Universal Prophylaxis Versus Pre-emptive Therapy With Posaconazole Post-Lung Transplant

Study Overview
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Brief Summary
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This trial will examine 2 ways of using the antifungal posaconazole to prevent invasive fungal disease and the precipitation of chronic rejection post lung transplantation.

Detailed Description
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Lung transplantation (LT) is an increasingly used treatment for end-stage respiratory disease. However, it is expensive, with hospital costs alone estimated at >US$500,000/transplant. Fungal infection and chronic lung allograft dysfunction (CLAD) are the major complications of LT. They pose the greatest threat to long-term survival and are reported to occur in 12-50% of LT recipients and cause death in 21.7-82% of these. Fungal infections occur in 3 major forms in LT recipients, namely colonisation, trachea-bronchial disease and invasive (or end-organ) disease. Whilst invasive fungal disease (IFD) is associated with the highest mortality, colonisation poses the greatest clinical challenge. It is the most common manifestation, can progress to IFD and can precipitate CLAD. Antifungal prophylaxis is used to minimise the risks associated with colonisation. Two main antifungal prophylaxis strategies are used. Universal prophylaxis (UP) is defined as the administration of antifungal agents to all patients post-LT. Most centres use UP. A systematic review and meta-analysis showed neither Aspergillus colonisation nor invasive aspergillosis (IA) (the commonest fungal infection in LT recipients) were reduced by UP. Yet it caused side-effects in 29.6%. The pre-emptive strategy is defined as the administration of antifungal agents when a fungal pathogen (including in donor specimens) is detected or there is serological evidence of a fungal pathogen in the absence of IFD from a post-LT surveillance bronchoscopy or other clinical investigations (i.e. colonisation).Observational data suggest that a pre-emptive strategy has similar IA incidence rates but fewer adverse drug reactions (ADR) than UP (16.1%). It has been estimated that a pre-emptive strategy can reduce antifungal drug use by 43%. No direct comparison of the efficacy, safety and cost of the two strategies has been performed to date. Thus, a randomised controlled trial (RCT) is needed to determine the optimal strategy to reduce the impact of fungal infection in LT recipients. However, before we embark on a definitive phase III RCT powered for clinical outcomes we will perform a pilot feasibility RCT to generate data and answer practical questions to better inform the design of the definitive phase III RCT powered for clinical outcomes.

Official Title
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Universal Posaconazole Prophylaxis Versus Pre-emptive Posaconazole Therapy for Fungal Infection Management Post-lung Transplantation

Conditions
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Fungal Infection

Intervention / Treatment
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* Other: Universal Posaconazole Prophylaxis
* Other: Pre-emptive Posaconazole Therapy


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male and female aged ≥ 18 years Undergoing bilateral sequential lung transplant (BSLT) or heart-lung transplant (HLT) including re-do transplant Able to give written informed consent Able to understand and comply with all trial requirements Exclusion Criteria: Less than 18 years of age Scheduled to undergo a single-lung transplant (known risk factor for IFD) Scheduled to undergo multi-organ transplant, other than HLT Recipients who will not be followed up for 1-year post-transplant at one of the trial sites Isolation of a mould within the 12 months prior to screening Evidence of a mycetoma within the 12 months prior to screening Proven or probable IFD within the 12 months prior to screening Patients with moderate or severe liver disease as defined by aspartate aminotransferase (AST) or alanine aminotransferase (ALT) > 5 times the upper limit of normal (ULN) Any other severe condition which in the site investigator's judgement may interfere with the trial evaluations or severely affect the patients safety Previous inclusion in the trial Currently enrolled in an antifungal or other investigational drug trial

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Universal posaconazole prophylaxis<br>Universal posaconazole prophylaxis: All patients will start posaconazole modified release tablet (300mg daily ) between Day 4 and Day 14 post lung or heart-lung transplantation for 3 months. | Other: Universal Posaconazole Prophylaxis<br>* All patients assigned to this arm will start posaconazole between Day 4 and Day 14 post lung or heart-lung transplant for a minimum of 3 months.<br>|
| Experimental: Pre-emptive posaconazole therapy<br>Pre-emptive posaconazole therapy: Posaconazole will be started if a fungal pathogen is identified or there is serological evidence of a fungal pathogen in the absence of any evidence of invasive fungal disease and given for 3 months. | Other: Pre-emptive Posaconazole Therapy<br>* Posaconazole will be started if a fungal pathogen is identified or there is serological evidence of a fungal pathogen in the absence of any evidence of invasive fungal disease for 3 months.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Composite of: screened that are eligible, eligible that are enrolled, lost to follow-up or are withdrawn from the trial, receive their allocated treatment throughout the trial participation and have missing data during trial data collection. | Feasibility outcome | 2 years and 3 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Composite of: at least one episode of fungal pneumonia, fungal tracheobronchitis, or bronchial anastomotic fungal infection; diagnosed as having CLAD or died regardless of cause | Efficacy outcome | 2 years and 3 months | 
| Fungal pneumonia, fungal tracheobronchitis, or bronchial anastomotic fungal infection rates | Efficacy outcome | 2 years and 3 months | 
| CLAD rates | Efficacy outcome | 2 years and 3 months | 
| All-cause mortality rates | Efficacy outcome | 2 years and 3 months | 
| Fungal pneumonia, fungal tracheobronchitis, or bronchial anastomotic fungal infection-related mortality rates | Efficacy outcome | 2 years and 3 months | 
| CLAD-related mortality rates | Efficacy outcome | 2 years and 3 months | 
| Time to development of fungal pneumonia, fungal tracheobronchitis, bronchial anastomotic fungal infection | Efficacy outcome | 2 years and 3 months | 
| Time to diagnosis of CLAD | Efficacy outcome | 2 years and 3 months | 
| Costs associated with allocated arm including number of hospital admissions | Efficacy outcome | 2 years and 3 months | 
| Quality of life (QoL) using Short Form Survey (sf-36) to measure patient health | Efficacy outcome | 2 years and 3 months | 
| Acute rejection rates | Safety outcome | 2 years and 3 months | 
| Posaconazole adverse drug reaction (ADR) rates | Safety outcome | 2 years and 3 months | 
| Proportion of patients who discontinue posaconazole because of an ADR | Safety outcome | 2 years and 3 months | 
| Total duration on posaconazole | Safety outcome | 2 years and 3 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Lung transplant, prophylaxis, pre-emptive