Acute Kidney Injury Due to Sepsis
Conditions
Brief summary
Clinical phase 3 study to investigate the effect of recAP on 28 day mortality in patients admitted to the ICU with acute kidney injury that is caused by sepsis. The study has three distinct SA-AKI trial populations: 1. The main trial population: Patients with a pre-AKI reference eGFR ≥45 mL/min/1.73 m2 and no proven or suspected SARS-CoV-2 at time of randomization. 2. A 'moderate' CKD population: Patients with a pre-AKI reference eGFR ≥25 and \<45 mL/min/1.73 m2 and no proven or suspected SARS-CoV-2 at time of randomization. 3. A Corona Virus Disease 2019 (COVID-19) population: Patients with proven or suspected SARS-CoV-2 at time of randomization with or without 'moderate' CKD. For patients in this population, COVID-19 should be the main cause of SA-AKI. In the main study population approximately 1400 patients will be enrolled and in the two cohorts with moderate CKD and COVID-19 each up to 100 patients. There are two arms in the study, one with active treatment and one with an inactive compound (placebo). Treatment is by 1 hour intravenous infusion, for three days. Patients are followed up for 28 days to see if there is an improvement on mortality, and followed for 90 and 180 days for mortality and other outcomes e.g. long-term kidney function and quality of life.
Detailed description
Sepsis is the leading cause of acute kidney injury (AKI) and a major cause of death. Patients with SA-AKI have a high mortality and morbidity and are at risk of developing chronic kidney disease. AP is a homodimeric endogenous enzyme present in many cells and organs, e.g., intestines, placenta, liver, bone, kidney, and granulocytes. It exerts detoxifying effects through dephosphorylation of endotoxins; pathogen associated molecular pattern molecules (PAMPS e.g., lipopolysaccharide) and damage-associated molecular pattern molecules (DAMPS e.g., adenosine tri- and di-phosphate). In animal models of sepsis and AKI, administration of AP attenuates the inflammatory response, improves renal function and/or reduces mortality. AM-Pharma B.V. is developing AP as a novel, recombinant chimeric human AP medicinal product, called recAP, to be used as an intravenous infusion for the treatment of SA-AKI. In the Phase 2 trial STOP-AKI, a survival benefit was observed in the two highest dose groups, 0.8 mg/kg and 1.6 mg/kg groups, compared to the placebo group. There were no safety or tolerability concerns for any of the doses tested (0.4, 0.8 and 1.6 mg/kg). The 1.6 mg/kg recAP dose was selected for this Phase 3 trial based on the significant survival benefit observed. PK/PD simulations also confirmed this dose to have the most pronounced treatment effect. The primary objective of this Phase 3 trial is to confirm the mortality benefit seen in STOP-AKI by demonstrating a reduction in 28 day all cause mortality in patients with SA-AKI treated with 1.6 mg/kg recAP.
Interventions
OTHERPlacebo
Placebo
BIOLOGICALRecombinant human alkaline phosphatase
patients with SA-AKI are randomly assigned in a 1:1 ratio to either placebo or 1.6 mg/kg recAP.
Sponsors
AM-Pharma
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. 18 years or older. 2. In the ICU or intermediate care unit for clinical reasons. 3. Have sepsis requiring vasopressor (norepinephrine, epinephrine, dopamine, phenylephrine, vasopressin, or angiotensin II) therapy, i.e.: 1. suspected or proven bacterial or viral infection. and 2. on vasopressor therapy (≥0.1 µg/kg/min norepinephrine or equivalent) for sepsis-induced hypotension for at least one hour despite adequate fluid resuscitation according to clinical judgement. Following the initial one hour on at least 0.1 µg/kg/min norepinephrine or equivalent, any dose of vasopressor counts as vasopressor therapy. The combination of a) and b) automatically ensures that patients fulfill the Sepsis 3 criteria as 0.1 µg/kg/min norepinephrine corresponds to a score of +4 on the Cardiovascular sub-score of the SOFA score. 4. Have AKI according to at least one of the below KDIGO criteria, a to d: 1. An absolute increase in serum or plasma creatinine (CR) by ≥0.3 mg/dL (≥26.5 µmol/L) within 48 hours. or 2. A relative increase in CR to ≥1.5 times the pre-AKI reference CR value which is known or presumed to have occurred within prior 7 days. or 3. A decrease in urinary output to \<0.5 mL/kg/hour for a minimum of 6 hours following adequate fluid resuscitation. or d) If the patient does not have a known history of CKD and there is no pre-AKI reference CR value available from the past 12 months available from the past 12 months: a CR value greater or equal to the levels presented in Table 1, with the increase in CR presumed to have occurred within prior 7 days. 5. Provision of signed and dated ICF in accordance with local regulations.
