## Protocol Section
### Identification Module
**NCT ID:** NCT03378479

**Acronym:** POSA-FLU

**Brief Title:** Posaconazole for the Prevention of Influenza-associated Aspergillosis in Critically Ill Patients

**Official Title:** A Phase iv, Interventional, Non-blinded, Randomized Controlled Multicenter Study of Posaconazole Prophylaxis for the Prevention of Influenza-associated Aspergillosis (IAA) in Critically Ill Patients

#### Organization Study ID Info
**ID:** POSA-FLU
#### Organization
**Class:** OTHER
**Full Name:** Universitaire Ziekenhuizen KU Leuven
### Status Module
#### Completion Date
**Date:** 2021-03-30

**Type:** ACTUAL

#### Expanded Access Info
#### Last Update Post Date
**Date:** 2022-06-30

**Type:** ACTUAL

**Last Update Submit Date:** 2022-06-29

**Overall Status:** COMPLETED

#### Primary Completion Date
**Date:** 2020-03-31

**Type:** ACTUAL

#### Start Date
**Date:** 2017-12-27

**Type:** ACTUAL

**Status Verified Date:** 2022-06

#### Study First Post Date
**Date:** 2017-12-19
**Type:** ACTUAL
**Study First Submit Date:** 2017-10-30
**Study First Submit QC Date:** 2017-12-18
### Sponsor Collaborators Module

#### Collaborators

**Class:** INDUSTRY

**Name:** Merck Sharp & Dohme LLC

#### Lead Sponsor

**Class:** OTHER

**Name:** Universitaire Ziekenhuizen KU Leuven

#### Responsible Party

**Investigator Affiliation:** Universitaire Ziekenhuizen KU Leuven

**Investigator Full Name:** Joost Wauters, prof. dr.

**Investigator Title:** Principal Investigator

**Type:** PRINCIPAL_INVESTIGATOR

### Oversight Module

**Is FDA Regulated Device:** False

**Is FDA Regulated Drug:** False

**Is US Export:** False

**Oversight Has DMC:** False

### Description Module

**Brief Summary:** The objective of this study is to deliver proof of concept that antifungal prophylaxis can reduce the incidence of Influenza Associated Aspergillosis (IAA) in ICU (intensive care unit) patients with severe influenza.

The investigators will perform an interventional non-blinded randomized controlled multicentric proof-of-concept study in patients with severe influenza admitted to the ICU. Patients will be randomized to the posaconazole prophylaxis group or to the SOC (standard of care) group. Oseltamivir will be started at the discretion of the investigator. Patients in the posaconazole group will receive posaconazole prophylaxis for 7 days.

addendum: pharmacokinetics of posaconazole as prophylaxis for invasive fungal disease on ICU

**Detailed Description:** Critically ill patients with PCR-confirmed influenza criteria) are eligible for inclusion in this study and will be randomized to or the posaconazole prophylaxis group or the SOC group.

If a patient is randomized to the posaconazole prophylaxis group, posaconazole (Noxafil, MSD) will be started intravenously from day 1 of randomization (2\*300mg( milligram) /d on day 1, followed by 1\*300mg/d from day 2 for 7 days) In both patient groups (prophylaxis and SOC) oseltamivir (non-IMP) will be started at the discretion of the treating physician from the first day of ICU admission as 2\*150 mg/day for 10 days. If oseltamivir had already been started up before ICU admission, oseltamivir treatment will be continued up to a total of 10 days.

Within 48 hours after influenza diagnosis a bronchoscopy with BAL (bronchoalveolar lavage) and a serum galactomannan will be performed as part of routine ICU care in this type of patients. If an IAA-infection is suspected based on the result of this BAL ((A) Aspergillus cultured from BAL, or (B) a galactomannan (GM)the patient will be withdrawn from the study and antifungal treatment will be started.

addendum: Extensive PK sampling (UZ Leuven and Radboud): full PK curve on day 2 and day 5 (predose, 1.5; 2,3,4,6,8,10,12,18,24 h post infusion).

on non PK days, until day 7, predose sample. PK in BAL fluid only in patients with mechanical ventilation and when medically indicated.

Limited PK sampling: on day 2 and day 5: 1.5-3h, 4-8 h;8-12h; 12-24h post dose. on non PK days: PK pre dose.

