Conditions: Candidemia Mycoses Fungal Infection Fungemia Invasive Candidiasis
Keywords: mycoses
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 207
Healthy volunteers: no

Brief summary:
The purpose of this study is to determine if intravenous CD101 is safe and effective in the treatment of candidemia and/or invasive candidiasis when compared to caspofungin (followed by oral fluconazole).

Detailed description:
This Bridging Extension is to determine if intravenous CD101 is safe \[Day 45- 52 for subjects with candidemia only, or Day 52- 59 for subjects with invasive candidiasis with or without candidemia\] and effective \[Day 14 (± 1 day)\] in the treatment of candidemia and/or invasive candidiasis when compared to caspofungin (followed by oral fluconazole).

Arms:
arm 1: Subjects in the CD101 IV treatment group 1 (Part A Only - up to 30 mITT subjects) will receive CD101 IV 400 mg on Day 1 and Day 8, with an optional dose of 400 mg on Day 15 (for all subjects) and an optional dose of 400 mg on Day 22 (only for subjects with IC), if needed.

Daily intravenous placebo infusion when not administered CD101. Daily oral placebo as step down. arm 2: Subjects in the caspofungin group will receive IV caspofungin (a single 70 mg loading dose on Day 1 followed by 50 mg once daily) for ≥3 days up to a maximum of 21 days for subjects with candidemia only and up to a maximum of 28 days for subjects with IC (with or without candidemia).

After ≥3 days of IV therapy, subjects in the caspofungin group can be switched to oral step-down therapy of fluconazole (a loading dose of 800 mg \[4 capsules\] on the first day followed by 400 mg \[2 capsules\]/day thereafter). 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. arm 3: Subjects in the CD101 IV treatment group 2 (Part B Only - up to 30 mITT subjects) will receive CD101 IV 400 mg on Day 1 and Day 8, with an optional dose of 200 mg on Day 15 (for all subjects) and an optional dose of 200 mg on Day 22 (only for subjects with IC), if needed.

Daily intravenous placebo infusion when not administered CD101. Daily oral placebo as step down.

Interventions: intervention 1: CD101 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 document:
Prot_000.pdf: 
Cidara Therapeutics, Inc. 
Protocol CD101.IV.2.03 A6 
Intravenous CD101
Protocol Amendment 6 
Confidential 
Page 1 of 128 
Title 
A Phase 2, Multicenter, Randomized, Double-blind Study of the Safety, 
Tolerability, and Efficacy of Intravenous CD101 vs Intravenous 
Caspofungin Followed by Oral Fluconazole Step-down in the Treatment 
of Subjects with Candidemia and/or Invasive Candidiasis 
Study Drug 
Intravenous CD101 
Original Protocol 
18FEB2016 
Amendment 1 
14MAY2016 
Amendment 1-IT (Italy only) 
02SEP2016 
Amendment 2 
14SEP2016 
Amendment 3 
23FEB2017 
Amendment 4 
05APR2017 
Amendment 5 
04AUG2017 
Amendment 6 
20APR2018 
Sponsor 
Cidara Therapeutics Inc. 
6310 Nancy Ridge Dr., Suite 101, San Diego CA 92121 
Telephone: 001-858.752.6170 
Facsimile: 001-858.408.3509 
Sponsor Medical Monitor 
Name: Taylor Sandison, MD MPH 
Company: Cidara Therapeutics Inc. 
Address: 6310 Nancy Ridge Dr., Suite 101, San Diego CA 92121 
Telephone: 001-858.249.7429 
Mobile: 001-858.249.9459 
Facsimile: 001-858.408.3509 
Sponsor Clinical Project 
Manager 
Name: Karen Mena 
Company: Cidara Therapeutics Inc. 
Address: 6310 Nancy Ridge Drive, Suite 101, San Diego, CA 92121 
Telephone: 001-858.249.7430 
Facsimile: 001-858.408.3509  
European Union Drug 
Regulating Authorities Clinical 
Trials (EudraCT) # 
2015-005599-51 
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 


Cidara Therapeutics, Inc. 
Intravenous CD 10 I 
Protocol: CD101.IV.2.03 
PROTOCOL APPROVAL PAGE 
 
Protocol CDIOI.IV.2.03 A6 
A Phase 2, Multicenter, Randomized, Double-blind Study of the Safety, Tolerability, 
and Efficacy of Intravenous CD101 vs Intravenous Caspofungin Followed By Oral 
Fluconazole Step-down in the Treatment of Subjects with Candidemia and/or 
Invasive Candidiasis 
Signature 
Original Protocol: 18FEB2016 
Amendment 1: 14MAY2016 
Amendment 1-IT (Italy only): 02SEP2016 
Amendment 2: 14SEP2016 
Amendment 3: 23FEB2017 
Amendment 4: 05APR2017 
Amendment 5: 04AUG2017 
Amendment 6: 20APR2018 
Date 
Taylor Sa 
son, MD MPH 
Chief Medical Officer 
Cidara Therapeutics, Inc. 
Protocol Amendment 6 
Con+ntial 
Page 2 of201 


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1.0 
PROTOCOL SYNOPSIS 
Sponsor: Cidara Therapeutics Inc., San Diego CA 
Product Name: Intravenous CD101  
Active Ingredients: CD101 acetate 
Protocol Title: A Phase 2, Multicenter, Randomized, Double-blind Study of the Safety, Tolerability, and 
Efficacy of Intravenous CD101 vs Intravenous Caspofungin Followed By Oral Fluconazole Step-down in the 
Treatment of Subjects with Candidemia and/or Invasive Candidiasis 
Planned Study Centers: Approximately 60 
Phase of Development: 2 
Objectives  
The primary objectives of this study are to: 
• 
Evaluate the safety and tolerability of intravenous CD101 (CD101 IV) in the Safety population 
• 
Evaluate overall success (mycological eradication and resolution of systemic signs attributable to 
candidemia and/or invasive candidiasis [IC]) of CD101 IV in subjects with candidemia and/or IC at Day 
14 (±1 day) in the Microbiological Intent-to-treat (mITT) population 
The secondary objectives of this study are to: 
• 
Evaluate overall success (mycological eradication and resolution of systemic signs attributable to 
candidemia and/or IC) of CD101 IV at Day 5, Day 28 (±2 days; only for subjects with IC), and Follow-up 
(FU, Days 45-52 for subjects with candidemia only or Days 52-59 for subjects with IC, with or without 
candidemia) in the mITT population 
• 
Evaluate mycological success (eradication) of CD101 IV at Day 5, Day 14 (±1 day), Day 28 (±2 days; 
only for subjects with IC), and FU (Days 45-52 for subjects with candidemia only or Days 52-59 for 
subjects with IC, with or without candidemia) in the mITT population 
• 
Evaluate clinical cure as assessed by the Investigator for CD101 IV at Day 14 (±1 day), Day 28 (±2 days; 
only for subjects with IC), and FU (Days 45-52 for subjects with candidemia only or Days 52-59 for 
subjects with IC, with or without candidemia) in the mITT population 
• 
Evaluate the pharmacokinetics (PK) of CD101 IV 
Study Design: This is a Phase 2, multicenter, prospective, randomized, double-blind, study of CD101 IV or IV 
caspofungin followed by oral fluconazole step-down therapy for treatment of subjects with candidemia and/or 
IC. In Part A, subjects will be randomized in a 1:1:1 ratio to receive CD101 IV treatment Group 1, CD101 IV 
treatment Group 2, or IV caspofungin (Figure 1, Figure 2, Figure 3, Table 1). Oral step-down therapy is 
allowed in all 3 treatment groups in Part A; oral placebo in the CD101 IV groups and oral fluconazole in the 
caspofungin group. After approximately 90 subjects have been enrolled in the mITT population in Part A, 
enrollment into Part A of the study will close and Part B will begin. In Part B, subjects will be randomized in a 
2:1 ratio to receive CD101 IV treatment or IV caspofungin (Figure 1, Figure 2, Figure 3, Table 1) until ≥45 
additional subjects and no more than 120 subjects have been enrolled. (Note: Subjects enrolled under 
Amendment 5 and assigned to CD101 IV receive Group 1 treatment and subjects enrolled under Amendment 6 
and assigned to CD101 IV receive Group 2 treatment. Subjects enrolled to Amendment 5 continue study 
participation according to the same amendment regardless of subsequent approval of Amendment 6.) Total 
enrollment will depend on the enrollment rate for the 6- to 8-month period between the end of Part A and the 
staged start of the Phase 3 study, which is the trigger for the rolling close-out of Part B. Oral step-down therapy 
is allowed in both treatment groups in Part B; oral placebo in the CD101 IV group and oral fluconazole in the 
caspofungin group. 
Subjects with candidemia only may be treated with study drug for a maximum of 21 days. Subjects with IC 
(with or without candidemia) may be treated with study drug for a maximum of 28 days.  For this study, 
subjects will be presumed to have IC if there is a positive culture for Candida spp. from a normally sterile site 
other than blood or if there is a positive sponsor-approved rapid in vitro diagnostic (IVD) or blood culture for 
Candida spp. combined with radiographic evidence of IC. 
Subjects in the CD101 IV treatment Group 1 will receive CD101 IV 400 mg on Day 1 and Day 8, with an 
optional dose of 400 mg on Day 15 (for all subjects) and an optional dose of 400 mg on Day 22 (only for 


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subjects with IC), if needed. Subjects in the CD101 IV treatment Group 2 will receive CD101 IV 400 mg on 
Day 1 and 200 mg on Day 8, with an optional dose of 200 mg on Day 15 (for all subjects) and an optional dose 
of 200 mg on Day 22 (only for subjects with IC), if needed. Subjects in the caspofungin group will receive IV 
caspofungin (a single 70 mg loading dose on Day 1 followed by 50 mg once daily) for ≥3 days up to a 
maximum of 21 days for subjects with candidemia only and up to a maximum of 28 days for subjects with IC 
(with or without candidemia). The optional doses of CD101 IV on Day 15 and Day 22 may be administered 
according to the subject’s clinical response and the medical judgment of the Principal Investigator (PI).  
After ≥3 days of IV therapy, subjects in the caspofungin group can be switched to oral step-down therapy of 
fluconazole (a loading dose of 800 mg [4 capsules] on the first day followed by 400 mg [2 capsules]/day 
thereafter) if criteria are met. In order to maintain the blind, subjects in the CD101 IV groups who have 
switched to oral step-down therapy will receive oral placebo (4 capsules on the first day followed by 2 capsules 
/day thereafter) and subjects in the caspofungin treatment group will receive IV placebo on Day 8, and on Days 
15 and 22 if study drug is administered through these timepoints. The total IV plus oral treatment duration will 
be ≥14 days and up to a maximum of 28 days.  
The dose and duration of any prior antifungal treatment taken within 4 weeks from randomization will be 
recorded at Screening. A retinal examination for evidence of a Candida eye infection, including 
endophthalmitis or chorioretinitis, will be performed during Screening or by 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 course of the study. 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 choriorentinitis should remain in the study and all subsequent antifungal drugs, 
interventions, and outcomes for endophthalmitis or chorioretinitis should be recorded. 
The Schedule of Assessments and Procedures is presented in Table 2. Study Day 1 is defined as the first day of 
study drug administration. Subsequent study days are defined by the number of consecutive calendar days 
thereafter. All subjects will be monitored for adverse events (AEs) and serious adverse events (SAEs) 
following signing of the Informed Consent Form at screening and throughout the study until the FU visit (Days 
45-52 for subjects with candidemia only or Days 52-59 for subjects with IC, with or without candidemia) for 
each treatment group. Vital signs (temperature, heart rate, blood pressure, respiratory rate) will be recorded 
daily while receiving IV study drug and at Day 4, Day 5, Day 14 (±1 day), Day 28 (±2 days; only for subjects 
with IC), End-of-Treatment (EOT) (+2 days allowed after last dose of study drug) and FU (Days 45-52 for 
subjects with candidemia only or Days 52-59 for subjects with IC, with or without candidemia). Hematology 
and chemistry laboratory tests will be performed at Screening; Days 2 and 4; Day 8, Day 14 (±1 day), EOT (+2 
days allowed after last dose of study drug), and at the FU visits. Coagulation laboratory tests (prothrombin 
time/international normalized ratio [PT/INR] and either partial thromboplastin time [PTT] or activated partial 
thromboplastin time [aPTT]) will be performed at Screening. Electrocardiograms (ECGs) will be performed at 
Screening (before subject randomization) and EOT (+2 days allowed after the last dose of study drug). 
Mycological diagnosis of candidemia or IC sufficient for inclusion in the study will be established by a positive 
microbiological test for yeast or Candida within 96 hours from time of collection of the sample until 
randomization. Acceptable positive microbiological tests for yeast or Candida include ≥1 blood culture 
positive for yeast or Candida, a Sponsor-approved rapid IVD test positive for Candida spp, or a positive Gram 
stain 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 from randomization, then an 
additional set of blood cultures must be obtained ≤12 hours before randomization. Blood cultures should be 
performed daily (preferred) or every other day until 2 blood cultures drawn ≥12 hours apart are negative 
without an intervening positive culture. Generally, blood cultures should involve 2 separate draws with ≥1 
draw from a peripheral vein without an IV catheter. Two bottles should be filled from each draw site, totaling 4 
bottles for each set of blood cultures. If possible, use 3 aerobic and 1 anaerobic bottle (if available at the site) 
for each blood culture set.  
In Part A only, blood samples will be collected for PK analysis from the OPPOSITE arm of the infusion on 
Day 1 (within 10 minutes before the end of infusion, between 15 minutes and 1 hour after the end of infusion, 
and between 2 hours and 12 hours after the end of infusion), Day 2 (random draw, with safety labs if possible), 
Day 4 (random draw, with safety labs if possible), Day 8 (predose only), and Day 15 (predose only). If therapy 
is stopped on or before Day 14 and there is no Day 15 dose, then the Day 15 PK sample should be drawn with 


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the safety laboratory samples for the Day 14 visit. For the purpose of maintaining the blind, blood samples will 
be collected from all subjects, when possible, in all 3 treatment groups in Part A, but only PK samples from the 
CD101 IV groups will be analyzed (using a validated assay) by an independent, central bioanalytical 
laboratory. In part B, PK samples will not be collected.  
Overall success and mycological eradication will be assessed at Day 5, Day 14 (±1 day), Day 28 (±2 days; only 
for subjects with IC), and FU (Days 45-52 for subjects with candidemia only or Days 52-59 for subjects with 
IC, with or without candidemia). Clinical response will be assessed at Day 14 (±1 day), Day 28 (±2 days; only 
for subjects with IC), and FU (Days 45-52 for subjects with candidemia only or Days 52-59 for subjects with 
IC, with or without candidemia).  
Number of Subjects  
In Part A, subjects will be randomized (1:1:1) until there are approximately 30 subjects in the CD101 IV 
treatment Group 1, 30 subjects in the CD101 IV treatment Group 2, and 30 subjects in the comparator group in 
the mITT population. It is expected that approximately 114 subjects will need to be randomized to achieve 90 
subjects in the mITT population (assuming 80% of randomized subjects will be included in mITT population).  
In Part B, subjects will be randomized (2:1) until there are ≥30 subjects in the CD101 IV treatment groups and 
≥15 subjects in the comparator group (≥45 additional subjects and no more than 120 subjects). Total enrollment 
will depend on the enrollment rate for the 6- to 8-month period between the end of Part A and the staged start 
of the Phase 3 study, which is the trigger for the rolling close-out of Part B.  
Figure 1:  
Study Randomization and Treatment Regimens 
 
 


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Figure 2:  
Study Design Diagram for Subjects with Candidemia Only 
 
Figure 3:  
Study Design Diagram for Subjects with Invasive Candidiasis (with or without 
Candidemia) 
 
 
Applies to CD101 Group 1 (Part A only) and Group 2 (Parts A and B) 
Applies to CD101 Group 1 (Part A only) and Group 2 (Parts A and B) 


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Inclusion Criteria 
Subjects must meet ALL of the following inclusion criteria to be enrolled: 
1. Males or females ≥18 years.  
2. Established mycological diagnosis of candidemia and/or IC from a sample taken ≤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 for yeast or positive culture for Candida spp. from a specimen obtained from a 
normally sterile site 
3. Willing to initiate or continue medical treatment to cure infections, including receipt of antibiotics and 
surgical procedures, if required. Subjects receiving only medications and measures for comfort and not 
cure should not be enrolled. 
4. Female subjects of child-bearing potential <2 years postmenopausal must agree to and comply with using 1 
barrier method (eg, female condom with spermicide) plus 1 other highly effective method of birth control 
(eg, oral contraceptive, implant, injectable, indwelling intrauterine device, vasectomized partner), or sexual 
abstinence while participating in this study. Male subjects must be vasectomized, abstain from sexual 
intercourse, or agree to use barrier contraception (condom with spermicide), and also agree not to donate 
sperm from first dose of CD101 (Day 1) until 90 days following last administration of study drug. 
5. Willing and able to provide written informed consent. If the subject is unable to consent for 
himself/herself, a legally acceptable representative must provide informed consent on their behalf. 
6. Presence of 1 or more systemic signs attributable to candidemia and/or IC (eg, fever, hypothermia, 
hypotension, tachycardia, tachypnea) 
Exclusion Criteria 
Subjects must NOT meet any of the following exclusion criteria to be enrolled: 
1. Any of the following forms of IC: 
a. 
Septic arthritis in a prosthetic joint (septic arthritis in a native joint is allowed) 
b. Osteomyelitis  
c. 
Endocarditis or myocarditis 
d. Meningitis, endophthalmitis, or any central nervous system infection 
2. Neutropenia (absolute neutrophil count ≤500/µL) at Screening or anticipated neutropenia during the study 
3. Alanine aminotransferase or aspartate aminotransferase levels >10-fold the upper limit of normal 
4. Severe hepatic impairment in subjects with a history of chronic cirrhosis (Child-Pugh score >9) 
5. Received systemic treatment with an antifungal agent at approved doses for treatment of candidemia or IC 
for >48 hours (for example, >2 doses of a once daily antifungal agent or >4 doses of a twice daily 
antifungal agent) in the last 96 hours before randomization 
a. 
Exception: Receipt of antifungal therapy to which any Candida spp. isolated at Screening in qualifying 
cultures is not susceptible 
6. Pregnant females  
7. Lactating females who are nursing  
8. Known hypersensitivity to CD101 IV, caspofungin, any echinocandin, or to any of their excipients 
9. Previous participation in this or any previous CD101 study.  
10. 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  
11. The PI considers that the subject should not participate in the study 
12. Presence of an indwelling vascular catheter or device that cannot be removed and is likely to be the source 
of candidemia 


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Test Product, Dose, and Mode of Administration  
Rezafungin for injection is a sterile product of lyophilized powder in a single-use vial for reconstitution with 
sterile water for injection prior to dilution into normal saline infusion bags. 
Subjects randomized to the CD101 IV treatment Group 1 will receive 1 dose of CD101 IV (400 mg) on Day 1 
and Day 8 (Table 1). Subjects in Group 1 who require >14 days of IV therapy will receive an optional third 
dose of CD101 IV (400 mg) on Day 15. Subjects in Group 1 with IC (with or without candidemia) who require 
>21 days of IV therapy will receive an optional fourth dose of CD101 IV (400 mg) on Day 22. Subjects in 
Group 1 will receive IV placebo on other study days in order to maintain the blind. 
Subjects randomized to the CD101 IV treatment Group 2 will receive 1 dose of CD101 IV 400 mg on Day 1 
and 200 mg on Day 8 (Table 1). Subjects in Group 2 who require >14 days of IV therapy will receive an 
optional third dose of CD101 IV (200 mg) on Day 15. Subjects in Group 2 with IC (with or without 
candidemia) who require >21 days of IV therapy will receive an optional fourth dose of CD101 IV (200 mg) 
on Day 22. Subjects in Group 2 will receive IV placebo on other study days in order to maintain the blind. 
Intravenous infusion of CD101 IV is nominally over 60 (±10) minutes, but the time may be increased as 
needed up to 180 (±10) minutes to manage symptoms of infusion reaction consistent with management of 
echinocandin class infusion reactions, whereby decreasing the rate of infusion often alleviates symptoms. 
(Note: infusion must be completed within the 4-hour stability limit, which starts at the time of reconstitution of 
rezafungin for injection lyophilized powder in the single-use vial.) Intravenous study drug is administered 24 
(±2) hours after study drug was administered on the previous day. Dosage adjustments of CD101 IV are not 
allowed. 
Subjects may receive oral step-down therapy after ≥3 days of IV therapy. Step-down therapy in both CD101 IV 
treatment groups will be oral placebo, in order to maintain the blind. Subjects with creatinine clearance >50 
mL/min will receive oral placebo (4 capsules on the first day followed by 2 capsules/day thereafter) in the 
CD101 treatment group. Subjects with creatinine clearance ≤50 mL/min will receive oral placebo (2 capsules 
on the first day followed by 1 capsule /day thereafter) in the CD101 treatment group. Subjects receiving 
hemodialysis will receive oral placebo (4 capsules on the first day followed by 2 capsules after each 
hemodialysis) in the CD101 treatment group. Subjects who have already switched to oral step-down therapy 
will receive both oral placebo and IV CD101 on Day 8, and if required on Day 15 and Day 22 for subjects who 
are administered study drug through these timepoints.  
Comparator 
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) for ≥3 days and up to a maximum of 21 days for subjects with 
candidemia only and up to a maximum of 28 days for subjects with IC (with or without candidemia) (Table 1). 
Intravenous infusion of caspofungin is nominally over 60 (±10) minutes, but the time may be increased as 
needed up to 180 (±10) minutes to manage symptoms of infusion reaction. Intravenous study drug is 
administered 24 (±2) hours after study drug was administered on the previous day. 
Use of concomitant cyclosporine should be limited to subjects for whom potential benefit outweighs potential 
risk of drug-drug interactions with caspofungin. 
Subjects in the caspofungin group with moderate hepatic impairment (Child-Pugh score of 7-9 with a history 
of chronic cirrhosis) will receive a loading dose of caspofungin of 70 mg on Day 1 and 35 mg/day thereafter. 
Subjects in the caspofungin group weighing >80 kg or on concomitant rifampin, nevirapine, efavirenz, 
phenytoin, dexamethasone, or carbamazepine may receive 70 mg caspofungin daily. Dose adjustment due to 
drug-drug interactions may be considered at the Investigator’s discretion.  
Subjects in Part A and Part B may receive oral step-down therapy after ≥3 days of IV therapy. Step-down 
therapy in the caspofungin treatment group will be oral fluconazole. Subjects with creatinine clearance >50 
mL/min will receive oral fluconazole (a loading dose of 800 mg [4 capsules] on the first day followed by 400 
mg [2 capsules]/day thereafter). Subjects in the caspofungin group with renal impairment who are switched to 
oral stepdown therapy may receive reduced doses of fluconazole. For subjects with creatinine clearance ≤50 
mL/min, the loading dose of fluconazole should be 400 mg [2 capsules] and the daily dose of fluconazole 
should be 200 [1 capsule] mg/day. For subjects receiving hemodialysis, the loading dose of fluconazole should 
be 800 mg [4 capsules] followed by 400 mg [2 capsules] of fluconazole after each hemodialysis. 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, and if required on Day 15 and Day 22 for subjects who are administered 
study drug through these timepoints.  


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Oral Step Down Therapy 
An oral step-down therapy is allowed in all treatment groups, provided the following criteria are met:  
• 
Able to take oral medication 
• 
≥3 days of IV study drug 
• 
The Candida species isolated is susceptible to fluconazole.  
• 
The subject’s clinical status is considered stable based on Investigator assessment 
• 
If a blood culture is positive at Screening, 2 post-baseline blood cultures drawn ≥12 hours apart are 
negative for Candida spp. without an intervening positive culture, and the first of the 2 cultures was drawn 
≥48 hours prior to oral study drug initiation 
• 
No evidence of moderate or severe hepatic insufficiency (alanine aminotransferase or aspartate 
aminotransferase >3× the upper limit of normal) 
• 
No history of hypersensitivity or any other contraindications to the use of fluconazole and, in the 
Investigator’s opinion, the subject can tolerate oral fluconazole therapy (refer to current fluconazole 
Prescribing Information)  
Oral step-down therapy will be fluconazole in the caspofungin group and oral placebo in the CD101 treatment 
groups. 
The total IV plus oral treatment duration will be ≥14 days and up to 28 days. 
Table 1:  
Study Treatments 
Study 
Day 
CD101 IV  
Group 1  
Group 2 
Caspofungin Group 
1 
IV CD101 (400 mg) 
IV caspofungin (a single 70 mg loading dose) 
2-3 a 
IV placebo 
IV caspofungin (50 mg/day) 
4-7 
IV placebo if not stepped down 
OR 
oral step-down therapy (placebo) if already 
stepped down 
IV caspofungin (50 mg/day) if not stepped down 
OR 
oral step-down therapy (fluconazole, a loading 
dose of 800 mg [4 capsules] on the first day 
followed by 400 mg [2 capsules]/day thereafter) 
if already stepped down 
8 b 
IV CD101 (400 mg Group 1; 200 mg 
Group 2) if not stepped down  
OR 
IV CD101 (400 mg Group 1; 200 mg 
Group 2) PLUS oral step-down therapy 
(placebo) if already stepped down 
IV caspofungin (50 mg/day) if not stepped down  
OR  
IV placebo PLUS oral step-down therapy 
(fluconazole, a loading dose of 800 mg [4 
capsules] on the first day followed by 400 mg [2 
capsules]/day thereafter) if already stepped down 
9-14 c 
IV placebo if not stepped down 
OR 
oral step-down therapy (placebo) if already 
stepped down 
IV caspofungin (50 mg/day) if not stepped down 
OR 
oral step-down therapy (fluconazole, a loading 
dose of 800 mg [4 capsules] on the first day 
followed by 400 mg [2 capsules]/day thereafter) 
if already stepped down 


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15 b  
(if 
needed) 
IV CD101 (400 mg Group 1; 200 mg 
Group 2) if not stepped down 
OR 
IV CD101 (optional) d (400 mg Group 1; 200 
mg Group 2) PLUS 
oral step-down therapy (placebo) if already 
stepped down 
OR  
No treatment 
IV caspofungin (50 mg/day) if not stepped down 
OR 
IV placebo (optional) d PLUS oral step-down 
therapy (fluconazole, a loading dose of 800 mg [4 
capsules] on the first day followed by 400 mg [2 
capsules]/day thereafter) if already stepped down 
OR  
No treatment 
16-21 e 
(if 
needed) 
IV placebo if not stepped down 
OR 
oral step-down therapy (placebo) if already 
stepped down 
OR  
No treatment 
IV caspofungin (50 mg/day) if not stepped down 
OR 
oral step-down therapy (fluconazole, a loading 
dose of 800 mg [4 capsules] on the first day 
followed by 400 mg [2 capsules]/day thereafter) 
if already stepped down 
OR  
No treatment 
22 b  
(if 
needed, 
only for 
subjects 
with IC) 
IV CD101 (400 mg Group 1; 200 mg 
Group 2) if not stepped down 
OR 
IV CD101 (optional) f (400 mg Group 1; 200 
mg Group 2) PLUS 
oral step-down therapy (placebo) if already 
stepped down 
OR  
No treatment 
IV caspofungin (50 mg/day) if not stepped down 
OR 
IV placebo (optional) f PLUS oral step-down 
therapy (fluconazole, a loading dose of 800 mg [4 
capsules] on the first day followed by 400 mg [2 
capsules]/day thereafter) if already stepped down 
OR  
No treatment 
23-28 g, h 
(if 
needed, 
only for 
subjects 
with IC) 
IV placebo if not stepped down 
OR 
oral step-down therapy (placebo) if already 
stepped down 
OR  
No treatment 
IV caspofungin (50 mg/day) if not stepped down 
OR 
oral step-down therapy (fluconazole, a loading 
dose of 800 mg [4 capsules] on the first day 
followed by 400 mg [2 capsules]/day thereafter) 
if already stepped down 
OR  
No treatment 
IC = invasive candidiasis; IV= intravenous 
a. 
Subjects must receive IV therapy for ≥3 days before switching to oral step-down therapy 
b. The Day 8, Day 14, Day 15, and Day 22 visits have a window of ±1 day if subject already stepped down to 
oral therapy and discharged from the study site 
c. 
Total IV plus oral treatment duration must be ≥14 days  
d. Subjects who require >14 days of therapy may receive an optional third dose of IV study drug on Day 15, 
if needed.  
e. 
Total IV plus oral treatment duration must be ≤21 days for subjects with candidemia only. 
f. 
Subjects with IC (with or without candidemia) who require >21 days of therapy may receive an optional 
fourth dose of IV study drug on Day 22, if needed 
g. The Day 28 visit has a window of ±2 days if subject already stepped down to oral therapy and discharged 
from the study site 
h. Total IV plus oral treatment duration must be ≤28 days for subjects with IC (with or without candidemia)  


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Protocol CD101.IV.2.03 A6 
Intravenous CD101 
 
 
Protocol Amendment 6 
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Duration of Treatment  
Study participation will require from 45 to 52 days for subjects with candidemia only (or from 52-59 days for 
subjects with IC, with or without candidemia) after the first dose of study drug; study drug administration from 
Day 1 up to Day 21 (for subjects with candidemia) or up to Day 28 (±2 days; only for subjects with IC); safety, 
tolerability, and efficacy assessments up to Day 21 (for subjects with candidemia only) or up to Day 28 (±2 
days; only for subjects with IC); and a FU visit (Days 45 to 52 for subjects with candidemia only or Days 52-
59 days for subjects with IC, with or without candidemia).  
Criteria for Evaluation 
Efficacy 
Efficacy assessments will be recorded on Day 5, Day 14 (±1 day), Day 28 (±2 days; only for subjects with IC), 
and FU (Days 45-52 for subjects with candidemia only or Days 52-59 for subjects with IC, with or without 
candidemia) 
The primary efficacy endpoint is overall success at Day 14 (±1 day), as defined below: 
• 
Mycological eradication defined as:  
o 
If positive blood culture at baseline: 2 negative blood cultures drawn ≥12 hours apart without 
intervening positive blood cultures  
 
OR 
o 
If positive culture from a normally sterile site (other than blood): 
― Documented mycological eradication: most recent culture on or prior to Day 14 (±1 day) from all 
normally sterile sites of baseline Candida infection (if accessible) is negative 
OR 
― Presumed mycological eradication: follow-up culture is not available (eg, normally sterile 
baseline site of Candida infection not accessible) in a subject with a successful clinical outcome 
(ie, did not receive rescue antifungal treatment and has resolution of systemic signs of IC that 
were present at baseline) and resolution or improvement of any baseline radiographic 
abnormalities due to IC 
AND 
• 
Resolution of attributable systemic signs of candidemia and/or IC that were present at baseline  
AND  
• 
No change of antifungal therapy for the treatment of candidemia and/or IC 
AND 
• 
The subject is not lost to follow up on the day of assessment  
 
Secondary efficacy outcome measures include: 
• 
Mycological eradication  
• 
Clinical cure as assessed by the Investigator  
Additional efficacy outcome measures include: 
• 
All-cause 30-day mortality 
• 
Time to first of 2 negative blood cultures drawn ≥12 hours apart, without an intervening positive culture 
 
Safety 
Safety will be assessed from the signing of the Informed Consent Form at Screening to the FU visit through the 
evaluation of AEs, vital signs (temperature, heart rate, blood pressure, and respiratory rate), ECGs, and clinical 
laboratory data (clinical chemistry panels, hematology evaluations, and urinalyses). 


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Protocol CD101.IV.2.03 A6 
Intravenous CD101 
 
 
Protocol Amendment 6 
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Pharmacokinetics (Part A only) 
Blood samples will be obtained from subjects to evaluate the PK of CD101 IV. Blood samples will be collected 
for all 3 treatment groups for the purpose of maintaining the blind, but only PK samples from the CD101 IV 
groups will be analyzed by a central bioanalytical laboratory. When >1 assessment occurs at any time point, the 
PK blood sample will be given priority and taken at the correct protocol-specified time. Plasma samples will be 
analyzed for the concentration of CD101 by a validated liquid chromatography-tandem mass spectrometry 
method. 
Blood for PK analyses will be drawn from the OPPOSITE arm of the infusion at the following times: 
On Day 1 (within 10 minutes [ie, >0 to 10 minutes] before the end of infusion, between 15 minutes and 1 hour 
after the end of infusion, and between 2 hours and 12 hours after the end of infusion), Day 2 (random draw with 
date of sample same as Day 2 date of dose, with safety labs if possible), Day 4 (random draw with date of 
sample same as Day 4 date of dose, with safety labs if possible), Day 8 (predose only), and Day 15 (predose 
only). Day 8 and Day 15 PK draws should be performed within 30 minutes before the second and third dose of 
study drug, regardless of the exact day and time of these infusions. If therapy is stopped on or before Day 14 
and there is no Day 15 dose, then the Day 15 PK sample should be drawn with the safety laboratory samples 
for the Day 14 visit. Ideally, PK samples would be drawn with the safety laboratory samples for that day to 
prevent multiple needle sticks. 
Statistical Methods 
The study is not powered for inferential statistical analysis. A sufficient number of subjects are randomized to 
the CD101 IV and caspofungin groups in Part A to provide an initial, substantive analysis of safety and 
tolerability, and estimate efficacy. In Part A, assuming a 73% overall success rate, the sample size of 30 
subjects in each CD101 IV group will yield a 95% confidence interval (CI) of 53.8% to 87.5%. With the 
addition of Part B subjects and assuming a 73% overall success rate, a total approximate sample size of 60 
subjects in the CD101 treatment group  (consisting of Group 1 from Amendment 5 and Group 2 from 
Amendment 6) will yield a 95% CI of 60.0% to 83.7%, and a total approximate sample size of 110 subjects in 
the CD101 treatment group   (consisting of Group 1 from Amendment 5 and Group 2 from Amendment 6) will 
yield a 95% CI of 63.7% to 81.0%. 
Analysis populations are: 
• 
The Intent-to-treat (ITT) population: all randomized subjects  
• 
The Safety population: all subjects who received any amount of study drug 
• 
The Microbiological Intent-to-treat population (mITT): all subjects who had documented Candida infection 
based on Central Laboratory evaluation of a blood culture obtained within 96 hours of randomization, or 
from a specimen obtained from a normally sterile site, and received ≥1 dose of study drug 
To demonstrate preliminary efficacy and safety of CD101 and to confirm the correct CD101 dose regimen is 
utilized in Part B, an unblinded interim analysis will be performed after approximately 40 to 60 subjects in the 
mITT population have been enrolled and completed study drug therapy. This unblinded interim analysis of a 
few key efficacy and safety outcomes will be performed by an independent unblinded statistician. Interim 
efficacy and safety summary tables will be produced, but the identity of the group assignment for each 
individual subject will remain blinded until the completion of the study and the database for both Parts A and B 
are locked. Once Part A is completed, the database will be locked and a full unblinded analysis with all 
summary tables will be performed on Part A alone. As with the initial interim analysis and to help avoid bias, 
the full Part A analysis will be performed by an independent unblinded statistician, keeping the identity of the 
group assignment for each individual subject blinded until the completion of the study and the database for both 
Parts A and B are locked. (Note: An addendum to the Unblinding Plan for Part A allowed for unblinded safety 
review of adverse events of interest identified during blinded safety review; the addendum allowed for no more 
than 5% of subjects to be unblinded.) 
A Statistical Analysis Plan (SAP) will be prepared and finalized before the interim analysis. Any changes to the 
SAP from the time of the interim analysis to the final database lock of Part B will be documented in an 
addendum to the SAP. Any deviations from the final SAP/addendum will be described and justified in the 
study report. All statistical analyses will be performed using SAS®. All analyses will be completed for Part A. 
Selected analyses will be completed only for Part B and for Part A and B combined. 
The primary efficacy outcome is overall response and is determined programmatically from the mycological 
response and assessment of systemic signs of infection attributable to candidemia and/or IC at Day 14 (±1 day). 


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Intravenous CD101 
 
 
Protocol Amendment 6 
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Page 14 of 128 
 
The number and percentage of subjects with a success, failure, or indeterminate will be presented by treatment 
group. Two-sided 95% CIs for the point estimates of success in the mITT population will be determined. 
Analyses will be completed for Part A, Part B, and combined Part A and B. 
Safety will be evaluated by presenting summaries of AEs, clinical laboratory evaluations (hematology 
evaluation, chemistry panel, urinalysis), vital signs, and ECGs. Safety variables will be tabulated and presented 
for all subjects by study drug. 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 FU visit. The incidence of TEAEs will be presented by 
system organ class and preferred term, by relationship to study drug, by severity, and by whether or not they 
resulted in alteration of administration of or discontinuation of study drug (IV and IV/oral). In addition, the 
incidence of serious TEAEs and TEAEs leading to discontinuation of study drug (IV and IV/oral) will be 
presented by system organ class and preferred term. Descriptive statistics for clinical laboratory test results, 
vital signs, and ECG parameters, including changes from baseline, will be presented by time point. Incidences 
of potentially clinically significant clinical laboratory results, vital signs, and ECG parameters, as defined in the 
SAP, will also be summarized by time point. Analyses will be completed for Part A and for combined Part A 
and B. 
In Part A only, PK parameter assessment will be reported separately for the PK Analysis population and may 
include: maximum plasma concentration (Cmax), time to Cmax, and area under the curve, if applicable.  


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Protocol CD101.IV.2.03 A6 
Intravenous CD101 
 
 
Protocol Amendment 6 
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Table 2: 
Schedule of Assessments and Procedures 
Study Day  
(window) 
Screen 
 
Study Drug Administration, Days 
 
 
 
EOT 
+2 days 
after last 
dose of 
study 
drug (IV 
and oral) 
FU 
Visit 
Days 45-52 
for subjects 
with 
candidemia 
only (or 
Days 52-59 
for IC 
subjects with 
or without 
candidemia) 
1a 
 
2 
 
3 
 
4 
 
 
5 
 
 
6, 7 
 
8b 
(±1) 
9-13 
 
 
14b 
(±1) 
15 b 
(±1) 
16-
21 
 
22b,c  
(±1) 
23- 
27c 
 
 
 
 
 
28b,d 
(±2) 
Informed consent e 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history f 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical examination 
including height and 
weight g 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
 
X 
 
X 
Calculate Child-Pugh 
score h 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Modified APACHE II 
score) with Glasgow 
coma scorei 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital signs j 
X 
X 
X 
X 
X 
X 
Xk 
X 
Xk 
X 
Xk 
Xk 
X 
Xk 
X 
X 
X 
12-lead ECG l  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Radiologic test  
results m 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Blood for hematology 
and chemistry tests n 
 X 
 
X 
 
X 
 
 
X 
 
X 
 
 
 
 
 
X 
X 
Blood for coagulation 
panel 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Protocol CD101.IV.2.03 A6 
Intravenous CD101 
 
 
Protocol Amendment 6 
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Page 16 of 128 
Table 2: 
Schedule of Assessments and Procedures 
Study Day  
(window) 
Screen 
 
Study Drug Administration, Days 
 
 
 
EOT 
+2 days 
after last 
dose of 
study 
drug (IV 
and oral) 
FU 
Visit 
Days 45-52 
for subjects 
with 
candidemia 
only (or 
Days 52-59 
for IC 
subjects with 
or without 
candidemia) 
1a 
 
2 
 
3 
 
4 
 
 
5 
 
 
6, 7 
 
8b 
(±1) 
9-13 
 
 
14b 
(±1) 
15 b 
(±1) 
16-
21 
 
22b,c  
(±1) 
23- 
27c 
 
 
 
 
 
28b,d 
(±2) 
Urine for urinalyses, 
microscopy 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Urine pregnancy test o 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Retinal examination 
for Candida eye 
infectionp 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Study randomization q 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Administer IV CD101 
or IV placebo 
 
Xr 
Xs 
Xs 
Xt 
Xt 
Xt 
Xu 
Xt 
Xt 
Xv 
Xw 
Xx 
Xy 
Xy 
 
 
Administer IV 
caspofungin or IV 
placebo  
 
Xr 
Xs 
Xs 
Xt 
Xt 
Xt 
Xu 
Xt 
Xt 
Xv 
Xw 
Xx 
Xy 
Xy 
 
 
Administer oral 
fluconazole or oral 
placebo step-down 
therapy if switched z 
 
 
 
 
Xt 
Xt 
Xt 
Xu 
Xt 
Xt 
Xv 
Xw 
Xx 
Xy 
Xy 
 
 
Record prior and/or 
concomitant 
medications aa 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 


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Protocol CD101.IV.2.03 A6 
Intravenous CD101 
 
 
Protocol Amendment 6 
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Page 17 of 128 
Table 2: 
Schedule of Assessments and Procedures 
Study Day  
(window) 
Screen 
 
Study Drug Administration, Days 
 
 
 
EOT 
+2 days 
after last 
dose of 
study 
drug (IV 
and oral) 
FU 
Visit 
Days 45-52 
for subjects 
with 
candidemia 
only (or 
Days 52-59 
for IC 
subjects with 
or without 
candidemia) 
1a 
 
2 
 
3 
 
4 
 
 
5 
 
 
6, 7 
 
8b 
(±1) 
9-13 
 
 
14b 
(±1) 
15 b 
(±1) 
16-
21 
 
22b,c  
(±1) 
23- 
27c 
 
 
 
 
 
28b,d 
(±2) 
Record adverse events 
bb 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
Blood or normally 
sterile tissue/fluid for 
culture cc  
Xdd 
Xee 
Xee 
Xee 
Xee 
Xee 
Xee 
Xee 
Xee 
Xee 
Xee 
Xee 
Xee 
Xee 
Xee 
Xee 
Xff 
Rapid In Vitro 
Diagnostic 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Determine overall 
response 
programmatically gg 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
 
X 
 
X 
Assess presence or 
absence of systemic 
signs and symptoms 
attributable to 
candidemia and/or IC 
Xhh 
 
 
 
 
Xii 
 
 
 
X 
 
 
 
 
X 
 
X 
Assess for clinical 
response jj 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
X 
 
X 
Blood for PK testing 
(Part A only) kk 
 
X 
X 
 
X 
 
 
X 
 
 
X 
 
 
 
 
 
 


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Protocol CD101.IV.2.03 A6 
Intravenous CD101 
 
 
Protocol Amendment 6 
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APACHE = Acute Physiology and Chronic Health Evaluation; ECG = electrocardiogram; EOT = End-of-Therapy; ESCMID = European Society Clinical 
Microbiology and Infectious Disease; FU = follow-up; IC = invasive candidiasis; IDSA = Infectious Diseases Society of America; IV = Intravenous; IVD = in 
vitro diagnostic; PK = pharmacokinetic. 
a. 
Study Day 1 is the first day of study drug administration; subsequent study days are consecutive calendar days. 
b. The time windows on Study Day 8, 14, 15, 22, and 28 visits apply only to subjects already stepped down to oral therapy and discharged from the study site. 
c. 
Continue study drug therapy and assessments if further therapy is clinically indicated; only for subjects with IC (with or without candidemia). Subjects will 
be presumed to have IC if there is a positive culture for Candida spp. from a normally sterile site other than blood or if there is a positive sponsor-approved 
rapid IVD or blood culture for Candida spp. combined with radiographic evidence of IC. 
d. The Day 28 visit is only for subjects with IC (with or without candidemia). Note that the Day 28 (±2 days) visit could be the same visit as the EOT visit if 
the subject receives ≥26 days of therapy. 
e. 
Written informed consent must be obtained prior to initiating any study related assessments or procedures. 
f. 
Medical history for the last 5 years and Candida risk factors for the last 3 months (eg, 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 admission and discharge (if applicable). Short-term central venous catheters (eg, peripherally-inserted central catheters, internal jugular or subclavian 
central venous catheters) and long-term central venous catheters (eg, tunneled catheters) are recommended to be removed within 48 hours after diagnosis 
with candidemia, consistent with IDSA and ESCMID guidelines 
g. Physical exams are required at Screening, on Day 14, Day 28 (±2 days; only for subjects with IC), and at the FU visit. Height is recorded at Screening. 
Weight is recorded at Screening, on Day 14, and at the FU visit. If a physical exam is performed at any other visit, abnormal findings that represent a new or 
worsening condition as compared to baseline should be recorded as an adverse event.  
h. Calculate Child-Pugh score only if the subject has a history of chronic cirrhosis 
i. 
APACHE II score can be calculated after enrollment, but should use the vital signs and laboratory results from the Screening visit. 
j. 
If hospitalized, record the range of vital signs; highest and lowest daily temperature and the method used (oral, rectal, temporal, tympanic, or core), highest 
and lowest heart rate, highest and lowest respiratory rate, and highest and lowest blood pressure measured. If not hospitalized, record single measurements 
for daily temperature and the method used (oral, rectal, temporal, tympanic, or core), heart rate, respiratory rate, and blood pressure. 
k. For subjects discharged from the hospital and in the community, vital signs (temperature, heart rate, blood pressure, respiratory rate) are only performed on 
Days 6-28 if the subject is seen for clinical assessment or IV study drug infusion 
l. 
ECG must be conducted before subject randomization. 
m. If radiologic test performed, record radiologic test type with Findings and Interpretation only if radiologic test provides evidence of IC, OR evidence of 
resolution of IC from previous radiographs. 
n. In general, the laboratory values to be entered into the electronic case report form will be from the first laboratory samples drawn each day with routine 
morning laboratory samples. 
o. Perform urine pregnancy test only for women of childbearing potential. Do not perform for women who are ≥2 years postmenopausal or surgically sterile.  
p. Perform a retinal examination for evidence of a Candida eye infection, including endophthalmitis or chorioretinitis, by Day 7 only on subjects with 
candidemia by blood culture, and repeat in subjects who were negative at baseline if the subject develops visual signs or symptoms of a Candida eye 
infection during the course of the study. 
q. Verify that the subject meets all study inclusion and exclusion criteria before randomization. 


