Acute Kidney Injury (AKI)
Conditions
Brief summary
The purpose of this study was to evaluate the efficacy of postsurgery treatment with ASP1128 in subjects at risk for AKI following CABG and/or valve surgery. This study also investigated the safety and tolerability of postsurgery treatment with ASP1128, and pharmacokinetic characteristics of ASP1128 in subjects at risk for AKI following CABG and/or valve surgery.
Detailed description
The study comprised of a screening visit, followed by CABG and/or valve surgery on Day 1, double-blind treatment period and a follow-up period up to Day 90 in subjects with moderate/severe risk of AKI at 2-22 hours post-surgery. Subjects with low risk of AKI at 2-22 hours post-surgery assessment were enrolled in the observational cohort to evaluate subject characteristics and biomarkers for exploratory objectives.
Interventions
DRUGASP1128
Intravenous Infusion
DRUGPlacebo
Intravenous Infusion
Sponsors
Astellas Pharma Inc
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
35 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Subject agrees not to participate in another interventional study after signing the informed consent form and until the end of study (EoS) visit has been completed. * Subject is ≥ 35 years of age at the time of screening (visit 1). * Subject undergoing non-emergent open chest cardiovascular surgery with the use of cardiopulmonary bypass pump (CPB) (i.e., coronary artery bypass graft (CABG) and/or valve surgery \[including aortic root and ascending aorta surgery without circulatory arrest\]) within 4 weeks of screening (visit 1). * Subject is at risk of developing acute kidney injury (AKI) following cardiovascular surgery, i.e., has 1 or more of the following AKI risk factors: * Age at screening of ≥ 70 years * Documented history of eGFR \< 60 mL/min per 1.73 m\^2 as per Modification of Diet in Renal Disease Study (MDRD) or Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation (or documented measured glomerular filtration rate assessment) (history needs to be present for at least 90 days prior to screening, and eGFR at screening or baseline needs to be \< 60 mL/min per 1.73 m\^2, as well as per CKD-EPI equation.) * Documented history of congestive heart failure requiring hospitalization. This condition should exist for ≥ 90 days prior to screening. * Documented history of diabetes mellitus (type 1 or 2) of ≥ 90 days prior to screening, and subject is on active antidiabetic medication treatment for ≥ 90 days. * Documented history of proteinuria/albuminuria at any time point before screening (urinary dipstick result of ≥ 2+, documented urinary albumin creatinine ratio measurement of ≥ 300 mg/g, or documented total quantity of protein in a 24-hour urine collection test ≥ 0.3 g/day) * Subject must have the ability and willingness to return for all scheduled visits and perform all assessments. * Female subject is eligible to participate if she is not pregnant and at least 1 of the following conditions applies: * Not a woman of childbearing potential (WOCBP), OR * WOCBP who agrees to follow the contraceptive guidance throughout the treatment period and for at least 30 days after the final study drug administration. * Female subject must agree not to breastfeed starting at screening and throughout the study period, and for 30 days after the final study drug administration. * Female subject must not donate ova starting at screening and throughout the study period, and for 30 days after the final study drug administration. * Male subject with female partner(s) of child-bearing potential must agree to use contraception during the treatment period and for at least 30 days after the final study drug administration. * Male subject must not donate sperm during the treatment period and for at least 30 days after the final study drug administration. * Male subject with a pregnant or breastfeeding partner(s) must agree to remain abstinent or use a condom for the duration of the pregnancy or time partner is breastfeeding throughout the study period and for 30 days after the final study drug administration.
