Phosphate-Containing Replacement Fluid for Patients Undergoing CRRT

Official title

A Randomized, Double-Blind, Parallel-Controlled, Multicenter, Phase III Clinical Trial to Evaluate the Efficacy and Safety of Phosphate-Containing Replacement Fluid in Continuous Renal Replacement Therapy

Overview

Brief Summary: Evaluating a New Phosphate-Containing Fluid for Blood Purification (CRRT) Why is this study being done? Patients in the Intensive Care Unit (ICU) often need a treatment called Continuous Renal Replacement Therapy (CRRT). This is a type of blood purification that acts like an artificial kidney to clear toxins and extra fluid from the body. A common problem during this treatment is that vital minerals, like phosphate, are washed out of the blood along with the toxins. Low phosphate can lead to muscle weakness and breathing problems. Currently, doctors must manually add phosphate to the treatment fluids, which can be inconsistent. This study aims to test a new, pre-mixed fluid that already contains phosphate to see if it works better and is safe. What are the main questions the study aims to answer? Does the new fluid help keep phosphate at a healthy level in the blood during the first 72 hours of treatment? How does the new fluid affect kidney function compared to the standard fluid? Is the new fluid safe for patients to use? Who can take part in this study? The study is looking for adults (18 and older) who: Are in the ICU and need CRRT treatment as decided by their doctor. Are expected to need this treatment for at least 72 hours. Are willing to participate (or have a legal guardian who agrees). People who are pregnant, have known allergies to the fluid ingredients, or have very low blood pressure that cannot be corrected may not be able to join. How will the research happen? This is a "double-blind" study involving 220 participants across 15 hospitals. This means neither the patients nor the doctors will know which fluid is being used until the study is over. Participants will be put into one of two groups by a computer: Group 1 (New Fluid): Receives the blood purification fluid that has phosphate already in it. Group 2 (Standard Fluid): Receives the standard fluid that does not have phosphate. What will participants have to do? Receive Treatment: Participants will receive their assigned fluid during their normal CRRT care for up to 7 days. Blood Tests: Doctors will take regular blood samples to check mineral levels and kidney health. Monitoring: The medical team will closely watch participants for any side effects or safety concerns. Follow-up: There will be a safety check-up 7 days after the treatment ends. Possible Benefits and Risks The new fluid may help prevent low phosphate levels, which could help with recovery. However, as with any medical treatment, there is a risk of side effects or electrolyte imbalances. The research team will monitor every participant 24/7 to ensure their safety.

Detailed description

Scientific Rationale and Study Objective:

Continuous renal replacement therapy (CRRT) is a standard life-support intervention in the ICU. However, standard phosphate-free replacement fluids frequently lead to unintended phosphorus removal, causing treatment-induced hypophosphatemia. This electrolyte imbalance is clinically significant, as it is linked to impaired muscle function and delayed respiratory weaning. This Phase III trial evaluates a novel, pre-mixed, phosphate-containing replacement fluid designed to maintain physiological phosphorus homeostasis and provide high-quality evidence for its standardized use in preventing CRRT-induced complications.

Study Design and Multicenter Implementation:

This is a randomized, double-blind, parallel-controlled trial conducted across 15 tertiary medical centers in China. A total of 220 participants requiring ≥ 72 hours of CRRT will be randomized 1:1 via a central Interactive Web Response System (IWRS). The study utilizes a dual-primary endpoint framework to demonstrate that the phosphate-containing fluid is non-inferior to standard therapy in renal replacement efficacy (creatinine clearance) and superior in preventing hypophosphatemia (serum phosphorus \< 0.81 mmol/L). All sites follow a standardized CRRT protocol, including unified blood flow rates and effluent dosing, to minimize confounding variables.

Blinding and Intervention Protocol:

To ensure the integrity of the double-blind design, the experimental phosphate-containing fluid and the control fluid are identical in appearance, labeling, and packaging. The intervention lasts for a maximum of 7 days, followed by a 7-day post-treatment follow-up. Clinical monitoring includes regular assessments of vital signs, fluid balance, and blood gas analysis. Secondary outcomes focus on organ function (SOFA scores), mechanical ventilation duration, and comprehensive metabolic stability, including glycemic and electrolyte balance.

Data Management and Quality Assurance:

Data integrity is managed through an Electronic Data Capture (EDC) system with rigorous Source Data Verification (SDV) at all 15 sites to ensure compliance with Good Clinical Practice (GCP). An independent Data Monitoring Committee (DMC) is established to periodically review safety data and protect participant welfare, ensuring the scientific rigor and safety of this multicenter clinical investigation.

