Safety Evaluation of Prismocitrate 18 in Patients Receiving CRRT

Study Overview
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Brief Summary
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Prismocitrate 18 is a continuous renal replacement therapy (CRRT) solution to be used as a renal replacement solution and as an anticoagulant to prevent blood clotting in the extracorporeal circuit. The objective of this study is to confirm the safety of Prismocitrate 18 in patients receiving CRRT using continuous venovenous hemodiafiltration (CVVHDF) or continuous venovenous hemofiltration (CVVH). The study period of the patient's CRRT will be up to 10 days.

Official Title
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A Safety Evaluation of Prismocitrate 18 in Patients Receiving Continuous Renal Replacement Therapy (CRRT)

Conditions
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Regional Citrate Anticoagulation (RCA), Continuous Renal Replacement Therapy (CRRT), Acute Kidney Injury (AKI)

Intervention / Treatment
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* Drug: Prismocitrate 18


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients must be >=18 years of age Patients who are candidates for CRRT Patients expected to survive for at least 24 hours Patients with a contraindication to heparin or an increased risk of hemorrhage Patient and/or legally-authorized representative has signed a written informed consent form (ICF) per 21 CFR Part 50.55(e) Exclusion Criteria: Patients with a known allergy to citrate or who have ever experienced an adverse reaction associated with citrate products, including patients with a prior history of citrate toxicity Patients with acute liver failure, defined by the occurrence of encephalopathy and hepatic synthetic dysfunction within 26 weeks of the first symptoms of liver disease and without evidence of chronic liver disease Patients with acute-on-chronic liver failure characterized by acute decompensation of cirrhosis and a Child-Pugh Liver Failure Score > 10 Patients with refractory shock and associated lactic acidosis (lactate > 4 mmol/L) Patients with a systemic ionized calcium concentration outside the normal physiologic range (1.0 - 1.3 mmol/L), or outside of the laboratory reference range (Note: It is acceptable to provide calcium supplementation or treatment for hypercalcemia to achieve a normal physiologic range prior to therapy initiation) Female patients of childbearing potential who are pregnant or breastfeeding. (Note: All female patients, who have not undergone a hysterectomy, bilateral oophorectomy with or without hysterectomy, or has medically documented ovarian failure before study Screening must have a negative serum beta human chorionic gonadotropic [B-hCG] pregnancy test at Screening) Patients who are currently participating in another interventional clinical study

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Prismocitrate 18<br> | Drug: Prismocitrate 18<br>* Prismocitrate 18 solution will be used in pre-dilution mode only; the rate of administration depends on the targeted citrate dose and the prescribed flow rate. The pre-filter infusion rate of Prismocitrate 18 solution will be indexed to the blood flow rate (BFR) to achieve a target blood citrate concentration of 3 mmol/L of blood. A BFR between 100 - 180 mL/min will be advised; a lower BFR can minimize patient citrate exposure, particularly in patients with lower body weight.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of participants with symptomatic hypocalcemia | Defined as symptomatic patients (e.g., tetany/spasms, seizures, or cardiac events secondary to a prolonged QT interval), with symptoms deemed attributable to hypocalcemia and with a confirmed systemic ionized calcium < 0.9 mmol/L. | Day 1 up to Day 10 | 
| Number of participants with symptomatic hypercalcemia | Defined as symptomatic patients (e.g., changes in mental status not explained by the interventions or underlying conditions or cardiac events secondary to a shortened QT interval), with symptoms deemed attributable to hypercalcemia and with a confirmed systemic ionized calcium > 1.4 mmol/L. | Day 1 up to Day 10 | 
| Number of participants with symptomatic citrate accumulation | Defined as symptomatic patients (e.g., refractory acidosis), with symptoms deemed attributable to citrate accumulation and with a systemic total calcium to ionized calcium ratio > 2.5. | Day 1 up to Day 10 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of participants with Adverse Events related to study product and/or procedure | Incidence of AE and SAE's are also considered secondary outcome measures and will be reported in the Adverse Event section | Day 1 up to Day 28 | 
| Lab measurement for Systemic Ionized Calcium by Time Point |  | Baseline (<=6 hours prior to Day 1 initiation of CRRT); Day 1 (1 hour after initiation of CRRT, 1 hour after any Prismocitrate dose change until stable) and every 6 hours (i.e., 6, 12, 18, 24) up to Day 10 | 
| Lab measurement for pH by Time Point |  | Baseline (<=6 hours prior to Day 1 initiation of CRRT); Day 1 (1 hour after initiation of CRRT, 1 hour after any Prismocitrate dose change until stable) and every 6 hours (i.e., 6, 12, 18, 24) up to Day 10 | 
| Lab measurement for Base Excess by Time Point |  | Baseline (<=6 hours prior to Day 1 initiation of CRRT); Day 1 (1 hour after initiation of CRRT, 1 hour after any Prismocitrate dose change until stable) and every 6 hours (i.e., 6, 12, 18, 24) up to Day 10 | 
| Lab measurement for Serum Bicarbonate by Time Point |  | Baseline (<=6 hours prior to Day 1 initiation of CRRT); Day 1 (1 hour after initiation of CRRT, 1 hour after any Prismocitrate dose change until stable) and every 6 hours (i.e., 6, 12, 18, 24) up to Day 10 | 
| Lab measurement for Serum Magnesium by Time Point |  | Baseline (<=6 hours prior to Day 1 initiation of CRRT); Day 1 every 6 hours after initiation of CRRT (i.e., 6, 12, 18, 24) up to Day 10 | 
| Lab measurement for Serum Potassium by Time Point |  | Baseline (<=6 hours prior to Day 1 initiation of CRRT); Day 1 every 6 hours after initiation of CRRT (i.e., 6, 12, 18, 24) up to Day 10 | 
| Lab measurement for Phosphate by Time Point |  | Baseline (<=6 hours prior to Day 1 initiation of CRRT); Day 1 every 12 hours after initiation of CRRT up to Day 10 | 
| Lab measurement for Systemic Total Calcium Level by Time Point |  | Baseline (<=6 hours prior to Day 1 initiation of CRRT); Day 1 every 12 hours after initiation of CRRT up to Day 10 | 
| Lab measurement for Total to Ionized Calcium Ratio by Time Point |  | Baseline (<=6 hours prior to Day 1 initiation of CRRT); Day 1 every 12 hours after initiation of CRRT up to Day 10 | 
| Extracorporeal Circuit Life |  | Day 1 to Day 10 | 
| Lab measurement for Post-filter Ionized Calcium Levels by Time Point |  | Baseline (<=6 hours prior to Day 1 initiation of CRRT); Day 1 (1 hour after initiation of CRRT, 1 hour after any Prismocitrate dose change until stable) and every 6 hours (i.e., 6h, 12h, 18h, 24h) up to Day 10 | 
| Number of Adverse Events leading to withdrawal | Incidence of AE and SAE's are also considered secondary outcome measures and will be reported in the Adverse Event section | Day 1 up to Day 28 |