Clinical trial NCT03667690
Conditions: Candidemia Mycoses Fungal Infection Invasive Candidiases
Keywords: 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
Sponsor: Cidara Therapeutics Inc.
Start date: 2018-10-07; Completion date: 2021-10-07
Enrollment: 199 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
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:
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.

Arms: arm 1: 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. arm 2: 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.
Interventions: intervention 1: Rezafungin for Injection intervention 2: Caspofungin intervention 3: Fluconazole intervention 4: intravenous placebo intervention 5: oral placebo
Intervention descriptions: intervention 1: Intravenous antifungal therapy intervention 2: Intravenous antifungal therapy intervention 3: Oral antifungal therapy intervention 4: Normal saline intervention 5: Microcrystalline cellulose

Protocol documents:
Prot_000.pdf: 
Study Protocol 
 
 
Title: 
A Phase 3, Multicenter, Randomized, Double-blind Study of the Efficacy 
and Safety of Rezafungin for Injection versus Intravenous Caspofungin 
Followed by Optional Oral Fluconazole Step-down in the Treatment of 
Subjects with Candidemia and/or Invasive Candidiasis (The ReSTORE 
Study) 
NCT Number: 
NCT03667690 
Document Date: 
15 OCT 2020 
 


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PROTOCOL TITLE PAGE 
Title 
A Phase 3, Multicenter, Randomized, Double-blind Study of the Efficacy and 
Safety of Rezafungin for Injection versus Intravenous Caspofungin Followed 
by Optional Oral Fluconazole Step-down in the Treatment of Subjects with 
Candidemia and/or Invasive Candidiasis (The ReSTORE Study) 
Study Drug 
Rezafungin for Injection 
Original Protocol 
14JUNE2018 
Protocol Amendment 1  
03AUG2018 
Protocol Amendment 2 
27AUG2018 
Protocol Amendment 3 
06NOV2018 
Protocol Amendment 4 
25APR2019 
Protocol Amendment 4-FR 
26NOV2019 
Protocol Amendment 4-DE 
10FEB2020 
Protocol Amendment 4.1-DE 
30APR2020 
Protocol Amendment 5 
15OCT2020 
Sponsor 
Cidara Therapeutics, Inc. 
6310 Nancy Ridge Drive, Suite 101 
San Diego, California 92121, USA 
Telephone: +1.858.752.6170 
Facsimile: +1.858.408.3509 
Sponsor Medical Monitor 
Taylor Sandison, MD MPH 
Cidara Therapeutics, Inc. 
6310 Nancy Ridge Drive, Suite 101 
San Diego, California 92121, USA 
Office: 
+1.858.249.7429 
Mobile: 
+1.858.249.9459 
Facsimile: +1.858.408.3509 
Email: tsandison@cidara.com 
Sponsor Clinical Trial 
Manager 
Lorena Kanu  
Cidara Therapeutics, Inc. 
6310 Nancy Ridge Drive, Suite 101 
San Diego, California 92121, USA 
Office/Mobile: +1.760.355.9288 
Facsimile: 
+1.858.408.3509 
Email: lkanu@cidara.com 
EudraCT Number 
2018-002630-21 
Confidentiality Statement: 
This document is a confidential communication from Cidara Therapeutics, Inc. Acceptance of this 
document constitutes an agreement by the recipient(s) that no information contained herein will 
be published or disclosed without prior written approval from Cidara Therapeutics, Inc., except 
that this document may be disclosed to appropriate Institutional Review Boards and/or Ethics 
Committees under the condition that they are also required to maintain confidentiality. 




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1.0 
PROTOCOL SYNOPSIS 
Sponsor: 
Cidara Therapeutics, Inc., San Diego, California, USA 
Product Name: 
Rezafungin for Injection 
Active Ingredients: rezafungin acetate 
Protocol Title: A Phase 3, Multicenter, Randomized, Double-blind Study of the Efficacy and Safety of 
Rezafungin for Injection versus Intravenous Caspofungin Followed by Optional Oral Fluconazole Step-down 
in the Treatment of Subjects with Candidemia and/or Invasive Candidiasis (The ReSTORE Study) 
Phase: 3 
Planned Study Centers: Approximately 120 clinical sites globally. 
Study Duration: Maximum study duration for an individual subject is 63 days, including Screening (≤4 days, 
96 hours), the Required Treatment Period (Day 1 to Day 14 [14 days]), the Optional Extended Treatment Period 
(Day 15 to Day 28), and Follow-up (Days 52–59). 
Objectives: 
The primary objectives of this study 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 mITT population (European Medicines Agency [EMA] primary objective) 
The secondary objectives of this study are to: 
• 
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), End of Treatment (EOT) 
(≤2 days of last dose), and Follow-up (Days 52–59) in the mITT population 
• 
Compare mycological eradication for 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) 
in the mITT population 
• 
Compare clinical cure as assessed by the Investigator for 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) in the mITT population 
• 
Compare 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) in the mITT population 
• 
Compare the safety and tolerability for subjects receiving Rezafungin for Injection and caspofungin 
in the safety population 
• 
Evaluate the pharmacokinetics (PK) of Rezafungin for Injection 
An exploratory objective of this study is to: 
• 
Compare resolution of systemic signs attributable to candidemia and/or invasive candidiasis for subjects 
receiving Rezafungin for Injection and caspofungin at Day 5, Day 14 (±1 day), Day 30 (-2 days), 
and Follow-up (Days 52–59) in the mITT population 


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Study Design and Methodology: 
The study design figure is provided in Figure 1. The Schedule of Assessments and Procedures for the Required 
Treatment, EOT, and Follow-up Periods is presented in Table 1 and the Schedule of Assessments and Procedures 
for the Optional Treatment Period is presented in Table 2. 
This is a Phase 3, multicenter, prospective, randomized, double-blind, efficacy and safety study of Rezafungin 
for Injection (intravenous [IV]) versus an active comparator regimen of caspofungin (IV) followed by optional 
oral fluconazole step-down therapy in subjects with candidemia and/or invasive candidiasis. Subjects will 
be randomly assigned (1:1 ratio) to receive either Rezafungin for Injection or caspofungin. After ≥3 days 
IV 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 step-down therapy by the Investigator if they meet the 
oral step-down therapy criteria. 
Challenges in Conducting a Pivotal Phase 3 Study During the COVID-19 Pandemic: 
Study participants will be enrolled in the ReSTORE study while hospitalized and receiving strict infection control 
practices to prevent nosocomial transmission of SARS-CoV-2. Once study participants are discharged from the 
hospital, they will be followed weekly as is the standard of care and according to the protocol. Study participants 
will be instructed to follow infection control practices such as physical distancing, frequent hand washing, 
and wearing face masks. This infection control practice will also be recommended to caregivers and all who 
reside with the study participant. If a study participant develops signs or symptoms that suggests COVID-19 
infection, we encourage them to be evaluated by their physician and have a diagnostic workup and management 
plan advised by the site’s national/regional/local guidelines for the management of COVID-19 infection. 
If a subject contracts COVID-19 during the study, the diagnosis will be captured as an adverse event and the 
resulting safety parameters and treatment will be captured in case report forms.  
Subjects Randomized to Rezafungin for Injection 
Subjects randomized to Rezafungin for Injection will receive a 400 mg loading dose in Week 1, followed by 
200 mg once weekly, for a total of 2 to 4 doses. To maintain the blind, subjects will also receive daily placebo 
to match for caspofungin IV, which will be administered on Days 2–7, Days 9–14 and during the optional dosing 
period on Days 16–21 and Days 23–28, or will receive daily placebo for oral step-down therapy (first eligibility 
on Day 4 or later as advised by a site’s national/regional/local guidelines), which will be administered every day 
including rezafungin infusion days (see Figure 1 and Figure 2).  
Subjects Randomized to Caspofungin 
Subjects randomized to caspofungin will receive a total treatment of ≥14 days beginning with a single 
caspofungin 70 mg IV loading dose on Day 1 followed by caspofungin 50 mg IV once daily with the option 
to continue treatment ≤28 days. After ≥3 days (or the minimum duration of IV therapy advised by the site’s 
national/regional/local guidelines, whichever is greater) of caspofungin treatment, subjects who meet the 
step-down therapy eligibility criteria (see Section 8.2.3.3) may be switched to oral fluconazole at a dose of 
6 mg/kg administered once daily (rounded to the nearest 200 mg increment) with a maximum daily dose of 
800 mg (e.g., a subject weighing 73 kg would receive fluconazole 400 mg dose [2 capsules of 200 mg each] 
based on a 6 mg/kg target dose [73 kg × 6 mg/kg = 438 mg]. NOTE: Refer to dosing section for alternative 
regimens of fluconazole in subjects with renal impairment in Section 8.2.3.5). To maintain the blind, subjects in 
the caspofungin treatment group who have switched to oral step-down therapy will receive matching IV placebo 
for Rezafungin for Injection once weekly on the days of scheduled Rezafungin for Injection doses until study 
drug is stopped (Day 8, Day 15 [if applicable] and Day 22 [if applicable]) (see Figure 1 and Figure 2). 
End of Treatment Visit and Follow-up Visits 
Subjects will complete an EOT visit within 2 calendar days after the last dose of study drug, and a Follow-up visit 
within the Day 52–59 period. Subjects who stop study drug prior to Day 22 AND are considered clinical failures 
(i.e., require a change in antifungal therapy to treat candidemia and/or invasive candidiasis) may have their 
Follow-up visit earlier, but the visit must still be ≥30 days following the last once weekly infusion of Rezafungin 
for Injection/placebo (i.e., Day 1, Day 8, Day 15, or Day 22). 
 
 
 


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Mycological Diagnosis 
Mycological diagnosis of candidemia and/or invasive candidiasis sufficient for inclusion in the study will be 
established by one of the following test results from a blood or normally sterile site sample collected ≤4 days 
(96 hours) before randomization: 
• 
≥1 blood culture positive for yeast or Candida 
• 
sponsor-approved rapid in vitro diagnostic (IVD) (e.g., T2Candida Panel, Septifast) test positive for 
Candida species (spp.) 
• 
a 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 
Note: If the positive blood culture used to qualify the subject for the study is drawn >12 hours prior to 
randomization, an additional set of blood cultures must be obtained ≤12 hours before randomization to determine 
which subjects are still candidemic at enrollment. Results from the blood cultures obtained ≤12 hours prior to 
randomization are not required to proceed with randomization. 
The dose and duration of any prior antifungal treatment received ≤4 weeks before randomization will be recorded 
at Screening. 
For diagnosis of invasive candidiasis, cultures should be obtained from purulent fluid or necrotic tissues from 
normally sterile sites. Drainage tubes following invasive procedures may only be used to acquire fluid for culture 
for up to 24 hours following placement of the tube (after 24 hours tubes could be colonized with non-infecting 
pathogens). While potentially indicative of disease, a urine culture may not be used as the qualifying culture for 
entry into the study, though the presence of a positive urine culture is not a reason to exclude a patient from 
participation. Additionally, a respiratory tract specimen would not be considered sufficient to prove invasive 
candidiasis as these specimens are rarely sterile and pulmonary infection with Candida spp. is extremely rare. 
Every reasonable effort must be made for source control of the Candida infection to properly evaluate the 
efficacy of study drug. Central catheters should be removed within 48 hours after diagnosis with candidemia, 
consistent with Infectious Diseases Society of America (IDSA) and European Society of Clinical Microbiology 
and Infectious Diseases (ESCMID) guidelines. For subjects with invasive candidiasis, surgical drainage 
or debridement of potentially infected fluid collections or necrotic tissues should be performed. 
Retinal Examination 
A retinal examination for evidence of a Candida eye infection, including endophthalmitis or chorioretinitis, 
should be performed on all subjects with candidemia during Screening when possible, although the exam may 
occur as late as Day 7. Retinal examination is standard of care for subjects with candidemia and should be 
performed by an ophthalmologist, when available. The retinal examination should be repeated in subjects who 
were negative at baseline if the subject develops visual signs or symptoms of a Candida eye infection during 
the study. Additionally, any neutropenic subjects who recover their neutrophil counts during the study should 
have an additional retinal examination. Subjects who were negative at baseline and diagnosed with a Candida 
eye infection after initiating study drug must discontinue study drug but may continue in the study at the 
Investigator’s discretion and all subsequent antifungal drugs, interventions, and outcomes for endophthalmitis 
or chorioretinitis will be recorded. 
Study Day Definition 
Study Day 1 is defined as the first day of study drug administration. Subsequent study days are counted as the 
number of consecutive calendar days thereafter. 
Efficacy Assessments 
Efficacy assessments for all subjects occur on Day 5, Day 14 (±1 day), Day 30 (-2 days), EOT (≤2 days of last 
dose), and the Follow-up visit (Days 52–59). Clinical cure, radiological cure (for qualifying invasive candidiasis 
subjects), mycological eradication, will be assessed on all efficacy assessment days. Survival status will be 
assessed at Day 30 (-2 days) and the Follow-up visit (Days 52–59). Subjects who complete Day 30 assessments 
on Day 28 or Day 29 (within the -2 days period) without further information thereafter will be considered alive at 
Day 30. For mycological response, the location of Candida infection determines how eradication will be 
demonstrated: 
 


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a. Subjects with ≥1 blood culture positive for Candida  
Blood cultures for efficacy following the first dose of study drug will be performed until the first 
negative blood culture result for Candida spp. with no subsequent positive culture (in cases when 
one or more samples are drawn and cultured after the first negative culture is available). Blood 
samples for cultures should be drawn daily when possible although may be drawn every other day 
until blood cultures are negative. Generally, blood cultures should involve samples from 2 separate 
draws with ≥1 draw from a peripheral vein without an IV catheter.  
b. Subjects with a positive culture for Candida spp. from a normally sterile site  
Note: only applies when infected sites are accessible; fluid samples from drainage tubes may only 
be collected for up to 24 hours following placement of the tube. Culture specimens for efficacy 
following the first dose of study drug should be collected from all normally sterile sites of baseline 
infection at least every other day until the first negative culture result for Candida spp. with no 
subsequent positive culture (in cases when one or more samples are drawn and cultured after the 
first negative culture is available). If access to the infected site is not possible, then mycological 
eradication will be determined based on clinical outcome (see Table 8).  
Safety Assessments 
Safety monitoring data is collected throughout the study. Adverse events (AEs) are collected from the time 
the informed consent document is signed through the Follow-up visit (Days 52–59). Vital signs will be measured 
at each study visit. A physical examination will be performed at the Screening, Day 5, Day 14 (±1 day), Day 30 
(-2 days), EOT (≤2 days of last dose), and Follow-up (Days 52–59) visits. Subjects will be assessed for signs and 
symptoms of tremor, ataxia, and peripheral neuropathy using a neurological exam at least at Screening and at 
EOT. More frequent neurological exams may be performed as directed by subject symptoms. Hematology 
and chemistry laboratory tests will be performed at the Screening, Day 1, Day 2, Day 4, Day 8 (±1 day), Day 14 
(±1 day), Day 30 (-2 days), EOT (≤2 days of last dose), and Follow-up visits (Days 52–59). Urinalysis will be 
performed at the Screening and EOT (≤2 days of last dose) visits. Coagulation laboratory tests (Prothrombin 
Time or International Normalized Ratio [PT/INR]) will be performed at the Screening visit. An 
electrocardiogram (ECG) will be performed at the Screening visit and on Day 1 at any time following 
administration of study drug (i.e., post-end IV infusion). An independent external Data and Safety Monitoring 
Board (DSMB) will review safety data when approximately 50% of subjects are randomized and as required for 
adverse events of special interest (AESIs) as provided in the DSMB Charter.  
PK Sampling 
Blood samples for PK analysis must be collected from the OPPOSITE arm of the infusion or through an arterial 
line during the infusion; after the infusion is complete, opposite arm or arterial line draws are preferred, but not 
mandatory. Blood samples will be collected as follows: 
• 
Day 1: within 10 minutes before the end of infusion, and one sample taken any time between end of 
infusion and 12 hours after the end of infusion 
• 
Day 2, 3, 4, or 5: One sample taken at any time on one day only 
• 
Day 8: Pre-dose  
• 
Day 14 (for subjects not receiving a Day 15 dose): One sample taken at any time 
• 
Day 15: Pre-dose (if applicable) 
• 
Day 22: Pre-dose (if applicable) 
For subjects completing treatment on Day 14 (±1 day), a PK sample should be drawn at the same time as 
hematology and chemistry blood draws (i.e., random PK draw). Note: Pre-dose samples should be collected 
≤30 minutes prior to the start of the infusion. For subjects receiving hemodialysis, an attempt should be made to 
obtain PK samples directly following hemodialysis if still within the required time window. 
Blood samples will be collected from all subjects receiving study drug, although only PK samples from subjects 
receiving Rezafungin for Injection will be analyzed. Pharmacokinetic sample analysis will be performed by an 
independent, central bioanalytical laboratory using a validated assay. 
Number of Subjects: 
Approximately 218 subjects will be randomized to treatment (1:1, Rezafungin for Injection to caspofungin). 
The target of 218 subjects assumes approximately 85% of randomized subjects will be evaluable for the mITT 


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population. Thus, 184 subjects will be in the mITT population (92 subjects in each treatment group). If the 
evaluability rate for the mITT population is higher than 85%, enrollment will be stopped when at least 
184 randomized subjects have met the criteria to be included in the mITT population.   
Criteria for Inclusion in the Study: 
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 (only possible if it corresponds to the subject's usual lifestyle) while participating in this 
study and at least 30 days from the last dose of study drug. 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. 
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 (see Appendix 1) 
3. Alanine aminotransferase or aspartate aminotransferase levels >10-fold the upper limit of normal 
(ULN). 


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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, including but not limited to hereditary sugar disorders (e.g., fructose intolerance, 
sucrose-isomaltase insufficiency), anaphylaxis, or echinocandin-induced exfoliative skin disorders 
(e.g., Stevens-Johnson syndrome or toxic epidermal necrolysis). 
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 severe neurotoxic medication (see Appendix 9) 
or with a known moderate neurotoxic medication (see Appendix 9) in a patient with ataxia, tremor, 
motor neuropathy, or sensory neuropathy of CTCAE version 5.0 Grade 1 or higher. 
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. 
Test Product, Dose, and Mode of Administration: 
Rezafungin for Injection is a lyophilized formulation of the active pharmaceutical ingredient, rezafungin acetate. 
Rezafungin for Injection is supplied in vials as a sterile lyophilized powder (200 mg) for reconstitution prior 
to dilution into normal saline infusion bags (250 mL). 
Rezafungin for Injection is administered IV with a 400 mg loading dose on Day 1 of Week 1, followed by 
200 mg once weekly, for a total of 2 to 4 doses. 
Intravenous infusion of Rezafungin for Injection and IV placebo is administered over 60 (±10) minutes, 
although the infusion time may be increased up to 180 minutes to manage evolving symptoms of infusion 
reaction consistent with management of echinocandin class infusion reactions, whereby decreasing the rate of 
infusion often alleviates symptoms. Dosage adjustments of Rezafungin for Injection are not allowed. Treatment 
will be initiated on an inpatient basis; a switch to outpatient IV treatment is allowed at the Investigator’s 
discretion. 
The daily dosing schedule for the required treatment period is presented in Figure 2 and the optional treatment 
period in Figure 3. The daily dosing schedule for the entire study period (required and optional) is presented 
in Table 3. 
Reference Therapy, Dose, and Mode of Administration: 
Active Comparator Regimens 
Caspofungin 
Subjects randomized to caspofungin will receive a total treatment of ≥14 days beginning with a single 70 mg 
loading dose on Day 1, followed by 50 mg once daily with the option to continue treatment ≤28 days, unless they 
qualify for an alternative caspofungin regimen per Section 8.2.2.4 or for oral step-down therapy after ≥3 days 
(or the minimum duration of IV therapy advised by the site’s national/regional/local guidelines, whichever is 
greater) of caspofungin IV treatment per Section 8.2.3. Doses are to be administered 24 (±2) hours after the start 
of study drug administration on the previous day. 
Intravenous infusion of IV caspofungin is administered over 60 (±10) minutes, although the infusion time may be 
increased up to 180 minutes to manage evolving symptoms of infusion reaction consistent with management of 
echinocandin class infusion reactions, whereby decreasing the rate of infusion often alleviates symptoms. 
Alternative Caspofungin Regimens and Guidance 
Subjects with moderate hepatic impairment (Child-Pugh score of 7–9) will receive a loading dose of 
caspofungin of 70 mg on Day 1 followed by 35 mg once daily.  


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Subjects weighing >80 kg or on concomitant rifampin, nevirapine, efavirenz, phenytoin, dexamethasone, 
or carbamazepine may receive caspofungin 70 mg once daily. Dose adjustment due to drug-drug 
interactions (DDIs) or weight may be considered according to the approved labeling and at the 
Investigator’s discretion. 
Use of concomitant cyclosporine should be limited to subjects for whom potential benefit outweighs 
potential risk of DDIs and hepatotoxicity with caspofungin. 
Oral Step-Down Regimen: Fluconazole 
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 who meet the step-down therapy eligibility 
criteria may be switched to oral fluconazole (earliest oral dose on Day 4 or later, as advised by a site’s 
national/regional/local guidelines). The total comparator treatment period (caspofungin plus fluconazole) is 
≤28 days. Subjects weighing over 130 kg will not be eligible for oral step-down therapy. Subjects with 
a creatinine clearance >50 mL/min (see Appendix 2) will receive oral fluconazole at a dose of 6 mg/kg 
administered once daily rounded to the nearest 200 mg increment with a maximum daily dose of 800 mg 
(e.g., a subject weighing 73 kg would receive a fluconazole 400 mg dose [2 capsules of 200 mg each] based 
on a 6 mg/kg target dose [73 kg × 6 mg/kg = 438 mg]). Subjects with creatinine clearance ≤50 mL/min will 
receive oral fluconazole at a dose of 3 mg/kg administered once daily rounded to the nearest 200 mg increment 
with a maximum daily dose of 400 mg (e.g., a subject weighing 73 kg would receive a fluconazole 200 mg dose 
[1 capsule of 200 mg] based on a 3 mg/kg target dose [73 kg × 3 mg/kg = 219 mg]). Subjects receiving 
hemodialysis receive the same dose as subjects with a creatinine clearance >50 mL/min; however, they are only 
dosed following hemodialysis. Subjects receiving continuous renal replacement therapy (CRRT) should be 
treated as a subject with normal renal function at 6 mg/kg rounded to the nearest 200 mg each day (Cousin 2003). 
Subjects receiving peritoneal dialysis should be treated with 1.5 mg/kg rounded to the nearest 200 mg each day 
(Cousin 2003). Investigators are advised to pay close attention to signs of overdosing and underdosing with 
underweight (<50 kg) and overweight (>85 kg) subjects, respectively. Additionally, signs of potential fluconazole 
toxicity, including hepatic toxicity and QT prolongation, should be closely monitored for any subject on oral 
step-down therapy. 
Oral Step-Down Therapy Eligibility Criteria 
An oral step-down therapy is allowed in both treatment groups (fluconazole for caspofungin, placebo for oral 
step-down therapy for Rezafungin for Injection), provided the following criteria are met: 
• 
Able to take oral medication 
• 
≥3 days of IV study drug (or the minimum duration of IV therapy advised by the site’s 
national/regional/local guidelines, whichever is greater) 
• 
The Candida spp. isolated is susceptible to fluconazole 
• 
All signs and symptoms of candidemia and/or invasive candidiasis that were present at baseline have 
resolved 
• 
The subject’s clinical status is considered stable based on Investigator assessment 
• 
Most recent blood culture must be drawn following the first dose of study drug AND ≥48 hours prior 
to oral study drug initiation AND must be negative for Candida spp. 
• 
No evidence of moderate or severe hepatic injury (alanine aminotransferase or aspartate 
aminotransferase >5× the ULN) 
• 
No history of hypersensitivity to any azole or any other contraindications to the use of fluconazole or its 
excipients, including concomitant use of the following medications: terfenadine, cisapride, astemizole, 
erythromycin, pimozide, and quinidine 
• 
No personal or family history of Long QT interval on ECG (QT) syndrome or a prolonged QT interval 
corrected for heart rate by Fridericia’s formula (QTcF) interval (>470 msec in males and >480 msec in 
females) 
• 
Investigator’s opinion, the subject can tolerate oral fluconazole therapy (refer to current fluconazole 
Prescribing Information) 
• 
Subject’s weight is ≤130 kg 


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While QT prolongation is rare with fluconazole without the contraindicated interacting medications listed above, 
investigators should monitor subjects with ECGs as clinically indicated. 
Subjects who are switched to oral step-down therapy may switch back to IV study drug therapy in the event 
of the development of an unforeseen condition that prevents the subject from taking oral medications 
(e.g., pancreatitis, urgent surgery), but may not switch back to IV study drug therapy for worsening or relapse 
of candidemia/invasive candidiasis or for intolerance or toxicity due to study drug. 
The daily dosing schedule with options for the required treatment period is presented in Figure 2 and for the 
optional treatment period is in Figure 3. The daily dosing schedule for the entire study period (required and 
optional) is presented in Table 3. 
Placebo, Dose, and Mode of Administration: 
In this double-blind, double-dummy, active comparator study, two placebo regimens are required; one for 
subjects randomized to Rezafungin for Injection and one for subjects randomized to caspofungin. In addition, 
because subjects in the caspofungin arm may be switched to oral step-down therapy, an oral placebo is required 
for subjects in the Rezafungin for Injection arm. Thus, placebo requirements for each treatment assignment 
are as follows: 
Treatment Assignment 
Placebo 
Rezafungin for Injection 
Placebo for caspofungin IV  
Placebo for oral step-down therapy (fluconazole) 
Caspofungin IV 
Placebo for Rezafungin for Injection 
In more detail, placebo regimens for each treatment assignment are as follows: 
Placebo Regimen for Rezafungin for Injection Treatment Assignment 
Subjects will receive a caspofungin IV equivalent regimen of daily placebo IV infusion in a blinded manner. 
Because subjects randomized to caspofungin may be switched to fluconazole oral step-down therapy, 
a fluconazole-equivalent regimen of daily oral placebo will be administered for subjects randomized to 
Rezafungin for Injection at that time. 
Placebo Regimen for Caspofungin IV Treatment Assignment 
Subjects who are switched to fluconazole oral step-down therapy will receive a Rezafungin for Injection 
equivalent regimen of weekly placebo IV infusion in a blinded manner. 
Duration of Treatment:  
The treatment period for study drug administration is ≥14 days to ≤28 days with the last required dose of study 
drug on Day 14 and the last possible dose of study drug on Day 28. Treatment may be stopped on any day 
between Day 14 and Day 28 at the discretion of the Investigator. 
Known and Potential Risks 
Known Risks 
Infusion reactions characterized by flushing, shortness of breath, and nausea have been observed with rezafungin 
and are similar to infusion reactions noted with other echinocandins. Symptoms of the infusion reaction may 
resolve without intervention or with either slowing of the infusion rate or interruption of the infusion. 
Mild photosensitivity to ultraviolet (UV) light has been demonstrated in subjects administered rezafungin in 
a Phase 1 clinical trial. Subjects should use measures to reduce sun and other UV light exposure while on study 
drug, and for 5 half-lives (approximately 30 days) after the last dose of rezafungin administered.  
The Investigator’s Brochure should be referenced for additional details or updated information throughout the 
conduct of the study. 
Potential Risks 
Echinocandins are typically well tolerated (Eraxis [anidulafungin] Prescribing Information; Mycamine 
[micafungin sodium] Prescribing Information; Cancidas [caspofungin acetate] Prescribing Information). 
Potential drug class effects include risk of abnormal liver function tests, hepatitis, and hepatic failure. General 
and administration site events (infusion related reactions, peripheral edema, rigors, infusion site inflammation, 


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and pyrexia) have been reported for echinocandins (Eraxis [anidulafungin] Prescribing Information; Mycamine 
[micafungin sodium] Prescribing Information; Cancidas [caspofungin acetate] Prescribing Information). Possible 
histamine-mediated symptoms have been reported in patients who received rapid infusions of echinocandins, 
including rash, urticaria, flushing, pruritus, dyspnea, hypotension, facial swelling, and vasodilation. 
Anaphylactic-like reactions have been reported with micafungin (Mycamine [micafungin sodium] Prescribing 
Information). While uncommon, subjects with a history of hypersensitivity to caspofungin or its excipients, 
including but not limited to anaphylaxis and exfoliative skin disorders, should be excluded from this study. 
Based on a fertility study in male rats, there is the potential risk for decreased sperm motility, increased 
incidences of abnormal sperm morphology, and testicular seminiferous tubular epithelial degeneration. These 
findings were noted at 2.5-fold the exposure (the estimated steady state plasma level in humans at 200 mg) for 
Rezafungin subjects in this clinical trial, who will receive 400 mg once weekly loading dose followed by 200 mg 
once weekly for a total of 2 to 4 doses. The risk to humans is unknown, thus the male contraception requirements 
in inclusion criterion 4 prohibit unprotected sexual intercourse and sperm donation within the study period and 
for 90 days thereafter (and a total of 120 days from the last dose of study drug). This risk is included in the 
informed consent form (ICF).  
In a 3-month study in monkeys, there were observations of tremors and histology consistent with Schwann cell 
hypertrophy/hyperplasia and demyelination in the dorsal root ganglia first appearing at week 6 of dosing. These 
observations occurred at 11-fold the exposure for the proposed rezafungin dosing regimen in this study. Given the 
late timing and high exposure relative to the rezafungin dosing regimen, the risk to study subjects is assessed as 
low. To collect further data on specific signs and symptoms associated with the neurologic events noted in these 
nonclinical studies, there will be periodic neurologic exams and follow up of neurologic adverse events of special 
interest (AESIs).  
Because there may be unknown and potential risks with administration of Rezafungin for Injection, all subjects 
will be closely monitored for safety and tolerability by repeated assessment of clinical, vital signs, ECGs, 
and clinical laboratory safety parameters and reporting of AEs. Additionally, there are AESIs, for which 
investigators will be trained to monitor closely and thorough investigations will occur (see Section 12.7). 
Finally, an independent DSMB will review all safety parameters throughout the study. 
Criteria for Evaluation: 
Efficacy 
The primary efficacy outcome for the FDA is ACM at Day 30 (-2 days). 
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). 
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 (confirmed by the DRC) at Day 5, Day 30 
(-2 days), EOT (≤2 days of last dose), and Follow-up (Days 52–59); mycological eradication, clinical cure, and 
radiological cure (for those subjects with invasive candidiasis documented by radiologic/imaging evidence at 
baseline) 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 subjects enrolled prior to amendment 5, and reported separately. 


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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 and abnormal laboratory values will be graded for severity 
using the National Cancer Institute CTCAE version 5.0.  
Statistical Methods: 
Sample Size and Stratification 
For the EMA endpoint of global cure (confirmed by the DRC), using a 20% non-inferiority (NI) margin, 
one-sided alpha of 0.025, 80% power, 1:1 randomization, a global cure of 70% in both the Rezafungin for 
Injection and caspofungin groups, and the sample size methodology based on a continuity corrected Z-statistic, 
a total of 184 subjects (92 subjects in each treatment group) are required in the mITT population. Assuming 85% 
of subjects will be evaluable for the mITT population, a total of approximately 218 subjects will be randomized. 
For the FDA endpoint of ACM at Day 30 (-2 days) in the mITT population, using a 20% NI margin, one-sided 
alpha of 0.025, an ACM at Day 30 rate of 20% in both treatment groups, 1:1 randomization, and the sample size 
methodology based on a continuity corrected Z-statistic, a total of 184 subjects in the mITT population provides 
an 89.7% power to show NI. 
Randomization will be stratified based on diagnosis (candidemia only; invasive candidiasis) and by Acute 
Physiology and Chronic Health Evaluation (APACHE II) score/absolute neutrophil count (ANC) (APACHE II 
score ≥20 OR ANC<500 cells/μL; APACHE II score <20 AND ANC≥500 cells/μL) at Screening.  
Analysis Populations 
The analysis populations are defined for this study as follows: 
• 
The intent-to-treat (ITT) population will include all randomized subjects 
• 
The Safety population will include all subjects who received any amount of study drug 
• 
The mITT population will include all subjects who had documented Candida infection based 
on Central Laboratory evaluation of a culture from blood or another normally sterile site obtained 
≤4 days (96 hours) before randomization and received ≥1 dose of study drug 
• 
The clinically evaluable (CE) population will include all subjects in the mITT population who also met 
inclusion criterion #4, did not meet exclusion criteria #1, #2, or #5, had an assessment of both 
mycological and clinical response at Day 14 in the window of Day 14 (±1 day) (subjects with invasive 
candidiasis documented by radiologic/imaging evidence also must have an assessment of radiologic 
response), and did not have any other factor that could confound the assessment of the global response at 
Day 14 
• 
Pharmacokinetic Analysis Population will include all Rezafungin for Injection subjects with at least 
1 plasma sample obtained for PK analysis 
Statistical Methodology 
The primary efficacy outcome for the FDA is ACM at Day 30 (-2 days). The number and percentage of subjects 
in each treatment group who are alive and deceased at Day 30 will be determined in the mITT population. 
A two-sided 95% confidence interval (CI) for the observed difference in the ACM rate (Rezafungin for Injection 
group minus caspofungin group) will be calculated using the unadjusted method of Miettinen and Nurminen. 
If the upper bound of the 95% CI is lower than 20%, NI of Rezafungin for Injection will be concluded. 
The primary efficacy outcome for the EMA is global cure (DRC confirmed) at Day 14 (±1 day) in the mITT 
population. The number and percentage of subjects in each treatment group who have a global response of cure, 
failure, or indeterminate, will be presented by treatment group at Day 14 (±1 day) in the mITT population. 
An adjusted (for the randomization stratification factors) two-sided 95% CI for the observed difference in the 
global cure rate (Rezafungin for Injection group minus caspofungin group) will be calculated using the method of 
Miettinen and Nurminen. If the lower bound of the 95% CI is greater than -20%, NI of Rezafungin for Injection 
will be concluded. 
The secondary efficacy outcomes are global cure (confirmed by the DRC), mycological response, clinical 
response, and radiological response (for subjects with invasive candidiasis documented by radiologic/imaging 


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evidence at baseline). The number and percentage of subjects with a global response of cure, failure, 
or indeterminate will be presented by treatment group in the mITT population at Day 5, Day 30 (-2 days), EOT 
(≤2 days of last dose), and Follow-up (Days 52–59). The number and percentage of subjects with a mycological 
response of eradication, failure, or indeterminate will be presented by treatment group in the mITT population at 
Day 5, Day 14 (±1 day), Day 30 (-2 days), EOT (≤2 days of last dose), and Follow-up (Days 52–59). The number 
and percentage of subjects with a clinical response of cure, failure, or indeterminate will be presented by 
treatment group in the mITT population at Day 5, Day 14 (±1 day), Day 30 (-2 days), EOT (≤2 days of last dose), 
and Follow-up (Days 52–59). The number and percentage of subjects with invasive candidiasis documented by 
radiologic/imaging evidence, a radiological cure, failure, or indeterminate will be presented by treatment group in 
the mITT population at Day 5, Day 14 (±1 day), Day 30 (-2 days), EOT (≤2 days of last dose), and Follow-up 
(Days 52–59). The 95% CIs for the treatment differences in global cure, mycological eradication, clinical cure as 
assessed by the Investigator, and radiological cure, will be determined. 
Safety will be evaluated by presenting summaries of AEs and serious adverse events (SAEs), clinical laboratory 
evaluations (hematology evaluation, chemistry panel, urinalysis), ECGs, and vital signs. Safety variables will 
be tabulated for the Safety population by treatment group. Adverse events will be coded using the Medical 
Dictionary for Regulatory Activities (MedDRA). A treatment-emergent adverse event (TEAE) is defined 
as an AE that occurs during or after study drug administration and up through the Follow-up visit (Days 52–59). 
The incidence of TEAEs will be presented by system organ class (SOC) and preferred term (PT), by relationship 
to study drug, and by CTCAE grade (version 5.0). In addition, the incidence of serious TEAEs and TEAEs 
leading to discontinuation of study drug will be presented by SOC and PT. Descriptive statistics for clinical 
laboratory test results, ECGs, and vital signs, including changes from Baseline, will be presented by time point. 
Incidences of potentially clinically significant (PCS) clinical laboratory results, ECGs, and vital signs, as defined 
in the Statistical Analysis Plan (SAP), will also be summarized by time point. The number and percentage of 
subjects with AEs of special interest of neuropathy and tremor will be provided by study drug group. Samples 
from this study may 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 subjects enrolled prior to amendment 5, and reported separately. The PK parameters that will be assessed in 
the PK Analysis Population include: maximum plasma concentration (Cmax), time to Cmax (Tmax), and area under 
the concentration-time curve (AUC), if applicable. 
Impact of the COVID-19 Pandemic on Analysis 
The COVID-19 pandemic may impact study participants’ ability to return to the clinic possibly resulting in 
premature discontinuation of study drug, premature discontinuation of the study, or missed study visits. 
Additionally, it is possible the COVID-19 pandemic may impact efficacy and safety outcomes. All missed visits 
due to COVID-19 will be noted as protocol deviations, and diagnoses of COVID-19 will be recorded as medical 
history or adverse events. Analyses to assess the possible impact of COVID-19 on the study results are described 
in the SAP. 


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Figure 1: 
Study Design Diagram 
 
 
 


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Figure 2: 
Dosing Schedule for Required Treatment Period 
 


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Figure 3: 
Dosing Schedule for Optional Treatment Period 
 
 


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Table 1: 
Schedule of Assessments and Procedures for the Required Treatment, End of Treatment, and Follow-up 
Periods 
Assessment or Procedure 
Screening 
Required Treatment Period (Days) 
Day 30 (-2) 
EOT 
Follow-up c 
≤4 days 
(96 hours) 
before 
randomization 
1 a 
2 
3 
4 
5–7 
8 (±1) b 
9–13 
14 (±1) b 
Efficacy, 
Safety 
≤2 days after  
last dose 
(IV or oral) 
Days 52–59 
Informed consent d 
X 
 
 
 
 
 
 
 
 
 
 
 
Medical history e 
X 
 
 
 
 
 
 
 
 
 
 
 
Physical examination, 
including weight and height f 
X 
X g 
X g 
X g 
X g 
X 
X g 
X g 
X 
X 
X 
X 
Neurological examination h 
X 
X h 
X h 
X h 
X h 
X h 
X h 
X h 
X h 
X h 
X  
X h 
Vital signs i 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Assess Central Venous 
Catheters j 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Blood for hematology 
and chemistry tests 
(see Appendix 3) 
X 
X 
X 
 
X 
 
X 
 
X 
X 
X 
X 
Blood for PT/INR 
(see Appendix 3) 
X 
 
 
 
 
 
 
 
 
 
 
 
Calculate Child-Pugh score k 
(see Appendix 4) 
X 
 
 
 
 
 
 
 
 
 
 
 
Calculate modified APACHE II 
with Glasgow coma score l 
X 
 
 
 
 
 
 
 
 
 
 
 
12-lead ECG m 
X 
X 
 
 
 
 
 
 
 
 
 
 
Radiologic test results n 
X 
 
 
 
 
 
 
 
 
 
X 
X 
Urine for urinalyses, 
microscopy o 
(see Appendix 3) 
X 
 
 
 
 
 
 
 
 
 
X 
 
Serum pregnancy test p 
X 
 
 
 
 
 
 
 
 
 
 
X 
Retinal examination for 
Candida eye infection q 
X q 
X q 
X q 
X q 
X q 
X q 
X q 
X q 
X q 
X q 
X q 
X q 
Blood or normally sterile 
tissue/fluid for culture r, s 
X r 
X s 
X s 
X s 
X s 
X s 
X s 
X s 
X s 
X s 
X s 
X s 


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Assessment or Procedure 
Screening 
Required Treatment Period (Days) 
Day 30 (-2) 
EOT 
Follow-up c 
≤4 days 
(96 hours) 
before 
randomization 
1 a 
2 
3 
4 
5–7 
8 (±1) b 
9–13 
14 (±1) b 
Efficacy, 
Safety 
≤2 days after  
last dose 
(IV or oral) 
Days 52–59 
Blood for Rapid IVD t 
X t 
 
 
 
 
 
 
 
 
 
 
 
Study randomization u 
 
X 
 
 
 
 
 
 
 
 
 
 
Administer study drug 
and/or placebo (See Table 3) 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Record prior and/or 
concomitant medications v 
X 
 
 
 
 
 
 
 
 
 
X 
X 
Record adverse events w 
X 
 
 
 
 
 
 
 
 
 
X 
X 
Assess presence or absence of 
systemic signs of candidemia/ 
invasive candidiasis 
X  
 
 
 
 
X z 
 
 
X 
X 
 
X 
Assess for clinical response y 
 
 
 
 
 
X z 
 
 
X 
X 
X 
X 
Assess for radiologic response aa 
 
 
 
 
 
X 
 
 
X 
X 
X 
X 
Assess ACM 
 
 
 
 
 
 
 
 
 
X 
 
X 
Blood for PK testing bb 
X cc 
X bb 
X dd 
X dd 
X dd 
X dd 
X bb 
 
X ee 
 
 
 
Abbreviations: ACM = all-cause mortality; APACHE II = Acute Physiology and Chronic Health Evaluation II; ECG = electrocardiogram; eCRF = electronic case report form; 
EOT = End of Treatment; ESCMID = European Society of Clinical Microbiology and Infectious Diseases; ICF = Informed Consent Form; ICH = International Council for 
Harmonisation; ICU = intensive care unit; IDSA = Infectious Diseases Society of America; IV = intravenous(ly); IVD = in vitro diagnostic; PCR = polymerase chain reaction; 
PI = Principal Investigator; PK = pharmacokinetic; spp. = species; PT/INR= Prothrombin Time/International Normalized Ratio. 
a 
Study Day 1 is defined as the first day of study drug administration; subsequent study days are counted as the number of consecutive calendar days thereafter. 
b 
Windows apply to subjects who are receiving oral step-down therapy on an outpatient basis or who are inpatient and are scheduled to be discharged by the next calendar day. 
c 
Follow-up is to occur on Days 52–59. Subjects who stop study drug prior to Day 22 AND are considered clinical failures (i.e., require a change in antifungal therapy to treat 
candidemia and/or invasive candidiasis) may have their Follow-up visit earlier but must still be ≥30 days following the last once weekly infusion of Rezafungin for 
Injection/placebo (i.e., Day 1, Day 8, Day 15, or Day 22). 
d 
Written informed consent must be obtained prior to initiating any study related assessments or procedures. Consent from a legally acceptable representative (i.e., acceptable 
to ICH and local law, as applicable) may be obtained if the subject is unable to consent for themselves. 
e 
Medical history for the last 5 years and Candida risk factors for the last 3 months (e.g., central line, active malignancy, broad-spectrum antibiotic therapy, diabetes mellitus, 
immunosuppression, major surgery, total parenteral nutrition, transplant recipient, trauma, dialysis, burns, pancreatitis) and ICU admission and discharge (if applicable).  
f 
Height at Screening only; weight at Screening, Day 14, and Follow-up (Days 52–59); all other assessments at specified visits. 
g 
A focused physical exam (including a neurological exam) should be performed as clinically indicated by adverse event screening and course of the underlying disease. 
h 
As part of the physical exam, a thorough neurologic exam is to be performed at Screening and at the EOT visit. At all other time points, a focused physical exam (including 
a neurological exam) is to be performed as clinically indicated, driven by the subject’s signs and symptoms. 


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i 
Temperature and the method used (oral, rectal, temporal, tympanic, or core), heart rate, blood pressure, and respiratory rate. Axillary temperatures are allowed, but not 
preferred. 
j 
Presence of central line during Screening or placed during the study should be documented with dates of insertion and removal. Short-term central venous catheters 
(e.g., peripherally-inserted central catheters, internal jugular, or subclavian central venous catheters) and long-term central venous catheters (e.g., tunneled catheters) 
are recommended to be removed within 48 hours after diagnosis with candidemia, consistent with IDSA and ESCMID guidelines. 
k 
Child-Pugh score is only required for subjects with a history of chronic cirrhosis. 
l 
APACHE II score is a stratification factor for randomization and must be calculated prior to enrollment using vital signs and laboratory results from Screening. If multiple 
vital signs and laboratory values are obtained during the Screening period, it is preferred to use those collected most closely to the time of randomization. See Appendix 5 for 
APACHE II and Appendix 6 for Glasgow coma score. 
m 
12-lead ECG must be conducted prior to randomization and at any time on Day 1 following administration of study drug (i.e., post-end IV infusion). 
n 
Radiologic test type with findings and interpretation should only be recorded if the test provides evidence of invasive candidiasis or evidence of progression, stabilization, 
improvement, or resolution of invasive candidiasis compared with previous radiographs. 
o 
While potentially indicative of disease, a positive urine culture for Candida spp. may not be used as the qualifying culture for entry into the study, though the presence 
of a positive urine culture is not a reason to exclude a patient from participation in the study. Subjects who are anuric do not require a urinalysis. 
p 
Serum pregnancy test required only for women of childbearing potential; do not perform for women ≥2 years postmenopausal or surgically sterile.  
q 
A retinal examination for evidence of a Candida eye infection, including endophthalmitis or chorioretinitis, should be performed in all subjects with candidemia during 
Screening when possible, although the exam may occur as late as Day 7. Retinal examination is standard of care for subjects with candidemia and should be performed by 
an ophthalmologist, when available. The retinal examination should be repeated in subjects who were negative at baseline if the subject develops visual signs or symptoms of 
a Candida eye infection during the study. Additionally, any neutropenic subjects who recover their neutrophil counts during the study should have an additional retinal 
examination. Subjects who were negative at baseline and diagnosed with a Candida eye infection after initiating study drug must discontinue study drug but may continue in 
the study at the Investigator’s discretion (see Section 7.4.2). 
r 
A culture must be obtained as part of the standard of care for inclusion in the study. Established mycological diagnosis of candidemia or invasive candidiasis from a sample 
taken ≤4 days (96 hours) before randomization defined as: ≥1 blood culture positive for yeast or Candida, a positive test for Candida from sponsor-approved rapid IVD, 
or a 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. If the 
positive blood culture used to qualify the subject for the study is drawn >12 hours prior to randomization, an additional set of blood cultures must be obtained ≤12 hours 
before randomization. Identification and susceptibility testing at the local laboratory for Candida for blood or normally sterile tissue/fluid for culture is required at Screening 
and for any positive culture requiring a change of antifungal therapy (i.e., local identification and susceptibility testing is not required for Candida isolates cultured from 
specimens on other study days provided there is no required change of antifungal therapy). 
s 
Specimens for culture for demonstration of efficacy, or when clinically indicated. Blood cultures should be repeated daily (preferred) or every other day until the first negative 
blood culture result for Candida spp. with no subsequent positive culture (in cases when one or more samples are drawn and cultured after the first negative culture is 
available). All fungal isolates cultured from blood and normally sterile tissue/fluid from Screening through Follow-up must be sent to the Central Laboratory. Record the spp. 
for any new bacteria isolated from blood and the spp. and susceptibilities for any new bacteria isolated from any other normally sterile site. 
t 
Sponsor-approved rapid IVDs are allowed to fulfill Inclusion Criteria #3 for entry into the study. However, a culture from blood or another normally sterile site obtained 
during the Screening period must be positive for Candida spp. for the subject to be eligible for the mITT population. Currently approved rapid IVDs include the T2Candida 
Panel and the Septifast PCR test.  
u 
Confirm all inclusion and exclusion criteria are met prior to randomization. 
v 
Record all prior and/or concomitant medications from Screening through Follow-up. All systemic antifungal therapy administered within 4 weeks and all non-antifungal 
therapy administered within 1 week prior to randomization will be documented and recorded in the eCRF. Subjects who received systemic treatment with an antifungal agent 
at approved doses for treatment of candidemia for >48 hours before randomization will be excluded from the study. 
w 
Adverse events are collected from the time the ICF is signed at Screening through Follow-up. 


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x 
The Screening period for assessing systemic signs of candidemia/ invasive candidiasis for inclusion in the study may include the 12 hours prior to the collection of the 
qualifying positive blood culture, when systemic signs of infection were the reason for specimen collection (blood culture or fluid from a sterile site culture or qualifying rapid 
IVD [e.g., T2Candida Panel]), through study randomization. 
y 
Clinical response is assessed by the PI. Criteria for cure, indeterminate, and failure responses are found in Table 9. 
z 
Assessment to be performed on Day 5 (i.e., not required for Day 6 and Day 7). 
aa 
Subjects diagnosed with invasive candidiasis with evidence of deep tissue disease by radiology or other imaging should have follow-up imaging to demonstrate progression, 
stabilization, improvement, or resolution of disease. Improvement or resolution of disease by imaging would indicate radiological cure, while stabilization or progression of 
disease by imaging would indicate radiological failure. Missing imaging following baseline evidence of invasive candidiasis will result in an indeterminate response. Criteria 
for cure, indeterminate, and failure responses are found in Table 10. 
bb 
Blood samples for PK analysis will be collected from the OPPOSITE arm of the infusion or through an arterial line during the infusion; after the infusion is complete, 
opposite arm or arterial line draws are preferred but not mandatory. Blood samples will be collected as follows: On Day 1, within 10 minutes before the end of infusion, 
and one sample taken anytime between end of infusion and 12 hours after the end of infusion; Day 2, 3, 4, or 5, one sample taken at any time on one day only; Day 8, 
pre-dose; Day 14 (for subjects not receiving a Day 15 dose), one sample taken at any time; Day 15, pre-dose (if applicable); Day 22, pre-dose (if applicable). Note: Pre-dose 
samples should be collected ≤30 minutes prior to the start of the infusion. For subjects receiving hemodialysis, an attempt should be made to obtain PK samples directly 
following hemodialysis if still within the required time window. 
cc 
Only for subjects enrolled prior to Amendment 5: Blood samples were obtained at any time during Screening (one blood sample for protein binding and one blood sample 
for albumin core analyses). To limit invasive procedures these samples were ideally collected at the same time into two vacutainers, though each sample could be collected 
separately. 
dd 
One blood sample for PK will be collected at any time on one of the following Days 2, 3, 4, or 5 (i.e., if blood sample for PK not collected on Day 2, must be collected on 
Day 3 [or Day 4 or Day 5]).  
ee 
Day 14 draw is only for subjects completing treatment on Day 14 and should be drawn at the same time as Day 14 hematology and chemistry blood draws (i.e., random 
PK draw). 
 


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Table 2: 
Schedule of Assessments and Procedures for the Optional Treatment Period 
 
Optional Treatment Period (Days) 
EOT 
Follow-up 
Assessment or Procedure 
15 (±1) 
16–21 
22 (±1) 
23–28 
≤2 days after  
last dose 
(IV or oral) 
Days 52–59 
Physical examination 
X  
X a 
X  
X a 
See Table 1. 
See Table 1. 
Neurological examination b 
X b 
X b 
X b 
X b 
Vital signs c 
X 
X 
X 
X 
Blood or normally sterile tissue/fluid for 
culture, if clinically indicated d 
X 
X 
X 
X 
Radiologic test results e 
 
 
 
 
Administer study drug and/or placebo 
(See Table 3) 
X 
X 
X 
X 
Record concomitant medications f 
 
 
 
 
Record adverse events g 
 
 
 
 
Blood for PK testing h 
X 
 
X 
 
 
 
Assess Central Venous Catheters i 
 
 
 
 
 
 
Abbreviations: EOT = End of Treatment; ESCMID = European Society of Clinical Microbiology and Infectious Diseases; ICF = Informed Consent Form; IDSA = Infectious 
Diseases Society of America; PK = pharmacokinetic. 
a 
A focused physical exam (including a neurological exam) should be performed as clinically indicated by adverse event screening and course of the underlying disease. 
b 
As part of the physical exam, a thorough neurologic exam is to be performed at Screening and at the EOT visit. At all other time points, a focused physical exam (including 
a neurological exam) is to be performed as clinically indicated, driven by the subject’s signs and symptoms (see Table 1). 
c 
Temperature and the method used [oral, rectal, temporal, tympanic, or core], heart rate, blood pressure, and respiratory rate. Axillary temperatures are allowed, but not 
preferred. 
d 
Cultures from blood or other normally sterile locations only if clinically indicated. Identification and susceptibility testing at the local laboratory for Candida for blood 
or normally sterile tissue/fluid for culture for any positive culture requiring a change of antifungal therapy (i.e., local identification and susceptibility testing is not required 
for Candida isolates cultured from specimens on other study days provided there is no required change of antifungal therapy). All fungal isolates must be sent to the Central 
Laboratory. 
e 
Radiologic test type with findings and interpretation should only be recorded if the test provides evidence of invasive candidiasis or evidence of progression, stabilization, 
improvement, or resolution of invasive candidiasis compared with previous radiographs. 
f 
Record all concomitant medications from Screening through Follow-up (Days 52–59). Systemic antifungal therapy is especially important to document. 
g 
Adverse events are collected from the time the ICF is signed at Screening through Follow-up (Days 52–59). 
h 
Blood will be collected pre-dose (≤30 minutes prior to the start of the infusion). 
i 
Presence of central line during Screening or placed during the study should be documented with dates of insertion and removal. Short-term central venous catheters 
(e.g., peripherally-inserted central catheters, internal jugular, or subclavian central venous catheters) and long-term central venous catheters (e.g., tunneled catheters) 
are recommended to be removed within 48 hours after diagnosis with candidemia, consistent with IDSA and ESCMID guidelines.


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Table 3: 
Dosing Schedule by Day 
Study Day 
Regimen a 
Randomized Treatment 
Rezafungin for Injection 
Caspofungin b with Oral Step-Down Option 
1 
Rezafungin for Injection 400 mg IV 
caspofungin 70 mg IV (loading dose) 
2–3 
placebo for caspofungin IV 
caspofungin 50 mg IV 
>3 
Optional switch to oral step-down therapy allowed c 
4–7 
 
 
IV only 
placebo for caspofungin IV 
caspofungin 50 mg IV 
oral step-down 
placebo for oral step-down therapy 
oral step-down therapy (fluconazole) 
8 (±1) 
 
 
IV only 
Rezafungin for Injection 200 mg IV 
caspofungin 50 mg IV 
oral step-down 
Rezafungin for Injection 200 mg IV  
 
-and- 
placebo for oral step-down therapy 
placebo for Rezafungin for Injection IV 
 
-and- 
oral step-down therapy (fluconazole) 
9–14 
 
 
IV only 
placebo for caspofungin IV 
caspofungin 50 mg IV 
oral step-down 
placebo for oral step-down therapy 
oral step-down therapy (fluconazole) 
15–28 
Optional treatment period begins. An End of Treatment visit is required within 
2 calendar days after the last dose of study drug. 
15 (±1) 
 
 
IV only 
Rezafungin for Injection 200 mg IV 
caspofungin 50 mg IV 
oral step-down 
Rezafungin for Injection 200 mg IV  
 
-and- 
placebo for oral step-down therapy 
placebo for Rezafungin for Injection IV 
 
-and- 
oral step-down therapy (fluconazole) 
16–21 
 
 
IV only 
placebo for caspofungin IV 
caspofungin 50 mg IV 
oral step-down 
placebo for oral step-down therapy 
oral step-down therapy (fluconazole) 
22 (±1) 
 
 
IV only 
Rezafungin for Injection 200 mg IV 
caspofungin 50 mg IV 
oral step-down 
Rezafungin for Injection 200 mg IV  
 
-and- 
placebo for oral step-down therapy 
placebo for Rezafungin for Injection IV 
 
-and- 
oral step-down therapy (fluconazole) 
23–28 
 
 
IV only 
placebo for caspofungin IV 
caspofungin 50 mg IV 
oral step-down 
placebo for oral step-down therapy 
oral step-down therapy (fluconazole) 
Abbreviation: CRRT = continuous renal replacement therapy; IV = intravenous(ly). 
a 
IV only regimen means the subject has not been switched to oral step-down therapy by the Investigator. Oral step-down 
regimen means the subject has been switched to oral step-down therapy by the Investigator. 
b 
Refer to dosing section for alternative regimens of caspofungin in subjects meeting hepatic impairment criteria or weight 
category criteria, and/or are receiving certain concomitant medications. 


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c 
Oral step-down therapy is as follows: Subjects weighing over 130 kg will not be eligible for oral step-down therapy. 
Subjects with a creatinine clearance >50 mL/min will receive oral fluconazole at a dose of 6 mg/kg administered once daily 
rounded to the nearest 200 mg increment with a maximum daily dose of 800 mg. Subjects with creatinine clearance 
≤50 mL/min will receive oral fluconazole at a dose of 3 mg/kg administered once daily rounded to the nearest 200 mg 
increment with a maximum daily dose of 400 mg. Subjects receiving hemodialysis receive the same dose as subjects with 
a creatinine clearance >50 mL/min; however, they are only dosed following hemodialysis. Subjects receiving CRRT should 
be treated as a subject with normal renal function at 6 mg/kg rounded to the nearest 200 mg each day (Cousin 2003). 
Subjects receiving peritoneal dialysis should be treated with 1.5 mg/kg rounded to the nearest 200 mg each day 
(Cousin 2003). 
Investigators are advised to pay close attention to signs of overdosing and underdosing with underweight (<50 kg) 
and overweight (>85 kg) subjects, respectively. Additionally, signs of potential fluconazole toxicity, including hepatic 
toxicity and QT prolongation, should be closely monitored for any subject on oral step-down therapy. 