Interventions

• Drug Phosphate-containing Replacement Fluid
  Phosphate-containing Replacement Fluid is an investigational Class 2.3 modified chemical drug approved by the NMPA (No. 2021LP00824). It is a premixed, electrolyte-balanced replacement fluid containing phosphorus. The solution is administered via the extracorporeal circuit during Continuous Renal Replacement Therapy (CRRT). The dosage and flow rate are standardized according to the subject's body weight and clinical requirements (typically 25-35 mL/kg/h).
• Drug Standard Phosphate-free Replacement Fluid
  A marketed phosphate-free replacement fluid (standard of care). Administration via extracorporeal circuit with doses identical to the experimental group. Treatment is expected for 72 hours, up to a maximum of 7 days, or until CRRT is clinically terminated. This comparator evaluates the efficacy of the phosphate-containing solution in preventing treatment-induced hypophosphatemia.

Primary outcome measures

• Change in Serum Creatinine at 72 Hours [Time frame: 72 hours]
• Incidence of Hypophosphatemia Within 72 Hours [Time frame: Up to 72 hours]

Secondary outcome measures (12)

• Percentage Change From Baseline in Serum Creatinine [Time frame: Baseline, 24 hours, 48 hours, and 72 hours after CRRT initiation, and every 12-24 hours thereafter until the end of treatment (up to 7 days).]
• Sequential Organ Failure Assessment (SOFA) Score [Time frame: Baseline, 24 hours, 48 hours, and 72 hours after CRRT initiation, and every 24 hours thereafter until the end of treatment (up to 7 days).]
• Total Amount of Exogenous Phosphorus Supplementation [Time frame: Within 24 hours, 48 hours, 72 hours, and during the entire treatment period (up to 7 days) after CRRT initiation.]
• Incidence of Exogenous Phosphorus Supplementation [Time frame: Within 24 hours, 48 hours, 72 hours, and during the entire treatment period (up to 7 days) after CRRT initiation.]
• Change From Baseline in Serum Phosphorus Levels [Time frame: Baseline, 24 hours, 48 hours, and 72 hours after CRRT initiation, and every 24 hours thereafter until the end of treatment (up to 7 days).]
• Duration of Mechanical Ventilation During the Treatment Period [Time frame: From the initiation of CRRT through 7 days after the completion of CRRT treatment.]
• Incidence of Hypophosphatemia (Excluding the 72-hour Primary Endpoint) [Time frame: Within 24 hours, 48 hours, and during the entire treatment period (up to 7 days) after CRRT initiation.]
• Duration of Hypophosphatemia [Time frame: Within the first 24 hours, 48 hours, 72 hours, and during the entire treatment period (up to 7 days) after CRRT initiation.]
• Incidence of Hyperphosphatemia [Time frame: Within the first 24 hours, 48 hours, 72 hours, and during the entire treatment period (up to 7 days) after CRRT initiation.]
• Duration of Hyperphosphatemia [Time frame: Within 24 hours, 48 hours, 72 hours, and during the entire treatment period (up to 7 days) after CRRT initiation.]
• Recovery Rate of Hyperphosphatemia [Time frame: 24 to 48 hours, 48 to 72 hours, and from 72 hours until the end of the treatment period (if treatment exceeds 72 hours).]
• Proportion of Participants With Normal Serum Phosphorus Levels [Time frame: At 48 hours, 72 hours after CRRT initiation, and every 24 hours thereafter until the end of treatment (up to 7 days).]

Eligibility criteria

Inclusion criteria

• Participants must meet all of the following criteria to be eligible for the study:

• Aged 18 years or older, regardless of gender.
• Meet the clinical indications for Continuous Renal Replacement Therapy (CRRT) as defined by the "Standard Operating Procedures for Blood Purification (2021 Edition)" and assessed by a qualified nephrologist or intensive care physician.
• Expected continuous blood purification duration is 72 hours or longer.
• The participant or their legal guardian has a full understanding of the purpose and significance of the trial, voluntarily agrees to participate and comply with the study procedures, and has signed the written Informed Consent Form (ICF).

