Phase 3 Randomized Study of Echinocandin Followed by Ibrexafungerp vs. Echinocandin Followed by Fluconazole in Invasive Candidiasis/Candidemia

The primary objective of this study is to demonstrate that the treatment of **Invasive Candidiasis/Candidemia** with intravenous (IV) echinocandin followed by oral ibrexafungerp is non-inferior to IV echinocandin followed by oral fluconazole or Best Available Therapy (BAT). This is clinically relevant as it may offer an alternative treatment regimen that is equally effective, potentially improving patient outcomes and expanding therapeutic options.

Secondary objectives include:

• To demonstrate that treatment with IV echinocandin followed by oral ibrexafungerp is non-inferior to IV echinocandin followed by oral fluconazole (or BAT), based on Global Response (clinical, radiological, and mycological response) at Day 14.
• To compare the efficacy of the treatment regimens based on Global Response at Day 30 and End of Therapy (EOT), Clinical Response, Mycological Response, no recurrence, and fungal-free survival.
• To evaluate the safety of the regimens.
• To evaluate the pharmacokinetics (PK) of ibrexafungerp.

The clinical trial investigating the treatment of **Invasive Candidiasis/Candidemia** involves a total of 168 participants. The study population comprises both male and female adults aged 18 years and older. Participants were selected based on a confirmed diagnosis of candidemia and/or invasive candidiasis, characterized by the presence of Candida species in a bloodstream or tissue culture from a normally sterile site, excluding specific areas such as the eye, cardiac tissue, bone tissue, central nervous system, or prosthetic devices. The trial includes individuals who exhibit related clinical signs or symptoms, such as fever, hypotension, or local signs of inflammation. The study population is diverse, including vulnerable groups, and does not specify particular lifestyle considerations such as diet or physical activity. The selection criteria ensure that participants have a relevant medical condition and meet the age and health status requirements necessary for the trial.

The clinical trial is designed as a **randomized**, **double-blind**, controlled study to evaluate the efficacy of two treatment regimens for **invasive candidiasis** and **candidemia**. The trial involves the administration of an intravenous **echinocandin** followed by either oral **ibrexafungerp** or oral **fluconazole**. The primary objective is to demonstrate that the treatment with intravenous echinocandin followed by oral ibrexafungerp is non-inferior to the regimen involving oral fluconazole. The trial is expected to span a duration of approximately four years, with an estimated recruitment start date in August 2022 and an anticipated end date in October 2026.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on specific criteria, such as age and diagnosis of candidemia or invasive candidiasis. The inclusion criteria require evidence of **Candida spp.** in a bloodstream or tissue culture from a normally sterile site, accompanied by related clinical signs or symptoms. Following the screening, participants will be randomized to receive one of the two treatment regimens. The study includes follow-up visits to monitor the participants' response to treatment and assess any adverse events. The primary endpoint is the all-cause mortality at Day 30, with secondary endpoints including successful global response and safety assessments at various time points, such as Day 14 and the end of treatment (EOT).

The expected length of participant involvement is up to six weeks post-EOT, with conditions for early termination including the occurrence of serious adverse events or withdrawal of consent. The study will also evaluate the pharmacokinetics of ibrexafungerp, with plasma concentrations being measured. Safety endpoints will include the frequency of treatment-emergent adverse events, drug-related adverse events, and discontinuations due to adverse events. The trial aims to provide comprehensive data on the efficacy and safety of the treatment regimens, contributing to the understanding of optimal therapeutic strategies for invasive candidiasis and candidemia.

The clinical trial involves the administration of several **antifungal** agents, each with specific characteristics and administration protocols. **Ibrexafungerp** is an experimental medication used in this study. It is administered in the form of a tablet, with a maximum daily dose of 1500 mg. The route of administration is oral, and the treatment period is up to 6 weeks. Ibrexafungerp is identified by the sponsor product code SCY-078 and is classified under the ATC code J02AX, indicating its use as an antifungal for systemic use.

**Voriconazole** is another medication used in the trial, administered orally. It is provided in a pharmaceutical form coded as PHF00230MIG, with a maximum daily dose of 800 mg. The treatment duration is also up to 6 weeks. Voriconazole is classified under the ATC code J02AC03, which denotes its role as an antifungal agent.

**Caspofungin acetate** is administered intravenously in this study. It is provided in a pharmaceutical form coded as PHF00230MIG. The maximum treatment period is 6 weeks, although specific dosing information is not provided. Caspofungin acetate is classified under the ATC code J02AX04, indicating its use as an antifungal agent.

**Anidulafungin** is also administered intravenously, with a pharmaceutical form coded as PHF00230MIG. The treatment period is up to 6 weeks, with no specific dosing information available. Anidulafungin is classified under the ATC code J02AX06, indicating its antifungal properties.

**Fluconazole** is administered orally in the form of capsules, with a maximum daily dose of 800 mg. The treatment period is up to 6 weeks. Fluconazole is classified under the ATC code J02AC01, denoting its role as an antifungal agent. The product used in the trial is identified as Fluconazol-GRY 200 mg Hartkapseln.

**Micafungin** is administered intravenously, with a pharmaceutical form coded as PHF00230MIG. The treatment period is up to 6 weeks, with no specific dosing information provided. Micafungin is classified under the ATC code J02AX05, indicating its use as an antifungal agent.

The trial also includes the use of placebos. A placebo for ibrexafungerp 250 mg is used in tablet form, and a placebo for fluconazole 200 mg is used in capsule form. These placebos are used to maintain the double-blind nature of the study and ensure unbiased results.

Efficacy in this clinical trial will be assessed using several primary and secondary endpoints. The primary endpoint is the **All-cause Mortality (ACM)** at Day 30 in the intention-to-treat (ITT) population. Additionally, the percentage of subjects with a Successful Global Response, as determined by the Data Review Committee (DRC) at the end of treatment (EOT), will be evaluated in the European Union (EU) only.

Secondary endpoints include the percentage of subjects with a Successful Global Response at Day 14, Day 30, and EOT, as determined by both the Principal Investigator (PI) and the DRC. This assessment will be based on clinical, mycological, and radiological responses when applicable. The trial will also measure the percentage of subjects with a Successful Clinical Response and a Successful Mycological Response at Day 14 and EOT. Furthermore, the percentage of subjects with no recurrence before EOT and at 2 weeks and 6 weeks after EOT will be evaluated. The percentage of subjects alive with a Successful Global Response and no recurrence at 6 weeks after EOT will also be assessed.

These efficacy parameters will be collected and analyzed at specified timepoints, including Day 14, Day 30, EOT, and follow-up periods at 2 weeks and 6 weeks post-EOT. The assessments will be conducted by the DRC and PI using predefined criteria to ensure consistency and reliability in the evaluation of treatment outcomes.