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2.0 
TABLE OF CONTENTS 
PROTOCOL TITLE PAGE .........................................................................................................1 
PROTOCOL APPROVAL PAGE ...............................................................................................2 
1.0 
PROTOCOL SYNOPSIS ..................................................................................................3 
2.0 
TABLE OF CONTENTS ................................................................................................24 
3.0 
LIST OF ACRONYMS, ABBREVIATIONS, AND DEFINITIONS OF TERMS ....30 
4.0 
BACKGROUND AND RATIONALE ...........................................................................33 
4.1 
Candidemia and Invasive Candidiasis ...................................................................33 
4.2 
Rezafungin for Injection ........................................................................................33 
4.3 
Nonclinical Efficacy Models .................................................................................35 
4.4 
Nonclinical Pharmacokinetics ...............................................................................35 
4.5 
Nonclinical Pharmacology and Toxicology ...........................................................37 
4.5.1 
Safety Pharmacology ............................................................................38 
4.5.2 
Nonclinical Toxicology .........................................................................38 
4.6 
Clinical Pharmacology ...........................................................................................40 
4.7 
Overview of Clinical Experience ...........................................................................42 
4.7.1 
Overview of Clinical Safety ..................................................................43 
4.7.2 
Overview of Clinical Efficacy ..............................................................43 
4.8 
Summary of Benefits and Risks .............................................................................44 
4.8.1 
Known Benefits .....................................................................................44 
4.8.2 
Potential Benefits ..................................................................................44 
4.8.3 
Known Risks .........................................................................................44 
4.8.4 
Potential Risks .......................................................................................44 
4.8.5 
Mitigation of Risks ................................................................................46 
4.9 
Justification for Dosing Regimen ..........................................................................46 
4.9.1 
Rezafungin for Injection .......................................................................46 
4.9.2 
Caspofungin with Option for Oral Step-Down Regimen of 
Fluconazole ...........................................................................................50 
4.10 
Population to be Studied ........................................................................................50 
4.11 
Rationale for Use of Rezafungin for Injection in Candidemia and Invasive 
Candidiasis .............................................................................................................51 
4.12 
Statement of Compliance .......................................................................................52 
5.0 
STUDY OBJECTIVES ....................................................................................................53 
6.0 
STUDY DESIGN ..............................................................................................................54 
6.1 
Description of the Study ........................................................................................54 
6.1.1 
Subjects Randomized to Rezafungin for Injection................................54 


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6.1.2 
Subjects Randomized to Caspofungin ..................................................54 
6.1.3 
End of Treatment Visit and Follow-up Visits .......................................55 
6.1.4 
Mycological Diagnosis..........................................................................55 
6.1.5 
Retinal Examination ..............................................................................56 
6.1.6 
Study Day Definition ............................................................................56 
6.1.7 
Efficacy Assessments ............................................................................56 
6.1.8 
Safety Assessments ...............................................................................57 
6.1.9 
PK Sampling .........................................................................................57 
6.2 
Number of Subjects................................................................................................58 
6.3 
Measures Taken to Minimize Bias ........................................................................58 
6.4 
Expected Duration of Subject Participation ...........................................................58 
6.5 
Method of Treatment Assignment and Blinding ...................................................58 
7.0 
SELECTION, DISCONTINUATION, AND WITHDRAWAL OF SUBJECTS ......60 
7.1 
Subject Inclusion Criteria ......................................................................................60 
7.1.1 
Rapid In Vitro Diagnostics for Candidemia and Invasive 
Candidiasis ............................................................................................61 
7.1.2 
Systemic Signs of Candidemia and Invasive Candidiasis ....................61 
7.2 
Subject Exclusion Criteria .....................................................................................62 
7.3 
Requalification for Entry .......................................................................................63 
7.4 
Subject Withdrawal Criteria ..................................................................................63 
7.4.1 
Withdrawal from Study Protocol ..........................................................63 
7.4.2 
Early Discontinuation from Study Drug Administration ......................64 
7.5 
Replacement of Subjects ........................................................................................67 
7.6 
Study Termination by Sponsor and Termination Criteria......................................67 
8.0 
STUDY DRUGS ...............................................................................................................68 
8.1 
Rezafungin for Injection ........................................................................................69 
8.1.1 
Formulation ...........................................................................................69 
8.1.2 
Directions for Use .................................................................................69 
8.1.3 
Drug Storage .........................................................................................70 
8.1.4 
Dose Adjustment ...................................................................................70 
8.2 
Placebo and Comparator Treatment.......................................................................70 
8.2.1 
Placebo ..................................................................................................70 
8.2.2 
Caspofungin ..........................................................................................70 
8.2.2.1 
Formulation ....................................................................................71 
8.2.2.2 
Directions for Use ..........................................................................71 
8.2.2.3 
Drug Storage ..................................................................................71 


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8.2.2.4 
Dose Adjustment ............................................................................72 
8.2.3 
Oral Step-Down Therapy: Fluconazole ................................................72 
8.2.3.1 
Formulation ....................................................................................72 
8.2.3.2 
Directions for Use ..........................................................................72 
8.2.3.3 
Oral Step-Down Therapy Eligibility Criteria ................................73 
8.2.3.4 
Drug Storage ..................................................................................74 
8.2.3.5 
Dose Adjustment for Renal Impairment ........................................74 
8.3 
Compliance ............................................................................................................74 
8.4 
Breaking the Blind .................................................................................................74 
8.5 
Prior and Concomitant Medications and Substances .............................................75 
8.6 
Accountability Procedures .....................................................................................76 
8.7 
Study Drug Handling and Disposal .......................................................................76 
9.0 
STUDY PROCEDURES .................................................................................................78 
9.1 
Screening (≤4 days [96 hours]) ..............................................................................78 
9.2 
Required Treatment Period ....................................................................................80 
9.2.1 
Day 1 .....................................................................................................80 
9.2.2 
Day 2 .....................................................................................................82 
9.2.3 
Day 3 .....................................................................................................83 
9.2.4 
Day 4 .....................................................................................................85 
9.2.5 
Days 5–7 ...............................................................................................87 
9.2.6 
Day 8 (±1 day) ......................................................................................88 
9.2.7 
Days 9–13 .............................................................................................90 
9.2.8 
Day 14 (±1 day) ....................................................................................91 
9.2.9 
Day 30 (-2 days) ....................................................................................93 
9.2.10 
End of Treatment (≤2 days of last dose) ...............................................94 
9.3 
Follow-up (Days 52–59) ........................................................................................95 
9.4 
Optional Treatment Period .....................................................................................97 
9.4.1 
Days 15 (±1 day) ...................................................................................97 
9.4.2 
Days 16–21 ...........................................................................................98 
9.4.3 
Day 22 (±1 day) ..................................................................................100 
9.4.4 
Days 23–28 .........................................................................................101 
10.0 
ASSESSMENT OF EFFICACY ...................................................................................103 
10.1 
Primary Efficacy Outcome ..................................................................................103 
10.2 
Secondary Efficacy Outcomes .............................................................................104 
10.2.1 
Mycological Response ........................................................................104 
10.2.2 
Clinical Response ................................................................................106 


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10.2.3 
Radiological Response ........................................................................106 
10.3 
Exploratory Outcomes .........................................................................................107 
11.0 
ASSESSMENT OF PHARMACOKINETIC/PHARMACODYNAMIC 
PARAMETERS..............................................................................................................108 
12.0 
ASSESSMENT OF SAFETY ........................................................................................109 
12.1 
Safety Parameters.................................................................................................109 
12.2 
Adverse Events ....................................................................................................109 
12.3 
Adverse Event Reporting .....................................................................................110 
12.3.1 
Notification of Serious Adverse Events ..............................................110 
12.3.2 
Notification of Adverse Events of Special Interest .............................111 
12.3.3 
Notification of Emerging Safety Issues ..............................................111 
12.4 
Definitions............................................................................................................111 
12.4.1 
Adverse Event .....................................................................................111 
12.4.2 
Suspected Adverse Reaction ...............................................................112 
12.4.3 
Life-Threatening AE or Life-Threatening Suspected Adverse 
Reaction...............................................................................................112 
12.4.4 
Serious Adverse Event or Serious Suspected Adverse Reaction ........112 
12.4.5 
Unexpected AE or Unexpected Suspected Adverse Reaction ............113 
12.4.6 
Emerging Safety Issue.........................................................................113 
12.4.7 
Urgent Safety Measure ........................................................................114 
12.5 
Adverse Event Classification ...............................................................................114 
12.5.1 
Relationship to Investigational Drug ..................................................114 
12.5.2 
Severity ...............................................................................................114 
12.5.3 
Serious Adverse Event ........................................................................115 
12.6 
Adverse Event Follow-up ....................................................................................115 
12.7 
Adverse Events of Special Interest ......................................................................115 
12.7.1 
Intravenous Infusion Intolerability ......................................................116 
12.7.2 
Phototoxicity .......................................................................................116 
12.7.3 
Ataxia, Neuropathy, and Tremors .......................................................116 
12.8 
Adverse Event Management ................................................................................116 
12.9 
Risks for Women of Childbearing Potential or During Pregnancy .....................116 
12.10 Risks for Males of Childbearing Potential ...........................................................117 
13.0 
STATISTICAL METHODS .........................................................................................118 
13.1 
Analysis Populations ............................................................................................118 
13.2 
Subject Characteristics .........................................................................................118 
13.3 
Study Drug Exposure ...........................................................................................119 
13.4 
Efficacy Analyses ................................................................................................119 


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13.4.1 
Primary Efficacy Analyses for the FDA .............................................119 
13.4.1.1 
Additional Analyses of the FDA Primary Efficacy Outcome .....120 
13.4.2 
Primary Efficacy Analyses for the EMA ............................................120 
13.4.3 
Secondary Efficacy Analyses ..............................................................122 
13.4.4 
Additional Efficacy Analyses .............................................................123 
13.5 
Safety Analyses ....................................................................................................123 
13.6 
Health Economics Outcome Research .................................................................124 
13.7 
Pharmacokinetic Analyses ...................................................................................124 
13.8 
Determination of Study Sample Size ...................................................................124 
13.9 
Data and Safety Monitoring Board ......................................................................125 
13.10 Handling of Dropouts and Missing, Unused, and Spurious Data ........................125 
13.11 Subject Disposition ..............................................................................................125 
13.12 Deviation Reporting .............................................................................................125 
13.13 Impact of the COVID-19 Pandemic on Analyses ................................................125 
14.0 
INVESTIGATOR REQUIREMENTS ........................................................................127 
14.1 
Protocol Adherence ..............................................................................................127 
14.2 
Electronic Case Report Forms .............................................................................127 
14.3 
Source Document Maintenance ...........................................................................127 
14.4 
Study Monitoring Requirements ..........................................................................127 
14.5 
Study Completion ................................................................................................128 
15.0 
QUALITY CONTROL AND QUALITY ASSURANCE ...........................................129 
16.0 
PROTECTION OF HUMAN SUBJECTS ..................................................................130 
16.1 
Informed Consent.................................................................................................130 
16.2 
IRB/IEC Approval ...............................................................................................130 
17.0 
DATA HANDLING AND RECORD KEEPING ........................................................131 
17.1 
Direct Access to Source Data/Documentation .....................................................131 
17.2 
Study Drug Accountability ..................................................................................131 
17.3 
Retention of Records............................................................................................131 
18.0 
FINANCING AND INSURANCE ................................................................................133 
19.0 
PUBLICATION POLICY .............................................................................................134 
20.0 
REFERENCES ...............................................................................................................135 
21.0 
APPENDICES ................................................................................................................139 


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LIST OF TABLES 
Table 1: 
Schedule of Assessments and Procedures for the Required Treatment, 
End of Treatment, and Follow-up Periods .................................................17 
Table 2: 
Schedule of Assessments and Procedures for the Optional Treatment 
Period .........................................................................................................21 
Table 3: 
Dosing Schedule by Day ............................................................................22 
Table 4: 
Predicted Pharmacokinetic-Pharmacodynamic Target Attainment for 
Rezafungin Regimens, Stratified by Week and Minimal Inhibitory 
Concentration, Against Candida albicans .................................................48 
Table 5: 
Predicted Pharmacokinetic-Pharmacodynamic Target Attainment for 
Rezafungin Regimens, Stratified by Week and Minimal Inhibitory 
Concentration, Against Candida glabrata .................................................49 
Table 6: 
Percent Probabilities of Pharmacokinetic-Pharmacodynamic Target 
Attainment by Anidulafungin, Caspofungin, Micafungin, and 
Rezafungin against Candida spp. ..............................................................50 
Table 7: 
Global Response ......................................................................................103 
Table 8: 
Mycological Response Definitions ..........................................................104 
Table 9: 
Investigator’s Assessment of Clinical Response Definitions ..................106 
Table 10: 
Radiological Response Definitions ..........................................................107 
Table 11: 
Guidelines for Assessing Relationship of Event to Study Drug ..............114 
Table 12: 
Guidelines for Severity Assessment by the CTCAE Version 5.0 ............115 
 
LIST OF FIGURES 
Figure 1: 
Study Design Diagram ...............................................................................14 
Figure 2: 
Dosing Schedule for Required Treatment Period ......................................15 
Figure 3: 
Dosing Schedule for Optional Treatment Period .......................................16 
Figure 4: 
Rezafungin Penetrates and Accumulates at a Higher Level at Site of 
Liver Infection than Micafungin ................................................................37 
Figure 5: 
Predicted Pharmacokinetic-Pharmacodynamic Target Attainment for 
Rezafungin Regimens, Against Candida albicans Relative to MIC 
Distribution ................................................................................................48 
Figure 6: 
Predicted Pharmacokinetic-Pharmacodynamic Target Attainment for 
Rezafungin Regimens, Against Candida glabrata Relative to MIC 
Distribution ................................................................................................49 
 


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3.0 
LIST OF ACRONYMS, ABBREVIATIONS, AND DEFINITIONS OF TERMS 
ACM 
all-cause mortality 
ADL 
activities of daily living 
AE 
adverse event 
AESI 
adverse event of special interest 
ANC 
absolute neutrophil count 
APACHE II 
Acute Physiology and Chronic Health Evaluation  
AUC 
area under the concentration-time curve 
AUC0-t 
area under the concentration-time curve from time 0 to the final sample 
BCRP 
breast cancer resistance protein transporter 
BMI 
body mass index 
CDC 
Centers for Disease Control and Prevention 
CE 
clinically evaluable 
CI 
confidence interval 
Cmax 
maximum plasma concentration 
COVID-19 
Coronavirus disease 2019 
CRRT 
continuous renal replacement therapy  
CTCAE 
common terminology criteria for adverse events 
CYP 
cytochrome P450 
DDI 
drug-drug interaction 
DRC 
Data Review Committee 
DSMB 
Data and Safety Monitoring Board 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
EDC 
electronic data capture 
EOT 
End of Treatment 
EMA 
European Medicines Agency 
ESCMID 
European Society of Clinical Microbiology and Infectious Diseases 
fAUC 
free-drug area under the rezafungin concentration-time curve 
fAUC0-168 
free-drug area under the rezafungin concentration-time curve from time 
0 to 168 hours  
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
GLP 
Good Laboratory Practice 
GS 
1,3-β-D-glucan synthase 
hERG 
human ether-à-go-go-related gene  
IC50 
half maximal inhibitory concentration 


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ICF 
informed consent form 
ICH 
International Council for Harmonisation 
ICU 
intensive care unit 
IDSA 
Infectious Diseases Society of America 
IEC 
Independent Ethics Committee 
IFD 
invasive fungal disease 
IM 
intramuscular 
IME 
important medical event terms 
IND 
investigational new drug 
IP 
intraperitoneal 
IRB 
Institutional Review Board 
IRT 
interactive response technology 
ITT 
intent-to-treat 
IV 
intravenous(ly) 
IVD 
in vitro diagnostic 
KM 
Kaplan-Meier 
LC-MS/MS 
liquid chromatography–tandem mass spectrometry 
LOAEL 
lowest-observed-adverse-effect level 
MAD 
multiple-ascending dose 
MALDI 
matrix-assisted laser desorption ionization 
MALDI-MS 
matrix-assisted laser desorption ionization mass spectrometry 
MALDI-MSI 
matrix-assisted laser desorption ionization mass spectrometry imaging 
MATE 
multidrug and toxin extrusion 
MedDRA 
Medical Dictionary for Regulatory Activities 
MIC 
minimal inhibitory concentration 
MIC50 
minimal inhibitory concentration required to inhibit the growth of 50% of 
the isolates 
MIC90 
minimal inhibitory concentration required to inhibit the growth of 90% of 
the isolates  
mITT 
modified intent-to-treat 
NI 
non-inferiority 
NOAEL 
no-observed-adverse-effect level 
OATP 
organic anion-transporting polypeptide transporter 
OCT 
organic cation transporter 
PCP 
Pneumocystis pneumonia 
PCR 
polymerase chain reaction 
PCS 
potentially clinically significant 


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PD 
pharmacodynamic(s) 
P-gp 
P-glycoprotein transporter 
PI 
Principal Investigator 
PK 
pharmacokinetic(s) 
PT 
Preferred Term 
PT/INR 
Prothrombin Time or International Normalized Ratio 
QTcF 
QT interval corrected for heart rate by Fridericia’s formula 
SAD 
single-ascending dose study 
SAE 
serious adverse event 
SAER 
serious adverse event report 
SAP 
statistical analysis plan 
SARS-CoV-2 
severe acute respiratory syndrome coronavirus 2 
SC 
subcutaneous 
SmPC 
Summary of Product Characteristics 
SOC 
System Organ Class 
SOP 
Standard Operating Procedure 
spp. 
species 
t½ 
half-life 
TEAE 
treatment-emergent adverse event 
Tmax 
time to Cmax 
ULN 
upper limit of normal 
US 
United States 
UV 
ultraviolet 
Vss 
volume of distribution at steady state 
Vz 
volume of distribution 


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4.0 
BACKGROUND AND RATIONALE 
4.1 
Candidemia and Invasive Candidiasis 
Rezafungin for Injection, a new echinocandin antifungal agent, is being developed to treat 
patients with systemic infections caused by Candida species (spp.). These serious and 
life-threatening infections represent a significant public health issue, particularly in highly 
vulnerable patient populations such as the elderly, post-surgical, critically ill, and other 
hospitalized patients with serious medical conditions (Magill 2014; Andes 2012; 
Wisplinghoff 2004). In addition, because of increasing resistance to existing antifungal drugs, 
there is an urgent need to develop new and more effective antifungal agents to treat these serious 
infections (Alexander 2013; Arendrup 2013; Ostrosky-Zeichner 2013; Pfaller 2012). The Centers 
for Disease Control and Prevention (CDC) recently warned that fluconazole-resistant 
Candida spp. have the potential to pose a serious threat to public health (CDC 2013; CDC 2016). 
However, since 2007, no new antifungal agents have been approved for treatment of candidemia 
(The White House 2014; Executive Office of the President 2014; CDC 2013). 
There are currently 3 commercially authorized echinocandins in the United States (US) and the 
European Union (EU): caspofungin, micafungin, and anidulafungin. These echinocandins are 
administered once daily via intravenous (IV) infusion and share similar pharmacokinetic (PK) 
parameters and safety profiles (Eraxis [anidulafungin] Prescribing Information; Mycamine 
[micafungin sodium] Prescribing Information; Cancidas [caspofungin acetate] Prescribing 
Information; Caspofungin acetate Prescribing Information; Ecalta [anidulafungin] Summary of 
Product Characteristics; Mycamine [micafungin sodium] Summary of Product Characteristics; 
Cancidas [caspofungin acetate] Summary of Product Characteristics).  
Caspofungin, the first US Food and Drug Administration (FDA) approved echinocandin, 
originated from the “pneumocandin” series of compounds, so named as they were first 
developed for Pneumocystis pneumonia (PCP), an Ascomycetes fungus with a high amount 
of 1,3-β-D-glucan in cell walls (Balkovec 2014). Development of the drug for this use was 
discontinued when PCP was considered less relevant in autoimmune deficiency syndrome 
(AIDS) patients due to advances in human immunodeficiency virus (HIV) therapy. Development 
was subsequently restarted for treatment of candidemia. 
Echinocandins are considered the first-line therapy for candidemia and invasive candidiasis by 
the Infectious Diseases Society of America (IDSA) guidelines (Pappas 2016) and the European 
Society of Clinical Microbiology and Infectious Diseases (ESCMID) guidelines (Cornely 2012; 
Ullmann 2012), regardless of immunosuppression. 
4.2 
Rezafungin for Injection 
Rezafungin is a novel semi-synthetic echinocandin synthesized from a fermentation product 
of Aspergillus nidulans that is administered by IV infusion. 


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Rezafungin is a water soluble and stable echinocandin with an extended half-life (t½) compared 
with echinocandins that have been approved for marketing. Rezafungin has a choline moiety 
at the C5 position of the 4,5-dihydroxyornithine residue of the cyclic hexapeptide core that 
affords greater stability as a solid, in aqueous buffered solutions, and in plasma relative to 
marketed echinocandins. 
Rezafungin acts through inhibiting the synthesis of 1,3-β-D-glucan, an essential component of 
the fungal cell wall of Candida species and regions of active cell growth of Aspergillus hyphae. 
Because 1,3-β-D-glucan is also present in the asci (cyst) form of Pneumocystis spp., rezafungin 
depletes asci and inhibits the organism from completing sexual reproduction and proliferation. 
The synthesis of 1,3-β-D-glucan is dependent upon the activity of 1,3-β-D-glucan synthase (GS), 
an enzyme complex in which the catalytic subunit is encoded by FKS1, FKS2, and FKS3 genes. 
Inhibition of GS by echinocandins results in rapid, concentration-dependent, fungicidal activity 
for Candida spp. 1,3-β-D-Glucan is not present in mammalian cells. 
Across in vitro studies performed to date, rezafungin consistently demonstrates potent activity 
against Candida spp. and Aspergillus spp. at concentrations comparable to other echinocandins. 
Rezafungin is included in the annual SENTRY international fungal surveillance program. 
In a pooled analysis of the 2016-2018 SENTRY data, rezafungin generated MIC50/90 values 
of 0.03/0.06 µg/mL against Candida albicans, Candida tropicalis, and Candida krusei, 
0.06/0.12 µg/mL against Candida glabrata and Candida dubliniensis, and 1/2 µg/mL against 
Candida parapsilosis. For the subset of 20 characterized fks hot spot mutants (C. glabrata 
n = 17, C. albicans n = 1, and C. tropicalis n = 2), rezafungin minimal inhibitory concentration 
(MIC) values ranged from 0.06–2 µg/mL. Overall, rezafungin activity was comparable to 
activity of anidulafungin, caspofungin, and micafungin, against the same wild-type and fks 
mutant isolates (Pfaller 2020).  
When tested against multiple clinical isolates of wild-type and echinocandin-resistant 
and/or azole-resistant Candida spp., rezafungin activity was similar with that of anidulafungin 
versus all strains tested with minimal inhibitory concentration required to inhibit the growth of 
90% of the isolates tested (MIC90) values ≤1 µg/mL for all species except C. parapsilosis, which 
was 2 µg/mL, consistent with the susceptibility profile of this species to echinocandins. The 
potency of rezafungin against strains with documented fks mutations was 2- to 8-fold greater 
than that of caspofungin and similar with that of anidulafungin. 
The activity of rezafungin was also tested against Candida auris, an emerging fungal pathogen 
that presents a serious global health threat. When evaluated against a CDC panel of 100 C. auris 
isolates representing 4 clades, rezafungin demonstrated strong activity with minimal inhibitory 
concentration required to inhibit the growth of 50% of the isolates (MIC50) and MIC90 values 
of 0.125 and 0.5 µg/mL, respectively (Berkow 2018). 


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4.3 
Nonclinical Efficacy Models 
A series of studies in the neutropenic mouse systemic candidiasis model show that rezafungin 
is efficacious when administered by either the IV, intraperitoneal (IP) or subcutaneous (SC) route 
across a wide range of doses. Dose-dependent reductions of C. albicans kidney burden have been 
observed in all studies. The lowest dose level to achieve a significant reduction in kidney burden 
in this model was 0.5 mg/kg IP and 0.6 mg/kg IV, both given once. Higher doses (≥1 mg/kg) 
have demonstrated a significant reduction in kidney burden relative to vehicle control for up 
to 7 days following a single IP dose. Rezafungin was also shown to be efficacious at doses of 
3 to 30 mg/kg against azole-resistant C. albicans spp. R357 and DPL001 in separate studies. For 
efficacy against echinocandin-resistant C. albicans strains, a heterozygous and a homozygous fks 
mutant strain with elevated minimal inhibitory concentration (MIC) and half maximal inhibitory 
concentration (IC50) values for micafungin and rezafungin were studied. Rezafungin at dose 
levels (10 to 60 mg/kg) selected to estimate the anticipated human exposure of once weekly 
Rezafungin for Injection, was found to be significantly more active than micafungin, especially 
at 48 hours. Against the highly resistant homozygous fks mutant, improved survival was noted 
only in the highest rezafungin dose group suggesting that a high dose of rezafungin may be 
efficacious to control severe echinocandin-resistant candidiasis where administration of the 
human therapeutic exposures of micafungin loses effect. Rezafungin, given IV twice a day for 
5 days in the treatment of murine A. fumigatus septicemia, was associated with a significant 
increase in the 10-day survival compared to the vehicle group. 
In response to C. auris as an emerging fungal pathogen that presents a serious global health 
threat, direct evidence of the in vivo efficacy of rezafungin in animal models of infection was 
obtained. Rezafungin at human exposure equivalent to 400 mg dose (mouse 20 mg/kg IP) was 
effective as treatment in neutropenic mouse models of disseminated C. auris candidiasis as 
measured by increased survival rate or by colony forming unit reduction compared with 
micafungin, amphotericin B, or fluconazole. 
4.4 
Nonclinical Pharmacokinetics 
Rezafungin was found to be stable in liver microsomes from all spp. tested. A cross-species 
stability study also determined that rezafungin is stable in intestinal microsomes and no 
metabolic products were identified during incubations of rezafungin with mouse, rat, monkey, 
or human liver microsomes, indicating good metabolic stability. In vivo, metabolite profiling of 
rat plasma and excreta samples is consistent with in vitro results confirming the lack 
of significant biotransformation. 
The PK profile of rezafungin was investigated in mice, rats, dogs, cynomolgus monkeys, 
and chimpanzees following IV administration, the intended clinical route of administration, 
and also after IP administration to mice, intramuscular (IM) to rats, SC to rats and cynomolgus 
monkeys, and orally to dogs, monkeys, and chimpanzees. Rezafungin consistently exhibited very 
low clearance, modest volume of distribution (Vz) or volume of distribution at steady state (Vss), 
and long t½. Across all spp. tested, rezafungin exhibited a favorable PK profile, mainly 


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attributable to lower clearance (resulting in a longer t½). Additionally, there was low to no drug 
accumulation or gender differences found with rezafungin across all spp. tested after multiple 
doses and routes of administration. 
Tissue distribution of rezafungin was evaluated in rats and mean area under the 
concentration-time curve (AUC) from time 0 to the final sample (AUC0-t) was lowest in brain 
tissue and highest in kidney tissue. Calculation of tissue/plasma AUC ratios indicated exposure 
relative to plasma was comparable between major organs (4- to 5-fold higher in kidney, lung, 
liver, and spleen) with the exception of much lower ratios in tissue from heart and brain (≤1). 
More importantly, rezafungin appears to concentrate within fungal lesions even after the 
majority of drug has been cleared from an infected organ, as shown in a separate study by Perlin 
and colleagues (Zhao 2016). In the study, the authors utilized matrix-assisted laser desorption 
ionization (MALDI) imaging mass spectrometry technology to image kidney and liver 
cross-sections of mice with invasive candidiasis. MALDI imaging allowed for multiplexed 
analysis of different molecules simultaneously in the same tissue section, providing 
semi-quantitative information of fungal lesions and drug localization. From cross-sections 
of liver and kidney, across different time points from 1 to 48 hours, Perlin and colleagues noted 
that rezafungin tissue levels begin to decline after reaching the maximum plasma concentration 
(Cmax) at 6 hours post-dose but increase and concentrate within fungal lesions at later time points 
(24 and 48 hours). 
A second study was carried out using a mouse model of intra-abdominal C. albicans candidiasis 
to determine drug distribution and concentration of rezafungin in infected tissues by 
matrix-assisted laser desorption ionization mass spectrometry imaging (MALDI-MSI) and liquid 
chromatography–tandem mass spectrometry (LC-MS/MS) quantitation in livers and kidneys of 
infected mice (Zhao 2017). C. albicans SC5314 was inoculated at 1×107 CFU in sterile stools 
and saline to induce peritonitis and abscess formation. A single dose of rezafungin at 20 mg/kg 
(equivalent to human 400 AUC exposure) was given on Day 3 post-inoculation and compared 
with once daily treatment of micafungin at 5 mg/kg (equivalent to human 150 mg therapeutic 
exposure) starting on Day 3 post-inoculation, with a total of 3 doses of micafungin administered. 
Livers and kidneys were collected up to 72 hours post first dose of each drug for MALDI 
imaging as well as drug concentration determination. 
It was observed that even as drug levels in the tissue declined, rezafungin was concentrated 
within the lesion 6 hours post-dose in both liver and kidney tissue. For example, it was noted that 
rezafungin had an extensive tissue distribution with a drug level of 80.1 µg/mL in the non-lesion 
part of liver at 6 hours after a single dose treatment at 20 mg/kg (Zhao 2017; Figure 4). 
Importantly, rezafungin was observed to quickly penetrate into abscesses as early as 3 hours 
and rapidly reach the necrotic core interacting with the main fungal population at 6 hours, with 
an average of 31.6 µg/mL drug in lesions (Zhao 2017). Given the long t½ of rezafungin, sustained 
drug penetration and accumulation within the lesion was continuously observed for all remaining 
time points included in the study. At the last time point of 72 hours following a single dose of 
rezafungin, drug levels inside the lesions were still close to 30 µg/mL, about 6-fold higher than 


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that for micafungin at steady-state (after 3 doses). Micafungin was found to penetrate more 
slowly into liver and kidney abscesses and reached detectable levels inside lesions at 6 hours 
after the first dose. The penetration improved upon multiple doses of treatment, and only at 
steady-state were drug signals observed from the necrotic core where a large number of fungal 
cells were found to proliferate. In this in vivo experiment, rezafungin demonstrated superior 
penetration and concentration at the site of the abscess versus micafungin suggesting that 
rezafungin offers the potential to fill an unmet need in invasive candidiasis patients. 
Figure 4: 
Rezafungin Penetrates and Accumulates at a Higher Level at Site of 
Liver Infection than Micafungin 
 
Abbreviations: GMS = Gömöri methenamine silver stain; MALDI-MS = matrix-assisted laser desorption ionization 
mass spectrometry; MCF = micafungin. 
With low clearance, a long t½, widespread penetration into tissues, no biotransformation, 
and extensive excretion as unchanged drug, rezafungin is suitable for once weekly treatment, 
providing high drug exposures relative to other echinocandins for candidemia and invasive 
candidiasis. 
4.5 
Nonclinical Pharmacology and Toxicology 
The summary of nonclinical information is considered accurate as of the date of this protocol 
amendment. The Investigator’s Brochure should be referenced for additional details or updated 
information throughout the study. 


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An overview of information on the efficacy, PK, and toxicology of rezafungin in animal models 
is provided below. Additional nonclinical data is available in the Investigator’s Brochure. 
4.5.1 
Safety Pharmacology 
The summary of safety pharmacology information provided in the protocol is considered 
accurate as of the date of this protocol amendment. The Investigator’s Brochure should be 
referenced for additional details or updated information throughout the conduct of the study. 
In the safety pharmacology studies, rezafungin was tested for effects on neurobehavioral, 
cardiovascular (hemodynamic and electrocardiographic), and respiratory functional endpoints. 
There were no clinical observations or statistically significant changes in neurobehavioral 
parameters or body temperatures that were attributed to administration of rezafungin when 
administered once every 3 days over one week by IV slow bolus to male rats at doses up 
to 45 mg/kg, nor were there changes in the gross behavioral, physiological, or neurological state 
of the animals.  
Rezafungin did not affect human ether-à-go-go-related gene (hERG) current at concentrations up 
to 1.1 μM, the maximum concentration able to be evaluated, which exceeds the estimated free 
drug Cmax in the clinic. At a total Cmax plasma level of 22.68 µg/mL observed in a study in 
healthy human subjects, the free drug Cmax plasma level is 0.43 μM, which is lower than the 
maximum concentration tested in the hERG assay. 
In a study in cynomolgus monkeys, there were no rezafungin-related changes in blood pressure, 
electrocardiographic, or respiratory parameters, or in body temperature, but there was a minimal 
and transient decrease in heart rate relative to vehicle control in restrained cynomolgus monkeys 
at ≥3 mg/kg that was of uncertain relationship to rezafungin. The no-observed-adverse-effect 
level (NOAEL) for cardiovascular and respiratory functions following a 20-minute IV infusion 
of rezafungin to male radio telemetry instrumented cynomolgus monkeys was 10 mg/kg, 
the highest dose tested. 
4.5.2 
Nonclinical Toxicology 
The summary of nonclinical toxicology information provided in the protocol is considered 
accurate as of the date of this protocol amendment. The Investigator’s Brochure should be 
referenced for additional details or updated information throughout the conduct of the study. 
Nonclinical safety of rezafungin was evaluated in 1) single and repeat dose toxicity studies up 
to 4 weeks in duration in rats and cynomolgus monkeys, 2) in vitro and in vivo in genotoxicity 
studies, 3) in vitro and in vivo phototoxicity, and 4) female fertility and early embryonic 
development in pregnant rats and embryo-fetal development in pregnant rats and rabbits. 
Findings from nonclinical toxicology studies are summarized below. The Investigator’s 
Brochure should be referenced for more information. 


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• Adverse toxicology findings were seen only in rats and were related to transient 
elevations in plasma histamine-associated acute clinical signs that were transient after 
the first dose in surviving rats and generally not seen after the third or fourth dose. 
• Important target organ toxicities (hepatotoxicity, renal toxicity, and skeletal muscle 
changes) reported with marketed echinocandins were not seen with rezafungin. 
• Rezafungin did not affect the gross behavioral, physiological, or neurological state of 
rats. 
• In a combined cardiovascular and respiratory study in cynomolgus monkey, there 
were no rezafungin-related changes in blood pressure, electrocardiogram (ECG) 
and respiratory parameters, and body temperature. 
• Mild rezafungin-induced hematological changes observed in rats primarily at the high 
dose, were not associated with histopathology, were not considered adverse, and were not 
seen in monkeys. 
• Minor clinical chemistry changes were noted in rats and monkeys at the higher doses 
used in the toxicology studies. 
• Rezafungin caused local vascular irritation in rats, but not in monkeys; local vascular 
injury in rats was confined to high dose males during the 4-week toxicity study. 
• Dose-related and transient acute histamine-mediated effects in rats associated with 
mortality at 15 and 45 mg/kg. The NOAEL for these Cmax-driven acute effects was 
5 mg/kg, which generated Cmax values of 8.04 and 10.4 µg/mL, in males and females 
respectively, after the first dose. These species-specific (rat) histamine effects are 
consistent with observations for marketed echinocandins. 
• In a fertility study in male rats, no rezafungin-related effects were seen on reproductive 
performance up to the highest dose tested (45 mg/kg), dose-related lower mean sperm 
motility, concentration, and/or increased incidence of abnormal sperm morphology, 
along with microscopic findings of testicular seminiferous tubular epithelial degeneration 
associated with an effect on spermiation were noted at ≥30 mg/kg. Based on these data, 
the NOAEL for male reproductive toxicity was 15 mg/kg (2.5-fold over the estimated 
steady state plasma level in humans at 200 mg). Based on the lack of any effects on 
intrauterine survival in females at any dosage level, the NOAEL for early embryonic 
toxicity was 45 mg/kg, the highest dose evaluated. 
• Rezafungin was administered IV to cynomolgus monkeys at 3, 10, 30, and 60/45 mg/kg 
once every 3 days for 3 consecutive months. The high dose of 60 mg/kg was lowered to 
45 mg/kg on Day 42 (during the seventh week of dosing) due to unexpected 
neurobehavioral effects and the 60/45 mg/kg group females were terminated on Day 49 
(during the eighth week of dosing) due to adverse clinical observations, including severe 
tremors. Throughout the remainder of the study, dose-related incidence of slight to 
moderate tremors were observed sporadically at ≥30 mg/kg. These lower grade tremors 
did not interfere with the daily normal function of the animals and demonstrated 


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reversibility during the recovery period and were therefore considered non-adverse. 
Rezafungin-related microscopic findings of Schwann cell inclusions (interpreted as 
phospholipidosis) were noted in the sensory ganglia at ≥3 mg/kg and in peripheral nerves 
at ≥30 mg/kg, with partially reversible Schwann cell hyperplasia in the ganglia at 
≥30 mg/kg; both changes are considered adaptive and nonadverse. Transmission electron 
microscopy confirmed the presence of phospholipidosis in Schwann cells and found no 
evidence of axonal degeneration or axonopathy.   
• The NOAEL level for neuropathology in monkeys is 30 mg/kg, which is approximately 
11.4-fold over the human plasma exposure. 
• As a follow-up to the 13-week GLP monkey study, an investigative 13-week study in 
female monkeys was conducted to evaluate the onset of neurotoxicity, through detailed 
neurobehavioral assessments and quantitative measures of nerve conduction velocities 
and amplitudes, as well as histopathological changes, and reversibility of any findings 
over a longer recovery period (13-weeks). Neurobehavioral findings consisted of barely 
perceptible (slight to moderate) tremors in limbs of all animals administered 30 mg/kg 
rezafungin beginning at Week 4; tremors reversed in all recovery group animals by 
recovery Day 30. Nerve conduction findings consisted of no change in nerve conduction 
pre-dose and after 5 and 8 weeks of dosing. After 13 weeks of dosing, minimal changes 
(<10% decrease in conduction) of peroneal motor nerve and sural sensory nerve; cauda 
equina measure was similar between rezafungin and control groups. Clear evidence of 
full recovery was observed in peroneal and sural nerve conduction measures by first 
assessment in recovery Week 7. Nervous system histopathology (after 13 weeks of 
dosing) consisted of Schwann cell inclusions (considered lysosomal accumulations of 
myelin/lipids). However, as evidenced in the initial GLP 13-week study, there was no 
evidence of axonal degeneration, thinning of myelin sheaths, or demyelination in the 
13-week investigative study, corroborating these findings.   
• Rezafungin was negative for mutagenic activity and induction of chromosome 
aberrations in vitro, and did not increase micronucleated polychromatic erythrocytes 
in the in vivo bone marrow micronucleus study in rats. 
• Rezafungin induced a phototoxicity response in vitro and in rats in which multiple doses 
generated a minimal phototoxic response at plasma concentrations 3.6-fold above those 
achieved clinically. 
4.6 
Clinical Pharmacology 
The summary of clinical pharmacology information provided in the protocol is considered 
accurate as of the date of this protocol amendment. The Investigator’s Brochure should be 
referenced for additional details or updated information throughout the conduct of the study. 


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Long Half-Life and Dose-Proportional 
The plasma PK of rezafungin was generally well-characterized following single doses of 50, 
100, 200, and 400 mg (Studies CD101.IV.1.01 and CD101.IV.1.02). Exposure to rezafungin 
increased with increasing Rezafungin for Injection doses. Time to reach maximum plasma 
concentration (i.e., Tmax) was observed at the end of infusion, as expected, at approximately 
1 hour after the start of study drug infusion for all doses. Elimination of rezafungin appears 
multiphasic. Area under the concentration-time curve (AUC) and Cmax increased in a dose 
proportional manner indicating linear kinetics. Total body clearance was slow (approximately 
0.2 L/h) throughout the dose levels with a long apparent terminal half-life (t½ ranged from 
127-146 hours). Volume of distribution (Vz) and volume of distribution at steady state (Vss) 
ranged from 33 to 48 L. The fraction of dose excreted in urine was <1% at all dose levels, 
indicating minor contribution of renal clearance in rezafungin excretion. The plasma PK of 
rezafungin was well characterized following 2 or 3 once weekly doses of rezafungin: 100 mg 
on Days 1 and 8; 200 mg on Days 1 and 8; and 400 mg on Days 1, 8, and 15. Exposures 
following the first dose were comparable to that observed in the single ascending dose (SAD) 
study, with AUC and Cmax generally increasing in a dose proportional manner. Minor 
accumulation was observed for the 400 mg dose; 1.74-fold as measured by Cmax ratio 
or 1.55-fold as measured by the area under the concentration time-curve from time 0 to 
168 hours (AUC0-168) ratio of last/first dose after 3 doses. 
Lack of Drug-Drug Interactions 
Pharmacokinetic results were obtained in a drug-drug interaction (DDI) study 
(Study CD101.IV.1.09) in 26 healthy subjects to assess effect of rezafungin on several 
substrates of cytochrome P450 (CYP) enzymes and/or drug transport proteins. Subjects 
were dosed each of three cocktails (tacrolimus and repaglinide; metformin, rosuvastatin, 
and pitavastatin; caffeine, efavirenz, midazolam, and digoxin) alone and in combination with 
rezafungin in a single sequence crossover study. Rezafungin was dosed at 600 mg on Day 1, 
and at 400 mg once weekly for two weeks to match peak exposure at the highest dose tested in 
Phase 2 with the first and subsequent doses. The geometric mean ratio of and 90% confidence 
interval (CI) for each probe drug when administered with rezafungin relative to when the probe 
drug given alone were largely within the default no effect boundary of 80–125%. No clinically 
significant drug interactions were observed, and no dose adjustments were necessary for these 
agents when combined with rezafungin. 
Elimination Primarily Non-Renal, with Inactive Metabolites Excreted in Urine 
During a study with [14C]rezafungin for Injection (Study CD101.IV.1.12), the radiocarbon was 
primarily excreted in feces. Based on interpolated data (using data from the subjects’ return visits 
to the clinical research unit [CRU] on Days 29 and 60), it was estimated that the majority of the 
dose (an overall mean estimate of 88.3%) would have been recovered had the subjects been 
continuously confined to the clinic through Day 60. Approximately 74.3% of this total was 


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recovered in feces and the total in urine was 25.7%, indicating that elimination is primarily 
nonrenal.  
Radiochemical analysis indicated that radioactivity in urine was primarily due to metabolites 
hydroxylated (in one of three positions) or dealkylation (resulting in des-pentyl), whereas 
radioactivity in feces was primarily rezafungin. In plasma, metabolites were present at low levels 
relative to parent. The AUC of rezafungin accounted for ~77% of total radiocarbon AUC, with 
individual metabolites accounting for less than 10% each. 
Based on a lack of correlation between creatinine clearance and rezafungin PK in a population 
PK analysis, renal elimination does not appear to be an important route of elimination for 
rezafungin. Therefore, no adjustment of dose is proposed for subjects with renal impairment. 
No Effect on QT Interval 
Rezafungin for Injection, in single doses up to 1400 mg did not prolong the QT interval 
(Study CD101.IV.1.06). There were no clinically significant findings in other cardiac 
parameters, including heart rate, PR interval, and QRS interval, between Rezafungin for 
Injection 600 mg or 1400 mg and placebo. 
Echocardiogram results post-dose were normal in all subjects indicating no effect on cardiac 
contractility or ejection fraction for single doses of rezafungin up to 1400 mg. 
Mild Increased Photosensitivity 
Due to results from a nonclinical phototoxicity study in rats, the photosensitivity of Rezafungin 
for Injection was examined in an assessor-blinded Phase 1 study (Study CD101.IV.1.07), with 
a 400 mg once weekly regimen administered (which provided almost double the exposure 
compared to the Phase 3 and proposed marketed dose regimen of 400 mg during the first week 
followed by 200 mg once weekly thereafter). The study demonstrated that within skin types 
and across multiple time points, there was mildly increased photosensitivity to rezafungin. One 
subject in the Phase 2 study (Study CD101.IV.2.03) had a treatment-emergent adverse event 
(TEAE) of sunburn following substantial sun exposure potentially representing photosensitivity. 
Future rezafungin subjects and patients are advised to avoid sun exposure and other sources of 
ultraviolet (UV) radiation without adequate protection. Photosensitivity is an adverse event of 
special interest (AESI), and investigators should report any AE potentially related to 
photosensitivity to the Sponsor. 
4.7 
Overview of Clinical Experience 
The summary of clinical safety and efficacy information provided in the protocol is considered 
current and accurate as of the date of this protocol amendment. The Investigator’s Brochure 
should be referenced for additional details or updated information throughout the conduct of the 
study. 


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4.7.1 
Overview of Clinical Safety 
In the Phase 2 STRIVE study (CD101.IV.2.03), there were no notable differences in TEAEs 
across the study groups. Between the rezafungin groups, there were no dose-related patterns in 
study drug-related TEAEs, severe TEAEs, serious adverse events (SAEs), related SAEs, or SAEs 
leading to death. There were no discernable differences between TEAE categories observed for 
the Rezafungin for Injections groups compared to caspofungin with the exception of the higher 
study drug discontinuation for the Rezafungin for Injection regimen of 400 mg once weekly up 
to 4 weeks, a higher dosing regimen than the one selected for ongoing or future studies. Most 
adverse events (AEs) were mild or moderate in severity. 
Adverse Events from tremor or neuropathy were equally represented between rezafungin 
and caspofungin arms (3%) in the Phase 2 STRIVE study. 
There was one episode of infusion reaction in the Phase 2 study that occurred with the fourth 
dose in the 400 mg once weekly dosing group. All symptoms resolved after stopping the infusion 
with no further interventions. The infusion was not restarted.  
In the Phase 1 multiple ascending dose study, 4 subjects in the Rezafungin for Injection group 
experienced mild, transient infusion reactions, characterized by flushing, sensation of warmth, 
nausea, and chest tightness. These infusion reactions were associated primarily with the third 
400 mg once weekly dose, occurred within minutes of infusion initiation, and disappeared within 
minutes without interruption or discontinuation of the study drug infusion. No pharmacological 
or procedural interventions were required or instituted for the infusion reactions. In another 
Phase 1 study (CD101.IV.1.07), an infusion reaction occurred during the fourth dose of a 400 mg 
once weekly for 4 weeks regimen. The third dose had been administered only 3 days prior 
(instead of 7 days) due to a delay in the return of the subject to the clinic. Symptoms of the 
infusion reaction resolved within a few minutes of infusion interruption without pharmacological 
interventions. The infusion was then restarted and completed at half the usual infusion rate with 
no resulting adverse symptoms or signs. 
The Investigator’s Brochure can be referenced for more details on the safety of rezafungin. 
4.7.2 
Overview of Clinical Efficacy 
In the Phase 2 STRIVE study, demographics were generally balanced across the groups with no 
differences in sex, race, ethnicity, or age that would appreciably affect clinical efficacy. 
Diagnosis at study entry was 79.2% candidemia and 20.8% invasive candidiasis with reasonable 
balance across the treatment groups. The study demonstrated efficacy for Rezafungin for 
Injection comparable to standard of care at Day 14 for all endpoints. The Rezafungin for 
Injection regimen starting with a 400 mg once weekly loading dose followed by 200 mg once 
weekly for a total of 2 to 4 doses, had robust results for the primary endpoint of overall success 
compared with standard of care (Rezafungin for Injection, 76.1%; caspofungin, 67.2%). 


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Secondary endpoints of mycological success, Investigator assessment of clinical cure, 
and all-cause mortality supported the primary endpoint. 
4.8 
Summary of Benefits and Risks 
4.8.1 
Known Benefits 
There are no known benefits of treatment with Rezafungin for Injection as of the date of the 
original protocol for this study. 
The therapeutic benefits of caspofungin and fluconazole for the treatment of fungal infections are 
documented in the prescribing information and published literature. Approximately half of the 
subjects enrolled in this study will be randomized to receive IV caspofungin with the option of 
oral fluconazole step-down therapy. 
4.8.2 
Potential Benefits 
In the Phase 2 STRIVE study, efficacy for Rezafungin for Injection was comparable to standard 
of care at Day 14 for all endpoints. 
4.8.3 
Known Risks 
Infusion reactions characterized by flushing, shortness of breath, and nausea have been observed 
with rezafungin and are similar to infusion reactions noted with other echinocandins. Symptoms 
of the infusion reaction may resolve without intervention or with either slowing of the infusion 
rate or interruption of the infusion. 
Mild photosensitivity to ultraviolet (UV) light has been demonstrated in subjects administered 
rezafungin in a Phase 1 clinical trial. Subjects should use measures to reduce sun and other UV 
light exposure while on study drug, and for 5 half-lives (approximately 30 days) after the last 
dose of rezafungin administered.  
The Investigator’s Brochure should be referenced for additional details or updated information 
throughout the conduct of the study. 
4.8.4 
Potential Risks 
Echinocandins are typically well tolerated (Eraxis [anidulafungin] Prescribing Information; 
Mycamine [micafungin sodium] Prescribing Information; Cancidas [caspofungin acetate] 
Prescribing Information). Potential drug class effects include risk of abnormal liver function 
tests, hepatitis, and hepatic failure. General and administration site events (infusion related 
reactions, peripheral edema, rigors, infusion site inflammation, and pyrexia) have been reported 
for echinocandins (Eraxis [anidulafungin] Prescribing Information; Mycamine [micafungin 
sodium] Prescribing Information; Cancidas [caspofungin acetate] Prescribing Information). 
Possible histamine-mediated symptoms have been reported in patients who received rapid 
infusions of echinocandins, including rash, urticaria, flushing, pruritus, dyspnea, hypotension, 


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facial swelling, and vasodilation. Anaphylactic-like reactions have been reported with 
micafungin (Mycamine [micafungin sodium] Prescribing Information). While uncommon, 
subjects with a history of hypersensitivity to caspofungin or its excipients, including but not 
limited to anaphylaxis and exfoliative skin disorders, should be excluded from this study. 
Based on a fertility study in male rats, there is the potential risk for decreased sperm motility, 
increased incidences of abnormal sperm morphology, and testicular seminiferous tubular 
epithelial degeneration. These findings were noted at 2.5-fold the exposure (the estimated steady 
state plasma level in humans at 200 mg) for Rezafungin subjects in this clinical trial, who will 
receive 400 mg once weekly loading dose followed by 200 mg once weekly for a total of 2 to 4 
doses. The risk to humans is unknown, thus the male contraception requirements in inclusion 
criterion 4 prohibit unprotected sexual intercourse and sperm donation within the study period 
and for 90 days thereafter (and a total of 120 days from the last dose of study drug). This risk is 
included in the informed consent form (ICF).  
No major findings occurred in monkeys after 4 weeks of dosing at 30 mg/kg, the highest dose 
tested. Therefore, for the 3-month toxicity study in monkeys the high dose was increased to 
60 mg/kg. Unexpected tremors occurred during the sixth week of dosing that led to lowering 
the high dose from 60 to 45 mg/kg. Beginning the seventh week of dosing, tremors began at 
30 mg/kg, though much less frequently than in the 60/45 mg/kg group. The low-grade tremors at 
30 mg/kg did not interfere with the daily function of the animals, and demonstrated reversibility 
during the recovery period; therefore, they were considered non-adverse. Due to presence of 
tremors, a detailed neuropathology assessment was performed including whole body perfusions 
and evaluations of plastic embedded and/or silver stained sections of peripheral nerves/axons 
and sensory ganglia. Dose-related microscopic findings of Schwann cell phospholipidosis 
(determined by electron microscopy) were observed in the ganglia (≥3 mg/kg) and peripheral 
nerves (≥30 mg/kg) and dose-related Schwann cell hyperplasia was observed in the ganglia at 
≥30 mg/kg; hyperplasia partially reversed but phospholipidosis was still present at the end 
of a 4-week recovery period.  
A follow-up 3-month investigative monkey study with a 3-month recovery period at 30 mg/kg 
(NC-154), confirmed the presence of a slight-moderate non-adverse tremoring but no adverse 
change in nerve conduction. Phospholipidosis in Schwann cells was identified, no change in 
myelin-to-axon nerve ratios was found, and no hyperplasia of Schwann cells was observed. 
These findings confirmed lack of neuronal and central nervous system microscopic changes, 
including no primary axonal degeneration/axonopathy. Tremoring reversed after 1 month of 
recovery but Schwann cell phospholipidosis was still present at the end of a 3-month recovery 
period. No other rezafungin-related microscopic changes, including no changes in neurons of the 
sensory ganglia or structures within the spinal cord or brain, were observed in monkeys. Given 
the high exposure relative to the Rezafungin for Injection dosing regimen, the risk to study 
subjects is assessed as low. Exclusions and higher acuity neurological monitoring measures have 
been included in the protocol to protect patients. 
  


