End-stage Renal Disease, Hemodiafiltration, Hemodialysis, Prevention of Thromboembolic Events
Conditions
Keywords
End-stage renal disease (ESRD), Hemodialysis
Brief summary
In this study researchers want to learn about the safety of drug Osocimab at lower-dose and higher-doses in adult participants with kidney disease undergoing regular dialysis (a procedure that uses a machine to get rid of toxins and extra fluids in the blood). Patients with kidney disease undergoing regular dialysis are at high risk for heart and blood vessels diseases. Osocimab is a human monoclonal antibody under development for the prevention of events caused by blood clots like heart attack, stroke and death due to heart or blood vessels diseases. It works by binding to and blocking the activated form of clotting factor XI which increases the formation and stability of clots. Researchers also want to find out how drug Osocimab works in human body and how the body absorbs, distributes and excretes the drug. Participants in this study will receive monthly injection of either Osocimab at a lower-dose or higher-dose or placebo (a placebo looks like a treatment but does not have any medicine in it). Both Osocimab and placebo will be injected into the tissue under the skin of the belly. Observation for each participant will last up to 23 months. Blood samples will be collected from the participants to monitor the safety and measure the blood level of the study drug.
Interventions
DRUGBAY1213790 (Osocimab)
Single loading dose as subcutaneous abdominal injection followed by monthly maintenance doses.
DRUGPlacebo
Subcutaneous administration in the same manner as Osocimab.
Sponsors
Bayer
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Participants must be at least 18 years of age * Patients with end-stage renal disease on hemodialysis (including hemodiafiltration) for ≥3 months, receiving dialysis at least 9 hours a week and stable in the view of the investigator * Body weight of at least 50 kg * Male and/or female. Contraceptive use by men or women should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies.
Exclusion criteria
* Recent (\<6 months before screening) clinically significant bleeding * Hemoglobin (Hb) \< 9.0 g/dL at screening * Platelet count \< 100 x 10\^9/L * aPTT or PT \> ULN (upper limit of normal) * Hepatic disease associated with ALT \> 3x ULN, or total bilirubin \>2x ULN with direct bilirubin \> 20% of the total * Sustained uncontrolled hypertension (diastolic blood pressure ≥100 mmHg and/or systolic blood pressure ≥ 180 mmHg) * Known intracranial neoplasm, arteriovenous malformation or aneurysm * Known bleeding disorders e.g. von-Willebrand disease or Hemophilia A, B or C * Recent (\<3 months before screening) thromboembolic event, e.g. acute coronary syndrome, stroke or VTE (except dialysis access thrombosis) * Recent (\<3 months before screening) major surgery or scheduled major surgery during study participation * Scheduled living donor renal transplant during study participation * Persistent heart failure as classified by the New York Heart Association (NYHA) classification of 3 or higher * Receiving antiplatelet therapy except daily ASA ≤ 150 mg/day * Receiving anticoagulation in therapeutic doses, other than standard anticoagulation during the hemodialysis procedure
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Cumulative Incidence Risk of the First Composite of Major Bleeding (MB) and Clinically-relevant Non-major Bleeding (CRNMB) Events as Assessed by Blinded Central Independent Adjudication Committee (CIAC) | From the first dose of study intervention up till 30 days after last study intervention in the main treatment period, up to 6 months | Cumulative incidence risk of the first Composite of MB and CRNMB (ISTH) at month 6 is reported in the table. Descriptive time to composite of MB and CRNMB Events is reported in statistical analysis. Descriptive time to composite of treatment emergent major and CRNMB events \[in alignment with International Society on Thrombosis and Haemostatsis (ISTH) guidelines\] analyses were performed. The cumulative incidence function for the event-of-interest together with the corresponding confidence interval were estimated for each treatment arm using Aalen-Johansen estimators. Cumulative incidence of events up to the day, inclusive. |
