Clinical trial NCT04117607
Conditions: Fungal Infection
Keywords: Dose Escalation Study Double-Blind Healthy Adult Subjects Phase 1 Rezafungin Safety and Pharmacokinetic
Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)
Start date: 2019-12-04; Completion date: 2020-05-11
Enrollment: 14 participants; Allocation: RANDOMIZED; Intervention model: SEQUENTIAL

Brief summary:
This is a Phase 1, double-blind, placebo-controlled trial in three parts. A single ascending dose (SAD) study in six cohorts receiving a single subcutaneous (SC) dose of 1, 10, 30, 60, 100, or 200 mg of rezafungin; a multiple ascending dose (MAD) study in four cohorts receiving 30 mg x 3 doses, 60 mg x 3 doses, 100 mg x 3 doses, or 200 mg x 3 doses of rezafungin SC with dosing frequency of once every 7 days; and a two-period cross-over bioavailability (BA) study receiving 100 mg of rezafungin. The two period cross-over BA study will be assessed unblinded in two sequences (10 subjects, 100 mg or maximum tolerated dose (MTD) of rezafungin in Part 1); 5 subjects will receive an SC injection of rezafungin in Period 1 followed by an intravenous (IV) infusion of rezafungin in Period 2, and 5 subjects will receive an IV infusion of rezafungin in Period 1 followed by an SC injection of rezafungin in Period 2. Each SAD (except cohort 1) and MAD cohort will contain 8 subjects (6 subjects will receive a SC injection of rezafungin and 2 subjects will receive placebo). Each SAD (except cohort 1) and MAD cohort will be conducted with sentinel dosing. SAD cohort 1 will be comprised of 4 subjects (3:1 rezafungin to placebo) with no sentinel dosing. Parts 2 and 3 of the study will only be conducted after FDA review for safety data and PK data from all subjects participating in Part 1; Part 3 may be run in parallel with the first cohort (Cohort 7) of Part 2. Individuals in the SAD cohorts will participate for approximately 58 days, including up to 28 days for screening and 30 days for dosing and follow-up (FU). Individuals in the MAD cohorts will participate for approximately 73 days, including up to 28 days for screening and 45 days for dosing and FU. Individuals in the BA cohorts will participate for approximately 80 days, including up to 28 days for screening and 52 days for dosing and FU. The study will have a duration of approximately 30 months. The primary objectives are to determine the: 1) safety and tolerability of single ascending SC doses (SAD) of rezafungin; 2) safety and tolerability of multiple ascending SC doses (MAD) of rezafungin; and 3) pharmacokinetic (PK) profile in plasma of rezafungin in healthy adult subjects.

Detailed description:
This is a Phase 1, double-blind, placebo-controlled trial in three parts. A single ascending dose (SAD) study in six cohorts receiving a single subcutaneous (SC) dose of 1, 10, 30, 60, 100, or 200 mg of rezafungin; a multiple ascending dose (MAD) study in four cohorts receiving 30 mg x 3 doses, 60 mg x 3 doses, 100 mg x 3 doses, or 200 mg x 3 doses of rezafungin SC with dosing frequency of once every 7 days; and a two-period cross-over bioavailability (BA) study receiving 100 mg of rezafungin. The two period cross-over BA study will be assessed unblinded in two sequences (10 subjects, 100 mg or maximum tolerated dose (MTD) of rezafungin in Part 1); 5 subjects will receive an SC injection of rezafungin in Period 1 followed by an intravenous (IV) infusion of rezafungin in Period 2, and 5 subjects will receive an IV infusion of rezafungin in Period 1 followed by an SC injection of rezafungin in Period 2. Each SAD (except cohort 1) and MAD cohort will contain 8 subjects (6 subjects will receive a SC injection of rezafungin and 2 subjects will receive placebo). Each SAD (except cohort 1) and MAD cohort will be conducted with sentinel dosing. SAD cohort 1 will be comprised of 4 subjects (3:1 rezafungin to placebo) with no sentinel dosing. Parts 2 and 3 of the study will only be conducted after FDA review for safety data and PK data from all subjects participating in Part 1; Part 3 may be run in parallel with the first cohort (Cohort 7) of Part 2. Individuals in the SAD cohorts will participate for approximately 58 days, including up to 28 days for screening and 30 days for dosing and follow-up (FU). Individuals in the MAD cohorts will participate for approximately 73 days, including up to 28 days for screening and 45 days for dosing and FU. Individuals in the BA cohorts will participate for approximately 80 days, including up to 28 days for screening and 52 days for dosing and FU. The study will have a duration of approximately 30 months. The primary objectives are to determine the: 1) safety and tolerability of single ascending SC doses (SAD) of rezafungin; 2) safety and tolerability of multiple ascending SC doses (MAD) of rezafungin; and 3) pharmacokinetic (PK) profile in plasma of rezafungin in healthy adult subjects. The secondary objective is to evaluate the BA of rezafungin when administered by SC injection relative to IV infusion in healthy adult subjects.

Arms: arm 1: 100 mg (1 injection of 1.0 ml) or maximum tolerated dose (MTD) determined in SAD of Rezafungin administered subcutaneously into the abdomen on Day 1, and 100 mg (250 ml) or MTD of Rezafungin administered via intravenous infusion on Day 22 in an open label manner. n=5. arm 2: 100 mg (250 ml) or maximum tolerated dose (MTD) determined in SAD of Rezafungin administered via intravenous infusion on Day 1, and 100 mg (1 injection of 1.0 ml) or MTD of Rezafungin administered subcutaneously into the abdomen on Day 22 in an open label manner. n=5. arm 3: 30 mg (1 injection of 0.3 ml) of Rezafungin administered subcutaneously into the abdomen as three doses, n=6 (1 sentinel, 5 non-sentinel), or matching placebo, n=2 (1 sentinel, 1 non-sentinel), on Days 1, 8, and 15 in a double-blind manner. arm 4: 60 mg (1 injection of 0.6 ml) of Rezafungin administered subcutaneously into the abdomen as three doses, n=6 (1 sentinel, 5 non-sentinel), or matching placebo, n=2 (1 sentinel, 1 non-sentinel), on Days 1, 8, and 15 in a double-blind manner. arm 5: 100 mg (1 injection of 1.0 ml) of Rezafungin administered subcutaneously into alternating abdominal quadrants as three doses, n=6 (1 sentinel, 5 non-sentinel), or matching placebo, n=2 (1 sentinel, 1 non-sentinel), on Days 1, 8, and 15 in a double-blind manner. arm 6: 200 mg (2 injections of 1.0 ml) of Rezafungin administered subcutaneously into alternating abdominal quadrants as three doses, n=6 (1 sentinel, 5 non-sentinel), or matching placebo, n=2 (1 sentinel, 1 non-sentinel), on Days 1, 8, and 15 in a double-blind manner. arm 7: 1 mg (1 injection of 0.1 ml diluted 1:10 in 5% Dextrose Injection, USP) of Rezafungin administered subcutaneously into the abdomen as a single dose, n=3 (no sentinel dosing), or matching placebo, n=1 (no sentinel dosing), on Day 1 in a double-blind manner. arm 8: 10 mg (1 injection of 0.1 ml) of Rezafungin administered subcutaneously into the abdomen as a single dose, n=6 (1 sentinel, 5 non-sentinel), or matching placebo, n=2 (1 sentinel, 1 non-sentinel), on Day 1 in a double-blind manner. arm 9: 30 mg (1 injection of 0.3 ml) of Rezafungin administered subcutaneously into the abdomen as a single dose, n=6 (1 sentinel, 5 non-sentinel), or matching placebo, n=2 (1 sentinel, 1 non-sentinel), on Day 1 in a double-blind manner. arm 10: 60 mg (1 injection of 0.6 ml) of Rezafungin administered subcutaneously into the abdomen as a single dose, n=6 (1 sentinel, 5 non-sentinel), or matching placebo, n=2 (1 sentinel, 1 non-sentinel), on Day 1 in a double-blind manner. arm 11: 100 mg (1 injection of 1.0 ml) of Rezafungin administered subcutaneously into alternating abdominal quadrants as a single dose, n=6 (1 sentinel, 5 non-sentinel), or matching placebo, n=2 (1 sentinel, 1 non-sentinel), on Day 1 in a double-blind manner. arm 12: 200 mg (2 injections of 1.0 ml) of Rezafungin administered subcutaneously into alternating abdominal quadrants as a single dose, n=6 (1 sentinel, 5 non-sentinel), or matching placebo, n=2 (1 sentinel, 1 non-sentinel), on Day 1 in a double-blind manner.
Interventions: intervention 1: Placebo intervention 2: Rezafungin intervention 3: Rezafungin
Intervention descriptions: intervention 1: 5% Dextrose Injection, USP, a sterile, nonpyrogenic solution of dextrose in water for injection. The solution has the osmolarity of 252 mOsmol/L, which is slightly hypotonic. This solution contains no bacteriostat, antimicrobial agent or added buffer. intervention 2: Rezafungin, 100 mg/mL, is a sterile liquid product supplied in single-dose vials containing 1.0 mL of extractable volume. The active pharmaceutical ingredient is rezafungin acetate, a water-soluble amorphous acetate salt. The inactive ingredient is mannitol. intervention 3: Rezafungin, 200 mg/vial, is a sterile product supplied as a white to pale yellow lyophilized powder in single-dose glass vials for reconstitution with Sterile Water for Injection, United States Pharmacopeia (USP). The reconstituted product is diluted in 0.9% Sodium Chloride Injection, USP for IV infusion. The active pharmaceutical ingredient is rezafungin acetate, a water-soluble amorphous acetate salt. The inactive ingredients include excipients of mannitol, polysorbate 80, and histidine.

Protocol documents:
ICF_000.pdf: 
APPROVED BY 
INTEGREVIEW IRB 
NOVEMBER 12, 2019 
 
INFORMED CONSENT DOCUMENT 
AGREEMENT TO BE IN A RESEARCH STUDY 
 
NAME OF SPONSOR COMPANY: 
Division of Microbiology and Infectious 
Disease   (DMID) 
 
 
 
 
PROTOCOL NUMBER AND TITLE OF STUDY:  
17-0088 “A Phase 1, Three-Part, Randomized, 
Double-Blind, 
Single 
and 
Multiple 
Subcutaneous Dose Escalation Study to 
Determine 
the 
Safety, 
Tolerability, 
and 
Pharmacokinetics of Rezafungin in Healthy 
Adult Subjects” 
NAME OF PERSON IN CHARGE OF THE RESEARCH  
STUDY (STUDY DOCTOR/INVESTIGATOR): 
  Dennis Ruff, MD 
 
 
TELEPHONE NUMBER(S), DAYTIME:                 
(210) 283-4500 
AFTER HOURS:                                                         
 (210) 283-4510 
 
INTRODUCTION 
 
You are deciding if you would like to volunteer for a medical research study. You must read and sign this 
form before you agree to take part in this study. This form will give you more information about this study. 
Please ask as many questions as you need to before you decide if you want to be in the study. Do not sign 
this form if you have any questions that have not been answered. 
 
The Study Doctor (investigator) is being paid by the sponsor, the National Institute of Health’s Division 
of Microbiology and Infectious Disease (DMID), to conduct this research study.   
 
You must be honest with the Study Doctor about your health history or you may harm yourself by 
participating in this study. 
 
PURPOSE OF THE STUDY 
 
The drug being tested in this study, rezafungin, is being developed by a drug company (Cidara 
Therapeutics) to treat or prevent fungal infections. This study drug (rezafungin) has not been approved for 
use by the FDA and has been given to patients by intravenous (IV) infusion (put directly into the vein by 
way of a tube) in clinical trials.  For the study you will participate in, the study drug would be given to 
you by injecting it under the skin, which is called subcutaneous (SC) dosing, or by injecting it into a vein 
in your arm, which is called intravenous (IV) dosing. When rezafungin is given by SC dosing, it is called 
an “investigational route of dosing”. “Investigational" means the FDA has not yet approved giving 
rezafungin to patients, either by IV dosing or SC dosing. 
 
The purpose of this study is: 
 
• 
to see how safe the study drug is and how the body tolerates the study drug when given under the skin 
(SC) one time (single dose) as well as several times (multiple dose); 
• 
to see how the body absorbs and breaks down the study drug when given SC one time (single dose) as 
well as several times (multiple dose); 
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Dennis Ruff, M.D. 
Informed Consent 
 
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APPROVED BY 
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NOVEMBER 12, 2019 
 
• 
to see how the body acts and how much of the drug circulates in the body when given by SC 
compared to when given IV. 
 
In this document, you may see the terms “medication”, “treatment”, and “treatment period”; these are 
terms used in research studies as mentioned above. This does not mean that you will be receiving medical 
treatment for any condition that you may have.  These terms apply to the investigational drug and parts of 
the study where you will be receiving this drug. 
 
Once enrolled in the study, each participant, including yourself, will be called a “subject” while being part 
of the study.  For Parts 1 and 2, there will be 8 subjects in each group, called a “cohort”. However, the 
first cohort will only have 4 subjects. For Part 3, there will be 5 subjects in each group.  In Parts 1 and 2 
of the study, two subjects in each cohort will be called “sentinels”. However, there will be no sentinel 
subjects in the first cohort. The 2 sentinel subjects will receive the study drug or placebo first, before the 
other 6 subjects.  After the Study Doctor reviews the information collected on the 2 sentinel subjects 
through Day 30 for Parts 1 and 2, and there are no safety concerns, the other 6 subjects in the cohort will 
be admitted to the study unit and receive study drug.  
 
This study is divided into three parts, Part 1, Part 2, and Part 3. If you agree to be in the study (enrolled), 
you will be assigned to either Part 1, Part 2, or Part 3.  All three parts of the study are designed to evaluate 
how safe the study drug is when given SC, how the body tolerates the study drug when given SC, and how 
it is broken down and absorbed by the body when given SC. Part 3 also compares any differences between 
giving the study drug by SC vs. IV. Part 1 subjects receive one dose of study drug; Part 2 subjects receive 
three (3) doses of study drug (one dose per week for 3 weeks), and Part 3 subjects receive one dose of 
study drug by SC and one dose of study drug by IV.  These parts will be described in more detail below.  
 
If you qualify for the study, you will receive either the investigational study drug (rezafungin) or what is 
called a placebo. Placebo looks like the study drug but does not contain any active ingredient. The first 
cohort will have 4 subjects, 3 will receive rezafungin and I will receive placebo. In cohorts 2-6 of Part 1 
and all cohorts of Part 2, 6 subjects receive rezafungin, and 2 subjects receive placebo. However, there is 
no placebo in Part 3. The drug you receive will be assigned by chance, like a lottery.   
 
The amount of drug you are given at one time is called a dose.  The doses are measured in weight 
(milligrams, or mg) and volume (in milliliters, or mL).  For comparison, 1/8 teaspoon of sugar weighs 
about 500 mg and 1/8 teaspoon of liquid is a little over 1/2 mL (0.60).   
 
If you are assigned to Part 1, Cohorts 1, 2, 3, 4, 5, or 6, you will receive one the following doses given 
subcutaneous (SC, under the skin) injections in the abdomen (stomach area) once (on Day 1):  
 
• 
Cohort 1:  1 mg rezafungin subcutaneous or placebo given in one 0.10 mL injection 
• 
Cohort 2:  10 mg rezafungin subcutaneous or placebo given in one 0.10 mL injection 
• 
Cohort 3:  30 mg rezafungin subcutaneous or placebo given in one 0.30 mL injection 
• 
Cohort 4:  60 mg rezafungin subcutaneous or placebo given in one 0.60 mL injection 
• 
Cohort 5:  100 mg rezafungin subcutaneous or placebo given in one 1.00 mL injection 
• 
Cohort 6:  200 mg rezafungin subcutaneous or placebo given in two 1.00 mL injections (given in 
different areas of your abdomen) 
 
The first cohort of 4 subjects will be dosed together. At each dosing level for cohorts 2-6, 2 subjects 
will be dosed and observed for at least 4 weeks after dosing for safety before the other 6 subjects in 
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Dennis Ruff, M.D. 
Informed Consent 
 
Page 3 of 31 
APPROVED BY 
INTEGREVIEW IRB 
NOVEMBER 12, 2019 
 
the group are dosed. Of those 2 subjects, 1 subject will receive placebo and 1 will receive active study 
drug. 
 
If you are assigned to Part 2, Cohorts 7, 8, 9, or 10, you will receive one of the following doses given as 
subcutaneous injections in the stomach area on three separate days (Day 1, Day 8 and Day 15): 
 
• 
Cohort 7:  30 mg rezafungin subcutaneous or placebo given in one 0.30 mL injection every 8 days 
(total 3 injections) 
• 
Cohort 8:  60 mg rezafungin subcutaneous or  placebo given in one 0.60 mL injection every 8 days 
(total 3 injections) 
• 
Cohort 9:  100 mg rezafungin subcutaneous or  placebo given in one 1.0 mL injection every 8 days 
(total 3 injections) 
• 
Cohort 10:  200 mg rezafungin subcutaneous or  placebo given in two 1.0 mL injections every 8 days 
(total 6 injections) 
  
At each dosing level, 2 subjects will be dosed and observed for at least 4 weeks after the final dose for 
safety before the other 6 subjects in the group are dosed.  Of the first 2 subjects, one (1) subject will 
receive placebo and 1 will receive active study drug. 
 
Parts 1 and 2 of this study are called “double-blind”, which means that neither you nor the investigators or 
study team you work with will know which drug (rezafungin or placebo) you are given. However, in case 
of emergency, the study staff can get this information. 
 
If you are assigned to Part 3, Cohort 11, you will receive one dose given either as a subcutaneous (SC) 
injection on Day 1, or you will receive the following dose level study drug into the vein (intravenous -IV) 
on Day 1.  Then on Day 22 you will receive the study drug in the route you did not receive study drug (i.e. 
Day 1 (SC) and Day 22 (IV) OR Day 1 (IV) and Day 22(SC)). 
 
• 
100 mg rezafungin SC or placebo given in two 1.0 mL injections once AND; 100 mg rezafungin IV 
infusion in 250 mL of normal saline over 60 minutes once.  
 
The dose amount you end up receiving may be adjusted to something different than what is shown above 
but it will not be more than 100 mg of rezafungin.  The dose will be by the highest level of rezafungin in 
the blood that was proven to be safe and well tolerated, as determined by evaluating the information 
gathered from Cohorts 1-6 in Part 1 of this study.  Part 3 is unblinded with no placebo.  This means you 
will receive study drug and that you and the study team will know what you are receiving.   
 
A Safety Monitoring Committee (SMC), made up of at least 3 independent experts, will monitor subject 
safety.  The SMC, along with the sponsor (DMID), will review all information and any specific safety 
issues during the study. They will meet at the end of Part 1 before deciding that the study is safe to 
continue to Parts 2 and 3. The Food and Drug Administration (FDA) will be reviewing this same 
information, and will only give permission to continue to Parts 2 and 3 if the study is safe .In addition to 
these reviews, there is an Independent Safety Monitor (ISM) assigned to this study. An ISM is a doctor 
that is not part of the study who can provide quick safety assessments, because they are located close to 
the study site. The ISM participates voluntarily and is not paid for providing this service.  
 
If changes are made to any of the above cohorts or cohort(s) are added once you are enrolled, you would 
be informed of these changes and asked to review and sign a new consent form. 
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Dennis Ruff, M.D. 
Informed Consent 
 
Page 4 of 31 
APPROVED BY 
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NOVEMBER 12, 2019 
 
HOW LONG THE STUDY WILL LAST AND HOW MANY PEOPLE WILL BE IN THE STUDY 
 
Approximately 86 healthy male and female participants aged 18 through 45 will be included in this study. 
The study will last approximately 58 to 80 days including an up to 28-day screening period between 
screening and dosing (timing depends on the Part and Cohort you will participate in). Refer to the chart 
below for timing of visits. You will be informed of which part and Cohort you will be participating in.  
 
Part 1 (Cohort 1, 2, 3, 4, 5, and 6): 
 
Visit 
Study day 
Type 
Description 
Visit 1 
Within 28 
days of Visit 
2 
Screening 
Outpatient visit; must fast (no food or drink other 
than water) for at least 8 hours before visit 
Visit 2 
Check in 
Day -1; 
Check out 
Day 7 
Dosing on Day 1 
In house stay (7 days); must fast (no food or drink
other than water) for at least 8 hours before check-in 
Visit 3 
Day 14 
Follow-up 
Outpatient visit 
Visit 4 
Day 21 
Follow-up 
Telephone follow-up to discuss any changes to the
injection site(s) since Visit 3 (Day 14). 
Visit 5 
Day 30 
Follow-up (End of 
Study) 
Outpatient visit; must fast (no food or drink other 
than water) for at least 8 hours before visit 
 
A full safety review is performed before proceeding with Part 2.   
 
Part 2 (Cohorts 7, 8, 9, and 10): 
 
Visit 
Study day 
Type 
Description 
Visit 1 
Within 28 
days of Visit 2 
Screening 
Outpatient visit; must fast (no food or drink other 
than water) for at least 8 hours before visit 
Visit 2 
Check in 
Day -1; 
Check out 
Day 21 
Dosing on Day 1 
Dosing on Day 8 
Dosing on Day 15 
In house stay (21 days); must fast (no food or drink 
other than water) for at least 8 hours before check-in 
Visit 3 
Day 30 
Follow-up 
Outpatient visit 
Visit 4 
Day 45 
Follow-up (End of 
Study) 
Outpatient visit; must fast (no food or drink other 
than water) for at least 8 hours before visit 
 
 
 
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Protocol number 17-0088 
Dennis Ruff, M.D. 
Informed Consent 
 
Page 5 of 31 
APPROVED BY 
INTEGREVIEW IRB 
NOVEMBER 12, 2019 
 
Part 3 (Cohort 11): 
 
Visit 
Study day 
Type 
Description 
Visit 1 
Within 28 days 
of Visit 2 
Screening 
Outpatient visit; must fast (no food or drink other 
than water) for at least 8 hours before visit 
Visit 2 
Check in 
Day -1; 
Check out 
Day 7 
Dosing on Day 1 
 
In house stay (7 days); must fast (no food or drink
other than water) for at least 8 hours before check-in 
Visit 4 
Day 14 
Follow-up 
Outpatient visit 
Visit 5 
Check in  
Day 21; 
Check out 
Day 28 
Dosing on Day 22 In house stay (7 days); must fast (no food or drink
other than water) for at least 8 hours before check-in 
Visit 6 
Day 35 
Follow-up 
Outpatient visit 
Visit 7 
Day 52 
Follow-up (End of 
Study) 
Outpatient visit; must fast (no food or drink other 
than water) for at least 8 hours before visit 
 
WHEN ARE YOU ELIGIBLE TO PARTICIPATE IN ANOTHER DRUG STUDY?  
 
The decision for when you can participate in another study is determined by the drug safety information 
gathered from the previous study.  Usually, you can participate in another study as soon as 30 days after 
you received the last dose of drug in the study you were in.  This information is true for most drugs.  
Some drugs may stay in your body longer and that may mean you may have to wait longer before starting 
another study.  These results are usually only known after the last blood sample taken from you is tested 
to look for left-over drug. We will always make this information available to you as soon as we know.  
Our goal is to keep you from doing anything that may be potentially harmful to you.  Your safety while 
participating in these studies is our primary concern.   
 
TO BE ENROLLED IN THIS STUDY 
 
You cannot be enrolled in the study if, at screening you: 
 
• 
Report a history of allergic reactions or oversensitivity to drugs like rezafungin or the inactive 
ingredients (mannitol, polysorbate 80, histidine) of the injectable form of rezafungin (Rezafungin for 
Injection); 
• 
experience symptoms of an illness within 14 days before the first dose of study drug, or if the Study 
Doctor feels you are not in good health; 
• 
if you weigh less than 50 kg (110 lbs.) and/or have a body mass index (BMI) calculated from your 
height and weight that is less than 18.5 kg/m2 or more than 35.0; 
• 
have a positive HIV or hepatitis test result, abnormal laboratory test results that are not due to a 
transient (passing) condition, or an abnormal electrocardiogram (ECG); 
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NOVEMBER 12, 2019 
 
• 
Are pregnant or planning to become pregnant during the study or a minimum of 30 days after the 
study, or if you are breastfeeding, or if you have any medical conditions that could make it potentially 
unsafe for you to participate in the study (for females); 
• 
are planning to have unprotected intercourse or donate sperm for at least 18 weeks (126 days) after 
receiving the study drug (for males); 
• 
have taken prescription drugs within 14 days of first receiving the study drug and throughout the 
study, except for birth control pills (hormonal contraceptives only); 
• 
had a vaccination with a live or killed vaccine or immunoglobulin within 14 days receiving the study 
drug; 
• 
if you have taken or if you take any non-prescription medications, vitamins or dietary supplements 
(including herbal supplements) within 14 days of getting the first dose of study drug, except for 
intermittent (not every day) normal doses of acetaminophen (i.e., Tylenol®) and ibuprofen (i.e. 
Advil®). 
• 
if you have used illicit (illegal) drugs, smoked or used nicotine products (smoking or smokeless 
tobacco, vaping, nicotine patches or gum) within 90 days before the Screening visit or during the 
study*;  
• 
if you have consumed alcohol or alcohol-containing food or beverages within 48 hours of the 
Screening visit*;  
• 
consumed foods or beverages containing caffeine or xanthines (coffee, tea, chocolate, energy drinks 
and colas) for 24 hours before dosing day(s) and until discharge; 
• 
if you have (or had within 6 months of screening and throughout the study) an alcohol or substance 
(illegal or prescription drugs) abuse problem*; 
• 
donated blood or blood products (such as plasma) or experienced significant blood loss within 60 
days of screening, and throughout the study; 
• 
had a blood transfusion within 14 days of screening; 
• 
if you previously participated in this trial, any other rezafungin trial, or had a treatment with any 
investigational products or treatments within 28 days before the dosing visit and during the study; 
• 
if it would be difficult or unsafe to draw blood samples from you or place a catheter in your arm; 
• 
if the results of your clinical evaluations or lab tests are abnormal, even after repeating (tests may be 
repeated one time to double-check); 
• 
if the Study Doctor feels you have a condition that would impact how the drug acts in your body or 
feels you should not participate for any reason not related to the above. 
 
*A urine test will be performed at Screening to check for the use of these drugs: amphetamines, 
barbiturates, cocaine, opiates, cannabinoids (marijuana), benzodiazepines, phencyclidine (PCP), and also 
for alcohol and cotinine (a chemical that indicates tobacco use). 
 
Subject Responsibilities: 
 
While participating in this research study, you will need to: 
 
• 
men must be vasectomized or agree to use barrier contraception (condom with spermicide) from first 
dose of study drug until 18 weeks (126 days) following the last dose of study drug, and refrain from 
sperm donation from first dose of study drug through 18 weeks (126 days) after last dose of study 
drug; 
 
 
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Informed Consent 
 
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• 
women who are able to become pregnant must agree to use allowable methods from 30 days before 
the first dose of study drug until 30 days after the last dose of study drug:  
o under the skin hormone (progestin) implants (for example, Nexplanon and Implanon);  
o copper IUD (intrauterine devices; for example, ParaGard);  
o hormone (levonorgestrel) releasing IUDs (for example, Mirena, Skyla, and Liletta)  
• 
be willing and able to follow the study directions and procedures; 
• 
tell the study staff about any side effects or problems; 
• 
ask questions as you think of them; 
• 
tell the Study Doctor or the study staff if you change your mind about staying in the study; 
• 
you must not use drugs of abuse throughout this study; 
• 
refrain from taking any over-the-counter medications (except for acetaminophen or ibuprofen), 
prescription medications (except for hormonal birth control), vitamins, or dietary supplements 
(including herbal supplements) within 14 days of dosing; 
• 
refrain from consuming caffeine or xanthine containing food or beverages (coffee, tea, chocolate, 
energy drinks and colas) 24 hours before dosing day and until discharge;   
• 
alcohol is not allowed for the duration of this study and you must refrain from use for at least 48 
hours before dosing day and until discharge; refrain from eating or drinking anything at least 8 hours 
before safety lab blood collection. (may have water only); 
• 
you must not smoke or use any tobacco products while enrolled in this study (tobacco use includes 
vaping, smoke tobacco, the use of snuff and chewing tobacco, and other nicotine or nicotine-
containing products);  
• 
you must refrain from strenuous physical activity that could cause muscle aches or injury, including 
contact sports, at any time from screening until completion of the trial; 
• 
you must not donate any blood or blood products (like plasma) while participating in this study and 
for at least 8 weeks after receiving the study drug; 
• 
be willing to avoid sun and ultraviolet (tanning bed) exposure during this study (using i.e. wide brim 
hat, sunscreen, etc..); 
• 
you will be given a “Memory Aid”. This is a diary to help you track any reactions you may be having 
to the study drug; 
• 
be willing to have a photograph taken of the skin in the area of your body where the drug is injected 
(abdomen) if you have a reaction to the drug. 
 
You cannot participate in any other clinical study during your participation in this study. This is a 
precaution to protect your safety and the conclusions of this study. 
 
WHAT WILL HAPPEN DURING THE STUDY 
 
Screening (all Parts and all Cohorts): 
 
Before the study starts, you will be asked to sign this consent form, give your health history, and tell 
study staff if you take any over-the-counter or prescription medicines, vitamins or herbs.  
 
The Study Doctor will do some tests to find out if you can be in the study. These tests include: 
 
• 
We will ask you how you are feeling and about any medications you may have taken; 
• 
the study doctor will review the study requirements to determine your eligibility to participate in this 
study; 
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Informed Consent 
 
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• 
we will ask you some personal information such as your race, date of birth, etc.;  
• 
we will ask you about your medical history, including any psychiatric, surgical, smoking, alcohol 
and/or drug history; 
• 
your vital signs  (Blood Pressure, Heart Rate, Oral Temperature, and Respiratory Rate) will be 
measured; 
• 
you will have an electrocardiogram (ECG – a recording of the heart’s electrical activity); 
• 
you will have a physical examination; 
• 
if female, we will ask about your menstrual cycle; 
• 
we will ask about current use of contraceptives (male and female); 
• 
your weight will be measured and your body mass index (BMI- a way of relating your weight to your 
height) will be calculated; 
• 
you will have blood drawn for lab tests: Must not eat or drink anything for at least 8 hours, water 
only.  These tests will be on the blood and urine, and include Chemistry tests (such as blood sugar, 
potassium, etc.), Hematology (such as red/white blood cell counts), Coagulation (how quickly your 
blood clots) and Urinalysis (testing your urine for protein, bacteria, etc.); 
• 
if a female of post-menopausal status, a blood test will be drawn to confirm; 
• 
if you are a female who is able to get pregnant, a blood pregnancy test will be performed; 
• 
you will be tested for hepatitis (A, B, and C) and human immunodeficiency virus (HIV). If the 
Screening HIV test is positive you will be referred to your personal physician or Medical Clinic of 
your choice for follow-up evaluation.  You will be told your results in private.;   
• 
you will give urine to be tested for drugs of abuse, cotinine (to test for tobacco use), and alcohol; 
• 
you be informed of which group you will be assigned to, either Part 1, Part 2, or Part 3; 
• 
you will be counseled on the avoidance of pregnancy for women able to get pregnant, and use of 
barrier contraception for men, and on the avoidance of vaccines, drugs, dietary supplements and 
dietary restrictions before admission. 
 
Day -1: Admission to the Clinical Research Unit (CRU) Study Procedures Parts 1-3 (All Cohorts): 
 
You will be admitted to the study site 1 day before you receive the study drug (Day -1). You must be 
fasting for at least 8 hours before your visit. The following procedures may be done on this study day: 
 
• 
Review the study requirements to determine that you are still able to participate in this study; 
• 
review any changes to your health and/or medications you have taken since screening visit; 
• 
measure weight; 
• 
vital signs after resting for at least 5 minutes;  
• 
lab tests: Must not eat or drink anything for at least 8 hours, water only.  These tests will be on the 
blood and urine, and include Chemistry tests Coagulation) and Urinalysis ; 
• 
blood pregnancy test for female subjects who have the potential to become pregnant; 
• 
urine test for drugs of abuse (illegal and/or prescription), alcohol, and for tobacco use 
• 
physical exam; 
• 
standard meals (Lunch, Dinner, Snack). 
 
 
 
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Dennis Ruff, M.D. 
Informed Consent 
 
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NOVEMBER 12, 2019 
 
Part 1 (Cohorts 1-6): 
 
Day 1 – Inpatient CRU 
 
• 
On the morning of Day 1, you will be assigned (randomized) to a cohort;  
• 
review any changes to your health and/or medications you have taken since being admitted; 
• 
vital signs after resting for at least 5 minutes; this is done again at multiple timepoints following study 
drug dosing; 
• 
physical exam; 
• 
electrocardiogram (ECG) after lying down for at least 5 minutes (to measure the electrical function of 
your heart) before study drug dosing and again at around 4 hours after dosing (and after lying down 
for at least 5 minutes); 
• 
on the morning of Day 1, study drug or placebo will be given by SC injection (using a syringe with 
needle) in the abdomen at a slow steady pace; 
• 
you will be given a “Memory Aid”. This is a diary to help you track any reactions you may be having 
to the study drug; 
• 
collect blood samples at multiple time points to measure the amount of study drug in the body; blood 
samples on this day will go into the night and possibly disturb your sleep; (we will not collect these 
samples from you if you are assigned to Cohort 1); 
• 
inspection of the injection site before and after injection, at multiple timepoints. 
 
Day 2 – Inpatient CRU 
 
• 
Review any changes to your health and/or medications; 
• 
vital signs after resting for at least 5 minutes; 
• 
physical exam; 
• 
collect fasting (must not eat or drink anything for at least 8 hours, water only) blood and urine for lab 
tests; 
• 
collect blood sample to measure the amount of study drug in the body; (we will not collect these 
samples from you if you are assigned to Cohort 1); 
• 
inspection of the injection site. 
 
Day 3 – Inpatient CRU 
 
• 
Review any changes to your health and/or medications you have taken since Day 1; 
• 
collect blood sample to measure the amount of study drug in the body; (we will not collect these 
samples from you if you are assigned to Cohort 1); 
• 
inspection of the injection site. 
 
Day 4 – Inpatient CRU 
 
• 
Review any changes to your health and/or medications you have taken; 
• 
vital signs after resting for at least 5 minutes;  
• 
physical exam; 
• 
inspection of the injection site. 
 
 
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Informed Consent 
 
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Day 5 – Inpatient CRU 
 
• 
Review any changes to your health and/or medications you have taken since Day 4; 
• 
collect blood sample to measure the amount of study drug in the body; (we will not collect these 
samples from you if you are assigned to Cohort 1); 
• 
inspection of the injection site. 
 
Day 6 – Inpatient CRU 
 
• 
Review any changes to your health and/or medications you have taken; 
 
• 
inspection of the injection site. 
 
Day 7 – Inpatient CRU 
 
• 
Review any changes to your health and/or medications you have taken since Day 6; 
• 
vital signs after resting for at least 5 minutes;  
• 
electrocardiogram (ECG) after lying down for at least 5 minutes (to measure the electrical function of 
your heart) 
• 
physical exam; 
• 
collect fasting (must not eat or drink anything for at least 8 hours, water only) blood and urine for lab 
tests; 
• 
collect blood sample to measure the amount of study drug in the body; (we will not collect these 
samples from you if you are assigned to Cohort 1); 
• 
inspection of injection site; 
• 
counselling on birth control and post-discharge instructions (dietary and medication/nonmedication 
restrictions); 
• 
instructions on how to properly complete the Memory Aid; 
• 
discharge from clinical research unit. 
 
Day 14 (±1 Day) – Follow-Up – Outpatient 
 
• 
Review any changes to your health and/or medications you have taken since Day 7; 
• 
review Memory Aid; 
• 
vital signs after resting for at least 5 minutes;  
• 
collect blood sample to measure the amount of study drug in the body; (we will not collect these 
samples from you if you are assigned to Cohort 1); 
• 
inspection of injection site; 
• 
reminder of birth control and post-discharge instructions (dietary and medication/nonmedication 
restrictions). 
 
Day 21 (±1 Day) –Telephone  Follow-Up  
 
• 
Study Doctor or study staff will call you to review any changes to your injection site (s) since the Day 
14 visit. 
• 
Review Memory Aid 
 
 
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Informed Consent 
 
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NOVEMBER 12, 2019 
 
Day 30 (±1 Day) – Follow-Up – Final Study Visit 
 
• 
Review any changes to your health and/or medications you have taken since Day 14; 
• 
review Memory Aid; 
• 
vital signs after resting for at least 5 minutes;  
• 
electrocardiogram (ECG) after lying down for at least 5 minutes (to measure the electrical function of 
your heart) 
• 
physical exam; 
• 
weight; 
• 
collect fasting (must not eat or drink anything for at least 8 hours, water only) blood and urine for lab 
tests; 
• 
collect blood sample to measure the amount of study drug in the body; (we will not collect these 
samples from you if you are assigned to Cohort 1); 
• 
inspection of injection site; 
• 
perform blood (serum) pregnancy test (females only), 
• 
review post-study instructions (birth control, pregnancy reporting). 
 
Part 1 Blood Samples: 
 
Blood samples will be taken by single needle-sticks or by a tube that is left in your arm.  You cannot 
choose how the blood is taken. 
 
There will be 6 blood draws for participants in Cohort 1; there will be about 30 blood draws for 
participants in Cohorts 2-6. The total amount of blood drawn will be about 90 ml (about 50 ml for first 
cohort) or a little over 1/3 cup.  For comparison, the standard blood donation is about 480 mL (two cups).   
 
Part 2 (Cohorts 7, 8, 9, and 10): 
 
Days 1, 8, and 15 – Inpatient CRU 
 
• 
On the morning of Day 1, you will be assigned (randomized) to a cohort. One Days 1, 8 and 15, the 
following procedures will be performed;  
• 
review any changes to your health and/or medications you have taken since being admitted; 
• 
review the study requirements to determine that you are still able to receive study drug; 
• 
vital signs (Blood Pressure, Heart Rate, Oral Temperature, and Respiratory Rate) after resting for at 
least 5 minutes; this is done at multiple timepoints; 
• 
physical exam; 
• 
electrocardiogram (ECG) after lying down for at least 5 minutes (to measure the electrical function of 
your heart) before dosing and again at around 4 hours after dosing (and after lying down for at least 5 
minutes); 
• 
collect blood samples at multiple time points to measure the amount of study drug in the body; blood 
samples on this day will go into the night and possibly disturb your sleep; 
• 
inspection of the injection site before and after injection, at multiple timepoints; 
• 
give the study drug by SC injection (using a syringe with needle) in the abdomen at a slow steady 
pace;  
• 
you will be given a “Memory Aid”. This is a diary to help you track any reactions you may be having 
to the study drug.  
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Dennis Ruff, M.D. 
Informed Consent 
 
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APPROVED BY 
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NOVEMBER 12, 2019 
 
Days 2, 9, and 16 – Inpatient CRU 
 
• 
Review any changes to your health and/or medications you have taken; 
• 
vital signs after resting for at least 5 minutes;  
• 
physical exam; 
• 
collect fasting (must not eat or drink anything for at least 8 hours, water only) blood and urine for lab 
tests; 
• 
collect blood sample to measure the amount of study drug in the body;  
• 
inspection of the injection site. 
 
Days 3, 10, and 17 – Inpatient CRU 
 
• 
Review any changes to your health and/or medications you have taken since Day 1, 9 or 15; 
• 
inspection of the injection site; 
• 
collect blood sample to measure the amount of study drug in the body. 
 
Days 4, 11, and 18 – Inpatient CRU 
 
• 
Review any changes to your health and/or medications you have taken; 
• 
vital signs after resting for at least 5 minutes;  
• 
physical exam; 
• 
inspection of the injection site. 
 
Days 5, 12, and 19 – Inpatient CRU 
 
• 
Review any changes to your health and/or medications you have taken since Day 4, 11 or 18; 
• 
collect fasting blood (must not eat or drink anything for at least 8 hours, water only) for lab tests;  
• 
collect blood sample to measure the amount of study drug in the body; 
• 
inspection of the injection site. 
 
Days 6, 13, and 20 – Inpatient CRU 
 
• 
Review any changes to your health and/or medications you have taken since Day 5, 12 or 19; 
• 
inspection of the injection site. 
 
Days 7, 14, and 21 – Inpatient CRU 
 
• 
Review any changes to your health and/or medications you have taken since Day 6, 13 or 20; 
• 
vital signs after resting for at least 5 minutes;  
• 
electrocardiogram (ECG) after lying down for at least 5 minutes (to measure the electrical function of 
your heart) (Day 21 only) 
• 
physical exam; 
• 
collect fasting blood (must not eat or drink anything for at least 8 hours, water only) and urine for lab 
tests; 
• 
collect blood sample to measure the amount of study drug in the body;  
• 
inspection of the injection site; 
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Dennis Ruff, M.D. 
Informed Consent 
 
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NOVEMBER 12, 2019 
 
• 
counselling on birth control and post-discharge instructions (dietary and medication/nonmedication 
restrictions); 
• 
instructions on how to properly complete the Memory Aid; 
• 
DAY 21 ONLY: discharge from clinical research unit. 
 
Day 30 (±1 Day) – Follow-Up – Outpatient 
 
• 
Review any changes to your health and/or medications you have taken since the last study visit 
• 
review Memory Aid; 
• 
vital signs after resting for at least 5 minutes;  
• 
electrocardiogram (ECG) after lying down for at least 5 minutes (to measure the electrical function of 
your heart) 
• 
physical exam; 
• 
collect blood sample to measure the amount of study drug in the body;  
• 
inspection of injection site; 
• 
review post-discharge instructions (birth control, pregnancy reporting). 
 
Day 45 (±1 Day) – Follow-Up – Final Study Visit 
 
• 
Review any changes to your health and/or medications you have taken since Day 30; 
• 
review Memory Aid; 
• 
vital signs after resting for at least 5 minutes;  
• 
electrocardiogram (ECG) after lying down for at least 5 minutes (to measure the electrical function of 
your heart) 
• 
physical exam; 
• 
weight; 
• 
collect fasting blood (must not eat or drink anything for at least 8 hours, water only) and urine for lab 
tests; 
• 
collect blood sample to measure the amount of study drug in the body;  
• 
inspection of injection site; 
• 
perform blood (serum) pregnancy test (females only); 
• 
review post-study instructions (birth control, pregnancy reporting). 
 
Part 2 Blood Samples: 
 
Blood samples will be taken by single needle-sticks or by a tube that is left in your arm.  You cannot 
choose how the blood is taken. 
 
There will be about 55 blood draws.  The total amount of blood drawn will be about 163 ml or slightly 
over 2/3 cup.  For comparison, the standard blood donation is about 480 mL (two cups).   
 
 
 
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Informed Consent 
 
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NOVEMBER 12, 2019 
 
Part 3 (Cohort 11): 
 
Days 1 and 22 – Inpatient CRU 
 
• 
On the morning of Day 1, you will be assigned (randomized) to a cohort;  
• 
review any changes to your health and/or medications you have taken since being admitted; 
• 
vital signs (Blood Pressure, Heart Rate, Oral Temperature, and Respiratory Rate) after resting for at 
least 5 minutes; this is done at multiple timepoints; 
• 
physical exam; 
• 
you will receive the study drug by  two SC injections into the abdomen (100 mg each, using a syringe 
and needle) in the morning on Day 1 and as an IV infusion (into a catheter placed in the vein of one 
arm) over 60 minutes in the morning on Day 22; or the study drug will be given via IV infusion over 
60 minutes in the morning on Day 1 and by SC injection in the morning on Day 22; 
• 
you will be given a “Memory Aid”. This is a diary to help you track any reactions you may be having 
to the study drug;  
• 
electrocardiogram (ECG) after lying down for at least 5 minutes (to measure the electrical function of 
your heart) before dosing 
• 
 electrocardiogram (ECG) after lying down for at least 5 minutes (to measure the electrical function 
of your heart) at around 4 hours after dosing if you had the SC injection 
• 
electrocardiogram (ECG) after lying down for at least 5 minutes (to measure the electrical function of 
your heart) at around 1 hour from the start of your infusion; if you had the IV 
• 
collect blood samples at multiple time points to measure the amount of study drug in the body; blood 
samples on this day will go into the night and possibly disturb your sleep;  
• 
inspection of the injection site/IV site before and after injection, at multiple timepoints. 
 
Days 2 and 23 – Inpatient CRU 
 
• 
Review any changes to your health and/or medications you have taken; 
• 
vital signs (Blood Pressure, Heart Rate, Oral Temperature, and Respiratory Rate) after resting for at 
least 5 minutes;  
• 
physical exam; 
• 
collect fasting blood (must not eat or drink anything for at least 8 hours, water only) and urine for lab 
tests (hematology/chemistry and urine for urinalysis); 
• 
collect blood sample to measure the amount of study drug in the body;  
• 
inspection of the injection site/IV site. 
 
Days 3 and 24 – Inpatient CRU 
 
• 
Review any changes to your health and/or medications you have taken since Day 1 or Day 22; 
• 
collect blood sample to measure the amount of study drug in the body; 
• 
inspection of the injection site/IV site. 
  
Days 4 and 25 – Inpatient CRU 
 
• 
Review any changes to your health and/or medications you have taken; 
• 
vital signs (Blood Pressure, Heart Rate, Oral Temperature, and Respiratory Rate) after resting for at 
least 5 minutes;  
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Informed Consent 
 
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• 
physical exam; 
• 
inspection of the injection site/IV site. 
 
Days 5 and 26 – Inpatient CRU 
 
• 
Review any changes to your health and/or medications you have taken since Day 4 or 25; 
• 
collect blood sample to measure the amount of study drug in the body; 
• 
inspection of the injection site/IV site. 
 
Days 6 and 27 – Inpatient CRU 
 
• 
Review any changes to your health and/or medications you have taken; 
• 
inspection of the injection site/IV site. 
 
Days 7 and 28 – Inpatient CRU 
 
• 
Review any changes to your health and/or medications you have taken since Day 5 or 26; 
• 
vital signs  after resting for at least 5 minutes;  
• 
physical exam; 
• 
collect fasting blood (must not eat or drink anything for at least 8 hours, water only) and urine for lab 
tests; 
• 
collect blood sample to measure the amount of study drug in the body;  
• 
inspection of the injection site/IV site; 
• 
counselling on birth control and post-discharge instructions (dietary and medication/nonmedication 
restrictions); 
• 
instructions on how to properly complete the Memory Aid; 
• 
discharge from clinical research unit. 
 
Days 14 and 35 (±1 Day) – Follow-Up – Outpatient 
 
• 
Review any changes to your health and/or medications you have taken since Day 7 or 28; 
• 
review Memory Aid; 
• 
vital signs after resting for at least 5 minutes;  
• 
physical exam; 
• 
inspection of injection site; 
• 
collect blood sample to measure the amount of study drug in the body;  
• 
review post-discharge instructions (birth control, pregnancy reporting). 
 
Day 52 (±1 Day) – Follow-Up – Final Study Visit 
 
• 
Review any changes to your health and/or medications you have taken since Day 35; 
• 
review Memory Aid; 
• 
vital signs after resting for at least 5 minutes; 
• 
electrocardiogram (ECG) after lying down for at least 5 minutes (to measure the electrical function of 
your heart)  
• 
physical exam; 
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NOVEMBER 12, 2019 
 
• 
weight; 
• 
collect fasting blood (must not eat or drink anything for at least 8 hours, water only) and urine for lab 
tests; 
• 
collect blood sample to measure the amount of study drug in the body;  
• 
perform blood (serum) pregnancy test (females only), 
• 
review post-study instructions (birth control, pregnancy reporting).  
 
Part 3 Blood Samples: 
 
Blood samples will be taken by single needle-sticks or by a tube that is left in your arm.  You cannot 
choose how the blood is taken. 
 
There will be about 49 blood draws.  The total amount of blood drawn will be about 146 mL or just over 
1/2 cup.  For comparison, the standard blood donation is about 480 mL (two cups).   
 
HIV AND HEPATITIS TESTING 
 
As required by the study, and in the event anyone is exposed to your blood, you must have your blood 
tested for the hepatitis viruses and for HIV. HIV is the virus that causes AIDS. If you have a positive HIV 
or hepatitis test, you cannot be in the study. If the HIV test is positive, a follow-up confirmatory test will 
be done.  If the follow-up test is also positive, you will be told in private and you will also be told about 
counseling. 
 
It may take weeks or months after being infected with HIV for the test to be positive.  The HIV test is not 
always right. 
 
According to Texas State Laws, cases of positive HIV, hepatitis B antigen, and hepatitis C antibody are 
all reportable to the Department of Health. In the event that your results are positive for any of these lab 
tests, the following personal information will be reported to the Department of Health via a “Notifiable 
Disease Report” form supplied by the local Health Department: 
 
• 
Your Name 
• 
Date of Birth 
• 
Sex 
• 
Race 
• 
Ethnicity 
• 
Address 
• 
Telephone Number 
 
If you have any questions, please ask the study doctor or staff. Although this testing is supposed to be 
private, this cannot be guaranteed. For example, it is possible for a court of law to get health or study 
records without your permission. 
 
POSSIBLE SIDE EFFECTS AND RISKS  
 
If you do not understand what any of these side effects mean, please ask the Study Doctor or study 
staff to explain these terms to you. 
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Informed Consent 
 
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Because this route of dosing of the study drug is investigational, all the side effects for this way of giving 
it may not be known.  There may be rare and unknown side effects. Some of these may be life 
threatening.  
 
You must tell the Study Doctor or study staff about all side effects that you have. If you are not honest about 
your side effects, you may harm yourself by staying in this study.  
 
You may be asked to return to the clinical unscheduled safety follow-up visits if deemed necessary by the 
study investigators.     
 
What are the possible side effects or harms of taking part? 
 
The study drug (rezafungin) is a new drug from the antifungal drug family called “echinocandins”.  The 
study drug is not yet approved for use by the FDA and is currently being studied by giving it to patients 
by intravenous (IV) infusion (put directly into the vein by way of a tube). The study drug has not been 
given to patients in the same way it will be given to you, should you choose to participate in the study (by 
injecting it under the skin).  The following information describes the side effects observed when 
giving the study drug to patients by IV infusion and to animals.  We do not know whether these side 
effects are also possible when giving the study drug by injection under the skin or by IV injection, as it 
will be given in this study.  It is also unknown whether side effects observed in animal studies will also be 
observed in human study participants.     
 
Risks to Healthy Human Participants 
 
So far, 42 healthy participants have received rezafungin in two studies in doses up to 400 mg (twice as 
much as the highest dose being given in this study) once weekly given for three weeks.  All side effects 
were mild (easy to tolerate and did not affect daily living) or moderate (caused some discomfort and 
changed normal routine to a limited amount).  There were no serious side effects observed.  There were 
no abnormal results from routine laboratory tests for participants taking rezafungin at any dose.  All side 
effects occurred in less than 10% of participants taking rezafungin.  The most commonly reported side 
effects in these two studies were: 
 
• 
Constipation 
• 
Flushing (redness of the skin, typically over the cheeks or neck, which is usually temporary) 
• 
Nausea 
 
Risks to Participants with Candidemia or Invasive Candidiasis (yeast infections) 
 
Additionally, 71 participants with candidemia or invasive candidiasis were treated with rezafungin.  The 
most commonly reported side effects for rezafungin were:  
 
• 
Decreases in potassium in the blood, which may cause muscle cramps, constipation, weakness, and 
abnormal heart rhythms, especially in people with heart disease.  This can cause you to feel 
lightheaded or faint.  A very low potassium level can even cause your heart to stop. 
• 
Diarrhea 
• 
Nausea 
• 
Anemia 
 
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Heart Beat Risks 
 
One serious side effect that was possibly related to the study drug was reported in this study, the side 
effect was a delay in the timing of the way the heart normally beats and resolved without treatment.   
 
Other Possible Risks 
 
In the group of participants with candidemia or invasive candidiasis, one participant in the rezafungin 
group had a side effect of sunburn (dosing group 400 mg on Day 1 and Day 8, with optional dosing on 
Days 15 and 21) following substantial sun exposure (photosensitivity).  There were two side effects 
(reported in 2.8% of participants) that may represent tremor or nerve injury causing numbness or 
weakness: intensive care unit acquired weakness (reported as moderate intensity), and tremor (reported as 
mild intensity).  These events of tremor/neuropathy that were potentially related to rezafungin were 
followed until resolution and both resolved. 
 
Risks seen in animal studies 
 
Based on a fertility study in male rats, there is a potential risk for decreased sperm motility (sperm may 
not swim properly), abnormal sperm morphology (change in size and shape of the sperm), and testicular 
seminiferous tubular epithelial degeneration (Seminiferous tubules are tubes located within the testicles, 
they are the specific location that produces sperm cells.) Damage to these specific cells was observed in 
mice at doses of rezafungin 2.5 times greater than the amounts used in this study.  However, the risk in 
participants taking rezafungin is currently unknown.  If you are a male and agree to participate on this 
study, you will be asked to avoid fathering a child or donating sperm until at least 18 weeks (126) days 
after your last dose of study drug.  If you are a female and agree to participate in this study, you will be 
asked to avoid becoming pregnant until at least 30 days after your last dose of study drug.    
 
Results from a 3-month animal study suggest a potential risk of unexpected tremors (shaking or 
movements of one or more body parts).  There were observations of tremors and intention tremors 
(increased tremors when attempting to make a movement) in animals after 6 weeks of dosing with 
rezafungin at amounts 11 times greater than the amounts of rezafungin used in this study.  These effects 
disappeared after rezafungin was stopped.  These effects were not observed in animals after 13 weeks of 
dosing with rezafungin at 4 times greater than the amounts of rezafungin used in this study.  These effects 
have also not been observed in clinical trials in patients taking IV rezafungin at similar doses to the 
highest dose to be given in this study.  Given the late timing, absence of these effects in IV rezafungin 
trials, and high amounts of drug necessary to cause this effect relative to this rezafungin dosing group 
regimen, the risk to study participants is believed to be low but cannot be sure. At the highest dose (about 
20 times greater than the proposed human dose), severe neurobehavioral effects were observed. These 
effects were not seen in the levels at 11.4 times the maximum exposure proposed for humans. 
 
Results from an animal study suggest a potential risk of skin sores at the site of subcutaneous 
injection.   In animals, there was inflammation and, in the most severe cases, open sores at the injection 
sites after 4 or more injections of a total volume and dose equal to the top dose per injection planned in 
this study. There was partial recovery of the sores after 4 weeks.   If you agree to participate in this study, 
you may develop sores on your abdomen (stomach) area where the drug is given. If you do develop sores 
on your abdomen, you are to contact the study doctor immediately once you first notice the sores. 
 
 
 
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Risks of other drugs like rezafungin 
 
Side effects for other drugs like rezafungin include: 
 
• 
Abnormal liver  tests  
• 
Hepatitis (inflammation of the liver) 
• 
Liver failure 
• 
Tremors (shaking) 
• 
Ataxia (loss of control of body movements, stumbling, slurred speech) 
• 
Hypoesthesia (loss of sensitivity to touch) 
• 
Paraesthesia (tingling, “pins and needles” sensations) 
• 
Chest discomfort 
• 
Flushing 
• 
Nausea 
• 
Myalgia (muscle pain) 
• 
Rash 
• 
Dyspnea (shortness of breath)  
• 
Pruritus (itching) 
• 
Urticaria (Hives) 
• 
Hypotension (Low blood pressure)  
• 
Facial Swelling 
• 
Nodules, thickening of the skin  
• 
Open sores at the injection site(s) 
• 
Phototoxicity (reaction to the sun that may cause damage to the skin) 
o It is recommended that you try to reduce direct sun exposure during this study 
 
ADDITIONAL RISKS OR DISCOMFORTS 
 
Blood Samples (taken by single needle-sticks or by a tube that is left in your arm): 
 
There may be side effects of having blood drawn such as: 
 
• 
Fainting 
• 
Redness 
• 
Pain 
• 
Bruising 
• 
Bleeding 
• 
Infection 
• 
Nerve damage 
• 
Blood clots, which may cause inflammation, swelling and pain 
 
If you feel faint tell the study staff right away. 
 