Exclusion criteria
At Screening: * Subject has received investigational drug within 30 days or 5 half-lives, whichever is longer, prior to screening. * Subject has received RRT within 30 days prior to screening. * Subject has CKD stage 4 or 5, or stage 3 (i.e., eGFR 30-59 mL/min per 1.73m\^2) with a known history of eGFR \< 30 mL/min per 1.73 m\^2 as per CKD-EPI or MDRD equation within 6 months prior to screening. * Subject has a prior kidney transplantation. * Subject has a known or suspected glomerulonephritis (other than Diabetic Kidney Disease). * Subject has confirmed or treated endocarditis or other current active infection requiring antibiotic treatment within 30 days prior to screening. * Subject is using prohibited. * Subject has a prior history of intravenous drug abuse within 1 year prior to screening. * Subject has a known chronic liver disorder with Child-Pugh B or C classification. * Subject has any of the following abnormal liver or kidney function parameters: * Alanine aminotransferase (ALT), aspartate aminotransferase (AST) \> 2 times the upper limit of normal (ULN) or bilirubin increased to \> 1.5 times the ULN. * eGFR \< 30 mL/min per 1.73 m\^2 as per CKD-EPI equation. * Subject has use of left ventricular assist device, intra-aortic balloon pump or other cardiac devices, or catecholamines within 7 days prior to screening. * Subject has surgery scheduled to be performed without CPB (i.e., Off-Pump surgery). * Subject has surgery scheduled to be performed under conditions of circulatory arrest, including planned deep hypothermic circulatory arrest. * Subject has surgery scheduled for aortic dissection. * Subject has surgery for a condition that is immediately life-threatening. * Subject has surgery scheduled to correct major congenital heart defect. * Subject has current or previous malignant disease. Subjects with a history of cancer are considered eligible if the subject has undergone therapy and the subject has been considered disease free or progression free for at least 5 years. Subject with completely excised basal cell carcinoma or squamous cell carcinoma of the skin and completely excised cervical cancer in situ are also considered eligible. Preoperatively on the Day of Surgery: *
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants Developing AKI Based on Serum Creatinine (SCr) Criteria Within 72 Hrs From End of Surgery (AKI-SCr72h) | From end of surgery up to 72 hrs | Development of AKI was based on SCr criteria from the kidney disease improving global outcomes (KDIGO) guideline (i.e., increase in SCr ≥ 0.3 milligram per deciliter (mg/dL) \[≥ 26.5 micromoles per liter {μmol/L}\] within any 48 hours or increase in SCr to ≥ 1.5 times baseline within 72 hours after end of surgery \[T0\]). Percentage of participants who developed AKI-SCr72h were reported. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants Developing AKI Based on Serum Creatinine (SCr) Criteria Within 7 Days From End of Surgery (AKI-SCr7d) | From end of surgery up to 7 days | Development of AKI was based on SCr criteria from the KDIGO guideline (i.e., increase in SCr ≥ 0.3 mg/dL \[≥ 26.5 μmol/L\] within any 48 hours or increase in SCr to ≥ 1.5 times baseline within 7 days after T0). Percentage of participants who developed AKI-SCr7d were reported. |
| Percentage of Participants Developing AKI Based on All Captured Criteria Within 72 Hrs From End of Surgery (AKI-KDIGO72h) | From end of surgery up to 72 hrs | Development of AKI was based on all captured criteria from KDIGO guideline (i.e., AKI-SCr stage 1 to 3: increase in SCr ≥ 0.3 mg/dL \[≥ 26.5 μmol/L\] within any 48 hours, increase in SCr to ≥ 1.5 times baseline, and/or AKI-urinary output (UO) stage 2 and 3: urine volume \< 0.5 mL/kg per hour for 12 consecutive hours) within 72 hours after T0. Percentage of participants who developed AKI-KDIGO72h were reported. |