Exclusion criteria
1. a) At sites where enrolment of 'moderate' CKD patients is allowed, patients with 'severe' CKD defined as a pre-AKI reference eGFR \<25 mL/min/1.73 m2 are excluded. * For patients with known CKD, the most recent eGFR prior to index hospitalization needs to be documented as ≥25 mL/min/1.73 m2. * For patients with known CKD but no known eGFR prior to hospitalization, presentation eGFR between 25-60 mL/min/1.73 m2 can also be used to rule out 'severe' CKD. b) At sites where enrolment of 'moderate' CKD patients is NOT allowed, patients with 'moderate' and 'severe' CKD defined as a pre-AKI reference eGFR \<45 mL/min/1.73 m2 are excluded. * For patients with known CKD, the most recent eGFR prior to index hospitalization needs to be documented as ≥45 mL/min/1.73 m2. * For patients with known CKD but no known eGFR prior to hospitalization, presentation eGFR between 45-60 mL/min/1.73 m2 can also be used to rule out 'moderate' and 'severe' CKD. 2. Advanced chronic liver disease, defined as a Child-Pugh score of 10 to 15 (Class C). 3. Acute pancreatitis without proven infection. 4. Urosepsis related to suspected or proven urinary tract obstruction. 5. Main cause of AKI not sepsis. 6. Proven or suspected SARS-CoV-2 infection. NOTE: This exclusion criterion does not apply to patients in the COVID-19 population, in which COVID-19 should be the main cause of SA-AKI. 7. Severe burns requiring ICU treatment. 8. Severely immunosuppressed, e.g. due to: * hematopoietic cell transplantation within past 6 months prior to Screening or acute or chronic graft-versus-host disease * solid organ transplantation * leukopenia not related to sepsis, i.e., preceding sepsis * Human Immunodeficiency Virus (HIV)/Acquired Immune Deficiency Syndrome (AIDS) * receiving chemotherapy within 30 days prior to Screening. 9. At high risk of being LTFU, e.g., due to known current or recent (within the last 6 months) IV drug abuse or known to be homeless. 10. Limitations to use of mechanical ventilation (MV), RRT or vasopressors and inotropes (NOTE: limitation of cardiopulmonary resuscitation (CPR) only is not an exclusion criterion). 11. Previous administration of recAP. 12. Use of a non-marketed drug within the last month or concurrent or planned participation in a clinical trial for a non-marketed drug or device. (NOTE: Co-enrollment or concurrent participation in observational, non-interventional trials using no protocolized treatments or procedures are always allowed. Co-enrollment or concurrent participation in trials using protocolized treatments or procedures, e.g. blood draws, requires pre-approval by the TSC). 13. Current or planned extracorporeal membrane oxygenation (ECMO). 14. On RRT \>24 hours before start of trial drug. 15. No longer on vasopressor therapy at time of randomization. 16. On continuous vasopressor therapy for \>72 hours before start of trial drug. 17. Estimated glomerular filtration rate (eGFR) \>60 mL/min/1.73 m2 based on the most recent available CR sample at time of screening (NOTE: will often be the sample used to diagnose AKI). eGFR should be calculated using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) formula. In Japan, the CKD-EPI formula with Japanese coefficient should be used. If local regulations prohibit correcting for race in the calculation of eGFR, it is acceptable to use the formula without correcting for race. 18. Not feasible to start trial drug within: 1. 48 hours from AKI diagnosis, when AKI diagnosis precedes start of vasopressor therapy. or 2. 24 hours from AKI diagnosis, when AKI is diagnosed after start of vasopressor therapy. 19. Pregnant or nursing women.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 28-day All-cause Mortality: Main Trial Population | 28 days | To demonstrate an effect of recAP on 28 day all cause mortality |
| 28-day All-cause Mortality: Moderate Chronic Kidney Disease Population | 28 days | To demonstrate an effect of recAP on 28 day all cause mortality |
| 28-day All-cause Mortality: COVID-19 Population | 28 days | To demonstrate an effect of recAP on 28 day all cause mortality |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Major Adverse Kidney Events Through Day 90: Combined Population | 90 Days | Major Adverse Kidney Events through day 90 (MAKE90A) : * death until day 90 * greater than 25% drop in estimated glomerular filtration rate at Day 90 * on renal replacement therapy (RRT) at day 90 OR on RRT through Day 28 |
| Days Alive and Free of Organ Support Through Day 28: Main Trial Population | 28 days | Days alive and free of organ support through Day 28, ie, days alive with no mechanical ventilation (MV), Renal Replacement Therapy (RRT), vasopressors, or inotropes (with death within 28 days counting as zero days) |
| Days Alive and Free of Organ Support Through Day 28: Moderate Chronic Kidney Disease Population | 28 days | Days alive and free of organ support through Day 28, ie, days alive with no mechanical ventilation (MV), Renal Replacement Therapy (RRT), vasopressors, or inotropes (with death within 28 days counting as zero days) |
| Days Alive and Free of Organ Support Through Day 28: COVID-19 Population | 28 days | Days alive and free of organ support through Day 28, ie, days alive with no mechanical ventilation (MV), Renal Replacement Therapy (RRT), vasopressors, or inotropes (with death within 28 days counting as zero days) |
| Days Alive and Out of the ICU Through Day 28: Main Trial Population | 28 days | Days alive and out of the ICU through Day 28 (with death within 28 days counting as zero days). |
| Major Adverse Kidney Events 90: Main Trial Population | 90 Days | Major adverse kidney events (MAKE) 90: dead by Day 90 or on Renal Replacement Therapy (RRT) at Day 90 or greater than or equal to 25% decline in estimated glomerular filtration rate (eGFR) on both Day 28 and Day 90 relative to the known or assumed pre-acute kidney injury reference level. |
| Days Alive and Out of the ICU Through Day 28: COVID-19 Population | 28 days | Days alive and out of the ICU through Day 28 (with death within 28 days counting as zero days). |
| 90-day All Cause Mortality: Main Trial Population | 90 days | 90-Day all-cause mortality |
| 90-day All Cause Mortality: Moderate Chronic Kidney Disease Population | 90 days | 90-Day all-cause mortality |
| 90-day All Cause Mortality: COVID-19 Population | 90 days | 90-Day all-cause mortality |
| Days Alive and Out of the ICU Through Day 28: Moderate Chronic Kidney Disease Population | 28 days | Days alive and out of the ICU through Day 28 (with death within 28 days counting as zero days). |
| Major Adverse Kidney Events 90: Moderate Chronic Kidney Disease Population | 90 Days | Major adverse kidney events (MAKE) 90: dead by Day 90 or on Renal Replacement Therapy (RRT) at Day 90 or greater than or equal to 25% decline in estimated glomerular filtration rate (eGFR) on both Day 28 and Day 90 relative to the known or assumed pre-acute kidney injury reference level. |
| Major Adverse Kidney Events 90: COVID-19 Population | 90 Days | Major adverse kidney events (MAKE) 90: dead by Day 90 or on Renal Replacement Therapy (RRT) at Day 90 or greater than or equal to 25% decline in estimated glomerular filtration rate (eGFR) on both Day 28 and Day 90 relative to the known or assumed pre-acute kidney injury reference level. |
Countries
Australia, Austria, Belgium, Canada, Denmark, Finland, France, Germany, Ireland, Japan, Netherlands, New Zealand, Spain, United Kingdom, United States
Participant flow
Recruitment details
The target participant population consisted of adult participants in the intensive care unit or intermediate care unit with sepsis and new, recent onset acute kidney injury.