### Conditions Module

**Conditions:**

- Aspergillosis; Pulmonary, Invasive (Etiology)

**Keywords:**

- Influenza

### Design Module

#### Design Info

**Allocation:** RANDOMIZED

**Intervention Model:** PARALLEL

##### Masking Info

**Masking:** NONE

**Primary Purpose:** PREVENTION

#### Enrollment Info

**Count:** 88

**Type:** ACTUAL

**Phases:**

- PHASE4

**Study Type:** INTERVENTIONAL

### Arms Interventions Module

#### Arm Group 1

**Description:** standard of care (SOC) treatment for influenza pneumonia +posaconazole 2\*300mg/d IV on day 1, followed by 1\*300mg/d IV from day 2 for 7 days; vials containing 18mg posaconazole /mL, 300mg posaconazole/vial in total)

**Intervention Names:**

- Drug: SOC +Posaconazole 18 MG/ML (milligram/milliliter)

- Other: standard of care (SOC)

**Label:** SOC + 'Posaconazole 18 MG/ML'

**Type:** OTHER

#### Arm Group 2

**Description:** standard of care treatment for influenza pneumonia (at the investigators discretion)

**Intervention Names:**

- Other: standard of care (SOC)

**Label:** Standard of Care

**Type:** OTHER

### Interventions

#### Intervention 1

**Arm Group Labels:**

- SOC + 'Posaconazole 18 MG/ML'

**Description:** .2\*300mg/d IV on day 1, followed by 1\*300mg/d IV from day 2 for 7 days (total 7 days)

**Name:** SOC +Posaconazole 18 MG/ML (milligram/milliliter)

**Other Names:**

- Noxafil

**Type:** DRUG

#### Intervention 2

**Arm Group Labels:**

- SOC + 'Posaconazole 18 MG/ML'

- Standard of Care

**Description:** treatment for influenza pneumonia at the investigators discretion

**Name:** standard of care (SOC)

**Type:** OTHER

### Outcomes Module

#### Primary Outcomes

**Description:** A patient with IAA-infection is defined as a patient having mycological evidence of Aspergillus and at least one Aspergillus compatible sign or symptom and radiological abnormalities

**Measure:** The incidence of IAA-infection at ICU discharge

**Time Frame:** from date of admission in ICU assessed up to ICU discharge, approximately 21 days

#### Secondary Outcomes

**Description:** days to IAA diagnosis

**Measure:** Time to IAA diagnosis

**Time Frame:** from date of inclusion to date of first sign/symptom of IAA infection, assessed up to ICU discharge, approximately 10 days

**Description:** amount of days at ICU

**Measure:** length of ICU stay

**Time Frame:** from date of admission in ICU to date of discharge from ICU, approximately 20 days

**Description:** admission days

**Measure:** length of hospital stay

**Time Frame:** from date of admission in hospital to date of discharge from hospital, approximately 25 days

**Description:** survival status

**Measure:** mortality

**Time Frame:** at day 30 and at day 90

**Description:** altered clearance of posaconazole in critically ill patients

**Measure:** identify changes in PK of posaconazole in critically ill patients

**Time Frame:** from day 1 until day 7

### Eligibility Module

**Eligibility Criteria:** Inclusion Criteria:

1. Written informed consent must be obtained from the patient or his/her legal representative prior to any study procedures
2. Adult patient (≥ 18 years)
3. PCR-confirmed influenza based on nasopharyngeal swab (NS), bronchial aspirate (BA) or broncho-alveolar lavage (BAL) within 7 days before ICU admission or within 48 hours after ICU admission. If PCR is not available a positive result of a rapid test is required (a negative rapid test does not imply absence of influenza and thus requires confirmation by PCR)
4. Influenza symptoms present for no more than 10 days before ICU admission
5. Respiratory distress as the main reason for ICU admission. Respiratory distress will be defined as tachypnea with an respiratory rate ≥ 25x/min and a paO2/fiO2-ratio (fraction of inspired oxygen) ≤ 300 with or without (bilateral) infiltrates.