| Percentage of Participants Developing AKI Based on All Captured Criteria Within 7 Days From End of Surgery (AKI-KDIGO7d) | From end of surgery up to 7 days | Development of AKI was based on all captured criteria from KDIGO guideline (i.e., AKI-SCr stage 1 to 3: increase in SCr ≥ 0.3 mg/dL \[≥ 26.5 μmol/L\] within any 48 hours, increase in SCr to ≥ 1.5 times baseline, and/or AKI-urinary output (UO) stage 2 and 3: urine volume \< 0.5 milliliter per kilogram (mL/kg) per hour for 12 consecutive hours) within 7 days after T0. Percentage of participants who developed AKI-KDIGO7d were reported. |
| Percentage of Participants With Major Adverse Kidney Events (MAKE) Within 30 Days After Day of Surgery (MAKE30) | From day of surgery up to 30 days | MAKE30 was defined as all-cause mortality, renal replacement therapy (RRT) and/or ≥ 25% sustained reduction in estimated glomerular filtration rate (eGFR) based on SCr within 30 days after day of surgery. Percentage of participants with MAKE30 were reported. |
| Percentage of Participants With MAKE Within 90 Days After Day of Surgery (MAKE90) | From day of surgery up to 90 days | MAKE90 was defined as all-cause mortality, renal replacement therapy (RRT) and/or ≥ 25% sustained reduction in estimated glomerular filtration rate (eGFR) based on SCr within 90 days after day of surgery. Percentage of participants with MAKE90 were reported. |
Countries
United States
Participant flow
Recruitment details
A total of 351 were enrolled in the study, of which 151 participants were randomized and 150 received treatment in double-blind treatment period, and the rest of 200 were enrolled in observational cohort.
Pre-assignment details
Participants who underwent coronary artery bypass graft (CABG) and/or valve surgery and had a moderate or high risk for developing acute kidney injury (AKI) based on serum creatinine (SCr) kidney disease improving global outcomes (KDIGO) criteria (AKI-SCr) postsurgery were enrolled in the study. Randomization was stratified for estimated glomerular filtration rate (eGFR) at \< 45 and ≥ 45 milliliter per minute (mL/min) per 1.73 square meter (m\^2).
Participants by arm
| Arm | Count |
|---|---|
| ASP1128 Participants received ASP1128 solution administered by 15 minutes intravenous infusion within 24 hours after the end of surgery and thereafter once daily for 2 days. | 69 |
| Placebo Participants received placebo matched to ASP1128 solution administered by 15 minutes intravenous infusion within 24 hours after the end of surgery and thereafter once daily for 2 days. | 81 |
| Observational Cohort Participant with postoperative negative NephroCheck® (NC) (AKIRisk score was ≤ 0.3 ng/mL\^2/1000 at all assessments between 2 to 22 hours after time point 0 (T0) were followed up for 90 days in observational cohort. Participants did not receive any intervention. | 200 |
| Total | 350 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Death | 3 | 2 | 6 |
| Overall Study | Lost to Follow-up | 2 | 1 | 8 |
| Overall Study | Miscellaneous | 2 | 3 | 0 |
| Overall Study | Study Terminated by Sponsor | 1 | 0 | 0 |
| Overall Study | Withdrawal by Subject | 1 | 4 | 1 |
Baseline characteristics
| Characteristic | Observational Cohort | Total | Placebo | ASP1128 |
|---|---|---|---|---|
| Age, Continuous | 69.4 Years STANDARD_DEVIATION 8.8 | 69 Years STANDARD_DEVIATION 8.8 | 68.7 Years STANDARD_DEVIATION 9.4 | 68.0 Years STANDARD_DEVIATION 8.3 |
| Estimated Glomerular Filtration Rate (eGFR) for randomization <45 mL/min per 1.73 m^2 | — | 12 Participants | 9 Participants | 3 Participants |
| Estimated Glomerular Filtration Rate (eGFR) for randomization >=45 mL/min per 1.73 m^2 | — | 138 Participants | 72 Participants | 66 Participants |
| Race/Ethnicity, Customized Ethnicity Hispanic or Latino | 15 Participants | 24 Participants | 5 Participants | 4 Participants |
| Race/Ethnicity, Customized Ethnicity Missing | 2 Participants | 3 Participants | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized Ethnicity Not Hispanic or Latino | 183 Participants | 323 Participants | 76 Participants | 64 Participants |
