Study of Rezafungin Compared to Caspofungin in Subjects With Candidemia and/or Invasive Candidiasis

Study Overview
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Brief Summary
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The purpose of this pivotal study is to determine if intravenous Rezafungin is efficacious and safe in the treatment of candidemia and/or invasive candidiasis when compared to caspofungin (followed by optional oral fluconazole).

Detailed Description
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A Phase 3, multicenter, prospective, randomized, double-blind, efficacy and safety study of Rezafungin for Injection versus an active comparator regimen of caspofungin followed by optional oral fluconazole step-down therapy in subjects with candidemia and/or invasive candidiasis.

Official Title
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A Phase 3, Multicenter, Randomized, Double-blind Study of the Efficacy and Safety of Rezafungin for Injection vs. Intravenous Caspofungin Followed by Oral Fluconazole Step Down in the Treatment of Subjects With Candidemia and/or Invasive Candidiasis

Conditions
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Candidemia, Mycoses, Fungal Infection, Invasive Candidiases

Intervention / Treatment
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* Drug: Rezafungin for Injection
* Drug: Caspofungin
* Drug: Fluconazole
* Drug: intravenous placebo
* Drug: oral placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Willing and able to provide written informed consent. If the subject is unable to consent for himself/herself, a legally acceptable representative must provide informed consent on his/her behalf. Males or females ≥18 years of age. Established mycological diagnosis of candidemia and/or invasive candidiasis from a sample taken ≤4 days (96 hours) before randomization defined as ≥1 blood culture positive for yeast or Candida OR Positive test for Candida from a Sponsor-approved rapid in vitro diagnostic (IVD) OR Positive gram stain (or other method of direct microscopy) for yeast or positive culture for Candida spp. from a specimen obtained from a normally sterile site. Presence of one or more systemic signs attributable to candidemia or invasive candidiasis appearing from ≤12 hours prior to the qualifying positive culture through time of randomization. Willing to initiate or continue medical treatment to cure infections, including receipt of antibiotics and surgical procedures, if required. Female subjects of childbearing potential (all female subjects between 18 years <2 years post-menopausal unless surgically sterile) must agree to and comply with using one barrier method (e.g., female condom with spermicide) plus one other highly effective method of birth control, or sexual abstinence while participating in this study. Male subjects must be vasectomized, abstain from sexual intercourse, or agree to use barrier contraception, and also agree not to donate sperm while participating in the study and for 90 days thereafter (and at least 120 days from the last dose of study drug). For Candidemia only subjects, drawing of a set of blood cultures within 12 hours prior to randomization in the study. The result of these blood cultures is not required for inclusion in the study. Exclusion Criteria: Any of the following forms of invasive candidiasis at baseline: Septic arthritis in a prosthetic joint (septic arthritis in a native joint is allowed) Osteomyelitis Endocarditis or myocarditis Meningitis, endophthalmitis, chorioretinitis, or any central nervous system infection Chronic disseminated candidiasis Urinary tract candidiasis due to ascending Candida infection secondary to obstruction or surgical instrumentation of the urinary tract Received systemic treatment with an antifungal agent at approved doses for treatment of candidemia for >48 hours (e.g., >2 doses of a once daily antifungal agent or >4 doses of a twice daily antifungal agent) ≤4 days (96 hours) before randomization a. Exception: Receipt of antifungal therapy to which any Candida spp. isolated in culture is not susceptible Alanine aminotransferase or aspartate aminotransferase levels >10-fold the upper limit of normal Severe hepatic impairment in subjects with a history of chronic cirrhosis (Child-Pugh score >9) Presence of an indwelling vascular catheter or device that cannot be removed or an abscess that cannot be drained and is likely to be the source of candidemia or invasive candidiasis Known hypersensitivity to Rezafungin for Injection, caspofungin, any echinocandin, or to any of their excipients Meets National Cancer Institute Common Terminology Criteria for Adverse Events, version 5, criteria for ataxia, tremor, motor neuropathy, or sensory neuropathy of Grade 2 or higher History of severe ataxia, tremor, or neuropathy or a diagnosis of multiple sclerosis or a movement disorder (including Parkinson's Disease or Huntington's Disease) Planned or ongoing therapy at Screening with a known neurotoxic medication Previous participation in this or any previous rezafungin study Current participation in another interventional treatment trial with an investigational agent Recent use of an investigational medicinal product within 28 days of the first dose of study drug or presence of an investigational device at the time of screening. Pregnant or lactating females The Principal Investigator (PI) is of the opinion the subject should not participate in the study

