| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Candidemia; invasive candidiasis. |
|
| E.1.1.1 | Medical condition in easily understood language |
| Candidemia; invasive candidiasis. |
|
| 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 | 10064954 |
| E.1.2 | Term | Invasive candidiasis |
| 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 | 10060573 |
| E.1.2 | Term | Candidemia |
| 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 |
The primary objectives are to:
• Demonstrate that Rezafungin for Injection is non-inferior to caspofungin for all-cause mortality (ACM) at Day 30 (-2 days) in the modified intent-to-treat (mITT) population (United States Food and Drug Administration [FDA] primary objective)
• Demonstrate that Rezafungin for Injection is non-inferior to caspofungin for global cure (clinical cure as assessed by the Investigator, radiological cure (for qualifying invasive candidiasis subjects), and mycological eradication, as confirmed by the Data Review Committee [DRC]) at Day 14 (±1 day) in the mITT2 population (European Medicines Agency [EMA] primary objective) |
|
| E.2.2 | Secondary objectives of the trial |
•Compare global cure (clinical cure as assessed by the Investigator, radiological cure [for qualifying invasive candidiasis subjects], and mycological eradication, as confirmed by the DRC) for subjects receiving Rezafungin and caspofungin at Day 14 (±1 day) in the mITT population
•Compare global cure (clinical cure as assessed by the Investigator, radiological cure [for qualifying invasive candidiasis subjects], and mycological eradication, as confirmed by the DRC) for subjects receiving Rezafungin for Injection and caspofungin at Day 5, Day 30 (-2 days), EoT (≤2 days of last dose), and F-UP (Days 52–59) in the mITT population
•Compare mycological eradication for subjects receiving Rezafungin and caspofungin at Day 5, Day 14 (±1 day), Day 30 (-2 days), EoT (≤2 days of last dose), and F-UP (Days 52–59) in the mITT population
•Compare the safety and tolerability for subjects receiving Rezafungin for Injection and caspofungin in the safety population |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Subjects must meet ALL the following inclusion criteria to qualify for the study:
1. Willing and able to provide written informed consent. If the subject is unable to consent for himself/herself, a legally acceptable
representative (i.e., acceptable to International Council on Harmonisation [ICH] and local law, as applicable) must provide informed
consent on his/her behalf.
2. Males or females ≥18 years of age.
3. Established mycological diagnosis of candidemia and/or invasive candidiasis from a sample taken ≤4 days (96 hours) before
randomization defined as:
a. ≥1 blood culture positive for yeast or Candida
OR
b. Positive test for Candida from a Sponsor-approved rapid IVD
OR
c. 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.
4. Presence of one or more systemic signs attributable to candidemia or invasive candidiasis (e.g., fever, hypothermia, hypotension, tachycardia,
tachypnea, local signs of inflammation) appearing from ≤12 hours prior to the qualifying positive culture through time of randomization.
5. Willing to initiate or continue medical treatment to cure infections, including receipt of antibiotics and surgical procedures, if required.
Patients receiving only medications and measures for comfort and not cure should not be enrolled.
6. Female subjects of childbearing potential (all female subjects between 18 years and <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 (e.g., oral contraceptive, implant, injectable, indwelling
intrauterine device, vasectomized partner), or sexual abstinence while participating in this study. Male subjects must be vasectomized, abstain from sexual intercourse, or agree to use barrier contraception (condom with spermicide), and also agree not to donate sperm while participating in this study and for 90 days thereafter (and at least 120 days from the last dose of study drug).
7, 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.
|
|
| E.4 | Principal exclusion criteria |
Subjects must NOT meet any of the following exclusion criteria to qualify
for the study:
1. Any of the following forms of invasive candidiasis at baseline:
a. Septic arthritis in a prosthetic joint (septic arthritis in a native joint is allowed)
b. Osteomyelitis
c. Endocarditis or myocarditis
d. Meningitis, endophthalmitis, chorioretinitis, or any central nervous system infection
e. Chronic disseminated candidiasis
f. Urinary tract candidiasis due to ascending Candida infection secondary to obstruction or surgical instrumentation of the urinary tract
2. 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) and ≤4 days (96 hours) before randomization
a. Exception: Receipt of antifungal therapy to which any Candida spp. isolated in culture is not susceptible