Risks of Subcutaneous (SC) Injections: 
 
• 
Infection 
• 
Pain 
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Dennis Ruff, M.D. 
Informed Consent 
 
Page 20 of 31 
APPROVED BY 
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NOVEMBER 12, 2019 
 
• 
Redness 
• 
Bruising 
• 
Local Swelling 
 
Risks of Using an Intravenous (IV) Catheter: 
 
• 
Infection 
• 
Pain 
• 
Redness 
• 
Bruising 
• 
Vein irritation from the fluids or medication being given 
• 
Local swelling due to IV fluid accidentally entering the tissue rather than the vein 
• 
Blood clots, which may cause inflammation, swelling and pain 
• 
Nerve Damage 
 
If you feel faint tell the study staff right away.  
 
Electrocardiogram (ECG): 
 
The ECG test is a recording of the electrical activity of your heart.  The sticky pads used may be cold 
when applied and sometimes cause some discomfort such as redness or itching.  If the hair under the 
patches needs to be shaved, irritation from shaving also could occur.  
 
What if new information becomes available? 
 
If any new information about the study product, study procedures or risks becomes available which could 
affect your willingness to participate or which have an impact on your follow-up, the study doctor will 
discuss what this will mean for you. If you choose to continue, you may have to sign a new subject 
informed consent. If you choose to discontinue, the study doctor will decide for your future care and 
treatment. 
 
BIRTH CONTROL, DANGERS OF PREGNANCY AND BREASTFEEDING 
 
Females who are able to get pregnant and who cannot get pregnant 
 
Females who are pregnant or breastfeeding must not participate in this study. 
 
Even if you use birth control during the study, there is a chance you could become pregnant.  If you are 
pregnant or become pregnant during the study, the study drug may involve unforeseeable risks to the 
unborn baby.  A pregnancy test is not always right, especially in the early stages of pregnancy. 
 
If you are a female, you must not get pregnant while in this study. The only certain way to not get 
pregnant is to not have sex.  If you are a female and choose to have sex, you must use a type of birth 
control listed below. Females must meet one of the following criteria to participate in the study. 
 
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Informed Consent 
 
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NOVEMBER 12, 2019 
 
• 
Post-menopausal defined as no menses for at least 12 months after stopping all hormone treatments 
and with follicle stimulating hormone (FSH) level in the post-menopausal range (confirmed by lab 
test); 
• 
documentation of irreversible surgical sterilization (but not tubal ligation only);  
• 
if of child bearing potential, you must agree to one of the acceptable methods of birth control listed 
below, starting at least 30 days before receiving the first dose of rezafungin and continue to use for at 
least 30 days after the last dose of rezafungin:  
o progestin-releasing subdermal implants (for example, Nexplanon and Implanon); 
o copper intrauterine devices (IUD) (for example, ParaGard); 
o levonorgestrel-releasing IUDs (for example, Mirena, Skyla, and Liletta).  
 
If at any time during the study, you think you may be pregnant, you must immediately contact the study 
doctor. You cannot be in the study if you are breastfeeding.  
 
Males 
 
The effects of rezafungin on reproduction (i.e. abnormalities in offspring or a decrease in the ability to get 
a partner pregnant) have shown potential risks in men (sperm abnormalities).   
 
Even if you use birth control during the study, there is a chance your partner could become pregnant.  If 
your partner becomes pregnant during the study, the study drug may involve unforeseeable risks to the 
unborn baby.     
 
Therefore, if you have not had a vasectomy, you must agree to use condoms with spermicide for birth 
control from the first day of the study until at least 18 weeks (126 days) after your last dose of rezafungin. 
 
You must also not donate sperm from the first day of the study until at least 18 weeks (126 days) after the 
last dose of rezafungin.  
 
If at any time during the study, your female partner becomes pregnant, you must immediately contact the 
study doctor. 
 
Questions/Questionnaires  
 
You may get tired or bored when we are asking you questions. You do not have to answer any question 
you do not want to answer.  
 
Confidentiality 
 
There is the risk that information about you may become known to people outside this study. 
 
POSSIBLE BENEFITS OF THE STUDY 
 
You will get no medical benefit from this study. However, the knowledge gained in this study may help 
those requiring treatment for fungal infections in the future. 
 
 
 
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Informed Consent 
 
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NOVEMBER 12, 2019 
 
ALTERNATIVES TO PARTICIPATING IN THE STUDY   
 
Since this study is for research only, the only other choice would be not to be in the study.  
 
AUTHORIZATION TO USE AND DISCLOSE INFORMATION FOR RESEARCH PURPOSES 
 
Federal regulations give you certain rights related to your health information. These include the right to 
know who will be able to get the information and why they may be able to get it. The research center 
(including the study doctor and study staff) must get your authorization (permission) to use or give out 
any health information that might identify you (protected health information). By signing this form, you 
allow the research center to use your information to carry out the study and to share your information for 
the study, as described in this form. 
 
PROTECTING THE PRIVACY OF YOUR HEALTH DATA 
 
The medical information obtained in this study that identifies you will be handled with the strictest 
confidence. It will be protected as required by laws and/or regulations. It will not be made publicly 
available. If the results of this study are published, you will not be identified by name. Certain people and 
organizations will need to see, copy, and use your health data so that they can do their part in the study, 
and some of these people and organizations will see your health data together with information that 
identifies you.  This is necessary to ensure the trial is conducted properly, to verify the accuracy of data 
collected about you and for regulatory purposes.  They are called “authorized users.”  Authorized users 
will be given access to and may make copies of your health data. In general, before the information about 
your health leaves the research clinic facility, it will be labeled with a code identifying you only by study 
subject number, and will not contain name, initials, or other items that could identify you personally; 
however there may be circumstances that require your health information along with information that 
identifies you be disclosed to authorized users outside of the study location. Specimens of your blood, 
urine or other samples will also be labeled with your study subject number and will not be labeled with 
your name or initials. The following people will have access to your study records and will use the 
information for purposes of conducting the study, for regulatory purposes or as described below. 
 
The following people will have access to your study records: 
 
• 
The study doctor and the study staff including other ICON Early Phase Services staff; 
• 
sponsor company, the sponsor’s associated companies, and representatives [including monitor(s) and 
auditor(s)]; 
• 
Cidara Therapeutics, the manufacturer of the study drug, and its collaborators will use the study data 
in furtherance of its research and development of the study drug; 
• 
The United States Food and Drug Administration (FDA); 
• 
other country, state or federal regulatory agencies; 
• 
IntegReview IRB. 
 
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as required by U.S. 
Law.  This Web site will not include information that can identify you.  At most, the Web site will include 
a summary of the results.  You can search this web site at any time. 
 
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Informed Consent 
 
Page 23 of 31 
APPROVED BY 
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NOVEMBER 12, 2019 
 
The Institutional Review Board (IRB), IntegReview, and accrediting agencies may inspect and copy your 
records, which may have your name on them.  Therefore, total confidentiality cannot be guaranteed.  If 
the study results are presented at meetings or printed in publications, your name will not be used. 
 
CERTIFICATE OF CONFIDENTIALITY 
 
To help us protect your privacy, we have a Certificate of Confidentiality from the National Institutes of 
Health (NIH). The researchers can use this Certificate to legally refuse to give information that may 
identify you in any federal, state, or local civil, criminal, administrative, legislative, or other Proceedings, 
for example, if there is a court subpoena. The researchers will use the Certificate to resist any demands for 
information that would identify you, (except for reporting of communicable diseases to State and local 
health departments, or as explained below, see “Disclosure is permitted only when”).  
 
The Certificate of Confidentiality cannot be used for information in your medical records.  
 
Disclosure is permitted only when:  
 
• 
Required by Federal, State, or local laws (e.g., as required by the Federal Food, Drug, and Cosmetic 
Act, or state laws requiring the reporting of communicable diseases to State and local health 
departments), excluding instances of disclosure in any Federal, State, or local civil, criminal, 
administrative, legislative, or other proceeding;  
• 
necessary for the medical treatment of the individual to whom the information, document, or 
biospecimen pertains and made with the consent of such individual;  
• 
made with the consent of the individual to whom the information, document, or biospecimen pertains; 
or  
• 
made for the purposes of other scientific research that follows Federal regulations governing the 
protection of human subjects in research.  
 
Certificate of Confidentiality does not prevent release of your information to the NIH, Food and Drug 
Administration (FDA), or federal funding agency.  
 
A Certificate of Confidentiality does not prevent you or a member of your family from voluntarily 
releasing information about yourself or your involvement in this research. If you give your consent to 
release information to a medical care provider, an insurer, or other person to receive research information, 
then the researchers will not withhold that information. 
 
IN CASE OF STUDY RELATED INJURY 
 
If you are injured during your participation in this study, you should contact the study doctor as soon as 
possible.  Contact the study doctor in person or at the telephone number listed on page one of this consent 
form. If you need immediate medical care, you should seek it in the same way you would ordinarily get 
emergency medical treatment. 
 
If you suffer a study-related injury, the reasonable costs of necessary medical treatment of the injury may 
be reimbursed to the extent these costs are covered by your private insurance or other third party 
coverage. A clinical trial insurance has been established to cover such reasonable and foreseeable costs. A 
study-related injury is a physical injury that is directly caused by the study drug that has been given as 
described in the study protocol or by medical procedures that are required by the study. The NIH and/or 
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Protocol number 17-0088 
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Informed Consent 
 
Page 24 of 31 
APPROVED BY 
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NOVEMBER 12, 2019 
 
Government and/or ICON do not provide long-term medical care or financial compensation for study-
related injuries. 
 
Injuries directly caused by any of the following are not considered study-related injuries: 
 
• 
The natural course of a disease or medical condition that you already had or have; 
• 
not following the instructions provided in this consent form or by study staff. 
 
No other forms of payment or compensation are offered for study-related injuries (for example, for lost 
wages or discomfort). 
 
Please be aware that some insurance plans may not pay for research-related injuries.  You should contact 
your insurance company for more information. 
 
No other form of compensation is offered for non-study related injuries. 
 
LEGAL RIGHTS 
 
You will not lose any of your legal rights by signing this consent form. 
 
CONTACT INFORMATION 
 
If you have questions, concerns, or complaints about this study or to report a study related injury, contact: 
 
Dennis Ruff, M.D. 
Daytime: 210-283-4500 
After hours: 210-283-4510 
 
If you are unable to reach anyone at the number(s) listed above and you require immediate (life 
threatening) medical attention, please go to the nearest emergency room. 
 
If you do not want to talk to the Study Doctor or study staff, if you have concerns or complaints about the 
research, or to ask questions about your rights as a study subject you may contact IntegReview.  
IntegReview is a group of people that has reviewed this research study.  The main goal of this review is to 
protect the rights and well-being of the human subjects participating in research studies. IntegReview’s 
policy indicates that all concerns/complaints are to be submitted in writing for review at a convened IRB 
meeting to: 
 
                    Mailing Address:            OR            Email Address: 
Chairperson 
IntegReview IRB 
3815 S. Capital of Texas Highway  
Suite 320 
Austin, Texas 78704 
integreview@integreview.com 
 
 
 
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Informed Consent 
 
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NOVEMBER 12, 2019 
 
If you are unable to provide your concerns/complaints in writing or if this is an emergency regarding 
subject safety, contact our office at: 
 
512-326-3001 or 
toll free at 1-877-562-1589 
between 8 a.m. and 5 p.m. Central Time 
 
IntegReview has approved the information in this consent form and has given approval for the Study 
Doctor to do the study. This does not mean IntegReview has approved your being in the study.  You must 
consider the information in this consent form for yourself and decide if you want to be in this study. 
 
COSTS AND PAYMENT FOR BEING IN THE STUDY 
 
There is no cost to you for participating in the study.  
 
PAYMENT FOR BEING IN THE STUDY 
 
Part 1 (Cohorts 1-6) Payment 
 
If in Part 1, you may receive up to $3300.00 for being in the study. You will be paid per completed visit 
as follows: You will receive two separate payments within 10 business days from Day 14 and Day 30.  
 
Visit   
Payment (amount) 
Screening 
$0.00  
Day -1 
$200.00  
Day 1 
$250.00  
Day 2 
$250.00  
Day 3 
$250.00  
Day 4 
$250.00  
Day 5 
$250.00  
Day 6 
$250.00  
Day 7 
$250.00  
Day 14 
$150.00  
Day 21 
$25.00 
Day 30 
$200.00  
Bonus 
$975.00  
*Total Payment* 
$3,300.00  
 
To ensure that each dosing group reaches the maximum number of subjects, extra subjects will be 
recruited. All participants will be asked to complete research study procedures up to the time of dosing. In 
the event that a study subject is unable to dose, another qualified subject will take that subject’s place on 
the study. If you complete all the requirements, but are not dosed, you will receive a pro-rated stipend 
check based on information below.  
 
If you not selected to be in the study, you will be paid $200.00 if you are released on day -1 and $400.00 if 
released on day 1.  As an alternate, you may be asked to participate in the next dosing group, which may 
require you to repeat Day -1 and Day 1 procedures. 
 
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Informed Consent 
 
Page 26 of 31 
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NOVEMBER 12, 2019 
 
Part 2 (Cohorts  7, 8, 9, and 10) Payment 
 
If in Part 2, you may receive up to $6,400.00 for being in the study. You will be paid per completed visit 
as follows: You will receive two separate payments within 10 business days from Day 21 and Day 45. 
  
Visit  
Payment (amount) 
Screening 
$0.00  
Day -1 
$200.00  
Day 1 
$250.00  
Day 2 
$250.00  
Day 3 
$250.00  
Day 4 
$250.00  
Day 5 
$250.00  
Day 6 
$250.00  
Day 7 
$250.00  
Day 8 
$250.00  
Day 9 
$250.00  
Day 10 
$250.00  
Day 11 
$250.00  
Day 12 
$250.00  
Day 13 
$250.00  
Day 14 
$250.00  
Day 15 
$250.00  
Day 16 
$250.00  
Day 17 
$250.00  
Day 18 
$250.00  
Day 19 
$250.00  
Day 20 
$250.00  
Day 21 
$250.00  
Day 30 
$175.00  
Day 45 
$175.00  
Bonus 
$600.00  
*Total Payment* 
$6,400.00  
 
To ensure that each dosing group reaches the maximum number of subjects, extra subjects will be 
recruited. All participants will be asked to complete research study procedures up to the time of dosing. In 
the event that a study subject is unable to dose, another qualified subject will take that subject’s place on 
the study. If you complete all the requirements, but are not dosed, you will receive a pro-rated stipend 
check based on information below.  
 
If you are not selected to be in the study, you will be paid $200.00 if you are released on day -1 and 
$400.00 if released on day 1.  As an alternate, you may be asked to participate in the next dosing group, 
which may require you to repeat Day -1 and Day 1 procedures. 
 
 
 
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Informed Consent 
 
Page 27 of 31 
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Part 3 Payment (Cohort 11) 
 
If in Part 3, you may receive up to $6000.00 for being in the study. You will be paid per completed visit 
as follows: You will receive two separate payments within 10 business days from Day 21 and Day 44.  
 
Visit   
Payment (amount) 
Screening 
$0.00  
Day -1 
$200.00  
Day 1 
$250.00  
Day 2 
$250.00  
Day 3 
$250.00  
Day 4 
$250.00  
Day 5 
$250.00  
Day 6 
$250.00  
Day 7 
$250.00  
Day 14 
$250.00  
Day 21 
$250.00  
Day 22 
$250.00  
Day 23 
$250.00  
Day 24 
$250.00  
Day 25 
$250.00  
Day 26 
$250.00  
Day 27 
$250.00  
Day 28 
$250.00  
Day 35 
$250.00  
Day 44 
$250.00  
Bonus 
$1,300.00  
*Total Payment* 
$6,000.00  
 
To ensure that each dosing group reaches the maximum number of subjects, extra subjects will be 
recruited. All participants will be asked to complete research study procedures up to the time of dosing. If 
a study subject is unable to dose, another qualified subject will take that subject’s place on the study. If 
you complete all the requirements, but are not dosed, you will receive a pro-rated stipend check based on 
information below.  
 
If you not selected to be in the study, you will be paid $200.00 if you are released on day -1 and $400.00 if 
released on day 1.  As an alternate, you may be asked to participate in the next dosing group, which may 
require you to repeat Day -1 and Day 1 procedures. 
 
You must follow the study and site unit rules, which will be explained and given to you. Failure to follow 
the rules may result in a $50.00 deduction for each offense.  You may be dropped from the study without 
your consent for any reason. If you are dropped from the study, you will be paid for the study visits that 
you completed before being dropped from the study.  
 
The research facility reserves the right to conduct an unscheduled drug, alcohol, and cotinine screen. 
Should you test positive for drugs, alcohol, or cotinine during the study you may be removed from 
participation and forfeit study payment. 
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Informed Consent 
 
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NOVEMBER 12, 2019 
 
No subject is officially enrolled into a study until the Study Doctor makes a final decision, usually upon 
review of all screening and admission procedures. All subjects are in an alternate status and may be 
dismissed from the unit at any time before dosing. Enrollment is generally based on timing of consent, 
prompt arrival, and acceptable screening results. No guarantee of enrollment is offered. 
 
You must give your social security number to receive payment. No deductions for state or federal 
withholdings (or other taxes) will be made on your behalf. You are responsible for reporting study 
payments on your federal and state tax returns for the payment of taxes. Taking part in this study does not 
make you an employee of the Sponsor, study site, or the US Food and Drug Administration. 
 
VOLUNTEERING TO BE IN THE STUDY 
 
It is your choice if you want to be in the study.  No one can force you to be in the study.  You may not 
want to be in this study or you may leave the study at any time without penalty or loss of benefits to 
which you are otherwise entitled.  You can still get healthcare in the future. You may want to inform your 
personal doctor of your choice to participate in this study. 
 
The Study Doctor, the sponsor company, IntegReview, or the FDA may take you out of the study without 
your permission, at any time, for the following reasons: 
 
• 
If you do not follow the Study Doctor’s instructions  
• 
If we find out you should not be in the study 
• 
If the study is stopped 
• 
If it becomes harmful to your health 
 
If you leave the study or if you are taken out of the study, you may be asked to return for a final visit to 
have some end of study evaluations or tests.  If information generated from this study is published or 
presented, your identity will not be revealed.  If you leave the study, no more information about you will 
be collected for this study.  However, all the information you gave us before you left the study will still be 
used.  
 
NEW FINDINGS 
 
If there is new information or any significant new findings that could relate to your willingness to 
continue participation we will tell you.  You can then decide if you still want to be in the study.   
 
Consent for Future Use of Stored Specimens and Data 
 
This consent form contains important information to help you decide if you want the residual (remaining/ 
left over) clinical samples collected during this study to be available for future research use by the 
sponsor company. These clinical samples will be shipped to and stored for up to 2 years at the Fisher 
Biorepository (DMID CMS) and may be shared with investigators at the participating site and with other 
investigators at other institutions. The samples will not be sold or used directly for production of any 
commercial product.  No human genetic tests will be performed on the samples.  Each sample will be 
encoded (labeled) only with a barcode and a unique tracking number to protect subject confidentiality. 
The recipients of specimens will be informed that these specimens have a NIH certificate of 
confidentiality. There will be no benefit to you in the collection, storage, and use of these specimens for 
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Informed Consent 
 
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NOVEMBER 12, 2019 
 
future research. Reports that may occur in the future will NOT be kept in your health records.  If you have 
any questions that are not answered in this consent form, ask one of the study staff.  
 
CONSENT   
 
 
  I AGREE to let my samples be used for future research and I also understand that I have the right to 
change my decision at any time by notifying the study doctors or study management team in writing. 
(Any data from previously collected samples may still be used for future research) 
OR 
  I DO NOT AGREE and wish my samples to be destroyed at the end of the trial  
 
 
_______________________________________________________ 
Printed Name of Adult Study Subject 
 
 
 
 
Signature of Adult Study Subject                                                                                          Date 
 
  
 
 
_______________________________________________________ 
Printed Name of Person Explaining Consent Form 
 
 
 
 
Signature of Person Explaining Consent Form                                                                     Date 
 
 
 
 
 
 
 
 
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Protocol number 17-0088 
Dennis Ruff, M.D. 
Informed Consent 
 
Page 30 of 31 
APPROVED BY 
INTEGREVIEW IRB 
NOVEMBER 12, 2019 
 
PHOTO RELEASE FORM 
 
Photographs may be taken to document side effects, such as a rash, for this study.  You give the company 
paying for this research study the right to use, copy, and give out any pictures taken of you.  
 
Your pictures may be used in scientific journals or magazines. 
 
Your pictures may be used as part of a larger presentation, along with other pictures, videotapes or things 
like that. Your pictures may also be edited.  
 
The company paying for this research study may give other people or companies permission to use your 
pictures. 
 
We will try to hide your identity.  Your name will not be on the pictures.  You have the right to review 
your pictures and cancel this Photo Release Form. 
 
Statement of Consent: 
 
I have read this release and understand its meaning. I understand I do need to sign this Photo Release 
Form in order to be in the study.  
 
 
______________________________________________________________________ 
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Signature of Adult Study Subject                                                                       
Date  
 
 
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Protocol number 17-0088 
Dennis Ruff, M.D. 
Informed Consent 
 
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APPROVED BY 
INTEGREVIEW IRB 
NOVEMBER 12, 2019 
 
AGREEMENT TO BE IN THE STUDY 
 
This consent form contains important information to help you decide if you want to be in the study.  If 
you have any questions that are not answered in this consent form, ask one of the study staff.  
 
Please answer YES or NO to the following questions: 
 
A. Is this document in a language you understand? 
 
 
 
 
 
 
 
 
B. Do you understand the information in this consent form? 
 
 
 
 
 
 
 
C. Have you been given enough time to ask questions and talk about the study?  
 
 
 
 
D. Have all your questions been answered to your satisfaction?  
 
 
 
 
 
 
E. Do you think you received enough information about the study? 
 
 
 
 
 
 
F. Do you volunteer to be in this study of your own free will and without being  
 
pressured by the Study Doctor or study staff? 
 
 
 
 
 
 
 
 
G. Do you know that you can leave the study at any time without giving 
 
a reason and without affecting your health care? 
 
 
 
 
 
 
 
 
H. Do you know that your health records from this study may be reviewed 
 
by the sponsor company and by government authorities? 
 
 
 
 
 
 
 
I. Do you know that you cannot be in another study while you are in this study?  
 
 
 
 
IF YOU ANSWERED “NO” TO ANY OF THE ABOVE QUESTIONS, 
OR YOU ARE UNABLE TO ANSWER ANY OF THE ABOVE QUESTIONS, 
YOU SHOULD NOT SIGN THIS CONSENT FORM. 
 
 
 
 
 
 
 
 
 
 
 
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SAP_002.pdf: 
CLINICAL RESEARCH IN INFECTIOUS DISEASES 
 
 
ANALYSIS PLAN 
for 
DMID Protocol 17-0088 
Study Title: 
A Phase 1, Three-Part, Randomized, Double-Blind, Single and Multiple 
Subcutaneous Dose Escalation Study to Determine the Safety, 
Tolerability, and Pharmacokinetics of Rezafungin in Healthy Adult 
Subjects 
NCT04117607 
 
Version 1.0 
 
DATE: 06-JUL-2020 
 
THIS COMMUNICATION IS PRIVILEGED AND CONFIDENTIAL  
 


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STUDY TITLE 
Protocol Number Code: 
DMID Protocol 17-0088 
Development Phase: 
Phase 1 
Products: 
Rezafungin and Placebo 
Form/Route: 
Solution/Subcutaneous (SC) or Solution/Intravenous (IV) 
Indication Studied: 
Fungal infections 
Sponsor: 
Division of Microbiology and Infectious Diseases 
National Institute of Allergy and Infectious Diseases 
National Institutes of Health 
Clinical Trial Initiation Date: 
04DEC2019 
Clinical Trial Completion Date: 
11MAY2020 
Date of the Analysis Plan: 
06JUL2020 
Version Number: 
1.0 
This study was performed in compliance with Good Clinical Practice. 
Information contained in this publication is the property of Division of Microbiology and Infectious Diseases and is confidential. This 
information may not be disclosed to third parties without written authorization from Division of Microbiology and Infectious Diseases. This 
report may not be reproduced, stored in a retrieval system or transmitted in any form or by any means - electronic, mechanical, recording or 
otherwise - without the prior authorization from Division of Microbiology and Infectious Diseases. This document must be returned to Division 
of Microbiology and Infectious Diseases upon request. 
 


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TABLE OF CONTENTS 
STUDY TITLE ............................................................................................................................... II 
TABLE OF CONTENTS ...............................................................................................................III 
LIST OF ABBREVIATIONS ......................................................................................................... V 
1. 
PREFACE .....................................................................................................................1 
2. 
INTRODUCTION ........................................................................................................2 
2.1. 
Purpose of the Analyses ................................................................................................2 
3. 
STUDY OBJECTIVES AND ENDPOINTS ................................................................3 
3.1. 
Study Objectives ...........................................................................................................3 
3.2. 
Endpoints ......................................................................................................................3 
3.3. 
Study Definitions and Derived Variables .....................................................................3 
3.3.1. 
Dose Group ...................................................................................................................3 
3.3.2. 
Baseline .........................................................................................................................3 
3.3.3. 
Study Day .....................................................................................................................4 
4. 
SAMPLE SIZE CONSIDERATIONS .........................................................................5 
5. 
GENERAL STATISTICAL CONSIDERATIONS ......................................................6 
5.1. 
General Principles .........................................................................................................6 
5.2. 
Timing of Analyses .......................................................................................................6 
5.3. 
Analysis Populations ....................................................................................................6 
5.3.1. 
Safety Population ..........................................................................................................6 
5.3.2. 
PK Analysis Population ................................................................................................6 
5.3.3. 
PK Analysis Subset.......................................................................................................6 
5.4. 
Covariates and Subgroups ............................................................................................7 
5.5. 
Missing Data .................................................................................................................7 
5.6. 
Interim Analyses and Data Monitoring ........................................................................7 
5.7. 
Multicenter Studies .......................................................................................................7 
5.8. 
Multiple Comparisons/Multiplicity ..............................................................................7 
6. 
STUDY SUBJECTS .....................................................................................................8 
6.1. 
Disposition of Subjects .................................................................................................8 
6.2. 
Protocol Deviations ......................................................................................................8 
7. 
SAFETY EVALUATION ............................................................................................9 
7.1. 
Demographic and Other Baseline Characteristics ........................................................9 


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7.1.1. 
Prior and Concurrent Medical Conditions ....................................................................9 
7.1.2. 
Prior and Concomitant Medications .............................................................................9 
7.2. 
Measurements of Treatment Compliance .....................................................................9 
7.3. 
Adverse Events .............................................................................................................9 
7.3.1. 
Solicited Reactogenicity Symptoms .............................................................................9 
7.3.2. 
Unsolicited Adverse Events ........................................................................................10 
7.4. 
Deaths, Serious Adverse Events and other Significant Adverse Events ....................11 
7.5. 
Pregnancies .................................................................................................................11 
7.6. 
Clinical Laboratory Evaluations .................................................................................11 
7.7. 
Vital Signs and Physical Evaluations .........................................................................12 
7.8. 
12-Lead Standard Electrocardiogram .........................................................................13 
7.9. 
Concomitant Medications ...........................................................................................14 
8. 
PHARMACOKINETICS ...........................................................................................15 
8.1. 
Noncompartmental Analysis ......................................................................................16 
9. 
REPORTING CONVENTIONS ................................................................................18 
10. 
TECHNICAL DETAILS ............................................................................................19 
11. 
SUMMARY OF CHANGES IN THE CONDUCT OF THE STUDY OR 
PLANNED ANALYSES ............................................................................................20 
12. 
REFERENCES ...........................................................................................................21 
13. 
LISTING OF TABLES, FIGURES, AND LISTINGS ..............................................22 
APPENDICES ...............................................................................................................................23 
APPENDIX 1. TABLE MOCK-UPS..........................................................................................23 
APPENDIX 2. FIGURE MOCK-UPS ........................................................................................62 
APPENDIX 3. LISTINGS MOCK-UPS .....................................................................................91 
 


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LIST OF ABBREVIATIONS 
AE 
Adverse Event/Adverse Experience 
ALT 
Alanine aminotransferase 
AST 
Aspartate aminotransferase 
ATC 
Anatomical Therapeutic Code 
AUC 
Area under the plasma concentration versus time curve 
AUCinf 
Area under the plasma concentration versus time curve from time 0 to infinite time 
AUClast 
Area under the plasma concentration versus time curve from time 0 to the time of the 
last quantifiable concentration 
BA 
Bioavailability 
BMI 
Body Mass Index 
BP 
Blood Pressure 
bpm 
Beats per minute 
BUN 
Blood Urea Nitrogen 
BQL 
Below Limit of Quantification 
CI 
Confidence Interval 
CL 
Total clearance 
CL/F 
Apparent clearance 
Cmax 
Maximum measured plasma concentration 
CSR 
Clinical Study Report 
CV % 
Coefficient of Variation 
DMID 
Division of Microbiology and Infectious Diseases 
ECG 
Electrocardiogram 
GM 
Geometric Mean 
λz 
The terminal phase elimination rate constant 
IV 
Intravenous 
LLOQ 
Lower Limit of Quantification 
MAD 
Multiple Ascending Dose 
Max 
Maximum 
MedDRA 
Medical Dictionary for Regulatory Activities 
Min 
Minimum 
MOP 
Manual of Procedures 
MTD 
Maximum tolerated dose 
N 
Number (typically refers to subjects) 
NCA 
Noncompartmental Analysis 
PE 
Physical Examination 
PI 
Principal Investigator 
PK 
Pharmacokinetics 
PR (interval) 
Interval measured from the beginning of the P wave to the beginning of the QRS 
complex in the heart’s electrical cycle as measured by electrocardiogram 
PT 
Preferred Term 
PTT 
Partial Thromboplastin Time 
QNS 
Quantity Not Sufficient 


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QRS (interval) The interval between the Q wave and the S wave in the heart’s electrical cycle as 
measured by electrocardiogram; principal deflection in the electrocardiogram 
QT (interval) 
A measure of the time between the start of the Q wave and the end of the T wave in 
the heart’s electrical cycle as measured by electrocardiogram 
QTc (interval) 
A measure of time between the start of the Q wave and the end of the T wave in the 
heart’s electrical cycle measured by electrocardiogram corrected for heart rate 
SAD 
Single Ascending Dose 
SAE 
Serious Adverse Event/Serious Adverse Experience 
SAP 
Statistical Analysis Plan 
SC 
Subcutaneous 
SD 
Standard Deviation 
SDTM 
Study Day Tabulation Model  
SOC 
System Organ Classes 
t1/2 
Terminal phase half-life 
TFL 
Tables, Figures, and Listings 
Tmax 
Time to reach maximum measured plasma concentration 
VS 
Vital Sign 
Vz/F 
Volume of distribution  
WBC 
White Blood Cell 
 
 


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1. 
PREFACE 
The Analysis Plan for “A Phase 1, Three-Part, Randomized, Double-Blind, Single and Multiple Subcutaneous 
Dose Escalation Study to Determine the Safety, Tolerability, and Pharmacokinetics of Rezafungin in Healthy 
Adult Subjects” (DMID Protocol 17-0088) describes and expands upon the statistical information presented in 
the protocol. 
The sponsor terminated the study on 27APR2020 due to safety concerns. No subjects were enrolled into 
Single Ascending Dose (SAD) Cohort 3 (30 mg) and above, any Multiple Ascending Dose (MAD) cohort, or 
the Bioavailability (BA) cohort. Accordingly, this SAP describes analyses of data from subjects in SAD 
Cohort 1 (1 mg) and Cohort 2 (10 mg) only. 
Due to early termination of the study, the sponsor confirmed an abbreviated clinical study report (CSR) will 
be provided. The statistical analysis plan noted in the protocol was not drafted and approved prior to study 
closure and was therefore deemed by the sponsor as not required. This document includes sufficient 
description of analyses, definitions, tables, figures, and listings (TFLs) for programming of the abbreviated 
CSR. Within the TFL mock-ups (Appendices 1, 2, and 3), references to abbreviated CSR sections are 
included. Any deviation from this SAP in the statistical analysis will be described and justified in the 
abbreviated CSR. 


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2. 
INTRODUCTION 
2.1. 
Purpose of the Analyses 
These analyses will assess the safety of single 1 mg or 10 mg subcutaneous doses of rezafungin given 
subcutaneously and pharmacokinetics (PK) of a single 10 mg subcutaneous dose. 


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3. 
STUDY OBJECTIVES AND ENDPOINTS 
3.1. 
Study Objectives 
Refer to Protocol v6.0. 
3.2. 
Endpoints 
Refer to Protocol v6.0. 
3.3. 
Study Definitions and Derived Variables  
3.3.1. 
Dose Group 
Dose Group defines a grouping of subjects used for statistical analysis, where subjects within a Dose Group 
received the same dose and dosing schedule under the same fasting status. Note that for data from a subject to 
be analyzed as part of their Dose Group, the subject must also qualify for inclusion into the respective 
analysis population (As described in Section 5.3) for that data. Definitions for each Dose Group to be 
analyzed in the report, and their ordering, are provided in the list below. 
• SAD Any Dose: Subjects from SAD cohorts who receive any dose of rezafungin. 
• SAD 1 mg: SAD, Cohort 1 subjects receiving 1 mg of active drug. 
• SAD 10 mg: SAD, Cohort 2 subjects receiving 10 mg of active drug. 
• Placebo: SAD subjects receiving placebo. 
The “SAD Any Dose” Dose Group will be included in analyses of safety endpoints only.  
3.3.2. 
Baseline 
For clinical laboratory results, and vital sign (VS) measurements, the baseline assessment is the last 
measurement recorded prior to dosing, except for height, weight, and BMI, which baseline will be defined as 
the measurements recorded at the initial Screening Visit. For electrocardiogram (ECG) results, baseline is 
defined as the median of the triplicate measurements taken within 60 minutes of dosing. If multiple triplicate 
measurements are taken prior to dosing, the median of last set of triplicates will be used as baseline.  
Age will be based on age at enrollment. Age at enrollment is an integer value with units of years and is 
calculated from the subject’s enrollment date (ENROLLDT) and birth date (BRTHDT) using the following 
algorithm. 
• If month(ENROLLDT) > month(BRTHDT), then AGE = year(ENROLLDT) – year(BRTHDT) 
• If month(ENROLLDT) < month(BRTHDT), then AGE = year(ENROLLDT) – year(BRTHDT) – 1 
• If month(ENROLLDT) = month(BRTHDT) and day(ENROLLDT) ≥ day(BRTHDT), then AGE = 
year(ENROLLDT) – year(BRTHDT) 
• If month(ENROLLDT) = month(BRTHDT) and day(ENROLLDT) < day(BRTHDT), then AGE = 
year(ENROLLDT) – year(BRTHDT) – 1 


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3.3.3. 
Study Day 
The day that the subject received study product is considered Study Day 1 for each subject. The day prior to 
dosing is considered Study Day = -1, not Study Day = 0. 


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4. 
SAMPLE SIZE CONSIDERATIONS 
No formal sample-size calculations based on testing a statistical hypothesis were constructed. There will be a 
total of 86 subjects in this three-part trial, 44 subjects in 6 cohorts will receive rezafungin or placebo via SC 
injection in Part 1/SAD, 32 subjects in 4 cohorts will receive rezafungin or placebo via SC injection in Part 
2/MAD, and 10 subjects will receive rezafungin via both SC and IV injections in Part 3/BA. The number of 
subjects was selected to allow sufficient evaluation of safety, tolerability, and PK of the various dose 
regimens, and to be consistent with standards of practice for Phase 1 trials. 


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5. 
GENERAL STATISTICAL CONSIDERATIONS 
5.1. 
General Principles 
Safety and PK data will be summarized by Dose Group, following the order shown in Section 3.3. Summary 
statistics for continuous data will include the mean, standard deviation (SD), median, minimum value (min), 
and maximum value (max). Summary statistics for discrete data will include counts and percent and may 
include confidence intervals (CIs) for the percent. When 95% CIs are given for a percent, Wilson Score CIs 
will be used. All subjects that are randomized will be included in the summaries of demographics, the Safety 
Population will be used for summaries of safety endpoints, and PK Population or PK Analysis Subset will be 
used for summaries of PK endpoints.  
Generally, for summaries of safety endpoints, denominators will use the number of subjects in the Safety 
Population. Denominators for study time points of solicited local reactogenicity symptoms, clinical laboratory 
results, VS, and ECG results will use the number of subjects with an observed result at the time point for the 
parameter or symptom. Denominators for the conceptual “Max Severity Post-Baseline” time point for 
solicited local reactogenicity symptoms, clinical laboratory results, VS, and ECG results will use the number 
of subjects with an observed result for the parameter obtained post-dose. 
The sort order of the listings as is indicated in the Implementation Note for each listing shell (Appendix 3). 
5.2. 
Timing of Analyses 
The final analysis will be performed after the clinical and non-clinical databases are locked. 
5.3. 
Analysis Populations 
A tabular listing (Listing 5) and summary table (Table 3) of all randomized and enrolled subjects excluded 
from the Safety Population, PK Analysis Population, or PK Analysis Subset will be included in the 
abbreviated CSR. Although there may be multiple reasons for exclusion from a PK Analysis Population or PK 
Analysis Subset, only one reason will be counted when summarizing reasons for exclusion from analysis 
populations. Priority for assigning reasons for exclusions will follow the order listed in Table 3.  
5.3.1. 
Safety Population 
All subjects that received any amount of study product will be included in the Safety Population. 
5.3.2. 
PK Analysis Population 
The PK Analysis Population will consist of all subjects who complete one full (as randomized, according to 
cohort) rezafungin dose and have one post-dose plasma sample with measurable rezafungin Note that all 
rezafungin concentration results will be included in listings, including results from placebo subjects.  
5.3.3. 
PK Analysis Subset 
The PK Analysis Subset will be a subset of the PK Analysis Population and will include all subjects in the PK 
Analysis Population who completed the PK part of the trial without any protocol violations that would likely 
affect the PK results and who have evaluable plasma concentration data for rezafungin from which at least a 
subset of the designated PK parameters can be determined. The statistician will review protocol deviations to 
determine a list of recommended exclusions due to protocol deviations likely to affect PK. The principal 


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investigator will review the list prior to unblinding and provide confirmation of any exclusions of subjects due 
to protocol deviations. 
5.4. 
Covariates and Subgroups 
The protocol does not define any formal subgroup analyses. 
5.5. 
Missing Data 
No imputation of missing data is planned. 
5.6. 
Interim Analyses and Data Monitoring 
No interim analysis was conducted prior to study termination.  
5.7. 
Multicenter Studies 
This is a single-site study.  
5.8. 
Multiple Comparisons/Multiplicity 
This is a Phase 1 first-in-human study with multiple primary endpoints. Because analyses of primary 
endpoints are descriptive rather than hypothesis tests, no adjustments for multiple testing are planned 


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6. 
STUDY SUBJECTS 
6.1. 
Disposition of Subjects 
Screened subjects who were ineligible for enrollment in the study (screen failures) or eligible but not enrolled 
will be summarized by inclusion and exclusion criteria (Table 4). Enrolled subjects who were ineligible for 
inclusion in analysis populations will be summarized by reason for subject exclusion and Dose Group 
(Table 3). Individual subject listings of subjects who were excluded from the Safety Population or a PK 
Analysis Population will be listed (Listing 5). 
Subject disposition will be summarized (Table 2), showing the number of subjects who screened, enrolled, 
received study product, completed all PK blood draws, completed final study visit, and early termination. 
Subjects who discontinued dosing or terminated early from the study will be listed (Listing 2). 
A flowchart showing the disposition of study subjects will be included (Figure 1). This figure will present the 
number of subjects screened, enrolled, lost to follow-up, and analyzed, by Dose Group. 
6.2. 
Protocol Deviations 
A summary of protocol deviations will be presented by deviation category, deviation type, and Dose Group 
(Table 1). This table will provide both the number of subjects and the number of deviations for each category. 
All subject-specific protocol deviations and non-subject-specific protocol deviations will be listed (Listing 3 
and Listing 4). 


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7. 
SAFETY EVALUATION 
All safety analyses will be performed using the Safety Population. 
Any medical condition that is present at the time that the subject is screened will be considered baseline and 
not reported as an AE unless it worsens in severity or increases in frequency during the study. The 
denominators for percent values will be indicated within the table or table header and denoted as N. 
Moreover, events summarized by subject will be coded to the highest severity observed over the indicated 
time period. Toxicity grading scales for adverse events, solicited reactogenicity symptoms, safety labs, VS, 
and ECG are provided in the protocol v6.0. 
7.1. 
Demographic and Other Baseline Characteristics 
Demographic summaries will include all subjects that were randomized. Sex, ethnicity, and race of all 
subjects will be summarized categorically by Dose Group (Table 5). Age at enrollment and height, weight, 
and BMI at screening will be summarized as continuous variables by Dose Group (Table 6). Individual 
subject listings will be presented for all demographic and baseline characteristics (Listing 6). 
7.1.1. 
Prior and Concurrent Medical Conditions 
All current illnesses and past pre-existing medical conditions will be MedDRA coded using MedDRA 
dictionary version 23.0 or higher. Summaries of subjects’ pre-existing medical conditions by MedDRA 
system organ class (SOC) will be presented by Dose Group (Table 7). Individual subject listings will be 
presented for all medical conditions (Listing 7). 
7.1.2. 
Prior and Concomitant Medications  
All medications will be coded using the current version of the WHO Drug dictionary. The use of prior and 
concomitant medications taken during the study will be summarized by Anatomical Therapeutic Code (ATC) 
1 and ATC 2 (separately in Table 33 for prior medications and Table 34 for concomitant medications). 
Individual subject listings will be presented for all prior and concomitant medications (separately in 
Listing 23 for prior medications and Listing 24 for concomitant medications). 
7.2. 
Measurements of Treatment Compliance 
Date and time of dosing will be presented in Listing 8. Concentration in plasma for Cohort 2 (including 
placebo) will be presented in Listing 31. 
7.3. 
Adverse Events 
When calculating the proportions of subjects with AEs within a given MedDRA category, each subject will 
only be counted once and any repetitions of AEs within a subject will be ignored, and the event will be 
reported according to the worst severity recorded (separately for related and unrelated AEs, when both 
severity and relatedness are tabulated). 
7.3.1. 
Solicited Reactogenicity Symptoms 
For each solicited local reactogenicity symptom, the number and percentage of subjects reporting each 
symptom will be summarized by maximum severity for a specified time point and Dose Group.  


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Maximum severity for each symptom based on functional grading and measurement grading criteria as 
described in protocol v6.0 will be summarized separately. All pre-dose and post-dose solicited local 
reactogenicity will be presented in Listing 9. 
The following summaries for solicited local reactogenicity symptoms will be presented: 
• The number and proportion of subjects with local symptoms, summarized by Dose Group and 
symptom. A 95% CI will be presented by Dose Group for each local symptom (Table 9). 
• The number and proportion of subjects with local symptoms, summarized by Dose Group, symptom, 
and maximum severity. A 95% CI will be presented by Dose Group for each local symptom 
(Table 10). 
• The number and proportion of subjects with local symptoms, summarized by Dose Group, symptom, 
time point, and maximum severity (including maximum severity post-baseline) (Table 11).  
• By Dose Group, bar charts of proportions of subjects with local symptoms by maximum severity (each 
subject counted once per symptom) (Figure 2). 
• By Dose Group and time point, bar charts of proportions of subjects with each local symptom by 
maximum severity (starting at Figure 3, continuing through Figure 16). 
The following solicited local reactogenicity symptoms will be presented (in order): 
• Pain, tenderness, pruritus (itching), ecchymosis (bruising) (functional grade), ecchymosis (bruising) 
(measurement grade), induration (hardness)/ swelling (functional grade), induration (hardness)/ 
swelling, (measurement grade), erythema (redness) (functional grade), erythema (redness) 
(measurement grade), nodule (functional grade), nodule (measurement grade), ulceration (functional 
grade), and ulceration (measurement grade). 
7.3.2. 
Unsolicited Adverse Events 
A brief overall summary of AEs by Dose Group including number of subjects with at least one solicited 
reactogenicity event of any severity, number of subjects with ulceration, number of subjects with at least one 
AE of any severity, number of subjects with at least one related AE of any severity, and number of subjects 
with at least one SAE (Table 8). 
All AEs will be presented in listings (Listing 10). A subject listing of non-serious AEs of moderate or greater 
severity will also be reported (Table 15). 
The following summaries for unsolicited adverse events will be presented: 
• The total number of AEs and the number and proportion of subjects reporting at least one unsolicited 
AE will be summarized by Dose Group, SOC, and PT. Denominators for percentages are the number 
of subjects in the Safety Population. A 95% CI will be presented by Dose Group for each SOC and PT 
(Table 12). 
• The number and proportion of subjects reporting at least one AE, summarized by Dose Group, SOC, 
PT, maximum severity, and relatedness (Table 13). 
• By Dose Group, bar charts of proportions of subjects with related serious and non-serious AEs by 
maximum severity and SOC. This figure describes the number of subjects with an event (each subject 
counted once per SOC) (Figure 17). 


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• By Dose Group, bar charts of numbers of related serious and non-serious AEs by severity and SOC. 
This figure describes the total number of occurrences of each event, including multiple occurrences 
per subject (Figure 18). 
7.4. 
Deaths, Serious Adverse Events and other Significant Adverse Events 
Individual data listings of deaths and other SAEs will be provided (Table 14). 
7.5. 
Pregnancies 
An individual data listing of pregnancy reports will be provided if a pregnancy occurs pose-dosing 
(Listing 25, Listing 26, Listing 27, Listing 28, Listing 29). Contraceptive method will be listed in Listing 30. 
7.6. 
Clinical Laboratory Evaluations 
If the time of sample collection for clinical laboratory evaluations was prior to 23DEC2019, then grading will 
follow toxicity grade criteria from protocol v3.0. If the time of sample collection was on or after 23DEC2019, 
then grading will follow toxicity grade criteria from protocol v4.0. Note that toxicity ranges from protocol 
v4.0 through v6.0 were identical. 
• CHEM: Total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, 
and triglycerides were removed from clinical lab collection after protocol v3.0.  
• COAG: Prothrombin time and activated PTT toxicity ranges were updated after protocol v3.0. 
• UA: Blood in urine (microscopic) toxicity ranges were updated after protocol v3.0. 
All screening and safety laboratory results will be listed in Listing 11 (CHEM), Listing 12 (HEM), Listing 13 
(COAG), Listing 14 (UA), Listing 15 (serology), Listing 16 (urine toxicity), and Listing 17 (pregnancy test). 
Abnormal laboratory results (laboratory results outside of the normal range on time of collection) will be 
listed in Table 16 (CHEM), Table 17 (HEM), Table 18 (COAG), and Table 19 (UA). 
Laboratory results will be summarized in tables and figures: 
• Tabularly, by parameter, Dose Group, time point, and toxicity grade (including maximum severity 
post-baseline). Summaries will be presented in Table 20 (CHEM), Table 22 (HEM), Table 24 
(COAG), and Table 26 (UA). When calculating the proportions of subjects with a laboratory toxicity, 
each subject will only be counted once per toxicity grade and any repetitions of laboratory toxicities 
within a subject will be ignored, and the event will be reported according to the worst severity 
recorded. Parameters with no specified toxicity ranges listed in protocol will be excluded from this 
summary.  
• Tabularly, by summary statistics for change from baseline, reported by parameter, Dose Group, and 
time point. Summaries will be presented in Table 21 (CHEM), Table 23 (HEM), and Table 25 
(COAG).  
• Graphically, using box plots of change from baseline by parameter, Dose Group, and time point. 
o CHEM: Beginning at Figure 19 and continuing through Figure 35.  
o HEM: Beginning at Figure 36 and continuing through Figure 45. 
o COAG: Figure 46, Figure 47, and Figure 48. 


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The following laboratory parameters will be presented (in order): 
• Chemistry (CHEM): sodium, potassium, calcium, phosphorus, chloride, total carbon dioxide, glucose, 
blood urea nitrogen, creatinine, total cholesterol, low-density lipoprotein cholesterol, high-density 
lipoprotein cholesterol, triglycerides, total protein, albumin, aspartate aminotransferase (AST), alanine 
aminotransferase (ALT), alkaline phosphatase, total bilirubin, direct bilirubin, creatine phosphokinase. 
Total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, and 
triglycerides parameters were removed after Protocol v3.0. Only Cohort 1 subjects have results for the 
specified parameters. Due to limited number of subjects with available results, total cholesterol, low-
density lipoprotein cholesterol, high-density lipoprotein cholesterol, and triglycerides will only be 
presented in Table 21 and Listing 11 and will be excluded from the change from baseline figures.   
• Hematology (HEM): hemoglobin, hematocrit, RBC count, WBC count, neutrophil count, lymphocyte 
count, monocyte count, eosinophil count, basophil count, platelet count.  
• Coagulation (COAG): prothrombin time, activated PTT, INR 
• Urinalysis (UA): protein, glucose, occult blood. 
By protocol, microscopic evaluation of urine or complete urinalysis is only performed if dipstick urinalysis is 
positive for blood. If complete UA or microscopic results were obtained in the absence of an abnormal 
dipstick result (or without dipstick tests being done), results of the complete UA or microscopy will still be 
summarized. Results determined using both methods will be listed. In tables, dipstick results will be presented 
prior to complete UA or microscopy results.  
Laboratory parameters that have grading criteria for both decreases (result lower than normal range) and 
increases (result higher than normal range) will be summarized separately by direction of change. For 
example, sodium will be summarized separately as “Sodium, Decrease” and “Sodium, Increase.” 
In tables summarizing toxicity grading, maximum severity observed after dosing will be summarized (max 
severity post-baseline, including unscheduled visits) for each parameter. Results of maximum severity for 
“Any Parameter” will be included for all clinical laboratory results. For “Any Parameter” results, the 
maximum severity across all laboratory parameters in the respective category is summarized by time point. 
Unscheduled clinical laboratory evaluations will be listed, but excluded from tabular and graphical 
summaries, except when calculating the maximum severity post-baseline. Any pre-existing abnormal lab 
results at screening will be graded and presented in listings but will not be reported as an AE unless they are 
treatment-emergent (i.e. it worsens after dosing, meaning for continuous parameters that an increase toxicity 
can only be assigned if the result is numerically higher than baseline and a decrease toxicity can only be 
assigned if the result is numerically lower than baseline.) 
7.7. 
Vital Signs and Physical Evaluations 
All VS measurements will be presented in Listing 18.  
VS will be summarized in tables and figures: 
• Tabularly, by parameter, Dose Group, time point, and toxicity grade (including maximum severity 
post-baseline). Respiratory rate measurements are not graded, and so will not be included in this 
summary. (Table 27). 
• Tabularly, by summary statistics for change from baseline, reported by parameter, Dose Group, and 
time point. (Table 28). 


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• Graphically, using box plots of change from baseline by parameter, Dose Group, and time point. 
(Figure 49, Figure 50, Figure 51, Figure 52, Figure 53). 
The following parameters will be reported (in order): systolic blood pressure (BP), diastolic BP, heart rate, 
respiratory rate, and temperature. 
VS parameters that have grading criteria for both decreases (result lower than normal range) and increases 
(result higher than normal range) will be summarized separately by direction of change. For example, systolic 
blood pressure will be summarized separately as “Systolic Blood Pressure, Decrease” and “Systolic Blood 
Pressure, Increase.” 
In tables summarizing toxicity grading, maximum severity observed after dosing will be summarized for each 
parameter. Results of maximum severity for “Any Parameter” will also be included. For “Any Parameter” 
results, the maximum severity across all vital sign parameters is summarized by time point. 
Unscheduled VS measurements will be listed, but excluded from tabular and graphical summaries, except 
when calculating the maximum severity post-baseline. Baseline for height, weight, and BMI will be the 
measurement taken at Screening Visit, baseline for the rest of the VS parameters is defined as the last vital 
sign parameter taken before dosing on Day 1 (including any repeats). Repeated VS due to clinic error or 
technical problem will be used for all analyses instead of the original vital sign result. Additional 
measurements taken as follow-up for safety will be included in listings and in computing maximum severity 
post baseline, but not as separate time points in summary tables. For repeats that were done due to delayed 
dosing, the last measurement prior to dosing will be considered as baseline for that subject.  
Abnormal PE findings will be listed in Listing 19. 
7.8. 
12-Lead Standard Electrocardiogram 
All 12-lead standard ECG measurement results, overall interpretation, and findings will be listed in 
Listing 20, Listing 21, and Listing 22. 
12-lead standard ECG results will be summarized in tables and figures: 
• Tabularly, 12-lead standard ECG change in overall interpretation from baseline will be shown by Dose 
Group and time point (Table 29). 
• Tabularly, by parameter, Dose Group, time point, and toxicity grade (including maximum severity 
post-baseline) (Table 30). 
• Tabularly, by summary statistics for change from baseline, reported by parameter, Dose Group, and 
time point (Table 31).  
• Tabularly, by Dose Group, time point, and sex based on QTcF categories according to the ICH 
Guideline E14 “Clinical Evaluation of QT/QTc Interval Prolongation and Proarrhythmic Potential for 
Non-Antiarrhythmic Drugs” (protocol v6.0 Section 10.5.2). (Table 32). 
• Graphically, using box plots of change from baseline by parameter, Dose Group, and time point 
(Figure 54, Figure 55, Figure 56, Figure 57, Figure 58, Figure 59). 
The following parameters will be presented (in order): PR interval, QRS duration, QT interval, QTcF interval, 
RR interval, and mean ventricular rate.  
Unscheduled 12-lead standard ECG measurements will be listed but excluded from tabular and graphical 
summaries. Individual interval measurements will be presented in listings along with overall interpretation 


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and comments. Other ECG findings besides interpretation will also be included in listings. Repeated ECG due 
to clinic error or technical problem will be used for all analyses instead of the original ECG result. Additional 
ECG measurements taken as follow-up for safety will be included in listings and in computing maximum 
severity post baseline, but not as separate time points in summary tables. For repeats that were done due to 
delayed dosing, the median of the last triplicate ECG measurement prior to dosing will be considered as 
baseline for that subject. 
7.9. 
Concomitant Medications 
All medications will be coded using the current version of the WHO Drug dictionary. The use of prior and 
concomitant medications taken during the study will be summarized by ATC 1 and ATC 2 (separately in 
Table 33 for prior medications and Table 34 for concomitant medications). Individual subject listings will be 
presented for all prior and concomitant medications (separately in Listing 23 for prior medications and 
Listing 24 for concomitant medications). 


