Isavuconazole (BAL8557) in the Treatment of Candidemia and Other Invasive Candida Infections

Study Overview
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Brief Summary
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The purpose of the study is to compare the safety and efficacy of isavuconazole versus caspofungin followed by voriconazole in the treatment of candidemia and other invasive Candida infections.

Detailed Description
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Candida infections, representing approximately 80% of all major systemic fungal infections, are the fourth most common cause of nosocomial bloodstream infections, with a mortality rate of 40%. Isavuconazole is not yet approved for the treatment of fungal infections. This study investigates the efficacy and safety of intravenous and oral isavuconazole. Patients are randomized to isavuconazole and the reference regimen. Patients with a positive blood- or deep tissue culture of candida fungi can be included.

Official Title
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A Phase III, Double-blind, Randomized Study to Evaluate the Safety and Efficacy of BAL8557 Versus a Caspofungin Followed by Voriconazole Regimen in the Treatment of Candidemia and Other Invasive Candida Infections

Conditions
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Candidiasis, Invasive, Candidemia, Mycoses

Intervention / Treatment
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* Drug: Isavuconazole
* Drug: Caspofungin
* Drug: Voriconazole


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients with candidemia or with an invasive Candida infection Presence of fever, hypothermia or other appropriate local sign of infection Female patients must be non-lactating and at no risk of pregnancy Exclusion Criteria: Patients with a sole diagnosis of mucocutaneous candidiasis, i.e. oropharyngeal, esophageal or genital candidiasis; or candidal lower urinary tract infection or Candida isolated solely from respiratory tract specimens Patients with candidemia who failed a previous antifungal therapy for the same infection Patients previously enrolled in a phase III study with isavuconazole Patients with a body weight <40kg

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
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Isavuconazole (ISA)<br>Participants received 3 intravenous (IV) loading doses of 200 mg of isavuconazole on days 1 and 2, followed by an IV maintenance dose of 200 mg once daily from day 3 to day 56. On day 11 at the discretion of the investigator, non-neutropenic patients could switch from IV to oral therapy. Oral therapy consisted of 200 mg isavuconazole twice daily. | Drug: Isavuconazole<br>* Administered by intravenous infusion.<br>* Other names: BAL8557;|
| Active Comparator: Caspofungin (CAS)/Voriconazole<br>Participants received 1 intravenous (IV) loading dose of 70 mg CAS on day 1, followed by an IV maintenance dose of 50 mg CAS from day 2 to day 56. On day 11 at the discretion of the investigator, non-neutropenic patients could switch from IV CAS to oral voriconazole comprising of a loading dose of 400 mg twice daily (BID) on the first day of oral therapy followed by standard dosing of 200 mg BID thereafter. | Drug: Caspofungin<br>* Administered by intravenous infusion.<br>* Other names: Cancidas;Drug: Voriconazole<br>* Administered by intravenous infusion.<br>* Other names: VFend;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With Overall Response of Success at the End of Intravenous Therapy (EOIV) as Determined by the Data Review Committee (DRC) Based on the Assessments of Clinical and Mycological Responses as Well as Alternative Systemic AFT Use | A Data Review Committee (DRC) was established from independent experts in the field of fungal infections to determine diagnosis and outcomes independently of the investigators and sponsor. Success was defined as clinical response (complete or partial) and mycological response (eradication or presumed eradication) without the use of alternative systemic antifungal therapy (AFT) within 48 hours after the last dose of IV study medication. | End of Intravenous Treatment (EOIV) (Days 11-56) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With Overall Response of Success at Follow Up Visit 1 (FU1-2 Weeks After End of Treatment (EOT)) as Determined by the DRC Based on the Assessments of Clinical, Mycological Responses and Antifungal Therapy (AFT) | A data review committee (DRC) was established from independent experts in the field of fungal infections to determine diagnosis and outcomes independently of the investigators and sponsor. Success was defined as clinical response (complete or partial) and mycological response (eradication or presumed eradication), without the use of alternative systemic AFT within 48 hours after the last dose of IV study medication. | End of Treatment (EOT) (Day 56) and FU1 (2 weeks after end of treatment) | 
| Percentage of Participants With Overall Response of Success at EOT and Follow Up Visit 2 (FU2) as Determined by the DRC Based on the Assessments of Clinical and Mycological Responses as Well as Alternative Systemic AFT Use at EOT and FU2 | A data review committee (DRC) was established from independent experts in the field of fungal infections to determine diagnosis and outcomes independently of the investigators and sponsor. Success was defined as clinical response (complete or partial) and mycological response (eradication or presumed eradication), without the use of alternative systemic antifungal therapy AFT within 48 hours after the last dose of IV study medication (for EOT analysis) or for continued treatment of the primary infection, or for recurrent or emergent infection by FU2, with no recurrent or emergent infection by FU2 (for FU2 analysis). | EOT (Day 56) and FU2 (6 weeks after end of treatment) | 
| Percentage of Participants With Clinical Response of Success at EOIV, EOT, FU1 and FU2 as Determined by the Data Review Committee (DRC) | A data review committee (DRC) was established from independent experts in the field of fungal infections to determine diagnosis and outcomes independently of the investigators and sponsor. Success was defined as clinical response (complete or partial). | EOIV (Days 11-56), EOT (Day 56), FU1 (2 weeks after end of treatment) and FU2 (6 weeks after end of treatment) | 
| Percentage of Participants With Mycological Response of Success at EOIV, EOT, FU1 and FU2 as Determined by the Data Review Committee (DRC) | A data review committee (DRC) was established from independent experts in the field of fungal infections to determine diagnosis and outcomes independently of the investigators and sponsor. Success was defined as mycological response (Eradication or Presumed Eradication). | EOIV (Days 11-56), EOT (Day 56), FU1 (2 weeks after end of treatment) and FU2 (6 weeks after end of treatment) | 
| Percentage of Participants With Mycological Response of Success at Day 7 and EOT as Determined by The Investigator | Success was defined as mycological response (eradication or presumed eradication). | Day 7 and EOT (Day 56) | 
| Percentage of Participants With Clinical Response of Success at Day 7 and EOT as Determined by The Investigator | Investigators defined clinical response as success if participants exhibited complete or partial clinical response after evaluation of clinical signs and symptoms. | Day 7 and EOT (Day 56) | 
| All-Cause Mortality (ACM) at Day 14 and Day 56 | All-cause mortality is represented as the percentage of participants who died on or before the analysis day. Participants who were lost to follow-up (i.e., unknown survival status) before the analysis day were counted as death. All-cause mortality was examined on Day 14 and Day 56. | Day 14 and Day 56 | 
| Time to First Confirmed Negative Culture | The first confirmed negative blood culture was defined as the first negative blood culture on or after first dose followed by a second negative blood culture at least 24 hours apart without any positive blood cultures in between. A participant without a confirmed negative blood culture was censored on the participant's last visit day. This endpoint was analyzed for mITT participants with candidemia only using the Kaplan-Meier method. Only participants with at least one positive blood culture on or prior to first dose and the culture not resolved prior to first dose were included in this analysis | Day 1 up to FU1 (2 weeks after EOT (Day 56)) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Invasive Candida infections, BAL8557, ASP9766, Isavuconazole, Candidemia, Candidemia and other invasive candida infections, Phase III study