End-Stage Kidney Disease, End-Stage Renal Disease, Kidney Failure, Chronic
Conditions
Brief summary
The purpose of this study is to evaluate the efficacy and safety of two different doses of MK-2060 (a monoclonal antibody against Factor XI) in end stage renal disease (ESRD) participants receiving hemodialysis via an arteriovenous graft (AVG). Data from this study will be used to aid dose selection of MK-2060 in future studies. The primary hypothesis is that at least one of the MK-2060 doses is superior to placebo in increasing the time to first occurrence of AVG event.
Interventions
DRUGMK-2060
MK-2060 lyophilized powder diluted in normal saline and administered via IV infusion
DRUGPlacebo
Normal saline administered via IV infusion
Sponsors
Merck Sharp & Dohme LLC
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Current diagnosis of ESRD. * Receiving hemodialysis (including hemodiafiltration) ≥3 times per week for a minimum of 3 hours per session via a mature normally functioning, uninfected AVG with at least 75% of the sessions meeting these criteria over the 4 weeks prior to randomization. * A female participant is not pregnant or breastfeeding, not a woman of child-bearing potential (WOCBP) or is a WOCBP and agrees to follow contraceptive guidance during the intervention period and for at least 90 days after the last dose of study intervention.
Exclusion criteria
* Recent history of cancer (\<1 year). Non-melanoma skin cancers are allowed. * Mechanical/prosthetic heart valve. * Recent hemorrhagic stroke or lacunar stroke (\<1 month). * Recent evidence (\<1 month) of bleeding requiring hospitalization or unplanned medical attention, a history (≤2 years) of recurrent bleeding episodes including epistaxis, gastrointestinal (GI) bleeds or genitourinary (GU) bleeds requiring medical treatment or events requiring treatment with blood products. * Recent history (\<1 year) of drug or alcohol abuse or dependence. * Currently receiving or planning to receive anticoagulants or antiplatelet medications (intradialytic heparin and aspirin are permitted). * Planning on receiving a living donor renal transplant within 12 months (participants are permitted to be candidates for deceased donor renal transplants). * Planning on receiving an arteriovenous fistula (AVF) placement within 12 months.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Time to First Arteriovenous Graft (AVG) Thrombosis Event | From date of randomization until the date of first occurrence of an AVG thrombosis event, assessed up to approximately 37 months | An AVG thrombosis event is defined as the sudden occlusion of the participant's AVG requiring thrombectomy/thrombolysis, or clinical evidence of thrombosis with surgical, radiological or pathological conformation of an AVG thrombosis. A blinded independent clinical adjudication committee (CAC) adjudicated AVG thrombosis events. A time-to-event methodology was used to evaluate the results. The incidence rate is presented. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Time to Each AVG Thrombosis Event (First and Recurrent) | Up to approximately 37 months | An AVG thrombosis event is defined as the sudden occlusion of the participant's AVG requiring thrombectomy/thrombolysis, or clinical evidence of thrombosis with surgical, radiological or pathological conformation of an AVG thrombosis. A blinded independent CAC adjudicated AVG thrombosis events. A time-to-event methodology was used to evaluate the results. The incidence rate is presented. |
| Number of Participants Who Experience One or More Adverse Events (AEs) | Up to approximately 40 months | 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 number of participants with one or more AEs is presented. |
| Time to First Event of International Society on Thrombosis (ISTH) Major Bleeding Event or a Clinically Relevant Non-Major Bleeding Event | From date of first dose of study intervention until the first ISTH major bleeding event or a clinically relevant non-major bleeding event. assessed up to approximately 40 months | Major bleeding events were defined as a having symptomatic presentation and including ≥1 of the following criteria: 1) Fatal bleeding 2) Symptomatic bleeding in a critical area or organ, such as intracranial, intraspinal, intraocular, retroperitoneal, intra-articular, pericardial, intramuscular with compartment syndrome 3) Bleeding causing decrease in hematocrit level of 20 g/L or more or leading to transfusion of ≥2 units of whole blood or red cells. Clinically relevant non-major bleeding events were defined as signs or symptoms of hemorrhage that do not meet criteria for major bleeding events but meet ≥1 of the following criteria: 1) Requiring medical intervention by healthcare professional 2) Leading to hospitalization or increased level of care 3) Prompting face-to-face evaluation by healthcare professional. A time-to-event methodology was used. The incidence rate is presented. |
| Number of Participants Who Discontinue Study Intervention Due to an AE | Up to approximately 37 months | 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 number of participants who discontinued study intervention due to an AE is presented. |
Countries
Argentina, Australia, Brazil, Bulgaria, Canada, Czechia, Germany, Greece, Italy, Portugal, Puerto Rico, Romania, Russia, Sweden, United States
Contacts
STUDY_DIRECTORMedical Director
Merck Sharp & Dohme LLC
Participant flow
Pre-assignment details
The participant with trial "Status Not Recorded" was discontinued from trial participation due to site termination of sponsor, but discontinuation form was not completed in the electronic data capture (EDC) in time by the terminated site.