| Cumulative Incidence Risk of Composite of Moderate and Severe Adverse Events (AEs) and Serious Adverse Events (SAEs) | From the first dose of study intervention up until 30 days after last study intervention in the main treatment period, up to 6 months | Cumulative incidence risk of composite of moderate and severe AEs and SAEs at month 6 is reported in the table. Descriptive time to the composite of Moderate and Severe AEs and SAEs is reported in statistical analysis. An AE was any untoward medical occurrence in a patient or clinical study participant, whether or not considered related to the study intervention. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Ratio of Activated Partial Thromboplastin Time (aPTT) at 6 Months Trough Levels Versus Baseline. | At 6 months (Visit 19 / Day 30 of the 6th month) | The aPTT at trough levels after 6 months were analyzed as ratio to baseline by providing the Geometric Mean (Standard Deviation). aPTT was measured via the kaolin-trigger method (clotting assay). |
| Ratio of Factor XI (FXI) Activity at 6 Months Trough Levels Versus Baseline | At 6 months (Visit 19 / Day 30 of the 6th month) | The Factor XI (FXI) activity at trough levels after 6 months were analyzed as ratio to baseline by providing the Geometric Mean (Standard Deviation). Factor XI activity was assessed with an aPTT-based coagulation test using FXI deficient plasma. |
Countries
Australia, Austria, Belgium, Bulgaria, Czechia, Greece, Hungary, Israel, Italy, Japan, Lithuania, Netherlands, Poland, Portugal, Russia, Spain, Turkey (Türkiye), Ukraine, United States
Participant flow
Recruitment details
Study was conducted at multiple centers in 19 countries/regions, between 28-Aug-2020 (first participant first visit) and 30-May-2022 (last participant last visit).
Pre-assignment details
A total of 859 participants were screened; 155 participants were not randomized. Most common reason for not being randomized was screen failure (144 participants). 704 participants were randomized to treatment; 18 participants did not receive treatment. The remaining 686 participants were treated.
Participants by arm
| Arm | Count |
|---|---|
| Higher-dose Osocimab Participants were randomized to receive Osocimab (BAY1213790) 210 mg single loading dose as subcutaneous abdominal injection, followed by monthly maintenance doses of 105 mg for 6 months in main treatment phase.
Participants received Osocimab (BAY1213790) at monthly maintenance doses of 105 mg up to a maximum of 12 months or until the last participant randomized to the study has performed the end of main treatment (EOMT) visit (whichever comes first) in extension treatment period. | 234 |
| Lower-dose Osocimab Participants were randomized to receive Osocimab (BAY1213790) 105 mg single loading dose as subcutaneous abdominal injection, followed by monthly maintenance doses of 52.5 mg for 6 months in main treatment phase.
Participants received Osocimab (BAY1213790) at monthly maintenance doses of 52.5 mg up to a maximum of 12 months or until the last participant randomized to the study has performed the end of main treatment (EOMT) visit (whichever comes first) in extension treatment period. | 235 |
| Placebo Participants were randomized to receive matching placebo subcutaneously in the same manner as Osocimab. | 235 |
| Total | 704 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Extension Treatment Period | Adverse Event | 6 | 7 | 9 |
| Extension Treatment Period | Death | 6 | 4 | 7 |
| Extension Treatment Period | Other | 2 | 6 | 6 |
| Extension Treatment Period | Physician Decision | 1 | 0 | 3 |
| Extension Treatment Period | Study drug never administered | 0 | 1 | 0 |
| Extension Treatment Period | Subject Decision | 5 | 2 | 4 |
| Extension Treatment Period | Withdrawal by Subject | 0 | 1 | 1 |
| Main Treatment Period | Adverse Event | 11 | 9 | 9 |
| Main Treatment Period | Death | 5 | 11 | 4 |
| Main Treatment Period | Other | 5 | 2 | 4 |
| Main Treatment Period | Physician Decision | 1 | 1 | 0 |
| Main Treatment Period | Study drug never adminstered | 10 | 3 | 5 |