| Race/Ethnicity, Customized Race American Indian or Alaska Native | 0 Participants | 1 Participants | 1 Participants | 0 Participants |
| Race/Ethnicity, Customized Race Asian | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Race Black or African American | 16 Participants | 21 Participants | 1 Participants | 4 Participants |
| Race/Ethnicity, Customized Race Native Hawaiian or Other Pacific Islander | 1 Participants | 1 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Race Other | 1 Participants | 1 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Race White | 182 Participants | 326 Participants | 79 Participants | 65 Participants |
| Sex: Female, Male Female | 65 Participants | 88 Participants | 7 Participants | 16 Participants |
| Sex: Female, Male Male | 135 Participants | 262 Participants | 74 Participants | 53 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 3 / 69 | 2 / 81 | 6 / 200 |
| other Total, other adverse events | 29 / 69 | 29 / 81 | 73 / 200 |
| serious Total, serious adverse events | 36 / 69 | 45 / 81 | 34 / 200 |
Outcome results
Primary
Percentage of Participants Developing AKI Based on Serum Creatinine (SCr) Criteria Within 72 Hrs From End of Surgery (AKI-SCr72h)
Development of AKI was based on SCr criteria from the kidney disease improving global outcomes (KDIGO) guideline (i.e., increase in SCr ≥ 0.3 milligram per deciliter (mg/dL) \[≥ 26.5 micromoles per liter {μmol/L}\] within any 48 hours or increase in SCr to ≥ 1.5 times baseline within 72 hours after end of surgery \[T0\]). Percentage of participants who developed AKI-SCr72h were reported.
Time frame: From end of surgery up to 72 hrs
Population: FAS consisted of all randomized participants who received at least 1 dose of study treatment. The outcome measure was planned to be analyzed for ASP1128 and Placebo only.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| ASP1128 | Percentage of Participants Developing AKI Based on Serum Creatinine (SCr) Criteria Within 72 Hrs From End of Surgery (AKI-SCr72h) | 24.6 percentage of participants |
| Placebo | Percentage of Participants Developing AKI Based on Serum Creatinine (SCr) Criteria Within 72 Hrs From End of Surgery (AKI-SCr72h) | 21.0 percentage of participants |
p-value: 0.59590% CI: [0.715, 1.927]Chi-squared
Secondary
Percentage of Participants Developing AKI Based on All Captured Criteria Within 72 Hrs From End of Surgery (AKI-KDIGO72h)
Development of AKI was based on all captured criteria from KDIGO guideline (i.e., AKI-SCr stage 1 to 3: increase in SCr ≥ 0.3 mg/dL \[≥ 26.5 μmol/L\] within any 48 hours, increase in SCr to ≥ 1.5 times baseline, and/or AKI-urinary output (UO) stage 2 and 3: urine volume \< 0.5 mL/kg per hour for 12 consecutive hours) within 72 hours after T0. Percentage of participants who developed AKI-KDIGO72h were reported.
Time frame: From end of surgery up to 72 hrs
Population: FAS Population. The outcome measure was planned to be analyzed for ASP1128 and Placebo only.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| ASP1128 | Percentage of Participants Developing AKI Based on All Captured Criteria Within 72 Hrs From End of Surgery (AKI-KDIGO72h) | 79.7 percentage of participants |
| Placebo | Percentage of Participants Developing AKI Based on All Captured Criteria Within 72 Hrs From End of Surgery (AKI-KDIGO72h) | 77.8 percentage of participants |
p-value: 0.77390% CI: [0.891, 1.179]Chi-squared
Secondary
Percentage of Participants Developing AKI Based on All Captured Criteria Within 7 Days From End of Surgery (AKI-KDIGO7d)
Development of AKI was based on all captured criteria from KDIGO guideline (i.e., AKI-SCr stage 1 to 3: increase in SCr ≥ 0.3 mg/dL \[≥ 26.5 μmol/L\] within any 48 hours, increase in SCr to ≥ 1.5 times baseline, and/or AKI-urinary output (UO) stage 2 and 3: urine volume \< 0.5 milliliter per kilogram (mL/kg) per hour for 12 consecutive hours) within 7 days after T0. Percentage of participants who developed AKI-KDIGO7d were reported.
