Acute Kidney Injury (AKI)
Conditions
Keywords
AKI
Brief summary
The purpose of the clinical study is to assess safety, tolerability and pharmacokinetics of RMC-035 for the prevention and treatment of acute kidney injury (AKI) in patients undergoing cardiac surgery.
Detailed description
This is a study with two parallel treatment groups where subjects are randomized to receive RMC-035 or a matching placebo in a double-blind fashion. The study will comprise of a screening visit, followed by CABG and/or valve replacement on Day 1, double-blind treatment period and a follow-up period up to Day 30.
Interventions
DRUGRMC-035
Multiple dosing during 48 hours following cardiac surgery
DRUGPlacebo
Multiple dosing during 48 hours following cardiac surgery
Sponsors
Guard Therapeutics AB
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 70 Years
Healthy volunteers
No
Inclusion criteria
Key Inclusion Criteria: * Female and male subjects with an age ≥18 years * Subject is scheduled for non-emergent (elective) CABG and/or valve surgery (single or multiple valves) with use of cardiopulmonary bypass (CPB) * Subject has at least ONE of the following risk factors for AKI at screening: * History of LVEF \<35% for at least 3 months prior to screening assessed by either echocardiography, cardiac MRI or nuclear scan. * History of previous open chest cavity cardiac surgery with or without CPB * Confirmed diagnosis of type 2 diabetes (T2DM) at least 3 months prior to screening AND ongoing treatment with an approved anti-diabetic drug * Age ≥70 years * Documented history of heart failure NYHA class II or higher for at least 3 months or longer at screening * Documented history of previous AKI before date of screening independent of the etiology of AKI * Documented history of anemia with hemoglobin ≤ 11 g/dL (≤6.8 mmol/L) for at least 3 months prior to screening * Documented history of albuminuria, defined as UACR \>30 mg/g or \> 30 mg/24 hour in a 24-hour urine collection. * eGFR is ≤ 60 mL/min/1.73 m2 using the Chronic Kidney Disease - Epidemiology Collaboration (CKD-EPI) equation Key
Exclusion criteria
* Estimated glomerular filtration rate (eGFR) is \<30 mL/min/1.73 m2 using the Chronic Kidney Disease - Epidemiology Collaboration (CKD-EPI) equation at screening or at baseline * Subject has surgery scheduled to be performed without CPB (off-pump) * Subject has surgery scheduled for aortic dissection * Subject is scheduled for CABG and/or valve surgery combined with additional non-emergent cardiac surgeries, e.g. for atrial fibrillation ablation * Subject is scheduled to undergo trans catheter aortic valve implantation (TAVI) or trans catheter aortic valve replacement (TAVR), or single vessel off-pump surgeries or left ventricular device (LVAD) implantation * Subject has a requirement for any of the following within one week prior to surgery: defibrillator or permanent pacemaker, mechanical ventilation, IABP, LVAD, other forms of mechanical circulatory support (MCS) (Note: The prophylactic insertion of an IABP preoperatively for reasons not related to existing LV pump function is not exclusionary)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Frequency of Adverse Events (AEs) | Baseline through day 30 | * number (%) of subjects with at least one AE * number (%) of subjects with at least one SAE * number (%) of subjects with at least one Treatment-Emergent AE (TEAE) * number (%) of subjects with at least one serious TEAE * number (%) of subjects with at least one non-serious TEAE * number (%) of subjects with at least one TEAE of special interest * number (%) of subjects with at least one TEAEs reported as related (possible/probable) to IMP * number (%) of subjects with at least one TEAEs leading to withdrawal of IMP |
| Severity of AEs | Within 4 days from first dose of IMP | \- Number of TEAEs per category (mild, moderate, severe life-threatening, death) |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Maximum Observed Concentration (Cmax) | Blood samples taken from pre-dose and up to two hours after start of Dose 5 | Analysis of RMC-035 concentration in plasma (AUC + t1/2) after fourth infusion. |
| Area Under the Curve (AUC) 0-24h | Blood samples taken from pre-dose and up to two hours after start of Dose 5 | Analysis of RMC-035 concentrations in plasma following the fourth infusion. |
| Elimination Half-life (T1/2) | Blood samples taken from pre-dose and up to two hours after start of Dose 5 | Analysis of RMC-035 concentration in plasma following the fourth infusion |
Countries
Germany
Participant flow
Pre-assignment details
In this study, 13 subjects were enrolled, ie agreed to participate in the study following completion of the informed consent process. However, 1 subject did not fulfill all eligibility criteria and was not randomization. Hence, 12 subjects started the study, ie were assigned to one of the treatment arms.