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Because there may be unknown and potential risks with administration of Rezafungin for 
Injection, all subjects will be closely monitored for safety and tolerability by repeated assessment 
of clinical, vital signs, ECGs, and clinical laboratory safety parameters and reporting of AEs. 
Additionally, there are AESIs, for which investigators will be trained to monitor closely 
and thorough investigations will occur (see Section 12.7). Finally, an independent Data 
and Safety Monitoring Board (DSMB) will review all safety parameters throughout the study. 
4.8.5 
Mitigation of Risks 
Due to findings of toxicity at elevated exposures in nonclinical toxicology studies and AEs noted 
in clinical studies, special measures have been instituted in this protocol.  
For the risk of an infusion reaction typically associated with echinocandins, the option to slow 
the infusion rate to alleviate symptoms has been included in this protocol. This is listed as 
an AESI and will entail a thorough assessment if it occurs. 
For the risk of photosensitivity with sun exposure, the Sponsor has notified investigators of the 
findings and added wording to the ICF for subjects to use measures to reduce sun exposure 
and other types of UV radiation while on study drug, and up to 30 days post dose. This is listed 
as an AESI and will entail a thorough assessment if it occurs. 
For the spermatogenesis findings in the nonclinical studies, all subjects will be informed 
of the risks in the informed consent and will be prohibited from unprotected sexual intercourse 
and sperm donation during the conduct of the study and for 90 days thereafter, and at least 
120 days from the last dose of study drug. 
For the neurologic findings in the 13-week cynomolgus monkey toxicology study, this protocol 
has enhanced exclusion criteria, physical exam monitoring including periodic neurological 
exams, and use of an independent DSMB to protect those who are potentially at the greatest risk 
of developing a neurological AE secondary to rezafungin use. 
4.9 
Justification for Dosing Regimen 
4.9.1 
Rezafungin for Injection 
A population PK model has been developed for rezafungin (Lakota 2018). Data from a subset of 
Phase 2 Part A data as well as data from a Phase 1 study was added to update the structural 
model and evaluate covariate effects. Preliminary data from the modeling was used to set doses 
for this study. 
In brief, these data were best described using a 4-compartment model with 0-order drug input 
via the IV infusion and first-order, linear elimination. This model fit the observed data with very 
little bias and excellent precision. 
Monte Carlo simulations for 2000 hypothetical patients were conducted to assess the 
probability of PK/PD target attainment using the weekly free-drug area under the rezafungin 


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concentration-time curve (fAUC) from time 0 to 168 hours (fAUC0-168) after each dose for the 
two dosing regimens tested in Part A; albumin, weight, and sex were bootstrapped (using random 
sampling and replacement) from the dataset of subjects and plasma protein binding of 97.4% was 
used. 
Nonclinical studies of C. albicans infection models in mice have shown that a rezafungin 
free-drug fAUC:MIC is the PK/PD parameter most predictive of efficacy, and fAUC0-168:MIC 
targets have been established in the mouse model for important pathogenic Candida spp. 
The PK/PD target attainment for the 2 regimens used in Part A (400 mg once weekly 
for 2 to 4 weeks and a 400 mg loading dose on Week 1 followed by 200 mg once weekly 
for a total of 2 to 4 weeks) relative to the reported MIC distribution (Pfaller 2020) is shown 
in Table 4 and Figure 5 for C. albicans and in Table 5 and Figure 6 for C. glabrata. Both 
regimens provided adequate PK/PD target attainment throughout 4 weeks of dosing, up to a MIC 
of 0.5 µg/mL for C.albicans, and up to an MIC of 16 µg/mL for C. glabrata. The 400 mg once 
weekly dosing regimen seems to provide some additional benefit in terms of target attainment, 
improving by 40 to 70% for an MIC = 1, but not until Week 2 or beyond. However, most of the 
benefits of antifungal treatment occur in the first week of therapy, and the incremental 
improvement for the 400 mg once weekly dose regimen for Weeks 2 and 3 will likely be of little 
real clinical benefit in the treatment of candidemia or invasive candidiasis. In fact, in comparison 
to other echinocandins, the 400 mg loading dose on Week 1, followed by 200 mg once-weekly 
dose regimen provides a significant advantage in terms of potential to cover pathogens with 
higher MICs (Table 6). 
The data from Part A indicate that both rezafungin regimens were comparable to each other 
and to caspofungin for efficacy and safety. There were no AEs that seemed to cluster in the 
400 mg once weekly group to indicate any concern for increased toxicity with the higher dose. 
However, the Phase 1 results do indicate that there are infusion reactions that can occur in the 
higher dose rezafungin regimen that are an echinocandin class effect and are related to the rate 
of infusion (mg/min). Thus, given there is no apparent clinical benefit to the 400 mg once weekly 
dose regimen over the regimen with a 400 mg loading dose in Week 1, followed by 200 mg once 
weekly, and that both options provide at least a three dilution MIC improvement in target 
attainment over the best of the currently approved echinocandins (Table 6), the regimen of 
a 400 mg loading dose in Week 1, followed by 200 mg once weekly for a total of 2 to 4 doses 
can be selected for safety and efficacy in the treatment of candidemia and/or invasive 
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Table 4: 
Predicted Pharmacokinetic-Pharmacodynamic Target Attainment for 
Rezafungin Regimens, Stratified by Week and Minimal Inhibitory 
Concentration, Against Candida albicans 
Regimen a 
Week 
MIC (mg/L) b 
0.06 
0.12 
0.25 
0.5 
1 
2 
400/400 
1 
100 
100 
100 
98.8 
35.1 
0.05 
2 
100 
100 
100 
99.95 
73.4 
2.45 
3 
100 
100 
100 
100 
84.3 
7.1 
4 
100 
100 
100 
100 
88.3 
10.75 
400/200 
1 
100 
100 
100 
98.8 
35.1 
0.05 
2 
100 
100 
100 
92.55 
14.95 
0 
3 
100 
100 
100 
91.05 
14.45 
0 
4 
100 
100 
100 
90.55 
15 
 
Abbreviation: MIC = minimal inhibitory concentration; PD = pharmacodynamic; PK = pharmacokinetic. 
a. 
Regimens defined by the weekly dose (e.g., 400/200 represents 400 mg for the first dose, followed by 200 mg IV once 
weekly). 
b. 
Shaded cells indicate PK/PD target attainment above 90%. 
Figure 5: 
Predicted Pharmacokinetic-Pharmacodynamic Target Attainment for 
Rezafungin Regimens, Against Candida albicans Relative to MIC 
Distribution 
 


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Table 5: 
Predicted Pharmacokinetic-Pharmacodynamic Target Attainment for 
Rezafungin Regimens, Stratified by Week and Minimal Inhibitory 
Concentration, Against Candida glabrata 
Regimen a 
Week 
MIC (mg/L) b 
0.12 
0.5 
2 
4 
8 
16 
400/400 
1 
100 
100 
100 
100 
100 
100 
2 
100 
100 
100 
100 
100 
100 
3 
100 
100 
100 
100 
100 
100 
4 
100 
100 
100 
100 
100 
100 
400/200 
1 
100 
100 
100 
100 
100 
100 
2 
100 
100 
100 
100 
100 
100 
3 
100 
100 
100 
100 
100 
100 
4 
100 
100 
100 
100 
100 
98.65 
Abbreviation: MIC = minimal inhibitory concentration; PD = pharmacodynamic; PK = pharmacokinetic. 
a. Regimens defined by the weekly dose (e.g., 400/200 represents 400 mg for the first dose, followed by 200 mg once weekly). 
Shaded cells indicate PK/PD target attainment above 90%. 
Figure 6: 
Predicted Pharmacokinetic-Pharmacodynamic Target Attainment for 
Rezafungin Regimens, Against Candida glabrata Relative to MIC 
Distribution 
 


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Table 6: 
Percent Probabilities of Pharmacokinetic-Pharmacodynamic Target 
Attainment by Anidulafungin, Caspofungin, Micafungin, and 
Rezafungin against Candida spp. 
MIC 
(µg/mL) 
Anidulafungin 
Caspofungin 
Micafungin 
Rezafungin* 
C. albicans
C. glabrata
C. albicans C. glabrata C. albicans C. glabrata
C. albicans
C. glabrata
0.008 
100a 
100a 
100a 
100a 
99.4a 
100a 
100a 
100a 
0.015 
99.1a 
100a 
100a 
100a 
71.2 
100a 
100a 
100a 
0.03 
52.7b 
99.2a 
100a,b 
100a 
10.1b 
97.5a,b 
100a,c 
100a,c 
0.06 
0.90 
54.3 
97.9a 
100a,b 
0.10 
49.9c 
100a,b 
100a 
0.12 
0 
0.95b,c 
76.7 
100a,c 
0 
3.4 
100a 
100a,b 
0.25 
0c 
0 
35.7c 
100a 
0c 
0 
100a 
100a 
0.5 
0 
0 
12.1 
97.0a 
0 
0 
90.55a 
100a 
1 
0 
0 
4.4 
73.2 
0 
0 
15 
100a 
2 
0 
0 
1.35 
33.9 
0 
0 
0 
100a 
4 
0 
0 
0.25 
11.3 
0 
0 
0 
100a 
8 
0 
0 
0.05 
4.35 
0 
0 
0 
100a 
Abbreviations: C. = Candida; MIC = minimal inhibitory concentration; MIC90 = minimal inhibitory concentration 
required to inhibit the growth of 90% of the isolates; PD = pharmacodynamic; PK = pharmacokinetic. 
a
Shaded cells indicate PK-PD target attainment values ≥90%. 
b
Bolded values represent the susceptible breakpoints for each agent against the respective Candida spp. 
c
Cells with bolded outlines represent the MIC90 values for each agent against the respective Candida spp. 
* 
400/200/200/200 at wk 4
Note: MIC and target attainment data for other echinocandins (Bader 2016).
4.9.2 
Caspofungin with Option for Oral Step-Down Regimen of Fluconazole 
Treatment regimens with caspofungin and fluconazole are consistent with standard of care 
regimens in approved labeling (Cancidas [caspofungin acetate] Prescribing Information; 
Diflucan [fluconazole] tablets Prescribing Information). 
4.10 
Population to be Studied 
Adult subjects with candidemia and/or invasive candidiasis. 


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4.11 
Rationale for Use of Rezafungin for Injection in Candidemia and Invasive 
Candidiasis 
Candidemia is a fungal bloodstream infection usually affecting patients who are already ill with 
other comorbidities. Invasive candidiasis defines a number of different organ-specific infections 
with Candida spp. Candidemia and invasive candidiasis may present without the other syndrome 
or may exist together as part of the same pathophysiology of disseminated candidiasis. Risk 
factors for candidemia and invasive candidiasis include recent surgery, organ and bone marrow 
transplants, broad-spectrum antibiotic use, receipt of total parenteral nutrition, end stage renal 
disease, indwelling vascular catheters or other devices, etc. While candidemia is often associated 
with other forms of invasive candidiasis, including intra-abdominal abscess, peritonitis, 
or pleuritic involvement, candidemia without other overt organ involvement is the most common 
form of invasive candidiasis diagnosed. A recent study by the ESCMID Fungal Infection Study 
Group reported the incidence of candidemia as 6.9 per 1000 intensive care unit (ICU) patients 
with mortality rates between 20% and 49% (Kett 2011; Gudlaugsson 2003; Arendrup 2011). 
Candidemia and invasive candidiasis are serious and potentially life-threatening infectious 
complications that require aggressive and timely antifungal management. 
The current IDSA and ESCMID guidelines recommend echinocandins as first-line therapy for 
candidemia and most forms of invasive candidiasis (Pappas 2016; Cornely 2012). There are 
currently 3 commercially authorized echinocandins in the US and the European Union: 
caspofungin, micafungin, and anidulafungin. These echinocandins are administered once daily 
via IV infusion and share similar PK parameters and safety profiles. Rezafungin is a novel 
echinocandin derived from another echinocandin (anidulafungin). Rezafungin has a more stable 
molecular structure compared to the other echinocandins, which results in a reduction in the 
formation of toxic metabolites and an improvement in the duration of exposure to active drug. 
This stability further translates into a potentially improved safety profile as demonstrated in 
both nonclinical and clinical studies, as well as a unique PK profile that allows for high dose, 
front-loaded exposures for improved fungal killing and once weekly IV dosing. 
Both in vitro and in vivo data have demonstrated the potency and efficacy of rezafungin against 
Candida and disseminated candidiasis (Section 4.1 and Investigator’s Brochure). In all 
nonclinical efficacy studies performed for Rezafungin in neutropenic disseminated candidiasis, 
rezafungin has performed as well as, or better than, currently approved echinocandin 
comparators. Furthermore, nonclinical data indicate the exposure of rezafungin is substantially 
higher in infected tissues compared to other echinocandins, indicating the potential to improve 
outcomes in invasive candidiasis (Zhao 2017). The completed Part A of the Phase 2 study 
demonstrated efficacy for Rezafungin for Injection comparable to standard of care at Day 14 for 
all endpoints. The Rezafungin for Injection regimen starting with a 400 mg once weekly loading 
dose followed by 200 mg once weekly for a total of 2 to 4 doses, had robust results for the 
primary endpoint of overall success compared with standard of care (Rezafungin for Injection, 
71.0%; caspofungin, 64.3%). Additionally, the Phase 2 results for Part A also indicated that 
Rezafungin for Injection appears to be well-tolerated at 400 mg once weekly and at 400 mg 


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loading dose Week 1 followed by 200 mg once weekly. In PK and PD models, the proposed 
Rezafungin for Injection dosing regimens for this Phase 3 study demonstrate 100% target 
attainment of wild-type C. albicans and C. glabrata (C. albicans data is presented in 
Section 4.9). The duration of antifungal therapy in standard practice depends on the time it takes 
to clear the Candida from infected blood or tissues, and thus patients with invasive candidiasis 
often require a longer duration of therapy than patients with candidemia alone. To that end, all 
subjects in this study must be administered study drug for at least 14 days followed by an 
optional third or fourth week of treatment if clinically indicated. 
This Phase 3 study is intended to confirm the efficacy and safety of Rezafungin for Injection 
administered at 400 mg loading dose in Week 1 followed by 200 mg once weekly for the 
treatment of patients with candidemia and/or invasive candidiasis. 
4.12 
Statement of Compliance 
This study will be conducted in compliance with the protocol, Good Clinical Practice (GCP), 
the ethical principles of the Declaration of Helsinki, and applicable regulatory and Institutional 
Review Board (IRB) or Independent Ethics Committee (IEC) requirements. 


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5.0 
STUDY OBJECTIVES 
The primary objectives of this study 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 
(US 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 mITT population (European Medicines 
Agency [EMA] primary objective) 
The secondary objectives of this study are to: 
• 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), End of Treatment (EOT) (≤2 days of last dose), and Follow-up 
(Days 52–59) in the mITT population 
• Compare mycological eradication for 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) in the mITT population 
• Compare clinical cure as assessed by the Investigator for 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) in the mITT population 
• Compare 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) in the mITT population 
• Compare the safety and tolerability for subjects receiving Rezafungin for Injection 
and caspofungin in the safety population 
• Evaluate the PKs of Rezafungin for Injection 
An exploratory objective of this study is to: 
• Compare resolution of systemic signs attributable to candidemia and/or invasive 
candidiasis for subjects receiving Rezafungin for Injection and caspofungin at Day 5, 
Day 14 (±1 day), Day 30 (-2 days) and Follow-up Days (52–59) in the mITT population 


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6.0 
STUDY DESIGN 
6.1 
Description of the Study 
The study design figure is provided in Figure 1. The Schedule of Assessments and Procedures 
for the Required Treatment, EOT, and Follow-up Periods is presented in Table 1 and the 
Schedule of Assessments and Procedures for the Optional Treatment Period is presented in 
Table 2. 
This is a Phase 3, multicenter, prospective, randomized, double-blind, efficacy and safety study 
of Rezafungin for Injection (IV) versus a comparator regimen of caspofungin (IV) followed by 
optional oral fluconazole step-down therapy in subjects with candidemia and/or invasive 
candidiasis. Subjects will be randomly assigned (1:1 ratio) to receive either Rezafungin for 
Injection or caspofungin. After ≥3 days IV 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 step-down therapy by the Investigator if they meet the oral step-down therapy 
criteria. 
6.1.1 
Subjects Randomized to Rezafungin for Injection 
Subjects randomized to Rezafungin for Injection will receive a 400 mg loading dose in Week 1, 
followed by 200 mg once weekly, for a total of 2 to 4 doses. To maintain the blind, subjects will 
also receive daily placebo to match for caspofungin IV, which will be administered on Days 2–7, 
Days 9–14, and during the optional dosing period on Days 16–21 and Days 23–28, or will 
receive daily placebo for oral step-down therapy (first eligibility on Day 4 or later as advised by 
a site’s national/regional/local guidelines), which will be administered every day including 
rezafungin infusion days (see Figure 1 and Figure 2).   
6.1.2 
Subjects Randomized to Caspofungin 
Subjects randomized to caspofungin will receive a total treatment of ≥14 days beginning with 
a single caspofungin 70 mg IV loading dose on Day 1, followed by caspofungin 50 mg IV once 
daily with the option to continue treatment ≤28 days. After ≥3 days (or the minimum duration 
of IV therapy advised by the site’s national/regional/local guidelines, whichever is greater) 
of caspofungin treatment, subjects who meet the oral step-down therapy eligibility criteria 
(see Section 8.2.3.3) may be switched to oral fluconazole at a dose of 6 mg/kg administered once 
daily (rounded to the nearest 200 mg increment) with a maximum daily dose of 800 mg 
(e.g., a subject weighing 73 kg would receive fluconazole 400 mg dose [2 capsules of 200 mg 
each] based on a 6 mg/kg target dose [73 kg × 6 mg/kg = 438 mg]. NOTE: Refer to dosing 
section for alternative regimens of fluconazole in subjects with renal impairment in 
Section 8.2.3.5). To maintain the blind, subjects in the caspofungin treatment group who have 
switched to oral step-down therapy will receive matching IV placebo for Rezafungin for 
Injection once weekly on the days of scheduled Rezafungin for Injection doses until study drug 
is stopped (Day 8; Day 15 [if applicable] and Day 22 [if applicable]) (see Figure 1 and Figure 2). 


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6.1.3 
End of Treatment Visit and Follow-up Visits 
Subjects will complete an EOT visit within 2 calendar days after the last dose of study drug, 
and a Follow-up visit within the Day 52–59 period. Subjects who stop study drug prior to Day 22 
AND are considered clinical failures (i.e., require a change in antifungal therapy to treat 
candidemia and/or invasive candidiasis) may have their Follow-up visit earlier, but the visit must 
still be ≥30 days following the last once weekly infusion of Rezafungin for Injection/placebo 
(i.e., Day 1, Day 8, Day 15, or Day 22). 
6.1.4 
Mycological Diagnosis 
Mycological diagnosis of candidemia and/or invasive candidiasis sufficient for inclusion in the 
study will be established by one of the following test results from a blood sample or normally 
sterile site collected ≤4 days (96 hours) before randomization: 
• ≥1 blood culture positive for yeast or Candida  
• sponsor-approved rapid in vitro diagnostic (IVD) (e.g., T2Candida Panel, Septifast) test 
positive for Candida spp. 
• a 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  
Note: If the positive blood culture used to qualify the subject for the study is drawn >12 hours 
prior to randomization, an additional set of blood cultures must be obtained ≤12 hours before 
randomization to determine which subjects are still candidemic at enrollment. Results of the 
blood cultures obtained ≤12 hours before randomization are not required prior to randomization.  
The dose and duration of any prior antifungal treatment received ≤4 weeks before randomization 
will be recorded at Screening. 
For diagnosis of invasive candidiasis, cultures should be obtained from purulent fluid or necrotic 
tissues from normally sterile sites. Drainage tubes following invasive procedures may only 
be used to acquire fluid for culture for up to 24 hours following placement of the tube 
(after 24 hours tubes could be colonized with non-infecting pathogens). While potentially 
indicative of disease, a urine culture alone may not be used as the qualifying culture for entry 
into the study, though the presence of a positive urine culture is not a reason to exclude a patient 
from participation. Additionally, a respiratory tract specimen would not be considered sufficient 
to prove invasive candidiasis as these specimens are rarely sterile and pulmonary infection with 
Candida spp. is extremely rare. 
Every reasonable effort must be made for source control of the Candida infection to properly 
evaluate the efficacy of study drug. Central catheters should be removed within 48 hours after 
diagnosis with candidemia, consistent with IDSA and ESCMID guidelines. For subjects with 
invasive candidiasis, surgical drainage or debridement of potentially infected fluid collections 
or necrotic tissues should be performed. 


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6.1.5 
Retinal Examination 
A retinal examination for evidence of a Candida eye infection, including endophthalmitis 
or chorioretinitis, should be performed on all subjects with candidemia during Screening when 
possible, although the exam may occur as late as Day 7. Retinal examination is standard of care 
for subjects with candidemia and should be performed by an ophthalmologist, when available. 
The retinal examination should be repeated in subjects who were negative at baseline if the 
subject develops visual signs or symptoms of a Candida eye infection during the study. 
Additionally, any neutropenic subjects who recover their neutrophil counts during the study 
should have an additional retinal examination. Subjects who were negative at baseline and 
diagnosed with a Candida eye infection after initiating study drug must discontinue study drug 
(see Section 7.4.2) but may continue in the study at the Investigator’s discretion; all subsequent 
antifungal drugs, interventions, and outcomes for endophthalmitis or chorioretinitis will be 
recorded. 
6.1.6 
Study Day Definition 
Study Day 1 is defined as the first day of study drug administration. Subsequent study days are 
counted as the number of consecutive calendar days thereafter. 
6.1.7 
Efficacy Assessments 
Efficacy assessments for all subjects occur on Day 5, Day 14 (±1 day), Day 30 (-2 days), 
EOT (≤2 days of last dose), and the Follow-up visit (Days 52–59). Clinical cure, radiological 
cure (for qualifying invasive candidiasis subjects), and mycological eradication will be assessed 
on all efficacy assessment days. Survival status will be assessed at Day 30 (-2 days) and the 
Follow-up visit (Days 52–59). Subjects who complete Day 30 assessments on Day 28 or Day 29 
(within the -2 days period) without further information thereafter will be considered alive at 
Day 30. For mycological response, the location of Candida infection determines how eradication 
will be demonstrated: 
a. Subjects with ≥1 blood culture positive for yeast or Candida  
Blood cultures for efficacy following the first dose of study drug will be performed 
until the first negative blood culture result for Candida spp. with no subsequent 
positive culture (in cases when one or more samples are drawn and cultured after the 
first negative culture is available). Blood samples for cultures should be drawn daily 
when possible although may be drawn every other day until blood cultures are 
negative. Generally, blood cultures should involve samples from 2 separate draws 
with ≥1 draw from a peripheral vein without an IV catheter.  
b. Subjects with a positive culture for Candida spp. from a normally sterile site  
Note: only applies when infected sites are accessible; fluid samples from drainage 
tubes may only be collected for up to 24 hours following placement of the tube. 
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collected from all normally sterile sites of baseline infection at least every other day 
until the first negative culture result for Candida spp. with no subsequent positive 
culture (in cases when one or more samples are drawn and cultured after the first 
negative culture is available). If access to the infected site is not possible, then 
mycological eradication will be determined based on clinical outcome (see Table 8). 
Any time there is a culture obtained from a normally sterile site, there should be 
a surgical procedure recorded in the Medical History or in Concomitant Procedures 
(depending upon the study interval during which the sample was obtained). 
6.1.8 
Safety Assessments 
Safety monitoring data is collected throughout the study. Adverse events are collected from the 
time the informed consent document is signed through the Follow-up visit (Days 52–59). Vital 
signs will be measured at each study visit. A physical examination will be performed at the 
Screening, Day 5, Day 14 (±1 day), Day 30 (-2 days), EOT (≤2 days of last dose), and Follow-up 
(Days 52–59) visits. Subjects will be assessed for signs and symptoms of tremor, ataxia, and 
peripheral neuropathy using a neurological exam at least at Screening and at EOT. More frequent 
neurological exams may be performed as directed by subject symptoms. Hematology and 
chemistry laboratory tests will be performed at the Screening, Day 1, Day 2, Day 4, Day 
8 (±1 day), Day 14 (±1 day), Day 30 (-2 days), EOT (≤2 days of last dose), and Follow-up visits 
(Days 52–59). Urinalysis will be performed at the Screening and EOT (≤2 days of last dose) 
visits. Coagulation laboratory tests (Prothrombin Time or International Normalized Ratio 
[PT/INR]) will be performed at the Screening visit. An ECG will be performed at the Screening 
visit and on Day 1 at any time following administration of study drug (i.e., post-end IV infusion). 
An independent external DSMB will review safety data when approximately 50% of subjects are 
randomized in the study and as required for AESIs as provided in the DSMB Charter.  
6.1.9 
PK Sampling 
Blood samples for PK analysis must be collected from the OPPOSITE arm of the infusion 
or through an arterial line during the infusion; after the infusion is complete, opposite arm 
or arterial line draws are preferred, but not mandatory. Blood samples will be collected as 
follows: 
•
Day 1: within 10 minutes before the end of infusion, and one sample taken any time
between end of infusion and 12 hours after the end of infusion
•
Days 2, 3, 4, or 5: One sample taken at any time on one day only
•
Day 8: Pre-dose
•
Day 14 (for subjects not receiving a Day 15 dose): One sample taken at any time
•
Day 15: Pre-dose (if applicable)
•
Day 22: Pre-dose (if applicable)


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For subjects completing treatment on Day 14, a PK sample should be drawn at the same time 
as hematology and chemistry blood draws (i.e., random PK draw). Note: Pre-dose samples 
should be collected ≤30 minutes prior to the start of the infusion. For subjects receiving 
hemodialysis, an attempt should be made to obtain PK samples directly following hemodialysis 
if still within the required time window. 
Blood samples will be collected from all subjects receiving study drug, although only PK 
samples from subjects receiving Rezafungin for Injection will be analyzed. PK sample analysis 
will be performed by an independent, central bioanalytical laboratory using a validated assay. 
6.2 
Number of Subjects 
Approximately 218 subjects will be randomized to treatment (1:1, Rezafungin for Injection 
to caspofungin). The target of 218 subjects assumes approximately 85% of randomized subjects 
will be evaluable for the mITT population. Thus, 184 subjects will be in the mITT population (92 
subjects in each treatment group). If the evaluability rate for the mITT population is higher than 
85%, enrollment will be stopped when at least 184 randomized subjects have met the criteria to 
be included in the mITT population.  
6.3 
Measures Taken to Minimize Bias 
Treatment assignment will be blinded to all blinded clinical site and sponsor personnel 
(double-blind) until the study database is locked. Unblinded personnel includes the site 
pharmacist preparing the infusions and the unblinded monitor to ensure study drug accountability 
and assignment throughout the trial as well as the Sponsor’s unblinded team. Blinding is 
maintained with a double-dummy design wherein all subjects receive daily infusions until 
switched to oral step-down therapy. Subjects switched to oral step-down therapy receive daily 
oral therapy and weekly infusions.  
6.4 
Expected Duration of Subject Participation 
Maximum study duration for an individual subject is 63 days, including Screening (≤4 days, 
96 hours), the Required Treatment Period (Day 1 to Day 14 [14 days]), the Optional Extended 
Treatment Period (Day 15 to Day 28), and Follow-up (Days 52–59). 
6.5 
Method of Treatment Assignment and Blinding 
After informed consent has been obtained, subjects will be screened for study eligibility before 
randomization. 
Subjects will be randomly assigned (1:1 ratio) to receive either Rezafungin for Injection 
or caspofungin. Randomization will be stratified based on diagnosis (candidemia only; invasive 
candidiasis) and by Acute Physiology and Chronic Health Evaluation (APACHE II) 
score/ absolute neutrophil count (ANC) (APACHE II score ≥20 OR ANC <500 cells/μL; 
APACHE II score <20 AND ANC ≥500 cells/μL) at Screening. If a subject has a positive result 


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for both blood culture/rapid IVD and culture specimen obtained from a normally sterile site, the 
subject will be randomized within the invasive candidiasis stratum.  
The study site’s pharmacist (or pharmacist designee) will obtain the study drug 
assignment via an Interactive Response Technology (IRT). Randomized subjects will be 
assigned the treatment corresponding to the next available randomization number from 
the computer-generated randomization schedule. A subject is considered randomized when 
a randomization transaction is recorded in the IRT. 
All study personnel, including the Sponsor, Investigator, and site personnel involved in study 
conduct, and subjects will remain blinded to study medication assignment until the study is 
completed and the database is locked with the exception of the pharmacy monitor, unblinded 
project manager, clinical supplies, document manager, and quality (per the Sponsor Blinding 
Plan) who may be unblinded to study medication at any time during study conduct. The DSMB 
will be unblinded to safety data for periodic safety reviews as defined in the DSMB Charter. The 
Pharmacy Monitor will monitor study drug preparation and accountability during the study and 
cases in which unblinding is required due to a safety or tolerability issue. To maintain study 
blinding, study drug preparation will be performed by an unblinded site pharmacist (or qualified 
unblinded personnel at the study site not involved with study procedures or evaluations).  
Instructions for study drug preparation and dosing are outlined in the Pharmacy Manual provided 
separately to the site. To maintain the blind, oral study drug pills must never be crushed. In the 
case of a medical emergency requiring the Investigator to know the identity of the study drug, 
the Investigator will follow the procedures outlined in Section 8.4. 
 
 


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7.0 
SELECTION, DISCONTINUATION, AND WITHDRAWAL OF SUBJECTS 
7.1 
Subject 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 (only possible if it 
corresponds to the subject's usual lifestyle) while participating in this study and at least 
30 days from the last dose of study drug. 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 the 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. 


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7.1.1 
Rapid In Vitro Diagnostics for Candidemia and Invasive Candidiasis 
The addition of rapid IVD for the identification of subjects with candidemia and/or invasive 
candidiasis is being employed to reduce the amount of prior empiric antifungal therapy being 
administered to potential study subjects. Rapid IVDs for Candida spp. used for inclusion in this 
study must be approved by the Sponsor prior to use in the study. Currently approved rapid IVDs 
include the T2Candida Panel (T2 Biosystems) and the Septifast polymerase chain reaction (PCR) 
test (Roche). Subjects may be enrolled based on a positive result from a Sponsor-approved rapid 
IVD, but a culture from blood or normally sterile tissue or fluid that is positive for Candida spp. 
will still be the required objective measure for candidemia or invasive candidiasis in the study 
analyses for efficacy. 
Potential subjects with 1 or more risk factors for candidemia and invasive candidiasis should 
have a Sponsor-approved rapid IVD for Candida spp. performed only if the site is drawing 
a blood sample for blood culture and if empiric antifungal therapy for candidiasis has been 
administered or will be administered within the subsequent day. Risk factors for candidemia 
and invasive candidiasis include (but are not limited to): 
• Immunosuppression 
• Central venous catheter 
• Recent abdominal surgery 
• Pancreatitis 
• End stage renal disease 
• Current daily administration of total parenteral nutrition 
• Systemic inflammatory response syndrome while on broad spectrum antibiotics 
Sites may choose to perform a sponsor-approved rapid IVD in potential subjects without the 
listed risk factors for candidemia and invasive candidiasis, but the potential subject still must 
have a blood culture drawn and empiric antifungal therapy administered. A call to the Medical 
Monitor is recommended for any questions about risk factors for candidemia and the appropriate 
subjects on which to perform a rapid IVD for Candida spp. 
7.1.2 
Systemic Signs of Candidemia and Invasive Candidiasis 
It is a requirement that at least 1 systemic sign attributable to candidemia and/or invasive 
candidiasis be present at Screening for the subject to be eligible for enrollment. The Screening 
period for assessing systemic signs for inclusion in the study may include the 12 hours prior to 
the collection of the qualifying positive culture when systemic signs of infection were the reason 
for specimen collection (blood culture or fluid from a sterile site culture or qualifying rapid IVD 
[e.g., T2Candida Panel]) through study randomization. The possible signs of infection that might 
be attributable to candidemia and/or invasive candidiasis at baseline include fever, hypothermia, 


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hypotension, tachycardia, tachypnea, and local signs of inflammation (erythema, edema, heat, 
and pain at the site of the qualifying blood culture). 
For the listed systemic signs of candidemia, the qualifying parameters are provided below: 
Systemic Sign of 
Candidemia 
Qualifying Parameters 
Fever 
Oral or axillary temperature ≥38°C (100.4°F) or a tympanic, temporal, rectal, or core body 
temperature ≥38.3°C (101°F)  
Hypothermia 
Tympanic, temporal, rectal, or core body temperature ≤35°C (95.2°F) 
Hypotension 
Systolic blood pressure <90 mm Hg or mean arterial pressure <70 mm Hg with 
a normovolemic or hypervolemic status 
Tachycardia 
Heart rate >100 beats per minute with a normovolemic or hypervolemic status 
Tachypnea 
Respiratory rate >20 breaths per minute 
Local Signs of 
Inflammation 
Erythema (rubor), edema (tumor), heat (calor), and pain (dolor) at the site of infection 
 
7.2 
Subject 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) ≤4 days (96 hours) before randomization. 
a. Exception: Receipt of antifungal therapy to which any Candida spp. isolated 
in culture is not susceptible (see Appendix 1) 
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). 


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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, including but not limited to hereditary sugar disorders 
(e.g., fructose intolerance, sucrose-isomaltase insufficiency), anaphylaxis, 
or echinocandin-induced exfoliative skin disorders (e.g., Stevens-Johnson syndrome 
or toxic epidermal necrolysis). 
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 severe neurotoxic medication 
(see Appendix 9) or with a known moderate neurotoxic medication (see Appendix 9) in 
a patient with ataxia, tremor, motor neuropathy, or sensory neuropathy of CTCAE 
version 5.0 Grade 1 or higher. 
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. 
7.3 
Requalification for Entry 
Subjects not fulfilling the entry criteria and not randomized may be rescreened for participation 
if their eligibility characteristics have changed. 
7.4 
Subject Withdrawal Criteria 
7.4.1 
Withdrawal from Study Protocol 
Subjects may withdraw consent to participate in this study at any time without penalty or loss of 
benefits to which the subject is otherwise entitled. Subjects on study drug who wish to withdraw 
completely from this clinical study should be encouraged to complete the assessments at EOT. 
Every reasonable effort should be made to determine the reason a subject withdraws 
prematurely, and this information should be recorded on the appropriate page(s) of the electronic 
case report form (eCRF). 


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Subjects may be withdrawn from the study for any of the following reasons: 
• Subject unable or unwilling to continue 
• Subject elects to withdraw informed consent 
• AE (whether related to study drug or not) that precludes further participation 
in the study in the judgment of the PI and/or Sponsor 
• Protocol non-compliance 
• Subject lost to follow up 
• The PI considers that it is in the subject’s best interest not to continue participation 
in the study 
Subjects withdrawn from the study may refuse to participate in the Follow-up visit; however, 
every effort should be made to collect survival data and safety assessments on Day 30 (-2 days) 
for all subjects who withdraw for reasons other than withdrawal of informed consent. Following 
enrollment, subjects diagnosed with invasive candidiasis involving one or more organ systems 
and normally excluded from study participation (Exclusion Criterion 1, Section 7.2) do not need 
to exit the study. Documentation of the disease should be placed in the eCRF along with any 
further interventions related to the disease. 
7.4.2 
Early Discontinuation from Study Drug Administration 
For subjects who prematurely discontinue study drug (i.e., before the anticipated full course of 
study drug therapy required for effective treatment of candidemia and/or invasive candidiasis), 
EOT assessments should be performed on the day of discontinuation. For premature study drug 
discontinuation, Day 14 efficacy assessments should also be performed at EOT, except when the 
subject is believed to be a clinical cure, then the efficacy assessments should still be performed 
at the Day 14 visit to ensure there is no relapse between EOT and Day 14. All safety assessments 
and assessment of mortality should be done for subjects who discontinue study drug early. The 
reason for premature discontinuation of study drug administration should be recorded on the 
appropriate page(s) of the eCRF. Reasons for withdrawal from study drug may include, but are 
not limited to: 
• Cultures negative for Candida spp. 
o Blood culture is positive for yeast at enrollment, but the final local blood culture 
results conclude the yeast is not Candida spp. 
o Subject is enrolled based on a rapid IVD test positive for Candida spp., but final local 
blood culture results from Screening or tissue/fluid culture results from a normally 
sterile site are negative for Candida spp. (withdrawal not required but based on the 
Investigator’s discretion) 


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• Safety 
o Subject unable or unwilling to continue or informed consent withdrawn 
o Occurrence of an AE that, in the opinion of the Investigator, warrants the subject’s 
permanent discontinuation from study drug therapy. This includes development of 
a clinically significant laboratory abnormality that requires discontinuation from 
study drug (IV and IV/oral) therapy. In the event of discontinuation from study drug 
therapy due to the occurrence of an AE, the study site should notify the Medical 
Monitor as soon as possible 
o Suspected or confirmed pregnancy or nursing during the study drug administration 
period 
• Excluded types of invasive candidiasis 
Echinocandins are not appropriate therapy for Candida infections of the eye or central 
nervous system due to low drug distribution to these sites (Pappas 2016; Cornely 2012). 
A retinal examination for evidence of a Candida eye infection, including endophthalmitis 
or chorioretinitis, should be performed in all subjects with candidemia during Screening 
when possible, although may occur as late as Day 7 only on subjects with candidemia by 
blood culture, and should be repeated in subjects who were negative at baseline if the 
subject develops visual signs or symptoms of a Candida eye infection during the study. 
Additionally, any neutropenic subjects who recover their neutrophil counts during the 
study should have an additional retinal examination. Subjects who were negative 
at baseline and diagnosed with a Candida eye infection after initiating study drug should 
have an urgent ophthalmologic consultation (if not already done), should stop study drug, 
and be initiated on appropriate therapy for Candida eye infection per the local guidelines. 
If possible, all subjects diagnosed with endophthalmitis or chorioretinitis should remain 
in the study and all subsequent antifungal drugs, interventions, and outcomes for 
endophthalmitis or chorioretinitis should be recorded. 
Study drug may be continued in the event of diagnosis of other forms of invasive 
candidiasis listed in the exclusion criteria if the involvement of other organ systems was 
thought to be present at the time of enrollment and the diagnosis was delayed. If, on the 
other hand, the spread of Candida infection to other organ systems was thought to have 
occurred following enrollment and initiation of study drug, the Investigator should 
consider a change of therapy due to insufficient therapeutic effect of study drug. In all 
cases of other forms of invasive candidiasis, the Investigator should consult local 
guidelines for the most appropriate management of disease and whether or not additional 
antifungal therapy may be warranted either during study drug administration or following 
completion of study drug therapy. 


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• Insufficient therapeutic effect  
An insufficient therapeutic effect may be determined prior to the planned duration of 
therapy in the study. This determination will require an assessment of clinical status 
including the synthesis of symptoms and signs data (both local and systemic). Subjects 
who are deemed to have an insufficient therapeutic effect should be discontinued from 
study drug therapy. 
If a subject has daily blood cultures positive for Candida spp. through Day 7 despite 
appropriate study drug administration, this should be considered an insufficient 
therapeutic effect and study drug should be discontinued and salvage therapy initiated. 
The subject should remain in the study through the Follow-up visit (Days 52–59) 
to complete safety assessments and assess for mortality. 
Seven days is the maximum number of daily positive blood cultures allowed prior 
to a change in antifungal therapy. The Investigator may determine that there is 
an insufficient therapeutic response prior to Day 7. 
• Investigator discretion 
o Resistant Pathogen(s): In the event an organism resistant to ≥1 of the potential study 
drugs is isolated, the Investigator will determine whether the subject remains on study 
drug therapy. The Investigator may decide to continue study drug therapy if, in the 
Investigator’s opinion, there is clear and continuing clinical improvement while on 
therapy. 
o The Investigator may decide to prematurely discontinue study drug therapy and to 
initiate an alternative and appropriate therapy if, in the Investigator’s opinion, 
the subject is not benefiting from study drug. 
NOTE: The Medical Monitor should be contacted to discuss whether to continue or prematurely 
discontinue a subject on the study drug in the event the subject requires systemic concomitant 
antifungal therapy. 
In the event salvage therapy is required due to either insufficient therapeutic effect 
or Investigator discretion, the Investigator should note that since the subject has failed 
echinocandin therapy, other echinocandins may not be the best choice for salvage therapy. 
If the subject is switched to oral step-down therapy prior to study drug failure, the Investigator 
should consider that subjects in the caspofungin arm will also have been taking fluconazole. 
In both circumstances, the Investigator should refer to the IDSA (Pappas 2016) or ESCMID 
(Cornely 2012; Ullmann 2012) guidelines for treatment failure in candidemia, and will need 
to determine whether or not breaking the blind is necessary to make an informed choice of future 
antifungal therapies. 


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7.5 
Replacement of Subjects 
Randomized subjects who are withdrawn will not be replaced. 
7.6 
Study Termination by Sponsor and Termination Criteria 
The Sponsor reserves the right to terminate an investigational site or this clinical study at any 
time. Reasons for termination may include, but are not limited to, the following: 
• The incidence or severity of AEs in this or other studies of Rezafungin for Injection 
indicate a potential health hazard to subjects 
• Serious or persistent noncompliance by the Investigator with the protocol, clinical 
research agreement, or applicable regulatory guidelines in conducting the study  
• IRB/IEC decision to terminate or suspend approval for the investigation 
or the Investigator 
• Investigator request to withdraw from participation 
• Subject enrollment is unsatisfactory 
 
 


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8.0 
STUDY DRUGS 
Subjects will be randomized in a 1:1 ratio to receive Rezafungin for Injection IV or Caspofungin 
IV. Oral step-down therapy is allowed in both treatment groups; oral placebo in the Rezafungin 
for Injection group and oral fluconazole in the Caspofungin group. The total IV plus oral 
treatment duration will be ≥14 days and up to a maximum of 28 days (Table 3). 
In order to stop study drug for successful completion of therapy prior to 28 days, the following 
criteria must be met: 
• ≥14 days of study drug 
• The subject’s clinical status is considered stable based on Investigator assessment 
• All systemic signs attributable to candidemia and/or invasive candidiasis that were present 
at baseline have resolved 
• For subjects with invasive candidiasis, there is documented or presumed eradication of 
invasive candidiasis 
• If a blood culture is positive at Screening, the most recent post-baseline blood culture 
is negative for Candida spp. 
Once these criteria are met, the total duration of study drug is at the discretion of the PI. 
Subjects randomized to the Rezafungin for Injection treatment group will receive 1 dose of 
Rezafungin for Injection IV (400 mg) nominally over 60 (±10) minutes on Day 1 and 200 mg on 
Day 8 (±1 day) (Table 3). Subjects in the Rezafungin for Injection treatment group who require 
>14 days of therapy will receive an optional third dose of Rezafungin or Injection IV (200 mg) 
on Day 15. Subjects in the Rezafungin for Injection treatment group who require >21 days of 
therapy will receive an optional fourth dose of Rezafungin IV (200 mg) on Day 22. Subjects 
in the Rezafungin for Injection treatment group will receive IV or oral placebo on other study 
days in order to maintain the blind. Intravenous study drug is administered 24 (±2) hours after 
study drug was administered on the previous day. 
Subjects may receive oral step-down therapy after ≥3 days of IV therapy or the minimum 
duration of IV therapy advised by the site’s national/regional/local guidelines, whichever is 
greater. Step-down therapy in the Rezafungin for Injection treatment group will be oral placebo, 
in order to maintain the blind. Subjects who have already switched to oral step-down therapy will 
receive both oral placebo and Rezafungin for Injection IV on Day 8 (±1 day), Day 15 (±1 day) 
for subjects who require >14 days of therapy, and Day 22 (±1 day) for subjects who require 
>21 days of therapy.  
Subjects randomized to the caspofungin group will receive IV caspofungin (a single 70 mg 
loading dose on Day 1 followed by 50 mg once daily over 60 (±10) minutes) for ≥3 days and up 
to a maximum of 28 days (Table 3). Intravenous study drug is administered 24 (±2) hours after 
study drug was administered on the previous day. 


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Step-down therapy in the caspofungin treatment group will be oral fluconazole (subjects with 
a creatinine clearance >50 mL/min will receive oral fluconazole at a dose of 6 mg/kg 
administered once daily rounded to the nearest 200 mg increment with a maximum daily dose of 
800 mg; subjects with creatinine clearance ≤50 mL/min will receive oral fluconazole at a dose of 
3 mg/kg administered once daily rounded to the nearest 200 mg increment with a maximum 
daily dose of 400 mg). In order to maintain the blind, subjects who have already switched to oral 
step-down therapy will receive both oral fluconazole and IV placebo on Day 8 (±1 day), Day 15 
(±1 day) for subjects who require >14 days of therapy, and Day 22 (±1 day) for subjects who 
require >21 days of therapy.  
Intravenous infusion of Rezafungin for Injection and IV placebo is administered over 60 (±10) 
minutes, although the infusion time may be increased up to 180 minutes to manage evolving 
symptoms of infusion reaction consistent with management of echinocandin class infusion 
reactions, whereby decreasing the rate of infusion often alleviates symptoms. Dosage 
adjustments of Rezafungin for Injection are not allowed. Treatment will be initiated on 
an inpatient basis; a switch to outpatient IV treatment is allowed at the Investigator’s discretion. 
The total IV plus oral treatment duration will be ≥14 days and up to 28 days. 
The daily dosing schedule with options (i.e., not switched versus switched to oral therapy) for 
the required treatment period is presented in Figure 2 and for the optional treatment period is in 
Figure 3. The daily dosing schedule for the entire study period (required and optional) with 
options (i.e., not switched versus switched to oral therapy) is presented in Table 3. 
8.1 
Rezafungin for Injection 
8.1.1 
Formulation 
Rezafungin for Injection is a lyophilized formulation of the active pharmaceutical ingredient, 
rezafungin acetate. Rezafungin for Injection is supplied in vials as a sterile lyophilized powder 
(200 mg) for reconstitution prior to dilution into normal saline infusion bags (250 mL). 
Excipients for rezafungin include polysorbate 80, histidine, and mannitol. 
8.1.2 
Directions for Use 
Rezafungin for Injection is administered IV with a 400 mg loading dose on Day 1 of Week 1, 
followed by 200 mg once weekly, for a total of 2 to 4 doses. 
Intravenous infusion of Rezafungin for Injection and IV placebo is administered over 
60 (±10) minutes, although the infusion time may be increased up to 180 minutes as needed to 
manage evolving symptoms of infusion reaction consistent with management of echinocandin 
class infusion reactions, whereby decreasing the rate of infusion often alleviates symptoms. 
Dosage adjustments of Rezafungin for Injection are not allowed. Treatment will be initiated on 
an inpatient basis; a switch to outpatient IV treatment is allowed at the Investigator’s discretion. 


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8.1.3 
Drug Storage 
Vials of Rezafungin for Injection and infusion bags with diluted Rezafungin for Injection should 
be stored per the directions presented in the study Pharmacy Manual. 
8.1.4 
Dose Adjustment 
Dosage adjustments are not allowed in this study. 
8.2 
Placebo and Comparator Treatment 
8.2.1 
Placebo 
In this double-blind, double-dummy, active comparator study, two placebo regimens are 
required; one for subjects randomized to Rezafungin for Injection and one for subjects 
randomized to caspofungin. In addition, because subjects in the caspofungin arm may be 
switched to oral step-down therapy, an oral placebo is required for subjects in the Rezafungin for 
Injection arm. Thus, placebo requirements for each treatment assignment are as follows: 
Treatment Assignment 
Placebo 
Rezafungin for Injection 
Placebo for caspofungin IV  
Placebo for oral step-down therapy (fluconazole) 
Caspofungin IV 
Placebo for Rezafungin for Injection 
In more detail, placebo regimens for each treatment assignment are as follows: 
Placebo Regimen for Rezafungin for Injection Treatment Assignment 
Subjects will receive a caspofungin IV equivalent regimen of daily placebo IV infusion in 
a blinded manner. Because subjects randomized to caspofungin may be switched to fluconazole 
oral step-down therapy, a fluconazole-equivalent regimen of daily oral placebo will be 
administered for subjects randomized to Rezafungin for Injection at that time. 
Placebo Regimen for Caspofungin IV Treatment Assignment 
Subjects who are switched to fluconazole oral step-down therapy will receive a Rezafungin for 
Injection equivalent regimen of weekly placebo IV infusion in a blinded manner. 
8.2.2 
Caspofungin 
Anaphylaxis has been reported with administration of caspofungin. If this occurs, caspofungin 
should be discontinued immediately and appropriate treatment administered. 
Possible histamine-like reactions, including rash, facial swelling, sensation of warmth, pruritis, 
and bronchospasm, have been observed during infusion of caspofungin. These reactions may 
require discontinuation of the infusion and/or administration of appropriate treatment. 


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Cases of Stevens-Johnson Syndrome and toxic epidermal necrolysis have been reported after 
post-marketing use of caspofungin. 
Finally, abnormal liver function tests have been observed with healthy volunteers and patients 
treated with caspofungin. In patients with serious underlying conditions, cases of clinically 
significant hepatic dysfunction, hepatitis, and hepatic failure have been reported without a causal 
relationship established. 
Levels of caspofungin may increase with concomitant administration of cyclosporine and may 
decrease with concomitant use of efavirenz, nevirapine, rifampin, dexamethasone, phenytoin, 
and carbamazepine. 
See Appendix 7A for potential caspofungin drug interactions, warnings, and precautions. The list 
is not exhaustive, and the Investigator must refer to the US Prescribing Information or Summary 
of Product Characteristics (SmPC). 
8.2.2.1 
Formulation 
Caspofungin IV is provided in its commercial formulation. Excipients for caspofungin include 
sucrose, mannitol, glacial acetic acid, and sodium hydroxide (refer to the US Prescribing 
Information or SmPC for excipients used in specific generic versions). 
8.2.2.2 
Directions for Use 
The manufacturer’s instructions for caspofungin dose preparation should be followed. 
Subjects randomized to caspofungin 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 once daily with the 
option to continue treatment ≤28 days, unless they qualify for an alternative caspofungin regimen 
per Section 8.2.2.4 or for step-down therapy after ≥3 days (or the minimum duration of IV 
therapy advised by the site’s national/regional/local guidelines, whichever is greater) of 
caspofungin IV treatment per Section 8.2.3. Doses are to be administered 24 (±2) hours after the 
start of study drug administration on the previous day. The infusion time for caspofungin is the 
same as for Rezafungin for Injection. The infusion time of time of 60 (±10) minutes may be 
increased as needed up to 180 minutes to manage evolving symptoms of infusion reaction 
consistent with management of echinocandin class infusion reactions, whereby decreasing the 
rate of infusion often alleviates symptoms.  
8.2.2.3 
Drug Storage 
The manufacturer’s instructions for caspofungin storage should be followed. 


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8.2.2.4 
Dose Adjustment  
Subjects with moderate hepatic impairment (Child-Pugh score of 7–9): loading dose of 
caspofungin of 70 mg on Day 1 followed by 35 mg once daily. 
Subjects weighing >80 kg or on concomitant rifampin, nevirapine, efavirenz, phenytoin, 
dexamethasone, or carbamazepine: caspofungin 70 mg once daily. Dose adjustment due to DDIs 
or weight may be considered according to the approved labeling and at the Investigator’s 
discretion. 
Use of concomitant cyclosporine should be limited to subjects for whom potential benefit 
outweighs potential risk of DDIs and hepatotoxicity with caspofungin. 
8.2.3 
Oral Step-Down Therapy: Fluconazole 
Fluconazole should not be co-administered with terfenadine, cisapride, astemizole, 
erythromycin, pimozide, quinidine, halofantrine, or any other drug metabolized via the CYP3A4 
enzymatic pathway and may cause prolongation of the QT interval.  
Fluconazole is a potent CYP2C9 inhibitor and a moderate CYP3A4 inhibitor and thus all 
subjects on fluconazole who are concomitantly taking drugs that are also metabolized through 
these pathways should be monitored closely. 
See Appendix 7B for potential fluconazole drug interactions, warnings, and precautions. The list 
is not exhaustive, and the investigator must refer to the US Prescribing Information or SmPC. 
8.2.3.1 
Formulation 
Commercial fluconazole tablets have been over-encapsulated for study blinding. Excipients for 
fluconazole include microcrystalline cellulose, dibasic calcium phosphate anhydrous, povidone, 
croscarmellose sodium, FD&C Red Dye No. 40 aluminum lake dye, and magnesium stearate. 
8.2.3.2 
Directions for Use 
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 who meet the step-down 
therapy eligibility criteria may be switched to oral fluconazole (earliest oral dose on Day 4 
or later, as advised by a site’s national/regional/local guidelines). The total comparator treatment 
period (caspofungin plus fluconazole) is ≤28 days. Subjects with a creatinine clearance 
>50 mL/min (see Appendix 2) will receive oral fluconazole at a dose of 6 mg/kg administered 
once daily rounded to the nearest 200 mg increment with a maximum daily dose of 800 mg 
(e.g., a subject weighing 73 kg would receive a fluconazole 400 mg dose [2 capsules of 200 mg 
each] based on a 6 mg/kg target dose [73 kg × 6 mg/kg = 438 mg). Subjects with creatinine 
clearance ≤50 mL/min will receive oral fluconazole at a dose of 3 mg/kg administered once daily 
rounded to the nearest 200 mg increment with a maximum daily dose of 400 mg (e.g., a subject 


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weighing 73 kg would receive a fluconazole 200 mg dose [1 capsule of 200 mg] based on 
a 3 mg/kg target dose [73 kg × 3 mg/kg = 219 mg]). Subjects receiving hemodialysis receive the 
same dose as subjects with a creatinine clearance >50 mL/min; however, they are only dosed 
following hemodialysis. Subjects receiving continuous renal replacement therapy (CRRT) should 
be treated as a subject with normal renal function at 6 mg/kg rounded to the nearest 200 mg each 
day (Cousin 2003). Subjects receiving peritoneal dialysis should be treated with 1.5 mg/kg 
rounded to the nearest 200 mg each day (Cousin 2003). 
Investigators are advised to pay close attention to signs of overdosing and underdosing with 
underweight (<50 kg) and overweight (>85 kg) subjects, respectively. Additionally, signs of 
potential fluconazole toxicity, including hepatic toxicity and QT prolongation, should be closely 
monitored for any subject on oral step-down therapy. Subjects weighing over 130 kg will not be 
eligible for oral step-down therapy. 
8.2.3.3 
Oral Step-Down Therapy Eligibility Criteria 
An oral step-down therapy is allowed in both treatment groups (fluconazole for caspofungin, 
placebo for oral step-down therapy for Rezafungin for Injection), provided the following criteria 
are met: 
• Able to take oral medication 
• ≥3 days of IV study drug (or the minimum duration of IV therapy advised by the site’s 
national/regional/local guidelines, whichever is greater) 
• The Candida spp. isolated is susceptible to fluconazole 
• All signs and symptoms of candidemia and/or invasive candidiasis that were present 
at baseline have resolved 
• The subject’s clinical status is considered stable based on Investigator assessment 
• Most recent blood culture must be drawn following the first dose of study drug AND 
≥48 hours prior to oral study drug initiation AND must be negative for Candida spp. 
• No evidence of moderate or severe hepatic injury (alanine aminotransferase or aspartate 
aminotransferase >5× the ULN) 
• No history of hypersensitivity to any azole or any other contraindications to the use of 
fluconazole or its excipients (Appendix 7B), including concomitant use of the following 
medications: terfenadine, cisapride, astemizole, erythromycin, pimozide, and quinidine  
• No personal or family history of Long QT interval on ECG (QT) syndrome 
or a prolonged QT interval corrected for heart rate by Fridericia’s formula (QTcF) 
interval (>470 msec in males and >480 msec in females) 
• In the Investigator’s opinion, the subject can tolerate oral fluconazole therapy (refer to 
current fluconazole Prescribing Information) 


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•
Subject’s weight is ≤130 kg
While QT prolongation is rare with fluconazole without the contraindicated interacting 
medications listed above, investigators should monitor subjects with ECGs as clinically 
indicated. 
Subjects who are switched to oral step-down therapy may switch back to IV study drug therapy 
in the event of the development of an unforeseen condition that prevents the subject from taking 
oral medications (e.g., pancreatitis, urgent surgery), but may not switch back to IV study drug 
therapy for worsening or relapse of candidemia/invasive candidiasis or for intolerance or toxicity 
due to study drug. 
The daily dosing schedule with options for the required treatment period is presented in Figure 2 
and for the optional treatment period is in Figure 3. The daily dosing schedule for the entire 
study period (required and optional) is presented in Table 3. 
8.2.3.4 
Drug Storage 
Capsule containing fluconazole tablets (over-encapsulated fluconazole) should be stored per the 
directions presented in the study Pharmacy Manual. 
8.2.3.5 
Dose Adjustment for Renal Impairment 
Subjects with creatinine clearance ≤50 mL/min (see Appendix 2) will receive oral fluconazole 
at a dose of 3 mg/kg administered once daily rounded to the nearest 200 mg increment with 
a maximum daily dose of 400 mg. Subjects receiving hemodialysis receive the same dose as 
subjects with a creatinine clearance >50 mL/min; however, they are only dosed following 
hemodialysis. Subjects receiving CRRT should be treated as a subject with normal renal function 
at 6 mg/kg rounded to the nearest 200 mg each day (Cousin 2003). Subjects receiving peritoneal 
dialysis should be treated with 1.5 mg/kg rounded to the nearest 200 mg each day (Cousin 2003). 
8.3 
Compliance 
Treatment compliance for IV study drugs will be documented in the eCRF by recording the date, 
start time, stop time, and whether the dose of study drug was completely infused. For oral 
fluconazole (caspofungin group) or placebo for oral step-down therapy (Rezafungin for Injection 
groups), treatment compliance will be documented by recording start date, end date, and pill 
counts. 
8.4 
Breaking the Blind 
The study is a double-blind design. The Sponsor, PI, study site personnel, and subjects will not 
make any effort to determine which blinded study drug therapy (Rezafungin for Injection 
or caspofungin with the option of step-down therapy) is being administered or received. 


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Unblinded pharmacy personnel will be responsible for preparing infusion bags such that the 
double-blind is maintained. 
Only in the case of an emergency, when knowledge of the study drug is essential for the clinical 
management or welfare of a specific subject, may the PI unblind a subject’s treatment 
assignment. 
As soon as possible and without revealing the subject’s study treatment assignment (unless 
important to the safety of subjects remaining in the study), the PI must notify the Sponsor if the 
blind is broken for any reason. The PI will record in source documentation the date and reason 
for revealing the blinded treatment assignment for that subject. 
Unblinded data will be provided to the DSMB for the interim analysis of safety as detailed in the 
DSMB charter. No interim unblinded data will be provided to the Sponsor. After the database 
is locked and the Statistical Analysis Plan (SAP) is final, the study blind codes will be broken.  
8.5 
Prior and Concomitant Medications and Substances 
All systemic antifungal therapy administered within 4 weeks and all non-antifungal therapy 
administered within 1 week prior to randomization will be documented and recorded in the 
eCRF. Subjects who 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 will be 
excluded from the study. 
Concomitant systemic antifungal agents, other than those listed as part of study drug therapy, 
are not permitted and their use, for any reason other than the subject being considered 
a treatment failure, must be discussed with the Medical Monitor before administration. 
Caspofungin is contraindicated in subjects with hypersensitivity to the active substance or any 
of the excipients (listed in Section 8.2.2.1). Hypersensitivity includes but is not limited to 
hereditary sugar disorders (e.g., fructose intolerance or sucrose-isomaltase deficiency), 
anaphylaxis and exfoliative skin disorders (e.g., Stevens-Johnson syndrome or toxic epidermal 
necrolysis), which may be severe.  
Caspofungin is not a substrate for P-glycoprotein and is a poor substrate for cytochrome P450 
enzymes. However, caspofungin has been shown to interact with other medicinal products in 
pharmacological and clinical studies.  
For subjects receiving caspofungin and tacrolimus, standard monitoring of tacrolimus trough 
whole blood concentrations and appropriate tacrolimus dosage adjustments are recommended. 
Rifampin is a potent CYP3A4 inducer and concomitant administration with caspofungin is 
expected to reduce the plasma concentrations of caspofungin. A similar effect could be expected 
for other medicinal products that induce metabolic enzymes, therefore subjects on rifampin 


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or the inducers efavirenz, nevirapine, dexamethasone, phenytoin, or carbamazepine may receive 
caspofungin 70 mg once daily. 
Use of concomitant cyclosporine should be limited to subjects for whom potential benefit 
outweighs potential risk of DDIs and hepatotoxicity with caspofungin. All other concomitant 
medications necessary for the health and wellbeing of the subject are permitted. 
Fluconazole is contraindicated in subjects with hypersensitivity to fluconazole and should be 
used with caution in subjects with hypersensitivity to other azoles. Hypersensitivity includes but 
is not limited to anaphylaxis and exfoliative skin disorders, which may be severe. Fluconazole 
should not be co-administered with terfenadine, cisapride, astemizole, erythromycin, pimozide, 
quinidine, or any other drug metabolized via the CYP3A4 enzymatic pathway and may cause 
prolongation of the QT interval. Fluconazole should be administered with caution in patients 
with evidence of hepatic toxicity or liver dysfunction. Patients who have or develop abnormal 
liver function tests during fluconazole therapy should be monitored for the development of more 
severe hepatic injury. Hepatic toxicity secondary to fluconazole is usually reversible. Finally, 
subjects should use caution when driving or operating machinery as dizziness and seizures can 
occur with fluconazole. 
Fluconazole is a potent CYP2C9 inhibitor and a moderate CYP3A4 and CYP2C9 inhibitor 
and thus all subjects on fluconazole who are concomitantly taking drugs that are also 
metabolized through these pathways should be monitored closely. Please refer to the US 
Prescribing Information or the European Union Summary of Product Characteristics for 
fluconazole for more information about the contraindications, warnings and precautions, 
and likely DDIs. 
8.6 
Accountability Procedures 
The pharmacy or other unblinded study personnel are responsible for ensuring that a current 
record of Rezafungin for Injection, caspofungin, fluconazole, and placebo inventory 
and accountability is maintained. 
A Pharmacy Monitor will be responsible for checking study drug accountability at the site. 
Inventory records must be readily available for inspection by regulatory authorities at any time. 
Each shipment of study drug will contain an acknowledgment of receipt section for site 
signature. Upon receipt of study drug, the pharmacy or study personnel will visually inspect the 
shipment and verify the number and condition of vials or capsules received. Refer to the study 
Pharmacy Manual for additional information. 
8.7 
Study Drug Handling and Disposal 
Unless expressly disallowed by institution rules, used and unused vials of study drug (including 
Rezafungin for Injection and caspofungin) will be retained at the study site until study drug 
accountability has been performed by the Pharmacy Monitor. Upon completion of the study, 


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termination of the study, or upon written authorization from the Sponsor, all retained unused 
and partially used study drug will be centrally destroyed. All records of disposal by a centralized 
destruction site will be maintained by the Sponsor. 


