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

Primary Purpose

Antifungal Agents, Invasive Fungal Infections, Mycoses

Status
Recruiting
Phase
Not Applicable
Locations
India
Study Type
Interventional
Intervention
Treatment strategy trial
Sponsored by
Postgraduate Institute of Medical Education and Research
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Antifungal Agents focused on measuring cirrhosis, Acute-On-Chronic Liver Failure, liposomal amphotericin B, Invasive Fungal Infections, empiric antifungal, pre-emptive antifungal

Eligibility Criteria

18 Years - 75 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria (All three must be present):

  1. ICU stay >48 hours or admission in a tertiary care hospital prior to the current admission

  2. Two or more risk factors for IFI from amongst the following:-

    1. Mechanically ventilated at least ≥ 48 hours
    2. Treatment with broad-spectrum antibacterial agents for more than 3 days
    3. Arterial or central vein catheter ≥ 2days
    4. Diabetes Mellitus
    5. Total parenteral nutrition ≥ 48 hours
    6. Acute renal failure requiring any form of renal replacement therapy ≥48hours
    7. Pancreatitis related hospitalization > 7days in last 3 months
    8. Steroid use, immunosuppressant use in the preceding 30 days
    9. High disease score as defined as MELD≥20 or APACHE II ≥16
    10. Refractory ascites, norfloxacin prophylaxis
    11. Gastrointestinal tract surgery, abdominal perforation or anastomotic leaks or any invasive procedures or surgeries in the last 7days
    12. Chronic pulmonary diseases including COPD or Tuberculosis
    13. Moderate to severe sarcopenia as defined by The Royal Free Hospital-global assessment (RFH-GA) scale60 (As per Appendix "4" )
    14. Firm diagnosis of H1N1 influenza infection in the last 3 months

  3. Clinical suspicion of IFI as defined by any of the following:

    1. Evidence of unresolved sepsis/SIRS(≥ 2/4) despite appropriate broad-spectrum antibiotics beyond 3days
    2. Recrudescence of fever after a period of defervescence of at least 48 hours while still on antibiotics and without other apparent cause
    3. Tracheobronchial ulcer, nodule, plaque or pseudo-membrane
    4. Sino-nasal infection: features of acute sinusitis with at least 1 of acute localized pain, nasal ulcer, eschar, orbital involvement or

    5. Respiratory symptoms:

      • Worsening respiratory insufficiency despite appropriate ventilator support and antibiotics
      • Any 2 of Pleuritic chest pain, pleural rub, dyspnea, hemoptysis
    6. Characteristic skin lesions suspected of fungal infection
    7. Unexplained worsening of encephalopathy after initial improvement

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

Sites / Locations

  • Postgraduate Institute of Medical education and ResearchRecruiting

Arms of the Study

Arm 1

Arm 2

Arm Type

Other

Active Comparator

Arm Label

Early Empiric group

Pre-emptive group

Arm Description

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.

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.

Outcomes

Primary Outcome Measures

Overall Survival
28-day overall survival

Secondary Outcome Measures

Incidence of proven or probable IFI
Incidence of proven or probable IFI at 28 days
In-hospital mortality
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)
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
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
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
Incidence of key events like new onset VAP, UTI, fungal SBP
Mechanical ventilation free days
Duration free from mechanical ventilation within 28 days of enrollment
Length of ICU and hospital stay
Effect on length of ICU, hospital stay within 28 day of enrollment
Treatment success rate
Treatment success rate, successful treatment being defined as Survival beyond 7 days of start of SAT with resolution of sepsis attributable to IFI Absence of new/ breakthrough IFI during treatment or within 7 days of completion Absence of treatment discontinuation related to toxicity/lack of efficacy

Full Information

First Posted
November 6, 2019
Last Updated
April 19, 2022
Sponsor
Postgraduate Institute of Medical Education and Research
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1. Study Identification

Unique Protocol Identification Number
NCT04157465
Brief Title
Anti-fungal Strategies in Acute-on-Chronic Liver Failure Patients
Official Title
Early Empirical Versus Pre-emptive Systemic Anti-fungal Therapy in Acute-on-Chronic Liver Failure Patients With Suspected Invasive Fungal Infections: a Randomized Controlled Trial
Study Type
Interventional

2. Study Status

Record Verification Date
April 2022
Overall Recruitment Status
Recruiting
Study Start Date
November 7, 2019 (Actual)
Primary Completion Date
December 31, 2023 (Anticipated)
Study Completion Date
June 30, 2024 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
Postgraduate Institute of Medical Education and Research

4. Oversight

Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Product Manufactured in and Exported from the U.S.
No
Data Monitoring Committee
Yes