Participants by arm
| Arm | Count |
|---|---|
| MK-2060 20 mg MK-2060 20 mg administered via IV infusion during dialysis as a loading dose: QOD during week 1 (3 administrations), then QW after week 1 | 171 |
| MK-2060 6 mg MK-2060 6 mg administered via intravenous (IV) infusion during dialysis as a loading dose: Every other day (QOD) during week 1 (3 administrations), then once a week (QW) after week 1 | 167 |
| Placebo Placebo (normal saline) administered via IV infusion during dialysis as a loading dose: QOD during week 1 (3 administrations), then once a week after week 1 | 168 |
| Total | 506 |
Baseline characteristics
| Characteristic | MK-2060 20 mg | MK-2060 6 mg | Placebo | Total |
|---|---|---|---|---|
| Age, Continuous | 62.2 Years STANDARD_DEVIATION 13.5 | 58.8 Years STANDARD_DEVIATION 12.8 | 60.5 Years STANDARD_DEVIATION 14.8 | 60.5 Years STANDARD_DEVIATION 13.8 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 77 Participants | 67 Participants | 65 Participants | 209 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 91 Participants | 98 Participants | 100 Participants | 289 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 3 Participants | 2 Participants | 3 Participants | 8 Participants |
| Previous Thrombosis of Active Arteriovenous Graft (AVG) No | 133 Participants | 132 Participants | 128 Participants | 393 Participants |
| Previous Thrombosis of Active Arteriovenous Graft (AVG) Yes | 38 Participants | 35 Participants | 40 Participants | 113 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 2 Participants | 1 Participants | 1 Participants | 4 Participants |
| Race (NIH/OMB) Asian | 6 Participants | 6 Participants | 4 Participants | 16 Participants |
| Race (NIH/OMB) Black or African American | 63 Participants | 73 Participants | 67 Participants | 203 Participants |
| Race (NIH/OMB) More than one race | 1 Participants | 1 Participants | 0 Participants | 2 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 2 Participants | 2 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 99 Participants | 86 Participants | 94 Participants | 279 Participants |
| Region non-US | 53 Participants | 50 Participants | 50 Participants | 153 Participants |
| Region US | 118 Participants | 117 Participants | 118 Participants | 353 Participants |
| Regular Aspirin Use up to 150 mg Daily at Baseline No | 99 Participants | 98 Participants | 101 Participants | 298 Participants |
| Regular Aspirin Use up to 150 mg Daily at Baseline Yes | 72 Participants | 69 Participants | 67 Participants | 208 Participants |
| Sex: Female, Male Female | 97 Participants | 81 Participants | 83 Participants | 261 Participants |
| Sex: Female, Male Male | 74 Participants | 86 Participants | 85 Participants | 245 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 50 / 171 | 43 / 167 | 41 / 168 |
| other Total, other adverse events | 111 / 170 | 106 / 164 | 109 / 168 |
| serious Total, serious adverse events | 110 / 170 | 95 / 164 | 112 / 168 |
Outcome results
Primary
Time to First Arteriovenous Graft (AVG) Thrombosis Event
An AVG thrombosis event is defined as the sudden occlusion of the participant's AVG requiring thrombectomy/thrombolysis, or clinical evidence of thrombosis with surgical, radiological or pathological conformation of an AVG thrombosis. A blinded independent clinical adjudication committee (CAC) adjudicated AVG thrombosis events. A time-to-event methodology was used to evaluate the results. The incidence rate is presented.