3. Alanine aminotransferase or aspartate aminotransferase levels >10- fold the upper limit of normal (ULN).
4. Severe hepatic impairment in subjects with a history of chronic cirrhosis (Child-Pugh score >9)
5. 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
6. Known hypersensitivity to Rezafungin for Injection, caspofungin, any echinocandin, or to any of their excipients
7. Meets National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE), version 5.0, criteria for ataxia, tremor, motor
neuropathy, or sensory neuropathy of Grade 2 or higher
8. 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)
9. Planned or ongoing therapy at Screening with a known neurotoxic medication
10. Previous participation in this or any previous rezafungin study
11. Current participation in another interventional treatment trial with an investigational agent.
12. 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
13. Pregnant or lactating females
14. The Principal Investigator (PI) is of the opinion the subject should not participate in the study
|
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
The primary efficacy outcome for the EMA is global cure (based on clinical cure as assessed by the Investigator, radiological cure [for those subjects with invasive candidiasis documented by radiologic/imaging evidence at baseline] and mycological eradication) confirmed by an independent DRC at Day 14 (±1 day).
The primary efficacy outcome for the FDA is ACM at Day 30 (-2 days). |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Day 14 (±1 day) for EMA / Day 30 (-2 days) for FDA |
|
| E.5.2 | Secondary end point(s) |
All-cause mortality at Day 30 (-2 days) is a secondary outcome for the EMA, and global cure at Day 14 (±1 day) is a secondary outcome for the
FDA.
Additional secondary efficacy outcome measures include global cure (clinical cure as assessed by Investigator, radiological cure [for qualifying invasive candidiasis subjects], and mycological eradication, as confirmed by the DRC) for subjects receiving Rezafungin for Injection and caspofungin at 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) in the mITT population;
Additional secondary efficacy outcome measures include mycological eradication, clinical cure as assessed by Investigator, and radiological cure for invasive candidiasis subjects, receiving Rezafungin for Injection and caspofungin at Day 5, Day 14 (±1 day), Day 30 (-2 days), EOT (≤2 days of last dose), and Follow-up (Days 52–59).
An exploratory efficacy outcome measure is resolution of attributable systemic signs of candidemia and/or invasive candidiasis that were
present at baseline, Day 5, Day 14 (±1 day), Day 30 (-2 days), EOT (≤2 days of last dose), and Follow-up (Days 52–59).
Pharmacokinetics and/or Pharmacodynamics
Blood samples will be collected from subjects to evaluate the PK of Rezafungin for Injection. Blood samples will be collected from all subjects, but only PK samples from subjects receiving Rezafungin for Injection will be analyzed. Plasma samples will be analyzed for the concentration of rezafungin at a central bioanalytical laboratory using a validated liquid chromatography-tandem mass spectrometry method. Samples from this study may also be included in a population PK analysis, which will be reported separately.
In addition, rezafungin plasma protein binding and albumin concentrations will be determined from pre-dose plasma samples from all subjects and reported separately.
Safety
Safety will be assessed through the evaluation of AEs, vital signs (temperature, heart rate, blood pressure, and respiratory rate), ECGs,
physical examinations (including neurological examinations), and clinical laboratory data (clinical chemistry panels, hematology evaluations, and urinalyses). Subjects will also be assessed at least at the Screening and EOT visits with a thorough neurologic evaluation to assess for signs and symptoms of tremor, ataxia, and peripheral neuropathy. Adverse events will be graded using the National Cancer Institute CTCAE version 5.0. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Day 30 (-2 days) for EMA / Day 14 (±1 day) for FDA |
|
| 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 | Yes |
| 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 | No |
| 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 | 7 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 36 |
| 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 |
| Australia |
| Belgium |
| Bulgaria |
| China |
| France |
| Germany |
| Greece |
| Israel |
| Italy |
| Korea, Republic of |
| Spain |
| Thailand |
| United States |
|
| E.8.7 | Trial has a data monitoring committee | Yes |
| 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
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 1 |
| E.8.9.1 | In the Member State concerned months | 9 |
| E.8.9.1 | In the Member State concerned days | 10 |
| E.8.9.2 | In all countries concerned by the trial years | 1 |
| E.8.9.2 | In all countries concerned by the trial months | 9 |
| E.8.9.2 | In all countries concerned by the trial days | 10 |
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