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9.0 
STUDY PROCEDURES 
Screening procedures are summarized in Section 9.1, the Required Treatment Period procedures 
and Follow-up procedures are summarized in Section 9.2 and Section 9.3, respectively, and the 
Optional Treatment Period (Days 15–28) procedures are summarized in Section 9.4. 
Study procedures should be completed within the windows provided in the Schedule of 
Assessments and Procedures for the Required Treatment, EOT, and Follow-up Periods 
in Table 1 and the Schedule of Assessments and Procedures for the Optional Treatment Period 
in Table 2, when applicable. However, if a subject is unable to attend a visit within the specified 
windows, the PI (or qualified designee) should discuss appropriate scheduling with the Medical 
Monitor (or appropriate designee). 
9.1 
Screening (≤4 days [96 hours]) 
• Obtain written informed consent prior to initiating any study related assessments 
or procedures. Consent from a legally acceptable representative (i.e. acceptable to ICH 
and local law, as applicable) may be obtained if the subject is unable to consent for 
themselves. 
• Obtain a complete medical history for the last 5 years and Candida risk factors for the 
last 3 months (e.g., central line, active malignancy, broad-spectrum antibiotic therapy, 
diabetes mellitus, immunosuppression, major surgery, total parenteral nutrition, 
transplant recipient, trauma, dialysis, burns, pancreatitis) and ICU admission and 
discharge (if applicable). 
• Record all prior and/or concomitant medications. 
• Presence of central line during Screening or placed during the study should be 
documented with dates and times of insertion and removal.  
• Short-term central venous catheters (e.g., peripherally-inserted central catheters, internal 
jugular, or subclavian central venous catheters) and long-term central venous catheters 
(e.g., tunneled catheters) are recommended to be removed within 48 hours after diagnosis 
with candidemia, consistent with IDSA (Pappas 2016) and ESCMID (Cornely 2012; 
Ullmann 2012) guidelines. 
• Record all systemic antifungal therapy administered within 4 weeks and all therapies 
(non-antifungal) within 1 week prior to randomization. 
• Clinical Assessments: 
o Conduct complete physical examination, including weight and height. 
o Conduct a thorough neurological examination as part of the physical examination to 
confirm no evidence of Grade 2 ataxia, tremor, sensory or motor neuropathy based on 
CTCAE version 5.0 criteria. 


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o Measure vital signs (temperature and the method used [oral, rectal, temporal, 
tympanic, or core], heart rate, blood pressure, and respiratory rate). Axillary 
temperatures are allowed, but not preferred. 
o Perform 12-lead ECG prior to randomization. 
o Assess presence or absence of systemic signs and symptoms and determine which are 
attributable to candidemia and/or invasive candidiasis. The Screening period for 
assessing systemic signs for inclusion in the study may include the 12 hours prior to 
the collection of the qualifying positive blood culture when systemic signs of 
infection were the reason for specimen collection (blood culture or fluid from a sterile 
site culture or qualifying rapid IVD [e.g., T2Candida Panel]) through study 
randomization. 
o Retinal examination for Candida eye infection (may occur as late as Day 7). Retinal 
examination is standard of care for subjects with candidemia and should be performed 
by an ophthalmologist, when available.  
• Laboratory assessments: 
o Draw blood for hematology and chemistry. 
o Draw blood for coagulation panel (PT/INR). 
o Only for subjects enrolled prior to Amendment 5: Draw PK blood sample for 
protein binding and for albumin core analyses. To limit invasive procedures these 
samples would ideally be collected at the same time into two vacutainers, though each 
sample could be collected separately. 
o Collect urine for urinalyses, microscopy. Subjects who are anuric do not need to 
complete this assessment. Urine microscopy is only required in the presence of 
abnormal urine chemistry tests. 
o Conduct serum pregnancy test (women of childbearing potential only; do not perform 
for women ≥2 years postmenopausal or surgically sterile).  
o A culture must be obtained as part of the standard of care for inclusion in the study. 
Established mycological diagnosis of candidemia or invasive candidiasis from 
a sample taken ≤4 days (96 hours) before randomization defined as one of the 
following:  
– ≥1 blood culture positive for yeast or Candida. 
– a positive test for Candida from sponsor-approved rapid IVD. 
– a 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. 


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NOTE: If the positive blood culture used to qualify the subject for the study is 
drawn >12 hours prior to randomization, an additional set of blood cultures must 
be obtained ≤12 hours before randomization. Identification and susceptibility 
testing at the local laboratory for Candida for blood or normally sterile tissue/fluid 
for culture is required at Screening and for any positive culture requiring a change 
of antifungal therapy (i.e., local identification and susceptibility testing is not 
required for Candida isolates cultured from specimens on other study days 
provided there is no required change of antifungal therapy). 
– If the subject is suspected of having invasive candidiasis, then all reasonable 
attempts to obtain a culture from the suspected site of infection should be made as 
early as possible before empiric therapy. 
– Perform identification and susceptibility testing at local laboratory for Candida 
for any positive blood culture or any positive culture from normally sterile site. 
– Record the spp. and susceptibilities for all bacteria isolated within 1 week prior to 
randomization from blood or any other normally sterile site. 
– Send all fungal isolates cultured from blood or normally sterile tissue/fluid to the 
Central Laboratory. 
• Calculate Child-Pugh score only if the subject has a history of chronic cirrhosis 
(see Appendix 4). 
• Record modified APACHE II parameters (see Appendix 5) with Glasgow Coma Score 
(see Appendix 6); note that the APACHE II score must be calculated prior to enrollment 
using the vital signs and laboratory results from the Screening visit. If multiple vital signs 
and laboratory values are obtained during the Screening period, it is preferred to use 
those collected most closely to the time of randomization. 
• Determine ANC for stratification from the most recent hematology results obtained prior 
to randomization. 
• If radiologic test is performed, record radiologic test type with Findings 
and Interpretation only if radiologic test provides evidence of invasive candidiasis. 
• Assess, identify, and record any AEs following signing of the ICF. 
• Confirm subject qualification by inclusion and exclusion criteria. 
9.2 
Required Treatment Period 
9.2.1 
Day 1 
• Randomize subject just prior to dosing. 
• Administer IV infusion of study drug over 60 (±10) minutes (refer to Section 8.0 
and Study Pharmacy Manual for additional infusion rate guidance). 
• Clinical Assessments: 


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o A focused physical exam (including a neurological exam) should be performed as 
clinically indicated by AE screening and course of the underlying disease. 
o Measure vital signs (temperature and the method used [oral, rectal, temporal, 
tympanic, or core], heart rate, blood pressure, and respiratory rate). Axillary 
temperatures are allowed, but not preferred.  
o If not completed during Screening, perform retinal examination for Candida eye 
infection for subjects with candidemia by blood culture (by Day 7). Additionally, 
any neutropenic subjects who recover their neutrophil counts during the study should 
have an additional retinal examination. The retinal examination should be repeated 
in subjects who were negative at baseline if the subject develops visual signs 
or symptoms of a Candida eye infection during the study. Subjects who were 
negative at baseline and diagnosed with a Candida eye infection after initiating study 
drug must discontinue study drug (see Section 7.4.2) but may continue in the study 
at the Investigator’s discretion; all subsequent antifungal drugs, interventions, 
and outcomes for endophthalmitis or chorioretinitis will be recorded. 
o Perform 12-lead ECG following administration of study drug (i.e., post-end IV 
infusion). 
• Laboratory Assessments: 
o Draw blood for hematology and serum chemistry tests (see Appendix 3); for subjects 
having routine daily blood draws for hematology and serum chemistry as standard of 
care, values to be entered into the eCRF will generally be the first draw of the day.  
o Draw blood or normally sterile tissue/fluid (if possible) for culture. 
– Perform identification and susceptibility testing for Candida for any positive 
culture requiring a change of antifungal therapy (i.e., identification and 
susceptibility testing not required for Candida isolates cultured from specimens 
obtained without a required change in antifungal therapy). 
– All fungal isolates cultured from blood and normally sterile tissue/fluid must be 
sent to the Central Laboratory. 
– Record the spp. for any new bacteria isolated from blood and the spp. and 
susceptibilities for any new bacteria isolated from any other normally sterile site. 
• One blood sample for PK will be collected within 10 minutes before the end of infusion, 
and one sample taken any time between the end of infusion and 12 hours after the end of 
infusion. Draw blood for PK analysis from the OPPOSITE arm or through an arterial line 
during the infusion; after the infusion is complete opposite arm or arterial line draws are 
preferred. For subjects receiving hemodialysis, an attempt should be made to obtain PK 
samples directly following hemodialysis if still within the required time window. 
• Record all prior and/or concomitant medications. 
• Record AEs. 


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•
Presence of central line during Screening or placed during the study should be 
documented with dates and times of insertion and removal.
•
Short-term central venous catheters (e.g., peripherally-inserted central catheters, internal 
jugular, or subclavian central venous catheters) and long-term central venous catheters 
(e.g., tunneled catheters) are recommended to be removed within 48 hours after diagnosis 
with candidemia, consistent with IDSA (Pappas 2016) and ESCMID (Cornely 2012; 
Ullmann 2012) guidelines.
•
If radiologic test is performed, record radiologic test type with Findings
and Interpretation only if radiologic test provides evidence of invasive candidiasis
or evidence of progression, stabilization, improvement, or resolution of invasive 
candidiasis from previous radiographs. Criteria for cure, indeterminate, and failure 
responses are found in Table 10.
9.2.2 
Day 2 
•
Administer IV infusion of study drug over 60 (±10) minutes (refer to Section 8.0
and Study Pharmacy Manual for additional infusion rate guidance).
•
Clinical Assessments:
o
A focused physical exam (including a neurological exam) should be performed as
clinically indicated by AE screening and course of the underlying disease.
o
Measure vital signs (temperature and the method used [oral, rectal, temporal,
tympanic, or core], heart rate, blood pressure, and respiratory rate). Axillary
temperatures are allowed, but not preferred.
o
If not completed during Screening, perform retinal examination for Candida eye
infection for subjects with candidemia by blood culture (by Day 7). Additionally, any
neutropenic subjects who recover their neutrophil counts during the study should
have an additional retinal examination. The retinal examination should be repeated
in subjects who were negative at baseline if the subject develops visual signs
or symptoms of a Candida eye infection during the study. Subjects who were
negative at baseline and are diagnosed with a Candida eye infection after initiating
study drug must discontinue study drug (see Section 7.4.2) but may continue in the
study at the Investigator’s discretion; all subsequent antifungal drugs, interventions,
and outcomes for endophthalmitis or chorioretinitis will be recorded.
•
Laboratory Assessments:
o
Draw blood for hematology and serum chemistry tests (see Appendix 1); for subjects
having routine daily blood draws for hematology and serum chemistry as standard of
care, values to be entered into the eCRF will generally be the first draw of the day.
o
Draw blood or normally sterile tissue/fluid (if possible) for culture.


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–
Perform identification and susceptibility testing for Candida for any
positive culture requiring a change of antifungal therapy (i.e., identification
and susceptibility testing not required for Candida isolates cultured from
specimens obtained without a required change in antifungal therapy).
–
All fungal isolates cultured from blood and normally sterile tissue/fluid must be
sent to the Central Laboratory.
–
Record the spp. for any new bacteria isolated from blood and the spp.
and susceptibilities for any new bacteria isolated from any other normally
sterile site.
o
One blood sample for PK will be collected at any time on one of the following
Days 2, 3, 4, or 5 (i.e., if blood sample for PK not collected on Day 2, must be
collected on Day 3 [or Day 4 or Day 5]). Draw blood for PK analysis from the
OPPOSITE arm or through an arterial line during the infusion; after the infusion is
complete opposite arm or arterial line draws are preferred. For subjects receiving
hemodialysis, an attempt should be made to obtain PK samples directly following
hemodialysis if still within the required time window.
•
Record all concomitant medications.
•
Record AEs.
•
Presence of central line during Screening or placed during the study should be 
documented with dates and times of insertion and removal.
•
Short-term central venous catheters (e.g., peripherally-inserted central catheters, internal 
jugular, or subclavian central venous catheters) and long-term central venous catheters 
(e.g., tunneled catheters) are recommended to be removed within 48 hours after diagnosis 
with candidemia, consistent with IDSA (Pappas 2016) and ESCMID (Cornely 2012; 
Ullmann 2012) guidelines.
•
If radiologic test is performed, record radiologic test type with Findings
and Interpretation only if radiologic test provides evidence of invasive candidiasis
or evidence of progression, stabilization, improvement, or resolution of invasive 
candidiasis from previous radiographs. Criteria for cure, indeterminate, and failure 
responses are found in Table 10.
9.2.3 
Day 3 
•
Administer IV infusion of study drug over 60 (±10) minutes (refer to Section 8.0
and Study Pharmacy Manual for additional infusion rate guidance).
•
Clinical Assessments:
o
A focused physical exam (including a neurological exam) should be performed as
clinically indicated by AE screening and course of the underlying disease.


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o Measure vital signs (temperature and the method used [oral, rectal, temporal, 
tympanic, or core], heart rate, blood pressure, and respiratory rate). Axillary 
temperatures are allowed, but not preferred. 
o If not completed during Screening, perform retinal examination for Candida eye 
infection for subjects with candidemia by blood culture (by Day 7). Additionally, any 
neutropenic subjects who recover their neutrophil counts during the study should 
have an additional retinal examination. The retinal examination should be repeated 
in subjects who were negative at baseline if the subject develops visual signs 
or symptoms of a Candida eye infection during the study. Subjects who were 
negative at baseline and are diagnosed with a Candida eye infection after initiating 
study drug must discontinue study drug (see Section 7.4.2) but may continue in the 
study at the Investigator’s discretion; all subsequent antifungal drugs, interventions, 
and outcomes for endophthalmitis or chorioretinitis will be recorded. 
• Laboratory Assessments: 
o Draw blood or normally sterile tissue/fluid (if possible) for culture if demonstrating 
mycological eradication (if not already done) or if clinically indicated. 
– Perform identification and susceptibility testing for Candida for any 
positive culture requiring a change of antifungal therapy (i.e., identification 
and susceptibility testing not required for Candida isolates cultured from 
specimens obtained without a required change in antifungal therapy). 
– All fungal isolates cultured from blood and normally sterile tissue/fluid must be 
sent to the Central Laboratory. 
– Record the spp. for any new bacteria isolated from blood and the spp. and 
susceptibilities for any new bacteria isolated from any other normally sterile site. 
o One blood sample for PK will be collected at any time on Days 2, 3, 4, or 5 
(i.e., if blood sample for PK not collected on Day 2, must be collected on Day 3 
[or Day 4 or Day 5]). Draw blood for PK analysis from the OPPOSITE arm 
or through an arterial line during the infusion; after the infusion is complete opposite 
arm or arterial line draws are preferred. For subjects receiving hemodialysis, 
an attempt should be made to obtain PK samples directly following hemodialysis 
if still within the required time window. 
• Record all concomitant medications. 
• Record AEs. 
• Presence of central line during Screening or placed during the study should be 
documented with dates and times of insertion and removal.  


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Protocol Amendment 5 
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•
Short-term central venous catheters (e.g., peripherally-inserted central catheters, internal 
jugular, or subclavian central venous catheters) and long-term central venous catheters 
(e.g., tunneled catheters) are recommended to be removed within 48 hours after diagnosis 
with candidemia, consistent with IDSA (Pappas 2016) and ESCMID (Cornely 2012; 
Ullmann 2012) guidelines.
•
If radiologic test is performed, record radiologic test type with Findings
and Interpretation only if radiologic test provides evidence of invasive candidiasis
or evidence of progression, stabilization, improvement, or resolution of invasive 
candidiasis from previous radiographs. Criteria for cure, indeterminate, and failure 
responses are found in Table 10.
9.2.4 
Day 4 
•
Administer study drug:
o
IV infusion of study drug over 60 (±10) minutes (refer to Section 8.0 and the Study
Pharmacy Manual for additional infusion rate guidance). Administration should occur
24 (±2) hours after study drug was administered on the previous day.
OR
o
Oral step-down therapy.
•
Clinical Assessments:
o
A focused physical exam (including a neurological exam) should be performed as
clinically indicated by AE screening and course of the underlying disease.
o
Measure vital signs (temperature and the method used [oral, rectal, temporal,
tympanic, or core], heart rate, blood pressure, and respiratory rate). Axillary
temperatures are allowed, but not preferred.
o
If not completed during Screening, perform retinal examination for Candida eye
infection for subjects with candidemia by blood culture (by Day 7). Additionally, any
neutropenic subjects who recover their neutrophil counts during the study should
have an additional retinal examination. The retinal examination should be repeated
in subjects who were negative at baseline if the subject develops visual signs
or symptoms of a Candida eye infection during the study. Subjects who were
negative at baseline and are diagnosed with a Candida eye infection after initiating
study drug must discontinue study drug (see Section 7.4.2) but may continue in the
study at the Investigator’s discretion; all subsequent antifungal drugs, interventions,
and outcomes for endophthalmitis or chorioretinitis will be recorded.
•
Laboratory Assessments:
o
Draw blood for hematology and serum chemistry tests (see Appendix 3); for subjects
having routine daily blood draws for hematology and serum chemistry as standard of
care, values to be entered into the eCRF with generally be the first draw of the day.


Cidara Therapeutics, Inc. 
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Rezafungin for Injection 
Protocol Amendment 5 
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o
Draw blood or normally sterile tissue/fluid (if possible) for culture if demonstrating
mycological eradication (if not already done) or if clinically indicated.
–
Perform identification and susceptibility testing for Candida for any
positive culture requiring a change of antifungal therapy (i.e., identification
and susceptibility testing not required for Candida isolates cultured from
specimens obtained without a required change in antifungal therapy).
–
All fungal isolates cultured from blood and normally sterile tissue/fluid must be
sent to the Central Laboratory.
–
Record the spp. for any new bacteria isolated from blood and the spp.
and susceptibilities for any new bacteria isolated from any other normally
sterile site.
o
One blood sample for PK will be collected at any time on Days 2, 3, 4, or 5
(i.e., if blood sample for PK not collected on Day 2 or Day 3, must be collected on
Day 4 [or Day 5]). Draw blood for PK analysis from the OPPOSITE arm or through
an arterial line during the infusion; after the infusion is complete opposite arm
or arterial line draws are preferred. For subjects receiving hemodialysis, an attempt
should be made to obtain PK samples directly following hemodialysis if still within
the required time window.
•
Record all concomitant medications.
•
Record AEs.
•
Presence of central line during Screening or placed during the study should be 
documented with dates and times of insertion and removal.
•
Short-term central venous catheters (e.g., peripherally-inserted central catheters, internal 
jugular, or subclavian central venous catheters) and long-term central venous catheters 
(e.g., tunneled catheters) are recommended to be removed within 48 hours after diagnosis 
with candidemia, consistent with IDSA (Pappas 2016) and ESCMID (Cornely 2012; 
Ullmann 2012) guidelines.
•
If radiologic test is performed, record radiologic test type with Findings
and Interpretation only if radiologic test provides evidence of invasive candidiasis
or evidence of progression, stabilization, improvement, or resolution of invasive 
candidiasis from previous radiographs. Criteria for cure, indeterminate, and failure 
responses are found in Table 10.


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9.2.5 
Days 5–7 
•
Administer study drug
o
IV infusion of study drug over 60 (±10) minutes (refer to Section 8.0 and the Study 
Pharmacy Manual for additional infusion rate guidance). Administration should occur 
24 (±2) hours after study drug was administered on the previous day.
OR
o
Oral step-down therapy.
•
Clinical Assessments:
o
Conduct complete physical examination on Day 5 only.
o
Conduct neurological examination as part of the physical examination, as clinically 
indicated.
o
On Day 6 and Day 7, conduct a focused physical examination (including neurological 
exam) only if clinically indicated by adverse event screening and course of the 
underlying disease.
o
Measure vital signs (temperature and the method used [oral, rectal, temporal, 
tympanic, or core], heart rate, blood pressure, and respiratory rate). Axillary 
temperatures are allowed, but not preferred.
o
If not completed during Screening, perform retinal examination for Candida eye 
infection for subjects with candidemia by blood culture (by Day 7). Additionally, any 
neutropenic subjects who recover their neutrophil counts during the study should have 
an additional retinal examination. The retinal examination should be repeated in 
subjects who were negative at baseline if the subject develops visual signs
or symptoms of a Candida eye infection during the study. Subjects who were negative 
at baseline and are diagnosed with a Candida eye infection after initiating study drug 
must discontinue study drug (see Section 7.4.2) but may continue in the study at the 
Investigator’s discretion; all subsequent antifungal drugs, interventions, and outcomes 
for endophthalmitis or chorioretinitis will be recorded.
o
Assess presence or absence of systemic signs and symptoms and determine which are 
attributable to candidemia and/or invasive candidiasis on Day 5 only.
o
Assess for clinical response on Day 5 only (Table 9).
•
Laboratory Assessments:
o
Draw blood or normally sterile tissue/fluid (if possible) for culture if demonstrating 
mycological eradication (if not already done) or if clinically indicated.


Cidara Therapeutics, Inc. 
Protocol CD101.IV.3.05 A5 
Rezafungin for Injection 
Protocol Amendment 5 
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–
Perform identification and susceptibility testing for Candida for any positive
culture requiring a change of antifungal therapy (i.e., identification and
susceptibility testing not required for Candida isolates cultured from specimens
obtained without a required change in antifungal therapy).
–
All fungal isolates cultured from blood and normally sterile tissue/fluid must be
sent to the Central Laboratory.
–
Record the spp. for any new bacteria isolated from blood and the spp.
and susceptibilities for any new bacteria isolated from any other normally
sterile site.
o
On Day 5, one blood sample for PK will be collected at any time if not collected on
Day 2 or Day 3 or Day 4. Draw blood for PK analysis from the OPPOSITE arm
or through an arterial line during the infusion; after the infusion is complete opposite
arm or arterial line draws are preferred. For subjects receiving hemodialysis,
an attempt should be made to obtain PK samples directly following hemodialysis
if still within the required time window.
•
Record all concomitant medications.
•
Record AEs.
•
Presence of central line during Screening or placed during the study should be 
documented with dates and times of insertion and removal.
•
Short-term central venous catheters (e.g., peripherally-inserted central catheters, internal 
jugular, or subclavian central venous catheters) and long-term central venous catheters 
(e.g., tunneled catheters) are recommended to be removed within 48 hours after diagnosis 
with candidemia, consistent with IDSA (Pappas 2016) and ESCMID (Cornely 2012; 
Ullmann 2012) guidelines.
•
If radiologic test is performed, record radiologic test type with Findings and Interpretation 
only if radiologic test provides evidence of invasive candidiasis
or evidence of progression, stabilization, improvement, or resolution of invasive 
candidiasis from previous radiographs. Criteria for cure, indeterminate, and failure 
responses are found in Table 10.
9.2.6 
Day 8 (±1 day) 
•
One blood sample for PK will be collected predose (≤30 minutes prior to the start of the
infusion). Draw blood for PK analysis from the OPPOSITE arm or through an arterial
line during the infusion; after the infusion is complete, opposite arm or arterial line draws
are preferred. For subjects receiving hemodialysis, an attempt should be made to obtain
PK samples directly following hemodialysis if still within the required time window.
•
Administer study drug:


Cidara Therapeutics, Inc. 
Protocol CD101.IV.3.05 A5 
Rezafungin for Injection 
Protocol Amendment 5 
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o
IV infusion of study drug over 60 (±10) minutes (refer to Section 8.0 and the Study
Pharmacy Manual for additional infusion rate guidance). Administration should occur
24 (±2) hours after study drug was administered on the previous day.
OR
o
IV infusion of study drug over 60 (±10) minutes (refer to Section 8.0 and the Study
Pharmacy Manual for additional infusion rate guidance). Administration should occur
24 (±2) hours after study drug was administered on the previous day PLUS oral
step-down therapy, if already stepped down.
•
Clinical Assessments:
o
A focused physical exam (including a neurological exam) should be performed as
clinically indicated by AE screening and course of the underlying disease.
o
Measure vital signs (temperature and the method used [oral, rectal, temporal,
tympanic, or core], heart rate, blood pressure, and respiratory rate). Axillary
temperatures are allowed, but not preferred.
o
The retinal examination should be repeated in subjects who were negative at baseline
if the subject develops visual signs or symptoms of a Candida eye infection during
the study. Additionally, any neutropenic subjects who recover their neutrophil counts
during the study should have an additional retinal examination. Subjects who were
negative at baseline and are diagnosed with a Candida eye infection after initiating
study drug must discontinue study drug (see Section 7.4.2) but may continue in the
study at the Investigator’s discretion; all subsequent antifungal drugs, interventions,
and outcomes for endophthalmitis or chorioretinitis will be recorded.
•
Laboratory Assessments:
o
Draw blood for hematology and serum chemistry tests (see Appendix 3); for subjects
having routine daily blood draws for hematology and serum chemistry as standard of
care, values to be entered into the eCRF with generally be the first draw of the day.
o
Draw blood or normally sterile tissue/fluid (if possible) for culture if demonstrating
mycological eradication (if not already done) or if clinically indicated.
–
Perform identification and susceptibility testing for Candida for any
positive culture requiring a change of antifungal therapy (i.e., identification
and susceptibility testing not required for Candida isolates cultured from
specimens obtained without a required change in antifungal therapy).
–
All fungal isolates cultured from blood and normally sterile tissue/fluid must be
sent to the Central Laboratory.
–
Record the spp. for any new bacteria isolated from blood and the spp.
and susceptibilities for any new bacteria isolated from any other normally
sterile site.


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Rezafungin for Injection 
Protocol Amendment 5 
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•
Record all concomitant medications.
•
Record AEs.
•
Presence of central line during Screening or placed during the study should be 
documented with dates and times of insertion and removal.
•
Short-term central venous catheters (e.g., peripherally-inserted central catheters, internal 
jugular, or subclavian central venous catheters) and long-term central venous catheters 
(e.g., tunneled catheters) are recommended to be removed within 48 hours after diagnosis 
with candidemia, consistent with IDSA (Pappas 2016) and ESCMID (Cornely 2012; 
Ullmann 2012) guidelines.
•
If radiologic test is performed, record radiologic test type with Findings and Interpretation 
only if radiologic test provides evidence of invasive candidiasis
or evidence of progression, stabilization, improvement, or resolution of invasive 
candidiasis from previous radiographs. Criteria for cure, indeterminate, and failure 
responses are found in Table 10.
9.2.7 
Days 9–13 
•
Administer study drug:
o
IV infusion of study drug over 60 (±10) minutes (refer to Section 8.0 and the Study
Pharmacy Manual for additional infusion rate guidance). Administration should occur
24 (±2) hours after study drug was administered on the previous day.
OR
o
Oral step-down therapy.
•
Clinical Assessments:
o
A focused physical exam (including a neurological exam) should be performed as
clinically indicated by AE screening and course of the underlying disease.
o
Measure vital signs (temperature and the method used [oral, rectal, temporal,
tympanic, or core], heart rate, blood pressure, and respiratory rate). Axillary
temperatures are allowed, but not preferred.
o
The retinal examination should be repeated in subjects who were negative at baseline
if the subject develops visual signs or symptoms of a Candida eye infection during
the study. Additionally, any neutropenic subjects who recover their neutrophil counts
during the study should have an additional retinal examination. Subjects who were
negative at baseline and are diagnosed with a Candida eye infection after initiating
study drug must discontinue study drug (see Section 7.4.2) but may continue in the
study at the Investigator’s discretion; all subsequent antifungal drugs, interventions,
and outcomes for endophthalmitis or chorioretinitis will be recorded.


Cidara Therapeutics, Inc. 
Protocol CD101.IV.3.05 A5 
Rezafungin for Injection 
Protocol Amendment 5 
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Page 91 of 156 
•
Laboratory Assessments:
o
Draw blood or normally sterile tissue/fluid (if possible) for culture if demonstrating 
mycological eradication (if not already done) or if clinically indicated.
–
Perform identification and susceptibility testing for Candida for any
positive culture requiring a change of antifungal therapy (i.e., identification
and susceptibility testing not required for Candida isolates cultured from 
specimens obtained without a required change in antifungal therapy).
–
All fungal isolates cultured from blood and normally sterile tissue/fluid must be 
sent to the Central Laboratory.
–
Record the spp. for any new bacteria isolated from blood and the spp.
and susceptibilities for any new bacteria isolated from any other normally sterile 
site.
•
Record all concomitant medications.
•
Record AEs.
•
Presence of central line during Screening or placed during the study should be 
documented with dates and times of insertion and removal.
•
Short-term central venous catheters (e.g., peripherally-inserted central catheters, internal 
jugular, or subclavian central venous catheters) and long-term central venous catheters 
(e.g., tunneled catheters) are recommended to be removed within 48 hours after diagnosis 
with candidemia, consistent with IDSA (Pappas 2016) and ESCMID (Cornely 2012; 
Ullmann 2012) guidelines.
•
If radiologic test is performed, record radiologic test type with Findings
and Interpretation only if radiologic test provides evidence of invasive
candidiasis or evidence of progression, stabilization, improvement, or resolution
of invasive candidiasis from previous radiographs. Criteria for cure, indeterminate,
and failure responses are found in Table 10.
9.2.8 
Day 14 (±1 day) 
•
Administer study drug:
o
IV infusion of study drug over 60 (±10) minutes (refer to Section 8.0 and the Study
Pharmacy Manual for additional infusion rate guidance). Administration should occur
24 (±2) hours after study drug was administered on the previous day.
OR
o
Oral step-down therapy.
•
Clinical Assessments:
o
Conduct complete physical examination, including weight.


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Rezafungin for Injection 
Protocol Amendment 5 
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o
Conduct neurological examination as part of the physical examination, as clinically
indicated.
o
Measure vital signs (temperature and the method used [oral, rectal, temporal,
tympanic, or core], heart rate, blood pressure, and respiratory rate). Axillary
temperatures are allowed, but not preferred.
The retinal examination should be repeated in subjects who were negative at baseline if 
the subject develops visual signs or symptoms of a Candida eye infection during the 
study. Additionally, any neutropenic subjects who recover their neutrophil counts during 
the study should have an additional retinal examination. Subjects who were negative at 
baseline and are diagnosed with a Candida eye infection after initiating study drug must 
discontinue study drug (see Section 7.4.2) but may continue in the study at the 
Investigator’s discretion; all subsequent antifungal drugs, interventions, and outcomes for 
endophthalmitis or chorioretinitis will be recorded.
o
Assess presence or absence of systemic signs and symptoms and determine which are 
attributable to candidemia and/or invasive candidiasis.
o
Assess for clinical response (Table 9).
Laboratory assessments:
o
Draw blood for hematology and chemistry.
o
Draw blood or normally sterile tissue/fluid (if possible) for culture if demonstrating 
mycological eradication (if not already done) or if clinically indicated.
–
Perform identification and susceptibility testing for Candida for any positive 
culture requiring a change of antifungal therapy (i.e., identification and 
susceptibility testing not required for Candida isolates cultured from specimens 
obtained without a required change in antifungal therapy).
–
All fungal isolates cultured from blood and normally sterile tissue/fluid must be 
sent to the Central Laboratory.
–
Record the spp. for any new bacteria isolated from blood and the spp.
and susceptibilities for any new bacteria isolated from any other normally sterile 
site.
o
For subjects not receiving a Day 15 dose, on Day 14, one blood sample for PK will be 
collected at any time. Draw blood for PK analysis from the OPPOSITE arm
or through an arterial line during the infusion; after the infusion is complete opposite 
arm or arterial line draws are preferred. For subjects receiving hemodialysis,
an attempt should be made to obtain PK samples directly following hemodialysis if 
still within the required time window.
Record all concomitant medications.
Record AEs.


Cidara Therapeutics, Inc. 
Protocol CD101.IV.3.05 A5 
Rezafungin for Injection 
Protocol Amendment 5 
Confidential 
Page 93 of 156 
•
Presence of central line during Screening or placed during the study should be 
documented with dates and times of insertion and removal.
•
Short-term central venous catheters (e.g., peripherally-inserted central catheters, internal 
jugular, or subclavian central venous catheters) and long-term central venous catheters 
(e.g., tunneled catheters) are recommended to be removed within 48 hours after diagnosis 
with candidemia, consistent with IDSA (Pappas 2016) and ESCMID (Cornely 2012; 
Ullmann 2012) guidelines.
•
If radiologic test is performed, record radiologic test type with Findings and Interpretation 
only if radiologic test provides evidence of invasive candidiasis or evidence of 
progression, stabilization, improvement, or resolution of invasive candidiasis from 
previous radiographs. Criteria for cure, indeterminate, and failure responses are found 
in Table 10.
9.2.9 
Day 30 (-2 days) 
•
Clinical Assessments:
o
Conduct complete physical examination.
o
Conduct neurological examination as part of the physical examination, as clinically 
indicated.
o
Measure vital signs (temperature and the method used [oral, rectal, temporal, 
tympanic, or core], heart rate, blood pressure, and respiratory rate). Axillary 
temperatures are allowed, but not preferred.
o
The retinal examination should be repeated in subjects who were negative at baseline 
if the subject develops visual signs or symptoms of a Candida eye infection during 
the study. Additionally, any neutropenic subjects who recover their neutrophil counts 
during the study should have an additional retinal examination.
o
Assess presence or absence of systemic signs and symptoms and determine which are 
attributable to candidemia and/or invasive candidiasis.
o
Assess for clinical response (Table 9).
o
Assess ACM.
•
Laboratory assessments:
o
Draw blood for hematology and chemistry.
o
Draw blood or normally sterile tissue/fluid (if possible) for culture if demonstrating 
mycological eradication (if not already done) or if clinically indicated.
–
Perform identification and susceptibility testing for Candida for any
positive culture requiring a change of antifungal therapy (i.e., identification
and susceptibility testing not required for Candida isolates cultured from 
specimens obtained without a required change in antifungal therapy).


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–
All fungal isolates cultured from blood and normally sterile tissue/fluid must be
sent to the Central Laboratory.
–
Record the spp. for any new bacteria isolated from blood and the spp.
and susceptibilities for any new bacteria isolated from any other normally
sterile site.
•
Record all concomitant medications.
•
Record AEs.
•
Presence of central line during Screening or placed during the study should be 
documented with dates and times of insertion and removal.
•
Short-term central venous catheters (e.g., peripherally-inserted central catheters, internal 
jugular, or subclavian central venous catheters) and long-term central venous catheters 
(e.g., tunneled catheters) are recommended to be removed within 48 hours after diagnosis 
with candidemia, consistent with IDSA (Pappas 2016) and ESCMID (Cornely 2012; 
Ullmann 2012) guidelines.
•
If radiologic test is performed, record radiologic test type with Findings
and Interpretation only if radiologic test provides evidence of invasive candidiasis
or evidence of progression, stabilization, improvement, or resolution of invasive 
candidiasis from previous radiographs. Criteria for cure, indeterminate, and failure 
responses are found in Table 10.
9.2.10 
End of Treatment (≤2 days of last dose) 
•
Clinical Assessments:
o
Assess for clinical response (Table 9).
o
Conduct complete physical examination.
o
Conduct a thorough neurological examination as part of the physical examination.
o
Measure vital signs (temperature and the method used [oral, rectal, temporal, 
tympanic, or core], heart rate, blood pressure, and respiratory rate). Axillary 
temperatures are allowed, but not preferred.
o
The retinal examination should be repeated in subjects who were negative at baseline 
if the subject develops visual signs or symptoms of a Candida eye infection during 
the study. Additionally, any neutropenic subjects who recover their neutrophil counts 
during the study should have an additional retinal examination.
•
Laboratory assessments:
o
Draw blood for hematology and chemistry.


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o
Collect urine for urinalyses, microscopy. Subjects who are anuric do not need to
complete this assessment. Urine microscopy is only required in the presence of
abnormal urine chemistry tests.
o
Draw blood or normally sterile tissue/fluid (if possible) for culture if demonstrating
mycological eradication (if not already done) or if clinically indicated.
–
Perform identification and susceptibility testing for Candida for any
positive culture requiring a change of antifungal therapy (i.e., identification
and susceptibility testing not required for Candida isolates cultured from
specimens obtained without a required change in antifungal therapy).
–
All fungal isolates cultured from blood and normally sterile tissue/fluid must be
sent to the Central Laboratory.
–
Record the spp. for any new bacteria isolated from blood and the spp.
and susceptibilities for any new bacteria isolated from any other normally
sterile site.
•
Record all concomitant medications.
•
Record AEs.
•
Presence of central line during Screening or placed during the study should be 
documented with dates and times of insertion and removal.
•
Short-term central venous catheters (e.g., peripherally-inserted central catheters, internal 
jugular, or subclavian central venous catheters) and long-term central venous catheters 
(e.g., tunneled catheters) are recommended to be removed within 48 hours after diagnosis 
with candidemia, consistent with IDSA (Pappas 2016) and ESCMID (Cornely 2012; 
Ullmann 2012) guidelines.
•
If radiologic test is performed, record radiologic test type with Findings
and Interpretation only if radiologic test provides evidence of invasive candidiasis
or evidence of progression, stabilization, improvement, or resolution of invasive 
candidiasis from previous radiographs. Criteria for cure, indeterminate, and failure 
responses are found in Table 10.
NOTE: The EOT visit may be performed at the same time as the Day 14 or Day 30 visit 
if completed within 2 calendar days of the last dose.
9.3 
Follow-up (Days 52–59) 
•
Clinical Assessments:
o
Conduct complete physical examination, including weight.


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o
Conduct neurological examination as part of the physical examination, as clinically 
indicated.
o
Measure vital signs (temperature and the method used [oral, rectal, temporal, 
tympanic, or core], heart rate, blood pressure, and respiratory rate). Axillary 
temperatures are allowed, but not preferred.
o
The retinal examination should be repeated in subjects who were negative at baseline 
if the subject develops visual signs or symptoms of a Candida eye infection during 
the study. Additionally, any neutropenic subjects who recover their neutrophil counts 
during the study should have an additional retinal examination.
o
Assess presence or absence of systemic signs and symptoms and determine which are 
attributable to candidemia and/or invasive candidiasis.
o
Assess for clinical response (Table 9).
o
Assess ACM.
•
Laboratory assessments:
o
Draw blood for hematology and chemistry.
o
Conduct serum pregnancy test (women of childbearing potential only; do not perform 
for women ≥2 years postmenopausal or surgically sterile).
o
Draw blood or normally sterile tissue/fluid (if possible) for culture only if clinically 
indicated.
–
Perform identification and susceptibility testing for Candida for any
positive culture requiring a change of antifungal therapy (i.e., identification
and susceptibility testing not required for Candida isolates cultured from 
specimens obtained without a required change in antifungal therapy).
–
All fungal isolates cultured from blood and normally sterile tissue/fluid must be 
sent to the Central Laboratory.
–
Record the spp. for any new bacteria isolated from blood and the spp.
and susceptibilities for any new bacteria isolated from any other normally sterile 
site.
•
Record all concomitant medications.
•
Record AEs.
•
If radiologic test is performed, record radiologic test type with Findings
and Interpretation only if radiologic test provides evidence of invasive candidiasis
or evidence of progression, stabilization, improvement, or resolution of invasive 
candidiasis from previous radiographs. Criteria for cure, indeterminate, and failure 
responses are found in Table 10.


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9.4 
Optional Treatment Period 
9.4.1 
Days 15 (±1 day) 
•
One blood sample for PK will be collected pre-dose (≤30 minutes prior to the start of the
infusion). Draw blood for PK analysis from the OPPOSITE arm or through an arterial
line during the infusion; after the infusion is complete, opposite arm or arterial line draws
are preferred. For subjects receiving hemodialysis, an attempt should be made to obtain
PK samples directly following hemodialysis if still within the required time window.
•
Administer study drug:
o
IV infusion of study drug over 60 (±10) minutes (refer to Section 8.0 and the Study
Pharmacy Manual for additional infusion rate guidance). Administration should occur
24 (±2) hours after study drug was administered on the previous day.
OR
o
IV infusion of study drug over 60 (±10) minutes (refer to Section 8.0 and the Study
Pharmacy Manual for additional infusion rate guidance). Administration should occur
24 (±2) hours after study drug was administered on the previous day PLUS oral
step-down therapy.
•
Clinical Assessments:
o
Conduct complete physical examination.
o
Conduct neurological examination as part of the physical examination, as clinically
indicated.
o
Measure vital signs (temperature and the method used [oral, rectal, temporal,
tympanic, or core], heart rate, blood pressure, and respiratory rate). Axillary
temperatures are allowed, but not preferred.
o
The retinal examination should be repeated in subjects who were negative at baseline
if the subject develops visual signs or symptoms of a Candida eye infection during
the study. Additionally, any neutropenic subjects who recover their neutrophil counts
during the study should have an additional retinal examination. Subjects who were
negative at baseline and are diagnosed with a Candida eye infection after initiating
study drug must discontinue study drug (see Section 7.4.2) but may continue in the
study at the Investigator’s discretion; all subsequent antifungal drugs, interventions,
and outcomes for endophthalmitis or chorioretinitis will be recorded.
•
Laboratory Assessments:
o
Draw blood or normally sterile tissue/fluid (if possible) for culture if demonstrating
mycological eradication (if not already done) or if clinically indicated.


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–
Perform identification and susceptibility testing for Candida for any positive
culture requiring a change of antifungal therapy (i.e., identification and
susceptibility testing not required for Candida isolates cultured from specimens
obtained without a required change in antifungal therapy).
–
All fungal isolates cultured from blood and normally sterile tissue/fluid must be
sent to the Central Laboratory.
–
Record the spp. for any new bacteria isolated from blood and the spp. and
susceptibilities for any new bacteria isolated from any other normally sterile site.
•
Record all concomitant medications.
•
Record AEs.
•
Presence of central line during Screening or placed during the study should be 
documented with dates and times of insertion and removal.
•
Short-term central venous catheters (e.g., peripherally-inserted central catheters, internal 
jugular, or subclavian central venous catheters) and long-term central venous catheters 
(e.g., tunneled catheters) are recommended to be removed within 48 hours after diagnosis 
with candidemia, consistent with IDSA (Pappas 2016) and ESCMID (Cornely 2012; 
Ullmann 2012) guidelines.
•
If radiologic test is performed, record radiologic test type with Findings
and Interpretation only if radiologic test provides evidence of invasive candidiasis
or evidence of progression, stabilization, improvement, or resolution of invasive 
candidiasis from previous radiographs. Criteria for cure, indeterminate, and failure 
responses are found in Table 10.
9.4.2 
Days 16–21 
•
Administer study drug:
o
IV infusion of study drug over 60 (±10) minutes (refer to Section 8.0 and the Study
Pharmacy Manual for additional infusion rate guidance); administration should occur
24 (±2) hours after study drug was administered on the previous day.
OR
o
Oral step-down therapy.
•
Clinical Assessments:
o
A focused physical exam (including a neurological exam) should be performed as
clinically indicated by AE screening and course of the underlying disease.
o
Measure vital signs (temperature and the method used [oral, rectal, temporal,
tympanic, or core], heart rate, blood pressure, and respiratory rate). Axillary
temperatures are allowed, but not preferred.


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o
The retinal examination should be repeated in subjects who were negative at baseline
if the subject develops visual signs or symptoms of a Candida eye infection during
the study. Additionally, any neutropenic subjects who recover their neutrophil counts
during the study should have an additional retinal examination. Subjects who were
negative at baseline and are diagnosed with a Candida eye infection after initiating
study drug must discontinue study drug (see Section 7.4.2) but may continue in the
study at the Investigator’s discretion; all subsequent antifungal drugs, interventions,
and outcomes for endophthalmitis or chorioretinitis will be recorded.
•
Laboratory Assessments:
o
Draw blood or normally sterile tissue/fluid (if possible) for culture if demonstrating 
mycological eradication (if not already done) or if clinically indicated.
–
Perform identification and susceptibility testing for Candida for any
positive culture requiring a change of antifungal therapy (i.e., identification
and susceptibility testing not required for Candida isolates cultured from 
specimens obtained without a required change in antifungal therapy).
–
All fungal isolates cultured from blood and normally sterile tissue/fluid must be 
sent to the Central Laboratory.
–
Record the spp. for any new bacteria isolated from blood and the spp.
and susceptibilities for any new bacteria isolated from any other normally sterile 
site.
•
Record all concomitant medications.
•
Record AEs.
•
Presence of central line during Screening or placed during the study should be 
documented with dates and times of insertion and removal.
•
Short-term central venous catheters (e.g., peripherally-inserted central catheters, internal 
jugular, or subclavian central venous catheters) and long-term central venous catheters 
(e.g., tunneled catheters) are recommended to be removed within 48 hours after diagnosis 
with candidemia, consistent with IDSA (Pappas 2016) and ESCMID (Cornely 2012; 
Ullmann 2012) guidelines.
•
If radiologic test is performed, record radiologic test type with Findings and Interpretation 
only if radiologic test provides evidence of invasive candidiasis
or evidence of progression, stabilization, improvement, or resolution of invasive 
candidiasis from previous radiographs. Criteria for cure, indeterminate, and failure 
responses are found in Table 10.


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9.4.3 
Day 22 (±1 day) 
• One blood sample for PK will be collected pre-dose (≤30 minutes prior to the start of the 
infusion). Draw blood for PK analysis from the OPPOSITE arm or through an arterial 
line during the infusion; after the infusion is complete opposite arm or arterial line draws 
are preferred. For subjects receiving hemodialysis, an attempt should be made to obtain 
PK samples directly following hemodialysis if still within the required time window. 
• Administer study drug: 
o IV infusion of study drug over 60 (±10) minutes (refer to Section 8.0 and the Study 
Pharmacy Manual for additional infusion rate guidance). Administration should occur 
24 (±2) hours after study drug was administered on the previous day. 
OR 
o IV infusion of study drug over 60 (±10) minutes (refer to Section 8.0 and the Study 
Pharmacy Manual for additional infusion rate guidance). Administration should occur 
24 (±2) hours after study drug was administered on the previous day PLUS oral 
step-down therapy. 
• Clinical Assessments: 
o Conduct complete physical examination. 
o Conduct neurological examination as part of the physical examination, as clinically 
indicated. 
o Measure vital signs (temperature and the method used [oral, rectal, temporal, 
tympanic, or core], heart rate, blood pressure, and respiratory rate). Axillary 
temperatures are allowed, but not preferred. 
o The retinal examination should be repeated in subjects who were negative at baseline 
if the subject develops visual signs or symptoms of a Candida eye infection during 
the study. Additionally, any neutropenic subjects who recover their neutrophil counts 
during the study should have an additional retinal examination. Subjects who were 
negative at baseline and are diagnosed with a Candida eye infection after initiating 
study drug must discontinue study drug (see Section 7.4.2) but may continue in the 
study at the Investigator’s discretion; all subsequent antifungal drugs, interventions, 
and outcomes for endophthalmitis or chorioretinitis will be recorded. 
• Laboratory Assessments: 
o Draw blood or normally sterile tissue/fluid (if possible) for culture if demonstrating 
mycological eradication (if not already done) or if clinically indicated. 
– Perform identification and susceptibility testing for Candida for any 
positive culture requiring a change of antifungal therapy (i.e., identification 
and susceptibility testing not required for Candida isolates cultured from 
specimens obtained without a required change in antifungal therapy). 


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–
All fungal isolates cultured from blood and normally sterile tissue/fluid must be
sent to the Central Laboratory.
–
Record the spp. for any new bacteria isolated from blood and the spp.
and susceptibilities for any new bacteria isolated from any other normally
sterile site.
•
Record all concomitant medications.
•
Record AEs.
•
Presence of central line during Screening or placed during the study should be 
documented with dates and times of insertion and removal.
•
Short-term central venous catheters (e.g., peripherally-inserted central catheters, internal 
jugular, or subclavian central venous catheters) and long-term central venous catheters 
(e.g., tunneled catheters) are recommended to be removed within 48 hours after diagnosis 
with candidemia, consistent with IDSA (Pappas 2016) and ESCMID (Cornely 2012; 
Ullmann 2012) guidelines.
•
If radiologic test is performed, record radiologic test type with Findings and Interpretation 
only if radiologic test provides evidence of invasive candidiasis or evidence of 
progression, stabilization, improvement, or resolution of invasive candidiasis from 
previous radiographs. Criteria for cure, indeterminate, and failure responses are found 
in Table 10.
9.4.4 
Days 23–28 
•
Administer study drug:
o
IV infusion of study drug over 60 (±10) minutes (refer to Section 8.0 and the Study
Pharmacy Manual for additional infusion rate guidance). Administration should occur
24 (±2) hours after study drug was administered on the previous day.
OR
o
Oral step-down therapy.
•
Clinical Assessments:
o
A focused physical exam (including a neurological exam) should be performed as
clinically indicated by AE screening and course of the underlying disease.
o
Measure vital signs (temperature and the method used [oral, rectal, temporal,
tympanic, or core], heart rate, blood pressure, and respiratory rate). Axillary
temperatures are allowed, but not preferred.


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o
The retinal examination should be repeated in subjects who were negative at baseline
if the subject develops visual signs or symptoms of a Candida eye infection during
the study. Additionally, any neutropenic subjects who recover their neutrophil counts
during the study should have an additional retinal examination. Subjects who were
negative at baseline and are diagnosed with a Candida eye infection after initiating
study drug must discontinue study drug (see Section 7.4.2) but may continue in the
study at the Investigator’s discretion; all subsequent antifungal drugs, interventions,
and outcomes for endophthalmitis or chorioretinitis will be recorded.
•
Laboratory Assessments:
o
Draw blood or normally sterile tissue/fluid (if possible) for culture if demonstrating 
mycological eradication (if not already done) or if clinically indicated.
–
Perform identification and susceptibility testing for Candida for any
positive culture requiring a change of antifungal therapy (i.e., identification
and susceptibility testing not required for Candida isolates cultured from 
specimens obtained without a required change in antifungal therapy).
–
All fungal isolates cultured from blood and normally sterile tissue/fluid must be 
sent to the Central Laboratory.
–
Record the spp. for any new bacteria isolated from blood and the spp.
and susceptibilities for any new bacteria isolated from any other normally sterile 
site.
•
Record all concomitant medications.
•
Record AEs.
•
Presence of central line during Screening or placed during the study should be 
documented with dates and times of insertion and removal.
•
Short-term central venous catheters (e.g., peripherally-inserted central catheters, internal 
jugular, or subclavian central venous catheters) and long-term central venous catheters 
(e.g., tunneled catheters) are recommended to be removed within 48 hours after diagnosis 
with candidemia, consistent with IDSA (Pappas 2016) and ESCMID (Cornely 2012; 
Ullmann 2012) guidelines.
•
If radiologic test is performed, record radiologic test type with Findings and Interpretation 
only if radiologic test provides evidence of invasive candidiasis or evidence of 
progression, stabilization, improvement, or resolution of invasive candidiasis from 
previous radiographs. Criteria for cure, indeterminate, and failure responses are found 
in Table 10.


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10.0 
ASSESSMENT OF EFFICACY 
Efficacy assessments for all subjects occur on Day 5, Day 14 (±1 day), Day 30 (-2 days), EOT 
(≤2 days of last dose), and the Follow-up visit (Days 52–59). 
10.1 
Primary Efficacy Outcome 
The primary efficacy outcome for the FDA is ACM at Day 30 (-2 days). All attempts will be 
made to determine the survival status of all subjects at Day 30. However, if it is unknown 
whether a subject is alive or deceased, the subject will be considered deceased for the primary 
efficacy outcome. 
The primary efficacy outcome for the EMA is global cure (based on clinical cure as assessed by 
the Investigator, radiological cure [for qualifying invasive candidiasis subjects], and mycological 
eradication) confirmed by an independent DRC at Day 14 (±1 day). Global response is 
determined from the clinical response as assessed by the Investigator, radiologic response (for 
those subjects with invasive candidiasis documented by radiologic/imaging evidence at 
baseline), and mycological response at Day 5, Day 14 (±1 day), Day 30 (-2 days), EOT (≤2 days 
of last dose) and Follow-up (Days 52–59) and confirmed by the DRC. The outcome of global 
response as determined by clinical response, radiological response, and mycological response is 
in Table 7. An independent blinded DRC will review subject data and confirm the determination 
of global response. The global response as determined by the DRC will used for analysis. The 
role of the DRC and procedures for outcome determination are described in the DRC Charter. 
Table 7: 
Global Response 
Global 
Response 
Definition 
Mycological Response 
Clinical Response as 
Assessed by the 
Investigator 
Radiological Response** 
Cure 
Eradication/Presumed Eradication* 
Cure 
Cure 
Failure 
Eradication/Presumed Eradication * 
Cure 
Failure 
Eradication/Presumed Eradication * 
Failure 
Cure, Failure or Indeterminate 
Eradication/Presumed Eradication * 
Indeterminate 
Failure 
Failure 
Cure, Failure or 
Indeterminate 
Cure, Failure or Indeterminate 
Indeterminate 
Failure 
Cure, Failure or Indeterminate 
Indeterminate 
Cure 
Failure 
Indeterminate 
Indeterminate 
Failure 
Indeterminate 
Eradication/Presumed Eradication * 
Cure 
Indeterminate 
Eradication/Presumed Eradication * 
Indeterminate 
Cure or Indeterminate 
Indeterminate 
Cure 
Cure or Indeterminate 
Indeterminate 
Indeterminate 
Cure or Indeterminate 
*  Presumed eradication is defined only for a culture from a normally sterile site and is not defined for a blood culture. 
** For those subjects with invasive candidiasis documented by radiologic/imaging evidence at baseline. 


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10.2 
Secondary Efficacy Outcomes 
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 are mycological eradication, clinical cure, 
and radiological cure (for those subjects with invasive candidiasis documented by 
radiologic/imaging evidence at baseline). Definitions for mycological eradication, clinical cure, 
and radiological cure are provided below in Section 10.2.1, Section 10.2.2, and Section 10.2.3, 
respectively. 
10.2.1 
Mycological Response  
Table 8: 
Mycological Response Definitions 
Mycological 
Response 
Definition 
Eradication* 
• If positive blood culture at baseline: 
o 
The last blood culture drawn on or prior to the day of assessments is negative without 
a subsequent positive culture from a sample drawn following the first dose of study drug  
• If positive culture from a normally sterile site at baseline (other than blood): 
o 
Documented mycological eradication: most recent culture on or prior to the day of 
assessment from all normally sterile sites of baseline Candida infection (if accessible) 
is negative and culture was obtained after the initiation of study drug, 
OR 
o 
Presumed mycological eradication: follow-up culture from all normally sterile sites of 
baseline Candida infection is not available (e.g., normally sterile baseline site of Candida 
infection not accessible) or the most recent culture from all normally sterile sites of 
baseline Candida infection obtained after the initiation of study drug is positive, in 
a subject with a successful clinical outcome as assessed by the Investigator (i.e., did not 
receive rescue antifungal treatment and has resolution of systemic signs and symptoms of 
invasive candidiasis that were present at baseline) and the subject has a successful 
radiological outcome (for those with documented evidence of disease from imaging at 
baseline), 
AND 
• There was no change of antifungal therapy for the treatment of candidemia and/or invasive 
candidiasis, 
AND 
• The subject is not lost to follow up on the day of assessment. 


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Mycological 
Response 
Definition 
Failure 
• If positive blood culture at baseline: 
o 
The last blood culture drawn on or prior to the day of assessment is positive for Candida 
spp. from a sample drawn following the first dose of study drug, 
OR 
• If positive culture from a normally sterile site at baseline: 
o 
Documented mycological persistence: most recent culture on or prior to the day of 
assessment from all normally sterile sites of baseline Candida infection (if accessible) 
is positive and culture was obtained after the initiation of study drug, 
OR 
o 
Presumed mycological persistence: follow-up culture from all normally sterile sites of 
baseline Candida infection is not available (e.g., normally sterile baseline site of Candida 
infection not accessible) OR the most recent culture from all normally sterile sites of 
baseline Candida infection obtained after initiation of study drug is positive in a subject 
without a successful clinical outcome as assessed by the Investigator or without 
a successful radiological outcome for those with documented evidence of disease 
from imaging at baseline, 
OR 
• The subject requires a change of antifungal therapy to treat candidemia and/or invasive 
candidiasis, 
OR 
• The subject dies of any cause prior to or on the day of assessment. 
Indeterminate 
Study data are not available for the evaluation of efficacy for any reason including: 
• If positive blood culture at baseline: A post-baseline blood specimen was not available to 
culture or the result was not available. 
• If positive culture from a normally sterile site at baseline: A sterile site/fluid post-baseline 
specimen was not available to culture or the result was not available AND an assessment 
clinical outcome by the Investigator was not available or radiographic assessments are not 
available. 
• Subject is lost to follow-up on the day of assessment. 
* Presumed eradication is defined only for a culture from a normally sterile site and is not defined for a blood culture. 