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Protocol CD101.IV.2.03 A6 
Intravenous CD101 
 
 
Protocol Amendment 6 
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r. 
On Day 1, subjects will receive IV CD101 or IV caspofungin 
s. 
On Days 2-3, subjects will receive IV caspofungin or IV placebo.  
t. 
On Days 4-7, and 9-14, subjects will receive either IV caspofungin; IV placebo (if in a CD101 group); oral fluconazole (caspofungin group) if already 
switched; or oral placebo (CD101 groups) if already switched. 
u. On Day 8, subjects will receive either IV CD101 (if in a CD101 group and not switched to oral therapy); IV caspofungin (if in caspofungin group and not 
switched to oral therapy), IV CD101 plus oral placebo (if in a CD101 group and already switched to oral therapy); or IV placebo plus oral fluconazole (if in 
caspofungin group and already switched to oral therapy).  
v. On Day 15, subjects may receive either IV CD101 (if in a CD101 group and not switched to oral therapy), if needed; IV caspofungin (if in caspofungin 
group and not switched to oral therapy), if needed; IV CD101 plus oral placebo (if in a CD101 group and already switched to oral therapy), if needed; IV 
placebo plus oral fluconazole (if in caspofungin group and already switched to oral therapy), if needed; or no treatment.  
w. On Days 16-21, subjects may receive either IV caspofungin (if in caspofungin group), if needed; IV placebo (if in a CD101 group), if needed; oral 
fluconazole (caspofungin group) if already switched and needed; oral placebo (CD101 groups) if already switched and needed; or no treatment 
x. On Day 22, subjects with IC (with or without candidemia) may receive either IV CD101 (if in a CD101 group and not switched to oral therapy), if needed; 
IV caspofungin (if in caspofungin group and not switched to oral therapy), if needed; IV CD101 plus oral placebo (if in a CD101 group and already switched 
to oral therapy), if needed; IV placebo plus oral fluconazole (if in caspofungin group and already switched to oral therapy), if needed; or no treatment.  
y. On Days 23-28, subjects may receive either IV caspofungin (if in caspofungin group), if needed; IV placebo (if in a CD101 group), if needed; oral 
fluconazole (caspofungin group) if already switched and needed; oral placebo (CD101 groups) if already switched and needed; or no treatment 
z. 
Oral step-down therapy will be fluconazole (a loading dose of 800 mg [4 capsules ] on the first day followed by 400 mg [2 capsules ]/day thereafter) in the 
caspofungin group and oral placebo (4 capsules on the first day followed by 2 capsules/day thereafter) in the CD101 groups. 
aa. Record all systemic antifungal therapy administered within 4 weeks and all non-antifungal therapy administered within 1 week prior to randomization 
Record concomitant antimicrobial agents, including all antifungal agents at each study visit.  
bb. Adverse events are collected following signing of the Informed Consent Form at Screening through the last study visit (FU) 
cc. Perform identification and susceptibility testing at local laboratory for Candida for any positive blood culture or positive culture from a specimen obtained 
from a normally sterile site at Screening and for any positive culture requiring a change of antifungal therapy (ie, identification and susceptibility testing not 
required for Candida isolates cultured from specimens obtained on other study days without a required change in antifungal therapy). 
dd. Blood for culture must be obtained as part of the standard of care for inclusion in the study. Established mycological diagnosis of candidemia and/or IC 
sufficient for inclusion in the study is defined as ≥1 blood culture positive for yeast or Candida, a Sponsor-approved rapid IVD test positive for Candida spp, 
or a positive Gram stain for yeast or positive culture for Candida spp. from a specimen obtained from a normally sterile site ≤96 hours before randomization. 
Record species and susceptibilities for all bacteria isolated within 1 week prior to randomization from blood or any other normally sterile site. If the positive 
blood culture used to qualify the subject for the study is drawn >12 hours from randomization, then an additional set of blood cultures must be obtained ≤12 
hours before randomization.  
ee. Obtain blood and/or normally sterile tissue/fluid for culture if demonstrating mycological eradication or if clinically indicated. Blood cultures should be 
repeated daily (preferred) or every other day until 2 negative blood cultures are obtained ≥12 hours apart, without an intervening positive culture. All fungal 
isolates cultured from blood and normally sterile tissue/fluid from Screening through the last study visit must be sent to the Central Laboratory. Record the 
species and susceptibilities for any new bacteria isolated from blood or any other normally sterile site.  


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Protocol Amendment 6 
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ff. Obtain blood for culture at FU. If feasible, and if there was a previous culture from a site positive for Candida spp., obtain culture from normally sterile 
tissue/fluid from the same site. All fungal isolates cultured from blood and normally sterile tissue/fluid from Screening through the last study visit must be 
sent to the Central Laboratory. Record the species and susceptibilities for any new bacteria isolated from blood or any other normally sterile site.  
gg. Overall success for subjects with candidemia occurs if 2 blood cultures are negative and ≥12 hours apart without intervening positive blood cultures, there 
was no change of antifungal therapy for the treatment of candidemia, and signs attributable to candidemia at baseline have resolved; blood cultures are 
drawn daily until the subject qualifies as a success. Success for subjects with IC (with or without candidemia) occurs if negative culture from a normally 
sterile site is either documented or presumed, there was no change of antifungal therapy for the treatment of IC, and signs attributable to IC at baseline have 
resolved: documented mycological eradication occurs if most recent culture on or prior to the day of assessment from all normally sterile sites of baseline 
Candida infection (if accessible) is negative; presumed mycological eradication occurs if follow-up culture is not available (eg, normally sterile baseline site 
of Candida infection not accessible) in a subject with a successful clinical outcome (ie, did not receive rescue antifungal treatment and has resolution of 
systemic signs of IC) and resolution or improvement of any baseline radiographic abnormalities due to IC. 
hh. The Screening period for assessing systemic signs for inclusion in the study may include the 4 hours prior to the drawing of the qualifying positive blood 
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. 
ii. On Day 5, assess presence or absence of systemic signs only (ie, not symptoms) and determine which are attributable to candidemia and/or IC 
jj. Principal Investigator to assess if the subject is a cure, indeterminate, or failure based on the criteria in Table 11; there is a specific electronic case report 
form page for completion of this assessment.  
kk. In Part A only, obtain blood for PK sampling from the OPPOSITE arm of the infusion on Day 1 (within 10 minutes [ie, >0 to 10 minutes] before the end of 
infusion, between 15 minutes and 1 hour after the end of infusion, and between 2 hours and 12 hours after the end of infusion), Day 2 (random draw with 
date of sample same as Day 2 date of dose, with safety labs if possible), Day 4 (random draw with date of sample same as Day 4 date of dose, with safety 
labs if possible), Day 8 (predose only), and Day 15 (predose only). Day 8 and Day 15 PK draws should be performed within 30 minutes before the second 
and third dose of study drug, regardless of the exact day and time of these infusions. If therapy is stopped on or before Day 14 and there is no Day 15 dose, 
then the Day 15 PK sample should be drawn with the safety laboratory samples for the Day 14 visit. Ideally, PK samples would be drawn with the safety 
laboratory samples for that day to prevent multiple needle sticks.  
 


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2.0 
TABLE OF CONTENTS 
1.0 
PROTOCOL SYNOPSIS .................................................................................................................. 3 
2.0 
TABLE OF CONTENTS ................................................................................................................ 21 
3.0 
LIST OF ACRONYMS, ABBREVIATIONS AND DEFINITIONS OF TERMS ......................... 25 
4.0 
BACKGROUND AND RATIONALE ........................................................................................... 28 
4.1 
Candidemia and invasive candidiasis ............................................................................... 28 
4.2 
CD101 ............................................................................................................................... 30 
4.3 
Nonclinical Pharmacology and Toxicology ...................................................................... 30 
4.4 
Clinical Experience ........................................................................................................... 33 
4.5 
Clinical Pharmacology ...................................................................................................... 35 
4.5.1 
Single Ascending Dose Pharmacokinetics (CD101.IV.1.01) ............................. 35 
4.5.2 
Multiple Ascending Dose Pharmacokinetics (CD101.IV.1.02) .......................... 36 
4.6 
Summary of Known Benefits and Potential Risks ............................................................ 37 
4.6.1 
Potential Benefits ................................................................................................ 37 
4.6.2 
Known Risks ...................................................................................................... 37 
4.6.3 
Potential Risks .................................................................................................... 38 
4.6.4 
Risk-Benefit Summary ....................................................................................... 38 
4.7 
Justification for Dosing Regimen ..................................................................................... 39 
4.8 
Population to be Studied ................................................................................................... 45 
4.9 
Statement of Compliance .................................................................................................. 45 
4.10 
Justification for Use of CD101 in Candidemia and Invasive Candidiasis ........................ 45 
4.11 
Justification of the Part B Study ....................................................................................... 46 
5.0 
STUDY PURPOSE AND OBJECTIVES ....................................................................................... 47 
6.0 
STUDY DESIGN ............................................................................................................................ 48 
6.1 
Description of the Study ................................................................................................... 48 
6.2 
Number of Subjects .......................................................................................................... 55 
6.3 
Measures Taken to Minimize Bias .................................................................................... 55 
6.4 
Expected Duration of Subject Participation ...................................................................... 55 
6.5 
Method of Treatment Assignment and Blinding ............................................................... 56 
7.0 
SELECTION, DISCONTINUATION, AND WITHDRAWAL OF SUBJECTS ........................... 57 
7.1 
Subject Inclusion Criteria ................................................................................................. 57 
7.1.1 
Rapid In Vitro Diagnostics for Candidemia and Invasive Candidiasis ............... 58 
7.1.2 
Systemic Signs of Candidemia and Invasive Candidiasis .................................. 58 
7.2 
Subject Exclusion Criteria ................................................................................................ 59 
7.3 
Requalification for Entry .................................................................................................. 60 
7.4 
Subject Withdrawal Criteria ............................................................................................. 60 
7.4.1 
Withdrawal from Study Protocol ........................................................................ 60 
7.4.2 
Early Discontinuation from Study Drug Administration .................................... 61 
7.5 
Replacement of Subjects ................................................................................................... 63 
7.6 
Study Termination by Sponsor and Termination Criteria ................................................. 63 
8.0 
STUDY DRUGS ............................................................................................................................. 63 
8.1 
CD101 for Injection .......................................................................................................... 67 
8.1.1 
Directions for Use ............................................................................................... 67 
8.1.2 
Drug Storage ....................................................................................................... 68 
8.2 
Caspofungin ...................................................................................................................... 68 
8.3 
Oral Step-Down Therapy .................................................................................................. 68 


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8.4 
Dose Adjustment ............................................................................................................... 69 
8.4.1 
CD101 IV ........................................................................................................... 69 
8.4.2 
Caspofungin ........................................................................................................ 69 
8.4.3 
Fluconazole ......................................................................................................... 69 
8.5 
Compliance ....................................................................................................................... 69 
8.6 
Breaking the Blind ............................................................................................................ 70 
8.7 
Previous and Concomitant Medications and Substances .................................................. 70 
8.8 
Accountability Procedures ................................................................................................ 71 
8.9 
Study Drug Handling And Disposal ................................................................................. 71 
9.0 
STUDY PROCEDURES................................................................................................................. 71 
9.1 
Screening .......................................................................................................................... 72 
9.2 
Days 1, 2, and 3 ................................................................................................................ 74 
9.3 
Days 4 to 7 ........................................................................................................................ 75 
9.4 
Day 8 (±1 day if already switched to oral step-down therapy and discharged from the 
study site) .......................................................................................................................... 77 
9.5 
Days 9 to 13 ...................................................................................................................... 79 
9.6 
Day 14 (±1 day if already switched to oral step-down therapy and discharged from 
the study site) .................................................................................................................... 80 
9.7 
Day 15 (±1 day if already switched to oral step-down therapy and discharged from 
the study site) .................................................................................................................... 82 
9.8 
Days 16 to 21 .................................................................................................................... 83 
9.9 
Day 22 (±1 day if already switched to oral step-down therapy and discharged from 
the study site) - Only Subjects With Invasive Candidiasis ............................................... 85 
9.10 
Days 23 to 27 - Only Subjects with Invasive Candidiasis ................................................ 86 
9.11 
Day 28 (±2 days if already switched to oral step-down therapy and discharged from 
the study site) - Only Subjects with Invasive Candidiasis ................................................ 88 
9.12 
End of Therapy (+2 days allowed after last dose of study drug) ...................................... 89 
9.13 
Follow-Up Visit (Days 45-52 for Subjects with Candidemia Only or Days 52-59 for 
Subjects with Invasive Candidiasis, With or Without Candidemia) ................................. 91 
10.0 
ASSESSMENT OF SAFETY ......................................................................................................... 92 
10.1 
Safety Parameters ............................................................................................................. 92 
10.2 
Adverse Events ................................................................................................................. 92 
10.3 
Adverse Event Reporting .................................................................................................. 92 
10.4 
Definitions ........................................................................................................................ 93 
10.4.1 
Adverse Event .................................................................................................... 93 
10.4.2 
Suspected Adverse Reaction ............................................................................... 94 
10.4.3 
Life-Threatening Adverse Event or Life-Threatening Suspected Adverse 
Reaction .............................................................................................................. 94 
10.4.4 
Serious Adverse Event or Serious Suspected Adverse Reaction ........................ 94 
10.4.5 
Unexpected Adverse Event or Unexpected Suspected Adverse Reaction .......... 95 
10.5 
Adverse Event Classification ............................................................................................ 95 
10.5.1 
Relationship to Investigational Drug .................................................................. 95 
10.5.2 
Severity ............................................................................................................... 96 
10.5.3 
Serious Adverse Event ........................................................................................ 96 
10.6 
Adverse Event Follow-up ................................................................................................. 97 
10.7 
Adverse Events of Special Interest ................................................................................... 98 
10.7.1 
CD101 IV Intolerability ...................................................................................... 98 
10.7.2 
Phototoxicity ....................................................................................................... 98 
10.7.3 
Neuropathy and Tremors .................................................................................... 98 
10.8 
Toxicity Management ....................................................................................................... 98 
10.9 
Risks for Women of Child-Bearing Potential or During Pregnancy ................................. 98 
10.10 
Risks for Males of ChildBearing Potential ....................................................................... 99 
11.0 
ASSESSMENT OF EFFICACY PARAMETERS .......................................................................... 99 


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12.0 
ASSESSMENT OF PHARMACOKINETIC PARAMETERS (Part A only) ............................... 102 
13.0 
STATISTICAL METHODS ......................................................................................................... 103 
13.1 
Analysis Populations ....................................................................................................... 104 
13.2 
Analysis of Study Population and Subject Characteristics ............................................. 104 
13.3 
Safety Analyses ............................................................................................................... 104 
13.4 
Efficacy Analyses ........................................................................................................... 105 
13.5 
Pharmacokinetic Analyses (Part A only) ........................................................................ 106 
13.6 
Determination of Study Sample Size .............................................................................. 107 
13.7 
Handling of Dropouts and Missing, Unused, and Spurious Data.................................... 107 
13.8 
Termination Criteria........................................................................................................ 107 
13.9 
Deviation Reporting ........................................................................................................ 107 
14.0 
INVESTIGATOR REQUIREMENTS .......................................................................................... 108 
14.1 
Protocol Adherence ......................................................................................................... 108 
14.2 
Electronic Case Report Forms ........................................................................................ 108 
14.3 
Source Document Maintenance ...................................................................................... 108 
14.4 
Study Monitoring Requirements ..................................................................................... 108 
14.5 
Study Completion ........................................................................................................... 108 
15.0 
QUALITY CONTROL AND QUALITY ASSURANCE ............................................................ 109 
16.0 
PROTECTION OF HUMAN SUBJECTS .................................................................................... 110 
16.1 
Informed Consent ........................................................................................................... 110 
16.2 
IRB/IEC Approval .......................................................................................................... 110 
17.0 
DATA HANDLING AND RECORD KEEPING ......................................................................... 110 
17.1 
Direct Access to Source Data/Documentation ................................................................ 111 
17.2 
Study Drug Accountability ............................................................................................. 111 
17.3 
Retention of Records....................................................................................................... 111 
18.0 
FINANCING AND INSURANCE ............................................................................................... 111 
19.0 
PUBLICATION POLICY ............................................................................................................. 111 
20.0 
REFERENCES .............................................................................................................................. 112 
21.0 
APPENDICES .............................................................................................................................. 118 
APPENDIX 1: CLINICAL and LABORATORY STANDARDS INSTITUTE (CLSI) and 
EUROPEAN COMMITTEE on ANTIMICROBIAL SUSCEPTIBILITY TESTING 
(EUCAST) BREAKPOINTS for CANDIDA spp: .......................................................... 118 
APPENDIX 2: Creatinine clearance ............................................................................................. 120 
Appendix 3: Safety Laboratory Tests ............................................................................................ 121 
Appendix 4: Child-Pugh Score ..................................................................................................... 122 
Appendix 5: MODIFIED ACUTE PHYSIOLOGY AND CHRONIC HEALTH  
       EVALUATION (APACHE) II SCORE ................................................................... 123 
Appendix 6: Glasgow Coma Score ............................................................................................... 125 
Appendix 7: Pharmacokinetic Sample Processing and Shipment (Part A only) ........................... 126 
Appendix 8: Investigator Signature ............................................................................................... 128 
 
 
 


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List of Tables 
 
Table 1:  
Study Treatments ..............................................................................................................10 
Table 2: 
Schedule of Assessments and Procedures .........................................................................15 
Table 3: 
Summary of Plasma CD101 Exposures Following Administration of 50, 100, 200,  
 
and 400 mg 1-hour Intravenous Infusion of CD101 .........................................................36 
Table 4: 
Summary of Plasma CD101 Exposures Following Administration of 100 mg  
 
(Day 1/Day8), 200 mg (Day 1/Day8), and 400 mg (Day 1/Day15) Weekly 1-hour  
 
Intravenous Infusion of CD101.........................................................................................37 
Table 5: 
Predicted Pharmacokinetic-Pharmacodynamic Target Attainment for Rezafungin  
 
Regimens, Stratified by Week and Minimal Inhibitory Concentration, against  
 
C. albicans ........................................................................................................................40 
Table 6: 
Predicted Pharmacokinetic-Pharmacodynamic Target Attainment for Rezafungin  
 
Regimens, Stratified by Week and Minimal Inhibitory Concentration, against  
 
C. glabrata ........................................................................................................................42 
Table 7: 
Percent Probabilities of Pharmacokinetic-Pharmacodynamic Target Attainment  
 
by Anidulafungin, Caspofungin, and Micafungin against Candida spp. ..........................44 
Table 6:  
Study Treatments ..............................................................................................................66 
Table 7:  
Guidelines for Assessing Relationship of Event to Study Drug .......................................96 
Table 8: 
Guidelines for Severity Assessments ................................................................................96 
Table 9:  
Mycological Outcome Categories at Day 5, Day 14 (±1 day), Day 28 (±2 days; only  
 
for subjects with invasive candidiasis), and Follow-up Visit ............................................99 
Table 10:  
Overall Response Categories at Day 5, Day 14 (±1 day), Day 28 (±2 days; only  
 
for subjects with invasive candidiasis), and Follow-up Visit ..........................................101 
Table 11: 
Investigator’s Assessment of Clinical Response at Day 14 (±1 day),  
 
Day 28 (±2 days; only for subjects with invasive candidiasis), and Follow-up Visit .....102 
 
List of Figures 
 
Figure 1:  
Study Randomization and Treatment Regimens .......................................................... 5 
Figure 2:  
Study Design Diagram for Subjects with Candidemia Only .............................................. 7 
Figure 3:  
Study Design Diagram for Subjects with Invasive Candidiasis  
 
(with or without Candidemia) ............................................................................................ 7 
Figure 4: 
Predicted Pharmacokinetic-Pharmacodynamic Target Attainment for  
 
Rezafungin Regimens, against C. albicans relative to MIC Distribution .........................41 
Figure 5: 
Predicted Pharmacokinetic-Pharmacodynamic Target Attainment for  
 
Rezafungin Regimens, against C. glabrata relative to MIC Distribution .........................43 
Figure 5: 
Study Randomization and Treatment Regimens ...............................................................48 
Figure 6:  
Study Design Diagram for Subjects with Candidemia Only .............................................53 
Figure 7:  
Study Design Diagram for Subjects with Invasive Candidiasis  
 
(with or without Candidemia) ...........................................................................................54 
 


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3.0 
LIST OF ACRONYMS, ABBREVIATIONS AND DEFINITIONS OF 
TERMS 
AE 
adverse event 
APACHE 
Acute Physiology and Chronic Health Evaluation 
aPTT 
activated partial thromboplastin time 
AUC 
area under the concentration time curve 
AUC0-168 
area under the concentration time curve from time 0 to 168 hours 
AUC0-∞ 
area under the curve from time 0 to infinity 
AUC0-t 
area under the curve from time 0 to the final sample  
BMI 
body mass index 
C144 
plasma concentration at 144 hours post start of infusion 
CD101 for Injection 
product name for the lyophilized form 
CD101 Injection 
product name for the liquid dosage form 
CD101 IV 
Intravenous CD101: CD101 Injection or CD101 for Injection 
CDC 
Centers for Disease Control and Prevention 
CLSI 
Clinical and Laboratory Standards Institute  
Cmax 
maximum plasma concentration 
eCRF 
electronic case report form 
ECG 
electrocardiogram 
EOT 
End-of-Treatment 
ESCMID 
European Society Clinical Microbiology and Infectious Diseases 
EUCAST 
European Committee on Antimicrobial Susceptibility Testing 
fAUC0-168 
free-drug area under the concentration time curve from time 0 to 168 hours 
FDA 
Food and Drug Administration 
FU 
Follow-up 
GCP 
Good Clinical Practice 
GLP 
Good Laboratory Practice 
IC 
invasive candidiasis 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonisation 
IDSA 
Infectious Diseases Society of America 
IEC 
Independent Ethics Committee 
IND 
Investigational New Drug 


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IRB 
Institutional Review Board 
ITT 
Intent-to-Treat 
IV 
intravenous 
IVD 
in vitro diagnostic 
IWRS 
Interactive Web Response System 
K2EDTA 
potassium ethylenediaminetetraacetic acid 
LC-MS/MS 
liquid chromatography- tandem mass spectrometry 
MAD 
multiple-ascending dose 
MALDI 
matrix-assisted laser desorption ionization 
MedDRA 
Medical Dictionary for Regulatory Activities 
MIC 
minimal inhibitory concentration 
MIC90 
minimal inhibitory concentration required to inhibit the growth of 90% of the isolates 
tested 
mITT 
Microbiological Intent-to-Treat 
NDA 
New Drug Application 
NOAEL 
no-observed-adverse-effect level 
OTC 
over the counter 
PD 
pharmacodynamic 
PI 
Principal Investigator 
PK 
Pharmacokinetic(s) 
PT/INR 
prothrombin time/international normalized ratio 
PTT 
partial thromboplastin time 
R 
resistant 
S 
sensitive 
SAD 
single-ascending dose 
SAE 
serious adverse event 
SAER 
serious adverse event report 
SAP 
Statistical Analysis Plan 
SOC 
System Organ Class 
SOP 
standard operating procedure 
t1/2 
terminal half-life 
TEAE 
treatment-emergent adverse event 
Tmax 
time to Cmax 


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UA 
urinalysis 
US 
United States 
Vss 
volume of distribution at steady state 
Vz 
volume of distribution 
WFI 
water for injection 


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4.0 
BACKGROUND AND RATIONALE 
4.1 
CANDIDEMIA AND INVASIVE CANDIDIASIS 
Intravenous CD101 (CD101 IV), a new echinocandin antifungal agent, is being 
developed specifically to treat patients with systemic infections caused by Candida. 
These serious and life-threatening infections represent a significant public health issue, 
particularly in highly vulnerable patient populations such as the elderly, postsurgical, 
critically ill, and other hospitalized patients with serious medical conditions (Magill et al., 
2014; Andes et al., 2012; Wisplinghoff et al., 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 et al., 2013; 
Arendrup et al., 2013; Ostrosky-Zeichner 2013; Pfaller, 2012). The Centers for Disease 
Control and Prevention (CDC) recently warned that fluconazole-resistant Candida 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). 
Candidemia and other forms of invasive candidiasis (IC) (eg, disseminated candidiasis, 
peritonitis, intra-abdominal abscess, hepatic candidiasis, endocarditis, and meningitis) are 
considered to be among the most critical invasive fungal infections in the United States 
(US) in terms of incidence and impact (Brown et al., 2012; Pfaller and Diekema, 2010; 
Arendrup et al. 2013; Azie et al., 2012; Menzin et al., 2009; Vincent et al., 2009). In a 
recent analysis of a large US patient database, Candida infections accounted for 40% of 
all invasive fungal infections and were associated with the highest excess length of stay, 
excess cost, and attributable mortality (Menzin et al., 2009). In fact, the mortality rate in 
patients with candidemia has been reported to be >40%, which is higher than that for 
some populations with invasive aspergillosis (Andes, et al. 2012; Wisplinghoff et al., 
2004; Mikulska et al., 2012; Falagas et al., 2006; Labelle et al., 2008; Pfaller and 
Diekema, 2010; Slavin et al., 2010; Mylonakis et al., 2015; Pfaller and Diekema, 2007).  
The US National Center for Health Statistics reported that the incidence of Candida 
infection is 8/100,000 population per year, but estimates range up to 26/100,000 in 
certain regions of the US, and the incidence continues to increase (Brown et al., 2012; 
Pfaller and Diekema, 2010; Menzin et al., 2009; Vincent et al., 2009; Cleveland et al., 
2012; Zilberberg et al., 2008a; Zilberberg et al., 2008b). In 2004, Candida was the fourth 
leading cause of healthcare-associated bloodstream infections overall (Wisplinghoff et 
al., 2004). In 2008, the National Healthcare Safety Network reported that Candida was 
the third most common cause of central line–associated bloodstream infections in US 
intensive care units (Hidron et al., 2008). However, the most recent survey reported that 
Candida was now the most common cause of hospital-acquired bloodstream infections in 
the US (Magill et al., 2014). Even more disturbing is that some of the highest rates of 
Candida infection have been observed among elderly hospitalized patients (Zaoutis et al., 
2005; Zilberberg et al., 2008b).  


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More than 50% of all Candida infections are caused by non-albicans Candida species, 
including Candida glabrata, which is the most common non-albicans Candida species in 
North America and Europe. The incidence of infections caused by C. glabrata in the US 
has increased by >4 fold over the past 20 years (Cleveland et al., 2012). In the US-based 
SENTRY Antifungal Surveillance Program, the frequency of C. glabrata as a cause of 
bloodstream infections recently increased from 18% in 2008/2009 to 25% in 2010/2011 
(Pfaller et al., 2014). Azole-resistant C. glabrata has recently been identified as a serious 
threat to public health (The White House, 2014; Executive Office of the President, 2014; 
CDC, 2013). In the US-based SENTRY Antifungal Surveillance Program, the rate of 
azole-resistant C. glabrata has recently increased from 9% in the 1992-2001 time period 
to 14% in the 2001-2007 time period (Pfaller et al., 2014; 2013; 2012; 2010a, 2010b, 
2009), but it has been reported to be as high as 30% in some centers (Alexander et al., 
2013).  
The increasing incidence of non-albicans Candida and the greater efficacy of 
echinocandins compared to azoles in Candida infections provided support for the 
recommendation in Infectious Diseases Society of America (IDSA) and European 
Society Clinical Microbiology and Infectious Diseases (ESCMID) guidelines that an 
echinocandin be used for initial treatment of candidemia (Pappas et al., 2016; Ullmann et 
al., 2012; Cornely et al., 2012). These guidelines allow for a subsequent “step-down” to 
an azole for treatment, if the Candida species has been identified and has been 
demonstrated to be susceptible to the azole. However, not all US hospitals are currently 
able to perform antifungal susceptibility testing, making it difficult for many hospitals to 
follow this recommendation. In the context of increasing rates of azole-resistant C. 
glabrata, the current treatment regimen would be ≥2 weeks of a daily echinocandin.  
Moreover, because of its haploid genome, C. glabrata has the potential to more rapidly 
develop resistance to antifungal agents than other Candida spp. in multiple drug classes, 
including echinocandins (Ostrosky-Zeichner, 2013; Pfaller et al., 2012, 2008). 
Echinocandins inhibit the 1,3-β-D-glucan synthase (encoded by FKS1, FKS2, and FKS3 
genes), which synthesizes a major component of the fungal cell wall. Mutations in “hot 
spot” regions of FKS1 and/or FKS2 are associated with elevated echinocandin minimal 
inhibitory concentration (MIC) values, reduced glucan synthase enzyme sensitivity, and 
unfavorable outcomes in animal models (Beyda et al., 2014; Alexander et al., 2013). FKS 
mutations have been identified in 8% to 32% of patients with C. glabrata candidemia, 
particularly in patients with prior echinocandin exposure. FKS mutations have been 
associated with higher clinical failure rates compared to non-FKS mutants (60% vs 23%) 
(Beyda et al., 2014; Shields et al., 2013). In fact, in a recently reported case series, the 
clinical failure rate among patients with echinocandin-resistant C. glabrata was reported 
to be 91% (Shields et al., 2013).  
The emergence of multidrug resistance in C. glabrata can be considered a major public 
health issue because neither the azoles nor the currently available echinocandins would 
be appropriate for treatment, and high dose amphotericin is the only alternative and is 
associated with renal toxicity, particularly in older, critically-ill patients with sepsis 
(Alexander and Wingard, 2005; Chapeland-Leclerc et al., 2010; Krogh-Madsen et al., 
2006; Pappas et al., 2016).  


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4.2 
CD101  
CD101 is a semi-synthetic echinocandin that inhibits the synthesis of 1,3-β-D-glucan, an 
essential component of the fungal cell wall of yeast forms of Candida species and regions 
of active cell growth of Aspergillus hyphae. The synthesis of 1,3-β-D-glucan is dependent 
upon the activity of 1,3-β-D-glucan synthase, an enzyme complex in which the catalytic 
subunit is encoded by FKS1, FKS2, and FKS3 genes. Inhibition of this enzyme results in 
rapid, concentration-dependent, fungicidal activity for Candida spp.  
CD101 is a broad-spectrum antifungal agent with excellent activity against wild-type and 
azole- and echinocandin-resistant strains of Candida spp. (Castanheira et al., 2014). 
CD101 demonstrated potent activity against representative strains of numerous fungal 
species, including Candida spp., Aspergillus spp., Trichophyton mentagrophytes, 
Trichophyton rubrum, and Microsporum gypseum, similar to that of anidulafungin. Poor 
activity was observed for single strains of Cryptococcus neoformans and Rhizopus 
oryzae, characteristic of echinocandins. When tested against multiple clinical isolates of 
wild-type and echinocandin-resistant and/or –azole resistant Candida spp., CD101 
activity was similar to that of anidulafungin versus all strains tested with MIC required to 
inhibit the growth of 90% of the isolates tested (MIC90) values ≤1 µg/mL for all species 
except Candida parapsilosis, which was 2 µg/mL. The potency of CD101 against strains 
with documented fks mutations was 2- to 8-fold greater than that of caspofungin and 
similar to that of anidulafungin. 
4.3 
NONCLINICAL PHARMACOLOGY AND TOXICOLOGY 
CD101 was found to be stable in liver microsomes from all species tested. A cross-
species stability study also determined that CD101 is stable in intestinal microsomes 
and no metabolic products were identified during incubations of CD101 with mouse, 
rat, monkey, or human liver microsomes, indicating a lack of biotransformation. In 
vivo, metabolite profiling of rat plasma and excreta samples is consistent with in vitro 
results confirming the lack of biotransformation.  
The pharmacokinetic (PK) profile of CD101 was investigated in mice, rats, dogs, 
cynomolgus monkeys, and chimpanzees following IV delivery, the intended clinical 
route of administration, and also after intraperitoneal administration to mice, 
intramuscular to rats, subcutaneous to rats and cynomolgus monkeys, and orally to 
dogs, monkeys, and chimpanzees. CD101 consistently exhibited very low clearance, 
modest volume of distribution (Vz) or volume of distribution at steady state (Vss), 
and long half-life (t1/2). Across all species tested, CD101 exhibited a favorable PK 
profile, mainly attributable to lower clearance (resulting in a longer t1/2). Additionally, 
there was low to no drug accumulation or gender differences found with CD101 
across all species tested after multiple doses and routes of administration.  


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Tissue distribution of CD101 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, CD101 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 David Perlin and colleagues from Rutgers (Zhao, 2017). 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 IC. 
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 timepoints 
from 1 to 48 hours, Perlin and colleagues noted that CD101 tissue levels begin to decline 
after reaching the maximum plasma concentration (Cmax) at 6 hours postdose, but 
increase and concentrate within fungal lesions at later timepoints (24 and 48 hours).  
CD101 has been evaluated in a full battery of Investigational New Drug (IND)-enabling 
toxicology studies up to 4 weeks in duration in rats and cynomolgus monkeys, and in 
bacterial and mammalian cell in vitro genetic toxicology studies. The pivotal nonclinical 
safety studies were conducted according to Good Laboratory Practices (GLP) guidances. 
CD101was evaluated in single dose and exploratory IV studies, in 2-week IV pilot 
toxicity studies, and in 4-week IV GLP toxicity studies. In addition, 3 Screening and 
investigative studies were conducted: one study compared the toxicity of CD101 to the 
marketed echinocandin, anidulafungin, with focus on assessing hepatotoxicity; a second 
study investigated different modes of IV tail vein administration in rats; and the third 
study measured plasma levels of histamine in rats. 
The main toxicology finding was a rat-specific histamine-release response that occurred 
primarily after the first dose. This histamine response was not seen in cynomolgus 
monkeys at Cmax levels that exceeded those where these effects were seen in rats. 
Echinocandins as a class are known to cause histamine release during infusions in rats, 
but not during infusions in monkeys when assessed during toxicity testing (Eraxis 
[anidulafungin] New Drug Application [NDA], Cancidas [caspofungin acetate] NDA). 
Rats appear to be much more sensitive to histamine-release responses of echinocandins 
versus primates, including humans where histamine-mediated infusion reactions appear 
to be uncommon (Eraxis [anidulafungin] Prescribing Information, 2013; Mycamine 
[micafungin sodium] Prescribing Information, 2013; Cancidas [caspofungin acetate] 
Prescribing Information, 2014). 
Hematological signs suggestive of red blood cell regeneration occurred in rats primarily 
at the high dose, were not considered adverse, and were not seen in monkeys.  
Local vascular injury was observed in rats, but adverse effects were confined to high dose 
males during the 4-week toxicity study; the no-observed-adverse-effect level (NOAEL) 
concentration for local injury is 6 mg/mL.  


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The safety margins appear to be large in rats and monkeys administered CD101 for up to 
4 weeks. The NOAEL for human relevant toxicities is 45 mg/kg in rats and 30 mg/kg in 
monkeys. These doses generate AUC plasma exposures 20-fold (rat) and 28-fold 
(monkey) over the efficacious plasma exposure determined in the neutropenic mouse 
systemic candidiasis model.  
No adverse CD101-related target organ toxicity was observed in either rats or monkeys 
over the 4-week dosing period.  
A CD101-related microscopic finding was seen in macrophages located in the lung of 
rats at ≥15 mg/kg that was characterized as a minimal alveolar histiocytosis. This change 
was not considered adverse since it was minimal, not associated with tissue injury, and 
reversible. This change was not observed in monkeys. 
Of importance is the lack of microscopic evidence for target organ toxicity previously 
identified in animals with marketed echinocandins dosed over a 4- or 5-week period 
(Eraxis [anidulafungin] NDA, Cancidas [caspofungin acetate] NDA, Mycamine 
[micafungin sodium] NDA). Target organs have included hepatotoxicity (anidulafungin, 
caspofungin and micafungin), renal toxicity (anidulafungin and micafungin), and skeletal 
muscle changes (anidulafungin). In addition, no CD101-related histopathological changes 
were seen in the spleen and bone marrow, whereas regenerative changes in these organs 
have been reported for anidulafungin and micafungin 
CD101 was negative for mutagenicity (bacteria) and clastogenicity (mammalian cells) 
during in vitro genetic toxicology studies and negative for clastogenicity in the in vivo 
bone marrow micronucleus assay in rats at doses up to 45 mg/kg IV. 
The results from the female fertility study in rats indicate no effects on reproductive 
performance and intrauterine survival up to the highest dose tested (45 mg/kg). Embryo-
fetal development studies in female rats (up to 45 mg/kg) and rabbits (up to 35 mg/kg) 
have been conducted and demonstrated no effects on fetal growth, survival, or fetal 
morphology. 
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, which is approximately 2-5 
fold over steady state following IV 200 mg weekly preceded by an IV loading dose of 
400 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. 


