Isavuconazole in the Treatment of Renally Impaired Aspergillosis and Rare Fungi

Study Overview
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Brief Summary
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The purpose of this study is to investigate the efficacy and safety of isavuconazole in the treatment of renally impaired participants with invasive fungal infections caused by Aspergillus and participants with invasive fungal disease caused by rare fungi.

Detailed Description
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Acute invasive fungal infections caused by aspergillus, rare moulds, yeasts or dimorphic fungi are life threatening diseases. Early treatment with highly effective anti-fungals reduces mortality. This study investigates the safety and efficacy of isavuconazole in participants with aspergillosis and renal impairment, and in participants suffering from invasive infections from rare fungi.

Official Title
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Open-label Study of Isavuconazole in the Treatment of Participants With Aspergillosis and Renal Impairment or of Participants With Invasive Fungal Disease Caused by Rare Moulds, Yeasts or Dimorphic Fungi

Conditions
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Aspergillosis, Invasive Fungal Infections

Intervention / Treatment
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* Drug: isavuconazole


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: •Participants meeting EORTC/MSG (European Organization for the Research and Treatment of Cancer/Mycoses Study Group) definition of proven or culture positive probable IFD (invasive fungal disease) caused by rare moulds, yeasts, or dimorphic fungi (i.e. fungal pathogens other than Aspergillus fumigatus or Candida species) whether renally impaired or not (including dialysis) who require primary therapy for their IFD at the time of enrollment. OR •Participants who had proven or probable zygomycosis, whether renally impaired or not (including dialysis), who require primary therapy. Zygomycosis must be documented by culture or histology / cytology. OR •Participants meeting EORTC/MSG definition of proven or culture positive probable IFD caused by rare moulds, yeasts, or dimorphic fungi (i.e., fungal pathogens other than Aspergillus fumigatus or Candida species), whether RI or not (including dialysis), who were refractory to current treatment defined as, Clear documentation of progression of disease. Note: radiological progression only in association with white blood cell (WBC) count recovery was not acceptable. Failure to improve clinically despite receiving at least 7 days of standard antifungal regimen. Prior to enrolling patients who fell into this category, the Medical Monitor was contacted for approval. OR • Participants meeting EORTC/MSG definition of proven or culture positive probable IFD caused by rare moulds, yeasts, or dimorphic fungi (i.e., fungal pathogens other than Aspergillus fumigatus or Candida species), whether RI or not (including dialysis), who were intolerant to current treatment for example: Doubling of serum creatinine value to higher than the upper limit of normal (ULN) within 48 hours. Serum creatinine > 2.0 mg/mL and current treatment with polyene or IV voriconazole. Other significant drug-related adverse reaction(s) to the current antifungal agent, resulting in discontinuation of the treatment, e.g., persistence of visual disturbance, allergic reaction, phototoxicity or severe infusion reaction (hypertensive crisis, severe chills or shock). Documented inability to achieve adequate blood levels of posaconazole, voriconazole or itraconazole. Exclusion Criteria: A known condition of the participants that may jeopardize adherence to the protocol requirements Participants who are unlikely to survive 30 days Participants with a body weight < 40 kg Women who are pregnant or breastfeeding