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10.2.2 
Clinical Response 
Table 9: 
Investigator’s Assessment of Clinical Response Definitions 
Clinical 
Response 
Definition 
Cure 
• Resolution of attributable systemic signs and symptoms of candidemia and/or invasive
candidiasis that were present at baseline,
AND 
• No new systemic signs or symptoms attributable to candidemia and/or invasive candidiasis,
AND
• No new systemic antifungal therapy to treat candidemia and/or invasive candidiasis,
AND
• The subject is alive.
Failure 
• Progression or recurrence of attributable systemic signs or symptoms of candidemia
and/or invasive candidiasis,
OR 
• Lack of resolution of attributable systemic signs or symptoms of candidemia and/or invasive
candidiasis,
OR 
• Requirement for new systemic antifungal or prolonged therapy to treat candidemia
and/or invasive candidiasis *,
OR 
• An AE requires discontinuation of study drug therapy (IV and IV/oral) on or prior to the day
of assessment,
OR 
• The subject died of any cause.
Indeterminate 
• Study data are not available for the evaluation of efficacy for any reason including:
o
Lost to follow-up,
o
Withdrawal of consent,
o
Extenuating circumstances that preclude the classification of clinical outcome of
candidemia and/or invasive candidiasis.
Abbreviations: AE = adverse event; IV = intravenous. 
* Prolonged antifungal therapy is defined as therapy for the treatment of candidemia and/or invasive candidiasis extending
beyond the allowable 28 days of study drug. The determination of prolonged therapy will only apply to the Follow-up visit
clinical response assessment.
10.2.3 
Radiological Response 
Radiological response is defined in Table 10. Only subjects with invasive candidiasis, with 
radiologic or other imaging studies at baseline that demonstrate evidence of invasive candidiasis, 
should be assessed for this outcome. 


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Table 10: 
Radiological Response Definitions 
Radiological 
Response 
Definition a
Cure 
• Improvement or resolution of radiological or other imaging findings of invasive candidiasis
that were present at baseline (i.e., the radiograph/imaging study that documented evidence of
the invasive candidiasis)
AND 
• No new radiological or other imaging findings attributable to invasive candidiasis,
AND
• The subject is alive.
Failure 
• Progression of or new radiological or other imaging findings of invasive candidiasis,
OR
• Lack of improvement of radiological or other imaging findings of invasive candidiasis,
OR
• The subject died of any cause.
Indeterminate 
• Radiological or imaging data are not available for the evaluation of efficacy for any reason
including:
o
Lost to follow-up,
o
Withdrawal of consent,
o
Radiology/Imaging not completed
o
Extenuating circumstances that preclude the classification of a radiological outcome of
invasive candidiasis
a Includes radiological or other imaging studies. Only for invasive candidiasis subjects with imaging performed 
at baseline who had radiological or other imaging studies that documents evidence of invasive candidiasis. 
10.3 
Exploratory Outcomes 
An exploratory efficacy outcome measure is resolution of attributable systemic signs of 
candidemia and/or invasive candidiasis that were present at baseline. These include fever, 
hypothermia, hypotension, tachycardia, tachypnea, and local signs of inflammation 
(i.e., erythema, edema, heat and pain at the site of the qualifying culture).  
Health economics outcomes research (HEOR) variables are also exploratory outcomes. These 
include total length of hospital stay and length of ICU stay. 


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11.0 
ASSESSMENT OF PHARMACOKINETIC/PHARMACODYNAMIC 
PARAMETERS 
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 subjects enrolled prior to amendment 5, and reported 
separately. 
Procedures for collection, storage, and shipping of PK samples are described in Appendix 8 
and in the Pharmacokinetics Manual. 


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12.0 
ASSESSMENT OF SAFETY 
12.1 
Safety Parameters 
Safety will be assessed through the evaluation of AEs, vital signs (temperature, heart rate, blood 
pressure, and respiratory rate), physical examinations (including neurological examinations), 
ECGs, and clinical laboratory data (clinical chemistry panels, hematology evaluations, and 
urinalyses). Subjects will also be assessed at Screening and at the EOT visit, prior to Rezafungin 
for Injection dosing, with a thorough neurologic evaluation to assess for signs and symptoms of 
tremor, ataxia, and peripheral neuropathy. Adverse events and abnormal laboratory values will 
be graded for severity using the National Cancer Institute CTCAE version 5.0 (Table 12) 
and coded using the Medical Dictionary for Regulatory Activities (MedDRA). 
12.2 
Adverse Events 
Adverse Events will be collected for all subjects from informed consent through Follow-up 
(Days 52–59). The Investigator will assess all AEs and SAEs and will record the following 
information on the appropriate eCRF page: 
•
Date of onset
•
Date of resolution or stabilization
•
Seriousness
•
AE severity
•
Causal relationship to study drug(s), including relationship to a specific study drug
if a determination can be made
•
Action taken with study medication
Medically indicated laboratory tests (emergency or unscheduled tests) should be conducted at the 
local laboratory. The Investigator should employ best medical judgment in determining how to 
manage AEs and SAEs. Any questions regarding AE or SAE management should be directed to 
the Medical Monitor. 
The Sponsor is responsible for: 
•
Confirming the seriousness assessment of all reported AEs and SAEs
•
Confirming the causal relationship between reported AEs/SAEs and the investigational
product
•
Assessment of SAEs for expectedness
The Sponsor will continuously assess the safety of the investigational product throughout the 
study. 


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12.3 
Adverse Event Reporting 
12.3.1 
Notification of Serious Adverse Events 
The Sponsor has requirements for expedited reporting of SAEs meeting specific criteria to 
worldwide regulatory authorities in accordance with ICH guidelines and local regulatory 
requirements. Therefore, the Investigator must notify the Sponsor immediately regarding any 
SAE that occurs after informed consent through the final follow-up visit (Days 52–59) via 
transmission of a Serious Adverse Event Report (SAER) by the study site to the safety vendor by 
email within 24 hours of awareness that an SAE has occurred, with a copy to the Medical 
Monitor. Contact details will be provided to all sites. An optional initial report can be made via 
telephone, but a completed SAER must still be emailed within 24 hours of the site’s knowledge 
of the event. 
The investigational site will be provided with SAER forms wherein the following information is 
requested: 
• Subject identification, Investigator name, and site number 
• SAE information: event term, onset date, AE severity, and causal relationship 
• The outcomes attributable to the event (e.g., death, a life-threatening AE, inpatient 
hospitalization, prolongation of existing hospitalization, a persistent or significant 
disability or incapacity, or other important medical event[s]) 
• A summary of relevant test results, pertinent laboratory data, and any other relevant 
medical history 
• The first and last dates of study drug administration (NOTE: as this is a double-blind 
study, SAERs should not indicate specific study drug assignments) 
• Indicate if the study drug was discontinued or the study drug administration schedule 
modified 
Supplemental information may be requested from the site, including hospital records, laboratory 
results, radiology reports, progress notes, admission and emergency room notes, holding 
and observation notes, discharge summaries, autopsy reports, and death certificates. 
Relevant case report form (CRF) pages can be appended to communicate information relevant to 
the SAE, including study drug administration details, medical history, concomitant medications, 
relevant laboratory test results and subject outcome information. The SAER should be emailed 
within 24 hours with as much of the above information as available at the time. The following 
minimum information is required for reporting an SAE: subject identification, reporting source, 
and an event or outcome. SAEs are to be reported immediately and under no circumstance 
should this reporting time exceed 24 hours following knowledge of the SAE. Supplemental 
information may be transmitted using a follow-up report and should not delay the initial report. 
The Sponsor may contact the investigational site to solicit additional information or follow up on 
the event. 


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The Investigator must take all therapeutic measures necessary for resolution of the SAE. 
Any medications or procedures necessary for treatment of the SAE must be recorded on the 
appropriate pages of the subject’s eCRF. 
If the Investigator becomes aware of any SAEs that occur after the study period that are believed 
to be causally related to use of the investigational product, they should notify the Sponsor 
immediately. 
The Sponsor will report all suspected unexpected serious adverse reactions (SUSARs) within the 
required regulatory timeframes to all applicable regulatory authorities and to Investigators as 
required. 
All SAEs that do not meet expedited reporting requirements will be summarized in the 
Development Safety Update Report (DSUR) and reported annually by the Sponsor as required. 
12.3.2 
Notification of Adverse Events of Special Interest 
The Investigator should also alert the Sponsor of any AESI (as described in Section 12.7) that 
occurs on the study within 24 hours of awareness by recording the information in the AE eCRF, 
even if the nature of the AE is deemed non-serious according to the usual regulatory criteria.  
12.3.3 
Notification of Emerging Safety Issues 
Additionally, the Investigator should alert the Sponsor immediately (under no circumstance 
should this reporting time exceed 24 hours) by contacting the Medical Monitor of any new 
findings that necessitate the implementation of urgent safety measures to protect subjects against 
any immediate hazard. If time permits, the Investigator should contact the Sponsor to discuss the 
hazard and any actions taken or to be taken prior to implementation.  
The Sponsor is responsible for informing other investigators who may need to implement the 
same procedures and for alerting the Competent Authorities and Ethics Committees of the new 
findings and measures taken in accordance with local regulations within the required timeframes. 
12.4 
Definitions 
12.4.1 
Adverse Event 
An AE means any untoward medical occurrence associated with the use of a drug in humans, 
whether or not considered drug related. An AE (also referred to as an adverse experience) can be 
any unfavorable and unintended sign (e.g., a clinically-significant abnormal laboratory finding), 
symptom, or disease temporally associated with the use of a drug and does not imply any 
judgment about causality. An AE can arise with any use of the drug (e.g., off-label use, use in 
combination with another drug) and with any route of administration, formulation, or dose, 
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Events that are related to the disease under study, candidemia or invasive candidiasis, should not 
be considered or recorded as AEs unless the event fits the definition for an SAE (Section 12.4.2), 
in which case the SAE form must be submitted for safety reporting in the appropriate timeframe 
and entered as an AE into the eCRF. 
Laboratory abnormalities should not be recorded as AEs or SAEs unless they are associated with 
clinical signs or symptoms, or require medical intervention. However, each laboratory 
abnormality (e.g., clinically significant changes detected on hematology, comprehensive 
metabolic panel, urinalysis) independent from any underlying medical condition that requires 
medical or surgical intervention, or that leads to interruption of study drug infusion 
or discontinuation, must be recorded as an AE, or SAE if applicable. If the laboratory 
abnormality is part of a clinical condition or syndrome, it should be recorded as the syndrome 
or diagnosis rather than as the individual laboratory abnormality. In addition, laboratory 
abnormalities or other abnormal test assessments (e.g., ECGs) that are associated with signs 
or symptoms must be recorded as AEs or SAEs if they meet the definition of an AE or SAE 
as described in Section 12.4.1 and Section 12.4.4, respectively. 
12.4.2 
Suspected Adverse Reaction 
A suspected adverse reaction is any AE for which there is a reasonable possibility that the drug 
caused the AE. For the purposes of Investigational New Drug (IND) safety reporting, 
‘‘reasonable possibility’’ means there is evidence to suggest a causal relationship between the 
drug and the AE. Suspected adverse reaction implies a lesser degree of certainty about causality 
than adverse reaction, which means any AE caused by a drug. 
12.4.3 
Life-Threatening AE or Life-Threatening Suspected Adverse Reaction 
An AE or suspected adverse reaction is considered ‘‘life threatening’’ if, in the view of either the 
Investigator or Sponsor, its occurrence places the patient or subject at immediate risk of death. 
It does not include an AE or suspected adverse reaction that, had it occurred in a more severe 
form, might have caused death. 
12.4.4 
Serious Adverse Event or Serious Suspected Adverse Reaction 
An AE or suspected adverse reaction is considered ‘‘serious’’ if, in the view of either the 
Investigator or Sponsor, it results in any of the following outcomes: 
• Death 
• Life-threatening AE – see definition above 
• Inpatient hospitalization or prolongation of existing hospitalization 
• A persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions 
• A congenital anomaly/birth defect in the offspring of a subject who received study drug 


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• Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered serious when, based upon appropriate medical 
judgment, they may jeopardize the patient or subject and may require medical or surgical 
intervention to prevent one of the outcomes listed in this definition. The EudraVigilance 
Expert Working Group has coordinated the development of an Important Medical Event 
Terms (IME) list that is intended for guidance purposes (European Medicines 
Agency 2019). Examples of such medical events include: 
o Blood dyscrasias 
o Convulsions that do not result in inpatient hospitalization  
o Development of drug dependency or drug abuse 
12.4.5 
Unexpected AE or Unexpected Suspected Adverse Reaction 
An AE or suspected adverse reaction is considered ‘‘unexpected’’: 
• If it is not listed in the Investigator’s Brochure or is not listed at the nature, severity, 
frequency, or outcome that has been observed 
• If an Investigator’s Brochure is not required or available, is not consistent with the risk 
information described in the general investigational plan or elsewhere in the current 
application, as amended 
• If it is not listed in the Prescribing Information (for marketed products) 
For example, under this definition, hepatic necrosis would be unexpected (by virtue of greater 
severity) if the Investigator’s Brochure referred only to elevated hepatic enzymes or hepatitis. 
Similarly, cerebral thromboembolism and cerebral vasculitis would be unexpected (by virtue of 
greater specificity) if the Investigator’s Brochure listed only cerebral vascular accidents. 
‘‘Unexpected,’’ as used in this definition, also refers to AEs or suspected adverse reactions that 
are mentioned in the Investigator’s Brochure as occurring with a class of drugs or as anticipated 
from the pharmacological properties of the drug, but are not specifically mentioned as occurring 
with the particular drug under investigation. 
12.4.6 
Emerging Safety Issue 
Any new safety information that may lead to a reassessment of the risk/benefit balance of the 
investigational product and/or impact subjects’ health. Examples include: 
• Any new safety issue relating to the conduct of the clinical trial that may impact the 
safety of the trial subjects such as significant safety results from a recently-completed 
non-clinical study or early termination or temporary suspension of a trial for safety 
reasons that is conducted on the same investigational product 
• Recommendations from the DSMB that may affect the safety of trial subjects  


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12.4.7 
Urgent Safety Measure 
An urgent safety measure (USM) is a procedure not defined by the protocol that can be put in 
place with immediately without prior authorization from Ethics Committees or Regulatory 
Authorities in order to protect study participants from any immediate hazard to their health 
and safety. 
12.5 
Adverse Event Classification 
12.5.1 
Relationship to Investigational Drug 
The Investigator’s assessment of causality must be provided for all AEs (serious 
and non-serious) (Table 11). An Investigator’s causality assessment is the determination 
of whether there exists a reasonable possibility that the study drug caused or contributed to 
an AE. 
Clinical failure that qualifies as an AE without evidence of study drug toxicity should be 
considered unrelated to study drug. 
These criteria, in addition to good clinical judgment, should be used as a guide for determining 
the causal assessment. If the event is thought to be unrelated to study drug administration, then 
an alternative explanation should be provided. 
Table 11: 
Guidelines for Assessing Relationship of Event to Study Drug 
Unrelated 
There is little or no chance that the Investigational Product caused the AE; other conditions, 
including concurrent illnesses, progression or expression of the disease state, or a reaction to 
a concomitant medication best explain the event 
Related 
The association of the AE with the Investigational Product is unknown; however, the AE is not 
clearly due to another condition, or a reasonable temporal association exists between the AE 
and treatment administration and, based on the Investigator's clinical experience, the association 
of the AE with the Investigational Product seems likely 
Abbreviation: AE = adverse event. 
12.5.2 
Severity 
All AEs will be graded for severity using the CTCAE grading criteria (version 5.0). The 
Investigator will assign a grade to the AE using the CTCAE definitions for Grade 1, Grade 2, 
Grade 3, Grade 4, or Grade 5.   


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Table 12: 
Guidelines for Severity Assessment by the CTCAE Version 5.0 
 
Definition 
Grade 1 
Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; intervention 
not indicated. 
Grade 2 
Moderate; minimal, local or noninvasive intervention indicated; limiting age appropriate 
instrumental ADL. 
Grade 3 
Severe or medically significant but not immediately life-threatening; hospitalization or 
prolongation of hospitalization indicated; disabling; limiting self-care ADL. 
Grade 4 
Life-threatening consequences; urgent intervention indicated.  
Grade 5 
Death related to AE. 
Abbreviations: ADL = activities of daily living; AE = adverse event; CTCAE = Common Terminology Criteria for 
Adverse Events. 
Each CTCAE term may not always be listed as expected. For example, the grading scale for 
pneumonia is referenced under the CTCAE term “lung infection,” for thrombocytopenia under 
the CTCAE term “platelet count decreased,” and for neutropenia under the CTCAE term 
“neutrophil count decreased.” 
Each System Organ Class (SOC) category contains an “Other” option. For example, “Immune 
Systems Disorders Other, specify.” When a CTCAE term is not listed under the SOC category, 
the grading scale for the “Other” option can be referenced to aid in severity assessment. 
12.5.3 
Serious Adverse Event 
Any adverse experience occurring at any dose of study medication that occurs between the time 
of informed consent and the Follow-up visit (Days 52–59) that results in any of the outcomes 
listed in Section 12.4.4. 
Hospitalization for a planned or elective procedure or surgery for a pre-existing condition that 
has not worsened is not considered an SAE. 
12.6 
Adverse Event Follow-up 
All unresolved SAEs, AESIs, and study drug-related AEs (“ongoing” at discharge) will be 
followed by the study staff until resolution or deemed stable, regardless of severity. 
12.7 
Adverse Events of Special Interest 
In addition to SAEs, the following are considered AESIs and should be promptly reported to the 
Sponsor within 24 hours of awareness by recording the information in the AE eCRF even if the 
nature of the AE is deemed non-serious according to the usual regulatory criteria. Entry of 
an AESI into the AE CRF page will trigger the notification to the Sponsor. 


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12.7.1 
Intravenous Infusion Intolerability 
Events that, in the opinion of the Investigator, may represent intolerance of the IV infusion of 
study drug. In general, these events would be temporally associated with the IV infusion of the 
Sponsor’s study drug. 
12.7.2 
Phototoxicity 
Due to results from a nonclinical phototoxicity study in rats and a Phase 1 clinical trial indicating 
mild photosensitivity with rezafungin use, subjects should be advised to avoid sun and other UV 
light exposure without adequate protection. Investigators should report any AE potentially 
related to phototoxicity to the Sponsor. 
12.7.3 
Ataxia, Neuropathy, and Tremors 
In a rezafungin 3-month toxicity study in monkeys, there were observations of tremors, 
and histology with Schwann cell hypertrophy/hyperplasia (reversible) and phospholipidosis in 
the dorsal root ganglia first appearing at week 6 of dosing and at 11-fold the exposure for the 
dosing regimen of Rezafungin for Injection used in this study. Ataxia, axonal neuropathy, 
hypoesthesia, paresthesia, peripheral motor neuropathy, peripheral neuropathy, peripheral 
sensory neuropathies, peripheral sensorimotor neuropathy, polyneuropathy, toxic neuropathy, 
and tremors will be considered AESIs. 
12.8 
Adverse Event Management 
The Investigator should employ best medical judgement in determining how to manage AEs, 
which may represent intolerability or toxicity to the study drug. Questions regarding AE 
management should be directed to the Medical Monitor. 
12.9 
Risks for Women of Childbearing Potential or During Pregnancy 
The risks of Rezafungin for Injection in pregnant or lactating women are unknown. Pregnant 
and lactating female subjects are excluded from this study. 
Subjects must be instructed to inform the Investigator immediately if they or their partner 
becomes pregnant during the study. In the case of a partner pregnancy, partner informed consent 
must be attained prior to collecting information related to the pregnancy and to allow the 
Investigator to follow them for the outcome of the pregnancy. In the event of a confirmed 
pregnancy, the following actions should be taken: 
• Study drug should be discontinued immediately in female subjects; male subjects may 
continue in the case of a partner pregnancy. 
• The pregnancy should be reported to the Sponsor within 24 hours of the subject notifying 
the Investigator using the applicable Pregnancy Reporting Form. 


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• The Investigator should counsel female subjects regarding the possible effects of 
Rezafungin for Injection exposure on the fetus prior to study drug discontinuation and the 
need to inform the study site of the outcome of the pregnancy. 
• The subject or subject’s partner, if consented, should be monitored until the postnatal day 
28 or until termination of the pregnancy. The outcome should be reported using the 
Pregnancy Reporting Form. 
Pregnancy is not an AE, in and of itself. However, any pregnancy complication or elective 
termination of a pregnancy for medical reasons will be recorded as an AE or SAE. 
A spontaneous abortion is always considered an SAE and will be reported as described in the AE 
and SAE sections. Furthermore, any SAE occurring as an adverse pregnancy outcome post-study 
must be reported to the Medical Monitor. 
12.10 
Risks for Males of Childbearing Potential 
Recent results from a nonclinical rat fertility study indicated adverse effects on sperm 
morphology and motility without interference with reproduction were seen at 5.4 times, 
but not at 2.5 times, the exposure of rezafungin in this study. The risks for rezafungin effects 
on spermatogenesis in non-human primates and in humans have yet to be defined. Partner 
pregnancies of male subjects should be followed according to Section 12.9, when possible. 
 
 


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13.0 
STATISTICAL METHODS 
A Statistical Analysis Plan (SAP) will be prepared and finalized prior to database lock. Any 
changes to the SAP after it has been signed and prior to the final database lock will be 
documented in an addendum to the SAP. Any deviations from the final SAP/addendum will be 
described and justified in the clinical study report. All statistical analyses will be performed 
using SAS®. 
Descriptive statistics, including the numbers and percentages for categorical variables, and the 
numbers, means, standard deviations, medians, minimums, and maximums for continuous 
variables, will be provided. Listings of individual subject data will also be produced. 
13.1 
Analysis Populations 
The analysis populations are defined for this study as follows: 
• The intent-to-treat (ITT) population will include all randomized subjects, regardless of 
whether the subject receives study drug.  
• The Safety population will include all subjects who received any amount of study drug. 
• The mITT population will include all subjects who had documented Candida infection 
based on Central Laboratory evaluation of a culture from blood or another normally 
sterile site obtained ≤4 days (96 hours) before randomization and received ≥1 dose of 
study drug. 
• The clinically evaluable (CE) population will include all subjects in the mITT population 
who also met inclusion criterion #4, did not meet exclusion criteria #1, #2, or #5, had 
an assessment of both mycological and clinical response at Day 14 in the window of 
Day 14 (±1 day) (subjects with invasive candidiasis documented by radiologic/imaging 
evidence also must have an assessment of radiologic response), and did not have any 
other factor that could confound the assessment of the global response at Day 14. 
• PK Analysis Population will include all Rezafungin for Injection subjects with at least 
1 plasma sample obtained for PK analysis. 
13.2 
Subject Characteristics 
Demographics (including age, race, and sex), diagnosis at randomization (candidemia 
and/or invasive candidiasis), diagnosis methodology(blood culture/rapid IVD and culture 
specimen obtained from a normally sterile site), ANC at randomization (<500 cells/µL 
and ≥500 cells/µL), medical history including subjects diagnosed with COVID-19, Candida risk 
factors, baseline assessments (including height, weight, body mass index [BMI], modified 
APACHE II score, and Glasgow coma score), mycological data, and systemic signs 
and symptoms will be summarized in the ITT and mITT populations. 


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13.3 
Study Drug Exposure 
Descriptive statistics for the duration of study drug therapy (IV and oral, and separately for IV 
therapy and oral therapy) will be summarized by treatment group for the mITT and Safety 
populations. The number and percentage of subjects with 1–7, 8–14, 15–28, and >28 days of 
exposure will be presented for IV and IV and oral therapy combined. The number and percentage 
of subjects with 1–3, 4–7, 8–14, 15–28, and >28 days of exposure will be presented for 
oral therapy. The number and percentage of subjects switching to oral study drug therapy 
and a frequency distribution of the day of oral switch will be summarized by treatment group 
for the Safety and mITT populations. 
13.4 
Efficacy Analyses 
For efficacy analyses, subject data will be analyzed in the treatment group to which the subject 
was randomized. 
13.4.1 
Primary Efficacy Analyses for the FDA 
The primary efficacy outcome for the FDA is ACM at Day 30 (-2 days). The addendum to ICH 
E9 introduces the concept of an estimand which translates the trial objective into a precise 
definition of the treatment effect that is to be estimated. The description of the estimand includes 
four attributes: the population, the variable (or endpoint) to be obtained for each patient, the 
specification of how to account for intercurrent events (ICE), and the population-level summary 
for the variable. The estimand attributes for ACM at Day 30 are provided in detail in the SAP. 
The number and percentage of subjects in each treatment group who are alive and deceased 
(or with missing data) at Day 30 will be determined in the mITT population.  
The null and alternative hypotheses are the following: 
H0: P1 − P2 ≥ ∆ 
H1: P1 – P2 < ∆ 
Where: 
P1 = the primary efficacy outcome in the Rezafungin for Injection group, 
P2 = the primary efficacy outcome in the caspofungin group,  
∆ = the non-inferiority (NI) margin of 20%. 
The NI hypothesis test is a 1-sided hypothesis test performed at the 2.5% level of significance. 
This is based on the upper limit of the 2-sided 95% CI for the observed difference in the rate of 
ACM at Day 30 (Rezafungin for Injection group minus the caspofungin group). The primary 
analysis is based on a CI computed using the unadjusted methodology of Miettinen 
and Nurminen. If the upper limit of the 95% CI for the difference in rates of ACM at Day 30 in 


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the mITT population is <20%, the null hypothesis will be rejected and the NI of Rezafungin for 
Injection to caspofungin will be concluded. 
An adjusted 95% CI (adjusted for the randomization stratification factors) will also be computed 
using the methodology of Miettinen and Nurminen. Cochran-Mantel-Haenszel weights will be 
used for the stratum weights in the calculation of the CI.  
13.4.1.1 
Additional Analyses of the FDA Primary Efficacy Outcome 
To control the overall alpha level, superiority of rezafungin for ACM at Day 30 will be tested in 
the following order: 
• If NI is declared for ACM at Day 30 in the mITT population and the rate of ACM at 
Day 30 in the rezafungin treatment group is lower than the caspofungin treatment group, 
the difference between the treatment groups will be tested for superiority. If the upper 
bound of the 95% CI is less than 0, superiority of rezafungin will be concluded. 
• For the subgroup of subjects with invasive candidiasis, a two-sided 95% CI for the 
observed difference in the rate of ACM at Day 30 will be calculated using the unadjusted 
methodology of Miettinen and Nurminen. If superiority is declared in the mITT 
population for ACM at Day 30 and the rate of ACM at Day 30 in the rezafungin 
treatment group is lower than the caspofungin group for invasive candidiasis subjects, 
superiority of rezafungin will be tested. If the upper bound of the 95% CI is less than 0, 
superiority of rezafungin will be concluded. 
All-cause mortality at Day 30 will be assessed separately across the randomization stratification 
factors of diagnosis (candidemia only; invasive candidiasis) and APACHE II score/ANC 
(APACHE II score ≥20 OR ANC <500 cells/μL; APACHE II score <20 AND ANC 
≥500 cells/μL). For each subgroup, the number and percentage of subjects alive and deceased at 
Day 30 will be determined by treatment group in the mITT population. A 2-sided 95% CI for the 
observed difference in rates of ACM at Day 30 will be calculated in the mITT population using 
the unadjusted methodology of Miettinen and Nurminen. Other subgroup analyses, including 
analyses by the pre-, peri-, and post-COVID-19 period will be conducted for descriptive 
purposes. Depending on the number of subjects in the study diagnosed with COVID-19, ACM 
at Day 30 may be analyzed in patients with and without COVID-19. 
A sensitivity analysis of the primary outcome using multiple imputation methods for missing 
data, as detailed in the SAP, for subjects whose survival status is not known at Day 30 will be 
conducted. 
13.4.2 
Primary Efficacy Analyses for the EMA 
The primary efficacy outcome for the EMA is global cure at Day 14 (±1 day) based on the DRCs 
determination. Global response is a composite estimand and ICEs are incorporated into the 


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variable/endpoint. The estimand attributes for global response are provided in more detail in the 
SAP.  
The number and percentage of subjects in each treatment group who have a global response of 
cure, failure and indeterminate at Day 14 (±1 day) will be determined in the mITT population.  
The null and alternative hypotheses are the following: 
H0: P1 − P2 ≤ -∆ 
H1: P1 – P2 > -∆ 
Where: 
P1 = the primary efficacy outcome in the Rezafungin for Injection group, 
P2 = the primary efficacy outcome in the caspofungin group,  
∆ = the NI margin of 20%. 
The NI hypothesis test is a 1-sided hypothesis test performed at the 2.5% level of significance. 
This is based on the lower limit of the adjusted (for the randomization stratification factors) 
2-sided 95% CI for the observed difference in global success rate (Rezafungin for Injection 
group minus the caspofungin group). The primary analysis is based on a CI computed using the 
method with stratification by Miettinen and Nurminen. Cochran-Mantel-Haenszel weights will 
be used for the stratum weights in the calculation of the CI. If the lower limit of the 95% CI for 
the difference in global success rates in the mITT population is >-20%, the null hypothesis 
will be rejected and the NI of Rezafungin for Injection to caspofungin will be concluded.  
To control the overall alpha level, superiority of rezafungin for global response will be tested in 
the following order: 
• If NI is declared and the percentage of subjects that have a global response of cure at 
Day 14 (±1 day) as confirmed by the DRC in the rezafungin treatment group is higher 
than the caspofungin treatment group, the difference between the treatment groups will 
be tested for superiority. If the lower bound of the 95% CI is greater than 0, superiority 
of rezafungin will be concluded. 
• For the subgroup of subjects with invasive candidiasis, a two-sided 95% CI for the 
observed difference in global cure at Day 14 for the mITT population will be calculated 
using the unadjusted methodology of Miettinen and Nurminen. If superiority is declared 
for the EMA primary efficacy outcome of global response at Day 14 in the mITT 
population, and the global cure rate in the rezafungin treatment group is higher than the 
caspofungin group for invasive candidiasis subjects, superiority of rezafungin will be 


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tested. If the lower bound of the 95% CI is greater than 0, superiority of rezafungin will 
be concluded. 
Global response will also be assessed separately across the randomization stratification factors of 
diagnosis (candidemia only; invasive candidiasis) and APACHE II score/ANC (APACHE II 
score ≥20 OR ANC <500 cells/μL; APACHE II score <20 AND ANC ≥500 cells/μL). For each 
subgroup, the number and percentage of subjects with a global response of cure, failure, 
and indeterminate at Day 14 (±1 day) will be determined by treatment group in the mITT 
population. A 2-sided 95% CI for the observed difference inglobal cure rates will be calculated 
in the mITT population using the unadjusted methodology of Miettinen and Nurminen. Other 
subgroup analyses, including analyses by the pre-, peri- and post-COVID-19 period, will be 
conducted for descriptive purposes. Depending on the number of subjects in the study diagnosed 
with COVID-19, global response may be analyzed in patients with and without COVID-19. 
The reasons for having a global response of failure or indeterminate at Day 14 (±1 day) will be 
presented using the number and percentage of subjects displayed by treatment group in the 
mITT population. Subjects who miss the efficacy assessment due to COVID-19 will have 
an indeterminate response and the number and percentage of subjects with an indeterminate 
response due to COVID-19 will be summarized. 
An unadjusted 95% CI will also be computed using the methodology of Miettinen 
and Nurminen. Additional analyses of the primary efficacy outcome for the EMA, including 
analyses in the ITT and CE populations, will be described in the SAP. 
13.4.3 
Secondary Efficacy Analyses 
All-cause mortality at Day 30 (-2 days) is a secondary outcome for the EMA and global cure at 
Day 14 (±1 day) as confirmed by DRC is a secondary outcome for the FDA. 
The secondary efficacy outcomes are global cure (as confirmed by the DRC), mycological 
response, radiological response (for subjects with invasive candidiasis documented by 
radiologic/imaging evidence at baseline), and clinical response. The number and percentage 
of subjects with a global response of cure, failure, or indeterminate will be presented by 
treatment group in the mITT population at Day 5, Day 30 (-2 days), EOT (≤2 days of last dose) 
and Follow-up (Days 52–59). The number and percentage of subjects with a mycological 
response of eradication, failure, or indeterminate will be presented by treatment group in the 
mITT population at Day 5, Day 14 (±1 day), Day 30 (-2 days), EOT (≤2 days of last dose), 
and Follow-up (Days 52–59). The number and percentage of subjects with invasive candidiasis 
documented by radiologic/imaging evidence with a radiological response of cure, failure, 
or indeterminate will be presented by treatment group in the mITT population at Day 5, Day 14 
(±1 day), Day 30 (-2 days), EOT (≤2 days of last dose), and Follow-up (Days 52–59). The 
number and percentage of subjects with a clinical response of cure, failure, or indeterminate 
will be presented by treatment group in the mITT population at Day 5, Day 14 (±1 day), Day 30 
(-2 days), EOT (≤2 days of last dose), and Follow-up (Days 52–59). 95% CIs for the treatment 


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differences in global cure, mycological eradication, radiological cure and clinical cure will be 
determined. 
Analyses of global response at Day 14 (±1 day) will also be conducted in two subsets of subjects 
defined based on the timing of the culture used to document the Candida infection: 1) subjects 
with a culture from blood drawn within 12 hours prior to randomization or within 72 hours after 
randomization, OR a culture from another normally sterile site obtained within 48 hours prior 
to randomization or within 72 hours after randomization, and 2) subjects with a culture from 
blood drawn within 12 hours prior to randomization or within 72 hours after randomization, 
OR a culture from another normally sterile site obtained within 96 hours prior to randomization 
or within 72 hours after randomization. For each subset of subjects, the number and percentage 
of subjects with a global response of cure, failure, or indeterminate will be presented by 
treatment group. The 95% CIs for the treatment differences in global cure will be determined. 
13.4.4 
Additional Efficacy Analyses 
The number and percentage of subjects with resolution of all systemic signs attributable at 
baseline to candidemia and/or invasive candidiasis at Day 5, Day 14 (±1 day), Day 30 (-2 days) 
and Follow-up (Days 52–59) will be presented by treatment group in the mITT population. 
The number and percentage of subjects who died up through the Follow-up visit (ACM) will be 
presented by treatment group in the mITT population. In addition, Kaplan-Meier (KM) methods 
will be utilized to analyze survival time in the mITT and ITT populations. Subjects who remain 
alive or are lost to follow-up will be censored at the last date known to be alive. Kaplan-Meier 
survival curves will be provided. The 25th, 75th percentiles and the median survival time as well 
as the probability of being alive at Day 5, Day 14, Day 30, and Day 55 will be determined by 
treatment group.  
The time to the first negative blood culture (for those subjects enrolled with a positive blood 
culture) without subsequent positive culture from a sample drawn following the first dose of 
study drug will be summarized using KM methods. Subjects will be censored if they receive 
an alternative antifungal (i.e., other than study drug) for the treatment of the candidemia, died 
or were lost to follow up prior to having the negative blood culture. Kaplan-Meier survival 
curves will be provided. The 25th, 75th percentiles and the median survival time will be 
determined by treatment group. 
13.5 
Safety Analyses 
All safety analyses will be conducted in the Safety population and will be summarized by study 
drug actually received.  
A TEAE is defined as an AE that occurs during or after the first dose of study drug up through 
the Follow-up visit (Days 52–59). An overall summary of AEs will be provided by treatment 
group. The incidence of TEAEs will be presented by SOC and Preferred Term (PT); SOC, PT 


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and relationship to the study drug administration; and SOC, PT, and CTCAE grade (version 5.0). 
Tables of any TEAE resulting in discontinuation of study drug and SAEs will also be provided. 
A table of TEAEs of coronavirus will be presented by PT and a listing of all TEAEs in subjects 
with COVID-19 (medical history or TEAE) will be provided. Depending upon the number of 
subjects diagnosed with COVID-19, a summary of TEAEs by SOC and PT may be provided. 
Descriptive statistics for clinical laboratory test results (hematology and chemistry) will be 
presented for all study visits. The change from baseline to each post-baseline visit and to the 
overall worst post-baseline value will be summarized by treatment group. Laboratory values will 
be graded using CTCAE version 5.0 and shift tables will be provided. Liver enzymes will be 
classified as > ULN, >3×, >5× and >10×ULN and the number and percentage of subjects with 
any post-baseline value in one of the categories will be presented by study drug. 
Descriptive statistics of vital sign parameters will be presented by treatment group and study 
visit, as well as the change from baseline at each study visit. Potentially clinically significant 
(PCS) values will be defined in the SAP and the number and percentage of subjects with a PCS 
value will be summarized by treatment group for the worst-post-baseline value. 
Descriptive statistics of ECG parameters will be presented by treatment group and will include 
change from baseline. 
13.6 
Health Economics Outcome Research 
Descriptive statistics of the total length of hospital stay and the total length of ICU stay will be 
provided by treatment group. 
13.7 
Pharmacokinetic Analyses 
Samples from this study may 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 subjects enrolled prior to amendment 5, 
and reported separately. The PK parameters that will be assessed in the PK Analysis Population 
include: Cmax and minimum plasma concentration (Cmin). 
13.8 
Determination of Study Sample Size 
For the EMA endpoint of global cure (confirmed by the DRC), using a 20% NI margin, 
one-sided alpha of 0.025, 80% power, 1:1 randomization, a global cure rate of 70% in both the 
Rezafungin for Injection and caspofungin groups, and the sample size methodology based on 
a continuity corrected Z-statistic, a total of 184 subjects (92 subjects in each treatment group) are 
required in the mITT population. Assuming 85% of subjects will be evaluable for the mITT 
population, a total of approximately 218 subjects will be randomized. 
For the FDA endpoint of ACM at Day 30 (-2 days), using a 20% NI margin, one-sided alpha of 
0.025, an ACM at Day 30 rate of 20% in both treatment groups, 1:1 randomization, and the 


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sample size methodology based on a continuity corrected Z-statistic, a total of 184 subjects in the 
mITT population provides an 89.7% power to show NI. 
Thus, a total of 218 randomized subjects provides sufficient power for the primary efficacy 
analyses for both the FDA and EMA in the mITT population.  
13.9 
Data and Safety Monitoring Board 
An independent external DSMB will be established to review safety data. The DSMB will 
review safety data when approximately 50% of subjects are randomized and as required for AEs 
of special interest as provided in the DSMB Charter. The DSMB will be comprised of clinicians 
and a statistician who are experienced in studies of fungal infections. A detailed charter will be 
developed, compliant with guidelines of the FDA and the ICH that describes the roles and 
responsibilities of the DSMB, the timing of the meetings, as well as the data to be provided for 
review. 
13.10 Handling of Dropouts and Missing, Unused, and Spurious Data 
Every effort will be made to collect all data at specified times. For primary outcome measure 
(FDA), if the subject’s survival status is unknown at Day 30, the subject will be assumed 
deceased. A sensitivity analysis of the primary outcome (FDA) will be conducted where missing 
data are imputed using a multiple imputation analysis. For the primary outcome measure for 
global cure for the EMA, missing data are considered an indeterminate response and are included 
in the denominator and are thus, are analyzed in the same manner as global failures. Sensitivity 
analyses of the EMA primary endpoint to assess the impact of missing data will be conducted 
and outlined in the SAP. Handling of other missing data will be provided in the SAP. 
13.11 Subject Disposition 
Enrollment and discontinuations from the study and from study drug will be summarized by 
treatment group, including the reasons for discontinuation from the study and from study drug. 
Subjects who prematurely discontinue the study or study drug due to COVID-19 will be 
summarized. 
13.12 Deviation Reporting 
Protocol deviations will be summarized by treatment group. Protocol deviations are defined as 
any variation from the protocol, including enrollment of a subject who did not meet all inclusion 
and exclusion criteria and failure to perform the assessments and procedures within the required 
time frame. 
13.13 Impact of the COVID-19 Pandemic on Analyses 
The COVID-19 pandemic may impact study participants’ ability to return to the clinic possibly 
resulting in premature discontinuation of study drug, premature discontinuation of the study, 


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or missed study visits. Additionally, it is possible the COVID-19 pandemic may impact efficacy 
and safety outcomes. All missed visits due to COVID-19 will be noted as protocol deviations 
and diagnoses of COVID-19 will be recorded as medical history or adverse events. Analyses to 
assess the possible impact of COVID-19 on the study results are described above and will be 
presented in the SAP. 
 
 


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14.0 
INVESTIGATOR REQUIREMENTS 
14.1 
Protocol Adherence 
The Investigator must adhere to the protocol as detailed in this document and agree that the 
Sponsor must approve any change to the protocol before seeking approval from the IRB/IEC. 
The Investigator will be responsible for enrolling only those subjects who have met the protocol 
inclusion and exclusion criteria. 
14.2 
Electronic Case Report Forms 
The contract research organization will make the eCRF accessible to authorized personnel over 
the internet from an Electronic Data Capture (EDC) system used for the recording of study data 
as specified by this protocol. All eCRFs must be completed by trained study personnel. The 
Investigator is responsible for ensuring that the eCRF data are entered and completed in a timely 
manner. 
Once all data queries and issues have been resolved for each subject, the Investigator will 
electronically sign each subject’s eCRF to attest to the accuracy of the data. 
14.3 
Source Document Maintenance 
Source documents are defined as documentation related to original observations and activities of 
a clinical investigation. Source documents may include, but are not limited to, study progress 
notes, study- or subject-specific e-mail correspondence, computer printouts, laboratory data, 
and recorded data from automated instruments. All source documents produced in this study will 
be maintained by the Investigator and made available for inspections by the Sponsor and by 
regulatory authorities. The original signed ICF for each participating subject shall be filed with 
records kept by the Investigator, and a copy shall be given to the subject. 
14.4 
Study Monitoring Requirements 
An authorized Sponsor representative will conduct site visits to inspect study data, subjects’ 
medical records, and eCRFs in accordance with ICH guidelines, GCPs, and the foreign 
regulations and guidelines, as applicable. A monitor will be utilized for monitoring ongoing drug 
accountability and adherence to protocol procedures. 
The Investigator will allow representatives of the Sponsor and regulatory authorities to inspect 
facilities and records relevant to this study. 


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14.5 
Study Completion 
The Sponsor requires the following data and materials before a study can be considered complete 
or terminated: 
• Laboratory findings, clinical data, and all special test results from Screening throughout 
the study until the Follow-up visit (Day 52-59)  
• eCRFs (including data queries) properly completed by appropriate study personnel and 
signed and dated by the Investigator 
• Copies of complete drug accountability records (drug inventory log and an inventory of 
returned or destroyed clinical material) 
• Copies of protocol amendments and IRB/IEC approval and notification, if appropriate 
• A summary of the study prepared by the Investigator (an IRB/IEC summary letter is 
acceptable) 
End of Study Conduct, for the purpose of clinical trial registries, end of trial notifications to 
regulatory authorities and Institutional Review Boards/Ethics Committees, will be the latest date 
on which the last visit in time of any study participant occurs. 


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15.0 
QUALITY CONTROL AND QUALITY ASSURANCE 
Written Standard Operating Procedures (SOPs) will be followed to ensure that the study is 
conducted, and data are generated, documented (recorded), and reported in compliance with the 
protocol, GCP, and the applicable regulatory requirements. Quality control will be applied to 
each stage of data handling. Regular monitoring, as defined in ICH GCP E6(R2), Section 1.38, 
“The act of overseeing the progress of a clinical trial, and of ensuring that it is conducted, 
recorded, and reported in accordance with the protocol, SOPs, GCP, and the applicable 
regulatory requirement(s)”, will be conducted throughout the conduct of the study. 
As defined in ICH GCP E6(R2), Section 5.18, the purpose of monitoring is to verify that: 
• Rights and well-being of the human subjects are protected 
• The reported study data are accurate, complete, and verifiable from source documents 
• The conduct of the study is in compliance with the currently approved 
protocol/amendment(s), with GCP, and with the applicable regulatory requirements 
• Monitoring is an integral role in the quality control of a clinical trial and is designed to 
verify the quality of the study 
To fulfill the Quality Assurance requirements of GCP, audits will be conducted to assess and 
assure the reliability and integrity of a study’s quality control systems and recognized standards. 
As defined in ICH GCP E6(R2), Section 5.19, the purposes of an audit are to: 
• Ensure participant safety 
• Assure compliance to study protocol procedures, regulatory requirements, and SOPs 
• Assure data quality 


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16.0 
PROTECTION OF HUMAN SUBJECTS 
This study will be conducted in compliance with the ICH Technical Requirements for 
Registration of Pharmaceuticals for Human Use E6 GCP: Consolidated Guidelines, the ethical 
principles of the Declaration of Helsinki, FDA GCP guidelines, and any additional national 
or IRB/IEC-required procedures. 
16.1 
Informed Consent 
This study will be conducted in compliance with ICH E6 GCP: Consolidated Guidelines 
pertaining to informed consent. Subjects will give written consent to participate in the study 
at the first visit, prior to initiation of any study-related procedures, after having been informed 
about the nature and purpose of the study, participation and termination conditions, risks, 
and benefits. If a subject is unable to provide written informed consent, the subject’s legally 
acceptable representative (i.e., acceptable to ICH and local law, as applicable) may provide 
written consent, as approved according to institution-specific guidelines. The ICF must be signed 
and dated by the subject, or the subject’s legally acceptable representative, prior to study 
participation. A copy of the ICF must be provided to the subject or the subject’s legally 
acceptable representative. If applicable, it will be provided in certified translation for 
non-English-speaking subjects. Signed ICFs must remain in the subject’s study file and be 
available for verification by Sponsor at any time. 
16.2 
IRB/IEC Approval 
This protocol, the ICF, and all relevant supporting data must be submitted to the IRB/IEC for 
approval. The protocol, ICF, and any advertisement used to recruit study subjects must be 
approved by the IRB/IEC. Approval by the IRB/IEC of the protocol and ICF must be obtained 
before the study may be initiated. 
The Investigator is responsible for informing the IRB/IEC of any changes made to the protocol, 
and to advise them, at least once a year, about the progress of the study. The Investigator is also 
responsible for notifying the IRB/IEC of any significant AEs that occur during the study. 


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17.0 
DATA HANDLING AND RECORD KEEPING 
Training sessions, regular monitoring of Investigators by Sponsor-designated personnel, 
instruction manuals, data verification, crosschecking, and data audits will be performed 
to ensure quality of all study data. Investigator meetings will be performed to prepare 
Investigators and other study personnel for appropriate collection of study data. 
The Sponsor will review and validate study data as defined in the monitoring plan. 
It will be the responsibility of the Investigator to ensure that the essential documents are 
available at the Investigator or institutional site. Any or all of these documents may be subject 
to, and should be available for, monitoring by the Sponsor or inspection by the regulatory 
authorities as defined in the monitoring plan. 
17.1 
Direct Access to Source Data/Documentation 
The Investigator agrees by his/her participation that the results of this study may be used for 
submission to national or international registration. If required, these authorities will be provided 
with the name of the Investigator and his or her address, qualifications, and extent of 
involvement. It is understood that the Investigator is required to provide Sponsor with all study 
data, complete reports, and access to all study records. 
Data generated by this study must be available for inspection by any regulatory authorities, 
by Sponsor and by the IRB/IEC as appropriate. At a subject’s request, medical information may 
be given to his or her personal physician or other appropriate medical personnel responsible for 
his or her welfare. Medical information obtained from subjects during the course of this study 
is confidential and disclosure to third parties other than those noted above is prohibited. 
17.2 
Study Drug Accountability 
All supplies of Rezafungin for Injection, oral fluconazole, placebo for Rezafungin for Injection, 
placebo for caspofungin IV, and placebo for oral step-down therapy required for completion of 
this study will be provided by the Sponsor. It is the responsibility of the unblinded Pharmacy 
staff or unblinded study staff to ensure that a current record of drug inventory and drug 
accountability is maintained. Inventory and accountability records must be readily available for 
inspection by the unblinded monitor and are open to inspection at any time by applicable 
regulatory authorities. 
17.3 
Retention of Records 
Essential documents should be retained until at least 2 years after the last approval of 
a marketing application in an ICH region and until there are no pending or contemplated 
marketing applications in an ICH region or at least 2 years have elapsed since the formal 
discontinuation of clinical development of the investigational product and shipment and delivery 
of the drug for investigational use is discontinued. These documents should be retained for 


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a longer period, however, if required by the applicable regulatory requirements of specific 
ICH- and non-ICH countries, or by an agreement with the Sponsor. The Sponsor will inform the 
Investigator/institution as to when these documents no longer need to be retained. 


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18.0 
FINANCING AND INSURANCE 
The financing and insurance for this study are outlined in the Clinical Trial Agreement. 


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19.0 
PUBLICATION POLICY 
The data generated in this clinical study are the exclusive property of the Sponsor and are 
confidential. Authorship on any publication of the results from this study will be based on 
contributions to study design, enrollment, data analysis, and interpretation of results. 
 
 


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20.0 
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Kett DH, Azoulay E, Echeverria PM, Vincent JL; Extended Prevalence of Infection in ICU 
Study (EPIC II) Group of Investigators. Candida bloodstream infections in intensive care units: 
analysis of the extended prevalence of infection in intensive care unit study. Crit Care Med. 2011 
Apr;39(4):665-70. 
Knaus WA, Draper EA, Wagner DP, Zimmerman JE. APACHE II: a severity of disease 
classification system. Crit Care Med. 1985 Oct;13(10):818-29. 
Lakota EA, Voon O, Flanagan S, Rubino CM. Population Pharmacokinetic Analyses for 
Rezafungin (CD101) Efficacy Using Phase 1 Data: Rezafungin (CD101) Population 
Pharmacokinetic Model. Antimicrob. Agents Chemother. Posted Online 19 March 2018.  
http://aac.asm.org/content/early/2018/03/14/AAC.02603-17.long 
Accessed April 26, 2018. 
Magill SS, Edwards JR, Bamberg W, Beldavs ZG, Dumyati G, Kainer MA, Lynfield R, Maloney 
M, McAllister-Hollod L, Nadle J, Ray SM, Thompson DL, Wilson LE, Fridkin SK; Emerging 
Infections Program Healthcare-Associated Infections and Antimicrobial Use Prevalence Survey 
Team. Multistate point-prevalence survey of health care-associated infections. N Engl J Med. 
2014 Mar 27;370(13):1198-208. 
Mycamine® (micafungin sodium) [Prescribing Information]. Northbrook, IL: Astellas Pharma 
US, Inc.; 2020 July. Available at https://www.us.astellas.com/docs/mycamine.pdf. Accessed 
19Sep2020. 
Mycamine (micafungin sodium) powder for concentrate for solution for infusion [Summary of 
Product Characteristics]. Leiden, Netherlands: Astellas Pharma Europe B.V.; 2020 January. 
Available at https://www.medicines.org.uk/emc/product/6315/smpc#gref. Accessed 13Oct2020. 
Ostrosky-Zeichner L. Candida glabrata and FKS mutations: witnessing the emergence of the 
true multidrug-resistant Candida. Clin Infect Dis. 2013; 56: 1733–4. 
Pappas PG, Kauffman CA, Andes DR, Clancy CJ, Marr KA, Ostrosky-Zeichner L, Reboli AC, 
Schuster MG, Vazquez JA, Walsh TJ, Zaoutis TE, Sobel JD. Clinical Practice Guideline for the 
Management of Candidiasis: 2016 Update by the Infectious Diseases Society of America. Clin 
Infect Dis. 2016 Feb 15;62(4):409-17. 
Pfaller MA. Antifungal drug resistance: mechanisms, epidemiology, and consequences for 
treatment. Am J Med. 2012; 125: S3–13. 
Pfaller MA, Carvalhaes C, Messer SA, Rhomberg PR, Castanheira M. Activity of a long-acting 
echinocandin, rezafungin, and comparator antifungal agents tested against contemporary 
invasive fungal isolates (SENTRY Program, 2016 to 2018). Antimicrob Agents Chemother. 
2020;64(4): e00099-20. 


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Subramony SH, May W, Lynch D, et al. Measuring Friedreich ataxia: Interrater reliability of a 
neurologic rating scale. Neurology. 2005; 64:1261–1262. 
Ullmann AJ, Akova M, Herbrecht R, Viscoli C, Arendrup MC, Arikan-Akdagli S, Bassetti M, 
Bille J, Calandra T, Castagnola E, Cornely OA, Donnelly JP, Garbino J, Groll AH, Hope WW, 
Jensen HE, Kullberg BJ, Lass-Flörl C, Lortholary O, Meersseman W, Petrikkos G, Richardson 
MD, Roilides E, Verweij PE, Cuenca-Estrella M; ESCMID Fungal Infection Study Group. 
ESCMID guideline for the diagnosis and management of Candida diseases 2012: adults with 
haematological malignancies and after haematopoietic stem cell transplantation (HCT). Clin 
Microbiol Infect. 2012 Dec;18 Suppl 7:53-67. 
Teasdale G, Jennett B. Assessment of coma and impaired consciousness. A practical scale. 
Lancet. 1974 Jul 13;2(7872):81-4. 
The White House. National Strategy for Combating Antibiotic Resistant Bacteria. September 
2014. 
Wisplinghoff H, Bischoff T, Tallent SM, Seifert H, Wenzel RP, Edmond MB. Nosocomial 
bloodstream infections in US hospitals: analysis of 24,179 cases from a prospective nationwide 
surveillance study. Clin Infect Dis. 2004; 39:309–17. 
Zhao Y, Perez WB, Jimenez-Ortigosa C, Hough G, Locke JB, Ong V, Bartizal K, Perlin DS. 
CD101: a novel long-acting echinocandin. Cell Microbiol. 2016. 18:1308-1316. 
Zhao Y, Prideaux B, Nagasaki Y, Lee MH, Chen PY, Blanc L, Ho H, Clancy CJ, Nguyen MH, 
Dartois V, Perlin DS. Unraveling Drug Penetration of Echinocandin Antifungals at the Site of 
Infection in an Intra-abdominal Abscess Model. Antimicrob Agents Chemother. 2017 Sep 
22;61(10). pii: e01009-17. 


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21.0 
APPENDICES 
APPENDIX 1: 
CLINICAL AND LABORATORY STANDARDS INSTITUTE 
(CLSI) AND EUROPEAN COMMITTEE ON ANTIMICROBIAL 
SUSCEPTIBILITY TESTING (EUCAST) BREAKPOINTS FOR 
CANDIDA SPP. 
The following table provides susceptibility breakpoints for both Clinical and Laboratory 
Standards Institute (CLSI) and European Committee on Antimicrobial Susceptibility Testing 
(EUCAST) and should be used as guidance in determining susceptibility of different Candida 
spp. to potential empiric antifungal drugs. Not all spp. or antifungal drugs are referenced here, 
and local determination of susceptibility and resistance may be used when appropriate. 


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MIC Breakpoints (mg/L) 
Antifungal 
Agent 
Standard 
C. albicans 
C. glabrata 
C. krusei 
C. parapsilosis 
C. tropicalis 
S ≤ 
R > 
S ≤ 
R > 
S ≤ 
R > 
S ≤ 
R > 
S ≤ 
R > 
Amphotericin B 
EUCAST 
1 
1 
1 
1 
1 
1 
1 
1 
1 
1 
CLSI 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
Anidulafungin 
EUCAST 
0.03 
0.03 
0.06 
0.06 
0.06 
0.06 
0.002 
4 
0.06 
0.06 
CLSI 
0.25 
0.5 
0.12 
0.25 
0.25 
0.5 
2 
4 
0.25 
0.5 
Caspofungin 
EUCAST 
 
 
 
 
 
 
 
 
 
 
CLSI 
0.25 
0.5 
0.125 
0.25 
0.25 
0.5 
2 
4 
0.25 
0.5 
Fluconazole 
EUCAST 
2 
4 
0.002 
32 
- 
- 
2 
4 
2 
4 
CLSI 
2 
4 
32 
(SDD) 
32 
- 
- 
2 
4 
2 
4 
Itraconazole 
EUCAST 
0.06 
0.06 
IE 
IE 
IE 
IE 
0.12 
0.12 
0.12 
0.12 
CLSI 
0.125 
0.5 
0.125 
0.5 
0.125 
0.5 
0.125 
0.5 
0.125 
0.5 
Micafungin 
EUCAST 
0.016 
0.016 
0.03 
0.03 
IE 
IE 
0.002 
2 
IE 
IE 
CLSI 
0.25 
0.5 
0.06 
0.12 
0.25 
0.5 
2 
4 
0.25 
0.5 
Posaconazole 
EUCAST 
0.06 
0.06 
IE 
IE 
IE 
IE 
0.06 
0.06 
0.06 
0.06 
CLSI 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 


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MIC Breakpoints (mg/L) 
Antifungal 
Agent 
Standard 
C. albicans 
C. glabrata 
C. krusei 
C. parapsilosis 
C. tropicalis 
S ≤ 
R > 
S ≤ 
R > 
S ≤ 
R > 
S ≤ 
R > 
S ≤ 
R > 
Voriconazole 
EUCAST 
0.125 
0.125 
IE 
IE 
IE 
IE 
0.125 
0.125 
0.125 
0.125 
CLSI 
0.125 
0.5 
 
 
0.5 
1 
0.125 
0.5 
0.125 
0.5 
Abbreviations: CLSI = Clinical and Laboratory Standards Institute; EUCAST = European Committee on Antimicrobial Susceptibility Testing; IE = insufficient evidence; 
R = resistant; S = susceptible; SDD = susceptible dose dependent. 
Source: Alastruey-Izquierdo 2015.


