Isavuconazole (BAL8557) for Primary Treatment of Invasive Aspergillosis

• ClinicalTrials.gov Identifier: NCT00412893
• Recruitment Status: Completed
• First Posted: December 19, 2006
• Results First Posted: March 31, 2015
• Last Update Posted: April 5, 2019
• Sponsor: Astellas Pharma Inc
• Collaborator: Basilea Pharmaceutica International Ltd
• Information provided by (Responsible Party): Astellas Pharma Inc

Study Description

Brief Summary:

The purpose of this study is to compare the efficacy and safety of isavuconazole versus voriconazole in the treatment of patients with invasive aspergillosis.

Condition or disease	Intervention/treatment	Phase
Aspergillosis; Invasive Fungal Infection	Drug: Isavuconazole; Drug: Voriconazole	Phase 3

Detailed Description:

Acute invasive fungal infections caused by aspergillus, zygomycetes and other filamentous fungi remain life threatening diseases. Early treatment with highly effective anti-fungals reduces mortality. This study investigates the efficacy and safety of isavuconazole in the treatment of invasive fungal diseases, caused by Aspergillus or other filamentous fungi.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 527 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Participant, Investigator)
• Primary Purpose: Treatment
• Official Title: A Phase III, Double Blind, Randomized Study to Evaluate Safety and Efficacy of BAL8557 Versus Voriconazole for Primary Treatment of Invasive Fungal Disease Caused by Aspergillus Species or Other Filamentous Fungi.
• Actual Study Start Date: March 7, 2007
• Actual Primary Completion Date: March 28, 2013
• Actual Study Completion Date: March 28, 2013

Arms and Interventions

Arm	Intervention/treatment
Experimental: Isavuconazole; Participants received a loading dose of isavuconazole, 200 mg three times a day by intravenous infusion (IV) for the first 2 days followed by a maintenance dose from Day 3 of 200 mg once daily either IV or orally until they reached a treatment endpoint or for a maximum of 84 days.	Drug: Isavuconazole; Loading doses were administered as IV infusion and maintenance doses were administered as IV infusion or oral (capsules).; Other Names: ASP9766; BAL8557
Active Comparator: Voriconazole; Participants received a loading dose of voriconazole, 6 mg/kg every 12 hours IV for the first 24 hours, followed by a maintenance dose of 4 mg/kg every 12 hours by IV on Day 2. Beginning on Day 3, participants received 4 mg/kg every 12 hours by IV or 200 mg every 12 hours orally, until they reached a treatment endpoint or for a maximum of 84 days.	Drug: Voriconazole; Loading doses were administered as IV infusion and maintenance doses were administered as IV infusion or oral (capsules).; Other Name: VFend

Outcome Measures

Primary Outcome Measures :

1. All-cause Mortality Through Day 42 [ Time Frame: Through Day 42 ]
   All-cause mortality is represented as the percentage of participants who died after first dose of study drug through Day 42 from any cause. Participants with unknown survival status through Day 42 were included as deaths in the calculation.

Secondary Outcome Measures :

1. Percentage of Participants With an Overall Outcome of Success Evaluated by the Data Review Committee (DRC) [ Time Frame: Day 42, Day 84 and End of Treatment. The median duration of study drug administration was 45 days. ]

   The DRC was an independent, blinded committee consisting of experts in the field of infectious disease who assessed patients' outcomes. The overall response was based on the DRC-assessed clinical, mycological and radiological responses.

   Success was defined as the resolution or partial resolution of all attributable clinical symptoms and physical findings, the eradication or presumed eradication of the original causative organism cultured or identified by histology/cytology at Baseline and a > 50% improvement in radiological response from Baseline (or improvement of at least 25% from Baseline for the Day 42 analysis or End of Treatment if it occurred prior to Day 42).

   End of treatment (EOT) is the last day of study drug administration. For the Day 42 and Day 84 analyses, any visits that the DRC assessed as Not Done were considered a failure for that visit. A death before Day 42 was also considered a failure, even if the DRC assessed the participant to be a success prior to death.

