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

NCT ID: NCT03561415

Last Updated: 2018-06-19

Basic Information

• Recruitment Status: UNKNOWN
• Clinical Phase: PHASE2
• Total Enrollment: 140 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2018-07-02
• Study Completion Date: 2020-09-30

Brief 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.

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.

Conditions

Fungal Infection

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: PREVENTION
• Blinding Strategy: NONE

Study Groups

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.

Group Type: EXPERIMENTAL

Universal Posaconazole Prophylaxis

Intervention Type: OTHER

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

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.

Group Type: EXPERIMENTAL

Pre-emptive Posaconazole Therapy

Intervention Type: OTHER

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.

Interventions

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.

Intervention Type: 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.

Intervention Type: OTHER

Eligibility Criteria

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

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Merck Sharp & Dohme LLC

INDUSTRY

Sponsor Role: collaborator

Bayside Health

OTHER_GOV

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Orla Morrissey

Role: STUDY_CHAIR

The Alfred

Locations

St. Vincent's Hospital

Sydney, New South Wales, Australia

The Prince Charles Hospital

Brisbane, Queensland, Australia

Alfred Health

Melbourne, Victoria, Australia

Countries

Australia

Central Contacts

Orla Morrissey

Role: CONTACT

o.morrissey@alfred.org.au

+61 3 90762631

Greg Snell

Role: CONTACT

g.snell@alfred.org.au

+61 90762000

Facility Contacts

Debbie Marriott, MD

Role: primary

Peter Hopkins, MD

Role: primary

Peter.Hopkins@health.qld.gov.au

+61 7 31394000

Daniel Chambers, MD

Role: backup

Daniel.Chambers@health.qld.gov.au

+61 7 31394000

Orla Morrissey, MD, PhD

Role: primary

o.morrissey@alfred.org.au

+61 3 90762000

Greg Snell, MD

Role: backup

g.snell@alfred.org.au

+ 61 3 90762000

Other Identifiers

204/17

Identifier Type: -

Identifier Source: org_study_id