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In a 3-month study in monkeys, during the sixth week of dosing, unexpected intention 
tremors were observed. Throughout the 3-month dosing period, dose-related incidence of 
sporadic slight to moderate tremors/intention tremors were seen at ≥ 30 mg/kg (30 mg/kg 
is 11-fold versus the Group 2 dose regimen). Tremors were typically seen during dosing 
days at or around the time of infusion and intention tremors were observed periodically 
on both dosing and nondosing days. The incidence of tremors and intention tremors 
reversed for most animals, but intention tremors were seen in one male at the high dose 
(60 mg/kg) near the end of the recovery period. Due to the observed neurobehavioral 
effects, a detailed neuropathology assessment was performed which identified 
axonal/nerve fiber degeneration of peripheral nerves and sensory ganglia, along with 
prominent Schwann cell hyperplasia/hypertrophy primarily within the sensory ganglia, at 
≥ 30 mg/kg. Schwann cell changes reversed, but axonal/nerve fiber degeneration was still 
present at the end of the 4-week recovery period. No other test article-related microscopic 
changes were observed, including no test article-related effects in neurons of the sensory 
ganglia and in structures within the spinal cord or brain, including cerebellum. Although 
slight increases in serum calcium were observed at ≥ 30 mg/kg, an extensive evaluation 
of calcium homeostasis (i.e., ionized calcium, calcitonin, parathyroid hormone) failed to 
associate the minor increase in serum calcium to the observed neuropathological changes. 
Given the prominent Schwann hyperplasia/hypertrophy, it is not clear whether the 
axonal/nerve fiber degenerative changes are primary or secondary to an effect on the 
Schwann cells. The NOAEL level for neuropathology in monkeys is 10 mg/kg, which is 
approximately 4-fold over the estimated steady state plasma level in humans at 200 mg. 
Results from a phototoxicity study in rats indicate evidence of phototoxicity at elevated 
CD101 exposures. Relative to the repeat-dose human plasma Cmax level at 400 mg, the 
NOAEL for phototoxicity was 1.7-fold higher and the lowest-observed-adverse-effect 
level, where minimal changes were seen, was 3.6-fold higher. Review of the human 
safety data for CD101 and the medical literature for echinocandins indicate no evidence 
of phototoxicity. Results of a Phase 1 phototoxicity study in healthy human volunteers to 
elucidate the true risk of phototoxicity in subjects are pending. 
 
Additional nonclinical data is available in the Investigator Brochure. 
4.4 
CLINICAL EXPERIENCE 
CD101 Injection was safe and well tolerated as a single dose up to 400 mg and multiple 
doses up to 400 mg. The overall safety, tolerability, and PK profile of CD101 support 
continued development as a once-weekly therapy for invasive fungal infections. 
A Phase 1, single-center, randomized, double-blind, single-ascending dose (SAD) study 
of CD101 administered by IV injection to healthy adult subjects (CD101.IV.1.01) has 
completed. The primary objective was to determine the safety, tolerability, and PK 
profile of CD101. In this study, subjects in 4 cohorts of 8 subjects (6 active, 2 placebo) 
each were randomized to receive single IV doses of CD101 Injection or placebo (normal 
saline) infused over 60 (±10) minutes. Dose levels of CD101 assessed follow an 
ascending single-dose regimen (50, 100, 200, or 400 mg).  


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A total of 32 subjects were randomized with 31 subjects completing all study 
assessments. One subject prematurely withdrew for personal reasons unrelated to safety 
or tolerability. Subjects were primarily White (97%), Hispanic (94%), and males and 
females were approximately equally represented (53% and 47%, respectively). There 
were no serious adverse events (SAEs), severe adverse events (AEs), or dose-response 
relationships for overall AEs. The majority of AEs were mild, and all AEs completely 
resolved by the end of the study. There were no drug-related AEs resulting from 
clinically significant hematology or clinical chemistry laboratory abnormalities at any 
dose. In addition, there were no safety issues related to electrocardiograms (ECGs), vital 
signs, or physical exam findings.  
A Phase 1, single-center, randomized, double-blind, multiple-ascending dose (MAD) 
study of CD101 administered by IV injection to healthy adult subjects (CD101.IV.1.02) 
has completed. The primary objective was to determine the safety, tolerability, and PK 
profile of CD101 when administered IV as multiple doses to healthy adult subjects. In 
this study, subjects in 3 cohorts of 8 subjects (6 active, 2 placebo) each were randomized 
to receive multiple IV doses of CD101 Injection or placebo (normal saline) infused over 
60 (±10) minutes. Dose levels of CD101 assessed follow an ascending multiple-dose 
regimen (100 mg ×2 doses, 200 mg ×2 doses, or 400 mg ×3 doses).  
A total of 24 subjects were randomized and all subjects completed the study. Subjects 
were primarily White (88%), Hispanic or Latino (88%), and had a mean body mass index 
(BMI) of 27.208 kg/m2 and a mean age of 42.8 years. Males and females were equally 
represented (50% each). There were no SAEs or severe AEs. The majority of AEs were 
mild, and all related AEs completely resolved by the end of the study. Four subjects in 
the CD101 group experienced mild, transient infusion reactions, characterized by 
flushing, sensation of warmth, nausea, and chest tightness. These infusion reactions were 
associated primarily with the 400 mg dose cohort and were most common with the third 
dose. These reactions occurred within minutes of infusion initiation and disappeared 
within minutes without interruption or discontinuation of the study drug infusion. There 
were no drug-related AEs resulting from clinically significant hematology or clinical 
chemistry laboratory abnormalities at any dose. In addition, there were no safety issues 
related to ECGs, vital signs, or physical exam findings. 
The safety and efficacy of rezafungin for injection is being evaluated in this Phase 2, 
multicenter, prospective, randomized, double-blind, comparator study (IV caspofungin 
with option for oral fluconazole step-down therapy) for the treatment of subjects with 
candidemia and/or invasive candidiasis. Subjects were randomly assigned to receive 1 of 
2 rezafungin for injection once weekly regimens or a daily IV caspofungin regimen with 
the option for oral fluconazole step-down therapy. Two rezafungin for injection dosing 
regimens were evaluated as follows: Group 1 was administered 400 mg ×2 weekly doses 
with a third optional weekly dose of 400 mg for all subjects and a fourth optional weekly 
dose 400 mg dose for subjects with invasive candidiasis; Group 1 was administered 


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400 mg ×1 weekly dose followed by 200 mg ×1 weekly dose with a third optional weekly 
dose of 200 mg for all subjects and a fourth optional weekly dose of 200 mg for subjects 
with invasive candidiasis. The reference therapy caspofungin regimen was as follows: 
70 mg ×1 day and 50 mg/day for 13 days with additional optional dosing 50 mg/day up to 
21 days for all subjects and additional optional dosing 50 mg/day up to 28 days for 
patients with invasive candidiasis. 
In Part A of this Phase 2 study, there were 107 subjects enrolled; 56.1% were male, most 
subjects were White (83%) with other identified races of Black or African American 
(11.2%) and Asian (3.7%). Ethnicity was primarily Not Hispanic/Latino (87.9%). Mean 
age was approximately 52 years. Diagnosis at study entry was 89.7% candidemia and 
10.3% 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. There are no notable imbalances in TEAEs across the study 
groups. Most adverse events were mild or moderate in severity. There were no notable 
imbalances in SAEs across the treatment groups and SAEs observed were not unexpected 
for the patient population. AEs of interest included those potentially representative of 
photosensitivity (results of Phase 1 photosensitivity study is pending) and neuropathy. 
One subject in a rezafungin for injection group had an AE of sunburn (Group 1) 
following substantial sun exposure. AEs in the rezafungin for injection groups potentially 
representing neuropathy were intensive care unit acquired weakness (Group 2, 1 subject, 
moderate severity), and tremor (Group 2, 1 subject, mild). An AE of intensive care unit 
acquired weakness also occurred in 1 subject receiving caspofungin (severe) and an AE 
of polyneuropathy (severe) occurred in 1 subject receiving caspofungin. These AEs of 
interest potentially representing study drug-related tremor/ataxia/neuropathy were 
followed until resolution; all resolved. The Investigator Brochure should be referenced 
for additional information. 
4.5 
CLINICAL PHARMACOLOGY 
The PK of CD101 has been well-characterized in healthy subjects for doses up to 400 mg 
for 3 weeks in the 2 Phase 1 studies: CD101.IV.1.01 (SAD study) and CD101.IV.1.02 
(MAD study). 
4.5.1 
Single Ascending Dose Pharmacokinetics (CD101.IV.1.01)  
Pharmacokinetics was determined by analyzing plasma and urine samples for 
concentration of CD101 obtained from subjects who received CD101 Injection in each 
cohort at various time points after administration of the single dose of the study drug. 
The plasma PK of CD101 was generally well-characterized following the 50, 100, 200, 
and 400 mg CD101 doses. Exposure to CD101 increased with increasing CD101 doses 
(Table 3). Time to reach Cmax (ie, Tmax) was observed at the end of infusion, as expected, 
at approximately 1 hour after the start of infusion for all doses. Elimination of CD101 
appears multiphasic. AUC and Cmax increased in a dose proportional manner and total 
body clearance was similar throughout the dose levels with t1/2 values of >80 hours 


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through the first week of plasma collection (a longer terminal t1/2 of 127-146 hours is 
calculated when incorporating data from later collection times). Total body clearance was 
approximately 4 mL/min across the CD101 doses, indicating linear kinetics for CD101 
across the doses investigated. Volume of distribution (Vz and 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 CD101 excretion. 
Table 3: 
Summary of Plasma CD101 Exposures Following Administration of 
50, 100, 200, and 400 mg 1-hour Intravenous Infusion of CD101 
Dose 
(mg) 
Cmax 
(µg/mL) 
C144 
(µg/mL) 
AUC0-168 
(µg⋅h/mL) 
t1/2 
(hours) 
50 
2.76 
0.481 
145 
86 
100 
4.84 
0.854 
254 
92 
200 
10.9 
2.01 
592 
91 
400 
22.7 
3.83 
1160 
84 
AUC0-168 = area under the curve from time 0 to 168 hours; C144 = plasma 
concentration at 144 hours post start of infusion; Cmax = maximum plasma 
concentration; t1/2 = half-life. 
4.5.2 
Multiple Ascending Dose Pharmacokinetics (CD101.IV.1.02)  
Pharmacokinetics was determined by analyzing plasma and urine samples for 
concentration of CD101 obtained from subjects who received CD101 Injection in each 
cohort at various time points after administration of study drug. 
The plasma PK of CD101 was also well characterized following 2 or 3 weekly doses of 
CD101: 100 mg (Day 1/ Day 8), 200 mg (Day 1/ Day 8), and 400 mg (Day 1/ Day 8/ Day 
15). Exposures following the first dose were very comparable to that observed in the 
SAD study, with AUC and Cmax generally increasing in a dose proportional manner 
(Table 4). Accumulation was minor, ranging from 14% to 34% (or 1.14 to 1.34) as 
measured by Cmax ratio of last/first dose and 30% to 55% (or 1.30 to 1.55), as measured 
by the area under the curve from time 0 to 168 hours (AUC0-168) ratio of last/first dose. 
 


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Table 4: 
Summary of Plasma CD101 Exposures Following Administration of 
100 mg (Day 1/Day8), 200 mg (Day 1/Day8), and 400 mg (Day 
1/Day15) Weekly 1-hour Intravenous Infusion of CD101 
Dose 
(mg) 
Day 
Cmax 
(µg/mL) 
AUC0-168 
(µg⋅h/mL) 
Accumulation Ratio 
Cmax 
AUC0-168 
100 
1 
5.67 
299 
1.14 
1.30 
8 
6.49 
390 
200 
1 
10.6 
570 
1.17 
1.43 
8 
12.4 
813 
400 
1 
22.7 
1190 
1.34 
1.55 
15 
30.5 
1840 
AUC0-168 = area under the curve from time 0 to 168 hours; Cmax = maximum plasma 
concentration. 
4.6 
SUMMARY OF KNOWN BENEFITS AND POTENTIAL RISKS 
4.6.1 
Potential Benefits 
It is anticipated that subjects participating in this study who are randomized to the CD101 
IV groups will experience at least similar therapeutic benefits as subjects randomized to 
the caspofungin group. Approximately two-thirds of the subjects enrolled in this study 
will be randomized to receive CD101 IV. 
The therapeutic benefits of caspofungin and fluconazole for the treatment of fungal 
infections are documented in the prescribing information and published literature. 
Approximately one-third of the subjects enrolled in this study will be randomized to 
receive IV caspofungin with the option of oral fluconazole step down therapy. 
4.6.2 
 Known Risks 
Safety and PK data from Study CD101.IV.1.01 and Study CD101.IV.1.02 are presented 
in Section 4.4.  
Nonclinical toxicology of CD101 is presented in Section 4.3 and described in the 
Investigator Brochure.  


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4.6.3 
Potential Risks  
Echinocandins are typically well tolerated (Eraxis [anidulafungin] Prescribing 
Information, 2013; Mycamine [micafungin sodium] Prescribing Information, 2013; 
Cancidas [caspofungin acetate] Prescribing Information, 2014). 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, 2013; Mycamine [micafungin sodium] 
Prescribing Information, 2013; Cancidas [caspofungin acetate] Prescribing Information, 
2014). 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 
2013). 
Results from a phototoxicity study in rats indicate evidence of phototoxicity at elevated 
CD101 exposures (Section 4.3). Because of the safety margin to the human-equivalent 
exposure of subjects in this study, the possibility of the rat-specific histamine release 
affecting the results, and the mild reaction seen in rats at 3.6-fold above the human 
equivalent plasma level, Cidara believes that the risk to humans is low. Nevertheless, 
pending resolution of this issue through a Phase 1 human clinical study, Cidara has 
notified investigators of the findings and added wording to the Informed Consent Form 
(ICF) for subjects to use measures to reduce sun exposure while on study drug. 
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 for Group 2. The risk to humans is unknown, thus the male contraception 
requirements in inclusion criterion 4 have been extended from first dose to 90 days with 
the inclusion of prohibited sperm donation within the period. This risk will be included in 
the ICF. 
In a 3-month study in monkeys, there were observations of tremors, intention tremors, 
and histology consistent with axonal degeneration (potentially consistent with clinical 
presentation of neuropathy) first appearing at week 6 of dosing. These observations 
occurred at 11-fold the exposure for Group 2. Given the late timing and high exposure 
relative to the Group 2 dosing regimen, the risk to study subjects is assessed as low. 
Because there may be unknown and potential risks with administration of CD101 IV, all 
subjects will be closely monitored for safety and tolerability by repeated assessment of 
clinical, vital signs, and clinical laboratory safety parameters and reporting of AEs. 
4.6.4 
Risk-Benefit Summary 
Overall, based on risk/benefit analysis, the current study appears to be fully justified in 
the planned population. 


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4.7 
JUSTIFICATION FOR DOSING REGIMEN 
A population PK model has been developed for rezafungin (Bader 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 is 
used to set doses for upcoming Phase 3 studies. 
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 concentration-time curve 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. (refer to Investigator Brochure). 
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 2017) is shown 
in Table 5 and Figure 4 for C. albicans and in Table 6 and Figure 5 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 7). 
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 adverse events 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 


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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 on 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 7), the regimen of a 400 mg 
loading dose on 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 
candidiasis. 
Table 5: 
Predicted Pharmacokinetic-Pharmacodynamic Target Attainment for 
Rezafungin Regimens, Stratified by Week and Minimal Inhibitory 
Concentration, against C. albicans 
Regimena 
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 
 
MIC = minimal inhibitory concentration. 
a. 
Regimens defined by the weekly dose (eg, 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%. 


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Figure 4: 
Predicted Pharmacokinetic-Pharmacodynamic Target Attainment for 
Rezafungin Regimens, against C. albicans relative to MIC 
Distribution 
 


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Table 6: 
Predicted Pharmacokinetic-Pharmacodynamic Target Attainment for 
Rezafungin Regimens, Stratified by Week and Minimal Inhibitory 
Concentration, against C. glabrata 
Regimena 
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 
MIC = minimal inhibitory concentration. 
a. 
Regimens defined by the weekly dose (eg, 400/200 represents 400 mg for the first dose, followed by 
200 mg once weekly). 
b. Shaded cells indicate PK-PD target attainment above 90%. 


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Figure 5: 
Predicted Pharmacokinetic-Pharmacodynamic Target Attainment for 
Rezafungin Regimens, against C. glabrata relative to MIC 
Distribution 
 


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Table 7: 
Percent Probabilities of Pharmacokinetic-Pharmacodynamic Target 
Attainment by Anidulafungin, Caspofungin, and Micafungin against 
Candida spp. 
MIC 
(mg/L) 
Anidulafungin 
Caspofungin 
Micafungin 
Rezafungin* 
Candida 
albicans 
Candida 
glabrata 
Candida 
albicans 
Candida 
glabrata 
Candida 
albicans 
Candida 
glabrata 
Candida 
albicans 
Candida 
glabrata 
0.008 
100a,b 
100 
100 
100 
99.4 
100 
100 
100 
0.015 
99.1 
100 
100 
100 
71.2 
100 
100 
100 
0.03 
100 
99.2 
100 
100 
10.1 
97.5 
100 
100 
0.06 
39.8 
54.3 
97.9 
100 
0.10 
49.9 
100 
100 
0.12 
0 
0.95 
76.7 
100 
0 
3.4 
100 
100 
0.25 
0 
0 
35.7 
100 
0 
40.1 
100 
100 
0.5 
0 
0 
12.1 
97.0 
0 
0.15 
90.55 
100 
1 
0 
0 
4.4 
73.2 
0 
0 
15 
100 
2 
0 
0 
1.35 
33.9 
0 
0 
0 
100 
4 
0 
0 
0.25 
11.3 
0 
0 
0 
100 
8 
0 
0 
0.05 
4.35 
0 
0 
0 
100 
Note:  Data for other echinocandins (Bader 2017) 
Abbreviations: MIC, minimal inhibitory concentration; MIC90, minimal inhibitory concentration required 
to inhibit 90% of isolates. 
a 
Shaded cells indicate PK-PD target attainment values ≥90%.  
b 
Cells with dotted outlines represent the MIC90 values for each agent against the respective Candida 
spp. 
* 400/200/200/200 at wk 4 
 


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4.8 
POPULATION TO BE STUDIED 
In this study, adult subjects with candidemia and/or IC will be included.  
4.9 
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. 
4.10 
JUSTIFICATION FOR USE OF CD101 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 IC may present without the other 
syndrome or may exist together as part of the same pathophysiology of disseminated 
candidiasis. Risk factors for candidemia and IC 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 IC, including intra-abdominal abscess, 
peritonitis, or pleuritic involvement, candidemia without other overt organ involvement is 
the most common form of IC diagnosed. A recent study by the ESCMID Fungal Infection 
Study Group reported the incidence of candidemia as 6.9 per 1000 intensive care unit 
patients with mortality rates between 20% and 49% (Kett et al., 2011; Gudlaugsson et al., 
2003; Arendrup et al., 2011). Candidemia and IC 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 IC (Pappas et al., 2016; Cornely et al., 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. CD101 is a novel echinocandin derived from another echinocandin 
(anidulafungin). CD101 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 better 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. 


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Both in vitro and in vivo data have demonstrated the potency and efficacy of CD101 
against Candida and disseminated candidiasis (Section 4.2, Section 4.3, and Investigator 
Brochure). In all nonclinical efficacy studies performed for CD101 in neutropenic 
disseminated candidiasis, CD101 has performed as well as, or better than, currently 
approved echinocandin comparators. This Phase 2 double-blind, randomized, controlled 
trial comparing 2 dose regimens of CD101 against caspofungin is the first efficacy study 
in humans for CD101. 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 IC 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 week (for subjects with either candidemia or IC) or fourth 
week (for subjects with IC only) of treatment if clinically indicated. 
In PK and PD models, both of the CD101 dosing regimens proposed for the Phase 2 
study demonstrate 100% target attainment of wild-type C. albicans and C. glabrata (C. 
albicans data is presented in Section 4.7). The 400-mg, once-weekly dosing regimen may 
have improved coverage of isolates with MICs >0.5 µg/mL, which is now of increasing 
prevalence in some institutions. Therefore, in this nonpowered study, both CD101 groups 
are expected to have equal efficacy with each other, as well as with the comparator. Since 
mild infusion reactions were observed in the Phase 1 studies, occurring most frequently 
in the third dose of the 400-mg dose group, it is possible that the lower dose regimen of 
CD101 may be better tolerated than the higher dose. This Phase 2 study is intended to 
assess, but not directly compare, the efficacy of both CD101 and the approved first-line 
comparator in the same patient population and to build confidence in the efficacy of 
CD101 for a larger powered Phase 3 study. Results from this study should help to discern 
any differences in safety and tolerability between the 2 CD101 dose groups and help to 
select the best CD101 dose and regimen for the Phase 3 study. 
4.11 
JUSTIFICATION OF THE PART B STUDY  
The addition of Part B in Amendment 5 of the protocol increased the study sample size 
by approximately 50% to 130% (depending on the rate of enrollment over the additional 
months to the staged start of the Phase 3 study, and the rolling close-out of Part B) with 
an interim analysis performed after approximately 40 to 60 subjects in the 
Microbiological Intent-to-Treat (mITT) population were enrolled and completed study 
drug therapy. The timing of this interim analysis enabled a smooth transition from the 
end of enrollment for Part A to the initiation of enrollment in Part B, and helped protect 
Part B subjects from unknown risks of low efficacy or safety findings prior to the start of 
the study extension.  
As detailed in Section 4.10, efficacy is expected to be equal between the 2 regimens in 
this study. There may be some advantages for the Group 1 subjects due to higher 
exposures, especially for Candida strains with higher MICs, but due to the low 
prevalence of these organisms, the effect of the higher exposure of Group 1 on the overall 
efficacy estimates is expected to be minimal.  


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The purpose of Part B is to further assess the safety and efficacy of CD101. Assessment 
of blinded safety data and data unblinded for safety purposes in Part A indicated that 
there were no known episodes of flushing, infusion reactions, or any evidence of target 
organ toxicity in Part A, and thus the focus of continued CD101 assessment in Part B was 
Group 1. Part B was initiated directly after the close of enrollment for Part A and 
continued during the analysis of Part A data. Following evaluation of the unblinded 
results from Part A, it was determined that the best CD101 dose regimen for Phase 3 was 
the 400 mg loading dose on Week 1 followed by 200 mg once weekly for a total of 
2 to 4 weeks (Group 2). Thus, with this amendment, enrollment in Group 1 will stop and 
Part B will continue enrollment of rezafungin for injection Group 2 and caspofungin 
enrolled in a 2:1 ratio. This extension is expected to at least double the size of the 
rezafungin for injection safety database. 
5.0 
STUDY PURPOSE AND OBJECTIVES 
The primary objectives of this study are to: 
• Evaluate the safety and tolerability of CD101 IV in the Safety population 
• Evaluate overall success (mycological eradication and resolution of systemic 
signs attributable to candidemia and/or IC) of CD101 IV in subjects with 
candidemia and/or IC at Day 14 (±1 day) in the Microbiological Intent-to-treat 
(mITT) population 
The secondary objectives of this study are to: 
• Evaluate overall success (mycological eradication and resolution of systemic 
signs attributable to candidemia and/or IC) of CD101 IV at Day 5, Day 28 (±2 
days; only for subjects with IC), and Follow-up (FU, Days 45-52 for subjects with 
candidemia only or Days 52-59 for subjects with IC, with or without candidemia) 
in the mITT population 
• Evaluate mycological success (eradication) of CD101 IV at Day 5, Day 14 (±1 
day), Day 28 (±2 days; only for subjects with IC), and FU (Days 45-52 for 
subjects with candidemia only or Days 52-59 for subjects with IC, with or without 
candidemia) in the mITT population 
• Evaluate clinical cure as assessed by the Investigator for CD101 IV at Day 14 (±1 
day), Day 28 (±2 days; only for subjects with IC), and FU (Days 45-52 for 
subjects with candidemia only or Days 52-59 for subjects with IC, with or without 
candidemia) in the mITT population 
• Evaluate the PK of CD101 IV 


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6.0 
STUDY DESIGN 
6.1 
DESCRIPTION OF THE STUDY 
This is a Phase 2, multicenter, prospective, randomized, double-blind study of CD101 IV 
or IV caspofungin followed by oral fluconazole step-down therapy for treatment of 
subjects with candidemia and/or IC. In Part A, subjects will be randomized in a 1:1:1 
ratio to receive CD101 IV treatment Group 1; CD101 IV treatment Group 2, or IV 
caspofungin (Figure 5, Figure 6, Figure 7, Table 6). Oral step-down therapy is allowed in 
all 3 treatment groups in Part A; oral placebo in the CD101 IV groups and oral 
fluconazole in the caspofungin group. After approximately 90 subjects have been 
enrolled in the mITT population in Part A, enrollment into Part A of the study will close 
and Part B will begin. In Part B, subjects will be randomized in a 2:1 ratio to receive 
CD101 IV treatment Group 1 or IV caspofungin (Figure 5, Figure 6, Figure 7, Table 6) 
until ≥45 additional subjects and no more than 120 subjects have been enrolled. (Note: 
Subjects enrolled under Amendment 5 and assigned to CD101 IV receive Group 1 
treatment and subjects enrolled under Amendment 6 and assigned to CD101 IV treatment 
receive Group 2 treatment. Subjects enroll under the current, approved amendment at the 
site at the time of randomization; subjects enrolled to Amendment 5 continue study 
participation according to the same amendment regardless of subsequent approval of 
Amendment 6.) Total enrollment will depend on the enrollment rate for the 6- to 8-month 
period between the end of Part A and the staged start of the Phase 3 study, which is the 
trigger for the rolling close-out of Part B. Oral step-down therapy is allowed in both 
treatment groups in Part B; oral placebo in the CD101 IV group and oral fluconazole in 
the caspofungin group. 
Figure 6: 
Study Randomization and Treatment Regimens 
 


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Subjects with candidemia only may be treated with study drug for a maximum of 
21 days. Subjects with IC (with or without candidemia) may be treated with study drug 
for a maximum of 28 days. Subjects will be presumed to have IC if there is a positive 
culture for Candida spp. from a normally sterile site other than blood or if there is a 
positive sponsor-approved rapid in vitro diagnostic (IVD) or blood culture for Candida 
spp. combined with radiographic evidence of IC. 
Subjects in the CD101 IV treatment Group 1 will receive CD101 IV 400 mg on Day 1 
and Day 8, with an optional dose of 400 mg on Day 15 (for all subjects) and an optional 
dose of 400 mg on Day 22 (only for subjects with IC), if needed.Subjects in the CD101 
IV treatment Group 2 will receive CD101 IV 400 mg on Day 1 and 200 mg on Day 8, 
with an optional dose of 200 mg on Day 15 (for all subjects) and an optional dose of 
200 mg on Day 22 (only for subjects with IC), if needed. Subjects in the caspofungin 
group will receive IV caspofungin (a single 70 mg loading dose on Day 1 followed by 
50 mg once daily) for ≥3 days up to a maximum of 21 days for subjects with candidemia 
only and up to a maximum of 28 days for subjects with IC (with or without candidemia). 
The optional doses of CD101 IV on Day 15 and Day 22 may be administered according 
to the subject’s clinical response and the medical judgment of the Principal Investigator 
(PI).  
After ≥3 days of IV therapy, subjects in the caspofungin group can be switched to oral 
step-down therapy of fluconazole (a loading dose of 800 mg [4 capsules] on the first day 
followed by 400 mg [2 capsules]/day thereafter) if criteria are met. In order to maintain 
the blind, subjects in the CD101 IV groups who have switched to oral step-down therapy 
will receive oral placebo (4 capsules on the first day followed by 2 capsules/day 
thereafter) and subjects in the caspofungin treatment group will receive IV placebo on 
Day 8, and on Days 15 and 22 if study drug is administered through these timepoints. The 
total IV plus oral treatment duration will be ≥14 days and up to a maximum of 28 days.  
The dose and duration of any prior antifungal treatment taken within 4 weeks of 
randomization will be recorded at Screening. A retinal examination for evidence of a 
Candida eye infection, including endophthalmitis or chorioretinitis, will be performed 
during Screening or by 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 course of the study. 
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 (Pappas et al., 2016; Cornely et al., 2012). 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.  


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The Schedule of Assessments and Procedures is presented in Table 2. Study Day 1 is 
defined as the first day of study drug administration. Subsequent study days are defined 
by the number of consecutive calendar days thereafter. All subjects will be monitored for 
AEs and SAEs following signing of the ICF at Screening and throughout the study until 
the FU visit (Days 45-52 for subjects with candidemia only or Days 52-59 for subjects 
with IC, with or without candidemia) for each treatment group. Vital signs (temperature, 
heart rate, blood pressure, respiratory rate) will be recorded daily while receiving IV 
study drug and at Day 14 (±1 day), Day 28 (±2 days; only for subjects with IC), End-of-
Treatment (EOT) (+2 days allowed after last dose of study drug), and FU (Days 45-52 for 
subjects with candidemia only or Days 52-59 for subjects with IC, with or without 
candidemia). Hematology and chemistry laboratory tests will be performed at Screening; 
Days 2 and 4; Day 8, Day 14 (±1 day), EOT (+2 days allowed after last dose of study 
drug) and at the FU visit. Coagulation laboratory tests (prothrombin time/international 
normalized ratio [PT/INR] and either partial thromboplastin time [PTT] or activated 
partial thromboplastin time [aPTT]) will be performed at Screening. ECGs will be 
performed at Screening (before subject randomization) and EOT (+2 days allowed after 
the last dose of study drug). 
Mycological diagnosis of candidemia or IC sufficient for inclusion in the study will be 
established by a positive microbiological test for yeast or Candida within 96 hours from 
time of collection of the sample until randomization. Acceptable positive microbiological 
tests for yeast or Candida include ≥1 blood culture positive for yeast or Candida, a 
Sponsor-approved rapid IVD test positive for Candida spp, or a positive Gram stain 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 from randomization, then an additional set of blood cultures must be obtained 
≤12 hours before randomization. Blood cultures should be performed daily (preferred) or 
every other day until 2 blood cultures drawn ≥12 hours apart are negative, without an 
intervening positive culture. Generally, blood cultures should involve 2 separate draws 
with ≥1 draw from a peripheral vein without an IV catheter. Two bottles should be filled 
from each draw site, totaling 4 bottles for each set of blood cultures. If possible, use 3 
aerobic and 1 anaerobic bottle (if available at the site) for each blood culture set, although 
2 aerobic and 2 anaerobic (if available) is also acceptable. 
In Part A only, blood samples will be collected for PK analysis from the OPPOSITE arm 
of the infusion on Day 1 (within 10 minutes before the end of infusion, between 15 
minutes and 1 hour after the end of infusion, and between 2 hours and 12 hours after the 
end of infusion), Day 2 (random draw, with safety labs if possible), Day 4 (random draw, 
with safety labs if possible), Day 8 (predose only), and Day 15 (predose only). If therapy 
is stopped on or before Day 14 and there is no Day 15 dose, then the Day 15 PK sample 
should be drawn with the safety laboratory samples for the Day 14 visit. For the purpose 
of maintaining the blind, blood samples will be collected from all subjects, when 
possible, in all 3 treatment groups in Part A, but only PK samples from the CD101 IV 


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groups will be analyzed (using a validated assay) by an independent, central bioanalytical 
laboratory. In Part B, PK samples will not be collected. 
Overall success and mycological eradication will be assessed at Day 5, Day 14, Day 28 
(±2 days; only for subjects with IC), and FU (Days 45-52 for subjects with candidemia 
only or Days 52-59 for subjects with IC, with or without candidemia). Clinical response 
will be assessed at Day 14 (±1 day), Day 28 (±2 days; only for subjects with IC), and FU 
(Days 45-52 for subjects with candidemia only or Days 52-59 for subjects with IC, with 
or without candidemia).


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Figure 7:  
Study Design Diagram for Subjects with Candidemia Only  
 


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Figure 8:  
Study Design Diagram for Subjects with Invasive Candidiasis (with or without Candidemia) 
 
 


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6.2 
NUMBER OF SUBJECTS 
In Part A, subjects will be randomized (1:1:1) until there are approximately 30 subjects in 
the CD101 IV treatment Group 1, 30 subjects in the CD101 IV treatment Group 2, and 30 
subjects in the comparator group in the mITT population. It is expected that 
approximately 114 subjects will need to be randomized to achieve 90 subjects in the 
mITT population (assuming 80% of randomized subjects will be included in mITT 
population).  
In Part B, subjects will be randomized (2:1) until there are ≥30 subjects in the CD101 IV 
treatment and ≥15 subjects in the comparator group (≥45 additional subjects and no more 
than 120 subjects). (Note: Subjects enrolled under Amendment 5 and assigned to CD101 
IV receive Group 1 treatment and subjects enrolled under Amendment 6 and assigned to 
CD101 IV treatment receive Group 2 treatment. Subjects enroll under the current, 
approved amendment at the site at the time of randomization; subjects enrolled to 
Amendment 5 continue study participation on the same amendment regardless of 
subsequent approval of Amendment 6.) Total enrollment will depend on the enrollment 
rate for the 6- to 8-month period between the end of Part A and the staged start of the 
Phase 3 study, which is the trigger for the rolling close-out of Part B.  
6.3 
MEASURES TAKEN TO MINIMIZE BIAS 
Bias is minimized by subject randomization and blinding in both Part A and Part B 
(Section 6.5).  
For the interim analysis, a few (≤5) efficacy and safety tables will be provided by an 
independent unblinded statistician without individual subject data to allow for 
continuation to Part B of the study. After the database for Part A is locked, summary 
tables of unblinded efficacy and safety data will be provided. Individual subjects will not 
be unblinded for either the interim analysis or the Part A analysis. (Note: An addendum 
to the Unblinding Plan for Part A allowed for unblinded safety review of adverse events 
of interest identified during blinded safety review; the addendum allowed for no more 
than 5% of subjects to be unblinded.) The data from Part B will only be unblinded and 
analyzed after database lock for Part B at completion of the study. 
6.4 
EXPECTED DURATION OF SUBJECT PARTICIPATION 
Study participation will require from 45 to 52 days for subjects with candidemia only (or 
from 52-59 days for subjects with IC, with or without candidemia) after the first dose of 
study drug: study drug administration from Day 1 up to Day 21 (for subjects with 
candidemia) or up to Day 28 (±2 days; only for subjects with IC); safety, tolerability, and 
efficacy assessments up to Day 21 (for subjects with candidemia) or up to Day 28 (±2 
days; only for subjects with IC); and a FU visit (Days 45 to 52 for subjects with 
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6.5 
METHOD OF TREATMENT ASSIGNMENT AND BLINDING 
After informed consent has been obtained, subjects will be screened for study eligibility 
before randomization. Subjects in Part A will be assigned a subject number and 
randomized (1:1:1) to receive CD101 IV treatment Group 1, CD101 IV treatment Group 
2, or caspofungin on Day 1 just prior to dosing. Subjects in Part B will be assigned a 
subject number and randomized (2:1) to receive CD101 IV treatment or caspofungin on 
Day 1 just prior to dosing. Randomization will be stratified based on the method used at 
Screening to establish the diagnosis (blood culture/rapid IVD and positive Gram 
stain/culture from a specimen obtained from a normally sterile site). If a subject has both 
a positive blood culture/rapid IVD and Gram stain/culture from a specimen obtained from 
a normally sterile site, the subject will be randomized within the positive Gram 
stain/culture from a specimen obtained from a normally sterile site stratum. The study 
site’s pharmacist (or pharmacist designee) will obtain the study drug assignment from a 
computer-generated randomization schedule. A subject is considered randomized when 
the randomization transaction is recorded in the Interactive Web Response System 
(IWRS). 
The data for the 40 to 60 subjects in the mITT population involved in the interim analysis 
will be locked prior to the unblinded interim analysis, and the database for Part A will be 
locked prior to the Part A analysis. The data from Part A will be unblinded after the 
database is locked for Part A, but likely prior to completion of Part B, and interim 
summary results and full Part A summary results will be reported when available.  
All study personnel, including the Sponsor, PI, and site personnel involved in study 
conduct, and subjects will remain blinded to by-subject study medication assignment for 
both Part A and Part B until the study is completed, with the exception of the pharmacy 
monitor, unblinded program manager, clinical supplies, document manager, and quality 
(per the Sponsor Blinding Plan). Additionally, in Part A only, some personnel from 
vendors, including the PK analyst and an independent unblinded statistician, will be 
unblinded, but will not be involved in study conduct or the final analysis. An independent 
unblinded statistician will perform the analysis on the interim and final unblinded Part A 
data. (Note: An addendum to the Unblinding Plan for Part A allowed for unblinded safety 
review of adverse events of interest identified during blinded safety review; the 
addendum allowed for no more than 5% of subjects to be unblinded.) 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. 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 


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crushed. In the case of a medical emergency requiring the PI to know the identity of the 
study drug, the PI will follow the procedures outlined in Section 8.6.  
7.0 
SELECTION, DISCONTINUATION, AND WITHDRAWAL OF 
SUBJECTS 
To be enrolled in this study, all subjects must meet all of the following inclusion criteria 
and none of the exclusion criteria.  
7.1 
SUBJECT INCLUSION CRITERIA 
Subjects in must meet ALL of the following inclusion criteria to be enrolled: 
1. Males or females ≥18 years.  
2. Established mycological diagnosis of candidemia and/or IC from a sample taken 
≤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 for yeast or positive culture for Candida spp. from a 
specimen obtained from a normally sterile site 
3. Willing to initiate or continue medical treatment to cure infections, including receipt 
of antibiotics and surgical procedures, if required. Subjects receiving only 
medications and measures for comfort, and not cure, should not be enrolled. 
4. Female subjects of child-bearing potential <2 years postmenopausal must agree to 
and comply with using 1 barrier method (eg, female condom with spermicide) plus 1 
other highly effective method of birth control (eg, oral contraceptive, implant, 
injectable, indwelling intrauterine device, vasectomized partner), or sexual abstinence 
while participating in this study. Male subjects must be vasectomized, abstain from 
sexual intercourse, or agree to use barrier contraception (condom with spermicide), 
and also agree not to donate sperm from first dose of CD101 (Day 1) until 90 days 
following last administration of study drug. 
5. Willing and able to provide written informed consent. If the subject is unable to 
consent for himself/herself, a legally acceptable representative must provide informed 
consent on their behalf. 
6. Presence of 1 or more systemic signs attributable to candidemia and/or IC (eg, fever, 
hypothermia, hypotension, tachycardia. tachypnea) (Section 7.1.2) 


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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 IC 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. Subjects may be 
enrolled based on a positive result at Screening 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 IC in the study analyses for 
efficacy. Subjects who are enrolled based on a positive rapid IVD test and have negative 
or missing blood culture at Screening and remain culture negative, may or may not have 
study therapy discontinued, but should continue to be followed in the study for safety 
assessments. 
Potential subjects with 1 or more risk factors for candidemia and IC 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 IC include (but are not limited to): 
• Immunosuppression without frank neutropenia 
• 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 IC, 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 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 4 hours prior to the 
drawing of the qualifying positive blood culture (when systemic signs of infection 
resulted in obtaining blood cultures), qualifying positive culture from a sterile site, or 
qualifying rapid IVD, through enrollment. The possible signs of infection that might be 


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attributable to candidemia and/or IC at baseline include fever, hypothermia, hypotension, 
tachycardia, and tachypnea. 
 
For the listed systemic signs of candidemia, the qualifying parameters are listed below: 
 
Fever: Oral 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 
7.2 
SUBJECT EXCLUSION CRITERIA 
Subjects must NOT meet any of the following exclusion criteria to be enrolled: 
1. Any of the following forms of IC: 
a. Septic arthritis in a prosthetic joint (septic arthritis in a native joint is allowed) 
b. Osteomyelitis  
c. Endocarditis or myocarditis 
d. Meningitis, endophthalmitis, or any central nervous system infection 
2. Neutropenia (absolute neutrophil count ≤500/µL) at Screening or anticipated 
neutropenia during the study 
3. Alanine aminotransferase or aspartate aminotransferase levels >10-fold the upper 
limit of normal 
4. Severe hepatic impairment in subjects with a history of chronic cirrhosis (Child-Pugh 
score >9) 
5. Received systemic treatment with an antifungal agent at approved doses for treatment 
of candidemia or IC for >48 hours (for example, >2 doses of a once daily antifungal 
agent or >4 doses of a twice daily antifungal agent) in the last 96 hours before 
randomization 
a. Exception: Receipt of antifungal therapy to which any Candida spp. isolated at 
Screening in qualifying cultures is not susceptible (Appendix 1) 
6. Pregnant females  
7. Lactating females who are nursing  


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8. Known hypersensitivity to CD101 IV, caspofungin, any echinocandin, or to any of 
their excipients 
9. Previous participation in this or any previous CD101 study  
10. 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  
11. The PI considers that the subject should not participate in the study 
12. Presence of an indwelling vascular catheter or device that cannot be removed and is 
likely to be the source of candidemia 
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 on study drug who wish to withdraw completely from this clinical study should 
be encouraged to complete the assessments at EOT. However, 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. 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). 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 or not related to study drug) 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 need not participate in the FU visit. 
Following enrollment, subjects diagnosed with IC involving 1 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. 


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7.4.2 
Early Discontinuation from Study Drug Administration  
For subjects who prematurely discontinue study drug (ie, before the anticipated full 
course of study drug therapy required for effective treatment of candidemia and/or IC), 
EOT assessments should be performed on the day of discontinuation. 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. 
• Safety  
o Subject unable or unwilling to continue or informed consent withdrawn  
○ 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 
○ Suspected or confirmed pregnancy or nursing during the study drug 
administration period.  
• 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. In the event that a subject 
is diagnosed with endophthalmitis or chorioretinitis or a central nervous system 
infection with Candida species, study drug should be stopped and appropriate therapy 
should be started based on local guidelines (Pappas et al., 2016; Cornely et al., 2012). 


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Study drug may be continued in the event of diagnosis of other forms of IC 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, then the investigator should 
consider a change of therapy due to insufficient therapeutic effect of study drug. In all 
cases of other forms of IC, 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. 
• Insufficient therapeutic effect 
An insufficient therapeutic effect may be determined prior to the planned EOT visit. 
This determination will require an assessment of clinical status including the 
synthesis of symptoms and signs data (both local and systemic) and available 
laboratory data. 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 then 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 FU visit 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 
○ Resistant Pathogen(s): In the event that 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.  
○ 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 that the subject requires 
systemic concomitant antifungal therapy.  


