Regional Anticoagulation of Dialysis Circuits With a Calcium-free Citrate-containing Dialysate (C2D)

• ClinicalTrials.gov Identifier: NCT03842657
• Recruitment Status: Recruiting
• First Posted: February 15, 2019
• Last Update Posted: August 21, 2019
• Sponsor: University Hospital, Toulouse
• Information provided by (Responsible Party): University Hospital, Toulouse

Study Description

Brief Summary:

Critically ill patients have a high risk of bleeding but also require prolonged intermittent dialysis. Thus, a heparin-free easy-to-use alternative type of anticoagulation within the dialysis circuit is required. In a non-comparative study, heparin-free regional citrate anticoagulation of the dialysis circuit using a calcium-free citrate-containing dialysate, with calcium reinjected according to ionic dialysance, was considered as safe and efficient. The aim of this study is to confirm the superiority of this approach compared to a anticoagulation based on heparin-grafted membrane.

Condition or disease	Intervention/treatment	Phase
Hemodialysis Complication; Bleeding	Combination Product: anticoagulation of the dialysis circuit	Phase 2

Detailed Description:

Critically ill patients have a high risk of bleeding but also require prolonged intermittent dialysis. Several modalities are used for heparin-free dialysis sessions. Iterative saline infusion and heparin-grafted membranes are easy to use and remain the standards-of-care for high-risk bleeding situations but efficiency is low: success rates from hemodialysis sessions range from 50% to 65% and 50% to 75%, respectively. Furthermore, sessions that last for greater than 240 minutes are rarely achievable and can be problematic when ensuring an adequate dose of dialysis and a negative water balance in patients who cannot tolerate a high ultrafiltration rate. Thus, the development of alternative regional anticoagulation methods is needed urgently to improve intermittent hemodialysis (IHD) in critically ill patients and to avoid systemic anticoagulation in patients with a high risk of bleeding.

An easy way to provide citrate inside the filter, to lower iCa below 0.45 mmol/L could be to use diffusive influx from the dialysate. It has been demonstrated recently that the use of citric acid as the acidic component of dialysate can enable a dose reduction of heparin and increase the efficiency of hemodialysis. However, the amount of citrate (0.8 mmol/L) and calcium (1.25-1.75 mmol/L) contained in this dialysate do not allow the target of iCa to be reached in the ECC. In contrast, a citrate dialysate that contains no calcium would provide enough calcium-free transfer to lower iCa below 0.45 mmol/L; however, a problem would be the large amount of calcium loss during the session.

Pivotal studies show that, during dialysis sessions performed with calcium-free dialysate, the rate of calcium reinjection required to compensate for calcium loss in the dialysate can be easily deducted from the ionic dialysance (ID), which is an online measurement of instantaneous small solute clearance, available from most dialysis monitors. ID has been also used as a surrogate marker for dialysis dose in ICU patients receiving IHD. Thus, the use of calcium-free citrate-containing dialysate with calcium reinjection according to ID could provide enough citrate to prevent coagulation within the filter, and calcium restitution can then be monitored by online ID without the need for systemic measurement of iCa. It may also improve the hemodynamic tolerance of IHD by avoiding acetate in the dialysate.

The objective of the present study was to show the efficiency of this approach using RCA for dialysis sessions (<4 hrs) of IHD in patients with moderate to high risk of bleeding, based on the success rate of hemodialysis without clotting. Each patient included in this study will receive two heparin-free dialysis sessions with heparin-grafted membrane (control group) or RCA with calcium-free citrate-containing dialysate and calcium reinjection according to the ionic dialysance (experimental group), alternatively. The order of anticoagulation will be randomized.

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 97 participants
• Allocation: Randomized
• Intervention Model: Crossover Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Regional Anticoagulation of Dialysis Extra-corporeal Circuits With a Calcium-free Citrate-containing Dialysate : Efficiency and Tolerance
• Actual Study Start Date: July 5, 2019
• Estimated Primary Completion Date: July 2021
• Estimated Study Completion Date: July 2021

Arms and Interventions

Arm	Intervention/treatment
calcium-free citrate-containing dialysate; Dialysis session will be performed with a non-heparin grafted membrane, a dialysate without calcium (0 mmol/L) and citrate 0.8 mmol/L, a reinjection of a calcium solution (300 mM) according to the ionic dialysance, and no heparin addition	Combination Product: anticoagulation of the dialysis circuit; Each patient included in this study will receive two heparin-free dialysis sessions with heparin-grafted membrane (control group) or RCA with calcium-free citrate-containing dialysate and calcium reinjection according to the ionic dialysance (experimental group), alternatively
heparin-grafted membrane; dialysis session will be performed with a heparin-grafted membrane, a dialysate with calcium (1.65 mmol/L) and citrate 0.8 mmol/L, and no heparin addition	Combination Product: anticoagulation of the dialysis circuit; Each patient included in this study will receive two heparin-free dialysis sessions with heparin-grafted membrane (control group) or RCA with calcium-free citrate-containing dialysate and calcium reinjection according to the ionic dialysance (experimental group), alternatively