| Main Treatment Period | Subject Decision | 5 | 7 | 3 |
| Main Treatment Period | Withdrawal by Subject | 3 | 3 | 4 |
Baseline characteristics
| Characteristic | Higher-dose Osocimab | Lower-dose Osocimab | Placebo | Total |
|---|---|---|---|---|
| Activated partial thromboplastin time (aPTT) value at baseline | 31.49 seconds STANDARD_DEVIATION 1.1 | 31.32 seconds STANDARD_DEVIATION 1.1 | 31.65 seconds STANDARD_DEVIATION 1.09 | 31.49 seconds STANDARD_DEVIATION 1.09 |
| Age, Continuous | 61.0 years STANDARD_DEVIATION 13.4 | 61.1 years STANDARD_DEVIATION 12.9 | 59.5 years STANDARD_DEVIATION 13.3 | 60.5 years STANDARD_DEVIATION 13.2 |
| Factor XI (FXI) activity at baseline | 100.54 percent STANDARD_DEVIATION 1.29 | 102.27 percent STANDARD_DEVIATION 1.28 | 103.09 percent STANDARD_DEVIATION 1.25 | 101.96 percent STANDARD_DEVIATION 1.27 |
| Race (NIH/OMB) American Indian or Alaska Native | 1 Participants | 0 Participants | 1 Participants | 2 Participants |
| Race (NIH/OMB) Asian | 21 Participants | 21 Participants | 21 Participants | 63 Participants |
| Race (NIH/OMB) Black or African American | 19 Participants | 18 Participants | 22 Participants | 59 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 1 Participants | 1 Participants | 2 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 193 Participants | 194 Participants | 190 Participants | 577 Participants |
| Sex: Female, Male Female | 85 Participants | 90 Participants | 81 Participants | 256 Participants |
| Sex: Female, Male Male | 149 Participants | 145 Participants | 154 Participants | 448 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 19 / 224 | 24 / 232 | 15 / 230 |
| other Total, other adverse events | 90 / 224 | 85 / 232 | 88 / 230 |
| serious Total, serious adverse events | 61 / 224 | 67 / 232 | 63 / 230 |
Outcome results
Primary
Cumulative Incidence Risk of Composite of Moderate and Severe Adverse Events (AEs) and Serious Adverse Events (SAEs)
Cumulative incidence risk of composite of moderate and severe AEs and SAEs at month 6 is reported in the table. Descriptive time to the composite of Moderate and Severe AEs and SAEs is reported in statistical analysis. An AE was any untoward medical occurrence in a patient or clinical study participant, whether or not considered related to the study intervention.
Time frame: From the first dose of study intervention up until 30 days after last study intervention in the main treatment period, up to 6 months
Population: SAF (Safety analysis set)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Higher-dose Osocimab | Cumulative Incidence Risk of Composite of Moderate and Severe Adverse Events (AEs) and Serious Adverse Events (SAEs) | 38.84 Percentage of participants |
| Lower-dose Osocimab | Cumulative Incidence Risk of Composite of Moderate and Severe Adverse Events (AEs) and Serious Adverse Events (SAEs) | 38.37 Percentage of participants |
| Placebo | Cumulative Incidence Risk of Composite of Moderate and Severe Adverse Events (AEs) and Serious Adverse Events (SAEs) | 32.17 Percentage of participants |
Comparison: Two-sided log-rank tests and Cox proportional hazards model were used in the analyses.p-value: =0.12890% CI: [0.98, 1.64]Log Rank
Comparison: Two-sided log-rank tests and Cox proportional hazards model were used in the analyses.p-value: =0.16690% CI: [0.96, 1.61]Log Rank
Primary
Cumulative Incidence Risk of the First Composite of Major Bleeding (MB) and Clinically-relevant Non-major Bleeding (CRNMB) Events as Assessed by Blinded Central Independent Adjudication Committee (CIAC)
Cumulative incidence risk of the first Composite of MB and CRNMB (ISTH) at month 6 is reported in the table. Descriptive time to composite of MB and CRNMB Events is reported in statistical analysis. Descriptive time to composite of treatment emergent major and CRNMB events \[in alignment with International Society on Thrombosis and Haemostatsis (ISTH) guidelines\] analyses were performed. The cumulative incidence function for the event-of-interest together with the corresponding confidence interval were estimated for each treatment arm using Aalen-Johansen estimators. Cumulative incidence of events up to the day, inclusive.
