Modified Autologous Leukocyte Cells for the Treatment of Acute Kidney Injury After Cardiac Surgery

This is a Phase II, multi-center, randomized, placebo-controlled clinical trial, with 2 treatment arms and single blind. After being informed about the study, participants who meet the eligibility criteria will be randomized in 1:1 ratio to treatment with a single administration of cell therapy with leukocyte cells from the participant himself/herself or placebo (approximately 49 subjects per group).

Acute kidney injury (AKI) is one of the main complications after cardiac surgery. In fact, AKI after cardiac surgery is associated with high morbidity and mortality. Currently, there are no effective therapies for kidney injury after cardiac surgery, but there is evidence that recovery is possible if the injury processes are overcome. Thus, due to the lack of preventive and therapeutic options at present, cell therapy has gained importance in recent years in different clinical trials. Thus, within this context, the use of modified leukocyte cells as cell therapy is also an alternative for the treatment of AKI due to their powerful immunomodulatory effect. On the other hand, the use of placebo is justified because there is currently no other pharmacological treatment available to serve as an active control. A placebo-controlled study is optimal to evaluate the efficacy and safety of an experimental treatment.

Researchers hypothesized that cell therapy with autologous leukocyte cells can be safe, well tolerated and clinically beneficial versus placebo for participants who develop AKI within the first 48 hours after cardiac surgery.

This study consists of 3 phases: the initial phase, the observation phase, and the follow-up phase. The total duration of each participant in the trial will be from 3 to 5 months:

• Initial phase: It starts when the participant signs the informed consent (IC) and it lasts until he or she receives the investigational drug/placebo. There are two possible scenarios: The participants undergoing cardiac surgery can sign the informed consent (IC) before the surgery (at a scheduled visit prior to his/her hospitalization or at the time of his/her hospitalization and prior to undergoing the procedure) or, alternatively, they can sign the informed consent (IC) after the surgery and the development of AKI within 48 hours. As indicated in the Inclusion criteria, only participants who present AKI within the first 48 hours post cardiac surgery will be included. The participants who meet all the inclusion criteria and none of the exclusion criteria will be randomized in a 1:1 ratio to one of the two study groups. A volume of at least 60 mL of peripheral blood will be extracted from the participant, from which the cell therapy will be prepared (in cases where the participant is included in the experimental group) The investigational product/placebo will be administered to the participant within 48 hours of AKI diagnosis.
• Observation phase: It includes the period from when the participant receives the investigational drug/placebo until he or she is discharged from the hospital. This period lasts 16 to 20 days, depending on the clinical evolution of the participants. During this phase, participants will be followed and will undergo different tests to evaluate the effectiveness and safety of the investigational treatment vs. placebo.
• Follow-up phase: It includes the period from when the participant receives hospital discharge and ends 90 days from the date of inclusion of the participant in the study. At this stage, participants will be monitored to evaluate the efficacy and safety of the experimental cell therapy drug vs. placebo.

Besides, if the participants give their consent, blood and urine samples will be collected to perform a metabolomic sub-study. The main objective is to identify biomarkers of efficacy of the treatment with M2RLAB 001.

Inclusion criteria

• Male or female participants older than 18 years of age, being able to understand and sign the Informed Consent.
• Participants undergoing elective valvular and/or coronary cardiac surgery performed with extracorporeal circulation.
• Participants must meet one of the following two criteria:

• Present pre-operative AKI risk more or equal to 30 percent according to the Leicester Cardiosurgery scale, in case the participants had signed the IC before.
• Participants that had signed the IC within 12 hours after the AKI diagnosis.
• Present AKI within the first 48 hours post cardiac surgery in one of the following classifications defined by the AKIN scale (Acute Kidney Injury Network):

AKIN 1: An increase in serum creatinine by at least 0.3 mg/dL (more or equal to 26.4 micromol/L) from baseline, or an increase to more or equal to 150-200 percent (corresponding to a 1.5- to 2-fold increase) from baseline. In addition, the participant must have a positive acute tubular necrosis score within the first 48 hours post cardiac surgery, defined as the presence of at least 3 of the following 4 scenarios: Sodium excretion fraction more than 2 percent, urinary osmolality lower than 400 mOsm/kg, urine sodium more than 40 mmol/L, presence of shock or nephrotoxic agents.

AKIN 2: An increase in serum creatinine to more than 200 percent and up to a maximum of 300 percent (corresponding to an increase of more than 2 and up to 3 times) over baseline.

AKIN 3: An increase in serum creatinine to more than 300 percent (corresponding to more than 3-fold increase) over baseline, or an increase in serum creatinine levels to more or equal to 4.0 mg/dl (more or equal to 354 micromol/l) with an acute increase of at least 0.5 mg/dl (44 micromol/l).

• In the case of women or men of childbearing age, for safety, those who undertake to follow the contraceptive measures required from their discharge from hospital until the end of their participation in the clinical trial.

Exclusion criteria

• Chronic Kidney Disease (CKD) in stage IV or V (glomerular filtration rate [GFR] less than 30 ml/min).
• AKI one month prior to heart surgery.
• Participants who have previously undergone renal replacement therapy.
• Participants who, due to their clinical situation (hemodynamic instability, oliguria, current or anticipated volume overload) are scheduled to start renal replacement therapy within the next 48 hours after AKI diagnosis.
• Interstitial glomerulonephritis or vasculitis.
• Pregnancy.
• Women in breastfeeding period
• Renal transplant history.
• Endocarditis.
• Participants with mechanical assistance devices: extracorporeal membrane oxygenation (ECMO), left ventricular assist device (LVAD), right ventricular assist device (RVAD), intra-aortic balloon pumps (IABP).
• Known severe ventricular dysfunction (left ventricular ejection fraction [LVEF] less than 30 percent).
• Post-surgical septic infectious condition.
• Clinically significant anemia with hemoglobin values below 100g/l.
• Positive serology for hepatitis C virus (HCV), hepatitis B virus antigen (HBSAg), human immunodeficiency virus (HIV) or syphilis (by RPR: Rapid Plasma Reagin). This criterion will be assessed once it has been confirmed that the participant has developed AKI.
• Participants enrolled in another clinical trial testing.