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In the event that 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 stepdown therapy prior to study drug failure, 
then 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 et al., 2016) or ESCMID (Ullmann et al., 2012; Cornely et al., 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. 
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 CD101 IV 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 
8.0 
STUDY DRUGS 
In Part A, subjects were randomized in a 1:1:1 ratio to receive CD101 IV treatment 
Group 1, CD101 IV treatment Group 2, or IV caspofungin. In Part B, subjects will be 
randomized in a 2:1 ratio to receive CD101 IV treatment Group 2 or IV caspofungin. 
(Note: Subjects enrolled under Amendment 5 and assigned to CD101 IV receive Group 1 
treatment and subjects enrolled under Amendment 6 and assigned to CD101 IV treatment 
receive Group 2 treatment. Subjects enroll under the current, approved amendment at the 
site at the time of randomization; subjects enrolled to Amendment 5 continue study 
participation on the same amendment regardless of subsequent approval of 
Amendment 6.) Oral step-down therapy is allowed in all treatment groups in Part A and 
Part B; oral placebo in the CD101 IV groups 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 6). 


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In order to stop study drug for successful completion of therapy prior to 21 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 IC that were present at baseline 
have resolved 
• For subjects with IC, there is documented or presumed eradication of IC 
• If a blood culture is positive at Screening, 2 post-baseline blood cultures collected 
≥12 hours apart are negative for Candida spp. without an intervening positive culture, 
and there are no subsequent blood cultures following the first qualifying negative 
culture that are positive 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 CD101 IV treatment Group 1 will receive 1 dose of CD101 
IV (400 mg) nominally over 60 (±10) minutes on Day 1 and Day 8 (Table 6). Subjects in 
Group 1 who require >14 days of IV therapy will receive an optional third dose of CD101 
IV (400 mg) on Day 15. Subjects in Group 1 with IC (with or without candidemia) who 
require >21 days of IV therapy will receive an optional fourth dose of CD101 IV (400 
mg) on Day 22. Subjects in Group 1 will receive IV placebo on other study days in order 
to maintain the blind. 
Subjects randomized to the CD101 IV treatment Group 2 will receive 1 dose of CD101 
IV (400 mg) nominally over 60 (±10) minutes on Day 1 and 200 mg on Day 8 (Table 6). 
Subjects in Group 2 who require >14 days of IV therapy will receive an optional third 
dose of CD101 IV (200 mg) on Day 15. Subjects in Group 2 with IC (with or without 
candidemia) who require >21 days of IV therapy will receive an optional fourth dose of 
CD101 IV (200 mg) on Day 22. Subjects in Group 1 will receive IV placebo on other 
study days in order to maintain the blind. 
For both CD101 IV groups, the time may be increased as needed up to 180 (±10) minutes 
to manage symptoms of infusion reaction consistent with management of echinocandin 
class infusion reactions, whereby decreasing the rate of infusion often alleviates 
symptoms. (Note: infusion must be completed within the 4-hour stability limit, which 
starts at the time of reconstitution of rezafungin for injection lyophilized powder in the 
single-use vial.) 
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. Step-down 
therapy in both CD101 IV treatment groups will be oral placebo, in order to maintain the 


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blind. Subjects who have already switched to oral step-down therapy will receive both 
oral placebo and CD101 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 with IC (with or without 
candidemia) 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 21 days for subjects with candidemia only and up to a 
maximum of 28 days for subjects with IC (with or without candidemia) (Table 6). 
Intravenous study drug is administered 24 (±2) hours after study drug was administered 
on the previous day. 
Step-down therapy in the caspofungin treatment group will be oral fluconazole (a loading 
dose of 800 mg [4 capsules] the first day followed by 400 mg [2 capsules]/day 
thereafter). 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 with IC (with or without candidemia) who require >21 days of therapy.  
The total IV plus oral treatment duration will be ≥14 days and up to 28 days. 


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Table 8:  
Study Treatments 
Study Day 
CD101 IV  
Group 1  
Group 2 
Caspofungin Group  
1 
IV CD101 (400 mg) 
IV caspofungin (a single 70 mg loading dose) 
2-3 a 
IV placebo 
IV caspofungin (50 mg/day) 
4-7 
IV placebo if not stepped down 
OR 
oral step-down therapy (placebo) if 
already stepped down 
IV caspofungin (50 mg/day) if not stepped down 
OR 
oral step-down therapy (fluconazole, a loading 
dose of 800 mg [4 capsules] on the first day 
followed by 400 mg [2 capsules]/day thereafter) 
if already stepped down 
8 b 
IV CD101 (400 mg Group 1, 200 mg 
Group 2) if not stepped down  
OR 
IV CD101 (400 mg Group 1, 200 mg 
Group 2) PLUS oral step-down therapy 
(placebo) if already stepped down 
IV caspofungin (50 mg/day) if not stepped down  
OR  
IV placebo PLUS oral step-down therapy 
(fluconazole, a loading dose of 800 mg [4 
capsules] on the first day followed by 400 mg [2 
capsules]/day thereafter) if already stepped 
down 
9-14 c 
IV placebo if not stepped down 
OR 
oral step-down therapy (placebo) if 
already stepped down 
IV caspofungin (50 mg/day) if not stepped down 
OR 
oral step-down therapy (fluconazole, a loading 
dose of 800 mg [4 capsules] on the first day 
followed by 400 mg [2 capsules]/day thereafter) 
if already stepped down 
15 b 
(if needed) 
IV CD101 (400 mg Group 1, 200 mg 
Group 2) if not stepped down 
OR 
IV CD101 (optional) d (400 mg Group 1, 
200 mg Group 2) PLUS 
oral step-down therapy (placebo) if 
already stepped down 
OR  
No treatment 
IV caspofungin (50 mg/day) if not stepped down 
OR 
IV placebo (optional) d PLUS oral step-down 
therapy (fluconazole, a loading dose of 800 mg 
[4 capsules] on the first day followed by 400 mg 
[2 capsules]/day thereafter) if already stepped 
down 
OR  
No treatment 
16-21 e 
(if needed) 
IV placebo if not stepped down 
OR 
oral step-down therapy (placebo) if 
already stepped down 
OR  
No treatment 
IV caspofungin (50 mg/day) if not stepped down 
OR 
oral step-down therapy (fluconazole, a loading 
dose of 800 mg [4 capsules] on the first day 
followed by 400 mg [2 capsules]/day thereafter) 
if already stepped down 
OR  
No treatment 


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Table 8:  
Study Treatments 
Study Day 
CD101 IV  
Group 1  
Group 2 
Caspofungin Group  
22 b  
(if needed, 
only for 
subjects 
with IC) 
IV CD101 (400 mg Group 1; 200 mg 
Group 2) if not stepped down 
OR 
IV CD101 (optional) f (400 mg Group 1; 
200 mg Group 2) PLUS 
oral step-down therapy (placebo) if 
already stepped down 
OR  
No treatment 
IV caspofungin (50 mg/day) if not stepped down 
OR 
IV placebo (optional) f PLUS oral step-down 
therapy (fluconazole, a loading dose of 800 mg 
[4 capsules] on the first day followed by 400 mg 
[2 capsules]/day thereafter) if already stepped 
down 
OR  
No treatment 
23-28 g,h 
(if needed, 
only for 
subjects 
with IC) 
IV placebo if not stepped down 
OR 
oral step-down therapy (placebo) if 
already stepped down 
OR  
No treatment 
IV caspofungin (50 mg/day) if not stepped down 
OR 
oral step-down therapy (fluconazole, a loading 
dose of 800 mg [4 capsules] on the first day 
followed by 400 mg [2 capsules]/day thereafter) 
if already stepped down 
OR  
No treatment 
IC = invasive candidiasis; IV= intravenous 
a. 
Subjects must receive IV therapy for ≥3 days before switching to oral step-down therapy. 
b. The Day 8, Day 14, Day 15, and Day 22 visits have a window of ±1 day if subject already stepped down 
to oral therapy and discharged from the study site. 
c. 
Total IV plus oral treatment duration must be ≥14 days.  
d. Subjects who require >14 days of therapy may receive an optional third dose of IV study drug on Day 
15, if needed. 
e. 
Total IV plus oral treatment duration must be ≤21 days for subjects with candidemia only. 
f. 
Subjects with IC (with or without candidemia) who require >21 days of therapy may receive a fourth 
dose of IV study drug on Day 22, if needed 
g. The Day 28 visit has a window of ±2 days if subject already stepped down to oral therapy and 
discharged from the study site 
h. Total IV plus oral treatment duration must be ≤28 days for subjects with IC (with or without 
candidemia). 
8.1 
CD101 FOR INJECTION 
CD101 for Injection (100 mg) is supplied as a sterile lyophilized powder for 
reconstitution prior to dilution into infusion bags. The product is limited to 
investigational use only. Please refer to the current Investigator Brochure for additional 
information.  
8.1.1 
Directions for Use 
One vial of CD101 for Injection will be reconstituted with 8 mL sterile water for 
injection (WFI) prior to diluting into infusion bags. Subject infusions must be completed 
within 4 hours of reconstitution of the lyophilized powder in the vial. Please refer to the 
Pharmacy Manual for detailed information on study drug preparation. 


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8.1.2 
Drug Storage 
Vials of CD101 for Injection and diluted infusion bags should be stored and used per the 
directions presented in the Pharmacy Manual. 
8.2 
CASPOFUNGIN 
Please refer to the prescribing information provided in the Pharmacy Manual for 
additional information. 
8.3 
ORAL STEP-DOWN THERAPY 
An oral step-down therapy is allowed in all treatment groups provided the following 
criteria are met:  
• Able to take oral medication 
• ≥3 days of IV study drug 
• The Candida species isolated is susceptible to fluconazole  
• The subject’s clinical status is considered stable based on Investigator assessment 
• If a blood culture is positive at Screening, 2 post-baseline blood cultures drawn ≥12 
hours apart are negative for Candida spp., without an intervening positive culture, 
and the first of the 2 cultures was drawn ≥48 hours prior to oral study drug initiation 
• No evidence of moderate or severe hepatic insufficiency (alanine aminotransferase or 
aspartate aminotransferase >3× the upper limit of normal) 
• No history of hypersensitivity or any other contraindications to the use of fluconazole 
and in the Investigator’s opinion, the subject can tolerate oral fluconazole therapy 
(refer to current fluconazole Prescribing Information)  
The principal contraindications to fluconazole use are hepatic injury, anaphylaxis 
(hypersensitivity), drug-induced exfoliative skin disorders, and pregnancy. Medical staff 
should also beware of the potential of QT prolongation, especially when administered to 
subjects with known heart disease or with other drugs that cause this same side effect. 
Fluconazole should be administered with caution to subjects with potentially 
proarrhythmic conditions. The potential for drug-drug interactions with fluconazole is 
summarized in Section 8.7. 
It is the responsibility of the PI to carefully read the list of requirements for the switch to 
oral fluconazole listed above, as well as the list of contraindications, warning and 
precautions, and drug-drug interactions in the US Package Insert or European Union 
Summary of Product Characteristics that are summarized here and in Section 8.3, in order 
to determine whether or not the subject may be eligible and safely started on oral 
fluconazole stepdown therapy. 
For subjects with creatinine clearance >50 mL/min (Appendix 2), oral step-down therapy 
will be fluconazole (a loading dose of 800 mg [4 capsules] on the first day followed by 
400 mg [2 capsules]/day thereafter) in the caspofungin treatment group and oral placebo 


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(4 capsules on the first day followed by 2 capsules/day thereafter) in the CD101 treatment 
groups.  
To maintain the blind, oral study drug pills must never be crushed. 
The total IV plus oral treatment duration will be ≥14 days and up to 28 days. 
8.4 
DOSE ADJUSTMENT 
8.4.1 
CD101 IV 
Dosage adjustments are not allowed in the CD101 IV groups. 
8.4.2 
Caspofungin 
Subjects in the caspofungin group with moderate hepatic impairment (Child-Pugh score 
of 7-9 with a history of chronic cirrhosis) will receive a loading dose of caspofungin of 
70 mg on Day 1 and 35 mg/day thereafter.  
Subjects in the caspofungin group weighing >80 kg or on concomitant rifampin, 
nevirapine, efavirenz, phenytoin, dexamethasone, or carbamazepine may receive 70 mg 
caspofungin daily. Dose adjustment based on potential drug-drug interactions may be 
considered at the Investigator’s discretion. 
8.4.3 
Fluconazole 
Subjects in the caspofungin group with renal impairment who are switched to oral 
stepdown therapy may receive reduced doses of fluconazole.  
For subjects with creatinine clearance ≤50 mL/min (Appendix 2), oral step-down therapy 
should be fluconazole (a loading dose of 400 mg [2 capsules] on the first day followed by 
200 mg [1 capsule]/day thereafter) in the caspofungin treatment group and oral placebo 
(2 capsules on the first day followed by 1 capsule/day thereafter) in the CD101 treatment 
groups.  
For subjects receiving hemodialysis, oral step-down therapy should be fluconazole (a full 
loading dose of 800 mg [4 capsules] followed by 400 mg [2 capsules] only after each 
episode of hemodialysis) in the caspofungin treatment group and oral placebo (4 capsules 
on the first day followed by 2 capsules after each hemodialysis) in the CD101 treatment 
groups. 
8.5 
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 oral placebo (CD101 groups), 
treatment compliance will be documented by recording start date, end date, and pill 
counts.  


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8.6 
BREAKING THE BLIND 
This study is a double-blind design. The PI, study personnel, and subjects will not make 
any effort to determine which study drug therapy is being received. Unblinded pharmacy 
personnel or unblinded study personnel (ie, PK analyst in Part A only and statistician in 
Part A and Part B) may be utilized in this study.  
The data for the 40 to 60 subjects in the mITT population involved in the interim analysis 
will be locked prior to the unblinded interim analysis, and the database for Part A will be 
locked prior to the Part A analysis. The data from Part A will be unblinded after the 
database is locked for Part A, but likely prior to completion of Part B, and interim 
summary results and full Part A summary results will be reported when available. 
Individual subjects will not be unblinded for either the interim analysis or the Part A 
analysis. Thus, no by-subject data will be made available to the Sponsor until after 
database lock for Part B. (Note: An addendum to the Unblinding Plan for Part A allowed 
for unblinded safety review of adverse events of interest identified during blinded safety 
review; the addendum allowed for no more than 5% of subjects to be unblinded.) The 
data from Part B will only be unblinded and analyzed after database lock for Part B at 
completion of the study.  
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. Prior to any unblinding, the PI is strongly advised to discuss 
options with the Medical Monitor or appropriate Sponsor study personnel. 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 and the PI was unable to contact the Sponsor prior to 
unblinding. The PI will record in source documentation the date and reason for revealing 
the blinded treatment assignment for that subject. 
8.7 
PREVIOUS 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 in will be documented in the 
CRF. 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.  
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.  


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Use of concomitant cyclosporine should be limited to subjects for whom potential benefit 
outweighs potential risk of drug-drug interactions 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. Fluconazole should 
not be co-administered with terfenadine, cisapride, astemizole, erythromycin, pimozide, 
quinidine, or any other drug metabolized via the cytochrome P450 (CYP)3A4 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. 
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. Please refer to the US Package 
Insert or the European Union Summary of Product Characteristics for fluconazole for 
more information about the contraindications, warnings and precautions, and likely drug-
drug interactions. 
8.8 
ACCOUNTABILITY PROCEDURES 
The pharmacy or study personnel are responsible for ensuring that a current record of 
CD101 IV, caspofungin, fluconazole, and over encapsulated placebo inventory and 
accountability is maintained.  
A Pharmacy Monitor will be responsible for checking 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 Pharmacy Manual for additional information.  
8.9 
STUDY DRUG HANDLING AND DISPOSAL 
Unless expressly disallowed by institution rules, used and unused vials of study drug 
(including CD101 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, 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. 
9.0 
STUDY PROCEDURES 
Study procedures should be completed within the windows provided in the Schedule of 
Assessments and Procedures located in Table 2. However, if a subject is unable to attend 


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a visit within the specified windows, the PI (or qualified designee) should discuss 
appropriate scheduling with the Medical Monitor (or appropriate designee). 
For Part A of this study, the blood sample for CD101 PK is a critical parameter and any 
postdose time point for blood sample needs to be collected within the specified window. 
All other procedures should be completed as close to the prescribed/scheduled time as 
possible. Any nonscheduled procedures required for urgent evaluation of safety concerns 
take precedence over all routine scheduled procedures.  
9.1 
SCREENING 
Unless otherwise indicated, Screening assessments should be performed within 48 hours 
of randomization.  
• Obtain signed informed consent prior to initiating any study-related assessments or 
procedures. Consent from a legally acceptable representative 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 (eg, 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 
admission and discharge (if applicable) 
• Short-term central venous catheters (eg, peripherally-inserted central catheters, 
internal jugular or subclavian central venous catheters) and long-term central venous 
catheters (eg, tunneled catheters) are recommended to be removed within 48 hours 
after diagnosis with candidemia, consistent with IDSA (Pappas et al., 2016) and 
ESCMID (Ullmann et al., 2012; Cornely et al., 2012) guidelines. 
• Record all systemic antifungal therapy administered within 4 weeks and all non-
antifungal therapy (including other anti-infective therapy) administered within 1 week 
prior to randomization 
• Clinical assessments 
o Conduct complete physical examination, including height and weight 
o Measure vital signs (temperature and the method used [oral, rectal, temporal, 
tympanic, or core], heart rate, blood pressure, and respiratory rate) 
− Record the highest and lowest daily temperature and the method used (oral, 
rectal, temporal, tympanic, or core), highest and lowest heart rate, highest and 
lowest respiratory rate, and highest and lowest blood pressure measured 
o Perform 12-lead ECG before subject randomization 


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o Perform retinal examination for Candida eye infection by Day 7 only on subjects 
with candidemia by blood culture. This assessment is the standard of care for 
subjects with candidemia, and ideally would be performed by an ophthalmologist, 
if available. 
o Assess presence or absence of systemic signs and symptoms and determine which 
are attributable to candidemia and/or IC. The Screening period for assessing 
systemic signs for inclusion in the study may include the 4 hours prior to the 
drawing of the qualifying positive blood culture (when systemic signs of infection 
resulted in obtaining blood cultures), qualifying positive culture from a sterile 
site, or sponsor-approved IVD, through enrollment. 
• Laboratory assessments 
○ Prior to the start of the Screening period, consider use of a Sponsor-approved 
rapid IVD for Candida spp. while drawing blood culture if the potential subject 
has known risk factors for candidemia and will be administered empiric 
antifungal therapy (Section 7.1.1) 
− All sites using rapid IVDs must label samples with subject identification 
number and date/time of blood draw and follow all necessary timing and 
procedures required for proper testing and interpretation of results  
− For commercial IVDs, sample handling and storage procedures should follow 
the package insert 
○ A culture must be obtained as part of the standard of care for inclusion in the 
study. Established mycological diagnosis of candidemia sufficient for inclusion in 
the study will be established by either ≥1 blood culture positive for yeast or 
Candida OR a Sponsor-approved rapid IVD test positive for Candida spp. OR a 
positive Gram stain for yeast or positive culture for Candida spp. from a specimen 
obtained from a normally sterile site from a sample taken ≤96 hours before 
randomization.  
− If the positive blood culture used to qualify the subject for the study is drawn 
>12 hours from randomization, then an additional set of blood cultures must 
be obtained ≤12 hours before randomization. 
− If the subject is suspected of having IC, 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 species and susceptibilities for all bacteria isolated within 1 week 
prior to randomization from blood or any other normally sterile site  


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Intravenous CD101 
 
 
Protocol Amendment 6 
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− Send all fungal isolates cultured from blood or normally sterile tissue/fluid to 
the Central Laboratory  
○ Perform urine pregnancy test on female subjects of childbearing potential. Do not 
perform on women who are ≥2 years postmenopausal or surgically sterile.  
○ Obtain blood samples for hematology tests, coagulation laboratory tests (PT/INR 
and either PTT or aPTT), and serum chemistry tests (Appendix 3) 
○ Obtain a urine sample for urinalysis (UA) and microscopy (Appendix 3) 
• Calculate Child-Pugh score only if the subject has a history of chronic cirrhosis 
(Appendix 4) 
• Record modified Acute Physiology and Chronic Health Evaluation (APACHE) II 
parameters (Appendix 5) with Glasgow Coma Score (Appendix 6); note that the 
APACHE II score can be calculated after enrollment, but should use the vital signs 
and laboratory results from the Screening visit. 
• If radiologic test performed, record radiologic test type with Findings and 
Interpretation only if radiologic test provides evidence of IC 
• Assess, identify, and record any AEs following signing of the ICF 
• Confirm subject qualification by inclusion/exclusion criteria 
9.2 
DAYS 1, 2, and 3 
• Randomize subject just prior to dosing (Day 1 only) 
• Administer study drug (Section 8.0 and Study Pharmacy Manual) 
o IV infusion of study drug over 60 (±10) minutes on Days 1, 2, and 3; 24 (±2) 
hours after study drug was administered on the previous day (for Days 2 and 3 
only) 
• Clinical assessments 
○ Measure vital signs (temperature, heart rate, blood pressure, and respiratory rate) 
− Record the highest and lowest daily temperature and the method used (oral, 
rectal, temporal, tympanic, or core), highest and lowest heart rate, highest and 
lowest respiratory rate, and highest and lowest blood pressure measured each 
day 
○ Perform retinal examination for Candida eye infection once by Day 7 only on 
subjects with candidemia by blood culture. This assessment is the standard of care 
for subjects with candidemia, and ideally would be performed by an 
ophthalmologist, if available. 


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Intravenous CD101 
 
 
Protocol Amendment 6 
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• Laboratory assessments 
○ Obtain blood samples for hematology and serum chemistry tests (Day 2 only) 
(Appendix 3); in general, the laboratory values to be entered into the eCRF will 
be from the first laboratory samples drawn each day with routine morning 
laboratory samples 
○ Obtain culture from blood and/or normally sterile tissue/fluid if demonstrating 
mycological eradication or if clinically indicated 
− Obtain blood for culture daily (preferred) or every other day until 2 blood 
cultures drawn ≥12 hours apart are negative, without an intervening positive 
culture 
− If feasible, and if there was a previous culture from a site positive for Candida 
spp., obtain culture from normally sterile tissue/fluid from the same site 
− Perform identification and susceptibility testing for Candida for any positive 
culture requiring a change of antifungal therapy (ie, 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 species and susceptibilities for any new bacteria isolated from 
blood or any other normally sterile site 
○ In Part A only, obtain blood samples for PK analysis from the OPPOSITE arm of 
the infusion on Day 1 (within 10 minutes [ie, >0 to 10 minutes] before the end of 
infusion, between 15 minutes and 1 hour after the end of infusion, and between 2 
hours and 12 hours after the end of infusion) and Day 2 (random draw with date 
of sample same as Day 2 date of dose, with safety labs if possible) 
• Record all concomitant medications including prescription, over the counter (OTC), 
and herbal medications 
• If radiologic test performed, record radiologic test type with Findings and 
Interpretation only if radiologic test provides evidence of IC, OR evidence of 
resolution of IC from previous radiographs 
• Assess, identify, and record any AEs 
9.3 
DAYS 4 to 7 
• Administer study drug (Section 8.0 and Study Pharmacy Manual) 
o IV infusion of study drug over 60 (±10) minutes, 24 (±2) hours after study drug 
was administered on the previous day  


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Intravenous CD101 
 
 
Protocol Amendment 6 
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OR  
 
o Oral step-down therapy if stepped down (Days 5, 6, and 7) 
― If on oral step-down therapy and discharged from study site, subject must 
mark date/time and number of capsules taken each day in Daily Subject Diary 
• Clinical assessments 
○ Measure vital signs (temperature, heart rate, blood pressure, and respiratory rate) 
only if receiving IV study drug 
− If hospitalized, record the highest and lowest daily temperature and the 
method used (oral, rectal, temporal, tympanic, or core), highest and lowest 
heart rate, highest and lowest respiratory rate, and highest and lowest blood 
pressure measured. 
− Vital signs are required on Days 4 and 5 (temperature, heart rate, blood 
pressure, respiratory rate) 
− For subjects discharged from the hospital and in the community, vital signs 
(temperature, heart rate, blood pressure, respiratory rate) are only performed 
on Days 6 to 7 if the subject is seen for clinical assessment or IV study drug 
infusion 
○ Perform retinal examination for Candida eye infection once by Day 7 only on 
subjects with candidemia by blood culture. This assessment is the standard of care 
for subjects with candidemia, and ideally would be performed by an 
ophthalmologist, if available. 
○ Assess presence or absence of systemic signs and determine which are 
attributable to candidemia and/or IC (Day 5 only)  
• Laboratory assessments 
○ Obtain blood samples for hematology and serum chemistry tests (Day 4 only) 
(Appendix 3); in general, the laboratory values to be entered into the eCRF will 
be from the first laboratory samples drawn each day with routine morning 
laboratory samples 
○ Obtain culture from blood and/or normally sterile tissue/fluid if demonstrating 
mycological eradication or if clinically indicated 
− Obtain blood for culture daily (preferred) or every other day until 2 blood 
cultures drawn ≥12 hours apart are negative, without an intervening positive 
culture 
− If feasible, and if there was a previous culture from a site positive for Candida 
spp., obtain culture from normally sterile tissue/fluid from the same site  


Cidara Therapeutics, Inc.  
 
 
 
 
 
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Intravenous CD101 
 
 
Protocol Amendment 6 
Confidential  
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− Perform identification and susceptibility testing for Candida for any positive 
culture requiring a change of antifungal therapy (ie, 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 species and susceptibilities for any new bacteria isolated from 
blood or any other normally sterile site 
• In Part A only, obtain blood samples for PK analysis on Day 4 (random draw with 
date of sample same as Day 4 date of dose, with safety labs if possible) 
• Record all concomitant medications including prescription, OTC, and herbal 
medications 
• If radiologic test performed, record radiologic test type with Findings and 
Interpretation only if radiologic test provides evidence of IC, OR evidence of 
resolution of IC from previous radiographs 
• Assess, identify, and record any AEs 
9.4 
DAY 8 (±1 day if already switched to oral step-down therapy and 
discharged from the study site) 
• Administer study drug (Section 8.0 and Study Pharmacy Manual) 
o IV infusion of study drug over 60 (±10) minutes, 24 (±2) hours after study drug 
was administered on the previous day, if not stepped down 
OR  
o IV infusion of study drug over 60 (±10) minutes, PLUS oral step-down therapy if 
already stepped down  
― Note that oral study drug must be taken every day if the subject has stepped 
down to oral therapy. 
― If on oral step-down therapy and discharged from study site, subject must 
mark date/time and number of capsules taken each day in Daily Subject Diary  
• Clinical assessments 
○ Measure vital signs (temperature, heart rate, blood pressure, and respiratory rate)  


Cidara Therapeutics, Inc.  
 
 
 
 
 
Protocol CD101.IV.2.03 A6 
Intravenous CD101 
 
 
Protocol Amendment 6 
Confidential  
Page 78 of 128 
 
− If hospitalized, record the highest and lowest daily temperature and the 
method used (oral, rectal, temporal, tympanic, or core), highest and lowest 
heart rate, highest and lowest respiratory rate, and highest and lowest blood 
pressure measured. 
− If not hospitalized, record single measurements for daily temperature and the 
method used (oral, rectal, temporal, tympanic, or core), heart rate, respiratory 
rate, and blood pressure 
○ Repeat retinal examination for Candida eye infection only on subjects with 
candidemia by blood culture and only if the subject develops visual signs or 
symptoms of Candida eye infection during the course of the study  
• Laboratory assessments 
○ Obtain culture from blood and/or normally sterile tissue/fluid if demonstrating 
mycological eradication or if clinically indicated 
− Obtain blood for culture if demonstrating mycological eradication (if not 
already done) or if clinically indicated 
− If feasible, and if there was a previous culture from a site positive for Candida 
spp., obtain culture from normally sterile tissue/fluid from the same site 
− Perform identification and susceptibility testing for Candida for any positive 
culture requiring a change of antifungal therapy (ie, 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 species and susceptibilities for any new bacteria isolated from 
blood or any other normally sterile site 
○ Obtain blood samples for hematology/serum chemistry tests (Appendix 3); in 
general, the laboratory values to be entered into the eCRF will be from the first 
laboratory samples drawn each day with routine morning laboratory samples 
○ Obtain blood samples for PK analysis (predose only; Part A only) 
• Record all concomitant medications including prescription, OTC, and herbal 
medications 
• If radiologic test performed, record radiologic test type with Findings and 
Interpretation only if radiologic test provides evidence of IC, OR evidence of 
resolution of IC from previous radiographs 


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Intravenous CD101 
 
 
Protocol Amendment 6 
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• Assess, identify, and record any AEs 
9.5 
DAYS 9 to 13 
• Administer study drug (Section 8.0 and Study Pharmacy Manual) 
o IV infusion of study drug over 60 (±10) minutes, 24 (±2) hours after study drug 
was administered on the previous day, if not stepped down 
OR  
o Oral step-down therapy if already stepped down 
― If on oral step-down therapy and discharged from study site, subject must 
mark date/time and number of capsules taken each day in Daily Subject Diary 
• Clinical assessments 
○ Measure vital signs (temperature, heart rate, blood pressure, and respiratory rate) 
only if receiving IV study drug 
− If hospitalized, record the highest and lowest daily temperature and the 
method used (oral, rectal, temporal, tympanic, or core), highest and lowest 
heart rate, highest and lowest respiratory rate, and highest and lowest blood 
pressure measured. 
− If not hospitalized, record single measurements for daily temperature and the 
method used (oral, rectal, temporal, tympanic, or core), heart rate, respiratory 
rate, and blood pressure 
− For subjects discharged from the hospital and in the community, vital signs 
(temperature, heart rate, blood pressure, respiratory rate) are only performed 
on Days 9 to 13 if the subject is seen for clinical assessment or IV study drug 
infusion 
• Repeat retinal examination for Candida eye infection only on subjects with 
candidemia by blood culture and only if the subject develops visual signs or 
symptoms of Candida eye infection during the course of the study 
•  Laboratory assessments 
○ Obtain culture from blood and/or normally sterile tissue/fluid if demonstrating 
mycological eradication or if clinically indicated 
− Obtain blood for culture if demonstrating mycological eradication (if not 
already done) or if clinically indicated 
− If feasible, and if there was a previous culture from a site positive for Candida 
spp., obtain culture from normally sterile tissue/fluid from the same site 


Cidara Therapeutics, Inc.  
 
 
 
 
 
Protocol CD101.IV.2.03 A6 
Intravenous CD101 
 
 
Protocol Amendment 6 
Confidential  
Page 80 of 128 
 
− Perform identification and susceptibility testing for Candida for any positive 
culture requiring a change of antifungal therapy (ie, 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 species and susceptibilities for any new bacteria isolated from 
blood or any other normally sterile site 
• Record all concomitant medications including prescription, OTC, and herbal 
medications 
• If radiologic test performed, record radiologic test type with Findings and 
Interpretation only if radiologic test provides evidence of IC, OR evidence of 
resolution of IC from previous radiographs 
• Assess, identify, and record any AEs if subject has a study visit 
9.6 
DAY 14 (±1 day if already switched to oral step-down therapy and 
discharged from the study site) 
• Administer study drug (Section 8.0 and Study Pharmacy Manual) 
o IV infusion of study drug over 60 (±10) minutes, 24 (±2) hours after study drug 
was administered on the previous day, if not stepped down 
OR  
o Oral step-down therapy if already stepped down 
― If on oral step-down therapy and discharged from study site, subject must 
mark date/time and number of capsules taken each day in Daily Subject Diary 
• Clinical assessments 
o Conduct complete physical examination, including weight 
○ Measure vital signs (temperature, heart rate, blood pressure, and respiratory rate) 
− If hospitalized, record the highest and lowest daily temperature and the 
method used (oral, rectal, temporal, tympanic, or core), highest and lowest 
heart rate, highest and lowest respiratory rate, and highest and lowest blood 
pressure measured.  
− If not hospitalized, record single measurements for daily temperature and the 
method used (oral, rectal, temporal, tympanic, or core), heart rate, respiratory 
rate, and blood pressure 


Cidara Therapeutics, Inc.  
 
 
 
 
 
Protocol CD101.IV.2.03 A6 
Intravenous CD101 
 
 
Protocol Amendment 6 
Confidential  
Page 81 of 128 
 
○ Repeat retinal examination for Candida eye infection only on subjects with 
candidemia by blood culture and only if the subject develops visual signs or 
symptoms of Candida eye infection during the course of the study 
○ Assess presence or absence of systemic signs and symptoms and determine which 
are attributable to candidemia and/or IC 
• Laboratory assessments 
○ Obtain culture from blood and/or normally sterile tissue/fluid if demonstrating 
mycological eradication or if clinically indicated 
− Review previous blood cultures drawn and obtain blood for culture if there is 
no evidence of mycological eradication (ie, 2 negative blood cultures drawn 
≥12 hours apart without intervening positive blood cultures) 
− If feasible, and if there was a previous culture from a site positive for Candida 
spp., obtain culture from normally sterile tissue/fluid from the same site 
− Perform identification and susceptibility testing for Candida for any positive 
blood culture requiring a change in antifungal therapy (ie, 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 species and susceptibilities for any new bacteria isolated from 
blood or any other normally sterile site 
○ Obtain blood samples for hematology/serum chemistry tests (Appendix 3); in 
general, the laboratory values to be entered into the eCRF will be from the first 
laboratory samples drawn each day with routine morning laboratory samples 
− In Part A only, if therapy is stopped on or before Day 14 and there is no Day 15 
dose, then the Day 15 PK sample should be drawn with the safety laboratory 
samples for the Day 14 visit 
• PI to assess clinical response. Refer to Table 11 for definitions of clinical cure and 
failure  
• Record all concomitant medications including prescription, OTC, and herbal 
medications 
• If radiologic test performed, record radiologic test type with Findings and 
Interpretation only if radiologic test provides evidence of IC, OR evidence of 
resolution of IC from previous radiographs 


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Protocol CD101.IV.2.03 A6 
Intravenous CD101 
 
 
Protocol Amendment 6 
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• Assess, identify, and record any AEs 
9.7 
DAY 15 (±1 day if already switched to oral step-down therapy and 
discharged from the study site) 
• Administer study drug (Section 8.0 and Study Pharmacy Manual) if further therapy is 
clinically indicated 
o IV infusion of study drug over 60 (±10) minutes, 24 (±2) hours after study drug 
was administered on the previous day, if not stepped down and if needed 
OR  
o IV infusion of study drug over 60 (±10) minutes, PLUS oral step-down therapy, if 
already stepped down and if needed 
― Note that oral study drug must be taken every day if the subject has stepped 
down to oral therapy.  
― If on oral step-down therapy and discharged from study site, subject must 
mark date/time and number of capsules taken each day in Daily Subject Diary 
OR 
o No treatment 
• Clinical assessments 
○ Measure vital signs (temperature, heart rate, blood pressure, and respiratory rate) 
only if receiving IV study drug 
− If hospitalized, record the highest and lowest daily temperature and the 
method used (oral, rectal, temporal, tympanic, or core), highest and lowest 
heart rate, highest and lowest respiratory rate, and highest and lowest blood 
pressure measured. 
− For subjects discharged from the hospital and in the community, vital signs 
(temperature, heart rate, blood pressure, respiratory rate) are only performed 
on Day 15 if the subject is seen for clinical assessment or IV study drug 
infusion 
• Repeat retinal examination for Candida eye infection only on subjects with 
candidemia by blood culture and only if the subject develops visual signs or 
symptoms of Candida eye infection during the course of the study 
• Laboratory assessments 
○ Obtain culture from blood and/or normally sterile tissue/fluid if demonstrating 
mycological eradication or if clinically indicated 


Cidara Therapeutics, Inc.  
 
 
 
 
 
Protocol CD101.IV.2.03 A6 
Intravenous CD101 
 
 
Protocol Amendment 6 
Confidential  
Page 83 of 128 
 
− Obtain blood for culture if demonstrating mycological eradication (if not 
already done) or if clinically indicated  
− If feasible, and if there was a previous culture from a site positive for Candida 
spp., obtain culture from normally sterile tissue/fluid from the same site  
− Perform identification and susceptibility testing for Candida for any positive 
culture requiring a change in antifungal therapy (ie, 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 species and susceptibilities for any new bacteria isolated from 
blood or any other normally sterile site 
○ In Part A only, obtain blood samples for PK analysis (predose only); if therapy is 
stopped on or before Day 14 and there is no Day 15 dose, then the Day 15 PK 
sample should be drawn with the safety laboratory samples for the Day 14 visit  
• Record all concomitant medications including prescription, OTC, and herbal 
medications 
• If radiologic test performed, record radiologic test type with Findings and 
Interpretation only if radiologic test provides evidence of IC, OR evidence of 
resolution of IC from previous radiographs 
• Assess, identify, and record any AEs 
 
9.8 
DAYS 16 to 21 
• Administer study drug (Section 8.0 and Study Pharmacy Manual) 
o IV infusion of study drug over 60 (±10) minutes, 24 (±2) hours after study drug 
was administered on the previous day, if not stepped down and if needed 
OR  
o Oral step-down therapy, if already stepped down and if needed 
― If on oral step-down therapy and discharged from study site, subject must 
mark date/time and number of capsules taken each day in Daily Subject Diary 
OR  
o No treatment 


Cidara Therapeutics, Inc.  
 
 
 
 
 
Protocol CD101.IV.2.03 A6 
Intravenous CD101 
 
 
Protocol Amendment 6 
Confidential  
Page 84 of 128 
 
• Clinical assessments 
○ Measure vital signs (temperature, heart rate, blood pressure, and respiratory rate) 
only if receiving IV study drug 
− If hospitalized, record the highest and lowest daily temperature and the 
method used (oral, rectal, temporal, tympanic, or core), highest and lowest 
heart rate, highest and lowest respiratory rate, and highest and lowest blood 
pressure measured.  
− For subjects discharged from the hospital and in the community, vital signs 
(temperature, heart rate, blood pressure, respiratory rate) are only performed 
on Days 16 to 21 if the subject is seen for clinical assessment or IV study drug 
infusion  
○ Repeat retinal examination for Candida eye infection only on subjects with 
candidemia by blood culture and only if the subject develops visual signs or 
symptoms of Candida eye infection during the course of the study 
• Laboratory assessments 
○ Obtain culture from blood and/or normally sterile tissue/fluid if demonstrating 
mycological eradication or if clinically indicated 
− Obtain blood for culture if demonstrating mycological eradication (if not 
already done) or if clinically indicated  
− If feasible, and if there was a previous culture from a site positive for Candida 
spp., obtain culture from normally sterile tissue/fluid from the same site  
− Perform identification and susceptibility testing for Candida for any positive 
culture requiring a change in antifungal therapy (ie, 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 species and susceptibilities for any new bacteria isolated from 
blood or any other normally sterile site 
• Record all concomitant medications including prescription, OTC, and herbal 
medications 
• If radiologic test performed, record radiologic test type with Findings and 
Interpretation only if radiologic test provides evidence of IC, OR evidence of 
resolution of IC from previous radiographs 
• Assess, identify, and record any AEs 


Cidara Therapeutics, Inc.  
 
 
 
 
 
Protocol CD101.IV.2.03 A6 
Intravenous CD101 
 
 
Protocol Amendment 6 
Confidential  
Page 85 of 128 
 
9.9 
DAY 22 (±1 day if already switched to oral step-down therapy and 
discharged from the study site) - Only Subjects With Invasive 
Candidiasis 
• Administer study drug (Section 8.0 and Study Pharmacy Manual) if further therapy is 
clinically indicated only for subjects with IC (with or without candidemia) 
o IV infusion of study drug over 60 (±10) minutes, 24 (±2) hours after study drug 
was administered on the previous day, if not stepped down and if needed 
OR  
o IV infusion of study drug over 60 (±10) minutes, PLUS oral step-down therapy, if 
already stepped down and if needed 
― Note that oral study drug must be taken every day if the subject has stepped 
down to oral therapy.  
― If on oral step-down therapy and discharged from study site, subject must 
mark date/time and number of capsules taken each day in Daily Subject Diary 
OR 
o No treatment 
• Clinical assessments 
○ Measure vital signs (temperature, heart rate, blood pressure, and respiratory rate) 
only if receiving IV study drug 
− If hospitalized, record the highest and lowest daily temperature and the 
method used (oral, rectal, temporal, tympanic, or core), highest and lowest 
heart rate, highest and lowest respiratory rate, and highest and lowest blood 
pressure measured. 
− For subjects discharged from the hospital and in the community, vital signs 
(temperature, heart rate, blood pressure, respiratory rate) are only performed 
on Day 22 if the subject is seen for clinical assessment or IV study drug 
infusion 
o Repeat retinal examination for Candida eye infection only on subjects with 
candidemia by blood culture and only if the subject develops visual signs or 
symptoms of Candida eye infection during the course of the study 
• Laboratory assessments 
○ Obtain culture from blood and/or normally sterile tissue/fluid if demonstrating 
mycological eradication or if clinically indicated 


Cidara Therapeutics, Inc.  
 