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APPENDIX 2: 
CREATININE CLEARANCE 
In the event the local laboratory does not calculate creatinine clearance based on the most recent 
serum creatinine value, estimate the patient’s creatinine clearance using the serum creatinine 
value provided by the local laboratory, actual body weight, and the appropriate Cockcroft-Gault 
formula. If necessary, convert serum creatinine values from µmol/L to mg/dL by dividing by 
88.4. For example, 100 µmol/L divided by 88.4 equals 1.131 mg/dL: 
 
Males: 
Creatinine clearance = 
(140 – [𝑖𝑖𝑖𝑖𝑖𝑖𝑖𝑖𝑖𝑖𝑖𝑖 𝑎𝑎𝑎𝑎𝑎𝑎 𝑖𝑖𝑖𝑖 𝑦𝑦𝑦𝑦𝑦𝑦𝑦𝑦𝑦𝑦]) × [𝑖𝑖𝑖𝑖𝑖𝑖𝑖𝑖𝑖𝑖𝑖𝑖 𝑤𝑤𝑤𝑤𝑤𝑤𝑤𝑤ℎ𝑡𝑡 𝑖𝑖𝑖𝑖 𝑘𝑘𝑘𝑘]
72 × [𝑖𝑖𝑖𝑖𝑖𝑖𝑖𝑖𝑖𝑖𝑖𝑖 𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠 𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐 𝑖𝑖𝑖𝑖 𝑚𝑚𝑚𝑚/𝑑𝑑𝑑𝑑]
  
Females:  
Creatinine clearance = 0.85 × 
(140 – [𝑖𝑖𝑖𝑖𝑖𝑖𝑖𝑖𝑖𝑖𝑖𝑖 𝑎𝑎𝑎𝑎𝑎𝑎 𝑖𝑖𝑖𝑖 𝑦𝑦𝑦𝑦𝑦𝑦𝑦𝑦𝑠𝑠]) × [𝑖𝑖𝑖𝑖𝑖𝑖𝑖𝑖𝑖𝑖𝑖𝑖 𝑤𝑤𝑤𝑤𝑤𝑤𝑔𝑔ℎ𝑡𝑡 𝑖𝑖𝑖𝑖 𝑘𝑘𝑘𝑘]
72 × [𝑖𝑖𝑖𝑖𝑖𝑖𝑖𝑖𝑖𝑖𝑖𝑖 𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠 𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐 𝑖𝑖𝑖𝑖 𝑚𝑚𝑚𝑚/𝑑𝑑𝑑𝑑]
  
 


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APPENDIX 3: 
LABORATORY TESTS 
Hematology 
Serum Chemistry  
hemoglobin 
blood urea nitrogen c 
hematocrit  
bilirubin (total and direct) 
total and differential leukocyte count 
alkaline phosphatase 
red blood cell count 
aspartate aminotransferase 
platelet count 
alanine aminotransferase 
Urinalysis 
albumin 
pH 
sodium 
specific gravity 
potassium 
protein a 
chloride 
glucose 
glucose  
ketones 
creatinine b 
bilirubin 
total protein 
blood a 
calcium (total) 
nitrite a 
bicarbonate d 
urobilinogen  
magnesium 
leukocyte esterase a 
 
Coagulation Tests 
Additional Tests 
PT/INR 
serum pregnancy (for females only) 
 
blood culture within 12 hours of randomization 
(required for candidemia subjects) 
Abbreviations: PT/INR = Prothrombin Time or International Normalized Ratio 
a. 
If urinalysis is positive for protein, blood, nitrite and/or leukocyte esterase, a microscopic examination (for red blood 
cells, white blood cells, bacteria, casts, and epithelial cells) will be performed. 
b. 
At Screening, creatinine clearance will be calculated using the Cockcroft-Gault formula (Appendix 2). 
c. 
Study sites that do not perform BUN testing may use a Urea test result, instead, for entry into EDC. If the Urea test result 
is reported in mg/dL, site staff will need to convert the Urea test result(s) for their subject(s) to a corresponding BUN 
value by using the following conversion factor:    
• 
Urea [mg/dL] x 0.467 = BUN [mg/dL] 
If the Urea test result is reported in mmol/L, site staff will not need to convert this, as Urea [mmol/L] = BUN [mmol/L]. 
In this circumstance, the Urea (mmol/L) value can be entered directly into the eCRF as BUN (mmol/L). File a copy of 
this memo in the On-Site Study File. 
d. 
Total CO2 may be used instead of bicarbonate as they are interchangeable and no conversion is required. 


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APPENDIX 4: 
CHILD-PUGH SCORE 
Calculate the Child-Pugh score only if the subject has a history of chronic cirrhosis.  
The Child-Pugh score employs 5 clinical measures of liver disease. Each measure is scored 
1 to 3, with 1 indicating the least severe and 3 indicating the most severe score. The sum of the 
5 measures is the total Child-Pugh point score. 
Parameter 
Points 
1 
2 
3 
Ascites 
None 
Medically controlled 
Poorly controlled 
Encephalopathy a 
None 
Medically controlled 
Poorly controlled 
Total bilirubin (mg/dL) 
<2 mg/dL  
(<34.2 μmol/L) 
2–3 mg/dL  
(34.2–51.3 μmol/L) 
>3 mg/dL  
(>51.3 μmol/L) 
Albumin (g/dL) 
>3.5 g/dL 
(>35 g/L) 
2.8–3.5 g/dL 
(28–35 g/L) 
<2.8 g/dL 
(<28 g/L) 
International Normalized Ratio 
 
OR 
PT prolongation in seconds 
<1.7 
 
<4 
1.7–2.3 
 
4–6 
>2.3 
 
>6 
Abbreviations: PT = prothrombin time. 
a. 
If sedated, use last known encephalopathy status before sedation. 


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APPENDIX 5: 
MODIFIED ACUTE PHYSIOLOGY AND CHRONIC HEALTH EVALUATION (APACHE) II SCORE 
Point Value 
4 
3 
2 
1 
0 
1 
2 
3 
4 
Total 
Glasgow Coma Score 
Score = 15 minus actual Glasgow Coma Score 
 
Temperature (ºC) 
≥41 
39–40.9 
 
38.5–38.9 
36–38.4 
34–35.9 
32–33.9 
30–31.9 
≤29.9 
 
Mean Arterial Pressure 
(mmHg) a 
≥160 
130–159 
110–129 
 
70–109 
 
50–69 
 
≤49 
 
Heart Rate (bpm) 
≥180 
140–179 
110–139 
 
70–109 
 
55–69 
40–54 
≤39 
 
Respiration Rate 
≥50 
35–49 
 
25–34 
12–24 
10–11 
6–9 
 
≤5 
 
Alveolar-Arterial Oxygen 
Gradient (if FiO2 ≥50%) 
OR 
PaO2 (mmHg) 
OR 
Oxygen Saturation, % 
≥500 
 
 
 
 
350 to 499 
 
 
 
 
200 to 349 
 
 
 
 
 
 
 
 
 
<200 
 
 
>70 
 
 
≥92 
 
 
 
61–70 
 
 
88–91 
 
 
 
 
 
 
 
 
55–60 
 
 
85–87 
 
 
 
<55 
 
 
<85 
 
Arterial pH 
OR 
Serum HCO3 (mEq/L) –
(venous- if ABG not 
performed) 
≥7.7 
 
 
≥52 
7.6–7.69 
 
 
41–51.9 
 
7.5–7.59 
 
 
32–40.9 
7.33–7.49 
 
 
22–31.9 
 
7.25–7.32 
 
 
18–21.9 
7.15–7.24 
 
 
15–17.9 
<7.15 
 
 
<15 
 
Serum Na+ (mMol/L) 
≥180 
160–179 
155–159 
150–154 
130–149 
 
120–129 
111–119 
≤110 
 
Serum K+ (mMol/L) 
≥7.0 
6.0–6.9 
 
5.5–5.9 
3.5–5.4 
3.0–3.4 
2.5–2.9 
 
<2.5 
 
Serum creatinine (mg/dL) 
≥3.5 
2.0–3.4 
1.5–1.9 
 
0.6–1.4 
 
<0.6 
 
 
 
Acute renal failure b 
×2 creatinine point score if patient has acute renal failure 
 
Hematocrit, % 
≥60 
 
50–59.9 
46–49.9 
30–45.9 
 
20–29.9 
 
<20 
 
WBC, (109 cells/L or mm3) 
≥40 
 
20–39.9 
15–19.9 
3–14.9 
 
1–2.9 
 
<1 
 
 
 


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Point Value 
4 
3 
2 
1 
0 
1 
2 
3 
4 
Total 
Severe organ failure  
(liver, heart, or lung) 
or immunocompromised c 
Add 5 points if patient is medical (no surgery) or postoperative for emergency surgery 
Add 2 points if patient is postelective surgery  
 
Age (years) points 
≤44 = 0; 45–54 = 2; 55–64 = 3; 65–74 = 5; ≥75 = 6 
 
 
Sum of all rows 
 
Source: Modified from Knaus 1985. 
a. 
Mean arterial pressure = (systolic blood pressure + [2 × diastolic blood pressure])/3 
b. 
Acute Renal Failure = a 0.5 mg/dL increase in serum creatinine if the baseline serum creatinine was ≤1.9 mg/dL, a 1.0 mg/dL increase in serum creatinine if the baseline 
serum creatinine was 2.0 to 4.9 mg/dL, and a 1.5 mg/dL increase in serum creatinine if the baseline serum creatinine was ≥5.0 mg/dL. 
c. 
Organ insufficiency or immunocompromised state must have been evident prior to this hospital admission and conform to the following criteria: 
Liver 
Biopsy proven cirrhosis and documented portal hypertension; episodes of past upper gastrointestinal bleeding attributed to portal 
hypertension; or prior episodes of hepatic failure/encephalopathy/coma.  
Cardiovascular 
New York Heart Association Class IV. 
Respiratory 
Chronic restrictive, obstructive, or vascular disease resulting in severe exercise restriction (i.e., unable to climb stairs or perform 
household duties; or documented chronic hypoxia, hypercapnia, secondary polycythemia, severe pulmonary hypertension 
(>40 mmHg), or respirator dependency.  
Renal 
Receiving chronic dialysis.  
Immunocompromised 
The patient has received therapy that suppresses resistance to infection (e.g., immunosuppression, chemotherapy, radiation, long term 
or recent high dose steroids, or has a disease that is sufficiently advanced to suppress resistance to infection, e.g., leukemia, 
lymphoma, AIDS). 
 
 
 
 


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APPENDIX 6: 
GLASGOW COMA SCORE 
Sedating and paralytic agent use may confound the assessment of the Glasgow Coma Score. 
If sedation is reduced and patients awakened daily to perform neurologic assessments, assess the 
score during the period when the patient is not sedated. If daily awakenings are not performed, 
please record the score as if the patient did not have sedating or paralytic agents preventing 
response. 
Neurologic Response 
Score 
Best Eye Response (E) 
Spontaneous-open with blinking at baseline 
4 
Opens to verbal command, speech or shout 
3 
Opens to pain (not applied to face) 
2 
None 
1 
Best Verbal Response (V) 
Oriented 
5 
Confused conversation, but can answer questions 
4 
Inappropriate responses, words discernible 
3 
Incomprehensible speech 
2 
None 
1 
Best Motor Response (M) 
Obeys commands for movement 
6 
Purposeful movement to painful stimulus 
5 
Withdraws from pain 
4 
Abnormal (spastic) flexion, decorticate posture 
3 
Extensor (rigid) response, decerebrate posture 
2 
None 
1 
Total Score 
 
Source: Teasdale 1974. 
 


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APPENDIX 7: 
POTENTIAL DRUG INTERACTIONS, WARNINGS, 
AND PRECAUTIONS 
Appendix 7A: 
Caspofungin Potential Drug Interactions, Warnings, and Precautions 
Caspofungin is contraindicated in subjects with hypersensitivity to the active substance or any 
of the excipients. Hypersensitivity includes but is not limited to hereditary sugar disorders 
(e.g., fructose intolerance or sucrose-isomaltase deficiency), anaphylaxis and exfoliative skin 
disorders (e.g., Stevens-Johnson syndrome or toxic epidermal necrolysis), which may be severe.  
Caspofungin is not a substrate for P-glycoprotein and is a poor substrate for cytochrome P450 
enzymes. However, caspofungin has been shown to interact with other medicinal products in 
pharmacological and clinical studies. 
Concomitant administration of the following medicinal products with caspofungin requires 
precaution and dose adjustments may be required: 
Cyclosporine 
May lead to an increase in caspofungin AUC and may increase the 
risk of hepatic toxicity 
Carbamazepine 
Limited data from population PK studies indicate that concomitant 
use of carbamazepine may result in a decrease of caspofungin 
AUC. When co-administering inducers of metabolic enzymes, 
an increase in the daily dose of caspofungin to 70 mg, following 
the 70 mg loading dose, should be considered in adult patients. 
Dexamethasone 
Limited data from population PK studies indicate that concomitant 
use of dexamethasone may result in a decrease of caspofungin 
AUC. When co-administering inducers of metabolic enzymes, 
an increase in the daily dose of caspofungin to 70 mg, following 
the 70 mg loading dose, should be considered in adult patients. 
Efavirenz 
Limited data from population PK studies indicate that concomitant 
use of efavirenz may result in a decrease of caspofungin AUC. 
When co-administering inducers of metabolic enzymes, 
an increase in the daily dose of caspofungin to 70 mg, following 
the 70 mg loading dose, should be considered in adult patients. 
Nevirapine 
Limited data from population PK studies indicate that concomitant 
use of nevirapine may result in a decrease of caspofungin AUC. 
When co-administering inducers of metabolic enzymes, 
an increase in the daily dose of caspofungin to 70 mg, following 
the 70 mg loading dose, should be considered in adult patients. 
Phenytoin 
Limited data from population PK studies indicate that concomitant 
use of phenytoin may result in a decrease of caspofungin AUC. 
When co-administering inducers of metabolic enzymes, 
an increase in the daily dose of caspofungin to 70 mg, following 
the 70 mg loading dose, should be considered in adult patients. 


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Rifampin (Rifampicin) 
Rifampicin caused a 60 % increase in AUC and 170 % increase 
in trough concentration of caspofungin on the first day of 
co-administration when both medicinal products were initiated 
together in healthy adult volunteers. Caspofungin trough levels 
gradually decreased upon repeated administration. After two 
weeks’ administration rifampicin had limited effect on AUC, but 
trough levels were 30% lower than in adult subjects who received 
caspofungin alone. The mechanism of interaction could possibly 
be due to an initial inhibition and subsequent induction of 
transport proteins. 
Tacrolimus 
Caspofungin reduced the trough concentration of tacrolimus by 
26% in healthy adult volunteers. For patients receiving both 
therapies, standard monitoring of tacrolimus blood concentrations 
and appropriate tacrolimus dosage adjustments are mandatory. 
 
Appendix 7B: 
Fluconazole Potential Drug Interactions, Warnings, and Precautions 
List of drugs that can cause prolonged QT interval when co-administered with fluconazole: 
terfenadine 
cisapride 
astemizole 
erythromycin 
pimozide 
quinidine 
halofantrine 
 
Concomitant use of the following supplements, such as St. John’s Wort, grapefruit, or Seville 
oranges should be avoided. Concomitant administration of the following medicinal products with 
fluconazole requires precaution and dose adjustments may be required: 
Alfentanil 
A reduction in clearance and distribution volume as well as 
prolongation of half-life of alfentanil following concomitant 
treatment with fluconazole was observed. Dosage adjustment of 
alfentanil may be necessary. 
Amitriptyline, nortriptyline 
Fluconazole increases the effect of amitriptyline and nortriptyline. 
5-nortriptyline and/or S-amitriptyline may be measured at 
initiation of the combination therapy and after one week. Dose of 
amitriptyline/ nortriptyline should be adjusted, if necessary. 
Azithromycin 
There was no significant pharmacokinetic interaction between 
fluconazole and azithromycin in a study of 18 healthy volunteers. 
Calcium channel blockers: nifedipine, 
isradipine, amlodipine, verapamil, 
and felodipine 
Certain calcium channel antagonists are metabolized by CYP3A4. 
Fluconazole has the potential to increase the systemic exposure of 
the calcium channel antagonists. Frequent monitoring for adverse 
events is recommended. 


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Carbamazepine 
Fluconazole inhibits the metabolism of carbamazepine 
and an increase in serum carbamazepine of 30% has been 
observed. There is a risk of developing carbamazepine toxicity. 
Dose adjustment of carbamazepine may be necessary depending 
on concentration measurements/effect. 
Celecoxib 
During concomitant treatment with fluconazole and celecoxib, 
the celecoxib Cmax and AUC increased by 68% and 134%, 
respectively. Half of the celecoxib dose may be necessary when 
combined with fluconazole. 
Coumarin-type anticoagulants 
(e.g., warfarin) 
Prothrombin time may be increased in patients receiving 
concomitant fluconazole and coumarin-type anticoagulants. 
Bleeding events (bruising, epistaxis, gastrointestinal bleeding, 
hematuria, and melena) have been reported in association with 
increases in prothrombin time in patients receiving fluconazole 
concurrently with warfarin. Careful monitoring of prothrombin 
time in patients receiving fluconazole and coumarin-type 
anticoagulants is recommended. Dose adjustment of the 
anticoagulant may be necessary. 
Cyclophosphamide 
Combination therapy with cyclophosphamide and fluconazole 
results in an increase in serum bilirubin and serum creatinine.  
Fentanyl 
One fatal case of fentanyl intoxication due to possible fentanyl 
fluconazole interaction was reported in the literature. Furthermore, 
it was shown in healthy volunteers that fluconazole delayed the 
elimination of fentanyl significantly. Elevated fentanyl 
concentration may lead to respiratory depression. Patients should 
be monitored closely for the potential risk of respiratory 
depression. Dosage adjustment of fentanyl may be necessary. 
HMG-CoA reductase inhibitors: 
simvastatin, atorvastatin, fluvastatin 
The risk of myopathy and rhabdomyolysis increases when 
fluconazole is co-administered with HMG-CoA reductase 
inhibitors metabolized through CYP3A4, such as atorvastatin 
and simvastatin, or through CYP2C9, such as fluvastatin. 
If concomitant therapy is necessary, the patient should be observed 
for symptoms of myopathy and rhabdomyolysis and creatine 
kinase should be monitored. HMG-CoA reductase inhibitors 
should be discontinued if a marked increase in creatine kinase is 
observed or myopathy/rhabdomyolysis is diagnosed or suspected. 
Ibrutinib 
Moderate inhibitors of CYP3A4 such as fluconazole increase 
plasma ibrutinib concentrations and may increase risk of toxicity. 
If the combination cannot be avoided, reduce the dose of ibrutinib 
as instructed in ibrutinib prescribing information and provide close 
clinical monitoring. 
Immunosuppresors: cyclosporine, 
everolimus, sirolimus, tacrolimus 
Fluconazole significantly increases the concentration and AUC of 
cyclosporine. This combination may be used by reducing the dose 
of cyclosporine depending on cyclosporine concentration. 
Although not studied in vivo or in vitro, fluconazole may increase 
serum concentrations of everolimus through inhibition of 
CYP3A4. 
Fluconazole increases plasma concentrations of sirolimus 
presumably by inhibiting the metabolism of sirolimus via 
CYP3A4 and P-glycoprotein. This combination may be used with 


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a dose adjustment of sirolimus depending on the 
effect/concentration measurements. 
Fluconazole may increase the serum concentrations of orally 
administered tacrolimus up to 5 times due to inhibition of 
tacrolimus metabolism through CYP3A4 in the intestines. 
No significant pharmacokinetic changes have been observed when 
tacrolimus is given intravenously. Increased tacrolimus levels have 
been associated with nephrotoxicity. Dose of orally administered 
tacrolimus should be decreased depending on tacrolimus 
concentration. 
Losartan 
Fluconazole inhibits the metabolism of losartan to its active 
metabolite (E-31 74) which is responsible for most of the 
angiotensin Il-receptor antagonism which occurs during treatment 
with losartan. Patients should have their blood pressure monitored 
continuously. 
Methadone 
Fluconazole may enhance the serum concentration of methadone. 
Dose adjustment of methadone may be necessary. 
NSAIDs 
The Cmax and AUC of flurbiprofen was increased by 23% 
and 81%, respectively, when co-administered with fluconazole 
compared to administration of flurbiprofen alone. Similarly, the 
Cmax and AUC of the pharmacologically active isomer [S-(+)-
ibuprofen] was increased by 15% and 82%, respectively, when 
fluconazole was co-administered with racemic ibuprofen (400 mg) 
compared to administration of racemic ibuprofen alone. Although 
not specifically studied, fluconazole has the potential to increase 
the systemic exposure of other NSAIDs that are metabolized by 
CYP2C9 (e.g., naproxen, lornoxicam, meloxicam, diclofenac). 
Frequent monitoring for adverse events and toxicity related to 
NSAIDs is recommended. Adjustment of dose of NSAIDs may be 
needed. 
Olaparib 
Moderate inhibitors of CYP3A4 such as fluconazole increase 
olaparib plasma concentrations; concomitant use is not 
recommended. If the combination cannot be avoided, reduce the 
dose of olaparib. 
Oral contraceptives 
Two pharmacokinetic studies with a combined oral contraceptive 
have been performed using multiple doses of fluconazole. There 
were no relevant effects on hormone level in the 50 mg 
fluconazole study, while at 200 mg daily, the AUCs of ethinyl 
estradiol and levonorgestrel were increased 40% and 24%, 
respectively. Thus, multiple dose use of fluconazole at these doses 
is unlikely to have an effect on the efficacy of the combined oral 
contraceptive. 
Oral hypoglycemics: tolbutamide, 
glyburide, and glipizide (or other 
sulfonylureas) 
Fluconazole has been shown to prolong the serum half-life 
of concomitantly administered oral sulfonylureas 
(e.g., chlorpropamide, glibenclamide, glipizide, tolbutamide) 
in healthy volunteers. Frequent monitoring of blood glucose 
and appropriate reduction of sulfonylurea dose is recommended 
during co-administration. 


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Phenytoin 
Fluconazole inhibits the hepatic metabolism of phenytoin. 
Concomitant repeated administration of 200 mg fluconazole 
and 250 mg phenytoin intravenously, caused an increase 
of the phenytoin AUC24 by 75% and Cmin by 128%. With 
co-administration, serum phenytoin concentration levels should 
be monitored in order to avoid phenytoin toxicity. 
Prednisone 
A case report in the literature reported that a liver-transplanted 
patient treated with prednisone developed acute adrenal cortex 
insufficiency when a three month therapy with fluconazole was 
discontinued. The discontinuation of fluconazole presumably 
caused an enhanced CYP3A4 activity which led to increased 
metabolism of prednisone. Patients on long-term treatment with 
fluconazole and prednisone should be carefully monitored for 
adrenal cortex insufficiency when fluconazole is discontinued. 
Rifabutin 
There have been reports that an interaction exists when 
fluconazole is administered concomitantly with rifabutin, leading 
to increased serum levels of rifabutin up to 80%. There have been 
reports of uveitis in patients to whom fluconazole and rifabutin 
were co-administered. Patients receiving rifabutin and fluconazole 
concomitantly should be monitored. 
Rifampin/rifampicin 
Concomitant administration of fluconazole and rifampicin resulted 
in a 25% decrease in the AUC and a 20% shorter half-life of 
fluconazole. Concomitant use should be avoided. 
Short acting benzodiazepines 
(e.g., midazolam, triazolam) 
Following oral administration of midazolam, fluconazole resulted 
in substantial increases in midazolam concentrations and 
psychomotor effects. Concomitant intake of fluconazole 200 mg 
and midazolam 7.5 mg orally increased the midazolam AUC 
and half-life 3.7-fold and 2.2-fold, respectively. Fluconazole 
200 mg daily given concurrently with triazolam 0.25 mg orally 
increased the triazolam AUC and half-life 4.4-fold and 2.3-fold, 
respectively. Potentiated and prolonged effects of triazolam have 
been observed at concomitant treatment with fluconazole. 
If concomitant benzodiazepine therapy is necessary in patients 
being treated with fluconazole, consideration should be given to 
decreasing the benzodiazepine dose, and the patients should be 
appropriately monitored. 
Theophylline 
In a placebo-controlled interaction study, the administration of 
fluconazole 200 mg for 14 days resulted in an 18% decrease in the 
mean plasma clearance rate of theophylline. Patients who are 
receiving high dose theophylline or who are otherwise at increased 
risk for theophylline toxicity should be observed for signs of 
theophylline toxicity while receiving fluconazole. Therapy should 
be modified if signs of toxicity develop. 
Tofacitinib 
Systemic exposure to tofacitinib is increased when tofacitinib is 
co-administered with fluconazole. Reduce the dose of tofacitinib 
when given concomitantly with fluconazole. 


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Tolvaptan 
Exposure to tolvaptan is significantly increased (200% in AUC; 
80% in Cmax) when tolvaptan, a CYP3A4 substrate, is 
co-administered with fluconazole, a moderate CYP3A4 inhibitor, 
with risk of significant increase in adverse effects particularly 
significant diuresis, dehydration, and acute renal failure. In case 
of concomitant use, the tolvaptan dose should be reduced and the 
patient managed cautiously. 
Vitamin A 
Based on a literature case report in one patient receiving 
combination therapy with all-trans-retinoid acid (an acid form of 
vitamin A) and fluconazole, CNS related undesirable effects have 
developed in the form of pseudotumour cerebri, which 
disappeared after discontinuation of fluconazole treatment. 
This combination may be used but the incidence of CNS-related 
undesirable effects should be borne in mind. 
Voriconazole 
Monitoring for adverse events and toxicity related to voriconazole 
is recommended, especially if voriconazole is started within 
24 hours after the last dose of fluconazole. 


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APPENDIX 8: 
PHARMACOKINETIC SAMPLE PROCESSING AND SHIPMENT 
Plasma PK sample collection and processing procedure  
1. Draw blood into a 4 mL lavender top potassium ethylenediaminetetraacetic acid 
(K2EDTA) Vacutainer tube. Label the tube. 
2. Mix the blood with the anticoagulant by gently inverting the tube 8 to 10 times, and then 
immediately place the tube on wet ice. It is preferable to leave the sample on wet ice for 
5 to 10 minutes before centrifuging.   
3. Centrifuge the blood samples for approximately 10 minutes at approximately 1006g 
in a centrifuge within approximately 60 minutes after blood sample collection.  
4. Immediately following centrifugation, gently remove the plasma from the packed cells 
and aliquot into 2 transfer vials. Into the first, aliquot ≥0.5 mL of plasma, and, into the 
second, aliquot the rest. 
5. Replace the caps on the transfer vials and freeze the samples immediately 
at approximately -20°C or colder.  
6. Note: No more than 60 minutes should elapse between blood collection and freezing 
the plasma samples. 
7. Keep the samples frozen at approximately -20°C or colder until shipment. 
8. Ship the primary sample on dry ice; retain the frozen backup sample until receipt of 
instructions regarding its shipment. 
NOTE: Wet ice is defined as a mixture of ice and water. Specific details for processing 
and shipment of PK samples are noted in the Laboratory Manual. 


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APPENDIX 9: 
LIST OF PROHIBITED NEUROTOXIC MEDICATIONS  
LIST OF PROHIBITED NEUROTOXIC CONCOMITANT MEDICATIONS a 
Definite High Risk 
vinca alkaloids (Vincristine) 
taxols (paclitaxel, docetaxel, cabazitaxel) 
Moderate Risk 
amiodarone (Cordarone) 
arsenic trioxide (Trisenox) 
bortezomib (Velcade) 
brentuximab vedotin (Adcetris) 
cetuximab (Erbitux) 
cisplatin & oxaliplatin 
colchicine (extended use) 
dapsone b 
didanosine (ddI, Videx) 
dichloroacetate 
disulfiram (Antabuse) 
eribulin (Halaven) 
gold salts 
ipilimumab (Yervoy) 
ixabepilone (Ixempra) 
leflunomide (Arava) 
lenalidomide (Revlimid) 
metronidazole/misonidazole (extended use) 
nitrofurantoin (Macrodantin, Furadantin, Macrobid) 
nitrous oxide 
nivolumab (Opdivo) 
pembrolizumab (Keytruda) 
perhexiline (not used in U.S.) 
pomalidomide (Pomalyst) 
stavudine (d4T, Zerit) 
suramin 
thalidomide 
zalcitabine (ddC, Hivid) 
a Adapted from the Charcot Marie Tooth Association list of neurotoxic medications. 


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APPENDIX 10: 
INVESTIGATOR SIGNATURE 
I have read and understand this protocol. I agree to the following: 
1) To conduct the trial in compliance with GCP, with applicable regulatory requirement(s), 
with the protocol agreed to by the Sponsor and given approval/favorable opinion by the 
IRB/IEC 
2) To comply with procedures for data recording and reporting 
3) To permit monitoring, auditing, and inspection by the Sponsor, its designated representatives, 
and regulatory authorities  
4) To retain the essential documents in the Investigator/institution files until the Sponsor 
informs the Investigator or institution that these documents are no longer needed 
INVESTIGATOR SIGNATURE 
 
 
 
Investigator Signature 
 
Date 
 
 
 
Investigator Printed Name 
 
 
Site Information 
Site Number: 
 
Site Name: 
 
Site Address: 
 
 

SAP_001.pdf: 
Statistical Analysis Plan 
 
 
Title: 
A Phase 3, Multicenter, Randomized, Double-blind Study of the Efficacy 
and Safety of Rezafungin for Injection versus Intravenous Caspofungin 
Followed by Optional Oral Fluconazole Step-down in the Treatment of 
Subjects with Candidemia and/or Invasive Candidiasis (The ReSTORE 
Study) 
NCT Number: 
NCT03667690 
Document Date: 
22 NOV 2021 
 


 
 
CONFIDENTIAL 
STATISTICAL ANALYSIS PLAN 
A Phase 3, Multicenter, Randomized, Double-blind Study of the Efficacy and 
Safety of Rezafungin for Injection versus Intravenous Caspofungin Followed 
by Optional Oral Fluconazole Step-down in the Treatment of Subjects with 
Candidemia and/or Invasive Candidiasis (The ReSTORE Study) 
Protocol Number: 
CD101.IV.3.05 
Protocol Version and Date: 
Amendment 5 15 October 2020 
Name of Test Drug: 
Rezafungin for Injection 
Indication: 
Candidemia and/or Invasive Candidiasis 
Phase: 
Phase 3 
Methodology: 
Multicenter, randomized, double-blind 
Sponsor: 
Cidara Therapeutics, Inc. 
6310 Nancy Ridge Drive, Suite 101 
San Diego, CA 92121 
Tel: (858) 752-6170 
Fax: (858) 408-3509 
Sponsor Representative: 
Taylor Sandison, MD MPH 
Chief Medical Officer 
Analysis Plan Date: 
 22 NOV 2021 
Analysis Plan Version: 
FINAL VERSION 4.0 
 
Confidentiality Statement 
The information contained herein is confidential and the proprietary property of 
Cidara Therapeutics, Inc. and any unauthorized use or disclosure of  
such information without the prior written authorization of  
Cidara Therapeutics, Inc. is expressly prohibited. 


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APPROVAL SIGNATURE PAGE 
Protocol Title: 
A Phase 3, Multicenter, Randomized, Double-blind Study of the 
Efficacy and Safety of Rezafungin for Injection versus Intravenous 
Caspofungin Followed by Optional Oral Fluconazole Step-down in 
the Treatment of Subjects with Candidemia and/or Invasive 
Candidiasis (The ReSTORE Study) 
Protocol Number: 
CD101.IV.3.05 
Sponsor: 
Cidara Therapeutics, Inc. 
6310 Nancy Ridge Drive, Suite 101 
San Diego, CA 92121 
Author: 
Cidara Therapeutics, Inc. 
6310 Nancy Ridge Drive, Suite 101 
San Diego, CA 92121 
 
MMS Holdings, Inc. 
6880 Commerce Blvd 
Canton, MI 48187 
 
 
 
 
 
Author Signatory: 
Sara Rhee, MS 
Principal Biostatistician,  
MMS Holdings, Inc. 
 
 
Signature:________________________________ 
 
Date:  ___________________________________ 
 
 
 
Sponsor Signatories: 
Anita Das, PhD 
Consulting Statistician,  
Cidara Therapeutics, Inc. 
 
 
 
Signature:________________________________ 
 
Date:  ___________________________________ 
 
 
 
Sponsor Signatories: 
Taylor Sandison, MD MPH 
Chief Medical Officer,  
Cidara Therapeutics, Inc. 
 
 
 
Signature:________________________________ 
 
Date:  ___________________________________ 
 
 


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TABLE OF CONTENTS 
APPROVAL SIGNATURE PAGE ........................................................................................... 2 
TABLE OF CONTENTS .......................................................................................................... 3 
TABLES INCLUDED IN THE TEXT ...................................................................................... 7 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS ................................................ 8 
1. 
INFORMATION FROM THE STUDY PROTOCOL .................................................. 11 
1.1. 
Introduction and Objectives ............................................................................. 11 
1.1.1. 
Introduction ....................................................................................... 11 
1.1.2. 
Study Objectives ............................................................................... 11 
1.2. 
Synopsis of Study Design................................................................................. 12 
1.2.1. 
Randomization and Blinding ............................................................. 13 
1.2.2. 
Unblinding ........................................................................................ 14 
2. 
DEFINITIONS OF OUTCOME MEASURES ............................................................. 15 
2.1. 
Primary Efficacy Outcome Measures ............................................................... 15 
2.1.1. 
Estimand Framework ......................................................................... 16 
Table 2-1: 
Estimand Attributes .............................................................................. 16 
2.2. 
Secondary Efficacy Outcomes .......................................................................... 16 
2.2.1. 
Global Response ................................................................................ 17 
Table 2-2: 
Global Response Categories ................................................................. 18 
2.2.2. 
Mycological response ........................................................................ 18 
Table 2-3: 
Mycological Response Definitions** .................................................... 19 
2.2.3. 
Investigator’s Assessment of Clinical Response ................................. 21 
Table 2-4: 
Investigator’s Assessment of Clinical Response Definitions ................. 22 
2.2.4. 
Radiological Response ...................................................................... 23 
Table 2-5: 
Radiological Response Definitions ....................................................... 23 
2.3. 
Exploratory Efficacy Outcomes ....................................................................... 24 


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2.3.1. 
Resolution of Attributable Systemic Signs of Candidemia 
and/or Invasive Candidiasis that were Present at Baseline .................. 24 
2.3.2. 
All-Cause Mortality (ACM) through the FU Visit .............................. 25 
2.3.3. 
Time to First Negative Blood Culture ................................................ 25 
2.3.4. 
Clinical Outcomes by Baseline Candida species ................................ 25 
2.4. 
Health Outcome Measures ............................................................................... 26 
2.5. 
Safety Outcome Measures ................................................................................ 26 
2.6. 
Population Definitions ..................................................................................... 26 
2.7. 
Protocol Deviations .......................................................................................... 27 
2.8. 
Subgroup analyses ........................................................................................... 27 
3. 
GENERAL STATISTICAL METHODS ..................................................................... 28 
3.1. 
Sample Size Justification.................................................................................. 28 
Table 3-1: 
Sample Size and Power Calculations .................................................... 29 
3.2. 
General Methods .............................................................................................. 29 
3.3. 
Computing Environment .................................................................................. 30 
3.4. 
Methods of Pooling Data .................................................................................. 30 
3.5. 
Multiple Comparisons/Multiplicity .................................................................. 30 
3.6. 
Withdrawals, Dropouts, Loss to Follow-up ...................................................... 31 
3.7. 
Missing, Unused, and Spurious Data ................................................................ 31 
3.8. 
Visit Windows ................................................................................................. 31 
3.9. 
Interim Analyses .............................................................................................. 32 
3.9.1. 
Data and Safety Monitoring Board .................................................... 32 
4. 
STATISTICAL ANALYSIS ........................................................................................ 32 
4.1. 
Study Population .............................................................................................. 32 
4.1.1. 
Analysis Populations and Subject Disposition.................................... 32 
4.1.2. 
Protocol Deviations ........................................................................... 33 
4.1.3. 
Demographics and Baseline Characteristics ....................................... 33 


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4.1.4. 
Medical and Surgical History ............................................................ 34 
4.1.5. 
Candida Risk Factors ......................................................................... 34 
4.1.6. 
Systemic Signs of Candidemia and/or IC ........................................... 35 
4.1.7. 
Baseline Candida Pathogens .............................................................. 35 
4.2. 
Extent of Exposure and Concomitant Procedures ............................................. 36 
4.2.1. 
Study Drug Exposure......................................................................... 36 
4.2.2. 
Prior and Concomitant Medications ................................................... 37 
4.2.3. 
Concomitant Procedures .................................................................... 37 
4.3. 
Analysis of Efficacy ......................................................................................... 38 
4.3.1. 
Primary Efficacy Analysis ................................................................. 38 
4.3.2. 
Secondary Efficacy Outcomes ........................................................... 41 
4.3.3. 
Subgroup Analyses of the Primary Outcomes .................................... 41 
4.3.4. 
Additional Efficacy Outcomes ........................................................... 42 
4.4. 
Analysis of Health Outcomes ........................................................................... 43 
4.5. 
Analysis of Safety Data .................................................................................... 43 
4.5.1. 
Adverse Events .................................................................................. 44 
Table 4-1: 
Higher Risk Subgroups ......................................................................... 45 
4.5.2. 
Clinical Laboratory Data ................................................................... 46 
Table 4-2: 
Criterion-based hepatic events .............................................................. 47 
4.5.3. 
Vital Signs ......................................................................................... 48 
Table 4-3: 
Criteria for Potentially Clinically Significant Vital Signs ...................... 48 
4.5.4. 
Electrocardiogram ............................................................................. 49 
4.5.5. 
Physical and Retinal Examinations .................................................... 49 
4.5.6. 
Neurological Questionnaires .............................................................. 49 
4.6. 
PK Sampling .................................................................................................... 49 
5. 
APPENDICES ............................................................................................................. 51 


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5.1. 
Appendix 1: Study Design Diagram ................................................................. 51 
5.2. 
Appendix 2: Schedule of Assessments and Procedures for the 
Required Treatment, End of Treatment, and Follow-up Periods........................ 52 
5.3. 
Appendix 3: Schedule of Assessments and Procedures for the 
Optional Treatment Period ............................................................................... 58 
5.4. 
Appendix 4: Dosing Schedule by Day .............................................................. 60 
5.5. 
Appendix 5: Directionality of Worst Laboratory Parameters ............................ 62 
Table 5-1: 
Directionality of Worst Laboratory Parameters ............................... 62 
5.6. 
Appendix 6: Clinical Laboratory Toxicity Grading Scales ................................ 63 
Table 5-2: 
Hematology Toxicity Grading Scale .................................................. 63 
Table 5-3: 
Chemistry Toxicity Grading Scale ..................................................... 64 
Table 5-4: 
Enzymes Toxicity Grading Scale ....................................................... 65 
5.7. 
Appendix 7: Laboratory Normals ..................................................................... 66 
5.8. 
Appendix 8: Adverse Event and Prior/Concomitant Medication Date 
Imputations ...................................................................................................... 68 
5.9. 
Appendix 9: Document Version History ........................................................... 70 
6. 
CHANGES TO PLANNED ANALYSES .................................................................... 72 
7. 
REFERENCES ............................................................................................................ 73 
 


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TABLES INCLUDED IN THE TEXT 
Table 2-1: 
Estimand Attributes .................................................................................................. 16 
Table 2-2: 
Global Response Categories ...................................................................................... 18 
Table 2-3: 
Mycological Response Definitions ............................................................................. 19 
Table 2-4: 
Investigator’s Assessment of Clinical Response Definitions ..................................... 22 
Table 2-5: 
Radiological Response Definitions ............................................................................ 23 
Table 3-1: 
Sample Size and Power Calculations ........................................................................ 29 
Table 4-1: 
Higher Risk Subgroups ............................................................................................. 45 
Table 4-2: 
Criterion-based hepatic events .................................................................................. 47 
Table 4-3: 
Criteria for Potentially Clinically Significant Vital Signs ........................................ 48 
Table 5-1: 
Directionality of Worst Laboratory Parameters ...................................................... 62 
Table 5-2: 
Hematology Toxicity Grading Scale ......................................................................... 63 
Table 5-3: 
Chemistry Toxicity Grading Scale ............................................................................ 64 
Table 5-4: 
Enzymes Toxicity Grading Scale .............................................................................. 65 
 


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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
Abbreviation 
Definition 
ACM 
all-cause mortality 
AE 
adverse event 
AESI 
adverse event of special interest 
ADaM 
Analysis Data Model  
ADaM IG 
Analysis Data Model Implementation Guide 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
ANC 
absolute neutrophil count 
APACHE II 
Acute Physiology and Chronic Health Evaluation 
AST 
aspartate aminotransferase 
ATC 
anatomical therapeutic chemical 
BMI 
body mass index 
C 
Celsius 
CE 
clinically evaluable 
CH 
Potentially Clinically Significant High 
CI 
Confidence Interval 
CL 
Potentially Clinically Significant Low 
CSR 
Clinical Study Report 
CTCAE 
Common Terminology Criteria for Adverse Events 
DAIDS 
Division of AIDs 
DILI 
Drug Induced Liver Injury  
DMID 
Division of Microbiology and Infectious Diseases 
DRC 
Data Review Committee 
DSMB 
Data and Safety Monitoring Board 
ECG 
electrocardiogram 
eCrCL 
estimated creatinine clearance 
eCRF 
electronic case report form 
EMA 
European Medicines Agency 
EOI 
End of infusion 
EOT 
End-of-Treatment 
ESCMID 
European Society of Clinical Microbiology and Infectious Diseases 
F 
Fahrenheit 
FDA 
Food and Drug Administration 
FU 
Follow-up 
IC 
Invasive Candidiasis 
ICE 
Intercurrent event 
ICH 
International Conference on Harmonisation 


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Abbreviation 
Definition 
ICU 
Intensive Care Unit 
IRT 
interactive response technology 
ITT 
intent-to-treat 
IV 
Intravenous(ly) 
IVD 
in vitro diagnostic 
kg 
kilogram 
KM 
Kaplan Meier 
LFT 
liver function test 
LLN 
lower limit of normal 
MedDRA 
Medical Dictionary for Regulatory Activities 
MIC 
minimal inhibitory concentration 
MIC50 
minimal inhibitory concentration required to inhibit the growth of 50% of 
the isolates 
MIC90 
minimal inhibitory concentration required to inhibit the growth of 90% of 
the isolates 
mg 
milligram 
mITT 
Modified Intent-to-treat 
NI 
non-inferiority 
NLM  
National Library of Medicine 
PCS 
potentially clinically significant 
PI 
Principal Investigator 
PICC 
Peripherally Inserted Central Catheter 
PK 
pharmacokinetic 
PT 
Preferred Term  
PT/INR 
Prothrombin time or International Normalized Ratio 
QLQ-CIPN20 
Chemotherapy-Induced Peripheral Neuropathy questionnaire 
QTcF 
QT interval corrected using Fridericia's formula 
RR 
respiratory rate 
SAE 
serious treatment-emergent adverse event 
SAP 
statistical analysis plan 
SARA 
Scale for the Assessment and Rating of Ataxia 
SD 
standard deviation 
SI 
Systeme Internationale  
SOC 
system organ class 
SMQ 
Standardized MedDRA query 
spp. 
species 
TBL 
total bilirubin 
TEAE 
treatment-emergent adverse event 
ULN 
upper limit of normal 


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Abbreviation 
Definition 
WHO 
World Health Organization 


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1. 
INFORMATION FROM THE STUDY PROTOCOL 
1.1. 
Introduction and Objectives 
1.1.1. 
Introduction 
This Statistical Analysis Plan (SAP) provides the framework for the summarization and analysis 
of the clinical data from the study, “A Phase 3, Multicenter, Randomized, Double-blind Study of 
the Efficacy and Safety of Rezafungin for Injection versus Intravenous Caspofungin Followed by 
Optional Oral Fluconazole Step-down in the Treatment of Subjects with Candidemia and/or 
Invasive Candidiasis (The ReSTORE Study)”. Changes made to the SAP after it has been signed 
but prior to database lock will be documented in a SAP amendment. Changes made to the 
analyses after database lock will be described in the clinical study report (CSR). Pharmacokinetic 
(PK) analyses except for the analyses based on the concentration described in Section 4.6 will 
not be included in this SAP. Additional supportive/exploratory analyses might be added once 
subject data is available. Table shells and data set specifications will be prepared on the basis of 
this document.  
1.1.2. 
Study Objectives 
Per regulatory authority’s expectations, the primary objectives of the study are separate for the 
United States Food and Drug Administration (FDA) and European Medicines Agency (EMA) as 
follows: 
 Demonstrate that Rezafungin for Injection is non-inferior to caspofungin in terms of 
all-cause mortality (ACM) at Day 30 (-2 days) in the modified intent-to-treat (mITT) 
population (FDA primary objective) 
 Demonstrate that Rezafungin for Injection is non-inferior to caspofungin in terms of 
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 mITT population (EMA primary 
objective) 
The secondary objectives of this study are to: 
 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), End of Treatment (EOT) (≤2 days of last dose), and Follow-up (Days 52-
59) in the mITT population 
 Compare mycological eradication for 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) in the mITT population 


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 Compare clinical cure as assessed by the Investigator for 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) in the mITT population 
 
Compare 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) in the mITT population 
 Compare the safety and tolerability for subjects receiving Rezafungin for Injection and 
caspofungin in the safety population 
 Evaluate the pharmacokinetics of Rezafungin for Injection 
An exploratory objective of this study is to:  
 Compare resolution of systemic signs attributable to candidemia and/or invasive 
candidiasis for subjects receiving of Rezafungin for Injection and caspofungin at Day 5, 
Day 14 (±1 day), Day 30 (-2 days) and Follow-up (Days 52-59) in the mITT population. 
1.2. 
Synopsis of Study Design 
This is a Phase 3, multicenter, prospective, randomized, double-blind, efficacy and safety study 
of intravenous (IV) Rezafungin for Injection (laboratory code: CD101) versus an active 
comparator regimen of caspofungin (IV) followed by optional oral fluconazole step-down 
therapy in subjects with candidemia and/or invasive candidiasis (IC). Subjects will receive either 
IV Rezafungin for Injection or IV caspofungin, randomized in a 1:1 ratio. Subjects can be 
switched to oral step-down treatment by the Investigator after ≥3 days of IV treatment (or the 
minimum duration of IV therapy advised by the site’s national/regional/local guidelines, 
whichever is greater) if they meet the oral step-down therapy criteria (as described in the 
Protocol Section 8.2.3.2).  
Subjects randomized to receive Rezafungin for Injection: 
Subjects will receive a loading dose of Rezafungin for Injection 400 milligram (mg) in 
Week 1, followed by 200 mg once weekly for a total of 2 to 4 doses. To maintain the 
blind, subjects will also receive placebo for caspofungin IV, which will be administered 
on Days 2-7, Days 9-14 and during the optional dosing period on Days 16-21 and Days 
23-28, or will receive daily placebo for oral step-down therapy (first eligibility on Day 4 
or later as advised by a site’s national/regional/local guidelines), which will be 
administered every day including rezafungin infusion days.  
Subjects randomized to caspofungin: 
Subjects will receive a total treatment of ≥14 days beginning with a single caspofungin 
70 mg IV loading dose on Day 1 followed by caspofungin 50 mg IV once daily with the 
option to continue treatment ≤28 days. After ≥3 days (or the minimum duration of IV 
therapy advised by the site’s national/regional/local guidelines, whichever is greater) of 
caspofungin treatment, subjects who meet the step-down therapy eligibility criteria may 


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be switched to oral fluconazole at a dose of 6 mg/kilogram (kg) (rounded to the nearest 
200 mg increment) with a maximum dose of 800 mg (e.g., a subject weighing 73 kg 
would receive fluconazole 400 mg dose [2 capsules of 200 mg each] based on a 6 mg/kg 
target dose of 438 mg based on weight [73 kg × 6 mg/kg = 438 mg). NOTE: Refer to 
dosing section of protocol for alternative regimens of fluconazole in subjects with renal 
impairment). To maintain the blind, subjects in the caspofungin treatment group who 
have switched to oral step-down therapy will receive placebo for Rezafungin for Injection 
IV once weekly on the days of scheduled Rezafungin for Injection doses until study drug 
is stopped (on Day 8, Day 15 and Day 22 [if applicable]). 
Subjects will complete an End of Treatment visit within 2 calendar days after the last dose of 
study drug and a Follow-up visit within the Day 52-59 period. Subjects who stop study drug 
prior to Day 22 and are considered clinical failures (i.e., require a change in antifungal therapy to 
treat candidemia and/or invasive candidiasis) may have their Follow-up visit earlier but the visit 
must still be ≥30 days following the last once weekly infusion of Rezafungin for 
Injection/placebo. 
The study design diagram is provided in Appendix 1 (Section 5.1). The schedule of Assessments 
and procedures for the required treatment, End of Treatment, and Follow-up periods can be 
found in Appendix 2 (Section 5.2). The schedule of assessments and procedures for the optional 
treatment period dosing schedule is shown in Appendix 3 (Section 5.3). The dosing schedule by 
day can be found in Appendix 4 (Section 5.4).  
Alternative caspofungin regimens and guidance for special populations (moderate hepatic 
impairment; subjects weighing >80 kg or on concomitant rifampin, nevirapine, efavirenz, 
phenytoin, dexamethasone, or carbamazepine; use of concomitant cyclosporine; or renal 
impairment) can be found in the protocol.  
1.2.1. 
Randomization and Blinding 
After informed consent has been obtained, subjects will be screened for study eligibility before 
randomization.  
Subjects will be assigned a subject number and randomized (1:1) to receive either IV Rezafungin 
for Injection or IV caspofungin. The randomization will be stratified based on the following 
factors at Screening: 
 diagnosis (candidemia only; invasive candidiasis) and 
 Acute Physiology and Chronic Health Evaluation (APACHE II) score/ absolute 
neutrophil count (ANC) (APACHE II score ≥20 OR ANC<500 cells/μL; APACHE II 
score <20 AND ANC≥500 cells/μL) at Screening 
If a subject has a positive result for both blood culture/rapid in vitro diagnostic (IVD) and culture 
specimen obtained from a normally sterile site, the subject will be randomized to the invasive 
candidiasis stratum. 


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The study site’s pharmacist (or pharmacist designee) will obtain the study drug assignment via 
an Interactive Response Technology (IRT). Randomized subjects will be assigned the study drug 
corresponding to the next available randomization number in the respective stratum from the 
computer-generated randomization schedule. A subject is considered randomized when the 
randomization transaction is recorded in the IRT. 
All study personnel, including the Sponsor, Principal Investigator (PI), and site personnel 
involved in study conduct, and subjects will remain blinded to study medication assignment until 
the study is completed and the database is locked, except for the pharmacy monitor, unblinded 
program manager, clinical supplies, document manager, and quality (additional details are 
presented in the Sponsor Blinding Plan). The Pharmacy Monitor will monitor drug preparation 
and drug accountability during the study and cases in which unblinding is required due to a 
safety or tolerability issue. The Data and Safety Monitoring Board (DSMB) will be unblinded to 
safety data for safety reviews as defined in the DSMB Charter.   
1.2.2. 
Unblinding 
This study is a double-blind design. The PI, study personnel, and subjects will not make any 
effort to determine which study drug treatment is being received. Unblinded pharmacy personnel 
and an independent unblinded statistician for preparation of the DSMB report will be utilized in 
this study.  
Unblinded data will be provided to the DSMB for the interim analyses of safety as detailed in the 
DSMB Charter. No interim unblinded data will be provided to the Sponsor. Only in the case of 
an emergency, when knowledge of the study drug treatment is essential for the clinical 
management or welfare of a specific subject, may the PI unblind a subject’s study drug 
assignment. As soon as possible and without revealing the subject’s study drug assignment 
(unless important to the safety of subjects remaining in the study), the PI must notify the Sponsor 
if the blind is broken for any reason. The PI will record in source documentation the date and 
reason for revealing the blinded study drug assignment for that subject. 
 As detailed in the country specific protocol amendment (A5-CN, 29Jan2021), there will be two 
database locks.  The first database lock will occur after approximately 184 subjects in the mITT 
population have been randomized and completed the study (primary enrollment).  The 
randomization of the last patient for the first database lock (for primary enrollment) occurred on 
Aug 16, 2021.  After the database is locked and the SAP is final (for primary enrollment), the 
study blind codes for only subjects who were randomized on or prior to Aug 16, 2021 will be 
broken for completion of analysis and reporting.  The Clinical Study Report (CSR) will be 
completed based on these data and analyses.  Enrollment will be extended only in China and the 
second database lock will occur when recruitment and follow-up from this extended enrollment 
is complete.  A SAP addendum will be completed and separate CSR for these subjects (from 
both primary and extended enrollment) will be written and will include separate analyses of 
subjects from China. 
 


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2. 
DEFINITIONS OF OUTCOME MEASURES 
2.1. 
Primary Efficacy Outcome Measures 
The primary efficacy outcome (for the FDA) is all-cause mortality (ACM) at Day 30 (-2 days), 
assessed for the mITT population. Subjects will be considered as meeting the ACM FDA 
endpoint at Day 30 if they have: 
 a non-missing death date on the electronic case report form (eCRF), and 
 study day for date of death is less than or equal to 30 days. Study Day 1 is defined as the 
first day of study drug administration. Subsequent study days are counted as the number 
of consecutive calendar days thereafter. 
All attempts will be made to determine survival status at Day 30 and the Follow-up visit; 
subjects who complete Day 30 assessments on Day 28 or Day 29 (within the -2 days period) 
without further information thereafter will be considered alive at Day 30. If their status was 
“alive” on Day 28 or 29, and died at Day 30 their status will be “died”. However, if it is 
unknown whether a subject is alive or deceased (and, subsequently, a death date is also not 
available), the subject will be considered deceased for the primary efficacy outcome. If it is 
known that the subject is deceased but only a partial death date is known, imputation rules for 
death date as outlined in Section 3.7 of this document will be followed. For the mITT population, 
the primary endpoint is calculated as the percentage of subjects that died out of the total number 
of subjects in the mITT population.  
The primary efficacy outcome (for the EMA) is global cure (based on clinical cure as assessed 
by the Investigator, radiological cure [for qualifying invasive candidiasis subjects], and 
mycological eradication), confirmed by an independent DRC, at Day 14 (±1 day) in the mITT 
population. A DRC that is external to the sponsor will adjudicate global response. The committee 
will be comprised of physicians who will determine the outcomes of each subject in a blinded 
fashion. The DRC determination will be utilized to determine the primary efficacy outcome. 
The DRC will assess global response and determine the responses as cure, failure and 
indeterminate. Subjects with missing data such that a response cannot be determined will be 
considered an indeterminate response. Since indeterminates are included in the denominator of 
the calculation of global cure success, these subjects are essentially failures. For the mITT 
population, the proportion of mITT subjects with a global cure success is defined using the 
following formula: 
Number of subjects with DRC global response = cure 
(Number of subjects with DRC global response = failure + DRC global response = indeterminate 
+ DRC global response = cure) 
All-cause mortality at Day 30 (-2 days) is a secondary outcome for the EMA and global cure at 
Day 14 (±1 day) as confirmed by DRC is a secondary outcome for the FDA. 


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2.1.1. 
Estimand Framework 
An addendum to ICH E9 introduces the concept of an estimand which translates the trial 
objective into a precise definition of the treatment effect that is to be estimated.  The description 
of the estimand includes four attributes: the population, the variable (or endpoint) to be obtained 
for each patient, the specification of how to account for intercurrent events (ICE), and the 
population-level summary for the variable.  These attributes are described below for the FDA 
and EMA primary efficacy outcomes. 
Table 2-1: 
Estimand Attributes 
 
ACM at Day 30 (FDA) 
Global Response at Day 14 
(EMA) 
Population 
mITT Population (see Section 
2.6) 
mITT Population (see Section 
2.6) 
Variable/Endpoint 
Deceased by Day 30 
DRC global response of cure 
Handling of intercurrent 
events 
Treatment policy estimand as 
measured irrespective of any 
ICE 
 Missing data 
considered deceased 
 
Composite estimand as the 
following ICE's are 
incorporated into the 
variable/endpoint: 
 Death (failure) 
 Receipt of rescue 
therapy (failure) 
 Discontinuation of 
study drug due to an 
adverse event (failure) 
 Missing data 
(classified as 
indeterminate but 
analyzed as a failure) 
Population-level summary 
Difference between treatment 
groups in percentage of 
subjects who died 
Difference between treatment 
groups in percentage of 
subjects with a DRC global 
response of cure 
 
2.2. 
Secondary Efficacy Outcomes 
All-cause mortality at Day 30 (-2 days) in the mITT population is a secondary outcome for the 
EMA, and global cure at Day 14 (± 1 day) in the mITT population is a secondary outcome for 
the FDA. Additional secondary efficacy outcome measures will be assessed in the mITT 
population and will include: 
 Global cure (based on clinical cure as assessed by the Investigator, radiological response 
(for those subjects with invasive candidiasis documented by radiologic/imaging evidence 


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at baseline), and mycological eradication) at Day 5, Day 30 (-2 days), End of Treatment 
(≤2 days of last dose), and Follow-up (Days 52-59), confirmed by the DRC 
 Mycological eradication (programmatically derived) at Day 5, Day 14 (±1 day), Day 
30 (-2 days), End of Treatment (≤2 days of last dose), and Follow-up (Days 52-59)  
 Clinical cure as assessed by the Investigator at Day 5, Day 14 (±1 day), Day 30 (-2 
days), End of Treatment (≤2 days of last dose), and Follow-up (Days 52-59)  
 Radiological cure as assessed by the Investigator for invasive candidiasis subjects at 
Day 5, Day 14 (±1 day), Day 30 (-2 days), End of Treatment (≤2 days of last dose), and 
Follow-up (Days 52–59)  
2.2.1. 
Global Response  
Global response is determined from the clinical response as assessed by the Investigator, 
radiological response (for those subjects with invasive candidiasis documented by 
radiologic/imaging evidence at baseline), and mycological response at Day 5, Day 14 (±1 day), 
Day 30 (-2 days), End of Treatment (≤2 days of last dose) and Follow-up (Days 52-59) as in 
Table 2-2 and confirmed by the DRC. An independent blinded DRC will review subject data and 
confirm the determination of global response. The global response as determined by the DRC 
will be used for analysis. The role of the DRC and procedures for outcome determination are 
described in the DRC Charter. 
Definitions for clinical response as assessed by the Investigator, mycological response and 
radiological response are included below in Section 2.2.3, Section 2.2.2 and Section 2.2.4 
respectively. 
 