Exclusion Criteria:

1. Patients with age \< 18 years
2. Pregnant women (based on a positive serum sample)
3. Expected survival on ICU admission ≤ 48h
4. Patients having influenza symptoms for more than 10 days before ICU admission
5. Patients being transferred from another hospital ward or another hospital who already have mycological evidence for an IAA-infection (based on sputum, BA or BAL culture, BAL or serum GM)
6. Patients with known intolerance or hypersensitivity to posaconazole or other azole antifungal agents
7. Patients that are being treated actively with antifungal agents for invasive aspergillosis
8. Patients with a QTc (corrected QT interval) interval ≥500 msec
9. Patients with liver cirrhosis (Child C)
10. Participation in another interventional clinical trial -

**Minimum Age:** 18 Years

**Sex:** ALL

**Standard Ages:**

- ADULT

- OLDER_ADULT

### Contacts Locations Module

#### Locations

**Location 1:**

**City:** Brugge

**Country:** Belgium

**Facility:** AZ Sint Jan

**Zip:** 8000

**Location 2:**

**City:** Gent

**Country:** Belgium

**Facility:** UZ Gent

**Zip:** 9000

**Location 3:**

**City:** Leuven

**Country:** Belgium

**Facility:** UZ Leuven

**Zip:** 3000

**Location 4:**

**City:** Roeselare

**Country:** Belgium

**Facility:** AZ Delta

**Zip:** 8800

**Location 5:**

**City:** Groningen

**Country:** Netherlands

**Facility:** Universitair Medisch Centrum

**Location 6:**

**City:** Nijmegen

**Country:** Netherlands

**Facility:** UMC Radboud

**Zip:** 6500

**Location 7:**

**City:** Rotterdam

**Country:** Netherlands

**Facility:** MC Erasmus

**Zip:** 3015

#### Overall Officials

**Official 1:**

**Affiliation:** UZ Leuven

**Name:** Joost Wauters, Phd

**Role:** PRINCIPAL_INVESTIGATOR

**Official 2:**

**Affiliation:** Radboud University Medical Center

**Name:** Paul Verweij, Phd

**Role:** PRINCIPAL_INVESTIGATOR

### IPD Sharing Statement Module

**IPD Sharing:** UNDECIDED

### References Module

#### References

**Citation:** Vanderbeke L, Janssen NAF, Bergmans DCJJ, Bourgeois M, Buil JB, Debaveye Y, Depuydt P, Feys S, Hermans G, Hoiting O, van der Hoven B, Jacobs C, Lagrou K, Lemiale V, Lormans P, Maertens J, Meersseman P, Megarbane B, Nseir S, van Oers JAH, Reynders M, Rijnders BJA, Schouten JA, Spriet I, Thevissen K, Thille AW, Van Daele R, van de Veerdonk FL, Verweij PE, Wilmer A, Bruggemann RJM, Wauters J; Dutch-Belgian Mycosis Study Group. Posaconazole for prevention of invasive pulmonary aspergillosis in critically ill influenza patients (POSA-FLU): a randomised, open-label, proof-of-concept trial. Intensive Care Med. 2021 Jun;47(6):674-686. doi: 10.1007/s00134-021-06431-0. Epub 2021 May 29.