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8. 
PHARMACOKINETICS 
Time points below the lower limit of quantification (LLOQ), referred to as below limit of quantification 
(BQL), preceding the first PK concentration above the LLOQ will be imputed as 0 for plotting and for all 
calculations including NCA and summary statistics. All other BQL values will be missing for analysis 
purposes. There will be no imputation of missing concentrations. A geometric mean (GM) of concentrations 
will be treated as missing for sets of data points containing more than 1 BQL value. 
Collection of plasma samples outside of the protocol defined time window for the time point will not result in 
exclusion of the sample result from noncompartmental analysis (NCA). Plasma samples collected out of 
window will be evaluated on a case-by-case basis. Samples will be considered substantially out of window if 
PK samples were not collected within ± 10 min for the 0.5 hour time point, ± 20 min of the targeted collection 
time (nominal time point) for time points 12 hours post-dose and earlier and within ± 1 hour for nominal time 
points from 24 to 144 hours post-dose, and ± 2 days on Day 14 and Day 30. Results from substantially out of 
window samples will be excluded from concentration summary statistics by nominal time points and plots of 
mean concentration, but included in NCA and in plots of individual concentrations.  
Drug concentrations in plasma will be listed for subjects in Cohort 2, including placebo, with BQL and PK 
analyses-excluded samples indicated and with separate columns for concentrations reported by the lab and 
concentrations used for analysis (Listing 31). The column containing concentrations reported from the lab 
may include codes such as “BQL” or “QNS” (Quantity Not Sufficient) while the column containing 
concentrations used for analysis will contain numeric data only, including imputed values such as zeros for 
pre-dose timepoints reported as BQL. The listings will also indicate the nominal time (i.e., the planned time) 
and actual post-dose time in h associated with the sample. 
The PK Analysis Subset will be used when summarizing PK concentrations. Summary statistics will be given 
for rezafungin concentrations by nominal time (Table 35).  
Rezafungin concentrations will be also be shown graphically: 
• Individual subject concentration-time profiles within 144 hours post-dose (Day 7) with y-axis on the 
linear scale (Figure 60). 
• Individual subject concentration-time profiles within 144 hours post-dose (Day 7) with y-axis on the 
logarithmic scale (Figure 61). 
• Individual subject concentration-time profiles for all time points with y-axis on the linear scale 
(Figure 62). 
• Individual subject concentration-time profiles for all time points with y-axis on the logarithmic scale 
(Figure 63). 
• GM concentration-time profiles within 144 hours post-dose (Day 7) y-axis on the linear scale. Error 
bars will show the mean ± 1 SD (Figure 64). 
• GM concentration-time profiles within 144 hours post-dose (Day 7) y-axis on the logarithmic scale 
(Figure 65). 
• GM concentration-time profiles for all time points with y-axis on the linear scale. Error bars will show 
the mean ± 1 SD (Figure 66). 
• GM concentration-time profiles for all time points with y-axis on the logarithmic scale (Figure 67).  


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8.1. 
Noncompartmental Analysis 
PK parameters will be estimated through an NCA using Phoenix® WinNonlin® version 8.2 or later (Certara, 
Princeton, NJ). Actual post-dose time will be used for the estimation of PK parameters instead of nominal 
time. Individual PK parameter estimates will be listed. PK Analysis Subset will be used when summarizing 
PK parameters. Summary tables including mean, SD, min, max, median, coefficient of variation (CV %), and 
GM will be presented (Table 36). Definition of CV is provided below.  
For an independent identically distributed random sample {𝑥𝑥1, 𝑥𝑥2, … , 𝑥𝑥𝑛𝑛 } from a log-normal distribution, let s2 
be the sample variance statistic of the natural log-transformed values of the sample. The CV was defined as: 
CV = ඥexp(𝑠𝑠2) −1 
Phoenix® WinNonlin® NCA will use the following settings to compute parameters from plasma rezafungin 
concentration data: 
• Linear Up Log Down calculation method 
• Uniform weighting 
• Extravascular Dosing 
• Lambda Z Acceptance Criteria 
− Rsq_adjusted ≥ 0.90 
− Span ≥ 3.0 half-lives 
− Includes at least 3 timepoints after Tmax 
All estimable PK parameters and terminal phase PK parameters that meet Lambda Z acceptance criteria will 
be listed in Listing 32. A definition for each PK parameter for the SAD cohorts are defined below. 
Cmax 
Maximum concentration (Cmax) is defined as the maximum observed drug concentration observed over all PK 
sample concentrations. It will be obtained from the Cmax parameter calculated by WinNonlin®. If there is no 
measurable concentration in the subject’s PK profile, then Cmax will be missing for that subject. Cmax will be 
reported in units of ng/mL. 
Tmax 
Time of maximum concentration (Tmax) is defined as the time at which the Cmax occurs. It will be obtained 
from the Tmax parameter calculated by WinNonlin®. If there is no measurable Cmax in the subject’s PK 
profile, then Tmax will be missing for that subject. Tmax will be reported in units of h. 
λz  
The terminal phase elimination rate constant (λz) is defined as the first-order rate constant describing the rate 
of decrease of drug concentration in the terminal phase (defined as the terminal region of the PK curve where 
drug concentration follows first-order elimination kinetics). λz will be computed as the slope of a terminal 
region consisting of ≥3 successive points in the plot of log-transformed concentration data versus time. λz will 
be estimated using uniform weighting.  
Time points used in the estimation of λz will be initially selected using the WinNonlin® automatic algorithm. 
Manually chosen time points may be used at the discretion of the PK analyst after examination of the 
automatically chosen points in the context of the semi-log profile. The set of points chosen must contain only 


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timepoints after Tmax, include at least 3 timepoints, and satisfy the Lambda Z Acceptance Criteria described 
above. Otherwise, the elimination rate constant and all derived parameters (apparent terminal elimination 
half-life [t1/2], AUC Extrapolated to Infinity [AUC0-inf], Apparent Clearance [CL/F], Apparent volume of 
distribution during terminal phase [Vz/F]) will be treated as missing. 
The range of concentrations used to estimate λz for each profile will be inspected by the PK analyst, who may 
adjust the set of concentrations used to estimate λz if deemed necessary, but manually selected ranges must 
satisfy the same acceptance criteria as those chosen automatically by the WinNonlin® algorithm. Sets of drug 
concentrations used to calculate λz will be indicated in the listing for concentration. This parameter will be 
obtained from the Lambda_z parameter calculated by WinNonlin®. λz will be reported in units of 1/h. 
t1/2 
The t1/2 is defined as the time required for the drug concentration to decrease by a factor of one-half in the 
terminal phase. The t1/2 can be estimated as ln(2) / λz. It will be obtained from the HL_Lambda_z parameter 
calculated by WinNonlin®. Half-life will be reported in units of h. 
AUC 
AUC0-last is defined as the area under the concentration-time curve from dosing (time 0) to the time of the last 
measured concentration. AUC0-last will be estimated using the Linear Up Log Down calculation method and 
obtained from the AUClast parameter calculated by WinNonlin®. 
AUC0-inf is defined as the total area under the concentration-time curve from dosing (time 0) taken to the limit 
as the end time becomes arbitrarily large. AUC0-inf can be calculated by adding AUC0-last to an extrapolated 
value equal to the last measured concentration greater than the LLOQ divided by λz: 
AUC0−inf = AUC0−last + Clast
𝛌𝛌𝛌𝛌, 
where Clast is the last measured concentration ≥ LLOQ. AUC0-inf will be obtained from the AUCINF_obs 
parameter calculated by WinNonlin®. If the amount extrapolated portion of AUC0-inf is >20%, the estimated 
AUC0-inf value will be flagged when listed in the report and will be excluded from statistical summaries of 
parameter estimates and downstream calculations. 
All AUCs will be reported in units of h*ng/mL. 
CL/F 
Apparent clearance (CL/F) will be computed as Dose/AUC0-inf. Clearance will be reported in units of L/h.  
Vz/F 
Apparent volume of distribution during terminal phase (Vz/F) after non-intravenous administration will be 
calculated as (CL/F)/ λz. Volume will be reported in units of L.  
 


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9. 
REPORTING CONVENTIONS 
The mean, median, SD, and any other statistics other than quantiles, will be reported to one decimal place 
greater than the original data. Order statistics, such as the min and max, will use the same number of decimal 
places as the original data. Proportions will be presented as two decimal places; values <0.01 will be 
presented as “<0.01”. Percentages will be reported to the nearest whole number; values < 1% will be 
presented as “<1”.  
For PK, AUCs will be reported as whole numbers (or using 3 significant digits if less than 100). t1/2, Tmax, 
CL/F, and Vz/F values will be reported to one decimal place (or to 2 decimal places if less than 1). λz values 
will be reported to 3 significant digits. Cmax will be reported to 3 significant digits. The mean, median, SD, 
and any other statistics other than quantiles will be reported one significant digit greater than the reported 
data. Order statistics, such as the min and max, will use the same number of significant digits as the original 
data. 
Listings of individual subject data include a Subject ID column. The subject identifiers assigned by site staff 
are replaced throughout this report with the Study Day Tabulation Model (SDTM) variable USUBJID to 
protect the confidentiality of those who volunteered to participate in this protocol. USUBJID has been created 
as a composite of the 3-letter EDC platform code followed by a numeric identifier assigned chronologically to 
enrolled subjects as well as screening failures across all sites and protocols in the EDC platform. Any data 
sharing activities will include the USUBJID and not the subject identifiers assigned at the site. 


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10. 
TECHNICAL DETAILS 
SAS version 9.4 or above or R versions 3.2 or above will be used to generate tables, figures, and listings. PK 
parameters will be estimated through an NCA using Phoenix® WinNonlin® version 8.2 or later (Certara, 
Princeton, NJ). 


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11. 
SUMMARY OF CHANGES IN THE CONDUCT OF THE STUDY OR 
PLANNED ANALYSES 
The sponsor terminated the study on 27APR2020 due to safety concerns. No subjects were enrolled into SAD 
Cohort 3 (30 mg) and above, any MAD cohort, or the BA cohort. Only SAD 1 mg and SAD 10 mg Dose 
Groups will be included in the final safety analysis and SAD 10 mg Dose Group will be included in the final 
PK analysis.  


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12. 
REFERENCES 


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13. 
LISTING OF TABLES, FIGURES, AND LISTINGS  
Table, figure, and listing shells are presented in Appendices 1, 2, and 3. 


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APPENDICES 
APPENDIX 1. TABLE MOCK-UPS 
LIST OF TABLES 
Table 1: 
Distribution of Protocol Deviations by Category, Type, and Dose Group .................25 
Table 2: 
Subject Disposition by Dose Group ...........................................................................26 
Table 3: 
Analysis Populations by Dose Group .........................................................................27 
Table 4: 
Ineligibility Summary of Screen Failures ...................................................................28 
Table 5: 
Summary of Categorical Demographic and Baseline Characteristics by Dose 
Group ..........................................................................................................................30 
Table 6: 
Summary of Continuous Demographic and Baseline Characteristics by Dose 
Group ..........................................................................................................................31 
Table 7: 
Summary of Subjects with Pre-Existing Medical Conditions by MedDRA 
System Organ Class and Dose Group .........................................................................32 
Table 8: 
Overall Summary of Adverse Events by Dose Group ................................................33 
Table 9: 
Number and Percentage of Subjects Experiencing Solicited Reactogenicity 
Symptoms with 95% Confidence Intervals by Symptom and Dose Group................34 
Table 10: Number and Percentage of Subjects Experiencing Solicited Reactogenicity 
Symptoms with 95% Confidence Intervals by Symptom, Severity, and Dose 
Group ..........................................................................................................................35 
Table 11: Number and Percentage of Subjects Experiencing Solicited Reactogenicity 
Symptoms by Symptom, Severity, Time Point, and Dose Group ..............................37 
Table 12: Summary of Unsolicited Adverse Events by MedDRA System Organ Class 
and Preferred Term, and Dose Group .........................................................................38 
Table 13: Unsolicited Adverse Events by MedDRA System Organ Class and Preferred 
Term, Severity, Relationship, and Dose Group ..........................................................39 
Table 14: Listing of Serious Adverse Events .............................................................................40 
Table 15: Listing of Non-Serious, Unsolicited, Moderate or Severe Adverse Events ...............41 
Table 16: Listing of Abnormal Laboratory Results – Chemistry ...............................................43 
Table 17: Listing of Abnormal Laboratory Results - Hematology .............................................44 
Table 18: Listing of Abnormal Laboratory Results - Coagulation .............................................45 
Table 19: Listing of Abnormal Laboratory Results - Urinalysis ................................................46 
Table 20: Chemistry Toxicity Grade by Parameter, Severity, Dose Group, and Time 
Point ............................................................................................................................47 


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Table 21: Chemistry Change from Baseline by Parameter, Dose Group, and Time 
Point ............................................................................................................................48 
Table 22: Hematology Toxicity Grade by Parameter, Severity, Dose Group, and Time 
Point ............................................................................................................................49 
Table 23: Hematology Change from Baseline by Parameter, Dose Group, and Time 
Point ............................................................................................................................49 
Table 24: Coagulation Toxicity Grade by Parameter, Dose Group, and Time Point .................50 
Table 25: Coagulation Change from Baseline by Parameter, Dose Group, and Time 
Point ............................................................................................................................50 
Table 26: Urinalysis Toxicity Grade by Parameter, Severity, Dose Group, and Time 
Point ............................................................................................................................51 
Table 27: Vital Sign Toxicity Grade by Parameter, Severity, Dose Group, and Time 
Point ............................................................................................................................52 
Table 28: Vital Sign Change from Baseline by Parameter, Dose Group, and Time Point .........53 
Table 29: ECG Overall Interpretations, Post Dose Compared to Baseline by Dose 
Group and Time Point ................................................................................................54 
Table 30: ECG Toxicity Grade by Parameter, Severity, Dose Group, and Time Point .............55 
Table 31: ECG Change from Baseline by Parameter, Dose Group, and Time Point .................56 
Table 32: Summary of QTcF by Dose Group and Time Point ...................................................57 
Table 33: Number and Percentage of Subjects with Prior Medications by WHO Drug 
Classification and Dose Group ...................................................................................58 
Table 34: Number and Percentage of Subjects with Concomitant Medications by WHO 
Drug Classification and Dose Group ..........................................................................59 
Table 35: Rezafungin Concentrations in Plasma, SAD 10 mg Dose Group ..............................60 
Table 36: Summary Statistics for Rezafungin PK Parameters in Plasma – SAD 10 mg 
Dose Group .................................................................................................................61 
 


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10.2 
Protocol Deviations 
Table 1: 
Distribution of Protocol Deviations by Category, Type, and Dose Group 
Category 
Deviation Type 
Number of Subjects (Number of Deviations) 
SAD 
1 mg 
(N=X) 
SAD 
10 mg 
(N=X) 
Placebo 
(N=X) 
All Subjects 
(N=X) 
Eligibility/enrollment 
Any type 
x (x) 
x (x) 
x (x) 
x (x) 
 
Did not meet inclusion criterion 
x (x) 
x (x) 
x (x) 
x (x) 
 
Met exclusion criterion 
x (x) 
x (x) 
x (x) 
x (x) 
 
ICF not signed prior to study procedures 
x (x) 
x (x) 
x (x) 
x (x) 
 
Other 
x (x) 
x (x) 
x (x) 
x (x) 
Treatment administration schedule 
Any type 
x (x) 
x (x) 
x (x) 
x (x) 
 
Out of window visit 
x (x) 
x (x) 
x (x) 
x (x) 
 
Missed visit/visit not conducted 
x (x) 
x (x) 
x (x) 
x (x) 
 
Missed treatment administration 
x (x) 
x (x) 
x (x) 
x (x) 
 
Delayed treatment administration 
x (x) 
x (x) 
x (x) 
x (x) 
 
Other 
x (x) 
x (x) 
x (x) 
x (x) 
Follow-up visit schedule 
Any type 
x (x) 
x (x) 
x (x) 
x (x) 
 
Out of window visit 
x (x) 
x (x) 
x (x) 
x (x) 
 
Missed visit/visit not conducted 
x (x) 
x (x) 
x (x) 
x (x) 
 
Other 
x (x) 
x (x) 
x (x) 
x (x) 
Protocol procedure/assessment 
Any type 
x (x) 
x (x) 
x (x) 
x (x 
 
Incorrect version of ICF signed 
x (x) 
x (x) 
x (x) 
x (x) 
 
Blood not collected 
x (x) 
x (x) 
x (x) 
x (x) 
 
Urine not collected 
x (x) 
x (x) 
x (x) 
x (x) 
 
Other specimen not collected 
x (x) 
x (x) 
x (x) 
x (x) 
 
Too few aliquots obtained 
x (x) 
x (x) 
x (x) 
x (x) 
 
Specimen result not obtained 
x (x) 
x (x) 
x (x) 
x (x) 
 
Required procedure not conducted 
x (x) 
x (x) 
x (x) 
x (x) 
 
Required procedure done incorrectly 
x (x) 
x (x) 
x (x) 
x (x) 
 
Study product temperature excursion 
x (x) 
x (x) 
x (x) 
x (x) 
 
Specimen temperature excursion 
x (x) 
x (x) 
x (x) 
x (x) 
 
Other 
x (x) 
x (x) 
x (x) 
x (x) 
Treatment administration 
Any type 
x (x) 
x (x) 
x (x) 
x (x) 
 
Required procedure done incorrectly 
x (x) 
x (x) 
x (x) 
x (x) 
 
Study product temperature excursion 
x (x) 
x (x) 
x (x) 
x (x) 
 
Other 
x (x) 
x (x) 
x (x) 
x (x) 
Blinding policy/procedure 
Any type 
x (x) 
x (x) 
x (x) 
x (x) 
 
Treatment unblinded 
x (x) 
x (x) 
x (x) 
x (x) 
 
Other 
x (x) 
x (x) 
x (x) 
x (x) 
Note: N = Number of subjects in Safety Population 
 


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14.1 
Description of Study Subjects 
14.1.1 Disposition of Subjects 
Table 2: 
Subject Disposition by Dose Group 
Subject Disposition 
SAD 
1 mg 
(N=X) 
SAD 
10 mg 
(N=X) 
Placebo 
(N=X) 
All Subjects 
(N=X) 
n (%) 
n (%) 
n (%) 
n (%) 
Screened 
- 
- 
- 
x (-) 
Enrolled/Randomized 
x (100) 
x (100) 
x (100) 
x (100) 
Received Study Product 
x (x) 
x (x) 
x (x) 
x (x) 
Completed all PK Blood Draws 
x (x) 
x (x) 
x (x) 
x (x) 
Completed Final Study Visit 
x (x) 
x (x) 
x (x) 
x (x) 
Early Termination 
x (x) 
x (x) 
x (x) 
x (x) 
Note: N= Number of subjects randomized. 
 


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Table 3: 
Analysis Populations by Dose Group 
[Implementation Note: Although subjects may meet multiple criteria for exclusion, they will be counted under 
only one reason for exclusion in this table. Priority for assigning reasons for exclusions will follow the order 
in the table.] 
Analysis Populations 
Reason Subjects Excluded 
SAD 
1 mg 
(N=X) 
SAD 
10 mg 
(N=X) 
Placebo 
(N=X) 
All 
Subjects 
(N=X) 
n (%) 
n (%) 
n (%) 
n (%) 
Safety Population 
No study product received 
x (x) 
x (x) 
x (x) 
x (x) 
PK Analysis Population 
Any Reason 
x (x) 
x (x) 
x (x) 
x (x) 
 
Subject received placebo or was enrolled in Cohort 1  
x (x) 
x (x) 
x (x) 
x (x) 
 
Assigned dose not received or completed 
x (x) 
x (x) 
x (x) 
x (x) 
 
Subject has no measurable concentration of drug 
x (x) 
x (x) 
x (x) 
x (x) 
PK Analysis Subset 
Any Reason 
x (x) 
x (x) 
x (x) 
x (x) 
 
Exclusion from PK Analysis Population 
x (x) 
x (x) 
x (x) 
x (x) 
 
Has protocol deviations that potentially impact PK 
x (x) 
x (x) 
x (x) 
x (x) 
 
PK data insufficient to estimate any PK parameters 
x (x) 
x (x) 
x (x) 
x (x) 
Note: N= Number of subjects randomized. 
 


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Table 4: 
Ineligibility Summary of Screen Failures 
[Implementation Note: Criteria displayed in the actual table will copy verbatim from the protocol with appropriate footnotes. The final summary table 
will include only inclusion/exclusion criterion with at least 1 subject. Criteria that were not met by any subjects will be excluded from final table.] 
 
 
Subjects Excluded 
Inclusion/Exclusion Category 
Inclusion/Exclusion Criterion 
na 
%b 
Inclusion and Exclusion 
Number of subjects failing any eligibility criterion 
x 
100 
Inclusion 
Any inclusion criterion 
x 
x 
 
Willing and able to provide written informed consent and authorization for use of PHI 
x 
x 
 
Willing and able to comply with protocol requirements and is likely to complete the study as planned 
x 
x 
 
Males are vasectomized or agree to use barrier contraception from first dose through 18 weeks post last dose of IP 
x 
x 
 
Females are of non-childbearing potential or agree to use specified BC for 30 days pre and post-dose 
x 
x 
 
Subject is in good health as deemed by the Investigator 
x 
x 
 
Subject has a BMI between 18.5 and 35.0 kg/m2, inclusive and a minimum weight of 50 kg 
x 
x 
 
Subject must refrain from strenuous physical activity from screening until completion of the trial 
x 
x 
 
Subjects must refrain from OTC/Rx meds, nutrition supplements from 14 days pre-dose to final visit 
x 
x 
 
Subject has adequate venous access for blood collection 
x 
x 
Exclusion 
Any exclusion criterion 
x 
x 
 
Subjects with clinical laboratory values outside the site reference ranges prior to initial dosing 
x 
x 
 
Abnormal ECGs.  
x 
x 
 
Female subject is pregnant, lactating or planning to become pregnant 
x 
x 
 
Received any prescription medications (with exceptions) within 14 days before first dose  
x 
x 
 
Received any non-prescription medications, vitamins or supplements within 14 days of initial dose 
x 
x 
 
Current smoker or tobacco use within 90 days prior to dosing or while subject is enrolled in study 
x 
x 
 
History of illicit/illegal drug use, alcohol/substance abuse, or vaping of non-nicotine products 
x 
x 
 
Consumed alcohol <= 48 hours of xanthines/caffeine <= 24 hours before first dose until discharge 
x 
x 
 
 Received any live or killed vaccines or immunoglobulins within 14 days of dosing 
x 
x 
 
 Donated blood or blood products or experienced significant blood loss within 60 days of dosing 
x 
x 
 
Received a blood transfusion within 14 days of dosing 
x 
x 


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Subjects Excluded 
Inclusion/Exclusion Category 
Inclusion/Exclusion Criterion 
na 
%b 
 
Previous participation in any trial within 28 days of dosing or plans to enroll in another trial  
x 
x 
 
The PI considers that the subject should not participate in the trial 
x 
x 
Eligible but Not Enrolled 
Any Reason 
x 
x 
 
[Reason 1] 
x 
x 
 
[Reason 2] 
x 
x 
a More than one criterion may be marked per subject. 
b Denominator for percentages is the total number of screen failures. 
 
 


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14.1.2 Demographic Data by Dose Group 
Table 5: 
Summary of Categorical Demographic and Baseline Characteristics by Dose Group 
Variable 
Characteristic 
SAD 
1 mg 
(N=X) 
SAD 
10 mg 
(N=X) 
Placebo 
(N=X) 
All Subjects 
(N=X) 
n (%) 
n (%) 
n (%) 
n (%) 
Sex  
Male 
x (x) 
x (x) 
x (x) 
x (x) 
 
Female 
x (x) 
x (x) 
x (x) 
x (x) 
Ethnicity  
Not Hispanic or Latino 
x (x) 
x (x) 
x (x) 
x (x) 
 
Hispanic or Latino 
x (x) 
x (x) 
x (x) 
x (x) 
 
Not Reported 
x (x) 
x (x) 
x (x) 
x (x) 
 
Unknown 
x (x) 
x (x) 
x (x) 
x (x) 
Race  
American Indian or Alaska Native 
x (x) 
x (x) 
x (x) 
x (x) 
 
Asian 
x (x) 
x (x) 
x (x) 
x (x) 
 
Native Hawaiian or Other Pacific Islander 
x (x) 
x (x) 
x (x) 
x (x) 
 
Black or African American 
x (x) 
x (x) 
x (x) 
x (x) 
 
White 
x (x) 
x (x) 
x (x) 
x (x) 
 
Multi-Racial 
x (x) 
x (x) 
x (x) 
x (x) 
 
Unknown 
x (x) 
x (x) 
x (x) 
x (x) 
Note: N= Number of subjects randomized. 
 
 


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Table 6: 
Summary of Continuous Demographic and Baseline Characteristics by Dose Group 
Variable 
Statistic 
SAD 
1 mg 
(N=X) 
SAD 
10 mg 
(N=X) 
Placebo 
(N=X) 
All Subjects 
(N=X) 
Age (years) 
Mean 
x 
x 
x 
x 
 
SD 
x 
x 
x 
x 
 
Median 
x 
x 
x 
x 
 
Min 
x 
x 
x 
x 
 
Max 
x 
x 
x 
x 
Height (cm) 
Mean 
x 
x 
x 
x 
 
SD 
x 
x 
x 
x 
 
Median 
x 
x 
x 
x 
 
Min 
x 
x 
x 
x 
 
Max 
x 
x 
x 
x 
Weight (kg) 
Mean 
x 
x 
x 
x 
 
SD 
x 
x 
x 
x 
 
Median 
x 
x 
x 
x 
 
Min 
x 
x 
x 
x 
 
Max 
x 
x 
x 
x 
BMI (kg/m2) 
Mean 
x 
x 
x 
x 
 
SD 
x 
x 
x 
x 
 
Median 
x 
x 
x 
x 
 
Min 
x 
x 
x 
x 
 
Max 
x 
x 
x 
x 
Note: N= Number of subjects randomized. 


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14.1.3 Prior and Concurrent Medical Conditions 
Table 7: 
Summary of Subjects with Pre-Existing Medical Conditions by MedDRA System Organ 
Class and Dose Group 
MedDRA System Organ Class 
SAD 
1 mg 
(N=X) 
SAD 
10 mg 
(N=X) 
Placebo 
(N=X) 
All Subjects 
(N=X) 
n (%) 
n (%) 
n (%) 
n (%) 
Any SOC 
 
 
 
 
[SOC 1] 
 
 
 
 
[SOC 2] 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Note: N= Number of subjects randomized. 


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14.3 
Safety Data 
14.3.1 Displays of Adverse Events 
Table 8: 
Overall Summary of Adverse Events by Dose Group 
[Implementation Note: Abnormal laboratory AEs assessed using the protocol toxicity tables will not be 
included in this summary.] 
 
SAD 
Any Dose 
(N=X) 
SAD 
1 mg 
(N=X) 
SAD 
10 mg 
(N=X) 
Placebo 
(N=X) 
Subjects with 
n (%) 
n (%) 
n (%) 
n (%) 
At least one solicited reactogenicity event 
x (x) 
x (x) 
x (x) 
x (x) 
At least one ulceration 
x (x) 
x (x) 
x (x) 
x (x) 
At least one mild (or worse) solicited reactogenicity event 
x (x) 
x (x) 
x (x) 
x (x) 
At least one moderate (or worse) solicited reactogenicity event 
x (x) 
x (x) 
x (x) 
x (x) 
At least one severe solicited reactogenicity event 
x (x) 
x (x) 
x (x) 
x (x) 
At least one adverse event 
x (x) 
x (x) 
x (x) 
x (x) 
At least one related adverse event 
x (x) 
x (x) 
x (x) 
x (x) 
At least one mild (or worse) related adverse event 
x (x) 
x (x) 
x (x) 
x (x) 
At least one moderate (or worse) related adverse event  
x (x) 
x (x) 
x (x) 
x (x) 
At least one severe related adverse event  
x (x) 
x (x) 
x (x) 
x (x) 
At least one serious adverse event 
x (x) 
x (x) 
x (x) 
x (x) 
At least one related, serious adverse event 
x (x) 
x (x) 
x (x) 
x (x) 
At least one adverse event leading to early termination 
x (x) 
x (x) 
x (x) 
x (x) 
Note: N = Number of subjects in Safety Population 
 


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14.3.1.1 
Solicited Reactogenicity Events 
Table 9: 
Number and Percentage of Subjects Experiencing Solicited Reactogenicity Symptoms 
with 95% Confidence Intervals by Symptom and Dose Group 
[Implementation Note: Each subject is counted once per symptom.] 
Symptom 
SAD 
Any Dose 
(N=X) 
SAD 
1 mg 
(N=X) 
SAD 
10 mg 
(N=X) 
Placebo 
(N=X) 
n 
% 
95% CI 
n 
% 
95% CI 
n 
% 
95% CI 
n 
% 95% CI 
Any Symptom 
x 
xx 
x.x, x.x 
x 
xx 
x.x, x.x 
x 
xx 
x.x, x.x 
x 
xx 
x.x, x.x 
Pain 
 
 
 
 
 
 
 
 
 
 
 
 
Tenderness 
 
 
 
 
 
 
 
 
 
 
 
 
Pruritus (Itching) 
 
 
 
 
 
 
 
 
 
 
 
 
Ecchymosis (Bruising), Functional Grade 
 
 
 
 
 
 
 
 
 
 
 
 
Ecchymosis (Bruising), Measurement Grade 
 
 
 
 
 
 
 
 
 
 
 
 
Induration (Hardness)/ Swelling, Functional Grade 
 
 
 
 
 
 
 
 
 
 
 
 
Induration (Hardness)/ Swelling, Measurement 
Grade 
 
 
 
 
 
 
 
 
 
 
 
 
Erythema (Redness), Functional Grade 
 
 
 
 
 
 
 
 
 
 
 
 
Erythema (Redness), Measurement Grade 
 
 
 
 
 
 
 
 
 
 
 
 
Nodule, Functional Grade 
 
 
 
 
 
 
 
 
 
 
 
 
Nodule, Measurement Grade 
 
 
 
 
 
 
 
 
 
 
 
 
Ulceration, Functional Grade 
 
 
 
 
 
 
 
 
 
 
 
 
Ulceration, Measurement Grade 
 
 
 
 
 
 
 
 
 
 
 
 
Note: N = Number of subjects in the Safety Population. 
 


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Table 10: 
Number and Percentage of Subjects Experiencing Solicited Reactogenicity Symptoms with 95% Confidence Intervals by 
Symptom, Severity, and Dose Group 
[Implementation Note: Each subject is counted once per symptom.] 
Symptom 
Severity 
SAD 
Any Dose 
(N=X) 
SAD 
1 mg 
(N=X) 
SAD 
10 mg 
(N=X) 
Placebo 
(N=X) 
n 
% 
95% CI 
n 
% 
95% CI 
n 
% 
95% CI 
n 
% 
95% CI 
Any Symptom 
None 
x 
xx 
x.x, x.x 
x 
xx 
x.x, x.x 
x 
xx 
x.x, x.x 
x 
xx 
x.x, x.x 
 
Mild 
 
 
 
 
 
 
 
 
 
 
 
 
 
Moderate 
 
 
 
 
 
 
 
 
 
 
 
 
 
Severe 
 
 
 
 
 
 
 
 
 
 
 
 
Pain 
None 
 
 
 
 
 
 
 
 
 
 
 
 
 
Mild 
 
 
 
 
 
 
 
 
 
 
 
 
 
Moderate 
 
 
 
 
 
 
 
 
 
 
 
 
 
Severe 
 
 
 
 
 
 
 
 
 
 
 
 
Tenderness 
None 
 
 
 
 
 
 
 
 
 
 
 
 
 
Mild 
 
 
 
 
 
 
 
 
 
 
 
 
 
Moderate 
 
 
 
 
 
 
 
 
 
 
 
 
 
Severe 
 
 
 
 
 
 
 
 
 
 
 
 
Pruritus (Itching) 
None 
 
 
 
 
 
 
 
 
 
 
 
 
 
Mild 
 
 
 
 
 
 
 
 
 
 
 
 
 
Moderate 
 
 
 
 
 
 
 
 
 
 
 
 
 
Severe 
 
 
 
 
 
 
 
 
 
 
 
 
Ecchymosis (Bruising), Functional Grade 
None 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
Ecchymosis (Bruising), Measurement Grade 
None 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
Induration (Hardness)/ Swelling, Functional Grade 
… 
 
 
 
 
 
 
 
 
 
 
 
 


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Symptom 
Severity 
SAD 
Any Dose 
(N=X) 
SAD 
1 mg 
(N=X) 
SAD 
10 mg 
(N=X) 
Placebo 
(N=X) 
n 
% 
95% CI 
n 
% 
95% CI 
n 
% 
95% CI 
n 
% 
95% CI 
Induration (Hardness)/ Swelling, Measurement Grade 
… 
 
 
 
 
 
 
 
 
 
 
 
 
Erythema (Redness), Functional Grade 
… 
 
 
 
 
 
 
 
 
 
 
 
 
Erythema (Redness), Measurement Grade 
… 
 
 
 
 
 
 
 
 
 
 
 
 
Nodule, Functional Grade 
… 
 
 
 
 
 
 
 
 
 
 
 
 
Nodule, Measurement Grade 
… 
 
 
 
 
 
 
 
 
 
 
 
 
Ulceration, Functional Grade 
… 
 
 
 
 
 
 
 
 
 
 
 
 
Ulceration, Measurement Grade 
… 
 
 
 
 
 
 
 
 
 
 
 
 
Note: N = Number of subjects in Safety Population 
 
 
 


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Table 11: 
Number and Percentage of Subjects Experiencing Solicited Reactogenicity Symptoms by 
Symptom, Severity, Time Point, and Dose Group 
Dose Group 
Time Point 
N 
None 
Mild  
Moderate 
Severe 
n 
% 
n 
% 
n 
% 
n 
% 
Any Symptoms 
SAD Any Dose 
Max Severity Post Baseline 
 
 
 
 
 
 
 
 
 
 
Day 1, 1 h Post-Dose 
 
 
 
 
 
 
 
 
 
 
Day 1, 4 h Post-Dose 
 
 
 
 
 
 
 
 
 
 
Day 2 
 
 
 
 
 
 
 
 
 
 
Day 3 
 
 
 
 
 
 
 
 
 
 
Day 4 
 
 
 
 
 
 
 
 
 
 
Day 5 
 
 
 
 
 
 
 
 
 
 
Day 6 
 
 
 
 
 
 
 
 
 
 
Day 7 
 
 
 
 
 
 
 
 
 
 
Max Severity Day 8 to Day 14 
 
 
 
 
 
 
 
 
 
 
Max Severity Day 15 to Day 21 
 
 
 
 
 
 
 
 
 
 
Max Severity Day 22 to Final Visit 
 
 
 
 
 
 
 
 
 
SAD 1 mg 
Max Severity Post Baseline 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
SAD 10 mg 
Max Severity Post Baseline 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
Placebo 
Max Severity Post Baseline 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
Pain 
SAD Any Dose 
… 
 
 
 
 
 
 
 
 
 
SAD 1 mg 
… 
 
 
 
 
 
 
 
 
 
SAD 10 mg 
… 
 
 
 
 
 
 
 
 
 
Tenderness 
Ecchymosis (Bruising), Functional Grade 
Ecchymosis (Bruising), Measurement Grade 
Induration (Hardness)/ Swelling, Functional Grade 
Induration (Hardness)/ Swelling, Measurement Grade 
Erythema (Redness), Functional Grade 
Erythema (Redness), Measurement Grade 
Nodule, Functional Grade 
Nodule, Measurement Grade 
Ulceration, Functional Grade 
Ulceration, Measurement Grade 
Note: N = Number of subjects in Safety Population with solicited reactogenicity symptoms assessed at the respective time point. 


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14.3.1.2 
Unsolicited Adverse Events 
Table 12: 
Summary of Unsolicited Adverse Events by MedDRA System Organ Class and Preferred 
Term, and Dose Group 
[Implementation Note: If there is only 1 PT for an SOC, there will be no “Any PT” row.] 
Dose Group 
MedDRA System Organ 
Class 
MedDRA Preferred 
Term 
N 
n (%) 
95% CI 
Number of 
Events 
SAD Any Dose 
Any SOC 
Any PT 
x 
x (x) 
(x.x, x.x) 
X 
 
[SOC 1] 
Any PT 
x 
x (x) 
(x.x, x.x) 
X 
 
 
[PT 1] 
x 
x (x) 
(x.x, x.x) 
X 
 
 
[PT 2] 
x 
x (x) 
(x.x, x.x) 
X 
 
Any SOC 
Any PT 
x 
x (x) 
(x.x, x.x) 
X 
SAD 1 mg 
… 
 
 
 
 
 
Note: N = Number of subjects in Safety Population 


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Table 13: 
Unsolicited Adverse Events by MedDRA System Organ Class and Preferred Term, 
Severity, Relationship, and Dose Group 
[Implementation Note: If there is only 1 PT for an SOC, there will be no “Any PT” row.] 
Dose Group 
MedDRA System Organ 
Class 
MedDRA Preferred 
Term 
Severity 
N 
Related 
n(%) 
Not Related 
n (%) 
Total 
n (%) 
SAD Any Dose 
Any SOC 
Any PT 
Any Severity 
x 
x (x) 
x (x) 
x (x) 
 
 
 
Mild 
x 
x (x) 
x (x) 
x (x) 
 
 
 
Moderate 
x 
x (x) 
x (x) 
x (x) 
 
 
 
Severe 
x 
x (x) 
x (x) 
x (x) 
 
[SOC 1] 
Any PT 
Any Severity 
x 
x (x) 
x (x) 
x (x) 
 
 
 
Mild 
x 
x (x) 
x (x) 
x (x) 
 
 
 
Moderate 
x 
x (x) 
x (x) 
x (x) 
 
 
 
Severe 
x 
x (x) 
x (x) 
x (x) 
 
 
[PT 1] 
Any Severity 
x 
x (x) 
x (x) 
x (x) 
 
 
 
Mild 
x 
x (x) 
x (x) 
x (x) 
 
 
 
Moderate 
x 
x (x) 
x (x) 
x (x) 
 
 
 
Severe 
x 
x (x) 
x (x) 
x (x) 
 
 
 
 
x 
x (x) 
x (x) 
x (x) 
SAD 1 mg  
Any SOC 
Any PT 
Any Severity 
x 
x (x) 
x (x) 
x (x) 
… 
… 
 
 
 
 
Note: N = Number of subjects in Safety Population 


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14.3.2 Listing of Deaths, Other Serious and Significant Adverse Events 
Table 14: 
Listing of Serious Adverse Events 
[Implementation Note: This listing is included in the table shells document, as it is included in the body of the abbreviated CSR. If the event is ongoing 
(no stop date), indicate “ongoing” for the “Duration”. If more than one reason is selected for the reason reported as an SAE, list all reasons in the 
column, separated by a comma. In the “If Not Related, Alternate Etiology” column, merge the 2 data fields for collecting alternate etiology, separate by a 
colon. Listing should be sorted by Dose Group, Subject ID, and AE Number.] 
Adverse 
Event 
MedDRA 
System 
Organ Class 
MedDRA 
Preferred 
Term 
Study Day 
Duration of 
AE in Days 
Study Day the 
Event Became 
Serious 
Reason 
Reported 
as an SAE 
Severity 
Relationship to 
Study Treatment 
(Alternate Etiology) 
Action Taken 
with Study 
Treatment 
Subject 
Discontinued 
Due to AE 
Outcome 
Dose Group: , Subject ID: , AE Number:  
 
 
 
 
 
 
 
 
 
 
 
 
Comments: 
Dose Group: , Subject ID: , AE Number:  
 
 
 
 
 
 
 
 
 
 
 
 
Comments: 
 


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Table 15: 
Listing of Non-Serious, Unsolicited, Moderate or Severe Adverse Events 
[Implementation Note: This listing is included in the tables document, as it is included in the body of the abbreviated CSR. If the event is ongoing (no 
stop date), indicate “ongoing” in the “Duration” column. In the “If Not Related, Alternate Etiology” column, merge the 2 data fields for collecting 
alternate etiology, separate by a colon. Listing should be sorted by Dose Group, Subject ID, and AE Number.] 
Adverse 
Event 
MedDRA 
System Organ 
Class 
MedDRA 
Preferred Term 
Study Day 
Duration of 
AE in Days 
Severity 
Relationship to 
Study Treatment 
(Alternate Etiology) 
Action Taken 
with Study 
Treatment 
Subject 
Discontinued 
Due to AE 
Outcome 
Dose Group: , Subject ID: , AE Number:  
 
 
 
 
 
 
 
 
 
 
Comments: 
Dose Group: , Subject ID: , AE Number:  
 
 
 
 
 
 
 
 
 
 
Comments: 
 


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14.3.3 Narratives of Deaths, Other Serious and Significant Adverse Events 
(not included in SAP, but this is a placeholder for the CSR) 
 


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14.3.4 Abnormal Laboratory Value Listings (by Subject) 
Table 16: 
Listing of Abnormal Laboratory Results – Chemistry 
[Implementation Note: This listing is included in the table shells document, as it is included in the body of the 
abbreviated CSR. This listing includes all abnormal Chemistry results (laboratory results outside of the 
normal range defined in the protocol). Normal chemistry results for other parameters that occurred on the 
same visit as the abnormal result will not be listed. There is a separate, complete listing of all Chemistry 
results. In the Laboratory Parameter column, indicate the units (LB.LBSTRESU) after the parameter, e.g., 
Sodium (mEq/L). This listing is not color-coded. Results that are outside the normal range but not mild, 
moderate, or severe will have ONR listed as severity. Similarly, results that meet grading criteria of mild, 
moderate, or severe but which are not treatment emergent (not worse than baseline) will be shown as ONR.  
Sort order: Dose Group, Subject ID, Time Point, and Parameter.] 
Dose Group 
Subject ID 
Sex 
Time Point 
Date of 
Assessment 
Laboratory Parameter 
(Units) 
Result 
Severity 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Table 17: 
Listing of Abnormal Laboratory Results - Hematology 
[Implementation Note: This listing is included in the table shells document, as it is included in the body of the 
abbreviated CSR. This listing includes all abnormal Hematology results (laboratory results outside of the 
normal range defined in the protocol). Normal hematology results for other parameters that occurred on the 
same visit as the abnormal result will not be listed. There is a separate, complete listing of all Hematology 
results. In the Laboratory Parameter column, indicate the units (LB.LBSTRESU) after the parameter, e.g., 
Hemoglobin (g/dL). This listing is not color-coded. Results that are outside the normal range but not mild, 
moderate, or severe will have ONR listed as severity. Similarly, results that meet grading criteria of mild, 
moderate, or severe but which are not treatment emergent (not worse than baseline) will be shown as ONR.. 
Sort order: Dose Group, Subject ID, Time Point, and Parameter.] 
Dose Group 
Subject ID 
Sex 
Time Point 
Date of 
Assessment 
Laboratory Parameter 
(Units) 
Result  
Severity 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Table 18: 
Listing of Abnormal Laboratory Results - Coagulation 
[Implementation Note: This listing is included in the table shells document, as it is included in the body of the 
abbreviated CSR. This listing includes all abnormal Coagulation results (laboratory results outside of the 
normal range defined in the protocol). Normal coagulation results for other parameters that occurred on the 
same visit as the abnormal result will not be listed. There is a separate, complete listing of all Coagulation 
results. In the Laboratory Parameter column, indicate the units (LB.LBSTRESU) after the parameter, e.g., 
(seconds).This listing is not color-coded. Results that are outside the normal range but not mild, moderate, or 
severe will have ONR listed as severity. Similarly, results that meet grading criteria of mild, moderate, or 
severe but which are not treatment emergent (not worse than baseline) will be shown as ONR.  
Sort order: Dose Group, Subject ID, Time Point, and Parameter.] 
Dose Group 
Subject ID 
Time Point 
Date of 
Assessment 
Laboratory Parameter 
(Units) 
Result  
Severity 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Table 19: 
Listing of Abnormal Laboratory Results - Urinalysis 
[Implementation Note: This listing is included in the table shells document, as it is included in the body of the 
abbreviated CSR. This listing includes all abnormal Urinalysis results (laboratory results outside of the 
normal range defined in the protocol). Normal urinalysis results for other parameters that occurred on the 
same visit as the abnormal result will not be listed. There is a separate, complete listing of all Urinalysis 
results. In the Laboratory Parameter column, indicate the units (LB.LBSTRESU) after the parameter, e.g., 
Leukocytes by Microscopy (/hpf). This listing is not color-coded. Results that are outside the normal range 
but not mild, moderate, or severe will have ONR listed as severity. Similarly, results that meet grading criteria 
of mild, moderate, or severe but which are not treatment emergent (not worse than baseline) will be shown as 
ONR. 
Sort order: Dose Group, Subject ID, Time Point, and Parameter.] 
Dose Group 
Subject ID 
Sex 
Time Point 
Date of 
Assessment 
Laboratory Parameter 
(Units) 
Result  
Severity 
 
 
 
 
 
Occult Blood by Dipstick 
Negative 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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14.3.5 Displays of Laboratory Results 
14.3.5.1 
Chemistry Results 
Table 20: 
Chemistry Toxicity Grade by Parameter, Severity, Dose Group, and Time Point 
[Implementation Note: Severity will be graded based on toxicity criteria in protocol. If there is not at least 1 
Mild, Moderate, or Severe Event for Max Severity Post-Baseline, then only the Max Severity Post-Baseline 
row will be shown for the parameter. Toxicities representing an increase in the laboratory result will be 
summarized separately from decreases.] 
Dose Group 
Time Point 
N 
Mild 
Moderate 
Severe 
n (%) 
n (%) 
n (%) 
Any Parameter 
SAD Any Dose 
Baseline 
x 
x (x) 
x (x) 
x (x) 
 
Max Severity Post-Baseline 
x 
x (x) 
x (x) 
x (x) 
 
Day 2 
x 
x (x) 
x (x) 
x (x) 
 
Day 7 
x 
x (x) 
x (x) 
x (x) 
 
Final Visit 
x 
x (x) 
x (x) 
x (x) 
SAD 1 mg 
Baseline 
x 
x (x) 
x (x) 
x (x) 
 
… 
x 
x (x) 
x (x) 
x (x) 
SAD 10 mg 
Baseline 
x 
x (x) 
x (x) 
x (x) 
 
… 
x 
x (x) 
x (x) 
x (x) 
Placebo  
Baseline 
x 
x (x) 
x (x) 
x (x) 
 
… 
x 
x (x) 
x (x) 
x (x) 
Sodium, Decrease 
SAD Any Dose 
Baseline 
x 
x (x) 
x (x) 
x (x) 
… 
… 
x 
x (x) 
x (x) 
x (x) 
Notes: The “Max Severity Post Baseline” rows indicate the maximum severity experienced by each subject at any time point post baseline, 
including unscheduled assessments.  
N=Number of subjects in the Safety Population with the laboratory result assessed at the respective time point. 
 


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Table 21: 
Chemistry Change from Baseline by Parameter, Dose Group, and Time Point 
Dose Group 
Time Point 
N 
Change from Baseline 
Mean 
SD 
Median 
Min, Max 
Sodium (mEq/L) 
 
SAD Any Dose 
Day 2 
x 
x 
x 
x 
x, x 
 
Day 7 
x 
x 
x 
x 
x, x 
 
Final Visit 
x 
x 
x 
x 
x, x 
SAD 1 mg 
Day 2 
x 
 
 
 
 
 
… 
x 
x 
x 
x 
x, x 
SAD 10 mg 
Day 2 
x 
 
 
 
 
 
… 
x 
x 
x 
x 
x, x 
 
… 
x 
x 
x 
x 
x, x 
Placebo 
Day 2 
x 
x 
x 
x 
x, x 
 
… 
x 
x 
x 
x 
x, x 
Potassium (mEq/L) 
 
SAD Any Dose 
Day 2 
x 
x 
x 
x 
x, x 
 
… 
x 
x 
x 
x 
x, x 
Note: N=Number of subjects in the Safety Population with the laboratory result assessed at the respective time point. 


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14.3.5.2 
Hematology Results 
Table 22: 
Hematology Toxicity Grade by Parameter, Severity, Dose Group, and Time Point 
[Implementation Note: Severity will be graded based on toxicity criteria in protocol. If there is not at least 1 
Mild, Moderate, or Severe Event for Max Severity Post-Baseline, then only the Max Severity Post-Baseline 
row will be shown for the parameter. Toxicities representing an increase in the laboratory result will be 
summarized separately from decreases.] 
This table will repeat Table 20 for Hematology parameters. 
 
Table 23: 
Hematology Change from Baseline by Parameter, Dose Group, and Time Point 
This table will repeat Table 21 for Hematology parameters. 
 
 


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14.3.5.3 
Coagulation Clinical Laboratory Results 
Table 24: 
Coagulation Toxicity Grade by Parameter, Dose Group, and Time Point 
[Implementation Note: Severity will be graded based on toxicity criteria in protocol. If there is not at least 1 
Mild, Moderate, or Severe Event for Max Severity Post-Baseline, then only the Max Severity Post-Baseline 
row will be shown for the parameter. Toxicities representing an increase in the laboratory result will be 
summarized separately from decreases.] 
This table will repeat Table 20 for Coagulation parameters. 
 
Table 25: 
Coagulation Change from Baseline by Parameter, Dose Group, and Time Point 
This table will repeat Table 21 for Coagulation parameters. 
 


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14.3.5.4 
Urinalysis Results 
Table 26: 
Urinalysis Toxicity Grade by Parameter, Severity, Dose Group, and Time Point 
[Implementation Note: Severity will be graded based on toxicity criteria in protocol. If there is not at least 1 
Mild, Moderate, or Severe Event for Max Severity Post-Baseline, then only the Max Severity Post-Baseline 
row will be shown for the parameter. Toxicities representing an increase in the laboratory result will be 
summarized separately from decreases.] 
This table will repeat Table 20 for Urinalysis parameters. 
 
 


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14.3.6 Displays of Vital Signs 
Table 27: 
Vital Sign Toxicity Grade by Parameter, Severity, Dose Group, and Time Point 
[Implementation Note: If there is not at least 1 Mild, Moderate, or Severe Event for Max Severity Post-
Baseline, then only the Max Severity Post-Baseline row will be shown for the parameter.] 
Dose Group 
Time Point 
N 
Mild 
n (%) 
Moderate 
n (%) 
Severe 
n (%) 
Any Parameter 
 
SAD Any Dose 
Baseline 
x 
x (x) 
x (x) 
x (x) 
 
Max Severity Post Baseline 
 
 
 
 
 
Day 1, 15 minutes Post-Dose 
x 
x (x) 
x (x) 
x (x) 
 
Day 1, 1 h Post-Dose 
x 
x (x) 
x (x) 
x (x) 
 
Day 1, 2 h Post-Dose 
x 
x (x) 
x (x) 
x (x) 
 
Day 2 
x 
x (x) 
x (x) 
x (x) 
 
Day 4 
x 
x (x) 
x (x) 
x (x) 
 
Day 7 
x 
x (x) 
x (x) 
x (x) 
 
Day 14 
x 
x (x) 
x (x) 
x (x) 
 
Final Visit 
x 
x (x) 
x (x) 
x (x) 
SAD 1 mg 
Baseline 
x 
x (x) 
x (x) 
x (x) 
 
… 
x 
x (x) 
x (x) 
x (x) 
SAD 10 mg 
Baseline 
x 
x (x) 
x (x) 
x (x) 
 
… 
x 
x (x) 
x (x) 
x (x) 
Placebo 
Baseline 
x 
x (x) 
x (x) 
x (x) 
 
… 
x 
x (x) 
x (x) 
x (x) 
Systolic Blood Pressure, Decrease 
 
SAD Any Dose 
Baseline 
x 
x (x) 
x (x) 
x (x) 
… 
… 
x 
x (x) 
x (x) 
x (x) 
Notes: The “Max Severity Post Baseline” rows indicate the maximum severity experienced by each subject at any time point post baseline, 
including unscheduled assessments.  
N = Number of subjects in Safety Population with the vital sign assessed for the respective time point. 
 


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Table 28: 
Vital Sign Change from Baseline by Parameter, Dose Group, and Time Point 
Dose Group 
Time Point 
N 
Change from Baseline 
Mean 
SD 
Median 
Min, Max 
Systolic Blood Pressure (mmHg) 
 
SAD Any Dose 
Day 1, 15 minutes Post-Dose 
x 
x 
x 
x 
x, x 
 
Day 1, 1 h Post-Dose 
x 
x 
x 
x 
x, x 
 
Day 1, 2 h Post-Dose 
x 
x 
x 
x 
x, x 
 
Day 2 
x 
x 
x 
x 
x, x 
 
Day 4 
x 
x 
x 
x 
x, x 
 
Day 7 
x 
x 
x 
x 
x, x 
 
Day 14 
x 
x 
x 
x 
x, x 
 
Final Visit 
x 
x 
x 
x 
x, x 
SAD 1 mg 
Day 1, 15 minutes Post-Dose 
x 
x 
x 
x 
x, x 
 
… 
x 
x 
x 
x 
x, x 
SAD 10 mg 
Day 1, 15 minutes Post-Dose 
x 
x 
x 
x 
x, x 
 
… 
x 
x 
x 
x 
x, x 
Placebo 
Day 1, 30 minutes Post-Dose 
x 
x 
x 
x 
x, x 
 
 
 
x 
x 
x 
x, x 
Diastolic Blood Pressure (mmHg) 
 
SAD Any Dose 
Day 1, 15 minutes Post-Dose 
x 
x 
x 
x 
x, x 
.. 
… 
x 
x 
x 
x 
x, x 
Note: N=Number of subjects in the Safety Population with the laboratory result assessed at the respective time point. 
 
 


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14.3.7 Displays of ECG Measurements  
Table 29: 
ECG Overall Interpretations, Post Dose Compared to Baseline by Dose Group and Time 
Point 
ECG Interpretation 
SAD Any Dose 
n (%) 
SAD 1 mg 
n (%) 
SAD 10 mg 
n (%) 
Placebo 
n (%) 
Day 1, 4 h Post-Dose 
N 
x 
x 
x 
x 
Normal at Both Times 
x (x) 
x (x) 
x (x) 
x (x) 
Normal to Abnormal, NCS 
x (x) 
x (x) 
x (x) 
x (x) 
Normal to Abnormal, CS 
 
 
 
 
Abnormal, NCS at Both Times 
x (x) 
x (x) 
x (x) 
x (x) 
Abnormal, NCS to Abnormal, CS 
 
 
 
 
Abnormal, NCS to Normal 
x (x) 
x (x) 
x (x) 
x (x) 
Day 7 
N 
x 
x 
x 
x 
Normal at Both Times 
x (x) 
x (x) 
x (x) 
x (x) 
… 
x (x) 
x (x) 
x (x) 
x (x) 
Final Visit 
N 
x 
x 
x 
x 
Normal at Both Times 
x (x) 
x (x) 
x (x) 
x (x) 
… 
x (x) 
x (x) 
x (x) 
x (x) 
Notes: N = Number of subjects in Safety Population with the ECG results assessed at the respective time point. 
CS= clinically significant; NCS= not clinically significant. 
 