Time frame: From date of randomization until the date of first occurrence of an AVG thrombosis event, assessed up to approximately 37 months
Population: The analysis population consisted of all randomized participants, excluding three participants with arteriovenous fistula (AVF) rather than an AVG at randomization.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| MK-2060 20 mg | Time to First Arteriovenous Graft (AVG) Thrombosis Event | 23.80 events per 100 person-years |
| MK-2060 6 mg | Time to First Arteriovenous Graft (AVG) Thrombosis Event | 22.98 events per 100 person-years |
| Placebo | Time to First Arteriovenous Graft (AVG) Thrombosis Event | 30.17 events per 100 person-years |
p-value: 0.4795% CI: [0.6, 1.26]Log Rank
95% CI: [0.57, 1.19]
Secondary
Number of Participants Who Discontinue Study Intervention Due to an AE
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 number of participants who discontinued study intervention due to an AE is presented.
Time frame: Up to approximately 37 months
Population: The analysis population consisted of all randomized participants who received at least one dose of study intervention.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| MK-2060 20 mg | Number of Participants Who Discontinue Study Intervention Due to an AE | 47 Participants |
| MK-2060 6 mg | Number of Participants Who Discontinue Study Intervention Due to an AE | 32 Participants |
| Placebo | Number of Participants Who Discontinue Study Intervention Due to an AE | 46 Participants |
Secondary
Number of Participants Who Experience One or More Adverse Events (AEs)
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 number of participants with one or more AEs is presented.
Time frame: Up to approximately 40 months
Population: The analysis population consisted of all randomized participants who received at least one dose of study intervention.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| MK-2060 20 mg | Number of Participants Who Experience One or More Adverse Events (AEs) | 161 Participants |
| MK-2060 6 mg | Number of Participants Who Experience One or More Adverse Events (AEs) | 143 Participants |
| Placebo | Number of Participants Who Experience One or More Adverse Events (AEs) | 155 Participants |
Secondary
Time to Each AVG Thrombosis Event (First and Recurrent)
An AVG thrombosis event is defined as the sudden occlusion of the participant's AVG requiring thrombectomy/thrombolysis, or clinical evidence of thrombosis with surgical, radiological or pathological conformation of an AVG thrombosis. A blinded independent CAC adjudicated AVG thrombosis events. A time-to-event methodology was used to evaluate the results. The incidence rate is presented.
Time frame: Up to approximately 37 months
Population: The analysis population consisted of all randomized participants, excluding three participants with AVF rather than an AVG at randomization.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| MK-2060 20 mg | Time to Each AVG Thrombosis Event (First and Recurrent) | 38.95 events per 100 person-years |
| MK-2060 6 mg | Time to Each AVG Thrombosis Event (First and Recurrent) | 37.85 events per 100 person-years |
| Placebo | Time to Each AVG Thrombosis Event (First and Recurrent) | 42.97 events per 100 person-years |
95% CI: [0.68, 1.21]
95% CI: [0.7, 1.23]
Secondary
Time to First Event of International Society on Thrombosis (ISTH) Major Bleeding Event or a Clinically Relevant Non-Major Bleeding Event
Major bleeding events were defined as a having symptomatic presentation and including ≥1 of the following criteria: 1) Fatal bleeding 2) Symptomatic bleeding in a critical area or organ, such as intracranial, intraspinal, intraocular, retroperitoneal, intra-articular, pericardial, intramuscular with compartment syndrome 3) Bleeding causing decrease in hematocrit level of 20 g/L or more or leading to transfusion of ≥2 units of whole blood or red cells. Clinically relevant non-major bleeding events were defined as signs or symptoms of hemorrhage that do not meet criteria for major bleeding events but meet ≥1 of the following criteria: 1) Requiring medical intervention by healthcare professional 2) Leading to hospitalization or increased level of care 3) Prompting face-to-face evaluation by healthcare professional. A time-to-event methodology was used. The incidence rate is presented.
Time frame: From date of first dose of study intervention until the first ISTH major bleeding event or a clinically relevant non-major bleeding event. assessed up to approximately 40 months
Population: The analysis population consisted of all randomized participants who received at least one dose of study intervention.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| MK-2060 20 mg | Time to First Event of International Society on Thrombosis (ISTH) Major Bleeding Event or a Clinically Relevant Non-Major Bleeding Event | 24.73 events per 100 person-years |
| MK-2060 6 mg | Time to First Event of International Society on Thrombosis (ISTH) Major Bleeding Event or a Clinically Relevant Non-Major Bleeding Event | 18.05 events per 100 person-years |
| Placebo | Time to First Event of International Society on Thrombosis (ISTH) Major Bleeding Event or a Clinically Relevant Non-Major Bleeding Event | 14.04 events per 100 person-years |
p-value: 0.02295% CI: [1.07, 2.62]Log Rank
p-value: 0.31195% CI: [0.8, 2]Log Rank