Participants by arm
| Arm | Count |
|---|---|
| RMC-035 Participants received RMC-035 intravenously
RMC-035: Multiple dosing during 48 hours following cardiac surgery | 8 |
| Placebo Participants received matching placebo solution intravenously
Placebo: Multiple dosing during 48 hours following cardiac surgery | 4 |
| Total | 12 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Withdrawal by Subject | 1 | 0 |
Baseline characteristics
| Characteristic | Total | RMC-035 | Placebo |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 9 Participants | 7 Participants | 2 Participants |
| Age, Categorical Between 18 and 65 years | 3 Participants | 1 Participants | 2 Participants |
| Age, Continuous | 73.3 years STANDARD_DEVIATION 10.3 | 74.6 years STANDARD_DEVIATION 8.7 | 70.4 years STANDARD_DEVIATION 14.1 |
| BMI | 27.69 kg/m^2 STANDARD_DEVIATION 3.4 | 29.04 kg/m^2 STANDARD_DEVIATION 3.42 | 24.99 kg/m^2 STANDARD_DEVIATION 0.71 |
| eGFR | 60.4 mL/min/1.73m^2 STANDARD_DEVIATION 17.8 | 52.6 mL/min/1.73m^2 STANDARD_DEVIATION 16.5 | 76.0 mL/min/1.73m^2 STANDARD_DEVIATION 6.3 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 11 Participants | 8 Participants | 3 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 12 Participants | 8 Participants | 4 Participants |
| Region of Enrollment Germany | 12 participants | 8 participants | 4 participants |
| Sex: Female, Male Female | 2 Participants | 2 Participants | 0 Participants |
| Sex: Female, Male Male | 10 Participants | 6 Participants | 4 Participants |
| Weight | 86.08 kilogram STANDARD_DEVIATION 13.11 | 89.75 kilogram STANDARD_DEVIATION 14.84 | 78.75 kilogram STANDARD_DEVIATION 2.99 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 1 / 8 | 0 / 4 |
| other Total, other adverse events | 6 / 8 | 1 / 4 |
| serious Total, serious adverse events | 3 / 8 | 1 / 4 |
Outcome results
Primary
Frequency of Adverse Events (AEs)
* number (%) of subjects with at least one AE * number (%) of subjects with at least one SAE * number (%) of subjects with at least one Treatment-Emergent AE (TEAE) * number (%) of subjects with at least one serious TEAE * number (%) of subjects with at least one non-serious TEAE * number (%) of subjects with at least one TEAE of special interest * number (%) of subjects with at least one TEAEs reported as related (possible/probable) to IMP * number (%) of subjects with at least one TEAEs leading to withdrawal of IMP
Time frame: Baseline through day 30
Population: All subject who received any dose of study drug.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| RMC-035 | Frequency of Adverse Events (AEs) | Subject with at least one AE | 6 Participants |
| RMC-035 | Frequency of Adverse Events (AEs) | Subject with at least one SAE | 3 Participants |
| RMC-035 | Frequency of Adverse Events (AEs) | Subjects with at least one TEAE | 5 Participants |
| RMC-035 | Frequency of Adverse Events (AEs) | Subjects with at least one non-serious TEAE | 5 Participants |
| RMC-035 | Frequency of Adverse Events (AEs) | Subjects with at least one serious TEAE | 2 Participants |
| RMC-035 | Frequency of Adverse Events (AEs) | Subjects with at least one TEAE of special interest | 0 Participants |
| RMC-035 | Frequency of Adverse Events (AEs) | Subjects with at least one TEAE reported as related (possible/probable) | 0 Participants |
| RMC-035 | Frequency of Adverse Events (AEs) | Subjects with at least one TEAE leading to withdrawal of IMP | 0 Participants |
| Placebo | Frequency of Adverse Events (AEs) | Subjects with at least one TEAE leading to withdrawal of IMP | 0 Participants |
| Placebo | Frequency of Adverse Events (AEs) | Subject with at least one AE | 1 Participants |
| Placebo | Frequency of Adverse Events (AEs) | Subjects with at least one serious TEAE | 1 Participants |
| Placebo | Frequency of Adverse Events (AEs) | Subject with at least one SAE | 1 Participants |
| Placebo | Frequency of Adverse Events (AEs) | Subjects with at least one TEAE reported as related (possible/probable) | 0 Participants |
| Placebo | Frequency of Adverse Events (AEs) | Subjects with at least one TEAE | 1 Participants |
| Placebo | Frequency of Adverse Events (AEs) | Subjects with at least one TEAE of special interest | 0 Participants |
| Placebo | Frequency of Adverse Events (AEs) | Subjects with at least one non-serious TEAE | 1 Participants |
Primary
Severity of AEs
\- Number of TEAEs per category (mild, moderate, severe life-threatening, death)
Time frame: Within 4 days from first dose of IMP
Population: Number of TEAEs occurring in 5 subjects on RMC-035 (N=8) and the # of TEAEs occurring in 1 subjects on placebo (N=4)
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| RMC-035 | Severity of AEs | Moderate | 5 TEAEs |
| RMC-035 | Severity of AEs | Life-threatening | 1 TEAEs |
| RMC-035 | Severity of AEs | Severe | 3 TEAEs |
| RMC-035 | Severity of AEs | Death | 1 TEAEs |
| RMC-035 | Severity of AEs | Mild | 3 TEAEs |
| Placebo | Severity of AEs | Death | 0 TEAEs |
| Placebo | Severity of AEs | Mild | 1 TEAEs |
| Placebo | Severity of AEs | Moderate | 2 TEAEs |
| Placebo | Severity of AEs | Severe | 2 TEAEs |
| Placebo | Severity of AEs | Life-threatening | 0 TEAEs |
Secondary
Area Under the Curve (AUC) 0-24h
Analysis of RMC-035 concentrations in plasma following the fourth infusion.
Time frame: Blood samples taken from pre-dose and up to two hours after start of Dose 5
Population: All subjects receiving RMC-035
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| RMC-035 | Area Under the Curve (AUC) 0-24h | 38.3 hours * microgram / milliliter | Standard Deviation 37.7 |
Secondary
Elimination Half-life (T1/2)
Analysis of RMC-035 concentration in plasma following the fourth infusion
Time frame: Blood samples taken from pre-dose and up to two hours after start of Dose 5
Population: All subjects receiving any RMC-035
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| RMC-035 | Elimination Half-life (T1/2) | 4.5 hours | Standard Deviation 1.6 |
Secondary
Maximum Observed Concentration (Cmax)
Analysis of RMC-035 concentration in plasma (AUC + t1/2) after fourth infusion.
Time frame: Blood samples taken from pre-dose and up to two hours after start of Dose 5
Population: All subjects receiving any study drug.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| RMC-035 | Maximum Observed Concentration (Cmax) | 12.3 mikrogram / milliliter | Standard Deviation 4.4 |