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Isavuconazole<br>Administration of isavuconazole 3 times a day in the vein (IV) or oral as a capsule for 2 days followed by daily administration of isavuconazole (IV) or oral | Drug: isavuconazole<br>* Administration of 200 mg isavuconazole 3 times a day in the vein (IV) or oral as a capsule for 2 days, followed by daily administration of 200 mg isavuconazole (IV) or oral<br>* Other names: ASP9766;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Crude Success Rate of Overall Outcome of Treatment Evaluated by the Data Review Committee (DRC) at Day 42, 84 and End of Treatment (EOT). | The DRC assessed overall response based on individual clinical, mycological and radiological response assessments. Overall response outcomes were described as Success (complete or partial). Complete success was defined as a resolution of all clinical symptoms and physical findings associated with IFD. Partial success was defined as a resolution of at least some clinical symptoms and physical findings associated with IFD End of treatment (EOT) is the last day of study drug administration, with an estimated duration up to 180 days. | Day 42, 84 and End of Treatment (EOT [Day 180]) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Crude Success Rate of Clinical Response to Treatment Evaluated by the Data Review Committee (DRC) at Day 42, 84 and EOT | The DRC evaluated clinical response to treatment at day 42, day 84 and EOT. Clinical response outcomes were described as Success [Resolution of all attributable clinical symptoms and physical findings and Partial resolution of attributable clinical symptoms and physical findings]. End of treatment (EOT) is the last day of study drug administration, with an estimated duration up to 180 days. | Day 42, 84 and End of Treatment (EOT [Day 180]) | 
| Crude Success Rate of Mycological Response to Treatment Evaluated by the Data Review Committee (DRC) at Day 42, 84 and EOT | The DRC evaluated mycological response to treatment at day 42, day 84 and EOT. Mycological response outcomes were described as Success [Eradication and Presumed eradication]. End of treatment (EOT) is the last day of study drug administration, with an estimated duration up to 180 days. | Day 42, 84 and End of Treatment (EOT [Day 180]) | 
| Crude Success Rate of Radiological Response to Treatment Evaluated by the Data Review Committee (DRC) at Day 42, 84 and EOT | The DRC evaluated radiological response to treatment at at day 42, day 84 and EOT. Radiological response outcomes were described as Success [Improvement of at least 25% from baseline for invasive aspergillosis and other filamentous mold infections], [Improvement of at least 50% from baseline for invasive aspergillosis and other filamentous mold infections]; and [Improvement of at least 25% from baseline if EOT occurs prior to day 42 and at least 50% improvement from baseline if EOT occurs after day 42 for invasive aspergillosis and other filamentous mold infections]. End of treatment (EOT) is the last day of study drug administration, with an estimated duration up to 180 days. | Day 42, 84 and End of Treatment (EOT [Day 180]) | 
| Crude Success Rate of Clinical Response to Treatment Evaluated by the Investigator at Day 42, Day 84 and EOT | The Investigator evaluated clinical response to treatment at day 42, day 84 and EOT. Clinical response outcomes were described as Success [Resolution of all attributable clinical symptoms and physical findings] and [Resolution of some attributable clinical symptoms and physical findings]. End of treatment (EOT) is the last day of study drug administration, with an estimated duration up to 180 days. | Day 42, Day 84 and End of Treatment (EOT [Day 180]) | 
| Crude Success Rate of Mycological Response to Treatment Evaluated by the Investigator at Day 42, Day 84 and EOT | The Investigator evaluated mycological response to treatment at day 42, day 84 and EOT. Mycological response outcomes were described as Success [Eradication,Presumed eradication]. End of treatment (EOT) is the last day of study drug administration, with an estimated duration up to 180 days. | Day 42, Day 84 and End of Treatment (EOT [Day 180]) | 
| Crude Success Rate of Radiological Response to Treatment Evaluated by the Investigator at Day 42, Day 84 and EOT | The Investigator evaluated radiological response to treatment at day 42, day 84 and EOT. Radiological response outcomes were described as Success [≥ 90% improvement,≥ 50% to < 90% improvement and ≥ 25% to < 50% improvement (for day 42 and EOT, if EOT occurs prior to day 42)]. End of treatment (EOT) is the last day of study drug administration, with an estimated duration up to 180 days. | Day 42, Day 84 and End of Treatment (EOT [Day 180]) | 
| All-cause Mortality Through Day 42 and Day 84 | All-cause Mortality was assessed through Day 42 and Day 84 and summarized for ITT population End of treatment (EOT) is the last day of study drug administration, with an estimated duration up to 180 days. | Baseline to End of Treatment (EOT [Day 180]) | 
| Safety - Overall Number of TEAEs | A Treatment Emergent Adverse Events (TEAE) is any adverse event that starts after the first administration of study drug until 28 days after the last dose of study drug. | From the first study drug administration until 28 days after the last dose of study drug | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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invasive fungal infections caused by rare molds, rare yeasts, BAL8557, Isavuconazole, Aspergillosis, or by dimorphic fungi, ASP9766