Exclusion criteria

• Participants meeting any of the following criteria will be excluded from the study:

• Known allergy to any component of the investigational drug, or individuals with an allergic constitution.
• Inability to establish suitable vascular access for CRRT.
• Persistent hypotension (Systolic Blood Pressure < 90 mmHg or Mean Arterial Pressure < 65 mmHg) that is difficult to correct, unless judged by the investigator as potentially correctable with intervention.
• Presence of malignant tumors with systemic metastasis (except for those who previously underwent radical surgery without recurrence).
• Pregnant or breastfeeding women.
• Receipt of any form of renal replacement therapy (RRT) or blood purification treatment within 24 hours prior to screening.
• Receipt of peritoneal dialysis within 24 hours prior to screening.
• Participation in any other clinical trial involving investigational drugs or devices within 1 month prior to screening.
• Any other condition or reason that, in the opinion of the investigator, makes the patient unsuitable for participation in the study.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Quadruple blind

Primary purpose

Treatment

Study locations

China · 15 centers

• The First Affiliated Hospital of Chongqing Medical University — Chongqing
• Nanfang Hospital, Southern Medical University — Guangzhou
• The First Affiliated Hospital, Sun Yat-Sen University — Guangzhou
• The Third Affiliated Hospital, Sun Yat-Sen Unive — Guangzhou
• Zhujiang Hospital, Southern Medical University — Guangzhou
• The People's Hospital of Guangxi Zhuang Autonomous Region — Nanning
• The First Affiliated Hospital of Henan University of Science & Technology — Luoyang
• The First Affiliated Hospital of Zhengzhou University — Zhengzhou
• … and 7 more centers

Publications

• Crowley KE, DeGrado JR, Charytan DM. Serum glucose and phosphorus concentrations during continuous renal replacement therapy using commercial replacement solutions with or without phosphorus. Hemodial Int. 2020 Jul;24(3):330-334. doi: 10.1111/hdi.12834. Epub 2020 Apr 29. PMID 32351011
• Pistolesi V, Zeppilli L, Polistena F, Sacco MI, Pierucci A, Tritapepe L, Regolisti G, Fiaccadori E, Morabito S. Preventing Continuous Renal Replacement Therapy-Induced Hypophosphatemia: An Extended Clinical Experience with a Phosphate-Containing Solution in the Setting of Regional Citrate Anticoagulation. Blood Purif. 2017;44(1):8-15. doi: 10.1159/000453443. Epub 2017 Feb 21. PMID 28219057
• Broman M, Carlsson O, Friberg H, Wieslander A, Godaly G. Phosphate-containing dialysis solution prevents hypophosphatemia during continuous renal replacement therapy. Acta Anaesthesiol Scand. 2011 Jan;55(1):39-45. doi: 10.1111/j.1399-6576.2010.02338.x. Epub 2010 Oct 29. PMID 21039362
• Godaly G, Carlsson O, Broman M. Phoxilium((R)) reduces hypophosphataemia and magnesium supplementation during continuous renal replacement therapy. Clin Kidney J. 2016 Apr;9(2):205-10. doi: 10.1093/ckj/sfv133. Epub 2015 Dec 19. PMID 26985370
• Pistolesi V, Zeppilli L, Fiaccadori E, Regolisti G, Tritapepe L, Morabito S. Hypophosphatemia in critically ill patients with acute kidney injury on renal replacement therapies. J Nephrol. 2019 Dec;32(6):895-908. doi: 10.1007/s40620-019-00648-5. Epub 2019 Sep 12. PMID 31515724
• Lim C, Tan HK, Kaushik M. Hypophosphatemia in critically ill patients with acute kidney injury treated with hemodialysis is associated with adverse events. Clin Kidney J. 2017 Jun;10(3):341-347. doi: 10.1093/ckj/sfw120. Epub 2017 Jan 5. PMID 28616212
• Hendrix RJ, Hastings MC, Samarin M, Hudson JQ. Predictors of Hypophosphatemia and Outcomes during Continuous Renal Replacement Therapy. Blood Purif. 2020;49(6):700-707. doi: 10.1159/000507421. Epub 2020 Apr 22. PMID 32320987
• Demirjian S, Teo BW, Guzman JA, Heyka RJ, Paganini EP, Fissell WH, Schold JD, Schreiber MJ. Hypophosphatemia during continuous hemodialysis is associated with prolonged respiratory failure in patients with acute kidney injury. Nephrol Dial Transplant. 2011 Nov;26(11):3508-14. doi: 10.1093/ndt/gfr075. Epub 2011 Mar 7. PMID 21382993

Identifiers

NCT: NCT07550894 · A1805-PL-LC-301

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