Acute-On-Chronic Liver Failure Clinical Trial
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.
Status | Recruiting |
Enrollment | 216 |
Est. completion date | June 30, 2024 |
Est. primary completion date | December 31, 2023 |
Accepts healthy volunteers | No |
Gender | All |
Age group | 18 Years to 75 Years |
Eligibility | 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 |
Country | Name | City | State |
---|---|---|---|
India | Postgraduate Institute of Medical education and Research | Chandigarh | UT |
Lead Sponsor | Collaborator |
---|---|
Postgraduate Institute of Medical Education and Research |
India,
Type | Measure | Description | Time frame | Safety issue |
---|---|---|---|---|
Other | Number of participants with adverse events due to antifungals requiring cessation of therapy | 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 | 28 day | |
Other | Out of pocket expenditure | Out of pocket expenditure incurred by the patients in two groups | 28 day | |
Primary | Overall Survival | 28-day overall survival | 28 day | |
Secondary | Incidence of proven or probable IFI | Incidence of proven or probable IFI at 28 days | 28 day | |
Secondary | In-hospital mortality | Number of participants dying in hospital due to any cause within 28 day of enrollment | 28 day | |
Secondary | 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. | 28 day | |
Secondary | 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 | 28 day | |
Secondary | 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 | 28 day | |
Secondary | 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 | 28 day | |
Secondary | Mechanical ventilation free days | Duration free from mechanical ventilation within 28 days of enrollment | 28 day | |
Secondary | Length of ICU and hospital stay | Effect on length of ICU, hospital stay within 28 day of enrollment | 28 day | |
Secondary | 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 |
28 day |
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