2. All-cause Mortality Through Day 84 [ Time Frame: Through Day 84 ]
   All-cause mortality is represented as the percentage of participants who died after first dose of study drug through Day 84 from any cause. Participants with unknown survival status through Day 84 were included as deaths in the calculation.
3. Percentage of Participants With an Overall Outcome of Success Evaluated by Investigator [ Time Frame: Day 42, Day 84 and End of Treatment. The median duration of study drug administration was 45 days. ]
   Overall response based on investigators' assessments was not derived as it was not deemed necessary because participants overall response status was determined by the DRC. All investigators' assessments of clinical, mycological and radiological responses are analyzed separately (see Outcome Measures 8-10).
4. Percentage of Participants With a Clinical Response Assessed by the DRC [ Time Frame: Day 42, Day 84 and End of Treatment. The median duration of study drug administration was 45 days. ]

   Blinded assessments of clinical symptoms and physical findings of invasive fungal disease were performed by the independent DRC.

   Clinical response is defined as the resolution or partial resolution of all attributable clinical symptoms and physical findings. Failure is defined as no resolution of any attributable clinical symptoms and physical findings and/or worsening. Participants with no attributable signs and symptoms present at Baseline and no symptoms attributable to invasive fungal disease (IFD) developed post-baseline were classified as "Not Applicable." End of treatment is the last day of study drug administration.

5. Percentage of Participants With a Mycological Response Assessed by the DRC [ Time Frame: Day 42, Day 84 and End of Treatment. The median duration of study drug administration was 45 days. ]

   Blinded mycological assessments of the participant's invasive fungal disease status were performed by the independent DRC using the results from fungal culture and isolation and/or histology/cytology of biopsy or biological fluid samples from the infected site.

   Mycological response is defined as eradication or presumed eradication of the original causative organism cultured or identified by histology/cytology at Baseline. Failure was defined as persistence or presumed persistence. Participants with no mycological evidence available at Baseline were classified as "Not Applicable".

   End of treatment is the last day of study drug administration.

6. Percentage of Participants With a Radiological Response Assessed by the DRC [ Time Frame: Day 42, Day 84 and End of Treatment. The median duration of study drug administration was 45 days. ]

   Independent reviews of radiology assessments were completed by radiology experts which were provided to the independent, blinded DRC. Blinded radiological assessments were performed by the DRC.

   Radiological response is defined as a ≥ 50% improvement from Baseline, or improvement of at least 25% from Baseline for the Day 42 analysis or if end of treatment occurred before Day 42. Participants without any radiology at Baseline were considered "Not Applicable." End of Treatment is the last day of study drug administration.

7. Percentage of Participants With a Clinical Response Assessed by the Investigator [ Time Frame: Day 42, Day 84 and End of Treatment. The median duration of study drug administration was 45 days. ]

   Assessment of clinical symptoms and physical findings of invasive fungal disease were performed by the investigator.

   Clinical response is defined as the resolution or partial resolution of all attributable clinical symptoms and physical findings. Failure is defined as no resolution of any attributable clinical symptoms and physical findings and/or worsening, or if results were unavailable or the participant was unevaluable. Participants with no attributable signs and symptoms present at Baseline were classified as "Not Applicable." End of treatment is the last day of study drug administration.

8. Percentage of Participants With a Mycological Response Assessed by the Investigator [ Time Frame: Day 42, Day 84 and End of Treatment. The median duration of study drug administration was 45 days. ]

   Mycological assessments of the participant's invasive fungal disease status were performed by the investigator using the results from fungal culture and isolation and/or histology/cytology of biopsy or biological fluid samples from the infected site.

   Mycological response is defined as eradication or presumed eradication of the original causative organism cultured or identified by histology/cytology at Baseline. Failure was defined as persistence or presumed persistence. Participants with no mycological evidence available at Baseline, or no mycological follow-up results available or indeterminate results were classified as "Not Applicable".

   End of treatment is the last day of study drug administration.

9. Percentage of Participants With a Radiological Response Assessed by the Investigator [ Time Frame: Day 42, Day 84 and End of Treatment. The median duration of study drug administration was 45 days. ]
   Radiological assessments were performed by the investigator. Radiological response is defined as a ≥ 50% improvement from Baseline, or improvement of at least 25% from Baseline for the Day 42 analysis or if end of treatment occurred before Day 42. Failure is defined as a < 25% improvement at any time or results not available. Participants with no signs on radiological images at Baseline were considered "Not Applicable." End of Treatment is the last day of study drug administration.
10. Number of Participants With Adverse Events, Reported by System Organ Class [ Time Frame: From the first study drug administration until 28 days after the last dose of study drug. The median duration of study drug administration was 45 days. ]