 
 
 
 
Protocol CD101.IV.2.03 A6 
Intravenous CD101 
 
 
Protocol Amendment 6 
Confidential  
Page 86 of 128 
 
− Obtain blood for culture if demonstrating mycological eradication (if not 
already done) or if clinically indicated  
− If feasible, and if there was a previous culture from a site positive for Candida 
spp., obtain culture from normally sterile tissue/fluid from the same site  
− Perform identification and susceptibility testing for Candida for any positive 
culture requiring a change in antifungal therapy (ie, 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 species and susceptibilities for any new bacteria isolated from 
blood or any other normally sterile site 
• Record all concomitant medications including prescription, OTC, and herbal 
medications 
• If radiologic test performed, record radiologic test type with Findings and 
Interpretation only if radiologic test provides evidence of IC, OR evidence of 
resolution of IC from previous radiographs 
• Assess, identify, and record any AEs 
9.10 
DAYS 23 to 27 - Only Subjects with Invasive Candidiasis 
• Administer study drug (Section 8.0 and Study Pharmacy Manual) only for subjects 
with IC (with or without candidemia) 
o IV infusion of study drug over 60 (±10) minutes, 24 (±2) hours after study drug 
was administered on the previous day, if not stepped down and if needed 
OR  
o Oral step-down therapy, if already stepped down and if needed 
― If on oral step-down therapy and discharged from study site, subject must 
mark date/time and number of capsules taken each day in Daily Subject Diary 
OR  
o No treatment 
• Clinical assessments 
○ Measure vital signs (temperature, heart rate, blood pressure, and respiratory rate) 
only if receiving IV study drug 


Cidara Therapeutics, Inc.  
 
 
 
 
 
Protocol CD101.IV.2.03 A6 
Intravenous CD101 
 
 
Protocol Amendment 6 
Confidential  
Page 87 of 128 
 
− If hospitalized, record the highest and lowest daily temperature and the 
method used (oral, rectal, temporal, tympanic, or core), highest and lowest 
heart rate, highest and lowest respiratory rate, and highest and lowest blood 
pressure measured. 
− For subjects discharged from the hospital and in the community, vital signs 
(temperature, heart rate, blood pressure, respiratory rate) are only performed if 
the subject is seen for clinical assessment or IV study drug infusion 
○ Repeat retinal examination for Candida eye infection only on subjects with 
candidemia by blood culture and only if the subject develops visual signs or 
symptoms of Candida eye infection during the course of the study 
• Laboratory assessments 
○ Obtain culture from blood and/or normally sterile tissue/fluid if demonstrating 
mycological eradication or if clinically indicated 
− Obtain blood for culture if demonstrating mycological eradication (if not 
already done) or if clinically indicated  
− If feasible, and if there was a previous culture from a site positive for Candida 
spp., obtain culture from normally sterile tissue/fluid from the same site  
− Perform identification and susceptibility testing for Candida for any positive 
culture requiring a change in antifungal therapy (ie, 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 species and susceptibilities for any new bacteria isolated from 
blood or any other normally sterile site 
• Record all concomitant medications including prescription, OTC, and herbal 
medications 
• If radiologic test performed, record radiologic test type with Findings and 
Interpretation only if radiologic test provides evidence of IC, OR evidence of 
resolution of IC from previous radiographs 
• Assess, identify, and record any AEs 


Cidara Therapeutics, Inc.  
 
 
 
 
 
Protocol CD101.IV.2.03 A6 
Intravenous CD101 
 
 
Protocol Amendment 6 
Confidential  
Page 88 of 128 
 
9.11 
DAY 28 (±2 days if already switched to oral step-down therapy 
and discharged from the study site) - Only Subjects with Invasive 
Candidiasis 
Perform Day 28 (±2 days) assessments and procedures only for subjects with IC (with or 
without candidemia). Note that the Day 28 (±2 days) visit could be the same visit as the 
EOT visit if the subject receives ≥26 days of therapy. 
• Administer study drug (Section 8.0 and Study Pharmacy Manual) only to subjects 
with IC (with or without candidemia) 
o IV infusion of study drug over 60 (±10) minutes, 24 (±2) hours after study drug 
was administered on the previous day, if not stepped down and if needed 
OR  
o Oral step-down therapy, if already stepped down and if needed 
― If on oral step-down therapy and discharged from study site, subject must 
mark date/time and number of capsules taken each day in Daily Subject Diary 
OR  
o No treatment 
• Clinical assessments 
o Conduct complete physical examination, including weight 
○ Measure vital signs (temperature, heart rate, blood pressure, and respiratory rate) 
− If hospitalized, record the highest and lowest daily temperature and the 
method used (oral, rectal, temporal, tympanic, or core), highest and lowest 
heart rate, highest and lowest respiratory rate, and highest and lowest blood 
pressure measured.  
− If not hospitalized, record single measurements for daily temperature and the 
method used (oral, rectal, temporal, tympanic, or core), heart rate, respiratory 
rate, and blood pressure 
○ Repeat retinal examination for Candida eye infection only on subjects with 
candidemia by blood culture and only if the subject develops visual signs or 
symptoms of Candida eye infection during the course of the study 
○ Assess presence or absence of systemic signs and symptoms and determine which 
are attributable to candidemia and/or IC 
• Laboratory assessments 


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○ Obtain culture from blood and/or normally sterile tissue/fluid if demonstrating 
mycological eradication or if clinically indicated 
− Review previous blood cultures drawn and obtain blood for culture if there is 
no evidence of mycological eradication (ie, 2 negative blood cultures drawn 
≥12 hours apart without intervening positive blood cultures) 
− If feasible, and if there was a previous culture from a site positive for Candida 
spp., obtain culture from normally sterile tissue/fluid from the same site 
− Perform identification and susceptibility testing for Candida for any positive 
culture requiring a change in antifungal therapy (ie, 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 species and susceptibilities for any new bacteria isolated from 
blood or any other normally sterile site 
• PI to assess clinical response. Refer to Table 11 for definitions of clinical cure and 
failure  
• Record all concomitant medications including prescription, OTC, and herbal 
medications 
• If radiologic test performed, record radiologic test type with Findings and 
Interpretation only if radiologic test provides evidence of IC, OR evidence of 
resolution of IC from previous radiographs 
• Assess, identify, and record any AEs 
9.12 
END OF THERAPY (+2 days allowed after last dose of study 
drug) 
Criteria for Completion of Study Drug Therapy (Section 8.0): 
In order to stop study drug for successful completion of therapy prior to 21 days (or prior 
to 28 days for subjects with IC), 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 IC that were present at baseline 
have resolved 
• For subjects with IC, there is documented or presumed eradication of IC 


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• If a blood culture is positive at Screening, 2 post-baseline blood cultures collected 
≥12 hours apart are negative for Candida spp. without an intervening positive culture, 
and there are no subsequent blood cultures following the first qualifying negative 
culture that are positive for Candida spp. 
Once these criteria are met, the total duration of study drug is at the discretion of the PI. 
• Clinical assessments 
○ Measure vital signs (temperature, heart rate, blood pressure, and respiratory rate) 
− If hospitalized, record the highest and lowest daily temperature and the 
method used (oral, rectal, temporal, tympanic, or core), highest and lowest 
heart rate, highest and lowest respiratory rate, and highest and lowest blood 
pressure measured. 
− If not hospitalized, record single measurements for daily temperature and the 
method used (oral, rectal, temporal, tympanic, or core), heart rate, respiratory 
rate, and blood pressure 
○ Perform 12-lead ECG 
○ Repeat retinal examination for Candida eye infection only on subjects with 
candidemia by blood culture and only if the subject develops visual signs or 
symptoms of Candida eye infection during the course of the study 
• Laboratory assessments 
○ Obtain culture from blood and/or normally sterile tissue/fluid if clinically 
indicated.  
− All fungal isolates cultured from blood and normally sterile tissue/fluid must 
be sent to the Central Laboratory 
− Record the species and susceptibilities for any new bacteria isolated from 
blood or any other normally sterile site 
○ Obtain blood samples for hematology/serum chemistry tests (Appendix 3); in 
general, the laboratory values to be entered into the eCRF will be from the first 
laboratory samples drawn each day with routine morning laboratory samples 
○ Obtain a urine sample for UA and microscopy (Appendix 3) 
• Record all concomitant medications including prescription, OTC, and herbal 
medications 
• If radiologic test performed, record radiologic test type with Findings and 
Interpretation only if radiologic test provides evidence of IC, OR evidence of 
resolution of IC from previous radiographs 


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• Assess, identify, and record any AEs 
9.13 
FOLLOW-UP VISIT (DAYS 45-52 for Subjects with Candidemia 
Only or Days 52-59 for Subjects with Invasive Candidiasis, With 
or Without Candidemia) 
• Clinical assessments 
o Conduct complete physical examination, including weight 
○ Measure vital signs (temperature, heart rate, blood pressure, and respiratory rate) 
− If hospitalized, record the highest and lowest daily temperature and the 
method used (oral, rectal, temporal, tympanic, or core), highest and lowest 
heart rate, highest and lowest respiratory rate, and highest and lowest blood 
pressure measured. 
− If not hospitalized, record single measurements for daily temperature and the 
method used (oral, rectal, temporal, tympanic, or core), heart rate, respiratory 
rate, and blood pressure 
○ Repeat retinal examination for Candida eye infection only on subjects with 
candidemia by blood culture and only if the subject develops visual signs or 
symptoms of Candida eye infection during the course of the study 
○ Assess presence or absence of systemic signs and symptoms of infection and 
determine which are attributable to candidemia and/or IC 
• Laboratory assessments 
○ Obtain blood samples for hematology and serum chemistry tests Appendix 3); in 
general, the laboratory values to be entered into the eCRF will be from the first 
laboratory samples drawn each day with routine morning laboratory samples 
○ Obtain culture from blood, and if feasible from normally sterile tissue/fluid 
− Obtain culture from blood  
− If feasible, and if there was a previous culture from a site positive for Candida 
spp., obtain culture from normally sterile tissue/fluid from the same site 
− All fungal isolates cultured from blood and normally sterile tissue/fluid must 
be sent to the Central Laboratory 
− Record the species and susceptibilities for any new bacteria isolated from 
blood or any other normally sterile site 
○ Perform urine pregnancy test on female subjects of childbearing potential. Do not 
perform on women who are ≥2 years postmenopausal or surgically sterile. 


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• PI to assess clinical response. Refer to Table 11 for definitions of clinical cure and 
failure 
• Record all concomitant medications including prescription, OTC, and herbal 
medications 
• If radiologic test performed, record radiologic test type with Findings and 
Interpretation only if radiologic test provides evidence of IC, OR evidence of 
resolution of IC from previous radiographs 
• Assess, identify, and record any AEs 
10.0 
ASSESSMENT OF SAFETY 
10.1 
SAFETY PARAMETERS 
Safety will be assessed from the signing of the ICF at Screening to the FU visit through 
the evaluation of AEs, vital signs, ECGs, and clinical laboratory data (clinical chemistry 
panels and hematology and UA evaluations) according to the Schedule of Assessments 
and Procedures (Table 2) and Appendix 3.  
10.2 
ADVERSE EVENTS 
AEs will be collected for all subjects from informed consent. 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 
• Severity 
• Relationship to study drug  
• 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. 
10.3 
ADVERSE EVENT REPORTING 
The Sponsor has requirements for expedited reporting of SAEs meeting specific criteria 
to worldwide regulatory authorities. Therefore, the Sponsor must be notified immediately 
regarding any SAE that occurs after informed consent.  
All SAEs must be reported to the Medical Monitor by phone or email within 24 hours of 
the investigational site’s knowledge of the event. 


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The study site will also transmit a Serious Adverse Event Report (SAER) to the safety 
vendor by facsimile or email within 24 hours. Contact details will be provided to all sites. 
An optional initial report can be made via telephone, but a completed SAER must still be 
faxed or 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, severity, and causal relationship 
• The outcomes attributable to the event (eg, 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 include the following hospital records: laboratory 
results, radiology reports, progress notes, admission and emergency room notes, 
holding and observation notes, discharge summaries, autopsy reports, and death 
certificates 
In addition, relevant case report form pages should be appended to communicate relevant 
study drug and subject outcome information. The SAER should be faxed or 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. 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.  
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. 
10.4 
DEFINITIONS 
10.4.1 
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 (eg, a clinically-significant 


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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 (eg, off-label use, use in combination with another drug) and with any route 
of administration, formulation, or dose, including an overdose. 
Events that are related to the disease under study, candidemia, should not be considered 
or recorded as AEs unless the event fits the definition for an SAE (Section 10.4.4), 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 (eg, clinically significant changes detected on hematology, 
comprehensive metabolic panel, UA) 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 (eg, 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 10.4.1 (or Section 10.4.4). 
10.4.2 
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 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. 
10.4.3 
Life-Threatening Adverse Event 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. 
10.4.4 
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 
• A life-threatening AE – see definition above  
• Inpatient hospitalization or prolongation of existing hospitalization 


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• A persistent or significant incapacity or substantial disruption of the ability to 
conduct normal life functions 
• A congenital anomaly/birth defect  
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. Examples of such 
medical events include allergic bronchospasm requiring intensive treatment in an 
emergency room or at home, blood dyscrasias, or convulsions that do not result in 
inpatient hospitalization, or the development of drug dependency or drug abuse. 
Hospitalization for a planned or elective procedure or surgery for a pre-existing condition 
that has not worsened is not considered a serious adverse event.  
10.4.5 
Unexpected Adverse Event or Unexpected Suspected Adverse 
Reaction 
An AE or suspected adverse reaction is considered ‘‘unexpected’’:  
• If it is not listed in the Investigator Brochure or is not listed at the specificity or 
severity that has been observed, or  
• If an Investigator 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 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 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 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. 
10.5 
ADVERSE EVENT CLASSIFICATION 
10.5.1 
Relationship to Investigational Drug 
The Investigator’s assessment of causality must be provided for all AEs (serious and non-
serious) (Table 7). 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. 


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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 9:  
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 
AE = adverse event. 
10.5.2 
Severity  
All AEs will be graded for severity (Table 8). 
The Investigator will use the terms: Mild, Moderate, or Severe to describe the maximum 
intensity of the AE. For purposes of consistency, these intensity grades are defined as 
follows: 
Table 10: 
Guidelines for Severity Assessments 
Mild 
Asymptomatic or mild symptoms; clinical or diagnostic 
observations only; intervention not indicated 
Moderate 
Minimal, local or noninvasive intervention indicated; 
limiting age-appropriate instrumental activities of daily 
living 
Severe 
Disabling; limiting self-care activities of daily living; 
urgent intervention indicated; death related to an AE 
AE = adverse event. 
10.5.3 
Serious Adverse Event 
Any adverse experience occurring at any dose of study medication that occurs between 
the time of informed consent and the FU visit (Days 45 to 52 for subjects with 
candidemia only or Days 52-59 for subjects with IC, with or without candidemia) that 
results in any of the following outcomes: 
• Death  
• Life-threatening situation (subject is at immediate risk of death) 
• Inpatient hospitalization or prolongation of existing hospitalization 


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• Persistent or significant disability/incapacity 
• Congenital anomaly/birth defect in the offspring of a subject who received study drug 
• Events that jeopardize the subject sufficiently that medical or surgical intervention 
may be required to prevent one of the above outcomes. Examples may include, but 
are not limited, to: 
○ Intensive treatment in an emergency room or at home for allergic bronchospasm 
○ Blood dyscrasias that do not result in hospitalization 
○ Seizures that do not result in hospitalization 
10.5.3.1 
SAE definition clarifications 
• Death is an outcome of an AE, and not an AE in itself 
• All deaths during study drug administration or up to the FU visit (Days 45 to 52 for 
subjects with candidemia only or Days 52-59 for subjects with IC, with or without 
candidemia), regardless of cause or relationship, must be reported 
• “Occurring at any dose” does not imply that the subject is actively receiving study 
drug at the time of the event 
• “Life-threatening” means that the subject was at immediate risk of death from the 
event as it occurred. This does not include an event that might have led to death, had 
it occurred with greater severity. 
• Complications that occur during hospitalizations are AEs. If an AE prolongs 
hospitalization, it is an SAE. 
• “Inpatient hospitalization” means the subject has been formally admitted to a hospital 
for medical reasons, for any length of time. This may or may not be overnight. It does 
not include presentation and care within an emergency department (although an 
emergency department visit may define a medically important event, which is also 
considered an SAE). 
• The Investigator should attempt to establish a diagnosis of the event based on signs, 
symptoms, and other clinical information. In such cases, the diagnosis should be 
documented as the AE or SAE, rather than as the individual signs or symptoms. 
10.6 
ADVERSE EVENT FOLLOW-UP 
All unresolved SAEs (“ongoing” at discharge) will be followed by the study staff until 
resolution or deemed stable. 


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10.7 
ADVERSE EVENTS OF SPECIAL INTEREST  
10.7.1 
CD101 IV Intolerability 
Events that, in the opinion of the Investigator, may represent intolerance of the IV 
infusion of IV study drug must be recorded as AEs on the eCRF. In general, these events 
will be temporally related to IV echinocandin infusion.  
10.7.2 
Phototoxicity 
Results from a phototoxicity study in rats indicate evidence of phototoxicity at elevated 
CD101 exposures (Section 4.3). Although there is not yet any evidence of risk to humans, 
Investigators should advise subjects to avoid sun exposure without adequate protection 
and to report any AE potentially related to phototoxicity to the Sponsor. 
10.7.3 
Neuropathy and Tremors 
In a CD101 3-month toxicity study in monkeys, there were observations of tremors, 
intention tremors, and histology consistent with Schwann cell hyperplasia/hypertrophy 
and axonal degeneration (potentially consistent with clinical presentation of neuropathy) 
first appearing at week 6 of dosing and at 11-fold the exposure for Group 2. Ataxia, 
axonal neuropathy, hypoesthesia, paresthesia, peripheral motor neuropathy, peripheral 
neuropathy, peripheral sensory neuropathies, peripheral sensorimotor neuropathy, 
polyneuropathy, toxic neuropathy, and tremors will be included in adverse events of 
special interest. 
10.8 
TOXICITY MANAGEMENT  
The Investigator should employ best medical judgment in determining how to manage 
AEs. Any questions regarding AE management should be directed to the Medical 
Monitor. 
10.9 
RISKS FOR WOMEN OF CHILD-BEARING POTENTIAL OR 
DURING PREGNANCY 
The risks of CD101 IV administration during pregnancy have not been evaluated. 
Pregnant or lactating females who are nursing are excluded from this study.  
Subjects must be instructed to inform the Investigator immediately if they or their partner 
becomes pregnant during the study. Partners must complete informed consent 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 all (and in only) female subjects  
• The pregnancy should be reported within 24 hours of notification using the applicable 
Pregnancy Report Form 


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• The Investigator should counsel the subject regarding the possible effects of prior 
CD101 IV exposure on the fetus 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 
immediate postnatal period or until termination of the pregnancy. The outcome 
should be reported using the Pregnancy Outcome or Abnormal Pregnancy Outcome 
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. 
10.10 
RISKS FOR MALES OF CHILDBEARING POTENTIAL 
Recent results from a CD101 nonclinical rat fertility study indicated adverse effects on 
sperm morphology and motility without interference with reproduction at 2.5 times the 
exposure of rezafungin Group 2. The risks for CD101 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 10.9, when possible. 
11.0 
ASSESSMENT OF EFFICACY PARAMETERS 
Mycological response will be programmatically determined at Day 5, Day 14 (±1 day), 
Day 28 (±2 days; only for subjects with IC), and FU (Days 45-52 for subjects with 
candidemia only or Days 52-59 for subjects with IC, with or without candidemia) in the 
mITT population as defined in Table 9. 
Table 11:  
Mycological Outcome Categories at Day 5, Day 14 (±1 day), 
Day 28 (±2 days; only for subjects with invasive candidiasis), 
and Follow-up Visit 
Outcome 
Definition 
Success  
(eradication/  
presumed  
eradication) 
• If positive blood culture at baseline: 
o 
The last blood culture drawn on or prior to the day of assessment and 
another blood culture drawn at least 12 hours prior are both negative for 
Candida spp. 
AND 
o 
Any intervening blood cultures drawn between the 2 qualifying negative 
blood cultures are also negative for Candida spp.  
OR 
• If positive culture from a normally sterile site: 
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 
OR 


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Table 11:  
Mycological Outcome Categories at Day 5, Day 14 (±1 day), 
Day 28 (±2 days; only for subjects with invasive candidiasis), 
and Follow-up Visit 
Outcome 
Definition 
o 
Presumed mycological eradication: follow-up culture is not available 
(eg, normally sterile baseline site of Candida infection not accessible) in 
a subject with a successful clinical outcome (ie, did not receive rescue 
antifungal treatment and has resolution of systemic signs of invasive 
candidiasis that were present at baseline) and resolution or improvement 
of any baseline radiographic abnormalities due to invasive candidiasis 
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 
Failure  
• If positive blood culture at baseline: 
o 
The last blood culture drawn on or prior to the day of assessment or any 
blood culture drawn prior to and within 12 hours of the last blood culture 
is positive for Candida spp. 
OR 
o 
The most recent blood culture drawn at least 12 hours prior to the last 
blood culture is positive for Candida spp. 
OR 
• If positive culture from a normally sterile site: 
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 
OR 
o 
Presumed mycological persistence: follow-up culture is not available 
(eg, normally sterile baseline site of Candida infection not accessible) in 
a subject without a successful clinical outcome or with continued (from 
baseline) radiographic abnormalities due to invasive candidiasis 
OR 
• The subject requires a change of antifungal therapy to treat candidemia  
OR 
• The subject dies of any cause prior to or on the day of assessment 
Indeterminate 
• If positive blood culture at baseline: A blood specimen was not available to 
culture or the result was not available 
• If positive culture from a normally sterile site: A sterile site tissue/fluid 
specimen was not available to culture or the result was not available AND an 
assessment of signs of invasive candidiasis was not available 
• Subject is lost to follow up on the day of assessment 
The primary efficacy outcome is overall response and is determined programmatically 
from the mycological response and assessment of systemic signs attributable to 
candidemia and/or IC (Table 10). The signs that may be present at baseline and 
attributable to candidemia and/or IC include fever, hypothermia, hypotension, 
tachycardia, and tachypnea (Section 7.1.2). Subjects who require a change of antifungal 
therapy to treat candidemia and/or IC prior to a given day of the overall response 
assessment (Day 5, Day 14, or FU visit) should have the assessment of systemic signs 


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attributable to candidemia and/or IC moved forward to the early EOT evaluation. 
Assessments of systemic signs performed prior to the early EOT will be unaffected. 
Table 12:  
Overall Response Categories at Day 5, Day 14 (±1 day), Day 28 (±2 
days; only for subjects with invasive candidiasis), and Follow-up 
Visit 
Overall 
Response 
Definition 
Mycological Response 
Clinical Signs  
Success  
Success 
(eradication/presumed 
eradication) 
Resolution of attributable systemic signs of candidemia 
and/or invasive candidiasis that were present at baseline 
Failure 
 
Success 
(eradication/presumed 
eradication) 
Recurrence or lack of resolution of attributable systemic 
signs of candidemia and/or invasive candidiasis 
Failure 
Resolution of attributable systemic signs of candidemia 
and/or invasive candidiasis that were present at baseline 
Failure 
Recurrence or lack of resolution of attributable systemic 
signs of candidemia and/or invasive candidiasis 
Failure 
Assessment of systemic signs was not completed for any 
reason (including death) 
 
Indeterminate 
Indeterminate 
Resolution of attributable systemic signs of candidemia 
and/or invasive candidiasis that were present at baseline 
Success 
(eradication/presumed 
eradication) 
Assessment of systemic signs was not completed for any 
reason  
The Investigator will make an assessment of clinical response at Day 14 (±1 day), Day 28 
(±2 days; only for subjects with IC), and FU, as detailed in Table 11. Subjects whose 
disease is progressing or who receive rescue antifungal therapy for candidemia prior to 
the Day 14 (±1 day) visit will be considered a clinical failure at the Day 14, Day 28 (±2 
days; only for subjects with IC), and FU visits. Subjects who are a clinical cure at Day 14 
(±1 day) and whose systemic signs or symptoms recur between Day 14 (±1 day) and Day 
28 (±2 days; only for subjects with IC) or FU, and who receive antifungal therapy, will be 
considered a failure at Day 28 (±2 days; only for subjects with IC) or FU. 


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Table 13: 
Investigator’s Assessment of Clinical Response at Day 14 (±1 day), 
Day 28 (±2 days; only for subjects with invasive candidiasis), and 
Follow-up Visit 
Clinical 
Response 
Definition 
Cure 
• Resolution of attributable systemic signs and symptoms of candidemia and/or IC that 
were present at baseline  
AND 
• No new systemic signs or symptoms attributable to candidemia and/or IC 
AND 
• No additional systemic antifungal therapy administered for candidemia and/or IC 
AND 
• The subject is alive  
Failure 
• Progression or recurrence of attributable systemic signs or symptoms of candidemia 
and/or IC  
OR 
• Lack of resolution attributable systemic signs or symptoms of candidemia and/or IC 
OR 
• Requirement for new or prolonged therapy to treat candidemia and/or ICa 
OR 
• An AE requires discontinuation of study drug (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: 
• 
Lost to follow up  
• 
Withdrawal of consent  
• 
Extenuating circumstances that preclude the classification of clinical outcome of 
candidemia and/or IC  
AE = adverse event; IC = invasive candidiasis; IV = intravenous 
a. 
Prolonged antifungal therapy is defined as therapy for the treatment of candidemia extending beyond 
the allowable 21 days of study drug or for the treatment of IC 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. 
12.0 
ASSESSMENT OF PHARMACOKINETIC PARAMETERS (Part A 
only) 
Blood PK samples will be drawn from the OPPOSITE arm of the infusion at the 
following specified time points. 
Blood for PK analyses will be drawn on Day 1 (within 10 minutes [ie, >0 to 10 minutes] 
before the end of infusion, between 15 minutes and 1 hour after the end of infusion, and 
between 2 hours and 12 hours after the end of infusion), Day 2 (random draw with date of 
sample same as Day 2 date of dose, with safety labs if possible), Day 4 (random draw 
with date of sample same as Day 4 date of dose, with safety labs if possible), Day 8 
(predose only), and Day 15 (predose only). Day 8 and Day 15 PK draws should be 
performed within 30 minutes before the second and third dose of study drug, regardless 


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of the exact day and time of these infusions. If therapy is stopped on or before Day 14 
and there is no Day 15 dose, then the Day 15 PK sample should be drawn with the safety 
laboratory samples for the Day 14 visit. Ideally, PK samples would be drawn with the 
safety laboratory samples for that day to prevent multiple needle sticks. 
For the purpose of maintaining the blind, blood samples will be collected from all 
subjects, when possible, in all 3 treatment groups in Part A, but only PK samples from 
the CD101 IV groups will be analyzed (using a validated assay) by an independent, 
central bioanalytical laboratory. When >1 assessment occurs at any time point, the PK 
blood sample will be given priority and taken at the correct protocol-specified time. 
Procedures for collection, storage, and shipping of PK samples are described in 
Appendix 7. 
Plasma samples from all subjects who received CD101 IV will be analyzed by liquid 
chromatography- tandem mass spectrometry (LC-MS/MS) for the concentration of 
CD101. The plasma PK parameters of CD101 IV will be determined based upon the 
CD101 concentrations. 
13.0 
STATISTICAL METHODS 
This is an exploratory study and, therefore, it is not powered for inferential statistical 
analyses. 
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 by study drug (CD101 IV or caspofungin). All 
data will be summarized separately by study drug. Listings of individual subject data will 
also be produced. All analyses will be completed for Part A. Selected analyses will be 
completed only for Part B and for Part A and B combined. 
To demonstrate preliminary efficacy and safety of CD101 and to confirm the correct 
CD101 dose regimen is utilized in Part B, an unblinded interim analysis will be 
performed after approximately 40 to 60 subjects in the mITT population have been 
enrolled and completed study drug therapy. This unblinded interim analysis of a few key 
efficacy and safety outcomes will be performed by an independent unblinded statistician. 
Interim efficacy and safety summary tables will be produced, but the identity of the group 
assignment for each individual subject will remain blinded until the completion of the 
study and the database for both Parts A and B are locked. Once Part A is completed, the 
database will be locked and a full unblinded analysis with all summary tables will be 
performed on Part A alone. As with the initial interim analysis and to help avoid bias, the 
full Part A analysis will be performed by an independent unblinded statistician, keeping 
the identity of the group assignment for each individual subject blinded until the 
completion of the study and the database for both Parts A and B are locked. 


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A Statistical Analysis Plan (SAP) will be prepared and finalized before the interim 
analysis. Any changes to the SAP from the time of the interim analysis to the final 
database lock of Part B will be documented in an addendum to the SAP. Any deviations 
from the final SAP/addendum will be described and justified in the study report. All 
statistical analyses will be performed using SAS®. All analyses will be completed for 
Part A. Selected analyses will be completed only for Part B and for Part A and B 
combined. 
13.1 
ANALYSIS POPULATIONS 
Analysis populations are: 
• Intent-to-Treat (ITT) population: all randomized subjects 
• Safety population: all subjects who receive any amount of study drug 
• The Microbiological Intent-to-treat (mITT) population: all subjects who had 
documented Candida infection based on Central Laboratory evaluation of a blood 
culture obtained within 96 hours of randomization, or from a specimen obtained from 
a normally sterile site, and received ≥1 dose of study drug 
o  
13.2 
ANALYSIS OF STUDY POPULATION AND SUBJECT 
CHARACTERISTICS 
Demographics (including age, race, and gender), diagnosis (candidemia and/or IC), 
medical history including Candida risk factors, baseline assessments (including height, 
weight, BMI, modified APACHE II score, and Glasgow coma score), mycological data, 
systemic signs and symptoms, and administration of study drug will be summarized in 
the ITT and mITT populations. All analyses will be conducted for Part A only. The SAP 
will detail which analyses are conducted for Part B and for Parts A and B combined. 
13.3 
SAFETY ANALYSES  
All subjects who receive any amount of study drug (Safety population) will be included 
in the safety analyses. All safety analyses will be conducted for Part A only and for Parts 
A and B combined. 
Safety will be evaluated by presenting summaries of AEs, clinical laboratory evaluations 
(hematology evaluation, chemistry panel, and UA), vital signs, and ECGs. Safety 
variables will be tabulated by treatment group.  


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Adverse events will be coded using Medical Dictionary for Regulatory Activities 
(MedDRA). AEs will be collected for each subject from the signing of the ICF at 
Screening through the last study visit at FU (Days 45 to 52 for subjects with candidemia 
only or Days 52-59 for subjects with IC, with or without candidemia). A treatment-
emergent adverse event (TEAE) is defined as an AE that occurs during or after study 
drug administration and up through the FU visit. The incidence of TEAEs will be 
presented by system organ class (SOC) and preferred term, by SOC, preferred term, and 
relationship to the study drug administration, and by SOC, preferred term, and severity. 
In addition, the incidence of serious TEAEs and TEAEs leading to discontinuation of 
study drug (IV and IV/oral) will be presented by SOC and preferred term.  
Descriptive statistics for clinical laboratory test results, ECG parameters and vital signs, 
and for changes from baseline, will be presented by time point. Baseline is defined as the 
measurement closest to, but prior to, the administration of study drug. Incidences of 
potentially clinically significant clinical laboratory results, ECG parameters, and vital 
signs, as defined in the SAP, will also be summarized by time point.  
13.4 
EFFICACY ANALYSES 
The number and percentage of subjects with an overall success (mycological 
eradication/presumed eradication and resolution of systemic signs of candidemia and/or 
IC that were present at baseline), failure, and indeterminate response at Day 14 in the 
mITT population will be presented. Exact 2-sided 95% CIs for the point estimates of 
overall success in each treatment group will be determined using the Clopper-Pearson 
method. Additional analysis of the primary efficacy outcome will be conducted. The 
number and percentage of subjects with each overall response (success, failure, 
indeterminate) will be determined separately for subjects with candidemia and with IC in 
the mITT population. Analyses will be conducted for Part A, Part B, and for Parts A and 
B combined. 
The number and percentage of subjects with each overall response (success, failure, 
indeterminate) will be determined in those subjects in the mITT population who did not 
receive concomitant antifungal therapy in addition to study drug and will be determined 
in those subjects with and without a positive blood culture at baseline for Candida spp. 
For this analysis, a baseline culture is defined as one taken within 12 hours before 
randomization. Subjects will be included in the positive culture at baseline group if the 
baseline blood culture is negative, or not done and the first blood culture after receipt of 
study drug is positive. Exact 2-sided 95% CIs for the point estimates of success in each 
treatment group will be determined using the Clopper-Pearson method. Analyses will be 
conducted for Part A and for Parts A and B combined. 
The number and percentage of subjects with an overall success, failure, and indeterminate 
response at Day 5, Day 28 (±2 days; only for subjects with IC), and at FU in the mITT 
population will be presented by treatment group. Exact 2-sided 95% CIs for the point 
estimates of success in each treatment group will be determined using the Clopper-
Pearson method. Analyses will be conducted for Part A, Part B, and for Parts A and B 
combined. 


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An additional analysis of overall response at FU will be conducted in which subjects who 
received a non-study antifungal after Day 21 for the treatment of an infection other than 
the candidemia (or after Day 28 for the treatment of an infection other than IC) will be 
excluded. Analyses will be conducted for Part A and for Parts A and B combined. 
Mycological outcome will be summarized by treatment group in the mITT population. 
The number and percentage of subjects with a success (mycological 
eradication/presumed eradication), failure, and indeterminate response at Day 5, Day 14, 
Day 28 (±2 days; only for subjects with IC) and at FU in the mITT population will be 
presented. Exact 2-sided 95% CIs for the point estimates of success in each treatment 
group will be determined using the Clopper-Pearson method. Analyses will be conducted 
for Part A, Part B, and for Parts A and B combined. Mycological outcome will also be 
analyzed in the subgroup of subjects with only a positive rapid in vitro diagnostic result 
and with only a positive baseline blood culture. 
The number and percentage of subjects with a clinical cure, failure, and indeterminate 
response based on the Investigator's assessment at Day 14, Day 28 (±2 days; only for 
subjects with IC), and at FU in the mITT population will be presented by treatment 
group. Exact 2-sided 95% CIs for the point estimates of success in each treatment group 
will be determined using the Clopper-Pearson method. Analyses will be conducted for 
Part A, Part B, and for Parts A and B combined. 
An additional analysis of Investigator's assessment of clinical response at FU will be 
conducted in which subjects who receive a non-study antifungal after Day 21 for the 
treatment of an infection other than the candidemia (or after Day 28 for the treatment of 
an infection other than IC) will be excluded. Analyses will be conducted for Part A and 
for Parts A and B combined. 
The number and percentage of subjects who died up through the FU Visit (all-cause 
mortality) will be presented by treatment group. Kaplan-Meier methods will be utilized to 
analyze the time to the first negative blood culture (for those subjects enrolled with a 
positive blood culture). Time to negative blood culture will be defined as the time to the 
first of the 2 negative blood cultures drawn ≥12 hours apart, without an intervening 
positive culture. Subjects will be censored if they receive an alternative antifungal (ie, 
other than study drug) for the treatment of the candidemia, or if they are lost to follow up 
prior to having 2 negative blood cultures. Analyses will be conducted for Part A and for 
Parts A and B combined. 
13.5 
PHARMACOKINETIC ANALYSES (Part A only)  
Plasma samples from subjects who received ≥1 complete dose of CD101 IV will be 
analyzed for the concentration of CD101 by a validated LC-MS/MS method in the PK 
Analysis population. Due to the sparse sampling for PK in this protocol, plasma 
concentrations will primarily be used to support population PK modeling in patients. PK 
parameter assessment will be reported separately for the PK Analysis population and may 
include: Cmax, Tmax, AUC0-168, and area under the CD101 concentration time curve from 
time zero to infinity [AUC0-∞], if applicable. 


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13.6 
DETERMINATION OF STUDY SAMPLE SIZE 
This is an exploratory study and therefore, is not powered for inferential statistical 
analyses. A sufficient number of subjects are randomized to the CD101 IV and 
caspofungin groups in Part A to provide an initial, substantive analysis of safety, 
tolerability, and estimate efficacy. 
In Part A, subjects will be randomized (1:1:1) until there are approximately 30 subjects in 
the CD101 IV treatment Group 1, 30 subjects in the CD101 IV treatment Group 2, and 30 
subjects in the comparator group in the mITT population. It is expected that 
approximately 114 subjects will need to be randomized to achieve 90 subjects in the 
mITT population (assuming 80% of randomized subjects will be included in the mITT 
population). 
In Part B, subjects will be randomized (2:1) until there are ≥30 subjects in the CD101 IV 
treatment groups at any dose and ≥15 subjects in the comparator group (≥45 additional 
subjects and no more than 120 subjects). Total enrollment will depend on the enrollment 
rate for the 6- to 8-month period between the end of Part A and the start of the Phase 3 
study, which is the trigger for Part B to stop enrollment. 
In Part A, assuming a 73% overall success rate, the sample size of 30 subjects in each 
CD101 IV group will yield a 95% CI of 53.8% to 87.5%. With the addition of Part B 
subjects and assuming a 73% overall success rate, a total approximate sample size of 60 
subjects in the CD101 treatment group (consisting of Group 1 from Amendment 5 and 
Group 2 from Amendment 6) will yield a 95% CI of 60.0% to 83.7%, and a total 
approximate sample size of 110 subjects in the CD101 treatment group (consisting of 
Group 1 from Amendment 5 and Group 2 from Amendment 6) will yield a 95% CI of 
63.7% to 81.0%. 
13.7 
HANDLING OF DROPOUTS AND MISSING, UNUSED, AND 
SPURIOUS DATA 
Every effort will be made to collect all data at specified times. For the primary and 
secondary efficacy outcomes, subjects with missing outcome data are considered to have 
an indeterminate response. Subjects with an indeterminate response are included in the 
denominator of the response calculation and thus, are treated in the same manner as 
failures in the analysis. Substitutions for other missing data will be specified in the SAP.  
13.8 
TERMINATION CRITERIA 
Enrollment and withdrawals from the study and from study drug will be summarized by 
treatment group. 
13.9 
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. 


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14.0 
INVESTIGATOR REQUIREMENTS 
14.1 
PROTOCOL ADHERENCE 
The Investigator must adhere to the protocol as detailed in this document (Appendix 8) 
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 eCRF will be supplied by the contract research organization or designee for the 
recording of all information and 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.  
The data from Part A will be locked separately from the data from Part B. 
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 International Conference on 
Harmonisation (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. 
14.5 
STUDY COMPLETION 
The Sponsor requires the following data and materials before a study can be considered 
complete or terminated: 


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• Laboratory findings, clinical data, and all special test results from Screening 
throughout the study until the FU visit (Days 45-52 for subjects with candidemia only 
or Days 52-59 for subjects with IC, with or without candidemia)  
• 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) 
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, 
Section 1.8, “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. 
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. 
The purpose of an audit is to: 
• Ensure participant safety 
• Assure compliance to study protocol procedures, regulatory requirements, and SOPs 


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• Assure data quality 
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 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. 
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. 


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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 CD101 IV, caspofungin, and fluconazole 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 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. 
18.0 
FINANCING AND INSURANCE 
The financing and insurance for this study are outlined in the Clinical Trial Agreement. 
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 
REFERENCES 
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test for fungi: clinical and laboratorial correlations in medical mycology. Rev Inst Med 
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Alexander BD, Johnson MD, Pfeiffer CD, Jiménez-Ortigosa C, Catania J, Booker R, 
Castanheira M, Messer SA, Perlin DS, Pfaller MA. Increasing echinocandin resistance in 
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minimum inhibitory concentrations. Clin Infect Dis 2013; 56:1724–32. 
Alexander BD, Wingard JR. Study of renal safety in amphotericin B lipid complex-
treated patients. Clin Infect Dis. 2005 May 1;40 Suppl 6:S414-21. 
Andes DR, Safdar N, Baddley JW, Playford G, Reboli AC, Rex JH, Sobel JD, Pappas 
PG, Kullberg BJ, Mycoses Study Group. Impact of treatment strategy on outcomes in 
patients with candidemia and other forms of invasive candidiasis: a patient-level 
quantitative review of randomized trials. Clin Infect Dis 2012; 54:1110–22. 
Arendrup MC, Dzajic E, Jensen RH, Johansen HK, Kjaeldgaard P, Knudsen JD, 
Kristensen L, Leitz C, Lemming LE, Nielsen L, Olesen B, Rosenvinge FS, Røder BL, 
Schønheyder HC. Epidemiological changes with potential implication for antifungal 
prescription recommendations for fungaemia: data from a nationwide fungaemia 
surveillance programme. Clin Microbiol Infect 2013; 19: E343–53. 
Arendrup MC, Sulim S, Holm A, Nielsen L, Nielsen SD, Knudsen JD, Drenck NE, 
Christensen JJ, Johansen HK. Diagnostic issues, clinical characteristics, and outcomes for 
patients with fungemia. J Clin Microbiol. 2011 Sep;49(9):3300-8. 
Azie N, Neofytos D, Pfaller M, Meier-Kriesche HU, Quan SP, Horn D. The PATH 
(Prospective Antifungal Therapy) Alliance registry and invasive fungal infections: update 
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Bader JC, Andes DR, Castanheira M, Ambrose PG, Bhavnan SM. ID Week 2017, San 
Diego, California. Poster 833. 2017Oct4-8. 
Beyda ND, John J, Kilic A, Alam MJ, Lasco TM, Garey KW. FKS mutant Candida 
glabrata: risk factors and outcomes in patients with candidemia. Clin Infect Dis. 
2014;59(6):819-25. 
Brown GD, Denning DW, Gow NA, Levitz SM, Netea MG, White TC. Hidden killers: 
human fungal infections. Sci Transl Med 2012; 4:165rv13. 
Cancidas (caspofungin) New Drug Application 21-227. Center for Drug Evaluation and 
Research Approval Package: Pharmacology Review. FDA, Washington, DC. 2001. 