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Table 30: 
ECG Toxicity Grade by Parameter, Severity, Dose Group, and Time Point 
[Implementation Note: If there is not at least 1 Mild, Moderate, or Severe Event for Max Severity Post-
Baseline, then only the Max Severity Post-Baseline row will be shown for the parameter.] 
Dose Group 
Time Point 
N 
Mild 
n (%) 
Moderate 
n (%) 
Severe 
n (%) 
PR Interval 
SAD Any Dose 
Baseline 
x 
x (x) 
x (x) 
x (x) 
 
Max Severity Post Baseline 
 
 
 
 
 
Day 1, 4 h Post-Dose 
x 
x (x) 
x (x) 
x (x) 
 
Day 7 
x 
x (x) 
x (x) 
x (x) 
 
Final Visit 
x 
x (x) 
x (x) 
x (x) 
SAD 1 mg 
Baseline 
x 
x (x) 
x (x) 
x (x) 
 
… 
x 
x (x) 
x (x) 
x (x) 
SAD 10 mg 
Baseline 
x 
x (x) 
x (x) 
x (x) 
 
… 
x 
x (x) 
x (x) 
x (x) 
Placebo 
Baseline 
x 
x (x) 
x (x) 
x (x) 
 
… 
x 
x (x) 
x (x) 
x (x) 
QTcF Interval 
SAD Any Dose 
Baseline 
x 
x (x) 
x (x) 
x (x) 
 
… 
x 
x (x) 
x (x) 
x (x) 
Notes: The “Max Severity Post Baseline” rows indicate the maximum severity of ECG Results Related to study treatment experienced by each 
subject at any time point post baseline, including unscheduled assessments.  
N = Number of subjects in Safety Population with the ECG results assessed at the respective time point. 
 
 


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Table 31: 
ECG Change from Baseline by Parameter, Dose Group, and Time Point 
Dose Group 
Time Point 
N 
Change from Baseline 
Mean 
SD 
Median 
Min, Max 
PR Interval (msec) 
 
SAD Any Dose 
Day 1, 4 h Post-Dose 
x 
x 
x 
x 
x, x 
 
Day 7 
x 
x 
x 
x 
x, x 
 
Final Visit 
x 
x 
x 
x 
x, x 
SAD 1 mg 
Day 1, 4 h Post-Dose 
x 
x 
x 
x 
x, x 
 
… 
x 
x 
x 
x 
x, x 
SAD 10 mg 
Day 1, 4 h Post-Dose 
x 
x 
x 
x 
x, x 
 
… 
x 
x 
x 
x 
x, x 
Placebo 
Day 1, 4 h Post-Dose 
x 
x 
x 
x 
x, x 
 
… 
x 
x 
x 
x 
x, x 
QRS Duration (msec) 
 
SAD Any Dose 
Day 1, 4 h Post-Dose 
x 
x 
x 
x 
x, x 
 
… 
x 
x 
x 
x 
x, x 
Note: N = Number of subjects in Safety Population with the ECG results assessed at the respective time point. 
 
 


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Table 32: 
Summary of QTcF by Dose Group and Time Point 
[Implementation Note: For all QTcF categories that specified gender, N based on gender should be used for 
calculating proportions] 
QTcF Category 
Time Point 
SAD Any Dose 
SAD 1 mg 
SAD 10 mg 
Placebo 
n / N (%) 
n / N (%) 
n / N (%) 
n / N (%) 
QTcF >450 ms, Male 
Day 1, 4 h Post-Dose 
x / x (x) 
x / x (x) 
x / x (x) 
x / x (x) 
 
Day 7 
x / x (x) 
x / x (x) 
x / x (x) 
x / x (x) 
 
Final Visit 
x / x (x) 
x / x (x) 
x / x (x) 
x / x (x) 
QTcF >470 ms, Female 
Day 1, 4 h Post-Dose 
x / x (x) 
x / x (x) 
x / x (x) 
x / x (x) 
 
… 
x / x (x) 
x / x (x) 
x / x (x) 
x / x (x) 
QTcF >480 ms 
Day 1, 4 h Post-Dose 
x / x (x) 
x / x (x) 
x / x (x) 
x / x (x) 
 
… 
x / x (x) 
x / x (x) 
x / x (x) 
x / x (x) 
QTcF >500 ms 
Day 1, 4 h Post-Dose 
x / x (x) 
x / x (x) 
x / x (x) 
x / x (x) 
 
… 
x / x (x) 
x / x (x) 
x / x (x) 
x / x (x) 
30 ms ≤ QTcF increases from baseline < 60 ms  
Day 1, 4 h Post-Dose 
x / x (x) 
x / x (x) 
x / x (x) 
x / x (x) 
 
… 
x / x (x) 
x / x (x) 
x / x (x) 
x / x (x) 
QTcF increases from baseline ≥ 60 ms 
Day 1, 4 h Post-Dose 
x / x (x) 
x / x (x) 
x / x (x) 
x / x (x) 
 
… 
x / x (x) 
x / x (x) 
x / x (x) 
x / x (x) 
N= Number of subjects in Safety Population with the ECG results assessed at the respective time point. N is calculated based on specified sex 
for "QTcF >450 ms, Male" and "QTcF >470 ms, Female" categories. 
 


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14.4 
Summary of Concomitant Medications 
Table 33: 
Number and Percentage of Subjects with Prior Medications by WHO Drug Classification 
and Dose Group 
[Implementation Note: Include prior medications (medications with an end date prior to first dose) only.] 
WHO Drug Code 
Level 1, Anatomic Group 
WHO Drug Code 
Level 2, Therapeutic Subgroup 
SAD 
1 mg 
(N=X) 
SAD 
10 mg 
(N=X) 
Placebo 
(N=X) 
All Subjects 
(N=X) 
n (%) 
n (%) 
n (%) 
n (%) 
Any Level 1 Codes 
Any Level 2 Codes 
 
 
 
 
[ATC Level 1 - 1] 
Any [ATC 1 – 1] 
 
 
 
 
 
[ATC 2 - 1] 
 
 
 
 
 
[ATC 2 - 2] 
 
 
 
 
 
[ATC 2 - 3] 
 
 
 
 
[ATC Level 1 – 2] 
[ATC 2 - 1] 
 
 
 
 
 
[ATC 2 - 2] 
 
 
 
 
 
[ATC 2 - 3] 
 
 
 
 
Note: N = Number of subjects in Safety Population 


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Table 34: 
Number and Percentage of Subjects with Concomitant Medications by WHO Drug 
Classification and Dose Group 
[Implementation Note: Include concomitant medications (medications that are ongoing or that have an end 
date after first dose) only] 
WHO Drug Code 
Level 1, Anatomic Group 
WHO Drug Code 
Level 2, Therapeutic Subgroup 
SAD 
1 mg 
(N=X) 
SAD 
10 mg 
(N=X) 
Placebo 
(N=X) 
All Subjects 
(N=X) 
n (%) 
n (%) 
n (%) 
n (%) 
Any Level 1 Codes 
Any Level 2 Codes 
 
 
 
 
[ATC Level 1 - 1] 
Any [ATC 1 – 1] 
 
 
 
 
 
[ATC 2 - 1] 
 
 
 
 
 
[ATC 2 - 2] 
 
 
 
 
 
[ATC 2 - 3] 
 
 
 
 
[ATC Level 1 – 2] 
[ATC 2 - 1] 
 
 
 
 
 
[ATC 2 - 2] 
 
 
 
 
 
[ATC 2 - 3] 
 
 
 
 
Note: N = Number of subjects in Safety Population 
 


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14.5 
Pharmacokinetics 
Table 35: 
Rezafungin Concentrations in Plasma, SAD 10 mg Dose Group 
Subject ID 
Nominal Timea (h) 
0 
0.5 
1 
2 
4 
6 
8 
12 
24 
48 
96 
144 
312 
(Day 14) 
696 
(Day 30) 
PHU.00123 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
PHU.00124 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
PHU.00125 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
… 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Statistics 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Nb 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Mean 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
SD 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
GM 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
CV % 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Min 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Max 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
a Times are relative to time of dosing. 
b Number of data points used to compute the summary statistics. For calculation of summary statistics, BQL values were imputed as 0 if they did not come after a PK sample concentration that is above the 
LLOQ and treated as missing otherwise. 
Note: Samples that were collected substantially outside of the protocol-defined window are excluded from summary statistics (but not from NCA) and are indicated by an asterisks (*). 


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Table 36: 
Summary Statistics for Rezafungin PK Parameters in Plasma – SAD 10 mg Dose Group 
Statistic 
PK Parameters 
Cmax 
(ng/mL) 
Tmax 
(h) 
AUC0-last  
(h*ng/mL) 
AUC0-inf 
(h*ng/mL) 
λz 
(1/h) 
t1/2 
(h) 
CL/F 
(L/h) 
Vz/F 
(L) 
N 
x 
x 
x 
x 
x 
x 
x 
x 
Mean 
x 
x 
x 
x 
x 
x 
x 
x 
SD 
x 
x 
x 
x 
x 
x 
x 
x 
Min 
x 
x 
x 
x 
x 
x 
x 
x 
Median 
x 
x 
x 
x 
x 
x 
x 
x 
Max 
x 
x 
x 
x 
x 
x 
x 
x 
CV % 
x 
x 
x 
x 
x 
x 
x 
x 
GM 
x 
x 
x 
x 
x 
x 
x 
x 
 


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APPENDIX 2. FIGURE MOCK-UPS 
LIST OF FIGURES 
Figure 1: 
CONSORT Flow Diagram .........................................................................................66 
Figure 2: 
Proportions of Subjects with Solicited Reactogenicity Symptoms by Dose 
Group and Severity .....................................................................................................67 
Figure 3: 
Proportions of Subjects with Solicited Reactogenicity Symptoms by Dose 
Group, Time Point, and Severity – Any Symptoms ...................................................68 
Figure 4: 
Proportions of Subjects with Solicited Reactogenicity Symptoms by Dose 
Group, Time Point, and Severity – Pain .....................................................................69 
Figure 5: 
Proportions of Subjects with Solicited Reactogenicity Symptoms by Dose 
Group, Time Point, and Severity – Tenderness ..........................................................69 
Figure 6: 
Proportions of Subjects with Solicited Reactogenicity Symptoms by Dose 
Group, Time Point, and Severity – Pruritus (Itching) ................................................69 
Figure 7: 
Proportions of Subjects with Solicited Reactogenicity Symptoms by Dose 
Group, Time Point, and Severity – Ecchymosis (Bruising), Functional Grade .........69 
Figure 8: 
Proportions of Subjects with Solicited Reactogenicity Symptoms by Dose 
Group, Time Point, and Severity – Ecchymosis (Bruising), Measurement 
Grade ...........................................................................................................................69 
Figure 9: 
Proportions of Subjects with Solicited Reactogenicity Symptoms by Dose 
Group, Time Point, and Severity – Induration (Hardness)/ Swelling, 
Functional Grade ........................................................................................................69 
Figure 10: Proportions of Subjects with Solicited Reactogenicity Symptoms by Dose 
Group, Time Point, and Severity – Induration (Hardness)/ Swelling, 
Measurement Grade ....................................................................................................69 
Figure 11: Proportions of Subjects with Solicited Reactogenicity Symptoms by Dose 
Group, Time Point, and Severity – Erythema (Redness), Functional Grade ..............69 
Figure 12: Proportions of Subjects with Solicited Reactogenicity Symptoms by Dose 
Group, Time Point, and Severity – Erythema (Redness), Measurement Grade .........70 
Figure 13: Proportions of Subjects with Solicited Reactogenicity Symptoms by Dose 
Group, Time Point, and Severity – Nodule, Functional Grade ..................................70 
Figure 14: Proportions of Subjects with Solicited Reactogenicity Symptoms by Dose 
Group, Time Point, and Severity – Nodule, Measurement Grade ..............................70 
Figure 15: Proportions of Subjects with Solicited Reactogenicity Symptoms by Dose 
Group, Time Point, and Severity – Ulceration, Functional Grade .............................70 
Figure 16: Proportions of Subjects with Solicited Reactogenicity Symptoms by Dose 
Group, Time Point, and Severity – Ulceration, Measurement Grade .........................70 


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Figure 17: Proportions of Subjects with Related Adverse Events by Dose Group, 
MedDRA SOC, and Severity ......................................................................................71 
Figure 18: Number of Related Adverse Events by Dose Group, MedDRA SOC, and 
Severity .......................................................................................................................72 
Figure 19: Chemistry Laboratory Results by Scheduled Visits: Change from Baseline 
by Parameter and Dose Group – Sodium ...................................................................73 
Figure 20: Chemistry Laboratory Results by Scheduled Visits: Change from Baseline 
by Laboratory Parameter and Dose Group – Potassium .............................................74 
Figure 21: Chemistry Laboratory Results by Scheduled Visits: Change from Baseline 
by Laboratory Parameter and Dose Group – Calcium................................................74 
Figure 22: Chemistry Laboratory Results by Scheduled Visits: Change from Baseline 
by Laboratory Parameter and Dose Group – Phosphorus ..........................................74 
Figure 23: Chemistry Laboratory Results by Scheduled Visits: Change from Baseline 
by Laboratory Parameter and Dose Group – Chloride ...............................................74 
Figure 24: Chemistry Laboratory Results by Scheduled Visits: Change from Baseline 
by Laboratory Parameter and Dose Group – Total Carbon Dioxide ..........................74 
Figure 25: Chemistry Laboratory Results by Scheduled Visits: Change from Baseline 
by Laboratory Parameter and Dose Group – Glucose ................................................74 
Figure 26: Chemistry Laboratory Results by Scheduled Visits: Change from Baseline 
by Laboratory Parameter and Dose Group – Blood Urea Nitrogen ...........................74 
Figure 27: Chemistry Laboratory Results by Scheduled Visits: Change from Baseline 
by Laboratory Parameter and Dose Group – Creatinine ............................................74 
Figure 28: Chemistry Laboratory Results by Scheduled Visits: Change from Baseline 
by Laboratory Parameter and Dose Group – Protein ..................................................75 
Figure 29: Chemistry Laboratory Results by Scheduled Visits: Change from Baseline 
by Laboratory Parameter and Dose Group – Albumin ...............................................75 
Figure 30: Chemistry Laboratory Results by Scheduled Visits: Change from Baseline 
by Laboratory Parameter and Dose Group – Creatine Phosphokinase .......................75 
Figure 31: Chemistry Laboratory Results by Scheduled Visits: Change from Baseline 
by Laboratory Parameter and Dose Group – Aspartate Aminotransferase ................75 
Figure 32: Chemistry Laboratory Results by Scheduled Visits: Change from Baseline 
by Laboratory Parameter and Dose Group – Alanine Aminotransferase ...................75 
Figure 33: Chemistry Laboratory Results by Scheduled Visits: Change from Baseline 
by Laboratory Parameter and Dose Group – Alkaline Phosphatase...........................75 
Figure 34: Chemistry Laboratory Results by Scheduled Visits: Change from Baseline 
by Laboratory Parameter and Dose Group – Total Bilirubin .....................................75 
Figure 35: Chemistry Laboratory Results by Scheduled Visits: Change from Baseline 
by Laboratory Parameter and Dose Group – Direct Bilirubin ....................................75 


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Figure 36: Hematology Laboratory Results by Scheduled Visits: Change from Baseline 
by Laboratory Parameter and Dose Group – Hemoglobin .........................................76 
Figure 37: Hematology Laboratory Results by Scheduled Visits: Change from Baseline 
by Laboratory Parameter and Dose Group – Hematocrit ...........................................76 
Figure 38: Hematology Laboratory Results by Scheduled Visits: Change from Baseline 
by Laboratory Parameter and Dose Group, – Red Blood Cell Count ........................76 
Figure 39: Hematology Laboratory Results by Scheduled Visits: Change from Baseline 
by Laboratory Parameter and Dose Group –White Blood Cell Count .......................76 
Figure 40: Hematology Laboratory Results by Scheduled Visits: Change from Baseline 
by Laboratory Parameter and Dose Group – Neutrophil Count .................................76 
Figure 41: Hematology Laboratory Results by Scheduled Visits: Change from Baseline 
by Laboratory Parameter and Dose Group – Lymphocyte Count ..............................76 
Figure 42: Hematology Laboratory Results by Scheduled Visits: Change from Baseline 
by Laboratory Parameter and Dose Group – Monocyte Count ..................................76 
Figure 43: Hematology Laboratory Results by Scheduled Visits: Change from Baseline 
by Laboratory Parameter and Dose Group – Eosinophil Count .................................77 
Figure 44: Hematology Laboratory Results by Scheduled Visits: Change from Baseline 
by Laboratory Parameter and Dose Group – Basophil Count ....................................77 
Figure 45: Hematology Laboratory Results by Scheduled Visits: Change from Baseline 
by Laboratory Parameter and Dose Group – Platelets ................................................77 
Figure 46: Coagulation Laboratory Results by Scheduled Visits: Change from Baseline 
by Laboratory Parameter and Dose Group – Prothrombin Time ...............................78 
Figure 47: Coagulation Laboratory Results by Scheduled Visits: Change from Baseline 
by Laboratory Parameter and Dose Group – Activated Partial 
Thromboplastin Time .................................................................................................78 
Figure 48: Coagulation Laboratory Results by Scheduled Visits: Change from Baseline 
by Laboratory Parameter and Dose Group – Prothrombin International 
Normalized Ratio ........................................................................................................78 
Figure 49: Vital Signs by Scheduled Visits: Change from Baseline by Parameter and 
Dose Groups – Systolic Blood Pressure .....................................................................79 
Figure 50: Vital Signs by Scheduled Visits: Change from Baseline by Parameter and 
Dose Groups – Diastolic Blood Pressure ....................................................................80 
Figure 51: Vital Signs by Scheduled Visits: Change from Baseline by Parameter and 
Dose Groups – Heart Rate ..........................................................................................80 
Figure 52: Vital Signs by Scheduled Visits: Change from Baseline by Parameter and 
Dose Groups – Respiration Rate .................................................................................80 
Figure 53: Vital Signs by Scheduled Visits: Change from Baseline by Parameter and 
Dose Groups – Temperature .......................................................................................80 


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Figure 54: ECG by Scheduled Visits: Change from Baseline by Parameter – PR Interval .........81 
Figure 55: ECG by Scheduled Visits: Change from Baseline by Parameter – QRS 
Duration ......................................................................................................................81 
Figure 56: ECG by Scheduled Visits: Change from Baseline by Parameter – QT 
Interval ........................................................................................................................82 
Figure 57: ECG by Scheduled Visits: Change from Baseline by Parameter – QTcF 
Interval ........................................................................................................................82 
Figure 58: ECG by Scheduled Visits: Change from Baseline by Parameter – RR 
Interval ........................................................................................................................82 
Figure 59: ECG by Scheduled Visits: Change from Baseline by Parameter –Ventricular 
Rate .............................................................................................................................82 
Figure 60: Individual Rezafungin Concentration within 144 h Post-Dose in Plasma 
Profiles – SAD 10 mg Dose Group ............................................................................83 
Figure 61: Semi-Log Individual Rezafungin Concentration within 144 h Post-Dose in 
Plasma Profiles – SAD 10 mg Dose Group ................................................................84 
Figure 62: Individual Rezafungin Concentration for All Time Points in Plasma Profiles 
– SAD 10 mg Dose Group ..........................................................................................85 
Figure 63: Semi-Log Individual Rezafungin Concentration for All Time Points in 
Plasma Profiles – SAD 10 mg Dose Group ................................................................86 
Figure 64: Mean Rezafungin Concentration within 144 h Post-Dose in Plasma Profiles 
– SAD 10 mg Dose Group ..........................................................................................87 
Figure 65: Semi-Log Mean Rezafungin Concentration within 144 h Post-Dose in 
Plasma Profiles – SAD 10 mg Dose Group ................................................................88 
Figure 66: Mean Rezafungin Concentration for All Time Points in Plasma Profiles – 
SAD 10 mg Dose Group .............................................................................................89 
Figure 67: Semi-Log Mean Rezafungin Concentration for All Time Points in Plasma 
Profiles – SAD 10 mg Dose Group ............................................................................90 
 


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10.1 
Disposition of Subjects 
Figure 1: 
CONSORT Flow Diagram 
[Implementation Note: CONSORT diagram will show numbers of subjects screened and enrolled, and by 
Dose Group will show number randomized, treated, and completed per protocol. Additionally, it will show 
the number of subjects excluded from analysis populations by reason for exclusion.] 
This is a place holder for Figure 1. The specifications for Figure 1 are in the implementation note. 
 


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14.3.1.1 Solicited Reactogenicity Symptoms 
Figure 2: 
Proportions of Subjects with Solicited Reactogenicity Symptoms by Dose Group and 
Severity 
[Implementation Note: All local reactogenicity symptoms will be listed using consistent symptom names as 
the solicited reactogenicity table shells, including “Any Symptoms”] 
 
 


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Figure 3: 
Proportions of Subjects with Solicited Reactogenicity Symptoms by Dose Group, Time 
Point, and Severity – Any Symptoms 
[Implementation Note: Maximum severity on Day 1 will be calculated based on all time points collected on 
Day 1 (Day 1, 1 h Post-Dose and Day 1, 4 h Post-Dose). Maximum severity on Day 14 and Final Visit will be 
calculated based on records in memory aid and in clinic assessments. ] 
 
 


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Figure 4: 
Proportions of Subjects with Solicited Reactogenicity Symptoms by Dose Group, Time 
Point, and Severity – Pain 
This figure will repeat Figure 3 for Pain 
 
Figure 5: 
Proportions of Subjects with Solicited Reactogenicity Symptoms by Dose Group, Time 
Point, and Severity – Tenderness 
This figure will repeat Figure 3 for Tenderness 
 
Figure 6: 
Proportions of Subjects with Solicited Reactogenicity Symptoms by Dose Group, Time 
Point, and Severity – Pruritus (Itching) 
This figure will repeat Figure 3 for Pruritus (Itching) 
 
Figure 7: 
Proportions of Subjects with Solicited Reactogenicity Symptoms by Dose Group, Time 
Point, and Severity – Ecchymosis (Bruising), Functional Grade 
This figure will repeat Figure 3 for Ecchymosis (Bruising), Functional Grade 
 
Figure 8: 
Proportions of Subjects with Solicited Reactogenicity Symptoms by Dose Group, Time 
Point, and Severity – Ecchymosis (Bruising), Measurement Grade 
This figure will repeat Figure 3 for Ecchymosis (Bruising), Measurement Grade 
 
Figure 9: 
Proportions of Subjects with Solicited Reactogenicity Symptoms by Dose Group, Time 
Point, and Severity – Induration (Hardness)/ Swelling, Functional Grade 
This figure will repeat Figure 3 for Induration (Hardness)/ Swelling, Functional Grade 
 
Figure 10: 
Proportions of Subjects with Solicited Reactogenicity Symptoms by Dose Group, Time 
Point, and Severity – Induration (Hardness)/ Swelling, Measurement Grade 
This figure will repeat Figure 3 for Induration (Hardness)/ Swelling, Measurement Grade 
 
Figure 11: 
Proportions of Subjects with Solicited Reactogenicity Symptoms by Dose Group, Time 
Point, and Severity – Erythema (Redness), Functional Grade 
This figure will repeat Figure 3 for Erythema (Redness), Functional Grade 


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Figure 12: 
Proportions of Subjects with Solicited Reactogenicity Symptoms by Dose Group, Time 
Point, and Severity – Erythema (Redness), Measurement Grade 
This figure will repeat Figure 3 for Erythema (Redness), Measurement Grade 
 
Figure 13: 
Proportions of Subjects with Solicited Reactogenicity Symptoms by Dose Group, Time 
Point, and Severity – Nodule, Functional Grade 
This figure will repeat Figure 3 for Nodule, Functional Grade 
 
Figure 14: 
Proportions of Subjects with Solicited Reactogenicity Symptoms by Dose Group, Time 
Point, and Severity – Nodule, Measurement Grade 
This figure will repeat Figure 3 for Nodule, Measurement Grade 
 
Figure 15: 
Proportions of Subjects with Solicited Reactogenicity Symptoms by Dose Group, Time 
Point, and Severity – Ulceration, Functional Grade 
This figure will repeat Figure 3 for Ulceration, Functional Grade 
 
Figure 16: 
Proportions of Subjects with Solicited Reactogenicity Symptoms by Dose Group, Time 
Point, and Severity – Ulceration, Measurement Grade 
This figure will repeat Figure 3 for Ulceration, Measurement Grade 


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14.3.1.2 Unsolicited Adverse Events 
Figure 17: 
Proportions of Subjects with Related Adverse Events by Dose Group, MedDRA SOC, 
and Severity 
[Implementation Note: This figure includes serious and non-serious unsolicited adverse events deemed related 
to study product. Note that this figure will present the number of subjects with types of adverse events, and a 
subject may not be counted more than once for the same type of adverse event but will be counted only once 
for the maximum severity of the respective type. Each figure panel will show counts for all SOCs observed in 
any Dose Group during the study (as a related AE). If the number of SOCs is too large to fit if using 2 rows of 
panels, then this figure will be split into multiple figures in the CSR, with 1 row of 2 panels in each figure. 
SOCs will be ordered alphabetically.] 
 
 


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Figure 18: 
Number of Related Adverse Events by Dose Group, MedDRA SOC, and Severity  
[Implementation Note: This figure includes serious and non-serious unsolicited adverse events deemed related 
to study product. Note that this figure will present total counts of adverse events, and a subject may be 
represented by more than one count for the same type of adverse event. Each figure panel will show counts 
for all SOCs observed in any Dose Group during the study (as a related AE). If the number of SOCs is too 
large to fit if using 2 rows of panels, then this figure will be split into multiple figures in the CSR, with 1 row 
of 2 panels in each figure. SOCs will be ordered alphabetically.] 
 
 
 


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14.3.5 
Displays of Laboratory Results 
14.3.5.1 
Chemistry Results 
Figure 19: 
Chemistry Laboratory Results by Scheduled Visits: Change from Baseline by 
Parameter and Dose Group – Sodium 
 


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Figure 20: 
Chemistry Laboratory Results by Scheduled Visits: Change from Baseline by 
Laboratory Parameter and Dose Group – Potassium 
This figure will repeat Figure 19 for Potassium. 
 
Figure 21: 
Chemistry Laboratory Results by Scheduled Visits: Change from Baseline by 
Laboratory Parameter and Dose Group – Calcium  
This figure will repeat Figure 19 for Calcium. 
 
Figure 22: 
Chemistry Laboratory Results by Scheduled Visits: Change from Baseline by 
Laboratory Parameter and Dose Group – Phosphorus 
This figure will repeat Figure 19 for Phosphorus. 
 
Figure 23: 
Chemistry Laboratory Results by Scheduled Visits: Change from Baseline by 
Laboratory Parameter and Dose Group – Chloride  
This figure will repeat Figure 19 for Chloride. 
 
Figure 24: 
Chemistry Laboratory Results by Scheduled Visits: Change from Baseline by 
Laboratory Parameter and Dose Group – Total Carbon Dioxide  
This figure will repeat Figure 19 for Total Carbon Dioxide. 
 
Figure 25: 
Chemistry Laboratory Results by Scheduled Visits: Change from Baseline by 
Laboratory Parameter and Dose Group – Glucose  
This figure will repeat Figure 19 for Glucose. 
 
Figure 26: 
Chemistry Laboratory Results by Scheduled Visits: Change from Baseline by 
Laboratory Parameter and Dose Group – Blood Urea Nitrogen 
This figure will repeat Figure 19 for Blood Urea Nitrogen. 
 
Figure 27: 
Chemistry Laboratory Results by Scheduled Visits: Change from Baseline by 
Laboratory Parameter and Dose Group – Creatinine 
This figure will repeat Figure 19 for Creatinine. 


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Figure 28: 
Chemistry Laboratory Results by Scheduled Visits: Change from Baseline by 
Laboratory Parameter and Dose Group – Protein 
This figure will repeat Figure 19 for Protein. 
 
Figure 29: 
Chemistry Laboratory Results by Scheduled Visits: Change from Baseline by 
Laboratory Parameter and Dose Group – Albumin 
This figure will repeat Figure 19 for Albumin. 
 
Figure 30: 
Chemistry Laboratory Results by Scheduled Visits: Change from Baseline by 
Laboratory Parameter and Dose Group – Creatine Phosphokinase 
This figure will repeat Figure 19 for Creatine Phosphokinase. 
 
Figure 31: 
Chemistry Laboratory Results by Scheduled Visits: Change from Baseline by 
Laboratory Parameter and Dose Group – Aspartate Aminotransferase 
This figure will repeat Figure 19 for Aspartate Aminotransferase. 
 
Figure 32: 
Chemistry Laboratory Results by Scheduled Visits: Change from Baseline by 
Laboratory Parameter and Dose Group – Alanine Aminotransferase 
This figure will repeat Figure 19 for Alanine Aminotransferase. 
 
Figure 33: 
Chemistry Laboratory Results by Scheduled Visits: Change from Baseline by 
Laboratory Parameter and Dose Group – Alkaline Phosphatase 
This figure will repeat Figure 19 for Alkaline Phosphatase. 
 
Figure 34: 
Chemistry Laboratory Results by Scheduled Visits: Change from Baseline by 
Laboratory Parameter and Dose Group – Total Bilirubin 
This figure will repeat Figure 19 for Total Bilirubin. 
 
Figure 35: 
Chemistry Laboratory Results by Scheduled Visits: Change from Baseline by 
Laboratory Parameter and Dose Group – Direct Bilirubin 
This figure will repeat Figure 19 for Direct Bilirubin. 


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14.3.5.2 
Hematology Results 
Figure 36: 
Hematology Laboratory Results by Scheduled Visits: Change from Baseline by 
Laboratory Parameter and Dose Group – Hemoglobin 
This figure will repeat Figure 19 for Hemoglobin. 
 
Figure 37: 
Hematology Laboratory Results by Scheduled Visits: Change from Baseline by 
Laboratory Parameter and Dose Group – Hematocrit 
This figure will repeat Figure 19 for Hematocrit. 
 
Figure 38: 
Hematology Laboratory Results by Scheduled Visits: Change from Baseline by 
Laboratory Parameter and Dose Group, – Red Blood Cell Count 
This figure will repeat Figure 19 for Red Blood Cell Count. 
 
Figure 39: 
Hematology Laboratory Results by Scheduled Visits: Change from Baseline by 
Laboratory Parameter and Dose Group –White Blood Cell Count 
This figure will repeat Figure 19 for White Blood Cell Count. 
 
Figure 40: 
Hematology Laboratory Results by Scheduled Visits: Change from Baseline by 
Laboratory Parameter and Dose Group – Neutrophil Count 
This figure will repeat Figure 19 for Neutrophil Count. 
 
Figure 41: 
Hematology Laboratory Results by Scheduled Visits: Change from Baseline by 
Laboratory Parameter and Dose Group – Lymphocyte Count 
This figure will repeat Figure 19 for Lymphocyte Count. 
 
Figure 42: 
Hematology Laboratory Results by Scheduled Visits: Change from Baseline by 
Laboratory Parameter and Dose Group – Monocyte Count 
This figure will repeat Figure 19 for Monocyte Count. 
 


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Figure 43: 
Hematology Laboratory Results by Scheduled Visits: Change from Baseline by 
Laboratory Parameter and Dose Group – Eosinophil Count 
This figure will repeat Figure 19 for Eosinophil Count. 
 
Figure 44: 
Hematology Laboratory Results by Scheduled Visits: Change from Baseline by 
Laboratory Parameter and Dose Group – Basophil Count 
This figure will repeat Figure 19 for Basophil Count. 
 
Figure 45: 
Hematology Laboratory Results by Scheduled Visits: Change from Baseline by 
Laboratory Parameter and Dose Group – Platelets 
This figure will repeat Figure 19 for Platelets. 


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14.3.5.3 
Coagulation Results 
Figure 46: 
Coagulation Laboratory Results by Scheduled Visits: Change from Baseline by 
Laboratory Parameter and Dose Group – Prothrombin Time 
This figure will repeat Figure 19 for Prothrombin Time. 
 
Figure 47: 
Coagulation Laboratory Results by Scheduled Visits: Change from Baseline by 
Laboratory Parameter and Dose Group – Activated Partial Thromboplastin Time 
This figure will repeat Figure 19 for Activated Partial Thromboplastin Time. 
 
Figure 48: 
Coagulation Laboratory Results by Scheduled Visits: Change from Baseline by 
Laboratory Parameter and Dose Group – Prothrombin International Normalized Ratio 
This figure will repeat Figure 19 for Prothrombin International Normalized Ratio. 


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14.3.6 Displays of Vital Signs 
Figure 49: 
Vital Signs by Scheduled Visits: Change from Baseline by Parameter and Dose Groups – 
Systolic Blood Pressure 
 


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Figure 50: 
Vital Signs by Scheduled Visits: Change from Baseline by Parameter and Dose Groups – 
Diastolic Blood Pressure 
This figure will repeat Figure 49 for Diastolic Blood Pressure. 
 
Figure 51: 
Vital Signs by Scheduled Visits: Change from Baseline by Parameter and Dose Groups – 
Heart Rate 
This figure will repeat Figure 49 for Heart Rate. 
 
Figure 52: 
Vital Signs by Scheduled Visits: Change from Baseline by Parameter and Dose Groups – 
Respiration Rate 
This figure will repeat Figure 49 for Respiration Rate. 
 
Figure 53: 
Vital Signs by Scheduled Visits: Change from Baseline by Parameter and Dose Groups – 
Temperature 
This figure will repeat Figure 49 for Temperature. 


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14.3.7 Displays of ECG Measurements 
Figure 54: 
ECG by Scheduled Visits: Change from Baseline by Parameter – PR Interval 
 
Figure 55: 
ECG by Scheduled Visits: Change from Baseline by Parameter – QRS Duration 
This figure will repeat Figure 54 for QRS Duration. 
 


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Figure 56: 
ECG by Scheduled Visits: Change from Baseline by Parameter – QT Interval 
This figure will repeat Figure 54 for QT Interval. 
 
Figure 57: 
ECG by Scheduled Visits: Change from Baseline by Parameter – QTcF Interval 
This figure will repeat Figure 54 for QTcF Interval. 
 
Figure 58: 
ECG by Scheduled Visits: Change from Baseline by Parameter – RR Interval 
This figure will repeat Figure 54 for RR Interval. 
 
Figure 59: 
ECG by Scheduled Visits: Change from Baseline by Parameter –Ventricular Rate 
This figure will repeat Figure 54 for Ventricular Rate. 
 


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Figure 60: 
Individual Rezafungin Concentration within 144 h Post-Dose in Plasma Profiles – SAD 
10 mg Dose Group 
 
 


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Figure 61: 
Semi-Log Individual Rezafungin Concentration within 144 h Post-Dose in Plasma 
Profiles – SAD 10 mg Dose Group 
 
 


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Figure 62: 
Individual Rezafungin Concentration for All Time Points in Plasma Profiles – SAD 10 
mg Dose Group 
 
 


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Figure 63: 
Semi-Log Individual Rezafungin Concentration for All Time Points in Plasma Profiles – 
SAD 10 mg Dose Group 
 
 


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Figure 64: 
Mean Rezafungin Concentration within 144 h Post-Dose in Plasma Profiles – SAD 10 mg 
Dose Group 
 
 


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Figure 65: 
Semi-Log Mean Rezafungin Concentration within 144 h Post-Dose in Plasma Profiles – 
SAD 10 mg Dose Group 
 
 


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Figure 66: 
Mean Rezafungin Concentration for All Time Points in Plasma Profiles – SAD 10 mg 
Dose Group 
 
 


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Figure 67: 
Semi-Log Mean Rezafungin Concentration for All Time Points in Plasma Profiles – SAD 
10 mg Dose Group 
 
 


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APPENDIX 3. LISTINGS MOCK-UPS 
LISTINGS 
Listing 1: 16.1.6: Listing of Subjects Receiving Investigational Product ...................................93 
Listing 2: 16.2.1: Early Terminations or Discontinued Subjects ................................................94 
Listing 3: 16.2.2.1: Subject-Specific Protocol Deviations ..........................................................95 
Listing 4: 16.2.2.2: Non-Subject-Specific Protocol Deviations ..................................................96 
Listing 5: 16.2.3: Subjects Excluded from Analysis Populations ...............................................97 
Listing 6: 16.2.4.1: Demographic Data .......................................................................................98 
Listing 7: 16.2.4.2: Pre-Existing and Concurrent Medical Conditions .......................................99 
Listing 8: 16.2.5: Compliance and/or Drug Concentration Data ..............................................100 
Listing 9: 16.2.7.2: Solicited Reactogenicity Events – Local Symptoms .................................101 
Listing 10: 16.2.7.3: Unsolicited Adverse Events .......................................................................102 
Listing 11: 16.2.8.1: Clinical Laboratory Results – Chemistry ..................................................103 
Listing 12: 16.2.8.2: Clinical Laboratory Results – Hematology ...............................................104 
Listing 13: Clinical Laboratory Results – Coagulation ...............................................................104 
Listing 14: 16.2.8.3: Clinical Laboratory Results – Urinalysis...................................................105 
Listing 15: Clinical Laboratory Results – Serology ....................................................................106 
Listing 16: Screening Laboratory Results – Urine Toxicology ..................................................107 
Listing 17: Laboratory Results – Serum hCG and Pregnancy Tests ...........................................108 
Listing 18: 16.2.9.1: Vital Signs .................................................................................................109 
Listing 19: 16.2.9.2: Physical Exam Findings ............................................................................110 
Listing 20: Listing of ECG Interval Measurements ....................................................................111 
Listing 21: Listing of ECG Overall Interpretation and Comments .............................................112 
Listing 22: Listing of ECG Findings ...........................................................................................113 
Listing 23: Prior Medications ......................................................................................................114 
Listing 24: 16.2.10: Concomitant Medications ...........................................................................115 
Listing 25: 16.2.11.1: Pregnancy Reports – Maternal Information ............................................116 
Listing 26: 16.2.11.2: Pregnancy Reports – Gravida and Para ...................................................116 
Listing 27: 16.2.11.3: Pregnancy Reports – Live Birth Outcomes .............................................117 
Listing 28: 16.2.11.4: Pregnancy Reports – Still Birth Outcomes ..............................................117 


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Listing 29: 16.2.11.5: Pregnancy Reports – Spontaneous, Elective, or Therapeutic 
Abortion Outcomes ...................................................................................................117 
Listing 30: Birth Control Listing.................................................................................................118 
Listing 31: Subject Level Drug Concentrations ..........................................................................119 
Listing 32: Subject-Specific PK Parameters ...............................................................................120 
 


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Listing 1: 
16.1.6: Listing of Subjects Receiving Investigational Product 
(This is a placeholder for the abbreviated CSR) 
 


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16.2 
Database Listings by Subject 
16.2.1 Discontinued Subjects 
Listing 2: 
16.2.1: Early Terminations or Discontinued Subjects 
[Implementation Note: Category will be either “Early Termination” or “Treatment Discontinuation.” In the “Reason” column, concatenate any “specify” 
fields, including AE number and DV number. Sort order: Dose Group, Subject ID, Category (in the case a subject both terminates early and discontinues 
treatment).] 
Dose Group 
 Subject ID 
Category 
Reason for Early Termination or Treatment Discontinuation 
Study Day 
SAD 1 mg 
PHU.00123 
Early Termination 
Lost to Follow-up 
7 
 
 
 
 
 


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16.2.2 Protocol Deviations 
Listing 3: 
16.2.2.1: Subject-Specific Protocol Deviations 
[Implementation Note: In the “Deviation” column, concatenate any and all “specify” fields (including visit number, etc.). If “Reason for Deviation” is 
“Other,” concatenate “specify” field, separate by a colon, e.g., “Other: Subject refusal.” Sort order: Dose Group, Subject ID, DV Number. If deviation 
resulted in AE or subject termination, or affected product stability, indicate which of those events occurred in the listing row, since columns for those 3 
events were concatenated to save space.] 
Dose Group 
Subject ID 
DV Number 
Deviation 
Deviation 
Category 
Study Day 
Reason for 
Deviation 
Deviation Resulted in AE or Subject 
Termination, or Affected Product Stability? 
Deviation 
Resolution 
Comments 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Listing 4: 
16.2.2.2: Non-Subject-Specific Protocol Deviations 
[Implementation Note: In the “Deviation” column, concatenate any and all “specify” fields (including visit number, etc.). If “Reason for Deviation” is 
“Other,” concatenate “specify” field, separate by a colon, e.g., “Other: Subject refusal.” Sort order: Start Date, Deviation.] 
Start Date  
Deviation 
End Date 
Reason for 
Deviation 
Deviation Resulted in 
Subject Termination? 
Deviation Affected 
Product Stability? 
Deviation 
Category 
Deviation 
Resolution 
Comments 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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16.2.3 Subjects Excluded from the Efficacy Analysis 
Listing 5: 
16.2.3: Subjects Excluded from Analysis Populations 
[Implementation Note: This data in this listing should be congruent with the “Analysis Populations by Dose Group” table. If subject not excluded from 
any analysis population, the subject will not appear in the listing. If the subject is excluded from multiple analysis populations, they will have one row 
per analysis population excluded from in the listing.  
Sort order: Dose Group, Subject ID, Analysis from which Subject is Excluded (order: Safety, PK Analysis Population, PK Analysis Subset).] 
Dose Group 
Subject ID 
Analysis from which Subject is Excluded 
Results Available? 
Reason Subject Excluded 
Reason Subject Excluded Specification 
SAD 1 mg 
PHU.00123 
PK Analysis Subset 
Yes 
Has protocol deviations that 
potentially impact PK 
Subject consumed food 1 hour prior to 
dosing 
 
 
 
 
 
 
 
 
 
 
 
 
Note: “Yes” in the “Results available” column indicates that available data were removed from the analysis. “No” indicates that no data were available for inclusion in the analysis. 
 
 


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16.2.4 Demographic Data 
Listing 6: 
16.2.4.1: Demographic Data 
[Implementation Note: If a subject is multi-racial, in “Race” column, note “Multiple: (list races, separated by a comma).”  
Sort order: Dose Group, Subject ID.] 
Dose Group 
 Subject ID 
Sex 
Age at Enrollment 
(years) 
Ethnicity 
Race 
Weight at Screening 
(kg) 
Height at Screening 
(cm) 
BMI at Screening 
(kg/m2) 
SAD 1 mg 
PHU.00123 
Female 
24 
Not Hispanic 
Black or African American 
xx 
xxx 
xx 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Listing 7: 
16.2.4.2: Pre-Existing and Concurrent Medical Conditions 
[Implementation Note: “Condition Start Day” and “Condition End Day” are relative to enrollment (which is Day 1, day before enrollment is Day -1). 
Rather than use exact study days, categorize as follows: 
• 5 years prior to enrollment 
• 1-5 years prior to enrollment 
• 1-12 months prior to enrollment 
• Within 1 month of enrollment 
• During study 
• If ongoing, display “Ongoing” in the “Condition End Day” column 
• Within 1 month of enrollment 
• During study 
• If ongoing, display “Ongoing” in the “Condition End Day” column 
It may be appropriate to add another category, based on exclusion criteria that restrict conditions within a particular time period (e.g., within 3 years prior 
to enrollment). In the CSR, Subject ID should be USUBJID (not PATID) for purposes of de-identification.  
Sort order: Dose Group, Subject ID, MH Number.] 
Dose Group 
Subject ID 
Medical History Number Medical History Term 
MedDRA System Organ Class 
MedDRA Preferred Term 
Condition Start Day 
Condition End Day 
SAD 1 mg 
PHU.00123 
1 
NUT ALLERGY 
IMMUNE SYSTEM DISORDERS 
FOOD ALLERGY 
>5 years prior to 
enrollment 
Ongoing 
 
 
 
 
 
 
 
 
 


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16.2.5 Compliance and/or Drug Concentration Data (if available) 
Listing 8: 
16.2.5: Compliance and/or Drug Concentration Data 
[Implementation Note: If not dosed according to protocol, details will be given in the Comments column (manually written, not programmed). If Dose is 
inapplicable for subject, the date and time columns for those doses will be “N/A” and for planned doses that did not occur the date and time columns for 
those doses will be “not dosed.” 
Sort order: Dose Group, Subject ID, Dose Date, Dose Time] 
Dose Group 
Subject ID 
Dosed According to Protocol? 
Dose Date 
Dose Time 
Comments 
SAD 1 mg 
PHU.00123 
Yes 
ddMMMyyyy 
hh:mm 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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16.2.7 Adverse Events 
Listing 9: 
16.2.7.2: Solicited Reactogenicity Events – Local Symptoms 
[Implementation Note: Functional grade will be displayed under “Functional Grade” column and measurement and measurement grade will be displayed 
together in “Measurement (Grade)” column ex: 30 (Mild) 
Sort order: Dose Group, Subject ID, Time Point] 
Dose Group  
Subject ID  
Time Point 
Assessmenta 
Location 
Symptom 
Functional Grade 
Measurement (Grade) 
 
 
 
Clinic 
Upper Left 
Pain 
Mild 
30 (Mild) 
 
 
 
MA 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
a MA = Data reported by subject on the Memory Aid and reviewed by clinic staff and reported in Solicited Reactogenicity Events eCRF. Clinic = Data collected by clinic staff during symptom 
assessment. 
 


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Listing 10: 
16.2.7.3: Unsolicited Adverse Events 
[Implementation Note: If the event is ongoing (no stop date), indicate “ongoing” in the “Duration” column. In the “If Not Related, Alternate Etiology” 
column, merge the 2 data fields for collecting alternate etiology, separate by a colon. This listing includes all unsolicited adverse events. Sort order: Dose 
Group, Subject ID, AE Number.] 
Adverse 
Event 
MedDRA System 
Organ Class 
MedDRA 
Preferred Term 
Study Day 
Duration of 
AE in Days 
Severity 
SAE? 
Relationship to Study 
Treatment 
(Alternate Etiology) 
Action Taken 
with Study 
Treatment 
Subject 
Discontinued 
Due to AE 
Outcome 
Dose Group: , Subject ID: , AE Number:  
 
 
 
 
 
 
 
 
 
 
 
Comments: 
Dose Group: , Subject ID: , AE Number:  
 
 
 
 
 
 
 
 
 
 
 
Comments: 
 
 


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16.2.8 Individual Laboratory Measurements 
Listing 11: 
16.2.8.1: Clinical Laboratory Results – Chemistry 
[Implementation Note: These listings (for hematology, chemistry, coagulation, and urinalysis) include all laboratory results, scheduled and unscheduled. 
These listings are not color-coded, but the severity should be included in parentheses after the result for abnormal results, e.g., 16.2 (Mild). Results not in 
the reference range, but not graded as Mild, Moderate, or Severe, should have ONR shown as the Severity Grade.  
Sort order: Parameter, Dose Group, Subject ID, and Time Point. Change from Baseline column will be blank for parameters that are not numerical.] 
Dose Group 
Subject ID 
Time Point 
Date of Assessment 
Sex 
Laboratory Parameter (Units) 
Result (Severity Grade) 
Change from Baseline 
Reference Range 
SAD 1 mg 
PHU.00123 
Day 2 
ddMMMyyyy 
Male 
Sodium (mmol/L) 
132 (Mild) 
-7 
135 -145 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Listing 12: 
16.2.8.2: Clinical Laboratory Results – Hematology 
Dose Group 
Subject ID 
Time Point 
Date of Assessment 
Sex 
Laboratory Parameter (Units) 
Result (Severity Grade) 
Change from Baseline 
Reference Range 
 
 
 
ddMMMyyyy 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Listing 13: 
Clinical Laboratory Results – Coagulation 
Dose Group 
Subject ID 
Time Point 
Date of Assessment 
Laboratory Parameter (Units) 
Result (Severity Grade) 
Change from Baseline 
Reference Range 
 
 
 
ddMMMyyyy 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Listing 14: 
16.2.8.3: Clinical Laboratory Results – Urinalysis 
[Implementation Notes: If parameter is determined using multiple methods, present the result from each method as a separate row, with Dipstick results 
preceding Complete UA results.] 
Dose Group 
Subject ID 
Time Point  Date of Assessment 
Sex  
Laboratory Parameter (Units)  
Result (Severity Grade) 
Reference Range 
SAD 1 mg 
PHU.00123 
Day 2 
ddMMMyyyy 
Male 
Total Protein by Dipstick 
Positive (ONR) 
Negative 
SAD 1 mg 
PHU.00123 
Day 2 
 
Male 
RBC Count by Microscopic Evaluation (/HPF) 
5 (Mild) 
<5 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Listing 15: 
Clinical Laboratory Results – Serology 
[Implementation Note: Listing will be sorted by Dose Group, Subject ID, then by Visit (order: Screening, then Unscheduled). If there are results for 
urine toxicology tests on an Unscheduled visit, the Study Day will be included in parentheses for the Visit.] 
Dose Group 
Subject ID 
Visit 
HIV Antibodies 
HCV Antibodies 
HBsAg 
SAD 1 mg 
PHU.00123 
Screening 
Negative 
Negative 
Negative 
SAD 1 mg 
PHU.00123 
Unscheduled 
(Day 4) 
Negative 
Negative 
Negative 
 


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Listing 16: 
Screening Laboratory Results – Urine Toxicology  
[Implementation Note: Listing will be sorted by Dose Group, Subject ID, then by Visit (order: Screening, then Unscheduled). If there are results for 
urine toxicology tests on an Unscheduled visit, the Study Day will be included in parentheses for the Visit.] 
Dose Group 
Subject ID 
Visit 
Cannabinoids Amphetamines Barbiturates 
Cocaine 
Opiates 
Benzodiazepines Phencyclidine 
Alcohol 
Cotinine 
SAD 1 mg 
PHU.00123 
Screening 
Negative 
Negative 
Negative 
Negative 
Negative 
Negative 
Negative 
 
 
SAD 1 mg 
PHU.00123 
Admission 
Negative 
Negative 
Negative 
Negative 
Negative 
Negative 
Negative 
 
 
SAD 1 mg 
PHU.00123 
Unscheduled (Day 4) 
Negative 
Negative 
Negative 
Negative 
Negative 
Negative 
Negative 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Listing 17: 
Laboratory Results – Serum hCG and Pregnancy Tests  
[Implementation Note: Listing will be sorted by Dose Group, Subject ID, then by Visit (order: Screening, then Admission, then Unscheduled). If there 
are results for serum hCG or serum/urine pregnancy tests on an Unscheduled visit, the Study Day will be included in parentheses for the Visit. FSH 
testing results, if obtained, will be shown in this listing.] 
Dose Group 
Subject ID 
Visit 
Serum HCG Result 
FSH Test Result 
SAD 1 mg 
PHU.00123 
Screening 
Negative 
ND 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Note: ND = Test not performed 
 


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16.2.9 Vital Signs and Physical Exam Findings 
Listing 18: 
16.2.9.1: Vital Signs 
[Implementation Note: This listing includes all vital sign assessments, scheduled and unscheduled. All height, weight, and BMI measurements will be 
included in this listing as well. These listings are not color-coded, but the severity should be included in parentheses after the result for abnormal 
assessments, e.g., 100.7 (Mild). Sort order: Dose Group, Subject ID, Parameter, Date of Assessment, and Time of Assessment.] 
Dose Group Subject ID 
Parameter (units) 
Time Point 
Date of Assessment 
Time of Assessment 
Result (Severity Grade) 
Change from Baseline 
Reason for Repeat 
SAD 1 mg 
PHU.00123 
Systolic Blood Pressure 
(mmHg) 
Day 1, 30 minutes 
Post-Dose  
ddMMMyyyy 
hh:mm 
142 (Mild) 
+10 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Listing 19: 
16.2.9.2: Physical Exam Findings 
[Implementation Note: This listing includes all physical exam findings, scheduled and unscheduled. If a subject does not have any findings upon 
examination, they will not be included in this listing. If reported as an AE, display “Yes” with the AE Number in parentheses, e.g., “Yes (RASH, 007)”. 
In the CSR, Subject ID should be USUBJID (not PATID) for purposes of de-identification. Sort order: Dose Group, Subject ID, Date of Assessment, 
Time of Assessment, Body System, and Finding.] 
Dose Group Subject ID 
Time Point 
Date of Assessment 
Time of Assessment 
Body System 
Abnormal Findings 
Reported as an AE? 
(AE Description; Number) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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16.2.10 
ECG Results and Findings 
Listing 20: 
Listing of ECG Interval Measurements 
[Implementation Note: This listing includes all ECG assessments, scheduled and unscheduled. These listings are not color-coded, but the severity should 
be included in parentheses after the result for abnormal assessments, e.g., 100.7 (Mild). For all change from baseline, show “+” or “-” next to the change 
from baseline results if an increase or decrease. 
Sort order: Dose Group, Subject ID, Parameter, Date of Assessment, and Time of Assessment.] 
Dose Group 
Subject ID 
Sex 
Parameter 
(units) 
Time Point 
Date of 
Assessment 
Time of 
Assessment 
Result (Severity 
Grade) 
Change from 
Baseline 
Replicate 
Number 
Reason for 
Repeat 
 
 
 
 
Pre-Dose 
ddMMMyyyy 
 
 
 
1 
 
 
 
 
 
Pre-Dose 
 
 
 
 
2 
 
 
 
 
 
Pre-Dose 
 
 
 
 
3 
 
SAD 1 mg 
PHU.00123 
Male 
QTcF (msec) 
Pre-Dose 
(Baseline) 
 
MEDIAN 
147 
 
 
 
SAD 1 mg 
PHU.00123 
Male 
QTcF (msec) 
Day 1, 2 h 
Post-Dose 
ddMMMyyyy 
hh:mm 
450 (Mild) 
+25 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Listing 21: 
Listing of ECG Overall Interpretation and Comments 
[Implementation Note: This listing includes all ECG assessments, scheduled and unscheduled.  
Sort order: Dose Group, Subject ID, Date of Assessment, and Time of Assessment.] 
Dose Group 
Subject ID 
Time Point 
Date of Assessment 
Time of Assessment 
Interpretation 
Comments 
SAD 1 mg 
PHU.00123 
Day 1, 2 h Post-Dose 
ddMMMyyyy 
hh:mm 
Abnormal, NCS  
Sinus Bradycardia 
 
 
 
 
 
Abnormal, CS 
 
 
 
 
 
 
 
 
 


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Listing 22: 
Listing of ECG Findings 
[Implementation Note: Sort order: Dose Group, Subject ID, Date of Assessment, Time of Assessment, Category, and Finding.] 
Dose Group 
Subject ID 
Time Point 
Date of Assessment 
Time of Assessment 
Category 
Finding 
SAD 1 mg 
PHU.00123 
Day 1, 2 h Post-Dose 
ddMMMyyyy 
hh:mm 
Arrhythmia 
Sinus arrhythmia 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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16.2.10 Concomitant Medications 
Listing 23: 
Prior Medications 
[Implementation Note: Include prior medications (medications with an end date prior to dosing) only. If start date is more than 30 days before enrollment 
then categorize as: 1-12 months prior to enrollment, 1-5 years prior to enrollment, or 5 years prior to enrollment.  
Sort order: Dose Group, Subject ID, and CM Number.] 
Dose Group 
Subject ID 
CM Number 
Medication 
Medication Start 
Day 
Medication End 
Day 
Indication 
Taken for a condition on Medical History? 
(MH Description; Number) 
ATC Level 1 
(ATC Level 2) 
SAD 1 mg 
PHU.00123 
001 
BENADRYL 
1-12 months prior 
to enrollment 
1-12 months prior 
to enrollment 
ITCHING 
No 
DERMATOLOGICALS 
(ANTIPRURITICS, INCL. 
ANTIHISTAMINES, 
ANESTHETICS, ETC.) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Listing 24: 
16.2.10: Concomitant Medications 
[Implementation Note: “Medication Start Day” and “Medication End Day” are relative to enrollment (which is Day 1, day before enrollment is Day -1). 
For medication start dates that are > 30 days prior to enrollment, rather than use exact study days, categorize as follows: 
• 5 years prior to enrollment 
• 1-5 years prior to enrollment 
• 1-12 months prior to enrollment 
If ongoing, display “Ongoing” in the “Medication End Day” column. If taken for an AE or MH, display “Yes” with the AE or MH Number in 
parentheses, e.g., “Yes (RASH, 007)”. In the CSR, Subject ID should be USUBJID (not PATID) for purposes of de-identification.  
Sort order: Dose Group, Subject ID, and CM Number.] 
Dose 
Group 
Subject ID 
CM 
Number 
Medication 
Medication 
Start Day 
Medication 
End Day 
Indication 
Taken for an AE? 
(AE Description; Number) 
Taken for a condition on 
Medical History? 
(MH Description; Number) 
ATC Level 1 
(ATC Level 2) 
SAD 1 mg PHU.00123 
001 
BENADRYL 
2 
2 
ITCHING 
Yes (MACULAR RASH; 
001) 
No 
DERMATOLOGICALS 
(ANTIPRURITICS, INCL. 
ANTIHISTAMINES, 
ANESTHETICS, ETC.) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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16.2.11 Pregnancy Reports 
Listing 25: 
16.2.11.1: Pregnancy Reports – Maternal Information 
Treatment 
Group  
Subject 
ID  
Pregnancy 
Number 
Study Day 
Corresponding 
to Estimated 
Date of 
Conception 
Source of 
Maternal 
Information 
Pregnancy 
Status 
Mother’s 
Pre-
Pregnancy 
BMI 
Mother’s 
Weight 
Gain 
During 
Pregnancy 
Tobacco, 
Alcohol, or 
Drug Use 
During 
Pregnancy? 
Medications 
During 
Pregnancy? 
Maternal 
Complications 
During 
Pregnancy? 
Maternal 
Complications 
During Labor, 
Delivery, or 
Post-Partum? 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Note: Maternal Complications are included in the Adverse Event listing. Medications taken during pregnancy are included in the Concomitant Medications Listing. 
 