Time frame: From end of surgery up to 7 days
Population: FAS Population. The outcome measure was planned to be analyzed for ASP1128 and Placebo only.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| ASP1128 | Percentage of Participants Developing AKI Based on All Captured Criteria Within 7 Days From End of Surgery (AKI-KDIGO7d) | 88.4 percentage of participants |
| Placebo | Percentage of Participants Developing AKI Based on All Captured Criteria Within 7 Days From End of Surgery (AKI-KDIGO7d) | 85.2 percentage of participants |
p-value: 0.56390% CI: [0.935, 1.152]Chi-squared
Secondary
Percentage of Participants Developing AKI Based on Serum Creatinine (SCr) Criteria Within 7 Days From End of Surgery (AKI-SCr7d)
Development of AKI was based on SCr criteria from the KDIGO guideline (i.e., increase in SCr ≥ 0.3 mg/dL \[≥ 26.5 μmol/L\] within any 48 hours or increase in SCr to ≥ 1.5 times baseline within 7 days after T0). Percentage of participants who developed AKI-SCr7d were reported.
Time frame: From end of surgery up to 7 days
Population: FAS Population. The outcome measure was planned to be analyzed for ASP1128 and Placebo only.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| ASP1128 | Percentage of Participants Developing AKI Based on Serum Creatinine (SCr) Criteria Within 7 Days From End of Surgery (AKI-SCr7d) | 30.4 percentage of participants |
| Placebo | Percentage of Participants Developing AKI Based on Serum Creatinine (SCr) Criteria Within 7 Days From End of Surgery (AKI-SCr7d) | 23.5 percentage of participants |
p-value: 0.33590% CI: [0.831, 2.026]Chi-squared
Secondary
Percentage of Participants With Major Adverse Kidney Events (MAKE) Within 30 Days After Day of Surgery (MAKE30)
MAKE30 was defined as all-cause mortality, renal replacement therapy (RRT) and/or ≥ 25% sustained reduction in estimated glomerular filtration rate (eGFR) based on SCr within 30 days after day of surgery. Percentage of participants with MAKE30 were reported.
Time frame: From day of surgery up to 30 days
Population: FAS Population. The outcome measure was planned to be analyzed for ASP1128 and Placebo only.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| ASP1128 | Percentage of Participants With Major Adverse Kidney Events (MAKE) Within 30 Days After Day of Surgery (MAKE30) | 13.0 percentage of participants |
| Placebo | Percentage of Participants With Major Adverse Kidney Events (MAKE) Within 30 Days After Day of Surgery (MAKE30) | 11.1 percentage of participants |
p-value: 0.71790% CI: [0.567, 2.429]Chi-squared
Secondary
Percentage of Participants With MAKE Within 90 Days After Day of Surgery (MAKE90)
MAKE90 was defined as all-cause mortality, renal replacement therapy (RRT) and/or ≥ 25% sustained reduction in estimated glomerular filtration rate (eGFR) based on SCr within 90 days after day of surgery. Percentage of participants with MAKE90 were reported.
Time frame: From day of surgery up to 90 days
Population: FAS Population. The outcome measure was planned to be analyzed for ASP1128 and Placebo only.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| ASP1128 | Percentage of Participants With MAKE Within 90 Days After Day of Surgery (MAKE90) | 15.9 percentage of participants |
| Placebo | Percentage of Participants With MAKE Within 90 Days After Day of Surgery (MAKE90) | 9.9 percentage of participants |
p-value: 0.26690% CI: [0.789, 3.3]Chi-squared