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Cancidas (caspofungin acetate) [Prescribing Information]. Whitehouse Station, NJ: 
Merck & Co., Inc.; 2014 September. Available at 
https://www.merck.com/product/usa/pi_circulars/c/cancidas/cancidas_pi.pdf. Accessed 
09May2015. 
Castanheira M, Messer SA, Rhomberg PR, Jones RN, Pfaller MA. Activity of a Novel 
Echinocandin Biafungin (CD101) Tested against Most Common Candida and 
Aspergillus Species, Including Echinocandin- and Azole-resistant Strains. Interscience 
Conference of Antimicrobial Agents and Chemotherapy 2014; Poster M-1082. 
Chapeland-Leclerc F, Hennequin C, Papon N, Noël T, Girard A, Socié G, Ribaud P, 
Lacroix C. Acquisition of flucytosine, azole, and caspofungin resistance in Candida 
glabrata bloodstream isolates serially obtained from a hematopoietic stem cell transplant 
recipient. Antimicrob Agents Chemother. 2010 Mar;54(3):1360-2. 
CDC 2013. Antibiotic resistance threats in the United States, 2013. 
http://www.cdc.gov/drugresistance/threat-report-2013/  
CDC Clinical Alert to U.S. Healthcare Facilities: Global emergence of invasive 
infections caused by the multidrug-resistant yeast Candida auris. 
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Cleveland AA, Farley MM, Harrison LH, Stein B, Hollick R, Lockhart SR, Magill SS, 
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candidemia: results from population- based laboratory surveillance in Atlanta and 
Baltimore, 2008–2011. Clin Infect Dis 2012; 55: 1352–61. 
Cornely OA, Bassetti M, Calandra T, Garbino J, Kullberg BJ, Lortholary O, Meersseman 
W, Akova M, Arendrup MC, Arikan-Akdagli S, Bille J, Castagnola E, Cuenca-Estrella 
M, Donnelly JP, Groll AH, Herbrecht R, Hope WW, Jensen HE, Lass-Flörl C, Petrikkos 
G, Richardson MD, Roilides E, Verweij PE, Viscoli C, Ullmann AJ; ESCMID Fungal 
Infection Study Group. ESCMID* guideline for the diagnosis and management of 
Candida diseases 2012: non-neutropenic adult patients. Clin Microbiol Infect. 2012 
Dec;18 Suppl 7:19-37. 
Ecalta [anidulafungin] European Medicines Agency Summary of Product Characteristics, 
23AUG2012. Available at 
http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-
_Product_Information/human/000788/WC500020673.pdf. Accessed 20JUL2017. 
Eraxis (anidulafungin) New Drug Applications 21-632 and 21-948. Center for Drug 
Evaluation and Research Approval Package: Pharmacology Review. FDA, Washington, 
DC. 2006. 
Eraxis (anidulafungin) [Prescribing Information]. New York, NY; Pfizer Roerig; 2013 
November. Available at http://labeling.pfizer.com/showlabeling.aspx?id=566. Accessed 
09May2015. 


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Executive Office of the President, President’s Council of Advisors on Science and 
Technology. Report to the President on Combating Antibiotic Resistance. September 
2014. 
Falagas ME, Apostolou KE, Pappas VD. Attributable mortality of candidemia: a 
systematic review of matched cohort and case-control studies. Eur J Clin Microbiol Infect 
Dis. 2006 Jul;25(7):419-25. 
Gudlaugsson O, Gillespie S, Lee K et al. Attributable mortality of nosocomial 
candidemia, revisited. Clin Infect Dis. 2003 37:1172–7. 
Hidron AI, Edwards JR, Patel J, Horan TC, Sievert DM, Pollock DA, Fridkin SK; 
National Healthcare Safety Network Team; Participating National Healthcare Safety 
Network Facilities. NHSN annual update: antimicrobial-resistant pathogens associated 
with healthcare-associated infections: annual summary of data reported to the National 
Healthcare Safety Network at the Centers for Disease Control and Prevention, 2006-
2007. Infect Control Hosp Epidemiol. 2008 Nov;29(11):996-1011. Erratum in: Infect 
Control Hosp Epidemiol. 2009 Jan;30(1):107. 
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. Critical Care Medicine 1985 13(10):818–29. 
Krogh-Madsen M, Arendrup MC, Heslet L, Knudsen JD. Amphotericin B and 
caspofungin resistance in Candida glabrata isolates recovered from a critically ill patient. 
Clin Infect Dis. 2006 Apr 1;42(7):938-44. 
Labelle AJ, Micek ST, Roubinian N, Kollef MH. Treatment-related risk factors for 
hospital mortality in Candida bloodstream infections. Crit Care Med. 2008 
Nov;36(11):2967-72. 
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;370:1198–208. 
Menzin J, Meyers JL, Friedman M, Perfect JR, Langston AA, Danna RP, Papadopoulos 
G. Mortality, length of hospitalization, and costs associated with invasive fungal 
infections in high risk patients. Am J Health Syst Pharm 2009; 66: 1711–7. 
Mikulska M, Del Bono V, Ratto S, Viscoli C. Occurrence, presentation and treatment of 
candidemia. Expert Rev Clin Immunol. 2012 Nov;8(8):755-65. 


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Mycamine (micafungin sodium) New Drug Application 21-754. Center for Drug 
Evaluation and Research Approval Package: Pharmacology Review. FDA, Washington, 
DC. 2005. 
Mycamine (micafungin sodium) [Prescribing Information]. Northbrook, IL: Astellas 
Pharma US, Inc.; 2013 June. Available at 
http://www.us.astellas.com/docs/mycamine.pdf. Accessed 09May2015. 
Mylonakis E, Clancy CJ, Ostrosky-Zeichner L, Garey KW, Alangaden GJ, Vazquez JA, 
Groeger JS, Judson MA, Vinagre YM, Heard SO, Zervou FN, Zacharioudakis IM, 
Kontoyiannis DP, Pappas PG. T2 Magnetic Resonance Assay for the Rapid Diagnosis of 
Candidemia in Whole Blood: A Clinical Trial. Clin Infect Dis. 2015 Jan 12 [Epub ahead 
of print]. 
Ostrosky-Zeichner L. Candida glabrata and FKS mutations: witnessing the emergence of 
the true multidrug-resistant Candida. Clin Infect Dis. 2013 Jun;56(12):1733-4. 
Ostrosky-Zeichner L, Pappas PG, Shoham S, Reboli A, Barron MA, Sims C, Wood C, 
Sobel JD. Improvement of a clinical prediction rule for clinical trials on prophylaxis for 
invasive candidiasis in the intensive care unit. Mycoses. 2009 Jan;54(1):46-51. 
Ostrosky-Zeichner L, Sable C, Sobel J, Alexander BD, Donowitz G, Kan V, Kauffman 
CA, Kett D, Larsen RA, Morrison V, Nucci M, Pappas PG, Bradley ME, Major S, 
Zimmer L, Wallace D, Dismukes WE, Rex JH. Multicenter retrospective development 
and validation of a clinical prediction rule for nosocomial invasive candidiasis in the 
intensive care setting. Eur J Clin Microbiol Infect Dis. 2007 Apr;26(4):271-6. 
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, Castanheira M, Lockhart SR, Ahlquist AM, Messer SA, Jones RN. 
Frequency of decreased susceptibility and resistance to echinocandins among 
fluconazole-resistant bloodstream isolates of Candida glabrata. J Clin Microbiol 2012; 
50: 1199–203. 
Pfaller MA, Castanheira M, Messer SA, Moet GJ, Jones RN. Variation in Candida spp. 
distribution and antifungal resistance rates among bloodstream infection isolates by 
patient age: report from the SENTRY Antimicrobial Surveillance Program (2008-2009). 
Diagn Microbiol Infect Dis. 2010a;68(3):278-83. 
Pfaller MA, Diekema DJ. Epidemiology of invasive mycoses in North America. Crit Rev 
Microbiol 2010; 36: 1–53. 


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Pfaller MA, Diekema DJ. Epidemiology of Invasive Candidiasis: a Persistent Public 
Health Problem Clin. Microbiol. Rev. Jan. 2007, p. 133–163. 
Pfaller MA, Diekema DJ, Gibbs DL, Newell VA, Nagy E, Dobiasova S, Rinaldi M, 
Barton R, Veselov A; Global Antifungal Surveillance Group. Candida krusei, a 
multidrug resistant opportunistic fungal pathogen: geographic and temporal trends from 
the ARTEMIS DISK Antifungal Surveillance Program, 2001 to 2005. J Clin Microbiol 
2008; 46:515–21. 
Pfaller MA, Diekema DJ, Gibbs DL, Newell VA, Barton R, Bijie H, Bille J, Chang SC, 
da Luz Martins M, Duse A, Dzierzanowska D, Ellis D, Finquelievich J, Gould I, Gur D, 
Hoosen A, Lee K, Mallatova N, Mallie M, Peng NG, Petrikos G, Santiago A, Trupl J, 
VanDen Abeele AM, Wadula J, Zaidi M; Global Antifungal Surveillance Group. 
Geographic variation in the frequency of isolation and fluconazole and voriconazole 
susceptibilities of Candida glabrata: an assessment from the ARTEMIS DISK Global 
Antifungal Surveillance Program. Diagn Microbiol Infect Dis. 2010b;67(2). 
Pfaller MA, Jones RN, Castanheira M. Regional data analysis of Candida non-albicans 
strains collected in United States medical sites over a 6-year period, 2006-2011. 
Mycoses. 2014;57(10):602-11.  
Pfaller MA, Messer SA, Hollis RJ, Boyken L, Tendolkar S, Kroeger J, Diekema DJ. 
Variation in susceptibility of bloodstream isolates of Candida glabrata to fluconazole 
according to patient age and geographic location in the United States in 2001 to 2007. J 
Clin Microbiol. 2009 Oct;47(10):3185-90. 
Pfaller MA, Messer SA, Rhomberg PR, Castanheira M. CD101, a long-acting 
echinocandin, and comparator antifungal agents tested against a global collection of 
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antifungal resistance. J Clin Microbiol. 2013;51(8):2571-81.  
Shields RK, Nguyen MH, Press EG, Updike CL, Clancy CJ. Caspofungin MICs correlate 
with treatment outcomes among patients with Candida glabrata invasive candidiasis and 
prior echinocandin exposure. Antimicrob Agents Chemother. 2013;57(8):3528-35. 
Slavin MA, Sorrell TC, Marriott D, Thursky KA, Nguyen Q, Ellis DH, Morrissey CO, 
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Candidaemia in adult cancer patients: risks for fluconazole-resistant isolates and death. J 
Antimicrob Chemother. 2010 May;65(5):1042-51. 
Teasdale G, Jennett B. Assessment of coma and impaired consciousness. A practical 
scale. Lancet. 1974 Jul 13;2(7872):81-4. 


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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. 
Vincent JL1, Rello J, Marshall J, Silva E, Anzueto A, Martin CD, Moreno R, Lipman J, 
Gomersall C, Sakr Y, Reinhart K; EPIC II Group of Investigators. International study of 
the prevalence and outcomes of infection in intensive care units. JAMA 2009; 302: 2323–
9. 
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. 
Zaoutis TE, Argon J, Chu J, Berlin JA, Walsh TJ, Feudtner C. The epidemiology and 
attributable outcomes of candidemia in adults and children hospitalized in the United 
States: a propensity analysis. Clin Infect Dis. 2005 Nov 1;41(9):1232-9. 
Zhao Y, Prideaux B, Chen P-Y, Nagasaki Y, Lee M-H, Hough G, Ong V, Perlin DS. 
Tissue Distribution and Pharmacokinetics of CD101 in an Immunocompetent Mouse 
Model of Invasive Candidiasis. 2016 American Society of Microbiology Microbe, 
Session 247. Available at 
http://files.abstractsonline.com/SUPT/1/4060/AllOralAbstracts.pdf. Access 17JAN2017. 
Zilberberg MD, Shorr AF, Kollef MH. Growth and geographic variation in 
hospitalizations with resistant infections, United States, 2000–2005. Emerg Infect Dis 
2008a; 14: 1756–8. 
Zilberberg MD, Shorr AF, Kollef MH. Secular trends in candidemia related 
hospitalization in the United States, 2000–2005. Infect Control Hosp Epidemiol 2008b; 
29: 978–80.


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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 CLSI and EUCAST and 
should be used as guidance in determining susceptibility of different Candida species to 
potential empiric antifungal drugs. Not all species 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 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
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 
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 et al., 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 – [insert age in years]) × [insert weight in kg]  
                  72 × [insert serum creatinine in mg/dL] 
Females:  
creatinine clearance = 0.85 × (140 – [insert age in years]) × [insert weight in kg]  
                              72 × [insert serum creatinine in mg/dL] 
 
 
 


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APPENDIX 3: SAFETY LABORATORY TESTS 
 
Hematology 
Serum Chemistry 
hemoglobin 
blood urea nitrogen 
hematocrit  
bilirubin (total and direct) 
total and differential leukocyte count 
alkaline phosphatase 
red blood cell count 
aspartate aminotransferase 
platelet count 
alanine aminotransferase 
Coagulation 
Prothrombin time/ International Normalized Ratio 
Partial thromboplastin time or activated partial thromboplastin time 
albumin 
sodium 
potassium 
Urinalysis 
chloride 
pH 
glucose 
specific gravity 
creatinine 
protein a 
total protein 
glucose 
calcium 
ketones 
bicarbonate 
procalcitonin c 
bilirubin b 
 
blood a 
 
nitrite a 
Additional Tests 
Urine pregnancy test for females 
of childbearing potential. Do not 
perform on women who are ≥2 
years postmenopausal or 
surgically sterile. 
 
urobilinogen b 
leukocyte esterase a 
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. Urobilinogen and bilirubin are optional tests. 
c. 
Procalcitonin is an optional test to be performed only at Screening 
 
 
 


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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 
2 – 3 
>3 
Albumin (g/dL) 
>3.5 
2.8 – 3.5 
<2.8 
International Normalized Ratio 
OR 
PT prolongation in seconds 
<1.7 
 
<4 
1.7 – 2.3 
 
4 – 6 
>2.3 
 
>6 
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 (rectal, 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 
 
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 
 


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Source: Modified from Knaus et al., 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 (ie, 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 (eg, immunosuppression, chemotherapy, radiation, long 
term or recent high dose steroids, or has a disease that is sufficiently advanced to suppress resistance to infection, eg, 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 and Jennet, 1974. 
 
 


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APPENDIX 7: PHARMACOKINETIC SAMPLE PROCESSING AND 
SHIPMENT (Part A only) 
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. 
Pharmacokinetic Sample Shipment 
Procedures for the shipping of PK samples, including contact information, is provided in 
the Pharmacokinetics Manual. 
 


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Protocol CD101.IV.2.03 A6 
Intravenous CD101 
 
 
Protocol Amendment 6 
Confidential  
Page 127 of 128 
 
 
 
 
Radius 
(cm) 
G-Force 
RPM 
10 
1006 
3000 
12 
1006 
2738 
14 
1006 
2535 
16 
1006 
2371 
18 
1006 
2236 
20 
1006 
2121 
22 
1006 
2022 
24 
1006 
1936 
26 
1006 
1860 
28 
1006 
1793 
 
 


Cidara Therapeutics, Inc.  
 
 
 
 
 
Protocol CD101.IV.2.03 A6 
Intravenous CD101 
 
 
Protocol Amendment 6 
Confidential  
Page 128 of 128 
 
APPENDIX 8: INVESTIGATOR SIGNATURE 
I have read and understand protocol CD101.IV.2.03 and the Investigator Brochure. 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 Name]  
 
 
[Site Number] 
 
 
[Site Name] 
 
 
[Site Address] 
 
 
 

SAP_001.pdf: 
CONFIDENTIAL 
Page 1 of 56 
STATISTICAL ANALYSIS PLAN 
A Phase 2, Multicenter, Randomized, Double-blind Study of the Safety, 
Tolerability, and Efficacy of Intravenous CD101 vs Intravenous Caspofungin 
Followed by Oral Fluconazole Step-down in the Treatment of Subjects with 
Candidemia and/or Invasive Candidiasis 
Protocol Number: 
CD101.IV.2.03 
Protocol Version and Date: 
Amendment 6, 20Apr2018 
Amendment 5, 04Aug2017 
Amendment 4, 05Apr2017 
Amendment 3, 23Feb2017 
Amendment 2, 14Sep2016 
Amendment 1, 14May2016 
Original, 18Feb2016 
Name of Test Drug: 
Intravenous CD101 
Indication: 
Candidemia and Invasive Candidiasis 
Phase: 
Phase 2 
Methodology: 
Multicenter, prospective, 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: 
17 May 2019 
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. 




 
Cidara Therapeutics, Inc. 
Statistical Analysis Plan, Protocol CD101.IV.2.03 
17 May 2019, FINAL Version 4.0 
 
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TABLE OF CONTENTS 
 
1. 
INFORMATION FROM THE STUDY PROTOCOL ...................................................... 9 
1.1. 
Introduction and Objectives ................................................................................... 9 
1.1.1. 
Introduction ............................................................................................. 9 
1.1.2. 
Study Objectives ..................................................................................... 9 
1.2. 
Study Design .......................................................................................................... 9 
1.2.1. 
Synopsis of Study Design ....................................................................... 9 
1.2.2. 
Randomization and Blinding ................................................................ 11 
1.2.3. 
Stopping Rules ...................................................................................... 12 
1.2.4. 
Unblinding ............................................................................................ 12 
1.2.5. 
Study Procedures .................................................................................. 13 
1.2.6. 
Definitions of Outcome Measures ........................................................ 19 
1.2.6.1. Efficacy Outcome Measures .................................................. 19 
1.2.6.2. Safety Outcome Measures ..................................................... 25 
2. 
SUBJECT POPULATION............................................................................................... 26 
2.1. 
Population Definitions ......................................................................................... 26 
2.2. 
Protocol Deviations .............................................................................................. 26 
3. 
GENERAL STATISTICAL METHODS ........................................................................ 28 
3.1. 
Sample Size Justification ..................................................................................... 28 
3.2. 
General Methods .................................................................................................. 28 
3.3. 
Computing Environment ...................................................................................... 29 
3.4. 
Baseline Definitions ............................................................................................. 29 
3.5. 
Methods of Pooling Data ..................................................................................... 29 
3.6. 
Adjustments for Covariates.................................................................................. 29 
3.7. 
Multiple Comparisons/Multiplicity ..................................................................... 29 
3.8. 
Subgroups ............................................................................................................ 30 
3.9. 
Withdrawals, Dropouts, Loss to Follow-up ......................................................... 31 
3.10. Missing, Unused, and Spurious Data ................................................................... 31 
3.11. Visit Windows ..................................................................................................... 31 
3.12. 
Interim Analyses .................................................................................................. 32 
3.13. Timing of Part A and Part B Analyses................................................................. 33 


 
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17 May 2019, FINAL Version 4.0 
 
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4. 
PATHOGEN DETERMINATION .................................................................................. 34 
5. 
STATISTICAL ANALYSIS ........................................................................................... 35 
5.1. 
Study Population .................................................................................................. 35 
5.1.1. 
Analysis Populations and Subject Disposition ..................................... 35 
5.1.2. 
Protocol Deviations............................................................................... 35 
5.1.3. 
Demographics and Baseline Characteristics ......................................... 35 
5.1.4. 
Medical and Surgical History ............................................................... 36 
5.1.5. 
Candida Risk Factors............................................................................ 36 
5.1.6. 
Systemic Signs of Candidemia and/or IC at Baseline .......................... 36 
5.1.7. 
Baseline Fungal Pathogens ................................................................... 36 
5.2. 
Extent of Exposure and Concomitant Procedures ............................................... 37 
5.2.1. 
Study Drug Exposure ............................................................................ 37 
5.2.2. 
Prior and Concomitant Medications ..................................................... 37 
5.2.3. 
Concomitant Procedures ....................................................................... 37 
5.3. 
Analysis of Efficacy ............................................................................................. 38 
5.3.1. 
Primary Efficacy Outcome - Overall Success at Day 14 
(±1 day) ................................................................................................. 38 
5.3.2. 
Secondary Efficacy Outcomes .............................................................. 39 
5.3.2.1. Overall Response at Day 5, Day 28 (±2) and 
Follow-up .............................................................................. 39 
5.3.2.2. Mycological Response at Day 5, Day 14 (±1), 
Day 28 (±2) and Follow-up ................................................... 40 
5.3.2.3. Investigator’s Assessment of Clinical Response at 
Day 14 (±1), Day 28 (±2), and the Follow-up 
Visit ....................................................................................... 40 
5.3.3. 
Additional Efficacy Outcomes.............................................................. 41 
5.3.3.1. All-cause Mortality through Day 30 and 
Follow-up .............................................................................. 41 
5.3.3.2. Time to Negative Blood Culture ............................................ 41 
5.3.3.3. Overall Success at Day 14 (±1) by Baseline 
Candida species .................................................................... 42 
5.3.3.4. Mycological Success at Day 14 (±1) by Baseline 
Candida species .................................................................... 42 
5.3.3.5. Investigator’s Assessment of Clinical Cure by 
Baseline Candida species ...................................................... 42 
5.3.3.6. Exploratory Overall Response at Day 14 (±1) and 


 
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17 May 2019, FINAL Version 4.0 
 
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Exploratory Mycological  Response at Day 14 
(±1) ........................................................................................ 42 
5.3.3.7. Exploratory Overall Success at Day 14 (±1) by 
Baseline Candida species ...................................................... 42 
5.3.3.8. Exploratory Mycological Success at Day 14 (±1) 
by Baseline Candida species ................................................. 43 
5.3.4. 
CD101 Plasma Concentration ............................................................... 43 
5.4. 
Analysis of Safety Data ....................................................................................... 43 
5.4.1. 
Adverse Events ..................................................................................... 43 
5.4.2. 
Clinical Laboratory Data ...................................................................... 44 
5.4.3. 
Vital Signs............................................................................................. 45 
5.4.4. 
Electrocardiogram ................................................................................. 46 
5.4.5. 
Physical and Retinal Examinations....................................................... 46 
5.4.6. 
Radiological Evaluations ...................................................................... 47 
6. 
APPENDICES ................................................................................................................. 48 
6.1. 
Appendix 1: Directionality of Worst Laboratory Parameters .............................. 48 
6.2. 
Appendix 2: Clinical Laboratory Toxicity Grading Scales ................................. 49 
6.3. 
Appendix 3: Laboratory Normals ........................................................................ 51 
7. 
CHANGES TO PLANNED ANALYSES ....................................................................... 53 
8. 
REFERENCES ................................................................................................................ 54 
9. 
REVISION HISTORY..................................................................................................... 56 
 


 
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17 May 2019, FINAL Version 4.0 
 
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Page 6 of 56 
TABLES INCLUDED IN THE TEXT 
Table 1-1: 
Schedule of Assessments and Procedures ....................................................................... 14 
Table 1-2: 
Overall Response Categories ........................................................................................... 19 
Table 1-3: 
Mycological Response Definitions ................................................................................. 20 
Table 1-4: 
Examples of Timing of Blood Cultures........................................................................... 22 
Table 1-5: 
Investigator’s Assessment of Clinical Response Definitions .......................................... 23 
Table 1-6: 
Exploratory Mycological Response Definitions ............................................................. 24 
Table 3-1: 
Subgroup Definitions and Associated Analysis .............................................................. 30 
Table 3-2: 
Visit Windows ................................................................................................................. 32 
Table 5-1: 
Criteria for Potentially Clinically Significant Vital Signs ............................................... 46 
Table 6-1: 
Directionality of Worst Laboratory Parameters .............................................................. 48 
Table 6-2: 
Hematology and Coagulation Toxicity Grading Scale .................................................... 49 
Table 6-3: 
Chemistry Toxicity Grading Scale .................................................................................. 50 
Table 6-4: 
Enzymes Toxicity Grading Scale .................................................................................... 51 
Table 6-5: 
Hematology Laboratory Normals .................................................................................... 51 
Table 6-6: 
Coagulation Laboratory Normals .................................................................................... 52 
Table 6-7: 
Serum Chemistry Laboratory Normals ........................................................................... 52 
 


 
Cidara Therapeutics, Inc. 
Statistical Analysis Plan, Protocol CD101.IV.2.03 
17 May 2019, FINAL Version 4.0 
 
CONFIDENTIAL 
Page 7 of 56 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
Abbreviation 
Definition 
AE 
Adverse event 
ALP 
Alkaline phosphatase 
ALT 
Alanine aminotransferase 
APTT 
Activated partial thromboplastin time 
AST 
Aspartate aminotransferase 
ATC 
Anatomical therapeutic chemical 
bpm 
Beats per minute 
BMI 
Body mass index 
BUN 
Blood urea nitrogen 
C 
Celsius 
CH 
Potentially Clinically Significant High 
CI 
Confidence Interval 
CL 
Potentially Clinically Significant Low 
CSR 
Clinical Study Report 
CTCAE 
Common Terminology Criteria for Adverse Events 
CV 
Coefficient of Variability 
dL 
deciliter 
DMID 
Division of Microbiology and Infectious Diseases 
DAIDS 
Division of AIDS 
ECG 
Electrocardiogram 
eCRF 
Electronic Case Report Form 
EOT 
End-of-Treatment 
FU 
Follow-up 
g 
Gram 
gm 
Gram 
ICH 
International Conference on Harmonisation 
IC 
Invasive Candidiasis 
ICU 
Intensive Care Unit 
IEC 
Independent Ethics Committee 
INR 
International normalized ratio 
IRB 
Institutional Review Board 
ITT 
Intent-to-treat 
IV 
Intravenous 
IVD 
In vitro diagnostic 
IWRS 
Interactive Web Response System 
kg 
kilogram 
L 
Liter 


 
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17 May 2019, FINAL Version 4.0 
 
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Abbreviation 
Definition 
LLN 
Lower limit of normal 
Max 
Maximum 
MedDRA 
Medical Dictionary for Regulatory Activities 
mEq 
Milliequivalence 
mg 
Milligram 
MIC 
Minimum inhibitory concentration 
Min 
Minimum 
mITT 
Microbiological Intent-to-treat 
mL 
Milliliter 
m2 
Square meter 
mm3 
Cubic millimeter 
mmHg 
Millimeter of mercury 
msec 
Millisecond 
NLM 
National Library of Medicine 
N 
Negative 
% 
Percent 
P 
Positive 
PCS 
Potentially Clinically Significant 
pH 
Hydrogen ion concentration 
PI 
Principal Investigator 
PK 
Pharmacokinetic 
PT 
Preferred Term or Prothrombin time 
PTT 
Partial thromboplastin time 
QTcF 
QT interval with Fridericia correction 
RBC 
Red blood cell (count) 
SAE 
Serious treatment-emergent adverse event 
SAP 
Statistical analysis plan 
SD 
Standard deviation 
SI 
Systeme Internationale  
SOC 
System organ class 
TEAE 
Treatment-emergent adverse event 
ULN 
Upper limit of normal 
US 
United States 
WBC 
White blood cell (count) 
WHO 
World Health Organization 


 
Cidara Therapeutics, Inc. 
Statistical Analysis Plan, Protocol CD101.IV.2.03 
17 May 2019, FINAL Version 4.0 
 
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Page 9 of 56 
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 2, Multicenter, Randomized, Double-blind Study 
of the Safety, Tolerability, and Efficacy of Intravenous CD101 vs Intravenous Caspofungin 
Followed by Oral Fluconazole Step-down in the Treatment of Subjects with Candidemia and/or 
Invasive Candidiasis.” 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 will 
not be included in this SAP. 
CD101 is a new semi-synthetic echinocandin antifungal agent that is being developed 
specifically to treat subjects with systemic infections caused by Candida. 
1.1.2. 
Study Objectives 
The primary objectives of this study are to: 
• Evaluate the safety and tolerability of intravenous CD101 (CD101 IV) in the Safety 
population. 
• Evaluate overall success (mycological eradication and resolution of systemic signs 
attributable to candidemia and/or invasive candidiasis [IC]) of CD101 IV in subjects 
with candidemia and/or IC at Day 14 (±1 day) in the Microbiological Intent-to-treat 
(mITT) population. 
The secondary objectives of this study are to: 
• Evaluate overall success (mycological eradication and resolution of systemic signs 
attributable to candidemia and/or IC) of CD101 IV at Day 5, Day 28 (±2 days; only for 
subjects with IC), and Follow-up (FU, Days 45-52 or Days 52-59 for subjects with IC) in 
the mITT population. 
• Evaluate mycological success (eradication) of CD101 IV at Day 5, Day 14 (±1 day), 
Day 28 (±2 days; only for subjects with IC) and FU (Days 45-52 or Days 52-59 for 
subjects with IC) in the mITT population. 
• Evaluate clinical cure as assessed by the Investigator for CD101 IV at Day 14 (±1 day), 
Day 28 (±2 days; only for subjects with IC), and FU (Days 45-52 or Days 52-59 for 
subjects with IC) in the mITT population. 
• Evaluate the PK of CD101 IV. 
1.2. 
Study Design 
1.2.1. 
Synopsis of Study Design 
This is a Phase 2, multicenter, prospective, randomized, double-blind study of CD101 IV or 
intravenous caspofungin followed by oral fluconazole step-down therapy for treatment of 
subjects with candidemia and/or IC. Subjects will be randomized at about 60 sites in North 
America (the United States [US] and Canada) and countries in Europe. 


 
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17 May 2019, FINAL Version 4.0 
 
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In Part A, subjects will be randomized in a 1:1:1 ratio to receive CD101 IV treatment group 1, 
CD101 IV treatment group 2, or IV caspofungin using an interactive web response system 
(IWRS). Upon meeting specified criteria, oral step-down therapy is allowed in all 3 treatment 
groups: oral placebo in the CD101 IV groups and oral fluconazole in the IV caspofungin group. 
After approximately 90 subjects have been enrolled in the mITT population in Part A, 
enrollment into Part A of the study will close and Part B will begin. It is expected that 
approximately 114 subjects need to be randomized to achieve 90 subjects in the mITT 
population for Part A. 
In Part B, subjects enrolled under Amendment 5 will be randomized in a 2:1 ratio until there are 
≥30 subjects in the CD101 IV treatment group 1 and ≥15 subjects in the comparator group (≥45 
additional subjects and no more than 120 subjects). Following the results of the unblinded 
analysis of Part A, the Part B subjects enrolled under Amendment 6 will be randomized in a 2:1 
ratio to receive the CD101 IV treatment group 2 or IV Caspofungin. Total enrollment for Part B 
will depend on the enrollment rate for the period between the end of Part A and the start of the 
Phase 3 study, which is the trigger for Part B to stop enrollment. Oral step-down therapy is 
allowed in both treatment groups in Part B; oral placebo in the CD101 IV 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 21 days total for subjects with candidemia and up to a maximum of 
28 days total for subjects with IC. 
Subjects randomized to the CD101 IV treatment group 1 will receive 1 dose of CD101 IV (400 
mg) over 60 (±10) minutes on Day 1 and Day 8 and IV placebo on other study days in order to 
maintain the blind; subjects who require >14 days of IV therapy will receive an optional third 
dose of CD101 IV (400 mg) on Day 15. Subjects with IC are allowed an optional CD101 IV 
dose (400 mg) on Day 22 if additional therapy is required. Subjects in group 1 will receive IV 
placebo on other study days in order to maintain the blind. Subjects randomized to the CD101 
IV treatment group 2 will receive 1 dose of CD101 IV (400 mg) over 60 (±10) minutes on Day 
1, 200 mg on Day 8 and IV placebo on other study days in order to maintain the blind; subjects 
who require >14 days of IV therapy will receive an optional third dose of CD101 IV (200 mg) 
on Day 15. Subjects with IC are allowed an optional CD101 IV dose (200 mg) on Day 22 if 
additional therapy is required. Subjects in group 2 will receive IV placebo on other study days in 
order to maintain the blind. Subjects may receive oral step-down therapy after ≥3 days of IV 
therapy, if criteria are met. Step-down therapy in both CD101 IV treatment groups 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 CD101 IV on Day 8 and optional oral placebo and 
CD101 IV on Day 15 for subjects who require >14 days of therapy. Dosage adjustments are not 
allowed. Intravenous study drug is administered 24 (±2) hours after study drug was 
administered on the previous day. 
Subjects randomized to the caspofungin group will receive IV caspofungin (70 mg loading dose 
on Day 1 and then 50 mg/day) for ≥3 days up to a maximum of 21 days for subjects with 
candidemia only or up to a maximum of 28 days for subjects with IC. After ≥3 days of IV 
therapy, subjects in the IV caspofungin group can be switched to oral step-down therapy if 
criteria are met. Step-down therapy in the caspofungin treatment group will be oral fluconazole 
(a loading dose of 800 mg [4 capsules] on the first day followed by 400 mg [2 capsules]/day 
thereafter). 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, Day 15 for subjects who 
require >14 days of therapy. Intravenous study drug is administered 24 (±2) hours after study 
drug was administered on the previous day. 


 
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Subjects in the caspofungin group with moderate hepatic impairment (Child-Pugh score of 7-9) 
will receive a loading dose of caspofungin of 70 mg on Day 1 and 35 mg/day thereafter. 
Subjects in the caspofungin group weighing >80 kg or on concomitant rifampin, nevirapine, 
efavirenz, phenytoin, dexamethasone, or carbamazepine may receive 70 mg caspofungin daily. 
Dose adjustment due to drug-drug interactions or subject weight may be considered at the 
Investigator’s discretion. Dosage adjustments in the CD101 IV treatment groups are not 
allowed. 
Subjects in the caspofungin group with renal impairment who are switched to oral step-down 
therapy may receive reduced doses of fluconazole. For subjects with creatinine clearance 
≤50 mL/min, oral step-down therapy should be fluconazole (a loading dose of 400 mg 
[2 capsules] on the first day followed by 200 mg [1 capsule]/day thereafter) in the caspofungin 
treatment group and oral placebo (2 capsules on the first day followed by 1 capsule/day 
thereafter) in the CD101 treatment groups. 
For subjects receiving hemodialysis, oral step-down therapy should be fluconazole (a full 
loading dose of 800 [4 capsules] followed by 400 mg [2 capsules] only after each episode of 
hemodialysis) in the caspofungin treatment group and oral placebo (4 capsules on the first day 
followed by 2 capsules after each hemodialysis) in the CD101 treatment groups. 
1.2.2. 
Randomization and Blinding 
After informed consent has been obtained, subjects will be screened for study eligibility before 
randomization. Subjects in Part A will be assigned a subject number and randomized (1:1:1) to 
receive CD101 IV treatment group 1, CD101 IV treatment group 2, or caspofungin on Day 1 
just prior to dosing. Subjects in Part B enrolled under Amendment 5 will be assigned a subject 
number and randomized (2:1) to receive CD1010 IV treatment group 1 or caspofungin on Day 1 
just prior to dosing. Subjects in Part B enrolled under Amendment 6 will be assigned a subject 
number and randomized (2:1) to receive CD1010 IV treatment group 2 or caspofungin. 
Randomization will be stratified based on the method used at Screening to establish the 
diagnosis (blood culture/rapid in vitro diagnostic [IVD] and positive Gram stain/culture from a 
specimen obtained from a normally sterile site). If a subject has both a positive blood 
culture/rapid IVD and Gram stain/culture from a specimen obtained from a normally sterile site, 
the subject will be randomized within the positive Gram stain/culture from a specimen obtained 
from a normally sterile site stratum. The study site’s pharmacist (or pharmacist designee) will 
obtain the study drug assignment from the IWRS. A subject is considered randomized when a 
randomization transaction has been recorded in the IWRS and the subject is assigned a 
randomization number. 
All subjects and study personnel, including the Sponsor, Principal Investigator (PI), and site 
personnel involved in study conduct will remain blinded to by subject study medication 
assignment for both Part A and Part B until the study is completed and the database is locked, 
with the exception of the Pharmacy Monitor to monitor drug preparation and drug 
accountability during the study and cases in which unblinding is required due to a safety or 
tolerability issue. Additionally, in Part A only, some personnel including the PK analyst and an 
unblinded statistician, will be unblinded but will not be involved in the study conduct or the 
final analysis. An unblinded statistician will perform the analysis on the interim and final 
unblinded Part A data. 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). 


 
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Instructions for study drug preparation and dosing are outlined in the Pharmacy Manual 
provided separately to the site. In the case of a medical emergency requiring the PI to know the 
identity of the study drug, the PI will follow the procedures outlined in SAP Section 1.2.3. 
1.2.3. 
Stopping Rules 
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 adverse events (AEs) in this or other studies of CD101 IV 
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 
• Institutional Review Board/ Independent Ethics Committee (IRB/IEC) decision to 
terminate or suspend approval for the investigation or the Investigator 
• Investigator request to withdraw from participation 
• Subject enrollment is unsatisfactory 
For subjects who prematurely discontinue study drug (ie, before the anticipated full course of 
study drug therapy required for effective treatment of candidemia and/or IC), End-of-Treatment 
(EOT) assessments should be performed on the day of discontinuation. Reasons for withdrawal 
from study drug may include, but are not limited to: 
• Screening cultures negative for Candida spp. 
• Safety 
• Invasive Candidiasis involving a site involving the central nervous system or eye 
• Insufficient therapeutic effect 
• Investigator discretion 
The decision to continue or discontinue a subject on the study drug in the event that the subject 
requires systemic concomitant antifungal therapy will be discussed between the PI and Medical 
Monitor. 
1.2.4. 
Unblinding 
This study is a double-blind design. 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. 
Prior to any unblinding, the PI is strongly advised to discuss options with the Medical Monitor 
or appropriate Sponsor study personnel. 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 and the PI was unable to 
contact the Sponsor prior to unblinding. The PI will record in source documentation the date and 
reason for revealing the blinded treatment assignment for that subject. 
The data from Part A will be unblinded for an interim analysis of select efficacy and safety 
outcomes but individual treatment assignments will not be made available to the Sponsor. After 
the database is locked for Part A, but prior to completion of Part B, Part A will be unblinded and 


 
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full summary results reported when available. Individual subject treatment assignments will not 
be made available the Sponsor at the time the summary results for Part A are reported. 
1.2.5. 
Study Procedures 
After informed consent is obtained, all potential study participants undergo screening 
evaluations, which include a medical history, clinical assessments, and laboratory assessments. 
Mycological diagnosis of candidemia at Screening will be established by ≥1 blood culture 
positive for yeast or Candida spp., a Sponsor-approved rapid IVD test positive for Candida 
spp., or a positive Gram stain for yeast or a positive culture for Candida spp. from a specimen 
obtained from a normally sterile site from a sample taken within 96 hours before randomization. 
If the positive blood culture used to qualify the subject for the study is drawn >12 hours from 
randomization, then an additional set of blood cultures must be obtained ≤12 hours before 
randomization. Assessments of mycological eradication and clinical response will be performed 
at Day 5, Day 14 (±1 day), Day 28 (±2 days) for subjects with IC and the FU visit (Days 45-52 
or Days 52-59 for IC subjects). Blood cultures should be performed daily or every other day 
until 2 blood cultures drawn ≥12 hours are negative without an intervening positive culture. The 
schedule of assessments and procedures, as outlined in the study protocol, is presented in 
Table 1-1. 
Study participation will require from 45 to 52 days (or 52-59 days for subjects with IC) after the 
first administration of study drug; study drug administration from Day 1 up to Day 21 (for 
subjects with candidemia) or up to Day 28 (±2 days; only for subjects with IC); PK assessments 
on Days 1, 2, 4, 8, and 15; safety, tolerability, and efficacy assessments up to Day 21 (for 
subjects with candidemia only) or up to Day 28 (±2 days; only for subjects with IC); and a FU 
visit at Days 45 to 52 (or 52-59 days for subjects with IC). 
 