Pre-assignment details
676 participants were enrolled; 21 were screening failures and were not randomized. 5 participants (2 in the active group and 3 in the placebo group) were randomized, but not been exposed to any trial drug. Consequently, 650 patients have been randomized and treated (modified ITT population according to protocol). The mITT population is the basis for the primary efficacy analysis and most of the secondary analyses reported in clintrials.gov (1-6,8-16).
Participants by arm
| Arm | Count |
|---|---|
| Placebo (Main Trial Population) Matching placebo; 3 daily 1-hour continuous intravenous infusions on Days 1, 2 and 3
Main Trial Population: Participants with a pre-AKI reference eGFR greater than or equal to 45 mL/min/1.73 m2 and no proven or suspected COVID-19 at time of randomization | 277 |
| recAP 1.6 mg/kg (Main Trial Population) Recombinant human alkaline phosphatase (recAP) 1.6mg/kg; 3 daily 1-hour continuous intravenous infusions on Days 1, 2 and 3
Main Trial Population: Participants with a pre-AKI reference eGFR greater than or equal to 45 mL/min/1.73 m2 and no proven or suspected COVID-19 at time of randomization | 279 |
| Placebo (Moderate CKD Population) Matching placebo; 3 daily 1-hour continuous intravenous infusions on Days 1, 2 and 3.
Moderate chronic kidney disease (CKD) Population: Participants with a pre-acute kidney injury reference estimated glomerular filtration rate more than or equal to 25 and less than 45 mL/min/1.73 m2 and no proven or suspected COVID-19 at time of randomization | 31 |
| recAP 1.6 mg/kg (Moderate CKD Population) Recombinant human alkaline phosphatase (recAP) 1.6mg/kg; 3 daily 1-hour continuous intravenous infusions on Days 1, 2 and 3 Moderate chronic kidney disease (CKD) Population: Participants with a pre-acute kidney injury reference estimated glomerular filtration rate more than or equal to 25 and less than 45 mL/min/1.73 m2 and no proven or suspected COVID-19 at time of randomization | 30 |
| Placebo (COVID-19 Population) Matching placebo; 3 daily 1-hour continuous intravenous infusions on Days 1, 2 and 3.
COVID-19 Population: Participants with proven or suspected COVID-19 at time of randomization with or without 'moderate' chronic kidney disease and, for patients in this population, COVID-19 should have been the main cause of sepsis-associated acute kidney injury | 13 |
| recAP 1.6 mg/kg (COVID-19 Population) Recombinant human alkaline phosphatase (recAP) 1.6mg/kg; 3 daily 1-hour continuous intravenous infusions on Days 1, 2 and 3 COVID-19 Population: Participants with proven or suspected COVID-19 at time of randomization with or without 'moderate' chronic kidney disease and, for patients in this population, COVID-19 should have been the main cause of sepsis-associated acute kidney injury | 20 |
| Total | 650 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 |
|---|---|---|---|---|---|---|---|
| Overall Study | Adverse Event | 5 | 10 | 1 | 0 | 0 | 0 |
| Overall Study | Physician Decision | 1 | 0 | 0 | 0 | 0 | 0 |
| Overall Study | Protocol Violation | 1 | 0 | 0 | 0 | 0 | 0 |
| Overall Study | Study terminated by sponsor | 17 | 20 | 3 | 0 | 0 | 0 |
| Overall Study | Withdrawal by Subject | 0 | 1 | 0 | 1 | 0 | 0 |
Baseline characteristics
| Characteristic | Total | recAP 1.6 mg/kg (COVID-19 Population) | Placebo (COVID-19 Population) | recAP 1.6 mg/kg (Moderate CKD Population) | Placebo (Moderate CKD Population) | recAP 1.6 mg/kg (Main Trial Population) | Placebo (Main Trial Population) |
|---|---|---|---|---|---|---|---|
| Acute kidney injury diagnosis creatinine | 209.00 μmol/L STANDARD_DEVIATION 140.799 | 211.30 μmol/L STANDARD_DEVIATION 148.803 | 176.20 μmol/L STANDARD_DEVIATION 42.57 | 210.11 μmol/L STANDARD_DEVIATION 93.54 | 270.10 μmol/L STANDARD_DEVIATION 286.051 | 200.06 μmol/L STANDARD_DEVIATION 123.685 | 212.43 μmol/L STANDARD_DEVIATION 138.656 |
| Acute kidney injury diagnosis estimated glomerular filtration rate | 32.39 mL/min/1.73 m² STANDARD_DEVIATION 15.045 | 35.42 mL/min/1.73 m² STANDARD_DEVIATION 16.461 | 33.54 mL/min/1.73 m² STANDARD_DEVIATION 7.002 | 30.97 mL/min/1.73 m² STANDARD_DEVIATION 20.116 | 25.93 mL/min/1.73 m² STANDARD_DEVIATION 12.042 | 33.10 mL/min/1.73 m² STANDARD_DEVIATION 14.958 | 32.28 mL/min/1.73 m² STANDARD_DEVIATION 14.888 |
| Acute Physiology and Chronic Health Evaluation II total score | 23.3 score STANDARD_DEVIATION 7.34 | 23.6 score STANDARD_DEVIATION 8.31 | 23.1 score STANDARD_DEVIATION 6.87 | 23.6 score STANDARD_DEVIATION 5.77 | 25.8 score STANDARD_DEVIATION 7 | 23.2 score STANDARD_DEVIATION 7.65 | 23.2 score STANDARD_DEVIATION 7.17 |
| Age, Continuous | 68.0 years STANDARD_DEVIATION 11.69 | 62.8 years STANDARD_DEVIATION 10.35 | 68.8 years STANDARD_DEVIATION 7.67 | 70.2 years STANDARD_DEVIATION 11.28 | 73.2 years STANDARD_DEVIATION 8.9 | 68.4 years STANDARD_DEVIATION 10.94 | 67.1 years STANDARD_DEVIATION 12.73 |
| Height | 170.7 centimeters STANDARD_DEVIATION 10.12 | 174.3 centimeters STANDARD_DEVIATION 10.06 | 170.0 centimeters STANDARD_DEVIATION 10.13 | 171.8 centimeters STANDARD_DEVIATION 8.98 | 171.2 centimeters STANDARD_DEVIATION 8.84 | 170.5 centimeters STANDARD_DEVIATION 10.3 | 170.4 centimeters STANDARD_DEVIATION 10.2 |
| KDIGO Chronic Kidney Disease stage 1 | 148 Participants | 3 Participants | 3 Participants | 2 Participants | 4 Participants | 69 Participants | 67 Participants |
