| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated | | Invasive Candidiasis/ Candidemia | |
| E.1.1.1 | Medical condition in easily understood language | | Invasive Candidiasis/ Candidemia | |
| E.1.1.2 | Therapeutic area | Diseases [C] - Bacterial Infections and Mycoses [C01] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 | | E.1.2 | Level | LLT | | E.1.2 | Classification code | 10060573 | | E.1.2 | Term | Candidemia | | E.1.2 | System Organ Class | 100000004862 | |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 | | E.1.2 | Level | LLT | | E.1.2 | Classification code | 10064954 | | E.1.2 | Term | Invasive candidiasis | | E.1.2 | System Organ Class | 100000004862 | |
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial | | • To demonstrate that treatment of Invasive Candidiasis/ Candidemia with intravenous (IV) echinocandin followed by oral ibrexafungerp is non inferior to IV echinocandin followed by oral fluconazole based on 30-day all-cause mortality (ACM). | |
| E.2.2 | Secondary objectives of the trial | Key Secondary Objective:
• To demonstrate that treatment of Invasive Candidiasis/ Candidemia with IV echinocandin followed by oral ibrexafungerp is non inferior to IV echinocandin followed by oral fluconazole based on Global Response (clinical, radiological, and mycological response, as confirmed by the Data Review Committee [DRC]) at Day 14.
Other Secondary Objectives:
• To compare the efficacy of the treatment regimens, based on:
o Global Response at Day 30 and End of Therapy (EOT) as determined by the PI and DRC,
o Clinical Response as determined by the PI and DRC,
o Mycological Response as determined by the DRC,
o no recurrence as determined by the DRC, and
o fungal-free survival as determined by the DRC.
• To evaluate the safety of the regimens.
• To evaluate the pharmacokinetics (PK) of ibrexafungerp.
| |
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria | KEY INCLUSION CRITERIA
Subjects must fulfill all of the following KEY criteria at Screening to be eligible for participating in the study:
1. Subject is a male or female adult ≥ 18 years of age on the day the study informed consent is signed.
2. Subject has a diagnosis of candidemia and/or invasive candidiasis, defined as evidence of Candida spp. in either a bloodstream or tissue culture from a normally sterile site (excluding eye, cardiac tissue, bone tissue, central nervous system or prosthetic device) collected ≤ 4 days (within 96 hours) prior to initiation of IV echinocandin accompanied by any related clinical sign and/or symptom (e.g., fever [on one occasion > 38°C], hypotension, or local signs of inflammation).
| |
| E.4 | Principal exclusion criteria | KEY EXCLUSION CRITERIA
A subject will be excluded from participation in the study if he or she meets any of the following KEY exclusion criteria:
1. Subject has any of the following forms of invasive candidiasis at Screening:
a. Septic arthritis in a prosthetic joint (septic arthritis in a native joint is allowed),
b. Osteomyelitis,
c. Endocarditis or myocarditis,
d. Meningitis, endophthalmitis, or any central nervous system infection,
e. Chronic disseminated candidiasis,
f. Urinary tract candidiasis due to ascending Candida infection secondary to unresolved obstruction or non-removeable device in the urinary tract,
g. Patients with a sole diagnosis of mucocutaneous candidiasis, i.e., oropharyngeal, esophageal, or genital candidiasis; or Candida lower urinary tract infection or Candida isolated solely from respiratory tract specimens,
h. Patients with concurrent invasive fungal infection other than Candida spp., e.g., cryptococcosis, mold infection or endemic fungal infection,
i. Patients who failed a previous antifungal therapy for the same infection,
j. Subject has an inappropriately controlled fungal disease source (e.g., indwelling vascular catheter or device that cannot be removed or an abscess that cannot be drained) that is likely to be the source of the candidemia or invasive candidiasis.
2. Subject has abnormal liver test parameters: alanine aminotransferase (ALT) or aspartate aminotransferase (AST) levels > 10-fold the upper limit of normal (ULN).
3. Subject has severe hepatic impairment and a history of chronic cirrhosis (Child-Pugh score > 9).
4. Subject has received more than 48 hours of non-echinocandin antifungal therapy for the treatment of invasive candidiasis (including candidemia) within 96 hours preceding initiation of IV echinocandin.
a. Exception: Receipt of antifungal therapy to which any Candida spp. isolated in qualifying culture is not susceptible.
5. Baseline QTcF ≥ 500 msec.
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| E.5 End points |
| E.5.1 | Primary end point(s) | | The primary endpoint of the study is ACM at Day 30 in the ITT population. | |
| E.5.1.1 | Timepoint(s) of evaluation of this end point | |
| E.5.2 | Secondary end point(s) | Key Secondary Endpoint:
The percentage of subjects with Successful Global Response, as determined by the DRC at Day 14.
Secondary Endpoints:
Efficacy Endpoints
• The percentage of subjects with Successful Global Response at Day 30 and EOT as determined by the PI and the DRC.
• The percentage of subjects with Successful Clinical Response at Day 14 and EOT as determined by the PI and the DRC.
• The percentage of subjects with Successful Mycological Response at Day 14 and EOT as determined by the DRC.
• The percentage of subjects with no recurrence before EOT and at 2 weeks and 6 weeks after EOT as determined by the DRC.
• The percentage of subjects alive with Successful Global Response and no recurrence at 6 weeks after EOT as determined by the DRC.
Safety Endpoints
• Frequency of treatment-emergent adverse events (TEAEs), drug-related adverse events (AEs), discontinuations due to AEs, serious adverse events (SAEs), and safety laboratory assessments.
PK Endpoint
• Ibrexafungerp plasma concentrations. | |
| E.5.2.1 | Timepoint(s) of evaluation of this end point | Key secondary endpoint at Day 14
Efficacy endpoint:
• At Day 30 and EOT
• Day 14 and EOT
• Day 14 and EOT
• At 2 weeks and 6 weeks after EOT
• At 6 weeks after EOT | |
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | Yes |
| E.8.2.3.1 | Comparator description | |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| E.8.3 | The trial involves single site in the Member State concerned | No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 5 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 42 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned | | Israel | | Korea, Republic of | | South Africa | | United States | | France | | Bulgaria | | Spain | | Czechia | | Germany | | Greece | | Italy | | Belgium | |
| E.8.7 | Trial has a data monitoring committee | No |
| E.8.8 | Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial | | EOT is end of all treatment, including IV and oral. | |
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 2 |
| E.8.9.1 | In the Member State concerned months | 7 |
| E.8.9.1 | In the Member State concerned days | 16 |
| E.8.9.2 | In all countries concerned by the trial years | 2 |
| E.8.9.2 | In all countries concerned by the trial months | 7 |
| E.8.9.2 | In all countries concerned by the trial days | 16 |