Time frame: From the first dose of study intervention up till 30 days after last study intervention in the main treatment period, up to 6 months
Population: SAF (Safety analysis set): All participants randomly assigned to study intervention who took at least 1 dose of study intervention. Participants were analyzed according to the intervention they actually received.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Higher-dose Osocimab | Cumulative Incidence Risk of the First Composite of Major Bleeding (MB) and Clinically-relevant Non-major Bleeding (CRNMB) Events as Assessed by Blinded Central Independent Adjudication Committee (CIAC) | 3.57 Percentage of participants |
| Lower-dose Osocimab | Cumulative Incidence Risk of the First Composite of Major Bleeding (MB) and Clinically-relevant Non-major Bleeding (CRNMB) Events as Assessed by Blinded Central Independent Adjudication Committee (CIAC) | 4.32 Percentage of participants |
| Placebo | Cumulative Incidence Risk of the First Composite of Major Bleeding (MB) and Clinically-relevant Non-major Bleeding (CRNMB) Events as Assessed by Blinded Central Independent Adjudication Committee (CIAC) | 6.09 Percentage of participants |
Comparison: Two-sided log-rank tests and Cox proportional hazards model were used in the analyses.p-value: =0.22290% CI: [0.28, 1.21]Log Rank
Comparison: Two-sided log-rank tests and Cox proportional hazards model were used in the analyses.p-value: =0.42790% CI: [0.36, 1.42]Log Rank
Secondary
Ratio of Activated Partial Thromboplastin Time (aPTT) at 6 Months Trough Levels Versus Baseline.
The aPTT at trough levels after 6 months were analyzed as ratio to baseline by providing the Geometric Mean (Standard Deviation). aPTT was measured via the kaolin-trigger method (clotting assay).
Time frame: At 6 months (Visit 19 / Day 30 of the 6th month)
Population: PDS (Pharmacodynamic analysis set): All participants with at least 1 PD sample in accordance with the PD sampling schedule and without deviation from the protocol that would have interfered with the evaluation of the PD data were included in the PD analysis. Participants in PDS with data available for this outcome measure
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Higher-dose Osocimab | Ratio of Activated Partial Thromboplastin Time (aPTT) at 6 Months Trough Levels Versus Baseline. | 1.26 Ratio | Standard Deviation 1.11 |
| Lower-dose Osocimab | Ratio of Activated Partial Thromboplastin Time (aPTT) at 6 Months Trough Levels Versus Baseline. | 1.19 Ratio | Standard Deviation 1.11 |
| Placebo | Ratio of Activated Partial Thromboplastin Time (aPTT) at 6 Months Trough Levels Versus Baseline. | 1.02 Ratio | Standard Deviation 1.08 |
Secondary
Ratio of Factor XI (FXI) Activity at 6 Months Trough Levels Versus Baseline
The Factor XI (FXI) activity at trough levels after 6 months were analyzed as ratio to baseline by providing the Geometric Mean (Standard Deviation). Factor XI activity was assessed with an aPTT-based coagulation test using FXI deficient plasma.
Time frame: At 6 months (Visit 19 / Day 30 of the 6th month)
Population: PDS (Pharmacodynamic analysis set). Participants in PDS with data available for this outcome measure
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Higher-dose Osocimab | Ratio of Factor XI (FXI) Activity at 6 Months Trough Levels Versus Baseline | 0.87 Ratio | Standard Deviation 1.27 |
| Lower-dose Osocimab | Ratio of Factor XI (FXI) Activity at 6 Months Trough Levels Versus Baseline | 0.94 Ratio | Standard Deviation 1.23 |
| Placebo | Ratio of Factor XI (FXI) Activity at 6 Months Trough Levels Versus Baseline | 0.96 Ratio | Standard Deviation 1.2 |