| KDIGO Chronic Kidney Disease stage 2 | 341 Participants | 13 Participants | 8 Participants | 9 Participants | 6 Participants | 153 Participants | 152 Participants |
| KDIGO Chronic Kidney Disease stage 3a | 110 Participants | 3 Participants | 2 Participants | 0 Participants | 2 Participants | 50 Participants | 53 Participants |
| KDIGO Chronic Kidney Disease stage 3b | 42 Participants | 0 Participants | 0 Participants | 17 Participants | 15 Participants | 7 Participants | 3 Participants |
| KDIGO Chronic Kidney Disease stage 4 | 7 Participants | 1 Participants | 0 Participants | 2 Participants | 3 Participants | 0 Participants | 1 Participants |
| KDIGO Chronic Kidney Disease stage 5 | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants |
| KDIGO Chronic Kidney Disease stage Missing | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants |
| Modified sequential organ failure assessment total score (eCRF) | 9.3 score STANDARD_DEVIATION 2.34 | 9.6 score STANDARD_DEVIATION 2.03 | 9.4 score STANDARD_DEVIATION 1.66 | 9.0 score STANDARD_DEVIATION 1.88 | 9.5 score STANDARD_DEVIATION 1.46 | 9.1 score STANDARD_DEVIATION 2.33 | 9.4 score STANDARD_DEVIATION 2.52 |
| Pre-acute kidney injury reference creatinine | 87.42 μmol/L STANDARD_DEVIATION 28.542 | 95.97 μmol/L STANDARD_DEVIATION 27.159 | 87.99 μmol/L STANDARD_DEVIATION 23.494 | 122.56 μmol/L STANDARD_DEVIATION 33.684 | 130.42 μmol/L STANDARD_DEVIATION 56.751 | 82.23 μmol/L STANDARD_DEVIATION 21.865 | 83.36 μmol/L STANDARD_DEVIATION 22.316 |
| Pre-acute kidney injury reference estimated glomerular filtration rate | 73.84 mL/min/1.73 m² STANDARD_DEVIATION 19.917 | 72.82 mL/min/1.73 m² STANDARD_DEVIATION 18.438 | 74.88 mL/min/1.73 m² STANDARD_DEVIATION 15.742 | 51.57 mL/min/1.73 m² STANDARD_DEVIATION 21.945 | 52.36 mL/min/1.73 m² STANDARD_DEVIATION 25.715 | 76.35 mL/min/1.73 m² STANDARD_DEVIATION 18.059 | 76.16 mL/min/1.73 m² STANDARD_DEVIATION 18.16 |
| Race (NIH/OMB) American Indian or Alaska Native | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 41 Participants | 1 Participants | 1 Participants | 0 Participants | 0 Participants | 16 Participants | 23 Participants |
| Race (NIH/OMB) Black or African American | 19 Participants | 3 Participants | 0 Participants | 1 Participants | 0 Participants | 6 Participants | 9 Participants |
| Race (NIH/OMB) More than one race | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 49 Participants | 1 Participants | 1 Participants | 3 Participants | 4 Participants | 22 Participants | 18 Participants |
| Race (NIH/OMB) White | 539 Participants | 15 Participants | 11 Participants | 26 Participants | 27 Participants | 233 Participants | 227 Participants |
| Sex: Female, Male Female | 237 Participants | 6 Participants | 2 Participants | 12 Participants | 8 Participants | 105 Participants | 104 Participants |
| Sex: Female, Male Male | 413 Participants | 14 Participants | 11 Participants | 18 Participants | 23 Participants | 174 Participants | 173 Participants |
| Weight | 87.6 kilograms STANDARD_DEVIATION 25.06 | 87.1 kilograms STANDARD_DEVIATION 19.39 | 98.9 kilograms STANDARD_DEVIATION 26.67 | 86.5 kilograms STANDARD_DEVIATION 16.94 | 87.3 kilograms STANDARD_DEVIATION 17.08 | 87.9 kilograms STANDARD_DEVIATION 25.67 | 86.9 kilograms STANDARD_DEVIATION 26.23 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk |
|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 92 / 276 | 108 / 280 | 14 / 31 | 7 / 30 | 11 / 13 | 7 / 20 |
| other Total, other adverse events | 142 / 276 | 131 / 280 | 18 / 31 | 13 / 30 | 5 / 13 | 12 / 20 |
| serious Total, serious adverse events | 112 / 276 | 125 / 280 | 18 / 31 | 11 / 30 | 11 / 13 | 7 / 20 |
Outcome results
Primary
28-day All-cause Mortality: COVID-19 Population
To demonstrate an effect of recAP on 28 day all cause mortality
Time frame: 28 days
Population: COVID-19 modified intent-to-treat Population
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Placebo | 28-day All-cause Mortality: COVID-19 Population | Participants with known survival status at Day 28 | 13 Participants |
| Placebo | 28-day All-cause Mortality: COVID-19 Population | Number of participants died by Day 28 | 11 Participants |
| Placebo | 28-day All-cause Mortality: COVID-19 Population | Participants where survival status is unknown at Day 28 | 0 Participants |
| recAP 1.6 mg/kg | 28-day All-cause Mortality: COVID-19 Population | Participants with known survival status at Day 28 | 20 Participants |
| recAP 1.6 mg/kg | 28-day All-cause Mortality: COVID-19 Population | Number of participants died by Day 28 | 5 Participants |
| recAP 1.6 mg/kg | 28-day All-cause Mortality: COVID-19 Population | Participants where survival status is unknown at Day 28 | 0 Participants |
p-value: 0.00895% CI: [0.001, 0.405]One-sided p-value
Primary
28-day All-cause Mortality: Main Trial Population
To demonstrate an effect of recAP on 28 day all cause mortality
Time frame: 28 days
Population: Main Trial modified intent-to-treat Population
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Placebo | 28-day All-cause Mortality: Main Trial Population | Participants with known survival status at Day 28 | 272 Participants |
| Placebo | 28-day All-cause Mortality: Main Trial Population | Number of participants died by Day 28 | 69 Participants |
| Placebo | 28-day All-cause Mortality: Main Trial Population | Participants where survival status is unknown at Day 28 | 5 Participants |
| recAP 1.6 mg/kg | 28-day All-cause Mortality: Main Trial Population | Participants with known survival status at Day 28 | 279 Participants |
