Isavuconazole for the Prevention of COVID-19-associated Pulmonary Aspergillosis

NCT ID: NCT04707703

Last Updated: 2022-11-25

Basic Information

• Recruitment Status: TERMINATED
• Clinical Phase: PHASE3
• Total Enrollment: 8 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2021-03-16
• Study Completion Date: 2021-10-25

Brief Summary

The objective of this study is to evaluate whether antifungal prophylaxis with isavuconazole can reduce the incidence of SARS-CoV-2-associated invasive aspergillosis in patients in the ICU (intensive care unit) with severe COVID-19 infection.

The investigators will perform an interventional, double-blinded, randomized-controlled, multi-center study in patients with severe COVID-19 infection admitted to the ICU. Patients will be randomized to the isavuconazole prophylaxis plus standard of care (SOC) group or the placebo plus SOC group. Participants will receive isavuconazole or placebo for up to 28 days or until discharge from the hospital (whichever occurs first).

Detailed Description

Adult patients with polymerase chain reaction (PCR)-confirmed SARS-CoV-2 (COVID-19) infection without a diagnosis of invasive aspergillosis who are hospitalized in the ICU are eligible for inclusion in this study and will be randomized to the isavuconazole plus standard of care (SOC) group or placebo plus SOC group.

If randomized to the isavuconazole group, participants will receive intravenous isavuconazonium sulfate 372 mg every 8 hours for 6 doses followed by intravenous isavuconazonium sulfate 372 mg once daily for up to 28 days. If randomized to the placebo group, participants will receive intravenous placebo every 8 hours for 6 doses followed by once daily for up to 28 days. Both groups will receive the usual SOC.

Following randomized to the two treatment arms, participants will be screened for invasive aspergillosis with thrice weekly fungal cultures from tracheal aspirate (TA) secretions or thrice weekly serum galactomannan (GM) testing (if TA unable to be performed, contraindicated, or participant is not intubated). If invasive aspergillosis or other invasive fungal infection is detected, antifungal therapy will be initiated (if the participant is in the placebo arm) or modified if needed (if the participant is in the isavuconazole arm).

Conditions

Severe Acute Respiratory Syndrome Coronavirus 2; Aspergillosis Invasive

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: PREVENTION
• Blinding Strategy: TRIPLE

Study Groups

SOC plus Isavuconazonium sulfate

SOC plus intravenous isavuconazonium sulfate 372 mg every 8 hours for 6 doses followed by 372mg once daily for up to 28 days

Group Type: EXPERIMENTAL

Isavuconazonium Injection [Cresemba]

Intervention Type: DRUG

Intravenous isavuconazonium sulfate 372 mg every 8 hours for 6 doses followed by intravenous isavuconazonium sulfate 372 mg once daily for up to 28 days

SOC plus Placebo

SOC plus intravenous placebo every 8 hours for 6 doses followed by once daily for up to 28 days

Group Type: PLACEBO_COMPARATOR

Placebo

Intervention Type: DRUG

Intravenous placebo every 8 hours for 6 doses followed by intravenous placebo once daily for up to 28 days

Interventions

Isavuconazonium Injection [Cresemba]

Intravenous isavuconazonium sulfate 372 mg every 8 hours for 6 doses followed by intravenous isavuconazonium sulfate 372 mg once daily for up to 28 days

Intervention Type: DRUG

Placebo

Intravenous placebo every 8 hours for 6 doses followed by intravenous placebo once daily for up to 28 days

Intervention Type: DRUG

Other Intervention Names

Isavuconazole; Cresemba

Eligibility Criteria

Inclusion Criteria

• Written informed consent obtained from the patient or his/her legally authorized person.
• Adult patient (> 18 years).
• PCR-confirmed SARS-CoV-2 based on nasopharyngeal swab (NPS), oropharyngeal swab (OPS), tracheal aspirate (TA), bronchial aspirate (BA), or bronchoalveolar lavage fluid (BALF) within 14 days prior to ICU admission or within 72 hours following ICU admission.
• Radiographic imaging consistent with SARS-CoV-2 infection (e.g. atypical pneumonia, organizing pneumonia, ground glass opacities) or acute respiratory distress syndrome (ARDS) within 7 days of diagnosis of SARS-CoV-2 infection.
• A negative pregnancy test in women of child-bearing age.
• If a woman is of child-bearing age, she must be willing to use an effective method of contraception for 28 days after the final dose of isavuconazole per manufacturer instructions

Exclusion Criteria

• Anticipated transfer to another medical center that is not a study site within hours of admission to the ICU.
• Pregnancy based on a positive human chorionic gonadotropin (HCG) test from serum or urine.
• Patient who is breastfeeding and unable to discontinue breastfeeding while taking the study drug.
• Patients with a diagnosis of invasive aspergillosis/detection of Aspergillus spp. by culture from sputum, TA, BA, or BALF or positive GM from serum or BALF at time of screening or randomization.
• History of invasive aspergillosis within the prior six months.
• Patients with a known intolerance or hypersensitivity to isavuconazole or other azole agents.
• History of familial short QT syndrome.
• Patients that are being treated with mold-active antifungal agents for invasive aspergillosis or another invasive fungal infection.
• Patients with severe hepatic impairment or liver cirrhosis (Child C) should be excluded from the study unless the treating physicians feel the benefits of treatment outweigh the risks.
• Treatment with Lopinavir/ritonavir for HIV infection.
• Prohibited Medications
• Co-administration with a strong CYP3A4 inhibitor or high-dose ritonavir as they may alter the plasma concentration of isavuconazole.
• Co-administration with a strong CYP3A4 inducer such as rifampin, carbamazepine, St. John's wort, or long acting barbiturates.

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

Sponsors

Astellas Pharma Global Development, Inc.

INDUSTRY

Sponsor Role: collaborator

Jeffrey Jenks, MD, MPH

OTHER

Sponsor Role: lead

Responsible Party

Jeffrey Jenks, MD, MPH

Assoc Physician

Responsibility Role: SPONSOR_INVESTIGATOR

Principal Investigators

Jeffrey Jenks, MD, MPH

Role: PRINCIPAL_INVESTIGATOR

University of California, San Diego

George Thompson, MD

Role: STUDY_CHAIR

University of California, Davis

Martin Hoenigl, MD

Role: STUDY_CHAIR

University of California, San Diego

Locations

University of California Irvine

Orange, California, United States

University of California Davis

Sacramento, California, United States

University of California San Diego

San Diego, California, United States

Countries

United States

References

Permpalung N, Chiang TP, Manothummetha K, Ostrander D, Datta K, Segev DL, Durand CM, Mostafa HH, Zhang SX, Massie AB, Marr KA, Avery RK. Invasive Fungal Infections in Inpatient Solid Organ Transplant Recipients With COVID-19: A Multicenter Retrospective Cohort. Transplantation. 2024 Jul 1;108(7):1613-1622. doi: 10.1097/TP.0000000000004947. Epub 2024 Jun 20.

Reference Type: DERIVED

PMID: 38419156 (View on PubMed)

Other Identifiers

200639

Identifier Type: -

Identifier Source: org_study_id