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Table 2-2: 
Global Response Categories 
 
Definition 
Global 
Response 
Mycological Response 
Clinical Response as assessed by 
the Investigator 
Radiological Response** 
Cure 
Eradication/Presumed 
Eradication* 
Cure 
Cure 
Failure 
Eradication/Presumed 
Eradication * 
Cure 
Failure 
Eradication/Presumed 
Eradication * 
Failure 
Cure, Failure or 
Indeterminate 
Eradication/Presumed 
Eradication * 
Indeterminate 
Failure 
Failure 
Cure, Failure or Indeterminate 
Cure, Failure or 
Indeterminate 
Indeterminate 
Failure 
Cure, Failure or 
Indeterminate 
Indeterminate 
Cure 
Failure 
Indeterminate 
Indeterminate 
Failure 
Indeterminate 
Eradication/Presumed 
Eradication * 
Cure 
Indeterminate 
Eradication/Presumed 
Eradication * 
Indeterminate 
Cure or Indeterminate 
Indeterminate 
Cure 
Cure or Indeterminate 
Indeterminate 
Indeterminate 
Cure or Indeterminate 
* Presumed eradication is defined only for a culture from a normally sterile site and is not defined for a blood 
culture. 
** For those subjects with invasive candidiasis documented by radiologic/imaging evidence at baseline. 
The global cure is the proportion of subjects with cure out of the total number of subjects in the 
specified analysis population. 
If a subject discontinued the study medication prior to Day 14 and the global response at the 
EOT visit is failure, the global response at Day 14 for that subject is failure.  If study drug was 
stopped early because the PI thought the subject was a clinical cure, the subject must be assessed 
during the Day 14 window. If the subject did not have the assessment, the global response for 
that subject at Day 14 is indeterminate. 
 
2.2.2. 
Mycological response  
Mycological response will be programmatically determined from the electronic case report form 
(eCRF) and central mycology data (or local mycology data if central is not available)  at Day 5, 
Day 14 (±1 day), Day 30 (-2 days), End of Treatment, and Follow-up (Days 52-59), according to 
the definitions in Table 2-3.  


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Table 2-3: 
Mycological Response Definitions** 
Mycological 
Response 
Definition 
Eradication* 
 If positive blood culture at baseline: 
o 
The last blood culture drawn following the first dose of study drug on or prior to 
the day of assessments is negative  
 If positive culture from a normally sterile site at baseline (other than blood): 
o 
Documented mycological eradication: most recent culture on or prior to the day of 
assessment from all normally sterile sites of baseline Candida infection (if 
accessible) is negative and culture was obtained after the initiation of study drug 
OR 
o 
Presumed mycological eradication: follow-up culture from all normally sterile sites 
of baseline Candida infection is not available (eg, normally sterile baseline site of 
Candida infection not accessible)  or the most recent culture from all normally 
sterile sites of baseline Candida infection obtained after the initiation of study drug 
is positive,  in a subject with a successful clinical outcome as assessed by the 
Investigator (ie, did not receive rescue antifungal treatment and has resolution of 
systemic signs and symptoms of invasive candidiasis that were present at baseline) 
and the subject has a successful radiological outcome (for those with documented 
evidence of disease from imaging at baseline), 
AND 
 There was no change of antifungal therapy for the treatment of candidemia and/or 
invasive candidiasis, 
AND 
 The subject is not lost to follow up on the day of assessment. 


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Mycological 
Response 
Definition 
Failure 
 If positive blood culture at baseline: 
o 
The last blood culture drawn on or prior to the day of assessment is positive for 
Candida spp from a sample drawn following the first dose of study drug, 
OR 
 If positive culture from a normally sterile site at baseline: 
o 
Documented mycological persistence: culture on the day of assessment from all 
normally sterile sites of baseline Candida infection (if accessible) is positive, 
OR 
o 
Presumed mycological persistence: follow-up culture from all normally sterile sites 
of baseline Candida infection is not available (eg, normally sterile baseline site of 
Candida infection not accessible) OR the most recent culture from all normally 
sterile sites of baseline Candida infection obtained after initiation of study drug is 
positive,  in a subject without a successful clinical outcome as assessed by the 
Investigator or without a successful radiological outcome for those with 
documented evidence of disease from imaging at baseline,  
OR 
 The subject requires a change of antifungal therapy to treat candidemia and/or invasive 
candidiasis***, 
OR 
 The subject dies of any cause prior to or on the day of assessment. 
Indeterminate 
Study data are not available for the evaluation of efficacy for any reason including: 
 If positive blood culture at baseline: A post-baseline blood specimen was not available 
to culture or the result was not available. 
 If positive culture from a normally sterile site at baseline: A sterile site/fluid 
post-baseline specimen was not available to culture or the result was not available 
AND an assessment clinical response by the Investigator was not available or 
radiographic assessments are not available. 
 Subject is lost to follow-up on the day of assessment. 
* Presumed eradication is defined only for a culture from a normally sterile site and is not defined for a blood 
culture. 
**Table includes clarifications that are not in the protocol. 
*** Defined as receipt of an antifungal with an indication of Candidemia/invasive candidiasis, Candida 
endophthalmitis/chorioretinitis or Candida endocarditis which started on or prior to the day of assessment or 
started on EOT (+ 1 day). 
Documented evidence of IC at baseline is defined as having a radiologic test prior to the first 
dose of study drug that indicates new radiologic evidence of IC.  Subjects who are diagnosed 
with IC by tissue/fluid culture whose first radiologic test is after the first dose of study drug are 
considered not to have a baseline radiologic test.  In these subjects, radiology is not used to 
determine response.   
Subjects who are diagnosed with candidemia at baseline (ie, prior to initiation of study drug) and 
progress to IC based on radiographic evidence or a tissue/fluid culture are considered to have IC 
for subsequent outcome assessments.  The radiograph or tissue/fluid culture used to document 
progression is considered the baseline radiograph or tissue/fluid culture for outcome assessment.  


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The mycological eradication rate is the proportion of subjects with success 
(eradication/presumed eradication) out of the total number of subjects in the specified analysis 
population. 
2.2.3. 
 
Investigator’s Assessment of Clinical Response  
The Investigator will make a determination of clinical cure at Day 5, Day 14 (±1 day), Day 30 
(-2 days), End of Treatment (≤2 days of last dose), and Follow Up (Days 52-59) according to the 
definitions in Table 2-4.  
Subjects whose disease is progressing or who receive rescue antifungal therapy for 
candidemia/IC prior to an assessment time point will be considered a clinical failure at the 
assessment time point and all subsequent time points. Subjects who do not have resolution of 
systemic signs and symptoms but are improving at the day of assessment are considered a 
clinical failure. As long as no rescue antifungal therapy for candidemia/IC was received, the 
subject may still qualify as a cure at future visits as long as they meet the criteria of clinical cure 
at those visits. For example, at Day 14 (±1 day) and Day 30 (-2 days), a subject who is on study 
drug can be a clinical cure if no rescue antifungal therapy for candidemia/IC was received and 
the subject meets the criteria of clinical cure even if they were assessed as a clinical failure at the 
Day 5 visit. 


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Table 2-4: 
Investigator’s Assessment of Clinical Response Definitions 
Clinical 
Response 
Definition 
Cure 
 Resolution of attributable systemic signs and symptoms of candidemia and/or invasive 
candidiasis that were present at baseline, 
AND 
 No new systemic signs or symptoms attributable to candidemia and/or invasive candidiasis, 
AND 
 No new systemic antifungal therapy to treat candidemia and/or invasive candidiasis, 
AND 
 The subject is alive. 
Failure 
 Progression or recurrence of attributable systemic signs or symptoms of candidemia and/or 
invasive candidiasis, 
OR 
 Lack of resolution of attributable systemic signs or symptoms of candidemia and/or invasive 
candidiasis, 
OR 
 Requirement for new systemic antifungal or prolonged therapy to treat candidemia and/or 
invasive candidiasis *, 
OR 
 An AE requires discontinuation of study drug therapy (IV and IV/oral) on or prior to the day 
of assessment, 
OR 
 The subject died of any cause. 
Indeterminate 
 Study data are not available for the evaluation of efficacy for any reason including: 
o 
Lost to follow-up, 
o 
Withdrawal of consent, 
o 
Extenuating circumstances that preclude the classification of clinical outcome of 
candidemia and/or invasive candidiasis, 
o 
Assessment not done. 
AE = adverse event; IV = intravenous. 
* Prolonged antifungal therapy is defined as therapy for the treatment of candidemia and/or invasive candidiasis 
extending beyond the allowable 28 days of study drug. The determination of prolonged therapy will only apply to 
the Follow-up visit clinical response assessment. 
The clinical cure as assessed by the Investigator rate is the proportion of subjects with a cure out 
of the total number of subjects in the specified analysis population. 
If a subject discontinued the study medication prior to Day 14 and the Investigator assessed 
response at the EOT visit is failure, the response at Day 14 for that subject is failure.  If study 
drug was stopped early because the Investigator thought the subject was a clinical cure, the 
subject must be assessed during the Day 14 window. If the subject did not have the assessment, 
the response for that subject at Day 14 is indeterminate. 
 


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2.2.4. 
Radiological Response  
Radiological response is defined in Table 2-5. Only subjects with invasive candidiasis, with 
radiologic or other imaging studies at baseline that demonstrate evidence of invasive candidiasis, 
should be assessed for this outcome. The radiologic response as assessed by investigator will be 
summarized.  
Table 2-5: 
Radiological Response Definitions 
Radiological  
Response 
Definition a 
Cure 
 Improvement or resolution of radiological or other imaging findings of invasive candidiasis 
that were present at baseline (i.e., the radiograph/imaging study that documented evidence of 
the invasive candidiasis) 
AND 
 No new radiological or other imaging findings attributable to invasive candidiasis, 
AND 
 The subject is alive. 
Failure 
 Progression of or new radiological or other imaging findings of invasive candidiasis, 
OR 
 Lack of improvement of radiological or other imaging findings of invasive candidiasis, 
OR 
 The subject died of any cause. 
Indeterminate 
 Radiological or imaging data are not available for the evaluation of efficacy for any reason 
including: 
o 
Lost to follow-up, 
o 
Withdrawal of consent, 
o 
Radiology/Imaging not completed 
o 
Extenuating circumstances that preclude the classification of a radiological outcome of 
invasive candidiasis 
a 
Includes radiological or other imaging studies. Only for invasive candidiasis subjects with imaging 
performed at baseline who had radiological or other imaging studies that documents evidence of invasive 
candidiasis. 
The radiological cure rate as assessed by the Investigator is the proportion of subjects with a cure 
out of the total number of subjects with invasive candidiasis documented by radiologic/imaging 
evidence at baseline in the specified analysis population. 
 


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2.3. 
Exploratory Efficacy Outcomes 
2.3.1. 
Resolution of Attributable Systemic Signs of Candidemia and/or Invasive 
Candidiasis that were Present at Baseline  
It is a requirement that at least 1 systemic sign attributable to candidemia and/or IC be present at 
Screening for the subject to be eligible for enrollment. The Screening period for assessing 
systemic signs for inclusion in the study may include the 12 hours prior to the drawing of the 
qualifying positive culture (when systemic signs of infection resulted in obtaining blood 
cultures), qualifying positive culture from a sterile site, or qualifying rapid in vitro diagnostic, 
through enrollment. The possible signs of infection that might be attributable to candidemia 
and/or IC at baseline include fever, hypothermia, hypotension, tachycardia, tachypnea, and local 
signs of inflammation. 
For the listed systemic signs of candidemia, the qualifying parameters are listed below: 
Fever: Oral or axillary temperature ≥38°Celsius (C) [100.4°Fahrenheit (F)] or a tympanic, 
temporal, rectal, or core body temperature ≥38.3°C [101°F] 
Hypothermia: Tympanic, temporal, rectal, or core body temperature ≤35°C [95.2°F] 
Hypotension: Systolic blood pressure <90 mmHg or mean arterial pressure <70 mmHg with a 
normovolemic or hypervolemic status 
Tachycardia: Heart rate >100 beats per minute with a normovolemic or hypervolemic status 
Tachypnea: Respiratory rate >20 breaths per minute 
Local signs of inflammation: Erythema, edema, heat and pain at the site of the qualifying 
culture 
Resolutions of systemic signs will be programmatically categorized as follows: 
o Yes (resolution): Resolution of all attributable systemic signs of candidemia and/or 
invasive candidiasis that were present at baseline and  no new attributable systemic 
signs that were not present at baseline 
o No (not resolved): New attributable systemic signs that were not present at baseline 
or lack of resolution of any attributable systemic signs of candidemia and/or invasive 
candidiasis that were present at baseline 
Subjects whose assessment of systemic signs was not completed at a visit or at baseline for any 
reason (including death) will not be included in the analysis.  
Resolution of systemic signs attributable to candidemia and/or invasive candidiasis for subjects 
receiving Rezafungin for Injection and caspofungin will be assessed at Day 5, Day 14 (±1 day), 
Day 30 (-2 days) and Follow-up (Days 52-59) in the mITT population.  


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2.3.2. 
All-Cause Mortality (ACM) through the FU Visit 
All-cause mortality through the FU Visit (Day 59) is defined as death due to any cause from the 
date and time of first dose of treatment through the FU Visit. Subjects who did not die or died 
after Day 59 or are lost to follow-up will be censored in the analysis at the last date known to be 
alive or Day 59, whichever is earlier. 
2.3.3. 
Time to First Negative Blood Culture 
Time to first negative blood culture is defined in hours from the first dose of study drug to the 
first negative blood culture without subsequent positive cultures following the first pre-treatment 
blood culture confirmed positive for any Candida species. Blood culture results from both 
location 1 and location 2 need to be negative if the samples were taken from 2 locations on the 
same day. Subjects will be censored at the earliest start date and time of receipt of a new 
antifungal (i.e., other than study drug) for the treatment of candidemia received any time on/after 
the date and time of the first dose of study drug if it was used prior to having a negative blood 
culture. If a subject is lost to follow-up or died prior to having a negative blood culture, the 
subject will be censored at the date of the last blood culture. The details about the censoring rules 
under different scenarios are shown in the following table: 
Blood Culture Result 
Antifungal Use 
Event (Negative 
Culture) or Censor 
Event or Censoring 
Date 
Negative blood culture 
without subsequent 
positive cultures  
Not used or used 
after negative blood 
culture 
Event 
Earliest blood culture 
date with negative 
result 
Negative blood culture 
obtained prior to first dose 
date and no subsequent 
positive cultures 
Not used or used 
after negative blood 
culture 
Censor 
First dose date 
No negative blood culture  
Not used 
Censor 
Last blood culture date 
No negative blood culture 
Used  
Censor 
Earlier date between 
the last blood culture 
date and the antifungal 
start date 
The number and percentage of subjects with a negative blood culture at 24 and 48 hours post 
first dose will also be provided by treatment group.  The denominator will include subjects who 
were either not censored in the time to negative blood culture analysis or who were censored 
after 24 or 48 hours, respectively.  
2.3.4. 
Clinical Outcomes by Baseline Candida species 
The number and percentage of subjects who died by Day 30 (-2), were a global cure (as 
confirmed by the DRC) at Day 14 (±1), were a mycological eradication at Day 14 (±1 days), 


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were a radiological response (for subjects with invasive candidiasis documented by 
radiologic/imaging evidence) at Day 14 (±1 days) and were a clinical cure at Day 14 (±1 day) 
will be summarized by baseline Candida spp. and treatment group for subjects in the mITT 
population. 
Mortality (Day 30 [-2]), global cure, mycological eradication, radiologic cure (for subjects with 
invasive candidiasis documented by radiologic/imaging evidence) and clinical cure by baseline 
Candida spp. and minimal inhibitory concentration (MIC) distribution for Rezafungin for 
Injection, caspofungin and fluconazole at Day 14 (-2) will be summarized by treatment group for 
subjects in the mITT population.  
2.4. 
Health Outcome Measures 
For subjects admitted to the Intensive Care Unit (ICU) on or after Study Day 1, the number of 
ICU admissions, the time to discharge for each admission and the total length of stay in the ICU 
across all admissions will be summarized by treatment group. The number and percentage of 
subjects re-admitted after discharge by Day 30 (-2 days) and by Follow-up (Days 52-59) will be 
presented by treatment group in the mITT population for all re-admissions, for re-admissions 
related to infectious disease and again for re-admissions related to Candidiasis. 
2.5. 
Safety Outcome Measures 
Safety will be assessed through the evaluation of adverse events (AEs), vital signs (temperature, 
heart rate, blood pressure, and respiratory rate), physical examinations (including neurological 
examinations), ECGs and clinical laboratory evaluations (hematology evaluations, chemistry 
panel, and urinalyses). Subjects will also be assessed at Screening and at the EOT visit, prior to 
Rezafungin for Injection dosing, with a thorough neurologic evaluation to assess for signs and 
symptoms of tremor, ataxia, and peripheral neuropathy. Adverse events will be graded for 
severity using the National Cancer Institute Common Terminology Criteria for Adverse Events 
(CTCAE) system version 5.0. 
2.6. 
Population Definitions 
The following analysis populations will be evaluated and used for presentation and analysis of 
the data: 
 The intent-to-treat (ITT) population will include all randomized subjects. 
 The safety population will include all subjects who received any amount of the study 
drug. Safety assessments will be performed on the safety population. Subjects who 
receive the wrong study drug for their entire course of study drug will be analyzed in the 
treatment group based on the drug received. Subjects who receive the wrong study drug 
for part of their course of study drug will be analyzed in the treatment group based on 
majority of (i.e., most frequent) doses received. 
 The mITT population will include all subjects who had a documented Candida infection 
based on Central Laboratory evaluation of a blood culture or a culture from a normally 


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sterile site obtained ≤4 days (96 hours) before randomization and received ≥1 dose of 
study drug.  
 The clinically evaluable (CE) population will include all subjects in the mITT population 
who also met inclusion criterion #4, did not meet exclusion criteria #1, #2, and #5, had a 
response other than indeterminate for both mycological and clinical response as assessed 
by DRC at Day 14 in the protocol specified window of Day 14 ± 1 day (subjects with 
invasive candidiasis documented by radiologic/imaging evidence also must have a 
radiological response by DRC other than indeterminate), and did not receive a 
concomitant antifungal  that could confound the assessment of the global response at Day 
14. 
 The Pharmacokinetic (PK) population will include all subjects who received any amount 
of study drug and have at least one blood sample with measurable concentrations. 
2.7. 
Protocol Deviations 
Protocol deviations are collected from time of informed consent until the last study visit. 
Protocol deviations are defined as any variation from the protocol, including enrollment of a 
subject who did not meet all inclusion and exclusion criteria and failure to perform the 
assessments and procedures within the required time frame. Protocol deviations will be 
categorized into types of deviations (concomitant medication, inclusion/exclusion, informed 
consent, procedures/assessments, randomization, serious adverse event reporting and adverse 
events of special interest, study treatment administration/dispensing/compliance, and study 
visits) and classified as major or minor. 
The Sponsor or designee will be responsible for producing the final protocol deviation file. 
2.8. 
Subgroup analyses 
Subgroup analyses will be conducted for the FDA and EMA primary efficacy endpoints. The 
purpose of the subgroup analyses is to assess the consistency of treatment effect across potential 
or expected prognostic factors. Additional subgroup analyses may be also be conducted. 
The list of subgroups will be finalized prior to database lock but will include:  
 Sex (male versus female) 
 Race (white versus non-white and Asian versus non-Asian) 
 Age category (<65 years versus ≥65 years) 
 Geographic region (United States/South America, Europe/Israel/Turkey, Asia-Pacific 
(excluding China/Taiwan), China/Taiwan) 
 Diagnosis at randomization (candidemia only versus IC) 


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 Final Diagnosis (candidemia only versus IC: progression from candidemia only to IC will 
be determined based on the radiological and/or tissue/fluid culture assessment through 
Day 14) 
 APACHE II score/ANC at Screening (APACHE II score ≥20 OR ANC<500 cells/μL 
versus APACHE II score <20 AND ANC≥500 cells/μL) 
 APACHE II score at Screening (≥20, <20, 10-19, <10) 
 ANC at Screening (<500 cells/μL versus ≥500 cells/μL)  
 Timing of culture used to document the Candida infection: 
o Positive culture at randomization definition 1: Subjects with a culture from blood 
drawn within 12 hours prior to randomization or within 72 hours after 
randomization, OR a culture from another normally sterile site obtained within 48 
hours prior to randomization or within 72 hours after randomization; and 
o Positive culture at randomization definition 2: Subjects with a culture from blood 
drawn within 12 hours prior to randomization or within 72 hours after 
randomization, OR a culture from another normally sterile site obtained within 96 
hours prior to randomization or within 72 hours after randomization 
 
3. 
GENERAL STATISTICAL METHODS 
3.1. 
Sample Size Justification 
The study is designed to show non-inferiority (NI) in the primary efficacy outcome of ACM at 
Day 30 (FDA) in the mITT population and global cure rate (EMA) at Day 14 following the first 
dose of test article in the mITT population. An NI margin of 20% will be used for the primary 
analyses. The NI margin was based on an analysis of studies where patients received no 
treatment or inadequate treatment, and the high unmet medical need in patients with candidemia 
and/or IC.  
Sample size justification for the Primary Efficacy Outcome FDA (Day 30 ACM): For the FDA 
endpoint of ACM, assuming 85% of subjects will be evaluable for the mITT population, using a 
20% NI margin, one-sided alpha of 0.025, an ACM rate of 20% in both treatment groups, 
1:1 randomization, and the sample size methodology based on a continuity corrected Z-statistic, 
a total of 184 subjects in the mITT population provides 89.7% power to show NI.  
Sample size justification for the Primary Efficacy Outcome EMA (Global cure): Using a 20% NI 
margin, one-sided alpha of 0.025, 80% power, 1:1 randomization, a global cure rate of 70% in 
both the Rezafungin for Injection and caspofungin groups, and the sample size methodology 
based on a continuity corrected Z-statistic, a total of 184 subjects (92 subjects in each treatment 


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group) are required in the mITT population. Assuming 85% of subjects will be evaluable for the 
mITT population, a total of approximately 218 subjects will be randomized.  
Thus, a total of 218 randomized subjects provide sufficient power for the primary efficacy 
analyses for both the FDA and the EMA in the mITT population. A summary of the sample size 
calculations and assumptions is provided in the Table 3-1 below: 
 
 
Table 3-1: 
Sample Size and Power Calculations 
 
Primary Efficacy Outcome FDA 
(Day 30 ACM) 
Primary Efficacy Outcome EMA 
(Global Cure) 
Population 
mITT 
mITT 
Outcome Rate 
20% 
70% 
NI Margin 
20% 
20% 
One-sided alpha 
0.025 
0.025 
Power 
89.7% 
80% 
Evaluability Rate 
85% 
85% 
N 
218 
218 
EMA = European Medicines Agency; FDA = United States Food and Drug Administration; mITT = modified 
intent-to-treat; N = total sample size. 
3.2. 
General Methods 
All tables, figures, and listings will be presented in landscape orientation in Courier New, 8-point 
font or higher, and will be incorporated into Microsoft Word, or Adobe Acrobat PDF files, sorted 
and labeled according to the International Conference on Harmonisation (ICH) 
recommendations, and formatted to the appropriate page size(s). 
 
Categorical parameters will be summarized using frequencies and percentages, while mean, 
standard deviation, median, 25th and 75th percentiles, minimum, and maximum will be used for 
continuous parameters. 
 
Decimal precision will be as follows: 
 Mean will contain one more decimal place than actual values. 
 Median will contain one more decimal place than actual values. 
 Standard deviation will contain two more decimal places than the actual values. 
 25th and 75th percentiles, minimum, and maximum will have the same precision as the 
actual values. 
 
All statistical testing will be 2-sided and performed at the 0.05 level unless otherwise noted. 
Since no inferential testing will be conducted for secondary efficacy outcome measures, no 
adjustment is needed for multiplicity.   
 


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The first day of study drug administration will be Study Day 1. Subsequent study days are 
counted as the number of consecutive calendar days thereafter.  
 
Individual subject listings of all data represented on the eCRFs will be provided to facilitate the 
investigation of tabulated values and to allow for the clinical review of all efficacy and safety 
parameters. All data listings and tables displaying by-subject data that contain an evaluation date 
will display study day (Study Day).  
 
If a safety laboratory result is reported relative to a lower/upper range of detection for an assay, 
for example “<10”, the numeric portion of the result (10) will be used for statistical analyses and 
the full result, including any symbols, will be provided in the subject listings. 
 
Sample sizes shown with summary statistics are the number of subjects with non-missing values. 
Where individual data points are missing, categorical data will be summarized based on reduced 
denominators (ie, only subjects with available data will be included in the denominators), unless 
otherwise specified. 
 
Time-to-event data will be summarized using Kaplan-Meier methodology using 25th, 50th 
(median), and 75th percentiles with associated 2-sided 95% confidence intervals (CIs), as well as 
percentage of censored observations. The Kaplan-Meier curves will be presented by treatment 
group. The number of subjects at risk and number died in each treatment group will be displayed 
below the x-axis at day=0, 5, 14, 30, 55.  
 
3.3. 
Computing Environment 
All statistical analyses will be performed using SAS statistical software v9.4 or higher, unless 
otherwise noted.  
The Analysis Data Model Version 2.1 (ADaM v2.1) and the ADaM Implementation Guide, 
Version 1.1 (ADaM IG v1.1) will be used for data standardization.  
Medical history, concomitant procedures and AEs will be coded using the Medical Dictionary 
for Regulatory Activities (MedDRA) 21.0 or higher.  
Prior and concomitant medications will be coded using the World Health Organization (WHO) 
Drug Dictionary March 2017 or higher. 
3.4. 
Methods of Pooling Data 
Data will be pooled across sites for all analyses. 
3.5. 
Multiple Comparisons/Multiplicity 
No adjustment for multiple comparison/multiplicity are to be used. 


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3.6. 
Withdrawals, Dropouts, Loss to Follow-up 
Randomized subjects who are withdrawn or discontinue from the study will not be replaced. 
3.7. 
Missing, Unused, and Spurious Data 
The following rules for missing data will be followed: 
 For the primary efficacy outcome measure of all-cause mortality for the FDA, subjects with a 
missing death date on the eCRF will be considered to have died.  The subject's vital status 
will be determined using available sources such as the subject, the subject's contacts, hospital 
and other medical records and public records. 
 For the primary efficacy outcome measure of global response for the EMA, subjects with a 
missing response are considered an indeterminate response and are included in the 
denominator for analyses in the mITT population. 
 Adverse Event, Death Date and Prior/Concomitant Medication Date Imputations will follow 
the rules described in Appendix 7 Adverse Event and Prior/Concomitant Medication Date 
Imputations. 
 The CTCAE grade and causality assessment for adverse events should not be missing (except 
in the case of a death reported only on the Survival Status eCRF which should be considered 
an adverse event of Death NOS) and will be queried for a value. Should there be missing data 
for adverse events other than Death NOS, adverse events with missing severity will be 
considered severe (Grade 3) and adverse events with missing causality will be considered 
related to study drug. For deaths from the Survival Status eCRF (and not on the Adverse 
Event eCRF), missing severity will be considered Grade 5 (death) and missing causality will 
be considered not related to study 
 Unless otherwise specified, missing values for other individual data points will remain as 
missing. Missing values will not be imputed and only observed values will be used in data 
analyses and presentation. 
3.8. 
Visit Windows 
Study procedures should be completed within the windows provided in the Schedule of 
Assessments and Procedures in Appendix 2.  Summaries of efficacy will be based on the 
nominal visits. Refer to Section 4.3 for the details. 
Summaries of safety outcomes will be provided by Study Day based on the visit windows as 
specified in the protocol. The safety measurements taken outside the protocol specified visit 
windows will be considered as unscheduled visit measurements and will not be included in by-
visit summaries but will be included in overall worst post-baseline summaries. If more than 1 
measurement is available within the visit window, the following rules will be used:   
 If there are measurements from both scheduled and unscheduled visits, the measurement 
taken on the scheduled visit will be used.  
 If no scheduled visit is available, the earliest measurement in the window will be used.  
 


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Summaries of PK concentrations will be provided by nominal time points. For the “10 minutes 
prior to end of infusion” time point, this time point will be summarized if it is within -30 minutes 
prior to end of infusion and 10 minutes after end of infusion. No other time point windows will 
apply.  
 
3.9. 
Interim Analyses 
No interim analysis except for the safety data review by DSMB as stated below is planned.   
3.9.1. 
Data and Safety Monitoring Board 
An independent external DSMB will be established to review safety data. The DSMB will 
review safety data once when approximately 50% of subjects are randomized and as required for 
AEs of special interest while the study is ongoing as provided in the DSMB Charter. The DSMB 
will be comprised of clinicians and a statistician who are experienced in studies of fungal 
infections. A detailed charter will be developed, compliant with guidelines of the FDA and ICH 
that describes the roles and responsibilities of the DSMB, the timing of the meetings, as well as 
the data to be provided for review. 
4. 
STATISTICAL ANALYSIS 
4.1. 
Study Population 
4.1.1. 
Analysis Populations and Subject Disposition 
Each subject providing informed consent in the study will be accounted for. The number and 
percentage of subjects in each of the analysis populations will be summarized overall and by 
treatment group. The number and percentage of subjects prematurely withdrawing from the 
study and the primary reason for premature withdrawal (including withdrawal due to COVID-19) 
will be summarized overall and by treatment group for the ITT and mITT populations as will the 
number and percentage of subjects prematurely discontinuing treatment regimen and the primary 
reason for premature discontinuation (including withdrawal due to COVID-19). A separate 
listing will be provided for those subjects who sign informed consent but are not randomized 
(screen failures), including their specific reason for exclusion. The number and percentage of 
randomized subjects identified as failing to meet at least 1 inclusion criterion or meeting at least 
1 exclusion criterion, and the specific inclusion criterion not met/exclusion criterion met, will be 
summarized by treatment group and overall, for the ITT population. A supportive by-subject 
listing will be generated for all inclusion criteria not met and exclusion criteria met.  
Number of subjects in the mITT, and Safety populations will be summarized. A supportive 
by-subject listing will be generated for all randomized subjects indicating all analysis population 
assignments and any reason for exclusion from analysis populations (wherever applicable). 
Inclusions and exclusions from analysis populations will be finalized prior to Database lock and 
unblinding.  


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4.1.2. 
Protocol Deviations 
The number and percentage of subjects with at least one, at least one minor and at least one 
major protocol deviation will be presented by treatment group and overall for the ITT 
population. The number and percentage of subjects with at least one major protocol deviation by 
type of deviation will be presented by treatment group and overall. A by-subject listing of all 
protocol deviations in the ITT population, with a flag for minor and major deviations by 
treatment group will be produced. All missed visits due to COVID-19 will be noted as protocol 
deviations and presented in the listing. 
4.1.3. 
Demographics and Baseline Characteristics 
Demographic and baseline characteristics information including: 
 sex, race, ethnicity, age at time of informed consent, female of child-bearing potential, 
age category (<65 year, ≥65 years) 
 diagnosis at randomization (candidemia only, IC) and final diagnosis (candidemia only vs 
IC) 
 Modified APACHE II score (≥20, <20, and within <20: 10-19, <10) 
 diagnostic methodology used ≤96 hours before randomization (for positive Candida from 
blood culture, rapid IVD, gram stain positive for yeast from a specimen obtained from a 
normally sterile site, and culture specimen obtained from a normally sterile site) 
 absolute neutrophil count at Baseline (<500/µL, ≥500/µL) 
 absolute neutrophil count,  modified APACHE II score and diagnosis at randomization 
(candidemia only, APACHE II ≥20 or ANC <500/µL; candidemia only, APACHE II 
score <20 and ANC ≥500/µL; IC, APACHE II ≥20 or ANC <500/µL; and IC, APACHE 
II score <20 and ANC ≥500/µL) 
 height, weight, body mass index (BMI) 
 estimated creatinine clearance (eCrCl, based on Cockcroft-Gault formula) 
 Child-Pugh score category (<7, 7-9, and no history of liver disease) 
 Geographic region (United States, Europe/Israel/Turkey, Asia-Pacific (excluding 
China/Taiwan), China/Taiwan, South America) 
will be summarized by treatment group and overall in the ITT and mITT populations.  
BMI (kg/m2), calculated by dividing weight (kg) by height (m2) will be captured in the eCRF. 
The Cockcroft-Gault formula for eCrCl is: 


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 where AIBW (adjusted ideal body weight) = ideal weight + [0.4 x (actual weight (kg) – ideal 
weight]; ideal weight = [height (cm) – 152.4] x 0.9 + 45.5 + 4.5 (if male) 
 
4.1.4. 
Medical and Surgical History 
Medical and surgical history, including procedures recorded at screening and subjects diagnosed 
with COVID-19 at screening will be summarized by treatment group, system organ class (SOC), 
and preferred term (PT) using the latest version of MedDRA in the Safety and mITT populations. 
For this summary, subjects with more than 1 medical/surgical history within the same SOC or PT 
will be counted only once for that SOC or PT. 
4.1.5. 
Candida Risk Factors 
The number and percentage of subjects with each of the following risk factors at Screening will 
be summarized by treatment group in the ITT and mITT populations.  
Risk factors for candidemia and IC include (but are not limited to):  
 Central venous catheter 
 PICC (Peripherally Inserted Central Catheter) 
 Active malignancy 
 Broad-spectrum antibiotic therapy 
 Diabetes mellitus 
 Immunosuppression  
 Major surgery 
 Total parenteral nutrition 
 Transplant recipient 
 Trauma  
 End stage renal disease/ dialysis 
 Burns 


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 Pancreatitis 
 Other 
For subjects who had a catheter and positive blood culture at Screening, a summary of the 
number and percentage of subjects by type of catheter will be provided. Descriptive statistics for 
the durations of catheter placement (any catheter and by type of catheter) since the catheter 
placement and since diagnosis (the first positive blood culture) will also be provided. The 
durations are defined as the number of days since the catheter placement or the number of hours 
since the first positive blood culture (if catheter was already in place prior to the first positive 
blood culture) to the catheter removal date and time. The catheters that were removed prior to the 
first positive blood culture are not included in the summary. If there is more than one catheter 
placed across multiple locations, the one with the longest duration is summarized. The number 
and percent of subjects who had their catheter removed within 48 hours after diagnosis with 
candidemia and subjects who did not have their catheter withdrawn will be summarized by 
treatment group in the mITT population. This analysis will be repeated for the subjects 
diagnosed with candidemia only in the mITT population. 
4.1.6. 
Systemic Signs of Candidemia and/or IC 
The number and percentage of subjects with each systemic sign at Screening determined to be 
attributed to candidemia and/or IC by the PI will be summarized by treatment group for subjects 
in the ITT and mITT populations. Signs include fever, hypothermia, hypotension, tachycardia, 
tachypnea, and local signs of inflammation. Symptoms include fatigue, pain and myalgia. If 
there are multiple assessments during Screening, the worst value for each sign or symptom will 
be used. A by-subject listing of systemic signs and symptoms assessed at Screening, Day 5, Day 
14 (±1), Day 30 (-2), and the Follow-up visit, including the other clinical signs and symptoms 
reported on the eCRFs, and the PI determination of whether or not the sign/symptom is 
attributable to candidemia will also be provided. 
4.1.7. 
Baseline Candida Pathogens 
The number and percentage of subjects with blood or normally sterile tissue/fluid samples 
collected for culture ≤ 96 hours before randomization will be summarized by treatment group in 
the ITT population. The draw location and the result (growth of Candida or no growth of 
Candida, mutually exclusive) and timing of the most recent positive culture prior to 
randomization will be summarized by treatment group in the ITT population. The genus and 
species of Candida pathogens identified from baseline blood and sterile site cultures (all unique 
Candida species from the cultures collected within 96 hours before randomization or prior to the 
first dose of study drug after randomization) will be summarized by treatment group for subjects 
in the mITT population.  
The number and percentage of subjects with the rapid diagnostic test performed will be 
summarized by treatment group in the ITT population, as well as the type of test, the results 
(positive or negative) and the Candida species.  


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For each baseline Candida species (defined as all unique Candida species from the cultures 
collected within 96 hours before randomization or prior to the first dose of study drug after 
randomization), a summary of the distribution of minimum inhibitory concentration (MIC) 
results from the central lab (or if not available, from the local lab) will be presented both by 
treatment group and for treatment groups combined for subjects in the mITT population in 
separate tables for each of Rezafungin for Injection, caspofungin, anidulafungin, micafungin, and 
fluconazole. In addition, for each baseline Candida species, the MIC50, MIC90, and MICRange for 
Rezafungin for Injection, caspofungin, fluconazole, anidulafungin, and micafungin will be 
summarized (MIC50 and MIC90 are presented only where there are at least 10 of a particular 
Candida species with susceptibility data available from the central mycology laboratory in each 
treatment group), will be summarized both by treatment group and for treatment groups 
combined for subjects in the mITT population. If there is more than 1 isolate of the same 
Candida species prior to first dose, the isolate that has the highest MIC to study drug received 
(i.e., the highest MIC to rezafungin for Rezafungin for Injection group, the highest MIC to 
caspofungin for Caspofungin group) is considered the baseline isolate. 
A by-subject listing will be provided displaying all MIC results for any baseline Candida species 
that is resistant to echinocandins; a separate by-subject listing will be provided displaying all 
MIC and disk diffusion zone diameter results for any baseline Candida species that is resistant to 
fluconazole. 
4.2. 
Extent of Exposure and Concomitant Procedures 
4.2.1. 
Study Drug Exposure 
Descriptive statistics for the duration of study drug therapy (IV and oral, and separately for IV 
therapy and oral therapy) will be summarized by treatment group for the mITT, and Safety 
populations.   
Study drug duration is defined as the 
date of the last dose of study drug - first dose of study drug + 1. 
The number and percentage of subjects with 1–7, 8-14, 15-28 and >28 days of exposure as 
defined above will be presented for IV and IV and oral therapy combined. The number and 
percentage of subjects with 1–3, 4-7, 8-14, 15-28 and >28 days of exposure as defined above will 
be presented for oral therapy. Descriptive statistics will also be provided separately for the 
duration of IV therapy and the duration of oral therapy. The number and percentage of subjects 
switching to oral study drug therapy and a frequency distribution of the day of oral switch will be 
summarized by treatment group for the Safety and mITT populations. 
A by-subject listing of all IV doses over time and a separate by-subject listing of the start and 
stop dates for oral therapy will be provided. 


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4.2.2. 
Prior and Concomitant Medications  
The number and percentage of subjects who received prior and concomitant medications will be 
summarized by WHO drug anatomical therapeutic chemical (ATC) classification level 3 and PT.  
Medications are considered prior if they are received prior to the first dose of study drug (start 
date and time [if applicable] is prior to the first dose of study drug) or if the start date is 
unknown. Medications are considered concomitant if they are received on or after the first dose 
of study drug (start date and time [if applicable] is on or after the first dose of study drug, stop 
date and time [if applicable] is after the first dose of study drug), or if the stop date is unknown 
or continuing. If the stop date is the same as the first dose date of study drug and the stop time is 
unknown, it will be assumed that the medication stopped prior to the first dose of study drug 
unless the medication start time is after first dose of study drug time. Date imputations will 
follow the rules described in Appendix 8 (Section 5.8).  
The number and percentage of subjects who receive the following categories of prior and 
concomitant medications will be summarized by treatment group: 
 Systemic antifungal medications received prior to the first dose of study drug (mITT 
population) 
 Systemic antifungal medications (excluding study drug) received on/after the first dose of 
study drug through the Follow-up visit (mITT population) 
 Non-antifungal medications received prior to the first dose of study drug (Safety 
population) 
 Non-antifungal medications received on/after the first dose of study drug through the 
Follow-up visit (Safety population). 
By-subject listings for non-antifungal medications and antifungal medications received prior to 
the first dose or administered after the first dose of study drug through the FU visit will be 
provided separately for the Safety population. 
4.2.3. 
Concomitant Procedures 
Concomitant procedures will be summarized by treatment group, SOC, and PT using the latest 
version of MedDRA in the mITT population. If the same procedure (based on PT) is reported for 
the same subject more than once, the procedure is counted only once for that PT. Procedures are 
considered concomitant if they are performed on or after the first dose of study drug (start date 
and time [if applicable] is on or after the first dose of study drug, stop date and time [if 
applicable] is after the first dose of study drug), or if the stop date is unknown or continuing. 
A by-subject listing will display procedures on/after the first dose of study drug through the FU 
visit and will include the verbatim description of the procedure, MedDRA PT, reason for the 
procedure, and date and time of the procedure. 


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By-subject listings for transfusions and hemodialysis received prior to the first dose or after the 
first dose of study drug through the FU visit will be provided separately for the Safety 
population. 
4.3. 
Analysis of Efficacy 
Unless otherwise stated, all efficacy analyses will be conducted in the mITT population. Subjects 
will be analyzed in the treatment group to which they were randomized.  
By subject listings of the primary and secondary efficacy outcomes will be provided. 
4.3.1. 
Primary Efficacy Analysis 
The analysis of the primary efficacy outcome for the FDA will be based on the mITT 
population.   
The non-inferiority test will be a one-sided hypothesis test performed at the 2.5% level of 
significance. This non-inferiority test will be based on the upper limit of the two-sided 95% 
confidence interval (CI). The primary efficacy outcome is the percentage of subjects that died at 
Day 30. 
The number and percentage of subjects in each treatment group that are alive and deceased (or 
with missing data) at Day 30 (-2 days) will be tabulated.   
The null and alternative hypotheses are as follows:  
, and 
 
, 
where p1 is the all-cause mortality rate at Day 30 (-2 days) in the Rezafungin for Injection 
treatment group, p2 is the primary ACM at Day 30 (-2 days) rate in the caspofungin treatment 
group, and Δ is the non-inferiority margin of 20%. 
To test the null hypothesis, a two-sided 95% CI for the observed difference in primary outcome 
rates (Rezafungin for Injection treatment group minus caspofungin treatment group) will be 
calculated for the mITT population using the unadjusted methodology of Miettinen and 
Nurminen (Miettinen and Nurminen, 1985). If the upper limit of the 95% CI for the difference in 
the mITT population is lower than 20%, then the null hypothesis will be rejected and 
non-inferiority of Rezafungin for Injection versus caspofungin will be declared.  
To control the overall alpha level, superiority of rezafungin for ACM at Day 30 will be tested in 
the following order: 
 If NI is declared for ACM at Day 30 in the mITT population and the rate of ACM at Day 
30 in the rezafungin treatment group is lower than the caspofungin treatment group, the 


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difference between the treatment groups will be tested for superiority. If the upper bound 
of the 95% CI is less than 0, superiority of rezafungin will be concluded. 
 
 
For the subgroup of subjects with invasive candidiasis (final diagnosis), a two-sided 95% 
CI for the observed difference in the rate of ACM at Day 30 will be calculated using the 
unadjusted methodology of Miettinen and Nurminen. If superiority is declared in the 
mITT population for ACM at Day 30 and the rate of ACM at Day 30 in the rezafungin 
treatment group is lower than the caspofungin group for invasive candidiasis subjects, 
superiority of rezafungin will be tested. If the upper bound of the 95% CI is less than 0, 
superiority of rezafungin will be concluded. 
The analysis of the primary efficacy outcome for the EMA will be based on the mITT 
population. The non-inferiority test will be a one-sided hypothesis test performed at the 2.5% 
level of significance. This non-inferiority test will be based on the lower limit of the two-sided 
95% confidence interval (CI). The primary efficacy outcome is the percentage of subjects that 
have a global response of cure at Day 14 (±1 day) as confirmed by the DRC.  
The number and percentage of subjects in each treatment group defined as global cure, failure 
and indeterminate will be tabulated, as will the overall category combining Failure and 
Indeterminate.   
The null and alternative hypotheses are as follows:  
, and 
 
, 
where p1 is the primary efficacy outcome rate in the Rezafungin for Injection treatment group, p2 
is the primary efficacy outcome rate in the caspofungin treatment group, and Δ is the 
non-inferiority margin of 20%. 
To test the null hypothesis, a two-sided 95% CI for the observed difference in primary outcome 
rates (Rezafungin for Injection treatment group minus caspofungin treatment group) will be 
calculated for the mITT population. If the lower limit of the 95% CI for the difference in the 
mITT population exceeds –20%, then the null hypothesis will be rejected and the non-inferiority 
of Rezafungin for Injection to caspofungin will be declared.  
To control the overall alpha level, superiority of rezafungin for global response will be tested in 
the following order: 
 If NI is declared and the percentage of subjects that have a global response of cure at Day 
14 (±1 day) as confirmed by the DRC in the rezafungin treatment group is higher than the 
caspofungin treatment group, the difference between the treatment groups will be tested 
for superiority. If the lower bound of the 95% CI is greater than 0, superiority of 
rezafungin will be concluded. 
 


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 For the subgroup of subjects with invasive candidiasis (final diagnosis), a two-sided 95% 
CI for the observed difference in global cure at Day 14 for the mITT population will be 
calculated using the unadjusted methodology of Miettinen and Nurminen. If superiority is 
declared for the EMA primary efficacy outcome of global response at Day 14 in the 
mITT population, and the global cure rate in the rezafungin treatment group is higher 
than the caspofungin group for invasive candidiasis subjects, superiority of rezafungin 
will be tested. If the lower bound of the 95% CI is greater than 0, superiority of 
rezafungin will be concluded. 
 
A stratified 95% CI will be determined based on the two randomization strata: diagnosis 
(candidemia only; invasive candidiasis) and APACHE II score/ANC (APACHE II score ≥20 OR 
ANC<500 cells/μL; APACHE II score <20 AND ANC≥500 cells/μL) at Screening. If there are 
<5 subjects within a stratum and treatment group, or there is a 0 count within a stratum for a 
treatment group the categories will be combined. The 95% CI interval will be computed using 
the stratified methodology of Miettinen and Nurminen. Cochran-Mantel-Haenszel weights will 
be used for the stratum weights in the calculation of the CI as follows, where 
i
n1 = number of 
subjects in Rezafungin for Injection treatment group in the ith stratum; 
i
n2 = number of subjects 
in caspofungin treatment in the ith stratum: 
i
i
i
i
i
n
n
n
n
W
2
1
2
1


. 
The reasons for having a global response of failure or indeterminate at Day 14 (±1 day) will be presented 
using the number and percentage of subjects displayed by treatment group in the mITT population. 
Subjects who miss the efficacy assessment due to COVID-19 will have an indeterminate 
response and the number and percentage of subjects with an indeterminate response due to 
COVID-19 will be summarized. 
 
Other subgroup analyses, including analyses by the pre-, peri- and post-COVID-19 period, will 
be conducted for descriptive purposes. Depending on the number of subjects in the study 
diagnosed with COVID-19, ACM at Day 30 and global response may be analyzed in patients 
with and without COVID-19. 
4.3.1.1. 
Additional Analyses of the Primary Efficacy Outcomes 
Sensitivity analyses of the primary outcome for FDA include:  
 The first sensitivity analysis will exclude subjects whose survival status is not known 
(these subjects are considered deaths in the primary analysis).   
 The second sensitivity analysis will calculate an adjusted (for the randomization 
stratification factors) 95% CI interval using the stratified methodology of Miettinen and 
Nurminen. As noted above, Cochran Mantel Haenszel weights will be used for the 
stratum weights in the calculation of the CI.  
 The third sensitivity analysis will be conducted using multiple imputation for missing 
data. Missing primary outcome data will be imputed with multiple imputation. Fifty data 
sets will be created by treatment group using a logistic regression in which the 
randomization stratification factors of diagnosis (candidemia only; invasive candidiasis) 


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and APACHE II score/ ANC (APACHE II score ≥20 OR ANC<500 cells/μL; APACHE 
II score <20 AND ANC≥500 cells/μL) at Screening are included as predictive variables. 
The seed number of 101305 will be used. The difference in mortality rate is calculated per 
each imputed dataset and the risk differences are combined using proc mianalyze. 
 
Sensitivity analyses of the primary outcome for EMA include: 
 The first sensitivity analysis will consider indeterminate responses as successes.  
 The second sensitivity analysis will present an unadjusted two-sided 95% CI for the 
observed difference in primary outcome rates (Rezafungin for Injection treatment group 
minus caspofungin treatment group) using the methodology of Miettinen and Nurminen.    
 The third sensitivity analysis will analyze the primary outcome for the EMA in the CE 
population. The number and percentage of subjects with a global response of cure and 
failure will be provided along with an adjusted (for the randomization stratification 
factors) two-sided 95% CI for the difference in global cure rates. 
4.3.2. 
Secondary Efficacy Outcomes 
The secondary efficacy endpoints of clinical response as assessed by Investigator, mycological 
response (programmatically derived), radiological response (for subjects with invasive 
candidiasis documented by radiologic/imaging evidence at baseline) will be presented using the 
number and percentage of subjects with a response of cure (eradication for mycological 
response), failure, or indeterminate, displayed by treatment group in the mITT population at 
Day 5, Day 14 (±1 day), Day 30 (-2 days), End of Treatment (≤2 days of last dose), and Follow-
up (Days 52-59).  
The number and percentage of subjects with a global response of cure, failure, or indeterminate 
(confirmed by the DRC) will be presented by treatment group in the mITT population at Day 5, 
Day 30 (-2 days), EOT (≤2 days of last dose) and Follow-up (Days 52–59). 95% CIs for the 
treatment differences in global cure will be determined.  
Treatment differences in secondary efficacy endpoints will be assessed using 95% CIs calculated 
at Day 5, Day 14 (±1 day), Day 30 (-2 days), End of Treatment (≤2 days of last dose), and 
Follow-up (Days 52-59). Two-sided 95% CIs will be constructed for the observed differences in 
the global cure, mycological eradication, radiologic cure and clinical cure rates using the method 
of Miettinen and Nurminen without stratification. The 95% CIs are for descriptive purposes only.  
Analyses by diagnosis (candidemia only; invasive candidiasis) and APACHE II score/ ANC 
(APACHE II score ≥20 OR ANC<500 cells/μL; APACHE II score <20 AND ANC≥500 
cells/μL) at Screening will also be provided.  
4.3.3. 
Subgroup Analyses of the Primary Outcomes 
Subgroup analyses of mortality through 30 days (-2 days) and global response at Day 14 
(±1 day) will be performed to investigate the consistency of the treatment effects for different 
groups of subjects. Forest plots will be presented to visually assess the presence of treatment by 
subgroup interactions. All-cause mortality and global response at Day 14 (±1 day) will be 
assessed separately within the following subgroups in the mITT population: sex (male versus 


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female), race (white versus non-white and Asian versus non-Asian), age category (<65 years 
versus ≥65 years), geographic region (United States/South America, Europe/Israel/Turkey, Asia-
Pacific (excluding China/Taiwan), China/Taiwan), final diagnosis (candidemia only versus IC), 
and APACHE II score/ANC at Screening (APACHE II score ≥20 OR ANC<500 cells/μL versus 
APACHE II score <20 AND ANC≥500 cells/μL), APACHE II score at Screening (≥20, <20, 10-
19,  <10), ANC at Screening (<500 cells/μL versus ≥500 cells/μL).   All-cause mortality through 
30 days (-2 days) and global response at Day 14 (±1 day) will also be summarized in the 
subgroups defined by timing of the culture used to document the Candida infection (positive 
culture at randomization definitions 1 and 2).  This subgroup will not be included in the Forest 
plots. 
For each subgroup, the number and percentage of subjects alive and deceased at Day 30 and the 
number and percentage of subjects with a global cure, failure and indeterminate response at Day 
14 (±1 day) will be determined by treatment group. Two-sided 95% CIs for the observed 
difference in mortality rates and global cure rates will be calculated in the mITT population, 
using the unadjusted methodology of Miettinen and Nurminen.  
4.3.4. 
Additional Efficacy Outcomes 
Analyses for the additional efficacy endpoints will be performed using the mITT population. 
Resolution of all systemic signs attributable at baseline to candidemia and/or invasive candidiasis 
for subjects receiving of Rezafungin for Injection and caspofungin at Day 5, Day 14 (±1 day), 
Day 30 (-2 days) and Follow-up (Days 52-59) will be presented by treatment group. This 
analysis will be repeated for subjects additionally with mycological eradication.  
All-cause mortality at Follow-up will be presented for the mITT population by treatment group 
using frequencies and percentage of subjects that were alive and deceased at Follow-up. In 
addition, Kaplan-Meier (KM) methods will be utilized to analyze survival time in the mITT and 
ITT populations. The probability of being alive at Day 5, Day 14, Day 30, and Day 55 will be 
determined by treatment group. In addition, the 25th, 50th (median), and 75th percentiles will be 
provided by treatment group. The number and percentage of subjects censored will be provided. 
KM survival curves will be provided. The number of subjects at risk and number died in each 
treatment group will be displayed below the x-axis at day= 0, 5, 14, 30, 55. Survival status will 
be provided in a by-subject listing. 
The time to the first negative blood culture without subsequent positive culture from a sample 
drawn following the first dose of study drug will be summarized using KM methods for mITT 
population. The calculation will be in reference to the first dose date. For subjects who have 
negative blood culture prior to the first dose of study drug without subsequent positive culture, 
the time to the first negative blood culture will be set to zero. A log-rank test will be performed 
to test for differences in survival curves between treatment groups. Subjects will be censored if 
they receive an alternative antifungal (i.e., other than study drug) for the treatment of the 
candidemia, died or were lost to follow up prior to having the negative blood culture (see Section 
2.3.3). KM survival curves will be provided. The 25th, 75th percentiles and the median survival 
time and 95% CIs will be determined by treatment group. This analysis will be repeated for the 
following subsets among the subjects with any post-baseline blood cultures: 1) Subjects with 


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positive culture at randomization definition 1 (defined in Section 2.8), 2) Subjects who did not 
receive systemic antifungal therapy prior to the first dose of study drug, 3) Subjects diagnosed 
with Candidemia only, and 4) Subjects diagnosed with Candidemia only with timing of positive 
culture at randomization definition 1 (defined in Section 2.8). 
Results of blood culture, tissue/fluid culture from a normally sterile site, rapid diagnostic and 
radiological (and other imaging) testing will be provided in by-subject listings. 
4.4. 
Analysis of Health Outcomes 
The number and percentage of subjects admitted to the Intensive Care Unit (ICU) on or after 
Study Day 1 will be summarized by treatment group in the mITT population. For those subjects 
who did not die before hospital/ICU discharge, the time to discharge for each admission to 
hospital and to ICU will be generated and the longest length of stay for each subject will be 
summarized using descriptive statistics by treatment group in the mITT population. For subjects 
admitted to the hospital and to the ICU, the number of hospital/ICU admissions will be 
determined and the number and the percentage of the subjects with no ICU admission, 1 ICU 
admission, and 2 ICU admissions will be presented. In addition, for those subjects who did not 
die before hospital/ICU discharge, the total number of days in hospital, in ICU, and in general 
ward across all admissions will be determined. The total number of days in hospital is defined as 
the total number of days in hospital during the study period (i.e., if admission date is earlier than 
the first dose date, the number of days is defined as discharge date – first dose date +1; if 
admission date is on or later than first dose date, the number of days is defined as discharge date 
– admission date +1). The number of days from the initial admission and the one from re-
admission (if applicable) will be summed to get the total number of days. For the subjects with 
missing hospital discharge date, the end of study date or the ICU discharge date, whichever is 
later, will be used for the discharge date. Descriptive statistics will be used to summarize the 
total number of days in hospital, in general ward, and for those admitted to the ICU, the total 
number of days in ICU, by treatment group in the mITT population. Similarly, the total number 
of days in hospital, in ICU, and in general ward at time of enrollment (defined as randomization 
date – admission date +1) will be summarized. 
The number and percentage of subjects re-admitted to hospital and to ICU (re-admitted to ICU 
during initial hospitalization) after discharge by Day 30 (-2 days) and by Follow-up (Days 52-59) 
will be presented by treatment group for all subjects in the mITT population who were 
discharged from hospital, where the initial discharge date was on or after Study Day 1. 
Descriptive statistics will be used to summarize the time to first re-admission from the previous 
discharge date. The analysis will be repeated for re-admissions related to infectious disease and 
for re-admissions related to Candidiasis. Hospital admissions and re-admissions will be provided 
in by-subject listings 
4.5. 
Analysis of Safety Data 
All safety analyses will be conducted in the Safety population. Subjects who receive the wrong 
study drug for their entire course of study drug will be analyzed in the treatment group based on 
the drug received. Subjects who receive the wrong study drug for part of their course of study 


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drug will be analyzed in the treatment group based on majority of (i.e., most frequent) doses 
received. 
4.5.1. 
Adverse Events 
Verbatim descriptions of AEs will be coded using the latest MedDRA version (version 23.0 or 
higher). Summary tables will be provided for all treatment-emergent adverse events (TEAEs). 
A TEAE is defined as an AE that occurs during or after study drug administration and up 
through the Follow Up visit (Days 52-59). An AE is programmatically defined as treatment 
emergent if the start date and time is on or after the start date and time of the first dose of study 
drug. If the time of an AE is missing, it is considered treatment emergent if it starts on the same 
date as the first dose of study drug. Date Imputations will follow the rules described in 
Appendix 8 (Section 5.8). 
Deaths obtained only through the Survival Status eCRF will not be recorded on the AE eCRF, 
but will be programmed as an AE with SOC and PT of "Death NOS" and analyzed as an 
AE/SAE with outcome of fatal. 
An overall summary of AEs and TEAEs will include the number and percentage of subjects in 
each treatment group who experienced at least 1 AE/TEAE in the following categories: any AE, 
any TEAE, any TEAE up through Day 7, any study drug-related TEAE, any grade 4/5 TEAE, 
any serious AE (SAE), any study drug-related SAE, any SAE leading to death (that includes 
SAE started during study with an outcome of death that occurred after the Follow-up Visit), any 
study drug-related SAE leading to death, any TEAE resulting in interruption of administration of 
study drug, any TEAE leading to discontinuation of study drug, and any TEAE resulting in study 
discontinuation. The overall summary of AEs will be repeated for the high risk subgroups 
defined in Table 4-1. 
Subjects with multiple events will be counted only once within each category. CTCAE grade 
(version 5.0) and relationship will be counted using the maximum grade and the strongest 
relationship respectively for a subject with multiple TEAEs. 
The number and percentage of subjects reporting a TEAE in each treatment group will be 
tabulated by SOC and PT; by SOC, PT, and maximum CTCAE grade (1, 2, 3, 4, or 5); and by 
SOC, PT, and relationship (unrelated or related) to study drug. The incidence of TEAEs in each 
treatment group that occur up through Day 7 will be summarized by SOC and PT.  The incidence 
of all TEAEs and all non-serious TEAEs that occur in at least 5% of subjects in the Rezafungin 
for Injection or caspofungin groups will be summarized separately by PT and treatment group, 
sorted by decreasing frequency in the Rezafungin for Injection group. The incidence of all 
TEAEs by SOC and PT will be also summarized by diagnosis (candidemia only versus IC) and 
by high risk subgroups defined in Table 4-1. For all analyses of TEAEs, if the same TEAE 
(based on PT) is reported for the same subject more than once, the TEAE is counted only once 
for that PT and at the highest grade and strongest relationship to study drug. 
The number and percentage of subjects in each treatment group reporting a SAE, reporting a 
study drug-related SAE, reporting a TEAE resulting in interruption of study drug administration, 


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reporting a TEAE leading to discontinuation of study drug, and reporting a fatal SAE will be 
summarized by SOC and PT. In addition to a listing of all reported AEs, by-subject listings of all 
SAEs (including any SAEs with an outcome of death), AEs of special interest, and all TEAEs 
resulting in the alteration of or leading to discontinuation of study drug will be provided. 
The number and percentage of subjects in each treatment group reporting a potential Drug 
Induced Liver Injury Adverse Events (DILI, Hepatic transaminase and Bilirubin elevations) will 
be presented. The following combination of Standardized MedDRA query (SMQ)/PTs will be 
used: Cholestasis and jaundice of hepatic origin (SMQ, broad), Liver related investigations, signs 
and symptoms (SMQ, broad), Liver-related coagulation and bleeding disturbances (SMQ, 
broad), Hepatic failure, fibrosis and cirrhosis and other liver damage-related conditions (SMQ, 
broad), Hepatitis, non-infectious (SMQ, broad), Bilirubin conjugated (PT), Bilirubin urine (PT), 
Bilirubinuria (PT), Blood bilirubin (PT), Urobilinogen urine (PT), Urobilinogen faeces abnormal 
(PT), Urobilinogen faeces increased (PT), Urobilinogen faeces (PT). 
Adverse Events of Special Interest (AESI) 
All AEs will be reported, but certain adverse events of special interest will be specifically 
evaluated including but not limited to 
 IV Infusion Intolerability Adverse Experiences 
 Phototoxicity 
 Ataxia, Neuropathy and Tremors (ataxia, axonal neuropathy, hypoesthesia, paresthesia, 
peripheral motor neuropathy, peripheral neuropathy, peripheral sensory neuropathies, 
peripheral sensorimotor neuropathy, polyneuropathy, toxic neuropathy, and tremors)  
The number and percentage of subjects in each treatment group reporting AESI in the categories 
above will be reported. Additional analyses by higher risk subgroups might be considered. 
Higher risk subgroups that will be considered include but are not limited to: 
Table 4-1: 
Higher Risk Subgroups 
Elderly  
≥65 years (yes/no) 
Moderate hepatic impairment 
Child-Pugh score of 7-9 (yes/no)  
Higher weight 
Baseline weight >80 kg (yes/no) 
Neutropenia 
(ANC<500, ANC≥500) 
APACHE II score  
(≥20, <20, 10-19, <10) 
Diagnosis at Randomization  
(candidemia only versus IC) 
 
Subjects Diagnosed with COVID-19 
Subjects diagnosed with COVID prior to entry into the study (based on medical history) or after 
the first dose of study drug (TEAE) will be presented in a listing with date of COVID-19 
infection and outcome.  