| recAP 1.6 mg/kg | 28-day All-cause Mortality: Main Trial Population | Number of participants died by Day 28 | 80 Participants |
| recAP 1.6 mg/kg | 28-day All-cause Mortality: Main Trial Population | Participants where survival status is unknown at Day 28 | 0 Participants |
p-value: 0.802595% CI: [0.805, 1.732]One-sided p-value
Primary
28-day All-cause Mortality: Moderate Chronic Kidney Disease Population
To demonstrate an effect of recAP on 28 day all cause mortality
Time frame: 28 days
Population: Moderate Chronic Kidney Disease modified intent-to-treat Population
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Placebo | 28-day All-cause Mortality: Moderate Chronic Kidney Disease Population | Participants with known survival status at Day 28 | 31 Participants |
| Placebo | 28-day All-cause Mortality: Moderate Chronic Kidney Disease Population | Number of participants died by Day 28 | 10 Participants |
| Placebo | 28-day All-cause Mortality: Moderate Chronic Kidney Disease Population | Participants where survival status is unknown at Day 28 | 0 Participants |
| recAP 1.6 mg/kg | 28-day All-cause Mortality: Moderate Chronic Kidney Disease Population | Participants with known survival status at Day 28 | 29 Participants |
| recAP 1.6 mg/kg | 28-day All-cause Mortality: Moderate Chronic Kidney Disease Population | Number of participants died by Day 28 | 6 Participants |
| recAP 1.6 mg/kg | 28-day All-cause Mortality: Moderate Chronic Kidney Disease Population | Participants where survival status is unknown at Day 28 | 1 Participants |
p-value: 0.182495% CI: [0.139, 2.131]One-sided p-value
Secondary
90-day All Cause Mortality: COVID-19 Population
90-Day all-cause mortality
Time frame: 90 days
Population: COVID-19 modified intent-to-treat Population
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Placebo | 90-day All Cause Mortality: COVID-19 Population | Participants with event | 11 Participants |
| Placebo | 90-day All Cause Mortality: COVID-19 Population | Participants censored | 2 Participants |
| recAP 1.6 mg/kg | 90-day All Cause Mortality: COVID-19 Population | Participants with event | 6 Participants |
| recAP 1.6 mg/kg | 90-day All Cause Mortality: COVID-19 Population | Participants censored | 14 Participants |
p-value: <0.000195% CI: [0.001, 0.054]One-sided p-value
Secondary
90-day All Cause Mortality: Main Trial Population
90-Day all-cause mortality
Time frame: 90 days
Population: Main Trial modified intent-to-treat Population
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Placebo | 90-day All Cause Mortality: Main Trial Population | Participants with event | 89 Participants |
| Placebo | 90-day All Cause Mortality: Main Trial Population | Participants censored | 188 Participants |
| recAP 1.6 mg/kg | 90-day All Cause Mortality: Main Trial Population | Participants with event | 97 Participants |
| recAP 1.6 mg/kg | 90-day All Cause Mortality: Main Trial Population | Participants censored | 182 Participants |
p-value: 0.691695% CI: [0.806, 1.437]One-sided p-value
Secondary
90-day All Cause Mortality: Moderate Chronic Kidney Disease Population
90-Day all-cause mortality
Time frame: 90 days
Population: Moderate Chronic Kidney Disease modified intent-to-treat Population
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Placebo | 90-day All Cause Mortality: Moderate Chronic Kidney Disease Population | Participants with event | 13 Participants |
| Placebo | 90-day All Cause Mortality: Moderate Chronic Kidney Disease Population | Participants censored | 18 Participants |
| recAP 1.6 mg/kg | 90-day All Cause Mortality: Moderate Chronic Kidney Disease Population | Participants with event | 7 Participants |
| recAP 1.6 mg/kg | 90-day All Cause Mortality: Moderate Chronic Kidney Disease Population | Participants censored | 23 Participants |
p-value: 0.062895% CI: [0.18, 1.234]One-sided p-value
Secondary
Days Alive and Free of Organ Support Through Day 28: COVID-19 Population
Days alive and free of organ support through Day 28, ie, days alive with no mechanical ventilation (MV), Renal Replacement Therapy (RRT), vasopressors, or inotropes (with death within 28 days counting as zero days)
Time frame: 28 days
Population: COVID-19 modified intent-to-treat Population
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Days Alive and Free of Organ Support Through Day 28: COVID-19 Population | Days alive and free of organ support through to Day 28 | 1.5 days | Standard Deviation 5.27 |
| Placebo | Days Alive and Free of Organ Support Through Day 28: COVID-19 Population | Number of days free of MV | 3.3 days | Standard Deviation 8.14 |
| Placebo | Days Alive and Free of Organ Support Through Day 28: COVID-19 Population | Number of days free of RRT | 2.3 days | Standard Deviation 7.74 |
| Placebo | Days Alive and Free of Organ Support Through Day 28: COVID-19 Population | Number of days free of vasopressors and inotropes | 3.6 days | Standard Deviation 8.83 |
| recAP 1.6 mg/kg | Days Alive and Free of Organ Support Through Day 28: COVID-19 Population | Number of days free of vasopressors and inotropes | 14.9 days | Standard Deviation 11.29 |
| recAP 1.6 mg/kg | Days Alive and Free of Organ Support Through Day 28: COVID-19 Population | Days alive and free of organ support through to Day 28 | 8.3 days | Standard Deviation 10.24 |
| recAP 1.6 mg/kg | Days Alive and Free of Organ Support Through Day 28: COVID-19 Population | Number of days free of RRT | 19.7 days | Standard Deviation 13.09 |
