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

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

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.

Study Overview

• Status: Unknown
• Conditions: Fungal Infection
• Intervention / Treatment: Other: Universal Posaconazole Prophylaxis; Other: Pre-emptive Posaconazole Therapy

Detailed 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.

• Study Type: Interventional
• Enrollment (Anticipated): 140
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Orla Morrissey; Phone Number: +61 3 90762631; Email: o.morrissey@alfred.org.au
• Study Contact Backup: Name: Greg Snell; Phone Number: +61 90762000; Email: g.snell@alfred.org.au

Study Locations

• Australia
  • New South Wales
    • Sydney, New South Wales, Australia, 2010
      • St. Vincent's Hospital
      • Contact: Debbie Marriott, MD
      • Principal Investigator: Debbie Marriott, MD
  • Queensland
    • Brisbane, Queensland, Australia, 4032
      • The Prince Charles Hospital
      • Contact: Peter Hopkins, MD; Phone Number: +61 7 31394000; Email: Peter.Hopkins@health.qld.gov.au
      • Contact: Daniel Chambers, MD; Phone Number: +61 7 31394000; Email: Daniel.Chambers@health.qld.gov.au
      • Principal Investigator: Peter Hopkins, MD
      • Sub-Investigator: Daniel Chambers, MD
  • Victoria
    • Melbourne, Victoria, Australia, 3004
      • Alfred Health
      • Contact: Orla Morrissey, MD, PhD; Phone Number: +61 3 90762000; Email: o.morrissey@alfred.org.au
      • Contact: Greg Snell, MD; Phone Number: + 61 3 90762000; Email: g.snell@alfred.org.au
      • Principal Investigator: Orla Morrissey, MD, PhD
      • Sub-Investigator: Greg Snell, MD
      • Sub-Investigator: Glen Westall, MD, PhD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: PREVENTION
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: NONE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: Universal posaconazole prophylaxis; 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; 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.
EXPERIMENTAL: Pre-emptive posaconazole therapy; 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; 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.

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Bayside Health
• Collaborators: Merck Sharp & Dohme LLC
• Investigators: Study Chair: Orla Morrissey, The Alfred

Study record dates

Study Major Dates

• Study Start (ANTICIPATED): July 2, 2018
• Primary Completion (ANTICIPATED): September 30, 2020
• Study Completion (ANTICIPATED): September 30, 2020

Study Registration Dates

• First Submitted: May 9, 2018
• First Submitted That Met QC Criteria: June 17, 2018
• First Posted (ACTUAL): June 19, 2018

Study Record Updates

• Last Update Posted (ACTUAL): June 19, 2018
• Last Update Submitted That Met QC Criteria: June 17, 2018
• Last Verified: June 1, 2018

More Information

Terms related to this study

• Keywords: Lung transplant, prophylaxis, pre-emptive
• Additional Relevant MeSH Terms: Bacterial Infections and Mycoses; Infections; Mycoses; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Enzyme Inhibitors; Hormones, Hormone Substitutes, and Hormone Antagonists; Cytochrome P-450 Enzyme Inhibitors; Hormone Antagonists; Antifungal Agents; Steroid Synthesis Inhibitors; Antiprotozoal Agents; Antiparasitic Agents; 14-alpha Demethylase Inhibitors; Trypanocidal Agents; Posaconazole
• Other Study ID Numbers: 204/17

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• 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