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A table of TEAEs of coronavirus infection will be presented by PT and a listing of all TEAEs in 
subjects with diagnosed COVID-19 will be provided. Depending upon the number of subjects 
diagnosed with COVID-19, a summary of TEAEs by SOC and PT may be provided.  
4.5.2. 
Clinical Laboratory Data 
Several analyses of clinical laboratory data will be presented. For descriptive statistics of actual 
values and the change from baseline, values will be normalized against normal ranges from a 
common source (US National Library of Medicine [NLM], MedlinePlus) according to the 
following Scale Model formula (Karvanen, 2003): s = x (Us/Ux), where s = the individual 
laboratory value normalized against the laboratory normal range from the common source; x = 
the original individual laboratory value; Ux is the upper limit of the normal range for an 
individual laboratory parameter; Us is the upper limit of the laboratory normal range for that 
laboratory parameter from the common source. WBC differentials in percent that are derived 
from the absolute counts will not be normalized because of the missing upper limit of the normal 
range in percent. For WBC differentials in percent with the non-missing upper limit, the 
maximum of the normalized values will be limited to 100%. Coagulation lab tests and urinalysis 
tests will not be normalized. 
Descriptive statistics (based on Systeme Internationale [SI] units) for chemistry and hematology 
parameters, as well as the change from baseline, will be summarized by treatment group for all 
study visits and for the worst overall post-baseline value. The directionality for determining the 
worst overall post-baseline value is provided in Section 5.5. Change from baseline will be 
calculated for each subject at the specified time point as the value at the specified time point 
minus the baseline value. If multiple values are obtained during the Screening period, the last 
non-missing values collected prior to the first dose of study drug will be used for the baseline. 
The laboratory values will be graded using the CTCAE version 5.0. If no CTCAE grade is 
available, Division of Microbiology and Infectious Disease (DMID) or Division of AIDS 
(DAIDS) will be used for grading. Shift tables will be presented to show the number of subjects 
with each toxicity grade (1,2,3, or 4/5) at baseline versus each post-baseline visit and the worst 
post-baseline grade (including any unscheduled visits). For those laboratory parameters for 
which high toxicity grades are specified for both low and high values (e.g., sodium, potassium), 
shifts in toxicity will be presented for high and low toxicities separately. The percentages will be 
based on the number of subjects with both a baseline and post-baseline (at the specified visit) 
assessment of the specific laboratory parameter. The number and percentage of subjects with at 
least a 2-grade increase from baseline at any post-baseline study visit, including unscheduled 
visits, will be summarized by laboratory parameter and treatment group. Percentages for each lab 
test will be based on the number of subjects with both a baseline and a post-baseline evaluation 
of the particular laboratory test. A listing will be provided which provides all results for a given 
laboratory test for subjects who have at least one 2-grade increase from baseline. 
Detailed subject listings of all laboratory data (including coagulation and urinalysis results) 
collected during the study will be provided. Laboratory values outside normal limits will be 
identified in the subject data listings. A column will display any applicable toxicity grading of 
the laboratory value. The results from pregnancy tests will also be listed. 


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Hepatic Safety Data 
Hepatic effects (liver function test (LFT) abnormality) will be identified with selected adverse 
events (as defined in Section 4.5.1 [Adverse Events of Special Interest]), and the laboratory 
parameters: AST (aspartate aminotransferase), ALT (alanine aminotransferase), ALP (alkaline 
phosphatase) and TBL (total bilirubin). 
Threshold values of interest for liver function tests are given below in Table 4-2: Criterion-
based hepatic events 
. The laboratory results meeting specified criteria standard table will be used to provide the 
number and percentage of patients having AST, ALT > 3, 5, 8, 10 x upper limit of normal (ULN) 
or TBL >1.5, 2 x ULN or ALP > 2, 3 x ULN and any other criteria specified in Table 4-2:
 
Criterion-based hepatic events 
 at any time post-baseline regardless of their baseline value. For a combined criterion to be 
fulfilled, all conditions must be fulfilled on the same lab measurement.  
The number and percentage of potential Hy’s Law cases will be presented by treatment group. 
The criteria for Hy’s law is: (ALT or AST) >3 ×ULN, ALP ≤2.0 ×ULN, and total bilirubin >2 
×ULN. A listing of subjects who meet either laboratory criteria for Hy’s law will also be 
provided. Subjects meeting either criteria based on any combination of post-baseline laboratory 
results, irrespective of their temporal association, as well as subjects meeting the criteria at the 
same time point, will be listed. All laboratory results for the parameters included in the criteria 
will be presented by visit for all subjects who meet the criteria. 
Table 4-2: 
Criterion-based hepatic events 
Parameter 
Criterion 
ALT 
>3xULN; >5xULN; >8xULN; >10xULN 
AST 
>3xULN; >5xULN; >8xULN; >10xULN 
ALT or AST 
>3xULN; >5xULN; >8xULN; >10xULN 
TBL 
>1.5xULN; >2xULN 
ALP 
>2xULN; >3xULN 
 
(ALT or AST) & TBL 
ALT or AST >3xULN & TBL >2xULN 
 
ALT or AST >5xULN & TBL >2xULN 
 
ALT or AST >8x ULN &TBL >2xULN  
 
ALT or AST >10xULN & TBL >2xULN 
 
 
(ALT or AST) & TBL & ALP 
ALT or AST >3xULN & TBL > 2.0xULN & 
ALP <=2xULN (potential Hy’s Law) 
 
AST = Aspartate aminotransferase; also known as SGOT, ALT = Alanine aminotransferase; also known as SGPT, 
ALP = Alkaline phosphatase, TBL = Total bilirubin. 
 


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Nephrotoxicity 
To evaluate the effect of Rezafungin for Injection on renal function, nephrotoxicity is defined as 
doubling of serum creatinine relative to baseline or an increase of ≥1 mg/dL in serum creatinine 
if baseline serum creatinine was above the upper limit of the normal range. The observed 
proportions of subjects with nephrotoxicity by visit and worst post-baseline value will be 
reported by treatment group.   
4.5.3. 
Vital Signs 
Descriptive statistics of the highest and lowest values at each visit and the highest and lowest 
value at any post-baseline visit (including unscheduled post-baseline measurements) will be 
summarized by study drug group for each vital sign parameter (heart rate, blood pressure, 
respiratory rate, and temperature).   
The change from baseline to the highest and lowest values at each post-baseline visit and the 
highest and lowest value at any post-baseline visit (including unscheduled post-baseline 
measurements) will be provided for each vital sign parameter by treatment group. Change from 
baseline to the highest and lowest values at each post-baseline visit will be calculated for each 
subject and parameter as the highest or lowest value at the specified visit minus the baseline 
highest or lowest value. If multiple values are obtained during the Screening period, the last non-
missing values collected prior to the first dose of study drug will be used for the baseline.  
A summary of potentially clinically significant (PCS) values, identified as values meeting both 
the criterion value and the change from baseline criterion listed in Table 4-3, will be provided 
for the worst post-baseline value (which includes unscheduled post-baseline measurements). The 
incidence of PCS values will be summarized by treatment group for the worst post-baseline 
value and will be listed and flagged in by-subject listings. 
For all analyses of temperature, temperatures obtained by non-oral methods of rectal or tympanic 
will be converted to oral temperatures by subtracting 0.3 °C from the temperature in °C. 
Temperatures obtained by temporal methods will be converted to oral temperatures by adding 
0.3°C to the temperature in °C.  
A by-subject listing of vital signs reported at each visit will be provided. 
Table 4-3: 
Criteria for Potentially Clinically Significant Vital Signs 
Vital Sign Parameter 
Flag 
Criterion Value 
Change from Baseline 
Systolic Blood Pressure (mm Hg) 
High (CH) 
180 mmHg 
Increase of 20 mmHg 
Low (CL) 
90 mmHg 
Decrease of 20 mmHg 
Diastolic Blood Pressure (mm Hg) 
High (CH) 
105 mmHg 
Increase of 15 mmHg 
Low (CL) 
50 mmHg 
Decrease of 15 mmHg 
Heart Rate (bpm) 
High (CH) 
120 bpm 
Increase of 15 bpm 


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Vital Sign Parameter 
Flag 
Criterion Value 
Change from Baseline 
Low (CL) 
50 bpm 
Decrease of 15 bpm 
Temperature (°C) 
High (CH) 
>38°C 
Increase of 1°C  
Low (CL) 
≤36 °C 
Decrease of 1°C  
Respiratory Rate (breaths/minute) 
High (CH) 
30 breaths/minute 
Increase of 10 breaths/minute 
Low (CL) 
8 breaths/minute 
Decrease of 4 breaths/minute 
4.5.4. 
Electrocardiogram 
Descriptive statistics of ECG parameters will be presented by treatment group and will include 
change from baseline. If multiple values are obtained during the Screening period, the last 
non-missing values collected prior to the first dose of treatment will be used for the baseline. 
QTcF is calculated using the formula: QTcF = QT (msec)/(RR in seconds)1/3 where RR (sec) can 
be calculated from 60 divided by Heart rate (bpm). The number and percentage of subjects with 
the change from baseline QTcF >=30 msec and >=60 msec will be presented. 
A by-subject listing of ECG parameters reported at each visit will be provided. 
4.5.5. 
Physical and Retinal Examinations 
Physical exam findings from Screening, Day 14 (±1), Day 30 (±2), End of Treatment (≤2 days of 
last dose), the Follow-up visit and unscheduled visits will be presented in a by-subject listing. 
Abnormal findings from retinal examinations and whether or not the subject had evidence of 
candida endophthalmitis or chorioretinitis will be provided in a by-subject listing. Signs and 
symptoms of tremor, ataxia and peripheral neuropathy determined from neurological 
examinations at Screening, End of Treatment (≤2 days of last dose) and unscheduled visits will 
be presented in a by-subject listing.  
4.5.6. 
Neurological Questionnaires 
Assessments of Chemotherapy-Induced Peripheral Neuropathy questionnaire (QLQ-CIPN20 
version 3.0) and Scale for the Assessment and Rating of Ataxia (SARA, version date 13 Jun 
2006) were conducted on patients enrolled prior to Protocol Amendment 3. Results from these 
two neurological questionnaires will be presented in by-subject listings. 
4.6. 
PK Sampling 
Blood samples will be collected from all subjects receiving study drug, although only PK 
samples from subjects receiving Rezafungin for Injection will be analyzed. Bioanalytical 
analysis will be performed by an independent, central bioanalytical laboratory using a validated 
assay. 
Only samples taken within the timepoint windows will be included in summary statistics and 
evaluations of safety and efficacy by PK tertiles described below. 
. 


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Timepoint windows are defined as follows: 
 Day 1, 10 Minutes before end of infusion (EOI): between 15 minutes prior to EOI and 5 
minutes after EOI. 
 Day 1, Between EOI and 12 Hours after EOI: between 5 minutes prior to EOI to 15 
hours after EOI. 
 DAY 2, 3, 4, or 5  Random Draw: any time 
 DAY 8 PRE-DOSE: within 30 minutes prior to Day 8 infusion start 
 DAY 14: any time. 
 DAY 15 PRE-DOSE: any time on Day 15 prior to Day 15 infusion start 
 DAY 22 PRE-DOSE: any time on Day 22 prior to Day 22 infusion start 
Summary statistics (number of subjects, arithmetic mean, SD, coefficient of variation (CV%), 
median, minimum, maximum, tertiles, and geometric mean of plasma concentration) will be 
provided for the PK Population by timepoint mentioned above. 
Timing of pharmacokinetic samples will be presented in a by-subject listing. 
The FDA and EMA primary endpoints of all‐cause mortality and global response, respectively, 
will be summarized by upper, mid, and lower tertiles of plasma concentration on Day 1 (10 
minutes before the end of infusion) and on Day 8 (pre-dose) in the PK Population. 
The number and percentage of any TEAE in the rezafungin group and any TEAEs occurring in 
>40% (by SOC and PT) will be summarized by upper, mid, and lower tertiles of plasma 
concentration on Day 1 (10 minutes before the end of infusion) and on Day 8 (pre-dose) in the 
PK Population 
The following rules will be applied prior to summarizing if plasma concentration values that are 
below the limit of quantification (BLQ), or missing (e.g., no result [NR]): 
 BLQ or NR values will be set to missing for summary purposes. Values that are BLQ 
will be displayed as “BLQ” in listings.  
 If there are fewer than 3 values in the data series, only the minimum, maximum and n 
will be presented. The other summary statistics will be denoted as not calculated (NC).  


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5. 
APPENDICES 
5.1. 
Appendix 1: Study Design Diagram 
 
 


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5.2. 
Appendix 2: Schedule of Assessments and Procedures for the Required Treatment, End of Treatment, and 
Follow-up Periods 
Assessment or Procedure 
Screening 
Required Treatment Period (Days) 
Day 30 (-2) 
EOT 
Follow-up c 
≤4 days 
(96 hours) 
before 
randomization 
1 a 
2 
3 
4 
5–7 
8 (±1) b 
9–13 
14 (±1) b 
Efficacy, 
Safety 
≤2 days after  
last dose 
(IV or oral) 
Days 52–59 
Informed consent d 
X 
 
 
 
 
 
 
 
 
 
 
 
Medical history e 
X 
 
 
 
 
 
 
 
 
 
 
 
Physical examination, 
including weight and height f 
X 
X g 
X g 
X g 
X g 
X h 
X g 
X g 
X 
X 
X 
X 
Neurological examination h 
X 
X h 
X h 
X h 
X h 
X h 
X h 
X h 
X h 
X h 
X  
X h 
Vital signs i 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Assess Central Venous 
Catheters j 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Blood for hematology 
and chemistry tests (see  
Appendix 3 of Protocol) 
X 
X 
X 
 
X 
 
X 
 
X 
X 
X 
X 
Blood for PT/INR 
(see Appendix 3 of Protocol) 
X 
 
 
 
 
 
 
 
 
 
 
 


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Assessment or Procedure 
Screening 
Required Treatment Period (Days) 
Day 30 (-2) 
EOT 
Follow-up c 
≤4 days 
(96 hours) 
before 
randomization 
1 a 
2 
3 
4 
5–7 
8 (±1) b 
9–13 
14 (±1) b 
Efficacy, 
Safety 
≤2 days after  
last dose 
(IV or oral) 
Days 52–59 
Calculate Child-Pugh score k 
(see Appendix 4 of Protocol) 
X 
 
 
 
 
 
 
 
 
 
 
 
Calculate modified APACHE II 
with Glasgow coma score l 
X 
 
 
 
 
 
 
 
 
 
 
 
12-lead ECG m 
X 
X 
 
 
 
 
 
 
 
 
 
 
Radiologic test results n 
X 
 
 
 
 
 
 
 
 
 
X 
X 
Urine for urinalyses, 
microscopy o (see Appendix 3 
of Protocol) 
X 
 
 
 
 
 
 
 
 
 
X 
 
Serum pregnancy test p 
X 
 
 
 
 
 
 
 
 
 
 
X 
Retinal examination for 
Candida eye infection q 
X r 
X q 
X q 
X q 
X q 
X q 
X q 
X q 
X q 
X q 
X q 
X q 
Blood or normally sterile 
tissue/fluid for culture r, s 
X r 
X s 
X s 
X s 
X s 
X s 
X s 
X s 
X s 
X s 
X s 
X s 
Blood for Rapid IVD t 
X t 
 
 
 
 
 
 
 
 
 
 
 


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Assessment or Procedure 
Screening 
Required Treatment Period (Days) 
Day 30 (-2) 
EOT 
Follow-up c 
≤4 days 
(96 hours) 
before 
randomization 
1 a 
2 
3 
4 
5–7 
8 (±1) b 
9–13 
14 (±1) b 
Efficacy, 
Safety 
≤2 days after  
last dose 
(IV or oral) 
Days 52–59 
Study randomization u 
 
X 
 
 
 
 
 
 
 
 
 
 
Administer study drug 
and/or placebo (See 
Appendix 4) 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Record prior and/or 
concomitant medications v 
X 
 
 
 
 
 
 
 
 
 
X 
X 
Record adverse events w 
X 
 
 
 
 
 
 
 
 
 
X 
X 
Assess presence or absence of 
systemic signs of candidemia/ 
invasive candidiasis 
X x 
 
 
 
 
X z 
 
 
X 
X 
 
X 
Assess for clinical response y 
 
 
 
 
 
X z 
 
 
X 
X 
X 
X 
Assess for radiologic responseaa 
 
 
 
 
 
X 
 
 
X 
X 
X 
X 
Assess ACM 
 
 
 
 
 
 
 
 
 
X 
 
X 
Blood for PK testing bb 
X cc 
X bb 
X dd 
X dd 
X dd 
X dd 
X bb 
 
X ee 
 
 
 


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Abbreviations: ACM = all-cause mortality; APACHE II = Acute Physiology and Chronic Health Evaluation II; ECG = electrocardiogram; eCRF = electronic case report 
form; EOT = End of Treatment; ESCMID = European Society of Clinical Microbiology and Infectious Diseases; ICF = Informed Consent Form; ICH = International Council 
for Harmonisation; ICU = intensive care unit; IDSA = Infectious Diseases Society of America; IV = intravenous(ly); IVD = in vitro diagnostic; PCR = polymerase chain 
reaction; PI = Principal Investigator; PK = pharmacokinetic; spp. = species; PT/INR= Prothrombin Time/International Normalized Ratio. 
a 
Study Day 1 is defined as the first day of study drug administration; subsequent study days are counted as the number of consecutive calendar days thereafter. 
b 
Windows apply to subjects who are receiving oral step-down therapy on an outpatient basis or who are inpatient and are scheduled to be discharged by the next calendar day. 
c 
Follow-up is to occur on Days 52–59. Subjects who stop study drug prior to Day 22 AND are considered clinical failures (i.e., require a change in antifungal therapy to treat 
candidemia and/or invasive candidiasis) may have their Follow-up visit earlier but must still be ≥30 days following the last once weekly infusion of Rezafungin for 
Injection/placebo (i.e., Day 1, Day 8, Day 15, or Day 22). 
d 
Written informed consent must be obtained prior to initiating any study related assessments or procedures. Consent from a legally acceptable representative (i.e., acceptable to 
ICH and local law, as applicable) may be obtained if the subject is unable to consent for themselves. 
e 
Medical history for the last 5 years and Candida risk factors for the last 3 months (e.g., central line, active malignancy, broad-spectrum antibiotic therapy, diabetes mellitus, 
immunosuppression, major surgery, total parenteral nutrition, transplant recipient, trauma, dialysis, burns, pancreatitis) and intensive care unit (ICU) admission and discharge 
(if applicable).  
f 
Height at Screening only; weight at Screening, Day 14, and Follow-up (Days 52–59); all other assessments at specified visits. 
g 
A focused physical exam (including a neurological exam) should be performed as clinically indicated by adverse event screening and course of the underlying disease. 
h 
As part of the physical exam, a thorough neurologic exam is to be performed at Screening and at the EOT visit. At all other time points, a focused physical exam (including a 
neurological exam) is to be performed as clinically indicated, driven by the subject’s signs and symptoms. 
i 
Temperature and the method used [oral, rectal, temporal, tympanic, or core], heart rate, blood pressure, and respiratory rate. Axillary temperatures are allowed but not 
preferred. 
j 
Presence of central line during Screening or placed during the study should be documented with dates of insertion and removal. Short-term central venous catheters 
(e.g., peripherally-inserted central catheters, internal jugular, or subclavian central venous catheters) and long-term central venous catheters (e.g., tunneled catheters) 
are recommended to be removed within 48 hours after diagnosis with candidemia, consistent with IDSA and ESCMID guidelines. 
k 
Child-Pugh score is only required for subjects with a history of chronic cirrhosis. 
l 
APACHE II score is a stratification factor for randomization and must be calculated prior to enrollment using vital signs and laboratory results from Screening. If multiple 
vital signs and laboratory values are obtained during the Screening period, it is preferred to use those collected most closely to the time of randomization. See  Appendix 5 of 
Protocol for APACHE II and Appendix 6 of Protocol for Glasgow coma score. 
m 
12-lead ECG must be conducted prior to randomization and at any time on Day 1 following administration of study drug (i.e., post-end IV infusion). 
n 
Radiologic test type with findings and interpretation should only be recorded if the test provides evidence of invasive candidiasis or evidence of progression, stabilization, 
improvement, or resolution of invasive candidiasis compared with previous radiographs. 
o 
While potentially indicative of disease, a positive urine culture for Candida spp. may not be used as the qualifying culture for entry into the study, though the presence 
of a positive urine culture is not a reason to exclude a patient from participation in the study. Subjects who are anuric do not require a urinalysis. 
p 
Serum pregnancy test required only for women of childbearing potential; do not perform for women ≥2 years postmenopausal or surgically sterile.  


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q 
A retinal examination for evidence of a Candida eye infection, including endophthalmitis or chorioretinitis, should be performed in all subjects with candidemia during 
Screening when possible, although the exam may occur as late as Day 7. Retinal examination is standard of care for subjects with candidemia and should be performed by an 
ophthalmologist, when available. The retinal examination should be repeated in subjects who were negative at baseline if the subject develops visual signs or symptoms of a 
Candida eye infection during the study. Additionally, any neutropenic subjects who recover their neutrophil counts during the study should have an additional retinal 
examination. Subjects who were negative at baseline and diagnosed with a Candida eye infection after initiating study drug must discontinue study drug but may continue in 
the study at the Investigator’s discretion (see Section 7.4.2 of Protocol). 
r 
A culture must be obtained as part of the standard of care for inclusion in the study. Established mycological diagnosis of candidemia or invasive candidiasis from a sample 
taken ≤4 days (96 hours) before randomization defined as: ≥1 blood culture positive for yeast or Candida, a positive test for Candida from sponsor-approved rapid IVD, or a 
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. If the positive 
blood culture used to qualify the subject for the study is drawn >12 hours prior to randomization, an additional set of blood cultures must be obtained ≤12 hours before 
randomization. Identification and susceptibility testing at the local laboratory for Candida for blood or normally sterile tissue/fluid for culture is required at Screening and for 
any positive culture requiring a change of antifungal therapy (i.e., local identification and susceptibility testing is not required for Candida isolates cultured from specimens 
on other study days provided there is no required change of antifungal therapy). 
s 
Specimens for culture for demonstration of efficacy, or when clinically indicated. Blood cultures should be repeated daily (preferred) or every other day until the first negative 
blood culture result for Candida spp. with no subsequent positive culture (in cases when one or more samples are drawn and cultured after the first negative culture is 
available). All fungal isolates cultured from blood and normally sterile tissue/fluid from Screening through Follow-up must be sent to the Central Laboratory. Record the spp 
for any new bacteria isolated from blood and the spp and susceptibilities for any new bacteria isolated from any other normally sterile site. 
t 
Sponsor-approved rapid IVDs are allowed to fulfill Inclusion Criteria #3 for entry into the study. However, a culture from blood or another normally sterile site obtained 
during the Screening period must be positive for Candida spp. for the subject to be eligible for the mITT population. Currently approved rapid IVDs include the T2Candida 
panel and the Septifast PCR test.  
u 
Confirm all inclusion and exclusion criteria are met prior to randomization. 
v 
Record all prior and/or concomitant medications from Screening through Follow-up. All systemic antifungal therapy administered within 4 weeks and all non-antifungal 
therapy administered within 1 week prior to randomization will be documented and recorded in the eCRF. Subjects who received systemic treatment with an antifungal agent 
at approved doses for treatment of candidemia for >48 hours before randomization will be excluded from the study. 
w 
Adverse events are collected from the time the ICF is signed at Screening through Follow-up. 
x 
The Screening period for assessing systemic signs of candidemia/ invasive candidiasis for inclusion in the study may include the 12 hours prior to the collection of the 
qualifying positive blood culture, when systemic signs of infection were the reason for specimen collection (blood culture or fluid from a sterile site culture or qualifying rapid 
IVD [e.g., T2Candida Panel]), through study randomization. 
y 
Clinical response is assessed by the PI. Criteria for cure, indeterminate, and failure responses are found in Table 2-4: 
Investigator’s Assessment of Clinical 
Response Definitions 
z 
. 
aa 
Assessment to be performed on Day 5 (i.e., not required for Day 6 and Day 7). 
bb 
Subjects diagnosed with invasive candidiasis with evidence of deep tissue disease by radiology or other imaging should have follow-up imaging to demonstrate progression, 
stabilization, improvement, or resolution of disease. Improvement or resolution of disease by imaging would indicate radiological cure, while stabilization or progression of 
disease by imaging would indicate radiological failure. Missing imaging following baseline evidence of invasive candidiasis will result in an indeterminate response.  Criteria 
for cure, indeterminate, and failure responses are found in Table 2-4. 


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cc 
Blood samples for PK analysis will be collected from the OPPOSITE arm of the infusion or through an arterial line during the infusion; after the infusion is complete, 
opposite arm or arterial line draws are preferred but not mandatory. Blood samples will be collected as follows: On Day 1, 10 minutes before the end of infusion, and one 
sample taken anytime between end of infusion and 12 hours after the end of infusion; Day 2, 3, 4, or 5, one sample taken at any time on one day only; Day 8, pre-dose; Day 
14 (for subjects not receiving a Day 15 dose), one sample taken at any time; Day 15, pre-dose (if applicable); Day 22, pre-dose (if applicable). Note: Pre-dose samples should 
be collected ≤30 minutes prior to the start of the infusion. For subjects receiving hemodialysis, an attempt should be made to obtain PK samples directly following 
hemodialysis if still within the required time window. 
dd 
Only for subjects enrolled prior to Amendment 5: Blood samples will be obtained at any time during Screening (one blood sample for protein binding and one blood 
sample for albumin core analyses). To limit invasive procedures these samples would ideally be collected at the same time into two vacutainers, though each sample could be 
collected separately. 
ee 
One blood sample for PK will be collected at any time on one of the following Days 2, 3, 4, or 5 (i.e., if blood sample for PK not collected on Day 2 or must be collected on 
Day 3 (or Day 4 or Day 5). 
ff 
Day 14 draw is only for subjects completing treatment on Day 14 and should be drawn at the same time as Day 14 hematology and chemistry blood draws (i.e., random 
PK draw). 


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5.3. 
Appendix 3: Schedule of Assessments and Procedures for the Optional Treatment Period 
 
Optional Treatment Period (Days) 
EOT 
Follow-up 
Assessment or Procedure 
15 (±1) 
16–21 
22 (±1) 
23–28 
≤2 days after  
last dose 
(IV or oral) 
Days 52–29 
Physical examination 
X  
X a 
X  
X a 
See Appendix 
5.2 
See Appendix 
5.2. 
Neurological examination b 
X b 
X b 
X b 
X b 
Vital signs c 
X 
X 
X 
X 
Blood or normally sterile tissue/fluid for 
culture, if clinically indicated d 
X 
X 
X 
X 
Radiologic test results e 
 
 
 
 
Administer study drug and/or placebo 
(See Appendix 4) 
X 
X 
X 
X 
Record concomitant medications f 
 
 
 
 
Record adverse events g 
 
 
 
 
Blood for PK testing h 
X 
 
X 
 
 
 
Assess Central Venous Catheters i 
 
 
 
 
 
 


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Abbreviations: EOT = End of Treatment; ESCMID = European Society of Clinical Microbiology and Infectious Diseases; ICF = Informed Consent Form; IDSA = Infectious 
Diseases Society of America; PK = pharmacokinetic. 
a 
A focused physical exam (including a neurological exam) should be performed as clinically indicated by adverse event screening and course of the underlying disease. 
b 
As part of the physical exam, a thorough neurologic exam is to be performed at Screening and at the EOT visit. At all other timepoints, a focused physical exam (including a 
neurological exam) is to be performed as clinically indicated, driven by the subject’s signs and symptoms (see Appendix 1 of Protocol). 
c 
Temperature and the method used [oral, rectal, temporal, tympanic, or core], heart rate, blood pressure, and respiratory rate. Axillary temperatures are allowed, but not 
preferred. 
d 
Cultures from blood or other normally sterile locations only if clinically indicated. Identification and susceptibility testing at the local laboratory for Candida for blood 
or normally sterile tissue/fluid for culture for any positive culture requiring a change of antifungal therapy (i.e., local identification and susceptibility testing is not required 
for Candida isolates cultured from specimens on other study days provided there is no required change of antifungal therapy). All fungal isolates must be sent to the Central 
Laboratory. 
e 
Radiologic test type with findings and interpretation should only be recorded if the test provides evidence of invasive candidiasis or evidence of progression, stabilization, 
improvement, or resolution of invasive candidiasis compared with previous radiographs. 
f 
Record all concomitant medications from Screening through Follow-up (Days 52–59). Systemic antifungal therapy is especially important to document. 
g 
Adverse events are collected from the time the ICF is signed at Screening through Follow-up (Days 52–59). 
h 
Blood will be collected pre-dose (≤30 minutes prior to the start of the infusion). 
i 
Presence of central line during Screening or placed during the study should be documented with dates of insertion and removal. Short-term central venous catheters 
(e.g., peripherally-inserted central catheters, internal jugular, or subclavian central venous catheters) and long-term central venous catheters (e.g., tunneled catheters) 
are recommended to be removed within 48 hours after diagnosis with candidemia, consistent with IDSA and ESCMID guidelines. 
 


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5.4. 
Appendix 4: Dosing Schedule by Day 
Study Day 
Regimen a 
Randomized Treatment 
Rezafungin for Injection 
Caspofungin b with Oral Step-Down Option 
1 
Rezafungin for Injection 400 mg IV 
caspofungin 70 mg IV (loading dose) 
2–3 
placebo for caspofungin IV 
caspofungin 50 mg IV 
≥3 
Optional switch to oral step-down therapy allowed c 
4–7 
 
 
IV only 
placebo for caspofungin IV 
caspofungin 50 mg IV 
oral step-down 
placebo for oral step-down therapy 
oral step-down therapy (fluconazole) 
8 (±1) 
 
 
IV only 
Rezafungin for Injection 200 mg IV 
caspofungin 50 mg IV 
oral step-down 
Rezafungin for Injection 200 mg IV  
 
-and- 
placebo for oral step-down therapy 
placebo for Rezafungin for Injection IV 
 
-and- 
oral step-down therapy (fluconazole) 
9–14 
 
 
IV only 
placebo for caspofungin IV 
caspofungin 50 mg IV 
oral step-down 
placebo for oral step-down therapy 
oral step-down therapy (fluconazole) 
15–28 
Optional treatment period begins. An End of Treatment visit is required within 2 calendar days 
after the last dose of study drug. 
15 (±1) 
 
 
IV only 
Rezafungin for Injection 200 mg IV 
caspofungin 50 mg IV 
oral step-down 
Rezafungin for Injection 200 mg IV  
 
-and- 
placebo for oral step-down therapy 
placebo for Rezafungin for Injection IV 
 
-and- 
oral step-down therapy (fluconazole) 
16–21 
 
 
IV only 
placebo for caspofungin IV 
caspofungin 50 mg IV 
oral step-down 
placebo for oral step-down therapy 
oral step-down therapy (fluconazole) 
22 (±1) 
 
 
IV only 
Rezafungin for Injection 200 mg IV 
caspofungin 50 mg IV 
oral step-down 
Rezafungin for Injection 200 mg IV  
 
-and- 
placebo for oral step-down therapy 
placebo for Rezafungin for Injection IV 
 
-and- 
oral step-down therapy (fluconazole) 
23–28 
 
 
IV only 
placebo for caspofungin IV 
caspofungin 50 mg IV 
oral step-down 
placebo for oral step-down therapy 
oral step-down therapy (fluconazole) 
Abbreviation: CRRT = continuous renal replacement therapy; IV = intravenous(ly). 
a 
IV only regimen means the subject has not been switched to oral step-down therapy by the Investigator. Oral step-down 
regimen means the subject has been switched to oral step-down therapy by the Investigator. 
b 
Refer to dosing section for alternative regimens of caspofungin in subjects meeting hepatic impairment criteria or weight 
category criteria, and/or are receiving certain concomitant medications. 


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c 
Oral step-down therapy is as follows: Subjects weighing over 130 kg will not be eligible for oral step-down therapy. 
Subjects with a creatinine clearance >50 mL/min will receive oral fluconazole at a dose of 6 mg/kg administered once daily 
rounded to the nearest 200 mg increment with a maximum daily dose of 800 mg. Subjects with creatinine clearance 
≤50 mL/min will receive oral fluconazole at a dose of 3 mg/kg administered once daily rounded to the nearest 200 mg 
increment with a maximum daily dose of 400 mg. Subjects receiving hemodialysis receive the same dose as subjects with 
a creatinine clearance >50 mL/min; however, they are only dosed following hemodialysis. Subjects receiving CRRT should 
be treated as a subject with normal renal function at 6 mg/kg rounded to the nearest 200 mg each day (Cousin 2003). 
Subjects receiving peritoneal dialysis should be treated with 1.5 mg/kg rounded to the nearest 200 mg each day 
(Cousin 2003). 
Investigators are advised to pay close attention to signs of overdosing and underdosing with underweight (<50 kg) 
and overweight (>85 kg) subjects, respectively. Additionally, signs of potential fluconazole toxicity, including hepatic 
toxicity and QT prolongation, should be closely monitored for any subject on oral step-down therapy. 


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5.5. 
Appendix 5: Directionality of Worst Laboratory Parameters 
Table 5-1: 
Directionality of Worst Laboratory Parameters  
Laboratory Test 
Parameter 
Worst Value 
Hematology 
Hemoglobin 
Lowest value 
 
Hematocrit 
Lowest value 
 
White blood cell count 
Both highest value and lowest value 
 
Neutrophils  
Both highest value and lowest value 
 
Lymphocytes  
Both highest value and lowest value 
 
Monocytes  
Both highest value and lowest value 
 
Eosinophils 
Highest value 
 
Basophils  
Highest value 
 
Red blood cell count 
Lowest value 
 
Platelets 
Both highest value and lowest value 
Chemistry 
Blood urea nitrogen (BUN) 
Highest value 
 
Bilirubin (total and direct) 
Highest value 
 
Alkaline phosphatase (ALP) 
Highest value 
 
Aspartate aminotransferase (AST/SGOT) 
Highest value 
 
Alanine aminotransferase (ALT/SGPT) 
Highest value 
 
Albumin  
Lowest value 
 
Sodium 
Both highest value and lowest value 
 
Potassium 
Both highest value and lowest value 
 
Chloride  
Both highest value and lowest value 
 
Glucose 
Both highest value and lowest value 
 
Creatinine 
Highest value 
 
Total protein 
Both highest value and lowest value 
 
Calcium 
Both highest value and lowest value 
 
Bicarbonate  
Both highest value and lowest value 
 
Magnesium 
Both highest value and lowest value 
 


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5.6. 
Appendix 6: Clinical Laboratory Toxicity Grading Scales 
Laboratory toxicity grades will be derived based on the available numeric criteria only without taking the clinical components into 
consideration.  
Table 5-2: 
Hematology Toxicity Grading Scale  
Hematology  
Parameter 
Direction 
Grade 0 / 
Normal 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Grade 5 
Hemoglobin 
Decrease 
≥LLN 
<LLN-10.0 g/dL 
<10.0-8.0 g/dL 
<8.0 g/dL 
Life Threatening 
Death 
Leukocytes 
Increase* 
<11,000/m
m3 
11,000-13,000 
/mm3 
>13,000-15,000 
/mm3 
>15,000-30,000 
/mm3 
>30,000  /mm3 
- 
Decrease 
≥LLN 
<LLN-3000/mm3 
<3000-2000/mm3 
<2000-1000/mm3 
<1000/mm3 
- 
Absolute Neutrophil 
Count 
Decrease 
≥LLN 
<LLN to 
1500/mm3 
<1500 to 1000/mm3 
<1000 to 500/mm3 
<500/mm3 
- 
Platelets 
Decrease 
≥LLN 
<LLN to 
75,000/mm3 
<75,000 to 
50,000/mm3 
<50,000 to 
25,000/mm3 
<25,000/mm3 
- 
*DMID 


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Table 5-3: 
Chemistry Toxicity Grading Scale  
Chemistry 
Parameter 
Direction 
Grade 0 / 
Normal 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Grade 5 
Blood urea nitrogen 
(BUN)* 
Elevation 
<1.25 
×ULN 
1.25-2.5 ×ULN 
>2.5-5 ×ULN 
>5-10 
×ULN 
>10 ×ULN 
- 
Bilirubin (total and direct) 
Elevation 
≤ULN 
>ULN – 1.5 x ULN 
>1.5 – 3.0 x 
ULN 
>3.0-10.0 
xULN 
>10.0 x ULN 
- 
Albumin 
Hypoalbuminemia 
≥LLN 
<LLN-3 g/dL 
<3-2 g/dL 
<2 g/dL 
Life-threatening 
consequences ; 
urgent intervention 
indicated 
Death 
Sodium 
Hyponatremia 
≥LLN 
<LLN-130 mmol/L 
- 
<130-120 
mmol/L 
<120 mmol/L 
Death 
Hypernatremia 
≤ULN 
>ULN-150 mmol/L 
>150-155 
mmol/L 
>155-160 
mmol/L 
>160 mmol/L 
Death 
Potassium 
Hypokalemia 
≥LLN 
<LLN – 3.0 mmol/L 
<LLN-3.0 
mmol/L; 
symptomatic; 
intervention 
indicated 
<3.0-2.5 
mmol/L 
<2.5 mmol/L 
Death 
Hyperkalemia 
≤ULN 
>ULN – 5.5 mmol/L 
>5.50-6.0 
mmol/L 
>6.0-7.0 
mmol/L 
>7.0-mmol/L 
Death 
Glucose (non-fasting) 
Hypoglycemia 
≥LLN 
<LLN-55 mg/dL 
<55-40 mg/dL 
<40-30 
mg/dL 
<30 mg/dL; Life 
threatening 
consequences; 
seizures 
Death 
Hyperglycemia** 
 
<116 
mg/dL 
116 -160 mg/dL 
>160-250 mg/dL 
>250-500 
mg/dL 
>500 mg/dL 
Death 
Chloride 
Not Available 
 
 
 
 
 
 
Creatinine 
Elevation 
≤ULN 
>ULN -1.5 ULN 
>1.5-3.0 x 
baseline: >1.5-
3.0 x ULN 
>3.0 
baseline; 
>3.0 – 6.0 
x ULN 
>6.0x ULN 
- 


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Total protein 
Not Available 
 
 
 
 
 
 
Calcium (corrected for 
albumin)*** 
Hypocalcemia 
≥LLN 
<LLN-8.0 mg/dL 
<8.0-7.0 mg/dL 
<7.0-6.0 
mg/dL 
<6.0 mg/dL 
Death 
Hypercalcemia 
≤ULN 
>ULN-11.5 mg/dL 
>11.5-12.5 
mg/dL 
>12.5-13.5 
mg/dL 
>13.5 mg/dL 
Death 
Bicarbonate** 
Low 
≥LLN 
16 mEq-<LLN 
11.0-<16 mEq/L 
8.0-<11 
mEq/L 
<8.0 mEq/L 
 
*DMID 
**DAIDS 
*** Corrected calcium (mg/dL) = Calcium (mg/dL) – 0.8 [albumin(g/dL) -4]  or Corrected calcium (mmol/L) = Calcium (mmol/L) +0.02 [40- albumin(g/L)]   
Table 5-4: 
Enzymes Toxicity Grading Scale  
Enzymes 
Parameter 
Direction 
Grade 0 / 
Normal 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Grade 5 
Alkaline phosphatase 
(ALP) 
Elevation 
≤ULN 
>ULN – 2.5 x 
ULN 
>2.5 – 5.0 ULN 
>5.0 – 20.0 
ULN 
>20.0 ULN 
- 
Aspartate 
aminotransferase 
(AST/SGOT) 
Elevation 
≤ULN 
>ULN – 3.0 x 
ULN 
>3.0 -5.0 ULN 
>5.0 – 20.0 
ULN 
>20.0 ULN 
- 
Alanine aminotransferase 
(ALT/SGPT) 
Elevation 
≤ULN 
>ULN – 3.0 x 
ULN 
>3.0 -5.0 ULN 
>5.0 – 20.0 
ULN 
>20.0 ULN 
- 
 


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5.7. 
Appendix 7: Laboratory Normals 
Lab test 
Lab test code 
SOURCE 
SEX 
LLN 
ULN 
UNIT [ 1] 
Albumin 
ALB 
NLM 
M 
34 
54 
g/L 
Albumin 
ALB 
NLM 
F 
34 
54 
g/L 
Alkaline Phosphatase 
ALP 
NLM 
M 
44 
147 
U/L 
Alkaline Phosphatase 
ALP 
NLM 
F 
44 
147 
U/L 
Alanine Aminotransferase 
ALT 
NLM 
M 
10 
40 
U/L 
Alanine Aminotransferase 
ALT 
NLM 
F 
7 
35 
U/L 
Aspartate Aminotransferase 
AST 
NLM 
M 
10 
34 
U/L 
Aspartate Aminotransferase 
AST 
NLM 
F 
10 
34 
U/L 
Basophils/Leukocytes 
BASOLE 
NLM 
M 
0.5 
1 
% 
Basophils/Leukocytes 
BASOLE 
NLM 
F 
0.5 
1 
% 
Bicarbonate 
BICARB 
NLM 
M 
23 
29 
mmol/L 
Bicarbonate 
BICARB 
NLM 
F 
23 
29 
mmol/L 
Direct Bilirubin 
BILDIR 
NLM 
M 
0 
5.13 
umol/L 
Direct Bilirubin 
BILDIR 
NLM 
F 
0 
5.13 
umol/L 
Bilirubin 
BILI 
NLM 
M 
5.13 
32.49 
umol/L 
Bilirubin 
BILI 
NLM 
F 
5.13 
32.49 
umol/L 
Calcium 
CA 
NLM 
M 
2.125 
2.55 
mmol/L 
Calcium 
CA 
NLM 
F 
2.125 
2.55 
mmol/L 
Chloride 
CL 
NLM 
M 
96 
106 
mmol/L 
Chloride 
CL 
NLM 
F 
96 
106 
mmol/L 
Creatinine 
CREAT 
NLM 
M 
61.88 
114.92 
umol/L 
Creatinine 
CREAT 
NLM 
F 
53.04 
97.24 
umol/L 
Eosinophils/Leukocytes 
EOSLE 
NLM 
M 
1 
4 
% 
Eosinophils/Leukocytes 
EOSLE 
NLM 
F 
1 
4 
% 
Glucose (Random) 
GLUC 
NLM 
M 
 
6.9375 
mmol/L 
Glucose (Random) 
GLUC 
NLM 
F 
 
6.9375 
mmol/L 
Hematocrit 
HCT 
NLM 
M 
0.407 
0.503 
fraction of 1 
Hematocrit 
HCT 
NLM 
F 
0.361 
0.443 
fraction of 1 
Hemoglobin 
HGB 
NLM 
M 
138 
172 
g/L 
Hemoglobin 
HGB 
NLM 
F 
121 
151 
g/L 
Potassium 
K 
NLM 
M 
3.7 
5.2 
mmol/L 
Potassium 
K 
NLM 
F 
3.7 
5.2 
mmol/L 
Lymphocytes/Leukocytes 
LYMLE 
NLM 
M 
20 
40 
% 
Lymphocytes/Leukocytes 
LYMLE 
NLM 
F 
20 
40 
% 
Magnesium 
MG 
NLM 
M 
0.85 
1.10 
mmol/L 
Magnesium 
MG 
NLM 
F 
0.85 
1.10 
mmol/L 
Monocytes/Leukocytes 
MONOLE 
NLM 
M 
2 
8 
% 
Monocytes/Leukocytes 
MONOLE 
NLM 
F 
2 
8 
% 
Neutrophils/Leukocytes 
NEUTLE 
NLM 
M 
40 
60 
% 
Neutrophils/Leukocytes 
NEUTLE 
NLM 
F 
40 
60 
% 
Platelet count 
PLAT 
NLM 
M 
150 
450 
X10(9)/L 
Platelet count 
PLAT 
NLM 
F 
150 
450 
X10(9)/L 
Protein 
PROT 
NLM 
M 
60 
83 
g/L 
Protein 
PROT 
NLM 
F 
60 
83 
g/L 
Erythrocytes 
RBC 
NLM 
M 
4.7 
6.1 
X10(12)/L 


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Erythrocytes 
RBC 
NLM 
F 
4.2 
5.4 
X10(12)/L 
Sodium 
SODIUM 
NLM 
M 
135 
145 
mmol/L 
Sodium 
SODIUM 
NLM 
F 
135 
145 
mmol/L 
Urea Nitrogen 
UREAN 
NLM 
M 
2.142 
7.14 
mmol/L 
Urea Nitrogen 
UREAN 
NLM 
F 
2.142 
7.14 
mmol/L 
Leukocytes 
WBC 
NLM 
M 
4.5 
10 
X10(9)/L 
Leukocytes 
WBC 
NLM 
F 
4.5 
10 
X10(9)/L 
[1] SI units 
 


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5.8. 
Appendix 8: Adverse Event and Prior/Concomitant Medication Date 
Imputations 
Adverse Event Start/Stop Date and Death Date Imputation  
Imputation Rules for Partial Dates (D = day, M = month, Y = year) 
Parameter 
Missing 
Additional Conditions 
Imputation 
Start date 
for AEs or  
Death Date 
 
D 
M and Y same as M and Y of first dose of test 
article 
Date of first dose of test article 
M and/or Y not same as date of first dose of test 
article 
First day of month 
D and M 
Y same as Y of first dose of test article 
Date of first dose of test article 
Y prior to Y of first dose of test article but same as 
Y of screening date 
Date of screening date 
D, M, Y 
None - date completely missing 
Date of first dose of test article 
Stop date 
for AEs 
 
D 
M and Y same as M and Y of last dose of test 
article 
Date of last dose of test article 
M and/or Y not same as date of last dose of test 
article 
Use last day of month 
D and M 
Y same as Y of last dose of test article 
Date of last dose of test article 
Y not same as Y of last dose of test article 
Use Dec 31 
D, M, Y 
None - date completely missing 
No imputation, but assume 
ongoing 
Note: In all cases, if an estimated start date is after a complete stop date, use the first day of the stop date month. 
Similarly, if the estimated stop date is before a complete or imputed start date, use the last day of the start day 
month. In all cases, if it cannot be determined if the adverse event occurred prior to or after the first dose of test 
article, the adverse event should be defined as treatment emergent. 


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Prior and Concomitant Medication Start Date Imputation  
Parameter 
Type of 
Medication 
Imputation 
Start date for con meds  
Non- 
Antifungal  
If it cannot be determined whether or not the start date of a 
medication (non-antifungal) is prior to the first dose of treatment, it 
will be assumed that the medication was received prior to the first 
dose of treatment  
Antifungal 
 
Missing start dates for antifungals will be queried for a value. If it 
cannot be determined whether or not the start date of an antifungal 
is prior to the first dose of test article, it will be assumed that the 
medication was received prior to the first dose of treatment unless 
the indication notes that the medication was received after the first 
dose of treatment. 
Stop date for con meds  
Non-
Antifungal 
If it cannot be determined whether or not the stop date of a 
medication (non-antifungal) is after the first dose of treatment, it 
will be assumed that the medication was received after the first dose 
of treatment 
Antifungal 
 
Missing stop dates for antifungals will be queried for a value. If it 
cannot be determined whether or not the stop date of an antifungal 
is after the first dose of treatment, it will be assumed that the 
medication was received after the first dose of treatment unless the 
indication notes that the medication was received prior to the first 
dose of treatment. If it cannot be determined whether the antifungal 
was received prior to any scheduled assessments, the antifungal will 
be assumed to have been received through the FU Visit. 
 
 


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5.9. 
Appendix 9: Document Version History  
DOCUMENT HISTORY 
Document 
Date 
Original SAP (based on Protocol Amendment V3) 
15 March 2019 
SAP V2.0 (based on Protocol Amendment V4) 
04 March 2020 
SAP V3.0 (based on Protocol Amendment V5) 
24 February 2021 
SAP V4.0 (based on Protocol Amendment V5) 
 02 November 2021 
 
Brief Summary of Changes in V2.0 from Original SAP: 
 
mITT2 population was newly defined and planned for EMA primary analysis (global cure) and for 
the secondary and additional efficacy analyses.  
 
Global cure in mITT population was moved to Secondary objective. 
 
Estimand attributes were added. 
 
Details for mycological response derivation for various scenarios were added. 
 
Radiologic response data collection was clarified. 
 
Final diagnosis was added to the list of subgroups. 
 
Sample size section was updated to include mITT2 population. 
 
A rule for adverse event with Death NOS was added. 
 
Visit window rules were updated. 
 
Concomitant medication definition was clarified. 
 
Neurological questionnaires and PK sampling Sections were added. 
 
A table of lab standard normal ranges was added. 
Brief Summary of Changes in V3.0 from V2.0: 
 
mITT2 population was removed from the analysis population, from the sample size section, and from 
the planned analyses based on mITT2. 
 
Population for EMA primary analysis was updated to use mITT. 
 
Details for time to first negative blood culture analysis for various scenarios were added. 


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 
Subsets of subjects based on timing of culture at randomization were defined. 
 
Sequence for the superiority tests was clarified for both ACM and global response analyses. 
 
Analyses related to COVID-19 including subgroup analyses based on pre-, peri-, and post-COVID 
period were added. 
 
Details for the health outcome derivation rules were added. 
 
Normalization rule for WBC differentials in % was updated. 
 
QTcF summary was added. 
Brief Summary of Changes in V4.0 from V3.0: 
 
Geographic region group was updated to include new sites. 
 
Estimated creatinine clearance formula was updated to use the adjusted ideal body weight 
 
Clarification was made on the duration of catheter placement, the baseline fungal pathogen 
summary, and SAE leading to death definition. 
 
Summary of hospitalization at the time of enrollment was added to the analysis of health 
outcome. 
 
AE overall summary and AEs by SOC and PT for higher risk subgroups, related AEs by PT, and 
related AEs leading to treatment interruption or discontinuation were added. 
 
Time to negative blood culture analysis for candidemia only subjects was added. 
 
 


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6. 
CHANGES TO PLANNED ANALYSES 
There are no changes between the protocol-defined statistical analyses and those presented in 
this SAP. 


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7. 
REFERENCES 
Cockcroft DW, Gault MH. Prediction of Creatinine Clearance from Serum Creatinine. Nephron 
1976; 16:31-41. 
Division of Microbiology and Infectious Diseases (DMID) Adult Toxicity Table Draft. 
https://www.niaid.nih.gov/LabsAndResources/resources/DMIDClinRsrch/Documents/dmidadult
tox.pdf. Published November 2007 Accessed August 18, 2016. 
Karvanen J. The Statistical Basis of Laboratory Data Normalization. Drug Information Journal, 
Vol. 37, pp. 101–107, 2003. 
Miettinen O, Nurminen M. Comparative analysis of two rates.  Statistics in Medicine.  
1985;4(2):213-226. 
National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE, Version 
4.0), https://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_5x7.pdf. 
Publish Date: 28 May 2009 Accessed October 26, 2016. 
U.S. Department of Health and Human Services, National Institutes of Health, National Institute 
of Allergy and Infectious Diseases, Division of AIDS. Division of AIDS (DAIDS) Table for 
Grading the Severity of Adult and Pediatric Adverse Events, Version 2.0. 
https://rsc.niaid.nih.gov/sites/default/files/daids-ae-grading-table-v2-nov2014.pdf Published 
November 2014 Accessed October 3, 2016.