| recAP 1.6 mg/kg | Days Alive and Free of Organ Support Through Day 28: COVID-19 Population | Number of days free of MV | 8.6 days | Standard Deviation 10.85 |
Comparison: Days alive and free of organ support through Day 28p-value: 1One-sided p-value from re-randomization
Comparison: Number of days free of MVp-value: 0.979One-sided p-value from re-randomization
Comparison: Number of days free of RRTp-value: 0.675One-sided p-value from re-randomization
Comparison: Number of days free of vasopressors and inotropesp-value: 0.031One-sided p-value from re-randomization
Secondary
Days Alive and Free of Organ Support Through Day 28: Main Trial Population
Days alive and free of organ support through Day 28, ie, days alive with no mechanical ventilation (MV), Renal Replacement Therapy (RRT), vasopressors, or inotropes (with death within 28 days counting as zero days)
Time frame: 28 days
Population: Main Trial modified intent-to-treat Population
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Days Alive and Free of Organ Support Through Day 28: Main Trial Population | Days alive and free of organ support through to Day 28 | 13.2 days | Standard Deviation 11.33 |
| Placebo | Days Alive and Free of Organ Support Through Day 28: Main Trial Population | Number of days free of MV | 14.7 days | Standard Deviation 11.93 |
| Placebo | Days Alive and Free of Organ Support Through Day 28: Main Trial Population | Number of days free of RRT | 18.4 days | Standard Deviation 12.4 |
| Placebo | Days Alive and Free of Organ Support Through Day 28: Main Trial Population | Number of days free of vasopressors and inotropes | 16.5 days | Standard Deviation 10.85 |
| recAP 1.6 mg/kg | Days Alive and Free of Organ Support Through Day 28: Main Trial Population | Number of days free of vasopressors and inotropes | 15.9 days | Standard Deviation 11.17 |
| recAP 1.6 mg/kg | Days Alive and Free of Organ Support Through Day 28: Main Trial Population | Days alive and free of organ support through to Day 28 | 12.8 days | Standard Deviation 11.34 |
| recAP 1.6 mg/kg | Days Alive and Free of Organ Support Through Day 28: Main Trial Population | Number of days free of RRT | 17.9 days | Standard Deviation 12.64 |
| recAP 1.6 mg/kg | Days Alive and Free of Organ Support Through Day 28: Main Trial Population | Number of days free of MV | 14.3 days | Standard Deviation 12.19 |
Comparison: Days alive and free of organ support through to Day 28p-value: 0.546One-sided p-value from re-randomization
Comparison: Number of days free of MVp-value: 0.677One-sided p-value from re-randomization
Comparison: Number of days free of RRTp-value: 0.993One-sided p-value from re-randomization
Comparison: Number of days free of vasopressors and inotropesp-value: 0.779One-sided p-value from re-randomization
Secondary
Days Alive and Free of Organ Support Through Day 28: Moderate Chronic Kidney Disease Population
Days alive and free of organ support through Day 28, ie, days alive with no mechanical ventilation (MV), Renal Replacement Therapy (RRT), vasopressors, or inotropes (with death within 28 days counting as zero days)
Time frame: 28 days
Population: Moderate Chronic Kidney Disease modified intent-to-treat Population
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Days Alive and Free of Organ Support Through Day 28: Moderate Chronic Kidney Disease Population | Days alive and free of organ support through to Day 28 | 10.5 days | Standard Deviation 10.59 |
| Placebo | Days Alive and Free of Organ Support Through Day 28: Moderate Chronic Kidney Disease Population | Number of days free of MV | 11.2 days | Standard Deviation 11.47 |
| Placebo | Days Alive and Free of Organ Support Through Day 28: Moderate Chronic Kidney Disease Population | Number of days free of RRT | 17.8 days | Standard Deviation 12.81 |
| Placebo | Days Alive and Free of Organ Support Through Day 28: Moderate Chronic Kidney Disease Population | Number of days free of vasopressors and inotropes | 14.8 days | Standard Deviation 11.15 |
| recAP 1.6 mg/kg | Days Alive and Free of Organ Support Through Day 28: Moderate Chronic Kidney Disease Population | Number of days free of vasopressors and inotropes | 19.4 days | Standard Deviation 10.58 |
| recAP 1.6 mg/kg | Days Alive and Free of Organ Support Through Day 28: Moderate Chronic Kidney Disease Population | Days alive and free of organ support through to Day 28 | 17.2 days | Standard Deviation 10.39 |
| recAP 1.6 mg/kg | Days Alive and Free of Organ Support Through Day 28: Moderate Chronic Kidney Disease Population | Number of days free of RRT | 21.4 days | Standard Deviation 11.71 |
| recAP 1.6 mg/kg | Days Alive and Free of Organ Support Through Day 28: Moderate Chronic Kidney Disease Population | Number of days free of MV | 18.1 days | Standard Deviation 11.11 |
Comparison: Days alive and free of organ support through Day 28p-value: 0.051One-sided p-value from re-randomization
Comparison: Number of days free of MVp-value: 0.013One-sided p-value from re-randomization
Comparison: Number of days free of RRTp-value: 0.025One-sided p-value from re-randomization
Comparison: Number of days free of vasopressors and inotropesp-value: 0.073One-sided p-value from re-randomization
Secondary
Days Alive and Out of the ICU Through Day 28: COVID-19 Population
Days alive and out of the ICU through Day 28 (with death within 28 days counting as zero days).