Outcome Measures

Primary Outcome Measures :

1. Premature termination of the first dialysis session (<4 hours) related to a coagulation of the dialysis circuit [ Time Frame: Visite T1 (3 days maximum after inclusion visit) ]
   Premature termination of the dialysis session (<4 hours) in connection with coagulation or pre-coagulation state of the dialysis circuit (thrombosis global index strictly greater than 1 (visual assessment) or elevation of transmembrane pressure above 350 mmHg)
2. Premature termination of the second dialysis session (<4 hours) related to a coagulation of the dialysis circuit [ Time Frame: Visite T2 (7 days maximum after inclusion visit) ]
   Premature termination of the dialysis session (<4 hours) in connection with coagulation or pre-coagulation state of the dialysis circuit (thrombosis global index strictly greater than 1 (visual assessment) or elevation of transmembrane pressure above 350 mmHg)

Secondary Outcome Measures :

1. Hemodynamic tolerance [ Time Frame: Visite T1 (3 days maximum after inclusion visit), Visite T2 (7 days maximum after inclusion visit) ]
   Number of cardiovascular events during the dialysis session
2. Clinical tolerance [ Time Frame: Visite T1 (3 days maximum after inclusion visit), Visite T2 (7 days maximum after inclusion visit) ]
   Clinical symptoms collected every 30 min on patient
3. Biological tolerance [ Time Frame: Visite T1 (3 days maximum after inclusion visit), Visite T2 (7 days maximum after inclusion visit) ]
   Measurement of total and ionized calcium and venous pH sampled on the arterial branch of the dialysis circuit
4. Systemic inflammation [ Time Frame: Visite T1 (3 days maximum after inclusion visit), Visite T2 (7 days maximum after inclusion visit) ]
   To determine the serum levels of cytokines (interleukine-6, interferon-γ, MCP1, Tumor Necrosis Factor-α) by ELISA.

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria: will be included in the study, patients

• hat require two sessions of dialysis that last for greater than 240 minutes in the 7 days following the inclusion.
• With a moderate to high risk of bleeding (platelets count below 150.000/mm3; platelet disorders; bleeding in the last 10 days, surgery or biopsy in the last 10 days or planned in the next 7 days; admission to the ICU)
• Older than 18 years of age
• That gave written informed consent

Exclusion Criteria: will be excluded from the study, patients with

• Heparin allergy
• On-going treatment by vitamin-K antagonists (INR > 1.2) or unfractionated heparin (anti-Xa activity > 0.10)..
• Known allergy to the Evodial (Baxter, France) or Cordiax FX100 (Fresenius, France) membranes
• On-going treatment by angiotensin converting enzyme inhibitors
• Pregnancy or risk of pregnancy
• Patient under guardianship

Contacts and Locations

Contacts

Contact: Stanislas FAGUER, MD; 05 61 32 24 75 ext 33; faguer.s@chu-toulouse.fr

Locations

France

Pellegrin Hospital; Not yet recruiting

Bordeaux, France

Contact: Valérie DE PRECIGOUT

Marseille Hospital; Not yet recruiting

Marseille, France

Contact: Thomas Robert

Montpellier Hospital; Not yet recruiting

Montpellier, France

Contact: Vincent PERNIN

Tenon Hospital; Not yet recruiting

Paris, France

Contact: Cédric RAFAT

CHU Toulouse; Recruiting

Toulouse, France

Contact: Stanislas Faguer

Sponsors and Collaborators

University Hospital, Toulouse

Investigators

• Principal Investigator: Stanislas FAGUER, MD; University Hospital, Toulouse

More Information

• Responsible Party: University Hospital, Toulouse
• ClinicalTrials.gov Identifier: NCT03842657 History of Changes
• Other Study ID Numbers: RC31/17/0451
• First Posted: February 15, 2019
• Last Update Posted: August 21, 2019
• Last Verified: August 2019

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by University Hospital, Toulouse:

citrate, dialysate; hemodialysis; coagulation

Additional relevant MeSH terms:

Hemorrhage; Pathologic Processes; Calcium, Dietary; Heparin; Calcium heparin; Citric Acid; Sodium Citrate; Dialysis Solutions; Calcium; Calcium-Regulating Hormones and Agents; Physiological Effects of Drugs; Bone Density Conservation Agents; Anticoagulants; Calcium Chelating Agents; Chelating Agents; Sequestering Agents; Molecular Mechanisms of Pharmacological Action; Fibrinolytic Agents; Fibrin Modulating Agents; Pharmaceutical Solutions