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: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Group 1: Rezafungin for Injection<br>Subjects in Rezafungin treatment group will receive a 400 mg loading dose in Week 1, followed by 200 mg once weekly, for a total of 2 to 4 doses. Daily intravenous placebo infusions, when not administered Rezafungin and a daily placebo for oral step-down therapy (first eligibility on Day 4 or later as advised by a site's national/regional/local guidelines) administered every day. | Drug: Rezafungin for Injection<br>* Intravenous antifungal therapy<br>Drug: oral placebo<br>* Microcrystalline cellulose<br>* Other names: encapsulated cellulose;|
| Active Comparator: Group 2: Caspofungin<br>Subjects in caspofungin arm will receive a total treatment of ≥14 days beginning with a single caspofungin 70 mg IV loading dose on Day 1 followed by 50 mg IV once daily up to 28 days. After ≥3 days of caspofungin treatment(or the minimum duration of IV therapy advised by the site's national/regional/local guidelines, whichever is greater), subjects may be switched to oral fluconazole if specific parameters are met. If the subject qualifies, then oral step-down therapy of fluconazole (6 mg/kg to the nearest 200 mg) is administered. After switch to oral step down before Day 8, subjects in the caspofungin group will receive IV placebo on Day 8 to preserve the study blind. | Drug: Caspofungin<br>* Intravenous antifungal therapy<br>* Other names: Cancidas;Drug: Fluconazole<br>* Oral antifungal therapy<br>* Other names: generic fluconazole;Drug: intravenous placebo<br>* Normal saline<br>* Other names: placebo infusion;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| All-Cause Mortality (US FDA Only) | The number and percentage of subjects in each treatment group who are alive and deceased (or with missing data) in the mITT population. | Day 30 (-2 days) | 
| Global Response as Assessed by Data Review Committee (EU European Medicines Agency [EMA] Only) | The number and percentage of subjects in each treatment group who have a global response of cure (clinical cure as assessed by the Investigator, radiological cure [for qualifying invasive candidiasis subjects at baseline], and mycological eradication, as confirmed by the Data Review Committee [DRC]), failure and indeterminate in the mITT population. A global response of cure is indicative of an efficacious outcome and the desired result, whereas a response of failure is indicative of a non-efficacious outcome and the undesired response. Indeterminate responses indicate there was not enough data obtained to determine if the response was cure or failure. Definitions for the global responses of cure, failure, and indeterminate are complex. Detailed definitions for the possible responses to this outcome measure type are provided in Table 7 (Global Response) of the clinical protocol. | Day 14 (±1 day) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Global Response as Assessed by Data Review Committee (US FDA Only) | The number and percentage of subjects in each treatment group who have a global response of cure (clinical cure as assessed by the Investigator, radiological cure [for qualifying invasive candidiasis subjects at baseline], and mycological eradication, as confirmed by the Data Review Committee [DRC]), failure and indeterminate in the mITT population. A global response of cure is indicative of an efficacious outcome and the desired result, whereas a response of failure is indicative of a non-efficacious outcome and the undesired response. Indeterminate responses indicate there was not enough data obtained to determine if the response was cure or failure. Definitions for the global responses of cure, failure, and indeterminate are complex. Detailed definitions for the possible responses to this outcome measure type are provided in Table 7 (Global Response) of the clinical protocol. | Day 14 (±1 day) | 
| All-Cause Mortality (EU EMA Only) | The number and percentage of subjects in each treatment group who are alive and deceased (or with missing data) in the mITT population. | Day 30 (-2 days) | 
| Comparison of Global Response (as Assessed by the DRC) by Visit | The number and percentage of subjects in each treatment group who have a global response of cure (clinical cure as assessed by the Investigator, radiological cure [for qualifying invasive candidiasis subjects at baseline], and mycological eradication, as confirmed by the Data Review Committee [DRC]), failure and indeterminate in the mITT population. A global response of cure is indicative of an efficacious outcome and the desired result, whereas a response of failure is indicative of a non-efficacious outcome and the undesired response. Indeterminate responses indicate there was not enough data obtained to determine if the response was cure or failure. Definitions for the global responses of cure, failure, and indeterminate are complex. Detailed definitions for the possible responses to this outcome measure type are provided in Table 7 (Global Response) of the clinical protocol. | Day 5, Day 30 (-2 days), End of Treatment (EOT) (≤2 days of last dose) and Follow-up (Days 52-59) | 