**PMID:** 34050768

## Annotation Section

### Unposted Annotation

#### Event: RELEASE

- Date: 2022-06-30

- Date Unknown: Unknown

#### Event: RESET

- Date: 2023-04-28

- Date Unknown: Unknown

## Derived Section

### Condition Browse Module - Ancestors

- ID: D000012141

- Term: Respiratory Tract Infections

- ID: D000007239

- Term: Infections

- ID: D000009976

- Term: Orthomyxoviridae Infections

- ID: D000012327

- Term: RNA Virus Infections

- ID: D000014777

- Term: Virus Diseases

- ID: D000012140

- Term: Respiratory Tract Diseases

- ID: D000009181

- Term: Mycoses

- ID: D000001423

- Term: Bacterial Infections and Mycoses

### Condition Browse Module - Browse Branches

- Abbrev: BC23

- Name: Symptoms and General Pathology

- Abbrev: All

- Name: All Conditions

- Abbrev: BC01

- Name: Infections

- Abbrev: BC08

- Name: Respiratory Tract (Lung and Bronchial) Diseases

- Abbrev: Rare

- Name: Rare Diseases

### Condition Browse Module - Browse Leaves

- ID: M19010

- Name: Critical Illness

- Relevance: LOW

- As Found: Unknown

- ID: M10295

- Name: Influenza, Human

- Relevance: HIGH

- As Found: Influenza

- ID: M4535

- Name: Aspergillosis

- Relevance: HIGH

- As Found: Aspergillosis

- ID: M10283

- Name: Infections

- Relevance: LOW

- As Found: Unknown

- ID: M6368

- Name: Communicable Diseases

- Relevance: LOW

- As Found: Unknown

- ID: M14978

- Name: Respiratory Tract Infections

- Relevance: LOW

- As Found: Unknown

- ID: M12902

- Name: Orthomyxoviridae Infections

- Relevance: LOW

- As Found: Unknown

- ID: M17522

- Name: Virus Diseases

- Relevance: LOW

- As Found: Unknown

- ID: M15149

- Name: RNA Virus Infections

- Relevance: LOW

- As Found: Unknown

- ID: M14977

- Name: Respiratory Tract Diseases

- Relevance: LOW

- As Found: Unknown

- ID: M12136

- Name: Mycoses

- Relevance: LOW

- As Found: Unknown

- ID: M4722

- Name: Bacterial Infections

- Relevance: LOW

- As Found: Unknown

- ID: M4721

- Name: Bacterial Infections and Mycoses

- Relevance: LOW

- As Found: Unknown

- ID: T511

- Name: Aspergillosis

- Relevance: HIGH

- As Found: Aspergillosis

### Condition Browse Module - Meshes

- ID: D000007251

- Term: Influenza, Human

- ID: D000001228

- Term: Aspergillosis

### Intervention Browse Module - Ancestors

- ID: D000000935

- Term: Antifungal Agents

- ID: D000000890

- Term: Anti-Infective Agents

- ID: D000014344

- Term: Trypanocidal Agents

- ID: D000000981

- Term: Antiprotozoal Agents

- ID: D000000977

- Term: Antiparasitic Agents

- ID: D000058888

- Term: 14-alpha Demethylase Inhibitors

- ID: D000065607

- Term: Cytochrome P-450 Enzyme Inhibitors

- ID: D000004791

- Term: Enzyme Inhibitors

- ID: D000045504

- Term: Molecular Mechanisms of Pharmacological Action

- ID: D000065088

- Term: Steroid Synthesis Inhibitors

- ID: D000006727

- Term: Hormone Antagonists

- ID: D000006730

- Term: Hormones, Hormone Substitutes, and Hormone Antagonists

- ID: D000045505

- Term: Physiological Effects of Drugs

### Intervention Browse Module - Browse Branches

- Abbrev: Infe

- Name: Anti-Infective Agents

- Abbrev: All

- Name: All Drugs and Chemicals

### Intervention Browse Module - Browse Leaves

- ID: M219015

- Name: Posaconazole

- Relevance: HIGH

- As Found: Venous Thromboembolism

- ID: M6252

- Name: Clotrimazole

- Relevance: LOW

- As Found: Unknown

- ID: M11796

- Name: Miconazole

- Relevance: LOW

- As Found: Unknown

- ID: M4254

- Name: Antifungal Agents

- Relevance: LOW

- As Found: Unknown

- ID: M4214

- Name: Anti-Infective Agents

- Relevance: LOW

- As Found: Unknown

- ID: M4298

- Name: Antiprotozoal Agents

- Relevance: LOW

- As Found: Unknown

- ID: M4294

- Name: Antiparasitic Agents

- Relevance: LOW

- As Found: Unknown

- ID: M7951

- Name: Enzyme Inhibitors

- Relevance: LOW

- As Found: Unknown

- ID: M30537

- Name: Cytochrome P-450 Enzyme Inhibitors

- Relevance: LOW

- As Found: Unknown

- ID: M9789

- Name: Hormones

- Relevance: LOW

- As Found: Unknown

- ID: M9788

- Name: Hormone Antagonists

- Relevance: LOW

- As Found: Unknown

### Intervention Browse Module - Meshes

- ID: C000101425

- Term: Posaconazole

### Misc Info Module

#### Submission Tracking

- Estimated Results First Submit Date: 2022-06-30

##### Submission Infos

- MCP Release N: Unknown

- Release Date: 2022-06-30

- Reset Date: 2023-04-28

- Unrelease Date: Unknown

- Unrelease Date Unknown: Unknown

- Version Holder: 2024-05-24
