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Antifungal AgentsNCT04157465

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

A study testing Treatment strategy trial in people with Antifungal Agents and Invasive Fungal Infections, run by Post Graduate Institute of Medical Education and Research, Chandigarh at 1 site in India.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
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Trial 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… Read more about this study

Who is it for?
Ages 18 to 75 years
What is being tested?
Treatment strategy trial
Type of treatment
Injection or infusion
Could I receive a placebo?
No, everyone receives an active treatment
How many people
216 participants
Where
1 siteIndia
Study dates
7 Nov 2019to 31 Dec 2024
Phase
Interventional
Are there results?
None posted in the registry

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 to 75 years
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • 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
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  • 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

Who cannot join

  • 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
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  • 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

Trial locations and contacts

1 site in 1 country.

India1 site
  • Postgraduate Institute of Medical education and Research

    Chandigarh, Uttarakhand, 160012

Other trials in India

About this study

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

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.

Read the 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

Being tested
Treatment strategy trial
Keywords
cirrhosis, Acute-On-Chronic Liver Failure, liposomal amphotericin B, Invasive Fungal Infections, empiric antifungal, pre-emptive antifungal
Medical subject headings
Invasive Fungal Infections, Mycoses, Acute-On-Chronic Liver Failure, Fibrosis

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • Treatment strategy trialOther

    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.

Study groups in NCT04157465
Study groupRoleWhat they receive
Early Empiric groupOtherParticipants 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.
Receives: Other: Treatment strategy trial
Pre-emptive groupActive comparatorParticipants 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.
Receives: Other: Treatment strategy trial

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. Overall Survival

    28-day overall survival

    Measured: 28 day

Secondary outcomes (9)
  1. Incidence of proven or probable IFI

    Incidence of proven or probable IFI at 28 days

    Measured: 28 day

  2. In-hospital mortality

    Number of participants dying in hospital due to any cause within 28 day of enrollment

    Measured: 28 day

  3. 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.

    Measured: 28 day

  4. 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

    Measured: 28 day

  5. 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

    Measured: 28 day

  6. 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

    Measured: 28 day

  7. Mechanical ventilation free days

    Duration free from mechanical ventilation within 28 days of enrollment

    Measured: 28 day

  8. Length of ICU and hospital stay

    Effect on length of ICU, hospital stay within 28 day of enrollment

    Measured: 28 day

  9. Treatment success rate

    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

    Measured: 28 day

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted8 Nov 2019
  2. Study start7 Nov 2019
  3. Primary completion31 Dec 2024
  4. Study completion31 Dec 2024

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase N/A
Primary purpose
Treatment
Allocation
Randomised
Intervention model
Parallel groups
Masking
Single blind
Who is masked
Outcomes assessor
Enrolment
216 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT04157465
Sponsor's protocol ID
PGI/IEC/2019/001924
Status last verified
Dec 2024
First submitted
6 Nov 2019
Last updated
8 Jun 2025
Results posted
No
Data monitoring committee
Yes
FDA-regulated drug
No
FDA-regulated device
No
Individual data sharing
No

Publications

  • 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.

    PubMed 41268913

Questions about this trial

What is this clinical trial studying?

A study testing Treatment strategy trial in people with Antifungal Agents and Invasive Fungal Infections, run by Post Graduate Institute of Medical Education and Research, Chandigarh at 1 site in India.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 26 inclusion and 10 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 8 Jun 2025. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 1 site in India. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

Are results available for this study?

The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Overall Survival (time frame: 28 day). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT04157465, which also lists 1 linked publication.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 8 Jun 2025.

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