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

• Patients must have proven, probable or possible invasive fungal disease caused by Aspergillus species or other filamentous fungi
• Female patients must be non-lactating and at no risk for pregnancy

Exclusion Criteria:

• Patients with invasive fungal infections other than Aspergillus species or other filamentous fungi
• Evidence of hepatic dysfunction at Baseline or moderate to severe renal dysfunction
• Patients with chronic aspergillosis, or aspergilloma or allergic bronchopulmonary aspergillosis
• Patients who have received more than 4 days of systemic antifungal therapy other than fluconazole within the 7 days prior to the first administration of study medication
• Patients previously enrolled in a Phase III study with isavuconazole
• Patients with a body weight </= 40 kg

Contacts and Locations

  Show 107 Study Locations

Sponsors and Collaborators

Astellas Pharma Inc

Basilea Pharmaceutica International Ltd

Investigators

• Study Director: Medical Director; Astellas Pharma Global Development

More Information

Additional Information:

Link to results on Astellas Clinical Study Results website 

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Kovanda LL, Kolamunnage-Dona R, Neely M, Maertens J, Lee M, Hope WW. Pharmacodynamics of Isavuconazole for Invasive Mold Disease: Role of Galactomannan for Real-Time Monitoring of Therapeutic Response. Clin Infect Dis. 2017 Jun 1;64(11):1557-1563. doi: 10.1093/cid/cix198. Erratum in: Clin Infect Dis. 2017 Oct 15;65(8):1431-1433.

Maertens JA, Raad II, Marr KA, Patterson TF, Kontoyiannis DP, Cornely OA, Bow EJ, Rahav G, Neofytos D, Aoun M, Baddley JW, Giladi M, Heinz WJ, Herbrecht R, Hope W, Karthaus M, Lee DG, Lortholary O, Morrison VA, Oren I, Selleslag D, Shoham S, Thompson GR 3rd, Lee M, Maher RM, Schmitt-Hoffmann AH, Zeiher B, Ullmann AJ. Isavuconazole versus voriconazole for primary treatment of invasive mould disease caused by Aspergillus and other filamentous fungi (SECURE): a phase 3, randomised-controlled, non-inferiority trial. Lancet. 2016 Feb 20;387(10020):760-9. doi: 10.1016/S0140-6736(15)01159-9. Epub 2015 Dec 10.

• Responsible Party: Astellas Pharma Inc
• ClinicalTrials.gov Identifier: NCT00412893 History of Changes
• Other Study ID Numbers: 9766-CL-0104; WSA-CS-004 ( Other Identifier: Basilea Protocol ID ); 2006-003868-59 ( EudraCT Number )
• First Posted: December 19, 2006
• Results First Posted: March 31, 2015
• Last Update Posted: April 5, 2019
• Last Verified: March 2019

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Yes
• Plan Description: Access to anonymized individual participant level data collected during the trial, in addition to study-related supporting documentation, is planned for trials conducted with approved product indications and formulations, as well as compounds terminated during development. Conditions and exceptions are described under the Sponsor Specific Details for Astellas on www.clinicalstudydatarequest.com.
• Supporting Materials: Study Protocol; Statistical Analysis Plan (SAP); Clinical Study Report (CSR)
• Time Frame: Access to participant level data is offered to researchers after publication of the primary manuscript (if applicable) and is available as long as Astellas has legal authority to provide the data.
• Access Criteria: Researchers must submit a proposal to conduct a scientifically relevant analysis of the study data. The research proposal is reviewed by an Independent Research Panel. If the proposal is approved, access to the study data is provided in a secure data sharing environment after receipt of a signed Data Sharing Agreement.
• URL: https://www.clinicalstudydatarequest.com/

Keywords provided by Astellas Pharma Inc:

Invasive fungal disease; BAL8557; Isavuconazole; ASP9766; Filamentous fungi; Phase III; Aspergillus species

Additional relevant MeSH terms:

Mycoses; Aspergillosis; Invasive Fungal Infections; Voriconazole; Isavuconazole; Antifungal Agents; Anti-Infective Agents; 14-alpha Demethylase Inhibitors; Cytochrome P-450 Enzyme Inhibitors; Enzyme Inhibitors; Molecular Mechanisms of Pharmacological Action; Steroid Synthesis Inhibitors; Hormone Antagonists; Hormones, Hormone Substitutes, and Hormone Antagonists; Physiological Effects of Drugs; Cytochrome P-450 CYP3A Inhibitors