Anti-fungal Strategies in Acute-on-Chronic Liver Failure Patients

NCT04157465 | Completed DMC

• 1 other identifier: PGI/IEC/2019/001924
• Study Type: interventional
• Target: 216
• Locations: 1 country
• Sites: 1

Brief Summary

Early treatment of invasive fungal infections (IFI) may prevent undue mortality in acute on chronic liver failure (ACLF) patients. We aim to study the impact of early empiric treatment (based on clinical suspicion) of IFI as compared to pre-emptive treatment (based on biomarkers and culture positivity) on the outcomes in ACLF patients with suspected IFI in a randomized trial. The ACLF patients with clinically suspected IFI would be randomly allocated to empiric treatment or pre-emptive treatment group and followed up clinically to assess the impact on survival, clinical outcomes and cost-effectiveness and safety of such an approach. The protocol is designed to cut- down unnecessary usage and to curtail the duration of antifungals use in ICUs based on biomarkers/culture-driven stoppage rules. The results will fuel further studies on formal cost-effective analysis and antimicrobial stewardship protocols in ACLF patients.

Conditions

Antifungal Agents; Invasive Fungal Infections; Mycoses; Acute-On-Chronic Liver Failure

Keywords

cirrhosis; Acute-On-Chronic Liver Failure; liposomal amphotericin B; Invasive Fungal Infections; empiric antifungal; pre-emptive antifungal

Outcome Measures

Primary Outcomes (1)

• Overall Survival

  28-day overall survival

  28 day

Secondary Outcomes (9)

• Incidence of proven or probable IFI

  28 day

• In-hospital mortality

  28 day

• Evolution of organ failures as assessed by chronic liver failure-sequential organ failure score (CLIF-SOFA)

  28 day

• Evolution of serum 1, 3 Beta-D Glucan (BDG; in pg/ml) levels throughout the study period

  28 day

• Evolution of serum Galactomannan index (GM; in %) throughout the study period

  28 day

Other Outcomes (2)

• Number of participants with adverse events due to antifungals requiring cessation of therapy

  28 day

• Out of pocket expenditure

  28 day

Study Arms (2)

Early Empiric group

OTHER

Participants will receive standard medical therapy along with the empiric strategy of treatment of invasive fungal infection (based on both risk factors and clinical suspicion of invasive fungal infection). The choice of drug will be as per institutional protocol i.e. Injection Liposomal Amphotericin B, 3-5 mg/kg of body weight as a 4- hour infusion in 5% dextrose solution. The infusion will be prepared ten minutes prior to administration by reconstituting the vial in dextrose solution by a Registered Nurse. Each vial contains 50 mg (50000U) encapsulated in liposomes. After reconstitution, the concentrate will contain 4mg/ml of the drug. During the first dose administration, 1mg will be administered with a micro drip set over ten minutes and then stopped to look for any reactions for 30 minutes. If there are no reactions, the rest of the drug is administered over 30-60 minutes period.

Other: Treatment strategy trial

Pre-emptive group

ACTIVE COMPARATOR

Participants will receive standard medical therapy along with the pre-emptive strategy of treatment of invasive fungal infection (based on risk factors, clinical suspicion and radiological or mycological evidence of invasive fungal infection). The choice of drug will be as per institutional protocol i.e. Injection Liposomal Amphotericin B, 3-5 mg/kg of body weight as a 4- hour infusion in 5% dextrose solution. The infusion will be prepared ten minutes prior to administration by reconstituting the vial in dextrose solution by a Registered Nurse. Each vial contains 50 mg (50000U) encapsulated in liposomes. After reconstitution, the concentrate will contain 4mg/ml of the drug. During the first dose administration, 1mg will be administered with a micro drip set over ten minutes and then stopped to look for any reactions for 30 minutes. If there are no reactions, the rest of the drug is administered over 30-60 minutes period.