 
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Table 1-1: 
Schedule of Assessments and Procedures 
Study Day 
(window) 
Screen 
 
Study Drug Administration, Days 
EOT 
+2 days 
after 
last 
dose of 
study 
drug  
(IV and 
oral) 
FU Visit 
Days 45-52 
for subjects 
with 
candidemia 
only  
(or Day 52-
59 for IC 
subjects 
with or 
without 
candidemia) 
1a 
 
2 
 
3 
 
4 
 
5 
 
6, 7 
 
8b 
(±1) 
9-13 
 
14b 
(±1) 
15b 
(±1) 
16-21 
 
22b,c 
(±1) 
23-
27c 
28b,d 
(±2) 
Informed consent e 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history f 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical examination 
including height and weight g 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
 
X 
 
X 
Calculate Child-Pugh score h 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Modified APACHE II score 
with Glasgow coma score i 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital signs j 
X 
X 
X 
X 
X 
X 
Xk 
X 
Xk 
X 
Xk 
Xk 
X 
Xk 
X 
X 
X 
12-lead ECG l  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Radiologic test results m 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Blood for hematology and 
chemistry tests n 
X 
 
X 
 
X 
 
 
X 
 
X 
 
 
 
 
 
X 
X 
Blood for coagulation panel 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urine for urinalyses, 
microscopy 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Urine pregnancy test o 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 


 
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Study Day 
(window) 
Screen 
 
Study Drug Administration, Days 
EOT 
+2 days 
after 
last 
dose of 
study 
drug  
(IV and 
oral) 
FU Visit 
Days 45-52 
for subjects 
with 
candidemia 
only  
(or Day 52-
59 for IC 
subjects 
with or 
without 
candidemia) 
1a 
 
2 
 
3 
 
4 
 
5 
 
6, 7 
 
8b 
(±1) 
9-13 
 
14b 
(±1) 
15b 
(±1) 
16-21 
 
22b,c 
(±1) 
23-
27c 
28b,d 
(±2) 
Retinal examination for 
Candida eye infection p 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Study randomization q 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Administer IV CD101 or IV 
placebo 
 
Xr 
Xs 
Xs 
Xt 
Xt 
Xt 
Xu 
Xt 
Xt 
Xv 
Xw 
Xx 
Xy 
Xy 
 
 
Administer IV caspofungin 
or IV placebo  
 
Xr 
Xs 
Xs 
Xt 
Xt 
Xt 
Xu 
Xt 
Xt 
Xv 
Xw 
Xx 
Xy 
Xy 
 
 
Administer oral fluconazole 
or oral placebo step-down 
therapy if switched z 
 
 
 
 
Xt 
Xt 
Xt 
Xu 
Xt 
Xt 
Xv 
Xw 
Xx 
Xy 
Xy 
 
 
Record prior and/or 
concomitant medications aa 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
Record adverse events bb 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
Blood or normally sterile 
tissue/fluid for culture cc 
Xdd 
Xee 
Xee 
Xee 
Xee 
Xee 
Xee 
Xee 
Xee 
Xee 
Xee 
Xee 
Xee 
Xee 
Xee 
Xee 
Xff 
Rapid In Vitro Diagnostic 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Determine overall response 
programmatically gg 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
 
X 
 
X 


 
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Study Day 
(window) 
Screen 
 
Study Drug Administration, Days 
EOT 
+2 days 
after 
last 
dose of 
study 
drug  
(IV and 
oral) 
FU Visit 
Days 45-52 
for subjects 
with 
candidemia 
only  
(or Day 52-
59 for IC 
subjects 
with or 
without 
candidemia) 
1a 
 
2 
 
3 
 
4 
 
5 
 
6, 7 
 
8b 
(±1) 
9-13 
 
14b 
(±1) 
15b 
(±1) 
16-21 
 
22b,c 
(±1) 
23-
27c 
28b,d 
(±2) 
Assess presence or absence 
of systemic signs and 
symptoms attributable to 
candidemia and/or IC 
Xhh 
 
 
 
 
Xii 
 
 
 
X 
 
 
 
 
X 
 
X 
Assess for clinical response jj 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
X 
 
X 
Blood for PK testing (Part A 
Only) kk 
 
X 
X 
 
X 
 
 
X 
 
 
X 
 
 
 
 
 
 
APACHE = Acute Physiology and Chronic Health Evaluation; ECG = electrocardiogram; EOT = End-of-Therapy; ESCMID = European Society Clinical 
Microbiology and Infectious Disease; FU = follow-up; IC = Invasive Candiasis; IDSA = Infectious Disease Society of America; IV=Intravenous; IVD = in vitro 
diagnostic; PK = pharmacokinetic. 
a. Study Day 1 is the first day of study drug administration; subsequent study days are consecutive calendar days. 
b.  The time windows on Study Day 8, 14, 15, 22, and 28 visits apply only to subjects already stepped down to oral therapy and discharged from the study site. 
c. Perform if further therapy is clinically indicated; only for subjects with IC (with or without candidemia). Subjects will be considered to have IC if there is a 
positive culture for Candida spp. from a normally sterile site other than blood or if there is a positive sponsor-approved rapid IVD or blood culture for 
Candida spp. combined with radiographic evidence of IC. 
d. The Day 28 visit is only for subjects with IC (with or without candidemia). Note that the Day 28 (±2 days) visit could be the same visit as the EOT visit if the 
subject receives ≥26 days of therapy. 
e. Written informed consent must be obtained prior to initiating any study related assessments or procedures. 
f. Medical history for the last 5 years and Candida risk factors for the last 3 months (eg, 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 admission and discharge (if applicable). Short-term central venous catheters (eg, peripherally-inserted central catheters, internal jugular or subclavian 
central venous catheters) and long-term central venous catheters (eg, tunneled catheters) are recommended to be removed within 48 hours after diagnosis with 
candidemia, consistent with IDSA and ESCMID guidelines  
g. Physical exams are required at Screening, on Day 14, Day 28 (±2 days; only for subjects with IC), and at the FU visit. Height is recorded at Screening. 
Weight is recorded at Screening, on Day 14, and at the FU visit. If a physical exam is performed at any other visit, abnormal findings that represent a new or 
worsening condition as compared to baseline should be recorded as an adverse event. 
h. Calculate Child-Pugh score only if the subject has a history of chronic cirrhosis 


 
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i. APACHE II score can be calculated after enrollment, but should use the vital signs and laboratory results from the Screening visit. 
j. If hospitalized, record the range of vital signs; highest and lowest daily temperature and the method used (oral, rectal, temporal, tympanic, or core), highest 
and lowest heart rate, highest and lowest respiratory rate, and highest and lowest blood pressure measured. If not hospitalized, record single measurements for 
daily temperature and the method used (oral, rectal, temporal, tympanic, or core), heart rate, respiratory rate, and blood pressure. 
k. For subjects discharged from the hospital and in the community, vital signs (temperature, heart rate, blood pressure, respiratory rate) are only performed on 
Days 6-28 if the subject is seen for clinical assessment or IV study drug infusion 
l. ECG must be conducted before subject randomization.  
m. If radiologic test performed, record radiologic test type with Findings and Interpretation only if radiologic test provides evidence of IC, OR evidence of 
resolution of IC from previous radiographs. 
n. In general, the laboratory values to be entered into the electronic case report form will be from the first laboratory samples drawn each day with routine 
morning laboratory samples. 
o. Perform urine pregnancy test only for women of childbearing potential. Do not perform for women who are ≥2 years post-menopausal or surgically sterile. 
p. Perform a retinal examination for evidence of a Candida eye infection, including endophthalmitis or chorioretinitis, by Day 7 only on subjects with 
candidemia by blood culture, and repeat in subjects who were negative at baseline if the subject develops visual signs or symptoms of a Candida eye infection 
during the course of the study. 
q. Verify that the subject meets all study inclusion and exclusion criteria before randomization. 
r. On Day 1, subjects will receive IV CD101 or IV caspofungin 
s.  On Days 2-3, subjects will receive IV caspofungin or IV placebo. 
t.  On Days 4-7, and 9-14, subjects will receive either IV caspofungin; IV placebo (if in a CD101 group); oral fluconazole (caspofungin group) if already 
switched; or oral placebo (CD101 groups) if already switched. 
u. On Day 8, subjects will receive either IV CD101 (if in a CD101 group and not switched to oral therapy); IV caspofungin (if in caspofungin group and not 
switched to oral therapy), IV CD101 plus oral placebo (if in a CD101 group and already switched to oral therapy); or IV placebo plus oral fluconazole (if in 
caspofungin group and already switched to oral therapy). 
v. On Day 15, subjects may receive either IV CD101 (if in a CD101 group and not switched to oral therapy), if needed; IV caspofungin (if in caspofungin group 
and not switched to oral therapy), if needed; IV CD101 plus oral placebo (if in a CD101 group and already switched to oral therapy), if needed; IV placebo 
plus oral fluconazole (if in caspofungin group and already switched to oral therapy), if needed; or no treatment. 
w.  On Days 16-21, subjects may receive either IV caspofungin (if in caspofungin group), if needed; IV placebo (if in a CD101 group), if needed; oral 
fluconazole (caspofungin group) if already switched and needed; oral placebo (CD101 groups) if already switched and needed; or no treatment. 
x. On Day 22, subjects with IC (with or without candidemia) may receive either IV CD101 (if in a CD101 group and not switched to oral therapy), if needed; IV 
caspofungin (if in caspofungin group and not switched to oral therapy), if needed; IV CD101 plus oral placebo (if in a CD101 group and already switched to 
oral therapy), if needed; IV placebo plus oral fluconazole (if in caspofungin group and already switched to oral therapy), if needed; or no treatment. 
y. On Days 23-28, subjects may receive either IV caspofungin (if in caspofungin group), if needed; IV placebo (if in a CD101 group), if needed; oral 
fluconazole (caspofungin group) if already switched and needed; oral placebo (CD101 groups) if already switched and needed; or no treatment 
z. Oral step-down therapy will be fluconazole (a loading dose of 800 mg [4 capsules ] on the first day followed by 400 mg [2 capsules ]/day thereafter) in the 
caspofungin group and oral placebo (4 capsules on the first day followed by 2 capsules/day thereafter) in the CD101 groups. 
aa. Record all systemic antifungal therapy administered within 4 weeks and all non-antifungal therapy administered within 1 week prior to randomization Record 
concomitant antimicrobial agents, including all antifungal agents at each study visit. 
bb. Adverse events are collected following signing of the informed consent form at Screening through the last study visit (FU) 


 
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cc. Perform identification and susceptibility testing at local laboratory for Candida for any positive blood culture or positive culture from a specimen obtained 
from a normally sterile site at Screening and for any positive culture requiring a change of antifungal therapy (ie, identification and susceptibility testing not 
required for Candida isolates cultured from specimens obtained on other study days without a required change in antifungal therapy). 
dd. Blood for culture must be obtained as part of the standard of care for inclusion in the study. Established mycological diagnosis of candidemia and/or IC 
sufficient for inclusion in the study is defined as ≥1 blood culture positive for yeast or Candida, a Sponsor-approved rapid IVD test positive for Candida spp, 
or a positive Gram stain for yeast or positive culture for Candida spp. from a specimen obtained from a normally sterile site ≤96 hours before randomization. 
Record species and susceptibilities for all bacteria isolated within 1 week prior to randomization from blood or any other normally sterile site. If the positive 
blood culture used to qualify the subject for the study is drawn >12 hours from randomization, then an additional set of blood cultures must be obtained ≤12 
hours before randomization. 
ee. Obtain blood and/or normally sterile tissue/fluid for culture if demonstrating mycological eradication or if clinically indicated. Blood cultures should be 
repeated daily (preferred) or every other day until 2 negative blood cultures are obtained ≥12 hours apart, without an intervening positive culture. All fungal 
isolates cultured from blood and normally sterile tissue/fluid from Screening through the last study visit must be sent to the Central Laboratory. Record the 
species and susceptibilities for any new bacteria isolated from blood or any other normally sterile site. 
ff. Obtain blood for culture at FU. If feasible, and if there was a previous culture from a site positive for Candida spp., obtain culture from normally sterile 
tissue/fluid from the same site. All fungal isolates cultured from blood and normally sterile tissue/fluid from Screening through the last study visit must be 
sent to the Central Laboratory. Record the species and susceptibilities for any new bacteria isolated from blood or any other normally sterile site. 
gg. Overall success for subjects with candidemia occurs if 2 blood cultures are negative and ≥12 hours apart without intervening positive blood cultures, there 
was no change of antifungal therapy for the treatment of candidemia, and signs attributable to candidemia at baseline have resolved; blood cultures are drawn 
daily until the subject qualifies as a success. Success for subjects with IC (with or without candidemia) occurs if negative culture from a normally sterile site 
is either documented or presumed, there was no change of antifungal therapy for the treatment of IC, and signs attributable to IC at baseline have resolved: 
documented mycological eradication occurs if most recent culture on or prior to the day of assessment from all normally sterile sites of baseline Candida 
infection (if accessible) is negative; presumed mycological eradication occurs if follow-up culture is not available (eg, normally sterile baseline site of 
Candida infection not accessible) in a subject with a successful clinical outcome (ie, did not receive rescue antifungal treatment and has resolution of systemic 
signs of IC) and resolution or improvement of any baseline radiographic abnormalities due to IC. 
hh. The Screening period for assessing systemic signs for inclusion in the study may include the 4 hours prior to the drawing of the qualifying positive blood 
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. 
ii. On Day 5, assess presence or absence of systemic signs only (ie, not symptoms) and determine which are attributable to candidemia and/or IC 
jj. Principal Investigator to assess if the subject is a cure, indeterminate, or failure based on the criteria in Table 1-5; there is a specific electronic case report 
form page for completion of this assessment. 
kk. In Part A only, obtain blood for PK sampling from the OPPOSITE arm of the infusion on Day 1 (within 10 minutes [ie, >0 to 10 minutes] before the end of 
infusion, between 15 minutes and 1 hour after the end of infusion, and between 2 hours and 12 hours after the end of infusion), Day 2 (random draw with date 
of sample same as Day 2 date of dose, with safety labs if possible), Day 4 (random draw with date of sample same as Day 4 date of dose, with safety labs if 
possible), Day 8 (predose only), and Day 15 (predose only). Day 8 and Day 15 PK draws should be performed within 30 minutes before the second and third 
dose of study drug, regardless of the exact day and time of these infusions. If therapy is stopped on or before Day 14 and there is no Day 15 dose, then the 
Day 15 PK sample should be drawn with the safety laboratory samples for the Day 14 visit. Ideally, PK samples would be drawn with the safety laboratory 
samples for that day to prevent multiple needle sticks. 
 


 
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1.2.6. 
Definitions of Outcome Measures 
1.2.6.1. 
Efficacy Outcome Measures 
Efficacy outcome measures include overall response, mycological response and Investigator’s 
Assessment of clinical response as well as all-cause mortality through FU, and time to negative 
blood culture. 
Overall Response 
The primary efficacy outcome measure is overall response at Day 14 (±1 day), which will be 
determined from the mycological response and assessment of systemic signs attributable to 
candidemia and/or IC (Table 1-2). Mycological response and assessment of systemic signs 
attributable to candidemia and/or IC are also determined at Day 5, Day 28 (±2 days; only for 
subjects with IC) and FU Visit (Days 45-52 or Days 52-59 for subjects with IC). The signs that 
may be present at baseline and attributable to candidemia and/or IC include fever, hypothermia, 
hypotension, tachycardia, and tachypnea. Subjects who require a change of antifungal therapy to 
treat candidemia and/or IC prior to a given day of the overall response assessment should have 
the assessment of systemic signs attributable to candidemia and/or IC moved forward to the 
early EOT evaluation. Assessments of systemic signs performed prior to the early EOT will be 
unaffected. 
Table 1-2: 
Overall Response Categories 
 
Definition 
Overall Response 
Mycological Response 
Systemic Signs 
Success 
Success (eradication/presumed 
eradication)* 
Resolution of attributable systemic signs of candidemia 
and/or invasive candidiasis that were present at baseline 
Failure 
Success (eradication/presumed 
eradication)* 
Recurrence or lack of resolution of attributable 
systemic signs of candidemia and/or invasive 
candidiasis  
Failure 
Resolution of attributable systemic signs of candidemia 
and/or invasive candidiasis that were present at baseline 
Failure 
Recurrence or lack of resolution of attributable 
systemic signs of candidemia and/or invasive 
candidiasis 
Failure 
Assessment of systemic signs was not completed at 
visit or at baseline for any reason (including death)  
Indeterminate 
Indeterminate 
Resolution of attributable systemic signs of candidemia 
and/or invasive candidiasis that were present at baseline 
Success (eradication/presumed 
eradication)* 
Assessment of clinical signs was not completed for any 
reason at visit or at baseline 
* Presumed eradication is defined only for a culture from a normally sterile site and is not defined for a blood 
culture. 
The overall success rate is the proportion of subjects with success out of the total number of 
subjects evaluated. 


 
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Mycological Response 
Mycological response will be programmatically determined from the electronic case report form 
(eCRF) and central mycology data at Day 5, Day 14 (±1 day), Day 28 (±2 days; only for 
subjects with IC) and FU (Days 45-52 or Days 52-59 for subjects with IC), according to the 
definitions in Table 1-3. Determination of the identification of fungal pathogens will follow the 
process defined in SAP Section 4. 
Table 1-3: 
Mycological Response Definitions 
Mycological 
Response 
Definition 
Success 
(eradication/presumed 
eradication) * 
• If positive blood culture at baseline: 
o 
The last blood culture drawn on or prior to the day of assessment and another 
blood culture drawn at least 12 hours prior are both negative for Candida spp and 
both blood cultures were drawn after initiation of study drug, 
AND 
o 
Any intervening blood cultures drawn between the 2 qualifying negative blood 
cultures are also negative for Candida spp. 
• If positive culture from a normally sterile site at baseline: 
o 
Documented mycological eradication: culture on day of assessment from all 
normally sterile sites of baseline Candida infection (if accessible) is negative OR if 
no culture on the day of assessment, the most recent culture obtained after the 
initiation of study drug is negative, 
OR 
o 
Presumed mycological eradication: follow-up culture is not available (eg, normally 
sterile baseline site of Candida infection not accessible) or the most recent culture 
obtained after the initiation of study drug is positive in a subject with a successful 
clinical outcome (ie, did not receive rescue antifungal treatment and has resolution 
of systemic signs of invasive candidiasis that were present at baseline) and 
resolution or improvement of any baseline radiographic abnormalities due to 
invasive candidiasis,  
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. 
 
Note: Subjects with positive cultures from both blood and a normally sterile site will need 
to meet success criteria for both blood and normally sterile site to be considered success. 


 
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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 or any blood 
culture drawn prior to and within 12 hours of the last blood culture is positive for 
Candida spp and both blood cultures were drawn after the initiation of study drug, 
OR 
o 
The most recent blood culture drawn at least 12 hours prior to the last blood 
culture is positive for Candida spp. and culture was obtained after the initiation of 
study drug. 
OR 
• If positive culture from a normally sterile site at baseline: 
o 
Documented mycological persistence: culture on day of assessment from all 
normally sterile sites of baseline Candida infection (if accessible) is positive, 
OR 
o 
Presumed mycological persistence: follow-up culture is not available  (eg, 
normally sterile baseline site of Candida infection not accessible) or the most 
recent culture obtained after the intiation of study drug is positive in a subject 
without a successful clinical outcome or with continued (from baseline) 
radiographic abnormalities due to invasive candidiasis,  
OR 
• The subject requires a change of antifungal therapy to treat candidemia, 
OR 
• The subject dies of any cause prior to or on the day of assessment. 
Indeterminate 
• If positive blood culture at baseline: A 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 of signs of invasive candiasis was 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 1-4 provides examples of timing of the blood cultures and how these are used for 
determination of the mycological response. 


 
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Table 1-4: 
Examples of Timing of Blood Cultures 
 
Blood Cultures 
Mycological Response [1] 
Example 1 
Day of Assessment: Day 14 (T=0 hours) 
Blood cultures: T=0 (N), T= -18 (N) 
Success (eradication) 
Example 2 
Day of Assessment: Day 14 (T=0 hours) 
Blood cultures: T=0 (N), T= -10 (P) T= -18 (N) 
Failure 
Example 3 
Day of Assessment: Day 14 (T=0 hours) 
Blood cultures: T= -20 (N), T= -28 (N) T= -34 (P) 
Failure 
Example 4 
Day of Assessment: Day 14 (T=0 hours) 
Blood cultures: T= -20 (N), T= -68 (N) 
Success (eradication) 
T = Time; time is relative to the date and time of assessment of mycological response. 
N = Blood culture negative for any Candida spp. 
P = Blood culture positive for any Candida spp. 
[1] For Success (eradication), assumes no other criteria for failure are met. 
The mycological success rate is the proportion of subjects with success (eradication/presumed 
eradication) out of the total number of subjects evaluated. 
Clinical Response 
The Investigator will make a determination of clinical response at Day 14 (±1 day), Day 28 
(±2 days; only for subjects with IC), and the FU visit (Days 45-52 or Days 52-59 for subjects 
with IC) according to the definitions in Table 1-5. Efficacy windows are to be applied for each 
timepoint and are listed in Table 3-2. Subjects whose disease is progressing or who receive 
rescue antifungal therapy for candidemia prior to Day 14 (±1 day) will be considered a clinical 
failure at Day 14 (±1 day), Day 28 (±2 days; only for subjects with IC), and the FU visits. 
Subjects who are a clinical cure at Day 14 (±1 day) and whose symptoms recur between Day 14 
(±1 day) and Day 28 (±2 days; only for subjects with IC) or FU or who receive rescue antifungal 
therapy will be considered a failure at the Day 28 (±2 days; only for subjects with IC) or FU 
visit. 


 
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Table 1-5: 
Investigator’s Assessment of Clinical Response Definitions 
Clinical 
Response 
Definition 
Cure 
• Resolution of attributable systemic signs and symptoms of candidemia and/or IC that were 
present at baseline, 
AND 
• No new systemic signs or symptoms attributable to candidemia and/or IC, 
AND 
• No additional systemic antifungal therapy administered for candidemia and/or IC, 
AND 
• The subject is alive. 
Failure 
• Progression or recurrence of attributable systemic signs or symptoms of candidemia and/or 
IC, 
OR 
• Lack of resolution of attributable systemic signs or symptoms of candidemia and/or IC, 
OR 
• Requirement for new or prolonged therapy to treat candidemia and/or IC *, 
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: 
• Lost to follow-up, 
• Withdrawal of consent, 
• Extenuating circumstances that preclude the classification of clinical outcome of 
candidemia and/or IC. 
AE = adverse event; IC = invasive candidiasis; IV = intravenous. 
* Prolonged antifungal therapy is defined as therapy for the treatment of candidemia extending beyond the 
allowable 21 days for study drug or for the treatment of IC 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 cure rate is the proportion of subjects with a cure clinical response out of the total number 
of subjects evaluated. 
 
Exploratory Mycological Response 
Exploratory mycological response will be programmatically determined from the electronic case 
report form (eCRF) and central mycology data at Day 14 (±1) and will be defined similarly to 
mycological response with only 1 blood sample used in the derivation. The responses will be 
derived according to the definitions in Table 1-6. 


 
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Table 1-6: 
Exploratory Mycological Response Definitions 
Exploratory 
Mycological 
Response 
Definition 
Success 
(eradication/presumed 
eradication) * 
• If positive blood culture at baseline: 
o 
The last blood culture drawn on or prior to the day of assessment is negative for 
Candida spp and blood culture was drawn after initiation of study drug, 
• If positive culture from a normally sterile site at baseline: 
o 
Documented mycological eradication: culture on day of assessment from all 
normally sterile sites of baseline Candida infection (if accessible) is negative OR if 
no culture on the day of assessment, the most recent culture obtained after the 
initiation of study drug is negative, 
OR 
o 
Presumed mycological eradication: follow-up culture is not available (eg, normally 
sterile baseline site of Candida infection not accessible) or the most recent culture 
obtained after the initiation of study drug is positive in a subject with a successful 
clinical outcome (ie, did not receive rescue antifungal treatment and has resolution 
of systemic signs of invasive candidiasis that were present at baseline) and 
resolution or improvement of any baseline radiographic abnormalities due to 
invasive candidiasis,  
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.  
 
Note: Subjects with positive cultures from both blood and a normally sterile site will need 
to meet success criteria for both blood and normally sterile site to be considered success. 
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 and blood culture was drawn after the initiation of study drug, 
OR 
• If positive culture from a normally sterile site at baseline: 
o 
Documented mycological persistence: culture on day of assessment from all 
normally sterile sites of baseline Candida infection (if accessible) is positive, 
OR 
o 
Presumed mycological persistence: follow-up culture is not available (eg, normally 
sterile baseline site of Candida infection not accessible) or the most recent culture 
obtained after the intiation of study drug is positive in a subject without a 
successful clinical outcome or with continued (from baseline) radiographic 
abnormalities due to invasive candidiasis,  
OR 
• The subject requires a change of antifungal therapy to treat candidemia, 
OR 
• The subject dies of any cause prior to or on the day of assessment. 


 
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Exploratory 
Mycological 
Response 
Definition 
Indeterminate 
• If positive blood culture at baseline: A 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 of signs of invasive candiasis was 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. 
 
Exploratory Overall Response 
Exploratory overall response will be programmatically determined in same way as defined in 
Table 1-2 with exploratory mycological response replacing the mycological response column. 
 
Additional efficacy outcome measures include: 
• All-cause mortality (ACM) through the FU Visit: defined as death due to any cause from 
the date and time of randomization through the FU Visit. Subjects who did not die or are 
lost to follow-up will be censored in the analysis at the last date known to be alive. 
• Time to negative blood culture: defined as the time, in hours from the first dose of study 
drug to the first of 2 negative blood cultures drawn ≥12 hours apart following the first 
pre-treatment blood culture confirmed positive for any Candida species. Determination 
of the identification of fungal pathogens will follow the process defined in SAP 
Section 4. Subjects will be censored at the earliest start date and time of receipt of an 
alternative antifungal (ie, 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 a subject is lost to 
follow-up prior to having 2 negative blood cultures, the subject will be censored at the 
date of the last blood culture. 
 
1.2.6.2. 
Safety Outcome Measures 
Safety will be assessed through the evaluation of AEs, 12-lead electrocardiograms (ECGs), 
radiologic tests, vital signs (temperature, heart rate, blood pressure, and respiratory rate), and 
clinical laboratory evaluations (hematology and coagulation evaluations, chemistry panel, and 
urinalyses). 


 
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2. 
SUBJECT POPULATION 
2.1. 
Population Definitions 
The following analysis populations will be evaluated and used for presentation and analysis of 
the data: 
• Intent-to-Treat (ITT) Population: All subjects randomized to treatment. A subject is 
considered randomized when a randomization transaction has been recorded in the 
IWRS, regardless of whether the subject actually receives study drug. 
• Safety Population: All subjects randomized to treatment and who received any amount 
of study drug. 
• Microbiological Intent-to-treat Population (mITT): A subset of subjects in the Safety 
population with documented Candida infection based on a Central Laboratory 
evaluation of an isolate from a blood culture obtained within 96 hours of randomization 
or from a specimen obtained from a normally sterile site. Determination of the 
identification of fungal pathogens will follow the process defined in SAP Section 4. 
• Microbiological Intent-to-treat 2 Population (mITT2): A subset of subjects in the mITT 
population had documented Candida infection based on Central Laboratory evaluation 
of: 
o a culture from blood drawn within 12 hours prior to randomization or within 72 
hours after randomization; OR  
 
o a culture from another normally sterile site obtained within 48 hours prior to 
randomization or within 72 hours after randomization. 
• Microbiological Intent-to-treat 3 Population (mITT3): A subset of subjects in the mITT 
population who had documented Candida infection based on Central Laboratory 
evaluation of:  
o a culture from blood drawn within 12 hours prior to randomization or within 72 
hours after randomization; OR  
o a culture from another normally sterile site obtained within 96 hours prior to 
randomization or within 72 hours after randomization. 
• Pharmacokinetics (PK) Population: All CD101 treated subjects with at least 1 plasma 
sample obtained for PK analysis. 
Demographics (including age, race, and gender), diagnosis (candidemia and/or IC), medical 
history, baseline assessments, mycological data, systemic signs and symptoms, and 
administration of study drug will be summarized for the ITT population, unless otherwise 
specified. The Safety population is the primary population for the analysis of safety endpoints. 
All efficacy analyses will be conducted in the mITT population, unless otherwise specified. A 
select set of efficacy analysis will also be perfomed in the mITT2 and mITT3 populations. 
2.2. 
Protocol Deviations 
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, and classified as major or minor. 


 
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The Sponsor or designee will be responsible for producing the final protocol deviation file 
(formatted as a Microsoft Excel file), in collaboration with Veristat and the data monitoring 
group as applicable. This file will be finalized prior to hard database lock. 


 
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3. 
GENERAL STATISTICAL METHODS 
3.1. 
Sample Size Justification 
This is an exploratory study and therefore, is not powered for inferential statistical analyses. A 
sufficient number of subjects are randomized to the CD101 IV and IV caspofungin treatment 
groups in Part A to provide an initial, substantive analysis of safety, tolerability, and estimate 
efficacy. 
It is expected that approximately 114 subjects in Part A will need to be randomized given an 
estimated discontinuation rate of 20%, in order to achieve 90 evaluable subjects in the mITT 
population. In Part A, assuming a 73% overall success rate, the sample size of 30 subjects in the 
mITT population in each CD101 IV treatment group and the IV Caspofungin group will yield a 
95% confidence interval (CI) for this success rate of 53.8% to 87.5%. 
The addition of Part B in Amendment 5 of the protocol increased the study sample size by 
approximately 50% to 130% (depending on the rate of enrollment over the additional months to 
the staged start of the Phase 3 study and the rolling close-out of Part B). In Part B, subjects will 
be randomized until there are at least 30 subjects in the CD101 IV treatment groups at any dose 
and 30 subjects in the comparator group (≥45 additional subjects and no more than 120 
subjects). In Part B, total enrollment will depend on the enrollment rate for the period between 
the end of Part A and the start of the Phase 3 study. With the addition of Part B subjects and 
assuming a 73% overall success rate, a total approximate sample size of 60 subjects in the 
CD101 treatment group (consisting of Group 1 from Amendment 5 and Group 2 from 
Amendment 6) will yield a 95% CI of 60.0% to 83.7%, and a total approximate sample size of 
110 subjects in the CD101 treatment group (consisting of Group 1 from Amendment 5 and 
Group 2 from Amendment 6) will yield a 95% CI of 63.7% to 81.0%. 
3.2. 
General Methods 
All tables, figures, and listings will be presented in landscape orientation in Courier New, 
8-point font. 
All tables, figures, and listings 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). 
All data listings and tables displaying by-subject data that contain an evaluation date will 
display a relative study day (Study Day). Study Day 1 is defined as the first day of study drug 
administration and subsequent study days are defined by the number of consecutive calendar 
days thereafter. The day prior to the first dose of study drug is Study Day -1; there is no Study 
Day 0. 
If a clinical 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. 
Tabulations will be produced for appropriate demographic, baseline, efficacy, and safety 
parameters. 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). 


 
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• For continuous variables, the number of subjects, mean, median, standard deviation 
(SD), minimum (min), and maximum (max) values will be presented. 
• Time-to-event data will be summarized using Kaplan-Meier methodology using 25th, 
50th (median), and 75th percentiles with associated 2-sided 95% CIs, as well as 
percentage of censored observations. 
• Point estimates for overall response, mycological success and clinical success with exact 
2-sided 95% CIs will be determined using the Clopper-Pearson method. 
3.3. 
Computing Environment 
All descriptive statistical analyses will be performed using SAS statistical software v9.3, unless 
otherwise noted. Medical history and AEs will be coded using the Medical Dictionary for 
Regulatory Activities (MedDRA) v19.0. Prior and concomitant medications will be coded using 
the World Health Organization (WHO) Drug Dictionary March 2016. 
3.4. 
Baseline Definitions 
For all analyses with exception of the analysis involving attributable systemic signs, baseline 
will be defined as the most recent measurement prior to the first administration of study drug. In 
the event the screening visit and treatment administration occur on the same date, baseline will 
be defined as measurements obtained at the screening visit. 
All blood and normally sterile site samples taken 96 hours before randomization will be used to 
determine the presence of Candida at baseline. In instances where multiple samples of the same 
type occur with the same pathogen within 96 hours before randomization, the sample with 
highest MIC to study drug will be used as baseline pathogen.  
For attributable systemic signs, all assessments of signs taken in the period 4 hours prior to the 
draw of the qualifying blood culture (when systemic signs of infection resulted in obtaining 
blood cultures), qualifying positive culture from a sterile site, or qualifying rapid IVD, through 
the first dose of study drug will be used to determine the presence of attributable systemic signs 
at baseline. 
3.5. 
Methods of Pooling Data 
Data will be pooled across sites for all analyses. Data for selected analyses (as described in 
Section 5) will also be pooled across Part A and B. 
3.6. 
Adjustments for Covariates 
No formal statistical analyses that adjust for possible covariate effects are planned. 
3.7. 
Multiple Comparisons/Multiplicity 
Multiplicity is not of concern for this study with a descriptive interpretation. 


 
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3.8. 
Subgroups 
The demographic and baseline characteristic subgroups shown in Table 3-1 will be used for 
select analyses. 
Table 3-1: 
Subgroup Definitions and Associated Analysis 
Parameter 
Subgroup Description 
Efficacy Outcomes 1 
Other: 
Select 
Demographics/ 
Baseline/ 
TEAEs 
Overall 
Myco-
logical 
Clinical 
Diagnosis 
- Candidemia Only 
- IC (with or without candidemia) 
Y 
Y 
Y 
 
Geographic Region 
- North America  
- Europe 
Y 
Y 
Y 
Y/Y/N 
Hepatic 
insufficiency at 
screening 
- History of Chronic Liver 
Disease/Cirrhosis and Child-Pugh >=7 
- No history or Child-Pugh < 7 
Y 
Y 
Y 
Y/Y/Y 
Renal function status 
at screening 
(based on 
normalized eCrCl)2 
- Severe / Early Stage Renal Disease 
(<30 or receiving dialysis)  
- Moderate (30 - <60)  
- Mild (60 - < 90)  
- Normal/Augmented (90+) 
Y 
Y 
Y 
Y/Y/Y 
Renal disease at 
screening (based on 
normalized eCrCl)2 
- Moderate/Severe/ESRD (<60) 
- Augmented/Normal/Mild (>=60) 
Y 
Y 
Y 
Y/Y/Y 
Baseline Candida 
species 3 
- albicans 
- dubliniensis 
- glabrata 
etc. 
Y 
Y 
Y 
 
Prior antifungal 
therapy activity 
within 4 days of 
treatment start 
- No therapy 
- 1‑<24 hours 
- ≥24 hours 
Y 
Y 
 
 
APACHE II score 
- <10 
- 10-19 
- ≥20 
Y 
Y 
Y 
 
Catheter status 
within 48 hours after 
diagnosis 
- Removed 
- Not Removed 
Y 
Y 
Y 
 
1 Efficacy outcomes at Day 14 (±1) will be presented for all subgroups listed. Efficacy outcomes at additional 
timepoints will also be presented for some subgroups as described in Section 5.3. 
2  Normalized estimated creatine clearance (eCrCl) is based on the Cockcroft-Gault formula normalized to an 
average height of 1.73 meters, using the lower of actual body weight and ideal body weight to calculate body 
surface area. The eCrCl results are in mL/min per 1.73*m2. 
3  For the Candida species subgroup analyses, only success (eradication or cure) rates for the corresponding efficacy 
outcomes will be provided. The other subgroup analyses will present all three response categories. 


 
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In addition to the above subgroups, overall response at Day 14 (±1) will be presented for the 
following subsets: 
• Subjects in the mITT population excluding those who received more than 1 dose of a 
systemic concomitant antifungal up to Day 14 for treatment of an infection other than 
candidemia/IC (with the exception of subjects who received a rescue antifungal for the 
treatment of candidemia). Any subjects deemed a success will be excluded if receiving 
more than 1 dose of systemic antifungal for any indication. 
• Subjects in the mITT2 population who receive no prior antifungal therapy.  
• Subjects in the mITT3 population who receive no prior antifungal therapy.   
Lastly, overall response and investigator’s clinical response at FU will be presented for the 
mITT population excluding both of the following two subsets:  
• Candidemia subjects deemed successes who received more than 1 dose of a systemic 
concomitant antifungal up through Day 21 for treatment of an infection other than 
candidemia/IC (with the exception of subjects who received a rescue antifungal for the 
treatment of candidemia) or who received more than 1 dose of a non-study antifungal 
after Day 21 for the treatment of an infection other than candidemia/IC.  
• IC subjects deemed successes who received more than 1 dose of a systemic concomitant 
antifungal up through Day 28 for treatment of an infection other than candidemia/IC 
(with the exception of subjects who received a rescue antifungal for the treatment of 
candidemia) or who received more than 1 dose of a non-study antifungal after Day 28 
for the treatment of an infection other than candidemia/IC.  
3.9. 
Withdrawals, Dropouts, Loss to Follow-up 
Randomized subjects who are withdrawn or discontinue from the study will not be replaced. 
3.10. 
Missing, Unused, and Spurious Data 
Every effort will be made to collect all data at specified times.  
For the efficacy response outcomes, subjects with missing response data are considered to have 
an indeterminate response unless the subject was a determined to be a failure at an earlier 
timepoint. Subjects with an indeterminate response are included in the denominator of the 
success/cure rate calculation and thus, are treated in the same manner as failures in the analysis. 
If the start time for a non-study medication starting on same day of treatment start is missing, 
the medication will be considered concomitant. If the start time for an adverse event starting on 
same day of treatment start is missing, the adverse event will be considered treatment-emergent. 
If start and end dates are missing entirely the event will be considered treatment-emergent. 
In general, there will be no substitutions made to accommodate missing data points. All data 
recorded on the eCRF will be included in data listings that will accompany the CSR. 
3.11. 
Visit Windows 
Study procedures should be completed within the windows provided in the Schedule of 
Assessments and Procedures in Table 1-1. Visit windows for each evaluation are specified in 
Table 3-2. 


 
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Table 3-2: 
Visit Windows 
Evaluation 
Protocol-Specified Interval 
Efficacy Analysis Window 
Screening 
Study Day -2 to Study Day 1 
Study Day -2 to Study Day 1 
Baseline 
Study Day 1 (last measurement prior to the 
administration of the first dose of study drug) 
Study Day 1 (last measurement prior to the 
administration of the first dose of study drug) 
Day 5 
Study Day 5 to Study Day 9 
Study Day 5 to Study Day 9 
Day 14 (±1 day) 
Study Day 13 to Study Day 15 
Study Day 13 to Study Day 21, unless study 
drug was terminated prior to Day 13 and had 
the efficacy assessment on EOT. 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. 
Day 28 (±2 day) 
Study Day 26 to Study Day 30 (for IC 
subjects) 
Study Day 26 to Study Day 30 (for IC 
subjects) 
Follow-up  
Study Day 45 to Study Day 52 (Study Day 52 
to Study Day 59 for IC subjects) 
Study Day 38 to Study Day 59 (Study Day 45 
to Study Day 66 for IC subjects) 
For summaries of safety, including vital signs, 12-lead ECGs, and clinical laboratory 
parameters, summaries will be provided by Study Day (as appropriate) while on therapy, at the 
EOT and FU visits. If more than 1 measurement is available within the EOT visit window 
(+2 days after last dose of study drug), the measurement taken closest to last dose of study drug 
will be used. If more than 1 measurement is available within the FU visit (Days 45-52; 
Days 52-59 for IC subjects), the measurement taken on the nominal visit will be used. If no 
nominal FU visit is available, the earliest measurement in the window will be used. 
3.12. 
Interim Analyses 
To demonstrate preliminary efficacy and safety of CD101, an interim analysis will be performed 
after approximately 50-70 subjects in the mITT population have been enrolled in Part A, 
completed study drug therapy, and the data are deemed clean. Several steps will be implemented 
to help avoid bias including: the analysis will be performed by an unblinded statistician who is 
not involved in the day to day statistical and data management aspects of the study, the tables 
will provide summary data by treatment group assignment but the group assignment of each 
individual subject will remain blinded until the completion of the study, and only a few key 
efficacy and safety tables will be provided. 
This unblinded interim analysis will consist of the 5 efficacy and safety tables listed below: 
• Table 14.2.1.1 Overall Response at Day 14 (mITT Population) 
• Table 14.2.4.1 Investigator’s Assessment of Clinical Response at Day 14 and 
Follow-up (mITT Population) 
• Table 14.3.1.1 Summary of Treatment-Emergent Adverse Events (Safety Population) 
• Table 14.3.1.3 Treatment-Emergent Adverse Events by System Organ Class, Preferred 
Term and Maximum Severity (Safety Population) 
• Table 14.3.3.3 Post-Baseline Shifts of >=2 Toxicity Grades for Laboratory Parameters 
(Safety Population) 


 
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Guidelines for determining continuation of Part B following the interim analysis will be 
provided in a note-to-file memo and will be utilized by the unblinded analysis team. The 
determination of whether or not to continue Part B as described in the protocol will be made by 
the unblinded analysis team and the recommendation will be forwarded on to Sponsor. If any of 
the ‘stopping criteria’ outlined in the memo are met, the medical team and statistician will be 
unblinded for the 5 tables only, and determine if it is safe to proceed to Part B. 
3.13. 
Timing of Part A and Part B Analyses 
Once Part A is completed, the database for Part A will be locked and a full unblinded analysis 
with all summary tables will be performed on Part A alone. Individual subject data will only be 
made available to the Sponsor if needed to better understand the efficacy and safety of CD101. 
The data from Part B will only be unblinded and analyzed after database lock for Part B at 
completion of the study. 
All analyses will be completed for Part A. Selected analyses will be completed only for Part B 
and for Parts A and B combined. 


 
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4. 
PATHOGEN DETERMINATION 
Fungal pathogen determination from blood specimens is based on the genus and species 
identification of isolates. If the genus identification is the same between the local and central 
mycology laboratory but the species identification is discrepant, the central laboratory 
identification will be used. If the local laboratory grows an isolate but the central laboratory is 
not able to grow the isolate, if isolates were lost during transportation or storage, or there are 
major discrepancies between the local and central laboratory in the identification of species, the 
central laboratory will request the local laboratory to resend the isolate. If the central laboratory 
identification is not available for an isolate, the local laboratory identification will be used. For 
any remaining major discrepancies in species identification between the central and local 
laboratory, the central laboratory identification will be used as the default identification. This 
procedure will be followed for identification of fungal pathogens at baseline and any post-
baseline time points. 
Any Candida species isolated from blood cultures or normally sterile sites will be considered 
pathogens in this study. Fungal isolates other than Candida and bacterial isolates from blood 
cultures will not be considered pathogens for this study. 