| Comparison of Mycological Eradication by Visit | The number and percentage of subjects in each treatment group who have a mycological response of eradication, failure, or indeterminate in the mITT population. A mycological response of eradication means clearance of objective evidence of infection and is indicative of an efficacious outcome and the desired result, whereas a response of failure is indicative of a non-efficacious outcome and the undesired response. Indeterminate responses indicate there was not enough data obtained to determine if the response was eradication or failure. Definitions for the mycological responses of eradication, failure, and indeterminate are complex. Detailed definitions for the possible responses to this outcome measure type are provided in Table 8 (Mycological Response) of the clinical protocol. Note: Eradication includes both documented and presumed eradication. | Day 5, Day 14 (±1 day), Day 30 (-2 days), End of Treatment (EOT) (≤2 days of last dose), and Follow-up (Days 52-59) | 
| Comparison of Investigators' Assessment of Clinical Response by Visit | The number and percentage of subjects in each treatment group for whom the Investigator determined a clinical response of cure, failure, or indeterminate in the mITT population. A clinical response of cure, as assessed by the Investigator, is indicative of an efficacious outcome and the desired result, whereas a response of failure is indicative of a non-efficacious outcome and the undesired response. Indeterminate responses indicate there was not enough data obtained to determine if the response was cure or failure. Definitions for the clinical responses of cure, failure, and indeterminate are complex. Detailed definitions for the possible responses to this outcome measure type are provided in Table 9 (Investigator's Assessment of Clinical Response) of the clinical protocol. | Day 5, Day 14 (±1 day), Day 30 (-2 days), End of Treatment (EOT) (≤2 days of last dose), and Follow-up (Days 52-59) | 
| Comparison of Radiological Response by Investigator by Visit | The number and percentage of subjects with invasive candidiasis (documented by radiologic/imaging evidence at baseline) in each treatment group who have a radiological response (as assessed by the Investigator) of cure, failure, and indeterminate in the mITT population. A radiological response of cure is indicative of an efficacious outcome and the desired result, whereas a response of failure is indicative of a non-efficacious outcome and the undesired response. Indeterminate responses indicate there was not enough data obtained to determine if the response was cure or failure. Definitions for the radiological responses of cure, failure, and indeterminate are complex. Detailed definitions for the possible responses to this outcome measure type are provided in Table 10 (Radiological Response) of the clinical protocol. | Day 5, Day 14 (±1 day), Day 30 (-2 days), End of Treatment (EOT) (≤2 days of last dose), and Follow-up (Days 52-59) | 
| Number of Subjects With Treatment-Emergent Adverse Events [Safety and Tolerability] | The number and percentage of subjects in each treatment group that experienced at least one treatment-emergent adverse event (TEAE) based on clinical chemistry, hematology and urine analysis laboratory test, vital sign, physical exams and electrocardiogram (ECG) abnormalities. Notes: A subject with multiple adverse events (AEs) was counted only once. TEAE was defined as an AE that occurred during or after study drug administration and up through the Follow-up visit. The maximum severity and strongest relationship were counted for subjects with multiple events. | Day 1 through Follow-up Visit (Days 52-59) | 
| Evaluate Pharmacokinetics (Cmax) | Evaluate the maximum plasma concentration (Cmax) of rezafungin for injection. | Day 1, 10 minutes before the end of infusion | 
| Evaluate Pharmacokinetics (Cmin) | Evaluate the minimum plasma concentration (Cmin) of rezafungin for injection. | Day 8, pre-dose, within 30 minutes prior to the start of infusion | 
| Evaluate Pharmacokinetics (Cmin) | Evaluate the minimum plasma concentration (Cmin) of rezafungin for injection. | Day 15, pre-dose, within 30 minutes prior to the start of infusion | 
| Evaluate Pharmacokinetics (Cmin) | Evaluate the minimum plasma concentration (Cmin) of rezafungin for injection. | Day 22, pre-dose, within 30 minutes prior to the start of infusion | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Mycoses, Candidiasis, Candidiasis, Invasive, Candidemia, Fungemia, Sepsis, Invasive Fungal Infections, Systemic Inflammatory Response Syndrome, Pathologic Processes, Fluconazole, Caspofungin, Echinocandins, Antifungal Agents, Anti-infective Agents, 14-alpha Demethylase Inhibitors, Cytochrome P-450 Enzyme Inhibitors, Enzyme Inhibitors, Molecular Mechanisms of Pharmacological Action, Steroid Synthesis Inhibitors, Physiological Effects of Drugs, Cytochrome P-450 CYP2C9 Inhibitors, Cytochrome P-450 CYP2C19 Inhibitors