Other: Treatment strategy trial

Interventions

Treatment strategy trial OTHER

Participants will be randomly allocated in a 1:1 ratio after meeting eligibility criteria to either early empiric or pre-emptive strategy of treatment with antifungals. The antifungal treatment initiation will be at the time of allocation in the empiric group. The treatment initiation rules in the pre-emptive group will include 1. Fungal Biomarkers positivity (Beta-D Glucan\>150 pg/ml, Galactomannan index\>1.0) 2. Mycological evidence of fungal infection on fungal cultures from a non-sterile site 3. Radiological evidence of fungal infection 4. Other Investigations suggestive of fungal infection viz. endophthalmitis, vegetations suspicious of fungal infection, Vegetations on echocardiography with negative blood cultures for bacteria that is non-responsive to appropriate antibiotics, refractory culture-negative spontaneous bacterial peritonitis Treatment duration will be guided by serum biomarkers (BDG and GM) and fungal cultures.

Early Empiric group; Pre-emptive group

Eligibility Criteria

• Age: 18 Years - 75 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• ICU stay \>48 hours or admission in a tertiary care hospital prior to the current admission
• Two or more risk factors for IFI from amongst the following:-
• Mechanically ventilated at least ≥ 48 hours
• Treatment with broad-spectrum antibacterial agents for more than 3 days
• Arterial or central vein catheter ≥ 2days
• Diabetes Mellitus
• Total parenteral nutrition ≥ 48 hours
• Acute renal failure requiring any form of renal replacement therapy ≥48hours
• Pancreatitis related hospitalization \> 7days in last 3 months
• Steroid use, immunosuppressant use in the preceding 30 days
• High disease score as defined as MELD≥20 or APACHE II ≥16
• Refractory ascites, norfloxacin prophylaxis
• Gastrointestinal tract surgery, abdominal perforation or anastomotic leaks or any invasive procedures or surgeries in the last 7days
• Chronic pulmonary diseases including COPD or Tuberculosis
• Moderate to severe sarcopenia as defined by The Royal Free Hospital-global assessment (RFH-GA) scale60 (As per Appendix "4" )

You may not qualify if:

• Neutrophil count of less than 500/mm3
• Current or recent antifungal treatment in the past 1 months
• Hepatocellular carcinoma or other active malignancy
• Known hypersensitivity or contraindication to Liposomal AmB or any other AmB preparation
• Human immunodeficiency virus seropositivity on rapid card test/ELISA, or currently on combination antiretroviral therapy (cART)
• Pregnancy as confirmed by urine pregnancy test or lactation
• Moribund patients as defined as
• ≥ 4 organ failure as per CLIF-SOFA score
• Signs of brainstem death- absent brainstem reflexes
• Expected ICU stay \<48 hours

Sponsors & Collaborators

• Post Graduate Institute of Medical Education and Research, Chandigarh: lead
• Indian Council of Medical Research: collaborator

Study Sites (1)

Postgraduate Institute of Medical education and Research

Chandigarh, Uttarakhand, 160012, India

Location

Related Publications (1)

• Verma N, Valsan A, Garg P, Sarabu S, Kaur P, Mohan N, De A, Premkumar M, Taneja S, Prinja S, Chakrabarti A, Shafiq N, Duseja A. Empirical Antifungal Therapy Improves Survival in Patients With Acute-on-Chronic Liver Failure With Suspected Invasive Fungal Infections: A Pragmatic Randomized Trial. Am J Gastroenterol. 2025 Nov 21. doi: 10.14309/ajg.0000000000003832. Online ahead of print.

  PMID: 41268913 DERIVED

MeSH Terms

Conditions

Invasive Fungal Infections; Mycoses; Acute-On-Chronic Liver Failure; Fibrosis

Condition Hierarchy (Ancestors)

Bacterial Infections and Mycoses; Infections; Liver Failure, Acute; Liver Failure; Hepatic Insufficiency; Liver Diseases; Digestive System Diseases; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Study Officials

• Nipun Verma, MD, DM

  Post Graduate Institute of Medical Education and Research, Chandigarh

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: RANDOMIZED
• Masking: SINGLE
• Who Masked: OUTCOMES ASSESSOR
• Masking Details: Single-center, prospective randomized, open-labeled with blinded end-point (PROBE) assessment
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Additional Professor

Study Record Dates

• First Submitted: November 6, 2019
• First Posted: November 8, 2019
• Study Start: November 7, 2019
• Primary Completion: December 31, 2024
• Study Completion: December 31, 2024
• Last Updated: June 8, 2025

Record last verified: 2024-12

Data Sharing

• IPD Sharing: Will not share

Locations

IN (1)