
Arms & Interventions
Part 1: Panel A- MK-2060 (8 mg)
Participants will receive a single 8-mg dose of MK-2060 via intravenous (IV) infusion.
Intervention: MK-2060
Part 1: Panel B- MK-2060 (20 mg)
Participants will receive a single 20-mg dose of MK-2060 via IV infusion.
Intervention: MK-2060
Part 1: Panel C- MK-2060 (40 mg)
Participants will receive a single 40-mg dose of MK-2060 via IV infusion.
Intervention: MK-2060
Part 1: Placebo
Participants will receive a single dose of placebo via IV infusion.
Intervention: Placebo
Part 2: MK-2060 25-mg Loading/ 25-mg Maintenance
Participants will receive three doses of up to 25 mg MK-2060 via IV infusion in the first week (Week 1), followed by a single dose of up to 25 mg MK-2060 via IV infusion weekly for 3 weeks (Weeks 2-4)
Intervention: MK-2060
Part 2: Placebo
Participants will receive three doses of placebo via IV infusion in the first week and then a single dose of placebo via IV infusion weekly for 3 weeks (Weeks 2-4)
Intervention: Placebo
Outcomes
Primary Outcomes
Part 2: Percentage of Participants With Any SAE
Time Frame: Up to 118 days
An SAE is an AE that results in death, is life threatening, requires or prolongs an existing hospitalization, results in persistent or significant disability or incapacity, is a congenital anomaly or birth defect, or is another important medical event deemed such by medical or scientific judgment. The percentage of participants who experienced an SAE was summarized.
Part 2: Percentage of Participants With a Systemic AE
Time Frame: Up to 118 days
An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a study intervention. The solicited systemic AEs assessed included but not limited to fever, vital sign (VS) changes (tachycardia/hypotension), pruritis, urticarial (hives), lip swelling, angioedema, bronchospasm, stridor, hoarseness, and shortness of breath.
Part 1: Percentage of Participants Discontinuing the Study Due to an AE
Time Frame: Up to 164 days
An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention. The percentage of participants that discontinued the study due to an AE was summarized.
Part 1: Percentage of Participants With Any Serious Adverse Event
Time Frame: Up to 164 days
A serious adverse event (SAE) is an AE that results in death, is life threatening, requires or prolongs an existing hospitalization, results in persistent or significant disability or incapacity, is a congenital anomaly or birth defect, or is another important medical event deemed such by medical or scientific judgment. The percentage of participants who experienced an SAE was summarized.
Part 1: Percentage of Participants With a Systemic AE
Time Frame: Up to 164 days
An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a study intervention. The solicited systemic AEs assessed included but not limited to fever, vital sign (VS) changes (tachycardia/hypotension), pruritis, urticarial (hives), lip swelling, angioedema, bronchospasm, stridor, hoarseness, and shortness of breath.
Part 1: Percentage of Participants With an Injection-Site AE
Time Frame: Up to 164 days
An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a study intervention. The solicited injection-site AEs assessed were pain, tenderness, erythema/redness, and induration/swelling.
Part 1: Percentage of Participants With Any Adverse Event (AE)
Time Frame: Up to 164 days
An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a study intervention. The percentage of participants that experienced an AE was summarized.
Part 2: Percentage of Participants With Any AE
Time Frame: Up to 118 days
An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a study intervention. The percentage of participants who experienced an AE was summarized.
Part 2: Percentage of Participants With an Injection-Site AE
Time Frame: Up to 118 days
An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a study intervention. The solicited injection-site AEs assessed were pain, tenderness, erythema/redness, and induration/swelling.
Part 2: Percentage of Participants Discontinuing Study Drug Due to an AE
Time Frame: Up to 4 weeks
An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention. The percentage of participants that had study drug discontinued regardless of study completion status was summarized.
Secondary Outcomes
- Part 1: Area Under the Plasma Concentration-Time Curve of MK-2060 From Time 0 to 168 Hours (AUC0-168)(Predose Day 1 and 1, 12, 24, 48, 52, 96, 168 hours postdose)
- Part 2: AUC0-168 of MK-2060(Up to 168 hours on Day 1 and Day 22)
- Fold Change From Baseline in aPTT of MK-2060: Part 2(Baseline and Day 8)
- Part 2: Tmax of MK-2060(Day 1 and Day 22)
- Part 1: Plasma Concentration of MK-2060 at 168 Hours (C168)(168 hours post dose)
- Part 1: Plasma Volume of Distribution (Vz) of MK-2060(Predose Day 1 and 1, 12, 24, 48, 52, 96, 168 hours postdose)
- Part 2: C168 of MK-2060(168 hours post dose on Days 1 and 22)
- Part 1: Area Under the Plasma Concentration-Time Curve of MK-2060 From 0 to Infinity (AUC0-inf)(Predose Day 1 and 1, 12, 24, 48, 52, 96, 168 hours postdose, then Days 12, 15, 22, 29, 60, 90, 120, 150)
- Part 2: Cmax of MK-2060(Day 1 and Day 22)
- Fold Change From Baseline in Activated Partial Thromboplastin Time (aPTT) of MK-2060: Part 1(Baseline and 168 hours post-dose (Day 8))
- Part 1: Plasma Elimination Terminal Half-life (t ½) of MK-2060(Predose Day 1 and 1, 12, 24, 48, 52, 96, 168 hours postdose)
- Part 1: Plasma Clearance (CL) of MK-2060(Predose Day 1 and 1, 12, 24, 48, 52, 96, 168 hours postdose)
- Part 1: Maximum Observed Plasma Concentration (Cmax) of MK-2060(Predose Day 1 and 1, 12, 24, 48, 52, 96, 168 hours postdose, then Days 12, 15, 22, 29, 60, 90, 120, 150)
- Part 1: Time to Maximum Observed Plasma Drug Concentration (Tmax) of MK-2060(Predose Day 1 and 1, 12, 24, 48, 52, 96, 168 hours postdose)