Time frame: 28 days
Population: COVID-19 modified intent-to-treat Population
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Days Alive and Out of the ICU Through Day 28: COVID-19 Population | 3.0 Days | Standard Deviation 7.39 |
| recAP 1.6 mg/kg | Days Alive and Out of the ICU Through Day 28: COVID-19 Population | 7.5 Days | Standard Deviation 9.6 |
p-value: 0.979One-sided p-value from re-randomization
Secondary
Days Alive and Out of the ICU Through Day 28: Main Trial Population
Days alive and out of the ICU through Day 28 (with death within 28 days counting as zero days).
Time frame: 28 days
Population: Main Trial modified intent-to-treat Population
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Days Alive and Out of the ICU Through Day 28: Main Trial Population | 11.4 Days | Standard Deviation 10.56 |
| recAP 1.6 mg/kg | Days Alive and Out of the ICU Through Day 28: Main Trial Population | 11.4 Days | Standard Deviation 10.42 |
p-value: 0.545One-sided p-value from re-randomization
Secondary
Days Alive and Out of the ICU Through Day 28: Moderate Chronic Kidney Disease Population
Days alive and out of the ICU through Day 28 (with death within 28 days counting as zero days).
Time frame: 28 days
Population: Moderate Chronic Kidney Disease modified intent-to-treat Population
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Days Alive and Out of the ICU Through Day 28: Moderate Chronic Kidney Disease Population | 8.1 Days | Standard Deviation 9.6 |
| recAP 1.6 mg/kg | Days Alive and Out of the ICU Through Day 28: Moderate Chronic Kidney Disease Population | 14.7 Days | Standard Deviation 10.09 |
p-value: 0.081One-sided p-value from re-randomization
Secondary
Major Adverse Kidney Events 90: COVID-19 Population
Major adverse kidney events (MAKE) 90: dead by Day 90 or on Renal Replacement Therapy (RRT) at Day 90 or greater than or equal to 25% decline in estimated glomerular filtration rate (eGFR) on both Day 28 and Day 90 relative to the known or assumed pre-acute kidney injury reference level.
Time frame: 90 Days
Population: COVID-19 modified intent-to-treat Population
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Placebo | Major Adverse Kidney Events 90: COVID-19 Population | Participants with unknown data on MAKE 90 | 0 Participants |
| Placebo | Major Adverse Kidney Events 90: COVID-19 Population | MAKE 90: On RRT | 0 Participants |
| Placebo | Major Adverse Kidney Events 90: COVID-19 Population | MAKE 90: Dead | 11 Participants |
| Placebo | Major Adverse Kidney Events 90: COVID-19 Population | MAKE 90: greater than or equal to 25% decline in eGFR rate on both Day 28 and Day 90 | 1 Participants |
| Placebo | Major Adverse Kidney Events 90: COVID-19 Population | Participants with missing data on MAKE 90 | 1 Participants |
| recAP 1.6 mg/kg | Major Adverse Kidney Events 90: COVID-19 Population | MAKE 90: greater than or equal to 25% decline in eGFR rate on both Day 28 and Day 90 | 0 Participants |
| recAP 1.6 mg/kg | Major Adverse Kidney Events 90: COVID-19 Population | Participants with missing data on MAKE 90 | 4 Participants |
| recAP 1.6 mg/kg | Major Adverse Kidney Events 90: COVID-19 Population | Participants with unknown data on MAKE 90 | 0 Participants |
| recAP 1.6 mg/kg | Major Adverse Kidney Events 90: COVID-19 Population | MAKE 90: Dead | 6 Participants |
| recAP 1.6 mg/kg | Major Adverse Kidney Events 90: COVID-19 Population | MAKE 90: On RRT | 0 Participants |
Secondary
Major Adverse Kidney Events 90: Main Trial Population
Major adverse kidney events (MAKE) 90: dead by Day 90 or on Renal Replacement Therapy (RRT) at Day 90 or greater than or equal to 25% decline in estimated glomerular filtration rate (eGFR) on both Day 28 and Day 90 relative to the known or assumed pre-acute kidney injury reference level.
