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

Not Applicable

• Conditions: Antifungal Agents; Invasive Fungal Infections; Acute-On-Chronic Liver Failure; Mycoses
• Interventions: Other: Treatment strategy trial

• Registration Number: NCT04157465
• Lead Sponsor: Post Graduate Institute of Medical Education and Research, Chandigarh

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.

Detailed Description

Research question: Does an early empiric antifungal therapy improve 28-day overall survival as compared to pre-emptive antifungal therapy in critically ill, non-neutropenic adult ACLF patients with suspected IFI?

This study will be a single-center prospective randomized open-label with blinded end-point PROBE assessment and conducted at Liver ICU.

ACLF patients aged 18 to 75 years with all three criteria will be included

1. ICU stay of 48 hours or recent hospitalization

2. Two or more risk factors for IFI 3. Clinical suspicion of IFI

Exclusion criteria A Neutrophil count of less than 500 per mm3 B Recent antifungal treatment in the past 1months C Hepatocellular carcinoma or other active malignancy D Known hypersensitivity or contraindication to Liposomal AmB E HIV positivity or on HAART F Pregnancy or lactation G Moribund patients

Eligible patients will be randomly assigned, in a 1:1 ratio to receive either early empiric systemic antifungal therapy (SAT: based on risk factors and clinical suspicion) or Pre-emptive SAT (based on risk factors, clinical suspicion and radiological/investigation based evidence of fungal infection) in addition to standard medical therapy SMT and followed up for a period of 28-days or transplant or death

Empirical therapy will be Liposomal AmB 3 to 5 mg per kg of body weight per day.

It is preferred because of maximum efficacy, widest spectrum, and safety in liver disease

Pre-emptive therapy with liposomal AmB will be given if the treatment initiation rules are met including fungal biomarkers positivity, Mycological or radiological evidence of IFI

Proven-IFI will be treated as per IDSA or ESCMID guidelines in either group Stoppage rules in both groups will be based on fungal biomarkers and cultures that will be done twice weekly and twice negative bio-markers or fungal cultures at day7 and 10 will be essential to stop treatment

In case of intolerable adverse effects or contraindications to LipoAmB, the patients will undergo treatment as per IDSA guidelines Standard Medical Therapy will be as indicated and will include nutritional support, rifaximin lactulose albumin diuretics proton-pump inhibitors multivitamins and antibiotics

Outcomes will include survival at 28-day, clinical outcomes, cost-effectiveness and safety of two approaches of antifungal therapy

Study Timeline

• Study First Submitted: 2019-11-06
• Study First Submitted QC: 2019-11-06
• Study Start: 2019-11-07
• Study First Posted: 2019-11-08
• Status Verified: 2022-04
• Last Update Submitted: 2022-04-19
• Last Update Posted: 2022-04-20
• Primary Completion: 2023-12-31
• Study Completion: 2024-06-30

Recruitment & Eligibility

• Status: UNKNOWN
• Sex: All
• Target Recruitment: 216

Inclusion Criteria

Not provided

Exclusion Criteria

1. Neutrophil count of less than 500/mm3

2. Current or recent antifungal treatment in the past 1 months

3. Hepatocellular carcinoma or other active malignancy

4. Known hypersensitivity or contraindication to Liposomal AmB or any other AmB preparation

5. Human immunodeficiency virus seropositivity on rapid card test/ELISA, or currently on combination antiretroviral therapy (cART)

6. Pregnancy as confirmed by urine pregnancy test or lactation

7. Moribund patients as defined as

   1. ≥ 4 organ failure as per CLIF-SOFA score
   2. Signs of brainstem death- absent brainstem reflexes
   3. Expected ICU stay <48 hours

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Pre-emptive group	Treatment strategy trial	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.
Early Empiric group	Treatment strategy trial	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.

Primary Outcome Measures

Name	Time	Method
Overall Survival	28 day	28-day overall survival

Secondary Outcome Measures

Name	Time	Method
Incidence of proven or probable IFI	28 day	Incidence of proven or probable IFI at 28 days
In-hospital mortality	28 day	Number of participants dying in hospital due to any cause within 28 day of enrollment
Evolution of organ failures as assessed by chronic liver failure-sequential organ failure score (CLIF-SOFA)	28 day	Development of new or worsening organ failures as defined by chronic liver failure -sequential organ failure (CLIF-SOFA) scores within 28 days of enrollment. CLIF-SOFA score ranges from 0-24 incorporating 6 organ systems and 0 being best and 24 being worst.
Evolution of serum 1, 3 Beta-D Glucan (BDG; in pg/ml) levels throughout the study period	28 day	Trends of 1, 3 Beta-D Glucan (BDG) throughout the study period that will be done on twice weekly intervals after enrollment
Evolution of serum Galactomannan index (GM; in %) throughout the study period	28 day	Trends of Galactomannan index (GM; in %) throughout the study period that will be done on twice weekly intervals after enrollment
Incidence of key events like new onset ventilator associated pneumonia, urinary tract infection, spontaneous fungal peritonitis	28 day	Incidence of key events like new onset VAP, UTI, fungal SBP
Mechanical ventilation free days	28 day	Duration free from mechanical ventilation within 28 days of enrollment
Length of ICU and hospital stay	28 day	Effect on length of ICU, hospital stay within 28 day of enrollment
Treatment success rate	28 day	Treatment success rate, successful treatment being defined as; 1. Survival beyond 7 days of start of SAT with resolution of sepsis attributable to IFI; 2. Absence of new/ breakthrough IFI during treatment or within 7 days of completion; 3. Absence of treatment discontinuation related to toxicity/lack of efficacy

Trial Locations

Locations (1)

Postgraduate Institute of Medical education and Research; 🇮🇳 Chandigarh, UT, India