 
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5. 
STATISTICAL ANALYSIS 
5.1. 
Study Population 
All analyses describing the study population (Section 5.1.1 through Section 5.1.7) will be 
conducted separately for Parts A and B unless otherwise noted. 
5.1.1. 
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 reason(s) for exclusion from the mITT population will be summarized and 
a corresponding listing for the ITT population will be provided showing each subject’s inclusion 
in or exclusion from the Safety and mITT populations and reason(s) for exclusion. The number 
and percentage of subjects prematurely withdrawing from the study and the primary reason for 
premature withdrawal will be summarized by treatment group for the ITT population as will the 
number and percentage of subjects prematurely discontinuing study drug regimen and the 
primary reason for premature discontinuation. 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 criterion not met and exclusion criterion met. 
5.1.2. 
Protocol Deviations 
A by-subject listing of all protocol deviations, with a flag for minor and major deviations by 
treatment group will be produced. 
5.1.3. 
Demographics and Baseline Characteristics 
Demographic information including sex, females of child-bearing potential, race, ethnicity, age, 
age category (<65 years versus ≥65 years), diagnosis (candidemia and/or IC), height, weight, 
body mass index (BMI), estimated creatinine clearance (based on Cockcroft-Gault formula), 
Child-Pugh score category for those subjects with a history of chronic cirrhosis (<7 and 7-9) and 
APACHE II score category (<10, 10-19, and ≥20) will be summarized by treatment group and 
overall for each study population. Age will be calculated and entered into the eCRF by the site 
and will be based on the date of informed consent (date of informed consent minus the date of 
birth, in years). BMI (kg/m2), calculated by dividing weight (kg) by height (m2) will be captured 
in the eCRF. 
The Cockcroft-Gault formula for estimated creatinine clearance (eCrCl) is: 
 
 
 
Demographic summaries by treatment group will also be presented for the ITT population in the 
geographic region, hepatic insufficiency, renal function status, and renal disease subgroups 
defined in Section 3.8. By-subject listings for all demographics and baseline characteristics will 
also be provided. 
)]
/
(
[
72
]
85
.0
[
)]
(
[
)]
(
[
140
dL
mg
Creatinine
Serum
Female
if
kg
Mass
Body
years
Age
eCrCl
×
×
×
−
=


 
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5.1.4. 
Medical and Surgical History 
Medical and surgical history, including procedures recorded at screening will be summarized by 
treatment group, system organ class (SOC), and preferred term (PT) using version 19.0 of 
MedDRA in the Safety population. For these summaries, subjects with more than 1 
medical/surgical history within the same SOC or PT will be counted only once for that SOC 
or PT. 
5.1.5. 
Candida Risk Factors 
Analyses of Candida risk factors will be completed for Part A and for combined Parts A and B. 
The number and percentage of subjects with each of the following risk factors at Screening will 
be summarized by treatment group in the mITT population: central vascular catheter (CVC), 
active malignancy, use of broad-spectrum antibiotic therapy, diabetes mellitus, 
immunosuppression, major surgery, total parenteral nutrition, transplant recipient (solid organ, 
bone marrow), trauma, dialysis, burns, pancreatitis, and admission to the Intensive Care Unit 
(ICU). For subjects admitted to the ICU, descriptive statistics for the length of time in days will 
be summarized. For subjects who had a catheter, a summary of the number and percentage of 
subjects by type of catheter will also be provided. Descriptive statistics for the longest duration 
of catheter placement by type of catheter for each subject at screening will also be provided. 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. 
5.1.6. 
Systemic Signs of Candidemia and/or IC at Baseline 
The number and percentage of subjects with systemic signs at baseline determined to be 
attributed to candidemia and/or IC by the PI will be summarized by treatment group for subjects 
in the mITT population. Signs include fever, hypothermia, hypotension, tachycardia, and 
tachypnea. A by-subject listing of systemic signs and symptoms assessed at baseline, Day 5 
(signs only), Day 14 (±1), Day 28 (±2 for IC subjects) and the FU 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. 
5.1.7. 
Baseline Fungal Pathogens 
The genus and species of fungal pathogens identified from baseline blood cultures and normally 
sterile sites will be summarized by treatment group for subjects in the mITT population. 
For each baseline Candida species, 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 CD101, caspofungin, anidulafungin, micafungin, and 
fluconazole. In addition, for each baseline Candida species, the MIC50, MIC90, and MICRange 
for CD101, caspofungin, and fluconazole will be summarized, 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. 
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 results for any baseline Candida species that is resistant to fluconazole. 


 
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5.2. 
Extent of Exposure and Concomitant Procedures 
Analyses of study drug exposure will be conducted for Part A, Part B, and Parts A and B 
combined. Analyses of prior and concomitant medications and procedures will be conducted 
separately for Parts A and B. 
5.2.1. 
Study Drug Exposure 
Descriptive statistics for the duration of study drug therapy (IV and oral) will be summarized by 
treatment group for the Safety and mITT populations. Treatment duration is defined as the date 
of the last dose of study drug - first dose of study drug +1 day. The number and percentage of 
subjects with 1–7, 8-14, 15-21 and >21 days of exposure (IV and oral) as defined above will be 
presented. 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 with 1-3, 4-7, 8-14 and 
15-21 days of IV therapy will be presented. Additionally, the study drug exposure summaries by 
treatment group will be presented for the Safety population in the geographic region, hepatic 
insufficiency, renal function status, and renal disease subgroups defined in Section 3.8. 
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. 
Analyses of study drug exposure in mITT population will only be conducted in Parts A and B 
combined. 
5.2.2. 
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) (March 2016) classification 
level 3 and PT. Medications are considered prior if they are received prior to the first dose of 
study drug (start date is prior to the first dose of study drug or in the case of antifungals if the 
start date and time is prior to the date and time of 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/time is on or after the first dose of study drug, stop date/time is 
after the first dose of study drug), or if the stop date is unknown or continuing. 
The number and percentage of subjects who receive the following categories of prior and 
concomitant medications will be summarized by treatment group in the mITT population for 
Parts A and B combined: 
• Systemic antifungal medications received prior to the first dose of study drug and given 
for indication of either candidemia or IC. 
• Systemic antifungal medications (excluding study drug) received on/after the first dose 
of study drug through the FU visit and given for indication of either candidemia or IC. 
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. 
5.2.3. 
Concomitant Procedures 
Concomitant procedures will be summarized by treatment group, SOC, and PT using 
version 19.0 of MedDRA in the mITT population. If the same procedure (based on PT) is 


 
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reported for the same subject more than once, the medical/surgical history 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/time is on or after the first dose of study drug, stop date/time 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. 
5.3. 
Analysis of Efficacy 
All efficacy analyses will be conducted in the mITT population for Part A, Part B, and Parts A 
and B combined, unless otherwise specified. Subjects will be analyzed in the treatment group to 
which they were randomized. By subject listings of the overall response, Investigator’s 
assessment of response and systemic signs and symptoms assessments will be provided. 
5.3.1. 
Primary Efficacy Outcome - Overall Success at Day 14 (±1 day) 
The number and percentage of subjects programmatically determined to be an overall success 
(mycological eradication and resolution of clinical signs of candidemia and/or IC), failure, or 
with an indeterminate overall response at Day 14 (±1) will be summarized by treatment group 
for subjects in the mITT population. Exact 2-sided 95% CIs for the percentage of subjects who 
achieve success in each treatment group will be determined using the Clopper-Pearson method. 
The overall response summary at Day 14 (±1 day) will also be summarized separately for the 
following subgroup analyses defined in Section 3.8: 
• Diagnosis of candidemia only and IC (with or without candidemia) 
• Geographic Region 
• Hepatic Insufficiency at Screening 
• Renal Function Status at Screening 
• Renal Disease at Screening 
• Prior antifungal therapy activity 
• APACHE II score 
• Catheter status at Baseline 
For these subgroup analyses, exact 2-sided 95% CIs for the percentage of subjects who achieve 
success in each treatment group within the subgroups will be determined using the Clopper-
Pearson method. If the number of subjects in the subgroup overall is <10, 95% CI will not be 
provided for the percentage of subjects who achieve success. The subgroup analyses by prior 
antifungal therapy, APACHE II score, and catheter status will only be summarized for Parts A 
and B combined. 
The reasons for failure or indeterminate overall response at Day 14 (±1) will be summarized by 
treatment group for all subjects in the mITT population with an overall response of failure or 
indeterminate at Day 14 (±1). 
A summary will be provided for overall response at Day 14 (±1) excluding those subjects in the 
mITT population who received more than 1 dose of a concomitant antifungal (with the 
exception of subjects who received a rescue antifungal for the treatment of candidemia) up 


 
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through Day 14 (±1) in addition to study drug. This subset to be excluded is described in 
Section 3.8. Exact 2-sided 95% CIs for the percentage of subjects who achieve success in each 
treatment group will be determined using the Clopper-Pearson method. 
A summary of overall response at Day 14 (±1) will be provided for Parts A and B combined in 
the mITT2 and mITT3 populations and for subjects in the mITT2 and mITT3 populations 
without prior antifungal therapy.  Exact 2-sided 95% CIs for the percentage of subjects who 
achieve success in each treatment group will be determined using the Clopper-Pearson method. 
If the number of subjects in a category (with prior antifungal therapy or without prior antifungal 
therapy) is <10, 95% CI will not be provided for the percentage of subjects who achieve success 
in that category. 
5.3.2. 
Secondary Efficacy Outcomes 
5.3.2.1. 
Overall Response at Day 5, Day 28 (±2) and Follow-up 
The number and percentage of subjects with an overall success, failure, and indeterminate 
response at Day 5 and FU will be summarized by treatment group for subjects in the mITT 
population. The overall response summary will also be performed by diagnosis. The overall 
response at Day 5 and FU will be performed for subjects with candidemia only in the mITT 
population and at Day 5, Day 28 and FU for subjects with IC (with or without candidemia) in 
the mITT population. Exact 2-sided 95% CIs for the percentage of subjects who achieve success 
in each treatment group will be determined using the Clopper-Pearson method. If the number of 
subjects with IC overall is <10, 95% CI will not be provided for the percentage of subjects who 
achieve success. 
An additional analysis of overall response at FU will be conducted excluding subjects who 
received more than 1 dose of a concomitant antifungal (with the exception of subjects who 
received a rescue antifungal for the treatment of candidemia and/or IC) up through Day 21 (for 
subjects with candidemia only) or Day 28 (for subjects with IC, with or without candidemia) or 
who receive more than 1 dose of a non-study antifungal after Day 21 or Day 28 for the 
treatment of an infection other than candidemia and/or IC. This subset to be excluded is 
described in Section 3.8. Exact 2-sided 95% CIs for the percentage of subjects who achieve 
success in each treatment group will be determined using the Clopper-Pearson method. 
The overall response summary at Day 5 and Follow-up will also be summarized separately for 
the following subgroup analyses defined in Section 3.8: 
• Diagnosis of candidemia only and IC (with or without candidemia) 
• Geographic Region 
• Hepatic Insufficiency at Screening 
• Renal Function Status at Screening 
• Renal Disease at Screening 
Additionally, the overall response summary at Day 28 (±2) will be summarized only for 
diagnosis of IC (with or without candidemia). For each subgroup analyses, exact 2-sided 95% 
CIs for the percentage of subjects who achieve success in each treatment group within the 
subgroups will be determined using the Clopper-Pearson method. If the number of subjects in 
the subgroup overall is <10, 95% CI will not be provided for the percentage of subjects who 
achieve success. 


 
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5.3.2.2. 
Mycological Response at Day 5, Day 14 (±1), Day 28 (±2) and Follow-up 
The number and percentage of subjects programmatically determined as having a mycological 
success (eradication), failure, or with an indeterminate mycological response at Day 5, Day 14 
(±1), and FU will be summarized, by treatment group for subjects in the mITT population. 
Exact 2-sided 95% CIs for the percentage of subjects who achieve success in each treatment 
group will be determined using the Clopper-Pearson method. If the number of subjects with IC 
overall is <10, 95% CI will not be provided for the percentage of subjects who achieve success. 
The mycological response summary at Day 5, Day 14 (±1), and Follow-up will also be 
summarized  separately for the following subgroup analyses defined in Section 3.8: 
• Diagnosis of candidemia only and IC (with or without candidemia) 
• Geographic Region 
• Hepatic Insufficiency at Screening 
• Renal Function Status at Screening 
• Renal Disease at Screening 
• Prior antifungal therapy activity 
• APACHE II score 
• Catheter status at Baseline 
Additionally, the mycological response summary at Day 28 (±2) will be summarized only for 
diagnosis of IC (with or without candidemia). For each subgroup analyses, exact 2-sided 95% 
CIs for the percentage of subjects who achieve success in each treatment group within the 
subgroups will be determined using the Clopper-Pearson method. If the number of subjects in 
the subgroup overall is <10, 95% CI will not be provided for the percentage of subjects who 
achieve success. The subgroup analyses by prior antifungal therapy, APACHE II score, and 
catheter status will only be summarized for Parts A and B combined. 
5.3.2.3. 
Investigator’s Assessment of Clinical Response at Day 14 (±1), Day 28 (±2), and 
the Follow-up Visit 
The number and percentage of subjects determined by the PI to be a clinical cure, failure, or 
with an indeterminate clinical response at Day 14 (±1) and at the FU visit will be summarized 
by treatment group for subjects. The Investigator’s assessment of clinical response will also be 
provided by diagnosis. The Investigator’s assessment of clinical response at Day 14 and FU will 
be performed for subjects with candidemia only in the mITT population and at Day 14, Day 28, 
and FU for subjects with IC (with or without candidemia) in the mITT population. Exact 2-sided 
95% CIs for the percentage of subjects who achieve cure in each treatment group will be 
determined using the Clopper-Pearson method. If the number of subjects with IC overall is <10, 
95% CI will not be provided for the percentage of subjects who achieve success.  
The reasons for failure or indeterminate clinical response at Day 14 (±1) and FU visit will be 
summarized by treatment group for all subjects in the mITT population. 
An additional analysis of clinical response at FU will be conducted excluding subjects who 
received more than 1 dose of a concomitant antifungal (with the exception of subjects who 
received a rescue antifungal for the treatment of candidemia and/or IC) up through Day 21 (for 
subjects with candidemia only) or Day 28 (for subjects with IC, with or without candidemia) or 


 
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who receive more than 1 dose of a non-study antifungal after Day 21 or Day 28 for the 
treatment of an infection other than candidemia and/or IC. This subset to be excluded is 
described in Section 3.8. Exact 2-sided 95% CIs for the percentage of subjects who achieve 
success in each treatment group will be determined using the Clopper-Pearson method.  
The clinical response summaries will also be stratified separately for the following subgroup 
analyses defined in Section 3.8: 
• Diagnosis of candidemia only and IC (with or without candidemia) 
• Geographic Region 
• Hepatic Insufficiency at Screening 
• Renal Function Status at Screening 
• Renal Disease at Screening 
• APACHE II score 
• Catheter status at Baseline 
For these subgroup analyses, exact 2-sided 95% CIs for the percentage of subjects who are 
determined to be a cure in each treatment group within the subgroups will be determined using 
the Clopper-Pearson method. If the number of subjects in the subgroup overall is <10, 95% CI 
will not be provided for the percentage of subjects who achieve success. The subgroup analyses 
by APACHE II score and catheter status will only be summarized for Parts A and B combined. 
A summary of subjects determined by the PI to be a clinical cure, failure, or with an 
indeterminate clinical response at Day 14 (±1) and at the FU visit will be provided for Parts A 
and B combined in the mITT2 and mITT3 populations and for subjects in the mITT2 and 
mITT3 populations without prior antifungal therapy. Exact 2-sided 95% CIs for the percentage 
of subjects who achieve success in each treatment group will be determined using the Clopper-
Pearson method. 
5.3.3. 
Additional Efficacy Outcomes 
5.3.3.1. 
All-cause Mortality through Day 30 and Follow-up 
The number and percentage of subjects who died up through the FU visit (all-cause mortality) 
will be summarized by treatment group in the ITT and mITT populations. The 25th, 50th 
(median), and 75th percentiles will be provided by treatment group using Kaplan-Meier 
methods. Subjects who do not die or who are lost to follow-up will be censored at the last date 
known to be alive. The number and percentage of subjects censored will be provided. The 
Kaplan-Meier estimate of 30-day all-cause mortality will also be provided along with the 95% 
CI calculated using Greenwoods formula. The Kaplan-Meier curve will be presented by 
treatment group. A listing of the primary cause of death will also be provided. 
5.3.3.2. 
 Time to Negative Blood Culture 
The time to negative blood culture (hours) will be analyzed using Kaplan-Meier methodology 
by treatment group, and for the CD101 treatment groups combined, in the mITT population. 
Summaries will include the 25th, 50th (median), and 75th percentiles. The number and percentage 
of subjects censored and the reason for censoring (receipt of more than 1 dose of non-study 
antifungal for the treatment of candidemia and/or IC [with the exception of a rescue antifungal], 


 
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lost to follow up prior to having 2 negative blood cultures) will also be provided. A graph of the 
Kaplan-Meier curves will be provided. 
5.3.3.3. 
Overall Success at Day 14 (±1) by Baseline Candida species 
The number and percentage of subjects programmatically determined to be an overall success 
(mycological eradication and resolution of clinical signs of candidemia) at Day 14 (±1) will be 
summarized by baseline Candida spp. and treatment group for subjects in the mITT population. 
Overall success by baseline Candida species and MIC cutoff for CD101, caspofungin and 
fluconazole at Day 14 (±1) will be summarized by treatment group for subjects in the mITT 
population. 
5.3.3.4. 
Mycological Success at Day 14 (±1) by Baseline Candida species 
The number and percentage of subjects determined to be a mycological success 
(eradication/presumed eradication) at Day 14 (±1) will be summarized by baseline Candida 
species and treatment group for subjects in the mITT population. 
Mycological success by baseline Candida species and MIC cutoff for CD101, caspofungin and 
fluconazole at Day 14 (±1) will be summarized by treatment group for subjects in the mITT 
population. 
5.3.3.5. 
Investigator’s Assessment of Clinical Cure by Baseline Candida species 
The number and percentage of subjects determined to be a clinical cure at Day 14 (±1) will be 
summarized by baseline Candida species and treatment group for subjects in the mITT 
population. The Investigator’s assessment of clinical cure by baseline Candida species and MIC 
cutoff for CD101, caspofungin and fluconazole at Day 14 (±1) will be summarized by treatment 
group for subjects in the mITT population. 
5.3.3.6. 
Exploratory Overall Response at Day 14 (±1) and Exploratory Mycological  
Response at Day 14 (±1) 
The number and percentage of subjects having overall success, failure, and indeterminate 
response at Day 14 (±1) will be summarized by treatment group for subjects in the mITT 
population. Exact 2-sided 95% CIs for the percentage of subjects who achieve success in each 
treatment group will be determined using the Clopper-Pearson method. 
The number and percentage of subjects programmatically determined as having a mycological 
success (eradication), failure, or with an indeterminate mycological response at Day 14 (±1) will 
be summarized by treatment group for subjects in the mITT population. Exact 2-sided 95% CIs 
for the percentage of subjects who achieve success in each treatment group will be determined 
using the Clopper-Pearson method. 
5.3.3.7. 
Exploratory Overall Success at Day 14 (±1) by Baseline Candida species 
The number and percentage of subjects with an exploratory overall success at Day 14 will be 
summarized by baseline Candida species and treatment group for subjects in the mITT 
population for Parts A and B combined. Exact 2-sided 95% CIs for the percentage of subjects 
who achieve success in each treatment group will be determined using the Clopper-Pearson 
method.  


 
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5.3.3.8. 
Exploratory Mycological Success at Day 14 (±1) by Baseline Candida species 
The number and percentage of subjects programmatically determined as having an exploratory 
mycological response at Day 14 (±1) of success (eradication) will be summarized by baseline 
Candida species and treatment group for subjects in the mITT population for Parts A and B 
combined. Exact 2-sided 95% CIs for the percentage of subjects who achieve success in each 
treatment group will be determined using the Clopper-Pearson method.  
5.3.4. 
CD101 Plasma Concentration 
Summary statistics (number of subjects, mean, SD, coefficient of variability % (CV%), median, 
min, max, geometric mean) of CD101 plasma concentration will be provided by time point and 
dose group for CD101 treated subjects in the PK population. Each CD101 dose group will be 
summarized separately for all timepoints and combined for all timepoints except Day 15. Only 
samples collected on Day1, Day 2, Day 4, Day 8 and Day 15 and within 10% of the nominal 
time (where applicable) will be included. Analyses of CD101 plasma concentration will only be 
conducted for Part A. 
5.4. 
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 treatment will be analyzed in the treatment group based on 
the drug received. All safety analyses will be completed for Part A, Part B, and for combined 
Parts A and B. 
5.4.1. 
Adverse Events 
Verbatim descriptions of AEs will be coded using MedDRA Version 19.0. Summary tables will 
be provided for all treatment-emergent adverse events (TEAE). A TEAE is defined as an AE 
that occurs during or after the administration of the first dose of study drug and up through the 
FU visit. 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. If 
AE start and end dates are missing entirely the event will be considered treatment-emergent. 
An overall summary of TEAEs will include the number and percentage of subjects in each 
treatment group who experienced at least 1 TEAE in the following categories: any TEAE, any 
study drug-related TEAE, any severe TEAE, any serious TEAE (SAE), any study drug-related 
SAE, any SAE leading to death, and any TEAE leading to discontinuation of study drug. 
Subjects with multiple events will be counted only once within each category. Severity and 
relationship will be counted using the maximum severity 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 severity (mild, moderate, or severe); and 
by SOC, PT, and relationship (unrelated or related) to study drug. The incidence of all TEAEs 
and all non-serious TEAEs that occur in at least 5% of subjects in the combined CD101 
treatment groups will be summarized separately by PT and treatment group, sorted by 
decreasing frequency in the combined CD101 treatment groups. 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 severity and strongest relationship to study 
drug. 


 
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The number and percentage of subjects in each treatment group reporting a SAE, reporting a 
study drug-related SAE, reporting a TEAE leading to discontinuation of study drug will be 
summarized by SOC and PT. 
The TEAE and maximum severity TEAE summaries by treatment group will also be presented 
for the Safety population in the hepatic insufficiency, renal function status, and renal disease 
subgroups defined in Section 3.8. 
In addition to a listing of all reported AEs, by-subject listings of all SAEs (including any SAEs 
with an outcome of death) and all TEAEs leading to discontinuation of IV/oral study drug will 
be provided. 
5.4.2. 
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): 
 
 
 
 
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. 
Descriptive statistics (based on Systeme Internationale [SI] units) for chemistry, hematology 
and coagulation (baseline and unscheduled post-baseline only), and urinalysis (only pH and 
specific gravity) 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 SAP 
Section 6.1. 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. 
The normalized laboratory values will be classified by toxicity grade according to the toxicity 
grading scales in SAP Section 6.2, which are based on the Division of Microbiology and 
Infectious Diseases (DMID) Adult Toxicity Scale, November 2007, the Division of AIDS 
(DAIDS) Table for Grading the Severity of Adult and Pediatric Adverse Events, 
December 2004, and the National Cancer Institute Common Terminology Criteria for Adverse 
Events (CTCAE, Version 4.0), Publish Date: 28 May 2009.  
Shift tables will be presented to show the number of subjects with each toxicity grade 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 (eg, 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 


 
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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. 
The number and percentage of subjects in each treatment group with an elevated transaminase 
level (>3 ×ULN, >5 ×ULN, and >10 ×ULN), an elevated total and direct bilirubin level 
(>1.5 ×ULN and >2 ×ULN) will be presented by study visit. A listing of subjects who meet the 
laboratory criteria for Hy’s law will also be provided for Parts A and B combined. Two 
alternative definitions of criteria for Hy’s law will be considered, defined as 1) (ALT or AST) 
>3 ×ULN, ALP ≤2.0 ×ULN, and total bilirubin >1.5 ×ULN; and 2) (ALT or AST) >3 ×ULN, 
ALP ≤2.0 ×ULN, and total bilirubin >2 ×ULN. Using a conservative approach for detecting any 
potential Hy’s law cases, subjects meeting either criteria based on any combination of post-
baseline laboratory results, irrespective of their temporal association, 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. 
Detailed patient listings of all laboratory data collected during the study will be provided. 
Laboratory values outside normal limits will be identified in the patient data listings. A column 
will display any applicable toxicity grading of the laboratory value. 
5.4.3. 
Vital Signs 
Several analyses of vital signs data will be presented. 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 treatment 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 value. For this summary, 
data for subjects who are no longer hospitalized at a particular visit will be included in both 
summaries of highest and lowest value for that visit, since highest and lowest values are only 
captured in the eCRF for visits during which a subject is hospitalized. 
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 5-1, will be provided 
for the worst post-baseline value (which includes unscheduled post-baseline measurements). 
Both the highest and lowest daily vital signs values will be entered into the eCRF for 
hospitalized subjects. The highest daily value will be used to assess PCS High (CH) values; the 
lowest daily value will be used to assess PCS Low (CL). 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. 


 
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Table 5-1: 
Criteria for Potentially Clinically Significant Vital Signs 
Vital Sign Parameter 
Flag 
Criterion Value 
Change from Baseline 
Systolic Blood Pressure (mm Hg) 
High (CH) 
≥180 mm Hg 
Increase of ≥20 mmHg 
Low (CL) 
≤90 mm Hg 
Decrease of ≥20 mmHg 
Diastolic Blood Pressure (mm Hg) 
High (CH) 
≥105 mm Hg 
Increase of ≥15 mmHg 
Low (CL) 
≤50 mm Hg 
Decrease of ≥15 mmHg 
Heart Rate (bpm) 
High (CH) 
≥120 bpm 
Increase of ≥15 bpm 
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 
 
5.4.4. 
Electrocardiogram 
Descriptive statistics for heart rate, PR interval, RR interval, QRS interval, QT interval, and QT 
interval with Fridericia correction (QTcF) at Baseline and the EOT visit and the change from 
baseline at the EOT visit will be summarized by treatment group for subjects in the Safety 
population. Change from baseline will be calculated for each subject as the value at the EOT 
visit minus the baseline value. QTcF will be derived programmatically using the QT and RR 
intervals captured in the eCRF according to the following formula (Fridericia): 
 
 
The number and percentage of subjects with any post-baseline increase in QTcF and any post-
baseline increase of >30 msec or >60 msec in QTcF will be summarized by treatment group. 
The number and percentage of subjects with a post-baseline QTcF of >450 msec or >500 msec 
will also be summarized by treatment group. The number and percentage of subjects with a 
post-baseline increase in QTcF of >30 msec resulting in a post-baseline QTcF of >450 msec or 
>500 msec will also be summarized by treatment group. The distribution of QTcF values 
(≤450 msec, >450 - ≤480 msec, >480 - ≤500 msec, and >500 msec) at EOT and the distribution 
of change from baseline in QTcF values at EOT (0 or less (no increase), 1-29 msec, 30-60 msec, 
and >60 msec) will be summarized by treatment group for subjects in the Safety population. 
A by subject listing of all measurements obtained from ECG assessments will be provided. 
5.4.5. 
Physical and Retinal Examinations 
Physical exam findings from Screening, Day 14 (±1), Day 28 (±2), and the FU visit will be 
presented in a by-subject listing. Abnormal findings from retinal examinations and whether or 
not the subject had evidence of Candida endophthalmitis will be provided in a by-subject 
listing. 
3 RR
QT
F
QTc
=


 
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5.4.6. 
Radiological Evaluations 
Results of radiological testing will be provided in by-subject listings. 


 
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6. 
APPENDICES 
6.1. 
Appendix 1: Directionality of Worst Laboratory Parameters 
Table 6-1: 
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 
Coagulation 
Prothrombin time 
Highest value 
 
International normalized ratio (INR) 
Highest value 
 
Partial thromboplastin time (PTT) 
Highest value 
 
Activated PTT 
Highest value 
 


 
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6.2. 
Appendix 2: Clinical Laboratory Toxicity Grading Scales 
Table 6-2: 
Hematology and Coagulation Toxicity Grading Scale 
Hematology and Coagulation 
Parameter 
Direction 
Grade 0 / 
Normal 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Source 
Hemoglobin 
Decrease 
>10.5 
gm/dL 
9.5 – 10.5 
gm/dL 
8.0 – 9.4 
gm/dL 
6.5 – 7.9 
gm/dL 
<6.5 gm/dL 
DMID 
WBCs 
Increase 
1,000-
10,999 
/mm3 
11,000-
13,000 
/mm3 
13,000-
15,000 
/mm3 
15,000-
30,000 /mm3 
>30,000 or 
<1,000 
/mm3 
DMID 
Absolute 
Neutrophil 
Count 
Decrease 
>1500 
/mm3 
1000-1500 
/mm3 
750-999 
/mm3 
500-749 
/mm3 
<500 /mm3 
DMID 
Platelets 
Decrease 
>99,999 
/mm3 
75,000-
99,999 
/mm3 
50,000-
74,999 
/mm3 
20,000-
49,999 /mm3 
<20,000 
/mm3 
DMID 
Prothrombin 
Time (PT) 
Increase 
<1.01 
×ULN 
1.01-1.25 
×ULN 
1.26-1.5 
×ULN 
1.51-3.0 
×ULN 
>3 ×ULN 
DMID 
Activated 
Partial 
Thromboplastin 
(APPT) 
Increase 
<1.01 
×ULN 
1.01-1.66 
×ULN 
1.67-2.33 
×ULN 
2.34-3 
×ULN 
>3 ×ULN 
DMID 


 
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Table 6-3: 
Chemistry Toxicity Grading Scale 
Chemistry 
Parameter 
Direction 
Grade 0 / 
Normal 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Source 
Blood urea 
nitrogen 
(BUN) 
Elevation 
<1.25 
×ULN 
1.25-2.5 
×ULN 
2.6-5 
×ULN 
5.1-10 
×ULN 
>10 
×ULN 
DMID 
Bilirubin 
(total and 
direct) 
Hyperbilirubinemia 
(when 
accompanied by 
any increase in 
other liver function 
test) 
<1.1 
×ULN 
1.1-<1.25 
×ULN 
1.25-<1.5 
×ULN 
1.5-1.75 
×ULN 
>1.75 
×ULN 
DMID 
Hyperbilirubinemia 
(when other liver 
functions are in the 
normal range) 
<1.1 
×ULN 
1.1-<1.5 
×ULN 
1.5-<2.0 
×ULN 
2.0-3.0 
×ULN 
>3.0 
×ULN 
DMID 
Albumin 
Hypoalbuminemia 
 
3.0 g/dL-
<LLN 
2.0-<3 
g/dL 
<2.0 g/dL 
N/A 
CTCAE 
Sodium 
Hyponatremia 
>135-
<146 
mEq/L 
130-135 
mEq/L 
123-129 
mEq/L 
116-122 
mEq/L 
<116 
mEq/L 
DMID 
Hypernatremia 
>135-
<146 
mEq/L 
146-150 
mEq/L 
151-157 
mEq/L 
158-165 
mEq/L 
>165 
mEq/L 
DMID 
Potassium 
Hypokalemia 
>3.4-<5.6 
mEq/L 
3.0-3.4 
mEq/L 
2.5-2.9 
mEq/L 
2.0-2.4 
mEq/L 
<2.0 
mEq/L 
DMID 
Hyperkalemia 
>3.4-<5.6 
mEq/L 
5.6-6.0 
mEq/L 
6.1-6.5 
mEq/L 
6.6-7.0 
mEq/L 
>7.0 
mEq/L 
DMID 
Glucose 
Hypoglycemia 
>64-<116 
mg/dL 
55-64 
mg/dL 
40-54 
mg/dL 
30-39 
mg/dL 
<30 
mg/dL 
DMID 
Hyperglycemia 
(nonfasting and no 
prior diabetes) 
>64-<116 
mg/dL 
116-160 
mg/dL 
161-250 
mg/dL 
251-500 
mg/dL 
>500 
mg/dL 
DMID 
Creatinine 
Elevation 
<1.1 
×ULN 
1.1-1.5 
×ULN 
1.6-3.0 
×ULN 
3.1-6 
×ULN 
>6 ×ULN 
DMID 
Total 
protein 
 
 
 
 
 
 
 
Calcium 
Hypocalcemia 
>8.4-
<10.6 
mg/dL 
8.4-7.8 
mg/dL 
7.7-7.0 
mg/dL 
6.9-6.1 
mg/dL 
<6.1 
mg/dL 
DMID 
Hypercalcemia 
>8.4-
<10.6 
mg/dL 
10.6-11.5 
mg/dL 
11.6-12.5 
mg/dL 
12.6-13.5 
mg/dL 
>13.5 
mg/dL 
DMID 
Bicarbonate 
Low 
 
16 mEq-
<LLN 
11.0-15.9 
mEq/L 
8.0-10.9 
mEq/L 
<8.0 
mEq/L 
DAIDS 


 
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Table 6-4: 
Enzymes Toxicity Grading Scale 
Enzymes 
Parameter 
Direction 
Grade 0 
/ Normal 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Source 
Alkaline 
phosphatase 
(ALP) 
Elevation 
<1.1 
×ULN 
1.1-<2.0 
×ULN 
2.0-<3.0 
×ULN 
3.0-8.0 
×ULN 
>8 ×ULN 
DMID 
Aspartate 
aminotransferase 
(AST/SGOT) 
Elevation 
<1.1 
×ULN 
1.1-<2.0 
×ULN 
2.0- <3.0 
×ULN 
3.0- 8.0 
×ULN 
>8 ×ULN 
DMID 
Alanine 
aminotransferase 
(ALT/SGPT) 
Elevation 
<1.1 
×ULN 
1.1-<2.0 
×ULN 
2.0-<3.0 
×ULN 
3.0-8.0 
×ULN 
>8 ×ULN 
DMID 
 
6.3. 
Appendix 3: Laboratory Normals 
Table 6-5: 
Hematology Laboratory Normals 
Hematology 
 
LLN 
ULN 
Source 
Hemoglobin 
 
 
 
Male 
13.8 gm/dL 
17.2 gm/dL 
NLM 
Female 
12.1 gm/dL 
15.1 gm/dL 
NLM 
Hematocrit 
 
 
 
Male 
40.7% 
50.3% 
NLM 
Female 
36.1% 
44.3% 
NLM 
White blood cell count 
4,500 cells/mcL 
10,000 cells/mcL 
NLM 
Differential leukocyte count 
 
 
 
Neturophils 
40% 
60% 
NLM 
Lymphocytes 
20% 
40% 
NLM 
Monocytes 
2% 
8% 
NLM 
Eosinophils 
1% 
4% 
NLM 
Basophils 
0.50% 
1% 
NLM 
Red blood cell count 
 
 
 
Male 
4.7 ×106 cells/mcL 
6.1 ×106 cells/mcL 
NLM 
Female 
4.2 ×106 cells/mcL 
5.4 ×106 cells/mcL 
NLM 
Platelet count 
150,000/dL 
450,000/dL 
NLM 


 
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Table 6-6: 
Coagulation Laboratory Normals 
Coagulation 
 
LLN 
ULN 
Source 
Prothrombin time (International 
Normalized Ratio) 
 
 
 
No warfarin 
11 seconds (0.8) 
13.5 seconds (1.1) 
NLM 
With warfarin 
(2.0) 
(3.0) 
NLM 
Partial thromboplastin time (PTT) or 
activated partial thromboplastin time 
(APTT) 
 
 
 
No warfarin 
25 seconds 
35 seconds 
NLM 
Table 6-7: 
Serum Chemistry Laboratory Normals 
Serum Chemistry 
 
LLN 
ULN 
Source 
Blood urea nitrogen 
6 mg/dL 
20 mg/dL 
NLM 
Bilirubin  
 
 
 
Direct 
0 mg/dL 
0.3 mg/dL 
NLM 
Total 
0.3 mg/dL 
1.9 mg/dL 
NLM 
Alkaline phosphatase (ALP) 
44 IU/L 
147 IU/L 
NLM 
Aspartate aminotransferase (AST/SGOT) 
10 U/L 
34 U/L 
NLM 
Alanine aminotransferase (ALT/SGPT) 
 
 
 
Male 
10 U/L 
40 U/L 
NLM 
Female 
7 U/L 
35 U/L 
NLM 
Albumin 
3.4 g/dL 
5.4 g/dL 
NLM 
Sodium 
135 mEq/L 
145 mEq/L 
NLM 
Potassium 
3.7 mEq/L 
5.2 mEq/L 
NLM 
Chloride 
96 mEq/L 
106 mEq/L 
NLM 
Calcium 
8.5 mg/dL 
10.2 mg/dL 
NLM 
Glucose 
 
 
 
Fasting 
70 mg/dL 
100 mg/dL 
NLM 
Random 
 
125 mg/dL 
NLM 
Creatinine 
 
 
 
Male 
0.7 mg/dL 
1.3 mg/dL 
NLM 
Female 
0.6 mg/dL 
1.1 mg/dL 
NLM 
Total Protein 
6.0 gm/dL 
8.3 gm/dL 
NLM 
Bicarbonate 
23 mEq/L 
29 mEq/L 
NLM 
Procalcitonin 
N/A 
N/A 
NLM 


 
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7. 
CHANGES TO PLANNED ANALYSES 
As of this date, there have been no changes between the protocol-defined statistical analyses and 
those presented in this SAP. 


 
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8. 
REFERENCES 
A.D.A.M. Medical Encyclopedia [Internet]. Atlanta (GA): A.D.A.M., Inc.; ©2005. 
CBC blood test; [updated 2016 Nov 26; cited 2016 Oct 03]; [about 6 p.]. Available from: 
https://medlineplus.gov/ency/article/003642.htm 
WBC count; [updated 2015 Jan 27; cited 2016 Oct 03]; [about 5 p.]. Available from: 
https://medlineplus.gov/ency/article/003643.htm 
Blood differential test; [updated 2015 Jan 27; cited 2016 Oct 03]; [about 6 p.]. Available 
from: https://medlineplus.gov/ency/article/003657.htm 
Prothrombin time (PT); [updated 2015 Jan 27; cited 2016 Oct 03]; [about 4 p.]. 
Available from: https://medlineplus.gov/ency/article/003652.htm 
Partial thromboplastin time (PTT); [updated 2015 Jan 27; cited 2016 Oct 03]; [about 4 
p.]. Available from: https://medlineplus.gov/ency/article/003653.htm 
Urine pH test; [updated 2015 Aug 29; cited 2016 Oct 03]; [about 4 p.]. Available from: 
https://medlineplus.gov/ency/article/003583.htm 
Urine concentration test; [updated 2015 Aug 29; cited 2016 Oct 03]; [about 4 p.]. 
Available from: https://medlineplus.gov/ency/article/003608.htm 
Protein urine test; [updated 2015 Aug 29; cited 2016 Oct 03]; [about 3 p.]. Available 
from: https://medlineplus.gov/ency/article/003580.htm 
Glucose urine test; [updated 2016 Mar 01; cited 2016 Oct 03]; [about 3 p.]. Available 
from: https://medlineplus.gov/ency/article/003581.htm 
Ketones urine test; [updated 2015 Nov 19; cited 2016 Oct 03]; [about 4 p.]. Available 
from: https://medlineplus.gov/ency/article/003585.htm 
Bilirubin urine test; [updated 2015 May 03; cited 2016 Oct 03]; [about 3 p.]. Available 
from: https://medlineplus.gov/ency/article/003595.htm 
RBC urine test; [updated 2015 Aug 29; cited 2016 Oct 03]; [about 3 p.]. Available from: 
https://medlineplus.gov/ency/article/003582.htm 
Urinalysis; [updated 2015 Jan 31; cited 2016 Oct 03]; [about 5 p.]. Available from: 
https://medlineplus.gov/ency/article/003579.htm 
BUN - blood test; [updated 2015 Apr 30; cited 2016 Oct 03]; [about 3 p.]. Available 
from: https://medlineplus.gov/ency/article/003474.htm 
Bilirubin blood test; [updated 2015 Feb 08; cited 2016 Oct 03]; [about 4 p.]. Available 
from: https://medlineplus.gov/ency/article/003479.htm 
ALP - blood test; [updated 2015 Apr 30; cited 2016 Oct 03]; [about 4 p.]. Available 
from: https://medlineplus.gov/ency/article/003470.htm 
Aspartate aminotransferase (AST) blood test; [updated 2015 Feb 08; cited 2016 Oct 03]; 
[about 4 p.]. Available from: https://medlineplus.gov/ency/article/003472.htm 
Alanine transaminase (ALT) blood test; [updated 2015 Feb 08; cited 2016 Oct 03]; 
[about 3 p.]. Available from: https://medlineplus.gov/ency/article/003473.htm 


 
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Albumin - blood (serum) test; [updated 2015 Feb 08; cited 2016 Oct 03]; [about 4 p.]. 
Available from: https://medlineplus.gov/ency/article/003480.htm 
Sodium blood test; [updated 2015 Nov 01; cited 2016 Oct 03]; [about 4 p.]. Available 
from: https://medlineplus.gov/ency/article/003481.htm 
Potassium test; [updated 2015 May 03; cited 2016 Oct 03]; [about 4 p.]. Available from: 
https://medlineplus.gov/ency/article/003484.htm 
Chloride test - blood; [updated 2015 May 03; cited 2016 Oct 03]; [about 3 p.]. Available 
from: https://medlineplus.gov/ency/article/003485.htm 
Blood sugar test - blood; [updated 2015 Jul 24; cited 2016 Oct 03]; [about 5 p.]. 
Available from: https://medlineplus.gov/ency/article/003482.htm 
Creatinine blood test; [updated 2015 Aug 29; cited 2016 Oct 03]; [about 4 p.]. Available 
from: https://medlineplus.gov/ency/article/003475.htm 
Total Protein; [updated 2015 May 03; cited 2016 Oct 03]; [about 3 p.]. Available from: 
https://medlineplus.gov/ency/article/003483.htm 
CO2 blood test; [updated 2015 Apr 30; cited 2016 Oct 03]; [about 4 p.]. Available from: 
https://medlineplus.gov/ency/article/003469.htm 
Calcium blood test; [updated 2015 Nov 11; cited 2017 Nov 15]; [about 4 p.]. Available 
from: https://medlineplus.gov/ency/article/003477.htm 
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/dmidadul
ttox.pdf. Published November 2007 Accessed August 18, 2016. 
Fridericia LS. Die Systolendauer im Elektrokardiogramm bei normalen Menschen und bei 
Herzkranken. [The duration of systole in the electrocardiogram of normal subjects and of 
patients with heart disease.] Acta Medica Scandinavica 53:469–486. 
Karvanen J. The Statistical Basis of Laboratory Data Normalization. Drug Information Journal, 
Vol. 37, pp. 101–107, 2003. 
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. http://rsc.tech-
res.com/docs/default-source/safety/daids_ae_grading_table_v2_nov2014.pdf. Published 
November 2014 Accessed October 3, 2016. 


 
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9. 
REVISION HISTORY 
The normalization method applied to clinical laboratory values described in Section 5.4.2 will 
now use the scale normalization formula instead of location-scale normalization formula 
described in previous versions of this document.