Listing 26: 
16.2.11.2: Pregnancy Reports – Gravida and Para 
 
 
 
Live Births 
 
 
 
 
 
Subject 
ID 
Pregnancy 
Number 
Gravida 
Extremely 
PBa 
Very 
Early 
PBa 
Early 
PBa 
Late 
PBa 
Early 
TBb 
Full 
TBb 
Late 
TBb 
Post 
TBb 
Still 
Births 
Spontaneous 
Abortion/ 
Miscarriage 
Elective 
Abortions 
Therapeutic 
Abortions 
Major 
Congenital 
Anomaly 
with 
Previous 
Pregnancy? 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Note: Gravida includes the current pregnancy, para events do not. 
a Preterm Birth 
b Preterm Birth 


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Listing 27: 
16.2.11.3: Pregnancy Reports – Live Birth Outcomes 
Subject 
ID 
Pregnancy 
Number 
Fetus 
Number 
Pregnancy 
Outcome (for 
this Fetus) 
Fetal Distress 
During Labor 
and Delivery? 
Delivery 
Method 
Gestational 
Age at Live 
Birth  
Size for 
Gestational 
Age 
Apgar 
Score, 1 
minute 
Apgar 
Score, 5 
minutes 
Cord pH 
Congenital 
Anomalies? 
Illnesses/ 
Hospitalizations 
within 1 Month of 
Birth? 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Note: Congenital Anomalies are included in the Adverse Event listing. 
 
Listing 28: 
16.2.11.4: Pregnancy Reports – Still Birth Outcomes 
Subject 
ID 
Date of 
Initial 
Report 
Fetus 
Number 
Pregnancy 
Outcome 
(for this 
Fetus) 
Fetal Distress 
During 
Labor and 
Delivery? 
Delivery 
Method 
Gestational 
Age at Still 
Birth 
Size for 
Gestational 
Age 
Cord pH 
Congenital 
Anomalies? 
Autopsy 
Performed? 
If Autopsy, Etiology 
for Still Birth 
Identified? 
 
 
 
 
 
 
 
 
 
 
 
 
 
Listing 29: 
16.2.11.5: Pregnancy Reports – Spontaneous, Elective, or Therapeutic Abortion Outcomes 
Subject 
ID 
Date of Initial 
Report 
Fetus Number 
Pregnancy Outcome 
(for this Fetus) 
Gestational Age at 
Termination 
Abnormality in Product of Conception? 
Reason for Therapeutic 
Abortion 
 
 
 
 
 
 
 
 


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Listing 30: 
Birth Control Listing 
[Implementation Note: If subject not of child bearing potential, indicate reason subject is not of child bearing 
potential in parentheses in the column Child Bearing Potential. If start date is more than 30 days before 
enrollment then categorize, rather than use exact study days, categorize as follows: 1-12 months prior to 
enrollment, 1-5 years prior to enrollment, or 5 years prior to enrollment. 
Sort Order: Dose Group, Subject ID, and then by Start Day.] 
Dose Group 
Subject ID 
Sex 
Child Bearing 
Potential 
Birth Control 
Method 
Birth Control 
Start Day 
Birth Control 
End Day 
SAD 1 mg 
PHU.00123 
Female 
Yes  
Hormonal Injections 
-2 
Ongoing 
 
 
 
 
 
 
 
 
 
 
 
 


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Listing 31: 
Subject Level Drug Concentrations  
[Implementation Note: Units of nominal time and actual time vary by time point and will be provided for each 
time rather than in the column heading. Laboratory Reported Drug Concentration will give verbatim value 
reported by lab (with minimal formatting, as needed) and will use a character variable such as PC.PCORRES. 
Analysis Drug Concentration will report the value actually used for analysis and will use a numeric variable 
such as ADPC.AVAL. If one or more samples are excluded from NCA, two additional columns will be 
provided in the PK report listing: Excluded from NCA (Yes/No) and Reason for Exclusion from NCA.  
Sort order: Dose Group, Subject ID, and Actual Time.] 
Dose Group 
Subject ID 
Nominal Timea 
Actual Timea 
Laboratory Reported 
Drug Concentration 
(ng/mL) 
Analysis Drug 
Concentration 
(ng/mL) 
Used in λz 
Calculations 
SAD 1 mg 
PHU.00123 
0 
0 
0 
0 
No 
 
 
 
 
 
 
 
aTimes are relative to time of previous dose.  
Note: Actual Times that were outside of protocol-defined time windows are indicated by an asterisk (*). Samples that were collected 
substantially outside of the protocol-defined window are excluded from summary statistics (but not from NCA) and are indicated by two 
asterisks (**). 


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Listing 32: 
Subject-Specific PK Parameters 
[Implementation Note: Sort order: Dose Group and Subject ID.] 
Dose 
Group 
Subject ID 
Cmax 
(ng/mL) 
Tmax 
(h) 
AUC0-last  
(h*ng/mL) 
AUC0-inf 
(h*ng/mL) 
λz 
(1/h) 
t1/2 
(h) 
CL/F 
(L/h) 
Vz/F 
(L) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

Prot_001.pdf: 
DMID Protocol 17-0088 
Version 6.0 
Safety and Pharmacokinetics of Rezafungin 
31 MAR 2020 
 ______________________________________________________________________________________________________  
 
DMID/NIAID/NIH 
 
 
 
 
 
 
 
 
 
1 
CONFIDENTIAL 
DMID eCTD Compliant Interventional Protocol Template and Instructions, Version 4.0, Dated May 18, 2018 
 
 
A Phase 1, Three-Part, Randomized, Double-Blind, Single and 
Multiple Subcutaneous Dose Escalation Study to Determine the 
Safety, Tolerability, and Pharmacokinetics of Rezafungin in Healthy 
Adult Subjects 
DMID Protocol Number: 17-0088 
DMID Funding Mechanism: HHSN272201500007I 
Pharmaceutical Support: Cidara Therapeutics, Inc. 
IND Sponsor: DMID 
Lead Principal Investigator: Dennis Ruff, MD 
DMID Clinical Project Manager: Maureen Mehigan, RN 
Version Number: 6.0 
 
31 MAR 2020 
 
 
 


DMID Protocol 17-0088 
Version 6.0 
Safety and Pharmacokinetics of Rezafungin 
31 MAR 2020 
 ______________________________________________________________________________________________________  
 
DMID/NIAID/NIH 
 
 
 
 
 
 
 
 
 
2 
CONFIDENTIAL 
DMID eCTD Compliant Interventional Protocol Template and Instructions, Version 4.0, Dated May 18, 2018 
 
STATEMENT OF ASSURANCE 
Each Institution will hold a current Federal Wide Assurance (FWA) issued by the Office for 
Human Research Protections (OHRP) for federally-funded human subjects research. Each FWA 
will designate at least one Institutional Review Board (IRB)/Independent Ethics Committee 
(IEC) registered with OHRP, for which the research will be reviewed and approved by the 
IRB/IEC and will be subject to continuing review [45 Code of Federal Regulations (CFR) 
46.103(b)]. The IRB/IEC designated under an FWA may include an institution’s IRB/IEC, an 
independent IRB/IEC, or an IRB/IEC of another institution after establishing a written agreement 
with that other institution. 


DMID Protocol 17-0088 
Version 6.0 
Safety and Pharmacokinetics of Rezafungin 
31 MAR 2020 
 ______________________________________________________________________________________________________  
 
DMID/NIAID/NIH 
 
 
 
 
 
 
 
 
 
3 
CONFIDENTIAL 
DMID eCTD Compliant Interventional Protocol Template and Instructions, Version 4.0, Dated May 18, 2018 
 
STATEMENT OF COMPLIANCE 
This trial will be carried out in accordance with Good Clinical Practice (GCP) and as required by 
the following: 
United States (US) CFR 45 CFR Part 46: Protection of Human Subjects 
Food and Drug Administration (FDA) Regulations, as applicable: 21 CFR Part 50 (Protection of 
Human Subjects), 21 CFR Part 54 (Financial Disclosure by Clinical Investigators), 21 CFR Part 
56 (IRBs), 21 CFR Part 11(Electronic Records and Electronic Signatures), and 21 CFR Part 312 
(Investigational New Drug Application) 
International Conference on Harmonization: GCP (ICH E6); 62 Federal Register 25691 (1997); 
and revisions 
Belmont Report: Ethical Principles and Guidelines for the Protection of Human Subjects of 
Research, Report of the National Commission for the Protection of Human Subjects of 
Biomedical and Behavioral Research 
National Institutes of Health (NIH) Office of Extramural Research, Research Involving Human 
Subjects, as applicable 
National Institute of Allergy and Infectious Diseases (NIAID) Clinical Terms of Award, as 
applicable 
Applicable Federal, State, and Local Regulations and Guidance 




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Safety and Pharmacokinetics of Rezafungin 
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TABLE OF CONTENTS 
STATEMENT OF ASSURANCE ...................................................................................................2 
STATEMENT OF COMPLIANCE .................................................................................................3 
SIGNATURE PAGE .......................................................................................................................4 
TABLE OF CONTENTS .................................................................................................................5 
LIST OF TABLES .........................................................................................................................12 
LIST OF FIGURES .......................................................................................................................13 
LIST OF ABBREVIATIONS ........................................................................................................14 
PROTOCOL SUMMARY .............................................................................................................18 
 
KEY ROLES.........................................................................................................................26 
 
BACKGROUND AND SCIENTIFIC RATIONALE ..........................................................27 
 
Background .................................................................................................................27 
 
Scientific Rationale .....................................................................................................29 
2.2.1 Purpose of Study ............................................................................................29 
2.2.2 Study Population ............................................................................................30 
 
Potential Risks and Benefits .......................................................................................30 
2.3.1 Potential Risks ...............................................................................................30 
2.3.2 Potential Benefits ...........................................................................................33 
 
STUDY DESIGN, OBJECTIVES AND ENDPOINTS OR OUTCOME MEASURES .....34 
 
Study Design Description ...........................................................................................34 
3.1.1 Dosing Scheme and Duration of Study ..........................................................34 
3.1.1.1 
Part 1 (SAD) .....................................................................................34 
3.1.1.2 
Part 2 (MAD) ....................................................................................35 
3.1.1.3 
Part 3 (BA) ........................................................................................36 
3.1.2 Rationale for Starting Dose ............................................................................37 
3.1.3 Dose Escalations ............................................................................................38 


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Study Objectives .........................................................................................................39 
3.2.1 Primary ...........................................................................................................39 
3.2.2 Secondary .......................................................................................................40 
 
Study Endpoints or Outcome Measures .....................................................................40 
3.3.1 Primary ...........................................................................................................40 
3.3.2 Secondary .......................................................................................................40 
 
STUDY INTERVENTION/INVESTIGATIONAL PRODUCT .........................................41 
 
Study Product Description ..........................................................................................41 
4.1.1 Formulation, Packaging, and Labeling ..........................................................41 
4.1.2 Product Storage and Stability .........................................................................43 
 
Acquisition/Distribution .............................................................................................43 
 
Dosage/Regimen, Preparation, Dispensing and Administration of Study 
Intervention/Investigational Product.........................................................................44 
 
Accountability Procedures for the Study Intervention/Investigational Product(s) .....45 
 
SELECTION OF SUBJECTS AND STUDY ENROLLMENT AND WITHDRAWAL ....46 
 
Eligibility Criteria .......................................................................................................46 
5.1.1 Subject Inclusion Criteria...............................................................................46 
5.1.2 Subject Exclusion Criteria .............................................................................48 
 
Withdrawal from the Study, Discontinuation of Study Product, or Study Termination
 ..................................................................................................................................50 
5.2.1 Withdrawal from the Study or Discontinuation of the Study Product ...........50 
5.2.2 Handling of Withdrawals and Discontinuation of Administration ................51 
5.2.3 Lost to Follow-Up ..........................................................................................51 
5.2.4 Subject Replacement ......................................................................................51 
5.2.5 Study Termination .........................................................................................52 
 
STUDY PROCEDURES ......................................................................................................53 
 
Recruitment .................................................................................................................53 


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Screening (Day -28 to Day -2) Parts 1-3 (All Cohorts) ..............................................53 
 
Admission to the CRU (Day -1) Parts 1 and 2 (All Cohorts) and Part 3 (Cohort 11) 
Days -1 and 21 ..........................................................................................................55 
 
Part 1 (Cohorts 1 through 6) .......................................................................................56 
6.4.1 Day 1 – Inpatient CRU ..................................................................................56 
6.4.2 Day 2 – Inpatient CRU ..................................................................................57 
6.4.3 Day 3 – Inpatient CRU ..................................................................................58 
6.4.4 Day 4 – Inpatient CRU ..................................................................................58 
6.4.5 Day 5 – Inpatient CRU ..................................................................................58 
6.4.6 Day 6 – Inpatient CRU ..................................................................................59 
6.4.7 Day 7 – Inpatient CRU ..................................................................................59 
6.4.8 Day 14 (±1 Day) – Follow-Up - Outpatient ...................................................60 
6.4.9 Day 21 (±1 Day) – Telephone Follow-Up .....................................................60 
6.4.10 Day 30 (±1 Day) – Follow-Up – Final Study Visit........................................61 
 
Part 2 (Cohorts 7 through 10) .....................................................................................61 
6.5.1 Days 1, 8, and 15 – Inpatient CRU ................................................................61 
6.5.2 Days 2, 9, and 16 – Inpatient CRU ................................................................63 
6.5.3 Days 3, 10, and 17 – Inpatient CRU ..............................................................63 
6.5.4 Days 4, 11, and 18 – Inpatient CRU ..............................................................63 
6.5.5 Days 5, 12, and 19 – Inpatient CRU ..............................................................64 
6.5.6 Days 6, 13, and 20 – Inpatient CRU ..............................................................64 
6.5.7 Days 7, 14, and 21 – Inpatient CRU ..............................................................64 
6.5.8 Day 30 (±1 Day) – Follow-Up - Outpatient ...................................................65 
6.5.9 Day 45 (±1 Day) – Follow-Up – Final Study Visit........................................66 
 
Part 3 (Cohort 11) .......................................................................................................66 
6.6.1 Days 1 and 22 – Inpatient CRU .....................................................................66 
6.6.2 Days 2 and 23 – Inpatient CRU .....................................................................68 


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6.6.3 Days 3 and 24 – Inpatient CRU .....................................................................68 
6.6.4 Days 4 and 25 – Inpatient CRU .....................................................................69 
6.6.5 Days 5 and 26 – Inpatient CRU .....................................................................69 
6.6.6 Days 6 and 27 – Inpatient CRU .....................................................................69 
6.6.7 Days 7 and 28 – Inpatient CRU .....................................................................69 
6.6.8 Days 14 (±1 Day) and 35 (±1 Day) – Follow-Up - Outpatient ......................70 
6.6.9 Day 52 (±1 Day) – Follow-Up – Final Study Visit........................................71 
6.6.10 Early Termination (ET) Visit (if needed) ......................................................71 
 
Unscheduled Study Visits ...........................................................................................72 
 
Protocol Deviations ....................................................................................................73 
 
DESCRIPTION OF CLINICAL AND LABORATORY EVALUATIONS .......................74 
 
Clinical Evaluations ....................................................................................................74 
7.1.1 Medical History .............................................................................................74 
7.1.2 Height, Weight, Body Mass Index (BMI)......................................................74 
7.1.3 Physical Examinations ...................................................................................74 
7.1.4 Local Reactogenicity Symptoms ...................................................................74 
7.1.5 Vital Signs ......................................................................................................76 
7.1.6 Electrocardiograms ........................................................................................76 
7.1.7 Assessment of Concomitant Medications/Treatments Other than Study 
Product ...........................................................................................................77 
 
Laboratory Evaluations ...............................................................................................78 
7.2.1 Clinical Laboratory Evaluations ....................................................................78 
7.2.2 Research Assays .............................................................................................80 
 
ASSESSMENT OF SAFETY ...............................................................................................86 
 
Assessing and Recording Safety Parameters ..............................................................86 
8.1.1 Adverse Events ..............................................................................................86 
8.1.2 Serious Adverse Events .................................................................................89 


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8.1.3 Adverse Events of Special Interest ................................................................90 
 
Specification of Safety Parameters .............................................................................91 
8.2.1 Injection Site Reactogenicity .........................................................................91 
8.2.2 New-Onset Chronic Medical Conditions .......................................................91 
8.2.3 Dose Escalation Criteria ................................................................................91 
 
Reporting Procedures ..................................................................................................92 
8.3.1 Reporting Serious Adverse Events ................................................................92 
 
Type and Duration of Follow-Up of Subjects after Adverts Events ..........................92 
8.4.1 Regulatory Reporting for Studies Conducted Under DMID-Sponsored IND
 ........................................................................................................................93 
8.4.2 Reporting of Pregnancy .................................................................................93 
 
Type and Duration of Follow-Up of Subjects after Adverse Events ..........................94 
 
Procedures to be Followed in the Event of Abnormal Laboratory Test Values or 
Abnormal Clinical Findings......................................................................................94 
 
Halting Rules ..............................................................................................................95 
8.7.1 Study Halting Rules .......................................................................................95 
8.7.2 Dose Escalation Halting Rules .......................................................................95 
8.7.3 Individual Halting Rules ................................................................................96 
 
Safety Oversight (ISM and SMC) ..............................................................................97 
8.8.1 Independent Safety Monitor...........................................................................97 
8.8.2 Safety Monitoring Committee .......................................................................98 
 
HUMAN SUBJECTS PROTECTION .................................................................................99 
 
Institutional Review Board/Independent Ethics Committee ......................................99 
 
Informed Consent Process ..........................................................................................99 
 
Consent for Future Use of Stored Specimens and Data ...........................................101 
 
Exclusion of Women, Minorities, and Children (Special Populations) ....................102 
 
Subject Confidentiality .............................................................................................102 


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Safety and Pharmacokinetics of Rezafungin 
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Certificate of Confidentiality ....................................................................................103 
 
Costs, Subject Compensation, and Research Related Injuries .................................104 
 
STATISTICAL CONSIDERATIONS ...............................................................................105 
 Study Hypotheses .....................................................................................................105 
 Sample Size Considerations .....................................................................................105 
 Treatment Assignment Procedures ...........................................................................105 
10.3.1 Randomization Procedures ..........................................................................105 
10.3.2 Masking Procedures .....................................................................................106 
10.3.2.1 Blinding ..........................................................................................106 
10.3.3 Emergency Unblinding ................................................................................107 
 Planned Interim Analyses .........................................................................................107 
10.4.1 Interim Safety Review .................................................................................107 
10.4.2 Interim Immunogenicity or Efficacy Review ..............................................108 
 Final Analysis Plan ...................................................................................................108 
10.5.1 Adverse and Serious Adverse Events ..........................................................108 
10.5.2 Clinical Safety Labs, Vital Signs, and Electrocardiograms .........................109 
10.5.3 Additional Safety Analyses ..........................................................................110 
10.5.4 PK Analysis Plan .........................................................................................110 
 
SOURCE DOCUMENTS AND ACCESS TO SOURCE DATA/DOCUMENTS ............112 
 Compliance with Standards of Medical Research/Deviations ..................................112 
 
QUALITY CONTROL AND QUALITY ASSURANCE .................................................113 
 
DATA HANDLING AND RECORD KEEPING ..............................................................114 
 Data Management Responsibilities ..........................................................................114 
 Data Management Responsibilities ..........................................................................115 
 Data Capture Methods ..............................................................................................115 
 Types of Data ............................................................................................................116 
 Study Records Retention ..........................................................................................116 


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CLINICAL MONITORING ...............................................................................................117 
 Site Monitoring Plan .................................................................................................117 
 
PUBLICATION POLICY ..................................................................................................118 
 
LITERATURE REFERENCES ..........................................................................................119 
 
APPENDICES ....................................................................................................................121 
 
Schedules of Events ........................................................................122 
 
TOXICITY TABLE ........................................................................129 


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LIST OF TABLES 
Table 1: Design for SC Dosing in SAD (Study Part 1) .................................................................35 
Table 2: Design for SC Dosing in MAD (Study Part 2) ................................................................36 
Table 3: Design for SC Dosing in Absolute BA Cohort (Study Part 3) ........................................37 
Table 4: Proposed Starting Dose Level in the Clinic .....................................................................38 
Table 5: Blood Sampling Timepoints for Rezafungin Pharmacokinetic Analysis Cohorts 
2, 3, 4, 5 and 6 SAD (Part 1) ...........................................................................................81 
Table 6: Blood Sampling Timepoints for Rezafungin Pharmacokinetic Analysis Cohorts 
7, 8, 9, and 10 MAD (Part 2) ..........................................................................................81 
Table 7: Blood Sampling Timepoints for Rezafungin Pharmacokinetic Analysis Cohort 
11 BA (Part 3) .................................................................................................................82 
Table 8: Total Volume of Blood Drawn From Each Subject - Part 1 (SAD) Cohorts 1-6 ............83 
Table 9: Total Volume of Blood Drawn From Each Subject - Part 2 (MAD) Cohorts 7-
10.....................................................................................................................................84 
Table 10: Total Volume of Blood Drawn From Each Subject - Part 3 (BA) Cohort 11 ...............85 
Table 11: Schedule of Study Procedures and Evaluations for Cohorts 1-6 in SAD (Part 
1) ...................................................................................................................................122 
Table 12: Schedule of Study Procedures and Evaluations for Cohorts 7-10 in MAD (Part 
2) ...................................................................................................................................124 
Table 13: Schedule of Study Procedures and Evaluations for Cohort 11 in BA (Part 3) ............126 
 
 


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Safety and Pharmacokinetics of Rezafungin 
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DMID eCTD Compliant Interventional Protocol Template and Instructions, Version 4.0, Dated May 18, 2018 
 
LIST OF FIGURES 
Figure 1: Study Schematic – SAD Study (Part 1) Cohorts 1, 2, 3, 4, 5, and 6 ..............................23 
Figure 2: Study Schematic – MAD Study (Part 2) Cohorts 7, 8, 9, and 10 ...................................24 
Figure 3: Study Schematic – Absolute BA Cross-over (Part 3) Cohort 11 ...................................25 
 
 
 


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LIST OF ABBREVIATIONS 
λz 
Apparent first-order terminal elimination rate constant 
AE 
Adverse Event/Adverse Experience 
AESI 
Adverse Event of Special Interest 
ALT 
Alanine aminotransferase 
AmB 
Amphotericin B 
AR 
Accumulation ratio 
AST 
Aspartate aminotransferase 
AUC 
Area under the plasma concentration versus time curve 
AUCinf 
Area under the plasma concentration versus time curve from time 0 
to infinite time 
AUClast 
Area under the plasma concentration versus time curve from time 0 
to the time of the last quantifiable concentration 
AV 
Atrioventricular block 
BA 
Bioavailability 
BMI 
Body Mass Index 
bpm 
Beats per minute 
BUN 
Blood Urea Nitrogen 
CFR 
Code of Federal Regulations 
CK 
Creatine Kinase 
CL 
Total clearance 
CL/F 
Apparent clearance 
Cmax 
Maximum measured plasma concentration 


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CMS 
Clinical Materials Services 
CROMS 
Clinical Research Operations and Management Support 
CRU 
Clinical Research Unit 
DCF 
Data Collection Form(s) 
DMID 
Division of Microbiology and Infectious Diseases 
ECG 
Electrocardiogram 
eCRF 
Electronic Case Report Form 
EDC 
Electronic Data Capture 
FDA 
Food and Drug Administration 
FEV 
Forced expiratory volume 
FU 
Follow-Up 
FWA 
Federal Wide Assurance 
GCP 
Good Clinical Practice 
HIV 
Human Immunodeficiency Virus 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonization 
IEC 
Independent Ethics Committee 
IFIs 
Invasive Fungal Infections 
IND 
Investigational New Drug Application 
INR 
International Normalized Ratio 
IP 
Investigational Product 
IRB 
Institutional Review Board 
ISM 
Independent Safety Monitor 


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IV 
Intravenous 
LC-MS/MS 
Liquid Chromatography-Mass Spectrometry/Mass Spectrometry 
MAD 
Multiple Ascending Dose 
MedDRA 
Medical Dictionary for Regulatory Activities 
MOP 
Manual of Procedures 
MTD 
Maximum tolerated dose 
N 
Number (typically refers to subjects) 
NIAID 
National Institute of Allergy and Infectious Diseases 
NIH 
National Institutes of Health 
OHRP 
Office for Human Research Protections 
PCP 
Pneumocystis pneumonia 
PE 
Physical Examination 
PI 
Principal Investigator 
PK 
Pharmacokinetics 
PR (interval) 
Interval measured from the beginning of the P wave to the 
beginning of the QRS complex in the heart’s electrical cycle as 
measured by electrocardiogram 
PT 
Prothrombin Time 
PTT 
Partial Thromboplastin Time 
QA 
Quality Assurance 
QC 
Quality Control 
QRS (interval) 
The interval between the Q wave and the S wave in the heart’s 
electrical cycle as measured by electrocardiogram; principal 
deflection in the electrocardiogram 


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QT (interval) 
A measure of the time between the start of the Q wave and the end 
of the T wave in the heart’s electrical cycle as measured by 
electrocardiogram 
QTc (interval) 
A measure of time between the start of the Q wave and the end of 
the T wave in the heart’s electrical cycle measured by 
electrocardiogram corrected for heart rate 
QTcB 
QT interval corrected for heart rate using Bazett’s formula 
SAD 
Single Ascending Dose 
SAE 
Serious Adverse Event/Serious Adverse Experience 
SAP 
Statistical Analysis Plan 
SC 
Subcutaneous 
SDCC 
Statistical and Data Coordinating Center 
SMC 
Safety Monitoring Committee 
SOC 
System Organ Classes 
SOP 
Standard Operating Procedure 
t1/2 
Terminal phase half-life 
Tmax 
Time to reach maximum measured plasma concentration 
TMP/SMX 
Trimethoprim/Sulfamethoxazole 
US 
United States 
USP 
United States Pharmacopeia 
VCT 
Verified Clinical Trials 
Vss or Vz/F 
Volume of distribution (adjusted for bioavailability) 
WBC 
White Blood Cell 
 


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PROTOCOL SUMMARY 
 
Title: 
A Phase 1, Three-Part, Randomized, Double-Blind, Single and 
Multiple Subcutaneous Dose Escalation Study to Determine the 
Safety, Tolerability, and Pharmacokinetics of Rezafungin in 
Healthy Adult Subjects 
Design of the Study: 
 
This is a Phase 1, double-blind, placebo-controlled trial in 
three parts. A single ascending dose (SAD) study in six cohorts 
receiving a single subcutaneous (SC) dose of 1, 10, 30, 60, 100, 
or 200 mg of rezafungin; a multiple ascending dose (MAD) 
study in four cohorts receiving 30 mg x 3 doses, 60 x 3 doses, 
100 mg x 3 doses, or 200 mg x 3 doses of rezafungin SC with 
dosing frequency of once every 7 days; and a two-period cross-
over bioavailability (BA) study receiving 100 mg of rezafungin. 
The two-period cross-over BA study will be assessed unblinded 
in two sequences (10 subjects, 100 mg or maximum tolerated 
dose (MTD) of rezafungin in Part 1); 5 subjects will receive an 
SC injection of rezafungin in Period 1 followed by an 
intravenous (IV) infusion of rezafungin in Period 2, and 
5 subjects will receive an IV infusion of rezafungin in Period 1 
followed by an SC injection of rezafungin in Period 2. Each 
SAD (except cohort 1) and MAD cohort will contain 8 subjects 
(6 subjects will receive a SC injection of rezafungin, and 2 
subjects will receive placebo). Each SAD (except cohort 1) and 
MAD cohort will be conducted with sentinel dosing. SAD cohort 
1 will be comprised of 4 subjects (3:1 rezafungin to placebo) 
with no sentinel dosing.  Parts 2 and 3 of the study will only be 
conducted after FDA review for safety data and PK data from all 
subjects participating in Part 1; Part 3 may be run in parallel with 
the first cohort (Cohort 7) of Part 2.  


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Study Phase: 
1 
Study Population: 
Approximately 86 healthy male and female subjects, aged 18-45 
years (inclusive) 
Number of Sites: 
1 
Description of Study 
Product or Intervention: 
Subcutaneous formulation: Rezafungin for Injection, 
Subcutaneous Use, 100 mg/mL, is a sterile liquid product 
supplied in single-dose vials containing 1.0 mL of extractable 
volume. The active pharmaceutical ingredient is rezafungin 
acetate, a water-soluble amorphous acetate salt. The inactive 
ingredient is mannitol.  
Intravenous (IV) formulation: Rezafungin for Injection, 
200 mg/vial, is a sterile product supplied as a white to pale 
yellow lyophilized powder in single-dose glass vials for 
reconstitution with Sterile Water for Injection, United States 
Pharmacopeia (USP). The reconstituted product is diluted in 
sterile, 0.9% Sodium Chloride Injection, USP for IV infusion. 
The active pharmaceutical ingredient is rezafungin acetate, a 
water-soluble amorphous acetate salt. The inactive ingredients 
include excipients of mannitol, polysorbate 80, and histidine. 
Placebo is 5% Dextrose Injection, USP, a sterile, nonpyrogenic 
solution of dextrose in water for injection. The solution has the 
osmolarity of 252 mOsmol/L, which is slightly hypotonic. 
For 1 mg subcutaneous doses, the Subcutaneous formulation will 
be diluted 1:10 in 5% Dextrose Injection, USP prior to 
administration. The diluent solution, 5% Dextrose Injection, USP 
is a sterile and nonpyrogenic parenteral solution. 
Reconstitution solution is Sterile Water for Injection, WFI, USP, 
which is a clear, colorless solution. 


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Study Objectives: 
 
Primary: 
• 
To determine the safety and tolerability of single-ascending 
SC doses (SAD) of rezafungin. 
• 
To determine the safety and tolerability of 
multiple-ascending SC doses (MAD) of rezafungin. 
• 
To determine the pharmacokinetic (PK) profile in plasma of 
rezafungin in healthy adult subjects; 
Secondary: 
To evaluate the bioavailability (BA) of rezafungin when 
administered by SC injection relative to IV infusion in 
healthy adult subjects. 


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Outcome Measures 
Primary: 
SAD 
Safety will be assessed by adverse events and serious adverse 
events (SAEs) from start of dosing to Day 30, clinical laboratory 
tests at baseline and from Day 2 to Day 30, ECGs at Screening 
and post-dose on Days 1, 7, and 30, physical exams at baseline 
and post-dose on Day 1 to Day 30, vital signs at baseline and 
from Day 1 to Day 30, and injection site evaluation from dosing 
to Day 30.  
Tolerability will be assessed by occurrence of solicited local 
reactogenicity (injection site evaluation) from dosing to Day 30. 
MAD 
Safety will be evaluated for multiple-ascending SC doses (MAD) 
of rezafungin. Safety will be assessed by adverse events and 
SAEs from start of dosing to Day 45, clinical laboratory tests at 
baseline and from Day 2 to Day 45, ECGs at Screening and post-
dose on Days 1, 8, 15, 21, 30, and 45, physical exams at baseline 
to Day 45, and vital signs at baseline to Day 45.  
Tolerability will be assessed by occurrence of solicited local 
reactogenicity (injection site evaluation) from first dose to 
Day 45.   
PK 
Pharmacokinetic (PK) profiles of rezafungin will be assessed by 
measurement of drug levels in plasma after SC administration in 
each cohort. Plasma for PK analysis will be collected at planned 
timepoints up to Day 30 in the SAD cohorts, and Day 45 in the 


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MAD cohorts. PK parameters will be estimated from the 
rezafungin plasma concentration-time data. 
 
Secondary: 
The BA of rezafungin when administered by SC injection 
relative to IV infusion will be assessed by measurement of drug 
levels in plasma after administration by SC injection or by IV 
infusion in each cross over period. Plasma samples will be 
collected at planned timepoints up to Day 52 for Part 3/BA The 
absolute BA will be calculated as the ratio of AUC for the SC 
injection and AUC for the IV infusion of administration. 
 
Duration of Individual 
Subject Participation: 
 
Part 1 SAD: Individual subjects will participate for 
approximately 58 days, including up to 28 days for screening 
and 30 days for dosing and follow-up (FU). 
Part 2 MAD: Individual subjects will participate for 
approximately 73 days, including up to 28 days for screening 
and 45 days for dosing and FU. 
Part 3 BA: Individual subjects will participate for approximately 
80 days, including up to 28 days for screening and 52 days for 
dosing and FU. 
Estimated Time to Last 
Subject/Last Study Day: 
Approximately 30 months 
 
 


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Figure 1 
 
Day 1
Vital signs (Vitals), Concomitant medications (Conmeds), Randomization,Physical exam (PE), ECG, Reactogenicity eval,
 Rezafungin administration (per cohort dose regimen),PK (pharmacokinetic) blood sampling (All Cohorts, except cohort 1)
pre-dose; 0.5 1, 2, 4, 6, 8 and 12 hours post-dose, Assess adverse events (AEs)
Cumulative Safety Data Review**
**for sentinels, through Day 30 prior to admit/dosing remainder of cohort;
for entire cohort, prior to dose escalation (next cohort)
Day 30 outpatient (+/- 1 day)
Weight/BMI, PE, Vitals, ECG, Conmeds, Clin labs, Reactogenicity eval,
PK blood sample collection (All Cohorts, except cohort 1), Assess AEs
Day 21 telephone follow-up (+/- 1 day)
Query subjects (All Cohorts) on any changes to injection site since Day 14
Day 14 outpatient (+/- 1 day)
Vitals, Conmeds, Reactogenicity eval
PK blood sample collection (All Cohorts, except cohort 1), Assess AEs
Counsel/reminders (post-discharge instructions)
Day 7
PE, Vitals, ECG, Conmeds, Clin labs
144 hour PK blood sample collection (All Cohorts, except cohort 1), Reactogenicity eval, Assess AEs
Counsel (post-discharge instructions), Discharge from CRU
Days 3-6 (confined)
Vitals on Day 4, Conmeds on Days 3 and 5,
48 (Day 3) and 96 (Day 5) hr PK blood sample collection (All Cohorts, except cohort 1), Reactogenicity eval, Assess AEs
PE on Day 4
Day 2 (confined)
Vitals, PE, Clin labs, Reactogenicity eval,
 24 hr PK blood sample collection (All Cohorts, except cohort 1), Assess AEs
Day -1
Enrollment and baseline assessments
Admitted and confined to Clinical Research Unit (CRU)*
*admit and dosing of 2 sentinel subjects.  Remainder of cohort is admitted and dosed following same schedule after cumulative safety data assessment (through Day 30,no halting criteria met).
Day -28 to Day -2
Screening
Study Schematic - SAD Study (Part 1) Cohorts 1, 2, 3, 4, 5, and 6


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Figure 2 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 Days 1, 8 and 15
Vitals, PE, Conmeds, ECG, Rezafungin administration (per cohort dose regimen), Reactogenicity evaluation
PK blood sampling pre-dose; 0.5 1, 2, 4, 6, 8 and 12 hours post-dose (Days 1 and 15 only)
 or pre-dose, 1, and 4 hours post-dose (Day 8 only), Assess AEs
Cumulative Safety Data Review**
**for sentinels, through Day 30 prior to admit/dosing remainder of cohort;
for entire cohort, through Day 30 prior to dose escalation (next cohort)
Days 30 & 45 outpatient (+/- 1 day)
Vitals, PE, ECG, Conmeds, Clin labs (Day 45 only), Reactogenicity evaluation (Day 30 only)
PK blood sample collection, Assess AEs
 Days 7, 14 and 21
Vitals, PE, ECG on Day 21, Conmeds, Clin labs, Reactogenicity evaluation
144 hour PK blood sample collection (All Days), Assess AEs
Discharge from CRU on Day 21
Days 3-6, 10-13 and 17-20
Vitals (Days 4, 11, and 18), Conmeds (Days 3, 5, 10, 12, 17, and 19,) Reactogenicity evaluation
48 hr (Days 3 & 17) and 96 hr (Days 5, 12, & 19) PK blood sample collection
PE on Days 4, 11 and 18 (all Cohorts), Assess AEs
 Days 2, 9 and 16
Vitals, PE, Clin labs, Reactogenicity evaluation
 24 hr PK blood sample collection (Days 2 and 16 only), Assess AEs
Day -1 (All Cohorts)
Enrollment and baseline assessments
Admitted and confined to CRU*
*admit and dosing of 2 sentinel subjects.  Remainder of cohort is admitted and dosed following same schedule after cumulative safety data assessment (through Day 45,no halting criteria met).
Day -28 to Day -2 (All cohorts)
Screening
Study Schematic - MAD Study (Part 2) Cohorts 7, 8, 9, and10


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Figure 3 
Figure 3 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
*For IV portion, PK blood draws are timed from start of infusion. 
Days 1 and 22
Conmeds, Vitals, Physical exam, ECG, Rezafungin administration (per cohort dose regimen)
Reactogenicity evaluation
PK blood sampling pre-dose; 0.5 1, 2, 4, 6, 8 and 12 hours post-dose*, Assess AEs
Day 52 (+/- 1 day)
Vitals, ECG, Clin labs, Conmeds, Physical exam
PK blood sample collection, Assess AEs
Days 14 & 35 outpatient (+/- 1 day)
PE, Vitals, Conmeds
PK blood sample collection
Reactogenicity eval, Assess AEs
Days 7 and 28
Physical exam, Vitals, Clin labs, Conmeds, Reactogenicity evaluation
144 hour PK blood sample collection (Days 7 and 28), Assess AEs
Discharge from CRU on Day 7 and Day 28
Days 3-6  and 24-27
Vitals (Days 4 and 25), Conmeds (Days 3 and 5), PE (Days 24 and 26), Reactogenicity evaluation
PK blood sampling 48 hr (Days 3 & 24,) and 96 hr (Days 5 & 26), Assess AEs
Days 2 and 23
Vitals, PE, Clin labs, Reactogenicity evaluation
 24 hr PK blood sample collection, Assess AEs
Days -1 and 21
Enrollment and baseline assessments
Admitted and confined to CRU
Day -28 to Day -2 (All cohorts)
Screening
Study Schematic - Absolute BA Cross-over (Part 3) Cohort 11


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KEY ROLES 
Lead Principal 
Investigator: 
 
 
 
DMID Clinical Project 
Manager: 
 
Dennis Ruff, MD 
ICON Early Phase Services, LLC 
8307 Gault Lane 
San Antonio, TX 78209 
Phone: 210-283-4572 
Email: Dennis.Ruff@iconplc.com  
 
Maureen Mehigan, RN 
5601 Fishers Lane, Room 7E19 
Rockville, MD 20852 
Phone: 240-627-3317 
Email: mmehigan@niaid.nih.gov  
Statistical and Data 
Coordinating Center: 
 
 
The Emmes Company 
401 North Washington Street, Suite 700 
Rockville, MD 20850 
Phone: 301-251-1161 
Email: phase1@emmes.com  
 
Contact information for additional key personnel is in the Manual of Procedures (MOP) for 
this trial. 


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BACKGROUND AND SCIENTIFIC RATIONALE 
 
Background  
Immunocompromised patients, particularly those with hematological malignancies undergoing 
chemotherapy, and those undergoing hematopoietic stem cell transplant or solid organ transplant, 
are at risk for invasive fungal infections (IFIs) caused by Pneumocystis, Candida, Aspergillus 
and other fungal pathogens. These patients have impaired immune defenses against fungi owing 
to their underlying diseases and treatments. 
Pneumocystis jirovecii causes lethal Pneumocystis pneumonia (PCP) in immunodeficient 
humans. Initially predominant among human immunodeficiency virus (HIV)+ individuals, PCP 
is now a public health concern for a broader population of immunosuppressed or otherwise 
immunodeficient patients, such as hematopoietic stem cell and solid organ transplant recipients; 
patients receiving cancer chemotherapy or biologic therapy, high-dose corticosteroids, 
immunotherapies, or anti-lymphocyte antibodies; patients with congenital immune deficiencies; 
and patients with autoimmune or chronic inflammatory disease1,2. 
PCP continues to be a problem worldwide even in the context of combined antiretroviral therapy 
in HIV+ patients3. The mortality rate of PCP remains unchanged at about 15% in HIV+ 
populations2. The rate in the developing world and certain urban areas of the US underserved by 
the healthcare establishment approaches 80%4. Recent evidence correlating P. jirovecii as a co-
morbidity agent in respiratory conditions like chronic obstructive pulmonary disease5, in 
association with anti-Tumor Necrosis Factor therapies6, or with lung cancers7 indicates a 
broadening of the PCP-susceptible population. Patients in these non-HIV+ categories fare worse 
than HIV+ patients. In a recent report, the mortality rate of non-HIV+ patients were 48% vs 17% 
in HIV+ patients8. A recent European estimate reported PCP incidence to be 1.5/100,000, with a 
fatality rate of 9.5%, lower than in past studies1. Though in support of previous evidence, lower 
mortality was observed in the HIV+ population (10-20%) compared with the non-HIV+ 
population (30-60%). Finally, productivity losses due to PCP have been calculated to be 
>$12 billion US dollars in 1999-20144. 
The current standard for PCP treatment is trimethoprim/sulfamethoxazole (TMP/SMX), which is 
also highly effective and widely recommended for PCP prophylaxis. The efficacy of TMP/SMX, 
along with limited alternative options, has likely contributed to acceptance of its safety and 
tolerability issues. However, these issues are not minor and have a significant clinical impact on 
the use of TMP/SMX for prophylaxis with adverse effects reported in more than half of cases, 


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and treatment-limiting toxicities occurring in up to one-third of cases. Potential side effects 
include myelosuppression, renal failure, liver dysfunction, and hyperkalemia; in some cases, side 
effects require permanent discontinuation of TMP/SMX. Additional agents in use include 
atovaquone, dapsone, and inhaled pentamidine, which are considered second- or third- line to 
TMP/SMX based on reduced relative efficacy and cause treatment-limiting adverse effects5. In 
addition, resistance to TMP/SMX has been reported and may impact the efficacy of this first-line 
therapy and prophylaxis9. Rezafungin was highly effective in preventing Pneumocystis infections 
through inhibition asci (cyst) forms in a 6-week immunosuppressed mouse model for PCP 
prophylaxis10. In this model, prophylaxis was equivalent to TMP/SMX at lower and/or less 
frequent doses than required for Candida. 
These safety/tolerability and resistance concerns may be a limiting factor to effective PCP 
prophylaxis. In addition to challenges to compliance, there is a lack of consensus on the 
appropriate duration of prophylaxis and longer durations, though warranted, may be difficult to 
implement with current agents. For example, in the context of transplantation, where practices 
vary by institution, transplant type, and individual immunosuppression risk, some patients may 
be recommended for lifetime prophylaxis2,5. 
Furthermore, evidence regarding the incidence and risks of late-onset PCP (> 1-year 
post-transplant) suggest a need for efficacious agents that can be tolerated in long-term 
prophylaxis6,7,11. 
The majority of IFIs in transplant and hematology are caused by Candida and Aspergillus 
species. Fluconazole, posaconazole, and micafungin are approved by the US FDA for the 
prevention of IFIs among HCT patients. Posaconazole is additionally approved for antifungal 
prophylaxis in those with hematological malignancies at least 13 years of age with prolonged 
neutropenia from chemotherapy. While the azoles are far more utilized for IFI prophylaxis and 
are better studies for this indication, these drugs are metabolized by cytochrome 
P450 isoenzymes, leading to the potential for serious drug interactions with concomitant 
administration of certain chemotherapeutic agents (including cyclophosphamide, vincristine, and 
thymidine kinase (TK) inhibitors or other immunosuppressants (including cyclosporine, 
tacrolimus and sirolimus). QT prolongation may be a limiting factor for patients on multiple 
medications. Administration of oral posaconazole in particular can be challenging in the 
presence of mucositis that prevents administration of food or nutritional supplements required for 
optimal posaconazole absorption. Discontinuations due to mucositis and colitis limit the utility of 
posaconazole prophylaxis. In a single-center, prospective study of patients with AML or after 
HCT taking posaconazole tablets, 80.5% of samples showed a concentration of at least 


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700 ng/mL at steady state, but 16% of patients stopped posaconazole prematurely owing to 
colitis, transaminase elevations and mucositis12. 
Voriconazole demonstrates wider inter-patient variability in serum concentrations that is due in 
part to variant CYP2C19 alleles. Individuals who are CYP2C19 ultra-rapid metabolizers have 
decreased voriconazole through concentrations, whereas poor metabolizers have increased 
through concentrations and are at increased risk of adverse experiences. Up to one-third of HCT 
recipients develop biochemical hepatotoxicity while on voriconazole that often leads to 
discontinuation of voriconazole by the clinicians regardless of causality. A long-term safety 
concern is the association of prolonged exposure to voriconazole with the development of 
non-melanoma skin cancers in HCT recipients. Use of amphotericin B (AmB) and its lipid 
derivatives for prophylaxis is problematic due to infusion and renal toxicities, as well as 
insufficient evidence regarding their efficacy in prophylaxis12. 
Echinocandins are the only class of antifungal agents at present that exerts activity on the fungal 
cell wall and not the cell membrane, resulting in no cross-reactivity with mammalian cell 
functions and thus reducing toxicity. Unlikely the azoles, echinocandins have significant 
fungicidal activity against Candida species and are currently recommended as first-line therapy 
for the treatment of candidemia. The echinocandins are generally very well tolerated with few 
adverse events (AEs) or drug interactions requiring discontinuation of the drug. Compared with 
the triazoles, the echinocandins had less than half the likelihood of discontinuation of therapy 
due to AEs. All the drugs in this class, caspofungin, micafungin, and anidulafungin, have a 
similar tolerability profile. The most common AE is injection site pain or phlebitis, occurring in 
up to 25% of patients receiving caspofungin, but in < 1% with anidulafungin13. 
 
Scientific Rationale 
2.2.1 
Purpose of Study 
Rezafungin is an investigational echinocandin with many of the favorable efficacy and safety 
profiles of its echinocandin class. As with other echinocandins, rezafungin has excellent activity 
against Candida, Aspergillus, dermatophytes, and even some less common fungal infections such 
as Talaromyces (formerly Penicilliosis) marneffei, which has a substantial mortality in HIV+ 
people in Southeast Asia. Additionally, rezafungin possesses unique attributes. Its efficacy 
against PCP, pharmacokinetic (PK) behavior, and stability/solubility are of particular importance 
to the current context. In a study, rezafungin was highly effective in preventing Pneumocystis 
infections through inhibition asci (cyst) forms in a 6-week immunosuppressed mouse model for 


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PCP prophylaxis10. The prolonged half-life of rezafungin allows for once-weekly (or longer) 
dosing14, and its stability/solubility enables subcutaneous (SC) formulation15 that had moderate 
to high BA in rats and monkeys (up to ~80%). The smaller dose requirement also supports the 
possibility of SC dosing volume, as it would require smaller volumes to be administered. Safety 
advantages of rezafungin compared with TMP/SMX include lack of myelosuppression, low/no 
risk of drug-drug interactions, and no risk of sulfa allergy. Additionally, rezafungin appears to 
have safety advantages compared to second-line PCP agents, azoles and AmB, which are often 
poorly tolerated. Currently marketed echinocandins are dosed IV once-daily and are therefore 
not practical for prolonged or outpatient prophylaxis. Based on these preliminary factors, further 
trial is warranted to explore the potential of rezafungin as antifungal prophylaxis as a once-
weekly IV or SC formulation. 
2.2.2 
Study Population 
Up to 86 subjects aged 18-45 (inclusive) who are in good health and meet all eligibility criteria 
will be enrolled in the study. The demographics in the local population should ensure that male, 
female, and minorities (African American, Native American, Asian, and Hispanics) will be 
represented in the enrolled population. Subjects will be recruited using IRB-approved 
advertising/web site listing of the essential inclusion and exclusion criteria. Subjects will self-
schedule online for a screening appointment based on their desire to participate and their 
evaluation of their suitability based on inclusion/exclusion criteria. Children, pregnant or breast-
feeding women, prisoners, and other vulnerable populations will not be enrolled. See Section 9.4. 
Neither women nor minorities will be excluded from participation in this study. Women of child- 
bearing potential may be included as per the inclusion criteria (Section 5.1). Subjects will be 
recruited without regard to gender or race. It is expected that race will reflect that within the 
community. 
 
Potential Risks and Benefits 
2.3.1 
Potential Risks 
This is the first study in humans using rezafungin via the SC route. The drug has been 
administered IV in multiple clinical trials. Risks of IV rezafungin exposure include possible 
histamine release reactions, including chest discomfort and flushing, as well as nausea and 
myalgia. The majority of events were mild, and all were transient. 


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Additionally, 71 participants with candidemia or invasive candidiasis were treated with rezafungin.  
The most commonly reported side effects for rezafungin were:  
• Decreases in potassium in the blood, which may cause muscle cramps, constipation, 
weakness, and abnormal heart rhythms, especially in people with heart disease.  This can 
cause you to feel lightheaded or faint.  A very low potassium level can even cause your 
heart to stop. 
• Diarrhea 
• Nausea 
• Anemia  
One serious side effect that was possibly related to the study drug was reported in this study, the 
side effect was a delay in the timing of the way the heart normally beats and resolved without 
treatment.   
In the group of participants with candidemia or invasive candidiasis, one participant in the 
rezafungin group had a side effect of sunburn (dosing group 400 mg on Day 1 and Day 8, with 
optional dosing on Days 15 and 21) following substantial sun exposure (photosensitivity).  There 
were two side effects (reported in 2.8% of participants) that may represent tremor or nerve injury 
causing numbness or weakness: intensive care unit acquired weakness (reported as moderate 
intensity), and tremor (reported as mild intensity).  These events of tremor/neuropathy that were 
potentially related to rezafungin were followed until resolution and both resolved 
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, urticarial, flushing, pruritus, dyspnea, 
hypotension, facial swelling, and vasodilation. Anaphylactic-like reactions have been reported 
with micafungin (Mycamine [micafungin sodium] Prescribing Information, 2013). 
Due to preliminary results from a nonclinical phototoxicity study in rats (positive response to in 
vitro UV absorption), subjects should be advised to avoid sun exposure and any other type of 


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ultraviolet radiation (including tanning beds) without adequate protection. Investigators should 
report any AE potentially related to phototoxicity to the Sponsor. 
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 expected at the 
highest dose in this study. The risk to humans is unknown, thus the male contraception 
requirements in inclusion criteria (see numbers 4 and 5 in Section 5.1.1) prohibit unprotected 
sexual intercourse and sperm donation within the study period and for 90 days thereafter (a total 
of 120 days from the last dose of study drug). 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. Dose-related microscopic findings of Schwann 
cell phospholipidosis were observed in the ganglia (≥3 mg/kg) and peripheral nerves (≥30 
mg/kg) and dose-related Schwann cell hyperplasia was observed in the ganglia at ≥30 mg/kg; 
hyperplasia partially reversed but phospholipidosis was still present at the end of a 4-week 
recovery period. Tremoring reversed after 1 month of recovery but Schwann cell 
phospholipidosis was still present at the end of a 3-month recovery period. These observations 
occurred at 11.4-fold the maximum intended dose in this study. Given the high nonclinical 
exposure, relative to the current dose levels and expected exposure, the risk to study subjects is 
assessed as low. At the highest dose (about 20 times greater than the proposed human dose), 
severe neurobehavioral effects were observed. These effects were not seen in the levels at 11.4 
times the maximum exposure proposed for humans. 
Potential risks include temporary physical discomfort and emotional stress due to the nature of 
the evaluations and specimen collection procedures in this trial. Subcutaneous drug exposure 
may also be associated with pain and irritation at the injection site, risk of nodules, thickening 
and open sores at the injection sites; as seen in the cynomolgus monkey study. There was partial 
recovery of the sores after 4 weeks at the 120 mg/kg dosing level. The risks associated with 
insertion of the indwelling catheter and frequent blood draws are fainting, pain, bruising, and 
scarring. The catheter may pose a risk for clotting and infection. These risks are discussed with 
the subject during the consent process. 


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2.3.2 
Potential Benefits 
There are no known benefits to subjects participating in this trial. The knowledge gained in this 
trial may help society, especially those requiring treatment or prophylaxis of invasive fungal 
infections. 


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STUDY DESIGN, OBJECTIVES AND ENDPOINTS OR 
OUTCOME MEASURES 
 
Study Design Description 
This is a Phase 1, single-center, three-part, prospective, randomized, double-blind trial of 
single- and multiple-ascending doses of rezafungin administered by SC injection to healthy adult 
subjects and a two-period crossover bioavailability study with two dosing sequences of 
rezafungin administered by SC → IV or IV → SC doses to healthy adult subjects. 
 
 
3.1.1 
Dosing Scheme and Duration of Study 
3.1.1.1 
Part 1 (SAD) 
In Part 1 of this trial, 44 subjects will be split into six cohorts – one cohort of 4 subjects (3 
rezafungin, 1 placebo) and five cohorts of 8 subjects each (6 rezafungin, 2 placebo) – will be 
randomized to receive single SC doses of rezafungin or placebo with dose escalation separated 
by a minimum of 4 weeks. Single-dose levels of rezafungin to be assessed will follow an 
ascending single-dose regimen in all except Cohort 1. The 1, 10, 30, 60, and 100 mg doses will 
be administered as 0.1 – 1.0 mL SC injections (abdomen) and the 200 mg dose as 2 x 1 mL 
injections (in same abdominal quadrant). A schematic of the SAD study design is shown in 
(Table 1). Administration details are included in the protocol-specific Manual of Procedures 
(MOP) to this study. 
 