5. Study Description

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 ICU stay of 48 hours or recent hospitalization 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

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
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

7. Study Design

Primary Purpose
Treatment
Study Phase
Not Applicable
Interventional Study Model
Parallel Assignment
Masking
Outcomes Assessor
Masking Description
Single-center, prospective randomized, open-labeled with blinded end-point (PROBE) assessment
Allocation
Randomized
Enrollment
216 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Early Empiric group
Arm Type
Other
Arm Description
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.
Arm Title
Pre-emptive group
Arm Type
Active Comparator
Arm Description
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.
Intervention Type
Other
Intervention Name(s)
Treatment strategy trial
Intervention Description
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 Fungal Biomarkers positivity (Beta-D Glucan>150 pg/ml, Galactomannan index>1.0) Mycological evidence of fungal infection on fungal cultures from a non-sterile site Radiological evidence of fungal infection 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.
Primary Outcome Measure Information:
Title
Overall Survival
Description
28-day overall survival
Time Frame
28 day
Secondary Outcome Measure Information:
Title
Incidence of proven or probable IFI
Description
Incidence of proven or probable IFI at 28 days
Time Frame
28 day
Title
In-hospital mortality
Description
Number of participants dying in hospital due to any cause within 28 day of enrollment
Time Frame
28 day
Title
Evolution of organ failures as assessed by chronic liver failure-sequential organ failure score (CLIF-SOFA)
Description
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.
Time Frame
28 day
Title
Evolution of serum 1, 3 Beta-D Glucan (BDG; in pg/ml) levels throughout the study period
Description
Trends of 1, 3 Beta-D Glucan (BDG) throughout the study period that will be done on twice weekly intervals after enrollment
Time Frame
28 day
Title
Evolution of serum Galactomannan index (GM; in %) throughout the study period
Description
Trends of Galactomannan index (GM; in %) throughout the study period that will be done on twice weekly intervals after enrollment
Time Frame
28 day
Title
Incidence of key events like new onset ventilator associated pneumonia, urinary tract infection, spontaneous fungal peritonitis
Description
Incidence of key events like new onset VAP, UTI, fungal SBP
Time Frame
28 day
Title
Mechanical ventilation free days
Description
Duration free from mechanical ventilation within 28 days of enrollment
Time Frame
28 day
Title
Length of ICU and hospital stay
Description
Effect on length of ICU, hospital stay within 28 day of enrollment
Time Frame
28 day
Title
Treatment success rate
Description
Treatment success rate, successful treatment being defined as Survival beyond 7 days of start of SAT with resolution of sepsis attributable to IFI Absence of new/ breakthrough IFI during treatment or within 7 days of completion Absence of treatment discontinuation related to toxicity/lack of efficacy
Time Frame
28 day
Other Pre-specified Outcome Measures:
Title
Number of participants with adverse events due to antifungals requiring cessation of therapy
Description
Number of participants out of whole group who would develop adverse events due to antifungals that will require cessation of therapy within 28 day of enrollment
Time Frame
28 day
Title
Out of pocket expenditure
Description
Out of pocket expenditure incurred by the patients in two groups
Time Frame
28 day

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
75 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria (All three must be present): 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" ) Firm diagnosis of H1N1 influenza infection in the last 3 months Clinical suspicion of IFI as defined by any of the following: Evidence of unresolved sepsis/SIRS(≥ 2/4) despite appropriate broad-spectrum antibiotics beyond 3days Recrudescence of fever after a period of defervescence of at least 48 hours while still on antibiotics and without other apparent cause Tracheobronchial ulcer, nodule, plaque or pseudo-membrane Sino-nasal infection: features of acute sinusitis with at least 1 of acute localized pain, nasal ulcer, eschar, orbital involvement or Respiratory symptoms: Worsening respiratory insufficiency despite appropriate ventilator support and antibiotics Any 2 of Pleuritic chest pain, pleural rub, dyspnea, hemoptysis Characteristic skin lesions suspected of fungal infection Unexplained worsening of encephalopathy after initial improvement Exclusion Criteria: 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
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Nipun Verma, MD, DM
Phone
+919914208562
Email
nipun29j@gmail.com
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Nipun Verma, MD, DM
Organizational Affiliation
Postgraduate Institute of Medical Education and Research
Official's Role
Principal Investigator
Facility Information:
Facility Name
Postgraduate Institute of Medical education and Research
City
Chandigarh
State/Province
UT
ZIP/Postal Code
160012
Country
India
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Nipun Verma, MD, DM
Phone
+919914208562
Email
nipun29j@gmail.com

12. IPD Sharing Statement

Plan to Share IPD
No

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

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