Time frame: 90 Days
Population: Main Trial modified intent-to-treat Population
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Placebo | Major Adverse Kidney Events 90: Main Trial Population | MAKE 90: Dead | 89 Participants |
| Placebo | Major Adverse Kidney Events 90: Main Trial Population | MAKE 90: On RRT | 2 Participants |
| Placebo | Major Adverse Kidney Events 90: Main Trial Population | Participants with missing data on MAKE 90 | 36 Participants |
| Placebo | Major Adverse Kidney Events 90: Main Trial Population | Participants with unknown data on MAKE 90 | 46 Participants |
| Placebo | Major Adverse Kidney Events 90: Main Trial Population | MAKE 90: greater than or equal to 25% decline in eGFR rate on both Day 28 and Day 90 | 15 Participants |
| recAP 1.6 mg/kg | Major Adverse Kidney Events 90: Main Trial Population | MAKE 90: greater than or equal to 25% decline in eGFR rate on both Day 28 and Day 90 | 7 Participants |
| recAP 1.6 mg/kg | Major Adverse Kidney Events 90: Main Trial Population | MAKE 90: Dead | 97 Participants |
| recAP 1.6 mg/kg | Major Adverse Kidney Events 90: Main Trial Population | Participants with unknown data on MAKE 90 | 34 Participants |
| recAP 1.6 mg/kg | Major Adverse Kidney Events 90: Main Trial Population | MAKE 90: On RRT | 0 Participants |
| recAP 1.6 mg/kg | Major Adverse Kidney Events 90: Main Trial Population | Participants with missing data on MAKE 90 | 49 Participants |
p-value: 0.389495% CI: [0.606, 1.454]One-sided p-value
Secondary
Major Adverse Kidney Events 90: Moderate Chronic Kidney Disease Population
Major adverse kidney events (MAKE) 90: dead by Day 90 or on Renal Replacement Therapy (RRT) at Day 90 or greater than or equal to 25% decline in estimated glomerular filtration rate (eGFR) on both Day 28 and Day 90 relative to the known or assumed pre-acute kidney injury reference level.
Time frame: 90 Days
Population: Moderate Chronic Kidney Disease modified intent-to-treat Population
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Placebo | Major Adverse Kidney Events 90: Moderate Chronic Kidney Disease Population | Participants with unknown data on MAKE 90 | 2 Participants |
| Placebo | Major Adverse Kidney Events 90: Moderate Chronic Kidney Disease Population | MAKE 90: On RRT | 0 Participants |
| Placebo | Major Adverse Kidney Events 90: Moderate Chronic Kidney Disease Population | MAKE 90: Dead | 13 Participants |
| Placebo | Major Adverse Kidney Events 90: Moderate Chronic Kidney Disease Population | MAKE 90: greater than or equal to 25% decline in eGFR rate on both Day 28 and Day 90 | 1 Participants |
| Placebo | Major Adverse Kidney Events 90: Moderate Chronic Kidney Disease Population | Participants with missing data on MAKE 90 | 7 Participants |
| recAP 1.6 mg/kg | Major Adverse Kidney Events 90: Moderate Chronic Kidney Disease Population | MAKE 90: greater than or equal to 25% decline in eGFR rate on both Day 28 and Day 90 | 1 Participants |
| recAP 1.6 mg/kg | Major Adverse Kidney Events 90: Moderate Chronic Kidney Disease Population | Participants with missing data on MAKE 90 | 7 Participants |
| recAP 1.6 mg/kg | Major Adverse Kidney Events 90: Moderate Chronic Kidney Disease Population | Participants with unknown data on MAKE 90 | 6 Participants |
| recAP 1.6 mg/kg | Major Adverse Kidney Events 90: Moderate Chronic Kidney Disease Population | MAKE 90: Dead | 7 Participants |
| recAP 1.6 mg/kg | Major Adverse Kidney Events 90: Moderate Chronic Kidney Disease Population | MAKE 90: On RRT | 0 Participants |
p-value: 0.123795% CI: [0.128, 1.697]One-sided p-value
Secondary
Major Adverse Kidney Events Through Day 90: Combined Population
Major Adverse Kidney Events through day 90 (MAKE90A) : * death until day 90 * greater than 25% drop in estimated glomerular filtration rate at Day 90 * on renal replacement therapy (RRT) at day 90 OR on RRT through Day 28
Time frame: 90 Days
Population: Combined population: From the 650 patients in the mITT population (321 Placebo and 329 recAP), 649 were analysed in the combined population (1 participant randomized and treated with placebo has been excluded as no efficacy data were available). In the combined population participants were analyzed as treated, resulting in 319 Placebo and 330 recAP participants (2 participants randomized to Placebo were treated with recAP, 1 participant randomized to recAP was treated with placebo).
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Placebo | Major Adverse Kidney Events Through Day 90: Combined Population | Death until day 90 | 111 Participants |
| Placebo | Major Adverse Kidney Events Through Day 90: Combined Population | On RRT at Day 90 visit OR on RRT through day 28 | 116 Participants |
| Placebo | Major Adverse Kidney Events Through Day 90: Combined Population | Greater than 25% drop in eGFR at Day 90 visit | 28 Participants |
| Placebo | Major Adverse Kidney Events Through Day 90: Combined Population | Rehospitalization | 30 Participants |
| Placebo | Major Adverse Kidney Events Through Day 90: Combined Population | MAKE90A | 206 Participants |
| recAP 1.6 mg/kg | Major Adverse Kidney Events Through Day 90: Combined Population | Rehospitalization | 28 Participants |
| recAP 1.6 mg/kg | Major Adverse Kidney Events Through Day 90: Combined Population | MAKE90A | 187 Participants |
| recAP 1.6 mg/kg | Major Adverse Kidney Events Through Day 90: Combined Population | Death until day 90 | 112 Participants |
| recAP 1.6 mg/kg | Major Adverse Kidney Events Through Day 90: Combined Population | Greater than 25% drop in eGFR at Day 90 visit | 19 Participants |
| recAP 1.6 mg/kg | Major Adverse Kidney Events Through Day 90: Combined Population | On RRT at Day 90 visit OR on RRT through day 28 | 93 Participants |
p-value: 0.01995% CI: [-15.4, -0.4]one-sided p-value