 


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Table 1: Design for SC Dosing in SAD (Study Part 1) 
Cohort 
Dose 
(mg) 
Dose 
Volume 
(mL) 
Number  
of Doses 
Number of Subjects* 
Rezafungin SC 
Injection 
Placebo 
1 
1 
0.1** 
1 
3 
1 
2 
10 
0.1 
1 
6 
2 
3 
30 
0.3 
1 
6 
2 
4 
60 
0.6 
1 
6 
2 
5 
100 
1 
1 
6 
2 
6 
200 
1 (in each of 2 
injections) *** 
1 
6 
2 
Total Number of Subjects 
33 
11 
44 
*Within each cohort two sentinel subjects will be admitted initially, and the randomization scheme will be designed 
to ensure that one subject will receive rezafungin and the other will receive placebo. All sentinel subject safety data 
through Day 30 will be reviewed by the PI prior to dosing the remainder of cohort. Safety data for each cohort 
through Day 30 will be confirmed by review of objective pre-defined criteria before continuing to the next cohort. 
**In order to administer this dose, the drug product solution from the SC drug product vial (Rezafungin Injection, 
for subcutaneous use, 100 mg/mL) will be diluted 1:10 in 5% Dextrose Injection, USP. Then 0.1 mL of the diluted 
solution will be administered. Details are included in the MOP for this study. 
***The 200 mg (2 x 1 mL) SC dose will be injected as 1 mL each in the same abdominal quadrant, separated by 
approximately 5 cm. Details are included in the MOP for this study. 
 
 
3.1.1.2 
Part 2 (MAD) 
The first cohort for Part 2 of this trial (Cohort 7) can begin after the FDA has reviewed and 
assessed the SAD safety and PK data and providing no halting criteria have been met. In Part 2, 
subjects in four cohorts of 8 subjects each (6 rezafungin, 2 placebo) will be randomized to 
receive SC doses of rezafungin or placebo on Days 1, 8, and 15 of the MAD portion of the study. 
Dose levels of rezafungin to be assessed will follow an ascending multiple-dose regimen (30 mg 
x 3 doses, 60 mg x 3 doses, 100 mg x 3 doses, and 200 mg x 3 doses). A schematic of the MAD 
study design is shown in (Table 2). 


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Table 2: Design for SC Dosing in MAD (Study Part 2) 
Cohort 
Dose 
(mg) 
Dose 
Volume 
(mL) 
Number  
of Doses 
Number of Subjects* 
Rezafungin SC 
Injection 
Placebo 
7 
30 
0.3 
3 
6 
2 
8 
60 
0.6 
3 
6 
2 
9 
100 
1 
3 
6 
2 
10 
200 
1 (in each of 2 
injections)** 
3 
6 
2 
Total Number of Subjects 
24 
8 
32 
*Within each cohort two sentinel subjects will be admitted initially, and the randomization scheme will be designed 
to ensure that one subject will receive rezafungin and the other will receive placebo. All sentinel subject safety data 
through Day 30 will be reviewed by the PI prior to dosing the remainder of cohort. Safety data for each cohort 
through Day 30 will be confirmed by review of objective pre-defined criteria before continuing to the next cohort. 
**The 200 mg (2 x 1 mL) SC dose will be injected as 1 mL each in the same abdominal quadrant, separated by 
approximately 5 cm. Each dose will be administered in a different quadrant (total 3 quadrants). Details are included 
in the MOP for this study. 
 
 
3.1.1.3 
Part 3 (BA) 
Part 3 of this study may be run in parallel with Cohort 7 of the Part 2 (MAD) portion of this 
study, upon completion of safety data review for all Cohorts 1-6 of Part 1 (SAD). In the 
unblinded Part 3 cross-over portion of this trial, 10 subjects will be randomized to one of two 
sequences of 5 subjects each to receive a SC→IV or IV→SC sequence of study drug 
administration. In sequence 1 (SC→IV), rezafungin (100 mg or MTD in Part 1) administered by 
SC injection on Day 1 followed by rezafungin (100 mg or MTD in Part 1) administered by IV 
infusion over 60 minutes on Day 22; or in Sequence 2 (IV→SC), rezafungin (100 mg or the 
maximum tolerated dose in Part 1) administered by IV infusion over 60 minutes on Day 1 
followed by rezafungin (100 mg or the maximum tolerated dose in Part 1) administered by SC 
injection on Day 22.  Maximum tolerated dose (MTD) is defined as the highest dose level with 
no withdrawals by subject or investigator due to AEs related to study product for Part 1 (SAD) 
Cohorts 1-6.  A schematic of the BA study design is shown in Table 3. 


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Table 3: Design for SC Dosing in Absolute BA Cohort (Study Part 3) 
Sequence 
 
Day 1 (Period 1) 
Dose/Volume/Route 
Day 22 (Period 2) 
Dose/Volume/Route 
Number of 
Subjects* 
1 (SC → IV) 
 
100 mg x 1 mL 
SC injection 
100 mg 250 mL 
IV infusion 
5 
2 (IV → SC) 
 
100 mg 250 mL 
IV infusion 
100 mg 1 mL 
SC injection 
5 
 
Total Number of Subjects 
10 
*Part 3 may be run following the cohort dosed at the same dose level (100 mg or MTD) in Part 1 (SAD).  
 
The BA of the SC dose compared to the IV dose will be determined as the ratio of the rezafungin 
area under the plasma concentration versus time curve (AUC) values from each administration.  
3.1.2 
Rationale for Starting Dose 
In the single-dose cynomolgus monkey trial (NC101), SC rezafungin 30 mg/kg (1 mL per 
injection of 100 mg/mL solution) was well tolerated with minor non-adverse skin findings 
ranging from very slight to slight erythema, and very slight to moderate edema. A multiple dose 
cynomolgus monkey trial (NC107), at doses of 30, 60, and 120 mg/kg (given as 1 mL per 
injection of 100 mg/mL solution in 1, 2, or 4 injections/animal every 3 days, respectively) was 
not tolerated, with all dose groups having adverse toxicity at the injection sites. Inflammation 
ranged from minimal to severe, with moderate severity and higher grades resulting in clinical 
and macroscopic observations of nodules, thickening, and in the most severe cases, open sores at 
the injection sites. At the low adverse effect level of 30 mg/kg, adverse observable skin lesions 
were first observed from Day 11 to 14 and were generally associated with the 4th (Day 9) 
injection (4-6 animals). One lesion was observed on Day 12 at the site of the 2nd (Day 3) 
injection, and one animal had no lesions. These findings reversed following 4 weeks of recovery 
at the low- and mid-dose levels and in all but one animal at the high-dose level.   A suitable 
starting dose was selected per Estimating the Maximum Safe Starting Dose in Initial Clinical 
Trials for Therapeutics in Adult Healthy Volunteers16. This guidance recommends that if local 
toxicities are dose limiting the “therapeutics should be normalized to concentration (e.g., mg/area 
of application) or amount of drug (mg) at the application sites”. 
In the NHP study, cynomolgus monkeys weighing approximately 3 kg were dosed multiple times 
with 30 mg/kg, or 90 mg of rezafungin.  


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As shown in Table 4, the SAD escalation will begin with a lower starting dose and propose an 
initial single-dose cohort of 1 mg/injection, which would represent roughly an hundred-fold 
safety margin (by total absolute dose)  from the 30 mg/kg dose cohort used in both the single 
dose subcutaneous toxicology study (NC-101) and the lowest dose tested from the repeat dose 
toxicology study (NC-107).  
Table 4: Proposed Starting Dose Level in the Clinic 
mg 
mg/kg dose 
Volume 
mL/kg 
Cynomolgus Monkey (~3 kg) 
100 
30 
1 mL 
0.33 
200 
60 
2 mL* 
0.67 
400 
120 
4 mL* 
1 
Human (~70 kg) 
1 
0.0143 
0.10 mL 
0.0014 
*Given as multiple 1-mL injections 
3.1.3 
Dose Escalations 
In Part 1/SAD, the initial cohort of 4 subjects will be administered 1 mg of rezafungin 
(3 subjects) or placebo (1 subject) as a single SC injection. 
Dose escalation to each successive cohort during Part 1 will occur if none of the predefined dose 
escalation halting criteria are met through Day 30 (final visit).  The FDA will review all safety 
and PK data from the SAD (Part 1) and determine if the study may proceed to the MAD (Part 2) 
and BA (Part 3) portions. Rezafungin doses for the MAD and BA portions will be determined 
after FDA review of the SAD data. Dose escalation during Part 2 will occur if none of the 
predefined dose escalation halting criteria are met through Day 30 after the first dose. This will 
be communicated through the following process: 
1. An email from the site to the SDCC attesting that all data entry has been completed after 
the last subject has had their Day 30 visit, then data cleaning, as applicable, prior to the 
SDCC being able to generate the report. 
2. A halting criteria report will be provided by the SDCC to DMID.  
3. If based on the entered data in EDC, none of the escalation criterion is met, then the 
SDCC will open the database for the following cohort after confirmation from DMID 
that the study may proceed to the next cohort.    
4. 
If any of the criterion is met, the SDCC will provide the dose escalation report and an 
ad-hoc SMC meeting will be convened to seek recommendation from the SMC.  


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Part 2 (MAD) and Part 3 (BA) may not begin until after FDA has reviewed all safety and 
PK data from Part 1 (SAD) and given agreement that it is safe to proceed. The doses for 
Parts 2 and 3 may be updated after FDA review of the SAD data. There will be a scheduled 
SMC data review meeting prior to start of Part 2 (MAD) Cohort 7.  
In order to efficiently identify the optimal therapeutic doses for use in future clinical trials, a 
flexible scheme of dose escalation, (based on ongoing study data) will be used that allows 
intermediate doses higher or lower than the planned doses (30, 60, 100, and 200 mg), upon 
protocol amendment and with IRB approval. However, no cohort will be dosed higher than the 
200 mg free base equivalent. 
Cohorts 2-6 in the SAD and all MAD cohorts will be conducted with sentinel dosing of 
rezafungin (i.e., dosing in 2 subjects followed by remaining six subjects). The randomization 
scheme will be designed to ensure that 1 subject will receive rezafungin and the other will 
receive placebo in sentinel dosing. The dosing of the remaining six subjects in the same cohort 
will not be initiated until a minimum of 4 weeks after the second sentinel dosing, and no serious 
adverse events (SAEs)/adverse events (AEs) have occurred that meet the predefined objective 
halting criteria for sentinels. The blinded safety and clinical laboratory data from all subjects in 
the cohort will be reviewed and confirm that none of the dose-escalation halting rules have been 
met before moving to the next higher dose cohort. If any of the predefined halting criteria is met, 
the study enrollment and dosing will be stopped until the SMC provides recommendations 
regarding continuation of the study (See Section 8.2.3). 
 
Study Objectives 
3.2.1 
Primary  
• To determine the safety and tolerability of single-ascending SC doses (SAD) of rezafungin. 
• To determine the safety and tolerability of multiple-ascending SC doses (MAD) of 
rezafungin. 
• To determine the pharmacokinetic (PK) profile in plasma of rezafungin in healthy adult 
subjects; 


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3.2.2 
Secondary 
To evaluate the bioavailability (BA) of rezafungin when administered by SC injection relative to 
IV infusion in healthy adult subjects. 
 
Study Endpoints or Outcome Measures 
3.3.1 
Primary  
• Safety and tolerability will be evaluated for single-ascending SC doses (SAD) of rezafungin.  
Safety will be assessed by adverse events and SAEs from start of dosing to Day 30, clinical 
laboratory tests at baseline and from Day 2 to Day 30, ECGs at Screening and post-dose on 
Days 1, 7, and 30, physical exams at baseline and post-dose on Day 1 to Day 30, vital signs 
at baseline and from Day 1 to Day 30, and injection site evaluation from dosing to Day 30. 
Tolerability will be assessed by occurrence of solicited local reactogenicity (injection site 
evaluation) from dosing to Day 30. 
• Safety will be evaluated for multiple-ascending SC doses (MAD) of rezafungin. Safety will 
be assessed by adverse events and SAEs from start of dosing to Day 45, clinical laboratory 
tests at baseline and from Day 2 to Day 45, ECGs at Screening and post-dose on Days 1, 8, 
15, 21, 30, and 45, physical exams at baseline to Day 45, and vital signs at baseline to Day 
45. Tolerability will be assessed by occurrence of solicited local reactogenicity (injection site 
evaluation) from first dose to Day 45.  
• Pharmacokinetic (PK) profiles of rezafungin will be assessed by measurement of drug levels 
in plasma after SC administration in each cohort (except for SAD Cohort 1). Plasma for PK 
analysis will be collected at planned timepoints up to Day 30 in the SAD cohorts, and Day 45 
in the MAD cohorts. PK parameters will be estimated from the rezafungin plasma 
concentration-time data. 
3.3.2 
Secondary 
The BA of rezafungin when administered by SC injection relative to IV infusion will be assessed 
by measurement of drug levels in plasma after administration by SC injection or by IV infusion 
in each cross over period. Plasma samples will be collected at planned timepoints up to Day 52 
for Part 3/BA The absolute BA will be calculated as the ratio of AUC for the SC injection and 
AUC for the IV infusion of administration. 


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STUDY INTERVENTION/INVESTIGATIONAL 
PRODUCT 
 
Study Product Description 
The active ingredient, rezafungin acetate, a cyclic hexapeptide, is a semi-synthetic echinocandin 
synthesized from a fermentation product of Aspergillus nidulans. Two formulations will be used 
for the study, one for SC administration and one for IV administration.   
Subcutaneous (SC) formulation: Rezafungin Injection, for Subcutaneous Use, 100 mg/mL, is a 
sterile liquid product supplied as a colorless to pale yellow liquid in single-dose vials containing 
1.0 mL of extractable volume. The active pharmaceutical ingredient is rezafungin acetate, a 
water-soluble amorphous acetate salt. The inactive ingredient is mannitol.  
Intravenous (IV) formulation: Rezafungin for Injection, 200 mg/vial, is a sterile product supplied 
as a white to pale yellow lyophilized powder in single-dose glass vials for reconstitution with 
Sterile Water for Injection, United States Pharmacopeia (USP). The reconstituted product is 
diluted in 0.9% Sodium Chloride Injection, USP for IV infusion. The active pharmaceutical 
ingredient is rezafungin acetate, a water-soluble amorphous acetate salt. The inactive ingredients 
include excipients of mannitol, polysorbate 80, and histidine. 
Placebo is 5% Dextrose Injection, USP, a sterile, nonpyrogenic solution of dextrose in water for 
injection. The solution has the osmolarity of 252 mOsmol/L, which is slightly hypotonic. This 
solution contains no bacteriostat, antimicrobial agent or added buffer. 
Reconstitution solution is Sterile Water for Injection, (WFI), USP, which is a clear, colorless 
solution. 
4.1.1 
Formulation, Packaging, and Labeling 
Subcutaneous Formulation: Rezafungin Injection, for Subcutaneous Use, 100 mg/mL 
Rezafungin Injection is a sterile liquid product supplied in single-dose 2 mL vials containing 
100 mg of rezafungin in 1.0 mL of extractable volume. The active pharmaceutical ingredient is 
rezafungin acetate, a water-soluble acetate salt. The inactive ingredient is mannitol.  
For SC administration for Parts 1, 2, and 3 of the study, the appropriate volume of solution is 
withdrawn via syringe for administration to the subject for doses of 10 mg and up. To administer 


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a 1 mg dose, the solution from the product vial (Rezafungin Injection, for Subcutaneous use, 100 
mg/mL) is diluted 1:10 in 5% Dextrose Injection, USP, then 0.1 mL of the diluted solution is 
injected. Further details are provided in the protocol-specific MOP.  
Rezafungin Injection, for Subcutaneous Use, 100 mg/mL, will be labelled according to 
manufacturer or regulatory specifications and will include the statement “Caution: New Drug – 
Limited by Federal Law to Investigational Use”. 
IV Formulation: Rezafungin for Injection, 200 mg/vial 
The IV formulation will be used for Part 3 of the study.  
Rezafungin for Injection, 200 mg/vial, is supplied as a white-to-pale-yellow lyophilized powder 
(200 mg/vial) in single-dose 20 mL glass vials for reconstitution with Sterile Water for Injection, 
USP. The reconstituted product is a clear, colorless to pale yellow solution free of visible 
particulate. The reconstituted product is diluted in 250 mL of normal saline and administered by 
IV infusion. Further details are provided in the protocol-specific Manual of MOP. 
The active pharmaceutical ingredient is rezafungin acetate, a water-soluble acetate salt. The 
inactive ingredients include excipients of mannitol, polysorbate 80, and histidine. 
Rezafungin for Injection, 200 mg/vial, will be labelled according to manufacturer or regulatory 
specifications and will include the statement “Caution: New Drug – Limited by Federal Law to 
Investigational Use”. 
Placebo (5% Dextrose Injection, USP) 
 
5% Dextrose Injection, USP solution is sterile and nonpyrogenic. It is a parenteral solution 
containing dextrose in water for injection intended for intravenous administration. Each 100 mL 
of 5% Dextrose Injection, USP, contains dextrose monohydrate, 5 g in water for injection. The 
caloric value is 170 kcal/L. The osmolarity is 252 mOsmol/L (calc.), which is slightly hypotonic. 
The solution pH is 4.3 (3.2 to 6.5). 
WFI (Reconstitution Solution)  
WFI is USP grade sterile water for injection that is nonpyrogenic and contains no bacteriostatic 
agent or added buffer. 
 
 


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4.1.2 
Product Storage and Stability 
Rezafungin Injection, for Subcutaneous Use, 100 mg/mL 
Store at 2-8°C (36-46°F). 
Rezafungin for Injection, 200 mg/vial 
Store at 20-25°C (68-77°F) (See USP Controlled Room Temperature; excursions between 15°C 
and 30°C [59-86°F] are permitted).  
Placebo (5% Dextrose Injection, USP) 
Store at 20-25°C (68-77°F) (See USP Controlled Room Temperature). Protect from freezing. 
WFI (Reconstitution Solution) 
Store at 20-25°C (68-77°F) (See USP Controlled Room Temperature; excursions between 15°C 
and 30°C [59-86°F] are permitted). Protect from freezing. 
 
Acquisition/Distribution 
Rezafungin Injection, for Subcutaneous Use, 100 mg/mL and Rezafungin for Injection, 
200 mg/vial 
Rezafungin will be provided by Cidara Therapeutics, Inc. Upon request by Division of 
Microbiology and Infectious Diseases (DMID), it will be shipped to the following address: 
DMID-Clinical Materials Services (CMS) 
Fisher BioServices 
20439 Seneca Meadows Parkway 
Germantown, MD 20876 
Tel: 240-477-1350 
Email: DMID.CMS@thermofisher.com 
Rezafungin will be shipped from DMID-CMS to the ICON Early Phase Services upon request 
and approval by DMID. 
Placebo (5% Dextrose Injection, USP) 
5% Dextrose Injection, USP will be supplied by ICON. 
WFI (Reconstitution Solution) 
WFI will be supplied by ICON. 


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Dosage/Regimen, Preparation, Dispensing and Administration of 
Study Intervention/Investigational Product 
See the protocol-specific MOP for detailed information on the preparation, labeling, storage, and 
administration of Rezafungin for Injection – SC (100 mg/mL) and Rezafungin for Injection-IV 
(200 mg). Study product preparation will be performed by the site’s unblinded research 
pharmacist on the same day of study drug administration. 
Visually inspect all study products/diluent upon receipt and prior to use. If the study 
products/diluent appear to have been damaged, contaminated, or discolored, contain visible 
particulate matter, or if there are any concerns regarding its integrity, do NOT use the affected 
study products/diluent. The affected study products/diluent must be quarantined at the 
appropriate temperature and labeled ‘Do Not Use’ (until further notice). The Site Principal 
Investigator (PI) or responsible person should immediately contact the DMID Product Support 
Team (see MOP for contact information) and DMID Clinical Project Manager for further 
instructions before any additional study product administrations are administered. Based on the 
information collected, DMID and/or the manufacturer will determine whether the affected study 
products/diluent can be used. If it cannot be used, the site will receive specific instructions on 
how to return the affected study products/diluent to the DMID CMS or destroy it on site. If the 
study products/diluent are unusable, study personnel will use another vial from the study supply. 
Replacement vials may be requested by contacting DMID. Additional instructions for quarantine 
and DMID contact information are provided in the protocol-specific MOP. 
Two formulations will be used for the study. 
Subcutaneous Formulation: Rezafungin Injection, for Subcutaneous Use, 100 mg/mL  
An appropriate volume of solution is withdrawn from the vial via syringe and administered for 
doses of 10 mg and up. To administer a 1 mg dose, the solution from the product vial 
(Rezafungin Injection, for Subcutaneous use, 100 mg/mL) is diluted 1:10 in 5% Dextrose 
Injection, USP, then 0.1 mL of the diluted solution is injected. Refer to the MOP for further 
details.  
IV Formulation: Rezafungin for Injection, 200 mg/vial  
The lyophilized powder is first reconstituted with Sterile Water for Injection, USP, and then 
diluted with Normal Saline, 0.9% Sodium Chloride Injection, USP, 250 mL, for infusion. For 
detailed instructions on reconstitution and/or dilution, refer to the MOP for this study. 


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Placebo (5% Dextrose Injection, USP) 
For placebo SC injection, the appropriate volume to match the volume to be administered in the 
active arm of the trial is withdrawn using a syringe. 
 
Accountability Procedures for the Study Intervention/Investigational 
Product(s) 
The Site PI is responsible for the distribution and disposition of study drug and has ultimate 
responsibility for its accountability. As this is a blinded trial, the Site PI will delegate this 
responsibility to the unblinded Site Pharmacist. The Site Pharmacist will be responsible for 
maintaining complete records and documentation of study drug receipt, accountability, 
dispensation, temperature monitoring, storage conditions, and final disposition. 
Study drugs, whether administered or not, will be documented on the appropriate study drug 
accountability record or dispensing log. Used and unused Rezafungin vials will be retained at 
temperature specified on the label until monitored and released for disposition as per DMID 
Requirements in the MOP. Any unused solution left in the IV infusion bag or IV tubing after 
administration to the subject will be discarded as biohazardous waste in accordance with local 
institutional policies. The infusion bag may be discarded prior to monitoring. 
Upon completion of this trial and after the final monitoring visit, any remaining unused study 
drug will either be returned or destroyed appropriately at the clinical site as per sponsor 
requirements and instructions, or in accordance with disposition plans. 


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SELECTION OF SUBJECTS AND STUDY 
ENROLLMENT AND WITHDRAWAL 
The inclusion/exclusion criteria for participation in this trial are listed below. All screening 
procedures must be completed during the screening period but may be performed on different 
days. Abnormal laboratory values may be confirmed at the PIs’ discretion and one repeat value 
can be used to determine eligibility. Subjects cannot be re-screened if they do not meet eligibility 
criteria. Subjects who meet criteria but fall outside the screening window (i.e. subjects screened 
as alternative subjects and not selected on dosing day) may be rescreened a maximum of one 
time. Subjects may only be enrolled once into this trial. 
No exemptions are granted on subject inclusion/exclusion criteria in DMID-sponsored studies. 
Questions about eligibility will be directed to the DMID Medical Officer. 
 
Eligibility Criteria 
5.1.1 
Subject Inclusion Criteria 
Subjects are eligible to enroll in this trial if they meet all the following criteria: 
1) Males and females aged 18 to 45 years, inclusive. 
2) Willing and able to provide written informed consent and authorization for use of protected 
health information; 
3) Willing and able to comply with protocol requirements, instructions, and protocol-stated 
restrictions (including confinement to the CRU) and is likely to complete the study as 
planned; 
4) Males must be vasectomized or agree to use barrier contraception (condom with spermicide) 
from first dose of study drug until at least 18 weeks following the last dose of study drug. 
5) Males must agree to refrain from sperm donation from first dose of IP through at least 18 
weeks after last dose of investigational product (IP). 


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6) Females are eligible if they are of non-childbearing potential3 or if they use a highly 
effective4 method of contraception for 30 days prior to dosing and for a minimum of 30 days 
after dosing; 
3Non-childbearing potential is defined as: Pre-menopausal with documentation of irreversible surgical 
sterilization (i.e., hysterectomy, bilateral oophorectomy, or bilateral salpingectomy (but not tubal ligation 
alone); or, Post-menopausal defined as amenorrhea for at least 12 months following cessation of all exogenous 
hormonal treatments and with FSH levels ≥40 mIU/mL at Screening. 
4A highly effective contraceptive method is, defined by <1% failure rate that is not affected by user adherence, 
include surgical sterilization and long-acting reversible contraception (LARC).  LARC comes in three forms: 
progestin-releasing subdermal implants (Nexplanon and Implanon [Merck]); copper intrauterine devices (IUD) 
(ParaGard [Teva]); and levonorgestrel-releasing IUDs (Mirena [Bayer], Skyla [Bayer], and Liletta 
[Allergan/Medicines360]. Subjects must use one of these three methods.  
7) Subject is in good health as deemed by the Investigator.1-2 
1Good health is defined by the absence of any medical condition described in the exclusion criteria in a subject 
who undergoes a medical history, with a normal complete physical examination including resting vital signs 
(heart rate of 51-60 bpm allowed, per PI discretion), and screening safety laboratory testing.   
2If the subject has an active, ongoing medical condition, the condition cannot meet any of the following criteria:  
1.) first diagnosed within 3 months of enrollment; 2.) is worsening in terms of clinical outcome in last 6 months; 
or 3.) involves need for medication that may pose a risk to subject’s safety or significantly impede assessment 
of adverse events if they participate in the study.   
8) Subjects with a body mass index (BMI) (weight in kg divided by height in m, squared) 
between 18.5 and/or 35.0 kg/m2, inclusive, and a minimum weight of 50 kg; 
9) Subjects must refrain from strenuous physical activity that could cause muscle aches or 
injury, including contact sports, at any time from screening until completion of the trial. 
10) Subjects must refrain from over-the-counter and prescription medications1 and nutritional 
supplements within 14 days before first study drug administration, and until after the final 
study visit.  
1except for hormonal contraceptives, acetaminophen or ibuprofen. 
11) Subject has adequate venous access for blood collection. 


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5.1.2 
Subject Exclusion Criteria 
Subjects must NOT meet any of the following exclusion criteria: 
1) History of any hypersensitivity or allergic reaction to echinocandins or excipients (mannitol, 
polysorbate 80, histidine) of the rezafungin for injection and rezafungin for infusion 
formulations. 
2) Subjects presenting with a clinically significant condition;5  
5Subjects with any of the following must not be included into the study: clinically significant oncologic, 
infectious, cardiovascular, pulmonary, hepatic, gastrointestinal, hematologic, metabolic, endocrine, neurologic, 
immunologic, renal, psychiatric, or other condition that in the opinion of the Investigator would preclude the 
safe participation of the subject in the study or would prevent the subject from meeting the study requirements. 
3) Any condition that in the opinion of the Investigator could significantly impact drug 
absorption, distribution, or elimination; 
4) Symptoms of acute illness or chronic disease within 14 days of initial dosing; 
5) Positive screen for hepatitis B virus surface antigen, hepatitis C virus antibody, or HIV 
antibody; 
6) Subjects with clinical laboratory values outside the site reference ranges1 prior to initial 
dosing; 
1Clinical laboratory values outside the site reference ranges, if considered by the site investigator to be clinically 
insignificant, are acceptable if not exceeding Grade 1 severity. One repeat of lab testing is allowed to make this 
determination during screening. 
7) Abnormal ECGs. See Section 7.1 Clinical Evaluations for exceptions; 
8) Female subject of childbearing potential who is pregnant,6 lactating, or planning to become 
pregnant during the study period or at least 30 days after the final dose of study product; 
6Having a positive serum pregnancy test at the Screening Visit or any other specified time point prior to the 
dose of study product. 
9) Received any prescription medications (except for hormonal contraceptives) within 14 days 
before first study drug administration; 


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10) Received any non-prescription medications, vitamins, herbal or dietary supplements7 within 
14 days of initial dosing, unless prior approval is granted by both the Investigator and the 
Sponsor; 
7Excluded from this list is intermittent use of acetaminophen at doses of ≤2 g/day or ibuprofen ≤1200 mg/day. 
However, acetaminophen only is accepted to treat AEs for pain (i.e. headaches) during in-clinic stay.  
11) Current smoker or tobacco8 use within 90 days prior to screening or while a subject is 
enrolled in the study;  
8Tobacco use includes vaping, smoking tobacco, the use of snuff and chewing tobacco, and other nicotine or 
nicotine- containing products 
12) History of illicit/illegal drug use prior to dosing or while a subject is enrolled in the study9 or 
reports an alcohol or substance abuse problem* within 6 months of dosing;  
9A urine drug test will be performed at screening and upon admission to the CRU.  Drug screen includes 
amphetamines, barbiturates, cocaine, opiates, cannabinoids, phencyclidine, and benzodiazepines. 
*Inclusive of vaping of non-nicotine products 
13) Consumed foods or beverages containing alcohol or xanthines/caffeine a,b: 
a. Alcohol: ≤ 48 hours before the first study drug administration, until discharge; 
b. Xanthines/caffeine: ≤ 24 hours before the first study drug administration, until discharge; 
14) Received any live or killed vaccines or immunoglobulins within 14 days of dosing; 
15) Donated blood or blood products or experienced significant blood loss within 60 days of 
dosing; 
16) Received a blood transfusion within 14 days of dosing; 
17) Previous participation in this trial, any other rezafungin trial, or any trial10 within 28 days of 
dosing. Plans to enroll in another clinical trial11;  
10 Includes trials that have a study intervention such as a drug, biologic, or device. 
11 Includes trials that could interfere with safety assessment of the investigational product at any time during the 
study period 
18) The PI considers that the subject should not participate in the trial. 


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Withdrawal from the Study, Discontinuation of Study Product, or 
Study Termination  
5.2.1 
Withdrawal from the Study or Discontinuation of the Study Product  
Subjects may withdraw their consent at any time without penalty or loss of benefits to which 
they are otherwise entitled. 
A Site PI may also withdraw a subject from the study or from receiving the study drug for any 
reason. Follow-Up safety evaluations will be conducted, if the subject agrees. If a subject 
withdraws or is withdrawn before completion of this trial, the reason(s) will be recorded in the 
electronic case report form (eCRF). In either case, the reason for withdrawal will be clearly 
documented and specifically if the reason for withdrawal was related to study drug intolerance or 
other adverse event. 
The reason(s) for withdrawal from the study might include, but are not limited to, the following: 
• Subject no longer meets eligibility criteria; 
• subject meets individual halting criteria (listed in Section 8.7.3); 
• subject becomes noncompliant; 
• medical disease or condition or new clinical finding(s) for which continued participation, in 
the opinion of the Site PI, might compromise the subject’s safety, interfere with the subject's 
successful completion of this trial, or interfere with the evaluation of responses; 
• subject is lost to FU; 
• determined by a physician’s discretion to require additional therapy not indicated in the 
protocol to ensure subject’s health and well-being. The reason(s) for discontinuation of the 
study drug might include, but are not limited to; 
o subject becomes pregnant; 
o determined by a physician’s discretion to require additional therapy not indicated 
in the protocol to ensure subject’s health and well-being.  


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The Site PI will be explicit regarding trial FU (e.g., safety FU) that might be carried out if the 
subject will not receive further study drug. If the subject consents, every attempt will be made to 
follow all AEs through resolution. The procedures that collect safety data for the purposes of 
research will be included in the original ICF or the Site PI may seek subsequent informed 
consent using an IRB/IEC-approved ICF with the revised procedures. 
The Site PI will inform the subject that data already collected will be retained and analyzed even 
if the subject withdraws from this trial.  
5.2.2 
Handling of Withdrawals and Discontinuation of Administration 
Subjects who sign and date the ICF but fail to be randomized will be defined as screen failures. 
Site personnel will maintain documentation for all subjects who sign an ICF. 
Subjects will be informed that they have the right to discontinue study drug and/or withdraw 
from this trial at any time for any reason without prejudice to their medical care. If the subject 
has received the study drug, data collected for withdrawn subjects will be evaluated for safety 
and PK. 
In all cases of withdrawal, the reason for withdrawal will be recorded. Subjects who receive any 
amount of study drug and who are discontinued from this trial will be asked to complete all FU 
safety assessments including FU of any AEs before termination from this trial. 
5.2.3 
Lost to Follow-Up 
If subjects fail to appear for a FU assessment, extensive effort, (i.e., three documented contact 
attempts via phone calls, email, etc., made on separate occasions and followed by a certified 
letter) will be made to locate or recall them, or at least to determine their health status. These 
efforts will be documented in the subjects’ records. 
5.2.4 
Subject Replacement 
Subjects who have not received any amount of study drug and discontinue their participation 
may be replaced.  
Additionally, the first subject in each cohort to discontinue from participation due to loss to 
follow up, after receiving any amount of study product, is not replaced; if more than one subject 
in any cohort discontinues participation, these subjects will be replaced. Replacement of any 
subject is at the discretion of the PI in consultation with the Sponsor. Replacement subjects 


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should be allocated to the same treatment as the subject they replaced. The SDCC must be 
contacted prior to enrolling a replacement subject. 
5.2.5 
Study Termination  
Although DMID has every intention of completing this trial, it reserves the right to terminate this 
trial at any time for clinical or administrative reasons. 
If this trial is prematurely terminated by the Sponsor, any regulatory authority, or the Site PI for 
any reason, the Site PI will promptly inform the subjects and assure appropriate therapy or FU 
for the subjects, as necessary. The Site PI will provide a detailed written explanation of the 
termination to the IRB/IEC. 


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STUDY PROCEDURES 
 
Recruitment 
Up to 86 subjects aged 18-45 years (inclusive) who are in good health and meet all eligibility 
criteria will be enrolled in this trial. The demographics in the local population should ensure that 
male, females, and minorities (African American, Native American, Asian and Hispanics) will 
be represented in the enrolled population. Subjects will be recruited using IRB-approved 
advertising/web site listings of the essential inclusion and exclusion criteria. Subjects will self-
schedule online for a screening appointment based on their desire to participate and their 
evaluation of their suitability based on inclusion/exclusion criteria. Children, pregnant or breast-
feeding women, prisoners, and other vulnerable populations will not be enrolled. 
Upon arrival to the Clinical Research Unit (CRU), individuals will be checked for eligibility 
through the Verified Clinical Trials (VCT) process (after signing the IRB-approved VCT ICF) 
and then given the IRB-approved ICF and HIPAA form, and be assigned to Part 1, 2 or 3 of the 
study for enrollment.  After presentation of the ICF and individuals indicate their desire to 
proceed, they will be brought to a private room and given an opportunity to ask questions of the 
licensed nurse or doctor delegated to perform consenting. After the subject signs the ICF, 
protocol procedures will be initiated. 
Trial retention strategies will include education and explanation of the trial schedule and 
procedures during Screening and Enrollment visits. In addition, reimbursements will be 
disbursed at specific timepoints during this trial with the amount contingent on completing trial 
procedures. Subjects will be reminded of visits ahead of time, and trial staff will contact subjects 
who miss appointments to encourage them to return for completion of safety evaluations. 
 
Screening (Day -28 to Day -2) Parts 1-3 (All Cohorts) 
After providing written informed consent, each subject will be assigned a subject identification 
number and undergo an eligibility assessment. The following will be done during the screening 
period (within 28 days before study drug administration). Results of screening tests and 
procedures will be evaluated by the Site PI to determine eligibility before enrollment and 
randomization. 


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• Record demographics including age, gender, race, and ethnicity. Obtain contact 
information. 
• Obtain medical history that includes: 
a) 
current medical diagnoses, 
b) 
past medical diagnoses, 
c) 
hospitalizations, 
d) 
major surgical procedure, 
e) 
blood transfusions or immunoglobulin administrations within 14 days of dosing, 
f) 
live vaccines within14 days of dosing, 
g) 
killed vaccines within 14 days of dosing, 
h) 
blood or blood product donation, or significant blood loss within 60 days of 
dosing, 
i) 
allergic reactions, 
j) 
drug and/or alcohol use or dependence, 
k) 
receipt of an investigational drug within 28 days of dosing. 
• Review concomitant medication history, including all medications taken within 14 days 
of dosing. 
• Review recent menstrual history (female subjects only) and current use of contraceptive 
method. 
• Perform complete PE by licensed clinician listed on Form FDA 1572. 
• Obtain height and weight and calculate BMI. 
• Take resting vital signs after being at rest for at least 5 minutes. 


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• Obtain fasting (at least 8 hours) blood samples for clinical chemistry, hematology, 
coagulation tests, serum pregnancy test [if female of childbearing potential], FSH [if 
female and post-menopausal], and serology screen (serum HIV, HBsAg, and HCV 
antibodies). 
• Obtain urine sample for urinalysis, urine drug screen and urine alcohol. 
• Obtain urine sample for cotinine test. 
• Obtain a 12-lead ECG, after at least 5 minutes in the supine position (triplicate readings, at 
least 1 minute apart within a 15-minute period) to assess heart rate, rhythm, and interval 
information such as PR, QRS, QT, and QTc, after being supine for at least 5 minutes. 
• Counsel on the avoidance of pregnancy for women of child-bearing potential and use of 
barrier contraception for men. 
• Counsel on the avoidance of vaccines, blood/blood product/sperm donation and drugs and 
dietary restrictions listed in Section 5.1. 
 
Admission to the CRU (Day -1) Parts 1 and 2 (All Cohorts) and Part 
3 (Cohort 11) Days -1 and 21  
Subjects will be admitted to the CRU on the day before injection (or infusion for Part 3) and the 
following procedures will be performed: 
• On admission to the CRU on Day-1, review inclusion/exclusion criteria to ensure the 
subject is eligible for enrollment.   For Part 3, Day 21, review inclusion criteria numbers 
2-7 and 10-11, and exclusion criteria numbers 2-4 and 8-18 (from Section 5.1.2) to ensure 
the subject remains eligible for dosing.  
• Update medical history. 
• Review and update concomitant medications. 
• Perform targeted PE. 


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• Obtain resting vital signs after being at rest for at least 5 minutes. 
• Obtain weight, calculate BMI. 
• Obtain blood samples for baseline fasting (at least 8 hours) clinical chemistry, 
hematology, coagulation tests, serum pregnancy test [if female of childbearing potential]); 
for the Day -1 visit, if clinical chemistry, hematology or coagulation test result(s) are 
outside of the reference range(s), they may not be repeated; if a result is not considered by 
the site investigator to be clinically insignificant, the subject is removed from the study. 
• For women of child-bearing potential, perform a serum pregnancy test (results must be 
confirmed negative before dosing). 
• Obtain blood and urine samples for safety clinical labs. 
• Obtain urine sample for drug screen and urine alcohol. 
• Obtain urine sample for cotinine test. 
• Part 3 (Cohort 11) only, Day 21 – review Memory Aid. 
 
Part 1 (Cohorts 1 through 6) 
6.4.1 
Day 1 – Inpatient CRU 
• On the morning of Day 1, study drug or placebo will be administered via SC injection in 
the abdomen at a slow steady pace. Subjects will be inpatients in the CRU and will 
undergo the following procedures, which are listed in the Schedule of Study Procedures 
and Evaluations (Appendix A) and detailed in Clinical Evaluations (Section 7).  
• Randomize the subject. 
• Obtain vital signs before study drug dosing (within 60 minutes of study drug dosing) after 
resting in a supine or semi-supine position for at least 5 minutes. This is to be documented 
as the Baseline prior to dosing. 
• Perform targeted PE. 


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• Obtain a 12-lead ECG after at least 5 minutes in the supine position (triplicate readings, at 
least 1 minute apart within a 15-minute period) and within 60 minutes before study drug 
dosing. 
• Baseline skin assessment at SC injection site area prior to study drug dosing (see Section 
7.1.3 and MOP for this study). 
• Administer study drug. 
• Obtain vital signs at 15 minutes (±5 min), 1 hour (±10 min), and 2 hours (±10 min) after 
dosing, after resting in a supine or semi-supine position for at least 5 minutes. 
• Collect PK blood samples for pre-dose, (collected within 60 minutes before study drug 
dosing) and at 0.5 h (±5 min), 1 h (±10 min), 2 h (±10 min), 4 h (±10 min), 6 h (±10 min), 
8 h (±10 min), and 12 h (±10 min). No PK blood samples collected in Cohort 1. 
• Assess reactogenicity at SC injection site(s) at 1 h (±10 min) and 4 h (±10 min) post-dose 
(see Section 7.1.3 and MOP for this study). 
• 12-lead ECG at 4 hours (±10 minutes) after injection after at least 5 minutes in the supine 
position (triplicate readings, at least 1 minute apart within a 15-minute period). 
• Assess AEs. 
• Review and record any concomitant medications and non-pharmacologic 
treatments/procedures since admission to the CRU. 
• Issue Memory Aid. Details regarding the subject Memory Aid are included in the MOP 
for this study. 
6.4.2 
Day 2 – Inpatient CRU 
• Obtain vital signs 24 hours (±30 min) after resting in a supine or semi-supine position for 
at least 5 minutes. 
• Perform targeted PE. 


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• Obtain blood for hematology/coagulation/chemistry and urine for urinalysis. 
• Obtain PK blood sample 24 hours (±30 min) after dosing. No PK blood samples collected 
in Cohort 1. 
• Assess reactogenicity at SC injection site at 24 h (±30 min) post-dose (see Section 7.1.3 
and MOP for this study). 
• Assess AEs. 
6.4.3 
Day 3 – Inpatient CRU 
• Obtain PK blood sample 48 hours (±30 min) after dosing. No PK blood samples collected 
in Cohort 1. 
• Assess reactogenicity at SC injection site(s) at 48 h (±30 min) post-dose (see Section 7.1.3 
and MOP for this study). 
• Assess AEs. 
• Review and record any concomitant medications and non-pharmacologic 
treatments/procedures since admission to the CRU. 
6.4.4 
Day 4 – Inpatient CRU 
• Obtain resting vital signs 72 h (±30 min) after being at rest for at least 5 minutes. 
• Perform targeted PE. 
• Assess reactogenicity at SC injection site(s) at 72 h (±30 min) post-dose (see Section 7.1.3 
and MOP for this study). 
• Assess AEs. 
6.4.5 
Day 5 – Inpatient CRU 
• Obtain PK blood sample 96 hours (±30 min) after dosing. No PK blood samples collected 
in Cohort 1. 


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• Assess reactogenicity at SC injection site(s) at 96 h (±30 min) post-dose (see Section 7.1.3 
and MOP for this study). 
• Assess AEs. 
• Review and record any concomitant medications and non-pharmacologic 
treatments/procedures since admission to the CRU. 
6.4.6 
Day 6 – Inpatient CRU 
• Assess reactogenicity at SC injection site(s) at 120 h (±30 min) post-dose (see Section 
7.1.3 and MOP for this study). 
• Assess AEs. 
6.4.7 
Day 7 – Inpatient CRU 
• Obtain resting vital signs 144 hours (±30 min) after being at rest for at least 5 minutes. 
• 12-lead ECG after at least 5 minutes in the supine position (triplicate readings, at least 1 
minute apart within a 15-minute period). 
• Perform targeted PE. 
• Obtain blood for hematology/coagulation/chemistries and urine for urinalysis. 
• Obtain PK blood sample 144 hours (±30 min) after dosing. No PK blood samples 
collected in Cohort 1. 
• Assess reactogenicity at SC injection site(s) at 144 h (±30 min) post-dose (see Section 
7.1.3 and MOP for this study). 
• Assess AEs. 
• Review and record any concomitant medications and non-pharmacologic 
treatments/procedures since admission to the CRU. 


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• Counsel on contraceptive use and provide post-discharge instructions (dietary and 
medication/nonmedication, vaccine and blood/blood product/sperm donation restrictions). 
• Train on proper completion of Memory Aid. 
• Subject discharge from CRU after all procedures are completed. 
6.4.8 
Day 14 (±1 Day) – Follow-Up - Outpatient 
• Obtain resting vital signs after being at rest for at least 5 minutes. 
• Obtain PK blood sample. No PK blood samples collected in Cohort 1. 
• Assess reactogenicity at SC injection site(s) (see Section 7.1.4 and MOP for this study). 
• Assess AEs. 
• Review and record any concomitant medications and non-pharmacologic 
treatments/procedures since admission to the CRU. 
• Review Memory Aid. 
• Reminder of contraceptive use and post-discharge instructions (dietary and 
medication/nonmedication, vaccine and blood/blood product/sperm donation restrictions). 
 
6.4.9 
Day 21 (±1 Day) – Telephone Follow-Up 
• Interview subjects for changes at SC injection site(s); refer subjects for unscheduled visit 
if changes at SC injection site(s) reported. 
• Review Memory Aid. 
• Remind subjects to report changes at SC injection site(s) immediately. 
 


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6.4.10 
Day 30 (±1 Day) – Follow-Up – Final Study Visit 
• Obtain resting vital signs after being at rest for at least 5 minutes. 
• 12-lead ECG after at least 5 minutes in the supine position (triplicate readings, at least 1 
minute apart within a 15-minute period). 
• Perform targeted PE. 
• Obtain weight, calculate BMI. 
• Obtain blood for hematology/coagulation/chemistry and urine for urinalysis. 
• Perform serum pregnancy test (females of childbearing potential only). 
• Obtain PK blood sample. No PK blood samples collected in Cohort 1. 
• Assess reactogenicity at SC injection site(s) (see Section 7.1.3 and MOP for this study). 
• Assess AEs. 
• Review Memory Aid. 
• Review and record any concomitant medications and non-pharmacologic 
treatments/procedures since admission to the CRU. 
• Review post-study instructions (contraceptive use, pregnancy reporting). 
 
 
Part 2 (Cohorts 7 through 10) 
6.5.1 
Days 1, 8, and 15 – Inpatient CRU 
Study drug or placebo will be administered via SC injection in the morning on Days 1, 8, and 15. 
Subjects will be inpatients in the CRU and will undergo the following procedures, which are 
listed in the Schedule of Study Procedures and Evaluations (Appendix A) and detailed in Clinical 
Evaluations (Section 7): 


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• Randomize the subject (Day 1 only). 
• Review inclusion criteria numbers 2-7 and 10-11, and exclusion criteria numbers 2-4 and 
8-18 (from Section 5.1.2) to ensure the subject remains eligible for dosing (Days 8 and 15 
only). 
• Obtain resting vital signs before study drug dosing (within 60 minutes of study drug 
dosing for Day 1). This is to be documented as the Baseline prior to dosing on Day 1. 
• Perform targeted PE. 
• Obtain a 12-lead ECG before study drug dosing (Day 1 only) after at least 5 minutes in the 
supine position (triplicate readings, at least 1 minute apart within a 15-minute period) and 
within 60 minutes before study drug dosing. 
• Baseline (Day 1) and pre-dose (Days 8 and 15) skin assessment at SC injection site area(s) 
prior to study drug dosing (see Section 7.1.3 and MOP for this study). 
• Administer study drug via SC injection in the abdomen at a slow, steady pace. 
• Obtain vital signs at 15 minutes (±5 min), 1 hour (±10 min), and 2 hours (±10 min) after 
dosing, after resting in a supine or semi-supine position for at least 5 minutes. 
• 12-lead ECG at 4 hours (±10 minutes) after injection after at least 5 minutes in the supine 
position (triplicate readings, at least 1 minute apart within a 15-minute period). 
• Obtain PK blood samples within 60 minutes prior to study drug dosing (for Day 1) and at 
0.5 h (±5 min), 1 h (±10 min), 2 h (±10 min), 4 h (±10 min), 6 h (±10 min), 8 h (±10 min), 
and 12 h (±10 min) after dosing (Days 1 and 15); or within 15 minutes prior to dosing and 
at 1 h (±10 min), and 4 h (±10 min) after dosing (Day 8 only). 
• Assess reactogenicity at SC injection site(s) at 1 h (±10 min) and 4 h (±10 min) post-dose 
(see Section 7.1.3 and MOP for this study). 
• Assess AEs. 


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• Review and record any concomitant medications and non-pharmacologic 
treatments/procedures since administration to the CRU, 
• Issue Memory Aid. Details regarding the subject Memory Aid are included in the MOP 
for this study. 
6.5.2 
Days 2, 9, and 16 – Inpatient CRU 
• Obtain resting vital signs 24 hours (±30 min) after being at rest for at least 5 minutes. 
• Perform targeted PE. 
• Assess reactogenicity at SC injection site(s) at 24 h (±30 min) post dose (see Section 7.1.3 
and MOP for this study). 
• Obtain blood for hematology/coagulation/chemistry and urine for urinalysis. 
• Obtain PK blood sample 24 hours (±30 min) after dosing (Days 2 and 16 only). 
• Assess AEs. 
6.5.3 
Days 3, 10, and 17 – Inpatient CRU 
• Obtain PK blood sample 48 hours (±30 min) after dosing (Days 3 and 17 only). 
• Assess reactogenicity at SC injection site(s) at 48 h (±30 min) post dose (see Section 7.1.3 
and MOP for this study). 
• Assess AEs. 
• Review and record any concomitant medications and non-pharmacologic 
treatments/procedures since admission to the CRU. 
6.5.4 
Days 4, 11, and 18 – Inpatient CRU 
• Obtain resting vital signs 72 hours (±30 min) after being at rest for at least 5 minutes. 
• Perform targeted PE. 


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• Assess reactogenicity at SC injection site(s) at 72 h (±30 min) post dose (see Section 7.1.3 
and MOP for this study). 
• Assess AEs. 
6.5.5 
Days 5, 12, and 19 – Inpatient CRU 
• Obtain PK blood sample 96 hours (±30 min) after dosing. 
• Assess reactogenicity at SC injection site(s) at 96 h (±30 min) post dose (see Section 7.1.3 
and MOP for this study). 
• Assess AEs. 
• Review and record any concomitant medications and non-pharmacologic 
treatments/procedures since admission to the CRU. 
6.5.6 
Days 6, 13, and 20 – Inpatient CRU 
• Assess reactogenicity at SC injection site(s) at 120 h (±30 min) post dose (see Section 
7.1.3 and MOP for this study). 
• Assess AEs. 
6.5.7 
Days 7, 14, and 21 – Inpatient CRU 
• Obtain resting vital signs 144 hours (±30 min) after being at rest for at least 5 minutes. 
• 12-lead ECG after at least 5 minutes in the supine position (triplicate readings, at least 1 
minute apart within a 15-minute period). (Day 21 only) 
• Perform targeted PE. 
• Obtain blood for hematology/coagulation/chemistry and urine for urinalysis. 
• Obtain PK blood sample 144 hours (±30 min) after dosing. 
• Assess reactogenicity at SC injection site(s) at 144 h (±30 min) post dose (see Section 
7.1.3 and MOP for this study). 


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• Assess AEs. 
• Review and record any concomitant medications and non-pharmacologic 
treatments/procedures since admission to the CRU.  
• Counsel on contraceptive use and provide post-discharge instructions (dietary and 
medication/nonmedication, vaccine and blood/blood product/sperm donation restrictions). 
• Train on proper completion of Memory Aid (Day 21 only). 
• Subject discharge from CRU after all procedures completed (Day 21 only). 
6.5.8 
Day 30 (±1 Day) – Follow-Up - Outpatient 
• Obtain resting vital signs after being at rest for at least 5 minutes. 
• 12-lead ECG after at least 5 minutes in the supine position (triplicate readings, at least 1 
minute apart within a 15-minute period). 
• Perform targeted PE. 
• Obtain PK blood sample. 
• Assess reactogenicity at SC injection site(s) (see Section 7.1.3 and MOP for this study). 
• Assess AEs. 
• Review Memory Aid. 
• Review and record any concomitant medications and non-pharmacologic 
treatments/procedures since discharge from the CRU. 
• Reminder of contraceptive use and post-discharge instructions (dietary and 
medication/nonmedication, vaccine and blood/blood product/sperm donation restrictions). 
 


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6.5.9 
Day 45 (±1 Day) – Follow-Up – Final Study Visit 
• Obtain resting vital signs after being at rest for at least 5 minutes. 
• 12-lead ECG after at least 5 minutes in the supine position (triplicate readings, at least 1 
minute apart within a 15-minute period). 
• Perform targeted PE. 
• Obtain weight, calculate BMI. 
• Obtain blood for hematology/coagulation/chemistry and urine for urinalysis. 
• Perform serum pregnancy test (females only). 
• Obtain PK blood sample. 
• Assess reactogenicity at SC injection site(s) (see Section 7.1.4 and MOP for this study). 
• Assess AEs. 
• Review and record any concomitant medications and non-pharmacologic 
treatments/procedures since Day 30. 
• Review Memory Aid. 
• Review post-study instructions (contraceptive use, pregnancy reporting).  
 
 
Part 3 (Cohort 11) 
6.6.1 
Days 1 and 22 – Inpatient CRU 
For Cohort 11, the subject will be randomized to sequence and either the study drug will be 
administered via SC injection in the morning on Day 1 and as an IV infusion over 60 (±5) 
minutes in the morning on Day 22; or the study drug will be administered via IV infusion over 
60 (±5) minutes in the morning on Day 1 and via SC injection in the morning on Day 22. 
Subjects will be inpatients in the CRU and will undergo the following procedures, which are 


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listed in the Schedule of Study Procedures and Evaluations (Appendix A) and detailed in Clinical 
Evaluations (Section 7): 
• Randomize the subject (Day 1 only). 
• Review inclusion criteria numbers 2-7 and 10-11, and exclusion criteria numbers 2-4 and 
8-18 (from Section 5.1.2) to ensure the subject remains eligible for dosing (Day 22 only). 
• Obtain resting vital signs before study drug dosing (within 60 minutes of study drug 
dosing. This is to be documented as the Baseline prior to dosing on Day 1. 
• Perform targeted PE. 
• Obtain a 12-lead ECG within 60 minutes of study drug dosing, (Day 1 only), after at least 
5 minutes in the supine position (triplicate readings, at least 1 minute apart within a 15-
minute period). 
• Baseline skin assessment at SC injection site area prior to study drug dosing: assess 
reactogenicity at SC injection site before study drug dosing on Day 22 (see Section 7.1.3 
and MOP for this study). 
• Administer study drug. 
• Obtain vital signs (SC): at 15 minutes (±5 min), 1 hour (±10 min), and 2 hours (±10 min) 
after dosing, after resting in a supine or semi-supine position for at least 5 minutes. 
• Obtain vital signs (IV): at 15 minutes (±5 min), 1 hour (±10 min), and 2 hours (±10 min) 
after start of infusion, and after resting in a supine or semi-supine position for at least 5 
minutes. 
• Obtain PK blood samples within 60minutes before study drug dosing and at 0.5 h 
(±5 min), 1 h (±10 min), 2 h (±10 min), 4 h (±10 min), 6 h (±10 min), 8 h (±10 min), and 
12 h (±10 min) after the start of infusion or injection. 
• Post dose ECG (SC) at 4 hours (±10 minutes) after SC injection, 12-lead ECG after at 
least 5 minutes in the supine position (triplicate readings, at least 1 minute apart within a 
15-minute period). 


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• Post dose ECG (IV) at 1 hour (±10 minutes) from beginning of IV infusion, 12-lead ECG 
after at least 5 minutes in the supine position (triplicate readings, at least 1 minute apart 
within a 15-minute period). 
• Assess reactogenicity at SC injection site at 1 h (±10 min) and 4 h (±10 min) post dose 
(see Section 7.1.3 and MOP for this study). 
• Assess AEs. 
• Review and record any concomitant medications and non-pharmacologic 
treatments/procedures since admission to the CRU. 
• Issue Memory Aid (Day 1 only). Details regarding the subject Memory Aid are included 
in the MOP for this study. 
6.6.2 
Days 2 and 23 – Inpatient CRU 
• Obtain resting vital signs 24 hours (±30 min) after being at rest for at least 5 minutes. 
• Perform targeted PE. 
• Assess reactogenicity at SC injection site at 24 h (±30 min) post dose (see Section 7.1.4 
and MOP for this study). 
• Obtain blood for hematology/coagulation/chemistry and urine for urinalysis. 
• Obtain PK blood sample 24 hours (±30 min) after dosing. 
• Assess AEs. 
6.6.3 
Days 3 and 24 – Inpatient CRU 
• Obtain PK blood sample 48 hours (±30 min) after dosing. 
• Assess reactogenicity at SC injection site at 48 h (±30 min) post dose (see Section 7.1.4 
and MOP for this study). 
• Assess AEs. 


