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

Fungal Infection Clinical Trial

— UPPRITE  

Official title:

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

Clinical Trial Details — Status: Not yet recruiting

Administrative data

• NCT number: NCT03561415
• Other study ID #: 204/17
• Status: Not yet recruiting
• Phase: Phase 2
• Start date: July 2, 2018
• Est. completion date: September 30, 2020

Study information

• Verified date: June 2018
• Source: Bayside Health
• Contact: Orla Morrissey
• Phone: +61 3 90762631
• Email: o.morrissey[@]alfred.org.au
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

Description:

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.

Recruitment information / eligibility

• Status: Not yet recruiting
• Enrollment: 140
• Est. completion date: September 30, 2020
• Est. primary completion date: September 30, 2020
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

1. Male and female aged = 18 years

2. Undergoing bilateral sequential lung transplant (BSLT) or heart-lung transplant (HLT) including re-do transplant

3. Able to give written informed consent

4. Able to understand and comply with all trial requirements

Exclusion Criteria:

1. Less than 18 years of age

2. Scheduled to undergo a single-lung transplant (known risk factor for IFD)

3. Scheduled to undergo multi-organ transplant, other than HLT

4. Recipients who will not be followed up for 1-year post-transplant at one of the trial sites

5. Isolation of a mould within the 12 months prior to screening

6. Evidence of a mycetoma within the 12 months prior to screening

7. Proven or probable IFD within the 12 months prior to screening

8. 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)

9. Any other severe condition which in the site investigator's judgement may interfere with the trial evaluations or severely affect the patients safety

10. Previous inclusion in the trial

11. Currently enrolled in an antifungal or other investigational drug trial

Related Conditions & MeSH terms

• Fungal Infection
• Infection
• Mycoses

Intervention

Other:
• Universal Posaconazole Prophylaxis
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.
• 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 for 3 months.

Locations

Country	Name	City	State
Australia	The Prince Charles Hospital	Brisbane	Queensland
Australia	Alfred Health	Melbourne	Victoria
Australia	St. Vincent's Hospital	Sydney	New South Wales

Sponsors (2)

Lead Sponsor	Collaborator
Bayside Health	Merck Sharp & Dohme Corp.

Country where clinical trial is conducted

Australia, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	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
Secondary	Fungal pneumonia, fungal tracheobronchitis, or bronchial anastomotic fungal infection rates	Efficacy outcome	2 years and 3 months
Secondary	CLAD rates	Efficacy outcome	2 years and 3 months
Secondary	All-cause mortality rates	Efficacy outcome	2 years and 3 months
Secondary	Fungal pneumonia, fungal tracheobronchitis, or bronchial anastomotic fungal infection-related mortality rates	Efficacy outcome	2 years and 3 months
Secondary	CLAD-related mortality rates	Efficacy outcome	2 years and 3 months
Secondary	Time to development of fungal pneumonia, fungal tracheobronchitis, bronchial anastomotic fungal infection	Efficacy outcome	2 years and 3 months
Secondary	Time to diagnosis of CLAD	Efficacy outcome	2 years and 3 months
Secondary	Costs associated with allocated arm including number of hospital admissions	Efficacy outcome	2 years and 3 months
Secondary	Quality of life (QoL) using Short Form Survey (sf-36) to measure patient health	Efficacy outcome	2 years and 3 months
Secondary	Acute rejection rates	Safety outcome	2 years and 3 months
Secondary	Posaconazole adverse drug reaction (ADR) rates	Safety outcome	2 years and 3 months
Secondary	Proportion of patients who discontinue posaconazole because of an ADR	Safety outcome	2 years and 3 months
Secondary	Total duration on posaconazole	Safety outcome	2 years and 3 months