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• Review and record any concomitant medications and non-pharmacologic 
treatments/procedures since admission to the CRU. 
6.6.4 
Days 4 and 25 – Inpatient CRU 
• Obtain resting vital signs 72 hours (±30 min) after being at rest for at least 5 minutes. 
• Perform targeted PE. 
• Assess reactogenicity at SC injection site at 72 h (±30 min) post dose (see Section 7.1.4 
and MOP for this study). 
• Assess AEs. 
6.6.5 
Days 5 and 26 – Inpatient CRU 
• Obtain PK blood sample 96 hours (±30 min) after dosing. 
• Assess reactogenicity at SC injection site at 96 h (±30 min) post dose (see Section 7.1.4 
and MOP for this study). 
• Assess AEs. 
• Review and record any concomitant medications and non-pharmacologic 
treatments/procedures since admission to the CRU. 
 
6.6.6 
Days 6 and 27 – Inpatient CRU 
• Assess reactogenicity at SC injection site at 120 h (±30 min) post dose (see Section 7.1.4 
and MOP for this study). 
• Assess AEs. 
6.6.7 
Days 7 and 28 – Inpatient CRU 
• Obtain resting vital signs 144 hours (±30 min) after being at rest for at least 5 minutes. 
• Perform targeted PE. 


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• Obtain blood for hematology/coagulation/chemistry and urine for urinalysis. 
• Obtain PK blood sample 144 hours (±30 min) after dosing. 
• Assess reactogenicity at SC injection site at 144 h (±30 min) post dose (see Section 7.1.4 
and MOP for this study). 
• Assess AEs. 
• Review and record any concomitant medications and non-pharmacologic 
treatments/procedures since admission to the CRU. 
• Counsel on contraceptive use and provide post-discharge instructions (dietary and 
medication/nonmedication, vaccine and blood/blood product/sperm donation restrictions), 
• Train on proper completion of Memory Aid (Day 7), refresher (Day 28). 
• Subject discharge from CRU after all procedures completed. 
6.6.8 
Days 14 (±1 Day) and 35 (±1 Day) – Follow-Up - Outpatient 
• Obtain vital signs after resting in a supine or semi-supine position for at least 5 minutes. 
• Perform targeted PE. 
• Obtain PK blood sample. 
• Assess reactogenicity at SC injection site (see Section 7.1.4 and MOP for this study). 
• Assess AEs. 
• Review and record any concomitant medications and non-pharmacologic 
treatments/procedures since discharge from the CRU.  
• Review Memory Aid. 
• Reminder of contraceptive use and post-discharge instructions (dietary and 
medication/nonmedication, vaccine and blood/blood product/sperm donation restrictions). 


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6.6.9 
Day 52 (±1 Day) – Follow-Up – Final Study Visit 
• Obtain vital signs after resting in a supine or semi-supine position for at least 5 minutes. 
• 12-lead ECG after at least 5 minutes in the supine position (triplicate readings, at least 1 
minute apart within a 15-minute period). 
• Perform targeted PE. 
• Obtain weight, calculate BMI. 
• Obtain blood for hematology/coagulation/chemistry and urine for urinalysis. 
• Perform serum pregnancy test (females only). 
• Obtain PK blood sample. 
• Assess AEs. 
• Review and record any concomitant medications and non-pharmacologic 
treatments/procedures since Day 35. 
• Review Memory Aid. 
• Review post-study instructions (contraceptive use, pregnancy reporting). 
 
6.6.10 
Early Termination (ET) Visit (if needed) 
The CRU will make every effort to perform all assessments listed for the last scheduled FU visit 
if a subject is terminated prematurely from this trial. All information collected will be 
documented in eCRFs or study records. 


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Unscheduled Study Visits  
Subjects will return to the CRU at the direction of the Site PI for FU and data from unscheduled 
visits or procedures (if any) and will be captured and presented in data listings. These data will 
be clearly identified as unscheduled observations. Safety assessments, including updated history, 
AEs, PE, and any other trial procedures deemed necessary by the PI, will be obtained. 
Subjects returning to the CRU for unscheduled visit(s) may undergo procedures, including but 
not limited to, the following, which are listed in the Schedule of Study Procedures and 
Evaluations (Appendix A) and detailed in Clinical Evaluations (Section 7): 
• Review and record any concomitant medications and non-pharmacologic 
treatments/procedures since last visit, 
• Obtain a 12-lead ECG after at least 5 minutes in the supine position (triplicate readings, at 
least 1 minute apart within a 15-minute period), 
• Obtain blood for hematology/coagulation/chemistry and urine for urinalysis, 
• Perform targeted PE including resting vital signs (heart rate, blood pressure, oral 
temperature, and respiration rate, taken after resting for at least 5 minutes). If abnormal, 
these measurements may be repeated once, 
• Review Memory Aid, 
• Assess AEs. 
 
 


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Protocol Deviations 
A protocol deviation is any noncompliance with this protocol, GCP, or protocol-specific MOP 
requirements. The noncompliance may be either on the part of the subject, the Site PI, or the site 
personnel. As a result of deviations, corrective actions will be developed by the site and 
implemented promptly. 
These practices are consistent with ICH E6: 
4.5 
Compliance with Protocol, Sections 4.5.1, 4.5.2, and 4.5.3 
5.1 
Quality Assurance (QA) and Quality Control (QC), Section 5.1.1 
5.20 
Noncompliance, Sections 5.20.1, and 5.20.2. 
It is the responsibility of the Site PI and personnel to use continuous vigilance to identify and 
report deviations within 5 working days of identification of the protocol deviation, or within 
5 working days of the scheduled protocol-required activity. All deviations must be promptly 
reported to DMID per the Statistical and Data Coordinating Center (SDCC) protocol deviation 
reporting procedures. 
All protocol deviations, as defined above, must be addressed in subject data collection forms 
(DCFs). Protocol deviations must be sent to the local IRB/IEC per their guidelines. The Site PI 
and personnel are responsible for knowing and adhering to their IRB requirements. 


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DESCRIPTION OF CLINICAL AND LABORATORY 
EVALUATIONS 
 
Clinical Evaluations 
7.1.1 
Medical History 
Medical history will be obtained by direct interview. Subjects will be queried regarding a history 
of significant medical disorders of the head, eyes, ears, nose, throat, mouth, cardiovascular 
system, lungs, gastrointestinal tract, liver, pancreas, kidney, urologic, nervous system, blood, 
lymph glands, endocrine system, musculoskeletal system, skin, and genital/reproductive tract. A 
history of any allergies, cancer, immunodeficiency, psychiatric illness, substance abuse, and 
autoimmune disease will be solicited. The medical history will include current and past medical 
diagnoses, hospitalizations and major surgical procedures. Demographic information (date of 
birth, gender, race, ethnicity) will be obtained as part of the medical history assessment. The 
medical history will be obtained at screening and updated upon admission to the CRU on Day -1. 
7.1.2 
Height, Weight, Body Mass Index (BMI) 
All subjects will have height measured (at Screening only) and be weighed following the CRU’s 
standard operating procedures at Screening, Day -1 and at the final study visit.  BMI is calculated 
as: (weight in kg divided by height in m, squared). Subjects who no longer meet inclusion 
criteria due to changes in weight or BMI after dosing remain eligible and will not be removed 
from the study.   
7.1.3 
Physical Examinations 
A complete PE at Screening will evaluate vital signs (taken after resting for at least 5 minutes); 
general appearance; head, eyes, ears, nose, and throat; neck; chest and lungs; cardiovascular 
system, abdomen, musculoskeletal system, lymph nodes, extremities/skin, and neurological 
system. 
A targeted PE will evaluate resting vital signs, skin, and suspected organ systems described in 
any solicited or unsolicited AEs, at times specified in Appendix A. 
7.1.4 
Local Reactogenicity Symptoms 
Reactogenicity assessments will include an assessment of AEs occurring after dose 
administration on Day 1 through Day 30 of Part 1 (SAD), Day 30 of Part 2 (MAD) or Day 35 of 


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Part 3 (BA), which includes an assessment of SC injection site reactions (see Additional 
Characterization of Reactogenicity at Injection Sites, below). Pre-administration (baseline) 
injection site skin assessments will be performed prior to each study injection to establish 
baseline, then the study injection will be given. 
The study SC injection site(s) will be examined pre-dose and at 1 and 4 h (±10 minutes), 24, 48, 
72, 96, 120, 144 h (±30 minutes) post-administration in all cohorts (SAD/MAD/BA). Additional 
injection site examinations will occur on Day 14 of Part 1 (SAD), Day 30 of Part 2 (MAD), and 
Days 14 and 35 of Part 3 (BA), and any AE/SAEs will be recorded on the appropriate data 
collection form. 
Additional Characterization of Reactogenicity at Injection Sites 
Lesions at the injection site will be characterized by the study site staff as follows:  
1. Ecchymosis: non-raised skin discoloration caused by the escape of blood into the tissues from 
ruptured blood vessels  
2. Erythema: localized redness  
3. Induration: (hardness)/swelling 
4. Nodule: solid or cystic raised bump in the skin  
5. Ulcer: an open lesion on the surface of the skin caused by superficial loss of tissue.  NOTE:  
Ulcers at the injection site, regardless of size or severity, are of special interest and must be 
measured as well as photographed*, according to the MOP for this study.  Please see Section 
8.1.3 for reporting details and Section 8.7 for halting rules. 
6. Healed**: previously observed lesion that has dried up without any persistent induration or 
ulcer.   
7. Scar**: replacement of normal skin with fibrous tissue 
*All SC site reactions will be photographed at each visit, scheduled and unscheduled until 
resolution. 
**Recorded, but not graded. 
 
 


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7.1.5 
Vital Signs 
Vital signs (body temperature, heart rate, respiration rate, and blood pressure) will be obtained at 
times specified in Appendix A. Vital signs will be measured after resting at least 5 minutes. The 
pre-dose vital signs on days of dosing will be measured within 60 minutes of study drug dosing; 
Day 1 post-dose vital signs measurements should be taken within ± 5 minutes of the 15-minute 
post-dose timepoint and within ± 10 minutes for additional post-dose timepoints. Other vital 
signs during the inpatient stay will be taken within ±30 minutes of the nominal timepoint. For 
outpatient visits, vital signs will be measured within the visit window. 
Day 1 post-dose timepoints for vital sign measurements for the IV portion of Part 3 will be based 
on the start of infusion.    
7.1.6 
Electrocardiograms 
Standard 12-lead ECGs to assess heart rate, rhythm, and PR, QRS, QT, and QTc interval 
durations will be obtained at times specified in Appendix A. 
ECGs (triplicate readings, at least 1 minute apart within a 15-minute period), will be taken after 
at least 5 minutes in the supine position. The pre-dose ECGs on days of dosing will be taken 
within 60 minutes of study drug dosing. Post dose ECGs on days of dosing will be taken at 4 
hours (±10 minutes) after SC dosing. Post dose ECGs on days of dosing will be taken at 1 hour 
(±10 minutes) from start of infusion for IV administration in Part 3. 
ECGs will also be taken at the following timepoints: 
• Day 7, Day 30, and Unscheduled visits for SAD 
• Day 21, Day 30, Day 45, and Unscheduled visits for MAD 
• Day 52 and Unscheduled visits for BA 
The screening ECG will be used by the PI to determine a subject’s eligibility for enrolment. The 
Day 1 pre-dose ECG will be reviewed to determine if subjects can be dosed. 
All ECGs will be reviewed by the PI or designee. ECGs with the following readings will be 
considered acceptable for trial participation and will not be considered abnormal for trial 
purposes unless the PI or physician designee believes they represent a new medical condition 
when compared to baseline ECGs. In such cases an AE will be documented, and the subject will 
be followed for safety evaluations as appropriate. The following pre-existing conditions 
identified at enrolment will not be considered AEs: 


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• Sinus bradycardia, 
• Sinus arrhythmia, 
• Subjects without a history of prolonged QTc and an abnormal QTc interval at Screening 
will undergo repeat ECG assessment within the screening period before randomization to 
confirm prolongation. If the repeat ECG QTcF is within normal limits (see Appendix B) 
the subject may be considered for enrolment. 
The Sponsor may review all or individual screening ECGs or may delegate to determine if meets 
intention of entry criteria goal of enrolling healthy normal subjects. 
If a subject has possible cardiac-related symptoms, repeat ECGs will be obtained every 
30 minutes (±3 minutes) until the waveform reverts to its baseline appearance, or symptoms 
resolve, or are determined not to be cardiac-related. Subjects with cardiac-related symptoms that 
are associated with ECG changes will be transferred to appropriate emergency department for 
further evaluation and treatment at the discretion of the PI. 
7.1.7 
Assessment of Concomitant Medications/Treatments Other than Study Product 
Subjects are required to abide by the following rules regarding intake of medications and other 
substances before and during the study: 
1) Refrain from the use of any prescription medications (with the exception of hormonal 
contraceptives), within 14 days before the first study drug administration and until after the 
final study visit. 
2) Refrain from the use of over-the-counter medications including vitamins, supplements, and 
herbal supplements (except for acetaminophen or ibuprofen) within 14 days before the first 
study drug administration, 
3) The use of tobacco product, including smoking and the use of snuff and chewing tobacco, 
and other nicotine or nicotine-containing products (including patches), is not permitted by a 
subject within 90 days of Screening for the study or while a subject is enrolled in the study. 
A urine test for cotinine will be performed at Screening and upon admission to the CRU. 
4) Refrain from consuming foods or beverages containing the following substances for the 
duration of the study: 
5) Alcohol: ≤48 hours before the first study drug administration until discharge. A urine alcohol 
test will be performed at Screening and upon admission to the CRU. 


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6) Xanthines/caffeine: ≤24 hours before the first study drug administration and until discharge.  
7) Refrain from receiving a live or killed vaccine, or immunoglobin, within 14 days prior to 
dosing. 
8) The use of illegal drugs is not permitted while a subject is enrolled in this study. A urine drug 
test will be performed at Screening and upon admission to the CRU. 
9) Previous participation in this trial, any other rezafungin trial, or any trial involving 
administration of drug product within 28 days of study drug dosing. Plans to enroll in another 
clinical trial that could interfere with safety assessment of the investigational product at any 
time during the study period; 
If a subject is unable to comply with the restrictions described above, the subject’s continued 
participation in the study will be re-evaluated by the Investigator, in consultation with the 
Medical Monitor. 
 
Laboratory Evaluations 
7.2.1 
Clinical Laboratory Evaluations 
All laboratory assessments will be done by the clinical site’s certified laboratory. Laboratory 
toxicity grading will be determined by use of the FDA Guidance for Industry: Toxicity Grading 
Scale for Healthy Adult and Adolescent Volunteers Enrolled in Preventive Vaccine Clinical 
Trials September 2007 and the Division of Microbiology and Infectious Diseases (DMID) Adult 
Toxicity Table November 2007, as modified for this study and appropriate for the administration 
of rezafungin (Appendix B. Toxicity Grading Criteria for Normal Human Subjects). 
At Screening, laboratory test values that fall outside the reference range on the laboratory reports 
and deemed not clinically significant by the Investigator may be repeated at the discretion of the 
Investigator (to assess for transitional conditions). Laboratory values that fall outside of the 
reference range on Day -1 (baseline), may not be repeated, and subject will be withdrawn from 
the study. (See Note below for exceptions). 
If a single repeat Screening evaluation is within the reference range, the subject may be further 
considered for study eligibility.   
Note: Hematuria during active menses causing urinalysis results outside the reference range will 
not be considered clinically significant (not an AE). 
 
 


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Viral Serology Testing 
Subjects will be screened for HIV antibody, hepatitis B surface antigen, and hepatitis C virus 
antibody. These tests must be negative for eligibility into this trial. In cases where a false positive 
result is suspected, confirmatory testing may be performed (e.g., Polymerase Chain Reaction). 
Drug, Alcohol, and Cotinine Testing 
The urine toxicology screen will be performed to detect the presence of amphetamines, 
barbiturates, cocaine, opiates, cannabinoids, phencyclidine, and benzodiazepines. The results 
must be negative for eligibility into this trial. A urine alcohol test will also be performed to detect 
alcohol use and must be negative prior to randomization. A urine cotinine test will also be 
performed to detect nicotine use and must be negative prior to randomization. 
Follicle Stimulating Hormone (FSH) and Pregnancy Testing 
For women of child-bearing potential, a serum pregnancy test will be done at screening and must 
be negative for eligibility into this trial. A serum pregnancy test will be done on Day -1, which 
must be reported as negative before dosing. A serum pregnancy test will be repeated at the final 
trial visit. Perform FSH test in postmenopausal females only, prior to randomization. 
Safety Laboratory Tests 
The following laboratory tests will be performed as specified in Appendix A. Subjects will be 
fasting. This means no food or drink (other than water) for at least 8 hours before sampling. 
• Hematology: complete blood count (CBC) with differential (red blood cell count, total and 
differential white blood cell counts, hemoglobin, hematocrit, and platelet count), 
• Coagulation; (activated partial thromboplastin time [APTT], prothrombin time [PT}, and 
international normalized ratio [INR]), 
 
 


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• All subjects must undergo clinical chemistry testing (albumin, glucose, blood urea 
nitrogen or urea, potassium, calcium, sodium, chloride, total protein, creatinine, total 
carbon dioxide (CO2), creatine phosphokinase (CK), phosphorus, alkaline phosphatase, 
aspartate aminotransferase (AST), alanine aminotransferase (ALT), total bilirubin, direct 
bilirubin at Screening and Baseline to assess protocol eligibility. Clinical chemistry tests 
will be performed thereafter as specified in the Schedule of Assessments and Procedures 
Appendix A. Subjects must fast a minimum of 8 hours before blood collection for a 
clinical chemistry panel. 
• Dipstick urinalysis: protein, blood, and glucose must be negative or trace (complete 
urinalysis to be performed if dipstick urinalysis is positive for blood). Menstruating 
females failing inclusion criteria due to a positive result may be retested following 
cessation of menses. Do not exclude subjects with >5 red blood cells/high power field if 
menstruating. 
Laboratory values will be entered in the Clinical Labs eCRF. 
7.2.2 
Research Assays  
Bioanalytical Assay 
Plasma concentrations of rezafungin in EDTA will be determined by a validated LC-MS/MS 
method. Details are provided in the MOP for sample collection time in each cohort for SAD 
(except cohort 1), MAD, and BA. 
For Part 1/SAD blood samples will be collected at the following scheduled timepoints for 
Cohorts 2, 3, 4, 5, and 6 (see Table 5). For Part 2/MAD, blood samples will be collected at the 
following scheduled timepoints for Cohorts 7, 8, 9, and 10 (see Table 6). For Part 3/BA, blood 
samples will be collected at the following scheduled timepoints for Cohort 11 (see Table 7). 
 
 


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Table 5: Blood Sampling Timepoints for Rezafungin Pharmacokinetic Analysis Cohorts 2, 
3, 4, 5 and 6 SAD (Part 1) 
Dosing Day 
Timepoint 
Day 1 (pre-dose) 
Taken within 60 minutes before study drug dosing 
Day 1 (hours post-dose) 
0.5 
1 
2 
4 
6 
8 
12 
Day 2 (hours post-dose) 
24 
 
Day 3 (hours post-dose) 
48 
 
Day 5 (hours post-dose) 
96 
 
Day 7 (hours post-dose) 
144 
 
Day 14 
±1 Day 
 
Day 30  
±1 Day 
 
 
 
Table 6: Blood Sampling Timepoints for Rezafungin Pharmacokinetic Analysis Cohorts 7, 
8, 9, and 10 MAD (Part 2) 
Dosing Day 
Timepoint 
Day 1, 8, and 15 (pre-dose) 
For Day 1 taken within 60 minutes before study drug 
dosing and for Days 8 and 15, taken within 15 minutes 
before study drug dosing 
Day 1 and 15 (hours post-dose) 
0.5 
1 
2 
4 
6 
8 
12 
Day 2 and 16 (hours post-dose) 
24 
 
Day 3 and 17 (hours post-dose) 
48 
 
Day 5, 12, and 19 (hours post-dose) 
96 
 
Day 7, 14, and 21 (hours post-dose) 
144 
 
Day 8 (hours post dose) 
1 and 4 
1 
 
4 
 
Day 30 
±1 Day 
 
Day 45 
±1 Day 
 
 
 
 
 
 


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Table 7: Blood Sampling Timepoints for Rezafungin Pharmacokinetic Analysis Cohort 11 
BA (Part 3) 
Dosing Day 
Timepoint 
Day 1 and 22 (pre-dose) 
Taken within 60 minutes before study drug dosing 
Day 1 and 22 (hours post-dose*) 
0.5 
1 
2 
4 
6 
8 
12 
Day 2 and 23 (hours post-dose*) 
24 
 
Day 3 and 24 (hours post-dose*) 
48 
 
Day 5 and 26 (hours post-dose*) 
96 
 
Day 7 and 2 (hours post-dose*) 
144 
 
Day 14 and 35 
±1 Day 
 
Day 52 
±1 Day 
 
*Post-dose timepoints for PK blood sampling for the IV portion of Part 3 will be based on the 
start of infusion 
 
Laboratory Specimen Preparation, Handling, and Storage 
Detailed instructions for plasma and urine for drug testing and urinalyses specimen preparation, 
handling and storage are outlined in the MOP for this study. 
 
 


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Total Blood Volume Drawn                 
The total volume of blood that will be drawn from each subject is described in Table 8: 
Table 8: Total Volume of Blood Drawn From Each Subject - Part 1 (SAD) Cohorts 1-6 
Laboratory Test 
Sample Volume (mL) Number of Samples Total Volume (mL) 
Safety: 
Clinical chemistry 
4 
5 
20 
 
Hematology 
2 
5 
10 
 
Coagulation 
2.7 
5 
13.5 
 
Serology 
4 
1 
4 
 
Pharmacokinetic:* 
3 
14 
42 
 
When using an indwelling catheter 1.0 mL of blood will be removed prior to sample collection
Total 
15.7 
30 
89.5 
 
Cohort 1 Total* 
12.7 
16 
47.5 
 
*No PK blood samples collected in Cohort 1. 
 
 


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Table 9: Total Volume of Blood Drawn From Each Subject - Part 2 (MAD) Cohorts 7-10 
Laboratory Test 
Sample Volume (mL) 
Number of Samples 
Total Volume (mL) 
Safety: 
Clinical chemistry 
4 
9 
36 
 
Hematology 
2 
9 
18 
 
Coagulation 
2.7 
9 
24.3 
 
Serology 
4 
1 
4 
 
Pharmacokinetic: 
3 
27 
81 
 
When using an indwelling catheter 1.0 mL of blood will be removed prior to sample collection
Total 
15.7 
55 
163.3 
 
 
 
 


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Table 10: Total Volume of Blood Drawn From Each Subject - Part 3 (BA) Cohort 11 
Laboratory Test 
Sample Volume (mL) 
Number of Samples 
Total Volume (mL) 
Safety: 
Clinical chemistry 
4 
7 
28 
Hematology 
2 
7 
14 
Coagulation 
2.7 
7 
18.9 
Serology 
4 
1 
4 
Pharmacokinetic: 
3 
27 
81 
When using an indwelling catheter 1.0 mL of blood will be removed prior to sample collection
Total 
15.7 
43 
145.9 
 
Laboratory PK Specimen Shipping 
All PK specimens will be shipped to the Fisher Biorepository for storage and/or transfer to the 
ICON ABL. Detailed instructions for shipping plasma are outlined in the MOP for this study.   
 


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ASSESSMENT OF SAFETY 
 
Assessing and Recording Safety Parameters 
Regulatory requirements including FDA regulations, ICH Guidelines for GCP, and European 
Union Clinical Trials Directive set forth safety monitoring and reporting responsibilities of the 
Sponsors and Site PI to ensure the safety and protection of human subjects participating in 
clinical trials. 
Responsibilities 
Site PIs participating in this trial are responsible for and will: 
• Evaluate subject safety including assessment of AEs for seriousness, severity, and 
causality; 
• notify the Sponsor of SAEs immediately; 
• provide detailed written reports, including necessary documentation requested by the 
Sponsor or IRB/IEC, promptly following immediate initial reports; 
• inform the IRB/IEC of AEs as requested by applicable regulatory requirements. 
8.1.1 
Adverse Events 
ICH E6 defines an AE as any untoward medical occurrence in a patient or clinical investigation 
subject administered a pharmaceutical product regardless of its causal relationship to the study 
treatment. FDA defines an AE as any untoward medical occurrence associated with the use of a 
drug in humans, whether or not considered drug-related. 
An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory 
finding), symptom, or disease temporally associated with the use of medicinal (investigational) 
product. The occurrence of an AE may come to the attention of study personnel during study 
visits and interviews of a study recipient presenting for medical care, or upon review by a study 
monitor.  
All AEs, including solicited local (injection site), starting from administration of the first dose of 
study drug until the final study visit will be captured on the appropriate data DCF and eCRF. 
Information to be collected for AEs includes event description, date of onset, assessment of 


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severity, relationship to study product, and alternate etiology (assessed only by those with the 
training and authority to make a diagnosis and listed on Form FDA 1572 as a PI), date of 
resolution, seriousness and outcome. AEs occurring during the trial collection and reporting 
period will be documented appropriately regardless of relationship. AEs will be followed 
through resolution or until assessed to be stable by the PI. 
Any medical condition that is present at the time that the subject is screened will be considered 
as baseline and not reported as an AE. However, if the severity of any pre-existing medical 
condition increases, it should be recorded as an AE. 
Adverse Events Grading 
All AEs (laboratory and clinical symptoms) will be graded for severity and assessed for 
relationship to study product (see definitions). Abnormalities present at baseline will not be 
reported as AEs unless worsening in severity post-dosing. AEs characterized as intermittent 
require documentation of onset and duration of each episode. The start and stop date of each 
reported AE will be recorded on the appropriate DCF and eCRF. For vital sign AEs, when 
multiple readings are taken within the same day the AE of highest severity will be documented to 
allow an assessment of the duration of the AE from the highest level of intensity. If a subject was 
enrolled in the trial with a laboratory value that is outside the reference range, but within the 
acceptable ranges, an AE will be recorded if it otherwise meets the definition of AE in Section 
8.1.1 and the on-study value is higher (if initially high) or lower (if initially low) than the 
screening value. 
Severity of Event:   
AEs will be assessed by the Site PI using a protocol-defined grading system (Appendix B). For 
events not included in the protocol-defined grading system, the following guidelines will be used 
to quantify severity: 
Mild (Grade 1): Events that are usually transient and may require only minimal or no treatment 
or therapeutic intervention and generally do not interfere with the subject’s usual activities of 
daily living, 
Moderate (Grade 2): Events that are usually alleviated with additional specific therapeutic 
intervention. The event interferes with usual activities of daily living, causing discomfort but 
poses no significant or permanent risk of harm to the subject, 


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Severe (Grade 3): Events interrupt usual activities of daily living, or significantly affects clinical 
status, or may require intensive therapeutic intervention. Severe events are usually 
incapacitating. 
 
 


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Relationship to Study Product: The assessment of the AE’s relationship to study product will 
be done by the licensed study physician indicated on Form FDA 1572 and the assessment will be 
part of the documentation process. Whether the AE is related or not, is not a factor in 
determining what is or is not reported in this trial. If there is any doubt as to whether a clinical 
observation is an AE, the event should be reported. 
In a clinical trial, the study product must always be suspect. The relationship to study product 
will be assessed for AEs using the terms related or not related: 
Related – There is a reasonable possibility that the study product caused the AE. Reasonable 
possibility means that there is evidence to suggest a causal relationship between the study 
product and the AE, 
Not Related – There is not a reasonable possibility that the administration of the study product 
caused the AE. 
8.1.2 
Serious Adverse Events 
An AE or suspected adverse reaction is considered a SAE if, in the view of either the Site PI or 
Sponsor, it results in any of the following outcomes: 
Death, 
a life-threatening adverse AE1, 
inpatient hospitalization or prolongation of existing hospitalization,  
a persistent or significant incapacity or substantial disruption of the ability to conduct normal life 
functions, or 
a congenital anomaly/birth defect, 
Important medical events that may not result in death, be life-threatening, or require 
hospitalizations 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, skin ulcers (open 
sores) at the injection site, blood dyscrasias or convulsions that do not result in inpatient 
hospitalization, or the development of drug dependency or drug abuse. 


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1 An AE is considered “life-threatening” if, in the view of either the Site PI or Sponsor, its 
occurrence places the patient or subject at immediate risk of death. It does not include an AE 
that, had it occurred in a more severe form, might have caused death. 
SAEs will be: 
Assessed for severity and relationship to study product and alternate etiology (if not related to 
study product) by a licensed study physician listed on Form FDA 1572 or by the Site PI or Sub-
Investigator. 
Recorded on the appropriate SAE DCF and eCRF. 
Followed through resolution by a licensed study physician (for Investigation New Drug (IND) 
studies, a physician listed on Form FDA 1572 as the Site PI or Sub-Investigator). 
Reviewed and evaluated by DMID, an Independent Safety Monitor (ISM) (as deemed 
necessary), the SMC (periodic review unless related), and the IRB/IEC. 
8.1.3 
Adverse Events of Special Interest 
In addition to SAEs, the following adverse events of special interest (AESIs) should be promptly 
reported to the Sponsor even if the nature of the adverse event is deemed non-serious according 
to the usual regulatory criteria. 
Intravenous Infusion Intolerability 
Events that, in the opinion of the Investigator, may represent intolerance of the IV infusion of the 
study drug must be recorded as AEs on the eCRF. In general, these events would be temporally 
associated with the IV infusion of the Sponsor’s study drug. 
Phototoxicity 
Due to preliminary results from a nonclinical phototoxicity study in rats, subjects should be 
advised to avoid sun exposure without adequate protection. Site PIs should report any AE 
potentially related to phototoxicity to the Sponsor. 
Neuropathy and Tremors 
In a rezafungin 3-month toxicity study in monkeys, there were observations of tremors, and 
histology consistent with axonal degeneration (potentially consistent with clinical presentation of 
neuropathy) first appearing at Week 6 of dosing and at 11-fold the exposure for the rezafungin 
for Injection dose in this study. Ataxia, axonal neuropathy, hypoesthesia, paresthesia, peripheral 


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motor neuropathy, peripheral neuropathy, peripheral sensory neuropathies, peripheral 
sensorimotor neuropathy, polyneuropathy, toxic neuropathy, and tremors should be considered 
AESIs. Site PIs should report any AE potentially related to neuropathy to the Sponsor. 
 
Skin Ulcers 
Skin ulcerations of any grade at study drug injection sites will be of special interest. Site PIs 
should report any skin ulcerations at injection sites to the Sponsor within 24 hours of site 
awareness. Sponsor will report skin ulcerations at injection sites to the FDA as per Expedited 
Reporting guidelines. Any skin ulcerations at site(s) of injection will be assessed daily while 
inpatient; following discharge from the unit, the Site PI will determine the frequency of 
monitoring until resolution or stabilization. The status of skin ulcerations will be followed until 
resolution.   
 
Specification of Safety Parameters 
Safety will be assessed by the frequency and severity of AEs following administration of 
rezafungin. 
8.2.1 
Injection Site Reactogenicity 
The local injection site(s) will be assessed for reactogenicity with respect to symptoms.  All Skin 
reactions at the injection site will also be measured and photographed, according to the MOP for 
this study. See Appendix B and Section 7.1.4 for additional information. 
8.2.2 
New-Onset Chronic Medical Conditions 
New-Onset Chronic Medical Conditions are defined as any new International Class of Diseases, 
Tenth Revision diagnosis that is applied to the subject during this trial, after receipt of the study 
agent, that is expected to continue for at least 3 months and requires continued health care 
intervention. 
8.2.3 
Dose Escalation Criteria 
Dose escalation to each successive cohort of subjects will occur if none of the predefined dose 
escalation halting criterion is met (for all subjects through Day 30 [SAD] or Day 30 [MAD]). 
The SDCC will provide notification to the PI upon analysis of data for the cohort (for all subjects 
through Day 30 [SAD] or Day 30 [MAD]) for halting criteria as described in Section 8.7 Study 


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Design, Objectives and Endpoints or Outcome Measures, Dose Escalation. If any of the criterion 
for dose escalation is met, or, at the discretion of the PI or DMID Medical Monitor, the study 
enrollment and dosing will be stopped until the SMC reviews the data and provides its 
recommendations. There will be a scheduled SMC data review meeting prior to start of Part 2 
(MAD).  
 
Reporting Procedures 
8.3.1 
Reporting Serious Adverse Events 
Any AE that meets a protocol-defined serious criterion must be submitted immediately (within 
24 hours of site awareness) on an SAE form to the DMID Pharmacovigilance Group, at the 
following address:  
DMID Pharmacovigilance Group 
Clinical Research Operations and Management Support (CROMS) 
6500 Rock Spring Dr. Suite 650 
Bethesda, MD 20817, USA 
SAE Hot Line: 1-800-537-9979 (US) or 1-301-897-1709 (outside US) 
SAE FAX Number: 1-800-275-7619 (US) or 1-301-897-1710 (outside US) 
SAE Email Address: PVG@dmidcroms.com 
In addition to the SAE form, select SAE data fields must also be entered into Advantage EDC. 
Please see the protocol-specific MOP for details regarding this procedure.  
Other supporting documentation of the event may be requested by the DMID Pharmacovigilance 
Group and should be provided as soon as possible.  
 
Type and Duration of Follow-Up of Subjects after Adverts Events 
The site will send a copy of the SAE report(s) to the ISM (as deemed necessary) when they are 
provided to the DMID Pharmacovigilance Group. The DMID Medical Monitor and DMID 
Clinical Project Manager will be notified of the SAE by the DMID Pharmacovigilance Group. 
The DMID Medical Monitor will review and assess the SAE for regulatory reporting and 
potential impact on study subject safety and protocol conduct. 


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At any time after completion of the study, if the site principal investigator or appropriate sub-
investigator becomes aware of an SAE that is suspected to be related to study product, the site PI 
or appropriate sub-investigator will report the event to the DMID Pharmacovigilance Group. 
8.4.1 
Regulatory Reporting for Studies Conducted Under DMID-Sponsored IND 
Following notification from the Site PI, DMID, the IND sponsor, will report any suspected 
adverse reaction that is both serious and unexpected. DMID will report an AE as a suspected 
adverse reaction only if there is evidence to suggest a causal relationship between the study drug 
and the AE. DMID will notify FDA and all participating PI’s (i.e., all PI’s to whom the Sponsor 
is providing drug under its IND or under the PI’s IND[s]) in an IND safety report of potential 
serious risks from clinical trials or any other source, as soon as possible, but in no case later than 
15 calendar days after the Sponsor determines that the information qualifies for reporting as 
specified in 21 CFR Part 312.32. DMID will also notify FDA of any unexpected fatal or 
life-threatening suspected adverse reaction as soon as possible, but in no case later than 
7 calendar days after the Sponsor’s initial receipt of the information. Relevant FU information to 
an IND safety report will be submitted as soon as the information is available. Upon request 
from FDA, DMID will submit to FDA any additional data or information that the agency deems 
necessary, as soon as possible, but in no case later than 15 calendar days after receiving the 
request. 
All serious events designated as “not related” to study drug will be reported to the FDA at least 
annually in a summary format. 
8.4.2 
Reporting of Pregnancy 
A Notification of Pregnancy form will be completed for any female study subject or for any 
female partner of a male study subject who becomes pregnant following their exposure to study 
product (Day 1) through 4 months (120 days) after the last dose of study product is administered. 
The site will discuss pregnancy reporting with subjects at the Final Study visit with instructions 
and provide contact information in case pregnancy occurs. The pregnant subject will be followed 
by monthly telephone calls until 2 months after the birth of the baby or until the end of the 
pregnancy (in case pregnancy is terminated) at which time the Pregnancy Outcome form will be 
completed. Infants born to these study subjects will also be monitored for SAEs for up to 
2 months after birth (information regarding SAEs will be captured on the Pregnancy Outcome 
form and the SAE form). If an SAE occurs during the pregnancy, the SAE will be reported on 
the appropriate SAE form and provided to DMID pharmacovigilance. Pregnancy Outcome forms 
will be used to collect, but not be limited to, data on the following information, should it be 


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identified during the monthly telephone calls, at the end of the pregnancy, or at the follow-up 
telephone call at 2 months after birth of the baby: 
1. 
Prior maternal history including congenital abnormalities or pregnancy complications; 
2. 
Estimated date of conception; 
3. 
Estimated and actual date of delivery or pregnancy termination; 
4. 
Mode of delivery; 
5. 
Maternal complications; 
6. 
Neonatal complications (i.e. lethal or nonlethal congenital abnormality). 
 
Type and Duration of Follow-Up of Subjects after Adverse Events 
SAEs will be followed until resolution even if this extends beyond the trial-reporting period. 
Resolution of an AE/SAE is defined as the return to pretreatment status or stabilization of the 
condition with the expectation that it will remain chronic. 
 
Procedures to be Followed in the Event of Abnormal Laboratory 
Test Values or Abnormal Clinical Findings 
Laboratory values will be graded according to Appendix B. Abnormal laboratory values, 
performed as part of hematology, chemistry panel, or urinalysis but not listed in Appendix B, 
will be evaluated by the study clinicians, recorded in the source document and, if clinically 
significant, considered AEs and graded according to the criteria details described in Section 8.1.  
The site principal investigator or appropriate sub-investigator is responsible for recording all AE 
and SAEs that are observed or reported during this study, regardless of the relationship to study 
product. AE and SAEs or abnormal clinical findings will be collected, assessed, documented, 
reported, and followed appropriately. 


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Halting Rules 
8.7.1 
Study Halting Rules 
Trial dosing can be halted at any time if medically indicated. Trial dosing will be stopped, and all 
available safety data will be reviewed by the SMC if any of the following occur: 
• Any SAE (regardless of the relationship to the study drug) throughout duration of study. 
• 5 or more subjects in study (cumulative among all cohorts) experience a same grade 2 (or 
higher) related AE (laboratory or systemic) which is coded in the same high-level group term                         
(HLGT) per MedDRA coding, throughout duration of study. Exception to this includes 
scenarios where there are obvious and acceptable physiological explanations for a Grade 2 or 
higher abnormality (e.g., Grade 3 hematuria in a menstruating female). 
• Any subject experiences skin ulceration of any grade at an injection site.  
8.7.2 
Dose Escalation Halting Rules 
Sentinel Subject Halting Rules  
If any of the criterion below are met, the cohort will be suspended (enrollment and dosing), and 
the SMC ad hoc meeting will convene:  
• Any SAE (regardless of the relationship to the study drug) through 48 hours post study drug 
administration. 
• Any Grade 2 (or higher) adverse event deemed to be related to the study medication by the 
PI, having an initial onset within the first 72 hours post study drug administration that does 
not resolve within 72 hours from onset. 
• Any subject experiences skin ulceration of any grade at an injection site.  
Cohort Dose Escalation Halting Rules  
If any of the criterion below are met, the escalation to the next cohort will be suspended 
(enrollment and dosing), and the SMC ad hoc meeting will convene.  
• 2 or more subjects in a cohort experience the same grade 2 (or higher) related AE (laboratory 
or systemic) which is coded in the same HLGT per MedDRA coding, through Day 30 (SAD) 
or Day 30 (MAD) of the study. 


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• Two or more subjects within a cohort with post-dose QTcF > 500 or change from baseline 
>60 ms.  
• Any subject experiences skin ulceration of any grade at an injection site.  
 
8.7.3 
Individual Halting Rules 
If any of the criterion below are met, the subject will be discontinued from further dosing:  
• Any SAE regardless of the relationship to the study drug, throughout the duration of the 
study. 
• Any other condition that the Site PI judges to unduly increase the risk to the subject. 
• Any subject experiences skin ulceration of any grade at an injection site. (Does not apply to 
infusion site). 
8.7.4 
Infusion Halting Rules (Part 3 for IV Dosing Only) 
Infusion of study drug will be halted if any of the following manifestations of anaphylaxis 
develop and will not be restarted: 
• Skin or mucous membrane manifestations: hives, moderate or severe pruritus, flushing, 
swollen joints, swollen lips, tongue or uvula. 
• Respiratory compromise: dyspnea, wheezing, stridor. 
• A decrease in systolic blood pressure to <90 mmHg or >30% decrease from baseline blood 
pressure or a decrease in diastolic blood pressure of >30% from baseline. 
• Tachycardia with an increase in resting heart rate to ≥130 beats per minute (bpm); or 
development of a ventricular dysrhythmia; or bradycardia <45 bpm (or <40 bpm in subjects 
with a baseline of <60 bpm) that is associated with complaints of dizziness, nausea, or 
feeling faint. 
• Syncope. 
• Confusion. 


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Safety Oversight (ISM and SMC) 
8.8.1 
Independent Safety Monitor 
An ISM is a physician with relevant expertise whose primary responsibility is to provide to 
DMID an independent safety assessment in a timely fashion. This ISM is identified by the 
investigator site and approved by DMID. Participation is for the duration of the DMID study and 
is a voluntary position that does not receive payment. The ISM must meet the requirements of 
the NIAID conflict of interest policy.   
The ISM: 
• Is near the site and has the authority and ability to readily access subject records in real time. 
• May be a member of the participating institution’s staff but preferably be from a different 
organizational group within the institution. 
• Should not be in a direct supervisory relationship with the PI. 
• Should have no direct involvement in the conduct of this trial. 
The ISM will: 
• Sign a Conflict of Interest certification at the time they are asked to participate and provide 
updates to this information as needed. 
• Receive reports of SAEs from the Site PI and will be notified by email when DMID is 
notified of the SAE. 
• Evaluate the SAE and report their clinical assessment to DMID, through DMID-CROMS 
system organ classes (SOCS) in a timely manner using the attached report form and email the 
report to DMID-CROMS SOCS. 
• Communicate with the Site PI as needed. 
• Review additional safety related events at the request of DMID. 
• Provide additional information to DMID by teleconference as requested. 


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8.8.2 
Safety Monitoring Committee 
This trial will utilize an SMC, an independent group of experts that advises DMID. The primary 
responsibility of the SMC is to monitor subject safety. The SMC is external to DMID and 
comprises at least 3 voting members. The SMC will consist of members with appropriate Phase 1 
trial expertise to contribute to the interpretation of data from this trial. Its activities will be 
delineated in a SMC charter that will describe the membership, responsibilities, and the scope 
and frequency of data reviews. The SMC will operate on a conflict-free basis independently of 
the trial team. DMID or the SMC may convene ad hoc meetings of the SMC according to 
protocol criteria or if there are concerns that arise during this trial. 
The SMC will review the safety data at the following timepoints: 
• Organizational meeting (before starting this trial). 
• Data review meeting, following completion of Part 1 and prior to Part 2 (MAD). 
• Ad hoc meeting(s). 
• Final review meeting, to be conducted 6-8 months after clinical database lock to review the 
cumulative unblinded safety data for this trial. Data will be provided in a standard summary 
format. The SMC may be asked to provide recommendations in response to questions posed 
by DMID. 
All SMC reviews will be performed using unblinded data. Only blinded data will be presented 
during the open session. Study drug administration data, including dose interruptions, 
modifications, and the associated reason(s), will be reported to the SMC. 


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HUMAN SUBJECTS PROTECTION 
 
Institutional Review Board/Independent Ethics Committee 
The site principal investigator will obtain IRB approval for this protocol to be conducted at his 
research site and send supporting documentation to the DMID before initiating recruitment of 
subjects. The investigator will submit applicable information to the IRB/IEC on which it relies 
for the review, to conduct the review in accordance with 45 CFR 46, ICH E6 GCP, and as 
applicable, 21 CFR 56 (Institutional Review Boards) and 21 CFR 50 (Protection of Human 
Subjects), other federal, state, and local regulations. DMID must receive the documentation that 
verifies IRB/IEC-approval for this protocol, associated informed consent documents, and upon 
request any recruitment material and handouts or surveys intended for the subjects, prior to the 
recruitment and enrollment of subjects.     
Any amendments to the protocol or consent materials will be approved by the IRB/IEC before 
they are implemented. IRB/IEC review and approval will occur at least annually throughout the 
enrollment and follow-up of subjects and may cease if annual review is no longer required by 
applicable regulations. The investigator will notify the IRB/IEC of deviations from the protocol 
and reportable SAEs, as applicable to the IRB/IEC policy. 
 
Informed Consent Process 
Informed consent is a process that is initiated before an individual agrees to participate in a trial 
and continuing throughout a subject’s participation in a trial. Before any trial procedures are 
performed, informed consent will be obtained and documented. Subjects will receive a concise 
and focused presentation of key information about the clinical trial, verbally and with a written 
ICF. The explanation will be organized and presented in lay terminology and language that 
facilitates understanding why one might or might not want to participate. 
The Site PI or designee will describe the protocol to potential subjects face-to-face. The key 
information about the purpose of this trial, the procedures and experimental aspects of this trial, 
risks and discomforts, and any expected benefits to the subject will be presented first to the 
subject.   
Subjects will also receive an explanation that this trial involves research, and a detailed summary 
of the proposed trial procedures and trial interventions/drugs. This will include aspects of this 


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trial that are experimental, the probability for random assignment to study drug groups, any 
expected benefits, all possible risks (including a statement that particular study drugs or 
procedures may involve risks to the subject or to the embryo or fetus, if the subject is or may 
become pregnant, that are currently unforeseeable), and the expected duration of the subject’s 
participation in this trial.  
Subjects will be informed that they will be notified in a timely manner if information becomes 
available that may be relevant to their willingness to continue participation in this trial. Subjects 
will receive an explanation as to whether any compensation and any medical treatments are 
available if injury occurs, and, if so, what they consist of, or where further information may be 
obtained. Subjects will be informed that there are no financial expenses to the subject for 
participating in this trial, as well as be informed of the anticipated prorated payments to the 
subject for participating in this trial. They will be informed of whom to contact (e.g., the Site PI) 
for answers to any questions relating to this trial.  
Information will also include the foreseeable circumstances and/or reasons under which the 
subject’s participation in this trial may be terminated. The subjects will be informed that 
participation is voluntary and that they are free to withdraw from this trial for any reason at any 
time without penalty or loss of benefits to which they were otherwise entitled.   
The extent of the confidentiality of the subjects’ records will be defined, and subjects will be 
informed that applicable data protection legislation will be followed. Subjects will be informed 
that the monitor(s), auditors(s), IRB, NIAID, and regulatory authorities will be granted direct 
access to the subject’s original medical records for verification of clinical trial procedures and/or 
data without violating the confidentiality of the subject, to the extent permitted by the applicable 
laws and regulations, and that, by signing a written ICF, the subject is authorizing such access.  
Subjects will be informed that records identifying the subject will be kept confidential and, to the 
extent permitted by the applicable laws and/or regulations, will not be made publicly available 
and, if the results of this trial are published, the subject’s identity will remain confidential. 
Subjects will be informed whether confidential information collected from this research and/or 
specimens will be used for additional research, even if identifiers are removed.   
Subjects will be allowed sufficient time to consider participation in this trial and to discuss this 
trial with their family, friends, or legally authorized representative, or think about it before 
agreeing to participate. 


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ICFs will be IRB-approved and subjects will be asked to read and review the ICF. Subjects will 
sign the ICF before starting any trial procedures being done specifically for this trial. 
Once signed, a copy of the ICF will be given to the subject(s) for their records. The subject(s) 
may withdraw consent at any time throughout the course of this trial. The rights and welfare of 
the subject(s) will be protected by emphasizing to them that the quality of their medical care will 
not be adversely affected if they decline to participate in this trial. 
Trial personnel may employ recruitment efforts before obtaining trial consent if a patient-specific 
screening consent is on record or if the IRB has agreed that chart review is allowed without a 
fully executed screening consent. In cases where there is not a patient-specific screening consent 
on record, site clinical staff may pre-screen via chart review and refer potential subjects to the 
research staff. Research staff would obtain written consent per the standard informed consent 
process before conducting protocol-specific screening activities. 
New information will be communicated by the Site PI or delegated staff to subjects who consent 
to participate in this trial in accordance with IRB requirements. The ICF will be updated and 
subjects will be re-consented per IRB requirements, if necessary. Subjects will be given a copy 
of all ICFs that they sign. 
 
Consent for Future Use of Stored Specimens and Data 
Residual clinical samples will be available upon the completion of the study; however, future use 
clinical samples may be requested from DMID and shipped from the DMID CMS at any time. 
These clinical samples will be shipped to and stored for up to 2 years at the Fisher Biorepository 
(DMID CMS).  
The samples will not be sold or used directly for production of any commercial product. No 
human genetic tests will be performed on the samples. Each sample will be encoded (labeled) 
only with a barcode and a unique tracking number to protect subject confidentiality. The 
recipients of specimens will be informed that these specimens have a NIH certificate of 
confidentiality. 
There are no benefits to subjects in the collection, storage and subsequent use of their specimens 
for future research. Reports about future research done with subjects’ samples will NOT be kept 
in their health records. 


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Subjects may be given the option to decide if they want their residual specimens to be used for 
future research or have these specimens destroyed at the end of this trial. The subject’s decision 
can be changed at any time by notifying the study doctors or nurses in writing. However, if the 
subject originally consents to the future use of residual specimens and subsequently changes 
his/her decision, any data from a previously collected specimen may still be used for future 
research. 
 
Exclusion of Women, Minorities, and Children (Special Populations) 
Children aged <18 years and elderly populations will be excluded from participation because 
insufficient data are available in adults to judge potential risk in children and elderly individuals, 
and as a Phase 1 trial in healthy subjects, there is no known benefit. For these same reasons, this 
trial will not include other special classes of subjects, such as fetuses, neonates, prisoners, 
institutionalized individuals, or others who may be considered vulnerable populations. 
Neither women nor minorities will be excluded from participation in this trial. Women of 
child-bearing potential may be included as per the inclusion criteria (Section 5.1.1). Subjects will 
be recruited without regard to gender or race. It is expected that race will reflect that within the 
community. 
 
Subject Confidentiality 
Subject confidentiality is strictly held in trust by the participating PI’s, their staff, and the 
Sponsor and their agents. This confidentiality includes documentation, investigation data, 
subject’s clinical information, and all other information generated during participation in this 
trial. No information concerning this trial, or the data generated from this trial will be released to 
any unauthorized third party without prior written approval of the DMID and the subject. Subject 
confidentiality will be maintained when trial results are published or discussed in conferences. 
The trial monitor or other authorized representatives of the Sponsor or governmental regulatory 
agencies may inspect all documents and records required to be maintained by the PI, including 
but not limited to, medical records (office, clinic, or hospital) and pharmacy records for the 
subjects in this trial. The CRU will permit access to such records. 
All records will be kept locked and all computer entry and networking programs will be carried 
out with coded numbers only and with password protected systems. All non-clinical specimens, 


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evaluation forms, reports, and other records that leave the site will be identified only by a coded 
number. 
 
Certificate of Confidentiality 
To protect privacy, we have received a Certificate of Confidentiality. With this Certificate, the 
researchers cannot be forced to release information that may identify the research subject, even 
by a court subpoena, in any federal, state, or local civil, criminal, administrative, legislative, or 
other proceedings. The researchers will use the Certificate to resist any demands for information 
that would identify the subject, except as explained below. 
The Certificate cannot be used to resist a demand for information from personnel of the US 
Government that is used for auditing or evaluation of federally funded projects, like this trial, or 
for information that must be released in order to meet the requirements of the FDA. 
A Certificate of Confidentiality does not prevent the subject from voluntarily releasing 
information about themselves or their involvement in this research. If any person or agency 
obtains a written consent to receive research information, then the researchers may not use the 
Certificate to withhold that information. 
The Certificate of Confidentiality does not prevent the researchers from reporting without the 
subject’s consent, information that would identify the subject as a participant in the research 
project regarding matters that must be legally reported including: child and elder abuse, sexual 
abuse, or wanting to harm themselves or others. 
The release of individual private information or specimens for other research will only occur if 
consent was obtained from the individual to whom the information, document, or biospecimen 
pertains, or for the purposes of other research that is in compliance with applicable Federal 
regulations governing the protection of human subjects in research. 
 
 


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Costs, Subject Compensation, and Research Related Injuries 
There is no cost to subjects for the research tests, procedures, and study drug while participating 
in this trial. Procedures and treatment for clinical care may be billed to the subject, subject’s 
insurance, or third party.   
Subjects may be compensated for their participation in this trial. Compensation will be in 
accordance with the local IRB’s policies and procedures, and subject to IRB approval. 
If the Site PI determines that an injury occurred to a subject as a direct result of the tests or 
treatments that are done for this trial, then referrals to appropriate health care facilities will be 
provided to the subject. Trial personnel will try to reduce, control, and treat any complications 
from this trial. Immediate medical treatment may be provided by the site. No financial 
compensation will be provided to the subject by the NIAID, NIH to the subject, or by the 
participating site for any injury suffered due to participation in this trial. 


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STATISTICAL CONSIDERATIONS 
A formal Statistical Analysis Plan (SAP) will be created prior to database lock. This document 
will provide a more technical and detailed description of the proposed data analysis methods and 
procedures. Any deviation from the analysis outlined in the protocol will be described in the 
SAP. 
For continuous variables, data will be summarized using descriptive statistics (such as sample 
size, mean, median, standard deviation, minimum, and maximum). For discrete variables, data 
will be summarized using frequencies and percentages. 
 
Study Hypotheses 
The objectives of this trial are to obtain safety, tolerability, and PK data for rezafungin. There are 
no formal hypotheses being tested in this trial. 
 
Sample Size Considerations 
No formal sample-size calculations based on testing a statistical hypothesis were constructed. 
There will be a total of 86 subjects in this three-part trial, 44 subjects in 6 cohorts will receive 
rezafungin or placebo via SC injection in Part 1/SAD, 32 subjects in 4 cohorts will receive 
rezafungin or placebo via SC injection in Part 2/MAD, and 10 subjects will receive rezafungin 
via both SC and IV injections in Part 3/BA. The number of subjects was selected to allow 
sufficient evaluation of safety, tolerability, and PK of the various dose regimens, and to be 
consistent with standards of practice for Phase 1 trials. 
 
Treatment Assignment Procedures 
10.3.1 
Randomization Procedures 
Each subject who completes the Screening assessment, meets all eligibility criteria, and is 
enrolled into this trial will randomized to rezafungin or placebo (Cohorts 1-10) or randomized to 
treatment sequence (Cohort 11),, except for replacement subjects. Replacement subjects will be 
assigned the same study drug dosing regimen as the replaced subject. 


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The randomization schedule will be generated centrally through AdvantageEDCSM (Electronic 
Data Capture [EDC] System, Emmes) by the unblinded biostatistician, and a list will be 
transferred to the unblinded Site Pharmacist before the start of this trial as an emergency 
back-up. Part 1 Cohort 1 will have 4 subjects randomized 3:1 to receive rezafungin or placebo, 
respectively. There will be no sentinel dosing for Cohort 1. Within cohorts 2-6 in Part 1 and all 
cohorts of Part 2, 8 subjects will be randomized 3:1 to receive rezafungin or placebo, 
respectively. In each dosing cohorts 2-6 in Part 1 and all cohorts of Part 2, the first two subjects 
will be randomized 1:1 to receive rezafungin or placebo to ensure that one of the first two 
subjects receives rezafungin and the other placebo. The study drug assignment of the remaining 
subjects in each cohort will be randomly assigned in a 5:1 ratio of active drug to placebo to 
ensure the 3:1 ratio for the entire dosing cohort. In Part 3, 10 subjects will be randomized in a 
1:1 ratio of dose route order (SC → IV or IV → SC). Enrollment will occur at one CRU. 
Per ICH guideline E6: GCP, screening records that document why an individual was screened 
but not enrolled will be kept at the CRU. Reasons for screen failures will also be recorded in 
AdvantageEDCSM. 
Subjects will be enrolled online using the enrollment module of AdvantageEDCSM. The 
randomization code will be prepared by statisticians at the SDCC and included in the enrollment 
module for this trial. AdvantageEDCSM will assign each subject to a rezafungin or placebo group 
after demographic and eligibility data have been entered into the system. A designated individual 
at the CRU will be provided with a code list for emergency unblinding purposes, which will be 
kept in a secure place. 
Instructions for using the enrollment module are included in the AdvantageEDCSM User’s Guide. 
Manual back-up procedures and instructions are provided for use in case the CRU temporarily 
loses access to the Internet or the online enrollment system is unavailable. 
10.3.2 
Masking Procedures 
10.3.2.1 
Blinding 
For SAD and MAD subjects, the Site Pharmacist will be unblinded as to randomization 
assignment. Subjects, the PI, and CRU personnel other than the Site Pharmacist, the 
bioanalytical laboratory staff, and Fisher repository personnel will remain blinded to all 
randomization assignments. The PK analyst(s) will be unblinded. The DMID Medical Monitor, 
other NIAID personnel, and ICON personnel will remain blinded to all randomization 


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assignments. For subjects enrolled in Part 3 (Bioavailability), the subjects, the PI, and CRU 
personnel will be unblinded to randomization assignment. 
Selected individuals not involved in conducting this trial, including members of the SMC, may 
have access to the unblinded data as needed for safety or other data review. The Site Pharmacist 
will remain unblinded during this trial. 
10.3.3 
Emergency Unblinding 
Emergency unblinding of study drug assignment for a subject may be necessary due to a medical 
emergency, or any other significant medical event, if knowledge of the subject’s study drug 
assignment impacts the subject’s care. If an SAE or other circumstance requires the blind to be 
broken to ensure a subject’s safety, the PI will immediately notify the DMID Medical Monitor if 
possible (within 24 hours) to discuss the case and reason for unblinding (a written narrative will 
follow within 48 hours of the event). 
Procedures for emergency unblinding are detailed in the MOP for this trial. 
 
Planned Interim Analyses 
10.4.1 
Interim Safety Review 
An interim safety review will be performed upon completion of the SAD cohorts (1-6) and prior 
to starting the MAD and BA parts of the study.  
An interim safety review will also be performed by the SMC upon completion of Day 30 for all 
subjects upon completion of the SAD cohorts (1-6) and prior to starting the MAD and BA parts 
of the study. This safety review may include but is not limited to enrollment, laboratory, and 
safety data. If criteria for halting the trial (as listed in Section 8.7) are met, an ad hoc SMC 
meeting will be held to review all available safety data and to make recommendations about the 
dosing of all further subjects in the trial. The SMC will receive data presented in aggregate (by 
cohort). Analysis by treatment assignment may be provided to the SMC in the closed session 
only. 
 
 


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10.4.2 
Interim Immunogenicity or Efficacy Review 
An interim PK analysis will be conducted upon the completion of the SAD cohorts (2-6).  
All safety and PK data will be provided to the FDA for review prior to initiation of the MAD and 
BA portions of the trial.  FDA will approve continued enrollment in the MAD and BA parts of 
the study and possibly recommend dose changes.  
 
Final Analysis Plan 
The safety analysis population will include all subjects that received any amount of study 
product and will be analyzed by treatment received. All subjects who receive a dose of 
rezafungin or placebo will be included in the safety analysis population. All subjects who receive 
a dose of rezafungin and have at least 1 measurable drug concentration after dosing in plasma 
will be included in the PK analysis population. 
Placebo subjects may be pooled across multiple cohorts for analysis. The PK analysis population 
will include all subjects with at least one measurable rezafungin plasma concentration. Missing 
data will not be imputed. Details of study analyses for safety and PK data and their presentation 
will be fully described in the SAP, prepared by the SDCC and finalized prior to data lock. 
10.5.1 
Adverse and Serious Adverse Events 
AEs will be coded using Medical Dictionary for Regulatory Activities® (MedDRA). All AEs 
occurring after study drug dosing will be summarized using frequency counts and percentages. 
Summaries will be presented by dose cohort and control group. The following summaries will be 
presented for AEs and SAEs: 
• Overall (i.e., regardless of severity or relationship to study drug, 
• By severity grade (mild, moderate, or severe), 
• By relationship to study drug, 
• By MedDRA level hierarchy (system organ class, HLGT and preferred term). 
Unless otherwise specified, at each level of subject summarization in reporting the incidence of 
the AEs, a subject will be counted once if the subject reported one or more AEs. If more than one 
occurrence of an AE is reported, the AE of the worst severity or the worst-case relationship 
assessment will be summarized. For crossover data, AEs will be summarized separately for each 


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treatment and the worst severity and worst-case relationship after each treatment will be 
summarized. An AE that began after the first treatment, continued into the second period, and 
worsened in severity after the second treatment will be considered a new AE associated with the 
second treatment. 
10.5.2 
Clinical Safety Labs, Vital Signs, and Electrocardiograms 
Baseline for clinical safety labs, vital signs, and ECGs will be defined as the last result obtained 
before the dose of study product. For crossover data, there will be a separate baseline for each 
treatment. Changes from baseline for clinical safety labs, vital signs, and ECGs results will be 
summarized by dose group and time point. Clinical safety labs and vital signs will be graded 
(Appendix B) and summarized by severity, group, and visit. Rules for analyzing replicates for a 
safety time point (labs, vital signs, ECG), if obtained, will be described in the SAP. 
Treatment-emergent abnormal laboratory test results will be identified. Treatment-emergent 
abnormal laboratory tests are tests for which the result was not graded as mild or worse at 
baseline but graded as mild or worse after dosing. Laboratory tests graded as mild at baseline, 
but moderate or worse any time after dosing will also be regarded as treatment-emergent 
abnormal laboratory test results. 
ECG measurements will include heart rate, RR interval, QT interval, QTcF interval, PR interval, 
and QRS duration. Baseline for ECG measurements is defined per protocol as the value 
pre-dosing on Day 1 (or pre-dosing on Day 21 for period 2 of Part 3). Change from baseline will 
be summarized descriptively by regimen at each scheduled evaluation. QTc results will be 
summarized categorically according to the ICH Guideline E14 “Clinical Evaluation of QT/QTc 
Interval Prolongation and Proarrhythmic Potential for Non-Antiarrhythmic Drugs” (October 
2005): 
• 
QTcF >450 ms, males only 
• 
QTcF >470 ms, females only 
• 
QTcF >480 ms  
• 
QTcF >500 ms 
• 
QTcF increases from baseline by at least 30 ms but less than 60 ms 
• 
QTcF increases from baseline by at least 60 ms 


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10.5.3 
Additional Safety Analyses 
Local reactogenicity at SC injection administration sites (Appendix B) will be summarized by 
type, toxicity grading, dose group, and time point. Skin ulcers at injection sites will be 
additionally summarized by size measurements and resolution. If there are multiple injection 
sites, the maximum severity across all injection sites will be summarized by day after injection at 
the respective sites. 
10.5.4 
PK Analysis Plan 
PK profiles for rezafungin in plasma samples from all subjects who received at least one dose of 
rezafungin will be analysed for concentration of rezafungin (except Cohort 1) by a validated LC-
MS/MS method. The following PK parameters will be estimated, by noncompartmental analysis 
methods using version 7.0 or higher of Phoenix WinNonlin®, for rezafungin concentrations in 
plasma. 
Cmax: The maximum concentration occurring at Tmax, 
Tmax: The time of maximum observed concentration sampled during a dosing interval, 
AUClast: The area under the curve (AUC) from the time of dosing to the last measurable 
concentration, 
AUC extrapolated to infinity from the observed value of the last non-zero [or last quantifiable] 
concentration, , 
AUC0-168: The AUC over the interval from time of first dose to 168 h after first dose (for Part 2 
MAD only), 
t1/2: Terminal half-life, 
λz: The first order rate constant associated with the terminal (log-linear) portion of the curve, 
CL: The total body clearance for intravenous administration,  
CL/F: The total body clearance for SC administration divided by the fraction of dose absorbed,  
Vz: The volume of distribution associated with the terminal slope following IV administration  
Vz/F: The volume of distribution associated with the terminal slope following SC administration 
divided by the fraction of dose absorbed,  


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F: The absolute BA will be calculated as the ratio of AUCinf for the SC injection and the IV 
infusion of rezafungin administration (Part 3), 
Dose proportionality for SAD and MAD in terms of Cmax and AUC will be assessed using a 
power model, 
AR: Drug observed accumulation ratio (Part 2) 
Other PK parameters may be estimated as appropriate. Additional details for analysis of PK 
endpoints will be provided in the SAP. 


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SOURCE DOCUMENTS AND ACCESS TO SOURCE 
DATA/DOCUMENTS 
The site will maintain appropriate medical and research records in compliance with ICH E6, 
Section 4.9 and regulatory and institutional requirements for the protection of confidentiality of 
subjects. The site will permit authorized representatives of the DMID, its designees, and 
appropriate regulatory agencies to examine (and when required by applicable law, to copy) 
clinical records for the purposes of QA reviews, audits, and evaluation of the trial safety and 
progress. These representatives will be permitted access to all source data and source documents, 
which include, but are not limited to, hospital records, clinical and office charts, laboratory notes, 
memoranda, subjects’ memory aid or evaluation checklists, pharmacy dispensing records, 
recorded data from automated instruments, copies or transcriptions certified after verification as 
being accurate and complete, microfiches, photographic negatives, microfilm or magnetic media, 
x-rays, and subject files and records kept at the pharmacies, laboratories, and medico-technical 
departments involved in the clinical trial. 
 
Compliance with Standards of Medical Research/Deviations 
This protocol will be conducted in accordance with applicable ICH guidelines and GCP. Any 
instance of noncompliance with the protocol will result in a documented deviation. If a change is 
deemed necessary to protect the safety, rights or welfare of a subject, the Sponsor and IRB/IEC 
will be notified as soon as possible and preferably before introducing the deviation. 


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QUALITY CONTROL AND QUALITY ASSURANCE 
Following a written DMID-accepted Program Quality Management Plan (cQMP), the 
participating site and its subcontractors are responsible for conducting routine quality assurance 
(QA) and quality control (QC) activities to internally monitor study progress and protocol 
compliance. The site principal investigator will provide direct access to all study-related sites, 
source data/data collection forms, and reports for the purpose of monitoring and auditing by the 
sponsor, and inspection by local and regulatory authorities. The site principal investigator will 
ensure all study personnel are appropriately trained and applicable documentations are 
maintained on site. 
The SDCC will implement quality control procedures beginning with the data entry system and 
generate data quality control checks that will be run on the database. Any missing data or data 
anomalies will be communicated to the participating site(s) for clarification and resolution. 
DMID-designated clinical monitors will verify that the clinical trial is conducted, and data are 
generated, documented (recorded), and reported in compliance with the protocol, ICH/GCP 
guidelines, and the applicable regulatory requirements. Clinical monitoring reports will be 
submitted to DMID. 
To ensure compliance with GCP and all applicable regulatory requirements, the Sponsor may 
conduct a quality assurance assessment and/or audit of the site records, and the regulatory 
agencies may conduct a regulatory inspection at any time during or after the completion of the 
study. In the event of an assessment, audit or inspection, the Investigator (and institution) must 
agree to grant the advisor(s), auditor(s), and inspector(s) direct access to all relevant documents 
and to allocate their time and the time of their staff to discuss the conduct of the study, any 
findings/relevant issues, and to implement any corrective and/or preventative actions to address 
any findings/issues identified. 


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DATA HANDLING AND RECORD KEEPING 
 
Data Management Responsibilities 
The investigator is responsible to ensure the accuracy, completeness, legibility, and timeliness of 
the data reported. All source documents should be completed in a neat, legible manner to ensure 
accurate interpretation of data. Black or blue permanent ink is required to ensure clarity of 
reproduced copies. When making changes or corrections, cross out the original entry with a 
single line, and initial and date the change. DO NOT ERASE, OVERWRITE, OR USE 
CORRECTION FLUID OR TAPE ON THE ORIGINAL. 
Copies of the eCRF will be provided for use as source data collection forms and maintained for 
recording data for each subject enrolled in the study. Data reported in the eCRF derived from 
source data collection forms should be consistent or the discrepancies should be explained. 
The sponsor and/or its designee will provide guidance to the site principal investigators and other 
study personnel on making corrections to the data collection forms and eCRF. 
Training will be provided for the Electronic Data Capture (EDC) system. All personnel using 
the EDC system must have the appropriate education, training, and experience, or any 
combination thereof. The Investigator will be provided with standard operating procedures 
(SOPs) (contained in the SPM or a vendor-specific SOP) on the use of the EDC system. 
Documentation for employee education, training, and previous experience that pertains to the 
EDC system must be present in the Investigator files. 
If electronic data systems other than those provided and maintained by the Sponsor are used for 
documentation and data capture, the Investigator must ensure that the systems are validated and 
ensure regular data back-up. 
The eCRF will be signed by the Investigator or a Sub-Investigator listed on the FDA 1572 
form. It is the responsibility of the Investigator to ensure the eCRFs are completed and 
submitted to the Sponsor (or designee) in an accurate and timely manner. The processing of 
eCRFs will include an audit trail (to include changes made, reason for change, date of change, 
and person making change). At the completion of the study, the Sponsor will be provided with a 
final copy of each eCRF. 
 
 


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Management of clinical data will be performed in accordance with applicable Sponsor 
standards and data cleaning procedures to ensure the integrity of the data (e.g., removing errors 
and inconsistencies in the data). Adverse events and concomitant medications will be coded 
using the MedDRA® and World Health Organization Drug (WHO DD) dictionaries 
respectively. Medical Electronic CRFs will be retained by the Sponsor and copies will be sent to 
the Investigator to maintain as the Investigator copy. 
 
Data Management Responsibilities 
Any source documents and laboratory reports must be reviewed by the clinical team and data 
entry staff, who will ensure their accuracy and completeness. AEs must be recorded on the 
appropriate data collection form, assessed for severity and relationship, and reviewed by the site 
principal investigator or appropriate sub-investigator. AEs must be graded based on the FDA 
Guidance for Industry: Toxicity Grading Scale for Healthy Adult and Adolescent Volunteers 
Enrolled in Preventive Vaccine Clinical Trials September 2007, as modified for this study and as 
appropriate for the administration of rezafungin; see Appendix B. 
Electronic data capture is the responsibility of the clinical trial staff at the site under the 
supervision of the site PI. During the study, the PI must maintain complete and accurate 
documentation for the study. 
Data collection is the responsibility of the study personnel at the participating clinical study site 
under the supervision of the site principal investigator. During the study, the site principal 
investigator must maintain complete and accurate documentation for the study. 
The data coordinating center for this study, Emmes, will be responsible for data management, 
quality review, analysis, and reporting of the study data. 
 
Data Capture Methods 
Clinical data (including, but not limited to, AEs, physical assessments, clinical laboratory values, 
and concomitant medications) will be entered into AdvantageEDCSM, a 21 CFR Part 
11-compliant EDC system managed by Emmes. AdvantageEDCSM access is password protected. 
Access is granted to specific individuals based on the roles identified for this trial. The site enters 
the data into AdvantageEDCSM from the DCFs completed by the study personnel. Data are 
validated through a query resolution process, comprising both automated and manual queries. 


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Types of Data 
Data for this trial will include but are not limited to all data for safety and PK deemed necessary 
for the analysis per protocol, demographic data, ECG data, clinical laboratory values, 
concomitant medications, AEs, photographs, and medical history. 
 
Study Records Retention 
Trial documents will be retained for 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 study drug. These documents will be retained for a longer period, 
however, if required by local regulations. No records will be destroyed without the written 
consent of the Sponsor. It is the responsibility of the Sponsor to inform the Site PI when these 
documents no longer need to be retained. 


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CLINICAL MONITORING 
 
Site Monitoring Plan 
Site monitoring is conducted to ensure that the human subject protections, trial and laboratory 
procedures, trial intervention administration, and data collection processes are of high quality 
and meet Sponsor, ICH/GCP guidelines, and applicable regulations, and that this trial is 
conducted in accordance with the protocol, protocol-specific MOP, and applicable Sponsor 
SOPs. DMID, the Sponsor, or its designee will conduct site-monitoring visits as detailed in the 
clinical monitoring plan. 
Site visits will be made at standard intervals as defined by DMID and may be made more 
frequently as directed by DMID. Monitoring visits will include, but are not limited to, review of 
regulatory files, accountability records, eCRFs, ICFs, medical and laboratory reports, and 
protocol and GCP compliance. Site monitors will have access to each site, trial personnel, and all 
trial documentation according to the DMID-approved site monitoring plan. Trial monitors will 
meet with Site PI to discuss any problems and actions to be taken and will document site visit 
findings and discussions. 


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PUBLICATION POLICY 
All investigators funded by the NIH must submit or have submitted for them to the National 
Library of Medicine’s PubMed Central (http://www.ncbi.nlm.nih.gov/pmc/) an electronic 
version of their final, peer-reviewed manuscripts upon acceptance for publication, to be made 
publicly available no later than 12 months after the official date of publication. The NIH Public 
Access Policy ensures the public has access to the published results of NIH funded research. It 
requires investigators to submit final peer-reviewed journal manuscripts that arise from NIH 
funds to the digital archive PubMed Central upon acceptance for publication. Further, the policy 
stipulates that these papers must be accessible to the public on PubMed Central no later than 
12 months after publication. 
Refer to: 
• 
NIH Public Access Policy, http://publicaccess.nih.gov/ 
• 
NIH Office of Extramural Research (OER) Grants and Funding, 
http://grants.nih.gov/grants/oer.htm 
As of January 2018, all clinical trials supported by the NIH must be registered on 
ClinicalTrials.gov, no later than 21 days after the enrollment of the first subject. Results of all 
clinical trials supported by the NIH, generally, need to be submitted no later than 12 months 
following the primary completion date. A delay of up to 2 years is available for trials that meet 
certain criteria and have applied for certification of delayed posting. 
As part of the result posting a copy of this protocol (and its amendments) and a copy of the 
Statistical Analysis Plan will be posted on ClincialTrials.gov. 
For this trial the responsible party is DMID, which will register the trial and post results.   
The responsible party does not plan to request certification of delayed posting. 
Refer to: 
• 
Public Law 110-85, Section 801, Clinical Trial Databases 
• 
42CFR11 
• 
NIH NOT-OD-16-149 


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LITERATURE REFERENCES 
1Schmiedel Y, Zimmerli S. Common invasive fungal diseases: an overview of invasive 
candidiasis, aspergillosis, cryptococcosis, and Pneumocystis pneumonia. Swiss Med Wkly. 
2016;146: w14281 
2Wang S, Adrianto I, Wiley GB, Lessard CJ, Kelly JA, et al. A functional haplotype of UBE2L3 
confers risk for systemic lupus erythematosus. Genes Immun. 2012 Jul;13(5):380-7. doi: 
10.1038/gene.2012.6. Epub 2012 Apr 5. 
3Monnet X, Vidal-Petiot E, Osman D, Hamzaoui O, Durrbach A, et al. Critical care management 
and outcome of severe Pneumocystis pneumonia in patients with and without HIV infection 
Crit Care. 2008;12(1): R28. doi: 10.1186/cc6806. Epub 2008 Jan 25. 
  
4Wickramasekaran RN, Jewell MP, Sorvillo F, Kuo T The changing trends and profile of 
pneumocystosis mortality in the United States, 1999-2014. Mycoses. 2017 Sep;60(9):607-615. 
doi: 10.1111/myc.12636. Epub 2017 May 31.  
 
5Martin SI, Fishman JA; AST Infectious Diseases Community of Practice. Pneumocystis 
pneumonia in solid organ transplantation. Am 2013 Mar;13 Suppl 4:272-9. doi: 
10.1111/ajt.12119. 
6Choi YI, Hwang GC, Park JM, Namgoong DH, Jung GW, et al. Clinical Outcomes of 
Pneumocystis carinii Pneumonia in Adult Liver Transplant Recipients. Transplant Proc. 2013 
Oct;45(8):3057-60. doi: 10.1016/j.transproceed.2013.08.074. 
7Iriart X, Challan Belval T, Fillaux J, Esposito L, Lavergne RA, et al. Risk Factors of 
Pneumocystis Pneumonia in Solid Organ Recipients in the Era of the Common Use of Post 
transplantation Prophylaxis. Am J Transplant. 2015 Jan;15(1):190-9. doi: 10.1111/ajt.12947. 
Epub 2014 Dec 12. 
 
8Ainoda Y, Hirai Y, Fujita T, Isoda N, Totsuka K. Analysis of clinical features of non-HIV 
Pneumocystis jirovecii Pneumonia. J Infect Chemother. 2012 Oct;18(5):722-8. doi: 
10.1007/s10156-012-0408-5. Epub 2012 Mar 30. 
 
9Ponce CA, Chabé M, George C, Cárdenas A, Durán L, et al. High prevalence of Pneumocystis 
jirovecii dihydropteroate synthase gene mutations in patients with a first episode of 
Pneumocystis pneumonia in Santiago, Chile, and clinical response to trimethoprim 


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sulfamethoxazole therapy. Antimicrob Agents Chemother. 2017 Jan 24;61(2). pii: e01290-16. 
doi: 10.1128/AAC.01290-16. Print 2017 Feb.  
10Cushion, MT, Ashbaugh, A, Lynch K, Linke MJ, Bartizal K Efficacy of CD101, a Novel 
Echinocandin, in Prevention of Pneumocystis Pneumonia (PCP): Thwarting the Biphasic Life 
Cycle of Pneumocystis, ASH 2016. 
 
11Zmarlicka M, Martin ST, Cardwell SM, Nailor MD. Tolerability of low-dose 
sulfamethoxazole/trimethoprim for Pneumocystis jirovecii pneumonia prophylaxis in kidney 
transplant recipients. Prog Transplant. 2015 Sep;25(3):210-6. doi: 10.7182/pit2015153. 
 
12Epstein DJ, Seo SK, Huang YT, Park JH, Klimek VM, et al. Micafungin versus posaconazole 
prophylaxis in acute leukemia or myelodysplastic syndrome: A randomized study. J Infect. 2018 
Sep;77(3):227-234. doi: 10.1016/j.jinf.2018.03.015. Epub 2018 May 7. 
13Mourad A, Perfect JR. Tolerability profile of the current antifungal armoury. J Antimicrob 
Chemother 2018; 73 Suppl 1: i26–i32, doi:10.1093/jac/dkx446. 
 
14Sandison T, Ong V, Lee J, Thye D. Safety and pharmacokinetics of CD101 IV, a novel 
echinocandin, in healthy adults. Antimicrob Agents Chemother. 2017 Jan 24;61(2). pii: e01627-
16. doi: 10.1128/AAC.01627-16. Print 2017 Feb. 
 
15Ong V, Hough G, Schlosser M, Bartizal K, Balkovec JM, et al. 
Preclinical evaluation of the stability, safety, and efficacy of CD101, a novel echinocandin. 
Antimicrob Agents Chemother. 2016 Oct 21;60(11):6872-6879. doi: 10.1128/AAC.00701-16. 
Print 2016.  
 
16Alert, Oprs. “Guidance for Industry Estimating the Maximum Safe Starting Dose in Initial 
Clinical Trials for Therapeutics in Adult Healthy Volunteers.” (2005) 
 
 


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APPENDICES 
 
 


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  Schedules of Events 
 
Table 11: Schedule of Study Procedures and Evaluations for Cohorts 1-6 in SAD (Part 1) 
Procedures/Day 
Screening 
Baseline 
Check-in 
Inpatient – Confined to CRU 
FU 
Phone  
FU 
FU/ 
ET 
Unscheduled 
-28 to -2 
-1 
1 
2 
3 
4 
5 
6 
7 
14 
(±1) 
 
21 
(±1) 
30 
(±1) 
Informed Consent 
Forma 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Assessment of 
Eligibility Criteria 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Heightb, Weight, BMI 
X 
X 
 
 
 
 
 
 
 
 
 
X 
 
Review of Medical 
History 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
Hepatitis and HIV 
testsc 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Follicle-stimulating 
hormone(FSH) testd 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy teste 
X 
X 
 
 
 
 
 
 
 
 
 
X 
 
Review of 
Concomitant 
Medications 
X 
X 
X 
 
X 
 
X 
 
X 
X 
 
X 
X 
Study drug 
randomization just 
prior to dosingf 
 
 
X 
 
 
 
 
 
 
 
 
 
 
Administration of 
study drugg 
 
 
X 
 
 
 
 
 
 
 
 
 
 
Vital signsh 
X 
X 
X 
X 
 
X 
 
 
X 
X 
 
X 
X 
Physical examinationi 
X 
X 
X 
X 
 
X 
 
 
X 
 
 
X 
X 
12-lead ECGsj 
X 
 
X 
 
 
 
 
 
X 
 
 
X 
X 
Blood for hematology 
& coagulationk 
X 
X 
 
X 
 
 
 
 
X 
 
 
X 
X 
Blood for chemistry 
panelk 
X 
X 
 
X 
 
 
 
 
X 
 
 
X 
X 
Urine for urinalysis, 
drug screen, alcoholl 
X 
X 
 
X 
 
 
 
 
X 
 
 
X 
X 
Urine cotinine 
X 
X 
 
 
 
 
 
 
 
 
 
 
 


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Procedures/Day 
Screening 
Baseline 
Check-in 
Inpatient – Confined to CRU 
FU 
Phone  
FU 
FU/ 
ET 
Unscheduled 
-28 to -2 
-1 
1 
2 
3 
4 
5 
6 
7 
14 
(±1) 
 
21 
(±1) 
30 
(±1) 
Blood for PK 
analysism 
 
 
X 
X 
X 
 
X 
 
X 
X 
 
X 
 
Reactogenicity 
evaluationn 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Assessment for AEso 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Counsel/remindersp 
X 
 
 
 
 
 
 
 
X 
X 
X 
X 
 
Memory Aidq 
 
 
X 
 
 
 
 
 
X 
X 
X 
X 
X 
Abbreviations: AE: adverse event; BMI: body mass index; CRU: clinical research unit; ECG: electrocardiogram; 
FU: follow-up; HIV: human immunodeficiency virus; PK: pharmacokinetic. 
a. 
Informed consent will be obtained before initiating any trial-related assessments and procedures, 
b. Height at Screening only, 
c. 
Screen (serum) for hepatitis B surface antigen, hepatitis C virus antibody, and HIV antibody, 
d. Perform FSH (serum) test in postmenopausal females only, 
e. 
Perform serum pregnancy tests at Screening, Day -1, and Day 30 females only, 
f. 
Randomize subjects on Day 1 just before dosing, 
g. A single dose of study drug will be administered via SC injection on Day 1, 
h. Vital signs will be obtained at Screening; on Day -1, on Day 1 prior to study drug administration 
(within 60 minutes prior to study drug) and at 15 minutes (±5 min), 1 hour (±10 min) and 2 
hours(±10 min)  post-dose;  at 24, 72, 144 hours (±30 min), post-dose( Days 2, 4, and 7), and 
Days 14 (±1 day), and 30 (±1 day), 
i. 
A complete PE will be performed at Screening and targeted PEs will be performed on Days -1, 1, 
2, 4, 7, and 30 (±1 day), 
j. 
ECGs will be obtained at Screening and on Day 1 within 60 minutes prior to study drug 
administration, and 4 hours (± 10 minutes) post-dose, Day 7, Day 30, and Unscheduled visits 
k. Fasting (at least 8 hours) blood samples will be collected for hematology, coagulation and 
chemistries at Screening and on Days -1, 2, 7, and 30 (±1 day), Hematology tests consist of CBC 
with differential; coagulation tests consist of PT/PTT/INR; Chemistries panel includes albumin, 
glucose, blood urea nitrogen or urea, potassium, calcium, sodium, chloride, total protein, 
creatinine, CO2, CK, phosphorus, alkaline phosphatase, AST, ALT, total bilirubin, direct 
bilirubin, 
l. 
Urine will be collected for urinalysis, urine drug screen and urine alcohol at Screening and on 
Day -1. Urine will be collected for urinalysis on Days 2, 7, and 30 (±1 day),   
m. Collect PK blood samples within 60 minutes before study drug dosing and at 0.5 (±5 min), 1, 2, 
4, 6, 8, and 12 hours (±10 min),on (Day 1; 24 hours (±30 min) on Day 2; 48 hours (±30 min) on  
Day 3; 96 hours (±30 min) onDay 5; and 144 hours (±30 min) onDay 7 after dosing; and on Days 
14 (±1 day) and 30 (±1 day), (No PK blood sample collection for Cohort 1) 


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n. Injection site assessment pre-dose and at 1 and 4 (± 10 min), 24, 48, 72, 96, 120, and 144 h (± 30 
min) post dose, Day 14 (±1 day), Day 21 (±1 day), and Day 30 (±1 day). Unscheduled visits are 
not timed.  
o. Subjects are to be assessed for AEs occurring from the time of the first dose of study drug 
through Day 30 (±1 day), 
 
p. Counsel/reminder on contraceptive use and post-discharge instructions (dietary and 
medication/nonmedication vaccine and blood/blood product/sperm donation restrictions);as 
described in Section 5.1. 
q. Memory Aid issued on Day 1, training on Day 7, and review on Days 14, 21, and 30 and at 
Unscheduled visits. 
 
Table 12: Schedule of Study Procedures and Evaluations for Cohorts 7-10 in MAD (Part 2) 
Procedures/Day 
Screening 
Baseline 
Check-in 
Inpatient – Confined to CRU 
FU 
FU/ 
ET 
Unscheduled 
-28 to -2 
-1 
1 
2 
3 
4 
5 
6 
7 
30 
(±1) 
45 
(±1) 
8 
9 
10 
11 
12 
13 
14 
15 
16 
17 
18 
19 
20 
21 
Informed Consent 
Forma 
X 
 
 
 
 
 
 
 
 
 
 
 
Assessment of 
Eligibility Criteria 
X 
X 
X 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
Heightb, Weight, BMI 
X 
X 
 
 
 
 
 
 
 
 
X 
X 
Review of Medical 
History 
X 
X 
 
 
 
 
 
 
 
 
 
 
Hepatitis and HIV 
testsc 
X 
 
 
 
 
 
 
 
 
 
 
 
Follicle-stimulating 
hormone (FSH) testd 
X 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy teste 
X 
X 
 
 
 
 
 
 
 
 
X 
 
Review of 
Concomitant 
Medications 
X 
X 
X 
 
X 
 
X 
 
X 
X 
X 
X 
Study drug 
randomization just 
prior to dosingf 
 
 
X 
 
 
 
 
 
 
 
 
 
Administration of 
study drugg 
 
 
X 
 
 
 
 
 
 
 
 
 
Vital signsh 
X 
X 
X 
X 
 
X 
 
 
X 
X 
X 
X 
Physical examinationi 
X 
X 
X 
X 
 
X 
 
 
X 
X 
X 
X 


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Procedures/Day 
Screening 
Baseline 
Check-in 
Inpatient – Confined to CRU 
FU 
FU/ 
ET 
Unscheduled 
-28 to -2 
-1 
1 
2 
3 
4 
5 
6 
7 
30 
(±1) 
45 
(±1) 
8 
9 
10 
11 
12 
13 
14 
15 
16 
17 
18 
19 
20 
21 
12-lead ECGsj 
X 
 
X 
 
 
 
 
 
X 
X 
X 
X 
Blood for hematology 
& coagulationk 
X 
X 
 
X 
 
 
 
 
X 
 
X 
X 
Blood for chemistry 
panelk 
X 
X 
 
X 
 
 
 
 
X 
 
X 
X 
Urine for urinalysis, 
drug screen, alcoholl 
X 
X 
 
X 
 
 
 
 
X 
 
X 
X 
Urine cotinine 
X 
X 
 
 
 
 
 
 
 
 
 
 
Blood for PK 
analysism 
 
 
X 
X 
X 
 
X 
 
X 
X 
X 
 
Reactogenicity 
evaluationn 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Assess for AEso 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Counsel/remindersp 
X 
 
 
 
 
 
 
 
X 
X 
X 
 
Memory Aidq 
 
 
X 
 
 
 
 
 
X 
X 
X 
X 
Abbreviations: AE: adverse event; BMI: body mass index; CRU: clinical research unit; ECG: electrocardiogram; 
FU: follow-up; HIV: human immunodeficiency virus; PK: pharmacokinetic. 
a. 
Informed consent will be obtained before initiating any trial-related assessments and procedures, 
b. Height at Screening only, 
c. 
Screen (serum) for hepatitis B surface antigen, hepatitis C virus antibody, and HIV antibody, 
d. Perform FSH (serum) test in postmenopausal females only, 
e. 
Perform serum pregnancy tests at Screening, Day -1, and Day 45 females only, 
f. 
Randomize subjects on Day 1 only, 
g. A single dose of study drug will be administered via SC injection on Days 1, 8, and 15, 
h. Vital signs will be obtained at Screening; on Day -1; on Day 1 within 60 minutes prior to study 
drug administration and at 15 minutes (±5 min), 1 hour (±10 min) and 2 hours (± 10 min) post-
dose; and at 24, 72 and 144 hours (±30 min) post-dose on Days 2, 4, 7, 8, 9, 11, 14, 15, 16, 18, 
and 21; and on Days 30 (±1 day), and 45 (±1 day), 
i. 
A complete PE will be performed at Screening and targeted PEs will be performed on Days -1, 1, 
2, 4, 7, 8, 9, 11, 14, 15, 16, 18, 21, 30 (± 1 day), and 45 (±1 day), 
j. 
ECGs will be obtained at Screening and on Day 1 within 30 minutes prior to study drug 
administration, and 4 hours (± 10 minutes) post-dose (Days 1, 8, and 15), Day 21, Day 30, Day 
45, and Unscheduled visits 
k. Fasting (at least 8 hours) blood samples will be collected for hematology, coagulation and 
chemistries at Screening and on Days -1, 2, 9, 16, 7, 14, 21 and 45 (±1 day). Hematology tests 
consist of CBC with differential; coagulation tests consist of PT/PTT/INR; Chemistries panel 
includes albumin, glucose, blood urea nitrogen or urea, potassium, calcium, sodium, chloride, 


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total protein, creatinine, CO2, CK, phosphorus, alkaline phosphatase, AST, ALT, total bilirubin, 
direct bilirubin, 
l. 
Urine will be collected for urinalysis, urine drug screen and urine alcohol at Screening, and on 
Day -1.  Urine will be collected for urinalysis on Days 2, 7, 9, 14, 16, 21, and 45 (±1 day), 
m. Blood for PK analysis (plasma) will be drawn pre-dose within 60 minutes before study drug 
dosing and at at 0.5 h (±5 min), 1 h (±10 min), 2 h (±10 min), 4 h (±10 min), 6 h (±10 min), 8 h 
(±10 min), and 12 h (±10 min),(Days 1 and 15); pre-dose within 15 minutes before study drug 
dosing and at 1 (±10 min), and 4 hours (±10 min), on Day 8; 24 hours (±30 min), on Days 2 and 
16; 48 hours (±30 min) on Days 3 and 17; 96 hours (±30 min, on Days 5, 12, and 19; and 144 
hours (±30 min) onDays 7, 14, and 21 after dosing; and on Days 30 (±1 day) and 45 (±1 day), 
n. Injection site assessment pre-dose and at 1 and 4 (± 10 min), 24, 48, 72, 96, 120, and 144 h (± 30 
min) post-dose, Day 30 (±1 day), and Day 45 (±1 day). Unscheduled visits are not timed. 
o. Subjects are to be assessed for AEs occurring from the time of the first dose of study drug 
through Day 45 (±1 day), 
p. Counsel/reminder on contraceptive use and post-discharge instructions (dietary and 
medication/nonmedication, vaccine and blood/blood product/sperm donation restrictions); as 
described in Section 5.1. 
q. Memory Aid issued on Day 1, training on Day 7, and review on Days 30, 45 and at Unscheduled 
visits. 
 
 
 
Table 13: Schedule of Study Procedures and Evaluations for Cohort 11 in BA (Part 3) 
Procedures/Day 
Screening 
Baseline 
Check-in 
Inpatient – Confined to CRU 
FU 
FU/ 
ET 
Unscheduled 
-28 to -2 
-1 and 21 
1 
2 
3 
4 
5 
6 
7 
14 
and 
35 
(±1) 
52 
(±1) 
22 
23 
24 
25 
26 
27 
28 
Informed Consent 
Forma 
X 
 
 
 
 
 
 
 
 
 
 
 
Assessment of 
Eligibility Criteria 
X 
X 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
Heightb, Weight, BMI 
X 
X 
 
 
 
 
 
 
 
 
X 
 
Review of Medical 
History 
X 
X 
 
 
 
 
 
 
 
 
 
 
Hepatitis and HIV 
testsc 
X 
 
 
 
 
 
 
 
 
 
 
 
Follicle-stimulating 
hormone (FSH) testd 
X 
 
 
 
 
 
 
 
 
 
 
 


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Procedures/Day 
Screening 
Baseline 
Check-in 
Inpatient – Confined to CRU 
FU 
FU/ 
ET 
Unscheduled 
-28 to -2 
-1 and 21 
1 
2 
3 
4 
5 
6 
7 
14 
and 
35 
(±1) 
52 
(±1) 
22 
23 
24 
25 
26 
27 
28 
Pregnancy teste 
X 
X 
 
 
 
 
 
 
 
 
X 
 
Review of 
Concomitant 
Medications 
X 
X 
X 
 
X 
 
X 
 
X 
X 
X 
X 
Study drug 
randomization just 
prior to dosingf 
 
 
X 
 
 
 
 
 
 
 
 
 
Administration of 
study drugg 
 
 
X 
 
 
 
 
 
 
 
 
 
Vital signsh 
X 
X 
X 
X 
 
X 
 
 
X 
X 
X 
X 
Physical examinationi 
X 
X 
X 
X 
 
X 
 
 
X 
X 
X 
X 
12-lead ECGsj 
X 
 
X 
 
 
 
 
 
 
 
X 
X 
Blood for hematology 
& coagulationk 
X 
X 
 
X 
 
 
 
 
X 
 
X 
X 
Blood for chemistry 
panelk 
X 
X 
 
X 
 
 
 
 
X 
 
X 
X 
Urine for urinalysis, 
drug screen, alcoholl 
X 
X 
 
X 
 
 
 
 
X 
 
X 
X 
Urine cotinine 
X 
X 
 
 
 
 
 
 
 
 
 
 
Blood for PK 
analysism 
 
 
X 
X 
X 
 
X 
 
X 
X 
X 
X 
Reactogenicity 
evaluationn 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
Assess for AEso 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Counsel/remindersp 
X 
 
 
 
 
 
 
 
X 
X 
X 
X 
Memory Aidq 
 
X 
X 
 
 
 
 
 
X 
X 
X 
X 
Abbreviations: AE: adverse event; BMI: body mass index; CRU: clinical research unit; ECG: electrocardiogram; 
FU: follow-up; HIV: human immunodeficiency virus; PK: pharmacokinetic. 
a. 
Informed consent will be obtained before initiating any trial-related assessments and procedures, 
b. Height at Screening only, 
c. 
Screen (serum) for hepatitis B surface antigen, hepatitis C virus antibody, and HIV antibody, 
d. Perform FSH (serum) test for postmenopausal (females only), 
e. 
Perform serum pregnancy tests at Screening Day -1 and Day 52 females only, 
f. 
Randomize subjects on Day 1 only, 
g. A single dose of study drug will be administered via SC injection/IV infusion on Days 1 and 22, 


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h. Vital signs will be obtained at Screening; on Day -1; on Days 1 and 22 within 60 minutes to 
study drug administration and at 15 minutes (±5 min), 1 and 2 hours (±10 min), post-dose; and on 
Days 2, 4, 7, 23, 25, 28 (±30 min) and 14 (±1 day), 35 (±1 day), and 52 (±1 day), 
i. 
A complete PE will be performed at Screening and targeted PEs will be performed on Days -1, 1, 
2, 4, 7, 14, 22, 23, 25, 28, 35, and 52. Days 14, 35, and 52 have (±1 day) window. 
j. 
ECGs will be obtained at Screening and on Day 1 within 60 minutes prior to study drug 
administration, and 4 hours (± 10 minutes) post-dose (SC) and 1 hour (± 10 minutes) post-dose 
(IV) from start of infusion for IV admin, Day 52, and Unscheduled visits 
k. Fasting (at least 8 hours) blood samples will be collected for hematology, coagulation and 
chemistries at Screening and on Days -1,2, 7, 23, 28, and 52 (±1 day), Hematology tests consist 
of CBC with differential; coagulation tests consist of PT/PTT/INR; Chemistries panel includes 
albumin, glucose, blood urea nitrogen or urea, potassium, calcium, sodium, chloride, total 
protein, creatinine, CO2, CK, phosphorus, alkaline phosphatase, AST, ALT, total bilirubin, direct 
bilirubin, 
l. 
Urine will be collected for urinalysis, urine drug screen and urine alcohol at Screening, and on 
Day -1. Urine will be collected for urinalysis on Days 2, 7, 23, 28, and 52 (±1 day), 
m. Blood for PK analysis (plasma) will be drawn pre-dose within 60 minutes before study drug 
dosing and at 0.5(±5 min), 1, 2, 4, 6, 8, and 12 hours (±10 min) on Days 1 and 22; 24 hours (±30 
min), on Days 2 and 23; 48 hours(±30 min) on Days 3 and 24; 96 hours (±30 min),  on Days 5 
and 26; and 144 hours (±30 min) on Days 7 and 28 after dosing; and on Days 14 and 35 (±1 day) 
and 52 (±1 day), 
n. Injection site assessment pre-dose and at 1 and 4 (± 10 min), 24, 48, 72, 96, 120, and 144 h (± 30 
min) post-dose, Day 14 (±1 day), and Day 35 (±1 day). Unscheduled visits are not timed. 
o. Subjects are to be assessed for AEs occurring from the time of the first dose of study drug 
through Day 52 (±1 day), 
p. Counsel/reminder on contraceptive use and post-discharge instructions (dietary and 
medication/nonmedication, vaccine and blood/blood product/sperm donation restrictions);as 
described in Section 5.1. 
q. Memory Aid issued on Day 1, training on Day 7 (refresher on Day 28), reviewed on Days 21, 14, 
35, 52 and at Unscheduled visits. 
 
 
 


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 TOXICITY TABLE 
Clinical Adverse Events 
VITAL SIGNS 
Mild 
(Grade 1) 
Moderate 
(Grade 2) 
Severe 
Grade 3 
Fever - °C 
  
 
38.0-38.4 
  
 
38.5-38.9 
  
 
>38.9 
  
 
Tachycardia - bpm 
101-115 
116-130 
>130 or ventricular 
dysrhythmias 
Bradycardia – bpm 
• 
Baseline ≥60 
OR, if 
                Baseline <60 
•   50-54  
OR, if Baseline 
<60,  
•   45-50 
•    45-49  
OR, if baseline <60,  
•         40-44 
•   <45  
OR, if baseline <60 
•     <40 
Hypertension (systolic) - mmHg 
141-150 
151-160 
>160 
Hypertension (diastolic) - mmHg 
91-95 
96-100 
>100 
Hypotension (systolic) - mmHg 
85-89 
80-84 
<80 
Tachypnea – breaths per min 
23-25 
26-30 
>30 
CARDIOVASCULAR 
Mild 
(Grade 1) 
Moderate 
(Grade 2) 
Severe 
(Grade 3) 
Arrhythmia 
   
Asymptomatic; transient signs; 
no medical intervention required  
Recurrent/persistent; 
symptomatic medical 
intervention required  
Hemorrhage, Blood Loss  
Estimated blood 
loss ≤100 mL  
Estimated blood loss >100 mL; 
no transfusion required 
Transfusion required 


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QTc (Fridericia’s correction)1 
 
 
Asymptomatic, 
QTc interval 
450-479 msec  
Asymptomatic; QTc interval 480 
to 499 msec OR Increase in 
interval 30-59 msec above 
baseline 
Asymptomatic; QTc 
interval ≥ 500 msec OR 
Increase in interval ≥ 60 
msec above baseline 
PR Interval (prolonged)1 
PR interval 
0.21-0.25 sec 
PR interval >0.25 
Type II 2nd degree AV 
block OR Ventricular 
pause >3.0 sec 
RESPIRATORY    
Mild 
(Grade 1) 
Moderate 
(Grade 2) 
Severe 
(Grade 3) 
Cough 
Transient; no 
treatment  
Persistent cough  
Interferes with daily 
activities 
Bronchospasm, Acute 
Transient; no 
treatment; 
FEV1 71-80% 
of predicted 
peak flow  
Requires medical intervention; 
normalizes with bronchodilator; 
FEV1 60-70% of predicted peak 
flow  
No normalization with 
bronchodilator; FEV1 
<60% of predicted peak 
flow 
Dyspnea   
Does not 
interfere with 
usual and social 
activities 
Interferes with usual and social 
activities; no treatment 
Prevents daily and 
usual social activity OR 
requires treatment 
GASTROINTESTINAL   
Mild 
(Grade 1) 
Moderate 
(Grade 2) 
Severe 
(Grade 3) 
Nausea  
No interference 
with activity 
Some interference with activity 
Prevents daily activities 
Vomiting  
No interference 
with activity 
OR 1-2 
episodes/24 
hours 
Some interference with activity 
OR >2 episodes/24 hours 
Prevents daily activity 
OR requires IV 
hydration OR requires 
medical intervention 
 
 
1Inclusion dependent upon protocol requirements. 


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Diarrhea  
2-3 loose or 
watery stools or 
<400 g/24 hours 
4-5 loose or watery stools or 
400-800 g/24 hours 
≥6 loose or watery 
stools or >800g/24 
hours OR requires IV 
hydration OR requires 
medical intervention 
REACTOGENICITY 
 
 
 
LOCAL REACTIONS 
Mild 
(Grade 1) 
Moderate 
(Grade 2) 
Severe 
(Grade 3) 
Pain – experienced without 
touching the injection site 
(spontaneous discomfort) 
Does not 
interfere with 
activity 
Repeated use of non-narcotic 
pain reliever >24 hours OR 
interferes with activity 
Any use of narcotic 
pain reliever OR 
prevents daily activity 
Tenderness – hurts only when 
injection site is touched, or the 
arm is moved 
Discomfort only 
to touch 
Discomfort with movement 
Significant discomfort 
at rest 
Pruritus (Itching) 
Does not 
interfere with 
daily activity 
Interferes with daily activity 
Prevents daily activity 
Ecchymosis (Bruising)* 
Does not 
interfere with 
daily activity 
Interferes with daily activity 
Prevents daily activity 
Erythema (Redness)* 
Does not 
interfere with 
daily activity 
Interferes with daily activity  
Prevents daily activity 
Induration (Hardness)/Swelling* 
Does not 
interfere with 
daily activity 
Interferes with daily activity  
Prevents daily activity 
Nodule 
Does not 
interfere with 
daily activity 
Interferes with daily activity  
Prevents daily activity 
Ulcer 
Does not 
interfere with 
daily activity 
Interferes with daily activity  
Prevents daily activity 
Ecchymosis (Bruising)* 
25 mm – 
50 mm 
51 mm – 100 mm 
>100 mm 


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Erythema (Redness)* 
25 mm – 
50 mm 
51 mm – 100 mm 
>100 mm 
Induration 
(Hardness)/Swelling* 
25 mm – 
50 mm 
51 mm – 100 mm 
>100 mm 
Nodule 
25 mm – 
50 mm 
51 mm – 100 mm 
>100 mm 
Ulcer 
1 mm – 50 mm 
51 mm – 100 mm 
>100 mm 
SYSTEMIC REACTIONS 
Mild 
(Grade 1) 
Moderate 
(Grade 2) 
Severe 
(Grade 3) 
Allergic Reaction  
Pruritus without 
rash  
Localized urticaria OR requires 
oral therapy 
Generalized urticaria; 
angioedema OR 
anaphylaxis OR 
requires epinephrine 
Headache  
No interference 
with activity 
Repeated use of non-narcotic 
pain reliever >24 hours OR some 
interference with activity 
Significant; any use of 
narcotic pain reliever 
OR prevents daily 
activity OR requires 
triptans  
Fatigue  
No interference 
with activity 
Some interference with activity 
Significant; prevents 
daily activity 
Myalgia 
No interference 
with activity 
Some interference with activity 
Significant; prevents 
daily activity 
All Other conditions 
Mild  
(Grade 1) 
Moderate  
(Grade 2) 
Severe  
(Grade 3)  
Illness or clinical AE (as 
defined according to applicable 
regulations) 
No interference 
with activity 
Some interference with activity 
not requiring medical 
intervention 
Prevents daily activity 
and requires medical 
intervention 
 
*Will not be used as halting criteria. 
 


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Laboratory and Vital Signs Reference Ranges, Eligibility Ranges, and Toxicity Grading 
Laboratory Adverse Events* 
Mild 
Moderate  
Severe 
(Grade 1) 
(Grade 2) 
(Grade 3) 
Blood, Serum, or Plasma 
Sodium (hyponatremia) – mEq/L 
131-132 
129-130 
<129 
Sodium (hypernatremia) – 
mEq/L 
144 – 145 
146 – 147 
>147 
Potassium (hyperkalemia) – 
mEq/L 
5.2 – 5.4 
5.5 – 5.6 
>5.6 
Potassium (hypokalemia) – 
mEq/L 
3.2-3.4 
3.0 – 3.1 
<3.0 
Glucose (hypoglycemia) – 
mg/dL 
65 – 69 
55 – 64 
<55 
Glucose (hyperglycemia) – 
mg/dL Fasting 
106 – 125 
126 – 200 
>200 
Blood Urea Nitrogen – mg/dL 
21-26 
27 – 31 
> 31 
Creatinine (Male) – mg/dL 
1.3 – 2.0 
2.1-2.3 
>2.3 
Creatinine (Female) – mg/dL 
1.0 – 1.7 
1.8 – 2.0 
>2.0 
Calcium (hypocalcemia) – 
mg/dL 
8 - <LLN 
7.5 – 7.9 
<7.5 
Calcium (hypercalcemia) – 
mg/dL 
ULN - 10.8  
10.9 – 11.4 
>11.4 
CK-U/L  
309-1000 
1001-1500 
>1500 
Albumin (hypoalbuminemia) – 
g/dL 
2.8 – 3.4 
2.5 – 2.7 
< 2.5 
AST – U/L (Male) 
40-97 
98-195 
>195 
AST – U/L (Female) 
32-77 
78-155 
>155 
ALT – U/L (Male) 
41-100 
101-200 
>200 
ALT – U/L (Female) 
33-80 
81-160 
>160 


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Laboratory Adverse Events* 
Mild 
Moderate  
Severe 
(Grade 1) 
(Grade 2) 
(Grade 3) 
Alkaline phosphatase – IU/L 
(Male) 
131-260 
261-390 
>390 
Alkaline phosphatase – IU/L 
(Female) 
106-210 
211-315 
>315 
Total Bilirubin (serum) – mg/dL 
1.3-1.5 
1.6-1.9 
>1.9 
Direct Bilirubin – mg/dL 
NA 
NA 
NA 
Chloride –mEq/L 
(hypochloremia) 
NA 
NA 
NA 
Chloride –mEq/L 
(hyperchloremia) 
NA 
NA 
NA 
CO2 –mEq/L  (hypo) 
NA 
NA 
NA 
CO2 –mEq/L (hyper) 
NA 
NA 
NA 
Total Protein – g/dL 
5.5 - 5.9 
5.0 - 5.4 
<5.0 
Phosphorus- mg/dl  (hypo) 
2.3-2.4 
2.1-2.2 
<2.0 
Phosphorus-mg/dl  (hyper) 
NA 
NA 
NA 
Hemoglobin (Male) – g/dL 
11.2 - 12.2 
10.0 – 11.1 
<10.0 
Hemoglobin (Female) – g/dL 
9.8 - 10.8 
8.5 - 9.7 
<8.5 
WBC Increase – cell/mm3 
10,001– 15,000 
15,001 – 20,000 
> 20,000 
WBC Increase – cell/mm3 
(African America Males) 
9,001 – 14, 000 
14,001 – 19, 000 
>19,000 
WBC Increase – cell/mm3 
(African American Females) 
11,001 – 15,000 
15,001 – 20,000 
>20,000 
WBC Decrease – cell/mm3 
2,500– 3,999 
1,500 – 2,499 
< 1,500 
WBC Decrease – cell/mm3 
(African American Males) 
2,200 – 2,499 
1,200 – 2,199 
<1,200 
WBC Decrease – cell/mm3 
(African American Females) 
2,200 – 2,499 
1,500 – 2,199 
<1,500 


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Laboratory Adverse Events* 
Mild 
Moderate  
Severe 
(Grade 1) 
(Grade 2) 
(Grade 3) 
Neutrophils Decrease – cell/mm3 
1,300 – 1,699 
1,000 – 1,299 
< 1,000 
Neutrophils Decrease – cell/mm3 
(African American Males) 
1,000 – 1,299 
800 - 999 
<800 
Neutrophils Decrease – cell/mm3 
(African American Females) 
1,100 – 1,299 
1,000 – 1,099 
<1,000 
Platelets Decreased – 10^3/mm3 
120 – 149 
100 – 119 
<100 
Hematocrit (Male) - % 
33.0 -36.1 
29.8 - 32.9 
< 29.8 
Hematocrit (Female) - %  
29.5 - 32.6 
26.0 – 29.4 
< 26.0 
RBC (Male) – x 106/uL   
3.9 - 4.1 
3.4 - 3.8 
< 3.4 
RBC (Female) – x 106/uL   
3.5 - 3.7 
3.0 - 3.4 
< 3.0 
Lymphocytes - cell/mm3 
decrease 
600- 799 
500 – 599 
< 500 
Monocytes – cell/mm3     
increase 
1001-2000 
2001-3000 
>3000 
Eosinophils - cell/mm3     
increase 
871 - 950 
951 - 1700 
>1700 
Basophils - cell/mm3       increase 
101 - 300 
301 - 800 
> 800 
PT (prothrombin time) – seconds 
11.6-12.6 
12.7-13.7 
>13.7 
PT INR (Prothrombin INR) 
1.2-1.4 
1.5-1.9 
2.0 or higher 
PTT (partial thromboplastin 
time) –seconds 
30.1-36.8 
36.9-43.6 
>43.6 
Urine 
Protein 
1+ 
2+ 
>2+ 
Glucose 
1+ 
2+ 
>2+ 
Blood (microscopic) - red blood 
cells per high power field 
(rbc/hpf)** 
3-10* 
11-50* 
>50 and/or 
gross blood** 


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Laboratory Adverse Events* 
Mild 
Moderate  
Severe 
(Grade 1) 
(Grade 2) 
(Grade 3) 
*Abnormal laboratory values, performed as part of hematology, chemistry panel, or urinalysis 
but not listed in Appendix B, will be evaluated by the study clinicians, recorded in the source 
document and, if clinically significant, considered AEs and graded according to the criterion 
described in Section 8.1.